id
stringlengths 40
40
| source
stringclasses 9
values | title
stringlengths 2
345
| clean_text
stringlengths 35
1.63M
| raw_text
stringlengths 4
1.63M
| url
stringlengths 4
498
| overview
stringlengths 0
10k
|
|---|---|---|---|---|---|---|
e17f5ecaa518637f049cd54beeaa9b2b29b2bb8e | cdc | Schistosomiasis | Schistosomiasis | Disease Directory | Travelers' Health | CDC
### What is schistosomiasis?
Schistosomiasis is a disease caused by a parasitic worm that lives in certain types of freshwater snails. The parasite leaves the snail and enters the water where it can enter a person’s body through the skin when a person wades or swims in contaminated freshwater.
Within days of becoming infected, a person may develop a rash or itchy skin. Fever, chills, cough, and muscle aches may begin within one to two months of infection. Most people have no symptoms early on, but left untreated, schistosomiasis can cause more serious health problems.
Children who are repeatedly infected can develop anemia, malnutrition, and learning difficulties. After years of infection, the parasite can also damage the liver, intestine, spleen, lungs, and bladder.
### Who is at risk?
Information by Destination
Where are you going?
-- Select One --AfghanistanAlbaniaAlgeriaAmerican SamoaAndorraAnegadaAngolaAnguilla (U.K.)AntarcticaAntigua and BarbudaArgentinaArmeniaArubaAustral IslandsAustraliaAustriaAzerbaijanAzoresBahamas, TheBahrainBangladeshBarbadosBarbudaBelarusBelgiumBelizeBeninBermuda (U.K.)BhutanBoliviaBonaireBora-BoraBosnia and HerzegovinaBotswanaBrazilBritish Indian Ocean Territory (U.K.)BruneiBulgariaBurkina FasoBurma (Myanmar)BurundiCaicos IslandsCambodiaCameroonCanadaCanary Islands (Spain)Cape VerdeCayman Islands (U.K.)Central African RepublicChadChileChinaChristmas Island (Australia)Cocos (Keeling) Islands (Australia)ColombiaComorosCongo, Republic of theCook Islands (New Zealand)Costa RicaCôte d'IvoireCroatiaCubaCuraçaoCyprusCzech RepublicDemocratic Republic of the CongoDenmarkDjiboutiDominicaDominican RepublicDubaiEaster Island (Chile)EcuadorEgyptEl SalvadorEnglandEquatorial GuineaEritreaEstoniaEswatini (Swaziland)EthiopiaFalkland Islands (Islas Malvinas)Faroe Islands (Denmark)FijiFinlandFranceFrench Guiana (France)French Polynesia (France)GabonGalápagos IslandsGambia, TheGeorgiaGermanyGhanaGibraltar (U.K.)GreeceGreenland (Denmark)GrenadaGrenadinesGuadeloupeGuam (U.S.)GuatemalaGuernseyGuineaGuinea-BissauGuyanaHaitiHoly SeeHondurasHong Kong SAR (China)HungaryIcelandIndiaIndonesiaIranIraqIrelandIsle of ManIsrael, including the West Bank and GazaItalyIvory CoastJamaicaJapanJerseyJordanJost Van DykeKazakhstanKenyaKiribatiKosovoKuwaitKyrgyzstanLaosLatviaLebanonLesothoLiberiaLibyaLiechtensteinLithuaniaLuxembourgMacau SAR (China)MadagascarMadeira Islands (Portugal)MalawiMalaysiaMaldivesMaliMaltaMarquesas IslandsMarshall IslandsMartinique (France)MauritaniaMauritiusMayotte (France)MexicoMicronesia, Federated States ofMoldovaMonacoMongoliaMontenegroMontserrat (U.K.)MooreaMoroccoMozambiqueMyanmar (Burma)NamibiaNauruNepalNetherlands, TheNew Caledonia (France)New ZealandNicaraguaNigerNigeriaNiue (New Zealand)Norfolk Island (Australia)North KoreaNorth MacedoniaNorthern IrelandNorthern Mariana Islands (U.S.)NorwayOmanPakistanPalauPanamaPapua New GuineaParaguayPeruPhilippinesPitcairn Islands (U.K.)PolandPortugalPuerto Rico (U.S.)QatarRéunion (France)RomaniaRotaRurutuRussiaRwandaSabaSaint BarthelemySaint CroixSaint Helena (U.K.)Saint JohnSaint Kitts and NevisSaint LuciaSaint MartinSaint Pierre and Miquelon (France)Saint ThomasSaint Vincent and the GrenadinesSaipanSamoaSan MarinoSão Tomé and PríncipeSaudi ArabiaScotlandSenegalSerbiaSeychellesSierra LeoneSingaporeSint EustatiusSint MaartenSlovakiaSloveniaSociety IslandsSolomon IslandsSomaliaSouth AfricaSouth Georgia and the South Sandwich Islands (U.K.)South KoreaSouth Sandwich IslandsSouth SudanSpainSri LankaSudanSurinameSwaziland (Eswatini)SwedenSwitzerlandSyriaTahitiTaiwanTajikistanTanzaniaThailandTimor-Leste (East Timor)TinianTobagoTogoTokelau (New Zealand)TongaTortolaTrinidad and TobagoTubuaiTunisiaTurkeyTurkmenistanTurks and Caicos Islands (U.K.)TuvaluUgandaUkraineUnited Arab EmiratesUnited KingdomUnited StatesUruguayUzbekistanVanuatuVatican CityVenezuelaVietnamVirgin GordaVirgin Islands, BritishVirgin Islands, U.S.Wake IslandWalesYemenZambiaZanzibarZimbabweGo
var e = document.getElementById("thlrdssl-traveler");
var value = e.options[e.selectedIndex].value;
var url = "/travel/destinations/traveler/none/" - value;
if (value == '0'){
window.location = "/travel/destinations/list";
window.location = url;
Travelers going to countries in Africa, South America, the Middle East, China, and Southeast Asia can get schistosomiasis. The freshwater snails that carry schistosomiasis are found in streams, rivers, and lakes in many countries around the world. Anyone who swims, bathes, or wades in freshwater streams, rivers, ponds, lakes, or untreated pools where snails that carry schistosomiasis live can get infected.
Many travelers who get schistosomiasis traveled to sub-Saharan Africa to popular tourist destinations. These include rivers and water sources such as Lake Malawi, Lake Tanganyika, Lake Victoria, the Omo River, the Zambezi River, and the Nile River.
Adventure travelers, Peace Corps volunteers, missionaries, soldiers, and ecotourists may be more likely to get schistosomiasis because of their work and activities. Local claims that there is no schistosomiasis in a body of freshwater are not reliable and precautions should be taken to prevent exposure.
### What can travelers do to prevent schistosomiasis?
If you are visiting or live in an area where schistosomiasis is a concern:
- Avoid swimming, bathing, or wading in freshwater sources, such as lakes, rivers, ponds, and wetlands. Swimming in the ocean and in chlorinated swimming pools is safe.
- Drink safe water.
- Although schistosomiasis is not transmitted by swallowing contaminated water, if contaminated water touches your mouth or lips, you could become infected.
- Because water coming directly from canals, lakes, rivers, streams, or springs may be contaminated with other infectious organisms, bring your water to a rolling boil for one minute or filter water before drinking it. A rolling boil for at least one minute will kill any harmful parasites, bacteria, or viruses present.
- Iodine treatment alone WILL NOT GUARANTEE that water is safe and free of all parasites.
- Boil water used for bathing. Bring the water to a rolling boil for 1 minute, then let it cool before bathing to avoid scalding. Water held in a storage tank for at least one to two days should be safe for bathing.
- Quickly dry off completely with a towel after an accidental, brief water exposure. This may help prevent parasites from penetrating the skin. However, do not rely on towel drying alone to prevent schistosomiasis.
|
### Schistosomiasis
### What is schistosomiasis?
Schistosomiasis is a disease caused by a parasitic worm that lives in certain types of freshwater snails. The parasite leaves the snail and enters the water where it can enter a person’s body through the skin when a person wades or swims in contaminated freshwater.
Within days of becoming infected, a person may develop a rash or itchy skin. Fever, chills, cough, and muscle aches may begin within one to two months of infection. Most people have no symptoms early on, but left untreated, schistosomiasis can cause more serious health problems.
Children who are repeatedly infected can develop anemia, malnutrition, and learning difficulties. After years of infection, the parasite can also damage the liver, intestine, spleen, lungs, and bladder.
### Who is at risk?
Information by Destination
Where are you going?
-- Select One --AfghanistanAlbaniaAlgeriaAmerican SamoaAndorraAnegadaAngolaAnguilla (U.K.)AntarcticaAntigua and BarbudaArgentinaArmeniaArubaAustral IslandsAustraliaAustriaAzerbaijanAzoresBahamas, TheBahrainBangladeshBarbadosBarbudaBelarusBelgiumBelizeBeninBermuda (U.K.)BhutanBoliviaBonaireBora-BoraBosnia and HerzegovinaBotswanaBrazilBritish Indian Ocean Territory (U.K.)BruneiBulgariaBurkina FasoBurma (Myanmar)BurundiCaicos IslandsCambodiaCameroonCanadaCanary Islands (Spain)Cape VerdeCayman Islands (U.K.)Central African RepublicChadChileChinaChristmas Island (Australia)Cocos (Keeling) Islands (Australia)ColombiaComorosCongo, Republic of theCook Islands (New Zealand)Costa RicaCôte d'IvoireCroatiaCubaCuraçaoCyprusCzech RepublicDemocratic Republic of the CongoDenmarkDjiboutiDominicaDominican RepublicDubaiEaster Island (Chile)EcuadorEgyptEl SalvadorEnglandEquatorial GuineaEritreaEstoniaEswatini (Swaziland)EthiopiaFalkland Islands (Islas Malvinas)Faroe Islands (Denmark)FijiFinlandFranceFrench Guiana (France)French Polynesia (France)GabonGalápagos IslandsGambia, TheGeorgiaGermanyGhanaGibraltar (U.K.)GreeceGreenland (Denmark)GrenadaGrenadinesGuadeloupeGuam (U.S.)GuatemalaGuernseyGuineaGuinea-BissauGuyanaHaitiHoly SeeHondurasHong Kong SAR (China)HungaryIcelandIndiaIndonesiaIranIraqIrelandIsle of ManIsrael, including the West Bank and GazaItalyIvory CoastJamaicaJapanJerseyJordanJost Van DykeKazakhstanKenyaKiribatiKosovoKuwaitKyrgyzstanLaosLatviaLebanonLesothoLiberiaLibyaLiechtensteinLithuaniaLuxembourgMacau SAR (China)MadagascarMadeira Islands (Portugal)MalawiMalaysiaMaldivesMaliMaltaMarquesas IslandsMarshall IslandsMartinique (France)MauritaniaMauritiusMayotte (France)MexicoMicronesia, Federated States ofMoldovaMonacoMongoliaMontenegroMontserrat (U.K.)MooreaMoroccoMozambiqueMyanmar (Burma)NamibiaNauruNepalNetherlands, TheNew Caledonia (France)New ZealandNicaraguaNigerNigeriaNiue (New Zealand)Norfolk Island (Australia)North KoreaNorth MacedoniaNorthern IrelandNorthern Mariana Islands (U.S.)NorwayOmanPakistanPalauPanamaPapua New GuineaParaguayPeruPhilippinesPitcairn Islands (U.K.)PolandPortugalPuerto Rico (U.S.)QatarRéunion (France)RomaniaRotaRurutuRussiaRwandaSabaSaint BarthelemySaint CroixSaint Helena (U.K.)Saint JohnSaint Kitts and NevisSaint LuciaSaint MartinSaint Pierre and Miquelon (France)Saint ThomasSaint Vincent and the GrenadinesSaipanSamoaSan MarinoSão Tomé and PríncipeSaudi ArabiaScotlandSenegalSerbiaSeychellesSierra LeoneSingaporeSint EustatiusSint MaartenSlovakiaSloveniaSociety IslandsSolomon IslandsSomaliaSouth AfricaSouth Georgia and the South Sandwich Islands (U.K.)South KoreaSouth Sandwich IslandsSouth SudanSpainSri LankaSudanSurinameSwaziland (Eswatini)SwedenSwitzerlandSyriaTahitiTaiwanTajikistanTanzaniaThailandTimor-Leste (East Timor)TinianTobagoTogoTokelau (New Zealand)TongaTortolaTrinidad and TobagoTubuaiTunisiaTurkeyTurkmenistanTurks and Caicos Islands (U.K.)TuvaluUgandaUkraineUnited Arab EmiratesUnited KingdomUnited StatesUruguayUzbekistanVanuatuVatican CityVenezuelaVietnamVirgin GordaVirgin Islands, BritishVirgin Islands, U.S.Wake IslandWalesYemenZambiaZanzibarZimbabweGo
function goSelectPage(){
var e = document.getElementById("thlrdssl-traveler");
var value = e.options[e.selectedIndex].value;
var url = "/travel/destinations/traveler/none/" + value;
if (value == '0'){
window.location = "/travel/destinations/list";
}else{
window.location = url;
}
}
Travelers going to countries in Africa, South America, the Middle East, China, and Southeast Asia can get schistosomiasis. The freshwater snails that carry schistosomiasis are found in streams, rivers, and lakes in many countries around the world. Anyone who swims, bathes, or wades in freshwater streams, rivers, ponds, lakes, or untreated pools where snails that carry schistosomiasis live can get infected.
Many travelers who get schistosomiasis traveled to sub-Saharan Africa to popular tourist destinations. These include rivers and water sources such as Lake Malawi, Lake Tanganyika, Lake Victoria, the Omo River, the Zambezi River, and the Nile River.
Adventure travelers, Peace Corps volunteers, missionaries, soldiers, and ecotourists may be more likely to get schistosomiasis because of their work and activities. Local claims that there is no schistosomiasis in a body of freshwater are not reliable and precautions should be taken to prevent exposure.
### What can travelers do to prevent schistosomiasis?
If you are visiting or live in an area where schistosomiasis is a concern:
* Avoid swimming, bathing, or wading in freshwater sources, such as lakes, rivers, ponds, and wetlands. Swimming in the ocean and in chlorinated swimming pools is safe.
* Drink safe water.
+ Although schistosomiasis is not transmitted by swallowing contaminated water, if contaminated water touches your mouth or lips, you could become infected.
+ Because water coming directly from canals, lakes, rivers, streams, or springs may be contaminated with other infectious organisms, bring your water to a rolling boil for one minute or filter water before drinking it. A rolling boil for at least one minute will kill any harmful parasites, bacteria, or viruses present.
+ Iodine treatment alone WILL NOT GUARANTEE that water is safe and free of all parasites.
* Boil water used for bathing. Bring the water to a rolling boil for 1 minute, then let it cool before bathing to avoid scalding. Water held in a storage tank for at least one to two days should be safe for bathing.
* Quickly dry off completely with a towel after an accidental, brief water exposure. This may help prevent parasites from penetrating the skin. However, do not rely on towel drying alone to prevent schistosomiasis.
### After Travel
**If you traveled and feel sick,** particularly if you have a fever, talk to a healthcare provider and tell them about your travel.
If you need medical care abroad, see [Getting Health Care During Travel](/travel/page/getting-health-care-abroad).
### More Information
* [Schistosomiasis](http://www.cdc.gov/parasites/schistosomiasis/)
* [Schistosomiasis FAQs](http://www.cdc.gov/parasites/schistosomiasis/gen_info/faqs.html)
* CDC Yellow Book: [Schistosomiasis](/travel/yellowbook/2020/travel-related-infectious-diseases/schistosomiasis)
| None | None |
efcaee691fe776a66ef782e27f151b5dea582273 | cdc | Tetanus | Tetanus | Disease Directory | Travelers' Health | CDC
### What is tetanus?
Tetanus is a disease caused by bacteria called - Clostridium tetani- . The bacteria are usually found in soil, dust, and manure (animal poop). These bacteria usually enter the body through breaks in the skin, like a cut, animal bite, or wound. A person with tetanus cannot spread the disease to others.
A prominent feature of tetanus is when the jaw muscles tighten, preventing a sick person from opening their mouth. This is sometimes called “lockjaw.” Other symptoms of tetanus include muscle spasms, painful muscle stiffness, trouble swallowing, seizure, headache, fever and sweating, difficulty breathing, and paralysis. Patients may also have changes in blood pressure and heart rate. Even with intensive care, 10%–20% of people with tetanus die. Most people who get sick will notice symptoms within 14 days of infection.
### Who is at risk?
Information by Destination
Where are you going?
-- Select One --AfghanistanAlbaniaAlgeriaAmerican SamoaAndorraAnegadaAngolaAnguilla (U.K.)AntarcticaAntigua and BarbudaArgentinaArmeniaArubaAustral IslandsAustraliaAustriaAzerbaijanAzoresBahamas, TheBahrainBangladeshBarbadosBarbudaBelarusBelgiumBelizeBeninBermuda (U.K.)BhutanBoliviaBonaireBora-BoraBosnia and HerzegovinaBotswanaBrazilBritish Indian Ocean Territory (U.K.)BruneiBulgariaBurkina FasoBurma (Myanmar)BurundiCaicos IslandsCambodiaCameroonCanadaCanary Islands (Spain)Cape VerdeCayman Islands (U.K.)Central African RepublicChadChileChinaChristmas Island (Australia)Cocos (Keeling) Islands (Australia)ColombiaComorosCongo, Republic of theCook Islands (New Zealand)Costa RicaCôte d'IvoireCroatiaCubaCuraçaoCyprusCzech RepublicDemocratic Republic of the CongoDenmarkDjiboutiDominicaDominican RepublicDubaiEaster Island (Chile)EcuadorEgyptEl SalvadorEnglandEquatorial GuineaEritreaEstoniaEswatini (Swaziland)EthiopiaFalkland Islands (Islas Malvinas)Faroe Islands (Denmark)FijiFinlandFranceFrench Guiana (France)French Polynesia (France)GabonGalápagos IslandsGambia, TheGeorgiaGermanyGhanaGibraltar (U.K.)GreeceGreenland (Denmark)GrenadaGrenadinesGuadeloupeGuam (U.S.)GuatemalaGuernseyGuineaGuinea-BissauGuyanaHaitiHoly SeeHondurasHong Kong SAR (China)HungaryIcelandIndiaIndonesiaIranIraqIrelandIsle of ManIsrael, including the West Bank and GazaItalyIvory CoastJamaicaJapanJerseyJordanJost Van DykeKazakhstanKenyaKiribatiKosovoKuwaitKyrgyzstanLaosLatviaLebanonLesothoLiberiaLibyaLiechtensteinLithuaniaLuxembourgMacau SAR (China)MadagascarMadeira Islands (Portugal)MalawiMalaysiaMaldivesMaliMaltaMarquesas IslandsMarshall IslandsMartinique (France)MauritaniaMauritiusMayotte (France)MexicoMicronesia, Federated States ofMoldovaMonacoMongoliaMontenegroMontserrat (U.K.)MooreaMoroccoMozambiqueMyanmar (Burma)NamibiaNauruNepalNetherlands, TheNew Caledonia (France)New ZealandNicaraguaNigerNigeriaNiue (New Zealand)Norfolk Island (Australia)North KoreaNorth MacedoniaNorthern IrelandNorthern Mariana Islands (U.S.)NorwayOmanPakistanPalauPanamaPapua New GuineaParaguayPeruPhilippinesPitcairn Islands (U.K.)PolandPortugalPuerto Rico (U.S.)QatarRéunion (France)RomaniaRotaRurutuRussiaRwandaSabaSaint BarthelemySaint CroixSaint Helena (U.K.)Saint JohnSaint Kitts and NevisSaint LuciaSaint MartinSaint Pierre and Miquelon (France)Saint ThomasSaint Vincent and the GrenadinesSaipanSamoaSan MarinoSão Tomé and PríncipeSaudi ArabiaScotlandSenegalSerbiaSeychellesSierra LeoneSingaporeSint EustatiusSint MaartenSlovakiaSloveniaSociety IslandsSolomon IslandsSomaliaSouth AfricaSouth Georgia and the South Sandwich Islands (U.K.)South KoreaSouth Sandwich IslandsSouth SudanSpainSri LankaSudanSurinameSwaziland (Eswatini)SwedenSwitzerlandSyriaTahitiTaiwanTajikistanTanzaniaThailandTimor-Leste (East Timor)TinianTobagoTogoTokelau (New Zealand)TongaTortolaTrinidad and TobagoTubuaiTunisiaTurkeyTurkmenistanTurks and Caicos Islands (U.K.)TuvaluUgandaUkraineUnited Arab EmiratesUnited KingdomUnited StatesUruguayUzbekistanVanuatuVatican CityVenezuelaVietnamVirgin GordaVirgin Islands, BritishVirgin Islands, U.S.Wake IslandWalesYemenZambiaZanzibarZimbabweGo
var e = document.getElementById("thlrdssl-traveler");
var value = e.options[e.selectedIndex].value;
var url = "/travel/destinations/traveler/none/" - value;
if (value == '0'){
window.location = "/travel/destinations/list";
window.location = url;
Anyone who is not vaccinated against tetanus can get it. Tetanus occurs throughout the world and people of all ages can get infected. Tetanus is more common in rural and agricultural regions, areas where contact with soil or manure is more likely, and areas where immunization is inadequate.
Travelers doing humanitarian aid work, such as building construction or demolition, may be more likely to get tetanus if not vaccinated.
In the United States, rare cases of tetanus happen in those who did not get all the recommended tetanus vaccinations or who don’t stay up to date on their 10-year booster shots.
### What can travelers do to prevent tetanus?
Getting vaccinated is the best way to protect against tetanus. Tetanus vaccines are combination vaccines. These vaccines protect against tetanus and diphtheria, and some also protect against pertussis (whooping cough). These vaccines are often called [DTaP, Tdap, or Td](https://www.cdc.gov/vaccines/vpd/dtap-tdap-td/public/index.html).
##### Babies and Children
Babies need three shots of DTaP to build up high levels of protection against diphtheria, tetanus, and whooping cough. Then, young children need two booster shots to maintain that protection through early childhood. CDC recommends doses at the following ages:
- 2 months
- 4 months
- 6 months
- 15 through 18 months
- 4 through 6 years
##### Preteens and Teens
Preteens should get one shot of Tdap between the ages of 11 and 12 years to boost their immunity. Teens who didn’t get Tdap as a preteen should get one shot the next time they visit their healthcare provider.
All adults should get a tetanus shot every 10 years after getting their most recent dose as an adolescent. All adults who have never received Tdap should get one shot followed by either a Td or Tdap shot every 10 years. Vaccine providers can give Tdap to an adult who has never received it at any time, regardless of when they last got Td.
Practice good [wound care to prevent infection](https://www.cdc.gov/disasters/woundcare.html). Don’t delay first aid of even minor, non-infected wounds like blisters, scrapes, or any break in the skin. [Wash hands often with soap and water](https://www.cdc.gov/handwashing/when-how-handwashing.html) or use an alcohol-based hand rub if washing is not possible.
|
### Tetanus
### What is tetanus?
Tetanus is a disease caused by bacteria called *Clostridium tetani*. The bacteria are usually found in soil, dust, and manure (animal poop). These bacteria usually enter the body through breaks in the skin, like a cut, animal bite, or wound. A person with tetanus cannot spread the disease to others.
A prominent feature of tetanus is when the jaw muscles tighten, preventing a sick person from opening their mouth. This is sometimes called “lockjaw.” Other symptoms of tetanus include muscle spasms, painful muscle stiffness, trouble swallowing, seizure, headache, fever and sweating, difficulty breathing, and paralysis. Patients may also have changes in blood pressure and heart rate. Even with intensive care, 10%–20% of people with tetanus die. Most people who get sick will notice symptoms within 14 days of infection.
### Who is at risk?
Information by Destination
Where are you going?
-- Select One --AfghanistanAlbaniaAlgeriaAmerican SamoaAndorraAnegadaAngolaAnguilla (U.K.)AntarcticaAntigua and BarbudaArgentinaArmeniaArubaAustral IslandsAustraliaAustriaAzerbaijanAzoresBahamas, TheBahrainBangladeshBarbadosBarbudaBelarusBelgiumBelizeBeninBermuda (U.K.)BhutanBoliviaBonaireBora-BoraBosnia and HerzegovinaBotswanaBrazilBritish Indian Ocean Territory (U.K.)BruneiBulgariaBurkina FasoBurma (Myanmar)BurundiCaicos IslandsCambodiaCameroonCanadaCanary Islands (Spain)Cape VerdeCayman Islands (U.K.)Central African RepublicChadChileChinaChristmas Island (Australia)Cocos (Keeling) Islands (Australia)ColombiaComorosCongo, Republic of theCook Islands (New Zealand)Costa RicaCôte d'IvoireCroatiaCubaCuraçaoCyprusCzech RepublicDemocratic Republic of the CongoDenmarkDjiboutiDominicaDominican RepublicDubaiEaster Island (Chile)EcuadorEgyptEl SalvadorEnglandEquatorial GuineaEritreaEstoniaEswatini (Swaziland)EthiopiaFalkland Islands (Islas Malvinas)Faroe Islands (Denmark)FijiFinlandFranceFrench Guiana (France)French Polynesia (France)GabonGalápagos IslandsGambia, TheGeorgiaGermanyGhanaGibraltar (U.K.)GreeceGreenland (Denmark)GrenadaGrenadinesGuadeloupeGuam (U.S.)GuatemalaGuernseyGuineaGuinea-BissauGuyanaHaitiHoly SeeHondurasHong Kong SAR (China)HungaryIcelandIndiaIndonesiaIranIraqIrelandIsle of ManIsrael, including the West Bank and GazaItalyIvory CoastJamaicaJapanJerseyJordanJost Van DykeKazakhstanKenyaKiribatiKosovoKuwaitKyrgyzstanLaosLatviaLebanonLesothoLiberiaLibyaLiechtensteinLithuaniaLuxembourgMacau SAR (China)MadagascarMadeira Islands (Portugal)MalawiMalaysiaMaldivesMaliMaltaMarquesas IslandsMarshall IslandsMartinique (France)MauritaniaMauritiusMayotte (France)MexicoMicronesia, Federated States ofMoldovaMonacoMongoliaMontenegroMontserrat (U.K.)MooreaMoroccoMozambiqueMyanmar (Burma)NamibiaNauruNepalNetherlands, TheNew Caledonia (France)New ZealandNicaraguaNigerNigeriaNiue (New Zealand)Norfolk Island (Australia)North KoreaNorth MacedoniaNorthern IrelandNorthern Mariana Islands (U.S.)NorwayOmanPakistanPalauPanamaPapua New GuineaParaguayPeruPhilippinesPitcairn Islands (U.K.)PolandPortugalPuerto Rico (U.S.)QatarRéunion (France)RomaniaRotaRurutuRussiaRwandaSabaSaint BarthelemySaint CroixSaint Helena (U.K.)Saint JohnSaint Kitts and NevisSaint LuciaSaint MartinSaint Pierre and Miquelon (France)Saint ThomasSaint Vincent and the GrenadinesSaipanSamoaSan MarinoSão Tomé and PríncipeSaudi ArabiaScotlandSenegalSerbiaSeychellesSierra LeoneSingaporeSint EustatiusSint MaartenSlovakiaSloveniaSociety IslandsSolomon IslandsSomaliaSouth AfricaSouth Georgia and the South Sandwich Islands (U.K.)South KoreaSouth Sandwich IslandsSouth SudanSpainSri LankaSudanSurinameSwaziland (Eswatini)SwedenSwitzerlandSyriaTahitiTaiwanTajikistanTanzaniaThailandTimor-Leste (East Timor)TinianTobagoTogoTokelau (New Zealand)TongaTortolaTrinidad and TobagoTubuaiTunisiaTurkeyTurkmenistanTurks and Caicos Islands (U.K.)TuvaluUgandaUkraineUnited Arab EmiratesUnited KingdomUnited StatesUruguayUzbekistanVanuatuVatican CityVenezuelaVietnamVirgin GordaVirgin Islands, BritishVirgin Islands, U.S.Wake IslandWalesYemenZambiaZanzibarZimbabweGo
function goSelectPage(){
var e = document.getElementById("thlrdssl-traveler");
var value = e.options[e.selectedIndex].value;
var url = "/travel/destinations/traveler/none/" + value;
if (value == '0'){
window.location = "/travel/destinations/list";
}else{
window.location = url;
}
}
Anyone who is not vaccinated against tetanus can get it. Tetanus occurs throughout the world and people of all ages can get infected. Tetanus is more common in rural and agricultural regions, areas where contact with soil or manure is more likely, and areas where immunization is inadequate.
Travelers doing humanitarian aid work, such as building construction or demolition, may be more likely to get tetanus if not vaccinated.
In the United States, rare cases of tetanus happen in those who did not get all the recommended tetanus vaccinations or who don’t stay up to date on their 10-year booster shots.
### What can travelers do to prevent tetanus?
Getting vaccinated is the best way to protect against tetanus. Tetanus vaccines are combination vaccines. These vaccines protect against tetanus and diphtheria, and some also protect against pertussis (whooping cough). These vaccines are often called [DTaP, Tdap, or Td](https://www.cdc.gov/vaccines/vpd/dtap-tdap-td/public/index.html).
##### Babies and Children
Babies need three shots of DTaP to build up high levels of protection against diphtheria, tetanus, and whooping cough. Then, young children need two booster shots to maintain that protection through early childhood. CDC recommends doses at the following ages:
* 2 months
* 4 months
* 6 months
* 15 through 18 months
* 4 through 6 years
##### Preteens and Teens
Preteens should get one shot of Tdap between the ages of 11 and 12 years to boost their immunity. Teens who didn’t get Tdap as a preteen should get one shot the next time they visit their healthcare provider.
##### Adults
All adults should get a tetanus shot every 10 years after getting their most recent dose as an adolescent. All adults who have never received Tdap should get one shot followed by either a Td or Tdap shot every 10 years. Vaccine providers can give Tdap to an adult who has never received it at any time, regardless of when they last got Td.
Practice good [wound care to prevent infection](https://www.cdc.gov/disasters/woundcare.html)**.** Don’t delay first aid of even minor, non-infected wounds like blisters, scrapes, or any break in the skin. [Wash hands often with soap and water](https://www.cdc.gov/handwashing/when-how-handwashing.html) or use an alcohol-based hand rub if washing is not possible.
### After Travel
**If you traveled and feel sick,** particularly if you have a fever, talk to a healthcare provider and tell them about your travel.
If you need medical care abroad, see [Getting Health Care During Travel](/travel/page/getting-health-care-abroad).
### More Information
* [Tetanus](http://www.cdc.gov/tetanus/)
* [Tetanus Vaccination](https://www.cdc.gov/vaccines/vpd/tetanus/index.html)
* CDC Yellow Book: [Tetanus](/travel/yellowbook/2020/travel-related-infectious-diseases/tetanus)
| None | None |
ff642d934fe5ceaacb27d722ff759efec01fc8f0 | cdc | Tick-borne Encephalitis | Tick-borne Encephalitis | Disease Directory | Travelers' Health | CDC
### Tick-borne Encephalitis
### What is tick-borne encephalitis?
Tick-borne encephalitis (TBE) is a disease caused by a virus. The virus spreads to people in a few ways:
- Bite from an infected tick
- Eating or drinking unpasteurized dairy products (milk and cheese) from infected goats, sheep, or cows.
Most people infected with tick-borne encephalitis do not feel sick. When symptoms occur, they may include fever, aches, loss of appetite, headache, nausea, and vomiting. Some people develop swelling of the brain and/or spinal cord, confusion, and sensory disturbances. Tick-borne encephalitis can sometimes cause death.
### Who can get tick-borne encephalitis?
Travelers to many parts of Europe and Asia may be at risk for infection with TBE virus. Check if this disease is a concern at [your destination](/travel/destinations/list).
Activities that increase a travelers’ chances getting tick-borne encephalitis include camping, hiking, and hunting. Travelers are more likely to get infected with TBE when traveling to affected areas April through November, this is when ticks are most active.
### What can travelers do to prevent tick-borne encephalitis?
Travelers can protect themselves against TBE by taking the following precautions:
Prevent Tick Bites
- Know where to expect ticks. Ticks live in grassy, brushy, or wooded areas, or even on animals. Spending time outside camping, gardening, or hunting could bring you in close contact with ticks. Many people get ticks in their own yard or neighborhood.
- Treat clothing and gear with products containing 0.5% permethrin. Permethrin can be used to treat boots, clothing and camping gear and remain protective through several washings. Alternatively, you can buy permethrin-treated clothing and gear.
- Use [Environmental Protection Agency (EPA)-registered insect repellents](https://www.epa.gov/insect-repellents) containing DEET, picaridin, IR3535, Oil of Lemon Eucalyptus (OLE), para-menthane-diol (PMD), or 2-undecanone. EPA’s helpful [search tool](https://www.epa.gov/insect-repellents/find-insect-repellent-right-you) can help you find the product that best suits your needs. Always follow product instructions. Do not use products containing OLE or PMD on children under 3 years old.
- Avoid Contact with Ticks
- Avoid wooded and brushy areas with high grass and leaf litter.
- Walk in the center of trails.
Find and Remove Ticks
- Check your clothing for ticks. Ticks may be carried into the house on clothing. Any ticks that are found should be removed. When possible, tumble dry clothes in a dryer on high heat for 10 minutes to kill ticks on dry clothing after you come indoors. If the clothes are damp, additional time may be needed. If the clothes require washing first, hot water is recommended. Cold and medium temperature water will not kill ticks.
- Examine gear and pets. Ticks can ride on clothing and pets, then attach to a person later, so carefully examine pets, coats, and daypacks.
- Shower soon after being outdoors. Showering within two hours of coming indoors has been shown to reduce your risk of getting tick-borne diseases. Showering may help wash off unattached ticks and it is a good opportunity to do a tick check.
- Check your body for ticks. Conduct a full body check upon return from potentially tick-infested areas. Use a hand-held or full-length mirror to view all parts of your body. Check these parts of your body for ticks:
- Under the arms
- In and around the ears
- Inside belly button
- Back of the knees
- In and around the hair
- Between the legs
- Around the waist
- If you find a tick attached to your skin, simply remove the tick as soon as possible.
Eat only pasteurized dairy products
Get vaccinated if recommended
Tick-borne encephalitis vaccine is recommended for travelers who are moving or traveling to a TBE-endemic area and will have [extensive exposure](https://www.cdc.gov/tick-borne-encephalitis/healthcare-providers/hcp-vaccine.html#vaccine-considerations) to ticks based on their planned outdoor activities and itinerary.
In addition, TBE vaccine may be considered for persons traveling or moving to a TBE-endemic area who might engage in outdoor activities in areas ticks are likely to be found. The decision to vaccinate should be based on an assessment of their planned activities and itinerary, risk factors for a poorer medical outcome, and personal perception and tolerance of risk.
|
### Tick-borne Encephalitis
### What is tick-borne encephalitis?
Tick-borne encephalitis (TBE) is a disease caused by a virus. The virus spreads to people in a few ways:
* Bite from an infected tick
* Eating or drinking unpasteurized dairy products (milk and cheese) from infected goats, sheep, or cows.
Most people infected with tick-borne encephalitis do not feel sick. When symptoms occur, they may include fever, aches, loss of appetite, headache, nausea, and vomiting. Some people develop swelling of the brain and/or spinal cord, confusion, and sensory disturbances. Tick-borne encephalitis can sometimes cause death.
### Who can get tick-borne encephalitis?
Travelers to many parts of Europe and Asia may be at risk for infection with TBE virus. Check if this disease is a concern at [your destination](/travel/destinations/list).
Activities that increase a travelers’ chances getting tick-borne encephalitis include camping, hiking, and hunting. Travelers are more likely to get infected with TBE when traveling to affected areas April through November, this is when ticks are most active.
### What can travelers do to prevent tick-borne encephalitis?
Travelers can protect themselves against TBE by taking the following precautions:
**Prevent Tick Bites**
* **Know where to expect ticks.** Ticks live in grassy, brushy, or wooded areas, or even on animals. Spending time outside camping, gardening, or hunting could bring you in close contact with ticks. Many people get ticks in their own yard or neighborhood.
* **Treat clothing and gear** with products containing 0.5% permethrin. Permethrin can be used to treat boots, clothing and camping gear and remain protective through several washings. Alternatively, you can buy permethrin-treated clothing and gear.
* **Use [Environmental Protection Agency (EPA)-registered insect repellents](https://www.epa.gov/insect-repellents)** containing DEET, picaridin, IR3535, Oil of Lemon Eucalyptus (OLE), para-menthane-diol (PMD), or 2-undecanone. EPA’s helpful [search tool](https://www.epa.gov/insect-repellents/find-insect-repellent-right-you) can help you find the product that best suits your needs. Always follow product instructions. Do not use products containing OLE or PMD on children under 3 years old.
* **Avoid Contact with Ticks**
+ Avoid wooded and brushy areas with high grass and leaf litter.
+ Walk in the center of trails.
**Find and Remove Ticks**
* **Check your clothing for ticks.** Ticks may be carried into the house on clothing. Any ticks that are found should be removed. When possible, tumble dry clothes in a dryer on high heat for 10 minutes to kill ticks on dry clothing after you come indoors. If the clothes are damp, additional time may be needed. If the clothes require washing first, hot water is recommended. Cold and medium temperature water will not kill ticks.
* **Examine gear and pets.** Ticks can ride on clothing and pets, then attach to a person later, so carefully examine pets, coats, and daypacks.
* **Shower soon after being outdoors.** Showering within two hours of coming indoors has been shown to reduce your risk of getting tick-borne diseases. Showering may help wash off unattached ticks and it is a good opportunity to do a tick check.
* **Check your body for ticks.** Conduct a full body check upon return from potentially tick-infested areas. Use a hand-held or full-length mirror to view all parts of your body. Check these parts of your body for ticks:
+ Under the arms
+ In and around the ears
+ Inside belly button
+ Back of the knees
+ In and around the hair
+ Between the legs
+ Around the waist
* If you find a tick attached to your skin, simply remove the tick as soon as possible.
**Eat only pasteurized dairy products**
**Get vaccinated if recommended**
Tick-borne encephalitis vaccine is recommended for travelers who are moving or traveling to a TBE-endemic area and will have [extensive exposure](https://www.cdc.gov/tick-borne-encephalitis/healthcare-providers/hcp-vaccine.html#vaccine-considerations) to ticks based on their planned outdoor activities and itinerary.
In addition, TBE vaccine may be considered for persons traveling or moving to a TBE-endemic area who might engage in outdoor activities in areas ticks are likely to be found. The decision to vaccinate should be based on an assessment of their planned activities and itinerary, risk factors for a poorer medical outcome, and personal perception and tolerance of risk.
### After Travel
**If you traveled and feel sick,** particularly if you have a fever, talk to a healthcare provider and tell them about your travel.
If you need medical care abroad, see [Getting Health Care During Travel](/travel/page/getting-health-care-abroad).
### Traveler Information
* [Tick-borne Encephalitis](https://www.cdc.gov/tick-borne-encephalitis/)
* [Avoid Bug Bites](/travel/page/avoid-bug-bites) - Information for travelers
* [Insect Repellent Use and Safety](http://www.cdc.gov/westnile/faq/repellent.html)
### Clinician Information
* [Tick-borne Encephalitis](https://www.cdc.gov/tick-borne-encephalitis/)
* [Tick-borne Encephalitis](/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/tickborne-encephalitis.htm) in CDC Yellow Book
* [Protection against Mosquitoes, Ticks, & Other Insects & Arthropods](/travel/yellowbook/2012/chapter-2-the-pre-travel-consultation/protection-against-mosquitoes-ticks-and-other-insects-and-arthropods.htm)
| None | None |
c37f972ffea1e689fb354c6d9309121683fd58fb | cdc | Tuberculosis (TB) | Tuberculosis (TB) | Disease Directory | Travelers' Health | CDC
### Tuberculosis (TB)
### What is tuberculosis?
[Tuberculosis (TB)](https://www.cdc.gov/tb/topic/basics/default.htm) is a disease caused by bacteria called - Mycobacterium tuberculosis- . People with TB can spread it in the air to others when they cough, speak, or sing. You can get sick when you breathe TB bacteria into your lungs. TB bacteria in the lungs can move through the blood to infect other parts of the body, such as the kidney, spine, and brain.
Symptoms of TB disease in the lungs include
- Cough that lasts 3 weeks or longer
- Pain in the chest
- Coughing up blood or mucus
- Weakness or fatigue
- Weight loss
- Loss of appetite
- Sweating at night
Symptoms of TB infection in other parts of the body depend on the area affected.
Not everyone infected with TB bacteria becomes sick or has symptoms. This is called [latent TB infection](https://www.cdc.gov/tb/topic/basics/tbinfectiondisease.htm). People with latent TB infection cannot spread TB to others. However, a person with latent TB infection can get sick years later if their immune system becomes weak. People with latent TB infection can take medicine to prevent developing TB Disease.
### Who is at risk?
Information by Destination
Where are you going?
-- Select One --AfghanistanAlbaniaAlgeriaAmerican SamoaAndorraAnegadaAngolaAnguilla (U.K.)AntarcticaAntigua and BarbudaArgentinaArmeniaArubaAustral IslandsAustraliaAustriaAzerbaijanAzoresBahamas, TheBahrainBangladeshBarbadosBarbudaBelarusBelgiumBelizeBeninBermuda (U.K.)BhutanBoliviaBonaireBora-BoraBosnia and HerzegovinaBotswanaBrazilBritish Indian Ocean Territory (U.K.)BruneiBulgariaBurkina FasoBurma (Myanmar)BurundiCaicos IslandsCambodiaCameroonCanadaCanary Islands (Spain)Cape VerdeCayman Islands (U.K.)Central African RepublicChadChileChinaChristmas Island (Australia)Cocos (Keeling) Islands (Australia)ColombiaComorosCongo, Republic of theCook Islands (New Zealand)Costa RicaCôte d'IvoireCroatiaCubaCuraçaoCyprusCzech RepublicDemocratic Republic of the CongoDenmarkDjiboutiDominicaDominican RepublicDubaiEaster Island (Chile)EcuadorEgyptEl SalvadorEnglandEquatorial GuineaEritreaEstoniaEswatini (Swaziland)EthiopiaFalkland Islands (Islas Malvinas)Faroe Islands (Denmark)FijiFinlandFranceFrench Guiana (France)French Polynesia (France)GabonGalápagos IslandsGambia, TheGeorgiaGermanyGhanaGibraltar (U.K.)GreeceGreenland (Denmark)GrenadaGrenadinesGuadeloupeGuam (U.S.)GuatemalaGuernseyGuineaGuinea-BissauGuyanaHaitiHoly SeeHondurasHong Kong SAR (China)HungaryIcelandIndiaIndonesiaIranIraqIrelandIsle of ManIsrael, including the West Bank and GazaItalyIvory CoastJamaicaJapanJerseyJordanJost Van DykeKazakhstanKenyaKiribatiKosovoKuwaitKyrgyzstanLaosLatviaLebanonLesothoLiberiaLibyaLiechtensteinLithuaniaLuxembourgMacau SAR (China)MadagascarMadeira Islands (Portugal)MalawiMalaysiaMaldivesMaliMaltaMarquesas IslandsMarshall IslandsMartinique (France)MauritaniaMauritiusMayotte (France)MexicoMicronesia, Federated States ofMoldovaMonacoMongoliaMontenegroMontserrat (U.K.)MooreaMoroccoMozambiqueMyanmar (Burma)NamibiaNauruNepalNetherlands, TheNew Caledonia (France)New ZealandNicaraguaNigerNigeriaNiue (New Zealand)Norfolk Island (Australia)North KoreaNorth MacedoniaNorthern IrelandNorthern Mariana Islands (U.S.)NorwayOmanPakistanPalauPanamaPapua New GuineaParaguayPeruPhilippinesPitcairn Islands (U.K.)PolandPortugalPuerto Rico (U.S.)QatarRéunion (France)RomaniaRotaRurutuRussiaRwandaSabaSaint BarthelemySaint CroixSaint Helena (U.K.)Saint JohnSaint Kitts and NevisSaint LuciaSaint MartinSaint Pierre and Miquelon (France)Saint ThomasSaint Vincent and the GrenadinesSaipanSamoaSan MarinoSão Tomé and PríncipeSaudi ArabiaScotlandSenegalSerbiaSeychellesSierra LeoneSingaporeSint EustatiusSint MaartenSlovakiaSloveniaSociety IslandsSolomon IslandsSomaliaSouth AfricaSouth Georgia and the South Sandwich Islands (U.K.)South KoreaSouth Sandwich IslandsSouth SudanSpainSri LankaSudanSurinameSwaziland (Eswatini)SwedenSwitzerlandSyriaTahitiTaiwanTajikistanTanzaniaThailandTimor-Leste (East Timor)TinianTobagoTogoTokelau (New Zealand)TongaTortolaTrinidad and TobagoTubuaiTunisiaTurkeyTurkmenistanTurks and Caicos Islands (U.K.)TuvaluUgandaUkraineUnited Arab EmiratesUnited KingdomUnited StatesUruguayUzbekistanVanuatuVatican CityVenezuelaVietnamVirgin GordaVirgin Islands, BritishVirgin Islands, U.S.Wake IslandWalesYemenZambiaZanzibarZimbabweGo
var e = document.getElementById("thlrdssl-traveler");
var value = e.options[e.selectedIndex].value;
var url = "/travel/destinations/traveler/none/" - value;
if (value == '0'){
window.location = "/travel/destinations/list";
window.location = url;
TB occurs throughout the world but is much more common in some countries. Most TB occurs in sub-Saharan Africa, Eastern Europe, and Asia. Some TB bacteria are resistant to the drugs used to treat infection ([drug-resistant TB](https://www.cdc.gov/tb/topic/drtb/default.htm)). Fortunately, drug-resistant TB is rare.
Travelers planning to work in health care settings should consult infection control or occupational health experts in the country before seeing patients.
People with weak immune systems, especially those with HIV infection, are much more likely to develop TB disease compared to people with healthy immune systems.
A traveler’s [chances of getting TB](https://www.cdc.gov/tb/topic/populations/travelers/default.htm) on a plane are very low.
### What can travelers do to prevent tuberculosis?
Travelers can protect themselves by taking the following steps
- Avoid being close to or around a person who could have TB for long periods of time. This is especially important for travelers spending time in crowded environments, like clinics, hospitals, prisons, or homeless shelters.
- Avoid close contact with people who are coughing and who look sick.
- Take special precautions around people known to have TB. Travelers spending time working in health care settings should talk to an infection control or occupational health expert about what steps they can take to prevent TB infection, such as wearing an N95 respirator. They should also talk to a doctor about being tested for TB infection before leaving the United States. If the test reaction is negative, have a repeat TB test 8 to 10 weeks after returning to the United States
A [TB vaccine](https://www.cdc.gov/tb/publications/factsheets/prevention/bcg.htm) exists, but CDC does not recommend it for travelers.
|
### Tuberculosis (TB)
### What is tuberculosis?
[Tuberculosis (TB)](https://www.cdc.gov/tb/topic/basics/default.htm) is a disease caused by bacteria called *Mycobacterium tuberculosis*. People with TB can spread it in the air to others when they cough, speak, or sing. You can get sick when you breathe TB bacteria into your lungs. TB bacteria in the lungs can move through the blood to infect other parts of the body, such as the kidney, spine, and brain.
Symptoms of TB disease in the lungs include
* Cough that lasts 3 weeks or longer
* Pain in the chest
* Coughing up blood or mucus
* Weakness or fatigue
* Weight loss
* Loss of appetite
* Chills
* Fever
* Sweating at night
Symptoms of TB infection in other parts of the body depend on the area affected.
Not everyone infected with TB bacteria becomes sick or has symptoms. This is called [latent TB infection](https://www.cdc.gov/tb/topic/basics/tbinfectiondisease.htm). People with latent TB infection cannot spread TB to others. However, a person with latent TB infection can get sick years later if their immune system becomes weak. People with latent TB infection can take medicine to prevent developing TB Disease.
### Who is at risk?
Information by Destination
Where are you going?
-- Select One --AfghanistanAlbaniaAlgeriaAmerican SamoaAndorraAnegadaAngolaAnguilla (U.K.)AntarcticaAntigua and BarbudaArgentinaArmeniaArubaAustral IslandsAustraliaAustriaAzerbaijanAzoresBahamas, TheBahrainBangladeshBarbadosBarbudaBelarusBelgiumBelizeBeninBermuda (U.K.)BhutanBoliviaBonaireBora-BoraBosnia and HerzegovinaBotswanaBrazilBritish Indian Ocean Territory (U.K.)BruneiBulgariaBurkina FasoBurma (Myanmar)BurundiCaicos IslandsCambodiaCameroonCanadaCanary Islands (Spain)Cape VerdeCayman Islands (U.K.)Central African RepublicChadChileChinaChristmas Island (Australia)Cocos (Keeling) Islands (Australia)ColombiaComorosCongo, Republic of theCook Islands (New Zealand)Costa RicaCôte d'IvoireCroatiaCubaCuraçaoCyprusCzech RepublicDemocratic Republic of the CongoDenmarkDjiboutiDominicaDominican RepublicDubaiEaster Island (Chile)EcuadorEgyptEl SalvadorEnglandEquatorial GuineaEritreaEstoniaEswatini (Swaziland)EthiopiaFalkland Islands (Islas Malvinas)Faroe Islands (Denmark)FijiFinlandFranceFrench Guiana (France)French Polynesia (France)GabonGalápagos IslandsGambia, TheGeorgiaGermanyGhanaGibraltar (U.K.)GreeceGreenland (Denmark)GrenadaGrenadinesGuadeloupeGuam (U.S.)GuatemalaGuernseyGuineaGuinea-BissauGuyanaHaitiHoly SeeHondurasHong Kong SAR (China)HungaryIcelandIndiaIndonesiaIranIraqIrelandIsle of ManIsrael, including the West Bank and GazaItalyIvory CoastJamaicaJapanJerseyJordanJost Van DykeKazakhstanKenyaKiribatiKosovoKuwaitKyrgyzstanLaosLatviaLebanonLesothoLiberiaLibyaLiechtensteinLithuaniaLuxembourgMacau SAR (China)MadagascarMadeira Islands (Portugal)MalawiMalaysiaMaldivesMaliMaltaMarquesas IslandsMarshall IslandsMartinique (France)MauritaniaMauritiusMayotte (France)MexicoMicronesia, Federated States ofMoldovaMonacoMongoliaMontenegroMontserrat (U.K.)MooreaMoroccoMozambiqueMyanmar (Burma)NamibiaNauruNepalNetherlands, TheNew Caledonia (France)New ZealandNicaraguaNigerNigeriaNiue (New Zealand)Norfolk Island (Australia)North KoreaNorth MacedoniaNorthern IrelandNorthern Mariana Islands (U.S.)NorwayOmanPakistanPalauPanamaPapua New GuineaParaguayPeruPhilippinesPitcairn Islands (U.K.)PolandPortugalPuerto Rico (U.S.)QatarRéunion (France)RomaniaRotaRurutuRussiaRwandaSabaSaint BarthelemySaint CroixSaint Helena (U.K.)Saint JohnSaint Kitts and NevisSaint LuciaSaint MartinSaint Pierre and Miquelon (France)Saint ThomasSaint Vincent and the GrenadinesSaipanSamoaSan MarinoSão Tomé and PríncipeSaudi ArabiaScotlandSenegalSerbiaSeychellesSierra LeoneSingaporeSint EustatiusSint MaartenSlovakiaSloveniaSociety IslandsSolomon IslandsSomaliaSouth AfricaSouth Georgia and the South Sandwich Islands (U.K.)South KoreaSouth Sandwich IslandsSouth SudanSpainSri LankaSudanSurinameSwaziland (Eswatini)SwedenSwitzerlandSyriaTahitiTaiwanTajikistanTanzaniaThailandTimor-Leste (East Timor)TinianTobagoTogoTokelau (New Zealand)TongaTortolaTrinidad and TobagoTubuaiTunisiaTurkeyTurkmenistanTurks and Caicos Islands (U.K.)TuvaluUgandaUkraineUnited Arab EmiratesUnited KingdomUnited StatesUruguayUzbekistanVanuatuVatican CityVenezuelaVietnamVirgin GordaVirgin Islands, BritishVirgin Islands, U.S.Wake IslandWalesYemenZambiaZanzibarZimbabweGo
function goSelectPage(){
var e = document.getElementById("thlrdssl-traveler");
var value = e.options[e.selectedIndex].value;
var url = "/travel/destinations/traveler/none/" + value;
if (value == '0'){
window.location = "/travel/destinations/list";
}else{
window.location = url;
}
}
TB occurs throughout the world but is much more common in some countries. Most TB occurs in sub-Saharan Africa, Eastern Europe, and Asia. Some TB bacteria are resistant to the drugs used to treat infection ([drug-resistant TB](https://www.cdc.gov/tb/topic/drtb/default.htm)). Fortunately, drug-resistant TB is rare.
Travelers planning to work in health care settings should consult infection control or occupational health experts in the country before seeing patients.
People with weak immune systems, especially those with HIV infection, are much more likely to develop TB disease compared to people with healthy immune systems.
A traveler’s [chances of getting TB](https://www.cdc.gov/tb/topic/populations/travelers/default.htm) on a plane are very low.
### What can travelers do to prevent tuberculosis?
Travelers can protect themselves by taking the following steps
* **Avoid being close to or around a person who could have TB for long periods of time**. This is especially important for travelers spending time in crowded environments, like clinics, hospitals, prisons, or homeless shelters.
* **Avoid close contact with people who are coughing and who look sick**.
* **Take special precautions around people known to have TB.** Travelers spending time working in health care settings should talk to an infection control or occupational health expert about what steps they can take to prevent TB infection, such as wearing an N95 respirator. They should also talk to a doctor about being tested for TB infection before leaving the United States. If the test reaction is negative, have a repeat TB test 8 to 10 weeks after returning to the United States
A [TB vaccine](https://www.cdc.gov/tb/publications/factsheets/prevention/bcg.htm) exists, but CDC does not recommend it for travelers.
### After Travel
**If you traveled and feel sick,** particularly if you have a fever, talk to a healthcare provider and tell them about your travel.
If you need medical care abroad, see [Getting Health Care During Travel](/travel/page/getting-health-care-abroad).
### More Information
* [Tuberculosis Information for International Travelers](http://www.cdc.gov/tb/publications/factsheets/general/tbtravelinfo.htm)
* [Basic TB Facts](https://www.cdc.gov/tb/topic/basics/default.htm)
* CDC Yellow Book: [Tuberculosis](/travel/yellowbook/2020/travel-related-infectious-diseases/tuberculosis)
| None | None |
bfe5fe48829a956138087e3259ea70b62525f038 | cdc | Typhoid Fever | Typhoid Fever | Disease Directory | Travelers' Health | CDC
### Typhoid Fever
### What is typhoid fever?
Typhoid fever and paratyphoid fever are similar diseases caused by bacteria. - Salmonella- Typhi bacteria cause typhoid fever. - Salmonella- Paratyphi bacteria cause paratyphoid fever.
People infected with these bacteria can spread them to others. This typically happens when an infected person uses the bathroom and does not wash their hands. The bacteria can stay on their hands and contaminate everything that the person touches, including food and drinks.
In countries with poor sanitation, the water used to rinse and prepare food and beverages, including tap water, can also be contaminated with these bacteria. Travelers who eat foods or drink beverages contaminated with these bacteria can then get sick.
Typhoid fever and paratyphoid fever cause similar symptoms. People with these diseases usually have a fever that can be as high as 103 to 104°F (39 to 40°C). They also may have weakness, stomach pain, headache, diarrhea or constipation, cough, and loss of appetite. Some people have a rash of flat, rose-colored spots. Internal bleeding and death can occur but are rare.
### Who is at risk?
Information by Destination
Where are you going?
-- Select One --AfghanistanAlbaniaAlgeriaAmerican SamoaAndorraAnegadaAngolaAnguilla (U.K.)AntarcticaAntigua and BarbudaArgentinaArmeniaArubaAustral IslandsAustraliaAustriaAzerbaijanAzoresBahamas, TheBahrainBangladeshBarbadosBarbudaBelarusBelgiumBelizeBeninBermuda (U.K.)BhutanBoliviaBonaireBora-BoraBosnia and HerzegovinaBotswanaBrazilBritish Indian Ocean Territory (U.K.)BruneiBulgariaBurkina FasoBurma (Myanmar)BurundiCaicos IslandsCambodiaCameroonCanadaCanary Islands (Spain)Cape VerdeCayman Islands (U.K.)Central African RepublicChadChileChinaChristmas Island (Australia)Cocos (Keeling) Islands (Australia)ColombiaComorosCongo, Republic of theCook Islands (New Zealand)Costa RicaCôte d'IvoireCroatiaCubaCuraçaoCyprusCzech RepublicDemocratic Republic of the CongoDenmarkDjiboutiDominicaDominican RepublicDubaiEaster Island (Chile)EcuadorEgyptEl SalvadorEnglandEquatorial GuineaEritreaEstoniaEswatini (Swaziland)EthiopiaFalkland Islands (Islas Malvinas)Faroe Islands (Denmark)FijiFinlandFranceFrench Guiana (France)French Polynesia (France)GabonGalápagos IslandsGambia, TheGeorgiaGermanyGhanaGibraltar (U.K.)GreeceGreenland (Denmark)GrenadaGrenadinesGuadeloupeGuam (U.S.)GuatemalaGuernseyGuineaGuinea-BissauGuyanaHaitiHoly SeeHondurasHong Kong SAR (China)HungaryIcelandIndiaIndonesiaIranIraqIrelandIsle of ManIsrael, including the West Bank and GazaItalyIvory CoastJamaicaJapanJerseyJordanJost Van DykeKazakhstanKenyaKiribatiKosovoKuwaitKyrgyzstanLaosLatviaLebanonLesothoLiberiaLibyaLiechtensteinLithuaniaLuxembourgMacau SAR (China)MadagascarMadeira Islands (Portugal)MalawiMalaysiaMaldivesMaliMaltaMarquesas IslandsMarshall IslandsMartinique (France)MauritaniaMauritiusMayotte (France)MexicoMicronesia, Federated States ofMoldovaMonacoMongoliaMontenegroMontserrat (U.K.)MooreaMoroccoMozambiqueMyanmar (Burma)NamibiaNauruNepalNetherlands, TheNew Caledonia (France)New ZealandNicaraguaNigerNigeriaNiue (New Zealand)Norfolk Island (Australia)North KoreaNorth MacedoniaNorthern IrelandNorthern Mariana Islands (U.S.)NorwayOmanPakistanPalauPanamaPapua New GuineaParaguayPeruPhilippinesPitcairn Islands (U.K.)PolandPortugalPuerto Rico (U.S.)QatarRéunion (France)RomaniaRotaRurutuRussiaRwandaSabaSaint BarthelemySaint CroixSaint Helena (U.K.)Saint JohnSaint Kitts and NevisSaint LuciaSaint MartinSaint Pierre and Miquelon (France)Saint ThomasSaint Vincent and the GrenadinesSaipanSamoaSan MarinoSão Tomé and PríncipeSaudi ArabiaScotlandSenegalSerbiaSeychellesSierra LeoneSingaporeSint EustatiusSint MaartenSlovakiaSloveniaSociety IslandsSolomon IslandsSomaliaSouth AfricaSouth Georgia and the South Sandwich Islands (U.K.)South KoreaSouth Sandwich IslandsSouth SudanSpainSri LankaSudanSurinameSwaziland (Eswatini)SwedenSwitzerlandSyriaTahitiTaiwanTajikistanTanzaniaThailandTimor-Leste (East Timor)TinianTobagoTogoTokelau (New Zealand)TongaTortolaTrinidad and TobagoTubuaiTunisiaTurkeyTurkmenistanTurks and Caicos Islands (U.K.)TuvaluUgandaUkraineUnited Arab EmiratesUnited KingdomUnited StatesUruguayUzbekistanVanuatuVatican CityVenezuelaVietnamVirgin GordaVirgin Islands, BritishVirgin Islands, U.S.Wake IslandWalesYemenZambiaZanzibarZimbabweGo
var e = document.getElementById("thlrdssl-traveler");
var value = e.options[e.selectedIndex].value;
var url = "/travel/destinations/traveler/none/" - value;
if (value == '0'){
window.location = "/travel/destinations/list";
window.location = url;
Typhoid and paratyphoid fever are most common in parts of the world where water and food may be unsafe and sanitation is poor. Travelers to Eastern and Southern Asia (especially Pakistan India, and Bangladesh), Africa, the Caribbean, Central and South America, and the Middle East are at increased risk for typhoid and paratyphoid fever.
People visiting friends or relatives are more likely than other travelers to get typhoid fever because they may stay in the country longer, may be less cautious about the food they eat or the beverages they drink because they eat local food prepared in people’s homes, and may not think to get vaccinated before traveling.
In the United States each year, about 425 people are diagnosed with typhoid fever and about 125 people are diagnosed with paratyphoid fever each year. Most of these people travelled internationally.
### What can travelers do to prevent typhoid fever?
Getting vaccinated, choosing food and drinks carefully, and washing your hands are the best ways to avoid getting typhoid.
Check if the typhoid fever vaccination is recommended for [your destination](/travel/destinations/list). Two typhoid vaccines are available in the United States. Visit your doctor or a travel clinic at least one month before traveling to discuss your options.
- Pill vaccine. People 6 years old and older can take the pill vaccine. Finish taking all four pills (one pill every other day) at least 1 week before travel.
- Shot vaccine. People 2 years old and older can get the shot vaccine. Get one shot (or a booster shot) at least 2 weeks before travel.
Typhoid vaccines are only 50 to 80% effective, so you should still be careful about what you eat and drink to lower your risk of getting typhoid fever. Also, there isn’t a vaccine that protects against paratyphoid fever. For these reasons, it’s very important that you also take the following steps to prevent typhoid.
Choose food and drinks carefully
- Only eat foods that are cooked and served hot
- Avoid food that has been sitting on a buffet
- Eat raw fruits and vegetables only if you have washed them in clean water or peeled them
- Only drink beverages from factory-sealed containers
- Avoid ice because it may have been made from unsafe water
- Only drink pasteurized milk
Wash your hands
- Wash hands often with soap and water for 20 seconds, especially after using the bathroom and before eating
- If soap and water are not readily available, use an alcohol-based hand sanitizer with at least 60% alcohol
- Keep your hands away from your face and mouth
|
### Typhoid Fever
### What is typhoid fever?
Typhoid fever and paratyphoid fever are similar diseases caused by bacteria. *Salmonella* Typhi bacteria cause typhoid fever. *Salmonella* Paratyphi bacteria cause paratyphoid fever.
People infected with these bacteria can spread them to others. This typically happens when an infected person uses the bathroom and does not wash their hands. The bacteria can stay on their hands and contaminate everything that the person touches, including food and drinks.
In countries with poor sanitation, the water used to rinse and prepare food and beverages, including tap water, can also be contaminated with these bacteria. Travelers who eat foods or drink beverages contaminated with these bacteria can then get sick.
Typhoid fever and paratyphoid fever cause similar symptoms. People with these diseases usually have a fever that can be as high as 103 to 104°F (39 to 40°C). They also may have weakness, stomach pain, headache, diarrhea or constipation, cough, and loss of appetite. Some people have a rash of flat, rose-colored spots. Internal bleeding and death can occur but are rare.
### Who is at risk?
Information by Destination
Where are you going?
-- Select One --AfghanistanAlbaniaAlgeriaAmerican SamoaAndorraAnegadaAngolaAnguilla (U.K.)AntarcticaAntigua and BarbudaArgentinaArmeniaArubaAustral IslandsAustraliaAustriaAzerbaijanAzoresBahamas, TheBahrainBangladeshBarbadosBarbudaBelarusBelgiumBelizeBeninBermuda (U.K.)BhutanBoliviaBonaireBora-BoraBosnia and HerzegovinaBotswanaBrazilBritish Indian Ocean Territory (U.K.)BruneiBulgariaBurkina FasoBurma (Myanmar)BurundiCaicos IslandsCambodiaCameroonCanadaCanary Islands (Spain)Cape VerdeCayman Islands (U.K.)Central African RepublicChadChileChinaChristmas Island (Australia)Cocos (Keeling) Islands (Australia)ColombiaComorosCongo, Republic of theCook Islands (New Zealand)Costa RicaCôte d'IvoireCroatiaCubaCuraçaoCyprusCzech RepublicDemocratic Republic of the CongoDenmarkDjiboutiDominicaDominican RepublicDubaiEaster Island (Chile)EcuadorEgyptEl SalvadorEnglandEquatorial GuineaEritreaEstoniaEswatini (Swaziland)EthiopiaFalkland Islands (Islas Malvinas)Faroe Islands (Denmark)FijiFinlandFranceFrench Guiana (France)French Polynesia (France)GabonGalápagos IslandsGambia, TheGeorgiaGermanyGhanaGibraltar (U.K.)GreeceGreenland (Denmark)GrenadaGrenadinesGuadeloupeGuam (U.S.)GuatemalaGuernseyGuineaGuinea-BissauGuyanaHaitiHoly SeeHondurasHong Kong SAR (China)HungaryIcelandIndiaIndonesiaIranIraqIrelandIsle of ManIsrael, including the West Bank and GazaItalyIvory CoastJamaicaJapanJerseyJordanJost Van DykeKazakhstanKenyaKiribatiKosovoKuwaitKyrgyzstanLaosLatviaLebanonLesothoLiberiaLibyaLiechtensteinLithuaniaLuxembourgMacau SAR (China)MadagascarMadeira Islands (Portugal)MalawiMalaysiaMaldivesMaliMaltaMarquesas IslandsMarshall IslandsMartinique (France)MauritaniaMauritiusMayotte (France)MexicoMicronesia, Federated States ofMoldovaMonacoMongoliaMontenegroMontserrat (U.K.)MooreaMoroccoMozambiqueMyanmar (Burma)NamibiaNauruNepalNetherlands, TheNew Caledonia (France)New ZealandNicaraguaNigerNigeriaNiue (New Zealand)Norfolk Island (Australia)North KoreaNorth MacedoniaNorthern IrelandNorthern Mariana Islands (U.S.)NorwayOmanPakistanPalauPanamaPapua New GuineaParaguayPeruPhilippinesPitcairn Islands (U.K.)PolandPortugalPuerto Rico (U.S.)QatarRéunion (France)RomaniaRotaRurutuRussiaRwandaSabaSaint BarthelemySaint CroixSaint Helena (U.K.)Saint JohnSaint Kitts and NevisSaint LuciaSaint MartinSaint Pierre and Miquelon (France)Saint ThomasSaint Vincent and the GrenadinesSaipanSamoaSan MarinoSão Tomé and PríncipeSaudi ArabiaScotlandSenegalSerbiaSeychellesSierra LeoneSingaporeSint EustatiusSint MaartenSlovakiaSloveniaSociety IslandsSolomon IslandsSomaliaSouth AfricaSouth Georgia and the South Sandwich Islands (U.K.)South KoreaSouth Sandwich IslandsSouth SudanSpainSri LankaSudanSurinameSwaziland (Eswatini)SwedenSwitzerlandSyriaTahitiTaiwanTajikistanTanzaniaThailandTimor-Leste (East Timor)TinianTobagoTogoTokelau (New Zealand)TongaTortolaTrinidad and TobagoTubuaiTunisiaTurkeyTurkmenistanTurks and Caicos Islands (U.K.)TuvaluUgandaUkraineUnited Arab EmiratesUnited KingdomUnited StatesUruguayUzbekistanVanuatuVatican CityVenezuelaVietnamVirgin GordaVirgin Islands, BritishVirgin Islands, U.S.Wake IslandWalesYemenZambiaZanzibarZimbabweGo
function goSelectPage(){
var e = document.getElementById("thlrdssl-traveler");
var value = e.options[e.selectedIndex].value;
var url = "/travel/destinations/traveler/none/" + value;
if (value == '0'){
window.location = "/travel/destinations/list";
}else{
window.location = url;
}
}
Typhoid and paratyphoid fever are most common in parts of the world where water and food may be unsafe and sanitation is poor. Travelers to Eastern and Southern Asia (especially Pakistan India, and Bangladesh), Africa, the Caribbean, Central and South America, and the Middle East are at increased risk for typhoid and paratyphoid fever.
People visiting friends or relatives are more likely than other travelers to get typhoid fever because they may stay in the country longer, may be less cautious about the food they eat or the beverages they drink because they eat local food prepared in people’s homes, and may not think to get vaccinated before traveling.
In the United States each year, about 425 people are diagnosed with typhoid fever and about 125 people are diagnosed with paratyphoid fever each year. Most of these people travelled internationally.
### What can travelers do to prevent typhoid fever?
Getting vaccinated, choosing food and drinks carefully, and washing your hands are the best ways to avoid getting typhoid.
Check if the typhoid fever vaccination is recommended for [your destination](/travel/destinations/list). Two typhoid vaccines are available in the United States. Visit your doctor or a travel clinic at least one month before traveling to discuss your options.
* **Pill vaccine**. People 6 years old and older can take the pill vaccine. Finish taking all four pills (one pill every other day) at least 1 week before travel.
* **Shot vaccine**. People 2 years old and older can get the shot vaccine. Get one shot (or a booster shot) at least 2 weeks before travel.
Typhoid vaccines are only 50 to 80% effective, so you should still be careful about what you eat and drink to lower your risk of getting typhoid fever. Also, there isn’t a vaccine that protects against paratyphoid fever. For these reasons, it’s very important that you also take the following steps to prevent typhoid.
**Choose food and drinks carefully**
* Only eat foods that are cooked and served hot
* Avoid food that has been sitting on a buffet
* Eat raw fruits and vegetables only if you have washed them in clean water or peeled them
* Only drink beverages from factory-sealed containers
* Avoid ice because it may have been made from unsafe water
* Only drink pasteurized milk
**Wash your hands**
* Wash hands often with soap and water for 20 seconds, especially after using the bathroom and before eating
* If soap and water are not readily available, use an alcohol-based hand sanitizer with at least 60% alcohol
* Keep your hands away from your face and mouth
### After Travel
**If you traveled and feel sick,** particularly if you have a fever, talk to a healthcare provider and tell them about your travel.
If you need medical care abroad, see [Getting Health Care During Travel](/travel/page/getting-health-care-abroad).
### More Information
* [Prevention Tips for Travelers](https://www.cdc.gov/typhoid-fever/prevention.html)
* [Typhoid Fever and Paratyphoid Fever](https://www.cdc.gov/typhoid-fever/index.html)
* CDC Yellow Book: [Typhoid & Paratyphoid Fever](/travel/yellowbook/2020/travel-related-infectious-diseases/typhoid-and-paratyphoid-fever)
* [Water Disinfection](/travel/yellowbook/2012/chapter-2-the-pre-travel-consultation/water-disinfection-for-travelers.htm)
| None | None |
e600f1b60d28c8cda1c7afbe9de779c7186d3bb6 | cdc | West Nile virus | West Nile virus | Disease Directory | Travelers' Health | CDC
### West Nile virus
### What is West Nile virus?
West Nile virus is mainly spread to people through the bite of an infected mosquito. However, there have been a very small number of cases where the virus was spread by blood transfusion, organ donation, or from mother to baby during pregnancy, birth, or when breastfeeding.
Most people who get West Nile virus infection do not feel sick. For people who do feel sick, symptoms can include fever, headache, tiredness, nausea, vomiting, muscle aches, and a rash. Symptoms usually last from a few days to a few weeks.
Some people can have more serious disease. Adults over 60 years old or people with certain medical conditions are more likely to get seriously ill. Symptoms of serious West Nile virus disease include high fever, headache, neck stiffness, disorientation, coma, tremors, convulsions, muscle weakness, vision loss, numbness, and paralysis.
### Who can get West Nile virus?
West Nile virus is found in countries throughout the world. Travelers going to Africa, Europe, the Middle East, west and central Asia, or North America can get West Nile virus.
The following activities can increase a traveler’s chance of getting infected:
- Spending a lot of time outdoors
- Traveling during times of the year when mosquitoes are more common, such as during the summer.
### What can travelers do to prevent West Nile virus?
There are no vaccines or medicines that prevent West Nile virus. Travelers can protect themselves against West Nile virus infection by preventing mosquito bites.
Use an EPA-registered insect repellent
- Use [Environmental Protection Agency (EPA)-registered insect repellents](https://www.epa.gov/insect-repellents) with one of the active ingredients below. When used as directed, EPA-registered insect repellents are proven safe and effective, even for pregnant and breastfeeding women. If also using sunscreen, always apply insect repellent after sunscreen.
- Picaridin (known as KBR 3023 and icaridin outside the US)
- Oil of lemon eucalyptus (OLE)
- Para-menthane-diol (PMD)
Find the right insect repellent for you by using [EPA's search tool](https://www.epa.gov/insect-repellents/find-repellent-right-you).
- Insect Repellent Tips for Babies and Children
- Dress your child in clothing that covers arms and legs.
- Cover strollers and baby carriers with mosquito netting.
- When using insect repellent on your child:
- Always follow label instructions.
- Do not use products containing oil of lemon eucalyptus (OLE) or para-menthane-diol (PMD) on children under 3 years old.
- Do not apply insect repellent to a child’s hands, eyes, mouth, cuts, or irritated skin.
- Adults: Spray insect repellent onto your hands and then apply to a child’s face.
- If also using sunscreen, always apply insect repellent after sunscreen.
Wear long-sleeved shirts and long pants
Treat clothing and gear with permethrin
- Use 0.5% permethrin to treat clothing and gear (such as boots, pants, socks, and tents) or buy permethrin-treated clothing and gear.
- Permethrin is an insecticide that kills or repels insects like mosquitoes and sand flies.
- Permethrin-treated clothing provides protection after multiple washings.
- Read product information to find out how long the protection will last.
- If treating items yourself, follow the product instructions.
- Do not use permethrin products directly on skin.
- Watch the CDC video [How to Use Permethrin](https://www.cdc.gov/mosquitoes/mosquito-bites/how-to-use-permethrin.html).
Keep mosquitoes out of your hotel room or lodging
- Choose a hotel or lodging with air conditioning or window and door screens.
- Use a mosquito net if you are unable to stay in a place with air conditioning or window and door screens or if you are sleeping outside.
Sleep under a mosquito net
- Sleep under a mosquito net if you are outside or when screened rooms are not available. Mosquitoes can live indoors and bite during the day and night.
- Buy a mosquito net at your local outdoor store or online before traveling overseas.
- Choose a mosquito net that is compact, white, rectangular, with 156 holes per square inch, and long enough to tuck under the mattress.
- [Permethrin-treated mosquito nets](https://www.cdc.gov/malaria/malaria_worldwide/reduction/itn.html) provide more protection than untreated nets.
- Permethrin is an insecticide that kills mosquitoes and other insects.
- To determine if you can wash a treated mosquito net, follow the label instructions.
If you are bitten by mosquitoes, avoid scratching the bites and apply over-the-counter anti-itch or antihistamine cream to relieve itching. See [Mosquito Bite Symptoms and Treatment](https://www.cdc.gov/mosquitoes/mosquito-bites/symptoms.html).
If you are bitten by mosquitoes, avoid scratching the bites and apply over-the-counter anti-itch or antihistamine cream to relieve itching. See [Mosquito Bite Symptoms and Treatment.](https://www.cdc.gov/mosquitoes/mosquito-bites/symptoms.html)
|
### West Nile virus
### What is West Nile virus?
West Nile virus is mainly spread to people through the bite of an infected mosquito. However, there have been a very small number of cases where the virus was spread by blood transfusion, organ donation, or from mother to baby during pregnancy, birth, or when breastfeeding.
Most people who get West Nile virus infection do not feel sick. For people who do feel sick, symptoms can include fever, headache, tiredness, nausea, vomiting, muscle aches, and a rash. Symptoms usually last from a few days to a few weeks.
Some people can have more serious disease. Adults over 60 years old or people with certain medical conditions are more likely to get seriously ill. Symptoms of serious West Nile virus disease include high fever, headache, neck stiffness, disorientation, coma, tremors, convulsions, muscle weakness, vision loss, numbness, and paralysis.
### Who can get West Nile virus?
West Nile virus is found in countries throughout the world. Travelers going to Africa, Europe, the Middle East, west and central Asia, or North America can get West Nile virus.
The following activities can increase a traveler’s chance of getting infected:
* Spending a lot of time outdoors
* Traveling during times of the year when mosquitoes are more common, such as during the summer.
### What can travelers do to prevent West Nile virus?
There are no vaccines or medicines that prevent West Nile virus. Travelers can protect themselves against West Nile virus infection by preventing mosquito bites.
**Use an EPA-registered insect repellent**
* Use [Environmental Protection Agency (EPA)-registered insect repellents](https://www.epa.gov/insect-repellents) with one of the active ingredients below. When used as directed, EPA-registered insect repellents are proven safe and effective, even for pregnant and breastfeeding women. If also using sunscreen, always apply insect repellent after sunscreen.
+ DEET
+ Picaridin (known as KBR 3023 and icaridin outside the US)
+ IR3535
+ Oil of lemon eucalyptus (OLE)
+ Para-menthane-diol (PMD)
+ 2-undecanone
Find the right insect repellent for you by using [EPA's search tool](https://www.epa.gov/insect-repellents/find-repellent-right-you).
* Insect Repellent Tips for Babies and Children
+ Dress your child in clothing that covers arms and legs.
+ Cover strollers and baby carriers with mosquito netting.
+ When using insect repellent on your child:
- Always follow label instructions.
- Do not use products containing oil of lemon eucalyptus (OLE) or para-menthane-diol (PMD) on children under 3 years old.
- Do not apply insect repellent to a child’s hands, eyes, mouth, cuts, or irritated skin.
* Adults: Spray insect repellent onto your hands and then apply to a child’s face.
- If also using sunscreen, always apply insect repellent after sunscreen.
**Wear long-sleeved shirts and long pants**
**Treat clothing and gear with permethrin**
* Use 0.5% permethrin to treat clothing and gear (such as boots, pants, socks, and tents) or buy permethrin-treated clothing and gear.
+ Permethrin is an insecticide that kills or repels insects like mosquitoes and sand flies.
+ Permethrin-treated clothing provides protection after multiple washings.
+ Read product information to find out how long the protection will last.
* If treating items yourself, follow the product instructions.
* Do not use permethrin products directly on skin.
* Watch the CDC video [How to Use Permethrin](https://www.cdc.gov/mosquitoes/mosquito-bites/how-to-use-permethrin.html).
**Keep mosquitoes out of your hotel room or lodging**
* Choose a hotel or lodging with air conditioning or window and door screens.
* Use a mosquito net if you are unable to stay in a place with air conditioning or window and door screens or if you are sleeping outside.
**Sleep under a mosquito net**
* Sleep under a mosquito net if you are outside or when screened rooms are not available. Mosquitoes can live indoors and bite during the day and night.
* Buy a mosquito net at your local outdoor store or online before traveling overseas.
* Choose a mosquito net that is compact, white, rectangular, with 156 holes per square inch, and long enough to tuck under the mattress.
* [Permethrin-treated mosquito nets](https://www.cdc.gov/malaria/malaria_worldwide/reduction/itn.html) provide more protection than untreated nets.
+ Permethrin is an insecticide that kills mosquitoes and other insects.
+ To determine if you can wash a treated mosquito net, follow the label instructions.
If you are bitten by mosquitoes, avoid scratching the bites and apply over-the-counter anti-itch or antihistamine cream to relieve itching. See [Mosquito Bite Symptoms and Treatment](https://www.cdc.gov/mosquitoes/mosquito-bites/symptoms.html).
If you are bitten by mosquitoes, avoid scratching the bites and apply over-the-counter anti-itch or antihistamine cream to relieve itching. See [Mosquito Bite Symptoms and Treatment.](https://www.cdc.gov/mosquitoes/mosquito-bites/symptoms.html)
### After Travel
**If you traveled and feel sick,** particularly if you have a fever, talk to a healthcare provider and tell them about your travel.
If you need medical care abroad, see [Getting Health Care During Travel](/travel/page/getting-health-care-abroad).
### More Information
* [CDC West Nile Virus website](http://www.cdc.gov/westnile/index.htm)
* [Avoid Bug Bites](/travel/page/avoid-bug-bites)
* [West Nile Virus: Information for Healthcare Providers](https://www.cdc.gov/westnile/healthcareproviders/index.html)
| None | None |
b2829831d85e0a255768cac90af3fc329736407f | cdc | Yellow Fever | Yellow Fever | Disease Directory | Travelers' Health | CDC
### Yellow Fever
### What is yellow fever?
Yellow fever is a serious disease caused by the yellow fever virus.
Most people infected with yellow fever virus do not get sick or have only mild symptoms. People who do get sick will start having [symptoms](http://www.cdc.gov/yellowfever/symptoms/index.html) (e.g., fever, chills, headache, backache, and muscle aches) 3–6 days after they are infected. About 12% of people who have symptoms go on to develop serious illness: jaundice, bleeding, shock, organ failure, and sometimes death.
### How does yellow fever spread?
Yellow fever virus is spread by mosquitoes.
### Who is at risk?
Yellow fever virus, and the mosquitoes that spread the virus, are found in certain parts of South America and Africa. Travelers going to these places are at risk for infection with the virus. Check to see if yellow fever vaccine is recommended or required [for your destination](/travel/destinations/list).
Yellow fever vaccine recommendations in Africa1,2
[View Larger Figure](/travel/content/images/yellowbook/2024/_465_MAP_5-_10_Yellow_fever_vaccine_recommendations_for_Africa1_2.jpg "Map 5-10 Yellow fever vaccine recommendations for Africa")
1Current as of November 2022. This map is an updated version of the 2010 map created by the Informal WHO Working Group on the Geographic Risk of Yellow Fever.
2Yellow fever (YF) vaccination is generally not recommended for travel to areas where the potential for YF virus exposure is low. Vaccination might be considered, however, for a small subset of travelers going to these areas who are at increased risk for exposure to YF virus due to prolonged travel, heavy exposure to mosquitoes, or inability to avoid mosquito bites. Factors to consider when deciding whether to vaccinate a traveler include destination-specific and travel-associated risks for YF virus infection; individual, underlying risk factors for having a serious YF vaccine-associated adverse event; and country entry requirements.
Yellow fever vaccine recommendations in the Americas1,2
[View Larger Figure](/travel/content/images/yellowbook/2024/_466_MAP_5-_11_Yellow_fever_vaccine_recommendations_for_the_Americas.jpg "Map 5-11 Yellow fever vaccine recommendations for the Americas")
1Current as of November 2022. This map is an updated version of the 2010 map created by the Informal WHO Working Group on the Geographic Risk of Yellow Fever.
2In 2017, the Centers for Disease Control and Prevention (CDC) expanded its yellow fever vaccine recommendations for travelers going to Brazil because of a large outbreak in multiple states in that country. For more information and updated recommendations, refer to the CDC [Travelers’ Health](/travel/) website.
3Yellow fever (YF) vaccination is generally not recommended for travel to areas where the potential for YF virus exposure is low. Vaccination might be considered, however, for a small subset of travelers going to these areas who are at increased risk for exposure to YF virus due to prolonged travel, heavy exposure to mosquitoes, or inability to avoid mosquito bites. Factors to consider when deciding whether to vaccinate a traveler include destination-specific and travel-associated risks for YF virus infection; individual, underlying risk factors for having a serious YF vaccine-associated adverse event; and country entry requirements.
### What can travelers do to protect themselves?
Get the yellow fever vaccine and take steps to prevent mosquito bites.
#### Yellow Fever Vaccine: Requirements and Recommendations
Some countries may require arriving travelers to show proof of yellow fever vaccination. Countries do this as a public health measure to keep travelers from importing the virus. Proof of vaccination requirements may apply to some or all arriving travelers. CDC has no control over other countries’ vaccine requirements or how they are enforced.
Separate from the individual country requirements, CDC makes yellow fever vaccine recommendations for travelers going to countries where there is a risk of yellow fever. CDC recommendations are designed to help keep individuals from getting infected with yellow fever virus during travel.
Check your destination(s) for [yellow fever vaccination requirements and recommendations](/travel/yellowbook/2020/preparing-international-travelers/yellow-fever-vaccine-and-malaria-prophylaxis-information-by-country).
#### Yellow Fever Vaccine: Getting Vaccinated
Visit a [yellow fever vaccination clinic](/travel/yellow-fever-vaccination-clinics/search.htm). Ask the health care provider at the clinic to confirm if vaccination against yellow fever is required and/or recommended for your destination(s).
Plan to get the vaccine at least 10 days before your travel since proof of vaccination is not valid until 10 days after getting the vaccine, the time needed to develop immunity to yellow fever virus.
A single dose of yellow fever vaccine protects most people for life, but a booster dose after 10 years may be recommended for some travelers. Talk to your health care provider for more information.
In rare cases, yellow fever vaccine can have serious and sometimes fatal side effects. People older than 60 years and people with weakened immune systems might be at higher risk of developing these side effects. Also, there are concerns for the babies of pregnant and nursing women who receive yellow fever vaccine. Before you get vaccinated against yellow fever, discuss your full medical history with your health care provider who can help inform you about the possible risks involved.
#### Yellow Fever Vaccine: Proof of Vaccination
The [International Certificate of Vaccination or Prophylaxis](/travel/yellowbook/2020/travel-related-infectious-diseases/yellow-fever#5622) (ICVP, sometimes called the “yellow card”) is your proof that you have been vaccinated against yellow fever. You will receive the ICVP when you get vaccinated. Along with your passport, present the original signed and stamped ICVP (not a photocopy or screenshot) to immigration officials in all countries requiring proof of vaccination.
#### Prevent mosquito bites:
Use an EPA-registered insect repellent
- Use [Environmental Protection Agency (EPA)-registered insect repellents](https://www.epa.gov/insect-repellents) with one of the active ingredients below. When used as directed, EPA-registered insect repellents are proven safe and effective, even for pregnant and breastfeeding women. If also using sunscreen, always apply insect repellent after sunscreen.
- Picaridin (known as KBR 3023 and icaridin outside the US)
- Oil of lemon eucalyptus (OLE)
- Para-menthane-diol (PMD)
Find the right insect repellent for you by using [EPA's search tool](https://www.epa.gov/insect-repellents/find-repellent-right-you).
- Insect Repellent Tips for Babies and Children
- Dress your child in clothing that covers arms and legs.
- Cover strollers and baby carriers with mosquito netting.
- When using insect repellent on your child:
- Always follow label instructions.
- Do not use products containing oil of lemon eucalyptus (OLE) or para-menthane-diol (PMD) on children under 3 years old.
- Do not apply insect repellent to a child’s hands, eyes, mouth, cuts, or irritated skin.
- Adults: Spray insect repellent onto your hands and then apply to a child’s face.
- If also using sunscreen, always apply insect repellent after sunscreen.
Wear long-sleeved shirts and long pants
Treat clothing and gear with permethrin
- Use 0.5% permethrin to treat clothing and gear (such as boots, pants, socks, and tents) or buy permethrin-treated clothing and gear.
- Permethrin is an insecticide that kills or repels insects like mosquitoes and sand flies.
- Permethrin-treated clothing provides protection after multiple washings.
- Read product information to find out how long the protection will last.
- If treating items yourself, follow the product instructions.
- Do not use permethrin products directly on skin.
- Watch the CDC video [How to Use Permethrin](https://www.cdc.gov/mosquitoes/mosquito-bites/how-to-use-permethrin.html).
Keep mosquitoes out of your hotel room or lodging
- Choose a hotel or lodging with air conditioning or window and door screens.
- Use a mosquito net if you are unable to stay in a place with air conditioning or window and door screens or if you are sleeping outside.
Sleep under a mosquito net
- Sleep under a mosquito net if you are outside or when screened rooms are not available. Mosquitoes can live indoors and bite during the day and night.
- Buy a mosquito net at your local outdoor store or online before traveling overseas.
- Choose a mosquito net that is compact, white, rectangular, with 156 holes per square inch, and long enough to tuck under the mattress.
- [Permethrin-treated mosquito nets](https://www.cdc.gov/malaria/malaria_worldwide/reduction/itn.html) provide more protection than untreated nets.
- Permethrin is an insecticide that kills mosquitoes and other insects.
- To determine if you can wash a treated mosquito net, follow the label instructions.
If you are bitten by mosquitoes, avoid scratching the bites and apply over-the-counter anti-itch or antihistamine cream to relieve itching. See [Mosquito Bite Symptoms and Treatment](https://www.cdc.gov/mosquitoes/mosquito-bites/symptoms.html).
#### If you are bitten by mosquitoes:
- Avoid scratching mosquito bites.
- Apply hydrocortisone cream or calamine lotion to reduce itching.
|
### Yellow Fever
### What is yellow fever?
Yellow fever is a serious disease caused by the yellow fever virus.
Most people infected with yellow fever virus do not get sick or have only mild symptoms. People who do get sick will start having [symptoms](http://www.cdc.gov/yellowfever/symptoms/index.html) (e.g., fever, chills, headache, backache, and muscle aches) 3–6 days after they are infected. About 12% of people who have symptoms go on to develop serious illness: jaundice, bleeding, shock, organ failure, and sometimes death.
### How does yellow fever spread?
Yellow fever virus is spread by mosquitoes.
### Who is at risk?
Yellow fever virus, and the mosquitoes that spread the virus, are found in certain parts of South America and Africa. Travelers going to these places are at risk for infection with the virus. Check to see if yellow fever vaccine is recommended or required [for your destination](/travel/destinations/list).
**Yellow fever vaccine recommendations in Africa**1,2
[View Larger Figure](/travel/content/images/yellowbook/2024/_465_MAP_5-_10_Yellow_fever_vaccine_recommendations_for_Africa1_2.jpg "Map 5-10 Yellow fever vaccine recommendations for Africa")
1Current as of November 2022. This map is an updated version of the 2010 map created by the Informal WHO Working Group on the Geographic Risk of Yellow Fever.
2Yellow fever (YF) vaccination is generally not recommended for travel to areas where the potential for YF virus exposure is low. Vaccination might be considered, however, for a small subset of travelers going to these areas who are at increased risk for exposure to YF virus due to prolonged travel, heavy exposure to mosquitoes, or inability to avoid mosquito bites. Factors to consider when deciding whether to vaccinate a traveler include destination-specific and travel-associated risks for YF virus infection; individual, underlying risk factors for having a serious YF vaccine-associated adverse event; and country entry requirements.
**Yellow fever vaccine recommendations in the Americas**1,2
[**View Larger Figure**](/travel/content/images/yellowbook/2024/_466_MAP_5-_11_Yellow_fever_vaccine_recommendations_for_the_Americas.jpg "Map 5-11 Yellow fever vaccine recommendations for the Americas")
1Current as of November 2022. This map is an updated version of the 2010 map created by the Informal WHO Working Group on the Geographic Risk of Yellow Fever.
2In 2017, the Centers for Disease Control and Prevention (CDC) expanded its yellow fever vaccine recommendations for travelers going to Brazil because of a large outbreak in multiple states in that country. For more information and updated recommendations, refer to the CDC [Travelers’ Health](/travel/) website.
3Yellow fever (YF) vaccination is generally not recommended for travel to areas where the potential for YF virus exposure is low. Vaccination might be considered, however, for a small subset of travelers going to these areas who are at increased risk for exposure to YF virus due to prolonged travel, heavy exposure to mosquitoes, or inability to avoid mosquito bites. Factors to consider when deciding whether to vaccinate a traveler include destination-specific and travel-associated risks for YF virus infection; individual, underlying risk factors for having a serious YF vaccine-associated adverse event; and country entry requirements.
### What can travelers do to protect themselves?
Get the yellow fever vaccine and take steps to prevent mosquito bites.
#### Yellow Fever Vaccine: Requirements and Recommendations
Some countries may **require** arriving travelers to show proof of yellow fever vaccination. Countries do this as a public health measure to keep travelers from importing the virus. Proof of vaccination requirements may apply to some or all arriving travelers. CDC has no control over other countries’ vaccine requirements or how they are enforced.
Separate from the individual country requirements, CDC makes yellow fever vaccine **recommendations** for travelers going to countries where there is a risk of yellow fever. CDC recommendations are designed to help keep individuals from getting infected with yellow fever virus during travel.
Check your destination(s) for [yellow fever vaccination requirements and recommendations](/travel/yellowbook/2020/preparing-international-travelers/yellow-fever-vaccine-and-malaria-prophylaxis-information-by-country).
#### Yellow Fever Vaccine: Getting Vaccinated
Visit a [yellow fever vaccination clinic](/travel/yellow-fever-vaccination-clinics/search.htm). Ask the health care provider at the clinic to confirm if vaccination against yellow fever is required and/or recommended for your destination(s).
Plan to get the vaccine at least 10 days before your travel since proof of vaccination is not valid until 10 days after getting the vaccine, the time needed to develop immunity to yellow fever virus.
A single dose of yellow fever vaccine protects most people for life, but a booster dose after 10 years may be recommended for some travelers. Talk to your health care provider for more information.
In rare cases, yellow fever vaccine can have serious and sometimes fatal side effects. People older than 60 years and people with weakened immune systems might be at higher risk of developing these side effects. Also, there are concerns for the babies of pregnant and nursing women who receive yellow fever vaccine. Before you get vaccinated against yellow fever, discuss your full medical history with your health care provider who can help inform you about the possible risks involved.
#### Yellow Fever Vaccine: Proof of Vaccination
The [International Certificate of Vaccination or Prophylaxis](/travel/yellowbook/2020/travel-related-infectious-diseases/yellow-fever#5622) (ICVP, sometimes called the “yellow card”) is your proof that you have been vaccinated against yellow fever. You will receive the ICVP when you get vaccinated. Along with your passport, present the original signed and stamped ICVP (not a photocopy or screenshot) to immigration officials in all countries requiring proof of vaccination.
#### Prevent mosquito bites:
**Use an EPA-registered insect repellent**
* Use [Environmental Protection Agency (EPA)-registered insect repellents](https://www.epa.gov/insect-repellents) with one of the active ingredients below. When used as directed, EPA-registered insect repellents are proven safe and effective, even for pregnant and breastfeeding women. If also using sunscreen, always apply insect repellent after sunscreen.
+ DEET
+ Picaridin (known as KBR 3023 and icaridin outside the US)
+ IR3535
+ Oil of lemon eucalyptus (OLE)
+ Para-menthane-diol (PMD)
+ 2-undecanone
Find the right insect repellent for you by using [EPA's search tool](https://www.epa.gov/insect-repellents/find-repellent-right-you).
* Insect Repellent Tips for Babies and Children
+ Dress your child in clothing that covers arms and legs.
+ Cover strollers and baby carriers with mosquito netting.
+ When using insect repellent on your child:
- Always follow label instructions.
- Do not use products containing oil of lemon eucalyptus (OLE) or para-menthane-diol (PMD) on children under 3 years old.
- Do not apply insect repellent to a child’s hands, eyes, mouth, cuts, or irritated skin.
* Adults: Spray insect repellent onto your hands and then apply to a child’s face.
- If also using sunscreen, always apply insect repellent after sunscreen.
**Wear long-sleeved shirts and long pants**
**Treat clothing and gear with permethrin**
* Use 0.5% permethrin to treat clothing and gear (such as boots, pants, socks, and tents) or buy permethrin-treated clothing and gear.
+ Permethrin is an insecticide that kills or repels insects like mosquitoes and sand flies.
+ Permethrin-treated clothing provides protection after multiple washings.
+ Read product information to find out how long the protection will last.
* If treating items yourself, follow the product instructions.
* Do not use permethrin products directly on skin.
* Watch the CDC video [How to Use Permethrin](https://www.cdc.gov/mosquitoes/mosquito-bites/how-to-use-permethrin.html).
**Keep mosquitoes out of your hotel room or lodging**
* Choose a hotel or lodging with air conditioning or window and door screens.
* Use a mosquito net if you are unable to stay in a place with air conditioning or window and door screens or if you are sleeping outside.
**Sleep under a mosquito net**
* Sleep under a mosquito net if you are outside or when screened rooms are not available. Mosquitoes can live indoors and bite during the day and night.
* Buy a mosquito net at your local outdoor store or online before traveling overseas.
* Choose a mosquito net that is compact, white, rectangular, with 156 holes per square inch, and long enough to tuck under the mattress.
* [Permethrin-treated mosquito nets](https://www.cdc.gov/malaria/malaria_worldwide/reduction/itn.html) provide more protection than untreated nets.
+ Permethrin is an insecticide that kills mosquitoes and other insects.
+ To determine if you can wash a treated mosquito net, follow the label instructions.
If you are bitten by mosquitoes, avoid scratching the bites and apply over-the-counter anti-itch or antihistamine cream to relieve itching. See [Mosquito Bite Symptoms and Treatment](https://www.cdc.gov/mosquitoes/mosquito-bites/symptoms.html).
#### If you are bitten by mosquitoes:
* Avoid scratching mosquito bites.
* Apply hydrocortisone cream or calamine lotion to reduce itching.
### After Travel
**If you traveled and feel sick,** particularly if you have a fever, talk to a healthcare provider and tell them about your travel.
If you need medical care abroad, see [Getting Health Care During Travel](/travel/page/getting-health-care-abroad).
### More Information
* [FAQ’s about Yellow Fever](http://www.cdc.gov/yellowfever/qa/index.html)
* [Avoid Bug Bites](/travel/page/avoid-bug-bites)-Information for travelers
* [Yellow Fever Vaccine Requirements and Recommendations, by Country](/travel/yellowbook/2010/chapter-2/yellow-fever-vaccine-requirements-and-recommendations.htm)
* [Authorized U.S. Yellow Fever Vaccine Centers](/travel/yellow-fever-vaccination-clinics/search.htm)
* CDC Yellow Book: [Yellow Fever](/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/yellow-fever.htm)
| None | None |
748ac4b5087b193671a0609ec5c423346fd3123f | cdc | Zika | Zika | Disease Directory | Travelers' Health | CDC
### About Zika
Many people infected with Zika virus do not get sick or only have mild symptoms. However, infection during pregnancy can cause severe birth defects.
Zika virus is present at low levels in many parts of the world, and outbreaks can occur. Because there is no vaccine or medicine for Zika, travelers should take steps to prevent getting Zika during travel. They should also take steps to prevent spreading it when they return home.
See [Zika Travel Information](/travel/page/zika-travel-information) for information on countries and territories with Zika.
### How is Zika virus spread?
Zika can spread several ways, including:
1. Through the bite of an infected mosquito. Mosquitoes become infected when they bite a person infected with the virus. Infected mosquitoes can then spread the virus to other people through bites.
2. From a pregnant woman to her developing fetus, or at the time of birth, if the mother is infected with Zika during pregnancy.
3. Through sex with a person who is infected with Zika. Zika can be sexually transmitted from an infected man or woman. But Zika can stay in a man’s semen longer than in a woman’s body fluids. Zika can stay in a man’s semen for months after infection and be transmitted through sex during that time.
See [How Zika Spreads](https://www.cdc.gov/zika/prevention/transmission-methods.html). Even if people with Zika do not have symptoms, they can still spread the virus.
### What can travelers do to prevent Zika?
- Pregnant women should NOT travel to areas with Zika outbreaks (red areas on the [map](/travel/page/zika-travel-information#map)). This is because Zika infection during pregnancy can cause serious birth defects.
- Before travel to other areas with risk of Zika (purple areas on the [map](/travel/page/zika-travel-information#map)), pregnant women and couples planning pregnancy in the next 3 months should discuss their travel plans with their health care provider and carefully consider the risks and possible consequences of travel to these areas. These areas have a potential risk of Zika, but we do not have accurate information on the current level of risk. As a result, detection and reporting of new outbreaks may be delayed.
- All travelers to areas with risk of Zika should (1) prevent mosquito bites and (2) use condoms or not have sex to protect against Zika during travel. They should continue to take these precautions after their trip to stop the spread of Zika to others back home. See more information below.
### Special Precautions for Specific Groups
CDC recommends special precautions for (1) [pregnant women](#pregnant), (2) [the partners of pregnant women](#partner), and (3) [those considering pregnancy](#ttc):
#### 1. Pregnant women
- Do NOT travel to areas with Zika outbreaks (red areas on the [map](/travel/page/zika-travel-information#map)) because Zika infection during pregnancy can cause serious birth defects.
- Before travel to other areas with risk of Zika (purple areas on the [map](/travel/page/zika-travel-information#map)), discuss your travel plans with your health care provider. Carefully consider the risks and possible consequences of travel to these areas. In deciding whether to travel, consider the destination, your reasons for traveling, your feelings about the potential risks, and your ability to prevent mosquito bites.
- If you - must- travel:
- Strictly follow [steps to prevent mosquito bites](https://www.cdc.gov/zika/prevention/prevent-mosquito-bites.html) during travel and for 3 weeks after your return.
- Strictly follow steps to prevent sexual transmission during your trip.
- See your health care provider after your return for routine prenatal care and if you experience any symptoms of Zika infection.
- Tell your health care provider at each prenatal care visit about any travel and about possible Zika exposure.
- If your partner travels (to red or purple areas on the [map](/travel/page/zika-travel-information#map)):
- Use condoms every time you have sex—or do not have sex—for the rest of the pregnancy, even if your partner does not have symptoms or feel sick.
[>> More Zika information for pregnant women](https://www.cdc.gov/zika/pregnancy/protect-yourself.html)
#### 2. Travelers to red or purple areas on the [map](/travel/page/zika-travel-information#map) who have a pregnant partner
- Strictly follow [steps to prevent mosquito bites](https://www.cdc.gov/zika/prevention/prevent-mosquito-bites.html) during travel and for 3 weeks after your return.
- Use condoms every time you have sex—or do not have sex— for the rest of the pregnancy, even if you do not have symptoms or feel sick.
|
### Zika
### About Zika
Many people infected with Zika virus do not get sick or only have mild symptoms. However, infection during pregnancy can cause severe birth defects.
Zika virus is present at low levels in many parts of the world, and outbreaks can occur. Because there is no vaccine or medicine for Zika, travelers should take steps to prevent getting Zika during travel. They should also take steps to prevent spreading it when they return home.
See [Zika Travel Information](/travel/page/zika-travel-information) for information on countries and territories with Zika.
### How is Zika virus spread?
Zika can spread several ways, including:
1. **Through the bite of an infected mosquito.** Mosquitoes become infected when they bite a person infected with the virus. Infected mosquitoes can then spread the virus to other people through bites.
2. **From a pregnant woman to her developing fetus,** or at the time of birth, if the mother is infected with Zika during pregnancy.
3. **Through sex** **with a person who is infected with Zika**. Zika can be sexually transmitted from an infected man or woman. But Zika can stay in a man’s semen longer than in a woman’s body fluids. Zika can stay in a man’s semen for months after infection and be transmitted through sex during that time.
See [How Zika Spreads](https://www.cdc.gov/zika/prevention/transmission-methods.html). Even if people with Zika do not have symptoms, they can still spread the virus.
### What can travelers do to prevent Zika?
* **Pregnant women should NOT travel to areas with Zika outbreaks (red areas on the [map](/travel/page/zika-travel-information#map)).** This is because Zika infection during pregnancy can cause serious birth defects.
* ****Before travel to other areas with risk of Zika (purple areas on the **[map](/travel/page/zika-travel-information#map)), **pregnant women and couples planning pregnancy in the next 3 months should discuss their travel plans with their health care **provider and carefully consider the risks and possible consequences of travel to these areas.********** These areas have a potential risk of Zika, but we do not have accurate information on the current level of risk. As a result, detection and reporting of new outbreaks may be delayed.
* **All travelers** **to areas with risk of Zika should (1) prevent mosquito bites and (2) use condoms or not have sex** to protect against Zika during travel. They should continue to take these precautions after their trip to stop the spread of Zika to others back home. See more information below.
### Special Precautions for Specific Groups
CDC recommends special precautions for (1) [pregnant women](#pregnant), (2) [the partners of pregnant women](#partner), and (3) [those considering pregnancy](#ttc):
#### **1. Pregnant women**
* Do NOT travel to areas with Zika outbreaks (red areas on the [map](/travel/page/zika-travel-information#map)) because Zika infection during pregnancy can cause serious birth defects.
* Before travel to other areas with risk of Zika (purple areas on the [map](/travel/page/zika-travel-information#map)), discuss your travel plans with your health care provider. Carefully consider the risks and possible consequences of travel to these areas. In deciding whether to travel, consider the destination, your reasons for traveling, your feelings about the potential risks, and your ability to prevent mosquito bites.
* If you *must* travel:
+ Strictly follow [steps to prevent mosquito bites](https://www.cdc.gov/zika/prevention/prevent-mosquito-bites.html) during travel and for 3 weeks after your return.
+ Strictly follow steps to prevent sexual transmission during your trip.
+ See your health care provider after your return for routine prenatal care and if you experience any symptoms of Zika infection.
+ Tell your health care provider at each prenatal care visit about any travel and about possible Zika exposure.
* If your partner travels (to red or purple areas on the [map](/travel/page/zika-travel-information#map)):
+ Use condoms every time you have sex—or do not have sex—**for the rest of the pregnancy,** even if your partner does not have symptoms or feel sick.
[>> More Zika information for pregnant women](https://www.cdc.gov/zika/pregnancy/protect-yourself.html)
#### **2. Travelers to red or purple areas on the [map](/travel/page/zika-travel-information#map) who have a pregnant partner**
* Strictly follow [steps to prevent mosquito bites](https://www.cdc.gov/zika/prevention/prevent-mosquito-bites.html) during travel and for 3 weeks after your return.
* Use condoms every time you have sex—or do not have sex— **for the rest of the pregnancy,** even if you do not have symptoms or feel sick.
[>> More information about protecting against Zika during pregnancy](https://www.cdc.gov/zika/pregnancy/index.html)
#### **3. Travelers to red or purple areas on the [map](/travel/page/zika-travel-information#map) considering pregnancy**
* Talk to your health care provider about your pregnancy plans and possible Zika risk before travel.
* Strictly follow [steps to prevent mosquito bites](https://www.cdc.gov/zika/prevention/prevent-mosquito-bites.html) during travel and for 3 weeks after your return.
* **If you’re a couple traveling together or a man traveling without your partner:** Wait at least 3 months after you return (or from the start of symptoms, if the man develops symptoms) before trying to conceive. During that time, use condoms or do not have sex to prevent passing Zika to your partner.
* **If you’re a woman (and your male partner does not travel):** Wait at least 2 months after you return (or from the start of symptoms, if you develop symptoms) before trying to conceive. During that time, use condoms or do not have sex to prevent passing Zika to your partner.
Men are advised to wait longer because Zika can stay in semen longer than in other body fluids and can be spread to partners during that time.
[>> More Zika information for those considering pregnancy](https://www.cdc.gov/zika/pregnancy/women-and-their-partners.html)
### During Travel: Protect Yourself
* [Prevent mosquito bites:](https://www.cdc.gov/zika/prevention/prevent-mosquito-bites.html)
+ Use EPA-registered insect repellents with one of the following active ingredients: DEET, picaridin, IR3535, oil of lemon eucalyptus, para-menthane-diol, or 2-undecanone. Always use as directed.
+ Cover exposed skin: Wear long-sleeved shirts and long pants
+ Stay in places with air conditioning or with window and door screens, or sleep under a mosquito bed net.
+ For extended stays take steps to control mosquitoes inside and outside, such as removing standing water. [[See more](https://www.cdc.gov/zika/prevention/controlling-mosquitoes-at-home.html)]
* [Prevent sexual transmission](https://www.cdc.gov/zika/prevention/sexual-transmission-prevention.html)**:**
+ Use condoms every time you have vaginal, anal, or oral sex—or do not have sex—if you are concerned about getting or passing Zika through sex. This is especially important if you or your partner is pregnant or planning to become pregnant. [[See more](https://www.cdc.gov/zika/prevention/sexual-transmission-prevention.html)]
### After Travel: Protect Others
* **Continue using mosquito repellent** for 3 weeks after your return, even if you do not feel sick. This will help prevent spreading Zika to uninfected mosquitoes that can spread the virus to other people.
* **To protect your partners, use condoms—or do not have sex—for at least 3 months** after travel if you are a man, and **for at least 2 months** after travel if you are a woman. If you and your partner travel together, use condoms for at least 3 months after your return. If your partner is pregnant, use condoms for the rest of her pregnancy.
### If you feel sick and think you may have Zika
* Talk to your health care provider if you develop common [symptoms](https://www.cdc.gov/zika/symptoms/symptoms.html) of Zika, including fever, rash, headache, joint pain, red eyes, or muscle pain.
* Tell your health care provider where you traveled.
* Take medicine, such as acetaminophen, to reduce fever and pain.
* Do not take aspirin or other non-steroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, until your health care provider is sure you don't have dengue. Dengue is another disease transmitted by mosquitoes that causes symptoms similar to Zika and can cause internal bleeding.
* If you are taking medicine for another condition or if you are pregnant, talk to your health care provider before taking additional medicines.
[A blood or urine test](https://www.cdc.gov/zika/symptoms/diagnosis.html) can identify Zika infection. For more about testing, see [CDC Testing Recommendations](https://www.cdc.gov/zika/symptoms/diagnosis.html).
### More Information
* [Zika Travel Information](/travel/page/zika-travel-information)
* [Zika: Information for Health Care Providers](http://www.cdc.gov/zika/hc-providers/index.html)
| None | None |
cb45a49edb18d426afde2aeebfc762990ab90279 | cma | **Poliomyelitis (polio) vaccine: Canadian Immunization Guide** | Poliomyelitis (polio) vaccine: Canadian Immunization Guide
# Key information
What
- Polio remains endemic in two countries - Afghanistan and Pakistan; additional countries are known or suspected of having re-established transmission of poliovirus. Several other countries have ongoing outbreaks due to importations of poliovirus.
- Children less than 5 years of age are more susceptible to polio infection.
- Inactivated poliomyelitis - containing vaccines (IPV) produce immunity in over 95% of vaccinees after 3 doses and in close to 100% following a booster dose.
- Adverse events following IPV vaccine are usually limited to mild injection site reactions.
- Oral poliomyelitis vaccine (OPV) is not used in Canada.
Who
- IPV-containing vaccine is recommended for:
+ routine immunization of infants and children
+ unimmunized or incompletely immunized children
+ unimmunized adults
+ as a booster dose for adults previously immunized against polio and at increased risk of polio exposure
How
- Routine polio immunization of infants and children: administer DTaP-IPV-Hib vaccine at 2, 4, 6 and 12 to 23 months of age (generally given at 18 months of age). If infant immunization for hepatitis B is undertaken, DTaP-HB-IPV-Hib vaccine may be used. Subsequently, administer a booster dose of either DTaP-IPV or Tdap-IPV vaccine at 4 to 6 years of age (school entry).
- Unimmunized or incompletely immunized children should have their vaccine series completed with IPV- containing vaccine as appropriate for age.
- Adults previously unimmunized with polio vaccine: administer a primary series of IPV-containing vaccine if a primary series of tetanus toxoid-containing vaccine is being given or if the adult is at increased risk for exposure to poliovirus; otherwise, administer polio in a combination vaccine with routine tetanus and diphtheria booster doses.
- Adults previously immunized with polio vaccine: for those at increased risk of exposure to polio (e.g., those travelling to, or planning to work in areas that have wild polio or vaccine-derived polio outbreaks), a single lifetime booster dose of IPV-containing vaccine is recommended.
- IPV-containing vaccines may be administered concomitantly with routine vaccines at different injection sites using separate needles and syringes.
Why
- Until polio eradication has been achieved globally, there remains a small risk of contracting polio with travel to countries with circulating poliovirus (endemic or outbreak) and importation of polio into Canada.
- The case fatality rate for paralytic polio is 2% to 5% among children and 15% to 30% for adults.
# Epidemiology
## Disease description
### Infectious agent
Polio is caused by poliovirus, a member of the enterovirus subgroup of the *Picornaviridae- family.
### Reservoir
Humans
### Transmission
Transmission of poliovirus occurs predominantly through the fecal-oral route. Respiratory spread may rarely occur. The incubation period for polio is 3 to 6 days for onset of non-specific symptoms. In those that progress to paralysis, this occurs in 7 to 21 days from exposure (can range up to 35 days). Communicability is greatest around the onset of illness when the virus is present in high concentrations in the throat and feces. Poliovirus can remain in feces for 3 to 6 weeks. In persons who have received oral polio vaccine (OPV), poliovirus can be present in the throat for 1 to 2 weeks following immunization and can remain in feces for several weeks. In rare cases, including among immunocompromised persons, poliovirus (from natural infection or OPV vaccine) can be excreted for prolonged periods of time (from greater than 6 months to a number of years).
### Risk factors
Polio infections are more common in children less than 5 years of age; however, any person who is not immune to poliovirus, regardless of age, can become infected.
### Seasonal and temporal patterns
In temperate climates, polio infection generally increases in the late summer and autumn months.
### Spectrum of clinical illness
Most polio infections (approximately 75%) are asymptomatic. In symptomatic persons, initial symptoms occur 3 to 6 days after exposure to the virus and include fever, fatigue, headache and vomiting. With increased disease severity, severe muscle pain and stiffness of the neck and back with or without paralysis may occur. Although paralysis is the most visible sign of polio infection, less than 1% of cases result in paralysis. The case fatality ratio for paralytic polio ranges from 2% to 5% among children and 15% to 30% for adults.
## Disease distribution
The incidence of polio in Canada was dramatically reduced by the introduction of immunization programs in the 1950s. In Canada, after many years of use, the OPV was replaced with an IPV in 1995/1996. The last indigenous case of wild poliovirus in Canada was in 1977. In 1994, Canada was certified as being free of wild poliovirus by the World Health Organization (WHO), with exceptionally rare cases of paralytic polio being associated with importations of wild or vaccine-derived poliovirus. The last nationally reported case of paralytic polio occurred in 1995 and was related to OPV receipt. More information on and in Canada can be found on PHAC's website.
Currently only type 1 wild poliovirus remains endemic in two countries globally. Type 2 wild poliovirus was declared eradicated in September 2015, with the last virus detected in 1999. Type 3 wild poliovirus was declared eradicated in October 2019. It was last detected in November 2012.
In April 2016, WHO coordinated a synchronized global withdrawal of the trivalent oral polio vaccine (tOPV) which contained the Sabin 2 strain of the virus. Since then, countries incorporating oral poliovirus routine immunization programs have been using a bivalent oral polio vaccine (bOPV) containing the attenuated Sabin 1 and 3 strains. Despite this change, circulating vaccine-derived poliovirus 2 (cVDPV2) outbreaks continue to occur, primarily due to inadequate vaccine coverage and response efforts to contain the outbreaks.
# Preparations authorized for use in Canada
## Poliomyelitis-containing vaccines
- ADACEL®-POLIO (adsorbed vaccine containing tetanus toxoid, reduced diphtheria toxoid and reduced acellular pertussis vaccine combined with inactivated poliomyelitis vaccine), Sanofi Pasteur Ltd. (Tdap-IPV)
- BOOSTRIX®-POLIO (adsorbed vaccine containing tetanus toxoid, reduced diphtheria toxoid and reduced acellular pertussis vaccine combined with inactivated poliomyelitis vaccine), GlaxoSmithKline Inc. (Tdap-IPV)
- IMOVAX®Polio (inactivated poliomyelitis vaccine (vero cell origin), Sanofi Pasteur SA (manufacturer), Sanofi Pasteur Ltd. (distributor). (IPV)
- INFANRIX®-IPV/Hib (adsorbed vaccine containing diphtheria and tetanus toxoids, acellular pertussis, inactivated poliomyelitis and conjugated *Haemophilus influenzae- type b vaccine), GlaxoSmithKline Inc. (DTaP-IPV-Hib)
- INFANRIX hexa™ (adsorbed vaccine containing diphtheria and tetanus toxoids, acellular pertussis, hepatitis B (recombinant), inactivated poliomyelitis and conjugated *Haemophilus influenzae- type b vaccine), GlaxoSmithKline Inc. (DTaP-HB-IPV-Hib)
- PEDIACEL® (adsorbed vaccine containing diphtheria and tetanus toxoids and acellular pertussis vaccine combined with inactivated poliomyelitis vaccine and *Haemophilus influenzae- type b conjugate vaccine), Sanofi Pasteur Ltd. (DTaP-IPV-Hib)
- QUADRACEL® (adsorbed vaccine containing diphtheria and tetanus toxoids and acellular pertussis vaccine combined with inactivated poliomyelitis vaccine), Sanofi Pasteur Ltd. (DTaP-IPV)
IPV contains three types of inactivated poliovirus (trivalent) and is available as a single vaccine or as a combination vaccine. Live attenuated OPV is no longer recommended or available in Canada because most cases of paralytic polio from 1980 to 1995 were associated with OPV vaccine. bOPV vaccine continues to be widely used internationally. Monovalent OPVs (e.g., mOPV1, mOPV2, mOPV3, and novel OPV2 ) are also available and used for outbreak management.
For complete prescribing information, consult the product leaflet or information contained within Health Canada's authorized product monographs available through the . Refer to Table 1 in in Part 1 for a list of all vaccines available for use in Canada and their contents.
# Efficacy, effectiveness and immunogenicity
IPV-containing vaccines produce immunity to all three types of poliovirus in over 95% of vaccinees following three doses of vaccine, and in close to 100% following a booster dose. Seroconversion rates are lower if the minimum age and minimum intervals for vaccine administration are used in infants less than 6 months of age.
# Recommendations for use
## Infants and children (2 months to 17 years of age)
An IPV-containing vaccine is recommended for routine infant immunization beginning at 2 months of age. DTaP-IPV (with or without Hib) vaccine is authorized for use in children less than 7 years of age. DTaP-HB-IPV-Hib vaccine is authorized for use in children 6 weeks to 23 months of age and may be given to children aged 24 months to less than 7 years, if necessary. DTaP-IPV or Tdap-IPV vaccine should be used as the booster dose for children at 4 to 6 years of age. Children 7 years of age and older should receive IPV vaccine or the adolescent/adult formulation of the diphtheria-tetanus-pertussis-polio-containing vaccine (Tdap-IPV). Tdap-IPV vaccine contains less pertussis and diphtheria toxoid than vaccines given to younger children and is less likely to cause reactions in older children. Tdap vaccine is generally administered to adolescents at 14 to 16 years of age as the first 10-year booster dose; however, Tdap-IPV vaccine should be used if IPV vaccine is also indicated.
## Adults (18 years of age and older)
Similar to vaccination of children, vaccination of adults is recommended to prevent polio. A complete series of IPV-containing vaccine is recommended for previously unimmunized adults who are also receiving a primary series of tetanus toxoid-containing vaccine. For other adults who are only unvaccinated against polio, vaccination efforts should be focused on those who are at increased risk of exposure to polioviruses (refer to ). Adults who are unvaccinated against polio but who do not need a primary series of tetanus and diphtheria toxoid-containing vaccine and who are not at increased risk of exposure can be provided with polio vaccinations when tetanus and diphtheria toxoid-containing vaccine booster doses are due.
Adults previously immunized with polio vaccine: for those at increased risk of exposure to polio (e.g., those travelling to, or planning to work in areas that have wild polio or vaccine-derived polio outbreaks) a single lifetime booster dose of IPV-containing vaccine is recommended (refer to ).
- Travellers to, or persons receiving travellers from, areas where poliovirus is known or suspected to be circulating
- Members of communities or specific population groups with disease caused by polio
- Health care workers who have close contact with patients who might be excreting wild type or vaccine type poliovirus
- People who come in close contact with those who may be excreting poliovirus (e.g., people working with refugees, or the military and people on humanitarian missions in endemic countries)
- Laboratory workers handling specimens that may contain poliovirus
- Family or close contacts of internationally adopted infants who may have been or will be vaccinated with OPV vaccine
## Persons with inadequate immunization records
Children and adults lacking adequate documentation of immunization should be considered unimmunized and started on an immunization schedule appropriate for their age and risk factors. Children who were not vaccinated against all three types of poliovirus (e.g., received bOPV vaccine after April 2016 without receipt of at least two doses of mOPV2, nOPV2 or IPV) remain at risk of VDPV2 and should be considered incompletely immunized.
If indicated, IPV vaccine can be given to unimmunized or incompletely immunized persons without concern about prior receipt of the polio-containing vaccine, because adverse events associated with repeated immunization with the vaccine have not been demonstrated. Refer to in Part 4 for additional information. Refer to in Part 3 for additional general information.
Fractional IPV (fIPV) corresponds to the intradermal administration of one fifth (1/5) of the regular IPV dose. fIPV has been used internationally (routine or outbreak immunization) in a context of IPV supply shortages. fIPV has been shown to offer adequate protection against polio and, as a result, the WHO Strategic Advisory Group of Experts on Immunization (SAGE) recommended a two-dose fIPV schedule to countries if needed.
## Pregnancy and breastfeeding
IPV vaccine may be considered for pregnant people who require immediate protection and are at increased risk of exposure to wild poliovirus (refer to ). There is no evidence to suggest a risk to the fetus or to the pregnancy from immunization of the pregnant person with inactivated vaccines, such as IPV vaccine. Refer to in Part 3 for additional general information.
## Infants born prematurely
Premature infants in stable clinical condition should be immunized with an IPV-containing vaccine at the same chronological age and according to the same schedule as full-term infants. Infants born prematurely (especially those weighing less than 1,500 grams at birth) are at higher risk of apnea and bradycardia following vaccination. Hospitalized premature infants should have continuous cardiac and respiratory monitoring for 48 hours after their first immunization. Refer to in Part 3 for additional general information.
## Persons/residents in health care institutions
Residents of long-term care facilities should receive all routine immunizations appropriate for their age and risk factors, including IPV-containing vaccine. Refer to in Part 3 for additional general information.
## Immunocompromised persons
IPV-containing vaccines may be administered to immunocompromised persons. When considering immunization of an immunocompromised person, consultation with the individual's attending physician may be of assistance in addition to the guidance provided in Immunocompromised persons in and in Part 4. For complex cases, referral to a physician with expertise in immunization or immunodeficiency is advised.
## Persons with chronic diseases
## Travellers
Unimmunized or incompletely immunized travellers should receive an IPV-containing vaccine as appropriate for age, particularly if they are children, or if travelling to areas where poliovirus is known or suspected to be circulating. Previously unimmunized children travelling to areas where poliovirus is known or suspected to be circulating should start a primary series of an IPV-containing vaccine, with consideration given to an accelerated schedule (refer to ). For infants embarking on travel, the first dose of DTaP-IPV-Hib or DTaP-HB-IPV-Hib vaccine can be given at 6 weeks of age. If IPV vaccine is not available in the region to which the child is travelling, children may complete their series with either IPV or bOPV vaccine while travelling. However, it is necessary to ensure that all IPV vaccine doses are received following return to Canada, since children with an incomplete schedule or those receiving bOPV only remain at risk of VDPV2. Parents of children receiving OPV vaccine should be informed that infants can excrete attenuated (vaccine-derived) poliovirus for up to 5 days following vaccination, so household contacts and caregivers of these infant should have up-to-date polio immunization. For vaccinees who are immunocompromised, the period of vaccine virus excretion might be longer. People should be instructed to wash their hands carefully after changing diapers. Household contacts who are vaccinated with OPV should not have contact with immunocompromised persons for six weeks after receipt of OPV. There is also a small risk of OPV vaccine-associated paralytic polio (approximately 1 per 2.4 million doses distributed).
Children with a complete primary series do not require additional doses of IPV vaccine before travelling. For adults previously immunized against polio, a single lifetime dose of polio-containing vaccine is recommended for travellers at increased risk of exposure to polio (e.g., military personnel, workers in refugee camps in endemic areas, or travellers to areas where poliovirus is known or suspected to be circulating) (refer to ). Refer to the Committee to Advise on Tropical Medicine and Travel (CATMAT) for more information.
## Persons new to Canada
Health care providers who see people newly arrived in Canada should review the immunization status and update immunization for these individuals if needed. Previous poliovirus vaccination is only considered valid if individuals have documented proof of age-appropriate complete immunization against the three types of poliovirus (e.g., receipt of IPV, fIPV, tOPV, or combination of bOPV and mOPV2). Refer to for more information.
Children who have received one or more doses of polio vaccine before arriving in Canada should have their vaccine series completed with IPV-containing vaccine as appropriate for age. Children who were not vaccinated against all three types of poliovirus (e.g., received bOPV vaccine after April 2016 without receipt of at least two doses of mOPV2, nOPV2 or IPV) remain at risk of infection. Those who received bOPV only should receive a complete age-appropriate IPV series to be optimally protected against polio, including VDPV2.
Similar to children, vaccination of adults is recommended to prevent the polio. A complete series of IPV-containing vaccine is recommended for previously unimmunized adults who are also receiving a primary series of tetanus toxoid-containing vaccine. Adults previously immunized with polio vaccine and at increased risk of exposure to polio should receive a single lifetime booster dose of IPV-containing vaccine. Refer to in Part 3 for additional general information.
## Workers
Workers who need a primary series of tetanus and diphtheria toxoid-containing vaccine should also receive IPV-containing vaccine if unvaccinated against polio. For other workers who are unvaccinated against polio, vaccination efforts should be focused on those who are at increased risk of exposure to polioviruses as identified in . If previously vaccinated with a primary series of tetanus and diphtheria toxoid-containing vaccine and not in an increased risk group (refer to ), adults unvaccinated against polio can receive IPV-containing vaccine when due for their next tetanus and diphtheria booster. Refer to in Part 3 for additional general information.
# Vaccine administration
## Dose, route of administration, and schedule
### Dose
Each dose of IPV-containing vaccine is 0.5 mL.
### Route of administration
Combination vaccines containing IPV vaccine must be administered intramuscularly. IPV vaccine when given as a separate vaccine, should be administered subcutaneously. Refer to in Part 1 for additional information.
### Schedule
### Infants and children (2 months to 6 years of age)
Routine polio immunization of infants: DTaP-IPV-Hib vaccine should be given at 2, 4, 6 and 12 to 23 months of age (generally given at 18 months of age).
If infant immunization for hepatitis B is undertaken, DTaP-HB-IPV-Hib vaccine may be used as an alternative to separately administered hepatitis B and DTaP-IPV-Hib vaccines. DTaP-HB-IPV-Hib vaccine is authorized for use in children 6 weeks to 23 months of age and may be given to children aged 24 months to less than 7 years, if necessary. DTaP-HB-IPV-Hib vaccine may be given at 2, 4, 6 and 12 to 23 months of age, but the fourth dose is unlikely to provide significant additional hepatitis B protection and will increase cost. Alternative schedules may be used as follow:
- DTaP-HB-IPV-Hib vaccine (2, 4 and 6 months of age) with DTaP-IPV-Hib vaccine at 12 to 23 months of age
- DTaP-HB-IPV-Hib vaccine (2, 4 and 12 to 23 months of age) with DTaP-IPV-Hib vaccine at 6 months of age.
A dose of IPV-containing vaccine is not required at 6 months of age for a complete primary series of polio vaccine; however, it is acceptable to give the additional dose of IPV vaccine in a combination vaccine for convenience of administration.
If rapid protection is required for an infant, the first dose of DTaP-IPV-Hib or DTaP-HB-IPV-Hib vaccine can be given at 6 weeks of age. The first three doses may be administered at intervals of 4 weeks and, optimally, the fourth dose given 12 months after the third dose. The fourth dose may be given at a minimum interval of 6 months after the third dose in certain situations (e.g., travel) but must be administered at or after 12 months of age for sustained immunity.
Children less than 7 years of age, not immunized in infancy: should receive three doses of DTaP-IPV (with or without Hib) vaccine with an interval of 8 weeks between doses, followed by a dose of DTaP-IPV vaccine 6 to 12 months after the third dose. A booster dose of either DTaP-IPV or Tdap-IPV vaccine should be administered at 4 to 6 years of age (school entry). The booster dose at 4 to 6 years of age is not required if the fourth dose of tetanus-toxoid containing vaccine was administered after the fourth birthday.
If rapid protection is required for a child less than 7 years of age not immunized in infancy, with imminent exposure to circulating poliovirus (e.g., during an outbreak or because of travel), the first three doses of vaccine may be administered at intervals of 4 weeks and, optimally, the fourth dose given 12 months after the third dose. The fourth dose may be given at a minimum interval of 6 months after the third dose in certain situations (e.g., travel).
Children (4 years of age and older) not immunized against polio in infancy and not requiring the additional antigens in combination vaccine should receive two doses of IPV vaccine, given 4 to 8 weeks apart, followed by a third dose administered 6 to 12 months after the second dose.
Children who received a primary series of IPV-containing vaccine and a booster dose 6-12 months later as outlined above, should receive a booster dose of either DTaP-IPV or Tdap-IPV vaccine at 4 to 6 years of age (school entry). The booster dose at 4 to 6 years of age is not required if the third dose of IPV-containing vaccine was administered after the fourth birthday. A dose of IPV-containing vaccine should be administered at 4 to 6 years of age, regardless of the number doses of IPV and tOPV vaccine administered prior to 4 years of age.
### Children and adolescents (7 years to 17 years of age)
For children and adolescents not previously immunized with tetanus, diphtheria and polio, refer to or in Part 4. Children 7 years of age and older needing only polio protection, should receive 2 doses of IPV-containing vaccine, given 4 to 8 weeks apart, followed by a third dose administered 6 to 12 months after the second dose.
### Adults (18 years of age and older)
For adults not previously immunized with tetanus, diphtheria and polio, refer to or in Part 4. Adults at increased risk for polio who only need polio protection, should receive two doses of IPV-containing vaccine, given 4 to 8 weeks apart, followed by a third dose 6 to 12 months after the second dose. Adults who are unimmunized against polio but are not at increased risk and have had a primary series of tetanus and diphtheria containing vaccine, should receive IPV-containing vaccine as part of their next tetanus and diphtheria booster.
## Booster doses and re-immunization
The preschool booster dose of either DTaP-IPV or Tdap-IPV vaccine should be administered at 4 to 6 years of age. For adults previously immunized against polio, a single lifetime booster dose of IPV-containing vaccine is recommended for those at increased risk of exposure to polio (e.g., military personnel, workers in refugee camps in endemic areas, travellers to areas where poliovirus is known or suspected to be circulating) (refer to ).
# Serologic testing
Serologic testing is not recommended before or after receiving IPV vaccine.
# Storage requirements
IPV-containing vaccines should be stored in a refrigerator at +2°C to +8°C and not frozen. Refer to in Part 1 for additional general information.
# Simultaneous administration with other vaccines
IPV-containing vaccines may be administered concomitantly with routine vaccines at different injection sites using separate needles and syringes. Refer to in Part 1 for additional general information.
# Vaccine safety and adverse events
## Common and local adverse events
Adverse events following IPV vaccine are usually limited to mild injection site reactions.
## Less common and serious or severe adverse events
Serious adverse events are rare following immunization with IPV-containing vaccine and, in most cases, data are insufficient to determine a causal association. Anaphylaxis following vaccination with IPV-containing vaccine may occur, but is very rare.
## Guidance on reporting Adverse Events Following Immunization (AEFI)
Vaccine providers are asked to report, through local public health officials, any serious or unexpected adverse event felt to be temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.
## Contraindications and precautions
IPV-containing vaccines are contraindicated in persons with a history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container (e.g. latex). Refer to Table 1 in in Part 1 for a list of all vaccines available for use in Canada and their contents. For IPV-containing vaccines, potential allergens include:
- ADACEL®-POLIO: neomycin, polymyxin B, streptomycin
- BOOSTRIX®-POLIO: latex in plunger stopper of pre-filled syringe, neomycin, polymyxin B
- IMOVAX®-POLIO: neomycin, polymyxin B, streptomycin
- INFANRIX hexa™: latex in plunger stopper of pre-filled syringe, neomycin, polymyxin B, yeast
- PEDIACEL®: neomycin, polymyxin B, streptomycin
- QUADRACEL®: neomycin, polymyxin B
Hypersensitivity to yeast is very rare and a personal history of yeast allergy is not generally reliable. In situations of suspected hypersensitivity or non-anaphylactic allergy to vaccine components, investigation is indicated, which may involve immunization in a controlled setting. Consultation with an allergist is advised.
Administration of IPV-containing vaccine should be postponed in persons with moderate or severe acute illness. Persons with minor acute illness (with or without fever) may be vaccinated.
# Other considerations
## Interchangeability of vaccines
The primary series of three doses of IPV-containing vaccine should be completed with an appropriate vaccine from the same manufacturer whenever possible. However, if the original vaccine is unknown or unavailable, an alternative combination vaccine from a different manufacturer may be used to complete the primary series. On the basis of expert opinion, an appropriate product from any manufacturer can be used for all booster doses. Refer to in Part 1 for additional general information. |
**Poliomyelitis (polio) vaccine: Canadian Immunization Guide**
==============================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-18-rabies-vaccine.html)
**Last partial content update (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): February 2023**
**February 2023:** The chapter was updated to include information on circulating vaccine-derived poliovirus 2 (cVDPV2) outbreaks outside of Canada. Guidance on the immunization of individuals previously immunized with bivalent oral polio vaccine (bOPV) is provided.
Last complete chapter revision: January 2015
On this page
------------
* [Key information](#p4c16a1)
* [Epidemiology](#p4c16a2)
* [Preparations authorized for use in Canada](#p4c16a3)
* [Efficacy, effectiveness and immunogenicity](#p4c16a4)
* [Recommendations for use](#p4c16a5)
+ [Table 1: Persons at increased risk of exposure to poliovirus](#p4c16t1)
* [Vaccine administration](#p4c16a6)
* [Serologic testing](#p4c16a7)
* [Storage requirements](#p4c16a8)
* [Simultaneous administration with other vaccines](#p4c16a9)
* [Vaccine safety and adverse events](#p4c16a10)
+ [Common and local adverse events](#p4c16a10a)
+ [Contraindications and precautions](#p4c16a10d)
* [Other considerations](#p4c16a11)
* [Selected references](#p4c16a12)
### Key information
What
* Polio remains endemic in two countries - Afghanistan and Pakistan; additional countries are known or suspected of having re-established transmission of poliovirus. Several other countries have ongoing outbreaks due to importations of poliovirus.
* Children less than 5 years of age are more susceptible to polio infection.
* Inactivated poliomyelitis - containing vaccines (IPV) produce immunity in over 95% of vaccinees after 3 doses and in close to 100% following a booster dose.
* Adverse events following IPV vaccine are usually limited to mild injection site reactions.
* Oral poliomyelitis vaccine (OPV) is not used in Canada.
Who
* IPV-containing vaccine is recommended for:
+ routine immunization of infants and children
+ unimmunized or incompletely immunized children
+ unimmunized adults
+ as a booster dose for adults previously immunized against polio and at increased risk of polio exposure
How
* **Routine polio immunization of infants and children:** administer DTaP-IPV-Hib vaccine at 2, 4, 6 and 12 to 23 months of age (generally given at 18 months of age). If infant immunization for hepatitis B is undertaken, DTaP-HB-IPV-Hib vaccine may be used. Subsequently, administer a booster dose of either DTaP-IPV or Tdap-IPV vaccine at 4 to 6 years of age (school entry).
* **Unimmunized or incompletely immunized children** should have their vaccine series completed with IPV- containing vaccine as appropriate for age.
* **Adults previously unimmunized with polio vaccine:** administer a primary series of IPV-containing vaccine if a primary series of tetanus toxoid-containing vaccine is being given or if the adult is at increased risk for exposure to poliovirus; otherwise, administer polio in a combination vaccine with routine tetanus and diphtheria booster doses.
* **Adults previously immunized with polio vaccine:** for those at increased risk of exposure to polio (e.g., those travelling to, or planning to work in areas that have wild polio or vaccine-derived polio outbreaks), a single lifetime booster dose of IPV-containing vaccine is recommended.
* IPV-containing vaccines may be administered concomitantly with routine vaccines at different injection sites using separate needles and syringes.
Why
* Until polio eradication has been achieved globally, there remains a small risk of contracting polio with travel to countries with circulating poliovirus (endemic or outbreak) and importation of polio into Canada.
* The case fatality rate for paralytic polio is 2% to 5% among children and 15% to 30% for adults.
### Epidemiology
#### Disease description
##### Infectious agent
Polio is caused by poliovirus, a member of the enterovirus subgroup of the *Picornaviridae* family.
##### Reservoir
Humans
##### Transmission
Transmission of poliovirus occurs predominantly through the fecal-oral route. Respiratory spread may rarely occur. The incubation period for polio is 3 to 6 days for onset of non-specific symptoms. In those that progress to paralysis, this occurs in 7 to 21 days from exposure (can range up to 35 days). Communicability is greatest around the onset of illness when the virus is present in high concentrations in the throat and feces. Poliovirus can remain in feces for 3 to 6 weeks. In persons who have received oral polio vaccine (OPV), poliovirus can be present in the throat for 1 to 2 weeks following immunization and can remain in feces for several weeks. In rare cases, including among immunocompromised persons, poliovirus (from natural infection or OPV vaccine) can be excreted for prolonged periods of time (from greater than 6 months to a number of years).
##### Risk factors
Polio infections are more common in children less than 5 years of age; however, any person who is not immune to poliovirus, regardless of age, can become infected.
##### Seasonal and temporal patterns
In temperate climates, polio infection generally increases in the late summer and autumn months.
##### Spectrum of clinical illness
Most polio infections (approximately 75%) are asymptomatic. In symptomatic persons, initial symptoms occur 3 to 6 days after exposure to the virus and include fever, fatigue, headache and vomiting. With increased disease severity, severe muscle pain and stiffness of the neck and back with or without paralysis may occur. Although paralysis is the most visible sign of polio infection, less than 1% of cases result in paralysis. The case fatality ratio for paralytic polio ranges from 2% to 5% among children and 15% to 30% for adults.
#### Disease distribution
The incidence of polio in Canada was dramatically reduced by the introduction of immunization programs in the 1950s. In Canada, after many years of use, the OPV was replaced with an IPV in 1995/1996. The last indigenous case of wild poliovirus in Canada was in 1977. In 1994, Canada was certified as being free of wild poliovirus by the World Health Organization (WHO), with exceptionally rare cases of paralytic polio being associated with importations of wild or vaccine-derived poliovirus. The last nationally reported case of paralytic polio occurred in 1995 and was related to OPV receipt. More information on [polio](/en/public-health/services/diseases/poliomyelitis-polio.html) and [polio surveillance](/en/public-health/services/diseases/poliomyelitis-polio/health-professionals.html#a12) in Canada can be found on PHAC's website.
Currently only type 1 wild poliovirus remains endemic in two countries globally. Type 2 wild poliovirus was declared eradicated in September 2015, with the last virus detected in 1999. Type 3 wild poliovirus was declared eradicated in October 2019. It was last detected in November 2012.
In April 2016, WHO coordinated a synchronized global withdrawal of the trivalent oral polio vaccine (tOPV) which contained the Sabin 2 strain of the virus. Since then, countries incorporating oral poliovirus routine immunization programs have been using a bivalent oral polio vaccine (bOPV) containing the attenuated Sabin 1 and 3 strains. Despite this change, circulating vaccine-derived poliovirus 2 (cVDPV2) outbreaks continue to occur, primarily due to inadequate vaccine coverage and response efforts to contain the outbreaks.
### Preparations authorized for use in Canada
#### Poliomyelitis-containing vaccines
* **ADACEL®-POLIO** (adsorbed vaccine containing tetanus toxoid, reduced diphtheria toxoid and reduced acellular pertussis vaccine combined with inactivated poliomyelitis vaccine), Sanofi Pasteur Ltd. (Tdap-IPV)
* **BOOSTRIX®-POLIO** (adsorbed vaccine containing tetanus toxoid, reduced diphtheria toxoid and reduced acellular pertussis vaccine combined with inactivated poliomyelitis vaccine), GlaxoSmithKline Inc. (Tdap-IPV)
* **IMOVAX®Polio** (inactivated poliomyelitis vaccine (vero cell origin), Sanofi Pasteur SA (manufacturer), Sanofi Pasteur Ltd. (distributor). (IPV)
* **INFANRIX®-IPV/Hib** (adsorbed vaccine containing diphtheria and tetanus toxoids, acellular pertussis, inactivated poliomyelitis and conjugated *Haemophilus influenzae* type b vaccine), GlaxoSmithKline Inc. (DTaP-IPV-Hib)
* **INFANRIX hexa™** (adsorbed vaccine containing diphtheria and tetanus toxoids, acellular pertussis, hepatitis B (recombinant), inactivated poliomyelitis and conjugated *Haemophilus influenzae* type b vaccine), GlaxoSmithKline Inc. (DTaP-HB-IPV-Hib)
* **PEDIACEL®** (adsorbed vaccine containing diphtheria and tetanus toxoids and acellular pertussis vaccine combined with inactivated poliomyelitis vaccine and *Haemophilus influenzae* type b conjugate vaccine), Sanofi Pasteur Ltd. (DTaP-IPV-Hib)
* **QUADRACEL®** (adsorbed vaccine containing diphtheria and tetanus toxoids and acellular pertussis vaccine combined with inactivated poliomyelitis vaccine), Sanofi Pasteur Ltd. (DTaP-IPV)
IPV contains three types of inactivated poliovirus (trivalent) and is available as a single vaccine or as a combination vaccine. Live attenuated OPV is no longer recommended or available in Canada because most cases of paralytic polio from 1980 to 1995 were associated with OPV vaccine. bOPV vaccine continues to be widely used internationally. Monovalent OPVs (e.g., mOPV1, mOPV2, mOPV3, and novel OPV2 [nOPV2]) are also available and used for outbreak management.
For complete prescribing information, consult the product leaflet or information contained within Health Canada's authorized product monographs available through the [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html). Refer to Table 1 in [Contents of Immunizing Agents Available for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for a list of all vaccines available for use in Canada and their contents.
### Efficacy, effectiveness and immunogenicity
IPV-containing vaccines produce immunity to all three types of poliovirus in over 95% of vaccinees following three doses of vaccine, and in close to 100% following a booster dose. Seroconversion rates are lower if the minimum age and minimum intervals for vaccine administration are used in infants less than 6 months of age.
### Recommendations for use
#### Infants and children (2 months to 17 years of age)
An IPV-containing vaccine is recommended for routine infant immunization beginning at 2 months of age. DTaP-IPV (with or without Hib) vaccine is authorized for use in children less than 7 years of age. DTaP-HB-IPV-Hib vaccine is authorized for use in children 6 weeks to 23 months of age and may be given to children aged 24 months to less than 7 years, if necessary. DTaP-IPV or Tdap-IPV vaccine should be used as the booster dose for children at 4 to 6 years of age. Children 7 years of age and older should receive IPV vaccine or the adolescent/adult formulation of the diphtheria-tetanus-pertussis-polio-containing vaccine (Tdap-IPV). Tdap-IPV vaccine contains less pertussis and diphtheria toxoid than vaccines given to younger children and is less likely to cause reactions in older children. Tdap vaccine is generally administered to adolescents at 14 to 16 years of age as the first 10-year booster dose; however, Tdap-IPV vaccine should be used if IPV vaccine is also indicated.
#### Adults (18 years of age and older)
Similar to vaccination of children, vaccination of adults is recommended to prevent polio. A complete series of IPV-containing vaccine is recommended for **previously unimmunized adults** who are also receiving a primary series of tetanus toxoid-containing vaccine. For other adults who are only unvaccinated against polio, vaccination efforts should be focused on those who are at increased risk of exposure to polioviruses (refer to [Table 1](#p4c16t1)). Adults who are unvaccinated against polio but who do not need a primary series of tetanus and diphtheria toxoid-containing vaccine and who are not at increased risk of exposure can be provided with polio vaccinations when tetanus and diphtheria toxoid-containing vaccine booster doses are due.
**Adults previously immunized with polio vaccine:** for those at increased risk of exposure to polio (e.g., those travelling to, or planning to work in areas that have wild polio or vaccine-derived polio outbreaks) a single lifetime booster dose of IPV-containing vaccine is recommended (refer to [Table 1](#p4c16t1)).
##### Table 1: Persons at increased risk of exposure to poliovirus
* Travellers to, or persons receiving travellers from, areas where poliovirus is known or suspected to be circulating
* Members of communities or specific population groups with disease caused by polio
* Health care workers who have close contact with patients who might be excreting wild type or vaccine type poliovirus
* People who come in close contact with those who may be excreting poliovirus (e.g., people working with refugees, or the military and people on humanitarian missions in endemic countries)
* Laboratory workers handling specimens that may contain poliovirus
* Family or close contacts of internationally adopted infants who may have been or will be vaccinated with OPV vaccine
Refer to [Schedule](#p4c16a6a1), [Travellers](#p4c16a5i) and [Booster doses and re-immunization](#p4c16a6b). Refer to [Diphtheria Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-4-diphtheria-toxoid.html), [Tetanus Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html), [Pertussis Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-15-pertussis-vaccine.html), [*Haemophilus influenzae* type b Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-5-haemophilus-influenzae-type-b-vaccine.html), and [Hepatitis B Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for additional information.
#### Persons with inadequate immunization records
Children and adults lacking adequate documentation of immunization should be considered unimmunized and started on an immunization schedule appropriate for their age and risk factors. Children who were not vaccinated against all three types of poliovirus (e.g., received bOPV vaccine after April 2016 without receipt of at least two doses of mOPV2, nOPV2 or IPV) remain at risk of VDPV2 and should be considered incompletely immunized.
If indicated, IPV vaccine can be given to unimmunized or incompletely immunized persons without concern about prior receipt of the polio-containing vaccine, because adverse events associated with repeated immunization with the vaccine have not been demonstrated. Refer to [Diphtheria Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-4-diphtheria-toxoid.html) in Part 4 for additional information. Refer to [Immunization of Persons with Inadequate Immunization Records](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-3-immunization-persons-inadequate-immunization-records.html) in Part 3 for additional general information.
Fractional IPV (fIPV) corresponds to the intradermal administration of one fifth (1/5) of the regular IPV dose. fIPV has been used internationally (routine or outbreak immunization) in a context of IPV supply shortages. fIPV has been shown to offer adequate protection against polio and, as a result, the WHO Strategic Advisory Group of Experts on Immunization (SAGE) recommended a two-dose fIPV schedule to countries if needed.
#### Pregnancy and breastfeeding
IPV vaccine may be considered for pregnant people who require immediate protection and are at increased risk of exposure to wild poliovirus (refer to [Table 1](#p4c16t1)). There is no evidence to suggest a risk to the fetus or to the pregnancy from immunization of the pregnant person with inactivated vaccines, such as IPV vaccine. Refer to [Immunization in Pregnancy and Breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3 for additional general information.
#### Infants born prematurely
Premature infants in stable clinical condition should be immunized with an IPV-containing vaccine at the same chronological age and according to the same schedule as full-term infants. Infants born prematurely (especially those weighing less than 1,500 grams at birth) are at higher risk of apnea and bradycardia following vaccination. Hospitalized premature infants should have continuous cardiac and respiratory monitoring for 48 hours after their first immunization. Refer to [Immunization of Infants Born Prematurely](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-5-immunization-infants-born-prematurely.html) in Part 3 for additional general information.
#### Persons/residents in health care institutions
Residents of long-term care facilities should receive all routine immunizations appropriate for their age and risk factors, including IPV-containing vaccine. Refer to [Immunization of Persons/Residents in Health Care Institutions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-6-immunization-patients-health-care-institutions.html) in Part 3 for additional general information.
#### Immunocompromised persons
IPV-containing vaccines may be administered to immunocompromised persons. When considering immunization of an immunocompromised person, consultation with the individual's attending physician may be of assistance in addition to the guidance provided in Immunocompromised persons in [Diphtheria Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-4-diphtheria-toxoid.html) and [Haemophilus influenzae type b Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-5-haemophilus-influenzae-type-b-vaccine.html) in Part 4. For complex cases, referral to a physician with expertise in immunization or immunodeficiency is advised.
Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional general information.
#### Persons with chronic diseases
Refer to [Tetanus Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html) and [Pertussis Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-15-pertussis-vaccine.html) in Part 4 for information regarding other components in IPV-containing combination vaccines. Refer to [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional general information.
#### Travellers
Unimmunized or incompletely immunized travellers should receive an IPV-containing vaccine as appropriate for age, particularly if they are children, or if travelling to areas where poliovirus is known or suspected to be circulating. Previously unimmunized children travelling to areas where poliovirus is known or suspected to be circulating should start a primary series of an IPV-containing vaccine, with consideration given to an accelerated schedule (refer to [Schedule](#p4c16a6a1)). For infants embarking on travel, the first dose of DTaP-IPV-Hib or DTaP-HB-IPV-Hib vaccine can be given at 6 weeks of age. If IPV vaccine is not available in the region to which the child is travelling, children may complete their series with either IPV or bOPV vaccine while travelling. However, it is necessary to ensure that all IPV vaccine doses are received following return to Canada, since children with an incomplete schedule or those receiving bOPV only remain at risk of VDPV2. Parents of children receiving OPV vaccine should be informed that infants can excrete attenuated (vaccine-derived) poliovirus for up to 5 days following vaccination, so household contacts and caregivers of these infant should have up-to-date polio immunization. For vaccinees who are immunocompromised, the period of vaccine virus excretion might be longer. People should be instructed to wash their hands carefully after changing diapers. Household contacts who are vaccinated with OPV should not have contact with immunocompromised persons for six weeks after receipt of OPV. There is also a small risk of OPV vaccine-associated paralytic polio (approximately 1 per 2.4 million doses distributed).
Children with a complete primary series do not require additional doses of IPV vaccine before travelling. For adults previously immunized against polio, a single lifetime dose of polio-containing vaccine is recommended for travellers at increased risk of exposure to polio (e.g., military personnel, workers in refugee camps in endemic areas, or travellers to areas where poliovirus is known or suspected to be circulating) (refer to [Table 1](#p4c16t1)). Refer to the Committee to Advise on Tropical Medicine and Travel (CATMAT) [Statement on poliovirus and the international traveller](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2014-40/ccdr-volume-40-13-july-10-2014/ccdr-volume-40-13-july-10-2014-2.html) for more information.
Refer to [Diphtheria Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-4-diphtheria-toxoid.html) in Part 4 for additional information. Refer to [Immunization of Travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) in Part 3 for additional general information.
#### Persons new to Canada
Health care providers who see people newly arrived in Canada should review the immunization status and update immunization for these individuals if needed. Previous poliovirus vaccination is only considered valid if individuals have documented proof of age-appropriate complete immunization against the three types of poliovirus (e.g., receipt of IPV, fIPV, tOPV, or combination of bOPV and mOPV2). Refer to [Persons with inadequate immunization records](#p4c16a5c) for more information.
Children who have received one or more doses of polio vaccine before arriving in Canada should have their vaccine series completed with IPV-containing vaccine as appropriate for age. Children who were not vaccinated against all three types of poliovirus (e.g., received bOPV vaccine after April 2016 without receipt of at least two doses of mOPV2, nOPV2 or IPV) remain at risk of infection. Those who received bOPV only should receive a complete age-appropriate IPV series to be optimally protected against polio, including VDPV2.
Similar to children, vaccination of adults is recommended to prevent the polio. A complete series of IPV-containing vaccine is recommended for previously unimmunized adults who are also receiving a primary series of tetanus toxoid-containing vaccine. Adults previously immunized with polio vaccine and at increased risk of exposure to polio should receive a single lifetime booster dose of IPV-containing vaccine. Refer to [Immunization of Persons New to Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-10-immunization-persons-new-canada.html) in Part 3 for additional general information.
#### Workers
Workers who need a primary series of tetanus and diphtheria toxoid-containing vaccine should also receive IPV-containing vaccine if unvaccinated against polio. For other workers who are unvaccinated against polio, vaccination efforts should be focused on those who are at increased risk of exposure to polioviruses as identified in [Table 1](#p4c16t1). If previously vaccinated with a primary series of tetanus and diphtheria toxoid-containing vaccine and not in an increased risk group (refer to [Table 1](#p4c16t1)), adults unvaccinated against polio can receive IPV-containing vaccine when due for their next tetanus and diphtheria booster. Refer to [Immunization of Workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html) in Part 3 for additional general information.
### Vaccine administration
#### Dose, route of administration, and schedule
##### Dose
Each dose of IPV-containing vaccine is 0.5 mL.
##### Route of administration
Combination vaccines containing IPV vaccine must be administered intramuscularly. IPV vaccine when given as a separate vaccine, should be administered subcutaneously. Refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for additional information.
##### Schedule
###### Infants and children (2 months to 6 years of age)
**Routine polio immunization of infants:** DTaP-IPV-Hib vaccine should be given at 2, 4, 6 and 12 to 23 months of age (generally given at 18 months of age).
If infant immunization for hepatitis B is undertaken, DTaP-HB-IPV-Hib vaccine may be used as an alternative to separately administered hepatitis B and DTaP-IPV-Hib vaccines. DTaP-HB-IPV-Hib vaccine is authorized for use in children 6 weeks to 23 months of age and may be given to children aged 24 months to less than 7 years, if necessary. DTaP-HB-IPV-Hib vaccine may be given at 2, 4, 6 and 12 to 23 months of age, but the fourth dose is unlikely to provide significant additional hepatitis B protection and will increase cost. Alternative schedules may be used as follow:
* DTaP-HB-IPV-Hib vaccine (2, 4 and 6 months of age) with DTaP-IPV-Hib vaccine at 12 to 23 months of age
* DTaP-HB-IPV-Hib vaccine (2, 4 and 12 to 23 months of age) with DTaP-IPV-Hib vaccine at 6 months of age.
A dose of IPV-containing vaccine is not required at 6 months of age for a complete primary series of polio vaccine; however, it is acceptable to give the additional dose of IPV vaccine in a combination vaccine for convenience of administration.
If rapid protection is required for an infant, the first dose of DTaP-IPV-Hib or DTaP-HB-IPV-Hib vaccine can be given at 6 weeks of age. The first three doses may be administered at intervals of 4 weeks and, optimally, the fourth dose given 12 months after the third dose. The fourth dose may be given at a minimum interval of 6 months after the third dose in certain situations (e.g., travel) but must be administered at or after 12 months of age for sustained immunity.
**Children less than 7 years of age, not immunized in infancy:** should receive three doses of DTaP-IPV (with or without Hib) vaccine with an interval of 8 weeks between doses, followed by a dose of DTaP-IPV vaccine 6 to 12 months after the third dose. A booster dose of either DTaP-IPV or Tdap-IPV vaccine should be administered at 4 to 6 years of age (school entry). The booster dose at 4 to 6 years of age is not required if the fourth dose of tetanus-toxoid containing vaccine was administered after the fourth birthday.
If rapid protection is required for a child less than 7 years of age not immunized in infancy, with imminent exposure to circulating poliovirus (e.g., during an outbreak or because of travel), the first three doses of vaccine may be administered at intervals of 4 weeks and, optimally, the fourth dose given 12 months after the third dose. The fourth dose may be given at a minimum interval of 6 months after the third dose in certain situations (e.g., travel).
Children (4 years of age and older) not immunized against polio in infancy and not requiring the additional antigens in combination vaccine should receive two doses of IPV vaccine, given 4 to 8 weeks apart, followed by a third dose administered 6 to 12 months after the second dose.
Children who received a primary series of IPV-containing vaccine and a booster dose 6-12 months later as outlined above, should receive a booster dose of either DTaP-IPV or Tdap-IPV vaccine at 4 to 6 years of age (school entry). The booster dose at 4 to 6 years of age is not required if the third dose of IPV-containing vaccine was administered after the fourth birthday. A dose of IPV-containing vaccine should be administered at 4 to 6 years of age, regardless of the number doses of IPV and tOPV vaccine administered prior to 4 years of age.
###### Children and adolescents (7 years to 17 years of age)
For children and adolescents not previously immunized with tetanus, diphtheria and polio, refer to [Tetanus Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html) or [Diphtheria Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-4-diphtheria-toxoid.html) in Part 4. Children 7 years of age and older needing only polio protection, should receive 2 doses of IPV-containing vaccine, given 4 to 8 weeks apart, followed by a third dose administered 6 to 12 months after the second dose.
###### Adults (18 years of age and older)
For adults not previously immunized with tetanus, diphtheria and polio, refer to [Tetanus Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html) or [Diphtheria Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-4-diphtheria-toxoid.html) in Part 4. Adults at increased risk for polio who only need polio protection, should receive two doses of IPV-containing vaccine, given 4 to 8 weeks apart, followed by a third dose 6 to 12 months after the second dose. Adults who are unimmunized against polio but are not at increased risk and have had a primary series of tetanus and diphtheria containing vaccine, should receive IPV-containing vaccine as part of their next tetanus and diphtheria booster.
#### Booster doses and re-immunization
The preschool booster dose of either DTaP-IPV or Tdap-IPV vaccine should be administered at 4 to 6 years of age. For adults previously immunized against polio, a single lifetime booster dose of IPV-containing vaccine is recommended for those at increased risk of exposure to polio (e.g., military personnel, workers in refugee camps in endemic areas, travellers to areas where poliovirus is known or suspected to be circulating) (refer to [Table 1](#p4c16t1)).
### Serologic testing
Serologic testing is not recommended before or after receiving IPV vaccine.
### Storage requirements
IPV-containing vaccines should be stored in a refrigerator at +2°C to +8°C and not frozen. Refer to [Storage and Handling of Immunizing Agents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-9-storage-handling-immunizing-agents.html) in Part 1 for additional general information.
### Simultaneous administration with other vaccines
IPV-containing vaccines may be administered concomitantly with routine vaccines at different injection sites using separate needles and syringes. Refer to [Timing of Vaccine Administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) in Part 1 for additional general information.
### Vaccine safety and adverse events
Refer to [Adverse events following immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) Part 2 for additional general information. Refer to [Diphtheria Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-4-diphtheria-toxoid.html), [Tetanus Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html), [Pertussis Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-15-pertussis-vaccine.html), [*Haemophilus influenzae* type b Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-5-haemophilus-influenzae-type-b-vaccine.html) and [Hepatitis B Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for additional information regarding other components in IPV-containing combination vaccines.
#### Common and local adverse events
Adverse events following IPV vaccine are usually limited to mild injection site reactions.
#### Less common and serious or severe adverse events
Serious adverse events are rare following immunization with IPV-containing vaccine and, in most cases, data are insufficient to determine a causal association. Anaphylaxis following vaccination with IPV-containing vaccine may occur, but is very rare.
#### Guidance on reporting Adverse Events Following Immunization (AEFI)
Vaccine providers are asked to report, through local public health officials, any serious or unexpected adverse event felt to be temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.
Refer to [Reporting Adverse Events Following Immunization](/en/public-health/services/immunization/reporting-adverse-events-following-immunization/user-guide-completion-submission-aefi-reports.html) in Canada for additional information about AEFI reporting.
#### Contraindications and precautions
IPV-containing vaccines are contraindicated in persons with a history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container (e.g. latex). Refer to Table 1 in [Contents of Immunizing Agents Available for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for a list of all vaccines available for use in Canada and their contents. For IPV-containing vaccines, potential allergens include:
* ADACEL®-POLIO: neomycin, polymyxin B, streptomycin
* BOOSTRIX®-POLIO: latex in plunger stopper of pre-filled syringe, neomycin, polymyxin B
* IMOVAX®-POLIO: neomycin, polymyxin B, streptomycin
* INFANRIX hexa™: latex in plunger stopper of pre-filled syringe, neomycin, polymyxin B, yeast
* PEDIACEL®: neomycin, polymyxin B, streptomycin
* QUADRACEL®: neomycin, polymyxin B
Hypersensitivity to yeast is very rare and a personal history of yeast allergy is not generally reliable. In situations of suspected hypersensitivity or non-anaphylactic allergy to vaccine components, investigation is indicated, which may involve immunization in a controlled setting. Consultation with an allergist is advised.
Administration of IPV-containing vaccine should be postponed in persons with moderate or severe acute illness. Persons with minor acute illness (with or without fever) may be vaccinated.
Refer to [General Contraindications and Precautions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html) in Part 2 for additional general information.
### Other considerations
#### Interchangeability of vaccines
The primary series of three doses of IPV-containing vaccine should be completed with an appropriate vaccine from the same manufacturer whenever possible. However, if the original vaccine is unknown or unavailable, an alternative combination vaccine from a different manufacturer may be used to complete the primary series. On the basis of expert opinion, an appropriate product from any manufacturer can be used for all booster doses. Refer to [Principles of Vaccine Interchangeability](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-7-principles-vaccine-interchangeability.html) in Part 1 for additional general information.
### Selected references
* American Academy of Pediatrics, Committee on Infectious Diseases. *Prevention of poliomyelitis: recommendations for use of only inactivated poliovirus vaccine for routine immunization*. Pediatrics 1999;104(6):1404-6.
* Buck P, Herman S, Scott C et al. Health Canada Working Group on Polio Eradication. *Protocol for the investigation of acute flaccid paralysis and suspected paralytic poliomyelitis.* Can Comm Dis Rep 1998;24(4):25-32.
* Caceres VM, Sutter RW. *Sabin monovalent oral polio vaccines: review of past experiences and their potential use after polio eradication*. Clin Infect Dis 2001;33(4):531-41.
* Centers for Disease Control and Prevention. *Epidemiologic notes and reports follow-up on poliomyelitis - United States, Canada, Netherlands*. MMWR Morb Mortal Wkly Rep 1997;46(50):1195-99.
* Centers for Disease Control and Prevention. *Isolation of wild poliovirus type 3 among members of a religious community objecting to vaccination - Alberta, Canada, 1993*. MMWR Morb Mortal Wkly Rep 1993;42(17):337-39.
* Centers for Disease Control and Prevention. *Poliomyelitis prevention in the United States: updated recommendations of the Advisory Committee on Immunization Practices (ACIP).* MMWR Morb Mortal Wkly Rep 2000;49(RR-5):1-22.
* Centers for Disease Control and Prevention. *The Pink Book: Epidemiology and Prevention of Vaccine Preventable Diseases*. Updated 11th ed.; May 2009.
* Centers for Disease Control and Prevention. *Updated Recommendations of the Advisory Committee on Immunization Practices (ACIP) Regarding Routine Poliovirus Vaccination*. MMWR Morb Mortal Wkly Rep. 2009;58(30):829-830.
* Committee to Advise on Tropical Medicine and Travel (CATMAT). *Poliomyelitis vaccination for international travellers*. Can Comm Dis Rep 2003;29(ACS-10):1-7.
* Gautret P, Wilder-Smith A. *Vaccination against tetanus, diphtheria, pertussis and poliomyelitis in adult travellers*. Travel Med Infect Dis 2010;8:155-60.
* GlaxoSmithKline Inc. *Product Monograph - BOOSTRIX®-POLIO,* June 2008.
* GlaxoSmithKline Inc. *Product Monograph - INFANRIX hexa™.* July 2008.
* Modlin J, Halsey N, Thomas M et al. *Humoral and mucosal immunity in infants induced by three sequential inactivated poliovirus vaccine-live attenuated oral poliovirus vaccine immunization schedules.* J Infect Dis 1997;175(Suppl 1):S228-34.
* National Advisory Committee on Immunization. *Statement on the recommended use of pentavalent and hexavalent vaccines.* Can Comm Dis Rep 2007;33(ACS-1):1-15.
* NVAC-ACIP Joint Working Group and Centers for Disease Control and Prevention. *Ensuring preparedness for potential poliomyelitis outbreaks: recommendations for the US poliovirus vaccine stockpile from the National Vaccine Advisory Committee and the Advisory Committee on Immunization Practices.* Arch Pediatr Adolesc Med 2004;158(12):1106-12.
* Patriarca P, Sutter R, Oostvogel P. *Outbreaks of paralytic poliomyelitis, 1976-1995*. J Infect Dis 1997;175(Suppl 1):S165-72.
* Plotkin S, Orenstein W. *Vaccines.* 3rd edition. Philadelphia: W.B. Saunders Company, 1999.
* Rutty C, Barreto L, Van Exan R et al. *Conquering the crippler: Canada and the eradication of polio*. Can J Public Health 2005;96(2):I1-I24.
* Sanofi Pasteur Ltd. *Product Monograph - ADACEL®-POLIO,* October 2010.
* Sanofi Pasteur Ltd. *Product Monograph - IMOVAX®Polio*, January 2007.
* Sanofi Pasteur Ltd. *Product Monograph - PEDIACEL®,* January 2009.
* Sanofi Pasteur Ltd. *Product Monograph - QUADRACEL®,* July 2008.
* Varughese P and Canadian Paediatric Society. Acute flaccid paralysis. In: *Canadian Paediatric Surveillance Program (CPSP): 2003 results*. Ottawa: CPS, 2003.
* Varughese P, Carter A, Acres S et al. *Eradication of indigenous poliomyelitis in Canada: impact of immunization strategies.* Can J Public Health 1989;80(5):363-68.
* Vidor E, Meschievitz C, Plotkin S. *Fifteen years of experience with Vero-produced enhanced potency inactivated poliovirus vaccine.* Pediatr Infect Dis J 1997;16(3):312-22.
* World Health Organization. Use of fractional dose IPV in routine immunization programmes: Considerations for decision-making [Internet]. Polio eradication initiative: April 2017. Available from: fipv-considerations-for-decision-making-april2017.pdf
* World Health Organization. Meeting of the Strategic Advisory Group of Experts on immunization, October 2016- conclusions and recommendations. Wkly Epidemiol Rec 2016;48:567-569.
* World Health Organization. *Acute flaccid paralysis surveillance: a global platform for detecting and responding to priority infectious diseases*. Wkly Epidemiol Rec 2004;79(48):425-32.
* World Health Organization. *Global polio eradication initiative, strategic plan 2004-2008.* Wkly Epidemiol Rec 2004;79(6):55-7.
* World Health Organization. *Progress towards global eradication of poliomyelitis, 2003 and January-April 2004*. Wkly Epidemiol Rec 2004;79(25):229-34.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-18-rabies-vaccine.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-17-poliomyelitis-vaccine.html&n=Poliomyelitis%20(polio)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-17-poliomyelitis-vaccine.html&title=Poliomyelitis%20(polio)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Email](mailto:?subject=Poliomyelitis%20(polio)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-17-poliomyelitis-vaccine.html%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-17-poliomyelitis-vaccine.html&t=Poliomyelitis%20(polio)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=Poliomyelitis%20(polio)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-17-poliomyelitis-vaccine.html%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-17-poliomyelitis-vaccine.html&title=Poliomyelitis%20(polio)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-17-poliomyelitis-vaccine.html&t=Poliomyelitis%20(polio)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-17-poliomyelitis-vaccine.html&media=&description=Poliomyelitis%20(polio)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-17-poliomyelitis-vaccine.html&title=Poliomyelitis%20(polio)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-17-poliomyelitis-vaccine.html)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-17-poliomyelitis-vaccine.html&name=Poliomyelitis%20(polio)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=Poliomyelitis%20(polio)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-17-poliomyelitis-vaccine.html)
* [Whatsapp](https://api.whatsapp.com/send?text=Poliomyelitis%20(polio)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-17-poliomyelitis-vaccine.html)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=Poliomyelitis%20(polio)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-17-poliomyelitis-vaccine.html%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2023-08-04
| None | None |
c2416606d1e0b9816e7ed9316a9de6316bf74e55 | cma | Hepatitis A vaccine: Canadian Immunization Guide | Hepatitis A vaccine: Canadian Immunization Guide
Key Information
What
- Hepatitis A (HA) infection usually causes clinical hepatitis in adults and older children; it often causes a febrile illness without jaundice or is asymptomatic in younger children.
- Pre-exposure HA immunization is at least 90% to 97% effective.
- Reactions to HA vaccine are generally mild and transient and include soreness and redness at the injection site.
Who
- Pre-exposure HA immunization is recommended for people at increased risk of infection or severe HA including:
+ Travellers to HA-endemic countries
+ Individuals with chronic liver disease
+ Men who have sex with men (MSM)
+ Injectable and non-injectable illicit drug users
+ Individuals living in communities at risk of HA outbreaks or in which HA is endemic
+ Household or close contacts of children adopted from HA-endemic countries
+ Military personnel and humanitarian relief workers
+ People receiving repeated replacement of plasma-derived clotting factors
+ Workers involved in research on HA virus or production of HA vaccine who may be exposed to HA virus
+ Zoo-keepers, veterinarians and researchers who handle non-human primates
- Post-exposure prophylaxis should be offered to susceptible:
+ household and close contacts of people infected with HA
+ contacts in group child care centres and kindergartens
+ co-workers and clients of infected food handlers
How
- Primary immunization is achieved with 1 dose of monovalent HA vaccine with a booster dose given 6 to 36 months later, depending on the product.
- With few exceptions, people with indications for both HA and hepatitis B (HB) vaccine should be immunized with combined HAHB vaccine. Refer to in Part 4 for additional information about HAHB vaccine.
- HA vaccines may be administered concomitantly with other vaccines.
Why
- HA occurs worldwide and is one of the most common vaccine-preventable diseases in travellers.
- Recovery from HA infection may take months; about 25% of adult cases require hospitalization.
Epidemiology
# Disease description
## Infectious agent
Hepatitis A (HA) virus is single serotype, ribonucleic acid (RNA) virus of the *Picornaviridae- family.
For additional information about HA virus, refer to the .
## Reservoir
Humans, rarely chimpanzees and other non-human primates
## Transmission
HA is transmitted via the fecal-oral route, which can occur from direct person-to-person contact, from contamination of the environment or objects, or through contaminated food or water. Transmission through infected blood or blood products has also been reported. Symptoms appear after an incubation period of 15 to 50 days (average 28 days). Cases are typically infectious 2 weeks before the onset of symptoms and remain infectious until 1 week after the onset of jaundice. The virus may remain infectious in the environment for several weeks. Viral shedding can be greatly prolonged in immunocompromised individuals.
## Risk factors
Although many reported cases of HA have no identifiable risk factor, following individuals are considered to be at increased risk of HA infection:
- Travellers to HA-endemic countries. Studies estimate that 44% to 55% of reported HA cases in Canada are linked to travel. Low-budget travellers, volunteer humanitarian workers, and Canadian-born children of new Canadians returning to their country of origin to visit friends and relatives, may be at increased risk. The risk of HA for susceptible travellers to developing countries is estimated to range from 0.1/1,000 to 1/1,000 per month.
- Individuals living in communities at risk of HA outbreaks or in which HA is endemic.
- Household or close contacts of children adopted from HA-endemic countries.
- Men who have sex with men (MSM).
- Injectable and non-injectable illicit drug users.
- Workers involved in research on HA virus or production of HA vaccine who may be exposed to HA virus.
- Military personnel and humanitarian relief workers who are likely to be posted to areas with high rates of HA.
- Zoo-keepers, veterinarians and researchers who handle non-human primates.
- People receiving repeated replacement of plasma-derived clotting factors.
Many reported cases of HA have no identifiable risk factors.
People at increased risk of severe illness or complications from HA infection include:
- Individuals with chronic liver disease
- Individuals over 60 years of age
## Spectrum of clinical illness
The severity of HA increases with age and can range from asymptomatic or a short lasting and mild illness to a severely disabling disease lasting several months. Children less than 6 years of age are commonly asymptomatic or present with mild disease without jaundice, and represent an important source of infection, particularly for household members and other close contacts. In older children and adults, HA is typically symptomatic with the majority of individuals developing anorexia, nausea, fatigue, fever and jaundice, usually lasting less than two months. Older persons, and individuals with chronic liver disease and immunocompromising conditions, have an increased risk of progressing to fulminant hepatic failure resulting in death.
Approximately 25% of adult cases are hospitalized. The overall case fatality rate is approximately 0.5%, but can reach 2.6% in adults over 60 years of age. Individuals with chronic liver disease and immunocompromising conditions have an increased risk of progressing to fulminant hepatic failure resulting in death. Chronic hepatitis and carrier states are not associated with HA; however, relapsing hepatitis lasting up to a year occurs in 15% of cases.
# Disease distribution
## Incidence and prevalence
### Global
HA occurs worldwide. The World Health Organization (WHO) estimates an annual total of 1.5 million case of hepatitis A worldwide, but seroprevalence data suggest that tens of millions of infections occur each year. Regions with higher levels of HA endemicity and risk of transmission include: South Asia, Sub-Saharan Africa, Central Asia, Latin America, North Africa, Middle East, and Oceania. A is available from the WHO.
### National
Since the introduction of HA vaccine in Canada in 1996, the incidence of HA has declined. The number of cases of HA reported annually has varied from 2,978 (1991) to 246 (2012). From 2006 to 2012, age specific-incidence was highest among children 5 to 9 years old with a rate of 2.24 per 100,000, followed by children aged 1 to 4 years of age. Given the under-diagnosis and under-reporting of HA and the occurrence of subclinical infections, the actual number of HA cases is estimated to be 7 times higher than reported. From 2006 to 2010, the annual hospitalization rate for individuals over 40 years of age was 30%.
Preparations Authorized for Use in Canada
# Hepatitis A-containing vaccines
- AVAXIM® (adult formulation) and AVAXIM®- Pediatric (paediatric formulation) (inactivated hepatitis A vaccine), Sanofi Pasteur Limited. (HA)
- HAVRIX 1440 (adult formulation) and HAVRIX 720 Junior (paediatric formulation) (inactivated hepatitis A vaccine), GlaxoSmithKline Inc. (HA)
- TWINRIX (adult formulation) and TWINRIX Junior (paediatric formulation) (combined hepatitis A and hepatitis B in Part 4 for additional information about HAHB vaccine.
- VAQTA® (adult presentation) and VAQTA® (pediatric/adolescent presentation) (inactivated hepatitis A vaccine), Merck Canada Inc. (HA)
# Human immunoglobulin
- GamaSTAN® (immunoglobulin ), Grifols Therapeutics LLC. (Ig)
Standard human immunoglobulin (GamaSTAN®) is a sterile, concentrated solution for intramuscular (IM) injection containing 15% to 18% immunoglobulin. It is obtained from pooled human plasma from screened donors and contains mainly IgG with small amounts of IgA and IgM.
Preparations authorized for use in Canada may not be currently available for sale. Refer to Health Canada's (DPD) for its drug status. Definitions of drug status can be found under .
For complete prescribing information, consult the product leaflet or information contained within the product monograph available through Health Canada's .
Immunogenicity, Efficacy and Effectiveness
# Immunogenicity
Protective concentrations of antibody against HA develop in 95% to 100% of vaccine recipients after 1 dose of HA vaccine, and nearly 100% seroconvert after receiving 2 doses of vaccine.
## Pre-exposure
HA vaccine is recommended for pre-exposure immunization of persons 6 months of age and older at increased risk of infection or severe HA (refer to ). People who wish to decrease their risk of acquiring HA should also be encouraged to be vaccinated. With few exceptions, people with indications for both HA and hepatitis B (HB) vaccine should be immunized with combined HAHB vaccine. Refer to in Part 4 for information about HAHB vaccine.
## Post-exposure
The use of HA vaccine in susceptible populations interrupts HA outbreaks. The protective efficacy of HA vaccine when used within 1 week of exposure is approximately 80%.
Recommendations For Use
# Pre-exposure immunization
## HA-containing vaccine
HA vaccine is recommended for pre-exposure immunization of persons 6 months of age and older at increased risk of infection or severe HA (refer to ). People who wish to decrease their risk of acquiring HA should also be encouraged to be vaccinated. With few exceptions, people with indications for both HA and hepatitis B (HB) vaccine should be immunized with combined HAHB vaccine. Refer to in Part 4 for information about HAHB vaccine.
## Schedule
### Monovalent HA vaccine
One dose of monovalent HA vaccine should be given for primary immunization with a booster dose given at least 6 to 36 months later, depending on the product. .
There is no international standard for HA antigen measurement. Each manufacturer uses different units of measurement.
Ages for which the vaccine is recommended for use
ELISA: enzyme-linked immunosorbent assay
### HAHB vaccine
Once an HAHB vaccine series is started, it is preferable to complete the series with an HAHB vaccine. Monovalent HA vaccine may be used to complete a HA series started with HAHB vaccine. Refer to for options for completing a HA vaccine series. Refer to in Part 4 for additional information about HAHB vaccine.
Once an HAHB vaccine series is started, it is preferable to complete the series with an HAHB vaccine. HA vaccine may be given if HAHB vaccine is not available and only HA protection is needed.
In children, 8 to 10 years of age, a 2 dose schedule with paediatric HAHB vaccine given at months 0 and 6 has been tested with good results.
In children, 12 months to less than 16 years of age, 2 doses of adult HAHB vaccine is a recommended schedule. In children, 16 to less than 19 years of age, vaccine provider discretion is advised as there is no evidence or authorized schedule for this situation; an adult schedule of 3 doses should be considered.
Abbreviations:
HA: hepatitis A
HAHB: hepatitis A, hepatitis B
### Human immunoglobulin (pre-exposure prophylaxis)
HA vaccine is the preferred agent for pre-exposure prophylaxis. Human immunoglobulin (Ig) will provide protection against HA when administered intramuscularly before exposure and may be indicated for pre-exposure prophylaxis in the following groups:
- Infants less than 6 months of age
- Immunocompromised persons because their immune response to HA vaccine may be suboptimal. Ig should be considered in this group in addition to HA vaccine
- People for whom HA vaccine is contraindicated, i.e. individuals with a history of anaphylaxis after previous administration of the HA vaccine and those with proven immediate or anaphylactic hypersensitivity to any component of HA vaccine or its container
The effectiveness of Ig depends upon the timing of administration and the dose given. Administering Ig immediately before travel will ensure that protective concentrations of antibody are adequate for travel. The recommended dose of Ig varies according to the duration of required protection. The following doses of GamaSTAN® are recommended for persons who plan to travel in areas where hepatitis A is common:
- Up to 1 month: 0.1 mL/kg of body weight
- Up to 2 months: 0.2 mL/kg
- 2 months and longer: repeat dose of 0.2 mL/kg every 2 months
# Booster doses and re-immunization
Protective concentrations of HA antibody will likely persist for at least 20 years, possibly for life, following immunization with 2 doses of HA-containing vaccine. Immune memory has been demonstrated, indicating that protection may persist even when antibodies are no longer measurable.
# Post-exposure immunization
Post-exposure prophylaxis should be offered to household and close contacts of proven or suspected cases of HA. It should be given to contacts when HA occurs in group child care centres and kindergartens, and should be offered to co-workers and clients of infected food handlers. Post-exposure prophylaxis is not necessary for other contacts, such as school, workplace or health care workers caring for HA cases, unless an outbreak is suspected.
## HA vaccine
HA vaccine is effective as post-exposure prophylaxis to prevent infection in household and close contacts and is recommended in preference to Ig for healthy people 6 months of age and older, unless contraindicated or unavailable. One dose of HA vaccine should be given to susceptible contacts as soon as possible and preferably within 14 days of last exposure. However, HA vaccine should still be considered if more than 14 days have elapsed since last exposure, as there are no data on the outer limit of efficacy.
Immunocompromised people and people with chronic liver disease should receive Ig in addition to HA vaccine. Susceptible adults, 60 years of age and older, may be given Ig in addition to HA vaccine.
## Human immunoglobulin (post-exposure prophylaxis)
Hepatitis A (HA) vaccine is the preferred agent for post-exposure prophylaxis. Ig is the recommended post-exposure immunoprophylactic agent in the following situations:
- for infants less than 6 months of age
- for persons with a history of anaphylaxis after previous administration of the HA vaccine and those with proven immediate or anaphylactic hypersensitivity to any component of the HA vaccine or its container
- for immunocompromised persons and people with chronic liver disease:
+ these individuals should receive Ig in addition to HA vaccine because of increased risk of severe disease and a suboptimal immune response to HA vaccine
- susceptible adults, 60 years of age and older who are household or close contacts of a case of HA, may be given Ig in addition to HA vaccine because of the reduced response to HA vaccine and increased risk of severe disease with increasing age
- if HA vaccine is unavailable
For post-exposure prophylaxis, the recommended dose of GamaSTAN® is 0.1 mL/kg of body weight. Ig should be given as soon as possible after an exposure. Efficacy of Ig is unknown if more than 14 days have elapsed since the last exposure, there is no recommendation for its use after this time period. Individuals receiving replacement intravenous Ig (IVIg, 400 mg/kg of body weight or higher) are considered protected and do not require Ig if the last dose of IVIg was received within the 3 weeks prior to HA exposure.
Vaccination of Specific Populations
# Persons with inadequate immunization records
Children and adults lacking adequate documentation of immunization should be considered unimmunized and started on an immunization schedule appropriate for their age and risk factors. HA vaccine may be given, if indicated, regardless of possible previous receipt of the vaccine or pre-existing immunity, because adverse events associated with repeated immunization have not been demonstrated.
# Pregnancy and breastfeeding
The efficacy and safety of HA vaccines given during pregnancy has not been studied, but there is no theoretical reason to suspect an increased risk of adverse events to the mother or the infant. HA vaccine should be considered for pregnant women in high risk situations when benefits outweigh risks, such as for post-exposure prophylaxis or travel to HA-endemic areas. HA vaccine may be administered, if indicated, to women who are breastfeeding.
# Persons with chronic diseases
## Chronic renal disease and patients on dialysis
HA vaccine is recommended for people with chronic renal disease or undergoing dialysis if they are at increased risk of HA infection or severe HA (refer to ). A study assessing the immune response of hemodialysis patients to standard doses of HA vaccine demonstrated a good HA antibody response and no serious adverse effects.
## Chronic liver disease
HA immunization is recommended for susceptible persons with chronic liver disease, including those infected with hepatitis C and chronic HB carriers, because they are at risk of more severe disease if infection occurs. Vaccination should be completed early in the course of the disease, as the immune response to vaccine is suboptimal in advanced liver disease.
## Non-malignant hematologic disorders
HA immunization is recommended for people receiving repeated replacement of plasma-derived clotting factors. The solvent-detergent method used to prepare plasma-derived clotting factor concentrates from pooled plasma may not reliably inactivate HA virus. However, historically, there has been no evidence of HA transmission from clotting factors in Canada and the risk of transfusion-related HA is extremely low because all pooled plasma is tested for HA. Due to a theoretical possibility of infection, HA immunization of individuals receiving large quantities of plasma-derived products used in the treatment of conditions requiring clotting factor substitution may be considered.
# Immunocompromised persons
HA vaccine may be administered to immunocompromised persons. Vaccine efficacy may be reduced in immunocompromised people; however, HA vaccine will provide some protection and should be considered for pre-exposure and post-exposure use when indicated. In addition to HA vaccine, Ig should be considered for pre-exposure and post-exposure management of immunocompromised persons unless receiving routine Ig replacement therapy. Serologic testing to determine immune status may be considered in immunocompromised people when considering the use of Ig prior to potential exposure (for example, travel to HA-endemic areas).
When considering immunization of an immunocompromised person, consultation with the individual's attending physician may be of assistance. For complex cases, referral to a physician with expertise in immunization or immunodeficiency is advised.
# Travellers
Hepatitis A is one of the most common vaccine-preventable diseases in travellers. Protection against HA is recommended for all travellers to HA-endemic countries, especially to rural areas or places with inadequate sanitary facilities. A is available from the WHO.
Given the long incubation period for HA and the demonstrated efficacy of post-exposure use of HA vaccine, HA vaccine may be administered up to the day of departure. Ig may be used for prophylaxis in people for whom HA vaccine is contraindicated or in people for whom HA vaccine may have reduced effectiveness, such as those who are immunocompromised. Refer to .
For travellers who are susceptible to both HA and HB virus, HAHB vaccine can be used, if appropriate. For travellers presenting less than 21 days before departure, monovalent HA and HB vaccines should be administered separately, with the completion of both vaccine series required after travel. Refer to .
Serologic testing may be considered in travellers likely to be already immune. Refer to . Refer to in Part 3 for additional information.
# Persons new to Canada
Health care providers who see persons newly arrived in Canada should review the immunization status and update immunization for these individuals, as necessary. In many countries outside of Canada, HA vaccine is in limited use.
HA vaccination should be considered for all persons from HA-endemic countries. Individuals born in HA-endemic countries are more likely to be immune to HA; therefore, serologic testing for immunity before HA immunization should be considered. If persons from HA-endemic countries are not immune, they should be offered HA immunization because they are at increased risk for HA exposure through visits to their country of origin, or when receiving friends and family from their country of origin.
In addition, persons new to Canada should be tested for hepatitis C antibody and susceptible persons chronically infected with hepatitis C should be vaccinated against HA and HB. Persons new to Canada should also be tested for HB and vaccinated against HA if found to be a HB carrier. Household or close contacts of children adopted from HA-endemic countries should be immunized with HA-containing vaccine. Adults travelling to pick up adopted children from HA-endemic countries should be vaccinated before departure.
# Workers
Pre-exposure HA vaccination is recommended for:
- Military personnel and humanitarian relief workers likely to be posted abroad to areas with high rates of HA
- Zoo-keepers, veterinarians and researchers who handle non-human primates
- Workers involved in research on HA virus or production of HA vaccine who may be exposed to HA virus
Serologic Testing
# Pre-immunization
Pre-immunization serologic testing should be considered in populations with potentially higher levels of pre-existing immunity, such as Canadians born before 1945, people from HA-endemic areas, and people with a history of hepatitis or jaundice that may have been caused by HA.
# Post-immunization
Serologic testing is not recommended after receiving HA-containing vaccine. Post-HA vaccine serologic testing has poor sensitivity. If the serologic test result is positive after immunization, the person can be presumed to be immune; however, a negative test result does not mean that the person is susceptible.
Administration Practices
# Dose
For the dosage of human immunoglobulin for post-exposure prophylaxis, refer to .
# Route of administration
HA-containing vaccine should be administered intramuscularly.
Large volumes of immunoglobulin for IM injection (greater than 2 mL for children or greater than 3 to 5 mL for adults, depending on muscle mass) should be divided and injected at 2 or more sites.
# Interchangeability of vaccines
Monovalent HA vaccines may be used interchangeably. Any HA-containing vaccine indicated for the age of the vaccine recipient will provide an effective booster dose after a first dose of vaccine from a different manufacturer.
# Concurrent administration of vaccines
HA vaccine may be administered concomitantly with other vaccines or with Ig. Different injection sites and separate needles and syringes must be used for concurrent parenteral injections.
If concurrently providing HA-containing vaccine and Ig, separate anatomic injection sites (different limbs) should be used for each injection.
Passive immunization with human Ig preparations can interfere with the immune response to measles-mumps-rubella (MMR), measles-mumps-rubella-varicella (MMRV) and univalent varicella vaccines (Var). These vaccines should be given at least 14 days prior to administration of a human Ig preparation, or delayed until the antibodies in the Ig preparation have degraded. Refer to in Part 1 for additional information.
Storage Requirements
Human Ig preparations should be stored at +2°C to +8°C. Do not freeze.
Safety and Adverse Events
# Common and local adverse events
## HA vaccine
HA vaccine is well tolerated. Reactions are generally mild and transient, and are usually limited to soreness and redness at the injection site. Other less frequent reactions include headache, irritability, malaise, fever, fatigue and gastrointestinal symptoms. Injection site reactions occur less frequently in children (21%) than in adults (56%) as do mild, systemic events (2% to 9% versus 16%). No significant difference in reactions is evident between initial and subsequent doses of vaccine or in the presence of pre-existing immunity.
## HAHB vaccine
## Ig
Injection site reactions following receipt of standard human Ig include tenderness, erythema and stiffness of local muscles, which may persist for several hours. Mild fever or malaise may occasionally occur.
# Less common and serious or severe adverse events
Less common side effects following receipt of standard human Ig include flushing, headache, chills and nausea. Urticaria, angioedema and anaphylactic reactions may occur rarely.
# Guidance on reporting Adverse Events Following Immunization (AEFI)
Vaccine providers are asked to report, through local public health officials, any serious or unexpected adverse event temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.
# Contraindications and precautions
HA-containing vaccines and Ig are contraindicated in persons with a history of anaphylaxis after previous administration of the product and in persons with proven immediate or anaphylactic hypersensitivity to any component of the product. Human Ig preparations should not be given to people with known isolated IgA deficiency unless the benefit outweighs the risk, in which case the product should be given with caution and under close observation. Refer to in Part 1 for lists of vaccines and passive immunizing agents authorized for use in Canada and their contents. Refer to in Part 4 for information about HAHB vaccine.
The efficacy and safety of HA vaccine given during pregnancy has not been studied in clinical trials, but there is no theoretical reason to suspect an increased risk of adverse events to the mother or the infant.
Administration of HA-containing vaccine should be postponed in persons with moderate or severe acute illness. Persons with minor acute illness, with or without fever, may be vaccinated. |
Hepatitis A vaccine: Canadian Immunization Guide
=================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-5-haemophilus-influenzae-type-b-vaccine.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html)
**Last partial chapter update** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): November 2021
**November 2021**: The immunoglobulin dosage for Hepatitis A pre-exposure and post-exposure prophylaxis was increased based on the Product Monograph update for GamaSTAN®, which is available on Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
**Last complete chapter revision (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html#t2018)): March 2018**
**Last complete chapter revision:** March 2018
On this page
------------
* [Key Information](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5a1)
* [Epidemiology](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5a2)
* [Preparations Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5a3)
* [Immunogenicity, Efficacy and Effectiveness](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5a4)
* [Recommendations for Use](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5a5)
+ [Pre-exposure immunization](#preexpIg)
- [Table 1: Dosages and Schedules for Hepatitis A-containing Vaccines](#p4c5t1)
- [Table 2: Options for Completing Hepatitis A Vaccination Series in Adults, Children and Adolescents](#p4c5t2)
* [Vaccination of Specific Populations](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5a6)
* [Serologic Testing](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5a7)
* [Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5a8)
* [Storage Requirements](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5a9)
* [Safety and Adverse Events](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5a10)
* [Selected References](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5a11)
Key Information
---------------
What
* Hepatitis A (HA) infection usually causes clinical hepatitis in adults and older children; it often causes a febrile illness without jaundice or is asymptomatic in younger children.
* Pre-exposure HA immunization is at least 90% to 97% effective.
* Reactions to HA vaccine are generally mild and transient and include soreness and redness at the injection site.
Who
* Pre-exposure HA immunization is recommended for people at increased risk of infection or severe HA including:
+ Travellers to HA-endemic countries
+ Individuals with chronic liver disease
+ Men who have sex with men (MSM)
+ Injectable and non-injectable illicit drug users
+ Individuals living in communities at risk of HA outbreaks or in which HA is endemic
+ Household or close contacts of children adopted from HA-endemic countries
+ Military personnel and humanitarian relief workers
+ People receiving repeated replacement of plasma-derived clotting factors
+ Workers involved in research on HA virus or production of HA vaccine who may be exposed to HA virus
+ Zoo-keepers, veterinarians and researchers who handle non-human primates
* Post-exposure prophylaxis should be offered to susceptible:
+ household and close contacts of people infected with HA
+ contacts in group child care centres and kindergartens
+ co-workers and clients of infected food handlers
How
* Primary immunization is achieved with 1 dose of monovalent HA vaccine with a booster dose given 6 to 36 months later, depending on the product.
* With few exceptions, people with indications for both HA and hepatitis B (HB) vaccine should be immunized with combined HAHB vaccine. Refer to [Hepatitis B Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for additional information about HAHB vaccine.
* HA vaccines may be administered concomitantly with other vaccines.
Why
* HA occurs worldwide and is one of the most common vaccine-preventable diseases in travellers.
* Recovery from HA infection may take months; about 25% of adult cases require hospitalization.
Epidemiology
------------
### Disease description
#### Infectious agent
Hepatitis A (HA) virus is single serotype, ribonucleic acid (RNA) virus of the *Picornaviridae* family.
For additional information about HA virus, refer to the [Pathogen Safety Data Sheet](/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/hepatitis-a-virus.html).
#### Reservoir
Humans, rarely chimpanzees and other non-human primates
#### Transmission
HA is transmitted via the fecal-oral route, which can occur from direct person-to-person contact, from contamination of the environment or objects, or through contaminated food or water. Transmission through infected blood or blood products has also been reported. Symptoms appear after an incubation period of 15 to 50 days (average 28 days). Cases are typically infectious 2 weeks before the onset of symptoms and remain infectious until 1 week after the onset of jaundice. The virus may remain infectious in the environment for several weeks. Viral shedding can be greatly prolonged in immunocompromised individuals.
#### Risk factors
Although many reported cases of HA have no identifiable risk factor, following individuals are considered to be at increased risk of HA infection:
* Travellers to HA-endemic countries. Studies estimate that 44% to 55% of reported HA cases in Canada are linked to travel. Low-budget travellers, volunteer humanitarian workers, and Canadian-born children of new Canadians returning to their country of origin to visit friends and relatives, may be at increased risk. The risk of HA for susceptible travellers to developing countries is estimated to range from 0.1/1,000 to 1/1,000 per month.
* Individuals living in communities at risk of HA outbreaks or in which HA is endemic.
* Household or close contacts of children adopted from HA-endemic countries.
* Men who have sex with men (MSM).
* Injectable and non-injectable illicit drug users.
* Workers involved in research on HA virus or production of HA vaccine who may be exposed to HA virus.
* Military personnel and humanitarian relief workers who are likely to be posted to areas with high rates of HA.
* Zoo-keepers, veterinarians and researchers who handle non-human primates.
* People receiving repeated replacement of plasma-derived clotting factors.
Many reported cases of HA have no identifiable risk factors.
People at increased risk of severe illness or complications from HA infection include:
* Individuals with chronic liver disease
* Individuals over 60 years of age
#### Spectrum of clinical illness
The severity of HA increases with age and can range from asymptomatic or a short lasting and mild illness to a severely disabling disease lasting several months. Children less than 6 years of age are commonly asymptomatic or present with mild disease without jaundice, and represent an important source of infection, particularly for household members and other close contacts. In older children and adults, HA is typically symptomatic with the majority of individuals developing anorexia, nausea, fatigue, fever and jaundice, usually lasting less than two months. Older persons, and individuals with chronic liver disease and immunocompromising conditions, have an increased risk of progressing to fulminant hepatic failure resulting in death.
Approximately 25% of adult cases are hospitalized. The overall case fatality rate is approximately 0.5%, but can reach 2.6% in adults over 60 years of age. Individuals with chronic liver disease and immunocompromising conditions have an increased risk of progressing to fulminant hepatic failure resulting in death. Chronic hepatitis and carrier states are not associated with HA; however, relapsing hepatitis lasting up to a year occurs in 15% of cases.
### Disease distribution
#### Incidence and prevalence
##### Global
HA occurs worldwide. The World Health Organization (WHO) estimates an annual total of 1.5 million case of hepatitis A worldwide, but seroprevalence data suggest that tens of millions of infections occur each year. Regions with higher levels of HA endemicity and risk of transmission include: South Asia, Sub-Saharan Africa, Central Asia, Latin America, North Africa, Middle East, and Oceania. A [map of countries and areas of risk for HA](http://gamapserver.who.int/mapLibrary/Files/Maps/Global_HepA_ITHRiskMap.png) is available from the WHO.
##### National
Since the introduction of HA vaccine in Canada in 1996, the incidence of HA has declined. The number of cases of HA reported annually has varied from 2,978 (1991) to 246 (2012). From 2006 to 2012, age specific-incidence was highest among children 5 to 9 years old with a rate of 2.24 per 100,000, followed by children aged 1 to 4 years of age. Given the under-diagnosis and under-reporting of HA and the occurrence of subclinical infections, the actual number of HA cases is estimated to be 7 times higher than reported. From 2006 to 2010, the annual hospitalization rate for individuals over 40 years of age was 30%.
Preparations Authorized for Use in Canada
-----------------------------------------
### Hepatitis A-containing vaccines
* **AVAXIM®** (adult formulation) and **AVAXIM®- Pediatric** (paediatric formulation) (inactivated hepatitis A vaccine), Sanofi Pasteur Limited. (HA)
* **HAVRIX 1440** (adult formulation) and **HAVRIX 720 Junior** (paediatric formulation) (inactivated hepatitis A vaccine), GlaxoSmithKline Inc. (HA)
* **TWINRIX** (adult formulation) and **TWINRIX Junior** (paediatric formulation) (combined hepatitis A and hepatitis B [HB] vaccine), GlaxoSmithKline Inc. (HAHB) Refer to [Hepatitis B Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for additional information about HAHB vaccine.
* **VAQTA®** (adult presentation) and **VAQTA®** (pediatric/adolescent presentation) (inactivated hepatitis A vaccine), Merck Canada Inc. (HA)
### Human immunoglobulin
* **GamaSTAN®** (immunoglobulin [human]), Grifols Therapeutics LLC. (Ig)
Standard human immunoglobulin (GamaSTAN®) is a sterile, concentrated solution for intramuscular (IM) injection containing 15% to 18% immunoglobulin. It is obtained from pooled human plasma from screened donors and contains mainly IgG with small amounts of IgA and IgM.
Preparations authorized for use in Canada may not be currently available for sale. Refer to Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html) (DPD) for its drug status. Definitions of drug status can be found under [DPD Terminology](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/terminology.html).
For complete prescribing information, consult the product leaflet or information contained within the product monograph available through Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
Refer to [Contents in Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for lists of vaccines and passive immunizing agents available for use in Canada and their contents.
Immunogenicity, Efficacy and Effectiveness
------------------------------------------
### Immunogenicity
Protective concentrations of antibody against HA develop in 95% to 100% of vaccine recipients after 1 dose of HA vaccine, and nearly 100% seroconvert after receiving 2 doses of vaccine.
#### Pre-exposure
HA vaccine is recommended for pre-exposure immunization of persons 6 months of age and older at increased risk of infection or severe HA (refer to [Risk factors](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#rf)). People who wish to decrease their risk of acquiring HA should also be encouraged to be vaccinated. With few exceptions, people with indications for both HA and hepatitis B (HB) vaccine should be immunized with combined HAHB vaccine. Refer to [Hepatitis B Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for information about HAHB vaccine.
#### Post-exposure
The use of HA vaccine in susceptible populations interrupts HA outbreaks. The protective efficacy of HA vaccine when used within 1 week of exposure is approximately 80%.
Recommendations For Use
-----------------------
### Pre-exposure immunization
#### HA-containing vaccine
HA vaccine is recommended for pre-exposure immunization of persons 6 months of age and older at increased risk of infection or severe HA (refer to [Risk factors](#rf)). People who wish to decrease their risk of acquiring HA should also be encouraged to be vaccinated. With few exceptions, people with indications for both HA and hepatitis B (HB) vaccine should be immunized with combined HAHB vaccine. Refer to [Hepatitis B Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for information about HAHB vaccine.
#### Schedule
##### Monovalent HA vaccine
One dose of monovalent HA vaccine should be given for primary immunization with a booster dose given at least 6 to 36 months later, depending on the product. [Refer to Table 1](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5t1).
Table 1: Dosages and Schedules for Hepatitis A-containing Vaccines
| Vaccine | Antigen(s)[Table 1 - Footnote 1](#p4c5t1fn1) | Dose | Schedule
(Months: 1st dose = month 0) | Age[Table 1 - Footnote 2](#p4c5t1fn2) |
| --- | --- | --- | --- | --- |
| AVAXIM® | 160 antigen units HA | 0.5 mL | 0, 6 to 36 | 12 years and older |
| AVAXIM®Pediatric | 80 antigen units HA | 0.5 mL | 0, 6 to 36 | 6 months to less than 16 years |
| HAVRIX 1440 | 1440 ELISA units HA | 1.0 mL | 0, 6 to 12 | 19 years and older |
| HAVRIX 720 Junior | 720 ELISA units HA | 0.5 mL | 0, 6 to 12 | 6 months to less than 19 years |
| VAQTA® (adult presentation) | 50 units HA | 1.0 mL | 0, 6 to 18 | 18 years and older |
| VAQTA® (pediatric/adolescent presentation) | 25 units HA | 0.5 mL | 0, 6 to 18 | 6 months to less than 18 years |
|
Table 1 - Footnote 1
There is no international standard for HA antigen measurement. Each manufacturer uses different units of measurement.
[Return to footnote 1 referrer](#p4c5t1fn1-rf)
Table 1 - Footnote 2
Ages for which the vaccine is recommended for use
[Return to footnote 2 referrer](#p4c5t1fn2-rf)
**Table 1 - Abbreviations**
ELISA: enzyme-linked immunosorbent assay
HA: hepatitis A |
##### HAHB vaccine
Once an HAHB vaccine series is started, it is preferable to complete the series with an HAHB vaccine. Monovalent HA vaccine may be used to complete a HA series started with HAHB vaccine. Refer to [Table 2](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5t2) for options for completing a HA vaccine series. Refer to [Hepatitis B Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for additional information about HAHB vaccine.
Table 2: Options for Completing Hepatitis A Vaccination Series in Adults, Children and Adolescents
| Adult presents with history of: | Options to complete HA series |
| --- | --- |
| 1 dose adult HAHB vaccine | 2 doses adult HAHB vaccine OR
2 doses adult HA vaccine[Table 2 - Footnote 1](#p4c5t2fn1),[Table 2 - Footnote 2](#p4c5t2fn2) |
| 2 doses adult HAHB vaccine | 1 dose adult HAHB vaccine OR
1 dose adult HA vaccine[Table 2 - Footnote 1](#p4c5t2fn1),[Table 2 - Footnote 2](#p4c5t2fn2) |
| 1 dose adult HA vaccine | 1 dose adult HA vaccine OR
2 doses adult HAHB vaccine[Table 2 - Footnote 1](#p4c5t2fn1) |
| Child or adolescent[Table 2 - Footnote 3](#p4c5t2fn3) presents with history of: | Options to complete HA series |
| --- | --- |
| 1 dose paediatric HAHB vaccine | 2 doses paediatric HAHB vaccine[Table 2 - Footnote 4](#p4c5t2fn4) OR
2 doses paediatric HA vaccine[Table 2 - Footnote 1](#p4c5t2fn1),[Table 2 - Footnote 2](#p4c5t2fn2) |
| 1 dose adult HAHB vaccine | 1 dose adult HAHB vaccine unless 16 years or older[Table 2 - Footnote 5](#p4c5t2fn5) OR
1 dose paediatric HA vaccine[Table 2 - Footnote 1](#p4c5t2fn1),[Table 2 - Footnote 2](#p4c5t2fn2) |
| 2 doses paediatric HAHB vaccine | 1 dose paediatric HAHB vaccine[Table 2 - Footnote 4](#p4c5t2fn4) OR
1 dose paediatric HA vaccine[Table 2 - Footnote 1](#p4c5t2fn1),[Table 2 - Footnote 2](#p4c5t2fn2) |
| 2 doses adult HAHB vaccine | No additional doses needed unless 16 years of age or older[Table 2 - Footnote 5](#p4c5t2fn5) |
| 1 dose paediatric HA vaccine | 1 dose paediatric HA vaccine |
|
Table 2 - Footnote \*1
Refer to [Hepatitis B Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for details of HB vaccine schedules. For adults and children (except children, 11 to less than 16 years of age), 3 doses of HB vaccine are required for HB protection.
[Return to footnote 1 referrer](#p4c5t2fn1-rf)
Table 2 - Footnote \*2
Once an HAHB vaccine series is started, it is preferable to complete the series with an HAHB vaccine. HA vaccine may be given if HAHB vaccine is not available and only HA protection is needed.
[Return to footnote 2 referrer](#p4c5t2fn2-rf)
Table 2 - Footnote \*3
Refer to [Table 1](#p4c5t1) for schedule and age recommendations for each product.
[Return to footnote 3 referrer](#p4c5t2fn3-rf)
Table 2 - Footnote \*4
In children, 8 to 10 years of age, a 2 dose schedule with paediatric HAHB vaccine given at months 0 and 6 has been tested with good results.
[Return to footnote 4 referrer](#p4c5t2fn4-rf)
Table 2 - Footnote \*5
In children, 12 months to less than 16 years of age, 2 doses of adult HAHB vaccine is a recommended schedule. In children, 16 to less than 19 years of age, vaccine provider discretion is advised as there is no evidence or authorized schedule for this situation; an adult schedule of 3 doses should be considered.
[Return to footnote 5 referrer](#p4c5t2fn5-rf)
**Abbreviations:**
HA: hepatitis A
HAHB: hepatitis A, hepatitis B
HB: hepatitis B |
##### Human immunoglobulin (pre-exposure prophylaxis)
HA vaccine is the preferred agent for pre-exposure prophylaxis. Human immunoglobulin (Ig) will provide protection against HA when administered intramuscularly before exposure and may be indicated for pre-exposure prophylaxis in the following groups:
* Infants less than 6 months of age
* Immunocompromised persons because their immune response to HA vaccine may be suboptimal. Ig should be considered in this group in addition to HA vaccine
* People for whom HA vaccine is contraindicated, i.e. individuals with a history of anaphylaxis after previous administration of the HA vaccine and those with proven immediate or anaphylactic hypersensitivity to any component of HA vaccine or its container
The effectiveness of Ig depends upon the timing of administration and the dose given. Administering Ig immediately before travel will ensure that protective concentrations of antibody are adequate for travel. The recommended dose of Ig varies according to the duration of required protection. The following doses of GamaSTAN® are recommended for persons who plan to travel in areas where hepatitis A is common:
* Up to 1 month: 0.1 mL/kg of body weight
* Up to 2 months: 0.2 mL/kg
* 2 months and longer: repeat dose of 0.2 mL/kg every 2 months
Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional information about the use of Ig for pre-exposure prophylaxis in individuals with specific immunocompromising conditions.
Refer to additional information contained within the product monograph available through Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
### Booster doses and re-immunization
Protective concentrations of HA antibody will likely persist for at least 20 years, possibly for life, following immunization with 2 doses of HA-containing vaccine. Immune memory has been demonstrated, indicating that protection may persist even when antibodies are no longer measurable.
### Post-exposure immunization
Post-exposure prophylaxis should be offered to household and close contacts of proven or suspected cases of HA. It should be given to contacts when HA occurs in group child care centres and kindergartens, and should be offered to co-workers and clients of infected food handlers. Post-exposure prophylaxis is not necessary for other contacts, such as school, workplace or health care workers caring for HA cases, unless an outbreak is suspected.
#### HA vaccine
HA vaccine is effective as post-exposure prophylaxis to prevent infection in household and close contacts and is recommended in preference to Ig for healthy people 6 months of age and older, unless contraindicated or unavailable. One dose of HA vaccine should be given to susceptible contacts as soon as possible and preferably within 14 days of last exposure. However, HA vaccine should still be considered if more than 14 days have elapsed since last exposure, as there are no data on the outer limit of efficacy.
Immunocompromised people and people with chronic liver disease should receive Ig in addition to HA vaccine. Susceptible adults, 60 years of age and older, may be given Ig in addition to HA vaccine.
#### Human immunoglobulin (post-exposure prophylaxis)
Hepatitis A (HA) vaccine is the preferred agent for post-exposure prophylaxis. Ig is the recommended post-exposure immunoprophylactic agent in the following situations:
* for infants less than 6 months of age
* for persons with a history of anaphylaxis after previous administration of the HA vaccine and those with proven immediate or anaphylactic hypersensitivity to any component of the HA vaccine or its container
* for immunocompromised persons and people with chronic liver disease:
+ these individuals should receive Ig in addition to HA vaccine because of increased risk of severe disease and a suboptimal immune response to HA vaccine
* susceptible adults, 60 years of age and older who are household or close contacts of a case of HA, may be given Ig in addition to HA vaccine because of the reduced response to HA vaccine and increased risk of severe disease with increasing age
* if HA vaccine is unavailable
For post-exposure prophylaxis, the recommended dose of GamaSTAN® is 0.1 mL/kg of body weight. Ig should be given as soon as possible after an exposure. Efficacy of Ig is unknown if more than 14 days have elapsed since the last exposure, there is no recommendation for its use after this time period. Individuals receiving replacement intravenous Ig (IVIg, 400 mg/kg of body weight or higher) are considered protected and do not require Ig if the last dose of IVIg was received within the 3 weeks prior to HA exposure.
Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional information about the use of Ig for post-exposure prophylaxis in individuals with specific immunocompromising conditions.
Refer to additional information contained within the product monograph available through Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
Vaccination of Specific Populations
-----------------------------------
### Persons with inadequate immunization records
Children and adults lacking adequate documentation of immunization should be considered unimmunized and started on an immunization schedule appropriate for their age and risk factors. HA vaccine may be given, if indicated, regardless of possible previous receipt of the vaccine or pre-existing immunity, because adverse events associated with repeated immunization have not been demonstrated.
Refer to [Immunization of Persons with Inadequate Immunization Records](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-3-immunization-persons-inadequate-immunization-records.html) in Part 3 for additional information about vaccination of people with inadequate immunization records.
### Pregnancy and breastfeeding
The efficacy and safety of HA vaccines given during pregnancy has not been studied, but there is no theoretical reason to suspect an increased risk of adverse events to the mother or the infant. HA vaccine should be considered for pregnant women in high risk situations when benefits outweigh risks, such as for post-exposure prophylaxis or travel to HA-endemic areas. HA vaccine may be administered, if indicated, to women who are breastfeeding.
Refer to [Hepatitis B Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for information about HAHB vaccine. Refer to [Immunization in Pregnancy and Breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3 for additional information about HA vaccination of women who are pregnant or breastfeeding.
### Persons with chronic diseases
Refer to [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional general information about vaccination of people with chronic diseases.
#### Chronic renal disease and patients on dialysis
HA vaccine is recommended for people with chronic renal disease or undergoing dialysis if they are at increased risk of HA infection or severe HA (refer to [Risk factors](#rf)). A study assessing the immune response of hemodialysis patients to standard doses of HA vaccine demonstrated a good HA antibody response and no serious adverse effects.
#### Chronic liver disease
HA immunization is recommended for susceptible persons with chronic liver disease, including those infected with hepatitis C and chronic HB carriers, because they are at risk of more severe disease if infection occurs. Vaccination should be completed early in the course of the disease, as the immune response to vaccine is suboptimal in advanced liver disease.
#### Non-malignant hematologic disorders
HA immunization is recommended for people receiving repeated replacement of plasma-derived clotting factors. The solvent-detergent method used to prepare plasma-derived clotting factor concentrates from pooled plasma may not reliably inactivate HA virus. However, historically, there has been no evidence of HA transmission from clotting factors in Canada and the risk of transfusion-related HA is extremely low because all pooled plasma is tested for HA. Due to a theoretical possibility of infection, HA immunization of individuals receiving large quantities of plasma-derived products used in the treatment of conditions requiring clotting factor substitution may be considered.
### Immunocompromised persons
HA vaccine may be administered to immunocompromised persons. Vaccine efficacy may be reduced in immunocompromised people; however, HA vaccine will provide some protection and should be considered for pre-exposure and post-exposure use when indicated. In addition to HA vaccine, Ig should be considered for pre-exposure and post-exposure management of immunocompromised persons unless receiving routine Ig replacement therapy. Serologic testing to determine immune status may be considered in immunocompromised people when considering the use of Ig prior to potential exposure (for example, travel to HA-endemic areas).
When considering immunization of an immunocompromised person, consultation with the individual's attending physician may be of assistance. For complex cases, referral to a physician with expertise in immunization or immunodeficiency is advised.
Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional information about vaccination of people who are immunocompromised.
### Travellers
Hepatitis A is one of the most common vaccine-preventable diseases in travellers. Protection against HA is recommended for all travellers to HA-endemic countries, especially to rural areas or places with inadequate sanitary facilities. A [map of countries and areas of risk for HA](http://gamapserver.who.int/mapLibrary/Files/Maps/Global_HepA_ITHRiskMap.png) is available from the WHO.
Given the long incubation period for HA and the demonstrated efficacy of post-exposure use of HA vaccine, HA vaccine may be administered up to the day of departure. Ig may be used for prophylaxis in people for whom HA vaccine is contraindicated or in people for whom HA vaccine may have reduced effectiveness, such as those who are immunocompromised. Refer to [Pre-exposure immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#preexpIg).
For travellers who are susceptible to both HA and HB virus, HAHB vaccine can be used, if appropriate. For travellers presenting less than 21 days before departure, monovalent HA and HB vaccines should be administered separately, with the completion of both vaccine series required after travel. Refer to [Table 1](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5t1).
Serologic testing may be considered in travellers likely to be already immune. Refer to [Serologic Testing](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5a7). Refer to [Immunization of Travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) in Part 3 for additional information.
### Persons new to Canada
Health care providers who see persons newly arrived in Canada should review the immunization status and update immunization for these individuals, as necessary. In many countries outside of Canada, HA vaccine is in limited use.
HA vaccination should be considered for all persons from HA-endemic countries. Individuals born in HA-endemic countries are more likely to be immune to HA; therefore, serologic testing for immunity before HA immunization should be considered. If persons from HA-endemic countries are not immune, they should be offered HA immunization because they are at increased risk for HA exposure through visits to their country of origin, or when receiving friends and family from their country of origin.
In addition, persons new to Canada should be tested for hepatitis C antibody and susceptible persons chronically infected with hepatitis C should be vaccinated against HA and HB. Persons new to Canada should also be tested for HB and vaccinated against HA if found to be a HB carrier. Household or close contacts of children adopted from HA-endemic countries should be immunized with HA-containing vaccine. Adults travelling to pick up adopted children from HA-endemic countries should be vaccinated before departure.
Refer to [Immunization of Persons New to Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-10-immunization-persons-new-canada.html) in Part 3 for additional information about vaccination of people who are new to Canada.
### Workers
Pre-exposure HA vaccination is recommended for:
* Military personnel and humanitarian relief workers likely to be posted abroad to areas with high rates of HA
* Zoo-keepers, veterinarians and researchers who handle non-human primates
* Workers involved in research on HA virus or production of HA vaccine who may be exposed to HA virus
Refer to [Immunization of Workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html) in Part 3 for additional information about vaccination of workers.
Serologic Testing
-----------------
### Pre-immunization
Pre-immunization serologic testing should be considered in populations with potentially higher levels of pre-existing immunity, such as Canadians born before 1945, people from HA-endemic areas, and people with a history of hepatitis or jaundice that may have been caused by HA.
### Post-immunization
Serologic testing is not recommended after receiving HA-containing vaccine. Post-HA vaccine serologic testing has poor sensitivity. If the serologic test result is positive after immunization, the person can be presumed to be immune; however, a negative test result does not mean that the person is susceptible.
Administration Practices
------------------------
### Dose
Refer to [Table 1](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#p4c5t1) for vaccine-specific dosage recommendations.
For the dosage of human immunoglobulin for post-exposure prophylaxis, refer to [Human immunoglobulin (post-exposure prophylaxis)](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html#pop).
### Route of administration
HA-containing vaccine should be administered intramuscularly.
Large volumes of immunoglobulin for IM injection (greater than 2 mL for children or greater than 3 to 5 mL for adults, depending on muscle mass) should be divided and injected at 2 or more sites.
Refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for additional information about pre-vaccination and post-vaccination counselling, vaccine preparation and administration technique, and infection prevention and control.
### Interchangeability of vaccines
Monovalent HA vaccines may be used interchangeably. Any HA-containing vaccine indicated for the age of the vaccine recipient will provide an effective booster dose after a first dose of vaccine from a different manufacturer.
Refer to [Principles of Vaccine Interchangeability](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-7-principles-vaccine-interchangeability.html) in Part 1 for additional information about interchangeability of vaccines.
### Concurrent administration of vaccines
HA vaccine may be administered concomitantly with other vaccines or with Ig. Different injection sites and separate needles and syringes must be used for concurrent parenteral injections.
If concurrently providing HA-containing vaccine and Ig, separate anatomic injection sites (different limbs) should be used for each injection.
Passive immunization with human Ig preparations can interfere with the immune response to measles-mumps-rubella (MMR), measles-mumps-rubella-varicella (MMRV) and univalent varicella vaccines (Var). These vaccines should be given at least 14 days prior to administration of a human Ig preparation, or delayed until the antibodies in the Ig preparation have degraded. Refer to [Blood Products, Human Immunoglobulin and Timing of Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) in Part 1 for additional information.
Refer to [Timing of Vaccine Administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) in Part 1 for additional information about concurrent administration of vaccines.
Storage Requirements
--------------------
Refer to [Storage and Handling of Immunizing Agents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-9-storage-handling-immunizing-agents.html) in Part 1 for storage and handling recommendations for HA-containing vaccines.
Human Ig preparations should be stored at +2°C to +8°C. Do not freeze.
Safety and Adverse Events
-------------------------
### Common and local adverse events
#### HA vaccine
HA vaccine is well tolerated. Reactions are generally mild and transient, and are usually limited to soreness and redness at the injection site. Other less frequent reactions include headache, irritability, malaise, fever, fatigue and gastrointestinal symptoms. Injection site reactions occur less frequently in children (21%) than in adults (56%) as do mild, systemic events (2% to 9% versus 16%). No significant difference in reactions is evident between initial and subsequent doses of vaccine or in the presence of pre-existing immunity.
#### HAHB vaccine
Refer to [Hepatitis B Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for information about HAHB vaccine.
#### Ig
Injection site reactions following receipt of standard human Ig include tenderness, erythema and stiffness of local muscles, which may persist for several hours. Mild fever or malaise may occasionally occur.
### Less common and serious or severe adverse events
Less common side effects following receipt of standard human Ig include flushing, headache, chills and nausea. Urticaria, angioedema and anaphylactic reactions may occur rarely.
### Guidance on reporting Adverse Events Following Immunization (AEFI)
Vaccine providers are asked to report, through local public health officials, any serious or unexpected adverse event temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.
Refer to [Reporting Adverse Events Following Immunization (AEFI) in Canada](http://www.phac-aspc.gc.ca/im/aefi-essi_guide/index-eng.php) and [Vaccine Safety and Pharmacovigilance](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) in Part 2 for additional information about AEFI reporting.
### Contraindications and precautions
HA-containing vaccines and Ig are contraindicated in persons with a history of anaphylaxis after previous administration of the product and in persons with proven immediate or anaphylactic hypersensitivity to any component of the product. Human Ig preparations should not be given to people with known isolated IgA deficiency unless the benefit outweighs the risk, in which case the product should be given with caution and under close observation. Refer to [Contents of Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for lists of vaccines and passive immunizing agents authorized for use in Canada and their contents. Refer to [Hepatitis B Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for information about HAHB vaccine.
The efficacy and safety of HA vaccine given during pregnancy has not been studied in clinical trials, but there is no theoretical reason to suspect an increased risk of adverse events to the mother or the infant.
Administration of HA-containing vaccine should be postponed in persons with moderate or severe acute illness. Persons with minor acute illness, with or without fever, may be vaccinated.
Refer to [Contraindications and Precautions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html) in Part 2 for additional information.
Selected References
-------------------
* American Academy of Pediatrics. In: Pickering LK, Baker CJ, Kimberlin DW, et al. (editors). *Red Book: 2009 Report of the Committee on Infectious Diseases*. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.
* Bryan J, Henry C, Hoffman A et al. *Randomized, cross-over, controlled comparison of two inactivated hepatitis A vaccines.* Vaccine 2001;19:743-50.
* Centers for Disease Control and Prevention. *The Pink Book: Epidemiology and Prevention of Vaccine Preventable Diseases*.(http://www.cdc.gov/vaccines/pubs/pinkbook/index.html) Updated 13th ed.;2015. Accessed September 2015.
* Centers for Disease Control and Prevention. *Update: Prevention of hepatitis A after exposure to hepatitis A virus and in international travelers. Updated Recommendations of the Advisory Committee on Immunization Practices (ACIP)*. MMWR Morbid Mortal Wkly Rep. 2007;56(41):1080-4.
* Centers for Disease Control and Prevention. *Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices* (ACIP). MMWR Morb Mortal Wkly Rep 2006;55(No. RR-7);1-23.
* Committee to Advise on Tropical Medicine and Travel. *Statement on international adoption*.
Can Comm Dis Rep. 2010;36(ACS-15):1-17.
* Committee to Advise on Tropical Medicine and Travel. *Statement on hepatitis vaccines for travellers*. Can Comm Dis Rep. 2008;34(ACS-2):1-24.
* Dagan R, Leventhal A, Anis E et al. *Incidence of hepatitis A in Israel following universal immunization of toddlers*. JAMA 2005;294:202-10.
* De Serres G, Duval B, Shadmani R et al. *Ineffectiveness of the current strategy to prevent hepatitis A in travelers.* J Travel Med 2002;9(1):10-6.
* De Serres G, Laliberte D. *Hepatitis A among workers from a waste water treatment plant during a small community outbreak*. Occup Environ Med 1997;54:60-2.
* Deshaies M, Dion R, Valiquette L et al. *Immunization against hepatitis A during an outbreak in a Jewish orthodox community Quebec 1997-1998*. Can Commun Dis Rep. 1998;24:145-51.
* Duval B, De Serres G, Ochnio J et al. *Nationwide Canadian study of hepatitis A antibody prevalence among children eight to thirteen years old*. Pediatr Infect Dis J. 2005;24:514-19.
* Duval B, Gîlca V, Boulianne N et al. *Immunogenicity of two paediatric doses of monovalent hepatitis B or combined hepatitis A and B vaccine in 8-10-year-old children*. Vaccine 2005;23(31):4082-87.
* Fiore AE. *Hepatitis A transmitted by food.* Clin Infect Dis. 2004;38:705-15.
* GlaxoSmithKline Inc. *Product Monograph - TWINRIX.* December 2011.
* GlaxoSmithKline Inc. *Product Monograph - HAVRIX.* July 2011.
* Grifols Therapeutics LLC. Product Monograph - GamaSTAN®. March 2019.
* Hockin J, Isaacs S, Kittle D et al. *Hepatitis A outbreak in a socially contained religious community in rural southern Ontario.* Can Commun Dis Rep. 1997;23:161-66.
* McMahon B, Beller M, Williams J et al. *A programme to control an outbreak of HAV in Alaska by using an inactivated hepatitis A vaccine*. Arch Pediatr Adolesc Med. 1996;150:733-39.
* Merck Canada Inc. *Product Monograph - VAQTA®.* May 2011.
* National Advisory Committee on Immunization. Update on the Recommeded use of Hepatitis A Vaccine. Accessed March 2018 at : https://www.canada.ca/en/public-health/services/publications/healthy-living/update-recommended-use-hepatitis-vaccine.html
* Navas E, Salleras L, Gisbert R et al. *Efficiency of the incorporation of the hepatitis A vaccine as a combined A+B vaccine to the hepatitis B vaccination programme of preadolescents in schools*. Vaccine 2005;23(17-18):2185-9.
* Pham B, Duval B, De Serres G et al. *Seroprevalence of hepatitis A infection in a low endemicity country: a systematic review*. BMC Infect Dis. 2005;5:56.
* Roberton D, Marshall H, Nolan T et al. *Reactogenicity and immunogenicity profile of a two-dose combined hepatitis A and B vaccine in 1-11-year-old children*. Vaccine 2005(43);23:5099-105.
* Sagliocca L, Amoroso P, Stroffolini T et al. *Efficacy of hepatitis A vaccine in prevention of secondary hepatitis A infection: a randomised trial.* Lancet 1999;353(9159):1136-39.
* Sanofi Pasteur Ltd. *Product Monograph - AVAXIM®- Pediatric.* November 2011.
* Sanofi Pasteur Ltd. *Product Monograph - AVAXIM®.* February 2011.
* Scheifele D. *Hepatitis A vaccine: the growing case for universal immunization of children.* Expert Opin Pharmacother.2005;6:157-64.
* Tejada-Strop A, et al (2017). Evaluation of potencies of immune globulin products against hepatitis A. JAMA Intern Med. 117(3) :430-432.
* Vento S, Garofano T, Renzini C et al. *Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis*. N Engl J Med. 1998;388:286-90.
* Werzberger A, Kuter B, Shouval D et al. *Anatomy of a trial: a historical view of the Monroe inactivated hepatitis A protective efficacy trial.* J Hepatol. 1993;18(Suppl.2):S46-S50.
* World Health Organization. *WHO position paper on hepatitis A vaccines - June 2012*. Wkly Epidemiol Rec 2012;28-29(87):261-76.
* Wu J, Zou S, Giulivi A. *Hepatitis A and its control.* In: Bloodborne Pathogens Division, Health Canada. *Viral hepatitis and emerging bloodborne pathogens in Canada*. Can Commun Dis Rep. 2001;27(S3):7-9.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-5-haemophilus-influenzae-type-b-vaccine.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-05-10
| None | None |
36a3610c12fb87708d2ba4de79cdb8c137ede73e | cma | NACI recommendations on the use of LAIV and HIV-infected individuals | NACI recommendations on the use of LAIV and HIV-infected individuals
# Abstract
Background: Annual influenza vaccination is recommended for all individuals six months of age and older, including those with HIV infection. Prior to this statement, the National Advisory Committee on Immunization (NACI) stated that live attenuated influenza vaccine (LAIV) was contraindicated for all individuals with HIV infection. The objective of this article is to update NACI’s guidance on the use of LAIV for HIV-infected individuals.
Methods: A systematic literature review of the use of LAIV in individuals with HIV was undertaken. The Canadian Adverse Events Following Immunization Surveillance System was searched for reports of adverse events following vaccination with LAIV in HIV-infected individuals. NACI approved the revised recommendations.
Results: NACI concluded that LAIV is immunogenic in children with HIV, and available data suggest that it is safe, although data were insufficient to detect possible uncommon adverse effects. LAIV may be considered as an option for vaccination of children 2–17 years old who meet the following criteria: 1) receiving highly active antiretroviral therapy for at least four months; 2) CD4 count of 500/µL or greater if age 2–5 years, or of 200/µL or greater if age 6–17 years; and 3) HIV plasma RNA less than 10,000 copies/mL. LAIV remains contraindicated for adults with HIV because of insufficient data. Intramuscular influenza vaccination is considered the standard for children living with HIV by NACI and the Canadian Paediatric & Perinatal HIV/AIDS Research Group, particularly for those without HIV viral load suppression (i.e. plasma HIV RNA is 40 copies/mL or greater). However, if intramuscular (IM) vaccination is not accepted by the patient or substitute decision-maker, LAIV would be reasonable for children meeting the criteria listed above.
Conclusion: LAIV may be considered as an option for annual vaccination of selected children with HIV.
# Introduction
Annual vaccination against influenza is recommended for all individuals with HIV infection who are six months of age or older. Live vaccines are generally contraindicated in persons with immunodeficiency. Nevertheless, criteria have been established to permit vaccination with measles-mumps-rubella and varicella vaccines when immune function is not severely impaired. These vaccines have been shown to be safe and are recommended for persons with HIV if the HIV infection is controlled and immune function is satisfactory. The National Advisory Committee on Immunization’s (NACI) previous recommendation against live attenuated influenza vaccine (LAIV) use for individuals with immune compromising conditions including HIV was based on expert opinion and the small number of studies available (NACI Recommendation Grade D). The product monograph states that LAIV administration to immunosuppressed individuals should be based on careful consideration of potential benefits and risks.
Immunization protocols state that LAIV is contraindicated for HIV-infected individuals in British Columbia, Alberta, Manitoba, Saskatchewan and New Brunswick, as well as in the United States. Some jurisdictions, such as Québec, the United Kingdom, and France and professional organizations including the Infectious Diseases Society of America and the British Children’s HIV Association state that LAIV may be given to individuals with HIV who meet specific criteria.
The objective of this advisory committee statement is to review the evidence for efficacy, effectiveness, immunogenicity and safety for LAIV use in HIV-infected individuals and to provide updated guidance on the use of LAIV in this population.
# Methods
A systematic review of literature on the use of LAIV in HIV-infected individuals was performed. The systematic review’s methodology was specified *a priori- in a written protocol that included review questions, search strategy, inclusion and exclusion criteria and quality assessment. The NACI Influenza Working Group (IWG) reviewed and approved the protocol.
Six electronic databases (EMBASE, MEDLINE, Scopus, ProQuest Public Health, ClinicalTrials.gov and PROSPERO) were searched from inception to April 13, 2018 using search terms for LAIV and HIV. Searches were restricted to articles published in English and French. In addition, hand searching of included studies was performed by checking reference lists to identify additional relevant publications. Hand searching of reference lists was also performed for any relevant retrieved secondary research articles.
Two reviewers independently screened the titles and abstracts and eligible full-text articles.
Studies were included if they met the following criteria:
1. The study population or subpopulation consisted of HIV-infected individuals
2. The study assessed efficacy or effectiveness, immunogenicity, safety (including impact on markers of HIV infection), or vaccine virus shedding
Studies were excluded if they met one or more of the following criteria:
1. The study did not present data on any of: efficacy and effectiveness, immunogenicity, safety or vaccine virus shedding outcomes for LAIV
2. The study was in a language other than English or French
3. The study was a non-human or *in vitro- study
4. The article was an editorial, opinion, or news report
5. The study presented only secondary research (e.g. literature review, systematic review, meta-analysis)
6. The LAIV investigated was not a seasonal LAIV based on the Ann Arbor backbone
Data were extracted into evidence tables. One reviewer extracted data and appraised the methodological quality of the eligible studies. A second reviewer validated the data extraction and quality assessment. The Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) was also searched for reports of adverse events (AE) following immunization (AEFI) with LAIV in HIV-infected individuals. A narrative synthesis of the extracted data was produced and a recommendation for LAIV use developed. NACI critically appraised the available evidence and approved the recommendation.
# Results
The systematic review retrieved 220 unique articles, of which eight were retained for data extraction and analysis. These eight articles reported findings from five studies investigating the immunogenicity, safety or both of LAIV in HIV-infected individuals. Four studies were of good quality and one was fair according to ratings of Harris *et- *al.*. No studies investigating the efficacy or effectiveness of LAIV in this population were identified. A flow diagram of the study selection process is presented in . Key study characteristics are summarized in .
Text description: Figure 1
Abbreviation: RCT, randomized controlled trial
Abbreviations of Table 1
Abbreviations: AE, adverse event; cART, combination antiretroviral therapy; HAART, highly active antiretroviral therapy; HI, hemagglutination inhibition; IgA, immunoglobulin A; IgG, immunoglobulin G; IIV3, trivalent inactivated influenza vaccine; LAIV, live attenuated influenza vaccine; LAIV3, trivalent live attenuated influenza vaccine; LAIV4, quadrivalent live attenuated influenza vaccine; MN, microneutralization; RCT, randomized controlled trial; RNA, ribonucleic acid; US, United States
## Immunogenicity
Three studies investigated the immunogenicity of LAIV in a total of 191 HIV-infected children and young adults, 2–25 years of age, and one study investigated the immunogenicity in 28 HIV-infected adults 18 years of age and older. All four studies were of good quality according to the Harris *et al.- criteria. Immunologic correlates of protection against influenza are relatively well established for hemagglutination inhibition (HI) antibodies for adults, but not for microneutralization (MN) antibodies for adults and not for any serological response for children.
There were no major differences in HI antibody responses following receipt of LAIV between individuals with and without HIV. In the study by Curtis *et- *al.*, HI response to influenza B/Yamagata was better in the group with HIV than in the HIV-negative control group. The proportions of HIV-infected individuals with HI titres of at least 40 vaccinated with LAIV or inactivated influenza vaccine (IIV) were similar for influenza A(H1N1) and A(H3N2) but higher with IIV for influenza B and antibody titres were statistically significantly higher with IIV for influenza A(H3N2) and B vaccine strains and for mismatched strains. A significant increase in MN titres was observed against mismatched, but not the vaccine A(H1N1) strain, in a study of HIV-infected children and young adults. The proportion of HIV-infected individuals with MN titres greater than or equal to 1:40 was similar post-vaccination for LAIV and IIV, but the magnitude of response was higher for IIV than LAIV.
LAIV induces humoral and mucosal antibody responses as well as T and B cell-mediated responses. Correlates of protection have not been established for LAIV or for cell-mediated responses, and HI titre may underestimate protection. Two studies looked at mucosal antibody responses. There was no important difference in nasal IgA antibody response to LAIV by HIV status, or in salivary IgG antibody response to LAIV and IIV in HIV-infected individuals. One study investigated memory B cell and T cell responses. The IgG memory B cell responses did not differ significantly by HIV status for influenza A(H1N1) or A(H3N2); however, a lower absolute response to B/Yamagata post-vaccination was observed in the HIV-infected group. The magnitude of the rise in T cell response did not differ by HIV status.
## Safety
Five studies reported AEFI with LAIV: three in a total of 191 HIV-infected children and young adults, one in 28 adults and one in 437 adults investigated only for vaccine-associated influenza-like illness (ILI). Four of the studies were of good quality and one was rated as fair.
In both children and adults with HIV, rates of AEFI with LAIV were comparable to rates observed in individuals without HIV receiving LAIV except for more muscle aches and decreased energy in those with HIV. Rates of AEFI in individuals with HIV receiving LAIV or IIV were also similar, with the exception of more frequent but expected nasopharyngeal symptoms (runny nose and nasal congestion) after LAIV. Reports of ILI after receiving LAIV were rare. No serious or severe AEFIs attributable to LAIV were reported in any study. There have been no reports to CAEFISS of AEFI with LAIV in HIV-infected individuals.
Effects of LAIV on HIV infection were assessed in two studies in children and one in adults. LAIV had no significant effect on HIV RNA viral load or CD4 count.
Four studies reported on the effect of HIV status on LAIV vaccine virus shedding: three in 191 HIV-infected children and young adults and one in 28 HIV-infected adults. Vaccine virus shedding did not differ by HIV infection status.
# NACI recommendation for individual level decision-making
Following thorough review of the evidence, NACI made the following recommendation:
NACI recommends that LAIV may be considered as an option for children 2–17 years of age with stable HIV infection on highly active antiretroviral therapy (HAART) and with adequate immune function\- (Discretionary NACI recommendation).
- NACI concludes that there is fair evidence based on immunogenicity data to recommend the use of LAIV vaccine as an option for children 2–17 years of age with stable HIV infection on HAART and with adequate immune function (Grade B Evidence)
- NACI concludes that, while LAIV appears to have a similar safety profile to IIV, there is insufficient evidence to detect uncommon AE related to the use of LAIV in HIV infected children (Grade I Evidence)
\*LAIV should be considered only in children with HIV who meet the following criteria:
- Receiving HAART for at least four months
- Have a CD4 count greater than or equal to 500/µL if 2–5 years of age, or greater than or equal to 200/µL if 6–17 years of age (measured within 100 days before administration of LAIV)
- Have a level of HIV plasma RNA fewer than 10,000 copies/mL (measured within 100 days before administration of LAIV)
While intramuscular (IM) influenza vaccination is considered the standard for children living with HIV by NACI and the Canadian Paediatric and Perinatal HIV/AIDS Research Group, particularly for those without HIV viral load suppression (i.e. IM, plasma HIV RNA more than 40 copies/mL), LAIV would be reasonable for children meeting the criteria outlined above, if vaccination is not accepted by the patient or substitute decision-maker.
The decision to use LAIV in children with stable HIV should be made on a case-by-case basis. The evidence is considered Grade B as there is no direct evidence on the efficacy or effectiveness of LAIV in HIV-infected individuals and the sample size for the evidence base is small.
- There is evidence that LAIV is immunogenic in children 2–17 years of age with stable HIV infection on HAART and with adequate immune function
- LAIV appears to have a similar safety profile to IIV; however, the total number of subjects assessed is insufficient to effectively detect uncommon or rare AE
- Children with HIV receive all the routine childhood vaccines and additional parenteral vaccines warranted by their actual or potential immunocompromised state. Offering intranasal LAIV instead of IIV avoids one IM injection annually. A discussion on preference for route of administration should take place prior to vaccination, and may improve acceptance of the seasonal influenza vaccine
NACI concluded that the quantity of evidence available on the immunogenicity and safety of LAIV in adults with HIV is insufficient to justify a change in the current recommendation against the use of LAIV in this group. (Grade I Evidence). This recommendation is based on expert opinion.
The detailed findings of the literature review and additional information supporting this recommendation can be found in the NACI advisory committee statement: *Recommendation on the Use of Live Attenuated Influenza Vaccine (LAIV) in HIV-Infected- *Individuals*.
# Conclusion
LAIV is immunogenic in children with HIV and appears to have a similar safety profile to IIV, although uncommon or rare AE may not have been detected. NACI recommends that LAIV may be considered as an option for children 2–17 years of age with stable HIV infection HAART and with adequate immune function. Studies with sufficient sample size to detect uncommon or rare AE or to address efficacy or effectiveness of LAIV in children may not be feasible, given the limited numbers of children with HIV in high income countries where LAIV is used. |
NACI recommendations on the use of LAIV and HIV-infected individuals
=====================================================================
 [Download this article as a PDF](/content/dam/phac-aspc/documents/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2020-46/issue-9-sept-3-2020/ccdrv46i09a08-eng.pdf "Summary of the NACI systematic review and recommendation on the use of live attenuated influenza vaccine (LAIV) in HIV-infected individuals")
**Published by: [The Public Health Agency of Canada](/en/public-health.html "The Public Health Agency of Canada")**
**Issue:** [Volume 46–9: Force Health Protection](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2020-46/issue-9-september-3-2020.html "Volume 46-9: Force Health Protection")
**Date published:** September 3, 2020
**ISSN:** 1481-8531
[Subscribe to CCDR](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/email-subscription.html "Subscribe to CCDR")
##### Submit a manuscript
* [Submit your manuscript](https://ccdr-rmtc.phac-aspc.gc.ca/index.php/ccdr-rmtc/user/setLocale/en_US?source=%2Findex.php%2Fccdr-rmtc "Submit your manuscript")
* [Information for authors](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/submit-a-manuscript-information-authors.html "Information for authors")
##### About CCDR
* [About CCDR](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/about-canada-communicable-disease-report.html "About CCDR")
* [Editorial board](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/editorial-board.html "Editorial board")
* [Contact us](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/contact-editors.html "Contact us")
##### Browse
* [Past issues](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/past-issues.html "Past issues")
**Volume 46–9, September 3, 2020: Force Health Protection**
Advisory committee statement
----------------------------
### Summary of the NACI systematic review and recommendation on the use of live attenuated influenza vaccine (LAIV) in HIV-infected individuals
Dorothy Moore1,2, Ian Gemmill3,4, Robyn Harrison5,6 on behalf of the National Advisory Committee on Immunization (NACI)
Affiliations
1 NACI Influenza Working Group Member
2 McGill University, Montréal, QC
3 NACI Influenza Working Group Chair
4 Queen’s University, Kingston, ON
5 NACI Influenza Working Group Vice Chair
6 University of Alberta, Alberta Health Services, Edmonton, AB
Correspondence
[[email protected]](mailto:[email protected])
Suggested citation
Moore D, Gemmill I, Harrison R, on behalf of the National Advisory Committee on Immunization (NACI). Summary of the NACI systematic review and recommendation on the use of live attenuated influenza vaccine (LAIV) in HIV-infected individuals. Can Commun Dis Rep 2020;46(9):299–304. https://doi.org/10.14745/ccdr.v46i09a08
Keywords: National Advisory Committee on Immunization, NACI, HIV, live attenuated influenza vaccine, literature review
### Abstract
**Background:** Annual influenza vaccination is recommended for all individuals six months of age and older, including those with HIV infection. Prior to this statement, the National Advisory Committee on Immunization (NACI) stated that live attenuated influenza vaccine (LAIV) was contraindicated for all individuals with HIV infection. The objective of this article is to update NACI’s guidance on the use of LAIV for HIV-infected individuals.
**Methods:** A systematic literature review of the use of LAIV in individuals with HIV was undertaken. The Canadian Adverse Events Following Immunization Surveillance System was searched for reports of adverse events following vaccination with LAIV in HIV-infected individuals. NACI approved the revised recommendations.
**Results:** NACI concluded that LAIV is immunogenic in children with HIV, and available data suggest that it is safe, although data were insufficient to detect possible uncommon adverse effects. LAIV may be considered as an option for vaccination of children 2–17 years old who meet the following criteria: 1) receiving highly active antiretroviral therapy for at least four months; 2) CD4 count of 500/µL or greater if age 2–5 years, or of 200/µL or greater if age 6–17 years; and 3) HIV plasma RNA less than 10,000 copies/mL. LAIV remains contraindicated for adults with HIV because of insufficient data. Intramuscular influenza vaccination is considered the standard for children living with HIV by NACI and the Canadian Paediatric & Perinatal HIV/AIDS Research Group, particularly for those without HIV viral load suppression (i.e. plasma HIV RNA is 40 copies/mL or greater). However, if intramuscular (IM) vaccination is not accepted by the patient or substitute decision-maker, LAIV would be reasonable for children meeting the criteria listed above.
**Conclusion:** LAIV may be considered as an option for annual vaccination of selected children with HIV.
### Introduction
Annual vaccination against influenza is recommended for all individuals with HIV infection[Footnote 1](#fn1) who are six months of age or older. Live vaccines are generally contraindicated in persons with immunodeficiency. Nevertheless, criteria have been established to permit vaccination with measles-mumps-rubella and varicella vaccines when immune function is not severely impaired. These vaccines have been shown to be safe and are recommended for persons with HIV if the HIV infection is controlled and immune function is satisfactory. The National Advisory Committee on Immunization’s (NACI) previous recommendation against live attenuated influenza vaccine (LAIV) use for individuals with immune compromising conditions including HIV was based on expert opinion and the small number of studies available (NACI Recommendation Grade D)[Footnote 2](#fn2). The product monograph states that LAIV administration to immunosuppressed individuals should be based on careful consideration of potential benefits and risks[Footnote 3](#fn3).
Immunization protocols state that LAIV is contraindicated for HIV-infected individuals in British Columbia, Alberta, Manitoba, Saskatchewan and New Brunswick, as well as in the United States[Footnote 4](#fn4)[Footnote 5](#fn5)[Footnote 6](#fn6)[Footnote 7](#fn7)[Footnote 8](#fn8)[Footnote 9](#fn9)[Footnote 10](#fn10). Some jurisdictions, such as Québec, the United Kingdom, and France[Footnote 11](#fn11)[Footnote 12](#fn12)[Footnote 13](#fn13) and professional organizations including the Infectious Diseases Society of America and the British Children’s HIV Association[Footnote 14](#fn14)[Footnote 15](#fn15) state that LAIV may be given to individuals with HIV who meet specific criteria.
The objective of this advisory committee statement is to review the evidence for efficacy, effectiveness, immunogenicity and safety for LAIV use in HIV-infected individuals and to provide updated guidance on the use of LAIV in this population.
### Methods
A systematic review of literature on the use of LAIV in HIV-infected individuals was performed. The systematic review’s methodology was specified *a priori* in a written protocol that included review questions, search strategy, inclusion and exclusion criteria and quality assessment. The NACI Influenza Working Group (IWG) reviewed and approved the protocol.
Six electronic databases (EMBASE, MEDLINE, Scopus, ProQuest Public Health, ClinicalTrials.gov and PROSPERO) were searched from inception to April 13, 2018 using search terms for LAIV and HIV. Searches were restricted to articles published in English and French. In addition, hand searching of included studies was performed by checking reference lists to identify additional relevant publications. Hand searching of reference lists was also performed for any relevant retrieved secondary research articles.
Two reviewers independently screened the titles and abstracts and eligible full-text articles.
Studies were included if they met the following criteria:
1. The study population or subpopulation consisted of HIV-infected individuals
2. The study assessed efficacy or effectiveness, immunogenicity, safety (including impact on markers of HIV infection), or vaccine virus shedding
Studies were excluded if they met one or more of the following criteria:
1. The study did not present data on any of: efficacy and effectiveness, immunogenicity, safety or vaccine virus shedding outcomes for LAIV
2. The study was in a language other than English or French
3. The study was a non-human or *in vitro* study
4. The article was an editorial, opinion, or news report
5. The study presented only secondary research (e.g. literature review, systematic review, meta-analysis)
6. The LAIV investigated was not a seasonal LAIV based on the Ann Arbor backbone
Data were extracted into evidence tables. One reviewer extracted data and appraised the methodological quality of the eligible studies. A second reviewer validated the data extraction and quality assessment. The Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) was also searched for reports of adverse events (AE) following immunization (AEFI) with LAIV in HIV-infected individuals. A narrative synthesis of the extracted data was produced and a recommendation for LAIV use developed. NACI critically appraised the available evidence and approved the recommendation.
### Results
The systematic review retrieved 220 unique articles, of which eight were retained for data extraction and analysis. These eight articles reported findings from five studies investigating the immunogenicity, safety or both of LAIV in HIV-infected individuals. Four studies were of good quality and one was fair according to ratings of Harris *et* *al.*[Footnote 16](#fn16). No studies investigating the efficacy or effectiveness of LAIV in this population were identified. A flow diagram of the study selection process is presented in [**Figure 1**](#fig1). Key study characteristics are summarized in [**Table 1**](#tbl1).
**Figure 1: Flow diagram of the study selection process for the systematic review on the efficacy, effectiveness, immunogenicity and safety of live attenuated influenza vaccine in HIV-infected individuals**
Text description: Figure 1
**Figure 1: Flow diagram of the study selection process for the systematic review on the efficacy, effectiveness, immunogenicity and safety of live attenuated influenza vaccine in HIV-infected individuals**
Figure 1 depicts a flow diagram of the study selection process for the systematic review. In the identification stage, 359 records were identified through database searching and an additional two records were identified through other sources. During the screening stage, 220 records remained after duplicates were removed. After the records were screened, 203 were excluded. In the eligibility stage, full-text articles were assessed and 17 articles were determined to be eligible. Nine full-text articles were excluded, including three reviews, one article that did not assess HIV-infected individuals, two that did not assess the seasonal influenza vaccine and three that had no full text. Eight articles were included in the synthesis, including five randomized controlled trails (three studies), two prospective cohort articles (one study), and one retrospective cohort.
Figure 1 footnote
Figure 1 - abbreviation
Abbreviation: RCT, randomized controlled trial
Table 1: Characteristics of studies included in the systematic review
| Author | Study design
(vaccine administered) | Study population | Outcomes |
| --- | --- | --- | --- |
| King *et al.*, 2000[Footnote 17](#fn17) | RCT(LAIV3 versus placebo) | Adults 18–58 years of age with HIV (n=57 total; 28 received LAIV3) and without HIV (n=54 total; 27 received LAIV3)Eligibility criteria for HIV-infected subject: Immune class A1-2, plasma HIV RNA less than 10,000 copies/mL, and more than 200 CD4 cells/µL; if less than or equal to 500 CD4 cells/µL, on stable antiretroviral regimen) within three months prior to vaccination | HI antibody responseAE within 10 days of vaccinationEffect on HIV replication and CD4 cell countsVaccine virus shedding |
| King *et al.*, 2001[Footnote 18](#fn18) | RCT(LAIV3) | Children younger than 8 years of age with HIV (n=24); without HIV (n=25)Eligibility criteria for HIV-infected subject: Immune class N1-2 or A1-2 and plasma HIV RNA less than 10,000 copies/mL within 100 days prior to enrolment | HI antibody responseAE within 10 days of vaccinationEffect on HIV replication and CD4 cell countsVaccine virus shedding |
| Levin *et al.*, 2008[Footnote 19](#fn19)Weinberg *et al.*, 2010a[Footnote 20](#fn20)Weinberg *et al.*, 2010b[Footnote 21](#fn21) | RCT(LAIV3 vs. IIV3) | Children 5 to less than 18 years of age with HIV (n=243 total; 122 received LAIV3; 121 received IIV3)Eligibility criteria for HIV-infected subject: Stable HIV on HAART for more than or equal to 16 weeks and with HIV-1 plasma RNA fewer than 60,000 copies/mL within 60 days prior to vaccination. All subjects had received IIV3 in at least one of the prior two years | HI, MN antibody response Salivary mucosal IgA and IgG antibody response T cell response AE within 28 days of vaccination Effect on HIV replication and CD4 cell counts Vaccine virus shedding |
| Curtis *et al.*, 2015[Footnote 22](#fn22) Weinberg *et al.*, 2016[Footnote 23](#fn23) | Prospective cohort study (LAIV4) | Children and young adults 2–25 years of age with HIV (n=45) and without HIV (n=55) Eligibility criteria for HIV-infected subject: CD4 greater than 15% or more than 200 cells/µL on cART, or greater than 25% or more than 500 cells/µL if not on cART. All subjects had received influenza vaccine in one or more previous seasons | HI, MN antibody response Nasal mucosal IgA response IgA and IgG memory B cell response; T cell response AE within six weeks of vaccination Vaccine virus shedding |
| Menegay *et al.*, 2017[Footnote 24](#fn24) | Retrospective cohort study(LAIV vs. IIV) | Adults—all active duty US Air Force members diagnosed with HIV (n=437) | Influenza-like illness within 30 days of vaccination |
|
Abbreviations of Table 1
Abbreviations: AE, adverse event; cART, combination antiretroviral therapy; HAART, highly active antiretroviral therapy; HI, hemagglutination inhibition; IgA, immunoglobulin A; IgG, immunoglobulin G; IIV3, trivalent inactivated influenza vaccine; LAIV, live attenuated influenza vaccine; LAIV3, trivalent live attenuated influenza vaccine; LAIV4, quadrivalent live attenuated influenza vaccine; MN, microneutralization; RCT, randomized controlled trial; RNA, ribonucleic acid; US, United States
|
#### Immunogenicity
Three studies investigated the immunogenicity of LAIV in a total of 191 HIV-infected children and young adults, 2–25 years of age[Footnote 18](#fn18)[Footnote 19](#fn19)[Footnote 20](#fn20)[Footnote 21](#fn21)[Footnote 22](#fn22)[Footnote 23](#fn23), and one study investigated the immunogenicity in 28 HIV-infected adults 18 years of age and older[Footnote 17](#fn17). All four studies were of good quality according to the Harris *et al.* criteria[Footnote 16](#fn16). Immunologic correlates of protection against influenza are relatively well established for hemagglutination inhibition (HI) antibodies for adults, but not for microneutralization (MN) antibodies for adults and not for any serological response for children.
There were no major differences in HI antibody responses following receipt of LAIV between individuals with and without HIV[Footnote 17](#fn17)[Footnote 18](#fn18)[Footnote 22](#fn22). In the study by Curtis *et* *al.*[Footnote 22](#fn22), HI response to influenza B/Yamagata was better in the group with HIV than in the HIV-negative control group[Footnote 22](#fn22)[Footnote 23](#fn23). The proportions of HIV-infected individuals with HI titres of at least 40 vaccinated with LAIV or inactivated influenza vaccine (IIV) were similar for influenza A(H1N1) and A(H3N2) but higher with IIV for influenza B and antibody titres were statistically significantly higher with IIV for influenza A(H3N2) and B vaccine strains[Footnote 19](#fn19) and for mismatched strains[Footnote 20](#fn20). A significant increase in MN titres was observed against mismatched, but not the vaccine A(H1N1) strain, in a study of HIV-infected children and young adults[Footnote 22](#fn22)[Footnote 23](#fn23). The proportion of HIV-infected individuals with MN titres greater than or equal to 1:40 was similar post-vaccination for LAIV and IIV, but the magnitude of response was higher for IIV than LAIV[Footnote 20](#fn20).
LAIV induces humoral and mucosal antibody responses as well as T and B cell-mediated responses. Correlates of protection have not been established for LAIV or for cell-mediated responses, and HI titre may underestimate protection[Footnote 25](#fn25). Two studies looked at mucosal antibody responses. There was no important difference in nasal IgA antibody response to LAIV by HIV status[Footnote 22](#fn22)[Footnote 23](#fn23), or in salivary IgG antibody response to LAIV and IIV in HIV-infected individuals[Footnote 19](#fn19)[Footnote 20](#fn20). One study investigated memory B cell and T cell responses. The IgG memory B cell responses did not differ significantly by HIV status for influenza A(H1N1) or A(H3N2); however, a lower absolute response to B/Yamagata post-vaccination was observed in the HIV-infected group[Footnote 22](#fn22)[Footnote 23](#fn23). The magnitude of the rise in T cell response did not differ by HIV status[Footnote 22](#fn22)[Footnote 23](#fn23).
#### Safety
Five studies reported AEFI with LAIV: three in a total of 191 HIV-infected children and young adults[Footnote 18](#fn18)[Footnote 19](#fn19)[Footnote 22](#fn22), one in 28 adults[Footnote 17](#fn17) and one in 437 adults investigated only for vaccine-associated influenza-like illness (ILI)[Footnote 24](#fn24). Four of the studies were of good quality and one was rated as fair.
In both children and adults with HIV, rates of AEFI with LAIV were comparable to rates observed in individuals without HIV receiving LAIV except for more muscle aches and decreased energy in those with HIV[Footnote 17](#fn17)[Footnote 18](#fn18)[Footnote 22](#fn22). Rates of AEFI in individuals with HIV receiving LAIV or IIV were also similar, with the exception of more frequent but expected nasopharyngeal symptoms (runny nose and nasal congestion) after LAIV[Footnote 19](#fn19). Reports of ILI after receiving LAIV were rare[Footnote 24](#fn24). No serious or severe AEFIs attributable to LAIV were reported in any study. There have been no reports to CAEFISS of AEFI with LAIV in HIV-infected individuals.
Effects of LAIV on HIV infection were assessed in two studies in children[Footnote 18](#fn18)[Footnote 19](#fn19) and one in adults[Footnote 17](#fn17). LAIV had no significant effect on HIV RNA viral load or CD4 count.
Four studies reported on the effect of HIV status on LAIV vaccine virus shedding: three in 191 HIV-infected children and young adults[Footnote 18](#fn18)[Footnote 19](#fn19)[Footnote 22](#fn22) and one in 28 HIV-infected adults[Footnote 17](#fn17). Vaccine virus shedding did not differ by HIV infection status[Footnote 17](#fn17)[Footnote 18](#fn18)[Footnote 19](#fn19)[Footnote 22](#fn22).
### NACI recommendation for individual level decision-making
Following thorough review of the evidence, NACI made the following recommendation:
**NACI recommends that LAIV may be considered as an option for children 2–17 years of age with stable HIV infection on highly active antiretroviral therapy (HAART) and with adequate immune function\* (Discretionary NACI recommendation).**
* NACI concludes that there is fair evidence based on immunogenicity data to recommend the use of LAIV vaccine as an option for children 2–17 years of age with stable HIV infection on HAART and with adequate immune function (Grade B Evidence)
* NACI concludes that, while LAIV appears to have a similar safety profile to IIV, there is insufficient evidence to detect uncommon AE related to the use of LAIV in HIV infected children (Grade I Evidence)
\*LAIV should be considered only in children with HIV who meet the following criteria:
* Receiving HAART for at least four months
* Have a CD4 count greater than or equal to 500/µL if 2–5 years of age, or greater than or equal to 200/µL if 6–17 years of age (measured within 100 days before administration of LAIV)
* Have a level of HIV plasma RNA fewer than 10,000 copies/mL (measured within 100 days before administration of LAIV)
While intramuscular (IM) influenza vaccination is considered the standard for children living with HIV by NACI and the Canadian Paediatric and Perinatal HIV/AIDS Research Group, particularly for those without HIV viral load suppression (i.e. IM, plasma HIV RNA more than 40 copies/mL), LAIV would be reasonable for children meeting the criteria outlined above, if vaccination is not accepted by the patient or substitute decision-maker.
The decision to use LAIV in children with stable HIV should be made on a case-by-case basis. The evidence is considered Grade B as there is no direct evidence on the efficacy or effectiveness of LAIV in HIV-infected individuals and the sample size for the evidence base is small.
* There is evidence that LAIV is immunogenic in children 2–17 years of age with stable HIV infection on HAART and with adequate immune function
* LAIV appears to have a similar safety profile to IIV; however, the total number of subjects assessed is insufficient to effectively detect uncommon or rare AE
* Children with HIV receive all the routine childhood vaccines and additional parenteral vaccines warranted by their actual or potential immunocompromised state. Offering intranasal LAIV instead of IIV avoids one IM injection annually. A discussion on preference for route of administration should take place prior to vaccination, and may improve acceptance of the seasonal influenza vaccine[Footnote 26](#fn26)[Footnote 27](#fn27)
NACI concluded that the quantity of evidence available on the immunogenicity and safety of LAIV in adults with HIV is insufficient to justify a change in the current recommendation against the use of LAIV in this group. (Grade I Evidence). This recommendation is based on expert opinion.
The detailed findings of the literature review and additional information supporting this recommendation can be found in the NACI advisory committee statement: *Recommendation on the Use of Live Attenuated Influenza Vaccine (LAIV) in HIV-Infected* *Individuals*[Footnote 28](#fn28).
### Conclusion
LAIV is immunogenic in children with HIV and appears to have a similar safety profile to IIV, although uncommon or rare AE may not have been detected. NACI recommends that LAIV may be considered as an option for children 2–17 years of age with stable HIV infection HAART and with adequate immune function. Studies with sufficient sample size to detect uncommon or rare AE or to address efficacy or effectiveness of LAIV in children may not be feasible, given the limited numbers of children with HIV in high income countries where LAIV is used.
### Authors’ statement
* DM — Writing, original draft, review, editing
* IG — Review, editing
* RH — Review, editing
The National Advisory Committee on Immunization (NACI) advisory committee statement: *Recommendation on the Use of Live Attenuated Influenza Vaccine (LAIV) in HIV-Infected Individuals* was prepared by D Moore, N Dayneka, L Zhao, A Sinilaite, K Young and I Gemmill, on behalf of the NACI Influenza Working Group and was approved by NACI.
#### Competing interests
None.
### Acknowledgements
**Influenza Working Group members:** I Gemmill (Chair), R Harrison (Vice-Chair), C Bancej, L Cochrane, N Dayneka, L Grohskopf, D Kumar, J Langley, P Wolfe-Roberge, J McElhaney, A McGeer, D Moore, S Smith, B Warshawsky and J Xiong
**NACI members:** C Quach (Chair), S Deeks (Vice-Chair), N Dayneka, P De Wals, V Dubey, R Harrison, K Hildebrand, C Rotstein, M Salvadori, B Sander, N Sicard and S Smith
**Liaison representatives:** LM Bucci (Canadian Public Health Association), E Castillo (Society of Obstetricians and Gynaecologists of Canada), A Cohn (Centers for Disease Control and Prevention, United States), J Emili (College of Family Physicians of Canada), M Naus (Canadian Immunization Committee), D Moore (Canadian Paediatric Society) and A Pham-Huy (Association of Medical Microbiology and Infectious Disease Canada)
**Ex-officio representatives:** J Gallivan (Marketed Health Products Directorate, Health Canada [HC]), E Henry (Centre for Immunization and Respiratory Infectious Diseases [CIRID], Public Health Agency of Canada [PHAC]), M Lacroix (Public Health Ethics Consultative Group, PHAC), J Pennock (CIRID, PHAC), R Pless (Biologics and Genetic Therapies Directorate, HC), G Poliquin (National Microbiology Laboratory, PHAC) and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada)
The National Advisory Committee on Immunization (NACI) acknowledges and appreciates the contribution of A House, M Laplante, S Ismail, M Tunis, and the Canadian Paediatric & Perinatal HIV/AIDS Research Group to this statement.
### Funding
The work of the National Advisory Committee on Immunization is supported by the Public Health Agency of Canada.
### References
Footnote 1
National Advisory Committee on Immunization. Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2019–2020. Ottawa (ON): NACI; 2019 (accessed 2020-02-17). https://www.canada.ca/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2019-2020.html
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
National Advisory Committee on Immunization. Recommendations on the use of live, attenuated influenza vaccine (FluMist®). Supplemental Statement on Seasonal Influenza Vaccine for 2011-2012. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2011;37(ACS-7):1-77. https://doi.org/10.14745/ccdr.v37i00a07
[Return to footnote 2 referrer](#fn2-rf)
Footnote 3
AstraZeneca. Product Monograph: FluMist® Quadrivalent. 2018 (accessed 2020-02-17). https://pdf.hres.ca/dpd\_pm/00047438.PDF
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
U.S. Department of Health and Human Services. AIDS Info. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children (accessed 2020-02-17). https://aidsinfo.nih.gov/guidelines/brief-html/5/pediatric-opportunistic-infection/0.
[Return to footnote 4 referrer](#fn4-rf)
Footnote 5
BC Centre for Disease Control. Human Immunodeficiency Virus (HIV) Infection. BCCDC; 2018 (accessed 2020-02-17). http://www.bccdc.ca/resource-gallery/Documents/Guidelines%20and%20Forms/Guidelines%20and%20Manuals/Epid/CD%20Manual/Chapter%202%20-%20Imms/Part2/HIV.pdf
[Return to footnote 5 referrer](#fn5-rf)
Footnote 6
Alberta Health. Immunization of Specific Populations (Immunosuppressed and Chronic Health Conditions). Government of Alberta; 2019 (accessed 2020-02-17). https://open.alberta.ca/dataset/aip/resource/8a92b77b-351b-4f1e-9d4d-31aaa9effdb3/download/AIP-Specific-Populations-Immunocompromised.pdf
[Return to footnote 6 referrer](#fn6-rf)
Footnote 7
Manitoba Health, Seniors and Active Living. Seasonal Influenza Immunization Program: Live Attenuated Influenza Vaccine (LAIV) (FluMist® Quadrivalent): Questions and Answers for Health Care Providers. Government of Manitoba; 2018 (accessed 2018-11-01). https://www.gov.mb.ca/health/flu/docs/flumist\_hcp.pdf
[Return to footnote 7 referrer](#fn7-rf)
Footnote 8
Government of New Brunswick. 2013-2014 FluMist®, Live Attenuated Influenza Vaccine, Information for Immunization Providers. Government of NB; 2014 (accessed 2020-02-17). https://www2.gnb.ca/content/dam/gnb/Departments/h-s/pdf/en/CDC/vaccines/FLUMISTInformationForImmunizationProviders.pdf
[Return to footnote 8 referrer](#fn8-rf)
Footnote 9
Government of Saskatchewan. Saskatchewan Immunization Manual. Chapter 7 – Immunization of Special Populations. Government of SK; 2015 (accessed 2020-02-17). https://www.ehealthsask.ca/services/manuals/Documents/sim-chapter7.pdf
[Return to footnote 9 referrer](#fn9-rf)
Footnote 10
Grohskopf LA, Alyanak E, Broder KR, Walter EB, Fry AM, Jernigan DB. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2019-20 Influenza Season. MMWR Recomm Rep 2019;68(3):1–21. https://doi.org/10.15585/mmwr.rr6803a1
[Return to footnote 10 referrer](#fn10-rf)
Footnote 11
Ministère de la Santé et des Services sociaux. Vaccinologie pratique: Immunodépression. MSSS; 2019 (accessed 2020-02-17). http://www.msss.gouv.qc.ca/professionnels/vaccination/piq-vaccinologie-pratique/immunodepression/
[Return to footnote 11 referrer](#fn11-rf)
Footnote 12
Public Health England. Influenza: the Green Book, Chapter 19. Government UK: (updated 2019-04-23; accessed 2020-02-17). https://www.gov.uk/government/publications/influenza-the-green-book-chapter-19
[Return to footnote 12 referrer](#fn12-rf)
Footnote 13
Haut Conseil de la santé publique. Vaccination des personnes immunodéprimées ou aspléniques. Recommandations actualisées. HCSP; 2014 (accessed 2020-02-17). https://www.hcsp.fr/explore.cgi/avisrapportsdomaine?clefr=504
[Return to footnote 13 referrer](#fn13-rf)
Footnote 14
Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M, Bousvaros A, Dhanireddy S, Sung L, Keyserling H, Kang I; Infectious Diseases Society of America. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014;58(3):309–18. https://doi.org/10.1093/cid/cit816
[Return to footnote 14 referrer](#fn14-rf)
Footnote 15
Children’s HIV Association (CHIVA). Vaccination of HIV infected children (UK schedule, 2018). CHIVA; 2018 (accessed 2020-02-17). https://www.chiva.org.uk/files/8315/4453/4519/Vaccination\_of\_HIV\_infected\_children\_2018.pdf
[Return to footnote 15 referrer](#fn15-rf)
Footnote 16
Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, Atkins D; Methods Work Group, Third US Preventive Services Task Force. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med 2001;20(3 Suppl):21–35. https://doi.org/10.1016/S0749-3797(01)00261-6
[Return to footnote 16 referrer](#fn16-1-rf)
Footnote 17
King JC Jr, Treanor J, Fast PE, Wolff M, Yan L, Iacuzio D, Readmond B, O’Brien D, Mallon K, Highsmith WE, Lambert JS, Belshe RB. Comparison of the safety, vaccine virus shedding, and immunogenicity of influenza virus vaccine, trivalent, types A and B, live cold-adapted, administered to human immunodeficiency virus (HIV)-infected and non-HIV-infected adults. J Infect Dis 2000;181(2):725–8. https://doi.org/10.1086/315246
[Return to footnote 17 referrer](#fn17-1-rf)
Footnote 18
King JC Jr, Fast PE, Zangwill KM, Weinberg GA, Wolff M, Yan L, Newman F, Belshe RB, Kovacs A, Deville JG, Jelonek M; HIV Influenza Study Group. Safety, vaccine virus shedding and immunogenicity of trivalent, cold-adapted, live attenuated influenza vaccine administered to human immunodeficiency virus-infected and noninfected children. Pediatr Infect Dis J 2001;20(12):1124–31. https://doi.org/10.1097/00006454-200112000-00006
[Return to footnote 18 referrer](#fn18-1-rf)
Footnote 19
Levin MJ, Song LY, Fenton T, Nachman S, Patterson J, Walker R, Kemble G, Allende M, Hultquist M, Yi T, Nowak B, Weinberg A. Shedding of live vaccine virus, comparative safety, and influenza-specific antibody responses after administration of live attenuated and inactivated trivalent influenza vaccines to HIV-infected children. Vaccine 2008;26(33):4210–7. https://doi.org/10.1016/j.vaccine.2008.05.054
[Return to footnote 19 referrer](#fn19-1-rf)
Footnote 20
Weinberg A, Song LY, Walker R, Allende M, Fenton T, Patterson-Bartlett J, Nachman S, Kemble G, Yi TT, Defechereux P, Wara D, Read JS, Levin M; IMPAACT P1057 Team. Anti-influenza serum and mucosal antibody responses after administration of live attenuated or inactivated influenza vaccines to HIV-infected children. J Acquir Immune Defic Syndr 2010;55(2):189–96. https://doi.org/10.1097/QAI.0b013e3181e46308
[Return to footnote 20 referrer](#fn20-1-rf)
Footnote 21
Weinberg A, Song LY, Fenton T, Nachman SA, Read JS, Patterson-Bartlett J, Levin MJ. T cell responses of HIV-infected children after administration of inactivated or live attenuated influenza vaccines. AIDS Res Hum Retroviruses 2010;26(1):51–9. https://doi.org/10.1089/aid.2009.0163
[Return to footnote 21 referrer](#fn21-1-rf)
Footnote 22
Curtis D, Ning MF, Armon C, Li S, Weinberg A. Safety, immunogenicity and shedding of LAIV4 in HIV-infected and uninfected children. Vaccine 2015;33(38):4790–7. https://doi.org/10.1016/j.vaccine.2015.07.082
[Return to footnote 22 referrer](#fn22-1-rf)
Footnote 23
Weinberg A, Curtis D, Ning MF, Claypool DJ, Jalbert E, Patterson J, Frank DN, Ir D, Armon C. Immune Responses to Circulating and Vaccine Viral Strains in HIV-Infected and Uninfected Children and Youth Who Received the 2013/2014 Quadrivalent Live-Attenuated Influenza Vaccine. Front Immunol 2016;7:142. https://doi.org/10.3389/fimmu.2016.00142
[Return to footnote 23 referrer](#fn23-1-rf)
Footnote 24
Menegay JL, Xu X, Sunil TS, Okulicz JF. Live versus attenuated influenza vaccine uptake and post-vaccination influenza-like illness outcomes in HIV-infected US Air Force members. J Clin Virol. 2017;95:72-5. https://doi.org/ 10.1016/j.jcv.2017.08.009
[Return to footnote 24 referrer](#fn24-1-rf)
Footnote 25
Mohn KG-I, Smith I, Sjursen H, Cox RJ. Immune responses after live attenuated influenza vaccination. Hum Vaccin Immunother. 2018;14(3):571-8. https://doi.org/10.1080/21645515.2017.1377376
[Return to footnote 25 referrer](#fn25-rf)
Footnote 26
Marien AG, Hochart A, Lagrée M, Diallo D, Martinot A, Dubos F. Parental acceptance of an intranasal vaccine: example of influenza vaccine. Arch Pediatr 2019 Feb;26(2):71–4. https://doi.org/10.1016/j.arcped.2018.11.002
[Return to footnote 26 referrer](#fn26-rf)
Footnote 27
Santibanez TA, Kahn KE, Bridges CB. Do parents prefer inactivated or live attenuated influenza vaccine for their children? Vaccine 2018 Nov;36(48):7300–5. https://doi.org/10.1016/j.vaccine.2018.10.042
[Return to footnote 27 referrer](#fn27-rf)
Footnote 28
National Advisory Committee on Immunization. Recommendation on the Use of Live Attenuated Influenza Vaccine (LAIV) in HIV-Infected Individuals. Ottawa (ON): NACI; 2020. https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/live-attenuated-influenza-vaccine-hiv-infected-individuals.html
[Return to footnote 28 referrer](#fn28-rf)
[](http://creativecommons.org/licenses/by/4.0/ "Creative Commons Attribution 4.0 International License")
This work is licensed under a [Creative Commons Attribution 4.0 International License](http://creativecommons.org/licenses/by/4.0/ "Creative Commons Attribution 4.0 International License")
* [Previous page](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2020-46/issue-9-september-3-2020/data-laboratory-exposure-canada-2019.html "Previous page")
* [Table of contents](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2020-46/issue-9-september-3-2020.html "Table of contents")
* [Next page](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2020-46/issue-9-september-3-2020/vaccine-injury-compensation-programs-quebec.html "Next page")
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Freports-publications%2Fcanada-communicable-disease-report-ccdr%2Fmonthly-issue%2F2020-46%2Fissue-9-september-3-2020%2Fnational-advisory-committee-immunization-laiv-hiv-infected-individuals.html%3Fhq_e%3Del%26hq_m%3D2122885%26hq_l%3D11%26hq_v%3D5a08d900b7&n=Use%20of%20live%20attenuated%20influenza%20vaccine%20(LAIV)%20in%20HIV-infected%20individuals%3A%20Summary%20of%20NACI%20systematic%20review%20and%20recommendation%2C%20CCDR%2046(9)%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Freports-publications%2Fcanada-communicable-disease-report-ccdr%2Fmonthly-issue%2F2020-46%2Fissue-9-september-3-2020%2Fnational-advisory-committee-immunization-laiv-hiv-infected-individuals.html%3Fhq_e%3Del%26hq_m%3D2122885%26hq_l%3D11%26hq_v%3D5a08d900b7&title=Use%20of%20live%20attenuated%20influenza%20vaccine%20(LAIV)%20in%20HIV-infected%20individuals%3A%20Summary%20of%20NACI%20systematic%20review%20and%20recommendation%2C%20CCDR%2046(9)%20-%20Canada.ca)
* [Email](mailto:?subject=Use%20of%20live%20attenuated%20influenza%20vaccine%20(LAIV)%20in%20HIV-infected%20individuals%3A%20Summary%20of%20NACI%20systematic%20review%20and%20recommendation%2C%20CCDR%2046(9)%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Freports-publications%2Fcanada-communicable-disease-report-ccdr%2Fmonthly-issue%2F2020-46%2Fissue-9-september-3-2020%2Fnational-advisory-committee-immunization-laiv-hiv-infected-individuals.html%3Fhq_e%3Del%26hq_m%3D2122885%26hq_l%3D11%26hq_v%3D5a08d900b7%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Freports-publications%2Fcanada-communicable-disease-report-ccdr%2Fmonthly-issue%2F2020-46%2Fissue-9-september-3-2020%2Fnational-advisory-committee-immunization-laiv-hiv-infected-individuals.html%3Fhq_e%3Del%26hq_m%3D2122885%26hq_l%3D11%26hq_v%3D5a08d900b7&t=Use%20of%20live%20attenuated%20influenza%20vaccine%20(LAIV)%20in%20HIV-infected%20individuals%3A%20Summary%20of%20NACI%20systematic%20review%20and%20recommendation%2C%20CCDR%2046(9)%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=Use%20of%20live%20attenuated%20influenza%20vaccine%20(LAIV)%20in%20HIV-infected%20individuals%3A%20Summary%20of%20NACI%20systematic%20review%20and%20recommendation%2C%20CCDR%2046(9)%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Freports-publications%2Fcanada-communicable-disease-report-ccdr%2Fmonthly-issue%2F2020-46%2Fissue-9-september-3-2020%2Fnational-advisory-committee-immunization-laiv-hiv-infected-individuals.html%3Fhq_e%3Del%26hq_m%3D2122885%26hq_l%3D11%26hq_v%3D5a08d900b7%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Freports-publications%2Fcanada-communicable-disease-report-ccdr%2Fmonthly-issue%2F2020-46%2Fissue-9-september-3-2020%2Fnational-advisory-committee-immunization-laiv-hiv-infected-individuals.html%3Fhq_e%3Del%26hq_m%3D2122885%26hq_l%3D11%26hq_v%3D5a08d900b7&title=Use%20of%20live%20attenuated%20influenza%20vaccine%20(LAIV)%20in%20HIV-infected%20individuals%3A%20Summary%20of%20NACI%20systematic%20review%20and%20recommendation%2C%20CCDR%2046(9)%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Freports-publications%2Fcanada-communicable-disease-report-ccdr%2Fmonthly-issue%2F2020-46%2Fissue-9-september-3-2020%2Fnational-advisory-committee-immunization-laiv-hiv-infected-individuals.html%3Fhq_e%3Del%26hq_m%3D2122885%26hq_l%3D11%26hq_v%3D5a08d900b7&t=Use%20of%20live%20attenuated%20influenza%20vaccine%20(LAIV)%20in%20HIV-infected%20individuals%3A%20Summary%20of%20NACI%20systematic%20review%20and%20recommendation%2C%20CCDR%2046(9)%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Freports-publications%2Fcanada-communicable-disease-report-ccdr%2Fmonthly-issue%2F2020-46%2Fissue-9-september-3-2020%2Fnational-advisory-committee-immunization-laiv-hiv-infected-individuals.html%3Fhq_e%3Del%26hq_m%3D2122885%26hq_l%3D11%26hq_v%3D5a08d900b7&media=&description=Use%20of%20live%20attenuated%20influenza%20vaccine%20(LAIV)%20in%20HIV-infected%20individuals%3A%20Summary%20of%20NACI%20systematic%20review%20and%20recommendation%2C%20CCDR%2046(9)%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Freports-publications%2Fcanada-communicable-disease-report-ccdr%2Fmonthly-issue%2F2020-46%2Fissue-9-september-3-2020%2Fnational-advisory-committee-immunization-laiv-hiv-infected-individuals.html%3Fhq_e%3Del%26hq_m%3D2122885%26hq_l%3D11%26hq_v%3D5a08d900b7&title=Use%20of%20live%20attenuated%20influenza%20vaccine%20(LAIV)%20in%20HIV-infected%20individuals%3A%20Summary%20of%20NACI%20systematic%20review%20and%20recommendation%2C%20CCDR%2046(9)%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Freports-publications%2Fcanada-communicable-disease-report-ccdr%2Fmonthly-issue%2F2020-46%2Fissue-9-september-3-2020%2Fnational-advisory-committee-immunization-laiv-hiv-infected-individuals.html%3Fhq_e%3Del%26hq_m%3D2122885%26hq_l%3D11%26hq_v%3D5a08d900b7)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Freports-publications%2Fcanada-communicable-disease-report-ccdr%2Fmonthly-issue%2F2020-46%2Fissue-9-september-3-2020%2Fnational-advisory-committee-immunization-laiv-hiv-infected-individuals.html%3Fhq_e%3Del%26hq_m%3D2122885%26hq_l%3D11%26hq_v%3D5a08d900b7&name=Use%20of%20live%20attenuated%20influenza%20vaccine%20(LAIV)%20in%20HIV-infected%20individuals%3A%20Summary%20of%20NACI%20systematic%20review%20and%20recommendation%2C%20CCDR%2046(9)%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=Use%20of%20live%20attenuated%20influenza%20vaccine%20(LAIV)%20in%20HIV-infected%20individuals%3A%20Summary%20of%20NACI%20systematic%20review%20and%20recommendation%2C%20CCDR%2046(9)%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Freports-publications%2Fcanada-communicable-disease-report-ccdr%2Fmonthly-issue%2F2020-46%2Fissue-9-september-3-2020%2Fnational-advisory-committee-immunization-laiv-hiv-infected-individuals.html%3Fhq_e%3Del%26hq_m%3D2122885%26hq_l%3D11%26hq_v%3D5a08d900b7)
* [Whatsapp](https://api.whatsapp.com/send?text=Use%20of%20live%20attenuated%20influenza%20vaccine%20(LAIV)%20in%20HIV-infected%20individuals%3A%20Summary%20of%20NACI%20systematic%20review%20and%20recommendation%2C%20CCDR%2046(9)%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Freports-publications%2Fcanada-communicable-disease-report-ccdr%2Fmonthly-issue%2F2020-46%2Fissue-9-september-3-2020%2Fnational-advisory-committee-immunization-laiv-hiv-infected-individuals.html%3Fhq_e%3Del%26hq_m%3D2122885%26hq_l%3D11%26hq_v%3D5a08d900b7)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=Use%20of%20live%20attenuated%20influenza%20vaccine%20(LAIV)%20in%20HIV-infected%20individuals%3A%20Summary%20of%20NACI%20systematic%20review%20and%20recommendation%2C%20CCDR%2046(9)%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Freports-publications%2Fcanada-communicable-disease-report-ccdr%2Fmonthly-issue%2F2020-46%2Fissue-9-september-3-2020%2Fnational-advisory-committee-immunization-laiv-hiv-infected-individuals.html%3Fhq_e%3Del%26hq_m%3D2122885%26hq_l%3D11%26hq_v%3D5a08d900b7%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2020-09-24
| None | None |
9aefcea945c042be0e40d92ca56124c5392bcfb6 | cma | Public health level recommendations on the use of pneumococcal vaccines in adults, including the use of 15-valent and 20-valent conjugate vaccines | Public health level recommendations on the use of pneumococcal vaccines in adults, including the use of 15-valent and 20-valent conjugate vaccines
Preamble
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing, and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI’s independent advice and recommendations, which are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC’s Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Summary of information contained in this NACI Statement
The following highlights key information for immunization providers. Please refer to the remainder of the Statement for details.
# 1. What
Pneumococcal disease in adults includes invasive pneumococcal disease (IPD), an acute and serious communicable disease with manifestations such as meningitis, bacteremia and bacteremic pneumonia and empyema, as well as non-invasive pneumococcal disease such as community acquired pneumonia and acute otitis media in children. It is caused by the *Streptococcus pneumoniae- bacterium. Of the more than 100 serotypes of this bacterium, a small number cause the majority of disease. Bacteremic pneumococcal pneumonia is the most common presentation of IPD among adults.
Based on immunogenicity data relative to previously authorized pneumococcal conjugate vaccines (PNEU-C) and pneumococcal polysaccharide vaccines (PNEU-P), Health Canada has recently authorized two new PNEU-C vaccines:
- PNEU-C-15 (15-valent) is authorised for infants, children, and adolescents from 6 weeks through 17 years of age and adults 18 years of age and older with an indication for prevention of IPD caused by 15 serotypes of *S. pneumoniae- (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F).
- PNEU-C-20 (20-valent) is authorized for adults 18 years of age and older with an indication for prevention of pneumonia and IPD caused by 20 serotypes of *S. pneumoniae- (1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F).
No efficacy data are currently available for either PNEU-C-15 or PNEU-C-20.
# 2. Who
IPD is most common in the very young, the elderly, and groups with medical conditions and/or other risk factors that place them at high risk of IPD ().
NACI recommends the use of PNEU-C-20, or PNEU-C-15 followed by pneumococcal polysaccharide vaccine, 23-valent pneumococcal polysaccharide vaccine (PNEU-P-23), in adults at a higher risk of invasive pneumococcal disease.
- All adults 65 years of age and older should receive a single dose of PNEU-C-20.
- Adults who are 50 to 64 years of age and living with underlying medical conditions and/or other risk factors that place them at high risk of IPD should receive a single dose of PNEU-C-20.
- Adults who are 18 years of age and older living with immunocompromising conditions (IC) should also receive a single dose of PNEU-C-20.
- PNEU-C-15 followed by PNEU-P-23 may be offered as an alternative if PNEU-C-20 is not available.
Additional details including immunization of adults who received a hematopoietic stem cell transplant, as well as intervals between previous pneumococcal vaccines and PNEU-C-15/PNEU-C-20 are discussed in Section VII.
- Chronic neurologic condition that may impair clearance of oral secretions
- Cochlear implants, including children and adults who are to receive implants
- Chronic heart disease
- Diabetes mellitus
- Chronic kidney disease
- Chronic liver disease, including hepatic cirrhosis due to any cause
- Chronic lung disease, including asthma requiring medical care in the preceding 12 months
- Congenital immunodeficiencies involving any part of the immune system, including B-lymphocyte (humoral) immunity, T-lymphocyte (cell) mediated immunity, complement system (properdin, or factor D deficiencies), or phagocytic functions
- Immunocompromising therapy, including use of long-term corticosteroids, chemotherapy, radiation therapy, and post-organ transplant therapy
- HIV infection
- Hematopoietic stem cell transplant (recipient)
- Malignant neoplasms, including leukemia and lymphoma
- Nephrotic syndrome
- Solid organ or islet transplant (candidate or recipient)
- who use illicit drugs
- with alcohol use disorder
- who are experiencing homelessness
- who live in communities or settings experiencing sustained high IPD rates.
Conditions considered to result in the highest risk of IPD
Generally, asplenia (functional or anatomic), sickle cell disease and other hemoglobinopathies are not considered immunocompromising conditions, but for the purposes of pneumococcal vaccine recommendations, they are included in this category
Hematopoietic Stem Cell Transplant (HSCT) recipients have specific pneumococcal vaccination recommendations
Can include long-term care facilities
# 3. How
PNEU-C-15 and PNEU-C-20 are supplied in a single-dose, prefilled syringe. Both PNEU-C-15 and PNEU-C-20 are to be administered intramuscularly. A standard schedule for immunization is one 0.5ml dose. Contraindications to administration of either PNEU-C-15 or PNEU-C-20 include hypersensitivity (e.g., anaphylaxis) to the vaccine or any of its components. Pneumococcal vaccines may be administered concurrently with other vaccines, except for a different formulation of pneumococcal vaccine (e.g., concurrent use of conjugate and polysaccharide).
# 4. Why
Pneumococcal infection can cause severe infections and can lead to significant mortality and morbidity with lifelong complications. The most effective way to prevent these infections is through immunization.
I. Introduction
# I.1 Guidance objective
The need for this National Advisory Committee on Immunization (NACI) Statement on the use of pneumococcal vaccines was triggered by the approvals of two additional pneumococcal conjugate vaccines for adults 18 years of age and older, a 15-valent vaccine, PNEU-C-15 (VaxneuvanceTM) on November 16, 2021, and a 20-valent vaccine, PNEU-C-20 (Prevnar 20TM) on May 9, 2022. The primary objective of this statement is to review the evidence on the efficacy, effectiveness, immunogenicity, safety, and cost-effectiveness of PNEU-C-15 and PNEU-C-20 vaccines and provide recommendations for their use in consideration of the disease burden in Canada among adults for whom pneumococcal vaccination is currently recommended:
- immunocompetent adults aged 65 and older
- immunocompetent adults at higher risk of pneumococcal disease (PD) ()
- immunocompetent adults residing in long term care facilities (LTCF)
- immunocompromised adults, including hematopoietic stem cell transplant recipients
# I.2 Background on pneumococcal vaccines, immunization programs and recommendations for adults in Canada
For prevention of IPD in adults, two vaccines are currently available in routine, publicly funded programs: PNEU-P-23 and PNEU-C-13. Conjugate vaccines induce formation of long-term memory cells, provide longer duration of protection, and provide ability for boosting by involving T cells in the immune response to the vaccine, in a way that polysaccharide vaccines do not.
PNEU-P-23 was previously recommended by NACI for the routine immunization against IPD of all adults 65 years of age and older. PNEU-P-23 was also recommended for adults 18 to 64 years old who are residents of LTCF, smokers or persons with an alcohol use disorder, and persons experiencing homelessness as well for those living with both immunocompromising and non-immunocompromising underlying medical conditions that put them at higher risk of IPD. A complete list of underlying medical conditions that increase the risk of IPD along with dose and schedule is available in the .
PNEU-C-13 in series with PNEU-P-23 was recommended by NACI in 2013 for adults 18 years of age and older with immunocompromising conditions resulting in high risk of IPD. For a complete list of immunosuppressing conditions that increase the risk of IPD, please refer to .
PNEU-C-13 was also recommended by NACI in 2016 and 2018 on an individual basis for immunocompetent adults aged 65 years and older who wish to protect themselves against the 13 serotypes included in the vaccine for prevention of community-acquired pneumonia (CAP) and IPD. PNEU-C-13 was not recommended for publicly funded routine immunization programs due to cost-effectiveness.
II. Methods
In brief, the stages in the preparation of a NACI advisory committee statement are:
1. Knowledge synthesis: retrieval and summary of individual studies, assessment of the risk of bias (RoB) of included studies (summarized in the ).
2. Summary of evidence: benefits (immunogenicity) and potential harms (safety), considering the certainty of the synthesized evidence and, where applicable, the magnitude of effects observed across the studies.
3. Use of the evidence to inform recommendations.
NACI also uses a published, peer-reviewed framework and evidence-informed tools to ensure that issues related to ethics, equity, feasibility, and acceptability (EEFA) are systematically assessed and integrated into its guidance. NACI evaluated the following ethical considerations when making its recommendations: promoting well-being and minimizing risk of harm, maintaining trust, respect for persons and fostering autonomy, and promoting justice and equity.
Further information on is available elsewhere.
For this statement, NACI reviewed evidence pertaining to the burden of IPD in the target population(s), the safety, immunogenicity, efficacy, and effectiveness of the vaccine(s), vaccine schedules, and other aspects of the overall adult pneumococcal vaccine immunization strategy. The knowledge synthesis was performed by NACI Secretariat and reviewed by the Pneumococcal Working Group. Following critical appraisal of individual studies, summary tables with ratings of the certainty of the evidence using GRADE methodology were prepared . An assessment using the Evidence to Decision (EtD) framework was prepared for each question, and proposed recommendations for vaccine use were developed . NACI reviewed the available evidence on May 19, 2022, July 4, 2022, and Sept 12, 2022. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described.
# II.1 Burden of IPD
IPD has been nationally notifiable in Canada to the Canadian Notifiable Disease Surveillance System (CNDSS) since 2000, with all provincial and territorial jurisdictions reporting cases meeting the national case definition. Cases not captured by CNDSS may include those that do not get medical attention, those where clinical measures were applied with no specimen being taken. Information such as serotype, antimicrobial susceptibility, vaccine coverage as well as other enhanced epidemiological patient information are not reported through the CNDSS.
The national surveillance line list data used to assess the burden of IPD among different age groups were available from the CNDSS for six provinces (BC, AB, SK, ON, QC, and PEI) and from the International Circumpolar Surveillance (ICS) program for the three territories (YK, NU, and NT). Some provinces (MB, NS, NL, NB) were not included in the national surveillance line list as they provided aggregate data with broad age group intervals which could not be broken down to compare the IPD burden in different age groups among older adults in Canada. All cases were presumed to meet the national case definition of IPD. More information about the CNDSS data is provided on the website.
Northern regions of Canada captured in the ICS system include Nunavut, Northwest Territories, Yukon, Northern Labrador, and Northern Quebec. The incidence of IPD in these regions was compared to IPD incidence from all other PTs using aggregate CNDSS data.
The National Microbiology Laboratory (NML) collaborates with provincial and territorial public health laboratories to conduct passive, laboratory-based surveillance of IPD in Canada . All IPD isolates from the provincial/territorial public health laboratories are serotyped by the NML, although specimen collection may be limited by variable regional standards, the preliminary nature of some data and the availability of bacterial isolates for testing. Serotype data may also be biased toward over representing more virulent serotypes for which medical treatment is sought and clinical specimens taken. Despite these limitations, the passive national surveillance program from 2015 – 2019, including additional data submitted by the provincial reference laboratories of Alberta and Quebec, provided timely reporting of serotype distributions, and accounted for 80 to 98% of all IPD cases reported to CNDSS. In 2020 , a total of 2,067 isolates were reported to the NML, representing 94.3% of the 2,193 reported by all PTs to the CNDSS (preliminary 2020 data).
For vaccine serotype groupings, serotype 6C was included with PNEU-C-13 serotypes due to cross protection with 6A . Serotypes 15B and 15C were grouped together as 15B/C because of reported reversible switching between them *in vivo- during infection, making it difficult to precisely differentiate between the two types .
# II.2 Literature Review of PNEU-C-15 and PNEU-C-20 studies
The policy question addressed in this statement is: What is the efficacy, effectiveness, and safety of PNEU-C-15 and PNEU-C-20, administered in series with or without PNEU-P-23, when used with the objective to reduce the risk of IPD in adults.
Population: Adults 50 years of age or older without IPD risk factors; adults 18 years or older with IPD risk factors ().
Intervention: PNEU-C-15 or PNEU-C-20, alone and in series with PNEU-P-23 (depending on the population group of interest).
Comparator: Currently recommended age and risk factor-appropriate pneumococcal vaccine schedule.
Outcomes: Death due to vaccine preventable serotype *S. pneumoniae*, IPD due to vaccine preventable pneumococcal serotype, IPD due to any pneumococcal serotype (vaccine preventable and not vaccine preventable), pneumococcal community-acquired pneumonia (pCAP) due to a vaccine preventable serotype, serious adverse events (SAEs), severe systemic adverse events (AEs), and mild/moderate systemic AEs following vaccination. Outcomes were accompanied by definitions and are summarized in the appendix (see ).
In the absence of disease endpoint and mortality data, immunogenicity (opsonophagocytic geometric mean titer ratios and percentage of seroresponders defined as greater or equal to a 4-fold increase in OPA GMT ratio from before vaccination to after vaccination) was evaluated.
Safety and immunogenicity data for PNEU-C-15 and PNEU-C-20 in adults from key clinical trials, published studies, and supplementary data obtained from manufacturers were reviewed. Data were extracted from eligible studies related to the study design, population, intervention, comparator, and outcomes of interest. The RoB () for each study was assessed using the Cochrane Risk of Bias Tool . The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework () was used to assess the certainty in evidence.
Meta-analytic techniques were used to synthesize adverse event data; statistical heterogeneity was considered using a combination of factors (direction of estimates, overlapping confidence intervals, and the Cochran Q and I-squared statistics). For I-squared statistics, a rough guide of low (0-25%), moderate (25-50%), substantial (50-75%), and considerable (75-100%) was used. For binary outcomes and where event rates were low (using 1% as a rough guide), the Peto Odds Ratio was used; otherwise, the Risk Ratio was used. Where possible to do so, relative effect measures were used to calculate risk differences, aligning with the GRADE approach. For immunogenicity, narrative syntheses were used, and heterogeneity was determined according to the direction of effect, using the magnitude of the estimates. The focus for GMT ratios was the study investigators’ demonstration of non-inferiority for shared serotypes between vaccines. For the percentage of seroresponders, point estimates were used to gauge the direction of effect based on those magnitudes. It is important to note, however, that no immunologic correlates of protection have been established for PD.
For the GRADE certainty of evidence assessments (), control group data from studies were used to estimate baseline risk. The use of surrogate measures was the main consideration for indirectness. The review information sizes of 400 people with events for binary data, at least 4,000 people analyzed for small event rates, and 800 people for continuous data were used to inform imprecision when confidence intervals were not importantly wide. Planned subgroup analyses was not undertaken for the age-based recommendation owing to the nature of the data and insufficient number of studies. Sensitivity analyses were undertaken to restrict analyses to studies at a low RoB, where applicable, to see if the results changed appreciably. Too few studies were located to perform a test for small study effects.
Modifications to scope and process during conduct of the review: (a) an evaluation for the 75 years and older age group was added for the age-based recommendation; (b) expansion of eligibility to include additional vaccines administered concurrently with pneumococcal vaccines; and (c) full verification of data extraction, RoB assessments, and GRADE assessments were reduced to partial verification or single person review to facilitate a rapid review of the evidence.
# II.3 Literature review of PNEU-C-15 and PNEU-C-20 cost-effectiveness
A systematic review of the cost-effectiveness of PNEU-C-15 and PNEU-C-20 vaccines for preventing IPD was conducted. The search included economic evaluations conducted in adults aged 18 years or older, comparing currently used vaccines to prevent IPD to PNEU-C-15 or PNEU-C-20. The components of the research question are summarized as:
- Population: Adults aged 18 years or older
- Intervention: PNEU-C-15 or PNEU-C-20 (alone or in series with other pneumococcal vaccines)
- Comparator: Current pneumococcal vaccines (PNEU-C-7, PNEU-C-10, PNEU-C-13, PNEU-P-23)
- Outcomes: Measures of cost-effectiveness (incremental cost per quality-adjusted life year , incremental cost per disability-adjusted life year , and cost per life year, etc.)
Additional details of the economic literature review are provided in a supplementary economic evidence appendix.
# II.4 NACI Cost-utility analysis and multi-model comparison
A model-based cost-utility analysis was conducted from health system and societal perspectives. A Markov cohort model was developed to compare the benefits (in QALYs) and costs (in 2022 Canadian dollars) associated with using PNEU-C-15 or PNEU-C-20, either alone or in series with PNEU-P-23, compared to PNEU-P-23 alone. Vaccination was evaluated at ages 50, 65, or 75. The Northern Canadian Territories were assessed separately from the rest of Canada to account for higher PD incidence in the north. The primary outcome was the incremental cost-effectiveness ratio (ICER). The analysis used a lifetime time horizon and 1.5% discount rate. Scenario and sensitivity analyses were conducted to examine the impact of uncertainties in model parameters and assumptions.
To evaluate the robustness of the cost-utility model, a multi-model comparison was conducted using two additional cost-utility models developed by the manufacturers of PNEU-C-15 and PNEU-C-20 with different structures and assumptions. Wherever possible, all models were modified to use the same input parameters. ICERs for a single base case were compared across models.
Additional details of the cost-utility analysis and multi-model comparison are provided in a supplementary economic evidence appendix.
III. Epidemiology
# III.1 IPD burden in Canada
Based on the data from CNDSS, the incidence rate of IPD in children under 5 years of age decreased from 41.8 cases to 15.7 cases per 100,000 population between 2003 and 2006. Following a few years of increasing incidence, IPD incidence rates in children under 5 years have remained relatively steady at around 12 cases per 100,000 population since 2012 (). Children aged 5 to17 years consistently had the lowest IPD incidence rate, remaining below 5 cases per 100,000 population during the 2001-2019 study period. Canadians aged 18 to 49, 50 to 64 and 65 years and older showed similar trends with increased IPD incidence from 2001 to 2004, probably due to improvements in diagnosis and reporting, followed by relatively stable incidence rates in the subsequent 15 years. The incidence rate in adults 65 year of age and older was reported to be consistently higher by approximately 10 to 15 cases per 100,000 population than in adults aged 50 to 64 years old (e.g., in 2019, it was reported at 25 cases and 14 cases per 100,000 population, respectively). Adults aged 18 to 49 years consistently had the second lowest IPD incidence rates compared to other age groups, maintaining an incidence around 5 cases per 100,000 population from 2001-2019.
Text Description
IPD incidence is directly proportional to age in persons 50 years of age and older (). From 2011-2019, IPD incidence rates were highest in the oldest age group (85 years and older). In the other age groups, the incidence rates fluctuated slightly but remained relatively steady from 2011-2019. In Canadians aged 85 years and over, however, the incidence decreased from 50 to 40 cases per 100,000 population between 2011 and 2016. After 2016, incidence rates fluctuated ranging from 39 to 46 cases per 100,000 population, with a mean of 42 cases per 100,000 population. Incidence rates in the other age groups were approximately: 12 to 13 cases per 100,000 population in the 50 to 64 year-old age group; 19-20 cases per 100,000 population in the 65 to 74 year-old age group; and 26-28 cases per 100,000 population in the 75-84 year-old age group.
Text Description
The Toronto Invasive Bacterial Diseases Network (TIBDN) , an active surveillance program in Metropolitan Toronto and the Peel region, found that between 2012/2013 and 2018/2019, the incidence of IPD in adults aged 15 to 64 years increased significantly from 3.7 to 5.4 cases/100,000/year. During this same period, the incidence of IPD in adults aged 65 years and older decreased from 22.8 to 18.7 cases/100,000/year; however, this change was not significant. TIBDN also found that from 2018/2019 to 2020, IPD incidence in adults aged 15 to 64 years decreased from 5.4 to 2.6 cases/100,00/year, and IPD incidence in adults 65 years and older decreased from 18.7 to 8.7 cases/100,000/year.
## III.1.2 IPD incidence in Northern Canada
The age-standardized incidence rate in Northern Canada, based on the data submitted to ICS, was significantly higher (25.8 cases per 100,000 population, 95% CI: 23.5 to 28.1%) than the rest of Canada (9.1 cases per 100,000 population, 95% CI: 9.1 to 9.2%) between 2001 and 2019 () .
In northern Canada, the IPD incidence rate in Indigenous Canadians was significantly higher at 31.3 cases per 100,000 population per year compared with non-Indigenous Canadians at 7.0 cases per 100,000 population per year (p<0.0001) for the same time period .
Text Description
The incidence rate of IPD was consistently and significantly higher in Northern Canada when compared to the rest of Canada, with an exception of the year 2017, which was the minimum IPD incidence rate in Northern Canada at around 15 cases per 100,000 population. In this year, the incidence was still higher in Northern Canada but not significantly. The maximum overall IPD incidence rate Northern Canada occurred in 2001 with 38 cases per 100,000 population. The incidence rate subsequently decreased to 16 cases per 100,000 population in 2005 following the introduction of pediatric pneumococcal immunization in Canada. Since 2005, the IPD incidence rate fluctuated yet remained relatively stable, and was most recently calculated as 23 cases per 100,000 population in 2021. IPD cases have remained slightly elevated from 2018 to 2021 when compared to 2015 to 2017.
# III.2 Distribution of IPD Serotypes in Canada, 2016 – 2020
Distribution of IPD Serotypes in Canada, 2016 – 2020
From 2016 to 2020, a combined 15,234 isolates of *S. pneumoniae- causing invasive disease were characterized by the NML with 34% of these being identified from adults 65 years of age or older. The majority of IPD cases were caused by vaccine-contained serotypes (). Serotypes 3 and 22F were identified as the most common causes of IPD overall and in older adults based on isolates submitted to NML ().
Overall, the proportion of IPD isolates covered by each vaccine (PNEU-C-13, PNEU-C-15/non-PNEU-C-13, PNEU-C-20/non-PNEU-C-15 and PNEU-P-23/non-PNEU-C-20) have remained relatively stable since 2016 (). In 2020, among adults 65 years old or older, 27.4% of circulating serotypes were covered by PNEU-C-13, 40.6% were covered by PNEU-C-15, 55.8% were covered by PNEU-C-20 and 66.9% were covered by PNEU-P-23. Circulating serotypes not covered by any pneumococcal vaccine amounted to 33.1%.
Serotype distribution for IPD among adults are summarized in .
\- Component of PNEU-C-13; \*\- Component of PNEU-C-15; ^ Component of PNEU-C-20; ~ Component of PNEU-P-23; ‡ Number of isolates for all ages and adults 65 years and older, respectively (2016-2020, combined total).
Text Description
\*Vaccine serotypes include PNEU-C-13 (1, 3, 4, 5, 6A/C, 6B, 7F, 9V, 14, 19A, 19F, 18C, 23F); PNEU-C-15 (all PNEU-C-13 plus 22F and 33F); PNEU-C-20 (All PNEU-C-15 plus 8, 10A, 11A, 12F, 15B/C) and PNEU-P-23 (PNEU-C-20 serotype except 6A, plus 2, 9N, 17F, 20); NVT = all serotypes not included in PNEU-C-13, PNEU-C-15, PNEU-C-20 and PNEU-P-23. Serotype 6C included in PNEU-C-13 Serotypes due to cross protection with 6A. Serotypes 15B and 15C were grouped together as 15B/C because of reported reversible switching between them in vivo during infection, making it difficult to precisely differentiate between the two types.
Text Description
non-PNEU-C-13
non-PNEU-C-15
non-PNEU-C-20
Distribution of IPD serotypes in Northern Canada
IPD distribution in Northern Canada was assessed using data from all five Arctic regions captured in the ICS system. Overall, there were 159 isolates of invasive *S. pneumoniae- characterized between 2016 and 2020: 26% of *S. pneumoniae- isolates were PNEU-C-13 serotypes, 14% were PNEU-C-15/non-PNEU-C-13 serotypes, 23% were PNEU-C-20/non-PNEU-C-15 serotypes, 20% were PNEU-P-23/non-PNEU-C-20 serotypes, and 16% were NVT serotypes. However, trends were difficult to ascertain due to the small number of cases and relatively smaller population in the North.
# III.3 Burden of Pneumococcal community acquired pneumonia in Canada
Using CIRN SOS Network data from 13 hospitals across five provinces, Leblanc et al. (2022) reported on CAP incidence in hospitalized adults from 2010 to 2017 . During this period, 14.2% (1264/8912) of all-cause CAP was found to be caused by *S. pneumoniae- with 64.1% (811/1264) being non-bacteremic, and 35.9% (455/1264) being bacteremic. Among pCAP cases in adults, 49.8% occurred in those over 65 years of age, 31.3% in those 50 to 64 years of age and 19.0% in those 16-49 years of age. Among all pCAP cases, 89.1% had one or more co-morbidity, and 28.6% had an immunocompromising condition. Of all *S. pneumoniae- CAP cases captured during the study period, the serotype distribution showed serotypes 3, 7F, 9N, 11A, 19A, and 22F as common.
Data from the 2018 to 2019 Discharge Abstract Database (Canadian Institute for Health Information 2022) reported inpatient CAP cases per 100,000 with pneumonia as a significant diagnosis (excluding pneumonia due to influenza). These data showed that for adults 75 years of age and older, there were 5,104 cases/100,000 population in Northern Canada and 2,846 cases/100,000 population across the rest of Canada; for adults 60 to 74, there were 1,777/100,000 population cases in Northern Canada and 871/100,000 population across the rest of Canada; and for adults 50 to 64 years, there were 569 cases/100,000 population in Northern Canada and 348 cases/100,000 population across the rest of Canada.
# III.4 High Risk Groups
The TIBDN found that, in their population, IPD incidence among individuals aged 15 to 64 years with chronic underlying illness increased significantly from 7.3 cases/100,000/year in 2012 to 11.0 cases/100,000/year in 2019. During the same time period, the IPD incidence among adults aged 65 years and older decreased in those with underlying illness mainly because IPD cases due to PNEU-C-13 contained serotypes decreased from 10.0 to 4.6 cases/100,000/year in people with an underlying chronic illness, and from 27.0 to 16.0 cases/100,000/year in people with immunocompromising conditions.
The Calgary Area *Streptococcus pneumonia- Epidemiology Research (CASPER) program, an active surveillance program in Calgary, found that between 2000 to 2013, IPD incidence rate among adults with underlying comorbidities decreased by 37% .
# III.5 Summary of Pneumococcal Immunization Coverage in Canada
The Vaccine Coverage and Effectiveness Monitoring program at PHAC collects pneumococcal vaccination coverage information among Canadians as part of the seasonal influenza vaccination coverage survey . The most recent survey conducted over the 2020-2021 influenza season showed that about 55% of adults65 years of age and over reported receiving a pneumococcal vaccine in adulthood. The coverage was higher for females (60%) than males (40%). Overall, 26% of adults 18 to 64 years old with underlying medical conditions reported receiving pneumococcal vaccination. The survey did not differentiate between the two different pneumococcal vaccines recommended for adults.
IV. Vaccine
# IV.1 Preparations authorized for use in Canada
Four preparations of pneumococcal vaccine are currently authorized for use in adults in Canada ().
PNEU-C-13 (Prevnar®13) is a sterile solution of polysaccharide capsular antigen of 13 serotypes of *S. pneumoniae- (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F). The antigens are individually conjugated to a diphtheria, *Corynebacterium diphtheriae- (CRM197), protein carrier. The CRM197 protein carrier is adsorbed on aluminum phosphate as an adjuvant. Each dose of vaccine contains 4.4 mcg of the 6B polysaccharide, and 2.2 mcg each of the remaining polysaccharides. PNEU-C-13 is available as a 0.5mL single dose, prefilled syringe.
PNEU-C-15 (Vaxneuvance®) is a sterile suspension of purified capsular polysaccharides from 15 serotypes of *S. pneumoniae- (PCV13 serotypes plus serotypes 22F and 33F). The antigens are individually conjugated to diphtheria CRM197 protein carrier. This CRM197 protein carrier is adsorbed on aluminum phosphate as an adjuvant. Each dose of vaccine contains 32 mcg of total pneumococcal polysaccharide (2.0 mcg each of polysaccharide Serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F, and 4.0 mcg of polysaccharide serotype 6B) conjugated to 30 mcg of CRM197 carrier protein. PNEU-C-15 is available as a 0.5mL single-dose prefilled syringe.
PNEU-C-20 (Prevnar 20TM) is a sterile saccharide suspension of the capsular antigens of 20 serotypes of *S. pneumoniae- (PCV13 serotypes + serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F). The antigens are individually conjugated to non-toxic diphtheria CRM197 protein. This CRM197 protein carrier is absorbed on aluminum phosphate as an adjuvant. Each dose of vaccine contains 4.4 mcg of the 6B polysaccharide, and 2.2 mcg each of the remaining polysaccharides. PNEU-C-20 is supplied as a 0.5mL single dose prefilled syringe.
PNEU-P-23 (Pneumovax®23) is a sterile solution of 23 highly purified capsular polysaccharides (PCV13 serotypes with the exception of 6A, plus serotypes 2, 9N,17F, and 20). PNEU-P-23 is available as a single-dose vial containing 0.5 ml of liquid vaccine and a 0.5mL single dose prefilled syringe.
aluminum (as aluminum phosphate adjuvant),
1.55mg of L-histidine, 1 mg of polysorbate 20,
4.50 mg of sodium chloride and water for
- Pregnancy (limited data)
- Breastfeeding (limited data)
- Pregnancy (limited data)
- Breastfeeding (no data)
- Pregnancy (limited data)
- Breastfeeding (limited data)
- Breastfeeding (no data)
# IV.2 Efficacy and effectiveness
There are currently no efficacy or effectiveness data available for PNEU-C-15 or PNEU-C-20 for any adult indication.
Recently reported systematic reviews continue to support the effectiveness of PNEU-C-13 against IPD and pneumococcal pneumonia among adults 65 and older . Two observational studies included in the systematic review by Childs et al found a PNEU-C-13 vaccine effectiveness against pneumonia caused by vaccine-contained serotypes in the range of 38 to 68%. Three observational studies from the systematic review by Farrar et al found a PNEU-C-13 effectiveness against IPD caused by vaccine-contained serotypes in the range of 59 to 68%.
A recent systematic review reported a pooled PNEU-P-23 effectiveness against IPD caused by vaccine-contained serotypes in adults 65 years of age and older to be 38%. Another systematic review found a limited protection against pneumonia caused by vaccine-contained serotypes (pooled effectiveness of 18% from 3 observational studies with PNEU-P-23 given to adults 65 years and older less than 5 years before illness onset).
# IV.3 Immunogenicity
## IV.3.1 Measures of Immunogenicity
OPA assays were used to assess immune response for PNEU-C-15 and PNEU-C-20. While no specific threshold of OPA titer has been identified that correlates with protection against IPD or pneumonia in adults, OPA responses have been used as an established surrogate of protection to infer efficacy when comparing to an efficacious vaccine.
Previously, OPA responses were used as a surrogate marker of vaccine efficacy for IPD and pneumonia in the approval of PNEU-C-13 in adults.
## IV.3.2 Immunogenicity of PNEU-C-15
Summary of PNEU-C-15 study characteristics
Immunogenicity of PNEU-C-15 was evaluated in two Phase 2 trials and five Phase 3 trials . Three studies evaluated medically stable, vaccine-naïve adults 50 years of age or older and one study focused on previously vaccinated adults 65 years of age and older. Data for adults 18 years of age and older with medical risk factors for PD were available in two studies (one as a study population subset analysis). One study evaluated adults with HIV. Most studies had participants of a majority white race and with gender balance (). Immunogenicity assessments were at a low RoB ().
Summary of PNEU-C-15 immunogenicity evidence
In immunocompetent pneumococcal vaccine-naïve adults 65 years of age and older, for shared serotypes, PNEU-C-15 demonstrated overall similar immune responses, including for serotype3, compared to PNEU-C-13 (). All analyses for serotypes not covered by PNEU-C-13 showed numerically higher responses with PNEU-C-15. However, seroresponses varied for the shared serotypes. Results from studies comparing PNEU-C-15 to PNEU-P-23 showed similar results, although seroresponse was higher with serotype3 with PNEU-C-15 (Appendix A, Tables and ).
While no studies evaluated non-inferiority for other age groups (50 to 64 years; 65 to 74 years; 75 years of age and older) observational comparisonsamong age groups and age subgroup data for seroresponse are reported in Appendix A, Tables and . Non-inferiority for shared serotypes was not evaluated in the comparison with PNEU-C-13 for adults with previous PNEU-P-23 vaccination (), and adults with immunocompromising conditions ().
In pneumococcal vaccine-naïve adults over the age of 65, PNEU-C-15 administered concurrently with quadrivalent seasonal influenza vaccine, seroresponses were found to be similar for serotype 3 but numerically lower for the other shared serotypes (). In adults who subsequently received PNEU-P-23 following the receipt of PNEU-P-15, there was an observed numerically lower proportion of seroresponders with serotype 3, PNEU-C-15 unique serotypes, as well as some shared serotypes when compared to seroresponse rates following previous PNEU-C-13 vaccination in series with PNEU-P-23 for some shared serotypes ().
Non-inferiority for shared serotypes was not evaluated in the comparison with PNEU-C-13 for adults with previous PNEU-P-23 vaccination (), as well as people with chronic medical conditions (CMC) 18 to 64 years of age () and with immunocompromising conditions ().
## IV.3.3. Immunogenicity of PNEU-C-20
Summary of PNEU-C-20 study characteristics
Immunogenicity of PNEU-C-20 was evaluated in one Phase 2 trial3 and two Phase 3 trials . Two trials evaluated vaccine-naïve healthy adults, as well as adults with underlying CMCs. Of these studies, one recruited participants 60 to 64 years of age while the other enrolled participants 18 years of age or older into three age cohorts (i.e., 18 to 49, 50 to 59, 60 years and older). One study evaluated immune responses in previously PNEU-P-23 vaccinated adults 65 years of age or older. Studies were assessed to be at low RoB ().
Summary of PNEU-C-20 immunogenicity evidence
Non-inferiority criteria were met following the administration of PNEU-C-20 in vaccine-naïve populations over age 60. However, there was an observed lower proportion of seroresponders compared to PNEU-C-13 for shared serotypes (). While PNEU-C-20 was not directly compared to PNEU-C-13 or PNEU-P-23, individuals previously vaccinated with PNEU-P-23, PNEU-C-13 or both, showed robust immune responses following PNEU-C-20 vaccination (Appendix A, Tables and ). PNEU-C-20 was not evaluated in adults with immunocompromising conditions.
# IV.4 Persistence of Immune Response
Persistence of PNEU-C- 15 immune response
Persistence of PNEU-C-15 immune response was observed 8 weeks , 6 months and 1 year following the sequential administration of PNEU-P-23 in adults 18 years of age or older living with immunocompromising conditions, in adults 18 to 49 living with CMCs and in healthy adults 65 years of age or older. In general, OPA GMTs at 8 weeks, 6 months and 1 year were lower than at day 30 post PNEU-C-15 vaccination but higher than at baseline. PNEU-C-15 elicited an immune response that was comparable to PNEU-C-13 at 30 days and 8 weeks, 6 months, and 12 months post- vaccination for the 13 shared serotypes and higher than PNEU-C-13 for the 2 serotypes 22F and 33F unique to PNEU-C-15.
Persistence of PNEU-C-20 immune response
Persistence of PNEU-C-20 immune response was observed at 12 months in healthy adults aged 60 through 64 years with no history of pneumococcal vaccination . OPA GMTs at 12 months declined compared with those at 30 days after vaccination but remained elevated above baseline. The same pattern of antibody decline in the 12 months after vaccination has previously been observed with PNEU-C-13. However, vaccine effectiveness against pneumonia caused by serotypes in the vaccine did not decline through 4 years of follow-up .
# IV.5 Vaccine Administration and Schedule
PNEU-C-15 and PNEU-C-20 are supplied in a single-dose, prefilled syringe.
A 0.5mL dose of PNEU-C-15 should be administered intramuscularly. The standard schedule for immunization is one dose. The need for a booster dose or re-immunization is not indicated. Please see the product monograph for additional details .
A 0.5mL dose of PNEU-C-20 should be administered intramuscularly. The standard schedule for healthy adults is one dose. Please see the product monograph for additional details .
# IV.6 Serological Testing
Serological testing is not recommended before or after receiving pneumococcal vaccine.
# IV.7 Storage Requirements
PNEU-C-15 should be refrigerated at 2°C to 8°C. The vaccine should not be frozen. Protect the vaccine from light. The prefilled syringes should be administered as soon as possible after being removed from the refrigerator .
PNEU-C-20 should be refrigerated at 2°C to 8°C. The pre-filled syringes should be stored horizontally in the refrigerator to minimize the re-dispersion time. The vaccine should be discarded if it has been frozen. The vaccine should be administered as soon as possible after being removed from the refrigerator .
# IV.8 Concurrent Administration with Other Vaccines
PNEU-C-15 and PNEU-C-20 can be concurrently administered with quadrivalent inactivated influenza vaccine (QIV) in adults, as concurrent administration has been demonstrated to be immunogenic and safe . However, lower pneumococcal OPA GMTs were reported when pneumococcal vaccines were co-administered with QIV compared with when pneumococcal vaccines were given alone . No data are available on co-administration of PNEU-C-15 or PNEU-C-20 with other adult vaccines. Preliminary data on the co-administration of PNEU-C-20 and the Pfizer-BioNTech Comirnaty mRNA COVID-19 vaccine showed no significant interference in the immune response .
# IV.9 Vaccine Safety
Summary of PNEU-C-15 study characteristics
Safety of PNEU-C-15 was evaluated in two Phase 2 trials and five Phase 3 trials . Data on local and systemic AEs were solicited through electronic vaccine report cards for two weeks after each dose, as well as follow up for serious events for 6 months. Reported outcomes included SAEs, vaccine-related SAEs, as well as mild/moderate and severe systemic AEs (i.e., fever, fatigue, headache, muscle, and joint pain). Safety data was reported for pneumococcal vaccine-naïve individuals, concurrent administration with season influenza vaccine, and for specific populations of interest including adults aged 18 to 64 years with chronic medical or immunocompromising conditions, and previously vaccinated adults aged 65 years or older. Six studies were at low RoB for all domains. In one study the reasons for missing data were not reported in the assessment of SAEs and vaccine-related SAEs, which is challenging.
Summary of PNEU-C-15 Safety
There was little to no difference reported in clinical trials between PNEU-C-15 and PNEU-P-23 or PNEU-C-13 for all mild/moderate and severe systemic AEs occurring within 14 days of vaccination as well as reported SAEs up to six months after vaccination in all evaluated populations (Appendix A, Tables , and to ). Results were similar following sequential administration of PNEU-P-23 after PNEU-C-15 or PNEU-C-13 in adults 65 years of age or older with an immunocompromising condition (Appendix A, Tables and ).
There was little to no difference in SAEs for PNEU-C-15 administered concomitantly with QIV for vaccine-naïve adults (). Results were similar with respect to severe fatigue, joint and muscle pain up to 14 days after vaccination. There was no difference between groups for severe and mild/moderate systemic AEs.
Summary of PNEU-C-20 study characteristics
The safety of PNEU-C-20 was primarily evaluated for GRADE in one Phase 2 trial and two Phase 3 trials . Data were available for pneumococcal vaccine-naïve adults 18 years of age and older, and previously vaccinated adults 65 years of age and older. The full safety evaluation included 6 pre-licensure clinical trials, with safety data collection including solicited local reactions within 10 days of vaccination and systemic events within 7 days. Unsolicited events were collected for 1 month after vaccination and SAEs and newly diagnosed CMCs within 6 months after vaccination.
Safety of PNEU-C-20
There was little to no difference between PNEU-C-20 and PNEU-C-13 in SAEs up to one month post-vaccination for vaccine-naïve adults aged 60 years or older. Results showed no difference for all mild/moderate and severe systemic AEs up to seven days post-vaccination. Certainty of evidence varied across assessments ranging from moderate to high ().
For adults 65 years of age and older previously vaccinated with PNEU-P-23 one to five years prior, SAEs up to six months and systemic AEs 7 days after vaccination were similar between PNEU-C-20 and PNEU-C-13 (). Findings were similar when PNEU-C-20 and PNEU-P-23 were compared among those previously vaccinated with PNEU-13 at least six months prior ().
# IV.10 Contraindications and Precautions
PNEU-C-15 and PNEU-C-20 are contraindicated in individuals with a history of a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine or any diphtheria toxoid-containing vaccine. Administration of vaccine should be postponed in persons suffering from acute severe febrile illness.
V. Vaccination of Specific Populations
# V.1. Immunization in Pregnancy and Breastfeeding
There are no adequate and well-controlled studies of PNEU-C-15 and PNEU-C-20 in individuals who are pregnant or breastfeeding.
# V.2. Immunization of Immunocompromised persons
Individuals with altered immunocompetence, including those receiving immunosuppressive therapy, may have a reduced immune response to the vaccine.
VI. Ethics, Equity, Feasibility and Acceptability Considerations
NACI uses a published, peer-reviewed framework and evidence-informed tools to ensure that issues related to ethics, equity, feasibility, and acceptability (EEFA) are systematically assessed and integrated into its guidance .
NACI evaluated the following ethical considerations when making its recommendations: promoting well-being and minimizing risk of harm, maintaining trust, respect for persons and fostering autonomy, and promoting justice and equity. NACI took into account the available evidence from the clinical studies of PNEU-C-15 and PNEU-C-20 along with the real-world evidence on the effectiveness and safety of currently available pneumococcal vaccines PNEU-C-13 and PNEU-P-23, as well as data on the burden of illness of PD and evolving serotype distribution, and risk factors in particular for IPD.
Achieving coverage of 80% of adults 65 years old or older vaccinated with a pneumococcal vaccine, as well as reducing overall burden of disease by 5% by 2025, is one of the goals of the Canadian national immunization strategy. However, vaccine uptake in adults 65 years of age or older is well below the target, with approximately 55% reporting receiving a pneumococcal vaccine in Canada. Uptake is even lower among younger adults 18 to 64 years of age with underlying medical conditions that predispose them to PD at approximately 26%). A survey conducted in Quebec in 2020 reported that lack of awareness that the pneumococcal vaccine is needed or recommended is the most frequent reason for not being vaccinated.
The new higher-valent pneumococcal conjugate vaccines offer an opportunity to protect individuals against additional serotypes and further reduce the burden of disease in adults. PNEU-C-20 covers more than 90% of serotypes included in PNEU-P-23, with the additional benefits of conjugate vaccines. Thus, PNEU-C-20 may be offered in programs as a single dose without a subsequent dose of PNEU-P-23, unlike PNEU-C-15 which is recommended to be administered in series with PNEU-P-23 to optimize protection. A single dose vaccine schedule minimizes complexity and cost in a vaccine program and can facilitate vaccination of populations that are otherwise difficult to reach to complete a series requiring more than one dose.
Among factors that may contribute to health inequity as described in NACI’s EFFA framework, pre-existing disease, social factors, place of residence, and age are important to consider with pneumococcal recommendations. Pneumococcal disease burden increases with age and adults with pre-existing conditions are at greater risk. Therefore, by providing age-based and risk-based recommendations as well as inclusion of settings of higher disease burden, inequity may be reduced.
First Nations, Metis, or Inuit communities in Canada have a younger age distribution compared to the general Canadian population but have also been observed to have increased risk for severe PD due to a variety of intersecting factors including underlying medical conditions and potential decreased access to health care. Therefore, age-based recommendations may need to be modified to offer effective protection to individuals in these communities. Autonomous decisions should be made by Indigenous Peoples with the support of healthcare and public health partners in accordance with the .
VII. Economics
A systematic review, de novo model-based economic evaluation, and a multi-model comparison were used as economic evidence to support decision-making for the use of PNEU-C-15 and PNEU-C-20.
Full details of these analysis, including assumptions and limitations, are provided in a supplementary appendix.
A review of the peer-reviewed and grey literature identified four cost-utility studies of PNEU-C-15 and PNEU-C-20 compared to current vaccination recommendations for adults in the United States (that are PNEU-P-23 plus optional PNEU-C-13 under shared clinical decision-making for adults aged 65 years or older; PNEU-P-23 at diagnosis of CMCs if under age 65 years; and PNEU-C-13 in series with PNEU-P-23 at diagnosis of immunocompromising condition if under age 65 years) . The studies generally found that PNEU-C-20 use in older adults was associated with increased QALYs, and with lower ICERs when the vaccine was used in adults aged 65 years and older compared to programs in adults aged 50 years and older. ICER estimates for PNEU-C-15 use in series with PNEU-P-23 at age 65 showed variability across studies. The estimated impact of adding risk-based programs for younger adults with IC/CMC to an age-based strategy depended on the vaccine product, with lower ICERs reported for PNEU-C-20 than for PNEU-C-15 in series with PNEU-P-23.
A cost-utility model developed by NACI was used to evaluate the cost-effectiveness of different age-based recommendations for PNEU-C-15 and PNEU-C-20 vaccines (used alone or in series with PNEU-P-23) in the Canadian population compared to current recommendations. Results are presented for the health system perspective. The base-case analysis, supported by scenario analyses, indicated that PNEU-C-20 used alone is likely a cost-effective strategy at age 65 or 75, with ICERs ranging from $6,500 to $17,400 per QALY gained. The ICERs for PNEU-C-20 at age 50 were higher than for ages 65 or 75. In sequential analysis that compared all possible vaccination strategies, PNEU-C-15 was dominated (more costly and less effective) or subject to extended dominance (i.e., would never be the optimal option regardless of the cost-effectiveness threshold) by PNEU-C-20. PNEU-C-20 plus PNEU-P-23 at age 65 or age 75 had ICERs ranging from 80,000 to $113,500 per QALY gained. Findings were sensitive to the assumed vaccine prices for PNEU-C-15 and PNEU-C-20 (see supplementary appendix). Analysis of populations in Northern Canada showed similar trends as the rest of Canada.
In a multi-model comparison, three cost-utility models with harmonized parameter values and using the same health system perspective and discount rate, showed qualitatively consistent results despite differing model structures and assumptions. The comparison supported the finding that, based on currently available data, PNEU-C-20 used alone ($4,100-106,000 per QALY gained) could be a cost-effective strategy for use in the adult Canadian population, depending on the cost-effectiveness threshold used. All models estimated PNEU-C-15 or PNEU-C-15 in series with PNEU-P-23 to be dominated (more costly and less effective) or subject to extended dominance (would never be the optimal option regardless of the cost-effectiveness threshold) by PNEU-C-20.
VIII. Recommendations
Following the review of available evidence summarized above, NACI makes the following recommendations for public health level decision-making. Considerations in the management options table should also be reviewed in order to inform decision making.
A *strong recommendation- applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
A *discretionary recommendation- may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.
Please see for a more detailed explanation of strength of NACI recommendations () and the GRADE assessment of the body of evidence ().
NACI will continue to carefully monitor the scientific developments related to pneumococcal vaccination in adults and will update recommendations as evidence evolves.
# VIII.1 Recommendations for Public Health Program Level Decision-Making
In considering NACI recommendations for publicly funded immunization programs and for the purposes of publicly funded program implementation, provinces and territories may take into account other local operational factors (e.g., current immunization programs, resources). Recognizing that there are differences in operational contexts across Canada, jurisdictions may wish to refer to Management Options Tables and below for a summary of the considerations for using different products (e.g., with respect to cost-effectiveness and feasibility).
For adults not previously vaccinated with a pneumococcal vaccine, or adults whose vaccination status is unknown
1. NACI recommends that pneumococcal conjugate vaccine PNEU-C-20 should be offered to pneumococcal vaccine naïve adults or adults whose vaccination status is unknown and who are 65 years of age and older, or who are 50 to 64 years of age living with risk factors placing them at higher risk of pneumococcal disease, or who are 18 to 49 years of age living with immunocompromising conditions. (Strong NACI recommendation).
Summary of evidence and rationale
- Conjugate vaccines induce memory, provide longer duration of protection, and provide ability for boosting by involving T cells in a way that polysaccharide vaccines cannot. The more durable protection offered by conjugate vaccines may result in fewer cases of PD, even though they protect against fewer serotypes than polysaccharide vaccine.
- In immunocompetent adults 65 years of age and older, PNEU-C-20 has been demonstrated to produce a similar (non-inferior) immune response compared to PNEU-C-13, although immune responses were noted to be lower following PNEU-C-20, and superior immune responses compared to PNEU-C-23 for shared serotypes.
- No PNEU-C-20 studies in immunocompromised adults have been conducted. Among persons with ICs for PD, PNEU-C-20 is expected to be similarly efficacious as PNEU-C-13 against disease attributable to the 13 matched serotypes.
- PNEU-C-20 has a comparable safety profile to PNEU-C-13 in adults.
- Immunization of older adults with PNEU-C-20 vaccine is expected to be cost-effective, based on the current burden of IPD and assumptions regarding pricing of the PNEU-C-15, PNEU-C-20, and PNEU-P-23.
- Individuals at increasing age and/or with certain underlying medical conditions (both non-immunocompromising and immunocompromising) and other risk factors are at higher risk of IPD (see ). Adults 65 years of age and older have the highest incidence rate of IPD compared to other adult age groups, followed by adults 50 to 64 years of age. However, the benefit of vaccinating adults 50 to 64 with underlying medical conditions or other risk factors that place them at higher risk for IPD are anticipated to be greater than vaccinating all adults in this age group.
- Age-based recommendations may need to be modified for communities with younger age distributions. In First Nations, Metis, or Inuit communities, autonomous decisions should be made by Indigenous Peoples with the support of healthcare and public health partners in accordance with the .
- Current uptake of pneumococcal vaccines among older adults and adults living with underlying medical conditions, both non-immunocompromising and immunocompromising, is well below national goals.
- Program feasibility and vaccine acceptability and uptake may be superior with single dose PNEU-C-20 as compared to a PNEU-C-15 + PNEU-P-23 strategy, the latter of which would require coordination of two doses of different vaccine products.
2. NACI recommends that PNEU-C-15 followed by PNEU-P-23 may be offered as an alternative to PNEU-C-20 to pneumococcal vaccine naïve adults or adults whose vaccination status is unknown and who are 65 years of age and older, or who are 50 to 64 years of age living with risk factors placing them at higher risk of pneumococcal disease, or who are 18 to 64 years of age living with immunocompromising conditions. (Discretionary NACI recommendation)
Summary of evidence and rationale
- In immunocompetent adults 65 years of age and older, PNEU-C-15 has demonstrated to produce a similar (non-inferior) immune response compared to PNEU-C-13 for shared serotypes.
- In adults with underlying medical conditions, including ICs, PNEU-C-15 has shown comparable immune responses to PNEU-C-13 for 13 shared serotypes.
- An interval between PNEU-C-15 and PNEU-P-23 of 1 year is recommended for adults 65 years of age and older and adults 50 to 64 years of age living with risk factors for PD to provide expanded protection to 8 additional serotypes not in PNEU-C-15.
- An interval between PNEU-C-15 and PNEU-P-23 of 8 weeks is recommended for adults 18 to 64 years of age living with ICs to provide expanded protection to additional serotypes not in PNEU-C-15 allowing for quicker completion of series in vulnerable population. A longer interval may result in less blunting of immune responses and could be considered if risk of pneumococcal infection if low.
- Although PNEU-C-15 is not expected to yield the same population-level epidemiological benefits as PNEU-C-20 and requires a second dose with PNEU-P-23, it is anticipated to improve disease outcomes compared to offering PNEU-P-23 alone.
- Although PNEU-C-20 dominated PNEU-C-15 + PNEU-P-23 in cost-effectiveness analyses, the results were sensitive to vaccine price. A large enough differential in vaccine price between PNEU-C-20 and PNEU-C-15 + PNEU-P-23 would result in similar cost-effectiveness (i.e., PNEU-C-15 + PNEU-P-23 would no longer be dominated).
For adults previously vaccinated with a pneumococcal vaccine
3. NACI recommends that pneumococcal conjugate vaccine PNEU-C-20 should be offered to adults 65 years of age and older who have been immunized previously with PNEU-P-23 alone, or PNEU-C-13 and PNEU-P-23 in series, if it has been at least 5 years from the last dose ofa previous pneumococcal vaccine (PNEU-P-23 or PNEU-C-13).(Strong NACI recommendation)
Summary of evidence and rationale
- Robust immune responses were reported for PNEU-C-20 in adults previously vaccinated with PNEU-P-23 alone or together with PNEU-C-13; however, the data were non-comparative to PNEU-C-13.
- PNEU-C-20 has shown little to no difference in safety profiles to PNEU-C-13 in adults 65 years of age and older previously vaccinated.
- An interval of 5 years between PNEU-P-23 and PNEU-C-20 takes advantage of the estimated effectiveness duration of PNEU-P-23 and the boosting anticipated with PNEU-C-20; it also maximizes the total duration of protection against pneumococcal infection.
- There may be benefit to offering PNEU-C-15 to adults 65 years of age and older who have received PNEU-P-23 alone if PNEU-C-20 is not available. For adults 65 years of age and older who are also at the highest risk of IPD, an additional dose of PNEU-P-23 may be offered one year later. There is limited benefit to giving PNEU-C-15 to individuals who received PNEU-C-13 as it will only offer protection against two additional serotypes.
4. NACI recommends that pneumococcal conjugate vaccine PNEU-C-20 may be offered to adults 65 years of age and older who have been immunized previously with PNEU-C-13 alone, if it has been 1 year from the last dose of PNEU-C-13. (Discretionary NACI recommendation)
Summary of evidence and rationale
- Robust immune responses were reported for PNEU-C-20 in adults previously vaccinated with PNEU-C-13 only; however, the data were non-comparative to PNEU-C-13.
- An interval of 1 year between PNEU-C-13 and PNEU-C 20 is to expand serotype coverage offered by PNEU-C-13 in a time-effective manner.
- A shorter interval of 8 weeks might be considered to align with immunization clinics and/or programs.
- The additional benefit of offering PNEU-C-15 is limited as PNEU-C-15 will only offer protection against two additional serotypes. However, PNEU-C-15 in series with PNEU-P-23 or PNEU-P-23 alone can be considered if PNEU-C-20 is unavailable or inaccessible.
For hematopoietic stem cell transplant recipients
5. NACI recommends that pneumococcal conjugate vaccine PNEU-C-20 should be offered to adults 18 years old or older who received a hematopoietic stem cell transplant (HSCT) after consultation with transplant specialist. A primary series of 3 doses of PNEU-C-20 starting 3 to 9 months after transplant should be administered at least 4 weeks apart, followed by a booster dose of PNEU-C-20 12 to 18 months post-transplant (6 to 12 months after the last dose of PNEU-C-20). (Strong NACI recommendation)
Summary of evidence and rationale
- No studies assessing immunogenicity and safety of PNEU-C-20 in HSCT recipients were available; however, PNEU-C-20 is expected to have similar immunogenicity and safety profiles to PNEU-C-13 in this population.
- The recommended timing of PNEU-C-20 for HSCT recipients should be determined in consultation with the recipient’s transplant specialist.
- PNEU-C-15 may be considered if PNEU-C-20 is unavailable or inaccessible to ensure these individuals will receive the needed protection.
Considerations for continued PNEU-C-13 and PNEU-P-23 use and other risk groups
- NACI supports the continued use of PNEU-C-13 and PNEU-P-23 in adults only when PNEU-C-15 and/or PNEU-C-20 are unavailable or inaccessible.
- At this time, there are no public health level recommendations on the use of PNEU-C-15 or PNEU-C-20 for adults 18 to 49 years of age with non-immunocompromising risk factors that place them at high risk of IPD as additional analyses on the cost-effectiveness of conjugate PNEU-C-15 and PNEU-C-20 in this population are needed. PNEU-C-15 or PNEU-C-20 may be considered at clinical discretion for these adults.
Management options
Options for the vaccine schedule, vaccine type (VT), age cohort and risk group are available, and the decision on which option is preferable may depend on one or more considerations outlined below.
PNEU-C-13 - Efficacy/Effectiveness data not yet available
- Immunogenicity (based on OPA GMTs and % seroresponse) non-inferior to PNEU-C-13 for shared serotypes however immune responses numerically lower
- Safety profile of PNEU-C-20 consistent with safety of PNEU-C-13, for both vaccine naïve and vaccine experienced
- Cost-utility analysis estimates that PNEU-C-20 use is likely a cost-effective strategy, regardless of age or region.
- Simplified recommendation with a single vaccine is expected to increase acceptability for both recipients and vaccine program implementation, thus the potential to prevent more disease
- PNEU-C-15 and PNEU-C-20 contain different serotypes, which can have different impacts on IPD rates based on local serotype epidemiology
Unknowns- Speed of serotype replacement
- Extent of serotype replacement
- Impact on disease burden in adults when higher valent pneumococcal conjugate vaccines become available for use in pediatric vaccine programs
Duration of protection- Waning protection from pneumococcal conjugate vaccines appears to occur at a slower rate compared to pneumococcal polysaccharide vaccines
Unknowns- VE and duration of protection of PNEU-C-15 and PNEU-C-20
Immunogenicity- Both PNEU-C-15 and PNEU-C-20 are immunogenic compared to PNEU-C-13
- PNEU-C-20 appears to have lower immune response compared to PNEU-C-13 for shared serotypes
- PNEU-C-15 appears to have higher immune response compared to PNEU-C-13 for shared serotype 3
Unknowns- Correlates of protection
Safety- Both vaccines are safe in immunocompetent individuals
Economics
Based on a cost utility analysis: - PNEU-C-20 was cost-effective compared to current recommendations in adults 65 years of age and older
- When PNEU-C-20 is available, PNEU-C-15 is more costly and less effective than giving PNEU-C-20 alone.
- If PNEU-C-20 is not available, PNEU-C-15 in series with PNEU-P-23 is more cost-effective than PNEU-C-15 alone
Unknowns- Cost-effectiveness in other high-risk populations
Feasibility/Acceptability- PNEU-C-15 should be offered in series with PNEU-P-23 to optimize protection against more serotypes. This would make it a 2-product series, compared to PNEU-C-20, which is 1 dose only. Consideration to improve adherence and acceptability of the 2nd dose, as well as additional operational costs for the administration of the 2nd dose would be required.
Unknowns- It is unknown what the adherence to the complete 2-product vaccination schedule with PNEU-C-15 and PNEU-P-23 will be
- Efficacy/effectiveness data not yet available
- Immunogenicity (based on OPA GMTs and % seroresponse) showed non-inferiority for shared serotypes with PNEU-C-13 and mixed results in the proportion of seroresponders compared with PNEU-C-13
- Safety profile of PNEU-C-15 consistent with safety of PNEU-C-13, for both vaccine naïve and vaccine experienced
- Administration costs of combined program with PNEU-P-23 higher than single dose PNEU-C-20 program regardless of age, region.
- To the extent that second doses are missed, effectiveness in preventing pneumococcal disease reduced
- PNEU-P-23 may be less effective for shared serotypes than PNEU-P-20, especially in the longer term
- Mixed schedule would require the coordination of two doses and products
- Efficacy and effectiveness data available
- PNEU-C-13 effective against IPD in adults 65 years and older
- Findings from observational studies support efficacy against vaccine type pneumonia and IPD
- Mixed schedule would require the coordination of two doses and products
- Acceptability of pneumococcal vaccination in adults at risk is below national target
Feasibility/Acceptability- PNEU-C-13 has the lowest serotype coverage of any of the authorized pneumococcal vaccines
- Some effectiveness data available, although limited and uncertain
- PNEU-P-23 may be preferred if the willingness to pay per QALY gained is lower than commonly used cost-effectiveness thresholds.
- Pooled analysis from 8 observational studies show that PNEU-P-23 is effective against IPD in adults 65 years and older.
- Pooled vaccine effectiveness against VT pneumonia from recent observational studies suggest PNEU-P-23 provides limited protection against VT pneumonia within 5 years of vaccination.
- Acceptability of PNEU-P-23 have been below national vaccination target for adults 65 years old or older and for adults 18 years old and older living with underlying medical conditions
Feasibility/Acceptability - PNEU-P-23 has the highest serotype coverage of any of the authorized pneumococcal vaccines.
- Waning protection occurring faster (within 5 years of vaccination) compared to conjugate vaccines due to its T cell independent mode of action.
- The risk of IPD associated with some medical conditions is unrelated to age
- There are no cost-effectiveness analyses for PNEU-C15 or PNEU-C-20 available for this group
- The incidence of CAP similarly increased with increasing age from 348/100,000 population (50 to -64 years) 871/100,000 (65 to -74 years) and 2846/100,000 (75 years and older). 20% of those estimated to be pneumococcal.
- PNEU-C-15 showed comparable immune responses to PNEU-C-13 for shared serotypes across all age groups. Immune responses did trend lower with increasing age
- PNEU-C-20 showed robust immune responses across all age groups
- Both PNEU-C-15 and PNEU-C-20 have comparable safety profile to PNEU-C-13/PNEU-P-23
- At age 65, the most efficient strategies (using PNEU-C-20) had estimated ICERs ranging from $6,500-80,300 per QALY gained (health system perspective) and $2,200-153,600 per QALY gained (societal perspective)
- At age 50, ICERs for the most efficient options (using PNEU-C-20) were higher than at age 65 with ICERs ranging from $16,300-81,900, depending on the strategy used and the region
- At age 75, ICERs for the most efficient strategies (using PNEU-C-20) were comparable to those at age 65. ICERs were somewhat higher in Northern Canada compared to vaccination at age 65.
- Lower burden of illness compared to older adult age groups and lower vaccine uptake (existing pneumococcal vaccination program) compared to older age groups
- Possible risk of waning protection by the time this cohort is at highest risk of IPD; therefore, will likely require a booster if protection wanes
- Higher ICERs than for the 65 years and older and 75 years and older age groups, but vaccination with PNEU-C-20 still likely to be considered cost-effective under commonly used thresholds
- Longer life expectancy than the 75 years and older age cohort; therefore, benefits of vaccination over a longer period
- Might need a booster
- ICERs suggest vaccination at this age with PNEU-C-20 would be cost-effective under commonly used thresholds
- Shorter life expectancy, one dose vaccination without the need for booster
- Vaccine uptake might be better compared to younger age groups
- Immunogenicity responses likely lowest in the oldest age groups due to immunosenescence
- ICERs suggest vaccination at this age with PNEU-C-20 would be cost-effective under commonly used thresholds
IX. Research priorities
- Estimates/assessments of the PNEU-C-15 and PNEU-C-20 vaccine effectiveness in the general population of individuals 65 years of age and older and in additional populations (e.g., indigenous people, people living with chronic medical, social, and immunocompromising conditions).
- Cost-effectiveness analyses on the use of PNEU-C-15 and PNEU-C-20 in adults 18 to 49 years of age with risk factors that place them at high risk of IPD.
- Assessment of the effects of community immunity and serotype replacement of PNEU-C-15 childhood programs over time on the incidence of IPD, VT IPD, CAP, and VT CAP and on carriage within the Canadian population of individuals 65 years of age and older and in additional populations (e.g., indigenous, people living with chronic medical, social, and immunocompromising conditions).
- Estimates of efficacy and effectiveness of PNEU-C-15 and PNEU-C-20 boosters in immunocompetent adults over 65 years of age.
- Assessment of pneumococcal vaccination programs on the reduction of myocardial infarction and stoke.
X. Surveillance issues
Ongoing surveillance is fundamental to planning, implementation, evaluation, and evidence-based decision-making. (Indicate if the disease to be prevented is reportable nationally.) To support such efforts, NACI encourages surveillance improvements in the following areas:
- Nationally representative data is not currently available on the burden of CAP and VT pCAP in Canada
- National surveillance data on vaccination status are not available for identified cases of IPD and VT IPD in Canada, which limits extension of findings
- National surveillance on pneumococcal vaccine coverage by age and time since vaccine administration (and in the future) and the number of doses received is limited
- Additional risk factors (e.g., comorbidities) are not available for identified cases of IPD and VT IPD, which limits extensions of findings to high-risk groups due to underlying health conditions
- Missing data was present within both the CNDSS and NML datasets.
- Enhanced surveillance that includes high risk individuals and can provide incidence of IPD stratified by risk factors and serotypes for individuals in the greater than 65-year age group.
- Epidemiological studies of non-invasive disease such as CAP or acute otitis media in children caused by *S. pneumoniae*.
XI. Characteristics of included studies
V114-002
Multicenter: 25 sites from across Canada, Denmark, Israel, Norway, Poland, Spain, Sweden, United States.
Study period: March 2012-February 2013
- PNEU-P-23
- PNEU-C-15 vs
- PNEU-C-13
PNEU-P-23 (N=231), or PNEU-C-13 (N=230)
Gender (total study): 53% female
Ethnicity (total study): 93% non-Hispanic or non-Latino
Race (total study): 93% White
Age (total study):- 50 to 64 years: 34.6%
- 65 to 74 years: 32.6%
- ≥75 years: 32.9%
V114-016
Multicenter: 22 sites from across United States, the Republic of Korea, Spain, Taiwan.
Study period: June 2018-December 2016
- PNEU-P-23 vs
- PNEU-C-13 +
- PNEU-P-23
Gender (total study): 56.8% female
Ethnicity (total study): 87.4% non-Hispanic or non-Latino
Race (total study): 61.6% White
Median age: 65.0 years
Age (total study):- 50 to 64 years: 49.9%
- 65 to 74 years: 37.9%
- ≥75 years: 12.1%
V114-019
Multicenter: 30 sites from across Canada, United States, Japan, Spain, Taiwan.
Study period: June 2019-March 2020
- PNEU-C-13
Gender (total study): 57.3% female
Ethnicity (total study): 78.0% non-Hispanic or non-Latino
Race (total study): 67.7% White
Median age: 66.0 years
Age (total study):- 50 to 64 years: 30.9%
- 65 to 74 years: 57.6%
- ≥75 years: 11.5%
V114-007
Multicenter: 17 sites in United States
Study period: November 2015-January 2016
- PNEU-C-13
Total randomized = 253
Gender (whole study): 59.7% female
Median Age (whole study): 72.0 years
Age distribution: 65-74 years, 70%; ≥75 years, 30%
Race (whole study): 94.1% White
Ethnicity (whole study): 84.6% non-Hispanic or non-Latino
Time since PNEU-P-23 vaccination: 1-3 years, 32.4%; >3 years, 67.6%
Authors state groups were similar for gender, age, ethnicity/race, pre-existing conditions, prior therapy, and time interval since
V114-017
Multicentred: 79 sites from 7 countries (United States, Canada, Chile, Poland, Russia, Australia, New Zealand).
Study period: July 2018 to July 2020
- PNEU-P-23 vs
- PNEU-C-13 +
- PNEU-P-23
- PNEU-P-23 (n=1135) or PNEU-C-13+
- PNEU-P-23 (n=380).
Total randomized: 1515.
Gender (total study): 52% female
Ethnicity (total study): 87% non-Hispanic or non-Latino
Race (total study): 51% White, 39% Indigenous (US. 39% of participants were from US Center for American Indian Health (CAIH) sites.
Mean age: 36.0 years
By risk factor (total study):
No risk factors: 25%
≥1 risk factor: 75%
Risk factors included: chronic lung disease including asthma, tobacco use, diabetes mellitus, chronic liver disease, chronic heart disease, and alcohol consumption.
All subjects with no risk factor and subjects with single risk factor of alcohol consumption were enrolled at CAIH sites.
V114-018
Multicenter: 13 sites from across France, Peru, South Africa, Thailand, United States.
Study period: July 2018-January 2020
- PNEU-C-13
- PNEU-C-15+
- PNEU-P-23 vs
- PNEU-C-13+
- PNEU-P-23
Vaccine series at 8-week interval
- PNEU-P-23 (n=152) or PNEU-C-13+
- PNEU-P-23 (n=150)
Gender (total study): 21% female
Ethnicity (total study): 68% non-Hispanic or non-Latino
Race (total study): 31% Black, 30% White, 21% more than one race, 18% Asian
Median age: 41y. Of the total study, 72% were 18-49y. Few participants (3.6%) were ≥65y.
By CD4+ T-cell count (cells/µL):- ≥50 to <200: 1.3%
- ≥200 to <500: 50.3%
V114-021
Multicenter: 45 sites in United States
Study period: September 24, 2018-June 24, 2019
Vs
Total randomized = 1200
Prior vaccination of PNEU-P-23 eligible if received >12 months before first study visit but designed to have at least 50% of participants vaccine-naive.
Gender (total study): 56.1% female
Ethnicity (total study): 78.8% non-Hispanic or non-Latino
Race (total study): 82.5% White
Median age: 65.0 years
Age (total study):- 50 to 64 years: 49.9%
- 65 to 74 years: 39.4%
- ≥75 years: 10.7%
Prior vaccination with PNEU-P-23: 20.9%
Multicenter: 14 sites from across United States
Study period: NR
placebo vs
- PNEU-C-13 +
- PNEU-P-23
(PNEU-C-13 arm) one month after first vaccination
Gender (total study): 56.0% female
Ethnicity (total study): 87.4% non-Hispanic or non-Latino
Race: 75.4% White
Median age: 62.0 years
Multicenter: Sites from across United States and Sweden
Study period: December 2018-December 2019
PNEU-C-13 followed by
PNEU-P-23 (1 month interval).
Participants ≥60 years of age were randomized to single dose of PNEU-C-20 (N=1514) or PNEU-C-13 (N=1495) followed by single dose saline (PNEU-C-20 arm) or PNEU-P-23 (PNEU-C-13 arm) one month after first vaccination.
Participants 50-59 years randomized to single dose PNEU-C-20 (N=334) or PNEU-C-13 (N=111).
Participants 18-49 years randomized to single dose PNEU-C-20 (N=336) or PNEU-C-13 (N=112).
Total randomized:- ≥60 years = 3009,
- 50-59 years = 445,
- 18-49 years = 448
Gender, % female (by age cohort):- ≥60 years: 59.3%
- 50-59 years: 59.3%
- 18-49 years: 65.1%
Ethnicity, % non-Hispanic or non-Latino (by age cohort):- ≥60 years: 87.8%
- 50-59 years: 94.4%
- 18-49 years: 89.9%
Race, % White (by age cohort):- ≥60 years: 84.5%
- 50-59 years: 82.7%
- 18-49 years: 83.9%
Age (≥60 year cohort):- 60 to 64 years: 66.2%
- 65 to 69 years: 20.8%
- 70 to 79 years: 11.5%
- ≥80 years: 2.3%
Multicenter: 33 sites in United States and 8 sites in Sweden.
Study period: February 2019-February 2020
current PNEU-C-20 vs Prior PNEU-P-23 +
current PNEU-C-13
2. Prior PNEU-C-13 vaccination +
PNEU-C-20 vs Prior PNEU-C-13 +
current PNEU-P-23
PNEU-P-23+
PNEU-C-20 (N=253) vs PNEU-P-23+
PNEU-C-13 (N=122)
PNEU-C-13+
PNEU-C-20 (N=248) vs PNEU-C-13+
PNEU-P-23 (N=127)
A third cohort with prior vaccination to both PNEU-P-23 and PNEU-C-13 was not in this review as it was not a randomized comparison.
Demographics (across relevant group subset):- Gender: range 52.5-56.5% female
- Ethnicity: range 94.0-97.6% non-Hispanic or non-Latino
- Race: range 90.2-93.3% White
- Mean age: range 69.6-70.7 years |
Public health level recommendations on the use of pneumococcal vaccines in adults, including the use of 15-valent and 20-valent conjugate vaccines
===================================================================================================================================================
[Download in PDF format](/content/dam/phac-aspc/documents/services/immunization/national-advisory-committee-on-immunization-naci/public-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines/recommendations-use-pneumococcal-vaccines-adults-15-20-valent-conjugate.pdf)
(1.3 MB, 88 pages)
**Organization:** [Public Health Agency of Canada](/en/public-health.html)
**Date published:** 2023-02-24
**Cat.:** HP5-153/1-2023E-PDF
**ISBN:** 978-0-660-47229-4
**Pub.:** 220712
**An Advisory Committee Statement (ACS)**
**National Advisory Committee on Immunization (NACI)**
Table of Contents
-----------------
* [Summary of information contained in this NACI Statement](#sum)
* [I. Introduction](#a1)
+ [I.1 Guidance objective](#a1.1)
+ [I.2 Background on pneumococcal vaccines, immunization programs and recommendations in Canada](#a1.2)
* [II. Methods](#a2)
+ [II.1 Burden of IPD](#a2.1)
+ [II.2 Literature Review of PNEU-C-15 and PNEU-C-20 studies](#a2.2)
+ [II.3 Literature review of PNEU-C-15 and PNEU-C-20 cost-effectiveness](#a2.3)
+ [II.4 NACI Cost-utility analysis and multi-model comparison](#a2.4)
* [III. Epidemiology](#a3)
+ [III.1 IPD burden in Canada.](#a3.1)
+ [III.2 Distribution of IPD Serotypes in Canada, 2016 – 2020](#a3.2)
+ [III.3 Burden of Pneumococcal community acquired pneumonia in Canada](#a3.3)
+ [III.4 High Risk Groups](#a3.4)
+ [III.5 Summary of Pneumococcal Immunization Coverage in Canada](#a3.5)
* [IV. Vaccine](#a4)
+ [IV.1 Preparations authorized for use in Canada](#a4.1)
+ [IV.2 Efficacy and effectiveness](#a4.2)
+ [IV.3 Immunogenicity](#a4.3)
+ [IV.4 Persistence of Immune Response](#a4.4)
+ [IV.5 Vaccine Administration and Schedule](#a4.5)
+ [IV.6 Serological Testing](#a4.6)
+ [IV.7 Storage Requirements](#a4.7)
+ [IV.8 Concurrent Administration with Other Vaccines](#a4.8)
+ [IV.9 Vaccine Safety](#a4.9)
+ [IV.10 Contraindications and Precautions](#a4.10)
* [V. Vaccination of Specific Populations](#a5)
+ [V.1. Immunization in Pregnancy and Breastfeeding](#a5.1)
+ [V.2. Immunization of Immunocompromised persons](#a5.2)
* [VI. Ethics, Equity, Feasibility and Acceptability Considerations](#a6)
* [VII. Economics](#a7)
* [VIII. Recommendations](#a8)
+ [VIII.1 Recommendations for Public Health Program Level Decision-Making](#a8.1)
* [IX. Research priorities](#a9)
* [X. Surveillance issues](#a10)
* [XI. Characteristics of included studies](#a11)
* [List of Abbreviations](#abbr)
* [Acknowledgments](#ack)
* [Appendix A: Tables](#appa)
+ [Evidence synthesis tables](#appa.1)
+ [Epidemiology tables](#appa.2)
* [References](#ref)
Preamble
--------
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing, and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI’s independent advice and recommendations, which are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC’s Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Summary of information contained in this NACI Statement
-------------------------------------------------------
The following highlights key information for immunization providers. Please refer to the remainder of the Statement for details.
### 1. What
Pneumococcal disease in adults includes invasive pneumococcal disease (IPD), an acute and serious communicable disease with manifestations such as meningitis, bacteremia and bacteremic pneumonia and empyema, as well as non-invasive pneumococcal disease such as community acquired pneumonia and acute otitis media in children. It is caused by the *Streptococcus pneumoniae* bacterium. Of the more than 100 serotypes of this bacterium, a small number cause the majority of disease. Bacteremic pneumococcal pneumonia is the most common presentation of IPD among adults.
Based on immunogenicity data relative to previously authorized pneumococcal conjugate vaccines (PNEU-C) and pneumococcal polysaccharide vaccines (PNEU-P), Health Canada has recently authorized two new PNEU-C vaccines:
* PNEU-C-15 (15-valent) is authorised for infants, children, and adolescents from 6 weeks through 17 years of age and adults 18 years of age and older with an indication for prevention of IPD caused by 15 serotypes of *S. pneumoniae* (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F).
* PNEU-C-20 (20-valent) is authorized for adults 18 years of age and older with an indication for prevention of pneumonia and IPD caused by 20 serotypes of *S. pneumoniae* (1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F).
No efficacy data are currently available for either PNEU-C-15 or PNEU-C-20.
### 2. Who
IPD is most common in the very young, the elderly, and groups with medical conditions and/or other risk factors that place them at high risk of IPD ([see Table 1](#t1)).
NACI recommends the use of PNEU-C-20, or PNEU-C-15 followed by pneumococcal polysaccharide vaccine, 23-valent pneumococcal polysaccharide vaccine (PNEU-P-23), in adults at a higher risk of invasive pneumococcal disease.
* All adults 65 years of age and older should receive a single dose of PNEU-C-20.
* Adults who are 50 to 64 years of age and living with underlying medical conditions and/or other risk factors that place them at high risk of IPD should receive a single dose of PNEU-C-20.
* Adults who are 18 years of age and older living with immunocompromising conditions (IC) should also receive a single dose of PNEU-C-20.
* PNEU-C-15 followed by PNEU-P-23 may be offered as an alternative if PNEU-C-20 is not available.
Additional details including immunization of adults who received a hematopoietic stem cell transplant, as well as intervals between previous pneumococcal vaccines and PNEU-C-15/PNEU-C-20 are discussed in Section VII.
Table 1. Medical conditions and other biological and/or social risk factors resulting in high risk of IPD
| Non-immunocompromising conditions | Immunocompromising conditions [Table 1 Footnote a](#t1fna) | Other risk factors |
| --- | --- | --- |
| * Chronic cerebrospinal fluid (CSF) leak
* Chronic neurologic condition that may impair clearance of oral secretions
* Cochlear implants, including children and adults who are to receive implants
* Chronic heart disease
* Diabetes mellitus
* Chronic kidney disease [Table 1 Footnote a](#t1fna)
* Chronic liver disease, including hepatic cirrhosis due to any cause [Table 1 Footnote a](#t1fna)
* Chronic lung disease, including asthma requiring medical care in the preceding 12 months
| * Sickle cell disease, congenital or acquired asplenia, or splenic dysfunction [Table 1 Footnote b](#t1fnb)
* Congenital immunodeficiencies involving any part of the immune system, including B-lymphocyte (humoral) immunity, T-lymphocyte (cell) mediated immunity, complement system (properdin, or factor D deficiencies), or phagocytic functions
* Immunocompromising therapy, including use of long-term corticosteroids, chemotherapy, radiation therapy, and post-organ transplant therapy
* HIV infection
* Hematopoietic stem cell transplant (recipient) [Table 1 Footnote c](#t1fnc)
* Malignant neoplasms, including leukemia and lymphoma
* Nephrotic syndrome
* Solid organ or islet transplant (candidate or recipient)
| Individuals* who smoke
* who use illicit drugs
* with alcohol use disorder
* who are experiencing homelessness
* who live in communities or settings [Table 1 Footnote d](#t1fnd) experiencing sustained high IPD rates.
|
|
Table 1 Footnote a
Conditions considered to result in the highest risk of IPD
[Return to footnote a referrer](#t1fna-rf)
Table 1 Footnote b
Generally, asplenia (functional or anatomic), sickle cell disease and other hemoglobinopathies are not considered immunocompromising conditions, but for the purposes of pneumococcal vaccine recommendations, they are included in this category
[Return to footnote b referrer](#t1fnb-rf)
Table 1 Footnote c
Hematopoietic Stem Cell Transplant (HSCT) recipients have specific pneumococcal vaccination recommendations
[Return to footnote c referrer](#t1fnc-rf)
Table 1 Footnote d
Can include long-term care facilities
[Return to footnote d referrer](#t1fnd-rf)
|
### 3. How
PNEU-C-15 and PNEU-C-20 are supplied in a single-dose, prefilled syringe. Both PNEU-C-15 and PNEU-C-20 are to be administered intramuscularly. A standard schedule for immunization is one 0.5ml dose. Contraindications to administration of either PNEU-C-15 or PNEU-C-20 include hypersensitivity (e.g., anaphylaxis) to the vaccine or any of its components. Pneumococcal vaccines may be administered concurrently with other vaccines, except for a different formulation of pneumococcal vaccine (e.g., concurrent use of conjugate and polysaccharide).
### 4. Why
Pneumococcal infection can cause severe infections and can lead to significant mortality and morbidity with lifelong complications. The most effective way to prevent these infections is through immunization.
I. Introduction
---------------
### I.1 Guidance objective
The need for this National Advisory Committee on Immunization (NACI) Statement on the use of pneumococcal vaccines was triggered by the approvals of two additional pneumococcal conjugate vaccines for adults 18 years of age and older, a 15-valent vaccine, PNEU-C-15 (VaxneuvanceTM) on November 16, 2021, and a 20-valent vaccine, PNEU-C-20 (Prevnar 20TM) on May 9, 2022. The primary objective of this statement is to review the evidence on the efficacy, effectiveness, immunogenicity, safety, and cost-effectiveness of PNEU-C-15 and PNEU-C-20 vaccines and provide recommendations for their use in consideration of the disease burden in Canada among adults for whom pneumococcal vaccination is currently recommended:
* immunocompetent adults aged 65 and older
* immunocompetent adults at higher risk of pneumococcal disease (PD) ([Table 1](#t1))
* immunocompetent adults residing in long term care facilities (LTCF)
* immunocompromised adults, including hematopoietic stem cell transplant recipients
### I.2 Background on pneumococcal vaccines, immunization programs and recommendations for adults in Canada
For prevention of IPD in adults, two vaccines are currently available in routine, publicly funded programs: PNEU-P-23 and PNEU-C-13. Conjugate vaccines induce formation of long-term memory cells, provide longer duration of protection, and provide ability for boosting by involving T cells in the immune response to the vaccine, in a way that polysaccharide vaccines do not.
PNEU-P-23 was previously recommended by NACI for the routine immunization against IPD of all adults 65 years of age and older. PNEU-P-23 was also recommended for adults 18 to 64 years old who are residents of LTCF, smokers or persons with an alcohol use disorder, and persons experiencing homelessness as well for those living with both immunocompromising and non-immunocompromising underlying medical conditions that put them at higher risk of IPD. A complete list of underlying medical conditions that increase the risk of IPD along with dose and schedule is available in the [Pneumococcal Vaccine Chapter of the Canadian Immunization Guide](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html).
PNEU-C-13 in series with PNEU-P-23 was recommended by NACI in 2013 [Footnote 1](#fn1) for adults 18 years of age and older with immunocompromising conditions resulting in high risk of IPD. For a complete list of immunosuppressing conditions that increase the risk of IPD, please refer to [Table 1 in the Pneumococcal Vaccine Chapter of the Canadian Immunization Guide](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html#risk-factors).
PNEU-C-13 was also recommended by NACI in 2016 [Footnote 2](#fn2) and 2018 [Footnote 3](#fn3) on an individual basis for immunocompetent adults aged 65 years and older who wish to protect themselves against the 13 serotypes included in the vaccine for prevention of community-acquired pneumonia (CAP) and IPD. PNEU-C-13 was not recommended for publicly funded routine immunization programs due to cost-effectiveness.
II. Methods
-----------
In brief, the stages in the preparation of a NACI advisory committee statement are:
1. Knowledge synthesis: retrieval and summary of individual studies, assessment of the risk of bias (RoB) of included studies (summarized in the [Summary of evidence tables in Appendix A](#appa.1)).
2. Summary of evidence: benefits (immunogenicity) and potential harms (safety), considering the certainty of the synthesized evidence and, where applicable, the magnitude of effects observed across the studies.
3. Use of the evidence to inform recommendations.
NACI also uses a published, peer-reviewed framework and evidence-informed tools to ensure that issues related to ethics, equity, feasibility, and acceptability (EEFA) are systematically assessed and integrated into its guidance. NACI evaluated the following ethical considerations when making its recommendations: promoting well-being and minimizing risk of harm, maintaining trust, respect for persons and fostering autonomy, and promoting justice and equity.
Further information on [NACI’s process and procedures](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/methods-process.html) is available elsewhere.
For this statement, NACI reviewed evidence pertaining to the burden of IPD in the target population(s), the safety, immunogenicity, efficacy, and effectiveness of the vaccine(s), vaccine schedules, and other aspects of the overall adult pneumococcal vaccine immunization strategy. The knowledge synthesis was performed by NACI Secretariat and reviewed by the Pneumococcal Working Group. Following critical appraisal of individual studies, summary tables with ratings of the certainty of the evidence using GRADE methodology were prepared [Footnote 4](#fn4) [Footnote 5](#fn5) [Footnote 6](#fn6). An assessment using the Evidence to Decision (EtD) framework was prepared for each question, and proposed recommendations for vaccine use were developed [Footnote 7](#fn7). NACI reviewed the available evidence on May 19, 2022, July 4, 2022, and Sept 12, 2022. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described.
### II.1 Burden of IPD
IPD has been nationally notifiable in Canada to the Canadian Notifiable Disease Surveillance System (CNDSS) since 2000, with all provincial and territorial jurisdictions reporting cases meeting the national case definition. Cases not captured by CNDSS may include those that do not get medical attention, those where clinical measures were applied with no specimen being taken. Information such as serotype, antimicrobial susceptibility, vaccine coverage as well as other enhanced epidemiological patient information are not reported through the CNDSS.
The national surveillance line list data used to assess the burden of IPD among different age groups were available from the CNDSS for six provinces (BC, AB, SK, ON, QC, and PEI) and from the International Circumpolar Surveillance (ICS) program for the three territories (YK, NU, and NT). Some provinces (MB, NS, NL, NB) were not included in the national surveillance line list as they provided aggregate data with broad age group intervals which could not be broken down to compare the IPD burden in different age groups among older adults in Canada. All cases were presumed to meet the national case definition of IPD. More information about the CNDSS data is provided on the [Notifiable Diseases Online](https://dsol-smed.phac-aspc.gc.ca/notifiable/) website.
Northern regions of Canada captured in the ICS system include Nunavut, Northwest Territories, Yukon, Northern Labrador, and Northern Quebec. The incidence of IPD in these regions was compared to IPD incidence from all other PTs using aggregate CNDSS data.
The National Microbiology Laboratory (NML) collaborates with provincial and territorial public health laboratories to conduct passive, laboratory-based surveillance of IPD in Canada [Footnote 8](#fn8). All IPD isolates from the provincial/territorial public health laboratories are serotyped by the NML, although specimen collection may be limited by variable regional standards, the preliminary nature of some data and the availability of bacterial isolates for testing. Serotype data may also be biased toward over representing more virulent serotypes for which medical treatment is sought and clinical specimens taken. Despite these limitations, the passive national surveillance program from 2015 – 2019, including additional data submitted by the provincial reference laboratories of Alberta and Quebec, provided timely reporting of serotype distributions, and accounted for 80 to 98% of all IPD cases reported to CNDSS. In 2020 [Footnote 9](#fn9), a total of 2,067 isolates were reported to the NML, representing 94.3% of the 2,193 reported by all PTs to the CNDSS (preliminary 2020 data).
For vaccine serotype groupings, serotype 6C was included with PNEU-C-13 serotypes due to cross protection with 6A [Footnote 10](#fn10). Serotypes 15B and 15C were grouped together as 15B/C because of reported reversible switching between them *in vivo* during infection, making it difficult to precisely differentiate between the two types [Footnote 11](#fn11) [Footnote 12](#fn12).
### II.2 Literature Review of PNEU-C-15 and PNEU-C-20 studies
The policy question addressed in this statement is: What is the efficacy, effectiveness, and safety of PNEU-C-15 and PNEU-C-20, administered in series with or without PNEU-P-23, when used with the objective to reduce the risk of IPD in adults.
**Population**: Adults 50 years of age or older without IPD risk factors; adults 18 years or older with IPD risk factors ([Table 1](#t1)).
**Intervention**: PNEU-C-15 or PNEU-C-20, alone and in series with PNEU-P-23 (depending on the population group of interest).
**Comparator**: Currently recommended age and risk factor-appropriate pneumococcal vaccine schedule.
**Outcomes**: Death due to vaccine preventable serotype *S. pneumoniae*, IPD due to vaccine preventable pneumococcal serotype, IPD due to any pneumococcal serotype (vaccine preventable and not vaccine preventable), pneumococcal community-acquired pneumonia (pCAP) due to a vaccine preventable serotype, serious adverse events (SAEs), severe systemic adverse events (AEs), and mild/moderate systemic AEs following vaccination. Outcomes were accompanied by definitions and are summarized in the appendix (see [Appendix A, Table 6](#t6)).
In the absence of disease endpoint and mortality data, immunogenicity (opsonophagocytic [OPA] geometric mean titer [GMT] ratios and percentage of seroresponders defined as greater or equal to a 4-fold increase in OPA GMT ratio from before vaccination to after vaccination) was evaluated.
Safety and immunogenicity data for PNEU-C-15 and PNEU-C-20 in adults from key clinical trials, published studies, and supplementary data obtained from manufacturers were reviewed. Data were extracted from eligible studies related to the study design, population, intervention, comparator, and outcomes of interest. The RoB ([Appendix A, Table 8](#t8)) for each study was assessed using the Cochrane Risk of Bias Tool [Footnote 13](#fn13). The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework ([Appendix A, Table 5](#t5)) was used to assess the certainty in evidence.
Meta-analytic techniques were used to synthesize adverse event data; statistical heterogeneity was considered using a combination of factors (direction of estimates, overlapping confidence intervals, and the Cochran Q [p<0.10] and I-squared statistics). For I-squared statistics, a rough guide of low (0-25%), moderate (25-50%), substantial (50-75%), and considerable (75-100%) was used. For binary outcomes and where event rates were low (using 1% as a rough guide), the Peto Odds Ratio was used; otherwise, the Risk Ratio was used. Where possible to do so, relative effect measures were used to calculate risk differences, aligning with the GRADE approach. For immunogenicity, narrative syntheses were used, and heterogeneity was determined according to the direction of effect, using the magnitude of the estimates. The focus for GMT ratios was the study investigators’ demonstration of non-inferiority for shared serotypes between vaccines. For the percentage of seroresponders, point estimates were used to gauge the direction of effect based on those magnitudes. It is important to note, however, that no immunologic correlates of protection have been established for PD.
For the GRADE certainty of evidence assessments ([Appendix A, Table 5](#t5)), control group data from studies were used to estimate baseline risk. The use of surrogate measures was the main consideration for indirectness. The review information sizes of 400 people with events for binary data, at least 4,000 people analyzed for small event rates, and 800 people for continuous data were used to inform imprecision when confidence intervals were not importantly wide. Planned subgroup analyses was not undertaken for the age-based recommendation owing to the nature of the data and insufficient number of studies. Sensitivity analyses were undertaken to restrict analyses to studies at a low RoB, where applicable, to see if the results changed appreciably. Too few studies were located to perform a test for small study effects.
Modifications to scope and process during conduct of the review: (a) an evaluation for the 75 years and older age group was added for the age-based recommendation; (b) expansion of eligibility to include additional vaccines administered concurrently with pneumococcal vaccines; and (c) full verification of data extraction, RoB assessments, and GRADE assessments were reduced to partial verification or single person review to facilitate a rapid review of the evidence.
### II.3 Literature review of PNEU-C-15 and PNEU-C-20 cost-effectiveness
A systematic review of the cost-effectiveness of PNEU-C-15 and PNEU-C-20 vaccines for preventing IPD was conducted. The search included economic evaluations conducted in adults aged 18 years or older, comparing currently used vaccines to prevent IPD to PNEU-C-15 or PNEU-C-20. The components of the research question are summarized as:
* Population: Adults aged 18 years or older
* Intervention: PNEU-C-15 or PNEU-C-20 (alone or in series with other pneumococcal vaccines)
* Comparator: Current pneumococcal vaccines (PNEU-C-7, PNEU-C-10, PNEU-C-13, PNEU-P-23)
* Outcomes: Measures of cost-effectiveness (incremental cost per quality-adjusted life year [QALY], incremental cost per disability-adjusted life year [DALY], and cost per life year, etc.)
Additional details of the economic literature review are provided in a supplementary economic evidence appendix.
### II.4 NACI Cost-utility analysis and multi-model comparison
A model-based cost-utility analysis was conducted from health system and societal perspectives. A Markov cohort model was developed to compare the benefits (in QALYs) and costs (in 2022 Canadian dollars) associated with using PNEU-C-15 or PNEU-C-20, either alone or in series with PNEU-P-23, compared to PNEU-P-23 alone. Vaccination was evaluated at ages 50, 65, or 75. The Northern Canadian Territories were assessed separately from the rest of Canada to account for higher PD incidence in the north. The primary outcome was the incremental cost-effectiveness ratio (ICER). The analysis used a lifetime time horizon and 1.5% discount rate. Scenario and sensitivity analyses were conducted to examine the impact of uncertainties in model parameters and assumptions.
To evaluate the robustness of the cost-utility model, a multi-model comparison was conducted using two additional cost-utility models developed by the manufacturers of PNEU-C-15 and PNEU-C-20 with different structures and assumptions. Wherever possible, all models were modified to use the same input parameters. ICERs for a single base case were compared across models.
Additional details of the cost-utility analysis and multi-model comparison are provided in a supplementary economic evidence appendix.
III. Epidemiology
-----------------
### III.1 IPD burden in Canada
Based on the data from CNDSS, the incidence rate of IPD in children under 5 years of age decreased from 41.8 cases to 15.7 cases per 100,000 population between 2003 and 2006. Following a few years of increasing incidence, IPD incidence rates in children under 5 years have remained relatively steady at around 12 cases per 100,000 population since 2012 ([Figure 1](#f1)). Children aged 5 to17 years consistently had the lowest IPD incidence rate, remaining below 5 cases per 100,000 population during the 2001-2019 study period. Canadians aged 18 to 49, 50 to 64 and 65 years and older showed similar trends with increased IPD incidence from 2001 to 2004, probably due to improvements in diagnosis and reporting, followed by relatively stable incidence rates in the subsequent 15 years. The incidence rate in adults 65 year of age and older was reported to be consistently higher by approximately 10 to 15 cases per 100,000 population than in adults aged 50 to 64 years old (e.g., in 2019, it was reported at 25 cases and 14 cases per 100,000 population, respectively). Adults aged 18 to 49 years consistently had the second lowest IPD incidence rates compared to other age groups, maintaining an incidence around 5 cases per 100,000 population from 2001-2019.
**Figure 1: Annual incidence rate of IPD by age group reported to Canadian Notifiable Disease Surveillance System, 2001-2019**
Text Description
Figure 1 shows the incidence rate of invasive pneumococcal disease (IPD) (vertical axis) per 100,000 population with respect to year in one-year increments (horizontal axis) from 2001 to 2019 in Canada, grouped by age category. The shaded boxes provide additional context concerning Canada's PNEU-C-7 implementation for the pediatric population (2002-2006), PNEU-C-13 implementation for the pediatric population (2010-2012). PNEU-P-23 recommendation for all Canadians 65 years and older (2018) is shown with a line. The incidence rates were calculated using data from the ICS program for Canada's three territories, and data from CNDSS for six provinces that had line list data available (AB, BC, ON, QC, SK, and PEI).
| Year | Age group | Incidence rate (per 100,000 population) |
| --- | --- | --- |
| **2001** | Under 5 years | 29.5 |
| 5 to 17 years | 2.2 |
| 18 to 49 years | 2.7 |
| 50 to 64 years | 5.9 |
| 65 years and older | 13.2 |
| **2002** | Under 5 years | 39.1 |
| 5 to 17 years | 2.2 |
| 18 to 49 years | 3.2 |
| 50 to 64 years | 7.5 |
| 65 years and older | 19.2 |
| **2003** | Under 5 years | 41.8 |
| 5 to 17 years | 2.4 |
| 18 to 49 years | 4.4 |
| 50 to 64 years | 10.0 |
| 65 years and older | 22.9 |
| **2004** | Under 5 years | 34.0 |
| 5 to 17 years | 2.2 |
| 18 to 49 years | 4.6 |
| 50 to 64 years | 11.9 |
| 65 years and older | 25.5 |
| **2005** | Under 5 years | 22.7 |
| 5 to 17 years | 2.9 |
| 18 to 49 years | 4.9 |
| 50 to 64 years | 11.4 |
| 65 years and older | 23.9 |
| **2006** | Under 5 years | 15.7 |
| 5 to 17 years | 2.6 |
| 18 to 49 years | 6.4 |
| 50 to 64 years | 10.5 |
| 65 years and older | 24.0 |
| **2007** | Under 5 years | 19.8 |
| 5 to 17 years | 2.5 |
| 18 to 49 years | 6.9 |
| 50 to 64 years | 13.3 |
| 65 years and older | 25.1 |
| **2008** | Under 5 years | 20.2 |
| 5 to 17 years | 2.4 |
| 18 to 49 years | 5.5 |
| 50 to 64 years | 12.8 |
| 65 years and older | 26.2 |
| **2009** | Under 5 years | 20.9 |
| 5 to 17 years | 2.9 |
| 18 to 49 years | 5.3 |
| 50 to 64 years | 12.5 |
| 65 years and older | 26.7 |
| **2010** | Under 5 years | 17.9 |
| 5 to 17 years | 2.5 |
| 18 to 49 years | 4.9 |
| 50 to 64 years | 13.1 |
| 65 years and older | 27.3 |
| **2011** | Under 5 years | 17.0 |
| 5 to 17 years | 3.2 |
| 18 to 49 years | 4.8 |
| 50 to 64 years | 12.9 |
| 65 years and older | 25.5 |
| **2012** | Under 5 years | 14.4 |
| 5 to 17 years | 3.1 |
| 18 to 49 years | 4.9 |
| 50 to 64 years | 13.4 |
| 65 years and older | 26.8 |
| **2013** | Under 5 years | 12.5 |
| 5 to 17 years | 2.3 |
| 18 to 49 years | 4.3 |
| 50 to 64 years | 12.1 |
| 65 years and older | 25.4 |
| **2014** | Under 5 years | 12.7 |
| 5 to 17 years | 2.3 |
| 18 to 49 years | 4.1 |
| 50 to 64 years | 12.0 |
| 65 years and older | 25.1 |
| **2015** | Under 5 years | 10.9 |
| 5 to 17 years | 2.4 |
| 18 to 49 years | 4.2 |
| 50 to 64 years | 12.4 |
| 65 years and older | 24.2 |
| **2016** | Under 5 years | 12.4 |
| 5 to 17 years | 2.3 |
| 18 to 49 years | 4.5 |
| 50 to 64 years | 12.6 |
| 65 years and older | 23.3 |
| **2017** | Under 5 years | 12.3 |
| 5 to 17 years | 2.2 |
| 18 to 49 years | 4.4 |
| 50 to 64 years | 12.8 |
| 65 years and older | 24.7 |
| **2018** | Under 5 years | 12.3 |
| 5 to 17 years | 2.2 |
| 18 to 49 years | 5.2 |
| 50 to 64 years | 15.6 |
| 65 years and older | 26.6 |
| **2019** | Under 5 years | 11.9 |
| 5 to 17 years | 2.1 |
| 18 to 49 years | 5.2 |
| 50 to 64 years | 13.6 |
| 65 years and older | 23.8 |
IPD incidence is directly proportional to age in persons 50 years of age and older ([Figure 2](#f2)). From 2011-2019, IPD incidence rates were highest in the oldest age group (85 years and older). In the other age groups, the incidence rates fluctuated slightly but remained relatively steady from 2011-2019. In Canadians aged 85 years and over, however, the incidence decreased from 50 to 40 cases per 100,000 population between 2011 and 2016. After 2016, incidence rates fluctuated ranging from 39 to 46 cases per 100,000 population, with a mean of 42 cases per 100,000 population. Incidence rates in the other age groups were approximately: 12 to 13 cases per 100,000 population in the 50 to 64 year-old age group; 19-20 cases per 100,000 population in the 65 to 74 year-old age group; and 26-28 cases per 100,000 population in the 75-84 year-old age group.
**Figure 2. Annual incidence rate of IPD in Canadian adults 50 years of age and older, reported to Canadian Notifiable Disease Surveillance System, 2001-2019**
Text Description
Figure 2 shows the incidence rate of IPD in Canadians over the age of 50 per 100,000 population (vertical axis) from 2011-2019 with one-year increments (horizontal axis), grouped by age category. The age categories used compare the incidence of IPD in the Canadian adult population and are plotted in distinct colors (50-64 in red, 65 to 74 in green, 75 to 84 in turquoise, and over 85 in purple). The incidence rates were calculated using data from the ICS program for Canada's three territories, and data from CNDSS for six provinces that had line list data available (AB, BC, ON, QC, SK, and PEI).
| Year | Age group | Incidence rate (per 100,000 population) |
| --- | --- | --- |
| **2011** | 50 to 64 years | 12.9 |
| 65 to 74 years | 18.3 |
| 75 to 84 years | 27.6 |
| 85 years and older | 49.8 |
| **2012** | 50 to 64 years | 13.4 |
| 65 to 74 years | 19.9 |
| 75 to 84 years | 28.8 |
| 85 years and older | 50.8 |
| **2013** | 50 to 64 years | 12.1 |
| 65 to 74 years | 19.3 |
| 75 to 84 years | 26.9 |
| 85 years and older | 47.6 |
| **2014** | 50 to 64 years | 12.0 |
| 65 to 74 years | 19.5 |
| 75 to 84 years | 26.6 |
| 85 years and older | 45.7 |
| **2015** | 50 to 64 years | 12.4 |
| 65 to 74 years | 18.3 |
| 75 to 84 years | 27.5 |
| 85 years and older | 41.8 |
| **2016** | 50 to 64 years | 12.6 |
| 65 to 74 years | 19.5 |
| 75 to 84 years | 23.4 |
| 85 years and older | 39.5 |
| **2017** | 50 to 64 years | 12.8 |
| 65 to 74 years | 19.9 |
| 75 to 84 years | 26.3 |
| 85 years and older | 41.8 |
| **2018** | 50 to 64 years | 15.6 |
| 65 to 74 years | 21.8 |
| 75 to 84 years | 27.2 |
| 85 years and older | 45.8 |
| **2019** | 50 to 64 years | 13.6 |
| 65 to 74 years | 19.7 |
| 75 to 84 years | 25.2 |
| 85 years and older | 39.1 |
The Toronto Invasive Bacterial Diseases Network (TIBDN) [Footnote 14](#fn14), an active surveillance program in Metropolitan Toronto and the Peel region, found that between 2012/2013 and 2018/2019, the incidence of IPD in adults aged 15 to 64 years increased significantly from 3.7 to 5.4 cases/100,000/year. During this same period, the incidence of IPD in adults aged 65 years and older decreased from 22.8 to 18.7 cases/100,000/year; however, this change was not significant. TIBDN also found that from 2018/2019 to 2020, IPD incidence in adults aged 15 to 64 years decreased from 5.4 to 2.6 cases/100,00/year, and IPD incidence in adults 65 years and older decreased from 18.7 to 8.7 cases/100,000/year.
#### III.1.2 IPD incidence in Northern Canada
The age-standardized incidence rate in Northern Canada, based on the data submitted to ICS, was significantly higher (25.8 cases per 100,000 population, 95% CI: 23.5 to 28.1%) than the rest of Canada (9.1 cases per 100,000 population, 95% CI: 9.1 to 9.2%) between 2001 and 2019 ([Figure 3](#f3)) [Footnote 15](#fn15).
In northern Canada, the IPD incidence rate in Indigenous Canadians was significantly higher at 31.3 cases per 100,000 population per year compared with non-Indigenous Canadians at 7.0 cases per 100,000 population per year (p<0.0001) for the same time period [Footnote 15](#fn15).
**Figure 3. Annual incidence rate of IPD in northern Canada, ICS 2001-2021, and rest of Canada, 2001-2019, CNDSS**
Text Description
Figure 3 shows the comparison of annual IPD incidence rates with 95% confidence intervals between Northern Canada (in red) and the rest of Canada (in blue) per 100,000 population (vertical axis) from 2001-2021 (horizontal axis). Data from Northern Canada was extracted from the ICS program and includes Canada’s three territories (Nunavut, Yukon, and Northwest territories), as well as Northern Labrador and Northern Quebec. Data for the rest of Canada came from CNDSS. IPD data for the rest of Canada for the years 2020-2021 were not yet available.
The incidence rate of IPD was consistently and significantly higher in Northern Canada when compared to the rest of Canada, with an exception of the year 2017, which was the minimum IPD incidence rate in Northern Canada at around 15 cases per 100,000 population. In this year, the incidence was still higher in Northern Canada but not significantly. The maximum overall IPD incidence rate Northern Canada occurred in 2001 with 38 cases per 100,000 population. The incidence rate subsequently decreased to 16 cases per 100,000 population in 2005 following the introduction of pediatric pneumococcal immunization in Canada. Since 2005, the IPD incidence rate fluctuated yet remained relatively stable, and was most recently calculated as 23 cases per 100,000 population in 2021. IPD cases have remained slightly elevated from 2018 to 2021 when compared to 2015 to 2017.
| Year | Northern Canada Crude incidence (per 100,000 population) | Rest of Canada Crude incidence (per 100,000 population) |
| --- | --- | --- |
| **2001** | 37.95 | 5.58 |
| **2002** | 25.78 | 7.24 |
| **2003** | 21.02 | 8.66 |
| **2004** | 23.39 | 9.19 |
| **2005** | 16.12 | 8.94 |
| **2006** | 18.78 | 8.92 |
| **2007** | 31.07 | 9.94 |
| **2008** | 23.12 | 9.67 |
| **2009** | 30.23 | 9.83 |
| **2010** | 20.51 | 9.90 |
| **2011** | 22.74 | 9.69 |
| **2012** | 16.61 | 9.92 |
| **2013** | 18.32 | 9.14 |
| **2014** | 25.71 | 9.00 |
| **2015** | 17.30 | 9.04 |
| **2016** | 16.49 | 9.19 |
| **2017** | 14.46 | 9.59 |
| **2018** | 28.49 | 10.96 |
| **2019** | 21.72 | 10.08 |
### III.2 Distribution of IPD Serotypes in Canada, 2016 – 2020
Distribution of IPD Serotypes in Canada, 2016 – 2020
From 2016 to 2020, a combined 15,234 isolates of *S. pneumoniae* causing invasive disease were characterized by the NML with 34% of these being identified from adults 65 years of age or older. The majority of IPD cases were caused by vaccine-contained serotypes ([Figure 4](#f4)). Serotypes 3 and 22F were identified as the most common causes of IPD overall and in older adults based on isolates submitted to NML ([Figure 4](#f4)).
Overall, the proportion of IPD isolates covered by each vaccine (PNEU-C-13, PNEU-C-15/non-PNEU-C-13, PNEU-C-20/non-PNEU-C-15 and PNEU-P-23/non-PNEU-C-20) have remained relatively stable since 2016 ([Figure 5](#f5)). In 2020, among adults 65 years old or older, 27.4% of circulating serotypes were covered by PNEU-C-13, 40.6% were covered by PNEU-C-15, 55.8% were covered by PNEU-C-20 and 66.9% were covered by PNEU-P-23. Circulating serotypes not covered by any pneumococcal vaccine amounted to 33.1%.
Serotype distribution for IPD among adults are summarized in [Appendix A, Tables 21-23](#t21).
**Figure 4. Proportion of isolates of invasive *S. pneumoniae* for all ages and adults 65 years and older in Canada, by serotype, 2016 to 2020, combined total**
\* Component of PNEU-C-13; \*\* Component of PNEU-C-15; ^ Component of PNEU-C-20; ~ Component of PNEU-P-23; ‡ Number of isolates for all ages and adults 65 years and older, respectively (2016-2020, combined total).
Text Description
Figure 4 shows a bar graph displaying the percentage of Streptococcus pneumoniae serotypes from 2016 to 2020 (combined total) based on the total number of isolates tested annually, for all ages and adults ≥65 years.
| Serotype (n by age group) | All ages (n=15234) | ≥65 years (n=5860) |
| --- | --- | --- |
| **1\* (5,1)‡** | 0.0% | 0.0% |
| **3\* (1638,653)** | 10.8% | 11.1% |
| **4\* (1120,194)** | 7.4% | 3.3% |
| **6A\* (51,31)** | 0.3% | 0.5% |
| **6B\* (46,32)** | 0.3% | 0.5% |
| **7F\* (509,83)** | 3.3% | 1.4% |
| **9V\* (157,44)** | 1.0% | 0.8% |
| **14\* (75,32)** | 0.5% | 0.5% |
| **18C\* (45,13)** | 0.3% | 0.2% |
| **19A\* (767,275)** | 5.0% | 4.7% |
| **19F\* (333,125)** | 2.2% | 2.1% |
| **23F\* (12,2)** | 0.1% | 0.0% |
| **22F\*\* (1346,624)** | 8.8% | 10.6% |
| **33F\*\* (500,183)** | 3.3% | 3.1% |
| **8^ (865,239)** | 5.7% | 4.1% |
| **10A^ (304,117)** | 2.0% | 2.0% |
| **11A^ (473,227)** | 3.1% | 3.9% |
| **12F^ (654,129)** | 4.3% | 2.2% |
| **15B/C^ (519,178)** | 3.4% | 3.0% |
| **2~ (5,1)** | 0.0% | 0.0% |
| **9N~ (933,361)** | 6.1% | 6.2% |
| **17F~ (156,73)** | 1.0% | 1.2% |
| **20~ (542,135)** | 3.6% | 2.3% |
| **6C (298,172)** | 2.0% | 2.9% |
| **7C (198,106)** | 1.3% | 1.8% |
| **15A (641,381)** | 4.2% | 6.5% |
| **16F (384,191)** | 2.5% | 3.3% |
| **23A (574,301)** | 3.8% | 5.1% |
| **23B (482,198)** | 3.2% | 3.4% |
| **31 (235,124)** | 1.5% | 2.1% |
| **34 (144,73)** | 0.9% | 1.2% |
| **35B (348,194)** | 2.3% | 3.3% |
| **35F (248,128)** | 1.6% | 2.2% |
| **38 (192,92)** | 1.3% | 1.6% |
| **Other (435,148)** | 2.9% | 2.5% |
[Figure 5](#f5) shows the proportion of IPD isolates by year among all isolates tested and older adults. In 2020, the proportion of isolates with PNEU-C-20/non-PNEU-C-13 (i.e., serotypes 8, 10A, 11A, 12F, 15B/C, 22F and 33F) among all IPD cases accounted for 30.4% and among IPD cases in adults 65 years old or older, for 28.4%. The proportion of IPD isolated covered by each vaccine among younger adults 18 to 49 and 50 to 64 years of age is shown in [Appendix A, Figure 6](#f6).
**Figure 5. Proportion of IPD isolates from 2016 to 2020 by vaccine, for all ages and adults 65 years of age and older**
\*Vaccine serotypes include PNEU-C-13 (1, 3, 4, 5, 6A/C, 6B, 7F, 9V, 14, 19A, 19F, 18C, 23F); PNEU-C-15 (all PNEU-C-13 plus 22F and 33F); PNEU-C-20 (All PNEU-C-15 plus 8, 10A, 11A, 12F, 15B/C) and PNEU-P-23 (PNEU-C-20 serotype except 6A, plus 2, 9N, 17F, 20); NVT = all serotypes not included in PNEU-C-13, PNEU-C-15, PNEU-C-20 and PNEU-P-23. Serotype 6C included in PNEU-C-13 Serotypes due to cross protection with 6A. Serotypes 15B and 15C were grouped together as 15B/C because of reported reversible switching between them in vivo during infection, making it difficult to precisely differentiate between the two types.
Text Description
Figure 5 shows a stacked bar graph displaying the percentage of Streptococcus pneumoniae collected from each vaccine category (PNEU-C-13, PNEU-C-15/non-PNEU-C-13, PNEU-C-20/non-PNEU-C-15, PNEU-P-23/non-PNEU-C-20 and other non-vaccine serotypes), for all ages and adults ≥65 years, from 2016 to 2020.
| Age Group | Year | PNEU-C-13
(%, N) | PNEU-C-15/
non-PNEU-C-13
(%, N) | PNEU-C-20/
non-PNEU-C-15
(%, N) | PNEU-P-23/
non-PNEU-C-20
(%, N) | NVT
(%, N) | Total |
| --- | --- | --- | --- | --- | --- | --- | --- |
| **All Ages** | 2016 | 32.9% | (938) | 12.6% | (360) | 18.4% | (526) | 8.8% | (251) | 27.3% | (780) | (2855) |
| 2017 | 32.2% | (1054) | 11.9% | (390) | 17.7% | (578) | 11.3% | (371) | 26.8% | (877) | (3270) |
| 2018 | 33.0% | (1099) | 11.7% | (388) | 19.1% | (634) | 10.7% | (357) | 25.5% | (850) | (3328) |
| 2019 | 32.6% | (1198) | 13.8% | (507) | 17.3% | (637) | 11.5% | (423) | 24.7% | (908) | (3673) |
| 2020 | 36.4% | (767) | 9.5% | (201) | 20.9% | (440) | 11.1% | (234) | 22.1% | (466) | (2108) |
| **≥65 years** | 2016 | 29.1% | (307) | 12.7% | (134) | 16.8% | (177) | 7.2% | (76) | 34.2% | (360) | (1054) |
| 2017 | 26.5% | (355) | 12.7% | (171) | 15.9% | (213) | 10.4% | (139) | 34.6% | (464) | (1342) |
| 2018 | 28.8% | (367) | 14.2% | (181) | 15.1% | (192) | 9.9% | (126) | 32.0% | (408) | (1274) |
| 2019 | 29.3% | (431) | 15.4% | (226) | 13.5% | (199) | 10.1% | (149) | 31.7% | (467) | (1472) |
| 2020 | 27.4% | (197) | 13.2% | (95) | 15.2% | (109) | 11.1% | (80) | 33.0% | (237) | (718) |
Distribution of IPD serotypes in Northern Canada
IPD distribution in Northern Canada was assessed using data from all five Arctic regions captured in the ICS system. Overall, there were 159 isolates of invasive *S. pneumoniae* characterized between 2016 and 2020: 26% of *S. pneumoniae* isolates were PNEU-C-13 serotypes, 14% were PNEU-C-15/non-PNEU-C-13 serotypes, 23% were PNEU-C-20/non-PNEU-C-15 serotypes, 20% were PNEU-P-23/non-PNEU-C-20 serotypes, and 16% were NVT serotypes. However, trends were difficult to ascertain due to the small number of cases and relatively smaller population in the North.
### III.3 Burden of Pneumococcal community acquired pneumonia in Canada
Using CIRN SOS Network data from 13 hospitals across five provinces, Leblanc et al. (2022) reported on CAP incidence in hospitalized adults from 2010 to 2017 [Footnote 16](#fn16). During this period, 14.2% (1264/8912) of all-cause CAP was found to be caused by *S. pneumoniae* with 64.1% (811/1264) being non-bacteremic, and 35.9% (455/1264) being bacteremic. Among pCAP cases in adults, 49.8% occurred in those over 65 years of age, 31.3% in those 50 to 64 years of age and 19.0% in those 16-49 years of age. Among all pCAP cases, 89.1% had one or more co-morbidity, and 28.6% had an immunocompromising condition. Of all *S. pneumoniae* CAP cases captured during the study period, the serotype distribution showed serotypes 3, 7F, 9N, 11A, 19A, and 22F as common.
Data from the 2018 to 2019 Discharge Abstract Database (Canadian Institute for Health Information 2022) reported inpatient CAP cases per 100,000 with pneumonia as a significant diagnosis (excluding pneumonia due to influenza). These data showed that for adults 75 years of age and older, there were 5,104 cases/100,000 population in Northern Canada and 2,846 cases/100,000 population across the rest of Canada; for adults 60 to 74, there were 1,777/100,000 population cases in Northern Canada and 871/100,000 population across the rest of Canada; and for adults 50 to 64 years, there were 569 cases/100,000 population in Northern Canada and 348 cases/100,000 population across the rest of Canada.
### III.4 High Risk Groups
The TIBDN [Footnote 17](#fn17) found that, in their population, IPD incidence among individuals aged 15 to 64 years with chronic underlying illness increased significantly from 7.3 cases/100,000/year in 2012 to 11.0 cases/100,000/year in 2019. During the same time period, the IPD incidence among adults aged 65 years and older decreased in those with underlying illness mainly because IPD cases due to PNEU-C-13 contained serotypes decreased from 10.0 to 4.6 cases/100,000/year in people with an underlying chronic illness, and from 27.0 to 16.0 cases/100,000/year in people with immunocompromising conditions.
The Calgary Area *Streptococcus pneumonia* Epidemiology Research (CASPER) [Footnote 18](#fn18) program, an active surveillance program in Calgary, found that between 2000 to 2013, IPD incidence rate among adults with underlying comorbidities decreased by 37% [from 11.8 cases/100,000/year before the introduction of pneumococcal conjugate vaccines (2000-2001) to 7.4 cases/100,000/year in the post-PNEU-C-13 period (2010-2013)].
### III.5 Summary of Pneumococcal Immunization Coverage in Canada
The Vaccine Coverage and Effectiveness Monitoring program at PHAC collects pneumococcal vaccination coverage information among Canadians as part of the seasonal influenza vaccination coverage survey [Footnote 19](#fn19). The most recent survey conducted over the 2020-2021 influenza season showed that about 55% of adults65 years of age and over reported receiving a pneumococcal vaccine in adulthood. The coverage was higher for females (60%) than males (40%). Overall, 26% of adults 18 to 64 years old with underlying medical conditions reported receiving pneumococcal vaccination. The survey did not differentiate between the two different pneumococcal vaccines recommended for adults.
IV. Vaccine
-----------
### IV.1 Preparations authorized for use in Canada
Four preparations of pneumococcal vaccine are currently authorized for use in adults in Canada ([Table 2](#t2)).
PNEU-C-13 (Prevnar®13) [Footnote 20](#fn20) is a sterile solution of polysaccharide capsular antigen of 13 serotypes of *S. pneumoniae* (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F). The antigens are individually conjugated to a diphtheria, *Corynebacterium diphtheriae* (CRM197), protein carrier. The CRM197 protein carrier is adsorbed on aluminum phosphate as an adjuvant. Each dose of vaccine contains 4.4 mcg of the 6B polysaccharide, and 2.2 mcg each of the remaining polysaccharides. PNEU-C-13 is available as a 0.5mL single dose, prefilled syringe.
PNEU-C-15 (Vaxneuvance®) [Footnote 21](#fn21) is a sterile suspension of purified capsular polysaccharides from 15 serotypes of *S. pneumoniae* (PCV13 serotypes plus serotypes 22F and 33F). The antigens are individually conjugated to diphtheria CRM197 protein carrier. This CRM197 protein carrier is adsorbed on aluminum phosphate as an adjuvant. Each dose of vaccine contains 32 mcg of total pneumococcal polysaccharide (2.0 mcg each of polysaccharide Serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F, and 4.0 mcg of polysaccharide serotype 6B) conjugated to 30 mcg of CRM197 carrier protein. PNEU-C-15 is available as a 0.5mL single-dose prefilled syringe.
PNEU-C-20 (Prevnar 20TM) [Footnote 22](#fn22) is a sterile saccharide suspension of the capsular antigens of 20 serotypes of *S. pneumoniae* (PCV13 serotypes + serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F). The antigens are individually conjugated to non-toxic diphtheria CRM197 protein. This CRM197 protein carrier is absorbed on aluminum phosphate as an adjuvant. Each dose of vaccine contains 4.4 mcg of the 6B polysaccharide, and 2.2 mcg each of the remaining polysaccharides. PNEU-C-20 is supplied as a 0.5mL single dose prefilled syringe.
PNEU-P-23 (Pneumovax®23) [Footnote 23](#fn23) is a sterile solution of 23 highly purified capsular polysaccharides (PCV13 serotypes with the exception of 6A, plus serotypes 2, 9N,17F, and 20). PNEU-P-23 is available as a single-dose vial containing 0.5 ml of liquid vaccine and a 0.5mL single dose prefilled syringe.
Table 2: Comparison of vaccines authorized for use in adults in Canada
| | PREVNAR® 13
(PNEU-C-13) | VAXNEUVANCE®
(PNEU-C-15) | PREVNAR 20TM
(PNEU-C-20) | PNEUMOVAX 23®
(PNEU-P-23) |
| Manufacturer | Pfizer | Merck | Pfizer | Merck |
| Date of initial authorization in Canada | December 21, 2009 | November 16, 2021 | May 9, 2022 | December 23, 1983 |
| Type of vaccine | Conjugate vaccine | Conjugate vaccine | Conjugate vaccine | Polysaccharide vaccine |
| Composition | 2.2 mcg of each saccharide for *S. pneumoniae* serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F and 23F, 4.4 mcg of saccharide for serotype 6B, 34 mcg of CRM197 carrier protein, 4.25 mg of sodium chloride, 100 mcg of polysorbate 80, 295 mcg of succinic acid and 125 mcg of aluminum as aluminum phosphate adjuvant and water for injection | 32 mcg of total pneumococcal polysaccharide (2.0 mcg each of polysaccharide serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F and 4.0 mcg of polysaccharide serotype 6B) conjugated to 30 mcg of CRM197 carrier protein, 125 mcg of
aluminum (as aluminum phosphate adjuvant),
1.55mg of L-histidine, 1 mg of polysorbate 20,
4.50 mg of sodium chloride and water for
injection | Approximately 2.2 mcg of each of *S. pneumoniae* serotypes 1, 3, 4, 5, 6A, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F and 33F saccharides, 4.4 mcg of 6B saccharide, 51 mcg of CRM197 carrier protein, 100 mcg of polysorbate 80, 295 mcg of succinic acid, 4.4 mg of sodium chloride and 125 mcg of aluminum as aluminum phosphate adjuvant and water for injection | 25 mcg of capsular polysaccharides from each of *S. pneumoniae* serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F, sodium chloride 0.9 % w/w, phenol 0.25% w/w and water for injection to volume |
| Schedule for immunocompetent adults | 1-dose schedule | 1-dose schedule | 1-dose schedule | 1-dose schedule |
| Route of administration | Intramuscular injection | Intramuscular injection | Intramuscular injection | Intramuscular or subcutaneous injection |
| Indications for adults | Indicated for active immunization of adults 18 years of age and older for prevention of pneumonia and invasive pneumococcal disease caused by *Streptococcus* *pneumoniae* serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F | Indicated for active immunization of adults 18 years of age of older for the prevention of invasive disease caused by *Streptococcus pneumoniae* serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F | Indicated for active immunization of adults 18 years of age and older for the prevention of pneumonia and invasive pneumococcal disease caused by *Streptococcus pneumoniae* serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F | Indicated for active immunization of adults 18 years of age and older for prevention of pneumococcal disease caused by pneumococcal types included in the vaccine (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F) |
| Contraindications | * Known hypersensitivity to any component of the vaccine, including diphtheria toxoid
| * History of a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine or any diphtheria toxoid-containing vaccine
| * Known hypersensitivity to the active substance or to any component of the vaccine, including diphtheria toxoid
| * Known hypersensitivity (e.g., anaphylaxis) to any component of the vaccine
|
| Precautions | * Individuals with immunocompromising conditions (limited data; may have reduced immune response)
* Pregnancy (limited data)
* Breastfeeding (limited data)
| * Individuals with immunocompromising conditions (may have reduced immune response)
* Pregnancy (limited data)
* Breastfeeding (no data)
| * Individuals with immunocompromising conditions (no data)
* Pregnancy (limited data)
* Breastfeeding (limited data)
| * Pregnancy (no data)
* Breastfeeding (no data)
|
| Storage Requirements | Single-dose prefilled syringe. Refrigerate at 2°C to 8°C. Do not freeze. Store in original package | Single-dose prefilled syringe. Refrigerate at 2°C to 8°C. Do not freeze. Protect from light. Administer as soon as possible after being removed from the refrigerator | Single-dose prefilled syringe. Refrigerate at 2°C to 8°C. Store syringes horizontally in the refrigerator. Do not freeze. Administer as soon as possible after being removed from the refrigerator | Multi-dose vial.
Refrigerate at 2°C to 8°C. Discard opened vial after 48 hours |
### IV.2 Efficacy and effectiveness
There are currently no efficacy or effectiveness data available for PNEU-C-15 or PNEU-C-20 for any adult indication.
Recently reported systematic reviews continue to support the effectiveness of PNEU-C-13 against IPD and pneumococcal pneumonia among adults 65 and older [Footnote 24](#fn24) [Footnote 25](#fn25). Two observational studies included in the systematic review by Childs et al found a PNEU-C-13 vaccine effectiveness against pneumonia caused by vaccine-contained serotypes in the range of 38 to 68%. Three observational studies from the systematic review by Farrar et al found a PNEU-C-13 effectiveness against IPD caused by vaccine-contained serotypes in the range of 59 to 68%.
A recent systematic review [Footnote 24](#fn24) reported a pooled PNEU-P-23 effectiveness against IPD caused by vaccine-contained serotypes in adults 65 years of age and older to be 38%. Another systematic review [Footnote 25](#fn25) found a limited protection against pneumonia caused by vaccine-contained serotypes (pooled effectiveness of 18% from 3 observational studies with PNEU-P-23 given to adults 65 years and older less than 5 years before illness onset).
### IV.3 Immunogenicity
#### IV.3.1 Measures of Immunogenicity
OPA assays were used to assess immune response for PNEU-C-15 and PNEU-C-20. While no specific threshold of OPA titer has been identified that correlates with protection against IPD or pneumonia in adults, OPA responses have been used as an established surrogate of protection to infer efficacy when comparing to an efficacious vaccine.
Previously, OPA responses were used as a surrogate marker of vaccine efficacy for IPD and pneumonia in the approval of PNEU-C-13 in adults.
#### IV.3.2 Immunogenicity of PNEU-C-15
**Summary of PNEU-C-15 study characteristics**
Immunogenicity of PNEU-C-15 was evaluated in two Phase 2 trials [Footnote 26](#fn26) [Footnote 27](#fn27) and five Phase 3 trials [Footnote 28](#fn28) [Footnote 29](#fn29) [Footnote 30](#fn30) [Footnote 31](#fn31) [Footnote 32](#fn32). Three studies evaluated medically stable, vaccine-naïve adults 50 years of age or older and one study focused on previously vaccinated adults 65 years of age and older. Data for adults 18 years of age and older with medical risk factors for PD were available in two studies (one as a study population subset analysis). One study evaluated adults with HIV. Most studies had participants of a majority white race and with gender balance ([Table 5](#t5)). Immunogenicity assessments were at a low RoB ([Appendix A, Table 8](#t8)).
**Summary of PNEU-C-15 immunogenicity evidence**
In immunocompetent pneumococcal vaccine-naïve adults 65 years of age and older, for shared serotypes, PNEU-C-15 demonstrated overall similar immune responses, including for serotype3, compared to PNEU-C-13 ([Appendix A Tables 9](#t9)). All analyses for serotypes not covered by PNEU-C-13 showed numerically higher responses with PNEU-C-15. However, seroresponses varied for the shared serotypes. Results from studies comparing PNEU-C-15 to PNEU-P-23 showed similar results, although seroresponse was higher with serotype3 with PNEU-C-15 (Appendix A, Tables [9](#t9) and [10](#t10)).
While no studies evaluated non-inferiority for other age groups (50 to 64 years; 65 to 74 years; 75 years of age and older) observational comparisonsamong age groups and age subgroup data for seroresponse are reported in Appendix A, Tables [9](#t9) and [10](#t10). Non-inferiority for shared serotypes was not evaluated in the comparison with PNEU-C-13 for adults with previous PNEU-P-23 vaccination ([Appendix A, Table 12](#t12)), and adults with immunocompromising conditions ([Appendix A, Table 14](#t14)).
In pneumococcal vaccine-naïve adults over the age of 65, PNEU-C-15 administered concurrently with quadrivalent seasonal influenza vaccine, seroresponses were found to be similar for serotype 3 but numerically lower for the other shared serotypes ([Appendix A, Table 11](#t11)). In adults who subsequently received PNEU-P-23 following the receipt of PNEU-P-15, there was an observed numerically lower proportion of seroresponders with serotype 3, PNEU-C-15 unique serotypes, as well as some shared serotypes when compared to seroresponse rates following previous PNEU-C-13 vaccination in series with PNEU-P-23 for some shared serotypes ([Appendix A, Table 15](t15)).
Non-inferiority for shared serotypes was not evaluated in the comparison with PNEU-C-13 for adults with previous PNEU-P-23 vaccination ([Appendix A, Table 12](#t12)), as well as people with chronic medical conditions (CMC) 18 to 64 years of age ([Appendix A, Table 13](#t13)) and with immunocompromising conditions ([Appendix A, Table 14](#t14)).
#### IV.3.3. Immunogenicity of PNEU-C-20
**Summary of PNEU-C-20 study characteristics**
Immunogenicity of PNEU-C-20 was evaluated in one Phase 2 trial3 [Footnote 33](#fn33) and two Phase 3 trials [Footnote 34](#fn34) [Footnote 35](#fn35). Two trials evaluated vaccine-naïve healthy adults, as well as adults with underlying CMCs. Of these studies, one recruited participants 60 to 64 years of age while the other enrolled participants 18 years of age or older into three age cohorts (i.e., 18 to 49, 50 to 59, 60 years and older). One study evaluated immune responses in previously PNEU-P-23 vaccinated adults 65 years of age or older. Studies were assessed to be at low RoB ([Appendix A, Table 8](#t8)).
**Summary of PNEU-C-20 immunogenicity evidence**
Non-inferiority criteria were met following the administration of PNEU-C-20 in vaccine-naïve populations over age 60. However, there was an observed lower proportion of seroresponders compared to PNEU-C-13 for shared serotypes ([Appendix A, Table 16](#t16)). While PNEU-C-20 was not directly compared to PNEU-C-13 or PNEU-P-23, individuals previously vaccinated with PNEU-P-23, PNEU-C-13 or both, showed robust immune responses following PNEU-C-20 vaccination (Appendix A, Tables [17](#t17) and [18](#t18)). PNEU-C-20 was not evaluated in adults with immunocompromising conditions.
### IV.4 Persistence of Immune Response
Persistence of PNEU-C- 15 immune response
Persistence of PNEU-C-15 immune response was observed 8 weeks [Footnote 29](#fn29), 6 months [Footnote 30](#fn30) and 1 year [Footnote 31](#fn31) following the sequential administration of PNEU-P-23 in adults 18 years of age or older living with immunocompromising conditions, in adults 18 to 49 living with CMCs and in healthy adults 65 years of age or older. In general, OPA GMTs at 8 weeks, 6 months and 1 year were lower than at day 30 post PNEU-C-15 vaccination but higher than at baseline. PNEU-C-15 elicited an immune response that was comparable to PNEU-C-13 at 30 days and 8 weeks, 6 months, and 12 months post- vaccination for the 13 shared serotypes and higher than PNEU-C-13 for the 2 serotypes 22F and 33F unique to PNEU-C-15.
Persistence of PNEU-C-20 immune response
Persistence of PNEU-C-20 immune response was observed at 12 months in healthy adults aged 60 through 64 years with no history of pneumococcal vaccination [Footnote 33](#fn33). OPA GMTs at 12 months declined compared with those at 30 days after vaccination but remained elevated above baseline. The same pattern of antibody decline in the 12 months after vaccination has previously been observed with PNEU-C-13. However, vaccine effectiveness against pneumonia caused by serotypes in the vaccine did not decline through 4 years of follow-up [Footnote 36](#fn36).
### IV.5 Vaccine Administration and Schedule
PNEU-C-15 and PNEU-C-20 are supplied in a single-dose, prefilled syringe.
A 0.5mL dose of PNEU-C-15 should be administered intramuscularly. The standard schedule for immunization is one dose. The need for a booster dose or re-immunization is not indicated. Please see the product monograph for additional details [Footnote 21](#fn21).
A 0.5mL dose of PNEU-C-20 should be administered intramuscularly. The standard schedule for healthy adults is one dose. Please see the product monograph for additional details [Footnote 22](#fn22).
### IV.6 Serological Testing
Serological testing is not recommended before or after receiving pneumococcal vaccine.
### IV.7 Storage Requirements
PNEU-C-15 should be refrigerated at 2°C to 8°C. The vaccine should not be frozen. Protect the vaccine from light. The prefilled syringes should be administered as soon as possible after being removed from the refrigerator [Footnote 21](#fn21).
PNEU-C-20 should be refrigerated at 2°C to 8°C. The pre-filled syringes should be stored horizontally in the refrigerator to minimize the re-dispersion time. The vaccine should be discarded if it has been frozen. The vaccine should be administered as soon as possible after being removed from the refrigerator [Footnote 22](#fn22).
### IV.8 Concurrent Administration with Other Vaccines
PNEU-C-15 and PNEU-C-20 can be concurrently administered with quadrivalent inactivated influenza vaccine (QIV) in adults, as concurrent administration has been demonstrated to be immunogenic and safe [Footnote 37](#fn37). However, lower pneumococcal OPA GMTs were reported when pneumococcal vaccines were co-administered with QIV compared with when pneumococcal vaccines were given alone [Footnote 32](#fn32) [Footnote 37](#fn37) [Footnote 38](#fn38). No data are available on co-administration of PNEU-C-15 or PNEU-C-20 with other adult vaccines. Preliminary data on the co-administration of PNEU-C-20 and the Pfizer-BioNTech Comirnaty mRNA COVID-19 vaccine showed no significant interference in the immune response [Footnote 39](#fn39).
### IV.9 Vaccine Safety
**Summary of PNEU-C-15 study characteristics**
Safety of PNEU-C-15 was evaluated in two Phase 2 trials [Footnote 26](#fn26) [Footnote 27](#fn27) and five Phase 3 trials [Footnote 28](#fn28) [Footnote 29](#fn29) [Footnote 30](#fn350) [Footnote 31](#fn31) [Footnote 32](#fn32). Data on local and systemic AEs were solicited through electronic vaccine report cards for two weeks after each dose, as well as follow up for serious events for 6 months. Reported outcomes included SAEs, vaccine-related SAEs, as well as mild/moderate and severe systemic AEs (i.e., fever, fatigue, headache, muscle, and joint pain). Safety data was reported for pneumococcal vaccine-naïve individuals, concurrent administration with season influenza vaccine, and for specific populations of interest including adults aged 18 to 64 years with chronic medical or immunocompromising conditions, and previously vaccinated adults aged 65 years or older. Six studies were at low RoB for all domains. In one study the reasons for missing data were not reported in the assessment of SAEs and vaccine-related SAEs, which is challenging.
Summary of PNEU-C-15 Safety
There was little to no difference reported in clinical trials between PNEU-C-15 and PNEU-P-23 or PNEU-C-13 for all mild/moderate and severe systemic AEs occurring within 14 days of vaccination as well as reported SAEs up to six months after vaccination in all evaluated populations (Appendix A, Tables [9](#t9), [10](#t10) and [13](#t13) to [15](#t15)). Results were similar following sequential administration of PNEU-P-23 after PNEU-C-15 or PNEU-C-13 in adults 65 years of age or older with an immunocompromising condition (Appendix A, Tables [14](#t14) and [15](#t15)).
There was little to no difference in SAEs for PNEU-C-15 administered concomitantly with QIV for vaccine-naïve adults ([Appendix A, Table 11](#t11)). Results were similar with respect to severe fatigue, joint and muscle pain up to 14 days after vaccination. There was no difference between groups for severe and mild/moderate systemic AEs.
Summary of PNEU-C-20 study characteristics
The safety of PNEU-C-20 was primarily evaluated for GRADE in one Phase 2 trial [Footnote 33](#fn33) and two Phase 3 trials [Footnote 34](#fn34) [Footnote 35](#fn35). Data were available for pneumococcal vaccine-naïve adults 18 years of age and older, and previously vaccinated adults 65 years of age and older. The full safety evaluation included 6 pre-licensure clinical trials, with safety data collection including solicited local reactions within 10 days of vaccination and systemic events within 7 days. Unsolicited events were collected for 1 month after vaccination and SAEs and newly diagnosed CMCs within 6 months after vaccination.
Safety of PNEU-C-20
There was little to no difference between PNEU-C-20 and PNEU-C-13 in SAEs up to one month post-vaccination for vaccine-naïve adults aged 60 years or older. Results showed no difference for all mild/moderate and severe systemic AEs up to seven days post-vaccination. Certainty of evidence varied across assessments ranging from moderate to high ([Appendix A, Table 16](#t16)).
For adults 65 years of age and older previously vaccinated with PNEU-P-23 one to five years prior, SAEs up to six months and systemic AEs 7 days after vaccination were similar between PNEU-C-20 and PNEU-C-13 ([Appendix A, Table 18](#t18)). Findings were similar when PNEU-C-20 and PNEU-P-23 were compared among those previously vaccinated with PNEU-13 at least six months prior ([Appendix A, Table 17](#t17)).
### IV.10 Contraindications and Precautions
PNEU-C-15 and PNEU-C-20 are contraindicated in individuals with a history of a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine or any diphtheria toxoid-containing vaccine. Administration of vaccine should be postponed in persons suffering from acute severe febrile illness.
V. Vaccination of Specific Populations
--------------------------------------
### V.1. Immunization in Pregnancy and Breastfeeding
There are no adequate and well-controlled studies of PNEU-C-15 and PNEU-C-20 in individuals who are pregnant or breastfeeding.
### V.2. Immunization of Immunocompromised persons
Individuals with altered immunocompetence, including those receiving immunosuppressive therapy, may have a reduced immune response to the vaccine.
VI. Ethics, Equity, Feasibility and Acceptability Considerations
----------------------------------------------------------------
NACI uses a published, peer-reviewed framework and evidence-informed tools to ensure that issues related to ethics, equity, feasibility, and acceptability (EEFA) are systematically assessed and integrated into its guidance [Footnote 40](#fn40).
NACI evaluated the following ethical considerations when making its recommendations: promoting well-being and minimizing risk of harm, maintaining trust, respect for persons and fostering autonomy, and promoting justice and equity. NACI took into account the available evidence from the clinical studies of PNEU-C-15 and PNEU-C-20 along with the real-world evidence on the effectiveness and safety of currently available pneumococcal vaccines PNEU-C-13 and PNEU-P-23, as well as data on the burden of illness of PD and evolving serotype distribution, and risk factors in particular for IPD.
Achieving coverage of 80% of adults 65 years old or older vaccinated with a pneumococcal vaccine, as well as reducing overall burden of disease by 5% by 2025, is one of the goals of the Canadian national immunization strategy. However, vaccine uptake in adults 65 years of age or older is well below the target, with approximately 55% reporting receiving a pneumococcal vaccine in Canada. Uptake is even lower among younger adults 18 to 64 years of age with underlying medical conditions that predispose them to PD at approximately 26%). A survey conducted in Quebec in 2020 reported that lack of awareness that the pneumococcal vaccine is needed or recommended is the most frequent reason for not being vaccinated.
The new higher-valent pneumococcal conjugate vaccines offer an opportunity to protect individuals against additional serotypes and further reduce the burden of disease in adults. PNEU-C-20 covers more than 90% of serotypes included in PNEU-P-23, with the additional benefits of conjugate vaccines. Thus, PNEU-C-20 may be offered in programs as a single dose without a subsequent dose of PNEU-P-23, unlike PNEU-C-15 which is recommended to be administered in series with PNEU-P-23 to optimize protection. A single dose vaccine schedule minimizes complexity and cost in a vaccine program and can facilitate vaccination of populations that are otherwise difficult to reach to complete a series requiring more than one dose.
Among factors that may contribute to health inequity as described in NACI’s EFFA framework, pre-existing disease, social factors, place of residence, and age are important to consider with pneumococcal recommendations. Pneumococcal disease burden increases with age and adults with pre-existing conditions are at greater risk. Therefore, by providing age-based and risk-based recommendations as well as inclusion of settings of higher disease burden, inequity may be reduced.
First Nations, Metis, or Inuit communities in Canada have a younger age distribution compared to the general Canadian population but have also been observed to have increased risk for severe PD due to a variety of intersecting factors including underlying medical conditions and potential decreased access to health care. Therefore, age-based recommendations may need to be modified to offer effective protection to individuals in these communities. Autonomous decisions should be made by Indigenous Peoples with the support of healthcare and public health partners in accordance with the [United Nations Declaration on the Rights of Indigenous Peoples](https://www.justice.gc.ca/eng/declaration/fact-fiche.html).
VII. Economics
--------------
A systematic review, de novo model-based economic evaluation, and a multi-model comparison were used as economic evidence to support decision-making for the use of PNEU-C-15 and PNEU-C-20.
Full details of these analysis, including assumptions and limitations, are provided in a supplementary appendix.
A review of the peer-reviewed and grey literature identified four cost-utility studies of PNEU-C-15 and PNEU-C-20 compared to current vaccination recommendations for adults in the United States (that are PNEU-P-23 plus optional PNEU-C-13 under shared clinical decision-making for adults aged 65 years or older; PNEU-P-23 at diagnosis of CMCs if under age 65 years; and PNEU-C-13 in series with PNEU-P-23 at diagnosis of immunocompromising condition if under age 65 years) [Footnote 41](#fn41). The studies generally found that PNEU-C-20 use in older adults was associated with increased QALYs, and with lower ICERs when the vaccine was used in adults aged 65 years and older compared to programs in adults aged 50 years and older. ICER estimates for PNEU-C-15 use in series with PNEU-P-23 at age 65 showed variability across studies. The estimated impact of adding risk-based programs for younger adults with IC/CMC to an age-based strategy depended on the vaccine product, with lower ICERs reported for PNEU-C-20 than for PNEU-C-15 in series with PNEU-P-23.
A cost-utility model developed by NACI was used to evaluate the cost-effectiveness of different age-based recommendations for PNEU-C-15 and PNEU-C-20 vaccines (used alone or in series with PNEU-P-23) in the Canadian population compared to current recommendations. Results are presented for the health system perspective. The base-case analysis, supported by scenario analyses, indicated that PNEU-C-20 used alone is likely a cost-effective strategy at age 65 or 75, with ICERs ranging from $6,500 to $17,400 per QALY gained. The ICERs for PNEU-C-20 at age 50 were higher than for ages 65 or 75. In sequential analysis that compared all possible vaccination strategies, PNEU-C-15 was dominated (more costly and less effective) or subject to extended dominance (i.e., would never be the optimal option regardless of the cost-effectiveness threshold) by PNEU-C-20. PNEU-C-20 plus PNEU-P-23 at age 65 or age 75 had ICERs ranging from 80,000 to $113,500 per QALY gained. Findings were sensitive to the assumed vaccine prices for PNEU-C-15 and PNEU-C-20 (see supplementary appendix). Analysis of populations in Northern Canada showed similar trends as the rest of Canada.
In a multi-model comparison, three cost-utility models with harmonized parameter values and using the same health system perspective and discount rate, showed qualitatively consistent results despite differing model structures and assumptions. The comparison supported the finding that, based on currently available data, PNEU-C-20 used alone ($4,100-106,000 per QALY gained) could be a cost-effective strategy for use in the adult Canadian population, depending on the cost-effectiveness threshold used. All models estimated PNEU-C-15 or PNEU-C-15 in series with PNEU-P-23 to be dominated (more costly and less effective) or subject to extended dominance (would never be the optimal option regardless of the cost-effectiveness threshold) by PNEU-C-20.
VIII. Recommendations
---------------------
Following the review of available evidence summarized above, NACI makes the following recommendations for public health level decision-making. Considerations in the management options table should also be reviewed in order to inform decision making.
A *strong recommendation* applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
A *discretionary recommendation* may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.
Please see [Appendix A](#appa) for a more detailed explanation of strength of NACI recommendations ([Table 19](#t19)) and the GRADE assessment of the body of evidence ([Table 6](#t6)).
NACI will continue to carefully monitor the scientific developments related to pneumococcal vaccination in adults and will update recommendations as evidence evolves.
### VIII.1 Recommendations for Public Health Program Level Decision-Making
In considering NACI recommendations for publicly funded immunization programs and for the purposes of publicly funded program implementation, provinces and territories may take into account other local operational factors (e.g., current immunization programs, resources). Recognizing that there are differences in operational contexts across Canada, jurisdictions may wish to refer to Management Options Tables [3](#t3) and [4](#t4) below for a summary of the considerations for using different products (e.g., with respect to cost-effectiveness and feasibility).
**For adults not previously vaccinated with a pneumococcal vaccine, or adults whose vaccination status is unknown**
1. **NACI recommends that pneumococcal conjugate vaccine PNEU-C-20 should be offered to pneumococcal vaccine naïve adults or adults whose vaccination status is unknown and who are 65 years of age and older, or who are 50 to 64 years of age living with risk factors placing them at higher risk of pneumococcal disease, or who are 18 to 49 years of age living with immunocompromising conditions. (Strong NACI recommendation).**
Summary of evidence and rationale
* Conjugate vaccines induce memory, provide longer duration of protection, and provide ability for boosting by involving T cells in a way that polysaccharide vaccines cannot. The more durable protection offered by conjugate vaccines may result in fewer cases of PD, even though they protect against fewer serotypes than polysaccharide vaccine.
* In immunocompetent adults 65 years of age and older, PNEU-C-20 has been demonstrated to produce a similar (non-inferior) immune response compared to PNEU-C-13, although immune responses were noted to be lower following PNEU-C-20, and superior immune responses compared to PNEU-C-23 for shared serotypes.
* No PNEU-C-20 studies in immunocompromised adults have been conducted. Among persons with ICs for PD, PNEU-C-20 is expected to be similarly efficacious as PNEU-C-13 against disease attributable to the 13 matched serotypes.
* PNEU-C-20 has a comparable safety profile to PNEU-C-13 in adults.
* Immunization of older adults with PNEU-C-20 vaccine is expected to be cost-effective, based on the current burden of IPD and assumptions regarding pricing of the PNEU-C-15, PNEU-C-20, and PNEU-P-23.
* Individuals at increasing age and/or with certain underlying medical conditions (both non-immunocompromising and immunocompromising) and other risk factors are at higher risk of IPD (see [Table 1](#t1)). Adults 65 years of age and older have the highest incidence rate of IPD compared to other adult age groups, followed by adults 50 to 64 years of age. However, the benefit of vaccinating adults 50 to 64 with underlying medical conditions or other risk factors that place them at higher risk for IPD are anticipated to be greater than vaccinating all adults in this age group.
* Age-based recommendations may need to be modified for communities with younger age distributions. In First Nations, Metis, or Inuit communities, autonomous decisions should be made by Indigenous Peoples with the support of healthcare and public health partners in accordance with the [United Nations Declaration on the Rights of Indigenous Peoples](https://www.justice.gc.ca/eng/declaration/fact-fiche.html).
* Current uptake of pneumococcal vaccines among older adults and adults living with underlying medical conditions, both non-immunocompromising and immunocompromising, is well below national goals.
* Program feasibility and vaccine acceptability and uptake may be superior with single dose PNEU-C-20 as compared to a PNEU-C-15 + PNEU-P-23 strategy, the latter of which would require coordination of two doses of different vaccine products.
2. **NACI recommends that PNEU-C-15 followed by PNEU-P-23 may be offered as an alternative to PNEU-C-20 to pneumococcal vaccine naïve adults or adults whose vaccination status is unknown and who are 65 years of age and older, or who are 50 to 64 years of age living with risk factors placing them at higher risk of pneumococcal disease, or who are 18 to 64 years of age living with immunocompromising conditions. (Discretionary NACI recommendation)**
Summary of evidence and rationale
* In immunocompetent adults 65 years of age and older, PNEU-C-15 has demonstrated to produce a similar (non-inferior) immune response compared to PNEU-C-13 for shared serotypes.
* In adults with underlying medical conditions, including ICs, PNEU-C-15 has shown comparable immune responses to PNEU-C-13 for 13 shared serotypes.
* An interval between PNEU-C-15 and PNEU-P-23 of 1 year is recommended for adults 65 years of age and older and adults 50 to 64 years of age living with risk factors for PD to provide expanded protection to 8 additional serotypes not in PNEU-C-15.
* An interval between PNEU-C-15 and PNEU-P-23 of 8 weeks is recommended for adults 18 to 64 years of age living with ICs to provide expanded protection to additional serotypes not in PNEU-C-15 allowing for quicker completion of series in vulnerable population. A longer interval may result in less blunting of immune responses and could be considered if risk of pneumococcal infection if low.
* Although PNEU-C-15 is not expected to yield the same population-level epidemiological benefits as PNEU-C-20 and requires a second dose with PNEU-P-23, it is anticipated to improve disease outcomes compared to offering PNEU-P-23 alone.
* Although PNEU-C-20 dominated PNEU-C-15 + PNEU-P-23 in cost-effectiveness analyses, the results were sensitive to vaccine price. A large enough differential in vaccine price between PNEU-C-20 and PNEU-C-15 + PNEU-P-23 would result in similar cost-effectiveness (i.e., PNEU-C-15 + PNEU-P-23 would no longer be dominated).
**For adults previously vaccinated with a pneumococcal vaccine**
3. **NACI recommends that pneumococcal conjugate vaccine PNEU-C-20 should be offered to adults 65 years of age and older who have been immunized** **previously** **with PNEU-P-23 alone, or PNEU-C-13 and PNEU-P-23 in series****,** **if it has been at least 5 years from the last dose of****a previous pneumococcal vaccine (****PNEU-P-23** **or PNEU-C-13)****.****(Strong NACI recommendation)**
Summary of evidence and rationale
* Robust immune responses were reported for PNEU-C-20 in adults previously vaccinated with PNEU-P-23 alone or together with PNEU-C-13; however, the data were non-comparative to PNEU-C-13.
* PNEU-C-20 has shown little to no difference in safety profiles to PNEU-C-13 in adults 65 years of age and older previously vaccinated.
* An interval of 5 years between PNEU-P-23 and PNEU-C-20 takes advantage of the estimated effectiveness duration of PNEU-P-23 and the boosting anticipated with PNEU-C-20; it also maximizes the total duration of protection against pneumococcal infection.
* There may be benefit to offering PNEU-C-15 to adults 65 years of age and older who have received PNEU-P-23 alone if PNEU-C-20 is not available. For adults 65 years of age and older who are also at the highest risk of IPD, an additional dose of PNEU-P-23 may be offered one year later. There is limited benefit to giving PNEU-C-15 to individuals who received PNEU-C-13 as it will only offer protection against two additional serotypes.
4. **NACI recommends that pneumococcal conjugate vaccine PNEU-C-20 may be offered to adults 65 years of age and older who have been immunized previously with PNEU-C-13 alone, if it has been 1 year from the last dose of PNEU-C-13.** **(Discretionary NACI recommendation)**
Summary of evidence and rationale
* Robust immune responses were reported for PNEU-C-20 in adults previously vaccinated with PNEU-C-13 only; however, the data were non-comparative to PNEU-C-13.
* An interval of 1 year between PNEU-C-13 and PNEU-C 20 is to expand serotype coverage offered by PNEU-C-13 in a time-effective manner.
* A shorter interval of 8 weeks might be considered to align with immunization clinics and/or programs.
* The additional benefit of offering PNEU-C-15 is limited as PNEU-C-15 will only offer protection against two additional serotypes. However, PNEU-C-15 in series with PNEU-P-23 or PNEU-P-23 alone can be considered if PNEU-C-20 is unavailable or inaccessible.
**For hematopoietic stem cell transplant recipients**
5. **NACI recommends that pneumococcal conjugate vaccine PNEU-C-20 should be offered to adults 18 years old or older who received a hematopoietic stem cell transplant (HSCT) after consultation with transplant specialist. A primary series of 3 doses of PNEU-C-20 starting 3 to 9 months after transplant should be administered at least 4 weeks apart, followed by a booster dose of PNEU-C-20 12 to 18 months post-transplant (6 to 12 months after the last dose of PNEU-C-20). (Strong NACI recommendation)**
Summary of evidence and rationale
* No studies assessing immunogenicity and safety of PNEU-C-20 in HSCT recipients were available; however, PNEU-C-20 is expected to have similar immunogenicity and safety profiles to PNEU-C-13 in this population.
* The recommended timing of PNEU-C-20 for HSCT recipients should be determined in consultation with the recipient’s transplant specialist.
* PNEU-C-15 may be considered if PNEU-C-20 is unavailable or inaccessible to ensure these individuals will receive the needed protection.
Considerations for continued PNEU-C-13 and PNEU-P-23 use and other risk groups
* NACI supports the continued use of PNEU-C-13 and PNEU-P-23 in adults only when PNEU-C-15 and/or PNEU-C-20 are unavailable or inaccessible.
* At this time, there are no public health level recommendations on the use of PNEU-C-15 or PNEU-C-20 for adults 18 to 49 years of age with non-immunocompromising risk factors that place them at high risk of IPD as additional analyses on the cost-effectiveness of conjugate PNEU-C-15 and PNEU-C-20 in this population are needed. PNEU-C-15 or PNEU-C-20 may be considered at clinical discretion for these adults.
**Management options**
Options for the vaccine schedule, vaccine type (VT), age cohort and risk group are available, and the decision on which option is preferable may depend on one or more considerations outlined below.
Table 3. Summary of management options according to choice of product
| Options:
Choice of Product | Factors for Consideration | Decision Points |
| --- | --- | --- |
| Pneumococcal conjugate vaccine – PNEU-C-20 | * Serotype coverage results in 15-20% greater coverage of IPD cases vs PNEU-C-15 and 30-32% greater than
PNEU-C-13 * Efficacy/Effectiveness data not yet available
* Immunogenicity (based on OPA GMTs and % seroresponse) non-inferior to PNEU-C-13 for shared serotypes however immune responses numerically lower
* Safety profile of PNEU-C-20 consistent with safety of PNEU-C-13, for both vaccine naïve and vaccine experienced
* Cost-utility analysis estimates that PNEU-C-20 use is likely a cost-effective strategy, regardless of age or region.
* Simplified recommendation with a single vaccine is expected to increase acceptability for both recipients and vaccine program implementation, thus the potential to prevent more disease
| Epidemiology* Age is a major risk factor for IPD. Incidence sharply increases among persons 65 years of age and older
* PNEU-C-15 and PNEU-C-20 contain different serotypes, which can have different impacts on IPD rates based on local serotype epidemiology
Unknowns* Speed of serotype replacement
* Extent of serotype replacement
* Impact on disease burden in adults when higher valent pneumococcal conjugate vaccines become available for use in pediatric vaccine programs
Duration of protection* Waning protection from pneumococcal conjugate vaccines appears to occur at a slower rate compared to pneumococcal polysaccharide vaccines
Unknowns* VE and duration of protection of PNEU-C-15 and PNEU-C-20
Immunogenicity* Both PNEU-C-15 and PNEU-C-20 are immunogenic compared to PNEU-C-13
* PNEU-C-20 appears to have lower immune response compared to PNEU-C-13 for shared serotypes
* PNEU-C-15 appears to have higher immune response compared to PNEU-C-13 for shared serotype 3
Unknowns* Correlates of protection
Safety* Both vaccines are safe in immunocompetent individuals
Economics
Based on a cost utility analysis: * PNEU-C-20 was cost-effective compared to current recommendations in adults 65 years of age and older
* When PNEU-C-20 is available, PNEU-C-15 is more costly and less effective than giving PNEU-C-20 alone.
* If PNEU-C-20 is not available, PNEU-C-15 in series with PNEU-P-23 is more cost-effective than PNEU-C-15 alone
Unknowns* Cost-effectiveness in other high-risk populations
Feasibility/Acceptability* PNEU-C-15 should be offered in series with PNEU-P-23 to optimize protection against more serotypes. This would make it a 2-product series, compared to PNEU-C-20, which is 1 dose only. Consideration to improve adherence and acceptability of the 2nd dose, as well as additional operational costs for the administration of the 2nd dose would be required.
Unknowns* It is unknown what the adherence to the complete 2-product vaccination schedule with PNEU-C-15 and PNEU-P-23 will be
|
| Pneumococcal conjugate vaccine – PNEU-C-15 | * Serotype coverage results in 10-12% greater coverage of IPD cases vs PNEU-C-13
* Efficacy/effectiveness data not yet available
* Immunogenicity (based on OPA GMTs and % seroresponse) showed non-inferiority for shared serotypes with PNEU-C-13 and mixed results in the proportion of seroresponders compared with PNEU-C-13
* Safety profile of PNEU-C-15 consistent with safety of PNEU-C-13, for both vaccine naïve and vaccine experienced
* Administration costs of combined program with PNEU-P-23 higher than single dose PNEU-C-20 program regardless of age, region.
* To the extent that second doses are missed, effectiveness in preventing pneumococcal disease reduced
* PNEU-P-23 may be less effective for shared serotypes than PNEU-P-20, especially in the longer term
* Mixed schedule would require the coordination of two doses and products
|
| Pneumococcal conjugate vaccine – PNEU-C-13 | * Fewer IPD cases caused by PNEU-C-13 serotypes than those covered by PNEU-C-15 and PNEU-C-20
* Efficacy and effectiveness data available
* PNEU-C-13 effective against IPD in adults 65 years and older
* Findings from observational studies support efficacy against vaccine type pneumonia and IPD
* Mixed schedule would require the coordination of two doses and products
* Acceptability of pneumococcal vaccination in adults at risk is below national target
| * PNEU-C-13 has been authorized for use in Canada and elsewhere for over 10 years and NACI recommendations for adults have been in place since 2013
Feasibility/Acceptability* PNEU-C-13 has the lowest serotype coverage of any of the authorized pneumococcal vaccines
|
| Pneumococcal polysaccharide vaccine
– PNEU-P-23 | * Greater proportion of IPD cases caused by PNEU-P-23 serotypes than PNEU-C-15 or PNEU-C-20
* Some effectiveness data available, although limited and uncertain
* PNEU-P-23 may be preferred if the willingness to pay per QALY gained is lower than commonly used cost-effectiveness thresholds.
* Pooled analysis from 8 observational studies show that PNEU-P-23 is effective against IPD in adults 65 years and older.
* Pooled vaccine effectiveness against VT pneumonia from recent observational studies suggest PNEU-P-23 provides limited protection against VT pneumonia within 5 years of vaccination.
* Acceptability of PNEU-P-23 have been below national vaccination target for adults 65 years old or older and for adults 18 years old and older living with underlying medical conditions
| * PNEU-P-23 has been authorized for use in Canada and elsewhere for almost 40 years and NACI recommendations have been in place since 1984
Feasibility/Acceptability * PNEU-P-23 has the highest serotype coverage of any of the authorized pneumococcal vaccines.
* Waning protection occurring faster (within 5 years of vaccination) compared to conjugate vaccines due to its T cell independent mode of action.
|
Table 4. Summary of management options according to age cohorts.
| Options Age Cohorts | Factors for consideration | Decision points |
| --- | --- | --- |
| 18 to 49 years of age with risk factors for IPD | * Risk of IPD is higher compared to the general population of adults 18 to 49 years of age
* The risk of IPD associated with some medical conditions is unrelated to age
* There are no cost-effectiveness analyses for PNEU-C15 or PNEU-C-20 available for this group
| 18 to 49 years of age* Increased risk for IPD due to underlying medical conditions (non-immunocompromising and immunocompromising) and other risk factors. Some risk factors can place individuals at higher risk of IPD than others (See [Table 1](#t1))
|
| 50 years of age and older | * Incidence of IPD in studies over the last decade found increasing incidence by increasing age, from 12 to 13 cases per 100,000 population in the 50 to 64 years age group to 36 to -49 cases per 100,000 among those over 85 years of age
* The incidence of CAP similarly increased with increasing age from 348/100,000 population (50 to -64 years) 871/100,000 (65 to -74 years) and 2846/100,000 (75 years and older). 20% of those estimated to be pneumococcal.
* PNEU-C-15 showed comparable immune responses to PNEU-C-13 for shared serotypes across all age groups. Immune responses did trend lower with increasing age
* PNEU-C-20 showed robust immune responses across all age groups
* Both PNEU-C-15 and PNEU-C-20 have comparable safety profile to PNEU-C-13/PNEU-P-23
* At age 65, the most efficient strategies (using PNEU-C-20) had estimated ICERs ranging from $6,500-80,300 per QALY gained (health system perspective) and $2,200-153,600 per QALY gained (societal perspective)
* At age 50, ICERs for the most efficient options (using PNEU-C-20) were higher than at age 65 with ICERs ranging from $16,300-81,900, depending on the strategy used and the region
* At age 75, ICERs for the most efficient strategies (using PNEU-C-20) were comparable to those at age 65. ICERs were somewhat higher in Northern Canada compared to vaccination at age 65.
| 50 years of age and older * Increased risk of IPD and pCAP, but mainly with risk factors including biological and social
* Lower burden of illness compared to older adult age groups and lower vaccine uptake (existing pneumococcal vaccination program) compared to older age groups
* Possible risk of waning protection by the time this cohort is at highest risk of IPD; therefore, will likely require a booster if protection wanes
* Higher ICERs than for the 65 years and older and 75 years and older age groups, but vaccination with PNEU-C-20 still likely to be considered cost-effective under commonly used thresholds
|
| 65 years of age and older | 65 years of age and older * Higher risk of IPD and pCAP compared to 50-64 years age group
* Longer life expectancy than the 75 years and older age cohort; therefore, benefits of vaccination over a longer period
* Might need a booster
* ICERs suggest vaccination at this age with PNEU-C-20 would be cost-effective under commonly used thresholds
|
| 75 years of age and older | 75 years of age and older * Risk of IPD and pCAP highest among this age group
* Shorter life expectancy, one dose vaccination without the need for booster
* Vaccine uptake might be better compared to younger age groups
* Immunogenicity responses likely lowest in the oldest age groups due to immunosenescence
* ICERs suggest vaccination at this age with PNEU-C-20 would be cost-effective under commonly used thresholds
|
IX. Research priorities
-----------------------
* Estimates/assessments of the PNEU-C-15 and PNEU-C-20 vaccine effectiveness in the general population of individuals 65 years of age and older and in additional populations (e.g., indigenous people, people living with chronic medical, social, and immunocompromising conditions).
* Cost-effectiveness analyses on the use of PNEU-C-15 and PNEU-C-20 in adults 18 to 49 years of age with risk factors that place them at high risk of IPD.
* Assessment of the effects of community immunity and serotype replacement of PNEU-C-15 childhood programs over time on the incidence of IPD, VT IPD, CAP, and VT CAP and on carriage within the Canadian population of individuals 65 years of age and older and in additional populations (e.g., indigenous, people living with chronic medical, social, and immunocompromising conditions).
* Estimates of efficacy and effectiveness of PNEU-C-15 and PNEU-C-20 boosters in immunocompetent adults over 65 years of age.
* Assessment of pneumococcal vaccination programs on the reduction of myocardial infarction and stoke.
X. Surveillance issues
----------------------
Ongoing surveillance is fundamental to planning, implementation, evaluation, and evidence-based decision-making. (Indicate if the disease to be prevented is reportable nationally.) To support such efforts, NACI encourages surveillance improvements in the following areas:
* Nationally representative data is not currently available on the burden of CAP and VT pCAP in Canada
* National surveillance data on vaccination status are not available for identified cases of IPD and VT IPD in Canada, which limits extension of findings
* National surveillance on pneumococcal vaccine coverage by age and time since vaccine administration (and in the future) and the number of doses received is limited
* Additional risk factors (e.g., comorbidities) are not available for identified cases of IPD and VT IPD, which limits extensions of findings to high-risk groups due to underlying health conditions
* Missing data was present within both the CNDSS and NML datasets.
* Enhanced surveillance that includes high risk individuals and can provide incidence of IPD stratified by risk factors and serotypes for individuals in the greater than 65-year age group.
* Epidemiological studies of non-invasive disease such as CAP or acute otitis media in children caused by *S. pneumoniae*.
XI. Characteristics of included studies
---------------------------------------
Table 5. Characteristics of included PNEU-C-15 and PNEU-C-20 studies
| Study | Comparisons | Study Design | Participants |
| --- | --- | --- | --- |
| PNEU-C-15 studies |
| --- |
| Ermlich et al., Vaccine, 2018;36 (45): 6875-6882.
V114-002
Multicenter: 25 sites from across Canada, Denmark, Israel, Norway, Poland, Spain, Sweden, United States.
Study period: March 2012-February 2013
Funder: Merck | * PNEU-C-15 vs
* PNEU-P-23
* PNEU-C-15 vs
* PNEU-C-13
| Phase 2. Randomized to PNEU-C-15 (N=230),
PNEU-P-23 (N=231), or PNEU-C-13 (N=230)
Total randomized = 691 | Community-dwelling adults aged ≥50 years who are vaccine-naïve
Gender (total study): 53% female
**Ethnicity (total study):** 93% non-Hispanic or non-Latino
Race (total study): 93% White
Age (total study):* 50 to 64 years: 34.6%
* 65 to 74 years: 32.6%
* ≥75 years: 32.9%
Authors state participants were similar across groups for distribution of age, gender, race/ethnicity, key pre-existing medical conditions (chronic heart disease, COPD, diabetes mellitus), and prior and concomitant treatment. |
| Song et al., Vaccine, 2021;39 (43): 6422-6436.
V114-016
Multicenter: 22 sites from across United States, the Republic of Korea, Spain, Taiwan.
Study period: June 2018-December 2016
Funding: Merck Sharp & Dohme Corp. | * PNEU-C-15 +
* PNEU-P-23 vs
* PNEU-C-13 +
* PNEU-P-23
Vaccine series at 12-month interval | Phase 3, Randomized to single dose of PNEU-C-15 (N=327) or PNEU-C-13 (N=325) at Day 1 followed by single dose PNEU-P-23 (both arms) at month 12
Total randomized = 652 | Adults aged ≥50 years, in good health and/or with stable underlying medical conditions, without a history of invasive pneumococcal disease, and who are vaccine-naïve.
Gender (total study): 56.8% female
**Ethnicity (total study):** 87.4% non-Hispanic or non-Latino
Race (total study): 61.6% White
**Median age:** 65.0 years
Age (total study):* 50 to 64 years: 49.9%
* 65 to 74 years: 37.9%
* ≥75 years: 12.1%
Authors state participants were similar across groups for distribution of variables including age, sex, race, and ethnicity. |
| Platt et al., Vaccine, 2022;40 (1): 162-172
V114-019
Multicenter: 30 sites from across Canada, United States, Japan, Spain, Taiwan.
Study period: June 2019-March 2020
Funding: Merck Sharp & Dohme Corp. | * PNEU-C-15 vs
* PNEU-C-13
| Phase 3, Randomized to single dose of PNEU-C-15 (N=604) or PNEU-C-13 (601)
Total randomized = 1205 | Adults aged ≥50 years, in good health and/or with stable underlying medical conditions, without a history of invasive pneumococcal disease, and who are vaccine-naïve
Gender (total study): 57.3% female
**Ethnicity (total study):** 78.0% non-Hispanic or non-Latino
Race (total study): 67.7% White
**Median age:** 66.0 years
Age (total study):* 50 to 64 years: 30.9%
* 65 to 74 years: 57.6%
* ≥75 years: 11.5%
Authors state participant demographics were similar between groups. |
| Peterson et al., Human vaccines & immunotherapeutics, 2019;15 (3): 540-548.
V114-007
Multicenter: 17 sites in United States
Study period: November 2015-January 2016
Funder: Merck | * PNEU-C-15 vs
* PNEU-C-13
| Phase 2. Randomized to PNEU-C-15 (N=127) or PNEU-C-13 (N=126)
Total randomized = 253
Randomization was stratified according to age and time since vaccination (groupings as shown in adjacent column). | Adults aged ≥65 years, with a history of prior PNEU-P-23 vaccination at least one year prior to study entry
Gender (whole study): 59.7% female
Median Age (whole study): 72.0 years
**Age distribution:** 65-74 years, 70%; ≥75 years, 30%
Race (whole study): 94.1% White
**Ethnicity (whole study):** 84.6% non-Hispanic or non-Latino
**Time since PNEU-P-23 vaccination:** 1-3 years, 32.4%; >3 years, 67.6%
Authors state groups were similar for gender, age, ethnicity/race, pre-existing conditions, prior therapy, and time interval since
PNEU-P-23 vaccination. |
| Hammitt et al., Open forum infectious diseases, 2022;9 (3): ofab605
V114-017
Multicentred: 79 sites from 7 countries (United States, Canada, Chile, Poland, Russia, Australia, New Zealand).
Study period: July 2018 to July 2020
Funder: Merck | * PNEU-C-15 +
* PNEU-P-23 vs
* PNEU-C-13 +
* PNEU-P-23
Vaccine series at 6-month interval | * Phase 3. Randomized 3:1 to PNEU-C-15+
* PNEU-P-23 (n=1135) or PNEU-C-13+
* PNEU-P-23 (n=380).
Total randomized: 1515.
Randomization stratified by site, type and number of risk factors, and alcohol use (≥5 AUDIT-C). | Adults aged 18-49 years who are immunocompetent and are with or without risk factor(s) for pneumococcal disease
Gender (total study): 52% female
**Ethnicity (total study):** 87% non-Hispanic or non-Latino
**Race (total study):** 51% White, 39% Indigenous (US. 39% of participants were from US Center for American Indian Health (CAIH) sites.
**Mean age:** 36.0 years
By risk factor (total study):
No risk factors: 25%
≥1 risk factor: 75%
**Risk factors included:** chronic lung disease including asthma, tobacco use, diabetes mellitus, chronic liver disease, chronic heart disease, and alcohol consumption.
All subjects with no risk factor and subjects with single risk factor of alcohol consumption were enrolled at CAIH sites.
Authors state that demographic and baseline characteristics were similar between groups. |
| Mohapi et al., AIDS (London, England), 2022;36 (3): 373-382
V114-018
Multicenter: 13 sites from across France, Peru, South Africa, Thailand, United States.
Study period: July 2018-January 2020
Funder: Merck | * PNEU-C-15 vs
* PNEU-C-13
* PNEU-C-15+
* PNEU-P-23 vs
* PNEU-C-13+
* PNEU-P-23
Vaccine series at 8-week interval
| * Phase 3. Randomized to PNEU-C-15+
* PNEU-P-23 (n=152) or PNEU-C-13+
* PNEU-P-23 (n=150)
Randomization stratified by CD4+ cell count, with intent of ≥50% participants enrolled in the middle stratum: ≥50 to <200; ≥200 to <500, and ≥500 cells/μL | Adults aged >=18 years who have HIV (CD4+ ≥50 cells/μL and plasma HIV RNA <50,000 copies/mL), are vaccine-naïve, and no IPD or culture-positive pneumococcal disease within prior 3 years.
Gender (total study): 21% female
**Ethnicity (total study):** 68% non-Hispanic or non-Latino
**Race (total study):** 31% Black, 30% White, 21% more than one race, 18% Asian
**Median age:** 41y. Of the total study, 72% were 18-49y. Few participants (3.6%) were ≥65y.
By CD4+ T-cell count (cells/µL):* ≥50 to <200: 1.3%
* ≥200 to <500: 50.3%
* ≥500: 48.3%
Authors state groups were similar for demographic and baseline characteristics. |
| Severance et al. Human Vaccines & Immunotherapeutics, 2022; 18 (1); e1976581
V114-021
Multicenter: 45 sites in United States
Study period: September 24, 2018-June 24, 2019
Funding: Merck Sharp & Dohme Corp. | PNEU-C-15+QIV, with placebo on day 30 (concurrent)
Vs
QIV + placebo, with PNEU-C-15 on day 30 (non-concomitant) | Phase 3, randomized to concomitant (N=600) or non-concomitant (N=600) groups.
Total randomized = 1200
Randomization was 1:1 but stratified according to age (50-64y, 65-74y, ≥75y) and history of PNEU-P-23 vaccination. | Adults aged ≥50 years, in good health and/or stable underlying medical conditions and without a history of invasive or other pneumococcal disease.
Prior vaccination of PNEU-P-23 eligible if received >12 months before first study visit but designed to have at least 50% of participants vaccine-naive.
Gender (total study): 56.1% female
Ethnicity (total study): 78.8% non-Hispanic or non-Latino
Race (total study): 82.5% White
Median age: 65.0 years
Age (total study):* 50 to 64 years: 49.9%
* 65 to 74 years: 39.4%
* ≥75 years: 10.7%
Prior vaccination with PNEU-P-23: 20.9%
Authors state that groups were similar for baseline characteristics, including age, sex, race, ethnicity, underlying medical conditions, and prior vaccination with PNEU-P-23. |
| PNEU-C-20 studies |
| Hurley et al., Clinical Infectious Diseases, 2021; 73 (7): e1489-1497
Multicenter: 14 sites from across United States
Study period: NR
Funding: Pfizer Inc. | * PNEU-C-20 +
placebo vs
* PNEU-C-13 +
* PNEU-P-23
Series delivered | Phase 2, Randomized to single dose of PNEU-C-20 (N=222) or PNEU-C-13 (N=222) followed by single dose saline (PNEU-C-20 arm) or PNEU-P-23
(PNEU-C-13 arm) one month after first vaccination
Total randomized = 444 | Adults aged 60-64 years, generally healthy (including those with stable underlying medical conditions), without a history of laboratory-confirmed invasive pneumococcal disease, and vaccine-naïve.
Gender (total study): 56.0% female
Ethnicity (total study): 87.4% non-Hispanic or non-Latino
Race: 75.4% White
Median age: 62.0 years
Authors state participant demographics were similar between groups. |
| Essink et al., Pivotal Phase 3 Randomized Clinical Trial of the Safety, Tolerability, and Immunogenicity of 20-valent Pneumococcal Conjugate Vaccine in Adults Aged ≥18 Years, Clinical Infectious Diseases, 2022; ciab990. Online ahead of print.
Multicenter: Sites from across United States and Sweden
Study period: December 2018-December 2019
Funding: Pfizer Inc. | Adults ≥60 years:
PNEU-C-13 followed by
PNEU-P-23 (1 month interval).
Adults 18-49 years and 50-59 years: PNEU-C-13 alone | Phase 3, Randomization stratified by age subgroup:
Participants ≥60 years of age were randomized to single dose of PNEU-C-20 (N=1514) or PNEU-C-13 (N=1495) followed by single dose saline (PNEU-C-20 arm) or PNEU-P-23 (PNEU-C-13 arm) one month after first vaccination.
Participants 50-59 years randomized to single dose PNEU-C-20 (N=334) or PNEU-C-13 (N=111).
Participants 18-49 years randomized to single dose PNEU-C-20 (N=336) or PNEU-C-13 (N=112).
Total randomized:* ≥60 years = 3009,
* 50-59 years = 445,
* 18-49 years = 448
| Adults aged ≥18 years without a serious chronic disorder or other acute or chronic medical or psychiatric condition, without a history of laboratory-confirmed invasive pneumococcal disease, and vaccine-naïve.
Gender, % female (by age cohort):* ≥60 years: 59.3%
* 50-59 years: 59.3%
* 18-49 years: 65.1%
Ethnicity, % non-Hispanic or non-Latino (by age cohort):* ≥60 years: 87.8%
* 50-59 years: 94.4%
* 18-49 years: 89.9%
Race, % White (by age cohort):* ≥60 years: 84.5%
* 50-59 years: 82.7%
* 18-49 years: 83.9%
Age (≥60 year cohort):* 60 to 64 years: 66.2%
* 65 to 69 years: 20.8%
* 70 to 79 years: 11.5%
* ≥80 years: 2.3%
Authors state participant demographics were similar between intervention groups for each of the age-specific cohorts. |
| Cannon et al., Vaccine, 2021: 39 (51):7494-7502.
Multicenter: 33 sites in United States and 8 sites in Sweden.
Study period: February 2019-February 2020
Funding: Pfizer Inc. | Comparison dependent on cohort: 1. Prior PNEU-P-23 +
current PNEU-C-20 vs Prior PNEU-P-23 +
current PNEU-C-13
2. Prior PNEU-C-13 vaccination +
PNEU-C-20 vs Prior PNEU-C-13 +
current PNEU-P-23
| Phase 3. Randomized 2:1:
PNEU-P-23+
PNEU-C-20 (N=253) vs PNEU-P-23+
PNEU-C-13 (N=122)
PNEU-C-13+
PNEU-C-20 (N=248) vs PNEU-C-13+
PNEU-P-23 (N=127)
Total randomized as relevant to this review: 750. | Adults aged ≥65 years with prior vaccination to PNEU-P-23 or PNEU-C-13. Participants with stable underlying medical conditions and without prior *S. pneumoniae* infection were eligible.
A third cohort with prior vaccination to both PNEU-P-23 and PNEU-C-13 was not in this review as it was not a randomized comparison.
Demographics (across relevant group subset):* Gender: range 52.5-56.5% female
* Ethnicity: range 94.0-97.6% non-Hispanic or non-Latino
* Race: range 90.2-93.3% White
* Mean age: range 69.6-70.7 years
Authors state that demographic characteristics were similar among groups. |
List of Abbreviations
---------------------
AE
Adverse event
CAPiTA
Community-Acquired Pneumonia immunization Trial in Adults
CAP
Community-acquired pneumonia
CI
Confidence Interval
CIRN
Canadian Immunization Research Network
CMC
Chronic Medical Condition
CNDSS
Canadian Notifiable Disease Surveillance System
CRM197
Corynebacterium diphtheriae
CSF
Chronic cerebrospinal fluid
DALY
Disability adjusted life years
EEFA
Ethics, equity, feasibility, acceptability
EtD
Evidence to Decision
GRADE
Grading of Recommendations, Assessment, Development and Evaluation
HIV
Human Immunodeficiency Virus
HSCT
Hematopoietic Stem Cell Transplant
IC
Immunocompromising conditions
ICD
International Classification of Diseases
ICER
Incremental cost-effective ratio
ICS
International Circumpolar Surveillance
IM
Intramuscularly
IPD
Invasive pneumococcal disease
GMT
Geometric mean titre
GMFR
Geometric mean fold rises
LLOQ
Lower limit of quantitation
LSPQ
Laboratoire de santé publique du Québec
LTCF
Long term care facility
NACI
National Advisory Committee on Immunization
NDCMC
Newly diagnosed chronic medical conditions
NML
National Microbiology Laboratory
NOC
Notice of compliance
NVT
Non-vaccine type
NWT
Northwest Territories
OPA
Opsonophagocytic Activity
OR
Odds ratio
pCAP
Pneumococcal community-acquired pneumonia
PD
Pneumococcal disease
Pop
Population
PP
Pneumococcal pneumonia
P-Y
Population per year
PHAC
Public Health Agency of Canada
PNEU-C
Pneumococcal conjugate vaccine
PNEU-C-15 (Vaxneuvance)
15-valent pneumococcal conjugate vaccine
PNEU-C-20 (PREVNAR20)
20-valent pneumococcal conjugate vaccine
PNEU-C-13 (PREVNAR13)
13-valent pneumococcal conjugate vaccine
PNEU-P
Pneumococcal polysaccharide vaccine
PNEU-P-23
23-valent pneumococcal polysaccharide vaccine
PWG
Pneumococcal Working Group
QALY
Quality adjusted life-years
QIV
Quadrivalent inactivated influenza vaccine
RCT
Randomized controlled trial
RoB
Risk of bias
SAE
Serious adverse events
SOS
Serious Outcome Surveillance
SSE
Solicited systemic events
ST3
Serotype 3
TIBDN
Toronto Invasive Bacterial Diseases Network
UAD
Urine antigen detection
US
United States
VT
Vaccine type
Acknowledgments
---------------
**This statement was prepared by:** K Hildebrand, A Nam, R Pless, A Stevens, A Tuite, A Wierzbowski, and E Wong on behalf of the NACI Pneumococcal Working Group and was approved by NACI.
**NACI gratefully acknowledges the contribution of** M Hersi, N Islam, CY Jeong, A Li, R MacTavish, A Golden, W Demczuk, A Griffith, I Martin, E Tarrataca, C Tremblay, M Tunis, MW Yeung, K Young, and R Ximenes.
NACI Pneumococcal Working Group
**Members:** K Hildebrand (Chair), J Bettinger, N Brousseau, P De Wals, D Fisman, J Kellner, A McGeer, J Papenburg, S Rechner, and G Tyrell
**Ex-officio representatives:** G Coleman (Biologic and Radiopharmaceutical Drugs Directorate [BRDD] Health Canada [HC]), M Kobayashi (Centre for Disease Control [CDC] United States), A Li (Vaccine Preventable Diseases Surveillance [VPDS] PHAC), I Martin (National Microbiology Lab [NML] PHAC), G Metz (Vaccine Safety [VS] PHAC), and A Monohan (First Nations and Inuit Health Branch [FNIHB], Indigenous Services Canada [ISC])
**PHAC Participants**: A Wierzbowski (Technical lead), R Pless (Medical lead), N Islam, A Y Li, I Martin, A Stevens, C Tremblay, A Tuite, and K Young
### NACI
**NACI members:** S Deeks (Chair), R Harrison (Vice-Chair), M Andrew, J Bettinger, N Brousseau, H Decaluwe, P De Wals, E Dubé, V Dubey, K Hildebrand, K Klein, M O’Driscoll, J Papenburg, A Pham-Huy, B Sander, and S Wilson.
Former NACI members: S Smith
**Liaison representatives:** L Bill / M Nowgesic (Canadian Indigenous Nurses Association), LM Bucci (Canadian Public Health Association), E Castillo (Society of Obstetricians and Gynaecologists of Canada), J Comeau (Association of Medical Microbiology and Infectious Disease Canada), J MacNeil (Centers for Disease Control and Prevention, United States), L Dupuis (Canadian Nurses Association), M Osmack (Indigenous Physicians Association of Canada), J Potter (College of Family Physicians of Canada), M Lavoie (Council of Chief Medical Officers of Health), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), and A Ung (Canadian Pharmacists Association).
**Former liaison representatives:** L Dupuis (Canadian Nurses Association), D Fell (Canadian Association for Immunization Research and Evaluation), J Hu (College of Family Physicians of Canada)
**Ex-officio representatives:** V Beswick-Escanlar (National Defence and the Canadian Armed Forces), E Henry (Centre for Immunization and Respiratory Infectious Diseases (CIRID), PHAC), M Lacroix (Public Health Ethics Consultative Group, PHAC), C Pham (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada), D MacDonald (COVID-19 Epidemiology and Surveillance, PHAC), S Ogunnaike-Cooke (CIRID, PHAC), P Fandja (Marketed Health Products Directorate, HC), M Routledge (National Microbiology Laboratory, PHAC), and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada).
**Former ex-officio representatives:** C Lourenco (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada), K Robinson (Marketed Health Products Directorate, HC)
Appendix A: Tables
------------------
Table 6. Description of GRADE ratings for synthesised results
| GRADE rating | Description |
| --- | --- |
| High | Very confident that the true effect lies close to that of the effect estimate. |
| Moderate | Moderately confident: the true effect is likely to be close to the effect, but there is a possibility that it is substantially different. |
| Low | Limited confidence: the true effect may be substantially different from the effect estimate. |
| Very Low | Very little confidence: true effect likely to be substantially different from the effect estimate. |
Table 7. Outcome definitions
| Outcome | Definition |
| --- | --- |
| Clinical outcomes: Benefits |
| --- |
| All Invasive Pneumococcal Disease (IPD) | Clinical evidence of pneumonia with bacteremia, bacteremia without a known site of infection, and/or meningitis with laboratory confirmation of infection and isolation of *Streptococcus pneumoniae* or its DNA from a normally sterile site. |
| Vaccine-type Invasive Pneumococcal Disease (VT IPD) | Clinical evidence of invasive disease (pneumonia with bacteremia, bacteremia without a known site of infection, and/or meningitis) with laboratory confirmation of infection and isolation of *Streptococcus pneumoniae* or its DNA from a normally sterile site confirmed by serotyping as *S. pneumoniae* serotype 4, 9V, 6B, 14, 18C, 19F, 23F, 1, 5, 7F, 3, 6A, 19A, 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, or 33F. |
| All Community-Acquired Pneumonia | Community acquired pneumonia is defined if a presentation occurred within 72 hours of hospital admission with a new or evolving pulmonary infiltrate on chest radiograph suggestive of pneumonia, with ≥2 signs or symptoms (temperature >38°C, cough, sputum production, shortness of breath, pleuritic chest pain, crackles, or consolidation on chest examination) |
| pneumococcal Community Acquired Pneumonia (pCAP) | A pCAP is a CAP case which has a confirmation of *S. pneumoniae* from urine antigen detection or isolation of *S. pneumoniae* from blood or sputum culture. |
| pCAP due to vaccine preventable serotype | Laboratory confirmation of infection and isolation of *Streptococcus pneumoniae* or its DNA from a non-sterile site (sputum) confirmed by serotyping as *S. pneumoniae* serotype 4, 9V, 6B, 14, 18C, 19F, 23F, 1, 5, 7F, 3, 6A, 19A, 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, or 33F. |
| Death due to vaccine preventable serotype | Death caused as a result of *S. pneumoniae* infection which was laboratory confirmed to be as *S. pneumoniae* serotype 4, 9V, 6B, 14, 18C, 19F, 23F, 1, 5, 7F, 3, 6A, 19A, 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, or 33F. |
| All-cause death | Death due to any cause. |
| Immunogenicity outcomes - Benefits |
| Determined by opsonophagocytic activity (OPA) | OPA represents functional antibodies capable of opsonizing pneumococcal capsular polysaccharides for presentation to phagocytic cells for engulfment and subsequent killing and is considered an important immunologic surrogate measure of protection against pneumococcal disease. |
| Immune responses | Assessed by serotype-specific OPA assay and OPA geometric mean titers (GMTs) after vaccination. It can also be measured as geometric mean fold rises (GMFRs) of serotype-specific OPA titers from before to after vaccination, percentage of participants with a >4-fold rise in OPA titers from before to after vaccination, and percentage of participants with OPA titers greater than or equal to the lower limit of quantitation (LLOQ) after vaccination. Percentage of participants with a >4-fold rise (seroresponders) in serotype-specific pneumococcal OPA titers from before vaccination to after vaccination along with corresponding 2-sided 95% CIs are calculated. |
| Non-inferiority | Defined based on the lower bound of the 2-sided 95% CI of the OPA GMT ratio between intervention and comparator to be greater than 0.5 at a pre-determined time (e.g.,30 days) post-vaccination. Based on the between-group comparisons of OPA GMTs and proportions of participants with a ≥4-fold rise in serotype-specific OPA titers from pre-vaccination to post-vaccination. |
| Superiority | Conclusion of superiority for serotype 3 is based on the lower bound of the 95% CI for the estimated GMT ratio (intervention/comparator) being > 1.2. Conclusion of superiority for the unique serotypes is based on the lower bound of the 95% CI for the estimated GMT ratio (comparator/intervention) being > 2.0. |
| Clinical outcomes - Harms |
| Local adverse reactions | Solicited reactions of redness, swelling, pain at the site of injection site monitored for a specified (7-10 days) period following the vaccination. |
| Redness | Redness and swelling defined as mild (greater than [>] e.g.,2.0 to 5.0 cm), moderate (>5.0 to 10.0 cm) and severe (>10.0 cm). |
| Pain | Pain at injection site was graded as mild (did not interfere with activity), moderate (interfered with activity), and severe (prevented daily activity). |
| Local systematic reaction | Solicited reactions of fatigue, headache, muscle pain, join paint, or fever monitored for a specific period of time (e.g.,7 days) post-vaccination.
Fever was defined as greater than or equal to (>) 38.0 degree Celsius (C) and categorized to >38.0 to 38.4 degree C, >38.4 to 38.9 degree C, >38.9 to 40.0 degree C and >40.0 degree C.
Fatigue, headache, muscle pain and joint pain were graded as mild (did not interfere with activity), moderate (some interference with activity) and severe (prevented daily routine activity). |
| Serious adverse events (SAE) within 6 months after vaccination | An SAE is defined as any untoward medical occurrence that results in death; is life-threatening (immediate risk of death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity (substantial disruption in the ability to conduct normal life functions); results in congenital anomaly/birth defect or that is considered to be an important medical event. |
| Newly Diagnosed Chronic Medical Conditions (NDCMCs) within 6 months after vaccination | Newly Diagnosed Chronic Medical Conditions (NDCMCs) defined as a disease or medical conditions, not previously identified, that are expected to be persistent or was otherwise long lasting in their effects. |
Table 8. Risk of bias assessments for included studies
| Study | Risk of Bias Domains [Table 8 Footnote a](#t8fna) |
| --- | --- |
| RSG | AC | B-PP | B-OA | MOD | BI | SR |
| Immunogenicity | AE | Immunogenicity | AE |
| PNEU-C-15 studies |
| --- |
| Ermlich 2018 | L | L | L | L | L | L | L | L | L |
| Song 2021 | L | L | L | L | L | L | L | L | L |
| Platt 2022 | L | L | L | L | L | L | L [Table 8 Footnote b](#t8fnb) | S [Table 8 Footnote b](#t8fnb) | L | L |
| Peterson 2018 | L | L | L | L | L | L | L | L | L |
| Hammitt 2022 | L | L | L | L | L | L | L | L | L |
| Mohapi 2022 | L | L | L | L | L | L | L | L | L |
| Severance 2022 | L | L | L | L | L | L | L | L | L |
| PNEU-C-20 studies |
| Hurley 2021 | L | L | L | L | L | L | L | L | L |
| Essink 2022 | L | L | L | L | L | L | L | L | L |
| Cannon 2021 | L | L | L | n/a | H | L | L | L | L |
| Abbreviations: AE = adverse events; L = low risk of bias; H = high risk of bias; n/a = not applicable; S=some concerns or unclear.
Table 8 Footnote a
Cochrane risk of bias tool domains: RSG = random sequence generation; AC = allocation concealment; B-PP = blinding of patients and personnel; B–OA = blinding of outcome assessors; MOD = missing outcome data; BI = baseline imbalance (other bias domain); SR = selective reporting.
[Table 8 Return to footnote a referrer](#t8fna-rf)
Table 8 Footnote b
Low risk for systemic AEs. Unclear risk (some concerns) for serious AEs and vaccine-related serious AEs.
[Return to footnote b referrer](#t8fnb-rf)
|
### Evidence synthesis tables
Table 9. Evidence synthesis: PNEU-C-15 versus PNEU-C-13 in vaccine-naïve adults 65 years of age and older
| Outcome | Studies contributing data; n/N (where available) | Synthesised result
(Relative effects as PNEU-C-15 vs PNEU-C-13. Relative and absolute effects shown with 95% CI in parentheses. For immunogenicity data, specific serotypes are provided in parentheses) | GRADE certainty of evidence rating (Table 1) |
| --- | --- | --- | --- |
| Geometric Mean Titers
(per protocol)
1 month after vaccine | 1 RCT (Platt 2022);
PNEU-C-15: Range N=594-598 analysed across serotypes
PNEU-C-13: Range N=586-598 analysed across serotypes | Shared serotypes
All except ST3: GMT ratio estimate ranged 0.68 (ST4) to 1.23 (ST6B). ST3: 1.60. Non-inferiority for PNEU-C-15 met for all shared serotypes (margin >0.5; lowest CI bound across serotypes 0.57 [ST4]).
Additional data (not GRADEd):
**Unique serotypes, 22F, 33F.** GMT ratio estimates 31.83 and 7.11, respectively. Numerically higher responses for the unique serotypes.
Two additional studies in adults ≥50 years provided immunogenicity information (combined n>500 by serotype analysis). One study used a non-inferiority threshold calculated for another comparison, while the other did not evaluate for non-inferiority. For both studies, most serotypes showed numerically higher GMT ratio point estimates and differed in which serotypes showed numerically lower point estimates (ST4 and 7F in one study; 19F in the other study).
**Subgroups for age (50 to 64y vs ≥65y).** No studies evaluated non-inferiority according to a 50 to 64y population. One study (V114-019; Platt 2022) provided sufficient information to evaluate overlap visually between 50 to 64y and ≥65y. There was substantive overlap for most shared serotypes. Serotypes 5, 14, and 23F had apparent higher numerical estimates, especially ST14. Overlapping but with a higher apparent estimate in the ≥65 y group was observed for ST3 when compared with the 50 to 64y group. There was substantive overlap with 22F and 33F. In general, there was congruency between subgroup across serotypes.
**Subgroups for age (65-74y vs ≥75y).** No studies evaluated non-inferiority according to a ≥75y population. One study (V114-019; Platt 2022) provided sufficient information to evaluate overlap visually between 65-74y and ≥75y. There was substantive overlap for most shared serotypes. Serotype19A had a higher apparent numerical estimate and especially that for 6B. For serotype18C, there was no overlap with PNEU-C-15 showing higher values. Substantive overlap in age groups for ST3 and the unique serotypes 22F and 33F. In general, there was congruency between subgroup across serotypes. | Moderate [Table 9 Footnote a](#t9fna)
PNEU-C-15 is probably not inferior to
PNEU-C-13 in immune response for shared serotypes. |
| % Seroresponders
(≥4-fold risk in risk in serotype specific OPA) –
Shared serotypes except ST3
1 month after vaccine | 3 RCTs (Platt 2022, Ermlich 2018, Song 2021)
PNEU-C-15: Range N=1031-1108 analysed across serotypes
PNEU-C-13: Range N=1044-1110 analysed across serotypes | **Shared serotypes except ST3**. Mixed results among studies. In the largest study (N~1100), almost two-thirds of serotypes showed a numerically lower proportion of seroresponders with PNEU-C-15 than PNEU-C-13. In the remaining studies (combined N~900-1000), most serotypes showed a greater numerical proportion of seroresponders with PNEU-C-15. ST6B, 18C, and 23F show numerically higher seroresponders across studies. No one serotype was consistently showing a lower seroresponse with PNEU-C-15 in all three studies.
Additional data (not GRADEd):
**Age subgroups (50 to 64y vs ≥65y).** One study (V114-002; Ermlich 2018) provided information by subgroup (50 to 64y, 65-74y, ≥75y), but is based on small sample sizes (range 132-144 analyzed across subgroups). Mixed results across serotypes. Serotypes 1, 3, and 9V show a higher numerical point estimate with PNEU-C-15 for all subgroups; a lower numerical point estimate was observed across the subgroups for serotypes 6A, 7F, and 19F. For serotype 5, the 50 to 64y and 65-74y both show a higher numerical point estimate. For serotype 6B, the 50 to 64y subgroup shows a lower numerical point estimate, in contrast to the other two subgroups. For serotypes 14, 18C, and 19A, only the 65-74y subgroup shows a higher numerical point estimate with PNEU-C-15.
**Age subgroups (65-74y vs ≥75y).** One study (V114-002; Ermlich 2018) provided information by subgroup (65-74y, ≥75y), but are based on small sample sizes (range 132-144 analyzed across subgroups). Similar results are observed for most serotypes. Conversely to the 65-74y age group, the ≥75y subgroup is showing fewer numerical seroresponders with PNEU-C-15 for serotypes 5, 14, 18C, 19A, and 23F. Both age groups are showing more numerical seroresponders with PNEU-C-15 for ST3 and fewer with 6A. | Low [Table 9 Footnote b](#t9fnb) [Table 9 Footnote c](#t9fnc)
There may be variability across shared serotypes (except ST3) as to whether a numerically higher proportion of seroresponders is observed with
PNEU-C-15. |
| % Seroresponders
(≥4-fold risk in risk in serotype specific OPA) –
Shared serotypes ST3
1 month after vaccine | 3 RCTs (Platt 2022, Ermlich 2018, Song 2021)
PNEU-C-15: Range N=1095 analysed
PNEU-C-13: Range N=1099 analysed | **Shared serotype, ST3**. Higher numerical seroresponse estimate with PNEU-C-15 (RR range 1.13 to 1.41; RD range 9.9% to 21%).
Additional data (not GRADEd): see above | Moderate [Table 9 Footnote c](#t9fnc) [Table 9 Footnote d](#t9fnd)
There is probably a higher numerical proportion of seroresponders with PNEU-C-15 for ST3. |
| % Seroresponders
(≥4-fold risk in GMFR) **– Unique serotypes**
1 month after vaccine | 3 RCTs (Platt 2022, Ermlich 2018, Song 2021)
PNEU-C-15: Range N 982 to 1093 analysed
PNEU-C-13: Range N 944 to 1068 analysed | **Unique serotypes.** Numerically higher proportion of seroresponders with PNEU-C-15. 22F: RR range 4.41 to 6.47; RD range 56.3% to 64.6%. 33F: RR 6.61 to 20.43; RD 50.4% to 58.3%.
Additional data (not GRADEd):
**Age subgroups (50 to 64y vs ≥65y).** Higher numerical point estimates are observed for serotypes 22F and 33F across subgroups (range 125-137 analyzed across subgroups).
**Age subgroups (65-74y vs ≥75y).** Higher numerical point estimates are observed for serotypes 22F and 33F across subgroups (range 125-137 analyzed across subgroups). | Moderate [Table 9 Footnote c](#t9fnc) [Table 9 Footnote d](#t9fnd)
There is probably a higher numerical proportion of seroresponders with PNEU-C-15 with serotypes 22F and 33F. |
| Vaccine-related Serious AE
Up to 6 months after vaccine | 2 RCTs (Platt 2022, Ermlich 2018)
PNEU-C-15: 0/645
PNEU-C-13: 0/644 | No vaccine-related SAE observed in either group. | Moderate [Table 9 Footnote c](#t9fnc) [Table 9 Footnote e](#t9fne) |
| Serious AE
Up to 6 months after vaccine | 2 RCTs (Platt 2022, Ermlich 2018)
PNEU-C-15: 13/645
(2.0%)
PNEU-C-13: 13/644
(2.0%) | Relative effects: Peto OR 1.00 (0.46 to 2.17)
Absolute effects: 0 fewer per 1,000 (11 fewer to 23 more)
SAEs reported in Ermlich 2018. PNEU-C-15: coronary artery occlusion, appendicitis, anal cancer, anxiety. PNEU-P-23: cardiac failure, myocardial infarction, vertigo, gastrointestinal disorder, death, appendicitis, benign urinary tract neoplasm.
The second study not providing a list of SAEs indicated that no deaths occurred during the study period. | Moderate [Table 9 Footnote c](#t9fnc) [Table 9 Footnote e](#t9fne)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of SAEs up to 6 months after vaccine administration. None of those events were deemed to be vaccine-related by study authors. |
| Severe Systemic AE - Fatigue
Up to 14 days after vaccine | 3 RCTs (Platt 2022, Ermlich 2018, Song 2021)
PNEU-C-15: 6/1158
(0.5%)
PNEU-C-13: 7/1154
(0.6%) | Relative effects: Peto OR 0.86 (0.29 to 2.55)
Absolute effects: 1 fewer per 1,000 (4 fewer to 9 more) | Moderate [Table 9 Footnote c](#t9fnc) [Table 9 Footnote e](#t9fne)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of severe fatigue within 14 days after vaccine administration. |
| Severe Systemic AE - Headache
Up to 14 days after vaccine | 3 RCTs (Platt 2022, Ermlich 2018, Song 2021)
PNEU-C-15: 6/1158
(0.5%)
PNEU-C-13: 7/1154
(0.6%) | Relative effects: Peto OR 0.86 (0.29 to 2.55)
Absolute effects: 1 fewer per 1,000 (4 fewer to 9 more) | Moderate [Table 9 Footnote c](#t9fnc) [Table 9 Footnote e](#t9fne)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of severe headache within 14 days after vaccine administration. |
| Severe Systemic AE – Muscle Pain
Up to 14 days after vaccine | 3 RCTs (Platt 2022, Ermlich 2018, Song 2021)
PNEU-C-15: 3/1158
(0.3%)
PNEU-C-13: 8/1154
(0.7%) | Relative effects: Peto OR 0.40 (0.12 to 1.31)
Absolute effects: 4 fewer per 1,000 (6 fewer to 2 more) | Moderate [Table 9 Footnote c](#t9fnc) [Table 9 Footnote e](#t9fne)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of severe muscle pain within 14 days after vaccine administration. |
| Severe Systemic AE – Joint Pain
Up to 14 days after vaccine | 3 RCTs (Platt 2022, Ermlich 2018, Song 2021)
PNEU-C-15: 2/1158
(0.2%)
PNEU-C-13: 2/1154
(0.2%) | Relative effects: Peto OR 1.00 (0.14 to 7.13)
Absolute effects: 0 fewer per 1,000 (1 fewer to 10 more) | Moderate [Table 9 Footnote c](#t9fnc) [Table 9 Footnote e](#t9fne)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of severe joint pain within 14 days after vaccine administration. |
| Severe Systemic AE - Fever
Up to 5 days after vaccine | 2 RCTs (Platt 2022, Song 2021)
PNEU-C-15: 3/925 (0.3%)
PNEU-C-13: 2/921 (0.2%) | Relative effects: Peto OR 1.49 (0.26 to 8.60)
Absolute effects: 1 more per 1,000 (2 fewer to 16 more) | Moderate [Table 9 Footnote c](#t9fnc) [Table 9 Footnote e](#t9fne)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of severe fever within 5 days after vaccine administration. |
| Mild/Moderate Systemic AE - Fatigue
Up to 14 days after vaccine | 3 RCTs (Platt 2022, Ermlich 2018, Song 2021)
PNEU-C-15: 232/1158
(20.0%)
PNEU-C-13: 197/1154
(17.1%) | Relative effects: RR 1.20 (0.89 to 1.63)
Absolute effects: 34 more per 1,000 (19 fewer to 108 more | Moderate [Table 9 Footnote c](#t9fnc) [Table 9 Footnote f](#t9fnf)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of mild/moderate fatigue within 14 days after vaccine administration. |
| Mild/Moderate Systemic AE - Headache
Up to 14 days after vaccine | 3 RCTs (Platt 2022, Ermlich 2018, Song 2021)
PNEU-C-15: 151/1158
(13.0%)
PNEU-C-13: 140/1154
(12.1%) | Relative effects: RR 1.11 (0.83 to 1.48)
Absolute effects: 13 more per 1,000 (21 fewer to 58 more) | Low [Table 9 Footnote c](#t9fnc) [Table 9 Footnote g](#t9fng)
There may be little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of mild/moderate headache within 14 days after vaccine administration. |
| Mild/Moderate Systemic AE - Muscle Pain
Up to 14 days after vaccine | 3 RCTs (Platt 2022, Ermlich 2018, Song 2021)
PNEU-C-15: 215/1158
(18.6%)
PNEU-C-13: 150/1154
(13.0%) | Relative effects: RR 1.43 (1.18 to 1.73)
Absolute effects: 56 more per 1,000 (23 more to 95 more) | Moderate [Table 9 Footnote c](#t9fnc) [Table 9 Footnote e](#t9fne)
There is probably a trivial difference between PNEU-C-15 and PNEU-C-13 in the occurrence of mild/moderate muscle pain within 14 days after vaccine administration. |
| Mild/Moderate Systemic AE - Joint Pain
Up to 14 days after vaccine | 3 RCTs (Platt 2022, Ermlich 2018, Song 2021)
PNEU-C-15: 90/1158
(7.8%)
PNEU-C-13: 90/1154
(7.8%) | Relative effects: RR 1.00 (0.76 to 1.31)
Absolute effects: 0 fewer per 1,000 (19 fewer to 24 more) | Moderate [Table 9 Footnote c](#t9fnc) [Table 9 Footnote e](#t9fne)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of mild/moderate joint pain within 14 days after vaccine administration. |
| Mild/Moderate Systemic AE - Fever
Up to 5 days after vaccine | 2 RCTs (Platt 2022, Song 2021)
PNEU-C-15: 4/925
(0.4%)
PNEU-C-13: 10/923
(1.1%) | Relative effects: Peto OR 0.42 (0.15 to 1.20)
Absolute effects: 6 fewer per 1,000 (9 fewer to 2 more) | Moderate [Table 9 Footnote c](#t9fnc) [Table 9 Footnote e](#t9fne)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of mild/moderate fever within 5 days after vaccine administration. |
| Abbreviations: AE = adverse events; OR = odds ratio; PNEU-C-13 = 13-valent pneumococcal conjugate vaccine; PNEU-C-15 = 15-valent pneumococcal conjugate vaccine; RCT = randomised controlled trial; RD = risk difference; RR = relative risk; SAE= serious adverse events; vs = versus; y=years.
Table 9 Footnote a
Downrating for indirectness due to use of immunogenicity measures in the absence of disease endpoints. We acknowledge that two-thirds of participants were of White race, but we do not expect substantively different results with diversity in race from a biological perspective. No downrating.
[Table 9 Return to footnote a referrer](#t9fna-rf)
Table 9 Footnote b
Downrating for indirectness due to use of immunogenicity measures in the absence of disease endpoints and for inconsistency in results across studies.
[Table 9 Return to footnote b referrer](#t9fnb-rf)
Table 9 Footnote c
Although about 40% of the study population was indirect for age, we do not consider this appreciable. Most participants were of White race, but we do not expect substantively different results with diversity in race from a biological perspective. No downrating.
[Table 9 Return to footnote c referrer](#t9fnc-rf)
Table 9 Footnote d
Downrating for indirectness due to use of immunogenicity measures in the absence of disease endpoints.
[Table 9 Return to footnote d referrer](#t9fnd-rf)
Table 9 Footnote e
Downrating for imprecision as did not meet the review information size (400 people with events or, for very few to no events, ≥4,000 sample size).
[Table 9 Return to footnote e referrer](#t9fne-rf)
Table 9 Footnote f
Downrating for inconsistency (I2=65%, p=0.06, lack of consistent overlap among study results). The visual outlier study (V114-016) showed appreciably greater absolute effects (114 per 1,000, 95% CI 32 more to 229 more).
[Table 9 Return to footnote f referrer](#t9fnf-rf)
Table 9 Footnote g
Downrating for inconsistency (I2=41%, p=0.18, some lack of overlap among study results); the visual outlier study (V114-002) showed appreciably greater absolute effects (64 more per 1,000, 95% CI 6 fewer to 175 more). Downrating for imprecision, as the review information size threshold of 400 people with events was not met.
[Table 9 Return to footnote g referrer](#t9fng-rf)
|
Table 10. Evidence synthesis: PNEU-C-15 versus PNEU-P-23 in vaccine-naïve adults 65 years of age and older
| Outcome | Studies contributing data; n/N (where available) | Synthesised result
(Relative effects as PNEU-C-15 vs PNEU-P-23. Relative and absolute effects shown with 95% CI in parentheses. For immunogenicity data, specific serotypes are provided in parentheses) | GRADE certainty of evidence rating |
| --- | --- | --- | --- |
| Geometric Mean Titers
(per protocol)
1 month after vaccine | 1 RCT (Ermlich 2018); * PNEU-C-15: Range N=207-210 analyzed across serotypes
* PNEU-P-23: Range N=201-207 analyzed across serotypes
| Shared serotypes
All except ST3: GMT ratio estimate ranged 0.77 (19F) to 5.64 (ST23F). ST3: 1.96. Non-inferiority for PNEU-C-15 met for all 14 shared serotypes (margin ≥0.33; lowest CI bound across serotypes 0.55 [19F]).
Additional data (not GRADEd):
**Unique serotype, 6A.** GMT ratio estimate 8.59. Numerically higher response for the unique serotype.
**Subgroups by Age.** GMT Ratios. Non-inferiority for the age 65-74y (n=65-67) and ≥75y age (n=70-72) groups were not available. Across serotypes, most GMT ratios >1 except 19F (both age groups). For ST3, GMT Ratios were 2.68 and 1.44, respectively. For ST6A, GMT ratios were 9.61 and 8.67, respectively. | Low [Table 10 Footnote a](#t10fna) [Table 10 Footnote b](#t10fnb)
PNEU-C-15 may be non-inferior to PNEU-P-23 in immune response for shared serotypes. |
| % Seroresponders (≥4-fold risk in risk in serotype specific OPA)
(per protocol)
1 month after vaccine | * 1 RCT (Ermlich 2018);
PNEU-C-15: Range N=208-210 analyzed across serotypes.
* PNEU-P-23: Range N=203-207 analyzed across serotypes.
| Shared serotypes:
All except ST3: RR range 0.92 to 1.24; RD range -5.4% (33F) to 17% (23F). ST3: RR 1.18, RD 12.9%. Favours PNEU-C-15 except for serotypes 7F, 14, 19F, 33F.
Unique serotype, 6A: RR 1.36, RD 21.6%.
Numerically higher proportion of seroresponders with most serotypes, favouring PNEU-C-15.
Additional data (not GRADEd):
Across serotypes, most show a higher numerical proportion of seroresponders with PNEU-C-15 in the 65-74y (RR 0.94 to 1.31; RD -4.61% to 18.46%) and ≥75y (RR 0.83 to 1.37; RD -12.02% to 21.86%) age groups, with variation in exceptions between age groups. ST6A values were the highest in those groups (RR 1.25 and RD 16.48; RR 1.51 and RD 26.06, respectively. | Low [Table 10 Footnote a](#t10fna) [Table 10 Footnote b](#t10fnb)
PNEU-C-15 may result in a numerically higher proportion of seroresponders for most serotypes compared with PNEU-P-23. |
| Vaccine-related Serious AE
Up to 6 months after vaccine | 1 RCT (Ermlich 2018); * PNEU-C-15: 0/229
* PNEU-P-23: 0/230
| No vaccine related serious AE observed in either group. | Moderate [Table 10 Footnote b](#t10fnb) [Table 10 Footnote c](#t10fnc) |
| SAE
Up to 6 months after vaccine | 1 RCT (Ermlich 2018); * PNEU-C-15: 4/229 (1.7%)
* PNEU-P-13: 7/230 (3.0%)
| Relative effects: Peto OR 0.58 (0.17 to 1.90)
Absolute effects: 13 fewer per 1,000 (from 25 fewer to 26 more)
SAEs reported * PNEU-C-15: coronary artery occlusion, appendicitis, anal cancer, anxiety.
* PNEU-P-23: cardiac failure, myocardial infarction, vertigo, gastrointestinal disorder, death, appendicitis, benign urinary tract neoplasm.
| Moderate [Table 10 Footnote b](#t10fnb) [Table 10 Footnote c](#t10fnc)
There is probably little to no difference in SAEs between PNEU-C-15 and PNEU-P-23. None were vaccine related. |
| Severe Systemic AE -
Fatigue
Up to 14 days after vaccine | 1 RCT (Ermlich 2018);* PNEU-C-15: 2/229 (0.9%)
* PNEU-P-13: 4/230 (1.7%)
| Relative effects: Peto OR 0.51 (0.10 to 2.56)
Absolute effects: 8 fewer per 1,000 (from 16 fewer to 26 more) | Moderate [Table 10 Footnote b](#t10fnb) [Table 10 Footnote c](#t10fnc)
There is probably little to no difference in severe fatigue between PNEU-C-15 and PNEU-P-23. |
| Severe Systemic AE -
Headache
Up to 14 days after vaccine | 1 RCT (Ermlich 2018); * PNEU-C-15: 3/229 (1.3%)
* PNEU-P-23: 1/230 (0.4%)
| Relative effects: Peto OR 2.75 (0.38 to 19.64)
Absolute effects: 8 more per 1,000 (3 fewer to 75 more) | Moderate [Table 10 Footnote b](#t10fnb) [Table 10 Footnote d](#t10fnd)
There is probably little to no difference in severe headache between PNEU-C-15 and PNEU-P-23. |
| Severe Systemic AE -
Muscle pain
Up to 14 days after vaccine | 1 RCT (Ermlich 2018); * PNEU-C-15: 3/229 (1.3%)
* PNEU-P-13: 6/230 (0.4%)
| Relative effects: Peto OR 0.51 (0.14 to 0.90)
Absolute effects: 13 fewer per 1,000 (22 fewer to 22 more) | Moderate [Table 10 Footnote b](#t10fnb) [Table 10 Footnote c](#t10fnc)
There is probably little to no difference in severe muscle pain between PNEU-C-15 and PNEU-P-23. |
| Severe Systemic AE -
Joint pain
Up to 14 days after vaccine | 1 RCT (Ermlich 2018); * PNEU-C-15: 1/229 (0.4%)
* PNEU-P-13: 3/230 (1.3%)
| Relative effects: Peto OR 0.37 (0.05 to 2.62)
Absolute effects: 8 fewer per 1,000 (12 fewer to 20 more) | Moderate [Table 10 Footnote b](#t10fnb) [Table 10 Footnote c](#t10fnc)
There is probably little to no difference in severe joint pain between PNEU-C-15 and PNEU-P-23. |
| Severe Systemic AE – Fever
Up to 14 days after vaccine | Not reported by severity |
| Mild/moderate Systemic AE - Fatigue
Up to 14 days after vaccine | 1 RCT (Ermlich 2018); * PNEU-C-15: 54/229 (23.6%)
* PNEU-P-23: 59/230 (25.7%)
| Relative effects: RR 0.92 (0.67 to 1.27)
Absolute effects: 21 fewer per 1,000 (85 fewer to 69 more) | Moderate [Table 10 Footnote b](#t10fnb) [Table 10 Footnote c](#t10fnc)
There is probably little to no difference in mild/moderate fatigue between PNEU-C-15 and PNEU-P-23. |
| Mild/moderate Systemic AE - Headache
Up to 14 days after vaccine | 1 RCT (Ermlich 2018); * PNEU-C-15: 38/229 (16.6%)
* PNEU-P-23: 25/230 (23.5%)
| Relative effects: RR 1.53 (0.95 to 2.44)
Absolute effects: 58 more per 1,000 (5 fewer to 157 more) | Moderate [Table 10 Footnote b](#t10fnb) [Table 10 Footnote d](#t10fnd)
There is probably little to no difference in mild/moderate headache between PNEU-C-15 and PNEU-P-23. |
| Mild/moderate Systemic AE - Muscle Pain
Up to 14 days after vaccine | 1 RCT (Ermlich 2018); * PNEU-C-15: 64/229 (27.9%)
* PNEU-P-23: 54/230 (23.5%)
| Relative effects: RR 1.19 (0.87 to 1.63)
Absolute effects: 45 more per 1,000 (31 fewer to 148 more) | Moderate [Table 10 Footnote b](#t10fnb) [Table 10 Footnote d](#t10fnd)
There is probably little to no difference in mild/moderate muscle pain between PNEU-C-15 and PNEU-P-23. |
| Mild/moderate Systemic AE - Joint Pain
Up to 14 days after vaccine | 1 RCT (Ermlich 2018); * PNEU-C-15: 38/229 (16.6%)
* PNEU-P-23: 38/230 (16.5%)
| Relative effects: RR 1.00 (0.67 to 1.51)
Absolute effects: 0 fewer per 1,000 (55 fewer to 84 more) | Moderate [Table 10 Footnote b](#t10fnb) [Table 10 Footnote c](#t10fnc)
There is probably little to no difference in mild/moderate joint pain between PNEU-C-15 and PNEU-P-23. |
| Mild/moderate Systemic AE – Fever
Up to 14 days after vaccine | Not reported by severity |
| Abbreviations: AE = adverse events; OR = odds ratio; PNEU-C-15 = 15-valent pneumococcal conjugate vaccine; PNEU-P-23 = 23-valent pneumococcal polysaccharide vaccine; RCT = randomized controlled trial; RD = risk difference; RR = relative risk; SAE = Serious adverse events; vs = versus; y=years.
Table 10 Footnote a
Downrating for indirectness due to use of immunogenicity measures in the absence of disease endpoints and for imprecision for <800 people in the analysis for continuous data (GMT ratio) and <400 people with events for the binary analysis (% seroresponders).
[Table 10 Return to footnote a referrer](#t10fna-rf)
Table 10 Footnote b
We acknowledge that about one-third of the study population was indirect for age, but do not consider this appreciable. The majority of participants were of White race, but we do not expect substantively different results with diversity in race from a biological perspective. No downrating occurred.
[Table 10 Return to footnote b referrer](#t10fnb-rf)
Table 10 Footnote c
Downrating for imprecision (<400 people with events).
[Table 10 Return to footnote c referrer](#t10fnc-rf)
Footnote d
Downrating for imprecision as the CI includes the possibility of an important increase.
[Table 10 Return to footnote d referrer](#t10fnd-rf)
|
Table 11. Evidence synthesis: PNEU-C-15 + QIV concomitantly versus PNEU-C-15 + QIV non-concomitantly in vaccine-naïve adults 65 years of age and older
| Outcome | Studies contributing data; n/N (where available) | Synthesised result
(Relative effects as PNEU-C-15+QIV concomitantly vs PNEU-C-15+QIV non-concomitantly. Relative and absolute effects shown with 95% CI in parentheses. For immunogenicity data, specific serotypes are provided in parentheses) | GRADE certainty of evidence rating |
| --- | --- | --- | --- |
| Geometric Mean Titers (per protocol)
1 month after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant: Range N= 581-593 across serotypes
* PNEU-C-15+QIV non-concomitant:
Range N= 556-567 across serotypes
| **All except ST3**: GMT ratio estimate ranged from 0.66 (ST1) to 1.02 (ST19F). **ST3**: 0.94. Non-inferiority for PNEU-C-15 administered concomitantly with QIV met for all 15 serotypes (margin >0.5; lowest CI bound across serotypes 0.54 [ST1]).
Additional data (not GRADEd):
**Influenza strains.** QIV administered concomitantly with PNEU-C-15 was not inferior to non-concomitant administration for all four influenza strains (margin >0.5; lowest CI bound across strains 0.86 [B-Victoria]).
**Subgroup by age.** One study (Severance 2022) reported GMT ratios for 50 to 64, 65-74, and ≥75 year olds. Across subgroups, serotype-specific GMT OPAs tended to be higher for the younger age group (50 to 64 years) compared to the older age groups, however, there was substantive overlap in the GMT ratio confidence intervals.
**Subgroup by PNEU-P- vaccination history.** The study also performed subgroup analysis by history of PNEU-P-23 vaccination and reported generally similar ratios as compared to the overall study population. | Moderate [Table 11 Footnote a](#t11fna)
PNEU-C-15 administered concomitantly with QIV is probably not inferior to PNEU-C-15 administered non-concomitantly with QIV. |
| % Seroresponders
(≥4-fold risk in serotype specific OPA) **– Serotypes except ST3.**
1 month after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant: Range N= 427-517 across serotype analyses
* PNEU-C-15+QIV non-concomitant: Range N 436-505 across serotype analyses
| **Serotypes except ST3**. Numerically lower proportion of seroresponders with concomitant administration compared to non-concomitant administration for all shared serotypes except serotypes 7F, 9V, 19F, and 23F.
Subgroup data by age and PNEU-P-23 vaccination history not provided. | Moderate [Table 11 Footnote a](#t11fna)
PNEU-C-15 administered with QIV probably results in a numerically lower proportion of seroresponders for most serotypes compared with PNEU-C-15 administered non-concomitantly with QIV. |
| % Seroresponders
(≥4-fold risk in serotype specific OPA) **– ST3.**
1 month after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant: 495
* PNEU-C-15+QIV non-concomitant: 493
| **ST3.** Similar seroresponse estimate between concomitant and non-concomitant administration of PNEU-C-15 and QIV (RR: 1.00; RD: -0.1%)
Subgroup data by age and PNEU-P-23 vaccination history not provided. | Moderate [Table 11 Footnote a](#t11fna)
PNEU-C-15 administered with QIV probably results in a similar proportion of seroresponders for ST3 compared to PNEU-C-15 administered non-concomitantly with QIV. |
| Vaccine-related Serious AE Through 7 months after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant: 0/300
* PNEU-C-15+QIV non-concomitant: 0/299
| No vaccine-related events observed in either group. | Moderate [Table 11 Footnote b](#t11fnb)
There is probably little to no difference between concomitant and non-concomitant administration of PNEU-C-15 and QIV in the occurrence of SAEs through 7 months after vaccine administration. None of those events were deemed to be vaccine-related by study authors.
AEs listed were for the study population as a whole, which included 50% of the population <65 years of age. |
| Serious AE Through 7 months after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant:
13/300 (4.3%)
* PNEU-C-15+QIV non-concomitant: 9/299
(3.0%)
| Relative effects: Peto OR 1.45 (0.62 to 3.40)
Absolute effects: 13 more per 1,000 (11 fewer to 65 more) |
| Severe Systemic AE - Fatigue
Up to 14 days after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant:
4/600 (0.7%)
* PNEU-C-15+QIV non-concomitant: 14/596 (2.3%)
| Relative effects: Peto OR 0.32 (0.13 to 0.82)
Absolute effects: 16 fewer per 1,000 (20 fewer to 4 fewer) | Moderate [Table 11 Footnote c](#t11fnc) [Table 11 Footnote d](#t11fnd)
There is probably a trivial difference between concomitant and non-concomitant administration of PNEU-C-15 and QIV in the occurrence of severe fatigue within 14 days after vaccine administration. |
| Severe Systemic AE - Headache
Up to 14 days after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant:
5/600 (0.8%)
* PNEU-C-15+QIV non-concomitant: 3/596
(0.5%)
| Relative effects: Peto OR 1.64 (0.41 to 6.59)
Absolute effects: 3 more per 1,000 (3 fewer to 27 more) | Moderate [Table 11 Footnote c](#t11fnc) [Table 11 Footnote d](#t11fnd)
There is probably little to no difference between concomitant and non-concomitant administration of PNEU-C-15 and QIV in the occurrence of severe headache within 14 days after vaccine administration. |
| Severe Systemic AE – Muscle Pain
Up to 14 days after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant:
4/600 (0.7%)
* PNEU-C-15+QIV non-concomitant: 12/596
(2.0%)
| Relative effects: Peto OR 0.36 (0.13 to 0.97)
Absolute effects: 13 fewer per 1,000 (17 fewer to 1 fewer) | Moderate [Table 11 Footnote c](#t11fnc) [Table 11 Footnote d](#t11fnd)
There is probably a trivial difference between concomitant and non-concomitant administration of PNEU-C-15 and QIV in the occurrence of severe muscle pain within 14 days after vaccine administration. |
| Severe Systemic AE – Joint Pain
Up to 14 days after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant:
1/600 (0.2%)
* PNEU-C-15+QIV non-concomitant: 11/596 (1.8%)
| Relative effects: Peto OR 0.18 (0.06 to 0.58)
Absolute effects: 15 fewer per 1,000 (17 fewer to 8 fewer) | Moderate [Table 11 Footnote c](#t11fnc) [Table 11 Footnote d](#t11fnd)
There is probably a trivial difference between concomitant and non-concomitant administration of PNEU-C-15 and QIV in the occurrence of severe joint pain within 14 days after vaccine administration. |
| Severe Systemic AE - Fever
Up to 5 days after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant:
0/600 (0.0%)
* PNEU-C-15+QIV non-concomitant: 3/596
(0.5%)
| Relative effects: Peto OR 0.13 (0.01 to 1.29)
Absolute effects: 4 fewer per 1,000 (5 fewer to 1 more) | Moderate [Table 11 Footnote c](#t11fnc) [Table 11 Footnote d](#t11fnd)
There is probably little to no difference between concomitant and non-concomitant administration of PNEU-C-15 and QIV in the occurrence of severe fever within 5 days after vaccine administration. |
| Mild/moderate Systemic AE - Fatigue
Up to 14 days after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant:
159/600 (26.5%)
* PNEU-C-15+QIV non-concomitant: 165/596
(27.7%)
| Relative effects: RR 0.96 (0.79 to 1.15)
Absolute effects: 11 fewer per 1,000 (58 fewer to 42 more) | Moderate [Table 11 Footnote d](#t11fnd) [Table 11 Footnote e](#t11fne)
There is probably little to no difference between concomitant and non-concomitant administration of PNEU-C-15 and QIV in the occurrence of mild/moderate fatigue within 14 days after vaccine administration. |
| Mild/moderate Systemic AE - Headache
Up to 14 days after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant: 124/600 (20.7%)
* PNEU-C-15+QIV non-concomitant: 138/600 (23.0%)
| Relative effects: RR 0.89 (0.72 to 1.11)
Absolute effects: 25 fewer per 1,000 (64 fewer to 25 more) | Moderate [Table 11 Footnote d](#t11fnd) [Table 11 Footnote e](#t11fne)
There is probably little to no difference between concomitant and non-concomitant administration of PNEU-C-15 and QIV in the occurrence of mild/moderate headache within 14 days after vaccine administration. |
| Mild/moderate Systemic AE - Muscle Pain
Up to 14 days after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant:
137/600 (22.8%)
* PNEU-C-15+QIV non-concomitant: 115/596 (19.3%)
| Relative effects: RR 1.18 (0.95 to 1.48)
Absolute effects: 35 more per 1,000 (10 fewer to 93 more) | Moderate [Table 11 Footnote d](#t11fnd) [Table 11 Footnote e](#t11fne)
There is probably little to no difference between concomitant and non-concomitant administration of PNEU-C-15 and QIV in the occurrence of mild/moderate muscle pain within 14 days after vaccine administration. |
| Mild/moderate Systemic AE - Joint Pain
Up to 14 days after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant:
55/600 (9.2%)
* PNEU-C-15+QIV non-concomitant: 58/596 (9.7%)
| Relative effects: RR 0.94 (0.66 to 1.34)
Absolute effects: 6 fewer per 1,000 (33 fewer to 33 more) | Moderate [Table 11 Footnote d](#t11fnd) [Table 11 Footnote e](#t11fne)
There is probably little to no difference between concomitant and non-concomitant administration of PNEU-C-15 and QIV in the occurrence of mild/moderate joint pain within 14 days after vaccine administration. |
| Mild/moderate Systemic AE - Fever
Up to 5 days after vaccine | 1 RCT (Severance 2022); * PNEU-C-15+QIV concomitant:
* PNEU-C-15+QIV non-concomitant:
| Relative effects: Peto OR 1.77 (0.62 to 5.08)
Absolute effects: 6 fewer per 1,000 (3 fewer to 33 more) | Moderate [Table 11 Footnote c](#t11fnc) [Table 11 Footnote d](#t11fnd)
There is probably little to no difference between concomitant and non-concomitant administration of PNEU-C-15 and QIV in the occurrence of mild/moderate fever within 5 days after vaccine administration. |
| Abbreviations: AE = adverse events; OR = odds ratio; RR = relative risk; RCT = randomised controlled trial; SAE = Serious adverse events; vs = versus.
Table 11 Footnote a
We downrate for indirectness by -1.00 due to use of immunogenicity measures in the absence of disease endpoints. We also downrate by an additional -0.25 as half of participants were under the age of 65, and we anticipate that this lower age subset of the study population may overestimate effects owing to a stronger immune response, as observed by the subgroup analysis for GMT ratios.
[Table 11 Return to footnote a referrer](#t11fna-rf)
Table 11 Footnote b
Downrating by -1 for imprecision due to wide CI.
[Table 11 Return to footnote b referrer](#t11fnb-rf)
Table 11 Footnote c
Downrating by -1 for imprecision as did not meet review information size (400 people with events or, for very few to no events, ≥4,000 sample size).
[Table 11 Return to footnote c referrer](#t11fnc-rf)
Table 11 Footnote d
50% of the study population were 50 to 64 years of age. In the face of trivial effects or little to no differences observed with these adverse effects, we would anticipate that a more representative population would only further decrease these trivial differences. We do not downrate.
[Table 11 Return to footnote d referrer](#t11fnd-rf)
Table 11 Footnote e
Downrating by -1 for imprecision as did not meet review information size (400 people with events).
[Table 11 Return to footnote e referrer](#t11fne-rf)
|
Table 12. Evidence synthesis: PNEU-C-15 versus PNEU-C-13 in adults aged 65 years or older previously vaccinated with PNEU-P-23.
| Outcome | Studies contributing data; n/N (where available) | Synthesised result
(Relative effects as PNEU-C-15 vs PNEU-C-13. Relative and absolute effects shown with 95% CI in parentheses. For immunogenicity data, specific serotypes are provided in parentheses.) | GRADE certainty of evidence rating |
| --- | --- | --- | --- |
| Geometric Mean Titers (per protocol)
1 month after vaccine | 1 RCT (Peterson); * PNEU-C-15: N=122 across serotype analyses
* PNEU-C-13: Range N=121-122 across serotype analyses
| Non-inferiority was not evaluated.
Additional data (not GRADEd)
Shared serotypes
**All except ST3**: GMT ratio estimate ranged 0.68 (4) to 1.23 (6B). **ST3**: 1.6.
**Unique serotypes. 22F:** 13.9; **33F:** 3.5. Numerically higher responses for the unique serotypes. | No GRADE rating [Table 12 Footnote a](#t12fna) |
| % Seroresponders(≥4-fold risk in GMFR) (per protocol)
1 month after vaccine | 1 RCT (Peterson); * PNEU-C-15: Range N 117 to 118 analyzed (across serotypes)
* PNEU-C-13: Range N 112 to 113 analyzed (across serotypes)
| Shared serotypes:
**All except ST3**: RR range 0.80 to 1.25. **ST3**: RR 1.37. Favours PNEU-C-15 except for serotypes 4, 5, 6A, 6B, and 7F.
**Unique serotypes,** **22F:** RR 5.13; **33F** : RR 6.10. Numerically higher proportion of seroresponders with most serotypes, favouring PNEU-C-15. | Low [Table 12 Footnote b](#t12fnb) [Table 12 Footnote c](#t12fnc)
PNEU-C-15 may result in a numerically higher proportion of seroresponders for most serotypes compared with PNEU-C-13. |
| Vaccine-related Serious AE
Up to 6 months after vaccine | 1 RCT (Peterson); * PNEU-C-15: 0/127
* PNEU-C-13: 0/126
| No vaccine related events observed in either group. | Moderate [Table 12 Footnote c](#t12fnc) [Table 12 Footnote d](#t12fnd)
There is probably little to no difference in SAEs between PNEU-C-15 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. None were vaccine related |
| Serious AE
Up to 6 months after vaccine | 1 RCT (Peterson); * PNEU-C-15: 0/127 (0%)
* PNEU-C-13: 2/126 (1.6%)
| Relative effects: Peto OR 0.13 (0.01 to 2.14)
Absolute effects: 14 fewer per 1,000 (from 16 fewer to 17 more)
The two AEs in the PNEU-C-13 group were acute myocardial infarction and periprosthetic fracture. |
| Severe Systemic AE – Fatigue
Up to 14 days after vaccine | 1 RCT (Peterson); * PNEU-C-15: 1/127 (0.8%)
* PNEU-C-13: 1/126 (0.8%)
| Relative effects: Peto OR: 0.99 (0.06 to 15.95)
Absolute effects: 7 fewer per 1,000 (from 16 fewer to 105 more) | Moderate [Table 12 Footnote c](#t12fnc) [Table 12 Footnote d](#t12fnd)
There is probably little to no difference in severe fatigue between PNEU-C-15 and PNEU-C-13. |
| Severe Systemic AE - Headache
Up to 14 days after vaccine | 1 RCT (Peterson); * PNEU-C-15: 0/127 (0%)
* PNEU-C-13: 1/126 (0.8%)
| Relative effects: Peto OR: 0.13 (0.003 to 6.77)
Absolute effects: 7 fewer per 1,000 (8 fewer to 21 more) | Moderate [Table 12 Footnote c](#t12fnc) [Table 12 Footnote d](#t12fnd)
There is probably little to no difference in severe headache between PNEU-C-15 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Severe Systemic AE - Muscle pain
Up to 14 days after vaccine | 1 RCT (Peterson); * PNEU-C-15: 1/127 (0.8%)
* PNEU-C-13: 0/126 (0%)
| Relative effects: Peto OR: 7.33 (0.15 to 369.5)
Absolute effectse: 10 more per 1,000 (10 fewer to 30 more per 1,000). | Moderate [Table 12 Footnote c](#t12fnc) [Table 12 Footnote d](#t12fnd)
There is probably little to no difference in severe muscle pain between PNEU-C-15 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Severe Systemic AE - Joint pain
Up to 14 days after vaccine | 1 RCT (Peterson); * PNEU-C-15: 0/127 (0%)
* PNEU-C-13: 0/126 (0%)
| No events observed in either group. | Moderate [Table 12 Footnote c](#t12fnc) [Table 12 Footnote d](#t12fnd)
There is probably little to no difference in severe joint pain between PNEU-C-15 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Severe Systemic AE – Fever
Up to 14 days after vaccine | 1 RCT (Peterson); * PNEU-C-15: 0/127 (0%)
* PNEU-C-13: 0/126 (0%)
| No events observed in either group. | Moderate [Table 12 Footnote c](#t12fnc) [Table 12 Footnote d](#t12fnd)
There is probably little to no difference in severe fever between PNEU-C-15 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Mild/moderate Systemic AE – Fatigue
Up to 14 days after vaccine | 1 RCT (Peterson);
PNEU-C-15: 22/127 (17.3%)
PNEU-C-13: 23/126
(18.3%) | Relative effects: RR 0.95 (0.56 to 1.61)
Absolute effects: 9 fewer per 1,000 (80 fewer to 111 more) | Moderatec,d
There is probably little to no difference in mild/moderate fatigue between PNEU-C-15 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Mild/moderate Systemic AE – Headache
Up to 14 days after vaccine | 1 RCT (Peterson); * PNEU-C-15: 17/127 (13.4%)
* PNEU-C-13: 19/126 (15.1%)
| Relative effects: RR 0.89 (0.48 to 1.63)
Absolute effects: 17 fewer per 1,000 (78 fewer to 95 more) | Moderate [Table 12 Footnote c](#t12fnc) [Table 12 Footnote d](#t12fnd)
There is probably little to no difference in mild/moderate headache between PNEU-C-15 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Mild/moderate Systemic AE - Muscle Pain
Up to 14 days after vaccine | 1 RCT (Peterson); * PNEU-C-15: 19/127 (15.0%)
* PNEU-C-13: 14/126 (11.1%)
| Relative effects: RR 1.33 (0.70 to 2.53)
Absolute effects: 37 more per 1,000 (33 fewer to 170 more) | Moderate [Table 12 Footnote c](#t12fnc) [Table 12 Footnote d](#t12fnd)
There is probably little to no difference in mild/moderate muscle pain between PNEU-C-15 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Mild/moderate Systemic AE - Joint Pain
Up to 14 days after vaccine | 1 RCT (Peterson); * PNEU-C-15: 7/127 (5.5%)
* PNEU-C-13: 11/126 (8.7%)
| Relative effects: RR 0.63 (0.25 to 1.58)
Absolute effects: 32 fewer per 1,000 (65 fewer to 51 more) | Moderate [Table 12 Footnote c](#t12fnc) [Table 12 Footnote d](#t12fnd)
There is probably little to no difference in mild/moderate joint pain between PNEU-C-15 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23 |
| Mild/moderate Systemic AE – Fever
Up to 14 days after vaccine | 1 RCT (Peterson); * PNEU-C-15: 2/127 (1.6%)
* PNEU-C-13: 0/126 (0%)
| Relative effects: Peto OR: 7.39 (0.46 to 118.80)
Absolute effects: 20 more per 1,000 (10 fewer to 40 more per 1,000) | Moderate [Table 12 Footnote c](#t12fnc) [Table 12 Footnote d](#t12fnd)
There is probably little to no difference in mild/moderate fever between PNEU-C-15 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Abbreviations: AE = adverse events; OR = odds ratio; PNEU-C-13 = 13-valent pneumococcal conjugate vaccine; PNEU-C-15 = 15-valent pneumococcal conjugate vaccine; PNEU-P-23 = 23-valent pneumococcal polysaccharide vaccine; RCT = randomised controlled trial; RD = risk difference; RR = relative risk; SAE = Serious adverse events; vs = versus; y=years.
Table 12 Footnote a
A key determinant of immunogenicity for this comparison is the ability for a newer pneumococcal vaccine to demonstrate non-inferiority compared with a previously approved one for shared serotypes. As non-inferiority was not evaluated in this study, no GRADE rating can be provided.
[Table 12 Return to footnote a referrer](#t12fna-rf)
Table 12 Footnote b
Downrating by –1 for indirectness due to use of immunogenicity measures in the absence of disease endpoints and by –1 for imprecision as did not meet the review information size (400 people with events or, for very few to no events, ≥4,000 sample size).
[Table 12 Return to footnote b referrer](#t12fnb-rf)
Table 12 Footnote c
The majority of participants were of White race, but we do not expect substantively different results with diversity in race from a biological perspective. No downrating.
[Table 12 Return to footnote c referrer](#t12fnc-rf)
Table 12 Footnote d
Downrating by –1 for imprecision due to low power (did not meet review information size).
[Table 12 Return to footnote d referrer](#t12fnd-rf)
Table 12 Footnote e
Could not be calculated using standard GRADE methods owing to no events in the control group. The absolute risk difference between groups is provided.
[Table 12 Return to footnote e referrer](#t12fne-rf)
|
Table 13. Evidence synthesis: PNEU-C-15 versus PNEU-C-13 in adults 18 to 64 years of age with chronic medical conditions that increase invasive pneumococcal disease risk.
| Outcome | Studies contributing data; n/N (where available) | Synthesised result
(Relative effects as PNEU-C-15 vs PNEU-C-13. Relative and absolute effects shown with 95% CI in parentheses. For immunogenicity data, specific serotypes are provided in parentheses) | GRADE certainty of evidence rating |
| --- | --- | --- | --- |
| Geometric Mean Titers (per protocol)
1 month after vaccine | 2 RCTs (Ermlich 2018; Hammitt 2022) * PNEU-C-15: N analyzed >1,250 across Serotypes
* PNEU-C-13: N analyzed >525 across Serotypes
| Shared serotypes
Non-inferiority was not evaluated in these studies.
Additional data (not GRADEd)
**Shared serotype data**. All except ST3. Varied results between studies and by condition, using GMT ratio of 1 as a threshold, but analyses by condition had low power. ST3. All analyses with GMT ratio >1.
**Unique serotypes, 22F, 33F.** GMT ratio estimates >1 across studies/analyses. Numerically higher responses for the unique serotypes, but some analyses had low power. | No GRADE rating [Table 13 Footnote a](#t13fna)
Whether PNEU-C-15 is non-inferior to PNEU-C-13 is not known. |
| % Seroresponders(≥4-fold risk in risk in serotype specific OPA)
1 month after vaccine | 2 RCTs (Ermlich 2018; Hammitt 2022) * PNEU-C-15: N analyzed >1,250 across serotypes
* PNEU-C-13: N analyzed >525 across serotypes
| **Shared serotypes except ST3.** Mixed results between studies and across conditions in serotypes showing a higher numerical seroresponse estimate with PNEU-C-15.
**ST3**. Numerically higher proportion of seroresponders with PNEU-C-15 (RR range 1.10 to 1.18; RD range 5.4% to 14%).
**Unique serotypes**. Analyses showing numerically higher proportion of seroresponders with PNEU-C-15 for all but one analysis (22F for diabetes subgroup). | Low [Table 13 Footnote b](#t13fnb)
There may be a higher numerical proportion of seroresponders with PNEU-C-15 for the unique serotypes (22F, 33F) and ST3 but unclear for remaining shared serotypes. |
| Vaccine-related Serious AE
Up to 6 months after vaccine | 1 RCT (Hammitt 2022) * PNEU-C-15: 0/1,019
* PNEU-C-13: 0/435
| No vaccine-related events observed. | Moderate [Table 13 Footnote c](#t13fnc)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of SAEs up to 6 months after vaccine administration. None of those events were deemed to be vaccine-related by study authors.
This study reported only on the number of deaths in each group (3 vs 2). |
| Serious AE
Up to 6 months after vaccine | 1 RCT (Hammitt 2022) * PNEU-C-15: 35/849 (4.1%)
* PNEU-C-13: 8/282 (2.8%)
| Relative effects: RR 1.45 (0.68 to 3.10)
Absolute effects: 13 more per 1,000 (9 fewer to 60 more)
SAEs by the relevant population group were not listed. |
| Severe Systemic AE – Fatigue
Up to 14 days after vaccine | 1 RCT (Hammitt 2022) * PNEU-C-15: 11/1134 (1.0%)
* PNEU-C-13: 3/378 (0.8%)
| Relative effects: Peto OR 1.21 (0.36 to 4.08)
Absolute effects: 2 more per 1,000 (5 fewer to 24 more) | Moderate [Table 13 Footnote c](#t13fnc)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of severe fatigue within 14 days after vaccine administration. |
| Severe Systemic AE – Headache
Up to 14 days after vaccine | 1 RCT (Hammitt 2022) * PNEU-C-15: 9/1134 (0.8%)
* PNEU-C-13: 2/378 (0.6%)
| Relative effects: Peto OR 1.21 (0.36 to 4.08)
Absolute effects: 1 more per 1,000 (3 fewer to 16 more) | Moderate [Table 13 Footnote c](#t13fnc)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of severe headache within 14 days after vaccine administration. |
| Severe Systemic AE – Muscle Pain
Up to 14 days after vaccine | 1 RCT (Hammitt 2022) * PNEU-C-15: 3/1134 (0.3%)
* PNEU-C-13: 2/378 (0.5%)
| Relative effects: Peto OR 0.45 (0.06 to 3.40)
Absolute effects: 3 fewer per 1,000 (5 fewer to 12 more) | Moderate [Table 13 Footnote c](#t13fnc)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of severe muscle pain within 14 days after vaccine administration. |
| Severe Systemic AE – Joint Pain
Up to 14 days after vaccine | 1 RCT (Hammitt 2022) * PNEU-C-15: 4/1134 (0.4%)
* PNEU-C-13: 0/378 (0%)
| Relative effects: Peto OR 3.80 (0.39 to 36.65)
Absolute effects: 0 per 1,000 (0 to 10 more) | Moderate [Table 13 Footnote c](#t13fnc)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of severe joint pain within 14 days after vaccine administration. |
| Severe Systemic AE – Fever
Up to 5 days after vaccine | No studies addressed this outcome |
| Mild/moderate Systemic AE - Fatigue
Up to 14 days after vaccine | 1 RCT (Hammitt 2022) * PNEU-C-15: 378/1134 (33.3%)
* PNEU-C-13: 136/378 (36.0%)
| Relative effects: RR 0.93 (0.79 to 1.08)
Absolute effects: 25 fewer per 1,000 (76 fewer to 29 more) | High
There is little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of mild/moderate fatigue within 14 days after vaccine administration. |
| Mild/moderate Systemic AE – Headache
Up to 14 days after vaccine | 1 RCT (Hammitt 2022) * PNEU-C-15: 291/1134 (25.7%)
* PNEU-C-13: 92/378 (24.3%)
| Relative effects: RR 1.05 (0.86 to 1.29)
Absolute effects: 12 more per 1,000 (34 fewer to 71 more) | Moderate [Table 13 Footnote c](#t13fnc)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of mild/moderate headache within 14 days after vaccine administration. |
| Mild/moderate Systemic AE - Muscle Pain
Up to 14 days after vaccine | 1 RCT (Hammitt 2022) * PNEU-C-15: 324/1134 (28.6%)
* PNEU-C-13: 98/378 (25.9%)
| Relative effects: RR 1.10 (0.91 to 1.34)
Absolute effects: 26 more per 1,000 (23 fewer to 88 more) | High
There is little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of mild/moderate muscle pain within 14 days after vaccine administration. |
| Mild/moderate Systemic AE - Joint Pain
Up to 14 days after vaccine | 1 RCT (Hammitt 2022) * PNEU-C-15: 140/1134 (12.3%)
* PNEU-C-13: 44/378 (11.6%)
| Relative effects: RR 1.06 (0.77 to 1.46)
Absolute effects: 7 more per 1,000 (27 fewer to 54 more) | Moderate [Table 13 Footnote d](#t13fnd)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of mild/moderate joint pain within 14 days after vaccine administration. |
| Mild/moderate Systemic AE – Fever
Up to 5 days after vaccine | No studies addressed this outcome |
| Abbreviations: AE = adverse events; OR = odds ratio; PNEU-C-13 = 13-valent pneumococcal conjugate vaccine; PNEU-C-15 = 15-valent pneumococcal conjugate vaccine; RCT = randomised controlled trial; RD = risk difference; RR = relative risk; SAE = Serious adverse events; vs = versus; y=years.
Table 13 Footnote a
A key determinant of immunogenicity for this comparison is the ability for a newer pneumococcal vaccine to demonstrate non-inferiority compared with a previously approved one for shared serotypes. As non-inferiority was not evaluated in these studies, no GRADE rating can be provided.
[Table 13 Return to footnote a referrer](#t13fna-rf)
Footnote b
Downrating by -1 for indirectness due to use of immunogenicity measures in the absence of disease endpoints and for inconsistency between studies in the direct of effect using the effect estimate.
[Table 13 Return to footnote b referrer](#t13fnb-rf)
Table 13 Footnote c
Downrating by -1 for imprecision as did not meet the review information size (400 people with events or, for very few to no events, ≥4,000 sample size).
[Table 13 Return to footnote c referrer](#t13fnc-rf)
Table 13 Footnote d
Downrating by -1 for imprecision as did not meet the review information size (400 people with events).
[Table 13 Return to footnote d referrer](#t13fnd-rf)
|
Table 14. Evidence synthesis: PNEU-C-15 versus PNEU-C-13 in adults 18 to 64 years of age with an immunocompromising condition who are vaccine-naïve
| Outcome | Studies contributing data; n/N (where available) | Synthesised result
(Relative effects as PNEU-C-15 vs PNEU-C-13. Relative and absolute effects shown with 95% CI in parentheses. For immunogenicity data, specific serotypes are provided in parentheses) | GRADE certainty of evidence rating |
| --- | --- | --- | --- |
| Geometric Mean Titers
(per protocol)
1 month after vaccine | 1 RCT (Mohapi 2022) | Non-inferiority was not evaluated
Additional data (not GRADEd):
One study (Mohapi 2022) in adults ≥18 years living with HIV reported OPA GMTs (range N 299-300 across groups by serotype analysis). All serotypes except serotypes 4 and 7F showed numerically higher GMTs for PNEU-C-15 compared to PNEU-C-13. GMT ratios ranged from 0.55 (4) to 1.81 (18C) for shared serotypes and the lowest 95% CI lower bound across serotypes was 0.38. For unique serotypes, GMT ratios were 42.86 (95% CI 26.53 to 69.25) and 5.41 (4.07 to 7.19) for ST22F and ST33F, respectively.
**Subgroups for age (18-49y vs ≥50y), shared serotypes.** One study (Mohapi 2022) reported OPA GMTs for 18-49 and ≥50 year subgroups; however, GMT ratios and corresponding 95% confidence intervals were not provided. GMTs were numerically higher for PNEU-C-15 across subgroups for the following serotypes: 1, 3, 6A, 6B, 9V, 14, 18C, 19A, and 19F. Serotype 4 showed a numerically lower GMT for PNEU-C-15 in both subgroups. For remaining serotypes (i.e., 5, 7F, 23F), GMTs were numerically higher for PNEU-C-15 for all three serotypes for the ≥50-year subgroup but numerically lower for the same serotypes for the 18-49 year subgroup.
**Subgroups for age (18-49y vs ≥50y), unique serotypes.** GMTs were numerically higher for PNEU-C-15 for both unique serotypes (i.e., 22F and 33F) across subgroups. | No GRADE rating [Table 14 Footnote a](#t14fna) |
| % Seroresponders
(≥4-fold risk in risk in serotype specific OPA) –
Shared serotypes except ST3
1 month after vaccine | 1 RCT (Mohapi 2022); * PNEU-C-15: Range N=108-126 analysed across serotypes
* PNEU-C-13: Range N=102-126 analysed across serotypes
| **Shared serotypes except ST3**. Numerically higher proportion of seroresponders with PNEU-C-15 than PNEU-C-13 for all shared serotypes except serotypes 1, 4, 5, and 7F. | Low [Table 14 Footnote b](#t14fnb)
PNEU-C-15 may result in a numerically higher proportion of seroresponders for most shared serotypes compared with PNEU-C-13. |
| % Seroresponders
(≥4-fold risk in risk in serotype specific OPA) –
ST3
1 month after vaccine | 1 RCT (Mohapi 2022); * PNEU-C-15: 126 analysed
* PNEU-C-13: 125 analysed
| **Shared serotype, ST3**. Higher numerical seroresponse estimate with PNEU-C-15 (RR 1.53; RD 20.3) | Low [Table 14 Footnote b](#t14fnb)
PNEU-C-15 may result in a numerically higher proportion of seroresponders for ST3 as compared to PNEU-C-13. |
| % Seroresponders
(≥4-fold risk in risk in serotype specific OPA) –
Unique serotypes
1 month after vaccine | 1 RCT (Mohapi 2022); * PNEU-C-15: Range N=108-122 analysed across serotypes
* PNEU-C-13: Range N=102-123 analysed across serotypes
| **Unique serotype, ST22F**. Higher numerical seroresponse estimate with PNEU-C-15 (RR 5.68; RD 64.1).
**Unique serotype, ST33F**. Higher numerical seroresponse estimate with PNEU-C-15 (RR 11.04; RD 49.2) | Low [Table 14 Footnote b](#t14fnb)
PNEU-C-15 may result in a numerically higher proportion of seroresponders for both unique serotypes as compared to PNEU-C-13. |
| Vaccine-related Serious AE
Up to week 8 | 1 RCT (Mohapi 2022);* PNEU-C-15: 0/152
* PNEU-C-13: 0/150
| No vaccine-related serious AE observed in either group. | Moderate [Table 14 Footnote c](#t14fnc) |
| Serious AE
Up to week 8 | 1 RCT (Mohapi 2022); * PNEU-C-15: 3/152 (2.0%)
* PNEU-C-13: 0/150 (0%)
| Relative effects: Peto OR 7.39 (0.76 to 71.59)
Absolute effects: 0 fewer per 1,000 (0 fewer to 0 fewer)
The three events with PNEU-C-15 were musculoskeletal/connective tissue disorder, transient ischaemic attack (nervous system), suicide.
Additional data (not GRADEd):
**Subgroups for age (18-49y vs ≥50y).** One study (Mohapi 2022) provided data on SAEs for 18-49 and ≥50 years olds. Due to too few studies, subgroup analyses could not be performed. Confidence intervals around relative effect estimates overlapped between age groups; however, there were small number of events [18-49 years – Peto OR 7.67, 95% CI: 0.15-386.82; ≥50 years – Peto OR 6.62, 95% CI: 0.40-108.34]. | Moderate [Table 14 Footnote c](#t14fnc)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in SAEs. None were vaccine related.
|
| Severe Systemic AE - Fatigue
Up to 14 days after vaccine | 1 RCT (Mohapi 2022); * PNEU-C-15: 0/152
* PNEU-C-13: 0/150
| No events observed. | Moderate [Table 14 Footnote c](#t14fnc)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of severe fatigue within 14 days after vaccine administration. |
| Severe Systemic AE - Headache
Up to 14 days after vaccine | 1 RCT (Mohapi 2022); * PNEU-C-15: 1/152 (0.7%)
* PNEU-C-13: 1/150 (0.7%)
| Relative effects: Peto OR 0.99 (0.06 to 15.85)
Absolute effects: 0 fewer per 1,000 (6 fewer to 89 more) | Moderate [Table 14 Footnote d](#t14fnd)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of severe headache within 14 days after vaccine administration. |
| Severe Systemic AE – Muscle Pain
Up to 14 days after vaccine | 1 RCT (Mohapi 2022); * PNEU-C-15: 0/152
* PNEU-C-13: 0/150
| No events observed. | Moderate [Table 14 Footnote c](#t14fnc)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of severe muscle pain within 14 days after vaccine administration. |
| Severe Systemic AE – Joint Pain
Up to 14 days after vaccine | 1 RCT (Mohapi 2022); * PNEU-C-15: 0/152
* PNEU-C-13: 0/150
| No events observed. | Moderate [Table 14 Footnote c](#t14fnc)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of severe joint pain within 14 days after vaccine administration. |
| Severe Systemic AE - Fever
Up to 5 days after vaccine | 1 RCT (Mohapi 2022); * PNEU-C-15: 0/152
* PNEU-C-13: 0/150
| No events observed. | Moderate [Table 14 Footnote c](#t14fnc)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of severe fever up to 5 days after vaccination. |
| Mild/moderate Systemic AE - Fatigue
Up to 14 days after vaccine | 1 RCT (Mohapi 2022);* PNEU-C-15: 31/152 (20.4%)
* PNEU-C-13: 20/150 (13.3%)
| Relative effects: RR 1.53 (0.91 to 2.56)
Absolute effects: 71 more per 1,000 (12 fewer to 208 more) | Moderate [Table 14 Footnote d](#t14fnd)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of mild/moderate fatigue within 14 days after vaccine administration. |
| Mild/moderate Systemic AE - Headache
Up to 14 days after vaccine | 1 RCT (Mohapi 2022); * PNEU-C-15: 19/152 (12.5%)
* PNEU-C-13: 14/150 (9.3%)
| Relative effects: RR 1.34 (0.70 to 2.57)
Absolute effects: 32 more per 1,000 (28 fewer to 147 more) | Moderate [Table 14 Footnote d](#t14fnd)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of mild/moderate headache within 14 days after vaccine administration. |
| Mild/moderate Systemic AE - Muscle Pain
Up to 14 days after vaccine | 1 RCT (Mohapi 2022); * PNEU-C-15: 19/152 (12.5%)
* PNEU-C-13: 14/150 (9.3%)
| Relative effects: RR 1.34 (0.70 to 2.57)
Absolute effects: 32 more per 1,000 (28 fewer to 147 more) | Moderate [Table 14 Footnote d](#t14fnd)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of mild/moderate muscle pain within 14 days after vaccine administration. |
| Mild/moderate Systemic AE - Joint Pain
Up to 14 days after vaccine | 1 RCT (Mohapi 2022); * PNEU-C-15: 5/152 (3.3%)
* PNEU-C-13: 6/150 (4.0%)
| Relative effects: Peto OR 0.82 (0.25 to 2.72)
Absolute effects: 7 fewer per 1,000 (30 fewer to 62 more) | Moderate [Table 14 Footnote c](#t14fnc)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of mild/moderate joint pain within 14 days after vaccine administration. |
| Mild/moderate Systemic AE - Fever
Up to 5 days after vaccine | 1 RCT (Mohapi 2022); * PNEU-C-15: 2/152 (1.3%)
* PNEU-C-13: 1/150 (0.7%)
| Relative effects: Peto OR 1.93 (0.20 to 18.7)
Absolute effects: 6 more per 1,000 (5 fewer to 105 more) | Moderate [Table 14 Footnote d](#t14fnd)
There is probably little to no difference between PNEU-C-15 and PNEU-C-13 in the occurrence of mild/moderate fever up to 5 days after vaccination. |
| Abbreviations: AE = adverse events; OR = odds ratio; PNEU-C-13 = 13-valent pneumococcal conjugate vaccine; PNEU-C-15 = 15-valent pneumococcal conjugate vaccine; RCT = randomised controlled trial; RD = risk difference; RR = relative risk; SAE = Serious adverse events; vs = versus; y=years.
Table 14 Footnote a
A key determinant of immunogenicity for this comparison is the ability for a newer pneumococcal vaccine to demonstrate non-inferiority compared with a previously approved one for shared serotypes. As non-inferiority was not evaluated in this study, no GRADE rating can be provided.
[Table 14 Return to footnote a referrer](#t14fna-rf)
Table 14 Footnote b
Downrating by –1 for indirectness due to use of immunogenicity measures in the absence of disease endpoints and by –1 for imprecision as did not meet the review information size (400 people with events or, for very few to no events, ≥4,000 sample size).
[Table 14 Return to footnote b referrer](#t14fnb-rf)
Table 14 Footnote c
Downrating by –1 for imprecision as did not meet the review information size (400 people with events or, for very few to no events, ≥4,000 sample size).
[Table 14 Return to footnote c referrer](#t14fnc-rf)
Table 14 Footnote d
Downrating by –1 for imprecision as the CI includes the possibility of an important increase.
[Table 14 Return to footnote d referrer](#t14fnd-rf)
|
Table 15. Evidence synthesis: PNEU-C-15+PNEU-P-23 versus PNEU-C-13+PNEU-P-23 in adults with an immunocompromising condition who are vaccine-naïve
| Outcome | Studies contributing data; n/N (where available) | Synthesised result
(Relative effects as PNEU-C-15+PNEU-P-23 vs PNEU-C-13+PNEU-P-23. Relative and absolute effects shown with 95% CI in parentheses. For immunogenicity data, specific serotypes are provided in parentheses) | GRADE certainty of evidence rating |
| --- | --- | --- | --- |
| Geometric Mean Titers
(per protocol)
12 weeks (1 month after PNEU-P-23 vaccine) | 1 RCT (Mohapi 2022) | No studies evaluated non-inferiority.
Additional data (not GRADEd):
One study in adults ≥18 years living with HIV reported OPA GMTs (range N 299-300 across groups by serotype analysis) but did not evaluate non-inferiority. All serotypes except serotypes 4 and 33F showed numerically higher GMTs for PNEU-C-15+PNEU-P-23 compared to PNEU-C-13+PNEU-P-23. GMT ratios ranged from 0.99 (ST4) to 1.57 (ST18C) for shared serotypes and the lowest 95% CI lower bound across serotypes was 0.72. For unique serotypes, GMT ratios were 1.15 (95% CI 0.81 to 1.64) and 0.90 (0.67 to 1.21) for ST22F and ST33F, respectively. | No GRADE rating [Table 15 Footnote a](#t15fna) |
| % Seroresponders
(≥4-fold risk in risk in serotype specific OPA) –
Shared serotypes except ST3
12 weeks (1 month after PNEU-P-23 vaccine) | 1 RCT (Mohapi 2022); * PNEU-C-15+
PNEU-P-23: Range N=109-119 analysed across serotypes
* PNEU-C-13+
PNEU-P-23: Range N=105-113 analysed across serotypes
| **Shared serotypes except ST3**. Numerically higher proportion of seroresponders with PNEU-C-15+PNEU-P-23 than PNEU-C-13+PNEU-P-23 for all shared serotypes except serotypes 9V. | Low [Table 15 Footnote b](#t15fnb)* PNEU-C-15+
* PNEU-P-23 may result in a numerically higher proportion of seroresponders for most shared serotypes compared with PNEU-C-13+
* PNEU-P-23.
|
| % Seroresponders
(≥4-fold risk in risk in serotype specific OPA) –
ST3
12 weeks (1 month after PNEU-P-23 vaccine) | 1 RCT (Mohapi 2022); * PNEU-C-15+PNEU-P-23: 119 analyzed
* PNEU-C-13+PNEU-P-23: 113 analyzed
| **Shared serotype, ST3**. Lower numerical seroresponse estimate with PNEU-C-15+PNEU-P-23 (RR 0.97; RD -1.8) compared to PNEU-C-13+PNEU-P-23. | Low [Table 15 Footnote b](#t15fnb)
PNEU-C-15+PNEU-P-23 may result in a numerically lower proportion of seroresponders for ST3 as compared to PNEU-C-13+PNEU-P-23. |
| % Seroresponders
(≥4-fold risk in risk in serotype specific OPA) –
Unique serotypes
12 weeks (1 month after PNEU-P-23 vaccine) | 1 RCT (Mohapi 2022); * PNEU-C-15+PNEU-P-23: Range N=102-117 analysed across serotypes
* PNEU-C-13+PNEU-P-23: Range N=105-111 analysed across serotypes
| **Unique serotype, ST22F**. Lower numerical seroresponse estimate with PNEU-C-15+PNEU-P-23 (RR 0.98; RD -1.7).
**Unique serotype, ST33F**. Lower numerical seroresponse estimate with PNEU-C-15+PNEU-P-23 (RR 0.90; RD -6.9) | Low [Table 15 Footnote b](#t15fnb)
PNEU-C-15+PNEU-P-23 may result in a numerically lower proportion of seroresponders for both unique serotypes as compared to PNEU-C-13+PNEU-P-23. |
| Vaccine-related Serious AE
From week 8 up to month 6 | 1 RCT (Mohapi 2022); * PNEU-C-15+PNEU-P-23: 0/150
* PNEU-C-13+PNEU-P-23: 0/148
| No vaccine-related serious AE observed in either group. | Moderate [Table 15 Footnote c](#t15fnc) |
| Serious AE
From week 8 up to month 6 | 1 RCT (Mohapi 2022); * PNEU-C-15+PNEU-P-23: 2/150 (1.3%)
* PNEU-C-13+PNEU-P-23: 6/148 (4.1%)
| Relative effects: Peto OR 0.35 (0.09 to 1.44)
Absolute effects: 26 fewer per 1,000 (37 fewer to 17 more)
The two events with PNEU-C-15+PNEU-P-23 were appendicitis and pulmonary embolism. Events with PNEU-C-13+PNEU-P-23 were chest pain, herpes zoster, peritonitis, soft tissue infection, foot fracture, and dry gangrene. | Moderate [Table 15 Footnote c](#t15fnc)
There is probably little to no difference between PNEU-C-15+PNEU-P-23 and PNEU-C-13+PNEU-P-23 in serious adverse events. None were vaccine related. |
| Severe Systemic AE - Fatigue
Up to 14 days after vaccination with PNEU-P-23 | 1 RCT (Mohapi 2022); * PNEU-C-15+PNEU-P-23: 1/150 (0.7%)
* PNEU-C-13+PNEU-P-23: 1/148 (0.7%)
| Relative effects: Peto OR 0.99 (0.06 to 15.85)
Absolute effects: 0 fewer per 1,000 (6 fewer to 91 more) | Moderate [Table 15 Footnote d](#t15fnd)
There is probably little to no difference between PNEU-C-15+PNEU-P-23 and PNEU-C-13+PNEU-P-23 in the occurrence of severe fatigue within 14 days after vaccine administration. |
| Severe Systemic AE - Headache
Up to 14 days after vaccination with PNEU-P-23 | 1 RCT (Mohapi 2022); * PNEU-C-15+PNEU-P-23: 0/150 (0%)
* PNEU-C-13+PNEU-P-23: 1/148 (0.7%)
| Relative effects: Peto OR 0.13 (0.00 to 6.73)
Absolute effects: 6 fewer per 1,000 (- to 37 more) | Moderate [Table 15 Footnote d](#t15fnd)
There is probably little to no difference between PNEU-C-15+PNEU-P-23 and PNEU-C-13+PNEU-P-23 in the occurrence of severe headache within 14 days after vaccine administration. |
| Severe Systemic AE – Muscle Pain
Up to 14 days after vaccination with PNEU-P-23 | 1 RCT (Mohapi 2022); * PNEU-C-15+PNEU-P-23: 1/150 (0.7%)
* PNEU-C-13+PNEU-P-23: 0/148 (0%)
| Relative effects: Peto OR 7.29 (0.14 to 367.49)
Absolute effects: 0 fewer per 1,000 (0 fewer to 0 fewer) | Moderate [Table 15 Footnote c](#t15fnc)
There is probably little to no difference between PNEU-C-15+PNEU-P-23 and PNEU-C-13+PNEU-P-23 in the occurrence of severe muscle pain within 14 days after vaccine administration. |
| Severe Systemic AE – Joint Pain
Up to 14 days after vaccination with PNEU-P-23 | 1 RCT (Mohapi 2022); * PNEU-C-15+PNEU-P-23: 1/150 (0.7%)
* PNEU-C-13+PNEU-P-23: 0/148 (0%)
| Relative effects: Peto OR 7.29 (0.14 to 367.49)
Absolute effects: 0 fewer per 1,000 (0 fewer to 0 fewer) | Moderate [Table 15 Footnote c](#t15fnc)
There is probably little to no difference between PNEU-C-15+PNEU-P-23 and PNEU-C-13+PNEU-P-23 in the occurrence of severe joint pain within 14 days after vaccine administration. |
| Severe Systemic AE - Fever
Up to 5 days after vaccine | 1 RCT (Mohapi 2022);* PNEU-C-15+PNEU-P-23: 0/150
* PNEU-C-13+PNEU-P-23: 0/148
| No events observed. | Moderate [Table 15 Footnote c](#t15fnc)
There is probably little to no difference between PNEU-C-15+PNEU-P-23 and PNEU-C-13+PNEU-P-23 in the occurrence of severe fever up to 5 days after vaccination. |
| Mild/moderate Systemic AE - Fatigue
Up to 14 days after vaccination with PNEU-P-23 | 1 RCT (Mohapi 2022); * PNEU-C-15+PNEU-P-23: 18/150
(12.0%)
* PNEU-C-13+PNEU-P-23: 15/148
(10.0%)
| Relative effects: RR 1.18 (0.62 to 2.26)
Absolute effects: 18 more per 1,000 (39 fewer to 128 more) | Moderate [Table 15 Footnote d](#t15fnd)
There is probably little to no difference between PNEU-C-15+PNEU-P-23 and PNEU-C-13+PNEU-P-23 in the occurrence of mild/moderate fatigue within 14 days after vaccine administration. |
| Mild/moderate Systemic AE - Headache
Up to 14 days after vaccination with PNEU-P-23 | 1 RCT (Mohapi 2022); * PNEU-C-15+PNEU-P-23: 13/150 (8.7%)
* PNEU-C-13+PNEU-P-23: 12/148 (8.1%)
| Relative effects: RR 1.07 (0.50 to 2.27)
Absolute effects: 6 more per 1,000 (41 fewer to 103 more) | Moderate [Table 15 Footnote d](#t15fnd)
There is probably little to no difference between PNEU-C-15+PNEU-P-23 and PNEU-C-13+PNEU-P-23 in the occurrence of mild/moderate headache within 14 days after vaccine administration. |
| Mild/moderate Systemic AE - Muscle Pain
Up to 14 days after vaccination with PNEU-P-23 | 1 RCT (Mohapi 2022); * PNEU-C-15+PNEU-P-23: 16/150
(10.7%)
* PNEU-C-13+PNEU-P-23: 18/148
(12.2%)
| Relative effects: RR 0.88 (0.47 to 1.65)
Absolute effects: 15 fewer per 1,000 (64 fewer to 79 more) | Moderate [Table 15 Footnote d](#t15fnd)
There is probably little to no difference between PNEU-C-15+PNEU-P-23 and PNEU-C-13+PNEU-P-23 in the occurrence of mild/moderate muscle pain within 14 days after vaccine administration. |
| Mild/moderate Systemic AE - Joint Pain
Up to 14 days after vaccination with PNEU-P-23 | 1 RCT (Mohapi 2022); * PNEU-C-15+PNEU-P-23: 3/150 (2.0%)
* PNEU-C-13+PNEU-P-23: 2/148 (1.4%)
| Relative effects: Peto OR 1.48 (0.25 to 8.64)
Absolute effects: 6 more per 1,000 (10 fewer to 92 more) | Moderate [Table 15 Footnote d](#t15fnd)
There is probably little to no difference between PNEU-C-15+PNEU-P-23 and PNEU-C-13+PNEU-P-23 in the occurrence of mild/moderate joint pain within 14 days after vaccine administration. |
| Mild/moderate Systemic AE - Fever
Up to 5 days after vaccine | 1 RCT (Mohapi 2022); * PNEU-C-15+PNEU-P-23: 4/150 (2.7%)
* PNEU-C-13+PNEU-P-23: 6/148 (4.1%)
| Relative effects: Peto OR 0.66 (0.19 to 2.28)
Absolute effects: 14 fewer per 1,000 (33 fewer to 52 more) | Moderate [Table 15 Footnote c](#t15fnc)
There is probably little to no difference between PNEU-C-15+PNEU-P-23 and PNEU-C-13+PNEU-P-23 in the occurrence of mild/moderate fever up to 5 days after vaccination. |
| Abbreviations: AE = adverse events; OR = odds ratio; PNEU-C-13 = 13-valent pneumococcal conjugate vaccine; PNEU-C-15 = 15-valent pneumococcal conjugate vaccine; PNEU-P-23 = 23-valent pneumococcal polysaccharide vaccine; RCT = randomised controlled trial; RD = risk difference; RR = relative risk; vs = versus; y=years.
Table 15 Footnote 1
A key determinant of immunogenicity for this comparison is the ability for a newer pneumococcal vaccine to demonstrate non-inferiority compared with a previously approved one for shared serotypes. As non-inferiority was not evaluated in this study, no GRADE rating can be provided.
[Table 15 Return to footnote a referrer](#t15fna-rf)
Table 15 Footnote b
Downrating by –1 for indirectness due to use of immunogenicity measures in the absence of disease endpoints and by –1 for imprecision as did not meet the review information size (400 people with events or, for very few to no events, ≥4,000 sample size).
[Table 15 Return to footnote b referrer](#t15fnb-rf)
Table 15 Footnote c
Downrating by –1 for imprecision as did not meet the review information size (400 people with events or, for very few to no events, ≥4,000 sample size).
[Table 15 Return to footnote c referrer](#t15fnc-rf)
Table 15 Footnote d
Downrating by –1 for imprecision as the CI includes the possibility of an important increase.
[Table 15 Return to footnote d referrer](#t15fnd-rf)
|
Table 16. Evidence synthesis: PNEU-C-20 versus PNEU-C-13 in vaccine-naïve adults 65 years of age and older
| Outcome | Studies contributing data; n/N (where available) | Synthesised result
(Relative effects as PNEU-C-20 vs PNEU-C-13. Relative and absolute effects shown with 95% CI in parentheses. For immunogenicity data, specific serotypes are provided in parentheses) | GRADE certainty of evidence rating |
| --- | --- | --- | --- |
| Geometric Mean Titers
(per protocol)
1 month after vaccine | 1 RCT (Essink 2021); * PNEU-C-20: Range N=1399-1430 analysed across serotypes
* PNEU-C-13: Range N=1390-1419 analysed across serotypes
| Shared serotypes
All except ST3: GMT ratio estimate ranged 0.76 (ST6A) to 1.00 (ST14). ST3: 0.85. Non-inferiority for PNEU-C-20 met for all shared serotypes (margin >0.5; lowest CI bound across serotypes 0.66 [ST6A]).
Additional data (not GRADEd):
**Shared serotypes.** One additional study (Hurley 2021) in adults 60-64 years provided immunogenicity information (range N 400-413 across groups by serotype analysis) but did not evaluate non-inferiority. All serotypes showed numerically lower GMT mean titers for PNEU-C-20 compared to PNEU-C-13 (GMT ratio <1.00 for all serotypes).
**Subgroups for age (50-59y vs 60-64y).** One study (Essink 2021) bridged PNEU-C-20 -elicited immune responses in younger participants (50-59 years) to those in older adults (60-64 years). PNEU-C-20 met non-inferiority for all 13 shared serotypes for participants aged 50-59 as compared to those 60-64 years. | Moderate [Table 16 Footnote a](#t16fna) [Table 16 Footnote b](#t16fnb)
PNEU-C-20 is probably not inferior to PNEU-C-13 in immune response for shared serotypes. |
| % Seroresponders
(≥4-fold risk in risk in serotype specific OPA) –
Shared serotypes except ST3
1 month after vaccine | 2 RCTs (Essink 2021, Hurley 2021) * PNEU-C-20: Range N=1525-1633 analysed across serotypes
* PNEU-C-13: Range N=1498-1622 analysed across serotypes
| **Shared serotypes except ST3**. Both studies report numerically lower proportion of seroresponders with PNEU-C-20 than PNEU-C-13 for all but one serotype. The only serotypes showing a higher proportion of seroresponders with PNEU-C-20 were ST14 in one study and ST6A in the second study. | Moderate [Table 16 Footnote a](#t16fna) [Table 16 Footnote b](#t16fnb)
PNEU-C-20 probably results in a numerically lower proportion of seroresponders for most serotypes compared with PNEU-C-13.
Data not available for unique serotypes for this comparison. |
| % Seroresponders
(≥4-fold risk in risk in serotype specific OPA) –
Shared serotypes ST3
1 month after vaccine | 2 RCTs (Essink 2021, Hurley 2021) * PNEU-C-20: 1612 analysed
* PNEU-C-13: 1605 analysed
| **Shared serotype, ST3**. Lower numerical seroresponse estimate with PNEU-C-20 (RR range 0.91-0.93; RD range
-5.2% to -5.6%). | Moderatea [Table 16 Footnote a](#t16fna) [Table 16 Footnote b](#t16fnb)
PNEU-C-20 probably results in a numerically lower proportion of seroresponders for ST3 as compared to PNEU-C-13. |
| Vaccine-related Serious AE
Up to 1 month after vaccine | 2 RCTs (Essink 2021, Hurley 2021) * PNEU-C-20: 0/1728
* PNEU-C-13: 0/1712
| No vaccine-related serious AE observed in either group. | Moderate [Table 16 Footnote b](#t16fnb) [Table 16 Footnote c](#t16fnc) |
| Serious AE
Up to 1 month after vaccine | 2 RCTs (Essink 2021, Hurley 2021) * PNEU-C-20: 8/1728 (0.5%)
* PNEU-C-13: 9/1712 (0.5%)
| Relative effects: Peto OR 0.88 (0.34 to 2.28)
Absolute effects: 1 fewer per 1,000 (3 fewer to 7 more)
Studies did not report type of SAEs that occurred after first vaccine (PNEU-C-20 or PNEU-C-13). Types of SAEs were only reported at longer follow-up (after second vaccine with saline or PNEU-P-23).
Additional data (not GRADEd):
**Subgroups for age (50-59y vs ≥60y)**. One study (Essink 2021) provided data on serious adverse events as well as mild/moderate and severe systemic adverse events for 50-59 and ≥60 year-olds. Due to too few studies, subgroup analyses could not be performed. Confidence intervals around relative effect estimates overlapped between age groups for serious adverse events and all systemic events; however, there were small number of events for some safety outcomes (i.e., serious adverse events and severe systemic events). | Moderate [Table 16 Footnote b](#t16fnb) [Table 16 Footnote c](#t16fnc)
There is probably little to no difference between PNEU-C-20 and PNEU-C-13 in the occurrence of serious adverse events after vaccine administration. None of those events were deemed to be vaccine-related by study authors. |
| Severe Systemic AE - Fatigue
Up to 7 days after vaccine | 2 RCTs (Essink 2021, Hurley 2021) * PNEU-C-20: 19/1725 (1.1%)
* PNEU-C-13: 22/1705 (1.3%)
| Relative effects: Peto OR 0.85 (0.46 to 1.58)
Absolute effects: 2 fewer per 1,000 (7 fewer to 7 more)
Additional data (not GRADEd):
Subgroups for age (50-59y vs ≥60y). As above. | Moderate [Table 16 Footnote b](#t16fnb) [Table 16 Footnote c](#t16fnc)
There is probably little to no difference between PNEU-C-20 and PNEU-C-13 in the occurrence of severe fatigue within 7 days after vaccine administration. |
| Severe Systemic AE - Headache
Up to 7 days after vaccine | 2 RCTs (Essink 2021, Hurley 2021)
PNEU-C-20: 11/1725 (0.6%)
PNEU-C-13: 7/1705 (0.4%) | Relative effects: Peto OR 1.55 (0.61 to 3.90)
Absolute effects: 2 more per 1,000 (2 fewer to 12 more)
Additional data (not GRADEd):
Subgroups for age (50-59y vs ≥60y). As above. | Moderate [Table 16 Footnote b](#t16fnb) [Table 16 Footnote c](#t16fnc)
There is probably little to no difference between PNEU-C-20 and PNEU-C-13 in the occurrence of severe headache within 7 days after vaccine administration. |
| Severe Systemic AE – Muscle Pain
Up to 7 days after vaccine | 2 RCTs (Essink 2021, Hurley 2021) * PNEU-C-20: 6/1725 (0.3%)
* PNEU-C-13: 7/1705 (0.4%)
| Relative effects: Peto OR 0.84 (0.28 to 2.51)
Absolute effects: 1 fewer per 1,000 (3 fewer to 6 more)
Additional data (not GRADEd):
Subgroups for age (50-59y vs ≥60y). As above. | Moderate [Table 16 Footnote b](#t16fnb) [Table 16 Footnote c](#t16fnc)
There is probably little to no difference between PNEU-C-20 and PNEU-C-13 in the occurrence of severe muscle pain within 7 days after vaccine administration. |
| Severe Systemic AE – Joint Pain
Up to 7 days after vaccine | 2 RCTs (Essink 2021, Hurley 2021) * PNEU-C-20: 5/1725 (0.3%)
* PNEU-C-13: 4/1705 (0.2%)
| Relative effects: Peto OR 1.23 (0.33 to 4.57)
Absolute effects: 1 more per 1,000 (2 fewer to 8 more)
Additional data (not GRADEd):
Subgroups for age (50-59y vs 60-64y). As above. | Moderate [Table 16 Footnote b](#t16fnb) [Table 16 Footnote c](#t16fnc)
There is probably little to no difference between PNEU-C-20 and PNEU-C-13 in the occurrence of severe joint pain within 7 days after vaccine administration. |
| Severe Systemic AE - Fever
Up to 7 days after vaccine | 2 RCTs (Essink 2021, Hurley 2021) * PNEU-C-20: 5/1725 (0.3%)
* PNEU-C-13: 3/1705 (0.2%)
| Relative effects: Peto OR 1.63 (0.41 to 6.51)
Absolute effects: 1 more per 1,000 (1 fewer to 10 more)
Additional data (not GRADEd):
Subgroups for age (50-59y vs 60-64y). As above. | Moderate [Table 16 Footnote b](#t16fnb) [Table 16 Footnote c](#t16fnc)
There is probably little to no difference between PNEU-C-20 and PNEU-C-13 in the occurrence of severe fever within 7 days after vaccine administration. |
| Mild/moderate Systemic AE - Fatigue
Up to 7 days after vaccine | 2 RCTs (Essink 2021, Hurley 2021) * PNEU-C-20: 503/1725 (29.2%)
* PNEU-C-13: 500/1705 (29.3%)
| Relative effects: RR 0.99 (0.90 to 1.10)
Absolute effects: 3 fewer per 1,000 (29 fewer to 29 more)
Additional data (not GRADEd):
Subgroups for age (50-59y vs 60-64y). As above. | High [Table 16 Footnote b](#t16fnb)
There is little to no difference between PNEU-C-20 and PNEU-C-13 in the occurrence of mild/moderate fatigue within 7 days after vaccine administration. |
| Mild/moderate Systemic AE - Headache
Up to 7 days after vaccine | 2 RCTs (Essink 2021, Hurley 2021) * PNEU-C-20: 359/1725 (20.8%)
* PNEU-C-13: 392/1705 (23.0%)
| Relative effects: RR 0.91 (0.80 to 1.03)
Absolute effects: 21 fewer per 1,000 (46 fewer to 7 more)
Additional data (not GRADEd):
Subgroups for age (50-59y vs 60-64y). As above. | High [Table 16 Footnote b](#t16fnb)
There is little to no difference between PNEU-C-20 and PNEU-C-13 in the occurrence of mild/moderate headache within 7 days after vaccine administration. |
| Mild/moderate Systemic AE - Muscle Pain
Up to 7 days after vaccine | 2 RCTs (Essink 2021, Hurley 2021) * PNEU-C-20: 677/1725 (39.2%)
* PNEU-C-13: 627/1705 (36.8%)
| Relative effects: RR 1.07 (0.98 to 1.16)
Absolute effects: 26 more per 1,000 (7 fewer to 59 more)
Additional data (not GRADEd):
Subgroups for age (50-59y vs 60-64y). As above. | High [Table 16 Footnote b](#t16fnb)
There is little to no difference between PNEU-C-20 and PNEU-C-13 in the occurrence of mild/moderate muscle pain within 7 days after vaccine administration. |
| Mild/moderate Systemic AE - Joint Pain
Up to 7 days after vaccine | 2 RCTs (Essink 2021, Hurley 2021) * PNEU-C-20: 218/1725 (12.6%)
* PNEU-C-13: 231/1705 (13.5%)
| Relative effects: RR 0.93 (0.79 to 1.11)
Absolute effects: 9 fewer per 1,000 (28 fewer to 15 more)
Additional data (not GRADEd):
Subgroups for age (50-59y vs 60-64y). As above. | High [Table 16 Footnote b](#t16fnb)
There is little to no difference between PNEU-C-20 and PNEU-C-13 in the occurrence of mild/moderate joint pain within 7 days after vaccine administration. |
| Mild/moderate Systemic AE - Fever
Up to 7 days after vaccine | 2 RCTs (Essink 2021, Hurley 2021) * PNEU-C-20: 9/1725 (0.5%)
* PNEU-C-13: 10/1705 (0.6%)
| Relative effects: Peto OR 0.89 (0.36 to 2.19)
Absolute effects: 1 fewer per 1,000 (4 fewer to 7 more) | Moderate [Table 16 Footnote b](#t16fnb) [Table 16 Footnote c](#t16fnc)
There is probably little to no difference between PNEU-C-20 and PNEU-C-13 in the occurrence of mild/moderate fever within 7 days after vaccine administration. |
| Abbreviations: AE = adverse events; OR = odds ratio; PNEU-C-13 = 13-valent pneumococcal conjugate vaccine; PNEU-P-23 = 23-valent pneumococcal polysaccharide vaccine; RR = relative risk; RCT = randomised controlled trial; vs = versus.
Table 16 Footnote a
Downrating for indirectness due to use of immunogenicity measures in the absence of disease endpoints.
[Table 16 Return to footnote a referrer](#t16fna-rf)
Table 16 Footnote b
We acknowledge that about two-thirds of the population were under 65 years of age, but we do not expect substantively different results for participants 60-64 years of age as compared to those 65 years of age and older. A majority of participants were of White race, but we do not expect substantively different results with diversity in race from a biological perspective. No downrating.
[Table 16 Return to footnote b referrer](#t16fnb-rf)
Table 16 Footnote c
Downrating for imprecision as did not meet the review information size (400 people with events or, for very few to no events, ≥4,000 sample size).
[Table 16 Return to footnote c referrer](#t16fnc-rf)
|
Table 17. Evidence synthesis: PNEU-C-20 versus PNEU-C-13 in adults aged 65 years and older previously vaccinated with PNEU-P-23 (1-5 years prior)
| Outcome | Studies contributing data; n/N (where available) | Synthesised result
(Relative effects as PNEU-C-20 vs PNEU-C-13. Relative and absolute effects shown with 95% CI in parentheses.) | GRADE certainty of evidence rating |
| --- | --- | --- | --- |
| Geometric Mean Titers | No comparative immunogenicity data are available |
| % Seroresponders |
| Vaccine-related Serious AE
Up to 6 months after vaccine | 1 RCT (Cannon 2021); * PNEU-C-20: 0/253
* PNEU-C-13: 0/121
| No vaccine related events observed in either group. | Low [Table 17 Footnote a](#t17fna)
There may be little to no difference in serious adverse events between PNEU-C-20 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. None were vaccine related. |
| Serious AE
Up to 6 months after vaccine | 1 RCT (Cannon 2021); * PNEU-C-20: 2/253 (0.8%)
* PNEU-C-13: 2/122 (1.6%)
| Relative effects: Peto OR 0.44 (0.05 to 3.65)
Absolute effects: 9 fewer per 1,000 (from 16 fewer to 41 more)
Type of serious AE not reported. |
| Severe Systemic AE – Fatigue
Up to 14 days after vaccine | 1 RCT (Cannon 2021); * PNEU-C-20: 0/253 (0%)
* PNEU-C-13: 3/121 (2.5%)
| Relative effects: Peto OR: 0.04 (0.004 to 0.51)
Absolute effects: 24 fewer per 1,000 (from 25 fewer to 12 fewer) | Low [Table 17 Footnote a](#t17fna)
There may be little to no difference in severe fatigue between PNEU-C-20 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Severe Systemic AE - Headache
Up to 14 days after vaccine | 1 RCT (Cannon 2021); * PNEU-C-20: 1/253 (0.4%)
* PNEU-C-13: 0/121 (0%)
| Relative effects: Peto OR: 4.39 (0.07 to 289.42)
Absolute effectsb: 0 per 1,000 (10 fewer to 20 more) | Low [Table 17 Footnote a](#t17fna)
There may be little to no difference in severe headache between PNEU-C-20 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Severe Systemic AE - Muscle pain
Up to 14 days after vaccine | 1 RCT (Cannon 2021); * PNEU-C-20: 1/253 (0.4%)
* PNEU-C-13: 3/121 (2.5%)
| Relative effects: Peto OR: 0.14 (0.02 to 1.15)
Absolute effects: 21 fewer per 1,000 (24 fewer to 4 more) | Low [Table 17 Footnote a](#t17fna)
There may be little to no difference in severe muscle pain between PNEU-C-20 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Severe Systemic AE - Joint pain
Up to 14 days after vaccine | 1 RCT (Cannon 2021); * PNEU-C-20: 0/253 (0%)
* PNEU-C-13: 1/121 (0.8%)
| Relative effects: Peto OR: 0.05 (0.001 to 3.00)
Absolute effects: 8 fewer per 1,000 (8 fewer to 16 more) | Low [Table 17 Footnote a](#t17fna)
There may be little to no difference in severe joint pain between PNEU-C-20 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Severe Systemic AE – Fever
Up to 14 days after vaccine | 1 RCT (Cannon 2021); * PNEU-C-20: 0/253
* PNEU-C-13: 0/121
| No events observed in either group. | Low [Table 17 Footnote a](#t17fna)
There may be little to no difference in severe fever between PNEU-C-20 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Mild/moderate Systemic AE – Fatigue
Up to 14 days after vaccine | 1 RCT (Cannon 2021); * PNEU-C-20: 73/253 (28.9%)
* PNEU-C-13: 24/121 (19.8%)
| Relative effects: RR 1.45 (0.97 to 2.19)
Absolute effects: 89 more per 1,000 (6 fewer to 236 more) | Low [Table 17 Footnote a](#t17fna)
There may be little to no difference in mild/moderate fatigue between PNEU-C-20 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Mild/moderate Systemic AE – Headache
Up to 14 days after vaccine | 1 RCT (Cannon 2021); * PNEU-C-20: 44/253 (17.4%)
* PNEU-C-13: 22/121 (18.2%)
| Relative effects: RR 0.96 (0.60 to 1.52)
Absolute effects: 7 fewer per 1,000 (73 fewer to 95 more) | Low [Table 17 Footnote a](#t17fna)
There may be little to no difference in mild/moderate headache between PNEU-C-20 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Mild/moderate Systemic AE - Joint Pain
Up to 14 days after vaccine | 1 RCT (Cannon 2021); * PNEU-C-20: 17/253 (6.7%)
* PNEU-C-13: 12/121 (9.9%)
| Relative effects: RR 0.68 (0.33 to 1.37)
Absolute effects: 32 fewer per 1,000 (66 fewer to 37 more) | Low [Table 17 Footnote a](#t17fna)
There may be little to no difference in mild/moderate joint pain between PNEU-C-20 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Mild/moderate Systemic AE - Muscle Pain
Up to 14 days after vaccine | 1 RCT (Cannon 2021); * PNEU-C-20: 80/253 (31.6%)
* PNEU-C-13: 35/121 (28.9%)
| Relative effects: RR 1.09 (0.78 to 1.53)
Absolute effects: 26 more per 1,000
(64 fewer to 153 more) | Low [Table 17 Footnote a](#t17fna)
There may be little to no difference in mild/moderate muscle pain between PNEU-C-20 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Mild/moderate Systemic AE – Fever
Up to 14 days after vaccine | 1 RCT (Cannon 2021); * PNEU-C-20: 2/253 (0.8%)
* PNEU-C-13: 0/121 (0%)
| Relative effects: Peto OR: 4.39 (0.23 to 85.53)
Absolute effectsb: 10 more per 1,000 (10 fewer to 20 more) | Low [Table 17 Footnote a](#t17fna)
There may be little to no difference in mild/moderate fever between PNEU-C-20 and PNEU-C-13 in individuals previously vaccinated with PNEU-P-23. |
| Abbreviations: AE = adverse events; OR = odds ratio; PNEU-C-13 = 13-valent pneumococcal conjugate vaccine; PNEU-C-20 = 20-valent pneumococcal conjugate vaccine; PNEU-P-23 = 23-valent pneumococcal polysaccharide vaccine; RCT = randomised controlled trial; RD = risk difference; RR = relative risk; vs = versus; y=years.
Table 17 Footnote a
Downrating -1 for risk of ascertainment bias due to lack of blinding and -1 for imprecision due to low power (did not meet review information size). The majority of participants were of White race, but we do not expect substantively different results from a biological perspective.
[Table 17 Return to footnote a referrer](#t17fna-rf)
Table 17 Footnote b
Could not be calculated using standard GRADE methods owing to no events in the control group. The absolute risk difference between groups is provided.
[Table 17 Return to footnote b referrer](#t17fnb-rf)
|
Table 18. Evidence synthesis: PNEU-C-20 versus PNEU-P-23 in adults aged 65 years and older previously vaccinated with PNEU-C-13 (at least 6 months prior)
| Outcome | Studies contributing data; n/N (where available) | Synthesised result
(Relative effects as PNEU-C-20 vs PNEU-P-23. Relative and absolute effects shown with 95% CI in parentheses.) | GRADE certainty of evidence rating |
| --- | --- | --- | --- |
| Geometric Mean Titers | No comparative immunogenicity data are available |
| % Seroresponders |
| Vaccine-related Serious AE
Up to 6 months after vaccine | 1 RCT (Cannon 2022); * PNEU-C-20: 0/246
* PNEU-P-23: 0/126
| No vaccine related events observed in either group. | Low [Table 18 Footnote a](#t18fna)
There may be little to no difference in serious adverse events between PNEU-C-20 and PNEU-P-23 in individuals previously vaccinated with PNEU-C-13. |
| Serious AE
Up to 6 months after vaccine | 1 RCT (Cannon 2022); * PNEU-C-20: 6/246 (2.4%)
* PNEU-P-23: 0/127 (0.0%)
| Relative effects: Peto OR 4.65 (0.85 to 25.46)
Absolute effectsb: 20 more per 1,000 (0 to 5 more)
Type of serious AE not provided. |
| Severe Systemic AE – Fatigue
Up to 14 days after vaccine | 1 RCT (Cannon 2022); * PNEU-C-20: 3/245 (1.2%)
* PNEU-P-23: 0/126 (0.0%)
| Relative effects: Peto OR: 4.58 (0.42 to 50.32)
Absolute effectsb: 10 more per 1,000 (10 fewer to 30 more) | Low [Table 18 Footnote a](#t18fna)
There may be little to no difference in severe fatigue between PNEU-C-20 and PNEU-P-23 in individuals previously vaccinated with PNEU-C-13. |
| Mild/moderate Systemic AE – Fatigue
Up to 14 days after vaccine | 1 RCT (Cannon 2022); * PNEU-C-20: 73/245 (29.8%)
* PNEU-P-23: 42/126 (33.3%)
| Relative effects: RR 0.89 (0.65 to 1.22)
Absolute effects: 37 fewer per 1,000
(127 fewer to 73 more) | Low [Table 18 Footnote a](#t18fna)
There may be little to no difference in mild/moderate fatigue between PNEU-C-20 and PNEU-P-23 in individuals previously vaccinated with PNEU-C-13. |
| Severe Systemic AE - Muscle pain
Up to 14 days after vaccine | 1 RCT (Cannon 2022); * PNEU-C-20: 0/245 (0.0%)
* PNEU-P-23: 3/126 (2.4%)
| Relative effects: Peto OR: 0.05 (0.01 to 0.57)
Absolute effects: 23 fewer per 1,000
(24 fewer to 10 fewer) | Low [Table 18 Footnote a](#t18fna)
There may be little to no difference in severe muscle pain between PNEU-C-20 and PNEU-P-23 in individuals previously vaccinated with PNEU-C-13. |
| Severe Systemic AE - Headache
Up to 14 days after vaccine | 1 RCT (Cannon 2022); * PNEU-C-20: 0/246
* PNEU-P-23: 0/126
| No events observed in either group. | Low [Table 18 Footnote a](#t18fna)
There may be little to no difference in severe headache between PNEU-C-20 and PNEU-P-23 in individuals previously vaccinated with PNEU-C-13. |
| Mild/moderate Systemic AE – Headache
Up to 14 days after vaccine | 1 RCT (Cannon 2022); * PNEU-C-20: 33/245 (13.5%)
* PNEU-P-23: 27/126 (21.4%)
| Relative effects: RR 0.63 (0.40 to 1.00)
Absolute effects: 79 fewer per 1,000
(129 fewer to 0 fewer) | Low [Table 18 Footnote a](#t18fna)
There may be little to no difference in mild/moderate headache between PNEU-C-20 and PNEU-P-23 in individuals previously vaccinated with PNEU-C-13. |
| Severe Systemic AE - Joint pain
Up to 14 days after vaccine | 1 RCT (Cannon 2022); * PNEU-C-20: 0/246
* PNEU-P-23: 0/126
| No events observed in either group. | Low [Table 18 Footnote a](#t18fna)
There may be little to no difference in severe joint pain between PNEU-C-20 and PNEU-P-23 in individuals previously vaccinated with PNEU-C-13. |
| Mild/moderate Systemic AE - Joint Pain
Up to 14 days after vaccine | 1 RCT (Cannon 2022); * PNEU-C-20: 29/245 (11.8%)
* PNEU-P-23: 20/126 (15.9%)
| Relative effects: RR 0.75 (0.44 to 1.26)
Absolute effects: 40 fewer per 1,000 (89 fewer to 41 more) | Low [Table 18 Footnote a](#t18fna)
There may be little to no difference in mild/moderate joint pain between PNEU-C-20 and PNEU-P-23 in individuals previously vaccinated with PNEU-C-13. |
| Severe Systemic AE – Fever
Up to 14 days after vaccine | 1 RCT (Cannon 2022); * PNEU-C-20: 0/246
* PNEU-P-23: 0/126
| No events observed in either group. | Low [Table 18 Footnote a](#t18fna)
There is maybe little to no difference in severe fever between PNEU-C-20 and PNEU-P-23 in individuals previously vaccinated with PNEU-C-13. |
| Mild/moderate Systemic AE - Muscle Pain
Up to 14 days after vaccine | 1 RCT (Cannon 2022); * PNEU-C-20: 83/245 (33.9%)
* PNEU-P-23: 55/126 (43.7%)
| Relative effects: RR 0.77 (0.60 to 1.01)
Absolute effects: 100 fewer per 1,000 (175 fewer to 4 more) | Low [Table 18 Footnote a](#t18fna)
There may be little to no difference in mild/moderate muscle pain between PNEU-C-20 and PNEU-P-23 in individuals previously vaccinated with PNEU-C-13. |
| Mild/moderate Systemic AE – Fever
Up to 14 days after vaccine | 1 RCT (Cannon 2022); * PNEU-C-20: 0/245 (0.0%)
* PNEU-P-23: 2/126 (1.6%)
| Relative effects: Peto OR: 0.05 (0.002 to 0.98)
Absolute effects: 15 fewer per 1,000
(16 fewer to 0 fewer) | Low [Table 18 Footnote a](#t18fna)
There may be little to no difference in mild/moderate fever between PNEU-C-20 and PNEU-P-23 in individuals previously vaccinated with PNEU-C-13. |
| Abbreviations: AE = adverse events; OR = odds ratio; PNEU-C-13 = 13-valent pneumococcal conjugate vaccine; PNEU-C-20 = 20-valent pneumococcal conjugate vaccine; PNEU-P-23 = 23-valent pneumococcal polysaccharide vaccine; RCT = randomised controlled trial; RD = risk difference; RR = relative risk; vs = versus; y=years.
Table 18 Footnote a
Downrating by –1 for risk of ascertainment bias due to lack of blinding and by -1 imprecision due to low power (did not meet review information size). The majority of participants were of White race, but we do not expect substantively different results from a biological perspective.
[Table 18 Return to footnote a referrer](#t18fna-rf)
|
Table 19. NACI strength of the recommendations
| | Strong | Discretionary |
| **Wording** | “should/should not be offered” | “may/may not be offered” |
| **Rationale** | Known/anticipated advantages outweigh known/anticipated disadvantages (“should”),
or
Known/anticipated disadvantages outweigh known/anticipated advantages (“should not”) | Known/anticipated advantages are closely balanced with known/anticipated disadvantages,
or
Uncertainty in the evidence of advantages and disadvantages exists |
| **Implications** | A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present. | A discretionary recommendation may be offered for some populations/individuals in some circumstances. Alternative approaches may be reasonable. |
### Epidemiology tables
Table 20: Summary of proportions of isolates of invasive *S. pneumoniae* for all ages in Canada, by serotype and year, 2016 to 2020
| Serotype (n by year) | 2016 (n=2855) | 2017 (n=3270) | 2018 (n=3328) | 2019 (n=3673) | 2020 (n=2108) |
| --- | --- | --- | --- | --- | --- |
| 1[Footnote \*](#t20fn1) (4,0,0,0,1)[Footnote ‡](#t20fn5) | 0.1% | 0.0% | 0.0% | 0.0% | 0.0% |
| 3[Footnote \*](#t20fn1) (272,312,398,427,229) | 9.5% | 9.5% | 12.0% | 11.6% | 10.9% |
| 4[Footnote \*](#t20fn1) (182,234,205,262,237) | 6.4% | 7.2% | 6.2% | 7.1% | 11.2% |
| 6A[Footnote \*](#t20fn1) (19,7,14,8,3) | 0.7% | 0.2% | 0.4% | 0.2% | 0.1% |
| 6B[Footnote \*](#t20fn1) (20,9,8,8,1) | 0.7% | 0.3% | 0.2% | 0.2% | 0.0% |
| 7F[Footnote \*](#t20fn1) (109,116,106,119,59) | 3.8% | 3.5% | 3.2% | 3.2% | 2.8% |
| 9V[Footnote \*](#t20fn1) (5,15,35,48,54) | 0.2% | 0.5% | 1.1% | 1.3% | 2.6% |
| 14[Footnote \*](#t20fn1) (16,29,13,11,6) | 0.6% | 0.9% | 0.4% | 0.3% | 0.3% |
| 18C[Footnote \*](#t20fn1) (9,8,4,15,9) | 0.3% | 0.2% | 0.1% | 0.4% | 0.4% |
| 19A[Footnote \*](#t20fn1) (179,165,181,154,88) | 6.3% | 5.0% | 5.4% | 4.2% | 4.2% |
| 19F[Footnote \*](#t20fn1) (46,91,75,75,46) | 1.6% | 2.8% | 2.3% | 2.0% | 2.2% |
| 23F[Footnote \*](#t20fn1) (4,2,2,2,2) | 0.1% | 0.1% | 0.1% | 0.1% | 0.1% |
| 22F[Footnote \*\*](#t20fn2) (260,283,292,362,149) | 9.1% | 8.7% | 8.8% | 9.9% | 7.1% |
| 33F[Footnote \*\*](#t20fn2) (100,107,96,145,52) | 3.5% | 3.3% | 2.9% | 3.9% | 2.5% |
| 8[Footnote ^](#t20fn3) (148,158,187,221,151) | 5.2% | 4.8% | 5.6% | 6.0% | 7.2% |
| 10A[Footnote ^](#t20fn3) (51,67,65,69,52) | 1.8% | 2.0% | 2.0% | 1.9% | 2.5% |
| 11A[Footnote ^](#t20fn3) (93,95,117,100,68) | 3.3% | 2.9% | 3.5% | 2.7% | 3.2% |
| 12F[Footnote ^](#t20fn3) (102,127,160,145,120) | 3.6% | 3.9% | 4.8% | 3.9% | 5.7% |
| 15B/C[Footnote ^](#t20fn3) (132,131,105,102,49) | 4.6% | 4.0% | 3.2% | 2.8% | 2.3% |
| 2[Footnote ~](#t20fn4) (0,1,4,0,0) | 0.0% | 0.0% | 0.1% | 0.0% | 0.0% |
| 9N[Footnote ~](#t20fn4) (141,214,189,254,135) | 4.9% | 6.5% | 5.7% | 6.9% | 6.4% |
| 17F[Footnote ~](#t20fn4) (29,38,37,35,17) | 1.0% | 1.2% | 1.1% | 1.0% | 0.8% |
| 20[Footnote ~](#t20fn4) (81,118,127,134,82) | 2.8% | 3.6% | 3.8% | 3.6% | 3.9% |
| 6C (73,66,58,69,32) | 2.6% | 2.0% | 1.7% | 1.9% | 1.5% |
| 7C (45,28,57,44,24) | 1.6% | 0.9% | 1.7% | 1.2% | 1.1% |
| 13 (9,6,10,9,4) | 0.3% | 0.2% | 0.3% | 0.2% | 0.2% |
| 15A (123,155,130,159,74) | 4.3% | 4.7% | 3.9% | 4.3% | 3.5% |
| 16F (72,77,71,107,57) | 2.5% | 2.4% | 2.1% | 2.9% | 2.7% |
| 21 (14,21,15,12,4) | 0.5% | 0.6% | 0.5% | 0.3% | 0.2% |
| 23A (108,155,115,132,64) | 3.8% | 4.7% | 3.5% | 3.6% | 3.0% |
| 23B (90,104,118,118,52) | 3.2% | 3.2% | 3.5% | 3.2% | 2.5% |
| 24F (24,27,24,20,4) | 0.8% | 0.8% | 0.7% | 0.5% | 0.2% |
| 28A (5,10,10,9,7) | 0.2% | 0.3% | 0.3% | 0.2% | 0.3% |
| 29 (10,4,7,6,1) | 0.4% | 0.1% | 0.2% | 0.2% | 0.0% |
| 31 (50,51,54,45,35) | 1.8% | 1.6% | 1.6% | 1.2% | 1.7% |
| 34 (30,29,33,35,17) | 1.1% | 0.9% | 1.0% | 1.0% | 0.8% |
| 35B (64,79,76,81,48) | 2.2% | 2.4% | 2.3% | 2.2% | 2.3% |
| 35F (58,51,46,55,38) | 2.0% | 1.6% | 1.4% | 1.5% | 1.8% |
| 38 (48,53,51,27,13) | 1.7% | 1.6% | 1.5% | 0.7% | 0.6% |
| NT (6,4,10,13,2) | 0.2% | 0.1% | 0.3% | 0.4% | 0.1% |
| Other (24,23,23,36,22) | 0.8% | 0.7% | 0.7% | 1.0% | 1.0% |
|
Footnote \*
Component of PNEU-C-13
[Return to footnote \* referrer](#t20fn1-rf)
Footnote \*\*
Component of PNEU-C-15
[Return to footnote \*\* referrer](#t20fn2-rf)
Footnote ^
Component of PNEU-C-20
[Return to footnote ^ referrer](#t20fn3-rf)
Footnote ~
Component of PNEU-P-23
[Return to footnote ~ referrer](#t20fn4-rf)
Footnote ‡
Number of isolates for all ages and adults 65 years and older, respectively (2016-2020, combined total)
[Return to footnote ‡ referrer](#t20fn5-rf)
|
Table 21. Distribution of serotypes among IPD isolates submitted to Canada’s National Microbiology Laboratory for adults 18 to 49 years of age, 2016-2020
| | Serotype | 2016 | 2017 | 2018 | 2019 | 2020 | Total |
| PNEU-C-13 | PNEU-C-13 all | 40.9% | (259) | 43.6% | (281) | 38.4% | (286) | 42.0% | (343) | 47.1% | (262) | 1431 |
| 4 | 15.0% | (95) | 16.9% | (109) | 11.8% | (88) | 14.5% | (118) | 20.9% | (116) | 526 |
| 6B | 0.2% | (1) | 0.0% | (0) | 0.1% | (1) | 0.2% | (2) | 0.0% | (0) | 4 |
| 9V | 0.3% | (2) | 0.8% | (5) | 1.1% | (8) | 2.1% | (17) | 5.6% | (31) | 63 |
| 14 | 0.6% | (4) | 0.6% | (4) | 0.5% | (4) | 0.2% | (2) | 0.5% | (3) | 17 |
| 18C | 0.5% | (3) | 0.3% | (2) | 0.0% | (0) | 0.5% | (4) | 0.4% | (2) | 11 |
| 19F | 1.7% | (11) | 2.6% | (17) | 1.9% | (14) | 2.2% | (18) | 2.0% | (11) | 71 |
| 23F | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.1% | (1) | 0.2% | (1) | 2 |
| 1 | 0.3% | (2) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.2% | (1) | 3 |
| 3 | 8.5% | (54) | 8.4% | (54) | 10.1% | (75) | 10.0% | (82) | 8.8% | (49) | 314 |
| 5 | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0 |
| 6A/C\* | 2.4% | (15) | 0.8% | (5) | 1.7% | (13) | 0.5% | (4) | 0.7% | (4) | 41 |
| 7F | 6.6% | (42) | 8.2% | (53) | 6.7% | (50) | 7.4% | (60) | 4.9% | (27) | 232 |
| 19A | 4.7% | (30) | 5.0% | (32) | 4.4% | (33) | 4.3% | (35) | 3.1% | (17) | 147 |
| PNEU-C-15
(non- PNEU-C-13) | PNEU-C-15 all | 10.0% | (63) | 7.8% | (50) | 7.7% | (57) | 10.5% | (86) | 6.7% | (37) | 293 |
| 22F | 6.8% | (43) | 5.9% | (38) | 5.8% | (43) | 6.9% | (56) | 4.5% | (25) | 205 |
| 33F | 3.2% | (20) | 1.9% | (12) | 1.9% | (14) | 3.7% | (30) | 2.2% | (12) | 88 |
| PNEU-C-20
(non- PNEU-C-15) | PNEU-C-20 all | 20.5% | (130) | 21.3% | (137) | 23.0% | (171) | 21.3% | (174) | 26.1% | (145) | 757 |
| 8 | 7.6% | (48) | 7.6% | (49) | 9.3% | (69) | 9.3% | (76) | 11.0% | (61) | 303 |
| 10A | 0.9% | (6) | 0.8% | (5) | 1.5% | (11) | 1.2% | (10) | 1.1% | (6) | 38 |
| 11A | 3.2% | (20) | 2.2% | (14) | 2.2% | (16) | 1.2% | (10) | 2.0% | (11) | 71 |
| 12F | 6.5% | (41) | 8.1% | (52) | 9.0% | (67) | 8.2% | (67) | 11.2% | (62) | 289 |
| 15B/C | 2.4% | (15) | 2.6% | (17) | 1.1% | (8) | 1.3% | (11) | 0.9% | (5) | 56 |
| PNEU-P-23 unique | PNEU-P-23 all | 11.7% | (74) | 12.9% | (83) | 13.2% | (98) | 11.9% | (97) | 10.1% | (56) | 408 |
| 2 | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0 |
| 9N | 6.2% | (39) | 7.1% | (46) | 6.0% | (45) | 7.1% | (58) | 5.9% | (33) | 221 |
| 17F | 0.8% | (5) | 0.5% | (3) | 1.3% | (10) | 0.6% | (5) | 0.2% | (1) | 24 |
| 20 | 4.7% | (30) | 5.3% | (34) | 5.8% | (43) | 4.2% | (34) | 4.0% | (22) | 163 |
| NVT | NVT all | 16.9% | (107) | 14.4% | (93) | 17.7% | (132) | 14.2% | (116) | 10.1% | (56) | 504 |
| 23A | 2.4% | (15) | 3.4% | (22) | 2.0% | (15) | 2.6% | (21) | 1.8% | (10) | 83 |
| 15A | 1.6% | (10) | 2.2% | (14) | 2.3% | (17) | 1.8% | (15) | 1.4% | (8) | 64 |
| 23B | 1.7% | (11) | 1.2% | (8) | 2.4% | (18) | 2.1% | (17) | 1.4% | (8) | 62 |
| 16F | 2.1% | (13) | 2.0% | (13) | 1.1% | (8) | 2.0% | (16) | 0.7% | (4) | 54 |
| 31 | 1.7% | (11) | 0.9% | (6) | 1.3% | (10) | 0.9% | (7) | 1.4% | (8) | 42 |
| 35B | 2.1% | (13) | 0.5% | (3) | 0.9% | (7) | 1.0% | (8) | 1.1% | (6) | 37 |
| 7C | 0.9% | (6) | 0.3% | (2) | 1.1% | (8) | 0.9% | (7) | 0.5% | (3) | 26 |
| 35F | 0.5% | (3) | 0.9% | (6) | 0.9% | (7) | 0.5% | (4) | 0.2% | (1) | 21 |
| 34 | 0.5% | (3) | 0.5% | (3) | 1.1% | (8) | 0.6% | (5) | 0.2% | (1) | 20 |
| 28A | 0.5% | (3) | 0.8% | (5) | 0.8% | (6) | 0.0% | (0) | 0.2% | (1) | 15 |
| 38 | 0.2% | (1) | 0.3% | (2) | 0.8% | (6) | 0.6% | (5) | 0.2% | (1) | 15 |
| Other | 2.8% | (18) | 1.4% | (9) | 3.0% | (22) | 1.3% | (11) | 0.9% | (5) | 65 |
| | Total | (633) | (644) | (744) | (816) | (556) | 3393 |
Table 22: Percentage (number) of IPD isolates by serotype for adults 50 to 64 years of age, 2016-2020
| | Serotype | 2016 | 2017 | 2018 | 2019 | 2020 | Total |
| PNEU-C-13 | PNEU-C-13 all | 35.7% | (274) | 37.1% | (332) | 37.1% | (357) | 32.8% | (337) | 37.8% | (249) | 1549 |
| 4 | 7.8% | (60) | 9.8% | (88) | 7.8% | (75) | 8.4% | (86) | 11.4% | (75) | 384 |
| 6B | 0.4% | (3) | 0.2% | (2) | 0.3% | (3) | 0.0% | (0) | 0.0% | (0) | 8 |
| 9V | 0.1% | (1) | 0.1% | (1) | 1.4% | (13) | 1.6% | (16) | 2.1% | (14) | 45 |
| 14 | 0.4% | (3) | 0.9% | (8) | 0.2% | (2) | 0.2% | (2) | 0.2% | (1) | 16 |
| 18C | 0.4% | (3) | 0.6% | (5) | 0.2% | (2) | 0.3% | (3) | 0.9% | (6) | 19 |
| 19F | 1.4% | (11) | 2.8% | (25) | 2.2% | (21) | 1.0% | (10) | 1.8% | (12) | 79 |
| 23F | 0.0% | (0) | 0.1% | (1) | 0.2% | (2) | 0.0% | (0) | 0.2% | (1) | 4 |
| 1 | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0 |
| 3 | 11.3% | (87) | 11.2% | (100) | 13.2% | (127) | 11.5% | (118) | 12.6% | (83) | 515 |
| 5 | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0 |
| 6A/C\* | 1.6% | (12) | 2.1% | (19) | 1.9% | (18) | 2.5% | (26) | 2.0% | (13) | 88 |
| 7F | 4.6% | (35) | 4.1% | (37) | 4.2% | (40) | 3.6% | (37) | 2.9% | (19) | 168 |
| 19A | 7.7% | (59) | 5.1% | (46) | 5.6% | (54) | 3.8% | (39) | 3.8% | (25) | 223 |
| PNEU-C-15
(non- PNEU-C-13) | PNEU-C-15 all | 12.6% | (97) | 11.7% | (105) | 10.0% | (96) | 12.2% | (126) | 7.1% | (47) | 471 |
| 22F | 8.9% | (68) | 8.4% | (75) | 7.3% | (70) | 9.4% | (97) | 5.2% | (34) | 344 |
| 33F | 3.8% | (29) | 3.3% | (30) | 2.7% | (26) | 2.8% | (29) | 2.0% | (13) | 127 |
| PNEU-C-20
(non- PNEU-C-15) | PNEU-C-20 all | 15.9% | (122) | 15.8% | (142) | 19.2% | (185) | 19.2% | (198) | 21.2% | (140) | 787 |
| 8 | 4.2% | (32) | 5.0% | (45) | 6.4% | (62) | 7.7% | (79) | 8.6% | (57) | 275 |
| 10A | 1.6% | (12) | 1.8% | (16) | 1.2% | (12) | 1.9% | (20) | 1.8% | (12) | 72 |
| 11A | 3.3% | (25) | 2.8% | (25) | 3.6% | (35) | 2.9% | (30) | 2.7% | (18) | 133 |
| 12F | 3.5% | (27) | 4.4% | (39) | 6.2% | (60) | 4.4% | (45) | 5.8% | (38) | 209 |
| 15B/C | 3.4% | (26) | 1.9% | (17) | 1.7% | (16) | 2.3% | (24) | 2.3% | (15) | 98 |
| PNEU-P-23 unique | PNEU-P-23 all | 11.7% | (90) | 14.6% | (131) | 12.3% | (118) | 15.7% | (162) | 13.8% | (91) | 592 |
| 2 | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0 |
| 9N | 6.6% | (51) | 7.9% | (71) | 5.9% | (57) | 8.9% | (92) | 6.8% | (45) | 316 |
| 17F | 1.7% | (13) | 1.6% | (14) | 1.1% | (11) | 0.9% | (9) | 0.8% | (5) | 52 |
| 20 | 3.4% | (26) | 5.1% | (46) | 5.2% | (50) | 5.9% | (61) | 6.2% | (41) | 224 |
| NVT | NVT all | 24.1% | (185) | 20.8% | (186) | 21.4% | (206) | 20.0% | (206) | 20.0% | (132) | 915 |
| 23A | 4.2% | (32) | 3.1% | (28) | 3.7% | (36) | 2.5% | (26) | 2.9% | (19) | 141 |
| 15A | 3.8% | (29) | 3.3% | (30) | 2.9% | (28) | 2.6% | (27) | 3.6% | (24) | 138 |
| 23B | 2.6% | (20) | 2.5% | (22) | 2.6% | (25) | 3.1% | (32) | 1.8% | (12) | 111 |
| 16F | 2.9% | (22) | 1.9% | (17) | 2.3% | (22) | 3.1% | (32) | 2.6% | (17) | 110 |
| 35B | 1.6% | (12) | 2.3% | (21) | 2.0% | (19) | 1.4% | (14) | 1.7% | (11) | 77 |
| 35F | 2.0% | (15) | 1.3% | (12) | 1.1% | (11) | 1.3% | (13) | 1.7% | (11) | 62 |
| 31 | 2.3% | (18) | 1.7% | (15) | 0.9% | (9) | 0.7% | (7) | 1.5% | (10) | 59 |
| 7C | 1.2% | (9) | 0.7% | (6) | 1.7% | (16) | 1.3% | (13) | 0.8% | (5) | 49 |
| 34 | 0.5% | (4) | 0.9% | (8) | 0.9% | (9) | 1.1% | (11) | 0.9% | (6) | 38 |
| 38 | 1.0% | (8) | 0.4% | (4) | 1.0% | (10) | 0.3% | (3) | 0.6% | (4) | 29 |
| Other | 2.1% | (16) | 2.6% | (23) | 2.2% | (21) | 2.7% | (28) | 2.0% | (13) | 101 |
| | Total | (768) | (896) | (962) | (1029) | (659) | 4314 |
Table 23. Percentage (number) of IPD isolates by serotype for adults 65 years of age and older, 2016-2020
| | Serotype | 2016 | 2017 | 2018 | 2019 | 2020 | Total |
| PNEU-C-13 | PNEU-C-13 all | 29.1% | (307) | 26.5% | (355) | 28.8% | (367) | 29.3% | (431) | 27.4% | (197) | 1657 |
| 4 | 2.4% | (25) | 2.7% | (36) | 3.2% | (41) | 3.6% | (53) | 5.4% | (39) | 194 |
| 6B | 1.3% | (14) | 0.5% | (7) | 0.3% | (4) | 0.4% | (6) | 0.1% | (1) | 32 |
| 9V | 0.2% | (2) | 0.7% | (9) | 0.9% | (12) | 0.8% | (12) | 1.3% | (9) | 44 |
| 14 | 0.8% | (8) | 1.0% | (14) | 0.3% | (4) | 0.3% | (5) | 0.1% | (1) | 32 |
| 18C | 0.2% | (2) | 0.1% | (1) | 0.2% | (2) | 0.5% | (7) | 0.1% | (1) | 13 |
| 19F | 1.4% | (15) | 2.6% | (35) | 2.2% | (28) | 2.1% | (31) | 2.2% | (16) | 125 |
| 23F | 0.1% | (1) | 0.1% | (1) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 2 |
| 1 | 0.1% | (1) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 1 |
| 3 | 9.1% | (96) | 9.6% | (129) | 12.4% | (158) | 13.2% | (195) | 10.4% | (75) | 653 |
| 5 | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 0 |
| 6A/C\* | 5.4% | (57) | 3.4% | (45) | 3.1% | (39) | 3.1% | (45) | 2.4% | (17) | 203 |
| 7F | 2.2% | (23) | 1.5% | (20) | 1.2% | (15) | 1.2% | (17) | 1.1% | (8) | 83 |
| 19A | 6.0% | (63) | 4.3% | (58) | 5.0% | (64) | 4.1% | (60) | 4.2% | (30) | 275 |
| PNEU-C-15
(non- PNEU-C-13) | PNEU-C-15 all | 12.7% | (134) | 12.7% | (171) | 14.2% | (181) | 15.4% | (226) | 13.2% | (95) | 807 |
| 22F | 10.1% | (106) | 10.1% | (135) | 11.0% | (140) | 11.5% | (169) | 10.3% | (74) | 624 |
| 33F | 2.7% | (28) | 2.7% | (36) | 3.2% | (41) | 3.9% | (57) | 2.9% | (21) | 183 |
| PNEU-C-20
(non- PNEU-C-15) | PNEU-C-20 all | 16.8% | (177) | 15.9% | (213) | 15.1% | (192) | 13.5% | (199) | 15.2% | (109) | 890 |
| 8 | 5.2% | (55) | 4.2% | (57) | 3.5% | (44) | 3.9% | (58) | 3.5% | (25) | 239 |
| 10A | 1.5% | (16) | 1.9% | (26) | 2.0% | (25) | 2.2% | (32) | 2.5% | (18) | 117 |
| 11A | 4.2% | (44) | 3.6% | (48) | 4.5% | (57) | 3.2% | (47) | 4.3% | (31) | 227 |
| 12F | 2.6% | (27) | 2.2% | (30) | 2.0% | (25) | 1.9% | (28) | 2.6% | (19) | 129 |
| 15B/C | 3.3% | (35) | 3.9% | (52) | 3.2% | (41) | 2.3% | (34) | 2.2% | (16) | 178 |
| PNEU-P-23 unique | PNEU-P-23 all | 7.2% | (76) | 10.4% | (139) | 9.9% | (126) | 10.1% | (149) | 11.1% | (80) | 570 |
| 2 | 0.0% | (0) | 0.1% | (1) | 0.0% | (0) | 0.0% | (0) | 0.0% | (0) | 1 |
| 9N | 4.2% | (44) | 6.8% | (91) | 6.2% | (79) | 6.3% | (93) | 7.5% | (54) | 361 |
| 17F | 0.9% | (10) | 1.3% | (17) | 1.2% | (15) | 1.4% | (20) | 1.5% | (11) | 73 |
| 20 | 2.1% | (22) | 2.2% | (30) | 2.5% | (32) | 2.4% | (36) | 2.1% | (15) | 135 |
| NVT | NVT all | 34.2% | (360) | 34.6% | (464) | 32.0% | (408) | 31.7% | (467) | 33.0% | (237) | 1936 |
| 15A | 7.1% | (75) | 7.1% | (95) | 6.0% | (77) | 6.8% | (100) | 4.7% | (34) | 381 |
| 23A | 5.0% | (53) | 6.7% | (90) | 3.8% | (49) | 5.1% | (75) | 4.7% | (34) | 301 |
| 16F | 3.2% | (34) | 3.2% | (43) | 2.8% | (36) | 3.3% | (48) | 4.2% | (30) | 198 |
| 35B | 2.8% | (30) | 3.4% | (45) | 3.3% | (42) | 3.4% | (50) | 3.8% | (27) | 194 |
| 23B | 2.9% | (31) | 3.4% | (46) | 4.0% | (51) | 3.3% | (49) | 2.9% | (21) | 191 |
| 35F | 2.7% | (28) | 1.8% | (24) | 1.7% | (22) | 2.1% | (31) | 3.2% | (23) | 128 |
| 31 | 1.9% | (20) | 2.1% | (28) | 2.7% | (34) | 1.7% | (25) | 2.4% | (17) | 124 |
| 38 | 2.2% | (23) | 1.9% | (26) | 1.6% | (20) | 1.0% | (15) | 1.1% | (8) | 106 |
| 7C | 1.9% | (20) | 1.5% | (20) | 2.4% | (30) | 1.5% | (22) | 1.9% | (14) | 92 |
| 34 | 2.0% | (21) | 1.0% | (13) | 1.1% | (14) | 1.2% | (17) | 1.1% | (8) | 73 |
| 24F | 1.1% | (12) | 1.0% | (13) | 0.9% | (11) | 0.5% | (7) | 0.3% | (2) | 45 |
| Other | 1.2% | (13) | 1.6% | (21) | 1.7% | (22) | 1.9% | (28) | 2.6% | (19) | 104 |
| | Total | (1054) | (1342) | (1274) | (1472) | (718) | 5860 |
**Figure 6. Proportion of IPD isolates from 2016 to 2020 by vaccine, for 18 to 49 and 50 to 64 age groups**
**\***Vaccine serotypes include PNEU-C-13 (1, 3, 4, 5, 6A/C, 6B, 7F, 9V, 14, 19A, 19F, 18C, 23F); PNEU-C-15 (all PNEU-C-13 plus 22F and 33F); PNEU-C-20 (All PNEU-C-15 plus 8, 10A, 11A, 12F, 15B/C) and PNEU-P-23 (PNEU-C-20 serotypes except 6A, plus 2, 9N, 17F, 20); NVT = all serotypes not included in PNEU-C-13, PNEU-C-15, PNEU-C-20 and PNEU-P-23. Serotype 6C included in PNEU-C-13 serotypes due to cross protection with 6A. Serotypes 15B and 15C were grouped together as 15B/C because of reported reversible switching between them in vivo during infection, making it difficult to precisely differentiate between the two types.
Text Description
Figure 6 shows a stacked bar graph displaying the percentage of Streptococcus pneumoniae collected from each vaccine category (PNEU-C-13, PNEU-C-15/non-PNEU-C-13, PNEU-C-20/non-PNEU-C-15, PNEU-P-23/non-PNEU-C-20 and other non-vaccine serotypes) for the 18 to 49 and 50 to 64 age groups, from 2016 to 2020.
| Age Group | Year | PNEU-C-13
(%, N) | PNEU-C-15/
non-PNEU-C-13
(%, N) | PNEU-C-20/
non-PNEU-C-15
(%, N) | PNEU-P-23/
non-PNEU-C-20
(%, N) | NVT
(%, N) | Total |
| --- | --- | --- | --- | --- | --- | --- | --- |
| **18-49 years** | 2016 | 40.9% | (259) | 10.0% | (63) | 20.5% | (130) | 11.7% | (74) | 16.9% | (107) | (657) |
| 2017 | 43.6% | (281) | 7.8% | (50) | 21.3% | (137) | 12.9% | (83) | 14.4% | (93) | (659) |
| 2018 | 38.4% | (286) | 7.7% | (57) | 23.0% | (171) | 13.2% | (98) | 17.7% | (132) | (762) |
| 2019 | 42.0% | (343) | 10.5% | (86) | 21.3% | (174) | 11.9% | (97) | 14.2% | (116) | (834) |
| 2020 | 47.1% | (262) | 6.7% | (37) | 26.1% | (145) | 10.1% | (56) | 10.1% | (56) | (567) |
| **50-64 years** | 2016 | 35.7% | (274) | 12.6% | (97) | 15.9% | (122) | 11.7% | (90) | 24.1% | (185) | (768) |
| 2017 | 37.1% | (332) | 11.7% | (105) | 15.8% | (142) | 14.6% | (131) | 20.8% | (186) | (896) |
| 2018 | 37.1% | (357) | 10.0% | (96) | 19.2% | (185) | 12.3% | (118) | 21.4% | (206) | (962) |
| 2019 | 32.8% | (337) | 12.2% | (126) | 19.2% | (198) | 15.7% | (162) | 20.0% | (206) | (1029) |
| 2020 | 37.8% | (249) | 7.1% | (47) | 21.2% | (140) | 13.8% | (91) | 20.0% | (132) | (659) |
References
----------
Footnote 1
Warshawsky B, Gemmill I, Crowcroft N, Et. Al. An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI): Statement on the Use of Conjugate Pneumococcal Vaccine – 13 Valent in Adults (PNEU-C-13) [Internet]. Public Health Agency of Canada. 2013 [cited 2022 Jun 16]. Available from: https://www.canada.ca/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2013-39/statement-on-use-conjugate-pneumococcal-vaccine-13-valent-adults-pneu-13.html
[Return to footnote 1](#fn1-rf)
Footnote 2
National Advisory Committee on Immunization (NACI). Update on the Use of 13-Valent Pneumococcal Conjugate Vaccine (PNEU-C-13) in Addition to 23-Valent Pneumococcal Polysaccharide Vaccine (PNEU-P-23) in Immunocompetent Adults 65 Years of Age and Older – Interim Recommendation [Internet]. Public Health Agency of Canada. 2016 [cited 2022 Jun 16]. Available from: https://www.canada.ca/en/public-health/services/publications/healthy-living/update-use-of-13-valent-pneumococcal-conjugate-vaccine-pneu-c-13-in-addition-to-23-valent-pneumococcal-polysaccharide-vaccine-pneu-p-23-immunocompetent-adults-65-years-and-older-interim-recommendation.html
[Return to footnote 2](#fn2-rf)
Footnote 3
Kraicer-Melamed H, Baclic O, De Wals P, Et. Al. An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI): Update on the Use of Pneumococcal Vaccines in Adults 65 Years of Age and Older – A Public Health Perspective [Internet]. Public Health Agency of Canada. 2018 [cited 2022 Jun 16]. Available from: https://www.canada.ca/en/public-health/services/publications/healthy-living/update-on-the-use-of-pneumococcal-vaccines-in-adult.html#a11
[Return to footnote 3](#fn3-rf)
Footnote 4
Guyatt G, Oxman A, Akl E, Et. Al. GRADE Guidelines: 1. Introduction-GRADE Evidence Profiles and Summary of Findings Tables. J Clin Epidemiol. 2011;64(4):383–94.
[Return to footnote 4](#fn4-rf)
Footnote 5
Balshem H, Helfand M, Schünemann H, Et. Al. GRADE Guidelines: 3. Rating the Quality of Evidence. J Clin Epidemiol. 2011;64(4):401–6.
[Return to footnote 5](#fn5-rf)
Footnote 6
Moher D, Shamseer L, Clarke M, Et. Al. Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 Statement. Syst Rev. 2015;4(1):1.
[Return to footnote 6](#fn6-rf)
Footnote 7
Alonso-Coello P, Schünemann H, Moberg J, Et Al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016;353:i2016.
[Return to footnote 7](#fn7-rf)
Footnote 8
Public Health Agency of Canada. National Laboratory Surveillance of Invasive Streptococcal Disease in Canada – Annual Summary 2019 [Internet]. Government of Canada. 2021 [cited 2022 Jun 6]. Available from: https://www.canada.ca/en/public-health/services/publications/drugs-health-products/national-laboratory-surveillance-invasive-streptococcal-disease-canada-annual-summary-2019.html
[Return to footnote 8](#fn8-rf)
Footnote 9
Golden A, Griffith A, Demczuk W, Et. Al. Invasive Pneumococcal Disease Surveillance in Canada, 2020. Can Commun Dis Rep. 2022;48(9):396–406.
[Return to footnote 9](#fn9-rf)
Footnote 10
Cooper D, Yu X, Sidhu M, Et. Al. The 13-Valent Pneumococcal Conjugate Vaccine (PCV13) Elicits Cross-Functional Opsonophagocytic Killing Responses in Humans to Streptococcus pneumoniae Serotypes 6C and 7A. Vaccine. 2011;29(41):7201–11.
[Return to footnote 10](#fn10-rf)
Footnote 11
Venkateswaran P, Stanton N, Austrian R. Type Variation of Strains of Streptococcus pneumoniae in Capsular Serogroup 15. J Infect Dis. 1983;147(6):1041–54.
[Return to footnote 11](#fn11-rf)
Footnote 12
van Selm S, van Cann L, Kolkman M, Et. Al. Genetic basis for the structural difference between Streptococcus pneumoniae serotype 15B and 15C capsular polysaccharides. Infect Immun. 2003;71(11):6192–8.
[Return to footnote 12](#fn12-rf)
Footnote 13
Higgins J, Altman D, Gøtzsche P, Et. Al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
[Return to footnote 13](#fn13-rf)
Footnote 14
Shigayeva A, Chung H, Kwong J, Et. Al. Burden of Invasive Pneumococcal Disease among Adults with Underlying Chronic Conditions Post Implementation of PCV13 Immunization Programs in South Central Ontario Canada. Poster presented at: ISPPD 12. Toronto (ON): Mount Sinai Hospital; 2022.
[Return to footnote 14](#fn14-rf)
Footnote 15
Huang G, Martin I, Tsang R, Et. Al. Invasive Bacterial Diseases in Northern Canada, 1999 to 2018. Can Commun Dis Rep. 2021;47(11):491–9.
[Return to footnote 15](#fn15-rf)
Footnote 16
LeBlanc J, El Sherif M, Ye L, Et. Al. Recalibrated Estimates of Non-Bacteremic and Bacteremic Pneumococcal Community Acquired Pneumonia in Hospitalized Canadian Adults From 2010 to 2017 With Addition of an Extended Spectrum Serotype-Specific Urine Antigen Detection Assay. Vaccine. 2022;40(18):2635–46.
[Return to footnote 16](#fn16-rf)
Footnote 17
Shigayeva A, Rudnick W, Green K, Et. Al. Invasive Pneumococcal Disease Among Immunocompromised Persons: Implications for Vaccination Programs. Clin Infect Dis. 2016;62(2):139, 147.
[Return to footnote 17](#fn17-rf)
Footnote 18
Cabaj J, Nettel-Aguirre A, MacDonald J, Et. Al. Influence of Childhood Pneumococcal Conjugate Vaccines on Invasive Pneumococcal Disease in Adults With Underlying Comorbidities in Calgary, Alberta (2000-2013). Clin Infect Dis. 2016;62(12):1521–6.
[Return to footnote 18](#fn18-rf)
Footnote 19
Government of Canada. Vaccination Coverage Goals and Vaccine Preventable Disease Reduction Targets by 2025 [Internet]. 2022 [cited 2022 Jul 10]. Available from: https://www.canada.ca/en/public-health/services/immunization-vaccine-priorities/national-immunization-strategy/vaccination-coverage-goals-vaccine-preventable-diseases-reduction-targets-2025.html
[Return to footnote 19](#fn19-rf)
Footnote 20
Pfizer Canada. Product Monograph: PrevnarTM 13 Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein) [Internet]. 2019 [cited 2022 Jul 10]. Available from: https://pdf.hres.ca/dpd\_pm/00052583.PDF
[Return to footnote 20](#fn20-rf)
Footnote 21
Merck Canada Inc. Product Monograph Including Patient Medication Information: Vaxneuvance® (Pneumococcal 15-Valent Conjugate Vaccine [Crm197 Protein], Adsorbed) [Internet]. 2021 [cited 2022 Jun 16]. Available from: https://pdf.hres.ca/dpd\_pm/00063580.PDF
[Return to footnote 21](#fn21-rf)
Footnote 22
Pfizer Canada U. Product Monograph Including Patient Medication Information: Prevnar 20tm (Pneumococcal 20-Valent Conjugate Vaccine (Diphtheria Crm197 Protein)) [Internet]. 2022 [cited 2022 Jun 16]. Available from: https://pdf.hres.ca/dpd\_pm/00065729.PDF
[Return to footnote 22](#fn22-rf)
Footnote 23
Merck Canada. Product Monograph: Pneumovax® 23 Pneumococcal Vaccine, Polyvalent, MSD Std. [Internet]. 2016 [cited 2022 Oct 24]. Available from: https://pdf.hres.ca/dpd\_pm/00035855.PDF
[Return to footnote 23](#fn23-rf)
Footnote 24
Farrar J, Kobayashi M, Childs L, Et. Al. Systematic Review and Meta-Analysis of Pneumococcal Vaccine Effectiveness against Invasive Pneumococcal Disease among Adults. Open Forum Infectious Diseases. 2021;8(Supp 1):S134–5.
[Return to footnote 24](#fn24-rf)
Footnote 25
Childs L, Kobayashi M, Farrar J. The Efficacy and Effectiveness of Pneumococcal Vaccines against Pneumococcal Pneumonia among Adults: A Systematic Review and Meta-Analysis. Open Forum Infectious Diseases. 2021;8(Supp 1):S130–1.
[Return to footnote 25](#fn25-rf)
Footnote 26
Ermlich S, Andrews C, Folkerth S, Et. Al. Safety and Immunogenicity of 15-Valent Pneumococcal Conjugate Vaccine in Pneumococcal Vaccine-Naïve Adults ≥50 Years of Age. Vaccine. 2018;36(45):6875–82.
[Return to footnote 26](#fn26-rf)
Footnote 27
Peterson J, Stacey H, MacNair J, Et. Al. Safety and Immunogenicity of 15-Valent Pneumococcal Conjugate Vaccine Compared to 13-Valent Pneumococcal Conjugate Vaccine in Adults ≥65 Years of Age Previously Vaccinated with 23-Valent Pneumococcal Polysaccharide Vaccine. Hum Vaccin Immunother. 2019;15(3):540–8.
[Return to footnote 27](#fn27-rf)
Footnote 28
Platt H, Cardona J, Haranaka M, Et. Al. A phase 3 Trial of Safety, Tolerability, and Immunogenicity of V114, 15-Valent Pneumococcal Conjugate Vaccine, Compared with 13-Valent Pneumococcal Conjugate Vaccine in Adults 50 Years of Age and Older (PNEU-AGE). Vaccine. 2022;40(1):162–72.
[Return to footnote 28](#fn28-rf)
Footnote 29
Mohapi L, Pinedo Y, Osiyemi O, Et. Al. Safety and Immunogenicity of V114, a 15-Valent Pneumococcal Conjugate Vaccine, in Adults Living with HIV. AIDS. 2022;36(3):373–82.
[Return to footnote 29](#fn29-rf)
Footnote 30
Hammitt L, Quinn D, Janczewska E, Et. Al. Immunogenicity, Safety, and Tolerability of V114, a 15-Valent Pneumococcal Conjugate Vaccine, in Immunocompetent Adults Aged 18-49 Years With or Without Risk Factors for Pneumococcal Disease: A Randomized Phase 3 Trial (PNEU-DAY). Open Forum Infect Dis. 2021;9(3):ofab605.
[Return to footnote 30](#fn30-rf)
Footnote 31
Song JY, Chang C, Andrews C, Et. Al. Safety, Tolerability, and Immunogenicity of V114, a 15-Valent Pneumococcal Conjugate Vaccine, Followed by Sequential PPSV23 Vaccination in Healthy Adults Aged ≥50Yyears: A Randomized Phase III Trial (PNEU-PATH). Vaccine. 2021;39(43):6422–36.
[Return to footnote 31](#fn31-rf)
Footnote 32
Severance R, Schwartz H, Dagan R, Et. Al. Safety, tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, administered concomitantly with influenza vaccine in healthy adults aged ≥50 years: a randomized phase 3 trial (PNEU-FLU). Hum Vaccin Immunother. 2022;18(1):1–14.
[Return to footnote 32](#fn32-rf)
Footnote 33
Hurley D, Griffin C, Young M, Et. Al. Safety, Tolerability, and Immunogenicity of a 20-Valent Pneumococcal Conjugate Vaccine (PCV20) in Adults 60 to 64 Years of Age. Clin Infect Dis. 2021;73(7):e1489–97.
[Return to footnote 33](#fn33-rf)
Footnote 34
Essink B, Sabharwal C, Cannon K, Et. Al. Pivotal Phase 3 Randomized Clinical Trial of the Safety, Tolerability, and Immunogenicity of 20-Valent Pneumococcal Conjugate Vaccine in Adults 18 Years and Older. Clin Infect Dis. 2021;75(3):390–8.
[Return to footnote 34](#fn34-rf)
Footnote 35
Cannon K, Elder C, Young M, Et. Al. A Trial To Evaluate the Safety and Immunogenicity of a 20-Valent Pneumococcal Conjugate Vaccine in Populations of Adults ≥65 Years of Age with Different Prior Pneumococcal Vaccination. Vaccine. 2021;39(51):7494–502.
[Return to footnote 35](#fn35-rf)
Footnote 36
Bonten M, Huijts S, Bolkenbaas M, Et. Al. Polysaccharide Conjugate Vaccine Against Pneumococcal Pneumonia in Adults. N Engl J Med. 2015;372(12):1114–25.
[Return to footnote 36](#fn36-rf)
Footnote 37
Kobayashi M, Farrar J, Gierke R, Et. Al. Use of 15-Valent Pneumococcal Conjugate Vaccine Among U.S. Children: Updated Recommendations of the Advisory Committee on Immunization Practices — United States, 2022. MMWR Morb Mortal Wkly Rep. 2022;71:1174–81.
[Return to footnote 37](#fn37-rf)
Footnote 38
Cannon, Et. Al. Immunogenicity and Safety of a 20-Valent Pneumococcal Conjugate Vaccine (PCV20) Administered Concomitantly With a Quadrivalent Inactivated Influenza Vaccine in Adults Over 65 Years of Age. Poster Presented At: 32nd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID). Lisbon (PT). 2022 Apr 23;
[Return to footnote 38](#fn38-rf)
Footnote 39
Fitz-Patrick, Et. Al. Safety, Tolerability, and Immunogenicity of BNT162b2 COVID-19 Vaccine Coadministered with 20-Valent Pneumococcal Conjugate Vaccine (PCV20) in Adults 65 Years of Age and Above. Poster Presented at: 32nd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID). Lisbon (PT). 2022 Apr 23;
[Return to footnote 39](#fn39-rf)
Footnote 40
Langley J. ARCHIVED - Canada Communicable Disease Report: Evidence-Based Recommendations for Immunization – Methods of the National Advisory Committee on Immunization [Internet]. Public Health Agency of Canada. 2009 [cited 2022 Jul 10]. Available from: https://www.canada.ca/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2009-35/methods-national-advisory-committee-immunization.html
[Return to footnote 40](#fn40-rf)
Footnote 41
Matanock A, Lee G, Gierke R, Et. Al. Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Adults Aged ≥65 Years: Updated Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68(46):1069–75.
[Return to footnote 41](#fn41-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Fpublic-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html&n=Use%20of%20pneumococcal%20vaccines%20in%20adults%2C%20including%20the%20use%20of%2015-valent%20and%2020-valent%20conjugate%20vaccines%3A%20NACI%20public%20health%20level%20recommendations.%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Fpublic-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html&title=Use%20of%20pneumococcal%20vaccines%20in%20adults%2C%20including%20the%20use%20of%2015-valent%20and%2020-valent%20conjugate%20vaccines%3A%20NACI%20public%20health%20level%20recommendations.%20-%20Canada.ca)
* [Email](mailto:?subject=Use%20of%20pneumococcal%20vaccines%20in%20adults%2C%20including%20the%20use%20of%2015-valent%20and%2020-valent%20conjugate%20vaccines%3A%20NACI%20public%20health%20level%20recommendations.%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Fpublic-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Fpublic-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html&t=Use%20of%20pneumococcal%20vaccines%20in%20adults%2C%20including%20the%20use%20of%2015-valent%20and%2020-valent%20conjugate%20vaccines%3A%20NACI%20public%20health%20level%20recommendations.%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=Use%20of%20pneumococcal%20vaccines%20in%20adults%2C%20including%20the%20use%20of%2015-valent%20and%2020-valent%20conjugate%20vaccines%3A%20NACI%20public%20health%20level%20recommendations.%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Fpublic-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Fpublic-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html&title=Use%20of%20pneumococcal%20vaccines%20in%20adults%2C%20including%20the%20use%20of%2015-valent%20and%2020-valent%20conjugate%20vaccines%3A%20NACI%20public%20health%20level%20recommendations.%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Fpublic-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html&t=Use%20of%20pneumococcal%20vaccines%20in%20adults%2C%20including%20the%20use%20of%2015-valent%20and%2020-valent%20conjugate%20vaccines%3A%20NACI%20public%20health%20level%20recommendations.%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Fpublic-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html&media=&description=Use%20of%20pneumococcal%20vaccines%20in%20adults%2C%20including%20the%20use%20of%2015-valent%20and%2020-valent%20conjugate%20vaccines%3A%20NACI%20public%20health%20level%20recommendations.%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Fpublic-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html&title=Use%20of%20pneumococcal%20vaccines%20in%20adults%2C%20including%20the%20use%20of%2015-valent%20and%2020-valent%20conjugate%20vaccines%3A%20NACI%20public%20health%20level%20recommendations.%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Fpublic-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Fpublic-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html&name=Use%20of%20pneumococcal%20vaccines%20in%20adults%2C%20including%20the%20use%20of%2015-valent%20and%2020-valent%20conjugate%20vaccines%3A%20NACI%20public%20health%20level%20recommendations.%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=Use%20of%20pneumococcal%20vaccines%20in%20adults%2C%20including%20the%20use%20of%2015-valent%20and%2020-valent%20conjugate%20vaccines%3A%20NACI%20public%20health%20level%20recommendations.%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Fpublic-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html)
* [Whatsapp](https://api.whatsapp.com/send?text=Use%20of%20pneumococcal%20vaccines%20in%20adults%2C%20including%20the%20use%20of%2015-valent%20and%2020-valent%20conjugate%20vaccines%3A%20NACI%20public%20health%20level%20recommendations.%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Fpublic-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=Use%20of%20pneumococcal%20vaccines%20in%20adults%2C%20including%20the%20use%20of%2015-valent%20and%2020-valent%20conjugate%20vaccines%3A%20NACI%20public%20health%20level%20recommendations.%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Fpublic-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2023-02-24
| None | None |
3096dac81b5801d9d3594401ad157c030f23df90 | cma | Statement on seasonal influenza vaccine for 2023-2024 | Statement on seasonal influenza vaccine for 2023-2024
Preamble
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge.
This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Summary of information contained in the NACI statement
The following highlights key information for immunization providers on seasonal influenza vaccine. Several influenza vaccines are authorized in Canada and the evidence on influenza immunization is continually evolving. NACI will continue to monitor the evidence and update its recommendations as needed. Please refer to the remainder of the statement for details.
# What
- Influenza in humans is a respiratory infection caused primarily by influenza A and B viruses. Seasonal influenza epidemics occur annually in Canada, generally in the late fall and winter months. Prior to the COVID-19 pandemic, influenza had an annual attack rate estimated at 5 to 10% in adults and 20 to 30% in children worldwide.
- Symptoms of influenza can range from mild to severe, and typically come on suddenly. They can include fever, cough, and muscle aches. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week to 10 days, but some people are at greater risk of severe complications, such as pneumonia. Influenza infection can also worsen certain chronic conditions, such as heart disease.
- Live attenuated influenza vaccine (LAIV), recombinant influenza vaccine (RIV) and inactivated influenza vaccines (IIV) (which include standard dose for a list of abbreviations used in this document for the different influenza vaccines.
- The influenza vaccines are safe and well-tolerated. The IIVs and RIV cannot cause influenza illness because they do not contain live virus. The live attenuated influenza vaccines contain weakened viruses.
# Who
NACI makes the following recommendations for individual-level and public health program-level decision making. Individual-level recommendations are intended for people wishing to protect themselves from influenza and for vaccine providers advising individual patients about preventing influenza. Program-level recommendations are intended for provinces and territories responsible for making decisions on publicly funded immunization programs. Individual-level and program-level recommendations may differ, as the important factors to consider when recommending a vaccine for a population (e.g., population demographics, economic considerations) may be different than for an individual.
## Recommendation for individual-level decision making
NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have a contraindication to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended. These groups include:
- People at high risk of severe disease, influenza-related complications, or hospitalization;
- People capable of transmitting influenza to those at high risk;
- People who provide essential community services; and
- People in direct contact with poultry infected with avian influenza during culling operations.
In infants less than 6 months of age, evidence is lacking to demonstrate that influenza vaccine would be effective. Currently, authorized influenza vaccines are not indicated for use in infants less than 6 months of age. For these reasons, NACI recommends that influenza vaccine should not be offered to infants less than 6 months of age. Since infants less than 6 months of age are at high risk of influenza-related illness, the influenza vaccine should be offered to individuals who are pregnant, breastfeeding, and any household contacts and care providers of young infants.
## Recommendation for public health program-level decision-making
The national goal of the annual influenza immunization programs in Canada is to prevent serious illness caused by influenza and its complications, including death. Programmatic decisions to provide influenza vaccination to target populations as part of publicly funded provincial and territorial programs depend on many factors, such as cost-effectiveness evaluation and other programmatic and operational factors.
- NACI recommends that influenza vaccine should be offered as a priority to the groups for whom influenza vaccination is particularly recommended.
# How
The benefits and risks of influenza vaccination should be discussed prior to vaccination, including the risks of not being immunized.
## Choice of influenza vaccine
A variety of influenza vaccines are authorized for use in Canada, some of which are authorized for use only in specific age groups. Furthermore, not all products will necessarily be made available in all jurisdictions and availability of some products as part of publicly funded provincial and territorial programs may be limited. Therefore, the choice of influenza vaccine has become more complex.
## Dose and route of administration
The dose and route of administration vary by influenza vaccine product:
- Most IIVs are administered as a 0.5 mL intramuscular (IM) injection
- IIV4-HD (Fluzone® High-Dose Quadrivalent) is administered as a 0.7 mL IM injection and authorized for adults 65 years of age and older.
- MF59-adjuvanted IIV3-Adj (Fluad®) is administered as a 0.5 mL IM injection and authorized for adults 65 years of age and older. A pediatric formulation is also available (Fluad Pediatric®), and is administered as a 0.25 mL IM injection for children 6 to 23 months of age.
- RIV4 (Supemtek™) is administered as a 0.5 mL IM injection and authorized for adults 18 years of age and older.
- LAIV (FluMist® Quadrivalent) is administered as 0.2 mL given intranasally (0.1 mL in each nostril) and authorized for individuals 2 to 59 years of age.
See for information on characteristics of all influenza vaccines expected to be available for use in Canada for the 2023–2024 influenza season.
## Schedule
NACI recommends that:
- Adults and children 9 years of age and older should receive 1 dose of influenza vaccine each year; and
- Children 6 months to less than 9 years of age who have never received the seasonal influenza vaccine in a previous influenza season should be given 2 doses of influenza vaccine in the current season, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been vaccinated with one or more doses of seasonal influenza vaccine in any previous season should receive 1 dose of influenza vaccine per season thereafter.
## Contraindications
For all influenza vaccines (IIV, RIV and LAIV), NACI recommends that influenza vaccination should not be given to:
- People who have had an anaphylactic reaction to a specific influenza vaccine, or to any of the components of a specific influenza vaccine, with the exception of egg
+ Egg allergy is not a contraindication for influenza vaccination, as there is a low risk of adverse events (AEs) associated with the trace amounts of ovalbumin allowed in some influenza vaccines manufactured using eggs. Egg-allergic individuals may be vaccinated against influenza using any age-appropriate product, including LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg, and in any setting where vaccines are routinely administered. Cell culture-based (IIV4-cc) and recombinant (RIV4) vaccines are egg-free (ovalbumin-free).
+ As with any vaccine product, all vaccine providers should be prepared to manage possible allergic reactions, including anaphylaxis, and have the necessary equipment to respond to a serious adverse event at all times.
+ If an individual is found to have an anaphylactic reaction to a component in one influenza vaccine, consideration may be given to offering another influenza vaccine that does not contain the implicated component, in consultation with an allergy specialist. Individuals who have an allergy to substances that are not components of the influenza vaccine are not at increased risk of allergy to influenza vaccine.
- People who have developed Guillain-Barré Syndrome (GBS) within 6 weeks of a previous influenza vaccination, unless another cause was found for the GBS
+ For these people, the potential risk for a recurrent episode of GBS associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.
For LAIV, in addition to the above-mentioned contraindications, NACI also recommends that LAIV should not be given to:
- People with severe asthma (defined as currently on oral or high-dose inhaled glucocorticosteroids or active wheezing) or medically attended wheezing in the 7 days prior to the proposed date of vaccination, due to increased risk of wheezing following administration of LAIV
+ LAIV is not contraindicated for people with a history of stable asthma or recurrent wheeze which is not active.
- Children less than 24 months of age, due to increased risk of wheezing following administration of LAIV
- Children 2 to 17 years of age currently receiving aspirin or aspirin-containing therapy, because of the association of Reye's syndrome with aspirin and wild-type influenza infection
- Pregnant individuals, because it is a live attenuated vaccine and there is a lack of safety data at this time
+ LAIV is not contraindicated in breastfeeding (lactating) individuals; however, there are limited data for the use of LAIV in this population.
- People who are immunocompromised due to underlying disease and/or therapy
+ LAIV is not considered to be contraindicated for children living with stable HIV infection on anti-retroviral therapy (ART; also sometimes referred to as highly active anti-retroviral therapy ) and with adequate immune function.
+ NACI previously concluded that the quantity of evidence available on the immunogenicity and safety of LAIV in adults with HIV is insufficient to justify a recommendation for the use of LAIV in this group. In addition, NACI considered that most studies found LAIV to have similar or slightly lower efficacy than IIV in adults and consequently recommends IIV for adults with chronic conditions.
LAIV should not be administered until 48 hours after the last dose of an antiviral agent active against influenza (e.g., oseltamivir, zanamivir), and such antiviral agents, unless medically indicated, should not be administered until 2 weeks after receipt of LAIV so that the antiviral agents do not inactivate the replicating vaccine virus.
- If these antiviral agents are administered within this time frame (i.e., from 48 hours pre-vaccination with LAIV to 2 weeks post-vaccination), re-vaccination should take place at least 48 hours after the antivirals are stopped, or a parenteral inactivated or recombinant influenza vaccine could be given at any time.
## Precautions
NACI recommends that:
- Influenza vaccination should usually be postponed in people with serious acute illnesses until their symptoms have abated;
+ Influenza vaccination should not be delayed because of minor or moderate acute illness, with or without fever. Immunizers should refer to for additional advice on this issue from PHAC.
+ More information on vaccinating individuals during acute illness can be found in the Canadian Immunization Guide's section on .
- If significant nasal congestion is present that might impede delivery of LAIV to the nasopharyngeal mucosa, parenteral inactivated or recombinant influenza vaccine can be administered or LAIV can be deferred until resolution of the congestion;
- LAIV recipients should avoid close contact with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection; and
- LAIV recipients who are less than 18 years of age should avoid the use of aspirin-containing products for at least 4 weeks after receipt of LAIV because of the association of Reye's syndrome with aspirin-containing products and wild-type influenza infection.
## Concurrent administration with other vaccines
NACI recommends that:
- Administration of COVID-19 vaccines may occur concurrently with (i.e., same day), or at any time before or after seasonal influenza immunization for those aged 6 months and older. Readers should consult the for updated NACI guidance on the concurrent administration of influenza and COVID-19 vaccines as the number of authorized COVID-19 vaccines and the age groups eligible to receive them expand.
+ It should be noted that no studies have been conducted on the co-administration of recombinant zoster vaccine (RZV) with adjuvanted or high-dose influenza vaccine. No immune response interference or safety concerns have been demonstrated when RZV is administered concurrently with standard, un-adjuvanted vaccine.
Different injection sites and separate needles and syringes should always be used for concurrent parenteral injections. If multiple injections in the same limb are required, the injection sites should be separated by at least 2.5 cm (1 inch).
# Why
- Vaccination is the most effective way to prevent influenza and its complications.
- Vaccination can help prevent the spread of influenza from person-to-person.
- Although most people will recover fully from influenza infection in 7 to 10 days, influenza can lead to severe disease, complications, or both, including hospitalization and death. Influenza is the most common vaccine preventable disease leading to hospitalization and death in adults.
- Annual vaccination is required because the specific strains in the vaccine are reviewed each year by WHO and are often changed to provide a better match against the viruses expected to circulate in that given year, and because the body's immune response to influenza vaccination may be transient and may not persist beyond a year.
I. Introduction
The National Advisory Committee on Immunization (NACI) provides PHAC with annual recommendations regarding the use of seasonal influenza vaccines, which reflect identified changes in influenza epidemiology, immunization practices and influenza vaccine products authorized and available for use in Canada. This document, the "National Advisory Committee on Immunization (NACI) Statement on Seasonal Influenza Vaccine for 2023–2024", updates NACI's recommendations regarding the use of seasonal influenza vaccines.
# I.1 New or updated information for 2023–2024
## Use of seasonal influenza vaccine in the context of coronavirus disease 2019 (COVID-19)
### Guidance on the use of seasonal influenza vaccine in the presence of COVID-19
Seasonal influenza presents an ongoing disease burden in Canada during the fall and winter months. Influenza vaccine is the most effective way to prevent influenza illness and influenza-related complications and is an important component of managing health care system capacity during the influenza season, particularly in the context of ongoing COVID-19 activity.
PHAC, in consultation with NACI and the Canadian Immunization Committee, has developed guidance on the administration of seasonal influenza vaccine to support provincial and territorial vaccine programs and primary care providers during the COVID-19 pandemic:
The guidance on this page is based on currently available scientific evidence and expert opinion and will be updated as necessary throughout the influenza season. This web page should be considered in concert with recommendations regarding the use of seasonal influenza vaccines provided in this NACI Statement*.*
### Guidance on concurrent administration of influenza and COVID-19 vaccines
NACI guidance outlines that administration of COVID-19 vaccines may occur at the same time as, or at any time before or after influenza immunization (including all parenteral or intranasal seasonal influenza vaccines) for those aged 6 months of age and older.
Readers should consult the for updated NACI guidance and further information on concurrent administration of COVID-19 vaccines with influenza vaccines and across all eligible age groups.
## Updated recommendations on the use of mammalian cell culture-based quadrivalent influenza vaccine (IIV4-cc)
Flucelvax® Quad (IIV4-cc) is a standard dose mammalian cell culture-based quadrivalent inactivated seasonal influenza vaccine that was first authorized for use in Canada in adults and children 9 years of age and older on November 22, 2019 with authorization extended to children 2 years of age and older on March 8, 2021. Recommendations and supporting evidence on the use of Flucelvax Quad in adults and children 9 years of age and older can be found in the and were also incorporated into the Statement on Seasonal Influenza Vaccine for 2021–2022. Recommendations and supporting evidence on the use of Flucelvax Quad in adults and children 2 years of age and older were incorporated into the .
On March 8, 2022, Health Canada approved an expanded age indication for the use of Flucelvax Quad in children down to 6 months of age and older. Based on a review of Health Canada assessments of clinical trial evidence submitted by the manufacturer in support of the age indication extension, NACI has concluded that Flucelvax Quad is safe and has non-inferior immunogenicity compared to standard quadrivalent inactivated influenza vaccines. Therefore,
NACI recommends that Flucelvax Quad may be considered among the quadrivalent influenza vaccines offered to adults and children 6 months of age and older. (Discretionary NACI recommendation).
## Updated recommendations on the use of egg-based quadrivalent influenza vaccine (IIV4-SD)
Influvac® Tetra (IIV4-SD) is a split virus standard quadrivalent inactivated influenza vaccine that was first authorized for use in Canada in adults on March 1, 2019 and subsequently in children 3 years of age and older on February 20, 2020. Recommendations and supporting evidence on the use of Influvac Tetra in adults and children 3 years of age and older were incorporated into the
On November 30, 2021, Health Canada approved an expanded age indication for the use of Influvac Tetra in children 6 months of age and older. Based on a review of Health Canada assessments of clinical trial evidence submitted by the manufacturer in support of the age indication extension, NACI has concluded that Influvac Tetra appears to be safe and well-tolerated (relative to the control non-influenza vaccines) based on direct evidence in children 6 to 35 months of age. However, there is currently insufficient evidence that Influvac Tetra is effective and elicits a protective immune response against seasonal influenza in children 6 to 35 months of age. Therefore:
NACI recommends that Influvac Tetra may be considered among the standard dose inactivated quadrivalent influenza vaccines offered to individuals 3 years of age and older. (Discretionary NACI recommendation)
At this time, NACI concludes that there is insufficient evidence for recommending vaccination with Influvac Tetra in children younger than 3 years of age. (Discretionary NACI recommendation).
NACI will continue to monitor the evidence as it emerges, and update recommendations as needed.
## Standard-dose trivalent inactivated influenza vaccine (IIV3-SD) authorization and availability
All standard dose, egg-based inactivated influenza vaccines authorized and available in Canada for the 2023–24 season are expected to be quadrivalent. There are no trivalent formulations (IIV3-SD) authorized (discontinued post-market) or available, but data that involve these vaccines continue to be included for reference.
## Updated presentation of the statement
The presentation of this document has been updated from previous seasons' statements to improve readability and access to information. The content in some sections has been reduced in length, while maintaining a focus on key information required for decision making. Links to other published NACI documents containing the more detailed content removed from the current statement have been integrated.
For a summary of clinical information on seasonal influenza vaccine administration for vaccine providers, please refer to the new
# I.2 Background
The are typically available in February of each year for the upcoming season in the Northern Hemisphere. The WHO recommends that three influenza strains be included in the trivalent seasonal influenza vaccine: one influenza A(H1N1), one influenza A(H3N2), and one influenza B. Quadrivalent seasonal influenza vaccines should contain the three strains recommended for the trivalent vaccine, as well as an influenza B virus from the lineage that is not included in the trivalent vaccine.
Health care providers in Canada should offer the seasonal influenza vaccine as soon as feasible after it becomes available and is delivered in the fall, since seasonal influenza activity may start as early as October in the Northern Hemisphere. Decisions regarding the precise timing of vaccination in a given setting or geographic area should be made according to local epidemiologic factors (influenza activity, timing, and intensity), opportune moments for vaccination, as well as programmatic considerations. Further advice regarding the timing of influenza vaccination programs may be obtained through consultation with local public health agencies.
Although vaccination before the onset of the influenza season is strongly preferred, influenza vaccine may still be administered up until the end of the season. Delayed administration may result in lost opportunities to prevent infection from exposures that occur prior to vaccination; therefore, individuals seeking or considering vaccination should be informed that vaccine administered during an influenza outbreak may not provide optimal protection. Vaccine providers should use every opportunity to administer influenza vaccine to individuals at risk who have not already been vaccinated during the current season, even after influenza activity has been documented in the community.
Every year, individuals with influenza and influenza-related complications increase the pressures on the healthcare system in the fall and winter months. Particularly given the added burden on the healthcare system during the COVID-19 pandemic, effective prevention of influenza by vaccination is a critical tool to mitigate on-going health system stress.
II. Methods
Details regarding NACI's evidence-based process for developing a statement are outlined in .
In brief, the broad stages in the preparation of this NACI advisory committee statement included:
- Knowledge synthesis
- Synthesis of the body of evidence of benefits and harms, considering the quality of the synthesized evidence and magnitude and certainty of effects observed across the studies
- Translation of evidence into recommendations
Annual influenza vaccine recommendations are developed by the Influenza Working Group (IWG) for consideration by NACI. Recommendation development includes review of a variety of issues including the burden of influenza illness and the target populations for vaccination; safety, immunogenicity, efficacy, and effectiveness of influenza vaccines; vaccine schedules. In addition, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing their recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels. These programmatic factors include cost-effectiveness, as well as ethics, equity, feasibility, and acceptability (EEFA). NACI uses a published, peer-reviewed framework and evidence-informed tools to ensure that issues related to EEFA are systematically assessed and integrated into its guidance. The NACI Secretariat applied this framework with accompanying evidence-informed tools (Ethics Integrated Filters, Equity Matrix, Feasibility Matrix, Acceptability Matrix) to systematically consider these programmatic factors for the development of clear, comprehensive, appropriate recommendations for timely, transparent decision-making. For details on the development and application of NACI's EEFA Framework and evidence-informed tools, please see .
The annual update of the *NACI Statement on Seasonal Influenza Vaccine- led by the NACI Influenza Working Group (IWG) involves a thorough review and evaluation of the literature as well as discussion and debate at the scientific and clinical practice levels. In the preparation of the 2023–2024 seasonal influenza vaccine recommendations, NACI's IWG identified the need for evidence reviews for new topics, and then reviewed and analyzed the available evidence, and proposed new or updated recommendations according to the NACI evidence-based process for developing recommendations. For the 2023–2024 influenza season, the NACI IWG reviewed evidence and developed new recommendations regarding the use of two vaccines with changes in authorization (expanded use in individuals six months of age and older): 1) Influvac Tetra, an egg-based, quadrivalent inactivated influenza vaccine (IIV4-SD) and 2) Flucelvax Quad, a mammalian cell culture-based, inactivated seasonal influenza vaccine (IIV4-cc). The NACI IWG reviewed and analyzed the available pre-licensure clinical trial data and Health Canada's Clinical Review Reports for these two vaccines. On October 3rd, 2022, the available evidence and the new recommendations proposed by the IWG were presented for consideration and approval by NACI. Following a thorough review of the evidence, the committee voted on specific recommendations. The description of relevant considerations, rationale for specific decisions, and identified knowledge gaps are described in this statement.
III. Epidemiology
# Disease description
Influenza is a respiratory illness caused by the influenza A and B viruses in humans and can cause mild to severe illness, including hospitalization or death. Certain populations, such as young children, older adults, and those with chronic health conditions, are at higher risk for serious influenza complications such as viral pneumonia, secondary bacterial pneumonia, and worsening of underlying medical conditions.
# Infectious agent
There are two main types of influenza virus that cause seasonal epidemics in humans: A and B. Influenza A viruses are classified into subtypes based on two surface proteins: hemagglutinin (HA) and neuraminidase (NA). Three subtypes of HA (H1, H2, and H3) and two subtypes of NA (N1 and N2) are recognized among influenza A viruses as having caused widespread human disease over the past decades. Immunity to the HA and NA proteins reduces the likelihood of infection and together with immunity to the internal viral proteins, lessens the severity of disease if infection occurs.
Influenza B viruses have evolved into two antigenically distinct lineages since the mid-1980s, represented by B/Yamagata/16/88-like and B/Victoria/2/87-like viruses. Viruses from both the B/Yamagata and B/Victoria lineages have contributed variably to influenza illness each year. Since the onset of the COVID-19 pandemic, a reduction in seasonal influenza virus diversity has been observed globally. In particular, an absence of B/Yamagata detections has been noted.
Over time, antigenic variation (antigenic drift) of strains occurs within an influenza A subtype or a B lineage. The possibility of antigenic drift, which may occur in one or more influenza virus strains, requires the formulation of seasonal influenza vaccines be re-evaluated annually, with one or more vaccine strains changing in most seasons.
# Transmission
Influenza is primarily transmitted by aerosols and droplets spread through coughing or sneezing, and through direct or indirect contact with respiratory secretions.
The incubation period of seasonal influenza is usually about 2 days but can range from 1 to 4 days. Adults may be able to spread influenza to others from 1 day before symptom onset to approximately 5 days after symptoms start. Children and people with weakened immune systems may be infectious longer.
# Risk factors
The people at greatest risk of influenza-related complications are adults and children with chronic health conditions (see ), residents of nursing homes and other chronic care facilities, adults 65 years of age and older, children 0 to 59 months of age, pregnant individuals, and Indigenous peoples.
# Seasonal and temporal patterns
Influenza activity in Canada is usually low in the late spring and summer, begins to increase over the fall, and peaks in the winter months. Depending on the year, one or more peaks may occur as early as the fall and into the spring. Influenza season in Canada usually begins in December and lasts 12 to 16 weeks but can start as early as October or as late as February, and last for as long as 20 weeks. Although one strain often predominates, more than one influenza strain typically circulates each season.
# Spectrum of clinical illness
Classically, symptoms of influenza include the sudden onset of fever, cough, and muscle aches. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. However, influenza can cause a range of symptoms, from asymptomatic infection through mild acute respiratory illness (a "cold") to severe influenza pneumonia. Most people will recover within a week or 10 days. More rarely, central nervous system manifestations, acute myositis, myocarditis, or pericarditis have been described. In addition, complications including pneumonia, respiratory failure, cardiovascular complications, or worsening of underlying chronic medical conditions may occur. Influenza is also associated with a significantly increased risk of myocardial infarction and stroke in the 7 to 14 days after infection, and with Guillain-Barre syndrome with onset 1 to 6 weeks after infection.
# Disease incidence
## Global
Before the COVID-19 pandemic, worldwide annual epidemics resulted in approximately one billion cases of influenza, three to five million cases of severe illness, and 290,000 to 650,000 deaths. The global annual attack rate is estimated to be 5 to 10% in adults and 20 to 30% in children. Global influenza circulation was at a historical low during the 2020-2021 influenza season, when public health measures (e.g., masking, social distancing) effectively suppressed seasonal influenza activity. During the 2021-2022 Northern Hemisphere season, influenza activity returned to varying degrees in different jurisdictions. During the 2022 Southern Hemisphere season, activity appeared to return to a pre-pandemic level, although incomplete data for the season, changes in testing associated with the pandemic, and the substantial inter-season variability of influenza activity make it difficult to make definitive conclusions.
For current international influenza activity information, refer to WHO's .
## National
Together, influenza and pneumonia are ranked among the top 10 leading causes of death in Canada. Nationally, influenza has been estimated to cause approximately 12,200 hospitalizations and approximately 3,500 deaths annually. The FluWatch program is Canada's national surveillance system, which monitors the spread of influenza and influenza-like illnesses (ILI) continually throughout the year. In the five seasons prior to the COVID-19 pandemic (2014–2015 to 2018-2019 season), an average of 40,000 laboratory-confirmed cases of influenza were reported to FluWatch each year. However, most influenza infections are not laboratory-confirmed, so the number of cases reported to FluWatch is a significant underestimate of the true number of infections.
The burden of influenza-associated illness and death varies every year, depending on various factors such as the type of circulating viruses in the season and the populations affected. Notably, Canada's 2020-2021 seasonal influenza activity did not reach seasonal threshold and was at a historical low in the context of the public health measures that were implemented to reduce COVID-19 transmission. Only 69 confirmed cases of influenza were identified during the 2020-2021 season, whereas over 50,000 laboratory confirmed cases are reported on average in a typical influenza season. During the 2021-2022 season, influenza circulation in Canada reached the national seasonal threshold that signals the start of seasonal influenza activity for the first time since the spring of 2020. The 2021-2022 influenza epidemic onset was in April 2022, which is an unusually late start to the influenza season. Although the potential impact of upcoming influenza seasons in the context of COVID-19 is unknown, future influenza outbreaks may be characterized by higher infection rates and severity. Influenza infection susceptibility may increase due to low immunity in the population given the extended periods of decreased influenza exposure and infection caused by the implementation of COVID-19-related public health measures. Moreover, disease severity may be exacerbated due to the co-circulation and simultaneous infection of COVID-19 and influenza viruses. Additionally, the resurgence of seasonal influenza may not follow usual seasonal patterns. Information about current influenza activity can be found on the . It should be noted that the incidence of influenza is often underreported since the illness may be confused with other viral illnesses and many people with ILI do not seek medical care or have viral diagnostic testing done.
IV. Seasonal influenza vaccines
# IV.1 Vaccine products authorized for use in Canada
The following sections describe the influenza vaccine products that are authorized for use in Canada for the 2023–2024 season. All influenza vaccines available in Canada have been authorized by Health Canada. However, not all products authorized for use are available in the marketplace. The vaccine manufacturers determine whether they will make any or all of their products available in each market. Provincial and territorial health authorities then determine which of the products available for purchase will be used in their respective publicly funded influenza immunization programs and for which population groups. Not all products will be made available in all jurisdictions and availability of some products may be limited. Officials in individual provinces and territories should be consulted regarding the products available in individual jurisdictions.
The antigenic characteristics of circulating influenza virus strains provide the basis for selecting the strains included in each year's vaccine. Vaccine selection by the WHO generally occurs in February for the fall's Northern Hemisphere influenza season to allow time for the vaccine manufacturers to produce the required quantity of vaccine. All manufacturers that distribute influenza vaccine products in Canada confirm to Health Canada that the vaccines to be marketed in Canada for the upcoming influenza season contain the WHO's recommended antigenic strains for the Northern Hemisphere. Vaccine producers may use antigenically equivalent strains because of their growth properties. The strains recommended for egg-based products may differ somewhat from the strains chosen for cell culture-based products to account for differences in the production platforms.
There are three categories of influenza vaccine authorized for use in Canada: IIV, RIV, and LAIV. Trivalent (3-strain) vaccines contain one A(H1N1) strain, one A(H3N2) strain, and one influenza B strain from one of the two lineages. Quadrivalent (4-strain) vaccines contain the strains in the trivalent vaccine plus an influenza B strain from the other lineage. Most influenza vaccines currently authorized for use in Canada are made from influenza viruses grown in chicken eggs. However, there are two exceptions. The influenza viruses used to produce Flucelvax Quad are propagated in a mammalian cell line (Madin-Darby Canine Kidney cells), while the Supemtek vaccine technology uses recombinant HA produced in a proprietary insect cell line using a baculovirus vector for protein expression.
A summary of the characteristics of influenza vaccines available in Canada during the 2023–2024 influenza season can be found in . For complete prescribing information, readers should consult the product monographs available through Health Canada's .
Should additional vaccine preparations become available for use in Canada after the release of this statement and prior to the 2023-24 influenza vaccine season, NACI will communicate relevant information regarding the new vaccine preparations if required.
## Inactivated influenza vaccine (IIV)
IIVs contain standardized amounts of the HA protein from representative seed strains of the two human influenza A subtypes (H3N2 and H1N1) and either one (for trivalent vaccines) or both (for quadrivalent vaccines) of the two influenza B lineages (Yamagata and Victoria). IIVs currently authorized for use in Canada are a mix of split virus and subunit vaccines, both consisting of disrupted virus particles. In split virus vaccines, the virus has been disrupted by a detergent. In subunit vaccines, HA and NA have been further purified by removal of other viral components. The amount of neuraminidase (NA) in the vaccines is not standardized and not reported. HA-based serum antibody produced to one influenza A subtype provides no protection against strains belonging to another subtype. The potential for trivalent vaccine to stimulate antibody protection across B lineages requires further evaluation and may be dependent upon factors such as age and prior antigenic experience with the two B lineages .
All IIVs currently available in Canada are produced in eggs, except for Flucelvax Quad (IIV4-cc), which is a mammalian cell culture-based quadrivalent inactivated, subunit influenza vaccine that is prepared from viruses propagated in mammalian cell lines adapted to grow freely in suspension in culture medium. The production of IIV4-cc does not depend on egg supply as it does not require egg-grown candidate vaccine viruses.
The IIVs available in Canada are in a standard dose formulation or in a formulation designed to enhance the immune response in specific age groups, using a higher dose of HA antigen or the inclusion of an adjuvant. Refer to in Part 1 of the CIG for more information about inactivated vaccines.
Standard-dose IIVs are available in Canada as quadrivalent formulations (IIV4-SD: Afluria® Tetra, Flulaval® Tetra, Fluzone Quadrivalent, and Influvac Tetra; IIV4-cc: Flucelvax Quad). These vaccines are un-adjuvanted, contain a standard dose of antigen (15 µg HA per strain), and are administered as a 0.5 mL dose by IM injection. Influvac Tetra may be administered by IM or deep subcutaneous injection. Trivalent formulations of standard dose unadjuvanted IIVs are no longer authorized or available for use in Canada.
The adjuvanted IIV currently authorized for use in Canada is a trivalent subunit vaccine (IIV3-Adj) that contains the adjuvant MF59, which is an oil-in-water emulsion composed of squalene as the oil phase that is stabilized with the surfactants polysorbate 80 and sorbitan triolate in citrate buffer. IIV3-Adj contains 7.5 µg HA per strain administered as a 0.25 mL dose by IM injection for children 6 to 23 months of age (Fluad Pediatric) or 15 µg HA per strain administered as a 0.5 mL dose by IM injection for adults 65 years of age and older (Fluad). Other IIVs do not contain an adjuvant.
There is one high-dose IIV (IIV-HD) currently authorized for use in Canada; a quadrivalent unadjuvanted, split virus IIV that contains 60 µg HA per strain and is administered as a 0.7 mL dose by IM injection (Fluzone High-Dose Quadrivalent).
## Recombinant influenza vaccine (RIV)
There is currently only one RIV authorized for use in Canada: Supemtek (RIV4), a quadrivalent unadjuvanted, baculovirus-expressed seasonal influenza vaccine that contains 45 µg HA per strain and is administered as a 0.5 mL dose by IM injection for adults 18 years of age and older. RIV contains recombinant HAs produced in an insect cell line using genetic sequences from cell-derived influenza viruses. The production of RIV does not depend on egg supply as it does not require egg-grown candidate vaccine viruses.
## Live attenuated influenza vaccine (LAIV)
LAIV contains standardized quantities of fluorescent focus units (FFU) of live attenuated influenza virus reassortants. The virus strains in LAIV are cold-adapted and temperature sensitive, so they replicate in the nasal mucosa rather than the lower respiratory tract, and they are attenuated, so they do not produce ILI. There have been no reported or documented cases, and no theoretical or scientific basis to suggest transmission of vaccine virus would occur to the individual administering LAIV. As a live replicating whole virus formulation administered intranasally by spray, it elicits mucosal immunity, which may more closely mimic natural infection.
A quadrivalent product (LAIV4; FluMist Quadrivalent) is authorized for use in Canada for children 2 to17 years of age and adults 18 to 59 years of age and is given as a 0.2 mL dose (0.1 mL in each nostril). The trivalent formulation (LAIV3) is no longer available in Canada.
# IV.2 Efficacy, effectiveness, and immunogenicity
## Efficacy and effectiveness
Influenza vaccine has been shown in randomized controlled clinical trials to be efficacious in providing protection against influenza infection and illness. However, the effectiveness of the vaccine—that is, how it performs in settings that are more reflective of usual health care practice—can vary from season to season and by influenza vaccine strain type and subtype. Influenza vaccine effectiveness (VE) depends on how well the vaccine strains match with circulating influenza viruses, the type and subtype of the circulating virus, as well as the health and age of the individual receiving the vaccine. Even when there is a less-than-ideal match or lower VE against one strain, the possibility of lower VE should not preclude vaccination, particularly for people at high risk of influenza-related complications and hospitalization, since vaccinated individuals are still more likely to be protected compared to those who are unvaccinated.
## Immunogenicity
Antibody response after vaccination depends on several factors, including the age of the recipient, prior and subsequent exposure to antigens, and the presence of immune compromising conditions. Protective levels of humoral antibodies, which correlate with protection against influenza infection, are generally achieved by 2 weeks after vaccination; however, there may be some protection afforded before that time.
## Additional information
Because of potential changes in the circulating influenza virus from year to year and waning immunity in vaccine recipients, annual influenza vaccination is recommended. Although some studies suggest vaccine induced protection may be greater in individuals who have no recent vaccine history, overall, the evidence shows no difference in the effectiveness of repeated influenza vaccination compared to vaccination in the current season only. Importantly, optimal protection against influenza is best achieved through annual influenza vaccination, as repeated vaccination including the current season is consistently more effective than no vaccination in the current season. Additional information regarding the effects of repeated influenza vaccination on vaccine effectiveness, efficacy, and immunogenicity can be found in the NACI Recommendation on Repeated Seasonal Influenza Vaccination. NACI will continue to monitor this issue.
NACI acknowledges that evidence related to influenza vaccine performance, particularly with respect to vaccine efficacy and effectiveness, is constantly evolving with advances in research methodology and accumulation of data over many influenza seasons. Therefore, the evidence summarized in may not include the latest studies. However, NACI continues to closely monitor the emerging evidence on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccines to update and make recommendations when warranted.
# IV.3 Vaccine administration
## Dose, route of administration, and schedule
With the variety of influenza vaccines available for use in Canada, it is important for vaccine providers to note the specific differences in age indication, route of administration, dosage, and schedule for the products that they will be using (see ). Key relevant details and differences between vaccine products are also highlighted in .
For influenza vaccines given by the IM route, the anterolateral thigh muscle is the recommended site in infants 6 to 12 months of age. The anterolateral thigh or the deltoid muscle can be used for toddlers and older children. The deltoid muscle of the arm is the preferred injection site in adolescents and adults. For more information on vaccine administration, please refer to in Part 1 of the CIG.
The first time that children 6 months to less than 9 years of age receive seasonal influenza vaccination, a two-dose schedule is required to achieve protection. Several studies have looked at whether these two initial doses need to be given in the same season. Englund et al. reported similar immunogenicity in children 6 to 23 months of age whether 2 doses were given in the same or separate seasons when there was no change, or only minor vaccine strain change, in vaccine formulation between seasons. However, seroprotection rates to the B component were considerably reduced in the group that received only one dose in the subsequent season when there was a major B lineage change, suggesting that the major change in B virus lineage reduced the priming benefit of previous vaccination. Issues related to effective prime-boost when there is a major change in influenza B lineage across sequential seasons require further evaluation. Because children 6 to 23 months of age are less likely to have had prior priming exposure to an influenza virus, special effort is warranted to ensure that a two-dose schedule is followed for previously unvaccinated children in this age group.
Afluria® Tetra (5 years and older), Flulaval® Tetra (6 months and older), Fluzone® Quadrivalent (6 months and older), Influvac® Tetra (3 years and older).
Flucelvax® Quad (6 months and older)
Fluad Pediatric®(6 to 23 months) or Fluad®(65 years and older)
Fluzone® High-Dose Quadrivalent (65 years and older)
Supemtek™ (18 years and older)
FluMist® Quadrivalent (2 to 59 years)
Evidence suggests moderate improvement in antibody response in infants, without an increase in reactogenicity, with the use of full vaccine doses (0.5 mL) for unadjuvanted inactivated influenza vaccines. This moderate improvement in antibody response without an increase in reactogenicity is the basis for the full dose recommendation for unadjuvanted inactivated vaccine for all ages. For more information, refer to .
Children 6 months to less than 9 years of age receiving seasonal influenza vaccine for the first time in their life should be given 2 doses of influenza vaccine, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been properly vaccinated with one or more doses of seasonal influenza vaccine in the past should receive 1 dose of influenza vaccine per season thereafter.
## Booster doses and revaccination
Booster doses are not required within the same influenza season. However, children 6 months to less than 9 years of age who have not previously received the seasonal influenza vaccine require 2 doses of influenza vaccine, with a minimum of 4 weeks between doses. Only one dose of influenza vaccine per season is recommended for everyone else. Two doses of seasonal influenza vaccine in older adults do not appear to improve the immune response to the vaccine compared to one dose.
## Serological testing
Serologic testing is not necessary or recommended before or after receiving seasonal influenza vaccine.
# IV.4 Storage requirements
Influenza vaccine should be stored at +2°C to +8°C and should not be frozen. Refer to the individual product monographs for further details. Refer to in Part 1 of the CIG for additional information.
# IV.5 Concurrent administration with other vaccines
All seasonal influenza vaccines, including LAIV, may be given at the same time as, or at any time before or after administration of other vaccines (either live or inactivated), including COVID-19 vaccines for those aged 6 months of age and older as.
NACI will continue to monitor the evidence base, including ongoing and anticipated trials investigating influenza vaccines administered at the same time as, or any time before or after, COVID-19 vaccines and update its recommendations as needed.
No studies were found on potential immune interference between LAIV and other live attenuated vaccines (oral or parenteral) administered within 4 weeks.
Studies on concurrent administration of LAIV3 with measles, mumps, rubella (MMR); measles, mumps, rubella, varicella (MMRV); or live oral polio vaccines did not find evidence of clinically significant immune interference. One study reported a statistically significant but not clinically meaningful decrease in seroresponse rates to rubella antigen when administered concomitantly with LAIV.
In theory, the administration of two live vaccines sequentially within less than 4 weeks could reduce the efficacy of the second vaccine. Possible immune mechanisms include: the inhibitory and immunomodulatory effects of systemic and locally produced cytokines on B- and T-cell response and viral replication; immunosuppression induced by certain viruses (such as measles); and direct viral interference as a result of competition for a common niche. Mucosal vaccines may have less impact on a parenteral vaccine and vice versa. The immune response with a mucosal vaccine may be compartmentalized to the mucosa while that to a parenteral vaccine is systemic. It is likely that there is some interaction between the systemic and mucosal compartments; however, the extent to which this interaction occurs is not known.
Given the lack of data for immune interference, and based on expert opinion, NACI recommends that LAIV can be given together with or at any time before or after the administration of any other live attenuated or inactivated vaccine. However, some vaccine providers may continue to choose to give LAIV and other live vaccines separated by at least 4 weeks, based on the theoretical possibility of immune interference, although NACI does not believe that this precaution is necessary for LAIV. The use of a parenteral inactivated or recombinant influenza vaccine would avoid this theoretical concern. Note that the timing rules related to two parenteral live vaccines (e.g., MMR and varicella vaccines) still apply. For more information regarding vaccination administration timing rules, please refer to in Part 1 of the CIG.
The target groups for influenza and pneumococcal polysaccharide vaccines overlap considerably. A recent study showed that compared to administration alone, concurrent administration of IIV4 with PCV15 in adults demonstrated non-inferiority of pneumococcal- and influenza-specific antibody responses. The immune response to many PCV components was decreased, but not influenza virus components. The clinical significance of this interaction is not known precisely. Vaccine providers should take the opportunity to vaccinate eligible people against pneumococcal disease when influenza vaccine is given.
When more than one injection is given at a single clinic visit, it is preferable to administer them in different limbs. If it is not possible to do so, injections given in one limb should be separated by a distance of at least 2.5 cm (1 inch). A separate needle and syringe should always be used for each injection.
## Concurrent administration with other adjuvanted vaccines
Data are limited regarding concurrent administration of newer adjuvanted influenza vaccines with other adjuvanted or non-adjuvanted vaccines.
RZV is an example of a recombinant adjuvanted subunit herpes zoster vaccine (Shingrix®, GlaxoSmithKline) that is authorized for use in Canada in adults 50 years of age and older, and adults 18 years of age or older who are or will be at increased risk of HZ due to immunodeficiency or immunosuppression caused by known disease or therapy; therefore, the target age group for herpes zoster vaccine and influenza vaccine overlap. RZV has been shown to be safe and effective when given concurrently with unadjuvanted, standard dose influenza vaccines. However, no studies have been conducted that have assessed the concurrent administration of RZV with adjuvanted or high dose influenza vaccine. It should be noted that RZV and IIV-adj currently authorized for use in Canada contain the adjuvants AS01B and MF59 respectively. How these adjuvants may interact when RZV and IIV-adj are administered concurrently is not known.
NACI will continue to review the evidence and update guidance accordingly.
# IV.6 Vaccine safety and adverse events
Post-marketing surveillance of influenza vaccines in Canada has shown that seasonal influenza vaccines have a safe and stable profile. In addition to routine surveillance, every year during the seasonal influenza vaccination campaigns, PHAC and the Federal/Provincial/Territorial Vaccine Vigilance Working Group (VVWG) of the Canadian Immunization Committee conduct weekly expedited surveillance of adverse events following immunization (AEFI) for current influenza vaccines to identify vaccine safety signals in a timely manner. Refer to the (CAEFISS) web page for more information on post-marketing surveillance and AEFIs in Canada. In addition, the Canadian National Vaccine Safety (CANVAS) Network, a national network of sites across Canada for active vaccine safety surveillance, collects and analyzes information on AEFIs after influenza vaccination to provide influenza vaccine safety information to public health authorities during the core weeks of the annual influenza vaccination campaign.
All influenza vaccines currently authorized for use in Canada are considered safe for use in people with latex allergies. The multi-dose vial formulations of inactivated influenza vaccine that are authorized for use in Canada contain minute quantities of thimerosal, which is used as a preservative to keep the product sterile. Large cohort studies of administrative health databases have found no association between childhood vaccination with thimerosal-containing vaccines and neurodevelopmental outcomes, including autistic-spectrum disorders. All single dose formulations of IIV, RIV and LAIV are thimerosal-free. Refer to in Part 2 of the CIG for additional information.
## Common adverse events
With IM administered influenza vaccines, injection site reactions are common but are generally classified as mild and transient. IIV3-Adj tends to produce more extensive injection site reactions than un-unadjuvantedIIV3, but these reactions are also generally mild and resolve spontaneously within a few days. IIV-HD tends to induce higher rates of systemic reactions compared to IIV-SD, but most of these reactions are mild and short-lived. Recombinant vaccines appear to have a similar safety profile to IIVs. The most common AEs experienced by recipients of LAIV are nasal congestion and runny nose.
## Less common and serious or severe adverse events
Serious adverse events (SAEs) are rare following influenza vaccination, and in most cases, data are insufficient to determine a causal association. Allergic responses to influenza vaccine are a rare consequence of hypersensitivity to some components of the vaccine or its container.
## Other reported adverse events and conditions
### Egg-allergic individuals
After careful review of clinical and post-licensure safety data, NACI has concluded that egg-allergic individuals may be vaccinated against influenza using any influenza vaccine, including egg-based vaccines and LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg and without any particular consideration, including vaccination setting. The amount of trace ovalbumin allowed in influenza vaccines that are authorized for use in Canada is associated with a low risk of AE, and in addition, two of the authorized products do not contain any ovalbumin. The observation period post-vaccination is as recommended in in Part 2 of the CIG. As with all vaccine administration, vaccine providers should be prepared with the necessary equipment, knowledge, and skills to respond to allergic reactions, including anaphylaxis, at all times.
### Guillain-Barré syndrome
In a review of studies conducted between 1976 and 2005, the United States Institute of Medicine concluded that the 1976 "swine flu" vaccine was associated with an elevated risk of GBS. However, evidence was inadequate to accept or to reject a causal relation between GBS in adults and seasonal influenza vaccination. The attributable risk of GBS in the period following seasonal and monovalent 2009 pandemic influenza vaccination is about one excess case per million vaccinations. In a self-controlled study that explored the risk of GBS after seasonal influenza vaccination and after influenza health care encounters (a proxy for influenza illness), the attributable risks were 1.03 GBS admissions per million vaccinations compared with 17.2 GBS admissions per million influenza-coded health care encounters.
These findings suggest that both influenza vaccination and influenza illness are associated with small attributable risks of GBS, but the risk of GBS associated with influenza illness is notably higher than with influenza vaccination. The self-controlled study also found that the risk of GBS after vaccination was highest during weeks 2 to 4, whereas for influenza illness, the risk was greatest within the first week after a health care encounter and decreased thereafter but remained significantly elevated for up to 4 weeks.
Although the evidence considering influenza vaccination and GBS is inadequate to accept or reject a causal relation between GBS in adults and seasonal influenza vaccination, avoiding subsequent influenza vaccination of individuals known to have had GBS without other known etiology within 6 weeks of a previous influenza vaccination appears prudent at this time. However, the potential risk of GBS recurrence associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination .
### Oculorespiratory syndrome
Oculorespiratory syndrome (ORS), the presence of bilateral red eyes and one or more associated respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, or sore throat) that starts within 24 hours of vaccination, with or without facial oedema, was identified during the 2000–2001 influenza season. Since then, there have been far fewer cases per year reported to CAEFISS. ORS is not an allergic response. People who have an occurrence or recurrence of ORS upon vaccination do not necessarily experience further episodes with future vaccinations.
Individuals who have experienced ORS without lower respiratory tract symptoms may be safely revaccinated with influenza vaccine. Individuals who experienced ORS with lower respiratory tract symptoms should have an expert review. Health care providers who are unsure whether an individual previously experienced ORS versus an immunoglobulin E (IgE) mediated hypersensitivity immune response should seek advice. Data on clinically significant AEs do not support the preference of one vaccine product over another when revaccinating those who have previously experienced ORS.
### Allergic reactions to previous vaccine doses
Expert review of the benefits and risks of vaccination should be sought for those who have previously experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of influenza vaccination, an apparent significant allergic reaction to the vaccine, or any other symptoms that could indicate a significant allergic reaction (e.g., throat constriction, difficulty swallowing) that raise concern regarding the safety of revaccination. This advice may be obtained from experts in infectious disease, allergy, and immunology, or public health that can be found in various health settings, including the .
In view of the considerable morbidity and mortality associated with influenza and rarity of true vaccine allergy, a diagnosis of allergy to an influenza vaccine should not be made without confirmation, which may involve consultation with an allergy or immunology expert.
### Drug interactions
Although influenza vaccine can inhibit the clearance of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine. Statins have effects on the immune system in addition to their therapeutic cholesterol-lowering actions. Two published studies have found that adults who are regular statin users (at least 65 years of age in one study and 45 years and older in the other) had a decreased response to influenza vaccination as measured by reduced geometric mean titres (GMT) or reduced VE against medically attended acute respiratory illness. Statins are widely used in the same adult populations who are also at-risk for influenza-related complications and hospitalizations. Therefore, if these preliminary findings are confirmed in future studies, concurrent statin use in adult populations could have implications for influenza VE and how this use is assessed in the measurement of VE. NACI will continue to monitor the literature related to this issue.
### Guidance on reporting adverse events following immunization
To ensure the ongoing safety of influenza vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in most jurisdictions, reporting is mandatory under the law.
An AEFI is any untoward medical occurrence that follows vaccination whether or not there is a causal relationship with the usage of a vaccine. The AEFI may be any unfavourable or unintended sign, abnormal laboratory finding, symptom, or disease. Any AEFI temporally related to vaccination and for which there is no other clear cause at the time of reporting should be reported. Of particular importance are those AEFIs which are serious or unexpected. A serious AEFI is an adverse event that is life threatening or results in death, requires hospitalization or prolongs an existing hospitalization, results in residual disability or causes congenital malformation. An unexpected AEFI is an event that is not listed in the approved product monograph but may be due to the vaccination, or one whose nature, severity, specificity, or outcome is not consistent with the term or description used in the product monograph. Vaccine providers are asked to and to check for specific AEFI reporting requirements in their province or territory. If there is any doubt as to whether or not an event should be reported, a conservative approach should be taken, and the event should be reported.
For influenza vaccines, the following AEFIs are of particular interest:
- ORS; and
- GBS within 6 weeks following vaccination
V. Recommendations
NACI makes the following recommendations for individual-level and public health program-level decision making. Individual-level recommendations are intended for people wishing to protect themselves from influenza or for vaccine providers wishing to advise individual patients about preventing influenza. Program-level recommendations are intended for provinces and territories responsible for making decisions on publicly funded immunization programs. Individual-level and program-level recommendations may differ, as the important factors to consider when recommending a vaccine for a population (e.g., population demographics, economic considerations) may be different than for an individual.
Recommendation for individual-level decision making
NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have a contraindication to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended (see ).
Recommendations for public health program-level decision making
The national goal of the annual influenza immunization programs in Canada is to prevent serious illness caused by influenza and its complications, including death. Programmatic decisions to provide influenza vaccination to target populations as part of publicly funded provincial and territorial programs depend on many factors, such as cost-effectiveness evaluation and other programmatic and operational factors, such as implementation strategies.
- NACI recommends that influenza vaccine should be offered as a priority to the groups for whom influenza vaccination is particularly recommended (see in the section below).
## List 1: Groups for whom influenza vaccination is particularly recommended
People at high risk of influenza-related complications or hospitalization
- All children 6 to 59 months of age
- Adults and children with the following chronic health conditions:
+ Cardiac or pulmonary disorders (includes bronchopulmonary dysplasia, cystic fibrosis, and asthma);
+ Diabetes mellitus and other metabolic diseases;
+ Cancer, immune compromising conditions (due to underlying disease, therapy, or both, such as solid organ transplant or hematopoietic stem cell transplant recipients);
+ Renal disease;
+ Anemia or hemoglobinopathy;
+ Neurologic or neurodevelopmental conditions (includes neuromuscular, neurovascular, neurodegenerative, neurodevelopmental conditions, and seizure disorders
+ Morbid obesity (defined as BMI of 40 kg/m² and over); and
+ Children 6 months to 18 years of age undergoing treatment for long periods with acetylsalicylic acid, because of the potential increase of Reye's syndrome associated with influenza
- All individuals who are pregnant;
- People of any age who are residents of nursing homes and other chronic care facilities;
- Adults 65 years of age and older; and
- Indigenous peoples.
People capable of transmitting influenza to those at high risk
- Health care and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk
- Household contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated:
+ household contacts of individuals at high risk
+ household contacts of infants less than 6 months of age, as these infants are at high risk but cannot receive influenza vaccine
+ members of a household expecting a newborn during the influenza season;
- Those providing regular child care to children 0 to 59 months of age, whether in or out of the home; and
- Those who provide services within closed or relatively closed settings to people at high risk (e.g., crew on a cruise ship).
Others
- People who provide essential community services; and
- People who are in direct contact with poultry infected with avian influenza during culling operations
List 1 - Footnote a
List 1 - Footnote b
# V.1 Choice of seasonal influenza vaccine
With the recent availability of a number of new influenza vaccines, some of which are designed to enhance immunogenicity in specific age groups, the choice of product is now more complex.
- IIV4-SD
- IIV4-cc
+ Currently, there is insufficient evidence for recommending vaccination with Influvac Tetra (IIV4-SD) in children younger than 3 years of age.
- If a quadrivalent vaccine is not available, a trivalent vaccine licensed for this age group should be used.
- IIV4-cc
- LAIV4
+ Currently, there is insufficient evidence for recommending vaccination with Influvac Tetra (IIV4-SD) in children younger than 3 years of age.
- LAIV4 may be given to children with:
+ stable, non-severe asthma;
+ cystic fibrosis who are not being treated with immunosuppressive drugs (e.g., prolonged systemic corticosteroids); and
+ stable HIV infection, i.e., if the child is currently being treated with ART (i.e., HAART) for at least 4 months and has adequate immune function.
- LAIV should not be used in children or adolescents for whom it is contraindicated or for whom there are warnings and precautions such as those with:
+ severe asthma (defined as currently on oral or high-dose inhaled glucocorticosteroids or active wheezing);
+ medically attended wheezing in the 7 days prior to vaccination;
+ current receipt of aspirin or aspirin-containing therapy;
+ immune compromising conditions, with the exception of stable HIV infection, i.e., if the child is currently being treated with HAART for at least 4 months and has adequate immune function;
+ pregnancy
- in pregnancy, IIV4-SD or IIV4-cc should be used instead.
- IIV4-cc
- RIV4
- LAIV4
+ There is some evidence that IIV may provide better efficacy than LAIV in healthy adults; and
- LAIV is not recommended for:
+ Pregnant individuals
- in pregnancy, IIV4-SD, IIV4-cc or RIV4 should be used instead.
+ adults with any of the chronic health conditions identified in , including immune compromising conditions; and
+ health care workers
- IIV4-cc
- RIV4
- IIV4-SD
- IIV4-HD
- IIV4-cc
- RIV4
+ Other than a recommendation for using IIV-HD over IIV-SD formulations, NACI has not made comparative individual-level recommendations on the use of the other available vaccines in this age group. In the absence of a specific product, any of the available age-appropriate influenza vaccines should be used.
+ There is insufficient evidence on the incremental value of different influenza vaccines (i.e., cost-effectiveness assessments have not been performed by NACI) to make comparative public health program-level recommendations on the use of the available vaccines.
IIV3-SD formulations will not be authorized or available for use in Canada during the 2023-2024 influenza season.
IIV3-HD formulations will not be authorized or available for use in Canada during the 2023-2024 influenza season.
# V.2 Children
## Burden of disease in children
Children experience a higher burden of disease due to influenza B infection compared to other age groups. Although children less than 24 months of age comprise approximately 2% of the Canadian population, children 0 to 23 months of age averaged 10.8% of reported influenza B cases (range: 8.3 to 13.7%), using case-based laboratory data from 2001–2012 (excluding 2009). With respect to severe outcomes (e.g., hospitalization, intensive care unit admission, and death), influenza B was confirmed in 15.5 to 58.3% (median: 38.4%) of pediatric influenza-associated hospitalizations (children 16 years of age and younger) reported by the Canadian Immunization Monitoring Program Active (IMPACT) surveillance network between 2004–2005 and 2012–2013 (excluding the 2009–2010 pandemic season). From 2010-2011 to 2018-2019, inclusively, 29% of IMPACT influenza admissions were for influenza B.
The IMPACT study also found that the proportion of deaths attributable to influenza (any strain) was significantly greater for children admitted to hospital with influenza B (1.1%) than for those admitted with influenza A (0.4%). The proportion of hospitalizations due to influenza B relative to all influenza hospitalizations has been generally similar to the proportion of influenza B detections relative to all influenza infections in the general population during the same time period. Additional information can be found in the
In the NACI , a review of B lineage antigens included in the Canadian influenza vaccines and the circulating strains each season indicates a match in five of the 12 seasons from 2001–2002 through to 2012–2013, a moderate match (about 50% from each lineage) in 1 season, and a mismatch in remaining 6 influenza seasons (i.e., 70% or more of the characterized B strains were of the opposite lineage to the antigen in that season's vaccine).
## Children 6 to 23 months of age
Three types of influenza vaccine are authorized and available for use in children 6 to 23 months of age: IIV3-Adj, IIV4-SD, and IIV4-cc.
Given the burden of influenza B disease in children and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine, NACI recommends that a quadrivalent influenza vaccine should be used. If a quadrivalent vaccine is not available, an available age-appropriate trivalent vaccine (IIV3-Adj) should be used.
The current evidence is insufficient for recommending vaccination with Influvac Tetra (IIV4-SD) in children younger than 3 years of age.
## Children 2 to 17 years of age
Three types of influenza vaccine are authorized and available for use in children 2 to 17 years of age: IIV4-SD, IIV4-cc, and LAIV4.
The current evidence does not support a recommendation for the preferential use of LAIV in children and adolescents 2 to 17 years of age. Refer to the NACI for information supporting this recommendation.
The current evidence is insufficient for recommending vaccination with Influvac Tetra (IIV4-SD) in children younger than 3 years of age.
### Children 2 to 17 years of age with chronic health conditions
NACI recommends that any age-appropriate influenza vaccine (IIV or LAIV) may be considered for children 2 to 17 years of age with chronic health conditions; however, LAIV should not be used for children with severe asthma (as defined as currently on oral or high-dose inhaled glucocorticosteroids or with active wheezing), those with medically attended wheezing in the 7 days prior to vaccination, those currently receiving aspirin or aspirin-containing therapy, and those with immune compromising conditions, excluding those with stable HIV infection on HAART and with adequate immune function. LAIV is also contraindicated in adolescents who are pregnant. Children and adolescents for whom LAIV is contraindicated should receive IIV. If IIV is used, NACI recommends that a quadrivalent vaccine should be used. If a quadrivalent vaccine is not available, an age-appropriate trivalent vaccine should be used.
NACI recommends that LAIV may be given to children with stable, non-severe asthma, children with cystic fibrosis who are not treated with immunosuppressive drugs, such as prolonged systemic corticosteroids, and children with stable HIV infection on HAART and with adequate immune function.
### Summary of vaccine characteristics for decision making
IIV4-SD, IIV4-cc, and LAIV4 are authorized for use in Canada for children 2 to 17 years of age. The comparison of the vaccine characteristics of IIV and LAIV, in below, may be considered in deciding on the preferred vaccine option(s) for use by an individual or a public health program. Note that although data comparing LAIV to IIV4-cc are not available, IIV-cc is comparable to egg-based IIV.
NACI has not assessed the comparative cost-effectiveness of authorized influenza vaccine types for children 2 to 17 years of age.
The trivalent formulation of LAIV (LAIV3) received a Notice of Compliance from Health Canada in June 2010 and was first used in publicly funded immunization programs in Canada for the 2012–2013 influenza season. The quadrivalent formulation (LAIV4) was approved for use in Canada for the 2014–2015 season and has been in use since that time. LAIV3 is no longer available in Canada.
The trivalent IIV3-SD formulations are not expected to be authorized or available in Canada for the 2023-2024 influenza season. Data comparing LAIV to IIV4-cc are not available, however IIV-cc is comparable to egg-based IIV.
# V.3 Adults
## Burden of disease in adults
A study focusing on estimates of deaths associated with influenza in the United States has established that the average annual rate of influenza-associated deaths for adults aged 65 years of age and older was 17.0 deaths per 100,000 (range: 2.4 to 36.7). The study also states that of deaths coded as being influenza- or pneumonia-related, persons 65 years of age and older accounted for 87.9% of the overall estimated annual average number of deaths. When influenza-related deaths among adults 65 years of age and older were estimated using codes for underlying respiratory and circulatory causes of death, these estimates increased to 66.1 deaths per 100,000 (range: 8.0 to 121.1) and 89.4%, respectively. This study described a wide variation in the estimated number of deaths from season to season, which was closely related to the influenza virus types and subtypes in circulation. Estimates presented in the study of yearly influenza-associated deaths with underlying pneumonia and influenza causes (1976 to 2007) reveal a large difference between influenza type A and B with a calculated median of greater than 6,000 deaths associated with influenza type A and half of that number for influenza type B (approximately 3,360) for persons 65 years of age and older. During the 22 seasons in which influenza A(H3N2) was the prominent strain, the average influenza-associated mortality rates were 2.7 times higher than for the nine seasons that it was not (all age groups combined), and on average, there were about 37% more annual influenza-associated deaths, regardless of the primary medical cause of death. A higher risk of hospitalization and death was also reported by Cromer et al. in adults 65 years of age and older, compared to younger adults in their assessment of the burden of influenza in England by age and clinical risk group.
Canadian surveillance data show that hospitalization rates among adults 65 years of age and older were higher during the A(H3N2)-predominant 2014–2015 season compared to the previous five influenza seasons and also compared to the 2012–2013 season when A(H3N2) also predominated; 2014–2015 was a season in which there was a vaccine mismatch with the circulating A(H3N2) strain. Similar to the hospitalization rates, death rates among older adults were highest in the 2014–2015 season compared to the previous five seasons and compared to the previous A(H3N2) season in 2012–2013. Mortality rates among other age groups were similar to or lower than the previous five influenza seasons. Laboratory detections over this same time period showed that influenza seasons in which influenza subtype A(H3N2) predominated, disproportionally affected adults 65 years of age and older, while seasons with greater A(H1N1) detections resulted in a higher proportion of positive cases in younger age groups.
## Adults 18 to 59 years of age
Four types of influenza vaccine are authorized and available for use in adults 18 to 59 years of age: IIV4-SD, IIV4-cc, RIV4, and LAIV4.
NACI recommends that any of the available influenza vaccines should be used in adults without contraindications to the vaccine. NACI previously found insufficient evidence to recommend the use of LAIV in adults with chronic health conditions due to the potentially better immune response following IIV compared to LAIV in healthy adults in some studies. As such, IIV or RIV should be used for adults with chronic health conditions identified in , HCWs or individuals who are pregnant (noting that limited published clinical data pertaining to safety of vaccination with RIV4 during pregnancy is currently available to inform vaccine-associated risks for this population). For further information, refer to .
## Adults 60 to 64 years of age
Three types of influenza vaccine are authorized and available for use in adults 60 to 64 years of age: IIV4-SD, IIV4-cc, and RIV4.
NACI recommends that any of the available age-appropriate influenza vaccines should be used.
## Adults 65 years of age and older
Five types of influenza vaccine are authorized and available for use in adults 65 years of age and older: IIV3-Adj, IIV4-SD, IIV4-cc, IIV4-HD, and RIV4.
### Recommendation for individual-level decision making
When available, IIV-HD should be used over IIV-SD, given the burden of influenza A(H3N2) disease and the good evidence of better protection of IIV3-HD compared to IIV3-SD in adults 65 years of age and older. Based on a review of pre-authorization trials, IIV4-HD is non-inferior to IIV3-HD and is therefore expected to provide the same enhanced protection against A(H3N2) compared to SD IIV, including IIV4-SD. Although IIV-HD is expected to provide better protection against influenza A(H3N2) for adults 65 years of age or older, the benefit of providing this vaccine to all adults 65 and over as opposed to any other influenza vaccine is not clear (refer to the next section). NACI is currently conducting an updated review of influenza vaccines in this population.
Any of the available influenza vaccines would be preferable to remaining unvaccinated or requesting individuals to return for vaccine. Therefore, in the absence of a specific product, NACI recommends that any of the available influenza vaccines authorized for this age group should be used.
### Recommendation for public health program-level decision making
IIV3-HD is expected to provide better protection compared to IIV3-SD. Similarly, IIV4-HD is expected to provide better protection compared to IIV4-SD. The previous assessment completed by NACI demonstrated insufficient evidence to make a comparative recommendation on the use of IIV3-HD over IIV3-SD at the programmatic level and a complete assessment that includes economic considerations has not yet been conducted for IIV4-HD. Therefore, NACI currently recommends that any of the available influenza vaccines should be used for public health programs. NACI is in the process of completing an updated assessment on influenza vaccines for adults 65 years of age and older.
### Summary of vaccine characteristics for decision making
There are four types of inactivated influenza vaccines (IIV3-Adj, IIV4-SD, IIV4-cc, and IIV4-HD) and one type of recombinant influenza vaccine (RIV4) authorized for use in Canada for adults 65 years of age and older. The comparison of vaccine characteristics across vaccine types, in below, may be considered when deciding on the preferred vaccine option(s) for use by an individual or a public health program. Due to the limited available data directly comparing the performance of IIV3-Adj, IIV-HD, IIV4-SD, IIV4-cc, or RIV4, considerations for these vaccines in are compared to IIV3-SD for which comparative data on efficacy, effectiveness, and/or immunogenicity with each of IIV3-Adj and IIV4-SD are available. Data directly comparing IIV4-cc and IIV4-HD to IIV3-SD are not available. Comparative data on efficacy, effectiveness, and/or immunogenicity of IIV3-cc and IIV3-SD are available.
NACI has not assessed the comparative cost-effectiveness of available influenza vaccine types for adults 65 years of age and older.
Data directly comparing IIV4-HD to IIV3-SD are not available; however, IIV4-HD has been shown to be non-inferior to IIV3-HD and has a comparable rate of systemic and local reactions. Therefore, information presented here is expected to apply to IIV4-HD as well.
Data directly comparing IIV4-cc to IIV3-SD are not available; however, IIV3-cc (licensure never sought in Canada) has been shown to be non-inferior to IIV3-SD. Therefore, information presented here is expected to apply to IIV4-cc as well.
Data directly comparing RIV4 to IIV3-SD are not available; however, RIV4 has been shown to provide better protection than IIV4-SD based on one study conducted during a single influenza season (2014-2015).
Data directly comparing RIV4 to IIV3-SD are not available; however, RIV4 has been shown to be non-inferior to IIV4-SD, IIV4-cc, IIV3-HD and IIV3-Adj against all tested influenza strains and has a comparable rate of AEs based on 3 influenza seasons (2014-2015, 2017-2018, 2018-2019). Therefore, information presented here is expected to apply to IIV3-SD as well.
## Adults with chronic health conditions
NACI recommends that any age-appropriate IIV or RIV, but not LAIV, should be offered to adults with chronic health conditions identified in , including those with immune compromising conditions.
## Pregnant individuals
NACI recommends that any age-appropriate IIV or RIV, but not LAIV, should be offered to pregnant individuals (noting that limited published clinical data pertaining to safety of vaccination with RIV4 during pregnancy is currently available to inform vaccine-associated risks).
Due to a lack of safety data at this time, LAIV should not be administered to pregnant individuals due to the theoretical risk to the fetus from administering a live virus vaccine. LAIV can be administered to breastfeeding individuals.
## Health care workers
NACI recommends that any age-appropriate IIV or RIV, but not LAIV, should be offered to HCWs.
Comparative studies in healthy adults have found IIV to be similarly or more efficacious or effective compared with LAIV. In addition, as a precautionary measure, LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection.
## Travellers
Influenza occurs year-round in the tropics. In temperate northern and southern countries, influenza activity generally peaks during the winter season (November to March in the Northern Hemisphere and April to October in the Southern Hemisphere).
- NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older, including travellers, who does not have a contraindication to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended (see ).
Vaccines prepared specifically for use in the Southern Hemisphere are not available in Canada, and the extent to which recommended vaccine components for the Southern Hemisphere may overlap with those in available Canadian formulations will vary. A decision for or against revaccination (i.e., boosting) of travellers to the Southern Hemisphere between April and October, if they had already been vaccinated in the preceding fall or winter with the Northern Hemisphere's vaccine, depends on individual risk assessment, the similarity between the Northern and Southern Hemisphere vaccines, the similarity between the Northern Hemisphere vaccine strains and currently circulating strains in the Southern Hemisphere, and the availability of a reliable and safe vaccine at the traveller's destination. Refer to in Part 3 of the CIG for additional general information.
# V.4 Particularly recommended vaccine recipients
The groups for whom influenza vaccination is particularly recommended are presented in . Additional information regarding these particularly recommended recipients is provided below.
## All children 6 to 59 months of age
On the basis of existing data, NACI recommends the inclusion of all children 6 to 59 months of age among those for whom influenza vaccine is particularly recommended.
## Adults and children with chronic health conditions
As noted in , a number of chronic health conditions are associated with increased risk of influenza-related complications and can be exacerbated by a flu infection. Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune-compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected people. Vaccine effectiveness may be lower in people with immune compromising conditions than in healthy adults.
## All individuals who are pregnant
NACI recommends the inclusion of all individuals who are pregnant, at any stage of pregnancy, among those who are particularly recommended to receive IIV or RIV. This is due to the risk of influenza-associated morbidity amongst those who are pregnant , evidence of adverse neonatal outcomes associated with respiratory hospitalization during pregnancy or influenza during pregnancy , evidence that vaccination of individuals who are pregnant protects their newborns from influenza and influenza-related hospitalization , and evidence that infants born during influenza season to vaccinated individuals are less likely to be premature, small for gestational age, and of low birth weight than if born to individuals that had not received an influenza vaccine . The risk of influenza-related hospitalization increases with length of gestation (i.e., it is higher in the third trimester than in the second).
The safety of IIV during pregnancy has been reviewed. Active studies of influenza vaccination during pregnancy have not shown evidence of harm to the pregnant individual or fetus associated with influenza vaccination. Although the cumulative sample size of active studies of influenza vaccination in pregnant individuals is relatively small, particularly in the first trimester, passive surveillance has not raised any safety concerns despite widespread use of IIV during pregnancy over several decades . Surveillance following the use of both adjuvanted and un-adjuvanted 2009 pandemic influenza A(H1N1) vaccines in more than 100,000 pregnant women in Canada and more than 488,000 pregnant women in Europe has not revealed any safety concerns.
Very limited peer-reviewed, published data pertaining to safety of vaccination with RIV4 during pregnancy is currently available to inform vaccine-associated risks. Refer to the for more information.
## People of any age who are residents of nursing homes and other chronic care facilities
Residents of nursing homes and other chronic care facilities often have one or more chronic health condition and live in institutional environments that may facilitate the spread of influenza.
## Adults 65 years of age and older
Hospitalization attributable to influenza in this age group is estimated at 125 to 228 per 100,000 healthy people, and influenza-attributed mortality rates increase with increased age.
## Indigenous peoples
Based on a body of evidence indicating a higher rate of influenza-associated hospitalization and death among Indigenous peoples, NACI recommends the inclusion of this population among those for whom the influenza vaccine is particularly recommended.
It has been proposed that the increased risk of severe influenza outcomes in the Indigenous populations is a consequence of many factors, including high prevalence of chronic health conditions (e.g., diabetes, chronic lung disease, end-stage kidney disease, cardiovascular disease, obesity), delayed access to health care, and increased susceptibility to disease because of poor housing and overcrowding. A review of the available evidence and update to the recommendations for Indigenous peoples as a group at high-risk of influenza-related complications is planned, with inclusion and consideration of key stakeholder engagement.
# V.5 People capable of transmitting influenza to those at high risk of influenza-related complications or hospitalization
People who are potentially capable of transmitting influenza to those at high risk should receive annual vaccination, regardless of whether the high-risk individual has been vaccinated. Vaccination of Health Care Workers (HCWs) decreases their own risk of illness, as well as the risk of death and other serious outcomes among the individuals for whom they provide care . Vaccination of HCWs and residents of nursing homes is associated with decreased risk of ILI outbreaks.
People who are more likely to transmit influenza to those at high risk of influenza-related complications or hospitalization include:
- HCWs and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk; and
- Contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated
## Health care workers and other care providers in facilities and community settings
### Vaccination of health care workers and other care providers
For the purposes of this statement, HCWs and other care providers in facilities and community settings refers to HCWs, essential care providers, emergency response workers, those who work in continuing care or long-term care facilities or residences, those who provide home care for people at high risk, and students of related health care services. HCWs include any person, paid or unpaid, who provides services, works, volunteers, or trains in a hospital, clinic, or other health care facility.
Transmission of influenza to patients at high risk of influenza-associated complications results in significant morbidity and mortality. Four cluster randomized controlled trials (RCTs) conducted in geriatric long-term care settings have demonstrated that vaccination of HCWs is associated with substantial decreases in influenza-like illness and all-cause mortality in the residents. In addition, due to their occupation and close contact with people who may be infected with influenza, HCWs are themselves at increased risk of infection.
As previously stated, children 0 to 59 months of age, adults and children with chronic health conditions, pregnant individuals, people of any age who are residents of nursing homes and other chronic care facilities, and adults 65 years of age and older are at greater risk of more severe complications from influenza or worsening of their underlying condition. Given the potential for HCWs and other care providers to transmit influenza to individuals at high risk and knowing that vaccination is the most effective way to prevent influenza, NACI recommends that, in the absence of contraindications, HCWs and other care providers in facilities and community settings should be vaccinated against influenza annually. NACI considers the receipt of influenza vaccination to be an essential component of the standard of care for all HCWs and other care providers for their own protection and that of their patients. This group should consider annual influenza vaccination as part of their responsibilities to provide the highest standard of care.
Although the current influenza vaccine coverage rate for HCWs is higher than for the general public, it remains below the national goal of 80% coverage for HCWs in Canada. Comprehensive vaccination programs should be adopted that address HCWs' acceptance of the vaccine and facilitate the process of vaccinating HCWs to improve uptake of the influenza vaccine beyond the current level. HCW influenza vaccination programs that have successfully increased vaccine coverage of HCWs have included a combination of education, increased awareness, accessible on-site vaccination delivery options for all HCWs, visible support from senior staff and other leaders, and regular review and improvement of vaccination strategies .
### Outbreak management in health care facilities
As noted in PHAC's *,- all health care organizations should have a written plan for managing an influenza outbreak in their facilities. Inherent in such plans should be policies and programs to optimize HCW's influenza vaccination. As part of outbreak management, the above-mentioned PHAC guidance suggests consideration of chemoprophylaxis for all unvaccinated HCWs, unless contraindications exist. Refer to the Canada (AMMI Canada) website for guidelines regarding the use of antiviral medications for prophylaxis.
## Contacts of individuals at high risk of influenza complications
Vaccination is recommended for contacts, both adults and children, of individuals at high risk of influenza-related complications or hospitalization (see ), whether or not the individual at high risk has been vaccinated. These contacts include: household contacts and care providers of individuals at high risk, household contacts and care providers of infants less than 6 months of age (as these infants are at high risk of complications from influenza but cannot receive influenza vaccine), members of a household expecting a newborn during the influenza season, household contacts and care providers (whether in or out of the home) of children 0 to 59 months of age, and providers of services within closed or relatively closed settings with people at high risk of influenza-related complications (e.g., crew on a passenger or cruise ship).
# V.6 Others
## People who provide essential community services
Vaccination for these individuals should be encouraged to minimize the disruption of services and routine activities during annual influenza epidemics. People who provide essential community services, including healthy working adults, should consider annual influenza vaccination, as this intervention has been shown to decrease work absenteeism due to respiratory and related illnesses .
## People in direct contact with poultry infected with avian influenza during culling operations
### Poultry handlers
Although seasonal influenza vaccination will not prevent avian influenza infection, some countries and provinces have recommended influenza vaccination on a yearly basis for those working with poultry, based on the rationale that preventing infection with human influenza strains may reduce the theoretical potential for human-avian reassortment of genes, should such workers become co-infected with human and avian influenza viruses.
NACI recommends seasonal influenza vaccination for people who may be in direct contact with poultry infected with avian influenza during culling operations, as these individuals may be at increased risk of avian influenza infection because of exposure during the culling operation . Refer to the for further information supporting this recommendation.
Direct contact may be defined as sufficient contact with infected poultry to allow transmission of an avian virus to the exposed person. The relevant individuals include those performing the cull, as well as others who may be directly exposed to the avian virus, such as supervising veterinarians and inspectors. It is recommended that biosecurity measures such as personal protective equipment and antivirals be used. Refer to for PHAC recommendations on the management of domestic avian influenza outbreaks.
### Swine workers
NACI has concluded that there is insufficient evidence at this time to recommend routine influenza vaccination specifically for swine workers; however, NACI recommends that influenza vaccination should be offered to anyone 6 months of age and older who does not have contraindications to the vaccine. |
Statement on seasonal influenza vaccine for 2023-2024
======================================================
[Download in PDF format](/content/dam/phac-aspc/documents/services/publications/vaccines-immunization/national-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024/national-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.pdf)
(690.5 KB, 76 pages)
**Organization:** [Public Health Agency of Canada](/en/public-health.html)
**Date published:** 2023-05-31
**Cat.:** HP37-45E-PDF
**ISBN:** 2817-3619
**Pub.:** 230053
An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)
On this page
------------
* [Summary of information contained in the NACI statement](#summary)
* [I. Introduction](#a1)
+ [I.1 New or updated information for 2023–2024](#a1.1)
+ [I.2 Background](#a1.2)
* [II. Methods](#a2)
* [III. Epidemiology](#a3)
* [IV. Seasonal influenza vaccines](#a4)
+ [IV.1 Vaccine products authorized for use in Canada](#a4.1)
+ [IV.2 Efficacy, effectiveness, and immunogenicity](#a4.2)
+ [IV.3 Vaccine administration](#a4.3)
+ [IV.4 Storage requirements](#a4.4)
+ [IV.5 Concurrent administration with other vaccines](#a4.5)
+ [IV.6 Vaccine safety and adverse events](#a4.6)
* [V. Recommendations](#a5)
+ [V.1 Choice of seasonal influenza vaccine](#a5.1)
+ [V.2 Children](#a5.2)
+ [V.3 Adults](#a5.3)
+ [V.4 Particularly recommended vaccine recipients](#a5.4)
+ [V.5 People capable of transmitting influenza to those at high risk of influenza- related complications or hospitalization](#a5.5)
+ [V.6 Others](#a5.6)
* [List of abbreviations](#a6)
* [Acknowledgments](#a7)
* [Appendix A: Abbreviations for influenza vaccines](#a8)
* [Appendix B: Characteristics of influenza vaccines available for use in Canada, 2023–2024](#a9)
* [Appendix C: Additional information on vaccine efficacy, effectiveness, immunogenicity, and safety](#a10)
* [References](#a11)
Preamble
--------
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge.
This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Summary of information contained in the NACI statement
------------------------------------------------------
The following highlights key information for immunization providers on seasonal influenza vaccine. Several influenza vaccines are authorized in Canada and the evidence on influenza immunization is continually evolving. NACI will continue to monitor the evidence and update its recommendations as needed. Please refer to the remainder of the statement for details.
### What
* Influenza in humans is a respiratory infection caused primarily by influenza A and B viruses. Seasonal influenza epidemics occur annually in Canada, generally in the late fall and winter months. Prior to the COVID-19 pandemic, influenza had an annual attack rate estimated at 5 to 10% in adults and 20 to 30% in children worldwide[Footnote 1](#fn1).
* Symptoms of influenza can range from mild to severe, and typically come on suddenly. They can include fever, cough, and muscle aches. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week to 10 days, but some people are at greater risk of severe complications, such as pneumonia. Influenza infection can also worsen certain chronic conditions, such as heart disease[Footnote 2](#fn2).
* Live attenuated influenza vaccine (LAIV), recombinant influenza vaccine (RIV) and inactivated influenza vaccines (IIV) (which include standard dose [SD], high dose [HD], cell culture-based [cc] or adjuvanted vaccines [Adj]) are all authorized for use in Canada; some protect against 3 strains of influenza virus (i.e., trivalent formulations: IIV3) and some protect against 4 strains of influenza virus (i.e., quadrivalent formulations: IIV4, RIV4, or LAIV4). See [Appendix A](#a8) for a list of abbreviations used in this document for the different influenza vaccines.
* The influenza vaccines are safe and well-tolerated. The IIVs and RIV cannot cause influenza illness because they do not contain live virus. The live attenuated influenza vaccines contain weakened viruses.
### Who
NACI makes the following recommendations for individual-level and public health program-level decision making. Individual-level recommendations are intended for people wishing to protect themselves from influenza and for vaccine providers advising individual patients about preventing influenza. Program-level recommendations are intended for provinces and territories responsible for making decisions on publicly funded immunization programs. Individual-level and program-level recommendations may differ, as the important factors to consider when recommending a vaccine for a population (e.g., population demographics, economic considerations) may be different than for an individual.
#### Recommendation for individual-level decision making
NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have a contraindication to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended. These groups include:
* People at high risk of severe disease, influenza-related complications, or hospitalization;
* People capable of transmitting influenza to those at high risk;
* People who provide essential community services; and
* People in direct contact with poultry infected with avian influenza during culling operations.
In infants less than 6 months of age, evidence is lacking to demonstrate that influenza vaccine would be effective[Footnote 3](#fn3). Currently, authorized influenza vaccines are not indicated for use in infants less than 6 months of age. For these reasons, NACI recommends that influenza vaccine should not be offered to infants less than 6 months of age. Since infants less than 6 months of age are at high risk of influenza-related illness, the influenza vaccine should be offered to individuals who are pregnant, breastfeeding, and any household contacts and care providers of young infants.
#### Recommendation for public health program-level decision-making
The national goal of the annual influenza immunization programs in Canada is to prevent serious illness caused by influenza and its complications, including death. Programmatic decisions to provide influenza vaccination to target populations as part of publicly funded provincial and territorial programs depend on many factors, such as cost-effectiveness evaluation and other programmatic and operational factors.
* NACI recommends that influenza vaccine should be offered as a priority to the groups for whom influenza vaccination is particularly recommended.
### How
The benefits and risks of influenza vaccination should be discussed prior to vaccination, including the risks of not being immunized.
#### Choice of influenza vaccine
A variety of influenza vaccines are authorized for use in Canada, some of which are authorized for use only in specific age groups. Furthermore, not all products will necessarily be made available in all jurisdictions and availability of some products as part of publicly funded provincial and territorial programs may be limited. Therefore, the choice of influenza vaccine has become more complex.
#### Dose and route of administration
The dose and route of administration vary by influenza vaccine product:
* Most IIVs are administered as a 0.5 mL intramuscular (IM) injection
* IIV4-HD (Fluzone® High-Dose Quadrivalent) is administered as a 0.7 mL IM injection and authorized for adults 65 years of age and older.
* MF59-adjuvanted IIV3-Adj (Fluad®) is administered as a 0.5 mL IM injection and authorized for adults 65 years of age and older. A pediatric formulation is also available (Fluad Pediatric®), and is administered as a 0.25 mL IM injection for children 6 to 23 months of age.
* RIV4 (Supemtek™) is administered as a 0.5 mL IM injection and authorized for adults 18 years of age and older.
* LAIV (FluMist® Quadrivalent) is administered as 0.2 mL given intranasally (0.1 mL in each nostril) and authorized for individuals 2 to 59 years of age.
See [Appendix B](#a9) for information on characteristics of all influenza vaccines expected to be available for use in Canada for the 2023–2024 influenza season.
#### Schedule
NACI recommends that:
* Adults and children 9 years of age and older should receive 1 dose of influenza vaccine each year; and
* Children 6 months to less than 9 years of age who have never received the seasonal influenza vaccine in a previous influenza season should be given 2 doses of influenza vaccine in the current season, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been vaccinated with one or more doses of seasonal influenza vaccine in any previous season should receive 1 dose of influenza vaccine per season thereafter.
#### Contraindications
For all influenza vaccines (IIV, RIV and LAIV), NACI recommends that influenza vaccination should not be given to:
* People who have had an anaphylactic reaction to a specific influenza vaccine, or to any of the components of a specific influenza vaccine, with the exception of egg
+ Egg allergy is not a contraindication for influenza vaccination, as there is a low risk of adverse events (AEs) associated with the trace amounts of ovalbumin allowed in some influenza vaccines manufactured using eggs. Egg-allergic individuals may be vaccinated against influenza using any age-appropriate product, including LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg, and in any setting where vaccines are routinely administered. Cell culture-based (IIV4-cc) and recombinant (RIV4) vaccines are egg-free (ovalbumin-free).
+ As with any vaccine product, all vaccine providers should be prepared to manage possible allergic reactions, including anaphylaxis, and have the necessary equipment to respond to a serious adverse event at all times.
+ If an individual is found to have an anaphylactic reaction to a component in one influenza vaccine, consideration may be given to offering another influenza vaccine that does not contain the implicated component, in consultation with an allergy specialist. Individuals who have an allergy to substances that are not components of the influenza vaccine are not at increased risk of allergy to influenza vaccine.
* People who have developed Guillain-Barré Syndrome (GBS) within 6 weeks of a previous influenza vaccination, unless another cause was found for the GBS
+ For these people, the potential risk for a recurrent episode of GBS associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.
For LAIV, in addition to the above-mentioned contraindications, NACI also recommends that LAIV should not be given to:
* People with severe asthma (defined as currently on oral or high-dose inhaled glucocorticosteroids or active wheezing) or medically attended wheezing in the 7 days prior to the proposed date of vaccination, due to increased risk of wheezing following administration of LAIV
+ LAIV is not contraindicated for people with a history of stable asthma or recurrent wheeze which is not active.
* Children less than 24 months of age, due to increased risk of wheezing following administration of LAIV
* Children 2 to 17 years of age currently receiving aspirin or aspirin-containing therapy, because of the association of Reye's syndrome with aspirin and wild-type influenza infection
* Pregnant individuals, because it is a live attenuated vaccine and there is a lack of safety data at this time
+ LAIV is not contraindicated in breastfeeding (lactating) individuals; however, there are limited data for the use of LAIV in this population.
* People who are immunocompromised due to underlying disease and/or therapy
+ LAIV is not considered to be contraindicated for children living with stable HIV infection on anti-retroviral therapy (ART; also sometimes referred to as highly active anti-retroviral therapy [HAART)]) and with adequate immune function.
+ NACI previously concluded that the quantity of evidence available on the immunogenicity and safety of LAIV in adults with HIV is insufficient to justify a recommendation for the use of LAIV in this group. In addition, NACI considered that most studies found LAIV to have similar or slightly lower efficacy than IIV in adults and consequently recommends IIV for adults with chronic conditions.
+ Refer to the [Recommendation on the Use of Live Attenuated Influenza Vaccine (LAIV) in HIV-Infected Individuals](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/live-attenuated-influenza-vaccine-hiv-infected-individuals.html#use)) for additional information.
LAIV should not be administered until 48 hours after the last dose of an antiviral agent active against influenza (e.g., oseltamivir, zanamivir), and such antiviral agents, unless medically indicated, should not be administered until 2 weeks after receipt of LAIV so that the antiviral agents do not inactivate the replicating vaccine virus.
* If these antiviral agents are administered within this time frame (i.e., from 48 hours pre-vaccination with LAIV to 2 weeks post-vaccination), re-vaccination should take place at least 48 hours after the antivirals are stopped, or a parenteral inactivated or recombinant influenza vaccine could be given at any time.
#### Precautions
NACI recommends that:
* Influenza vaccination should usually be postponed in people with serious acute illnesses until their symptoms have abated;
+ Influenza vaccination should not be delayed because of minor or moderate acute illness, with or without fever. Immunizers should refer to [Guidance on the use of influenza vaccine in the presence of COVID-19](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-use-influenza-vaccine-covid-19.html) for additional advice on this issue from PHAC.
+ More information on vaccinating individuals during acute illness can be found in the Canadian Immunization Guide's section on [Contraindications and precautions associated with specific conditions: Acute Illness](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html#a4).
* If significant nasal congestion is present that might impede delivery of LAIV to the nasopharyngeal mucosa, parenteral inactivated or recombinant influenza vaccine can be administered or LAIV can be deferred until resolution of the congestion;
* LAIV recipients should avoid close contact with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection; and
* LAIV recipients who are less than 18 years of age should avoid the use of aspirin-containing products for at least 4 weeks after receipt of LAIV because of the association of Reye's syndrome with aspirin-containing products and wild-type influenza infection.
#### Concurrent administration with other vaccines
NACI recommends that:
* Administration of COVID-19 vaccines may occur concurrently with (i.e., same day), or at any time before or after seasonal influenza immunization for those aged 6 months and older. Readers should consult the [Canadian Immunization Guide COVID-19 chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) for updated NACI guidance on the concurrent administration of influenza and COVID-19 vaccines as the number of authorized COVID-19 vaccines and the age groups eligible to receive them expand.
+ It should be noted that no studies have been conducted on the co-administration of recombinant zoster vaccine (RZV) with adjuvanted or high-dose influenza vaccine. No immune response interference or safety concerns have been demonstrated when RZV is administered concurrently with standard, un-adjuvanted vaccine[Footnote 4](#fn4).
Different injection sites and separate needles and syringes should always be used for concurrent parenteral injections. If multiple injections in the same limb are required, the injection sites should be separated by at least 2.5 cm (1 inch).
### Why
* Vaccination is the most effective way to prevent influenza and its complications.
* Vaccination can help prevent the spread of influenza from person-to-person.
* Although most people will recover fully from influenza infection in 7 to 10 days, influenza can lead to severe disease, complications, or both, including hospitalization and death. Influenza is the most common vaccine preventable disease leading to hospitalization and death in adults.
* Annual vaccination is required because the specific strains in the vaccine are reviewed each year by WHO and are often changed to provide a better match against the viruses expected to circulate in that given year, and because the body's immune response to influenza vaccination may be transient and may not persist beyond a year.
I. Introduction
---------------
The National Advisory Committee on Immunization (NACI) provides PHAC with annual recommendations regarding the use of seasonal influenza vaccines, which reflect identified changes in influenza epidemiology, immunization practices and influenza vaccine products authorized and available for use in Canada. This document, the "National Advisory Committee on Immunization (NACI) Statement on Seasonal Influenza Vaccine for 2023–2024", updates NACI's recommendations regarding the use of seasonal influenza vaccines.
### I.1 New or updated information for 2023–2024
#### Use of seasonal influenza vaccine in the context of coronavirus disease 2019 (COVID-19)
##### Guidance on the use of seasonal influenza vaccine in the presence of COVID-19
Seasonal influenza presents an ongoing disease burden in Canada during the fall and winter months. Influenza vaccine is the most effective way to prevent influenza illness and influenza-related complications and is an important component of managing health care system capacity during the influenza season, particularly in the context of ongoing COVID-19 activity.
PHAC, in consultation with NACI and the Canadian Immunization Committee, has developed guidance on the administration of seasonal influenza vaccine to support provincial and territorial vaccine programs and primary care providers during the COVID-19 pandemic:
* [Guidance on the use of seasonal influenza vaccine in the presence of COVID-19](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-use-influenza-vaccine-covid-19.html)
The guidance on this page is based on currently available scientific evidence and expert opinion and will be updated as necessary throughout the influenza season. This web page should be considered in concert with recommendations regarding the use of seasonal influenza vaccines provided in this NACI Statement*.*
##### Guidance on concurrent administration of influenza and COVID-19 vaccines
NACI guidance outlines that administration of COVID-19 vaccines may occur at the same time as, or at any time before or after influenza immunization (including all parenteral or intranasal seasonal influenza vaccines) for those aged 6 months of age and older.
Readers should consult the [COVID-19 vaccine: Canadian Immunization Guide chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) for updated NACI guidance and further information on concurrent administration of COVID-19 vaccines with influenza vaccines and across all eligible age groups.
#### Updated recommendations on the use of mammalian cell culture-based quadrivalent influenza vaccine (IIV4-cc)
Flucelvax® Quad (IIV4-cc) is a standard dose mammalian cell culture-based quadrivalent inactivated seasonal influenza vaccine that was first authorized for use in Canada in adults and children 9 years of age and older on November 22, 2019 with authorization extended to children 2 years of age and older on March 8, 2021. Recommendations and supporting evidence on the use of Flucelvax Quad in adults and children 9 years of age and older can be found in the [NACI Supplemental Statement – Mammalian Cell Culture-Based Influenza Vaccines](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/mammalian-cell-culture-based-influenza-vaccines.html) and were also incorporated into the Statement on Seasonal Influenza Vaccine for 2021–2022. Recommendations and supporting evidence on the use of Flucelvax Quad in adults and children 2 years of age and older were incorporated into the [Statement on Seasonal Influenza Vaccine for 2022–2023](/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html).
On March 8, 2022, Health Canada approved an expanded age indication for the use of Flucelvax Quad in children down to 6 months of age and older. Based on a review of Health Canada assessments of clinical trial evidence submitted by the manufacturer in support of the age indication extension, NACI has concluded that Flucelvax Quad is safe and has non-inferior immunogenicity compared to standard quadrivalent inactivated influenza vaccines. Therefore,
NACI recommends that Flucelvax Quad may be considered among the quadrivalent influenza vaccines offered to adults and children 6 months of age and older. (Discretionary NACI recommendation).
#### Updated recommendations on the use of egg-based quadrivalent influenza vaccine (IIV4-SD)
Influvac® Tetra (IIV4-SD) is a split virus standard quadrivalent inactivated influenza vaccine that was first authorized for use in Canada in adults on March 1, 2019 and subsequently in children 3 years of age and older on February 20, 2020. Recommendations and supporting evidence on the use of Influvac Tetra in adults and children 3 years of age and older were incorporated into the [Statement on Seasonal Influenza Vaccine for 2021–2022.](/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2021-2022.html)
On November 30, 2021, Health Canada approved an expanded age indication for the use of Influvac Tetra in children 6 months of age and older. Based on a review of Health Canada assessments of clinical trial evidence submitted by the manufacturer in support of the age indication extension, NACI has concluded that Influvac Tetra appears to be safe and well-tolerated (relative to the control non-influenza vaccines) based on direct evidence in children 6 to 35 months of age. However, there is currently insufficient evidence that Influvac Tetra is effective and elicits a protective immune response against seasonal influenza in children 6 to 35 months of age. Therefore:
NACI recommends that Influvac Tetra may be considered among the standard dose inactivated quadrivalent influenza vaccines offered to individuals 3 years of age and older. (Discretionary NACI recommendation)
At this time, NACI concludes that there is insufficient evidence for recommending vaccination with Influvac Tetra in children younger than 3 years of age. (Discretionary NACI recommendation).
NACI will continue to monitor the evidence as it emerges, and update recommendations as needed.
#### Standard-dose trivalent inactivated influenza vaccine (IIV3-SD) authorization and availability
All standard dose, egg-based inactivated influenza vaccines authorized and available in Canada for the 2023–24 season are expected to be quadrivalent. There are no trivalent formulations (IIV3-SD) authorized (discontinued post-market) or available, but data that involve these vaccines continue to be included for reference.
#### Updated presentation of the statement
The presentation of this document has been updated from previous seasons' statements to improve readability and access to information. The content in some sections has been reduced in length, while maintaining a focus on key information required for decision making. Links to other published NACI documents containing the more detailed content removed from the current statement have been integrated.
For a summary of clinical information on seasonal influenza vaccine administration for vaccine providers, please refer to the new [Influenza vaccine chapter of the Canadian Immunization Guide.](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html)
### I.2 Background
The [World Health Organization's (WHO) recommendations on the composition of influenza virus vaccines](https://www.who.int/teams/global-influenza-programme/vaccines/who-recommendations) are typically available in February of each year for the upcoming season in the Northern Hemisphere. The WHO recommends that three influenza strains be included in the trivalent seasonal influenza vaccine: one influenza A(H1N1), one influenza A(H3N2), and one influenza B. Quadrivalent seasonal influenza vaccines should contain the three strains recommended for the trivalent vaccine, as well as an influenza B virus from the lineage that is not included in the trivalent vaccine.
Health care providers in Canada should offer the seasonal influenza vaccine as soon as feasible after it becomes available and is delivered in the fall, since seasonal influenza activity may start as early as October in the Northern Hemisphere. Decisions regarding the precise timing of vaccination in a given setting or geographic area should be made according to local epidemiologic factors (influenza activity, timing, and intensity), opportune moments for vaccination, as well as programmatic considerations. Further advice regarding the timing of influenza vaccination programs may be obtained through consultation with local public health agencies.
Although vaccination before the onset of the influenza season is strongly preferred, influenza vaccine may still be administered up until the end of the season. Delayed administration may result in lost opportunities to prevent infection from exposures that occur prior to vaccination; therefore, individuals seeking or considering vaccination should be informed that vaccine administered during an influenza outbreak may not provide optimal protection. Vaccine providers should use every opportunity to administer influenza vaccine to individuals at risk who have not already been vaccinated during the current season, even after influenza activity has been documented in the community.
Every year, individuals with influenza and influenza-related complications increase the pressures on the healthcare system in the fall and winter months. Particularly given the added burden on the healthcare system during the COVID-19 pandemic, effective prevention of influenza by vaccination is a critical tool to mitigate on-going health system stress.
II. Methods
-----------
Details regarding NACI's evidence-based process for developing a statement are outlined in [Evidence-based recommendations for immunization − Methods of the National Advisory Committee on Immunization](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2009-35/methods-national-advisory-committee-immunization.html).
In brief, the broad stages in the preparation of this NACI advisory committee statement included:
* Knowledge synthesis
* Synthesis of the body of evidence of benefits and harms, considering the quality of the synthesized evidence and magnitude and certainty of effects observed across the studies
* Translation of evidence into recommendations
Annual influenza vaccine recommendations are developed by the Influenza Working Group (IWG) for consideration by NACI. Recommendation development includes review of a variety of issues including the burden of influenza illness and the target populations for vaccination; safety, immunogenicity, efficacy, and effectiveness of influenza vaccines; vaccine schedules. In addition, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing their recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels. These programmatic factors include cost-effectiveness, as well as ethics, equity, feasibility, and acceptability (EEFA). NACI uses a published, peer-reviewed framework and evidence-informed tools to ensure that issues related to EEFA are systematically assessed and integrated into its guidance. The NACI Secretariat applied this framework with accompanying evidence-informed tools (Ethics Integrated Filters, Equity Matrix, Feasibility Matrix, Acceptability Matrix) to systematically consider these programmatic factors for the development of clear, comprehensive, appropriate recommendations for timely, transparent decision-making. For details on the development and application of NACI's EEFA Framework and evidence-informed tools, please see [A framework for the systematic consideration of ethics, equity, feasibility, and acceptability in vaccine program recommendations](https://doi.org/10.1016/j.vaccine.2020.05.051).
The annual update of the *NACI Statement on Seasonal Influenza Vaccine* led by the NACI Influenza Working Group (IWG) involves a thorough review and evaluation of the literature as well as discussion and debate at the scientific and clinical practice levels. In the preparation of the 2023–2024 seasonal influenza vaccine recommendations, NACI's IWG identified the need for evidence reviews for new topics, and then reviewed and analyzed the available evidence, and proposed new or updated recommendations according to the NACI evidence-based process for developing recommendations. For the 2023–2024 influenza season, the NACI IWG reviewed evidence and developed new recommendations regarding the use of two vaccines with changes in authorization (expanded use in individuals six months of age and older): 1) Influvac Tetra, an egg-based, quadrivalent inactivated influenza vaccine (IIV4-SD) and 2) Flucelvax Quad, a mammalian cell culture-based, inactivated seasonal influenza vaccine (IIV4-cc). The NACI IWG reviewed and analyzed the available pre-licensure clinical trial data and Health Canada's Clinical Review Reports for these two vaccines. On October 3rd, 2022, the available evidence and the new recommendations proposed by the IWG were presented for consideration and approval by NACI. Following a thorough review of the evidence, the committee voted on specific recommendations. The description of relevant considerations, rationale for specific decisions, and identified knowledge gaps are described in this statement.
III. Epidemiology
-----------------
### Disease description
Influenza is a respiratory illness caused by the influenza A and B viruses in humans and can cause mild to severe illness, including hospitalization or death. Certain populations, such as young children, older adults, and those with chronic health conditions, are at higher risk for serious influenza complications such as viral pneumonia, secondary bacterial pneumonia, and worsening of underlying medical conditions.
### Infectious agent
There are two main types of influenza virus that cause seasonal epidemics in humans: A and B. Influenza A viruses are classified into subtypes based on two surface proteins: hemagglutinin (HA) and neuraminidase (NA). Three subtypes of HA (H1, H2, and H3) and two subtypes of NA (N1 and N2) are recognized among influenza A viruses as having caused widespread human disease over the past decades. Immunity to the HA and NA proteins reduces the likelihood of infection and together with immunity to the internal viral proteins, lessens the severity of disease if infection occurs.
Influenza B viruses have evolved into two antigenically distinct lineages since the mid-1980s, represented by B/Yamagata/16/88-like and B/Victoria/2/87-like viruses. Viruses from both the B/Yamagata and B/Victoria lineages have contributed variably to influenza illness each year. Since the onset of the COVID-19 pandemic, a reduction in seasonal influenza virus diversity has been observed globally[Footnote 5](#fn5)[Footnote 6](#fn6). In particular, an absence of B/Yamagata detections has been noted[Footnote 5](#fn5).
Over time, antigenic variation (antigenic drift) of strains occurs within an influenza A subtype or a B lineage. The possibility of antigenic drift, which may occur in one or more influenza virus strains, requires the formulation of seasonal influenza vaccines be re-evaluated annually, with one or more vaccine strains changing in most seasons.
### Transmission
Influenza is primarily transmitted by aerosols and droplets spread through coughing or sneezing, and through direct or indirect contact with respiratory secretions.
The incubation period of seasonal influenza is usually about 2 days but can range from 1 to 4 days[Footnote 7](#fn7). Adults may be able to spread influenza to others from 1 day before symptom onset to approximately 5 days after symptoms start. Children and people with weakened immune systems may be infectious longer.
### Risk factors
The people at greatest risk of influenza-related complications are adults and children with chronic health conditions (see [List 1](#l1)), residents of nursing homes and other chronic care facilities, adults 65 years of age and older, children 0 to 59 months of age, pregnant individuals, and Indigenous peoples.
### Seasonal and temporal patterns
Influenza activity in Canada is usually low in the late spring and summer, begins to increase over the fall, and peaks in the winter months. Depending on the year, one or more peaks may occur as early as the fall and into the spring. Influenza season in Canada usually begins in December and lasts 12 to 16 weeks but can start as early as October or as late as February, and last for as long as 20 weeks. Although one strain often predominates, more than one influenza strain typically circulates each season.
### Spectrum of clinical illness
Classically, symptoms of influenza include the sudden onset of fever, cough, and muscle aches. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. However, influenza can cause a range of symptoms, from asymptomatic infection through mild acute respiratory illness (a "cold") to severe influenza pneumonia. Most people will recover within a week or 10 days. More rarely, central nervous system manifestations, acute myositis, myocarditis, or pericarditis have been described. In addition, complications including pneumonia, respiratory failure, cardiovascular complications, or worsening of underlying chronic medical conditions may occur. Influenza is also associated with a significantly increased risk of myocardial infarction and stroke in the 7 to 14 days after infection, and with Guillain-Barre syndrome with onset 1 to 6 weeks after infection[Footnote 8](#fn8).
### Disease incidence
#### Global
Before the COVID-19 pandemic, worldwide annual epidemics resulted in approximately one billion cases of influenza, three to five million cases of severe illness, and 290,000 to 650,000 deaths. The global annual attack rate is estimated to be 5 to 10% in adults and 20 to 30% in children[Footnote 1](#fn1). Global influenza circulation was at a historical low during the 2020-2021 influenza season, when public health measures (e.g., masking, social distancing) effectively suppressed seasonal influenza activity. During the 2021-2022 Northern Hemisphere season, influenza activity returned to varying degrees in different jurisdictions. During the 2022 Southern Hemisphere season, activity appeared to return to a pre-pandemic level, although incomplete data for the season, changes in testing associated with the pandemic, and the substantial inter-season variability of influenza activity make it difficult to make definitive conclusions.
For current international influenza activity information, refer to WHO's [Global Influenza Program website](https://www.who.int/teams/global-influenza-programme/surveillance-and-monitoring/influenza-updates/current-influenza-update).
#### National
Together, influenza and pneumonia are ranked among the top 10 leading causes of death in Canada[Footnote 9](#fn9). Nationally, influenza has been estimated to cause approximately 12,200 hospitalizations and approximately 3,500 deaths annually[Footnote 10](#fn10)[Footnote 11](#fn11). The FluWatch program is Canada's national surveillance system, which monitors the spread of influenza and influenza-like illnesses (ILI) continually throughout the year. In the five seasons prior to the COVID-19 pandemic (2014–2015 to 2018-2019 season), an average of 40,000 laboratory-confirmed cases of influenza were reported to FluWatch each year. However, most influenza infections are not laboratory-confirmed, so the number of cases reported to FluWatch is a significant underestimate of the true number of infections.
The burden of influenza-associated illness and death varies every year, depending on various factors such as the type of circulating viruses in the season and the populations affected[Footnote 12](#fn12). Notably, Canada's 2020-2021 seasonal influenza activity did not reach seasonal threshold and was at a historical low in the context of the public health measures that were implemented to reduce COVID-19 transmission[Footnote 13](#fn13)[Footnote 14](#fn14)[Footnote 15](#fn15). Only 69 confirmed cases of influenza were identified during the 2020-2021 season[Footnote 13](#fn13), whereas over 50,000 laboratory confirmed cases are reported on average in a typical influenza season[Footnote 13](#fn13). During the 2021-2022 season, influenza circulation in Canada reached the national seasonal threshold that signals the start of seasonal influenza activity for the first time since the spring of 2020. The 2021-2022 influenza epidemic onset was in April 2022, which is an unusually late start to the influenza season. Although the potential impact of upcoming influenza seasons in the context of COVID-19 is unknown, future influenza outbreaks may be characterized by higher infection rates and severity[Footnote 14](#fn14)[Footnote 15](#fn15). Influenza infection susceptibility may increase due to low immunity in the population given the extended periods of decreased influenza exposure and infection caused by the implementation of COVID-19-related public health measures[Footnote 13](#fn13)[Footnote 16](#fn16)[Footnote 17](#fn17)[Footnote 18](#fn18). Moreover, disease severity may be exacerbated due to the co-circulation and simultaneous infection of COVID-19 and influenza viruses. Additionally, the resurgence of seasonal influenza may not follow usual seasonal patterns[Footnote 19](#fn19)[Footnote 20](#fn20). Information about current influenza activity can be found on the [FluWatch website](/en/public-health/services/diseases/flu-influenza/influenza-surveillance.html). It should be noted that the incidence of influenza is often underreported since the illness may be confused with other viral illnesses and many people with ILI do not seek medical care or have viral diagnostic testing done.
IV. Seasonal influenza vaccines
-------------------------------
### IV.1 Vaccine products authorized for use in Canada
The following sections describe the influenza vaccine products that are authorized for use in Canada for the 2023–2024 season. All influenza vaccines available in Canada have been authorized by Health Canada. However, not all products authorized for use are available in the marketplace. The vaccine manufacturers determine whether they will make any or all of their products available in each market. Provincial and territorial health authorities then determine which of the products available for purchase will be used in their respective publicly funded influenza immunization programs and for which population groups. Not all products will be made available in all jurisdictions and availability of some products may be limited. Officials in individual provinces and territories should be consulted regarding the products available in individual jurisdictions.
The antigenic characteristics of circulating influenza virus strains provide the basis for selecting the strains included in each year's vaccine. Vaccine selection by the WHO generally occurs in February for the fall's Northern Hemisphere influenza season to allow time for the vaccine manufacturers to produce the required quantity of vaccine. All manufacturers that distribute influenza vaccine products in Canada confirm to Health Canada that the vaccines to be marketed in Canada for the upcoming influenza season contain the WHO's recommended antigenic strains for the Northern Hemisphere. Vaccine producers may use antigenically equivalent strains because of their growth properties. The strains recommended for egg-based products may differ somewhat from the strains chosen for cell culture-based products to account for differences in the production platforms.
There are three categories of influenza vaccine authorized for use in Canada: IIV, RIV, and LAIV. Trivalent (3-strain) vaccines contain one A(H1N1) strain, one A(H3N2) strain, and one influenza B strain from one of the two lineages. Quadrivalent (4-strain) vaccines contain the strains in the trivalent vaccine plus an influenza B strain from the other lineage. Most influenza vaccines currently authorized for use in Canada are made from influenza viruses grown in chicken eggs. However, there are two exceptions. The influenza viruses used to produce Flucelvax Quad are propagated in a mammalian cell line (Madin-Darby Canine Kidney [MDCK] cells), while the Supemtek vaccine technology uses recombinant HA produced in a proprietary insect cell line using a baculovirus vector for protein expression.
A summary of the characteristics of influenza vaccines available in Canada during the 2023–2024 influenza season can be found in [Appendix B](#a9). For complete prescribing information, readers should consult the product monographs available through Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
Should additional vaccine preparations become available for use in Canada after the release of this statement and prior to the 2023-24 influenza vaccine season, NACI will communicate relevant information regarding the new vaccine preparations if required.
Refer to [Contents of immunizing agents available for use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 of the CIG for a list of all vaccines authorized for use in Canada.
#### Inactivated influenza vaccine (IIV)
IIVs contain standardized amounts of the HA protein from representative seed strains of the two human influenza A subtypes (H3N2 and H1N1) and either one (for trivalent vaccines) or both (for quadrivalent vaccines) of the two influenza B lineages (Yamagata and Victoria). IIVs currently authorized for use in Canada are a mix of split virus and subunit vaccines, both consisting of disrupted virus particles. In split virus vaccines, the virus has been disrupted by a detergent. In subunit vaccines, HA and NA have been further purified by removal of other viral components. The amount of neuraminidase (NA) in the vaccines is not standardized and not reported. HA-based serum antibody produced to one influenza A subtype provides no protection against strains belonging to another subtype. The potential for trivalent vaccine to stimulate antibody protection across B lineages requires further evaluation and may be dependent upon factors such as age and prior antigenic experience with the two B lineages [Footnote 21](#fn21)[Footnote 22](#fn22) [Footnote 23](#fn23)[Footnote 24](#fn24) [Footnote 25](#fn25)[Footnote 26](#fn26).
All IIVs currently available in Canada are produced in eggs, except for Flucelvax Quad (IIV4-cc), which is a mammalian cell culture-based quadrivalent inactivated, subunit influenza vaccine that is prepared from viruses propagated in mammalian cell lines [proprietary 33016-PF Madin-Darby Canine Kidney (MDCK) cell lines] adapted to grow freely in suspension in culture medium. The production of IIV4-cc does not depend on egg supply as it does not require egg-grown candidate vaccine viruses.
The IIVs available in Canada are in a standard dose formulation or in a formulation designed to enhance the immune response in specific age groups, using a higher dose of HA antigen or the inclusion of an adjuvant. Refer to [Basic immunology and vaccinology](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-14-basic-immunology-vaccinology.html) in Part 1 of the CIG for more information about inactivated vaccines.
Standard-dose IIVs are available in Canada as quadrivalent formulations (IIV4-SD: Afluria® Tetra, Flulaval® Tetra, Fluzone Quadrivalent, and Influvac Tetra; IIV4-cc: Flucelvax Quad). These vaccines are un-adjuvanted, contain a standard dose of antigen (15 µg HA per strain), and are administered as a 0.5 mL dose by IM injection. Influvac Tetra may be administered by IM or deep subcutaneous injection. Trivalent formulations of standard dose unadjuvanted IIVs are no longer authorized or available for use in Canada.
The adjuvanted IIV currently authorized for use in Canada is a trivalent subunit vaccine (IIV3-Adj) that contains the adjuvant MF59, which is an oil-in-water emulsion composed of squalene as the oil phase that is stabilized with the surfactants polysorbate 80 and sorbitan triolate in citrate buffer. IIV3-Adj contains 7.5 µg HA per strain administered as a 0.25 mL dose by IM injection for children 6 to 23 months of age (Fluad Pediatric) or 15 µg HA per strain administered as a 0.5 mL dose by IM injection for adults 65 years of age and older (Fluad). Other IIVs do not contain an adjuvant.
There is one high-dose IIV (IIV-HD) currently authorized for use in Canada; a quadrivalent unadjuvanted, split virus IIV that contains 60 µg HA per strain and is administered as a 0.7 mL dose by IM injection (Fluzone High-Dose Quadrivalent).
#### Recombinant influenza vaccine (RIV)
There is currently only one RIV authorized for use in Canada: Supemtek (RIV4), a quadrivalent unadjuvanted, baculovirus-expressed seasonal influenza vaccine that contains 45 µg HA per strain and is administered as a 0.5 mL dose by IM injection for adults 18 years of age and older. RIV contains recombinant HAs produced in an insect cell line using genetic sequences from cell-derived influenza viruses. The production of RIV does not depend on egg supply as it does not require egg-grown candidate vaccine viruses.
#### Live attenuated influenza vaccine (LAIV)
LAIV contains standardized quantities of fluorescent focus units (FFU) of live attenuated influenza virus reassortants. The virus strains in LAIV are cold-adapted and temperature sensitive, so they replicate in the nasal mucosa rather than the lower respiratory tract, and they are attenuated, so they do not produce ILI. There have been no reported or documented cases, and no theoretical or scientific basis to suggest transmission of vaccine virus would occur to the individual administering LAIV. As a live replicating whole virus formulation administered intranasally by spray, it elicits mucosal immunity, which may more closely mimic natural infection.
A quadrivalent product (LAIV4; FluMist Quadrivalent) is authorized for use in Canada for children 2 to17 years of age and adults 18 to 59 years of age and is given as a 0.2 mL dose (0.1 mL in each nostril). The trivalent formulation (LAIV3) is no longer available in Canada.
### IV.2 Efficacy, effectiveness, and immunogenicity
#### Efficacy and effectiveness
Influenza vaccine has been shown in randomized controlled clinical trials to be efficacious in providing protection against influenza infection and illness. However, the effectiveness of the vaccine—that is, how it performs in settings that are more reflective of usual health care practice—can vary from season to season and by influenza vaccine strain type and subtype. Influenza vaccine effectiveness (VE) depends on how well the vaccine strains match with circulating influenza viruses, the type and subtype of the circulating virus, as well as the health and age of the individual receiving the vaccine. Even when there is a less-than-ideal match or lower VE against one strain, the possibility of lower VE should not preclude vaccination, particularly for people at high risk of influenza-related complications and hospitalization, since vaccinated individuals are still more likely to be protected compared to those who are unvaccinated.
#### Immunogenicity
Antibody response after vaccination depends on several factors, including the age of the recipient, prior and subsequent exposure to antigens, and the presence of immune compromising conditions. Protective levels of humoral antibodies, which correlate with protection against influenza infection, are generally achieved by 2 weeks after vaccination; however, there may be some protection afforded before that time.
#### Additional information
Refer to [Appendix C](#a10) for further information on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccines that are authorized for use in Canada by type: IIV, RIV and LAIV.
Because of potential changes in the circulating influenza virus from year to year and waning immunity in vaccine recipients, annual influenza vaccination is recommended. Although some studies suggest vaccine induced protection may be greater in individuals who have no recent vaccine history, overall, the evidence shows no difference in the effectiveness of repeated influenza vaccination compared to vaccination in the current season only. Importantly, optimal protection against influenza is best achieved through annual influenza vaccination, as repeated vaccination including the current season is consistently more effective than no vaccination in the current season[Footnote 27](#fn27)[Footnote 28](#fn28). Additional information regarding the effects of repeated influenza vaccination on vaccine effectiveness, efficacy, and immunogenicity can be found in the NACI Recommendation on Repeated Seasonal Influenza Vaccination. NACI will continue to monitor this issue.
NACI acknowledges that evidence related to influenza vaccine performance, particularly with respect to vaccine efficacy and effectiveness, is constantly evolving with advances in research methodology and accumulation of data over many influenza seasons. Therefore, the evidence summarized in [Appendix C](#a10) may not include the latest studies. However, NACI continues to closely monitor the emerging evidence on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccines to update and make recommendations when warranted.
### IV.3 Vaccine administration
#### Dose, route of administration, and schedule
With the variety of influenza vaccines available for use in Canada, it is important for vaccine providers to note the specific differences in age indication, route of administration, dosage, and schedule for the products that they will be using (see [Table 1](#t1)). Key relevant details and differences between vaccine products are also highlighted in [Appendix B](#a9).
For influenza vaccines given by the IM route, the anterolateral thigh muscle is the recommended site in infants 6 to 12 months of age. The anterolateral thigh or the deltoid muscle can be used for toddlers and older children. The deltoid muscle of the arm is the preferred injection site in adolescents and adults. For more information on vaccine administration, please refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 of the CIG.
The first time that children 6 months to less than 9 years of age receive seasonal influenza vaccination, a two-dose schedule is required to achieve protection[Footnote 29](#fn29)[Footnote 30](#fn30)[Footnote 31](#fn31). Several studies have looked at whether these two initial doses need to be given in the same season[Footnote 23](#fn23)[Footnote 24](#fn24)[Footnote 32](#fn32). Englund et al. reported similar immunogenicity in children 6 to 23 months of age whether 2 doses were given in the same or separate seasons when there was no change, or only minor vaccine strain change, in vaccine formulation between seasons[Footnote 23](#fn23)[Footnote 24](#fn24). However, seroprotection rates to the B component were considerably reduced in the group that received only one dose in the subsequent season when there was a major B lineage change, suggesting that the major change in B virus lineage reduced the priming benefit of previous vaccination[Footnote 22](#fn22)[Footnote 24](#fn24). Issues related to effective prime-boost when there is a major change in influenza B lineage across sequential seasons require further evaluation[Footnote 33](#fn33). Because children 6 to 23 months of age are less likely to have had prior priming exposure to an influenza virus, special effort is warranted to ensure that a two-dose schedule is followed for previously unvaccinated children in this age group.
Table 1: Recommended dose and route of administration, by age, for influenza vaccine types authorized for the 2023-2024 influenza season
| Age group | Influenza vaccine type
(route of administration) | Number of doses required |
| --- | --- | --- |
| IIV4-SD[Table 1 Footnote a](#t1fna)
(IM) | IIV4-cc[Table 1 Footnote b](#t1fnb)
(IM) | IIV3-Adj[Table 1 Footnote c](#t1fnc)
(IM) | IIV4-HD[Table 1 Footnote d](#t1fnd)
(IM) | RIV4[Table 1 Footnote e](#t1fne)
(IM) | LAIV4[Table 1 Footnote f](#t1fnf)
(intranasal) |
| 6 to 23 months | 0.5 mL[Table 1 Footnote g](#t1fng) | 0.5 mL | 0.25 mL | - | - | - | 1 or 2[Table 1 Footnote h](#t1fnh) |
| 2 to 8 years | 0.5 mL | 0.5 mL | - | - | - | 0.2 mL
(0.1 mL per nostril) | 1 or 2[Table 1 Footnote h](#t1fnh) |
| 9 to 17 years | 0.5 mL | 0.5 mL | - | - | - | 0.2 mL
(0.1 mL per nostril) | 1 |
| 18 to 59 years | 0.5 mL | 0.5 mL | - | - | 0.5 mL | 0.2 mL
(0.1 mL per nostril) | 1 |
| 60 to 64 years | 0.5 mL | 0.5 mL | - | - | 0.5 mL | - | 1 |
| 65 years and older | 0.5 mL | 0.5 mL | 0.5 mL | 0.7 mL | 0.5 mL | - | 1 |
| **Abbreviations:** IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV4-cc: quadrivalent mammalian cell culture based inactivated influenza vaccine; IIV4-HD: high-dose quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; RIV4: quadrivalent recombinant influenza vaccine; IM: intramuscular; LAIV4: quadrivalent live attenuated influenza vaccine. |
|
Table 1 - Footnote a
Afluria® Tetra (5 years and older), Flulaval® Tetra (6 months and older), Fluzone® Quadrivalent (6 months and older), Influvac® Tetra (3 years and older).
[Return to Table 1 Footnote a referrer](#t1fna-rf)
Table 1 - Footnote b
Flucelvax® Quad (6 months and older)
[Return to Table 1 Footnote b referrer](#t1fnb-rf)
Table 1 - Footnote c
Fluad Pediatric®(6 to 23 months) or Fluad®(65 years and older)
[Return to Table 1 Footnote c referrer](#t1fnc-rf)
Table 1 - Footnote d
Fluzone® High-Dose Quadrivalent (65 years and older)
[Return to Table 1 Footnote d referrer](#t1fnd-rf)
Table 1 - Footnote e
Supemtek™ (18 years and older)
[Return to Table 1 Footnote e referrer](#t1fne-rf)
Table 1 - Footnote f
FluMist® Quadrivalent (2 to 59 years)
[Return to Table 1 Footnote f referrer](#t1fnf-rf)
Table 1 - Footnote g
Evidence suggests moderate improvement in antibody response in infants, without an increase in reactogenicity, with the use of full vaccine doses (0.5 mL) for unadjuvanted inactivated influenza vaccines[Footnote 10](#fn10)[Footnote 11](#fn11). This moderate improvement in antibody response without an increase in reactogenicity is the basis for the full dose recommendation for unadjuvanted inactivated vaccine for all ages. For more information, refer to [Statement on Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-acs-5.html).
[Return to Table 1 Footnote g referrer](#t1fng-rf)
Table 1 - Footnote h
Children 6 months to less than 9 years of age receiving seasonal influenza vaccine for the first time in their life should be given 2 doses of influenza vaccine, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been properly vaccinated with one or more doses of seasonal influenza vaccine in the past should receive 1 dose of influenza vaccine per season thereafter.
[Return to Table 1 Footnote h referrer](#t1fnh-rf)
|
#### Booster doses and revaccination
Booster doses are not required within the same influenza season. However, children 6 months to less than 9 years of age who have not previously received the seasonal influenza vaccine require 2 doses of influenza vaccine, with a minimum of 4 weeks between doses. Only one dose of influenza vaccine per season is recommended for everyone else. Two doses of seasonal influenza vaccine in older adults do not appear to improve the immune response to the vaccine compared to one dose[Footnote 34](#fn34).
#### Serological testing
Serologic testing is not necessary or recommended before or after receiving seasonal influenza vaccine.
### IV.4 Storage requirements
Influenza vaccine should be stored at +2°C to +8°C and should not be frozen. Refer to the individual product monographs for further details. Refer to [Storage and Handling of Immunizing Agents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-9-storage-handling-immunizing-agents.html) in Part 1 of the CIG for additional information.
### IV.5 Concurrent administration with other vaccines
All seasonal influenza vaccines, including LAIV, may be given at the same time as, or at any time before or after administration of other vaccines (either live or inactivated), including COVID-19 vaccines for those aged 6 months of age and older as.
NACI will continue to monitor the evidence base, including ongoing and anticipated trials investigating influenza vaccines administered at the same time as, or any time before or after, COVID-19 vaccines and update its recommendations as needed.
Refer to the [COVID-19 vaccine: CIG chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) and latest NACI COVID-19 vaccine guidance for any additional emerging guidance on concurrent administration with COVID-19 vaccines as new products are authorized or there are COVID-19 age eligibility expansions.
No studies were found on potential immune interference between LAIV and other live attenuated vaccines (oral or parenteral) administered within 4 weeks.
Studies on concurrent administration of LAIV3 with measles, mumps, rubella (MMR); measles, mumps, rubella, varicella (MMRV); or live oral polio vaccines did not find evidence of clinically significant immune interference[Footnote 35](#fn35)[Footnote 36](#fn36)[Footnote 37](#fn37). One study reported a statistically significant but not clinically meaningful decrease in seroresponse rates to rubella antigen when administered concomitantly with LAIV.
In theory, the administration of two live vaccines sequentially within less than 4 weeks could reduce the efficacy of the second vaccine. Possible immune mechanisms include: the inhibitory and immunomodulatory effects of systemic and locally produced cytokines on B- and T-cell response and viral replication; immunosuppression induced by certain viruses (such as measles); and direct viral interference as a result of competition for a common niche. Mucosal vaccines may have less impact on a parenteral vaccine and vice versa. The immune response with a mucosal vaccine may be compartmentalized to the mucosa while that to a parenteral vaccine is systemic. It is likely that there is some interaction between the systemic and mucosal compartments; however, the extent to which this interaction occurs is not known.
Given the lack of data for immune interference, and based on expert opinion, NACI recommends that LAIV can be given together with or at any time before or after the administration of any other live attenuated or inactivated vaccine. However, some vaccine providers may continue to choose to give LAIV and other live vaccines separated by at least 4 weeks, based on the theoretical possibility of immune interference, although NACI does not believe that this precaution is necessary for LAIV. The use of a parenteral inactivated or recombinant influenza vaccine would avoid this theoretical concern. Note that the timing rules related to two parenteral live vaccines (e.g., MMR and varicella vaccines) still apply. For more information regarding vaccination administration timing rules, please refer to [Timing of Vaccine Administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) in Part 1 of the CIG.
The target groups for influenza and pneumococcal polysaccharide vaccines overlap considerably. A recent study showed that compared to administration alone, concurrent administration of IIV4 with PCV15 in adults demonstrated non-inferiority of pneumococcal- and influenza-specific antibody responses[Footnote 38](#fn38). The immune response to many PCV components was decreased, but not influenza virus components. The clinical significance of this interaction is not known precisely. Vaccine providers should take the opportunity to vaccinate eligible people against pneumococcal disease when influenza vaccine is given.
When more than one injection is given at a single clinic visit, it is preferable to administer them in different limbs. If it is not possible to do so, injections given in one limb should be separated by a distance of at least 2.5 cm (1 inch). A separate needle and syringe should always be used for each injection.
#### Concurrent administration with other adjuvanted vaccines
Data are limited regarding concurrent administration of newer adjuvanted influenza vaccines with other adjuvanted or non-adjuvanted vaccines.
RZV is an example of a recombinant adjuvanted subunit herpes zoster vaccine (Shingrix®, GlaxoSmithKline) that is authorized for use in Canada in adults 50 years of age and older, and adults 18 years of age or older who are or will be at increased risk of HZ due to immunodeficiency or immunosuppression caused by known disease or therapy; therefore, the target age group for herpes zoster vaccine and influenza vaccine overlap. RZV has been shown to be safe and effective when given concurrently with unadjuvanted, standard dose influenza vaccines[Footnote 4](#fn4). However, no studies have been conducted that have assessed the concurrent administration of RZV with adjuvanted or high dose influenza vaccine[Footnote 39](#fn39). It should be noted that RZV and IIV-adj currently authorized for use in Canada contain the adjuvants AS01B and MF59 respectively. How these adjuvants may interact when RZV and IIV-adj are administered concurrently is not known.
NACI will continue to review the evidence and update guidance accordingly.
### IV.6 Vaccine safety and adverse events
Post-marketing surveillance of influenza vaccines in Canada has shown that seasonal influenza vaccines have a safe and stable profile. In addition to routine surveillance, every year during the seasonal influenza vaccination campaigns, PHAC and the Federal/Provincial/Territorial Vaccine Vigilance Working Group (VVWG) of the Canadian Immunization Committee conduct weekly expedited surveillance of adverse events following immunization (AEFI) for current influenza vaccines to identify vaccine safety signals in a timely manner. Refer to the [Canadian Adverse Events Following Immunization Surveillance System](/en/public-health/services/immunization/canadian-adverse-events-following-immunization-surveillance-system-caefiss.html) (CAEFISS) web page for more information on post-marketing surveillance and AEFIs in Canada. In addition, the Canadian National Vaccine Safety (CANVAS) Network, a national network of sites across Canada for active vaccine safety surveillance, collects and analyzes information on AEFIs after influenza vaccination to provide influenza vaccine safety information to public health authorities during the core weeks of the annual influenza vaccination campaign.
All influenza vaccines currently authorized for use in Canada are considered safe for use in people with latex allergies. The multi-dose vial formulations of inactivated influenza vaccine that are authorized for use in Canada contain minute quantities of thimerosal, which is used as a preservative[Footnote 40](#fn40)[Footnote 41](#fn41) to keep the product sterile. Large cohort studies of administrative health databases have found no association between childhood vaccination with thimerosal-containing vaccines and neurodevelopmental outcomes, including autistic-spectrum disorders[Footnote 42](#fn42). All single dose formulations of IIV, RIV and LAIV are thimerosal-free. Refer to [Vaccine Safety](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) in Part 2 of the CIG for additional information.
#### Common adverse events
With IM administered influenza vaccines, injection site reactions are common but are generally classified as mild and transient. IIV3-Adj tends to produce more extensive injection site reactions than un-unadjuvantedIIV3, but these reactions are also generally mild and resolve spontaneously within a few days. IIV-HD tends to induce higher rates of systemic reactions compared to IIV-SD, but most of these reactions are mild and short-lived. Recombinant vaccines appear to have a similar safety profile to IIVs. The most common AEs experienced by recipients of LAIV are nasal congestion and runny nose.
#### Less common and serious or severe adverse events
Serious adverse events (SAEs) are rare following influenza vaccination, and in most cases, data are insufficient to determine a causal association. Allergic responses to influenza vaccine are a rare consequence of hypersensitivity to some components of the vaccine or its container.
#### Other reported adverse events and conditions
##### Egg-allergic individuals
After careful review of clinical and post-licensure safety data, NACI has concluded that egg-allergic individuals may be vaccinated against influenza using any influenza vaccine, including egg-based vaccines and LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg and without any particular consideration, including vaccination setting. The amount of trace ovalbumin allowed in influenza vaccines that are authorized for use in Canada is associated with a low risk of AE, and in addition, two of the authorized products do not contain any ovalbumin. The observation period post-vaccination is as recommended in [Vaccine Safety](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) in Part 2 of the CIG. As with all vaccine administration, vaccine providers should be prepared with the necessary equipment, knowledge, and skills to respond to allergic reactions, including anaphylaxis, at all times.
Refer to the [Statement on Seasonal Influenza Vaccine for 2018–2019](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2018-2019.html) for safety data supporting this recommendation for IIV and LAIV.
##### Guillain-Barré syndrome
In a review of studies conducted between 1976 and 2005, the United States Institute of Medicine concluded that the 1976 "swine flu" vaccine was associated with an elevated risk of GBS. However, evidence was inadequate to accept or to reject a causal relation between GBS in adults and seasonal influenza vaccination[Footnote 43](#fn43). The attributable risk of GBS in the period following seasonal and monovalent 2009 pandemic influenza vaccination is about one excess case per million vaccinations[Footnote 44](#fn44)[Footnote 45](#fn45). In a self-controlled study that explored the risk of GBS after seasonal influenza vaccination and after influenza health care encounters (a proxy for influenza illness), the attributable risks were 1.03 GBS admissions per million vaccinations compared with 17.2 GBS admissions per million influenza-coded health care encounters[Footnote 45](#fn45).
These findings suggest that both influenza vaccination and influenza illness are associated with small attributable risks of GBS, but the risk of GBS associated with influenza illness is notably higher than with influenza vaccination. The self-controlled study also found that the risk of GBS after vaccination was highest during weeks 2 to 4, whereas for influenza illness, the risk was greatest within the first week after a health care encounter and decreased thereafter but remained significantly elevated for up to 4 weeks.
Although the evidence considering influenza vaccination and GBS is inadequate to accept or reject a causal relation between GBS in adults and seasonal influenza vaccination, avoiding subsequent influenza vaccination of individuals known to have had GBS without other known etiology within 6 weeks of a previous influenza vaccination appears prudent at this time. However, the potential risk of GBS recurrence associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination [Footnote 46](#fn46)[Footnote 47](#fn47) [Footnote 48](#fn48)[Footnote 49](#fn49).
##### Oculorespiratory syndrome
Oculorespiratory syndrome (ORS), the presence of bilateral red eyes and one or more associated respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, or sore throat) that starts within 24 hours of vaccination, with or without facial oedema, was identified during the 2000–2001 influenza season[Footnote 50](#fn50). Since then, there have been far fewer cases per year reported to CAEFISS[Footnote 51](#fn51). ORS is not an allergic response. People who have an occurrence or recurrence of ORS upon vaccination do not necessarily experience further episodes with future vaccinations.
Individuals who have experienced ORS without lower respiratory tract symptoms may be safely revaccinated with influenza vaccine. Individuals who experienced ORS with lower respiratory tract symptoms should have an expert review. Health care providers who are unsure whether an individual previously experienced ORS versus an immunoglobulin E (IgE) mediated hypersensitivity immune response should seek advice. Data on clinically significant AEs do not support the preference of one vaccine product over another when revaccinating those who have previously experienced ORS.
##### Allergic reactions to previous vaccine doses
Expert review of the benefits and risks of vaccination should be sought for those who have previously experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of influenza vaccination, an apparent significant allergic reaction to the vaccine, or any other symptoms that could indicate a significant allergic reaction (e.g., throat constriction, difficulty swallowing) that raise concern regarding the safety of revaccination. This advice may be obtained from experts in infectious disease, allergy, and immunology, or public health that can be found in various health settings, including the [Special Immunization Clinic (SIC) network](https://cirnetwork.ca/network/special-immunization/).
In view of the considerable morbidity and mortality associated with influenza and rarity of true vaccine allergy, a diagnosis of allergy to an influenza vaccine should not be made without confirmation, which may involve consultation with an allergy or immunology expert.
##### Drug interactions
Although influenza vaccine can inhibit the clearance of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine. Statins have effects on the immune system in addition to their therapeutic cholesterol-lowering actions. Two published studies have found that adults who are regular statin users (at least 65 years of age[Footnote 52](#fn52) in one study and 45 years and older in the other[Footnote 53](#fn53)) had a decreased response to influenza vaccination as measured by reduced geometric mean titres (GMT)[Footnote 52](#fn52) or reduced VE against medically attended acute respiratory illness[Footnote 53](#fn53). Statins are widely used in the same adult populations who are also at-risk for influenza-related complications and hospitalizations. Therefore, if these preliminary findings are confirmed in future studies, concurrent statin use in adult populations could have implications for influenza VE and how this use is assessed in the measurement of VE. NACI will continue to monitor the literature related to this issue.
##### Guidance on reporting adverse events following immunization
To ensure the ongoing safety of influenza vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in most jurisdictions, reporting is mandatory under the law.
An AEFI is any untoward medical occurrence that follows vaccination whether or not there is a causal relationship with the usage of a vaccine. The AEFI may be any unfavourable or unintended sign, abnormal laboratory finding, symptom, or disease. Any AEFI temporally related to vaccination and for which there is no other clear cause at the time of reporting should be reported. Of particular importance are those AEFIs which are serious or unexpected. A serious AEFI is an adverse event that is life threatening or results in death, requires hospitalization or prolongs an existing hospitalization, results in residual disability or causes congenital malformation[Footnote 54](#fn54). An unexpected AEFI is an event that is not listed in the approved product monograph but may be due to the vaccination, or one whose nature, severity, specificity, or outcome is not consistent with the term or description used in the product monograph[Footnote 54](#fn54). Vaccine providers are asked to [report AEFIs through local public health officials](/en/public-health/services/immunization/federal-provincial-territorial-contact-information-aefi-related-questions.html) and to check for specific AEFI reporting requirements in their province or territory. If there is any doubt as to whether or not an event should be reported, a conservative approach should be taken, and the event should be reported.
For influenza vaccines, the following AEFIs are of particular interest:
* ORS; and
* GBS within 6 weeks following vaccination
Refer to [Reporting Adverse Events Following Immunization (AEFI) in Canada](/en/public-health/services/immunization/reporting-adverse-events-following-immunization/form.html) for additional information about AEFI reporting and to [Vaccine Safety](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) in Part 2 of the CIG for general vaccine safety information, including information on the management of adverse events.
V. Recommendations
------------------
NACI makes the following recommendations for individual-level and public health program-level decision making. Individual-level recommendations are intended for people wishing to protect themselves from influenza or for vaccine providers wishing to advise individual patients about preventing influenza. Program-level recommendations are intended for provinces and territories responsible for making decisions on publicly funded immunization programs. Individual-level and program-level recommendations may differ, as the important factors to consider when recommending a vaccine for a population (e.g., population demographics, economic considerations) may be different than for an individual.
**Recommendation for individual-level decision making**
NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have a contraindication to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended (see [List 1](#l1)).
**Recommendations for public health program-level decision making**
The national goal of the annual influenza immunization programs in Canada is to prevent serious illness caused by influenza and its complications, including death. Programmatic decisions to provide influenza vaccination to target populations as part of publicly funded provincial and territorial programs depend on many factors, such as cost-effectiveness evaluation and other programmatic and operational factors, such as implementation strategies.
* NACI recommends that influenza vaccine should be offered as a priority to the groups for whom influenza vaccination is particularly recommended (see [List 1](#l1) in the section below).
#### List 1: Groups for whom influenza vaccination is particularly recommended
**People at high risk of influenza-related complications or hospitalization**
* All children 6 to 59 months of age
* Adults and children with the following chronic health conditions[List 1 Footnote a](#l1fna):
+ Cardiac or pulmonary disorders (includes bronchopulmonary dysplasia, cystic fibrosis, and asthma);
+ Diabetes mellitus and other metabolic diseases;
+ Cancer, immune compromising conditions (due to underlying disease, therapy, or both, such as solid organ transplant or hematopoietic stem cell transplant recipients);
+ Renal disease;
+ Anemia or hemoglobinopathy;
+ Neurologic or neurodevelopmental conditions (includes neuromuscular, neurovascular, neurodegenerative, neurodevelopmental conditions, and seizure disorders [and, for children, includes febrile seizures and isolated developmental delay], but excludes migraines and psychiatric conditions without neurological conditions)[List 1 Footnote b](#l1fnb)
+ Morbid obesity (defined as BMI of 40 kg/m² and over); and
+ Children 6 months to 18 years of age undergoing treatment for long periods with acetylsalicylic acid, because of the potential increase of Reye's syndrome associated with influenza
* All individuals who are pregnant;
* People of any age who are residents of nursing homes and other chronic care facilities;
* Adults 65 years of age and older; and
* Indigenous peoples.
**People capable of transmitting influenza to those at high risk**
* Health care and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk
* Household contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated:
+ household contacts of individuals at high risk
+ household contacts of infants less than 6 months of age, as these infants are at high risk but cannot receive influenza vaccine
+ members of a household expecting a newborn during the influenza season;
* Those providing regular child care to children 0 to 59 months of age, whether in or out of the home; and
* Those who provide services within closed or relatively closed settings to people at high risk (e.g., crew on a cruise ship).
**Others**
* People who provide essential community services; and
* People who are in direct contact with poultry infected with avian influenza during culling operations
List 1 - Footnote a
Refer to [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) and [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 of the CIG for additional information about vaccination of people with chronic diseases.
[Return to List 1 Footnote a referrer](#l1fna-rf)
List 1 - Footnote b
Refer to the [NACI Statement on Seasonal Influenza Vaccine for 2018–201](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2018-2019.html)9 for rationale supporting the decision to include persons with neurologic or neurodevelopment conditions among the groups for whom influenza vaccination is particularly recommended and the [Literature Review on Individuals with Neurologic or Neurodevelopment Conditions and Risk of Serious Influenza-Related Complications](/en/public-health/services/publications/healthy-living/executive-summary-literature-review-individuals-neurologic-neurodevelopment-conditions-risk-serious-influenza-related-complications.html) for additional details of the evidence reviews that were conducted.
[Return to List 1 Footnote b referrer](#l1fnb-rf)
### V.1 Choice of seasonal influenza vaccine
With the recent availability of a number of new influenza vaccines, some of which are designed to enhance immunogenicity in specific age groups, the choice of product is now more complex.
[Table 2](#t2) provides age group-specific recommendations for the age-appropriate influenza vaccine types authorized and available for use in Canada for individual and public health program-level decision making. Additional information for these recommendations are provided in the section below.
Table 2: Recommendations on choice of influenza vaccine type for individual- and public health program-level decision making by age group
| Recipient by age group | Vaccine types authorized[Table 2 Footnote a](#t2fna)[Table 2 Footnote b](#t2fnb) and available for use | Recommendations on choice of influenza vaccine |
| --- | --- | --- |
| 6 to 23 months | * IIV3-Adj
* IIV4-SD
* IIV4-cc
| * A quadrivalent influenza vaccine authorized for this age group should be used in infants and young children without contraindications, given the burden of influenza B disease in this age group and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine.
+ Currently, there is insufficient evidence for recommending vaccination with Influvac Tetra (IIV4-SD) in children younger than 3 years of age.
* If a quadrivalent vaccine is not available, a trivalent vaccine licensed for this age group should be used.
|
| 2 to 17 years[Table 2 Footnote c](#t2fnc) | * IIV4-SD
* IIV4-cc
* LAIV4
| * An age-appropriate quadrivalent influenza vaccine (IIV4-SD, LAIV4, or IIV4-cc) should be used in children without contraindications or precautions (see text below applicable to LAIV), including those with chronic health conditions, given the burden of influenza B disease in this age group and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine.
+ Currently, there is insufficient evidence for recommending vaccination with Influvac Tetra (IIV4-SD) in children younger than 3 years of age.
* LAIV4 may be given to children with:
+ stable, non-severe asthma;
+ cystic fibrosis who are not being treated with immunosuppressive drugs (e.g., prolonged systemic corticosteroids); and
+ stable HIV infection, i.e., if the child is currently being treated with ART (i.e., HAART) for at least 4 months and has adequate immune function.
* LAIV should not be used in children or adolescents for whom it is contraindicated or for whom there are warnings and precautions such as those with:
+ severe asthma (defined as currently on oral or high-dose inhaled glucocorticosteroids or active wheezing);
+ medically attended wheezing in the 7 days prior to vaccination;
+ current receipt of aspirin or aspirin-containing therapy;
+ immune compromising conditions, with the exception of stable HIV infection, i.e., if the child is currently being treated with HAART for at least 4 months and has adequate immune function;
+ pregnancy
- in pregnancy, IIV4-SD or IIV4-cc should be used instead.
|
| 18 to 59 years | * IIV4-SD
* IIV4-cc
* RIV4
* LAIV4
| * Any of the available influenza vaccines authorized for this age group should be used in adults 18-59 years without contraindications or precautions, noting the following consideration and exceptions:
+ There is some evidence that IIV may provide better efficacy than LAIV in healthy adults; and
* LAIV is not recommended for:
+ Pregnant individuals
- in pregnancy, IIV4-SD, IIV4-cc or RIV4 should be used instead.
+ adults with any of the chronic health conditions identified in [List 1](#l1), including immune compromising conditions; and
+ health care workers
|
| 60 to 64 years | * IIV4-SD
* IIV4-cc
* RIV4
| * Any of the available influenza vaccines authorized for this age group should be used in adults 60 to 64 years without contraindications.
|
| 65 years and older[Table 2 Footnote d](#t2fnd) | * IIV3-Adj
* IIV4-SD
* IIV4-HD
* IIV4-cc
* RIV4
| Individual-level decision-making | Public health program-level decision-making |
| * IIV-HD should be used over IIV-SD, given the burden of influenza A(H3N2) disease and the good evidence of IIV3-HD providing better protection compared to IIV3-SD in adults 65 years of age and older.
+ Other than a recommendation for using IIV-HD over IIV-SD formulations, NACI has not made comparative individual-level recommendations on the use of the other available vaccines in this age group. In the absence of a specific product, any of the available age-appropriate influenza vaccines should be used.
| * Any of the available influenza vaccines authorized in this age group should be used.
+ There is insufficient evidence on the incremental value of different influenza vaccines (i.e., cost-effectiveness assessments have not been performed by NACI) to make comparative public health program-level recommendations on the use of the available vaccines.
|
| **Abbreviations:** ART: antiretroviral therapy; HAART: highly active antiretroviral therapy; IIV: inactivated influenza vaccine; IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-cc: quadrivalent mammalian cell –culture-based inactivated influenza vaccine; IIV4-HD: high-dose quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; RIV4: quadrivalent recombinant influenza vaccine; LAIV: live attenuated influenza vaccine; LAIV4: quadrivalent live attenuated influenza vaccine. |
|
Table 2 - Footnote a
IIV3-SD formulations will not be authorized or available for use in Canada during the 2023-2024 influenza season.
[Return to Table 2 Footnote a referrer](#t2fna-rf)
Table 2 - Footnote b
IIV3-HD formulations will not be authorized or available for use in Canada during the 2023-2024 influenza season.
[Return to Table 2 Footnote b referrer](#t2fnb-rf)
Table 2 - Footnote c
Refer to [Table 3](#t3) for a summary of vaccine characteristics of LAIV compared with IIV in children 2 to 17 years of age.
[Return to Table 2 Footnote c referrer](#t2fnc-rf)
Table 2 - Footnote d
Refer to [Table 4](#t4) for a comparison of the vaccine characteristics of influenza vaccine types available for use in adults 65 years of age and older.
[Return to Table 2 Footnote d referrer](#t2fnd-rf)
|
### V.2 Children
#### Burden of disease in children
Children experience a higher burden of disease due to influenza B infection compared to other age groups. Although children less than 24 months of age comprise approximately 2% of the Canadian population[Footnote 55](#fn55), children 0 to 23 months of age averaged 10.8% of reported influenza B cases (range: 8.3 to 13.7%), using case-based laboratory data from 2001–2012 (excluding 2009). With respect to severe outcomes (e.g., hospitalization, intensive care unit admission, and death), influenza B was confirmed in 15.5 to 58.3% (median: 38.4%) of pediatric influenza-associated hospitalizations (children 16 years of age and younger) reported by the Canadian Immunization Monitoring Program Active (IMPACT) surveillance network between 2004–2005 and 2012–2013 (excluding the 2009–2010 pandemic season)[Footnote 56](#fn56). From 2010-2011 to 2018-2019, inclusively, 29% of IMPACT influenza admissions were for influenza B.
The IMPACT study also found that the proportion of deaths attributable to influenza (any strain) was significantly greater for children admitted to hospital with influenza B (1.1%) than for those admitted with influenza A (0.4%). The proportion of hospitalizations due to influenza B relative to all influenza hospitalizations has been generally similar to the proportion of influenza B detections relative to all influenza infections in the general population during the same time period. Additional information can be found in the [Statement on Seasonal Influenza Vaccine for 2014–2015.](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/statement-on-seasonal-influenza-vaccine-2014-2015.html)
In the NACI [Literature Review on Quadrivalent Influenza Vaccines](http://publications.gc.ca/site/eng/469075/publication.html), a review of B lineage antigens included in the Canadian influenza vaccines and the circulating strains each season indicates a match in five of the 12 seasons from 2001–2002 through to 2012–2013, a moderate match (about 50% from each lineage) in 1 season, and a mismatch in remaining 6 influenza seasons (i.e., 70% or more of the characterized B strains were of the opposite lineage to the antigen in that season's vaccine).
#### Children 6 to 23 months of age
Three types of influenza vaccine are authorized and available for use in children 6 to 23 months of age: IIV3-Adj, IIV4-SD, and IIV4-cc.
Given the burden of influenza B disease in children and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine, NACI recommends that a quadrivalent influenza vaccine should be used. If a quadrivalent vaccine is not available, an available age-appropriate trivalent vaccine (IIV3-Adj) should be used.
The current evidence is insufficient for recommending vaccination with Influvac Tetra (IIV4-SD) in children younger than 3 years of age.
#### Children 2 to 17 years of age
Three types of influenza vaccine are authorized and available for use in children 2 to 17 years of age: IIV4-SD, IIV4-cc, and LAIV4.
The current evidence does not support a recommendation for the preferential use of LAIV in children and adolescents 2 to 17 years of age. Refer to the NACI [Statement on Seasonal Influenza Vaccine for 2018–2019](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2018-2019.html) for information supporting this recommendation.
The current evidence is insufficient for recommending vaccination with Influvac Tetra (IIV4-SD) in children younger than 3 years of age.
##### Children 2 to 17 years of age with chronic health conditions
NACI recommends that any age-appropriate influenza vaccine (IIV or LAIV) may be considered for children 2 to 17 years of age with chronic health conditions; however, LAIV should not be used for children with severe asthma (as defined as currently on oral or high-dose inhaled glucocorticosteroids or with active wheezing), those with medically attended wheezing in the 7 days prior to vaccination, those currently receiving aspirin or aspirin-containing therapy, and those with immune compromising conditions, excluding those with stable HIV infection on HAART and with adequate immune function. LAIV is also contraindicated in adolescents who are pregnant. Children and adolescents for whom LAIV is contraindicated should receive IIV. If IIV is used, NACI recommends that a quadrivalent vaccine should be used. If a quadrivalent vaccine is not available, an age-appropriate trivalent vaccine should be used.
NACI recommends that LAIV may be given to children with stable, non-severe asthma, children with cystic fibrosis who are not treated with immunosuppressive drugs, such as prolonged systemic corticosteroids, and children with stable HIV infection on HAART and with adequate immune function.
Refer to the NACI [Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist®): Supplemental Statement on Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-2.html) for additional information supporting these recommendations.
##### Summary of vaccine characteristics for decision making
IIV4-SD, IIV4-cc, and LAIV4 are authorized for use in Canada for children 2 to 17 years of age. The comparison of the vaccine characteristics of IIV and LAIV, in [Table 3](#t3) below, may be considered in deciding on the preferred vaccine option(s) for use by an individual or a public health program. Note that although data comparing LAIV to IIV4-cc are not available, IIV-cc is comparable to egg-based IIV.
Table 3: Vaccine characteristics of live attenuated influenza vaccine (LAIV) compared with inactivated influenza vaccine (IIV) in children 2 to 17 years of age
| Considerations[Table 3 Footnote a](#t3fna) | LAIV[Table 3 Footnote b](#t3fnb) compared with IIV[Table 3 Footnote c](#t3fnc) |
| --- | --- |
| Efficacy and effectiveness | There was early evidence of superior efficacy of LAIV3 compared with IIV3-SD in children less than 6 years of age from randomized controlled trials, with weaker evidence of superior efficacy in older children. However, later post-marketing and surveillance studies across multiple influenza seasons found comparable protection against influenza for LAIV and IIV, with findings of reduced effectiveness for LAIV against A(H1N1) in some studies. |
| Like IIV4-SD, LAIV4 is expected to provide additional protection against the influenza B strain not contained in IIV3-SD. |
| Immunogenicity | LAIV3 has been shown to be as immunogenic as IIV3-SD, depending on age, with LAIV4 being non-inferior to LAIV3. |
| Safety | Rhinitis (runny nose) and nasal congestion are more common with LAIV. Clinical studies and post-marketing studies showed a similar safety profile to IIV. |
| Contraindications | There are vaccine contraindications specific to LAIV. LAIV is contraindicated for children with severe asthma, medically attended wheezing in the 7 days prior to vaccination, and immune compromising conditions (with the exception of children with stable HIV infection on HAART and with adequate immune function), as well as those currently receiving aspirin or aspirin-containing therapy. LAIV is also contraindicated for pregnant adolescents. |
| Acceptability | Delivery of LAIV as a nasal spray may be preferable for children who are averse to receiving the vaccine by needle injection. |
| **Abbreviations:** HAART: highly active antiretroviral therapy; IIV: inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; LAIV: live attenuated influenza vaccine; LAIV3: trivalent live attenuated influenza vaccine; LAIV4: quadrivalent live attenuated influenza vaccine. |
|
Table 3 - Footnote a
NACI has not assessed the comparative cost-effectiveness of authorized influenza vaccine types for children 2 to 17 years of age.
[Return to Table 3 Footnote a referrer](#t3fna-rf)
Table 3 - Footnote b
The trivalent formulation of LAIV (LAIV3) received a Notice of Compliance from Health Canada in June 2010 and was first used in publicly funded immunization programs in Canada for the 2012–2013 influenza season. The quadrivalent formulation (LAIV4) was approved for use in Canada for the 2014–2015 season and has been in use since that time. LAIV3 is no longer available in Canada.
[Return to Table 3 Footnote b referrer](#t3fnb-rf)
Table 3 - Footnote c
The trivalent IIV3-SD formulations are not expected to be authorized or available in Canada for the 2023-2024 influenza season. Data comparing LAIV to IIV4-cc are not available, however IIV-cc is comparable to egg-based IIV.
[Return to Table 3 Footnote c referrer](#t3fnc-rf)
|
### V.3 Adults
#### Burden of disease in adults
A study focusing on estimates of deaths associated with influenza in the United States has established that the average annual rate of influenza-associated deaths for adults aged 65 years of age and older was 17.0 deaths per 100,000 (range: 2.4 to 36.7)[Footnote 57](#fn57). The study also states that of deaths coded as being influenza- or pneumonia-related, persons 65 years of age and older accounted for 87.9% of the overall estimated annual average number of deaths. When influenza-related deaths among adults 65 years of age and older were estimated using codes for underlying respiratory and circulatory causes of death, these estimates increased to 66.1 deaths per 100,000 (range: 8.0 to 121.1) and 89.4%, respectively. This study described a wide variation in the estimated number of deaths from season to season, which was closely related to the influenza virus types and subtypes in circulation. Estimates presented in the study of yearly influenza-associated deaths with underlying pneumonia and influenza causes (1976 to 2007) reveal a large difference between influenza type A and B with a calculated median of greater than 6,000 deaths associated with influenza type A and half of that number for influenza type B (approximately 3,360) for persons 65 years of age and older. During the 22 seasons in which influenza A(H3N2) was the prominent strain, the average influenza-associated mortality rates were 2.7 times higher than for the nine seasons that it was not (all age groups combined), and on average, there were about 37% more annual influenza-associated deaths, regardless of the primary medical cause of death. A higher risk of hospitalization and death was also reported by Cromer et al. in adults 65 years of age and older, compared to younger adults in their assessment of the burden of influenza in England by age and clinical risk group[Footnote 58](#fn58).
Canadian surveillance data show that hospitalization rates among adults 65 years of age and older were higher during the A(H3N2)-predominant 2014–2015 season compared to the previous five influenza seasons and also compared to the 2012–2013 season when A(H3N2) also predominated; 2014–2015 was a season in which there was a vaccine mismatch with the circulating A(H3N2) strain. Similar to the hospitalization rates, death rates among older adults were highest in the 2014–2015 season compared to the previous five seasons and compared to the previous A(H3N2) season in 2012–2013. Mortality rates among other age groups were similar to or lower than the previous five influenza seasons. Laboratory detections over this same time period showed that influenza seasons in which influenza subtype A(H3N2) predominated, disproportionally affected adults 65 years of age and older, while seasons with greater A(H1N1) detections resulted in a higher proportion of positive cases in younger age groups.
#### Adults 18 to 59 years of age
Four types of influenza vaccine are authorized and available for use in adults 18 to 59 years of age: IIV4-SD, IIV4-cc, RIV4, and LAIV4.
NACI recommends that any of the available influenza vaccines should be used in adults without contraindications to the vaccine. NACI previously found insufficient evidence to recommend the use of LAIV in adults with chronic health conditions due to the potentially better immune response following IIV compared to LAIV in healthy adults in some studies. As such, IIV or RIV should be used for adults with chronic health conditions identified in [List 1](#l1), HCWs or individuals who are pregnant (noting that limited published clinical data pertaining to safety of vaccination with RIV4 during pregnancy is currently available to inform vaccine-associated risks for this population). For further information, refer to [Recommendations on the use of live, attenuated influenza vaccine (FluMist®) Supplemental Statement on Seasonal Influenza Vaccine for 2011-2012](https://www.canada.ca/content/dam/phac-aspc/migration/phac-aspc/publicat/ccdr-rmtc/11vol37/acs-dcc-7/assets/pdf/acs-dcc-7-eng.pdf).
#### Adults 60 to 64 years of age
Three types of influenza vaccine are authorized and available for use in adults 60 to 64 years of age: IIV4-SD, IIV4-cc, and RIV4.
NACI recommends that any of the available age-appropriate influenza vaccines should be used.
#### Adults 65 years of age and older
Five types of influenza vaccine are authorized and available for use in adults 65 years of age and older: IIV3-Adj, IIV4-SD, IIV4-cc, IIV4-HD, and RIV4.
##### Recommendation for individual-level decision making
When available, IIV-HD should be used over IIV-SD, given the burden of influenza A(H3N2) disease and the good evidence of better protection of IIV3-HD compared to IIV3-SD in adults 65 years of age and older. Based on a review of pre-authorization trials, IIV4-HD is non-inferior to IIV3-HD and is therefore expected to provide the same enhanced protection against A(H3N2) compared to SD IIV, including IIV4-SD. Although IIV-HD is expected to provide better protection against influenza A(H3N2) for adults 65 years of age or older, the benefit of providing this vaccine to all adults 65 and over as opposed to any other influenza vaccine is not clear (refer to the next section). NACI is currently conducting an updated review of influenza vaccines in this population.
Any of the available influenza vaccines would be preferable to remaining unvaccinated or requesting individuals to return for vaccine. Therefore, in the absence of a specific product, NACI recommends that any of the available influenza vaccines authorized for this age group should be used.
##### Recommendation for public health program-level decision making
IIV3-HD is expected to provide better protection compared to IIV3-SD. Similarly, IIV4-HD is expected to provide better protection compared to IIV4-SD. The previous assessment completed by NACI demonstrated insufficient evidence to make a comparative recommendation on the use of IIV3-HD over IIV3-SD at the programmatic level and a complete assessment that includes economic considerations has not yet been conducted for IIV4-HD. Therefore, NACI currently recommends that any of the available influenza vaccines should be used for public health programs. NACI is in the process of completing an updated assessment on influenza vaccines for adults 65 years of age and older.
Refer to the NACI [Literature Review Update on the Efficacy and Effectiveness of High-Dose (Fluzone® High-Dose) and MF59-Adjuvanted (Fluad) Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older](/en/public-health/services/publications/healthy-living/executive-summary-literature-review-update-efficacy-effectiveness-fluzone-high-dose-fluad-trivalent-inactivated-influenza-vaccines-adults-65-older.html) for additional information supporting these recommendations.
##### Summary of vaccine characteristics for decision making
There are four types of inactivated influenza vaccines (IIV3-Adj, IIV4-SD, IIV4-cc, and IIV4-HD) and one type of recombinant influenza vaccine (RIV4) authorized for use in Canada for adults 65 years of age and older. The comparison of vaccine characteristics across vaccine types, in [Table 4](#t4) below, may be considered when deciding on the preferred vaccine option(s) for use by an individual or a public health program. Due to the limited available data directly comparing the performance of IIV3-Adj, IIV-HD, IIV4-SD, IIV4-cc, or RIV4, considerations for these vaccines in [Table 4](#t4) are compared to IIV3-SD for which comparative data on efficacy, effectiveness, and/or immunogenicity with each of IIV3-Adj and IIV4-SD are available. Data directly comparing IIV4-cc and IIV4-HD to IIV3-SD are not available. Comparative data on efficacy, effectiveness, and/or immunogenicity of IIV3-cc and IIV3-SD are available.
Table 4: Comparison of the vaccine characteristics of influenza vaccine types available for use in adults 65 years of age and older
| Considerations[Table 4 Footnote a](#t4fna) | Influenza vaccine type |
| --- | --- |
| IIV3-Adj | IIV4-HD[Table 4 Footnote b](#t4fnb) | IIV4-SD | IIV4-cc[Table 4 Footnote c](#t4fnc) | RIV4 |
| Burden of disease | Although influenza-associated morbidity and mortality varies each season, in general there is an increased burden of severe disease in adults 65 years of age and older during influenza seasons when influenza A(H3N2) predominates[Footnote 59](#fn59). |
| Efficacy and effectiveness | Overall, insufficient comparative evidence with IIV3-SD to draw conclusion. | Expected[Table 4 Footnote b](#t4fnb) better protection compared with IIV3-SD, particularly against influenza A(H3N2).
Better protection against the influenza B strain not contained in IIV3-HD. | Better protection against the influenza B strain not contained in IIV3-SD. | Expected[Table 4 Footnote c](#t4fnc) better protection against the influenza B strain not contained in IIV3-SD. | Expected[Table 4 Footnote d](#t4fnd) better protection against the influenza B strain not contained in IIV3-SD.
Potentially[Table 4 Footnote d](#t4fnd) better protection compared with IIV4 SD. |
| Immunogenicity | Non-inferior immune response compared to IIV3-SD. Superiority to IIV3-SD has not been consistently demonstrated. | Expected[Table 4 Footnote b](#t4fnb) superior immune response to influenza A strains compared to IIV3-SD. Superior immune response to the additional B strain compared to IIV3-HD. | Non-inferior immune response to the strains contained in IIV3-SD with superior immune response to the additional B strain. | Non-inferior immune response to the strains contained in IIV3-cc. Superior immune response against the influenza B strain not contained in IIV3-SD. Non-inferior response expected[Table 4 Footnote c](#t4fnc) compared to IIV3-SD. | Expected[Table 4 Footnote e](#t4fne) non-inferior immune response compared to IIV4-HD, IIV4-cc, IIV3-HD, IIV3-Adj. |
| Contraindications | Same contraindications as IIV3-SD. |
| Safety | Higher rate of injection site reactions than IIV3-SD. Higher or comparable systemic reactions compared to IIV3-SD; systemic reactions were mild to moderate and transient.
SAEs were comparable to IIV3-SD and were uncommon. | Higher rate of some systemic reactions than IIV4-SD and the same is expected[Table 4 Footnote b](#t4fnb) compared to IIV3-SD; most systemic reactions were mild and transient.
SAEs were rare and similar in frequency to IIV4-SD and the same is expected compared to IIV3-SD[Table 4 Footnote b](#t4fnb). | Pre-licensure clinical trials and post-marketing surveillance showed a similar safety profile to IIV3-SD. | Pre-licensure clinical trials showed a similar safety profile to IIV3-cc. Similar safety profile to IIV3-SD is expected[Table 4 Footnote c](#t4fnc). | Pre-licensure clinical trials showed a similar safety profile to IIV4-SD, IIV3-HD and IIV-Adj. Similar safety profile to IIV3-SD is expected. |
| **Abbreviations:** IIV3-Adj: adjuvanted egg-based trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-cc: standard-dose cell culture-based quadrivalent inactivated influenza vaccine; IIV4-HD: high-dose quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; RIV4: quadrivalent recombinant influenza vaccine; SAE: serious adverse event. |
|
Table 4 - Footnote a
NACI has not assessed the comparative cost-effectiveness of available influenza vaccine types for adults 65 years of age and older.
[Return to Table 4 Footnote a referrer](#t4fna-rf)
Table 4 - Footnote b
Data directly comparing IIV4-HD to IIV3-SD are not available; however, IIV4-HD has been shown to be non-inferior to IIV3-HD and has a comparable rate of systemic and local reactions. Therefore, information presented here is expected to apply to IIV4-HD as well.
[Return to Table 4 Footnote b referrer](#t4fnb-rf)
Table 4 - Footnote c
Data directly comparing IIV4-cc to IIV3-SD are not available; however, IIV3-cc (licensure never sought in Canada) has been shown to be non-inferior to IIV3-SD. Therefore, information presented here is expected to apply to IIV4-cc as well.
[Return to Table 4 Footnote c referrer](#t4fnc-rf)
Table 4 - Footnote d
Data directly comparing RIV4 to IIV3-SD are not available; however, RIV4 has been shown to provide better protection than IIV4-SD based on one study conducted during a single influenza season (2014-2015).
[Return to Table 4 Footnote d referrer](#t4fnd-rf)
Table 4 - Footnote e
Data directly comparing RIV4 to IIV3-SD are not available; however, RIV4 has been shown to be non-inferior to IIV4-SD, IIV4-cc, IIV3-HD and IIV3-Adj against all tested influenza strains [A(H1N1), A(H3N2), B/Yamagata lineage, and B/Victoria lineage] and has a comparable rate of AEs based on 3 influenza seasons (2014-2015, 2017-2018, 2018-2019). Therefore, information presented here is expected to apply to IIV3-SD as well.
[Return to Table 4 Footnote e referrer](#t4fne-rf)
|
#### Adults with chronic health conditions
NACI recommends that any age-appropriate IIV or RIV, but not LAIV, should be offered to adults with chronic health conditions identified in [List 1](#l1), including those with immune compromising conditions.
#### Pregnant individuals
NACI recommends that any age-appropriate IIV or RIV, but not LAIV, should be offered to pregnant individuals (noting that limited published clinical data pertaining to safety of vaccination with RIV4 during pregnancy is currently available to inform vaccine-associated risks).
Due to a lack of safety data at this time, LAIV should not be administered to pregnant individuals due to the theoretical risk to the fetus from administering a live virus vaccine. LAIV can be administered to breastfeeding individuals.
#### Health care workers
NACI recommends that any age-appropriate IIV or RIV, but not LAIV, should be offered to HCWs.
Comparative studies in healthy adults have found IIV to be similarly or more efficacious or effective compared with LAIV[Footnote 60](#fn60). In addition, as a precautionary measure, LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection.
#### Travellers
Influenza occurs year-round in the tropics. In temperate northern and southern countries, influenza activity generally peaks during the winter season (November to March in the Northern Hemisphere and April to October in the Southern Hemisphere).
* NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older, including travellers, who does not have a contraindication to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended (see [List 1](#l1)).
Vaccines prepared specifically for use in the Southern Hemisphere are not available in Canada, and the extent to which recommended vaccine components for the Southern Hemisphere may overlap with those in available Canadian formulations will vary. A decision for or against revaccination (i.e., boosting) of travellers to the Southern Hemisphere between April and October, if they had already been vaccinated in the preceding fall or winter with the Northern Hemisphere's vaccine, depends on individual risk assessment, the similarity between the Northern and Southern Hemisphere vaccines, the similarity between the Northern Hemisphere vaccine strains and currently circulating strains in the Southern Hemisphere, and the availability of a reliable and safe vaccine at the traveller's destination. Refer to [Immunization of Travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) in Part 3 of the CIG for additional general information.
### V.4 Particularly recommended vaccine recipients
The groups for whom influenza vaccination is particularly recommended are presented in [List 1](#l1). Additional information regarding these particularly recommended recipients is provided below.
#### All children 6 to 59 months of age
On the basis of existing data, NACI recommends the inclusion of all children 6 to 59 months of age among those for whom influenza vaccine is particularly recommended.
Refer to the [Statement on Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-acs-5.html) for additional details on children 6 to 23 months of age and to the [Statement on Seasonal Influenza Vaccine for 2012–2013](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2012-38/statement-on-seasonal-influenza-vaccine-2012-2013.html) for children 24 to 59 months of age.
#### Adults and children with chronic health conditions
As noted in [List 1](#l1), a number of chronic health conditions are associated with increased risk of influenza-related complications and can be exacerbated by a flu infection. Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune-compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected people. Vaccine effectiveness may be lower in people with immune compromising conditions than in healthy adults.
#### All individuals who are pregnant
NACI recommends the inclusion of all individuals who are pregnant, at any stage of pregnancy, among those who are particularly recommended to receive IIV or RIV. This is due to the risk of influenza-associated morbidity amongst those who are pregnant [Footnote 61](#fn61)[Footnote 62](#fn62) [Footnote 63](#fn63)[Footnote 64](#fn64) [Footnote 65](#fn65), evidence of adverse neonatal outcomes associated with respiratory hospitalization during pregnancy or influenza during pregnancy[Footnote 66](#fn66)[Footnote 67](#fn67) [Footnote 68](#fn68)[Footnote 69](#fn69), evidence that vaccination of individuals who are pregnant protects their newborns from influenza and influenza-related hospitalization [Footnote 70](#fn70)[Footnote 71](#fn71) [Footnote 72](#fn72)[Footnote 73](#fn73), and evidence that infants born during influenza season to vaccinated individuals are less likely to be premature, small for gestational age, and of low birth weight than if born to individuals that had not received an influenza vaccine [Footnote 74](#fn74)[Footnote 75](#fn75) [Footnote 76](#fn76)[Footnote 77](#fn77). The risk of influenza-related hospitalization increases with length of gestation (i.e., it is higher in the third trimester than in the second).
The safety of IIV during pregnancy has been reviewed[Footnote 76](#fn76). Active studies of influenza vaccination during pregnancy have not shown evidence of harm to the pregnant individual or fetus associated with influenza vaccination[Footnote 78](#fn78). Although the cumulative sample size of active studies of influenza vaccination in pregnant individuals is relatively small, particularly in the first trimester, passive surveillance has not raised any safety concerns despite widespread use of IIV during pregnancy over several decades [Footnote 63](#fn63)[Footnote 64](#fn64) [Footnote 79](#fn79)[Footnote 80](#fn80). Surveillance following the use of both adjuvanted and un-adjuvanted 2009 pandemic influenza A(H1N1) vaccines in more than 100,000 pregnant women in Canada and more than 488,000 pregnant women in Europe[Footnote 81](#fn81) has not revealed any safety concerns.
Very limited peer-reviewed, published data pertaining to safety of vaccination with RIV4 during pregnancy is currently available to inform vaccine-associated risks. Refer to the [Supplemental Statement on Recombinant Influenza Vaccines](/en/public-health/services/publications/vaccines-immunization/recombinant-influenza-vaccines-supplemental-statement-canadian-immunization-guide-seasonal-influenza-vaccine-2022-2023.html) for more information.
Refer to the [Statement on Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-acs-5.html) and the [Statement on Seasonal Influenza Vaccine for 2012–2013](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2012-38/statement-on-seasonal-influenza-vaccine-2012-2013.html) for further details on influenza vaccination during pregnancy.
#### People of any age who are residents of nursing homes and other chronic care facilities
Residents of nursing homes and other chronic care facilities often have one or more chronic health condition and live in institutional environments that may facilitate the spread of influenza.
#### Adults 65 years of age and older
Hospitalization attributable to influenza in this age group is estimated at 125 to 228 per 100,000 healthy people[Footnote 82](#fn82), and influenza-attributed mortality rates increase with increased age[Footnote 83](#fn83).
#### Indigenous peoples
Based on a body of evidence indicating a higher rate of influenza-associated hospitalization and death among Indigenous peoples, NACI recommends the inclusion of this population among those for whom the influenza vaccine is particularly recommended.
It has been proposed that the increased risk of severe influenza outcomes in the Indigenous populations is a consequence of many factors, including high prevalence of chronic health conditions (e.g., diabetes, chronic lung disease, end-stage kidney disease, cardiovascular disease, obesity)[Footnote 84](#fn84), delayed access to health care, and increased susceptibility to disease because of poor housing and overcrowding[Footnote 85](#fn85)[Footnote 86](#fn86)[Footnote 87](#fn87). A review of the available evidence and update to the recommendations for Indigenous peoples as a group at high-risk of influenza-related complications is planned, with inclusion and consideration of key stakeholder engagement.
### V.5 People capable of transmitting influenza to those at high risk of influenza-related complications or hospitalization
People who are potentially capable of transmitting influenza to those at high risk should receive annual vaccination, regardless of whether the high-risk individual has been vaccinated. Vaccination of Health Care Workers (HCWs) decreases their own risk of illness[Footnote 88](#fn88)[Footnote 89](#fn89), as well as the risk of death and other serious outcomes among the individuals for whom they provide care [Footnote 90](#fn90)[Footnote 91](#fn91) [Footnote 92](#fn92)[Footnote 93](#fn93). Vaccination of HCWs and residents of nursing homes is associated with decreased risk of ILI outbreaks[Footnote 94](#fn94).
People who are more likely to transmit influenza to those at high risk of influenza-related complications or hospitalization include:
* HCWs and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk; and
* Contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated
#### Health care workers and other care providers in facilities and community settings
##### Vaccination of health care workers and other care providers
For the purposes of this statement, HCWs and other care providers in facilities and community settings refers to HCWs, essential care providers, emergency response workers, those who work in continuing care or long-term care facilities or residences, those who provide home care for people at high risk, and students of related health care services. HCWs include any person, paid or unpaid, who provides services, works, volunteers, or trains in a hospital, clinic, or other health care facility.
Transmission of influenza to patients at high risk of influenza-associated complications results in significant morbidity and mortality. Four cluster randomized controlled trials (RCTs) conducted in geriatric long-term care settings have demonstrated that vaccination of HCWs is associated with substantial decreases in influenza-like illness[Footnote 91](#fn91)[Footnote 92](#fn92)[Footnote 93](#fn93) and all-cause mortality[Footnote 90](#fn90)[Footnote 91](#fn91) [Footnote 92](#fn92)[Footnote 93](#fn93)in the residents. In addition, due to their occupation and close contact with people who may be infected with influenza, HCWs are themselves at increased risk of infection[Footnote 95](#fn95).
As previously stated, children 0 to 59 months of age, adults and children with chronic health conditions, pregnant individuals, people of any age who are residents of nursing homes and other chronic care facilities, and adults 65 years of age and older are at greater risk of more severe complications from influenza or worsening of their underlying condition. Given the potential for HCWs and other care providers to transmit influenza to individuals at high risk and knowing that vaccination is the most effective way to prevent influenza, NACI recommends that, in the absence of contraindications, HCWs and other care providers in facilities and community settings should be vaccinated against influenza annually. NACI considers the receipt of influenza vaccination to be an essential component of the standard of care for all HCWs and other care providers for their own protection and that of their patients. This group should consider annual influenza vaccination as part of their responsibilities to provide the highest standard of care.
Although the current influenza vaccine coverage rate for HCWs is higher than for the general public[Footnote 96](#fn96)[Footnote 97](#fn97), it remains below the national goal of 80% coverage for HCWs in Canada[Footnote 98](#fn98). Comprehensive vaccination programs should be adopted that address HCWs' acceptance of the vaccine and facilitate the process of vaccinating HCWs to improve uptake of the influenza vaccine beyond the current level. HCW influenza vaccination programs that have successfully increased vaccine coverage of HCWs have included a combination of education, increased awareness, accessible on-site vaccination delivery options for all HCWs, visible support from senior staff and other leaders, and regular review and improvement of vaccination strategies [Footnote 99](#fn99)[Footnote 100](#fn100) [Footnote 101](#fn101)[Footnote 102](#fn102) [Footnote 103](#fn103)[Footnote 104](#fn104).
##### Outbreak management in health care facilities
As noted in PHAC's [Guidance: Infection Prevention and Control Measures for Healthcare Workers in Acute Care and Long-term Care Settings for seasonal influenza](/en/public-health/services/infectious-diseases/nosocomial-occupational-infections/guidance-infection-prevention-control-measures-healthcare-workers-acute-care-long-term-care-settings.html)*,* all health care organizations should have a written plan for managing an influenza outbreak in their facilities. Inherent in such plans should be policies and programs to optimize HCW's influenza vaccination[Footnote 105](#fn105). As part of outbreak management, the above-mentioned PHAC guidance suggests consideration of chemoprophylaxis for all unvaccinated HCWs, unless contraindications exist. Refer to the [Association of Medical Microbiology and Infectious Disease](https://www.ammi.ca/guidelines/) Canada (AMMI Canada) website for guidelines regarding the use of antiviral medications for prophylaxis.
#### Contacts of individuals at high risk of influenza complications
Vaccination is recommended for contacts, both adults and children, of individuals at high risk of influenza-related complications or hospitalization (see [List 1](#l1)), whether or not the individual at high risk has been vaccinated. These contacts include: household contacts and care providers of individuals at high risk, household contacts and care providers of infants less than 6 months of age (as these infants are at high risk of complications from influenza but cannot receive influenza vaccine), members of a household expecting a newborn during the influenza season, household contacts and care providers (whether in or out of the home) of children 0 to 59 months of age, and providers of services within closed or relatively closed settings with people at high risk of influenza-related complications (e.g., crew on a passenger or cruise ship).
### V.6 Others
#### People who provide essential community services
Vaccination for these individuals should be encouraged to minimize the disruption of services and routine activities during annual influenza epidemics. People who provide essential community services, including healthy working adults, should consider annual influenza vaccination, as this intervention has been shown to decrease work absenteeism due to respiratory and related illnesses [Footnote 88](#fn88)[Footnote 89](#fn89) [Footnote 106](#fn106)[Footnote 107](#fn107) [Footnote 108](#fn108).
#### People in direct contact with poultry infected with avian influenza during culling operations
##### Poultry handlers
Although seasonal influenza vaccination will not prevent avian influenza infection, some countries[Footnote 109](#fn109) and provinces have recommended influenza vaccination on a yearly basis for those working with poultry, based on the rationale that preventing infection with human influenza strains may reduce the theoretical potential for human-avian reassortment of genes, should such workers become co-infected with human and avian influenza viruses[Footnote 110](#fn110).
NACI recommends seasonal influenza vaccination for people who may be in direct contact with poultry infected with avian influenza during culling operations, as these individuals may be at increased risk of avian influenza infection because of exposure during the culling operation [Footnote 111](#fn111)[Footnote 112](#fn112) [Footnote 113](#fn113)[Footnote 114](#fn114). Refer to the [Statement on Seasonal Influenza Vaccine for 2013–2014](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2013-39/statement-on-seasonal-influenza-vaccine-2013-2014.html) for further information supporting this recommendation.
Direct contact may be defined as sufficient contact with infected poultry to allow transmission of an avian virus to the exposed person. The relevant individuals include those performing the cull, as well as others who may be directly exposed to the avian virus, such as supervising veterinarians and inspectors. It is recommended that biosecurity measures such as personal protective equipment and antivirals be used. Refer to [Human Health Issues Related to Avian Influenza in Canada](/en/public-health/services/reports-publications/human-health-issues-related-avian-influenza.html) for PHAC recommendations on the management of domestic avian influenza outbreaks.
##### Swine workers
NACI has concluded that there is insufficient evidence at this time to recommend routine influenza vaccination specifically for swine workers; however, NACI recommends that influenza vaccination should be offered to anyone 6 months of age and older who does not have contraindications to the vaccine.
Refer to the [Statement on Seasonal Influenza Vaccine for 2013–2014](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2013-39/statement-on-seasonal-influenza-vaccine-2013-2014.html) for further information supporting this recommendation.
List of Abbreviations
---------------------
Adj
Adjuvanted
AE
Adverse event
AEFI
Adverse event following immunization
ART
Antiretroviral therapy
CAEFISS
Canadian Adverse Events Following Immunization Surveillance System
cc
Cell cultured
CI
Confidence interval
CIG
Canadian Immunization Guide
DIN
Drug Identification Number
FFU
Fluorescent focus units
GBS
Guillain-Barré syndrome
GMT
Geometric mean titre
GMTR
Geometric mean titre ratio
HA
Hemagglutinin
HAART
Highly active antiretroviral therapy
HCW
Health care worker
HD
High dose
HIV
Human immunodeficiency virus
Ig
Immunoglobulin
IIV
Inactivated influenza vaccine
IIV3
Trivalent inactivated influenza vaccine
IIV3-Adj
Adjuvanted trivalent inactivated influenza vaccine (egg-based)
IIV3-HD
High-dose trivalent inactivated influenza vaccine (egg-based)
IIV3-SD
Standard-dose trivalent inactivated influenza vaccine (egg-based)
IIV4
Quadrivalent inactivated influenza vaccine
IIV4-cc
Mammalian cell culture-based quadrivalent inactivated influenza vaccine
IIV4-HD
High-dose quadrivalent inactivated influenza vaccine (egg-based)
IIV4-SD
Standard-dose quadrivalent inactivated influenza vaccine (egg-based)
ILI
Influenza-like illness
IM
Intramuscular
IMPACT
Immunization Monitoring Program Active
LAIV
Live attenuated influenza vaccine (egg based)
LAIV3
Trivalent live attenuated influenza vaccine (egg based)
LAIV4
Quadrivalent live attenuated influenza vaccine (egg based)
MDCK
Madin-Darby Canine Kidney
MMR
Measles, mumps, and rubella
NA
Neuraminidase
NACI
National Advisory Committee on Immunization
ORS
Oculorespiratory syndrome
PHAC
Public Health Agency of Canada
RCT
Randomized controlled trial
RIV
Recombinant influenza vaccine
RIV4
Recombinant quadrivalent influenza vaccine
RNA
Ribonucleic acid
rVE
Relative vaccine efficacy
RZV
Recombinant zoster vaccine
SAE
Serious adverse event
VE
Vaccine effectiveness
WHO
World Health Organization
Acknowledgments
---------------
**This statement was prepared by:** A Sinilaite, A Gil, W Siu and J Papenburg, on behalf of the NACI Influenza Working Group and was approved by NACI.
**NACI gratefully acknowledges the contribution of:** F Crane, P Doyon-Plourde, C Tremblay, M Tunis, C Williams, M Xi, K Gusic and J Zafack
**NACI Influenza Working Group**
**Members:** J Papenburg (Chair), P De Wals, D Fell, I Gemmill, R Harrison, J Langley, A McGeer, and D Moore
**Former members:** D Kumar, N Dayneka, K Klein, J McElhaney, and S Smith
**Liaison representatives:** L Grohskopf (Centers for Disease Control and Prevention [CDC], United States)
**Ex-officio representatives:** C Bancej (Centre for Immunization and Respiratory Infectious Diseases [CIRID], PHAC), K Daly (First Nations and Inuit Health Branch [FNIHB], Indigenous Services Canada [ISC]), B Warshawsky (Vice President's Office, Infectious Disease Prevention and Control Branch [IDPCB]), and M Russell (Biologics and Genetic Therapies Directorate [BGTD], Health Canada [HC]).
**NACI**
**Members:** S Deeks (Chair), R Harrison (Vice-Chair), J Bettinger, N Brousseau, P De Wals, E Dubé, V Dubey, K Hildebrand, K Klein, J Papenburg, A Pham-Huy, C Rotstein, B Sander, S Smith, and S Wilson.
**Liaison representatives:** L Bill (Canadian Indigenous Nurses Association), LM Bucci (Canadian Public Health Association), E Castillo (Society of Obstetricians and Gynaecologists of Canada), A Cohn (Centers for Disease Control and Prevention, United States), L Dupuis (Canadian Nurses Association), P Emberley (Canadian Pharmacists Association), J Emili (College of Family Physicians of Canada), D Fell (Canadian Association for Immunization Research and Evaluation), S Funnel (Indigenous Physicians Association of Canada), J Hu (College of Family Physicians of Canada), Noah Ivers (College of Family Physicians of Canada), M Lavoie (Council of Chief Medical Officers of Health), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), A Pham-Huy (Association of Medical Microbiology and Infectious Disease Canada), and A Ung (Canadian Pharmacists Association).
**Ex-officio representatives:** V Beswick-Escanlar (National Defence and the Canadian Armed Forces), E Henry (Centre for Immunization and Respiratory Infectious Diseases [CIRID], PHAC), M Lacroix (Public Health Ethics Consultative Group, PHAC), C Lourenco (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada),D MacDonald (CIRID, PHAC), S Ogunnaike-Cooke (CIRID, PHAC), G Poliquin (National Microbiology Laboratory, PHAC), K Robinson (Marketed Health Products Directorate, HC) and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada).
Appendix A: Abbreviations for influenza vaccines
------------------------------------------------
| Influenza vaccine category | Valency | Type | Current NACI abbreviation[Appendix A Footnote a](#tappafna) |
| --- | --- | --- | --- |
| Inactivated influenza vaccine (IIV) | Trivalent
(IIV3) | Standard dose[Appendix A Footnote b](#tappafnb), unadjuvanted,
IM administered, egg-based | IIV3-SD |
| Adjuvanted[Appendix A Footnote c](#tappafnc),
IM administered, egg-based | IIV3-Adj |
| High dose[Appendix A Footnote d](#tappafnd),
unadjuvanted,
IM administered, egg-based | IIV3-HD |
| Quadrivalent (IIV4) | Standard dose[Appendix A Footnote b](#tappafnb),
unadjuvanted,
IM administered, egg-based | IIV4-SD |
| Standard dose[Appendix A Footnote b](#tappafnb), unadjuvanted, IM administered, mammalian cell culture-based | IIV4-cc |
| High dose[Appendix A Footnote d](#tappafnd),
unadjuvanted,
IM administered, egg-based | IIV4-HD |
| Recombinant influenza vaccine (RIV) | Quadrivalent (RIV4) | Recombinant[Appendix A Footnote e](#tappafne),
unadjuvanted,
IM administered | RIV4 |
| Live attenuated influenza vaccine (LAIV) | Trivalent (LAIV3) | Unadjuvanted,
Nasal spray, egg-based | LAIV3 |
| Quadrivalent (LAIV4) | Unadjuvanted,
Nasal spray, egg-based | LAIV4 |
| **Abbreviations:** IIV: inactivated influenza vaccine; IIV3: trivalent inactivated influenza vaccine; IIV3-Adj: adjuvanted egg-based trivalent inactivated influenza vaccine; IIV3-HD: high-dose egg-based trivalent inactivated influenza vaccine; IIV3-SD: standard-dose egg-based trivalent inactivated influenza vaccine; IIV4: quadrivalent inactivated influenza vaccine; IIV4-cc: standard-dose cell culture-based quadrivalent inactivated influenza vaccine; IIV4-HD: high-dose egg-based quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose egg-based quadrivalent inactivated influenza vaccine; IM: intramuscular; RIV: recombinant influenza vaccine; RIV4: recombinant quadrivalent influenza vaccine; LAIV: live attenuated influenza vaccine; LAIV3: egg-based trivalent live attenuated influenza vaccine; LAIV4: egg-based quadrivalent live attenuated influenza vaccine. |
|
Appendix A - Footnote a
The numeric suffix denotes the number of antigens contained in the vaccine ("3" refers to the trivalent formulation and "4" refers to the quadrivalent formulation). The hyphenated suffix "-SD" (where "SD" is used to denote "standard dose" for an IIV) is used when referring to IIV products that do not have an adjuvant, contain 15 µg hemagglutinin (HA) per strain and are administered as a 0.5 mL dose by intramuscular injection; "-cc" (where "cc" denotes "cell culture") refers to an IIV product that is made from influenza virus grown in cell cultures instead of chicken eggs Flucelvax® Quad); "-Adj" (where "Adj" is used to abbreviate "adjuvanted") refers to an IIV with an adjuvant (IIV3-Adj for Fluad® or Fluad Pediatric®); and "-HD" refers to an IIV that contains higher antigen content than 15 µg HA per strain standard IIV dose (IIV3-HD for Fluzone® High-Dose or IIV4-HD for Fluzone® High-Dose Quadrivalent).
[Return to Appendix A Footnote a referrer](#tappafna-rf)
Appendix A - Footnote b
15 µg HA per strain.
[Return to Appendix A Footnote b referrer](#tappafnb-rf)
Appendix A - Footnote c
7.5 µg (in 0.25 mL) or 15 µg (in 0.5 mL) HA per strain.
[Return to Appendix A Footnote c referrer](#tappafnc-rf)
Appendix A - Footnote d
60 µg HA per strain.
[Return to Appendix A Footnote d referrer](#tappafnd-rf)
Appendix A - Footnote e
45 µg HA per strain.
[Return to Appendix A Footnote e referrer](#tappafne-rf)
|
Appendix B: Characteristics of influenza vaccines available for use in Canada, 2023–2024[Appendix B Footnote a](#tappbfna)
--------------------------------------------------------------------------------------------------------------------------
| Product name (manufacturer) | Vaccine Characteristic |
| --- | --- |
| Vaccine type | Route of administration | Authorized ages for use | Antigen content for each vaccine strain | Adjuvant | Formats available | Post-puncture shelf life for multi-dose vials | Thimerosal | Antibiotics (traces) | Production medium |
| Quadrivalent |
| --- |
| **Flulaval® Tetra
(GSK)** | IIV4-SD
(split virus) | IM | 6 months and older | 15 µg HA
/0.5 mL dose | None | 5 mL multi-dose vial | 28 days | Yes
(multi-dose vial only) | None | Egg (Avian) |
| **Fluzone® Quadrivalent
(Sanofi)** | IIV4-SD
(split virus) | IM | 6 months and older | 15 µg HA
/0.5 mL dose | None | 5 mL multi-dose vial
Single-dose pre-filled syringe without attached needle | Up to expiry date indicated on vial label | Yes
(multi-dose vial only) | None | Egg (Avian) |
| **Afluria® Tetra
(Seqirus)** | IIV4-SD
(split virus) | IM | 5 years and older | 15 µg HA
/0.5 mL dose | None | 5 mL multi-dose vial
Single dose pre-filled syringe without attached needle | Up to expiry date indicated on vial label | Yes
(multi-dose vial only) | Neomycin and polymyxin B | Egg (Avian) |
| **Influvac® Tetra
(BGP Pharma ULC, operating as Mylan, d.b.a. Viatris Canada)** | IIV4-SD
(subunit) | IM or deep subcutaneous injection | 6 months and older | 15 µg HA
/0.5 mL dose | None | Single dose pre-filled syringe with or without attached needle | Not applicable | No | Gentamicin or neomycin and polymyxin B[Appendix B Footnote b](#tappbfnb) | Egg (Avian) |
| **Flucelvax® Quad
(Seqirus)** | IIV4-cc
(subunit) | IM | 6 months and older | 15 µg HA
/0.5 mL dose | None | 5 mL multi-dose vial
Single dose pre-filled syringe without attached needle | 28 days | Yes
(multi-dose vial only) | None | Cell culture (Mammalian) |
| **Fluzone® High-Dose Quadrivalent
(Sanofi)** | IIV4-HD
(split virus) | IM | 65 years and older | 60 µg HA
/0.7 mL dose | None | Single dose pre-filled syringe without attached needle | Not applicable | No | None | Egg (Avian) |
| **Supemtek™
(Sanofi)** | RIV4
(recombinant protein) | IM | 18 years and older | 45 µg HA
/0.5 mL dose | None | Single dose pre-filled syringe without attached needle | Not applicable | No | None | Recombinant (Insect vector-expressed) |
| **FluMist® Quadrivalent
(AstraZeneca)** | LAIV4
(live attenuated) | Intranasal | 2 to 59 years | 106.5-7.5 FFU of live attenuated reassortants
/0.2 mL dose
(given as 0.1 mL in each nostril) | None | Single use pre-filled glass sprayer | Not applicable | No | Gentamicin | Egg (Avian) |
| Trivalent |
| **Fluad Pediatric® and Fluad®
(Seqirus)** | IIV3-Adj
(subunit) | IM | * **Pediatric:**
6 to 23 months
* **Adult:**
65 years and older
| * **Pediatric:**
7.5 µg HA
/0.25 mL dose
* **Adult:**
15 µg HA
/0.5 mL dose
| MF59 | Single dose pre-filled syringe without a needle | Not applicable | No | Kanamycin and neomycin | Egg (Avian) |
| **Abbreviations:** FFU: fluorescent focus units; HA: hemagglutinin; IIV3-Adj: adjuvanted egg-based trivalent inactivated influenza vaccine; inactivated influenza vaccine; IIV4-cc: standard-dose cell culture-based quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose egg-based quadrivalent inactivated influenza vaccine; RIV4: quadrivalent recombinant influenza vaccine; IM: intramuscular; LAIV4: quadrivalent live attenuated influenza vaccine; NA: neuraminidase. |
|
Appendix B - Footnote a
Full details of the composition of each vaccine authorized for use in Canada, including other non-medicinal ingredients, and a brief description of its manufacturing process can be found in the product monograph.
[Return to Appendix B Footnote a referrer](#tappbfna-rf)
Appendix B - Footnote b
Neomycin and polymyxin B are only used if gentamicin cannot be used. No trace amounts of neomycin or polymyxin B are present if gentamicin was used.
[Return to Appendix B Footnote b referrer](#tappbfnb-rf)
|
Appendix C: Additional information on vaccine efficacy, effectiveness, immunogenicity, and safety
-------------------------------------------------------------------------------------------------
### Inactivated Influenza Vaccine (IIV)
#### Immunological considerations related to children
Young children have a high burden of illness and their vaccine-induced immune response is not as robust as older children. However, some studies suggest moderate improvement in antibody response in young children, without an increase in reactogenicity, with the use of a full vaccine dose (0.5 mL) for IIV-SDs[Footnote 115](#fn115)[Footnote 116](#fn116)[Footnote 117](#fn117). Based on this moderate improvement in antibody response without an increase in reactogenicity, NACI recommends the use of a 0.5 mL dose for all recipients of IIV-SDs, including young children.
#### Immunological considerations related to older adults and those with immune compromising conditions
The initial antibody response in older adults is lower to some influenza vaccine components [particularly A(H3N2) antigens when compared to those in other age groups, a literature review identified no evidence for a subsequent antibody decline that was any more rapid in older adults than in younger age groups[Footnote 118](#fn118).
Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected patients [Footnote 119](#fn119)[Footnote 120](#fn120) [Footnote 121](#fn121)[Footnote 122](#fn122).
Most studies have shown that administration of a second dose of influenza vaccine in the same season to older adults or other individuals who may have an altered immune response does not result in a clinically significant antibody boost [Footnote 35](#fn35)[Footnote 123](#fn123) [Footnote 124](#fn124)[Footnote 125](#fn125).
### Standard-dose, egg-based, trivalent inactivated influenza vaccine (IIV3-SD)
The following trivalent formulations of standard-dose inactivated influenza vaccines have recently been discontinued and are no longer authorized or available for use in Canada:
* Agriflu®(Seqirus)
* Influvac®(BGP Pharma ULC, operating as Mylan, doing business as (d.b.a.) Viatris Canada)
All IIV-SD products expected to be available in Canada for the 2023-2024 season are quadrivalent. Refer to the [Statement on Seasonal Influenza Vaccine for 2022-2023](/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html) for more detailed information on the use of IIV3-SD and a summary of efficacy, effectiveness, immunogenicity, and safety evidence across eligible age groups.
### Adjuvanted inactivated influenza vaccine (IIV3-Adj)
Vaccines currently authorized for use:
* Fluad®(Seqirus)
* Fluad Pediatric®(Seqirus)
#### Fluad® (adults 65 years of age and older)
**Efficacy and effectiveness**
There is fair evidence that the MF59-adjuvanted Fluad (IIV3-Adj) may be effective at reducing the risk of hospitalization for influenza and influenza complications in older adults compared to unvaccinated individuals. However, there is insufficient evidence that IIV3-Adj is more effective at reducing the risk of hospitalization for influenza and influenza complications in older adults compared to those who received un-adjuvanted subunit IIV3-SD. Refer to the NACI Literature Review Update on the Efficacy and Effectiveness of High-Dose and MF59-Adjuvanted Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older for more information on the efficacy and effectiveness of IIV3-Adj in adults 65 years of age and older. for more information on the efficacy and effectiveness of IIV3-Adj in adults 65 years of age and older.
**Immunogenicity**
The mechanism of action of MF59 is not fully determined and has primarily been studied using in vitro and mouse models. From these studies, it appears that MF59 may act differently from aluminum-based adjuvants. These studies show that MF59 acts in the muscle fibres to create a local immune-stimulatory environment at the injection site[Footnote 126](#fn126). MF59 allows for an increased influx of phagocytes (e.g., macrophages, monocytes) to the site of injection. The recruited phagocytes are further stimulated by MF59, thereby increasing the production of chemokines to attract more innate immune cells and inducing differentiation of monocytes into dendritic cells[Footnote 127](#fn127)[Footnote 128](#fn128). MF59 further facilitates the internalization of antigen by these dendritic cells[Footnote 127](#fn127)[Footnote 129](#fn129). The overall higher number of cells available locally increases the likelihood of interaction between an antigen presenting cell and the antigen, leading to more efficient transport of antigen to the lymph nodes, with resulting improved T cell priming[Footnote 127](#fn127).
There is evidence from RCTs that IIV3-Adj elicits non-inferior immune responses compared to the unadjuvanted subunit and split virus IIV3-SDs; however, superiority of IIV3-Adj to these vaccines by pre-defined criteria has not been consistently demonstrated. Refer to the [Statement on Seasonal Influenza Vaccine for 2018–2019](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2018-2019.html) for more information on the immunogenicity of IIV3-Adj in adults 65 years of age and older. for more information on the immunogenicity of IIV3-Adj in adults 65 years of age and older.
**Safety**
IIV3-Adj produces injection site reactions (pain, erythema, and induration) significantly more frequently than IIV3-SD, but they are classified as mild and transient. Systemic reactions (myalgia, headache, fatigue, and malaise) are comparable or more frequent with IIV3-Adj compared to IIV3-SD and are rated as mild to moderate and transient. SAEs were uncommon and were comparable to IIV3-SD. Refer to the [Recommendations on the use of MF59-adjuvanted Trivalent Influenza Vaccine (Fluad®): Supplemental Statement of Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-4.html) for additional information on the safety of IIV3-Adj in adults 65 years of age and older. for additional information on the safety of IIV3-Adj in adults 65 years of age and older.
#### Fluad Pediatric® (children 6 to 23 months of age)
**Efficacy and effectiveness**
A pre-licensure efficacy trial in children 6 to 71 months of age found a higher relative efficacy for IIV-Adj than the unadjuvanted IIV3-SD[Footnote 130](#fn130). However, the findings of this study should be interpreted with caution. The comparator unadjuvanted IIV3 used in this trial was shown, in an unrelated study, to induce a lower immune response compared to another unadjuvanted IIV3-SD. There were concerns raised by a European Medicines Agency inspection about the quality of diagnostic laboratory testing and validity of ascertainment of influenza cases. The study administered 0.25 mL doses of the comparator unadjuvanted IIV3-SD for children less than 36 months of age, which is lower than the dose of 0.5 mL of unadjuvanted IIV3-SD or IIV4-SD that is recommended for this age group in Canada. Refer to the NACI [Literature Review on Pediatric Fluad Influenza Vaccine Use in Children 6 to 72 Months of Age](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/literature-review-on-pediatric-fluad-influenza-vaccine-use-children-6-72-months.html) for more information on the efficacy and effectiveness of IIV3-Adj in children. for more information on the efficacy and effectiveness of IIV3-Adj in children.
**Immunogenicity**
In children, there is limited but consistent evidence that IIV3-Adj is more immunogenic than IIV3-SD against both influenza A and B [Footnote 130](#fn130)[Footnote 131](#fn131) [Footnote 132](#fn132)[Footnote 133](#fn133) [Footnote 134](#fn134)[Footnote 135](#fn135). In particular, a single dose of IIV3-Adj is more immunogenic than a single dose of IIV3-SD and has been shown in one study to produce greater GMTs than 2 doses of IIV3-SD against influenza A[Footnote 135](#fn135). However, similar to IIV3-SD, IIV3-Adj generally induced a weaker hemagglutination-inhibition antibody response against B strains compared to A strains and therefore 2 doses of IIV3-Adj are still necessary for first-time recipients to achieve a satisfactory immune response against influenza B.
Almost all of the pre-licensure pediatric studies used vaccine formulations of 0.25 mL in children 6 to 35 months of age, both for IIV3-Adj and the comparator unadjuvanted influenza vaccine (NACI recommends 0.5 mL dosage of IIV3-SD or IIV4-SD for all age groups). There is limited immunogenicity evidence comparing IIV3-Adj at 0.25 mL dose to IIV3-SD or IIV4-SD at 0.5 mL dose in the 6 to 23 month age group. Refer to the NACI [Literature Review on Pediatric Fluad Influenza Vaccine Use in Children 6 to 72 Months of Age](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/literature-review-on-pediatric-fluad-influenza-vaccine-use-children-6-72-months.html#s4) for more information on the immunogenicity of IIV3-Adj in children. for more information on the immunogenicity of IIV3-Adj in children.
**Safety**
The safety data in children are consistent with what is known about IIV3-Adj's safety profile in adults. In pediatric trials, IIV3-Adj was more reactogenic than IIV3-SD, with recipients experiencing 10 to 15% more solicited local and systemic reactions. However, most reactions were mild and resolved quickly. A dose-ranging study of MF59-Adj and unadjuvanted IIV3 and IIV4 did not find an increased risk of AEs associated with increased MF59 dose, antigen dose, or the addition of a second B strain; however, the reactogenicity of 15 µg formulations were slightly higher for both adjuvanted and unadjuvanted vaccines compared to the corresponding 7.5 µg formulations[Footnote 133](#fn133).
There are currently no data on the effects of long-term or repeated administration of adjuvanted influenza vaccines in children. The most significant experience with an adjuvanted influenza vaccine in children was the AS03-Adj A(H1N1) pandemic vaccine that has been associated with an increased risk of narcolepsy. A study comparing two AS03-Adj A(H1N1) vaccine products (Pandemrix and Arepanrix) has suggested that the underlying immune mediated mechanism associated with the increased narcolepsy risk may not be initiated by the adjuvant, but by the A(H1N1) nucleoprotein viral antigen, given that the study found significant antigenic differences between the two A(H1N1) pandemic vaccines[Footnote 136](#fn136). However, the pandemic vaccine was a single strain adjuvanted vaccine administered only during one season, and it is unknown what effects a multi-strain adjuvanted vaccine or an adjuvanted vaccine administered for more than one season may have in young children.
Refer to the NACI [Literature Review on Pediatric Fluad Influenza Vaccine Use in Children 6-72 Months of Age](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/literature-review-on-pediatric-fluad-influenza-vaccine-use-children-6-72-months.html#s4d) for additional information on the safety of IIV3-Adj in children.
### Standard-dose, egg-based, quadrivalent inactivated influenza vaccine (IIV4-SD)
Vaccines currently authorized for use:
* Afluria® Tetra (Seqirus)
* Flulaval® Tetra (GlaxoSmithKline)
* Fluzone® Quadrivalent (Sanofi)
* Influvac® Tetra (BGP Pharma ULC, operating as Mylan, d.b.a. Viatris Canada)
#### Literature review on quadrivalent influenza vaccines (IIV4)
In July 2014, NACI published a systematic literature review of the efficacy, effectiveness, immunogenicity, and safety of IIV4 to inform recommendations on immunization against influenza in adults and children 6 months of age and older using quadrivalent influenza vaccines. Refer to the [Literature Review on Quadrivalent Influenza Vaccines](http://publications.gc.ca/site/eng/469075/publication.html) for additional details.
**Efficacy and effectiveness**
One study assessed the efficacy of IIV4-SD in children 3 to 8 years of age. In this study, efficacy was estimated to be 59%, in comparison to children who received hepatitis A vaccine[Footnote 137](#fn137).
**Immunogenicity**
The results of phase II and III trials that compared trivalent formulations to quadrivalent formulations generally showed non-inferiority of the quadrivalent products for the A(H3N2), A(H1N1), and B strain contained in the trivalent formulations. As expected, these studies showed that the immune response to the B strain that was not in the trivalent formulation was better in subjects who received the quadrivalent vaccine, which contained the additional B strain.
**Safety**
Pre-licensure clinical trials (refer to [Literature Review on Quadrivalent Influenza Vaccines](http://publications.gc.ca/site/eng/469075/publication.html)) and post-marketing surveillance showed that IIV4-SD had a similar safety profile to IIV3-SD[Footnote 138](#fn138).
#### Influvac® Tetra (BGP Pharma ULC, operating as Mylan, d.b.a. Viatris Canada)
Following the vaccination recommendations on the use of standard-dose, egg based, quadrivalent inactivated influenza vaccines (IIV4-SD) published in the NACI [Statement on Seasonal Influenza Vaccine for 2022–2023](/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html), an expanded age indication for the use Influvac Tetra was authorized.
Influvac Tetra was first authorized by Health Canada for use in adults 18 years of age and older on March 1, 2019. Subsequently, an expanded age indication down to children 3 years to 17 years of age was authorized on February 20, 2020, based on a review of the Health Canada assessment of data from phase 3 RCTs conducted in several European countries. One RCT was conducted in adults 18 years of age and older (n=1,980), and one RCT was conducted in children 3 to 17 years of age (n=1,200). Both RCTs compared Influvac Tetra to its trivalent formulation (Influvac; IIV3-SD), which had previously been authorized for use in persons 18 years of age and older. Recommendations on the use of Influvac Tetra in adults and children three years of age and older can be found in the NACI Statement on Seasonal Influenza Vaccine for 2021–2022.
A second age indication extension to children 6 to 35 months was authorized on March 8, 2022. NACI reviewed the Health Canada assessment of the efficacy, immunogenicity, and safety of Influvac Tetra compared to non-influenza vaccines (NIVs) in children 6 to 35 months of age (n=2,007). The RCT was conducted across Europe and Asia over three influenza seasons (Southern Hemisphere 2019 and the 2017–2018 and 2018–2019 Northern Hemisphere influenza seasons). Refer to the [product monograph](https://www.mylan.ca/-/media/mylanca/documents/english/product-pdf/influvac-tetra-pm-en.pdf?la=en-ca) for further details and supporting evidence on the use of Influvac Tetra in the various age groups mentioned above.
**Efficacy and effectiveness**
The absolute vaccine efficacy of Influvac Tetra compared with NIV against any seasonal strain in children 6 to 35 months was 54% (VE: 0.54; 95% CI: 0.37 to 0.66%). The estimated vaccine efficacy was higher for antigenically matching strains (VE: 0.68; 95% CI: 0.45 to 0.81%). Vaccine efficacy was estimated to be 21% in children 6 to 11 months of age (VE: 0.21; 95 % CI: -0.70 to 0.64%); however, the study was not powered for subgroup analyses by age group[Footnote 139](#fn139).
**Immunogenicity**
Results from the two pivotal trials conducted in adults and children 3 years of age and older demonstrated that Influvac Tetra met the non-inferiority criteria for the adjusted GMT ratio for all tested influenza strains when compared to the trivalent formulation. Recipients of the trivalent formulations showed, to a lesser degree, some immune response to the B strain not contained in the trivalent formulation. In the RCT conducted in adults, seroconversion and seroprotection rates for all four strains in the Influvac Tetra group were higher than the European Medicines Agency (EMA) and United States Food and Drug Administration (FDA) criteria for influenza vaccines. In the RCT conducted in children 3 to 17 years of age, seroconversion rates were over 60% across all vaccination groups for all four strains.
A review of clinical data submitted to Health Canada by the manufacturer was conducted to examine the use of Influvac Tetra in children 6 months to less than 3 years (i.e., 35 months) of age. Specifically, the immunogenicity of Influvac Tetra was assessed in a phase 3 RCT conducted in children 6 to 35 months of age. Participants experienced a substantial increase in hemagglutinin inhibition antibody titres in response to vaccination against influenza type A [A(H1N1) and A(H3N2)], based on GMTs, geometric mean fold increase (GMFI), seroconversion rates and seroprotection rates. However, immunogenicity results for influenza type B (B/Yamagata lineage and B/Victoria lineage) were noted to be low for the four immunogenicity outcomes included in the study. Refer to the [product monograph](https://www.mylan.ca/-/media/mylanca/documents/english/product-pdf/influvac-tetra-pm-en.pdf?la=en-ca) for additional details.
**Safety**
The analysis of vaccine safety across all three phase 3 clinical trials including adults and children 6 months of age and older, demonstrated that Influvac Tetra was well tolerated and no new safety signals were observed. The incidence of solicited (local and systemic), unsolicited AEs and SAEs were generally comparable between the two intervention groups. AEs were mild to moderate in severity. Notably, no deaths were reported across the three clinical trials.
### Standard dose mammalian cell culture-based quadrivalent inactivated influenza vaccine (IIV4-cc)
Vaccine currently authorized for use:
* Flucelvax® Quad (Seqirus)
**Methods**
Following the IIV4-cc vaccination recommendations published in the NACI [Statement on Seasonal Influenza Vaccine for 2022–2023](/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html), an expanded age indication for the use of IIV4-cc in children 6 months to 47 months was authorized.
Flucelvax Quad was first authorized for use in adults and children 9 years of age and older on November 22, 2019. In support of this, NACI conducted a systematic review of the literature to examine vaccine efficacy, effectiveness, immunogenicity, and safety data for children in this age group. Refer to the [NACI Supplemental Statement on Mammalian Cell Culture-Based Influenza Vaccines](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/mammalian-cell-culture-based-influenza-vaccines.html) and to the [Statement on Seasonal Influenza Vaccine for 2022–2023](/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html) for further details.
An age indication extension for the use of Flucelvax Quad in adults and children 2 years and older was authorized on March 8, 2021.Recommendations were developed based on a review of the Health Canada assessment of a multi-country phase 3/4 RCT on the efficacy, immunogenicity and safety of Flucelvax Quad in children 2 years to less than18 years of age conducted over three influenza seasons (Southern Hemisphere 2017 influenza season and the 2017–2018 and 2018–2019 Northern Hemisphere influenza seasons). Refer to the [Statement on Seasonal Influenza Vaccine for 2022–2023](/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html) for further details.
A second age indication extension to children 6 months to 47 months was authorized on March 8, 2022. To support this age indication extension, NACI reviewed the Health Canada assessment of a Phase 3 randomized clinical trial of the immunogenicity and safety of IIV4-cc compared to Afluria Tetra (IIV4-SD) in healthy children (N=2402) 6 to 47 months of age submitted by the manufacturer. The clinical trial was conducted in 47 sites across the United States during the 2019-2020 influenza season. The analysis of vaccine immunogenicity and safety in children 6 months to 47 months were consistent with the findings of the previous NACI systematic literature review and the Health Canada clinical assessment.
**Efficacy and effectiveness**
Evidence for the effectiveness of IIV4-cc is based on the studies included in the systematic review presented in the [NACI Supplemental Statement on Mammalian Cell Culture-Based Influenza Vaccines](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/mammalian-cell-culture-based-influenza-vaccines.html) and the Health Canada assessment of clinical trial evidence supporting the extended age indication for the use of the vaccine in adults and children 2 years of age and older. Evidence related to the efficacy of the trivalent formulation, IIV3-cc, was used to supplement existing evidence for the efficacy of IIV4-cc. For further details refer to the [NACI Influenza and Statement on Seasonal Influenza Vaccine for 2022–2023](/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html).
**Immunogenicity**
In support of extended age indication for the use of the vaccine in adults and children 6 months of age and older, immunogenicity was assessed in a subset of the phase 3/4 RCT study participants 6 months to 47 months of age during the Northern Hemisphere 2019-2020 influenza season. Non-inferiority criteria were met for all tested influenza strains [A(H1N1), A(H3N2), B/Yamagata lineage, B/Victoria lineage], based on GMT ratios and seroconversion rates. Overall, there is fair evidence that IIV4-cc has non-inferior immunogenicity to IIV4-SD.
**Safety**
The analysis of vaccine safety in a clinical trial in children 6 to 47 months of age demonstrated that IIV4-cc is well tolerated, and no new safety signals were observed. The majority of solicited (local and systemic) were short in duration. There were no observable differences in the occurrence of AEs between participants who received Flucelvax Quad and versus those who received the comparator vaccine. A small proportion of participants experienced at least one SAE in each study arm. No SAE were determined to be related to receipt of the study vaccines. Overall, there is fair evidence that IIV4-cc is a safe and well-tolerated alternative to conventional egg-based influenza vaccines for children and adults.
### High-dose inactivated influenza vaccine (IIV-HD)
Vaccines currently authorized for use:
* Fluzone® High-Dose Quadrivalent (Sanofi)
The trivalent formulations of high-dose inactivated influenza vaccines have recently been discontinued and are no longer authorized or available for use in Canada. All IIV-HD products expected to be available in Canada for the 2023-2024 season are quadrivalent.
**Methods**
In 2018, NACI published a literature review on the efficacy and effectiveness of high dose trivalent inactivated vaccines (IIV3-HD) in older adults. Refer to NACI's [Literature review update on the efficacy and effectiveness of high-dose (Fluzone® High-Dose) and MF59-adjuvanted (Fluad®) trivalent inactivated influenza vaccines in adults 65 years of age and older](/en/public-health/services/publications/healthy-living/executive-summary-literature-review-update-efficacy-effectiveness-fluzone-high-dose-fluad-trivalent-inactivated-influenza-vaccines-adults-65-older.html) for further details.
Fluzone High-Dose Quadrivalent (IIV4-HD) builds on the clinical development of its trivalent predecessor Fluzone High-Dose (IIV3-HD) since both vaccines have the same manufacturing process and overlapping compositions. Therefore, data on the efficacy, effectiveness, immunogenicity, and safety of IIV3-HD are relevant and inferred to IIV4-HD.
**Efficacy and effectiveness**
There is good evidence that Fluzone High-Dose (IIV3-HD) provides better protection compared with IIV3-SD in adults 65 years of age and older. Two studies found that IIV3-HD may provide greater benefit in adults 75 years of age and older compared to adults 65 to 74 years of age[Footnote 140](#fn140)[Footnote 141](#fn141). The efficacy results for IIV3-HD are inferred to IIV4-HD based on the non-inferior immunogenicity, described in the next section.
**Immunogenicity**
There is evidence that immunization with IIV3-HD elicits a higher immune response compared to immunization with IIV3-SD in older adults [Footnote 142](#fn142)[Footnote 143](#fn143) [Footnote 144](#fn144)[Footnote 145](#fn145) [Footnote 146](#fn146)[Footnote 147](#fn147) [Footnote 148](#fn148)[Footnote 149](#fn149). Across all three influenza vaccine strains, rates of seroconversion were found to be about 19% higher (ranging from 8 to 39% higher) for the IIV3-HD group. The post-vaccination GMT ratios (GMTR) of participants' responses to IIV3-HD was about 1.5 to 1.8 times higher than those receiving IIV3-SD (cite). There is good evidence that the immunogenicity for Fluzone High Dose Quadrivalent (IIV4-HD) is non-inferior to IIV3-HD[Footnote 150](#fn150)[Footnote 151](#fn151). In a pivotal RCT, IIV4-HD met all non-inferiority criteria set by the US Food and Drug Administration, based on GMTR and seroconversion rates when compared to IIV3-HD[Footnote 151](#fn151). Immunogenicity for IIV4-HD was superior for the influenza B strain not contained within the trivalent high dose vaccine[Footnote 151](#fn151).
**Safety**
IIV3-HD has been observed to produce a higher rate of some systemic and local reactions than IIV3-SD. Studies have reported higher rates of malaise, myalgia, and moderate to severe fever. Most systemic reactions were mild and resolved within 3 days. SAEs were rare and similar in frequency between standard-dose and high-dose vaccines. When comparing the two high dose vaccine products, IIV4-HD has been shown to produce a comparable rate of systemic and local reactions compared to IIV3-HD. A comparable proportion of study participants also experienced unsolicited and serious AEs[Footnote 151](#fn151).
### Recombinant quadrivalent influenza vaccine (RIV4)
Vaccines currently authorized for use:
* Supemtek™ (Sanofi)
**Methods**
A systematic literature review and meta-analysis was conducted on the vaccine efficacy, effectiveness, immunogenicity, and safety of RIV4 in adults 18 years of age and older. NACI used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework to review the evidence and develop relevant recommendations on the use of RIV4. Further information on this framework can be found in the [GRADE handbook](https://training.cochrane.org/resource/grade-handbook).
The complete details of this review, rationale, relevant considerations and additional information supporting this recommendation can be found in the NACI Supplemental Statement – [Recombinant Influenza Vaccines and the Statement on Seasonal Influenza Vaccine for 2022-2023](/en/public-health/services/publications/vaccines-immunization/recombinant-influenza-vaccines-supplemental-statement-canadian-immunization-guide-seasonal-influenza-vaccine-2022-2023.html).
**Efficacy and effectiveness**
One RCT that evaluated the efficacy of RIV4 demonstrated that Supemtek was statistically significantly more efficacious than egg-based IIV4-SD in preventing laboratory confirmed influenza illness in adults 50 years of age and older[Footnote 152](#fn152). Non-inferiority assessments suggested that RIV4 may be more effective than IIV4-SD influenza vaccines against laboratory-confirmed influenza A virus infection, but not laboratory-confirmed influenza B virus infection in older adults. Overall, there is fair evidence (of low certainty) that the efficacy of RIV4 is non-inferior to traditional egg-based comparators, based on data in adults aged 50 years and older.
**Immunogenicity**
Eight RCTs[Footnote 152](#fn152)[Footnote 153](#fn153) [Footnote 154](#fn154)[Footnote 155](#fn155) [Footnote 156](#fn156)[Footnote 157](#fn157) [Footnote 158](#fn158)[Footnote 159](#fn159) assessed the immunogenicity of RIV4. The immunogenicity outcomes reported included seroconversion rates [Footnote 152](#fn152)[Footnote 153](#fn153) [Footnote 154](#fn154)[Footnote 155](#fn155) [Footnote 156](#fn156)[Footnote 157](#fn157) [Footnote 158](#fn158)[Footnote 159](#fn159), seroprotection rates [Footnote 152](#fn152)[Footnote 153](#fn153) [Footnote 154](#fn154)[Footnote 159](#fn159), and GMTR [Footnote 152](#fn152)[Footnote 155](#fn155) [Footnote 159](#fn159)[Footnote 160](#fn160). Across the eight studies, Supemtek demonstrated non-inferiority compared to previously authorized IIVs (IIV3-HD, IIV3-Adj, IIV4-SD, and IIV4-cc) against A(H1N1), most strains of A(H3N2), and B/Yamagata lineage. In some studies, RIV4 did not meet non-inferiority criteria against B/Victoria lineage compared to previously authorized IIVs based on seroconversion[Footnote 152](#fn152)[Footnote 155](#fn155), seroprotection[Footnote 152](#fn152), and GMTR[Footnote 161](#fn161).
Pooled seroconversion data from three[Footnote 152](#fn152)[Footnote 154](#fn154)[Footnote 157](#fn157) of the eight RCTs conducted in adult participants 50 years of age and older identified that RIV4 induced similar antibody responses compared to IIV4-SD, IIV3-HD, and IIV3-Adj.
Overall, there is fair evidence (of moderate certainty) that the immunogenicity for RIV4 is non-inferior to traditional egg-based comparators, based on data in adults aged 18 years and older.
**Safety**
Six studies[Footnote 152](#fn152)[Footnote 154](#fn154) [Footnote 155](#fn155)[Footnote 157](#fn157) [Footnote 162](#fn162)[Footnote 163](#fn163) assessed the safety of RIV4 in adults, including five RCTs and one post-marketing surveillance study using data from the United States Vaccine Adverse Event Reporting System (VAERS)[Footnote 162](#fn162). The five RCTs found RIV4 to be safe and well-tolerated compared to conventional egg-based IIVs (noting that no published clinical data pertaining to safety of vaccination with RIV4 during pregnancy were available at the time of the review). Most AE reported to VAERS following RIV4 administration were non-serious. When data from two RCTs[Footnote 152](#fn152)[Footnote 154](#fn154) conducted among adult participants 50 years of age and older were pooled, no difference in the odds of experiencing a SAE following administration of RIV4 and traditional egg-based IIV3-HD and IIV4-SD vaccine comparators was detected. Overall, there is evidence of moderate certainty that RIV4 is a safe and well-tolerated alternative to conventional egg-based influenza vaccines for adults.
### Live Attenuated Influenza Vaccine (LAIV)
Vaccine currently authorized for use:
* FluMist® Quadrivalent (AstraZeneca)
All LAIV products expected to be available in Canada for the 2023-2024 season are quadrivalent.
**Efficacy and effectiveness**
After careful review of the available Canadian and international LAIV VE data over many influenza seasons, NACI concluded that the current evidence is consistent with LAIV providing comparable protection against influenza to that afforded by IIV and does not support a recommendation for the preferential use of LAIV in children 2 to 17 years of age. Additionally, NACI concluded that there is insufficient evidence on the immunogenicity and safety supporting the use of LAIV in adults with immunocompromised conditions and does not support the use of LAIV in this group.
Observational studies from the United States found low effectiveness of LAIV against circulating post-2009 pandemic A(H1N1) [A(H1N1)pdm09], in 2013–2014 and 2015–2016; however, reduced LAIV effectiveness was not observed in Canada or any other countries that have investigated the issue. Manufacturer investigation identified potential reduced replicative fitness of the A(H1N1)pdm09-like LAIV viruses in the nasal mucosa from the two affected A(H1N1)-dominant seasons compared to pre-2009 pandemic influenza A(H1N1) LAIV viruses as contributing to the poor LAIV effectiveness against circulating A(H1N1)[Footnote 60](#fn60). This finding led to the manufacturer replacing the A(H1N1)pdm09 component of LAIV with new strains, with the A/Slovenia/2903/2015 being the strain that has been used since the 2017–2018 season. In adults, studies have found IIV-SD to be similarly or more efficacious or effective compared with LAIV.
Refer to the [Statement on Seasonal Influenza Vaccine for 2018–2019](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2018-2019.html) for detailed information supporting this recommendation.
**Immunogenicity**
LAIV, which is administered by the intranasal route, is thought to result in an immune response that mimics that induced by natural infection with wild-type viruses, with the development of both mucosal and systemic immunity. Local mucosal antibodies protect the upper respiratory tract and may be more important for protection than serum antibody.
Studies have demonstrated that the presence of a hemagglutination-inhibition antibody response after the administration of LAIV3 is predictive of protection. However, efficacy studies have shown protection in the absence of a significant antibody response as well[Footnote 164](#fn164). In these studies, LAIV3 has generally been shown to be equally, if not more, immunogenic compared to IIV3-SD for all 3 strains in children, whereas IIV3-SD was typically more immunogenic in adults than LAIV3. Greater rates of seroconversion to LAIV3 occurred in baseline seronegative individuals compared to baseline seropositive individuals in both pediatric and adult populations, because pre-existing immunity may interfere with response to a live vaccine. Refer to the NACI [Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist®): Supplemental Statement on Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-2.html) for further details regarding the immunogenicity of LAIV3.
LAIV4 has shown non-inferiority based on immunogenicity compared to LAIV3 in both children and adults. The immune response to the B strain found only in the quadrivalent formulation was better in children who received the quadrivalent vaccine[Footnote 165](#fn165)[Footnote 166](#fn166)[Footnote 167](#fn167).
**Safety**
The most common AEs experienced by recipients of LAIV3 are nasal congestion and runny nose, which are also reported for LAIV4. In a large efficacy trial, rates of wheezing were statistically higher among children 6 to 23 months of age for LAIV3 compared to IIV3-SD[Footnote 164](#fn164). This finding is expected to be the same for recipients of LAIV4; however, pre-licensure clinical studies for LAIV4 were conducted only in adults and children 2 years of age and older. LAIV4 is not authorized in children less than 2 years of age.
Studies on LAIV3 have shown that vaccine virus can be recovered by nasal swab in children and adults following vaccination (i.e., "shedding"). The frequency of shedding decreases with increasing age and time since vaccination. Shedding is generally below the levels needed to transmit infection, although in rare instances, shed vaccine viruses can be transmitted from vaccine recipients to unvaccinated people. Refer to the NACI [Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist®): Supplemental Statement on Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-2.html) for more information on LAIV and viral shedding.
#### Considerations related to children living with HIV infection
Following a review of the literature regarding the use of LAIV in individuals living with HIV, NACI concluded that LAIV is immunogenic in children with stable HIV infection on HAART and with adequate immune function. In addition, NACI concluded that LAIV appears to have a similar safety profile as IIV in children on HAART and with stable HIV infection with regard to frequency and severity of AEs[Footnote 168](#fn168). As expected, injection site reactions were seen only with IIV and nasal symptoms were more common with LAIV. However, the evidence base is too small to effectively detect uncommon, rare, and very rare AEs related to the use of LAIV in in this population. Nasal spray may be preferable to IM injection for some individuals who are averse to receiving the vaccine by injection. Therefore, NACI recommends that LAIV may be considered as an option for children 2 to 17 years of age with stable HIV infection on HAART and with adequate immune function. LAIV should be considered only in children with HIV who meet all of the following criteria:
* Receiving ART for 4 months or longer
* CD4 count equal to or greater than 500/µL if 2 to 5 years of age, or ≥200/µL if 6 to 17 years of age (measured within 100 days before administration of LAIV)
HIV plasma RNA less than 10,000 copies/mL (measured within 100 days before administration of LAIV)
IM influenza vaccination is still considered the standard for children living with HIV by NACI and the Canadian Pediatric and Perinatal HIV/AIDS Research Group, particularly for those without HIV viral load suppression (i.e., plasma HIV RNA >40 copies/mL). However, if IM vaccination is not accepted by the individual or substitute decision maker, LAIV would be a reasonable option for children meeting the criteria listed above.
Refer to the [NACI Statement on the Use of LAIV in HIV-Infected Individuals](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/live-attenuated-influenza-vaccine-hiv-infected-individuals.html) for more information on the use of LAIV in this population.
References
----------
Footnote 1
World Health Organization. Influenza (seasonal): fact sheet N°211 [Internet]. Vol. 2016. 2014. Available from: http://www.who.int/mediacentre/factsheets/fs211/en/
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
Mamas MA, Fraser D, Neyses L. Cardiovascular manifestations associated with influenza virus infection. IntJCardiol. 2008;130(3):304–9.
[Return to footnote 2 referrer](#fn2-rf)
Footnote 3
Moriarty L, Omer S. Infants and the seasonal influenza vaccine. A global perspective on safety, effectiveness, and alternate forms of protection. Hum Vaccin Immunother. 2014;10(9):2721–8.
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
Schwarz TF, Aggarwal N, Moeckesch B, Schenkenberger I, Claeys C, Douha M, et al. Immunogenicity and Safety of an Adjuvanted Herpes Zoster Subunit Vaccine Coadministered With Seasonal Influenza Vaccine in Adults Aged 50 Years or Older. JInfectDis. 2017;216(11):1352–61.
[Return to footnote 4 referrer](#fn4-rf)
Footnote 5
Koutsakos M, Wheatley A, Laurie K, et. al. Influenza Lineage Extinction during the COVID-19 Pandemic? Nature Reviews Microbiology.
[Return to footnote 5 referrer](#fn5-rf)
Footnote 6
Dhanasekaran V, Sullivan S, Edwards KM, Xie R, Khvorov A, Valkenburg SA, et al. Human seasonal influenza under COVID-19 and the potential consequences of influenza lineage elimination. Nat Commun. 2022 Dec;13(1):1721.
[Return to footnote 6 referrer](#fn6-rf)
Footnote 7
Lessler J, Reich N, Brookmeyer R, et. al. Incubation periods of acute respiratory viral infections: a systematic review. Lancet Infect Dis. 2009;9:291–300.
[Return to footnote 7 referrer](#fn7-rf)
Footnote 8
Behrouzi B, Bhatt D, Cannon C, et. al. Association of Influenza Vaccination with Cardiovascular Risk: A Meta-analysis. JAMA Netw Open. 2022;5(4):e228873.
[Return to footnote 8 referrer](#fn8-rf)
Footnote 9
Statistics Canada. The 10 leading causes of death, 2011 [Internet]. Vol. 2015. 2014. Available from: http://www.statcan.gc.ca/pub/82-625-x/2014001/article/11896-eng.htm
[Return to footnote 9 referrer](#fn9-rf)
Footnote 10
Schanzer DL, McGeer A, Morris K, Et. Al. Statistical estimates of respiratory admissions attributable to seasonal and pandemic influenza for Canada. Influenza and Other Respiratory Viruses. 2013;7(5):799–808.
[Return to footnote 10 referrer](#fn10-rf)
Footnote 11
Schanzer DL, Sevenhuysen C, Winchester B, Et. Al. Estimating Influenza Deaths in Canada, 1992–2009. PLoS ONE. 2013;8(11):e80481.
[Return to footnote 11 referrer](#fn11-rf)
Footnote 12
World Health Organization. Fact Sheet: Estimating Disease Burden of Influenza [Internet]. Available from: https://www.who.int/europe/activities/estimating-disease-burden-of-influenza
[Return to footnote 12 referrer](#fn12-rf)
Footnote 13
Nwosu A, Lee L, Schmidt K, et. al. National Influenza Annual Report, Canada, 2020–2021, in the global context. Can Commun Dis Rep. 2021;47(10):405–13.
[Return to footnote 13 referrer](#fn13-rf)
Footnote 14
Groves HE, Papenburg J, Mehta K, Bettinger JA, Sadarangani M, Halperin SA, et al. The effect of the COVID-19 pandemic on influenza-related hospitalization, intensive care admission and mortality in children in Canada: A population-based study. The Lancet Regional Health - Americas. 2022 Mar;7:100132.
[Return to footnote 14 referrer](#fn14-rf)
Footnote 15
He D, Lui R, Wang L, et. al. Global Spatio-temporal Patterns of Influenza in the Post-pandemic Era. Sci Rep. 2015;5(1):11013.
[Return to footnote 15 referrer](#fn15-rf)
Footnote 16
The Academy of Medical Sciences. COVID-19: Preparing for the future. London, UK. AMS [Internet]. 2021 [cited 2021 Jul 30]; Available from: https://acmedsci.ac.uk/file-download/4747802
[Return to footnote 16 referrer](#fn16-rf)
Footnote 17
Baker RE, Park SW, Yang W, Vecchi GA, Metcalf CJE, Grenfell BT. The impact of COVID-19 nonpharmaceutical interventions on the future dynamics of endemic infections. Proc Natl Acad Sci USA. 2020 Dec 1;117(48):30547–53.
[Return to footnote 17 referrer](#fn17-rf)
Footnote 18
Centers for Disease Control and Prevention. Selecting Viruses for the Seasonal Influenza Vaccine. Atlanta (GA). [cited 2021 Aug 30]; Available from: https://www.cdc.gov/flu/prevent/vaccine-selection.htm
[Return to footnote 18 referrer](#fn18-rf)
Footnote 19
Government of Canada. Respiratory Virus Detections in Canada [Internet]. Available from: canada.ca/en/public-health/services/surveillance/respiratory-virus-detections-canada.html
[Return to footnote 19 referrer](#fn19-rf)
Footnote 20
Tang JW, Bialasiewicz S, Dwyer DE, Dilcher M, Tellier R, Taylor J, et al. Where have all the viruses gone? Disappearance of seasonal respiratory viruses during the COVID‐19 pandemic. J Med Virol. 2021 Jul;93(7):4099–101.
[Return to footnote 20 referrer](#fn20-rf)
Footnote 21
Heckler R, Baillot A, Engelmann H, Neumeier E, Windorfer A. Cross-protection against homologous drift variants of influenza A and B after vaccination with split vaccine. Intervirology. 2007;50(1):58–62.
[Return to footnote 21 referrer](#fn21-rf)
Footnote 22
Walter EB, Neuzil KM, Zhu Y, Fairchok MP, Gagliano ME, Monto AS, et al. Influenza vaccine immunogenicity in 6- to 23-month-old children: are identical antigens necessary for priming? Pediatrics. 2006;118(3):e570–8.
[Return to footnote 22 referrer](#fn22-rf)
Footnote 23
Englund JA, Walter EB, Fairchok MP, Monto AS, Neuzil KM. A comparison of 2 influenza vaccine schedules in 6- to 23-month-old children. Pediatrics. 2005;115(4):1039–47.
[Return to footnote 23 referrer](#fn23-rf)
Footnote 24
Englund JA, Walter EB, Gbadebo A, Monto AS, Zhu Y, Neuzil KM. Immunization with trivalent inactivated influenza vaccine in partially immunized toddlers. Pediatrics. 2006;118(3):e579-85.
[Return to footnote 24 referrer](#fn24-rf)
Footnote 25
Levandowski RA, Gross PA, Weksler M, Staton E, Williams MS, Bonelli J. Cross-reactive antibodies induced by a monovalent influenza B virus vaccine. JClinMicrobiol. 1991;29(7):1530–2.
[Return to footnote 25 referrer](#fn25-rf)
Footnote 26
Levandowski RA, Regnery HL, Staton E, Burgess BG, Williams MS, Groothuis JR. Antibody responses to influenza B viruses in immunologically unprimed children. Pediatrics. 1991;88(5):1031–6.
[Return to footnote 26 referrer](#fn26-rf)
Footnote 27
McLean HQ, Thompson MG, Sundaram ME, Et. Al. Influenza Vaccine Effectiveness in the United States During 2012-2013: Variable Protection by Age and Virus Type. Journal of Infectious Diseases. 2015;211(10):1529–40.
[Return to footnote 27 referrer](#fn27-rf)
Footnote 28
McLean HQ, Thompson MG, Sundaram ME, Meece JK, McClure DL, Friedrich TC, et al. Impact of repeated vaccination on vaccine effectiveness against influenza A(H3N2) and B during 8 seasons. ClinInfectDis. 2014;59(10):1375–85.
[Return to footnote 28 referrer](#fn28-rf)
Footnote 29
Ritzwoller DP, Bridges CB, Shetterly S, Yamasaki K, Kolczak M, France EK. Effectiveness of the 2003-2004 influenza vaccine among children 6 months to 8 years of age, with 1 vs 2 doses. Pediatrics. 2005;116(1):153–9.
[Return to footnote 29 referrer](#fn29-rf)
Footnote 30
Neuzil KM, Jackson LA, Nelson J, Klimov A, Cox N, Bridges CB, et al. Immunogenicity and reactogenicity of 1 versus 2 doses of trivalent inactivated influenza vaccine in vaccine-naive 5-8-year-old children. JInfectDis. 2006;194(8):1032–9.
[Return to footnote 30 referrer](#fn30-rf)
Footnote 31
Shuler CM, Iwamoto M, Bridges CB, Marin M, Neeman R, Gargiullo P, et al. Vaccine effectiveness against medically attended, laboratory-confirmed influenza among children aged 6 to 59 months, 2003-2004. Pediatrics. 2007;119(3):e587-95.
[Return to footnote 31 referrer](#fn31-rf)
Footnote 32
Allison MA, Daley MF, Crane LA, Barrow J, Beaty BL, Allred N, et al. Influenza vaccine effectiveness in healthy 6- to 21-month-old children during the 2003-2004 season. JPediatr. 2006;149(6):755–62.
[Return to footnote 32 referrer](#fn32-rf)
Footnote 33
Skowronski DM, Hottes TS, De Serres G, Ward BJ, Janjua NZ, Sabaiduc S, et al. Influenza B/Victoria antigen induces strong recall of B/Yamagata but lower B/Victoria response in children primed with two doses of B/Yamagata. PediatrInfectDisJ. 2011;30(10):833–9.
[Return to footnote 33 referrer](#fn33-rf)
Footnote 34
McElhaney JE, Hooton JW, Hooton N, Bleackley RC. Comparison of single versus booster dose of influenza vaccination on humoral and cellular immune responses in older adults. Vaccine. 2005;23(25):3294–300.
[Return to footnote 34 referrer](#fn34-rf)
Footnote 35
Breiman RF, Brooks WA, Goswami D, Lagos R, Borja-Tabora C, Lanata CF, et al. A multinational, randomized, placebo-controlled trial to assess the immunogenicity, safety, and tolerability of live attenuated influenza vaccine coadministered with oral poliovirus vaccine in healthy young children. Vaccine. 2009;27(40):5472–9.
[Return to footnote 35 referrer](#fn35-rf)
Footnote 36
Lum LC, Borja-Tabora C, Breiman RF, Vesikari T, Sablan BP, Chay OM, et al. Influenza vaccine concurrently administered with a combination measles, mumps, and rubella vaccine to young children. Vaccine. 2010;28(6):1566–74.
[Return to footnote 36 referrer](#fn36-rf)
Footnote 37
Nolan T, Bernstein DI, Block SL, Hilty M, Keyserling HL, Marchant C, et al. Safety and immunogenicity of concurrent administration of live attenuated influenza vaccine with measles-mumps-rubella and varicella vaccines to infants 12 to 15 months of age. Pediatrics. 2008;121(3):508–16.
[Return to footnote 37 referrer](#fn37-rf)
Footnote 38
Severance R, Schwartz H, Dagan R, Et. Al. Safety, tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, administered concomitantly with influenza vaccine in healthy adults aged ≥50 years: a randomized phase 3 trial (PNEU-FLU). Hum Vaccin Immunother. 2022;18(1):1–14.
[Return to footnote 38 referrer](#fn38-rf)
Footnote 39
National Advisory Committee on Immunization. Updated Recommendations on the Use of Herpes Zoster Vaccines. Ottawa: Public Health Agency of Canada [Internet]. 2018. 2018. Available from: https://www.canada.ca/en/services/health/publications/healthy-living/updated-recommendations-use-herpes-zoster-vaccines.html
[Return to footnote 39 referrer](#fn39-rf)
Footnote 40
National Advisory Committee on Immunization. Statement on thimerosal. CanCommunDisRep. 2003;29(1):1–12.
[Return to footnote 40 referrer](#fn40-rf)
Footnote 41
National Advisory Committee on Immunization. Thimerosal: updated statement. An Advisory Committee Statement (ACS). CanCommunDisRep. 2007;33(6):1–13.
[Return to footnote 41 referrer](#fn41-rf)
Footnote 42
Gerber JS, Offit PA. Vaccines and autism: a tale of shifting hypotheses. ClinInfectDis. 2009;48(4):456–61.
[Return to footnote 42 referrer](#fn42-rf)
Footnote 43
Institute of Medicine of the National Academies. Immunization safety review: influenza vaccines and neurological complications. Institute of Medicine of the National Academies. Washington, DC: National Academy of Sciences; 2008.
[Return to footnote 43 referrer](#fn43-rf)
Footnote 44
Centers for Disease Control and Prevention. Preliminary results: surveillance for Guillain-Barré syndrome after receipt of influenza A (H1N1) 2009 monovalent vaccine - United States, 2009-2010. MMWR MorbMortalWklyRep. 2010;59(21):657–61.
[Return to footnote 44 referrer](#fn44-rf)
Footnote 45
Kwong JC, Vasa PP, Campitelli MA, Hawken S, Wilson K, Rosella LC, et al. Risk of Guillain-Barré syndrome after seasonal influenza vaccination and influenza health-care encounters: a self-controlled study. Lancet Infect Dis. 2013;13(9):769–76.
[Return to footnote 45 referrer](#fn45-rf)
Footnote 46
Sivadon-Tardy V, Orlikowski D, Porcher R, Sharshar T, Durand MC, Enouf V, et al. Guillain-Barre syndrome and influenza virus infection. ClinInfectDis. 2009;48(1):48–56.
[Return to footnote 46 referrer](#fn46-rf)
Footnote 47
Stowe J, Andrews N, Wise L, Miller E. Investigation of the temporal association of Guillain-Barre syndrome with influenza vaccine and influenza like illness using the United Kingdom General Practice Research Database. AmJEpidemiol. 2009;169(3):382–8.
[Return to footnote 47 referrer](#fn47-rf)
Footnote 48
Tam CC, O'Brien SJ, Petersen I, Islam A, Hayward A, Rodrigues LC. Guillain-Barre syndrome and preceding infection with campylobacter, influenza and Epstein-Barr virus in the general practice research database. PLoS One. 2007;2(4):e344.
[Return to footnote 48 referrer](#fn48-rf)
Footnote 49
Andrews N, Stowe J, Al-Shahi Salman R, Miller E. Guillain-Barre syndrome and H1N1 (2009) pandemic influenza vaccination using an AS03 adjuvanted vaccine in the United Kingdom: self-controlled case series. Vaccine. 2011;29(45):7878–82.
[Return to footnote 49 referrer](#fn49-rf)
Footnote 50
National Advisory Committee on Immunization. Supplementary statement on influenza vaccination: continued use of Fluviral® influenza vaccine in the 2000-2001 season. Can Commun Dis Rep. 2001;27(ACS-1):1-3(Journal Article).
[Return to footnote 50 referrer](#fn50-rf)
Footnote 51
Ahmadipour N WK Fréchette M, Coulby C, Anyoti H, Johnson K. Vaccine safety surveillance in Canada: Reports to CAEFISS, 2013–2016. Can Commun Dis Rep. 2018;44((9)):206–14.
[Return to footnote 51 referrer](#fn51-rf)
Footnote 52
Black S, Nicolay U, Del Giudice G, Rappuoli R. Influence of statins on influenza vaccine response in elderly individuals. JInfectDis. 2016;213(8):1224–8.
[Return to footnote 52 referrer](#fn52-rf)
Footnote 53
Omer SB, Phadke VK, Bednarczyk RA, Chamberlain AT, Brosseau JL, Orenstein WA. Impact of statins on influenza vaccine effectiveness against medically attended acute respiratory illness. JInfectDis. 2016;213(8):1216–23.
[Return to footnote 53 referrer](#fn53-rf)
Footnote 54
Public Health Agency of Canada. Reporting adverse events following immunization (AEFI) in Canada: User guide to completion and submission of the AEFI reports. Ottawa, PHAC [Internet]. Vol. 2019. 2004. Available from: https://www.canada.ca/en/public-health/services/immunization/reporting-adverse-events-following-immunization/user-guide-completion-submission-aefi-reports.html
[Return to footnote 54 referrer](#fn54-rf)
Footnote 55
Statistics Canada. Table 051-0001 - Estimates of population, by age group and sex for July 1, Canada, provinces and territories, annual (persons unless otherwise noted), CANSIM (database) [Internet]. Vol. 2015. 2014. Available from: http://www.statcan.gc.ca/tables-tableaux/sum-som/l01/cst01/demo10a-eng.htm
[Return to footnote 55 referrer](#fn55-rf)
Footnote 56
Tran D, Vaudry W, Moore D, et. al. Hospitalization for Influenza A versus B. Pediatrics. Pediatrics. 2016;138(3):e20154643.
[Return to footnote 56 referrer](#fn56-rf)
Footnote 57
Centers for Disease Control and Prevention. Estimates of deaths associated with seasonal influenza — United States, 1976-2007. MMWR MorbMortalWklyRep. 2010;59(33):1057–62.
[Return to footnote 57 referrer](#fn57-rf)
Footnote 58
Cromer D, van Hoek AJ, Jit M, Edmunds WJ, Fleming D, Miller E. The burden of influenza in England by age and clinical risk group: a statistical analysis to inform vaccine policy. JInfect. 2014;68(4):363–71.
[Return to footnote 58 referrer](#fn58-rf)
Footnote 59
Groves H, Piché-Renaud P, Peci A, et. al. The impact of the COVID-19 pandemic on influenza, respiratory syncytial virus, and other seasonal respiratory virus circulation in Canada: A population-based study. Lancet Reg Health Am. 2021;1:100015.
[Return to footnote 59 referrer](#fn59-rf)
Footnote 60
Grohskopf L, Sokolow L, Fry A, et. al. Update: ACIP Recommendations for the Use of Quadrivalent Live Attenuated Influenza Vaccine (LAIV4) - United States, 2018-19 Influenza Season. MMWR Morb Mortal Wkly Rep. 2018;67(22):643–5.
[Return to footnote 60 referrer](#fn60-rf)
Footnote 61
Louie JK, Acosta M, Jamieson DJ, Honein MA, California Pandemic (H1N1) WG. Severe 2009 H1N1 influenza in pregnant and postpartum women in California. Aranki F, Byron-Cooper O, Cheung M, Cody S, Farley S, Ginsberg M, et al., editors. NEnglJMed. 2010;362(1):27–35.
[Return to footnote 61 referrer](#fn61-rf)
Footnote 62
Siston AM, Rasmussen SA, Honein MA, Fry AM, Seib K, Callaghan WM, et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA. 2010;303(15):1517–25.
[Return to footnote 62 referrer](#fn62-rf)
Footnote 63
Mak TK, Mangtani P, Leese J, Watson JM, Pfeifer D. Influenza vaccination in pregnancy: current evidence and selected national policies. Lancet InfectDis. 2008;8(1):44–52.
[Return to footnote 63 referrer](#fn63-rf)
Footnote 64
McNeil S, Halperin B, MacDonald N. Influenza in pregnancy: the case for prevention. AdvExpMedBiol. 2009;634(Journal Article):161–83.
[Return to footnote 64 referrer](#fn64-rf)
Footnote 65
Rasmussen SA, Jamieson DJ, Bresee JS. Pandemic influenza and pregnant women. EmergInfectDis. 2008;14(1):95–100.
[Return to footnote 65 referrer](#fn65-rf)
Footnote 66
Centers for Disease Control and Prevention. Maternal and infant outcomes among severely ill pregnant and postpartum women with 2009 pandemic influenza A (H1N1)--United States, April 2009-August 2010. MMWR MorbMortalWklyRep. 2011;60(35):1193–6.
[Return to footnote 66 referrer](#fn66-rf)
Footnote 67
Pierce M, Kurinczuk J, Spark P, Brocklehurst P, Knight M. Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study. BMJ. 2011;342(Journal Article):d3214–d3214.
[Return to footnote 67 referrer](#fn67-rf)
Footnote 68
Goldenberg R, Culhane J, Iams J, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75–84.
[Return to footnote 68 referrer](#fn68-rf)
Footnote 69
McNeil SA, Dodds LA, Fell DB, Allen VM, Halperin BA, Steinhoff MC, et al. Effect of respiratory hospitalization during pregnancy on infant outcomes. AmJObstetGynecol. 2011;204(6):S54-7.
[Return to footnote 69 referrer](#fn69-rf)
Footnote 70
Zaman K, Roy E, Arifeen SE, Rahman M, Raqib R, Wilson E, et al. Effectiveness of maternal influenza immunization in mothers and infants. NEnglJMed. 2008;359(15):1555–64.
[Return to footnote 70 referrer](#fn70-rf)
Footnote 71
Poehling K, Szilagyi P, Staat M, Snively B, Payne D, Bridges C, et al. Impact of maternal immunization on influenza hospitalizations in infants. ObstetGynecol. 2011;204(6):S141–8.
[Return to footnote 71 referrer](#fn71-rf)
Footnote 72
Eick AA, Uyeki TM, Klimov A, Hall H, Reid R, Santosham M, et al. Maternal influenza vaccination and effect on influenza virus infection in young infants. ArchPediatrAdolescMed. 2011;165(2):104–11.
[Return to footnote 72 referrer](#fn72-rf)
Footnote 73
France EK, McClure D, Hambidge S, Xu S, Yamasaki K, Shay D, et al. Impact of maternal influenza vaccination during pregnancy on the incidence of acute respiratory illness visits among infants. ArchPediatrAdolescMed. 2006;160(12):1277–83.
[Return to footnote 73 referrer](#fn73-rf)
Footnote 74
Steinhoff M, Omer S, Roy E, El Arifeen S, Raqib R, Dodd C, et al. Neonatal outcomes after influenza immunization during pregnancy: a randomized controlled trial. CMAJ. 2012;184(6):645–53.
[Return to footnote 74 referrer](#fn74-rf)
Footnote 75
Fell DB, Sprague AE, Liu N, Yasseen AS 3, Wen SW, Smith G, et al. H1N1 influenza vaccination during pregnancy and fetal and neonatal outcomes. AmJPublic Health. 2012;102(6):e33-40.
[Return to footnote 75 referrer](#fn75-rf)
Footnote 76
Omer S, Goodman D, Steinhoff M, Rochat R, Klugman K, Stoll B, et al. Maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study. PLoS Med. 2011;8(5):e1000441.
[Return to footnote 76 referrer](#fn76-rf)
Footnote 77
Dodds L, MacDonald N, Scott J, Spencer A, Allen VM, McNeil SA. The association between influenza vaccine in pregnancy and adverse neonatal outcomes. J Obstetr Gynecol Can. 2012;34(8):714–20.
[Return to footnote 77 referrer](#fn77-rf)
Footnote 78
MacDonald NE, Riley LE, Steinhoff MC. Influenza immunization in pregnancy. ObstetGynecol. 2009;114(2):365–8.
[Return to footnote 78 referrer](#fn78-rf)
Footnote 79
Tamma PD, Ault KA, del Rio C, Steinhoff MC, Halsey N, Omer S. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol. 2009;201(6):547–52.
[Return to footnote 79 referrer](#fn79-rf)
Footnote 80
Moro PL, Broder K, Zheteyeva Y, Walton K, Rohan P, Sutherland A, et al. Adverse events in pregnant women following administration of trivalent inactivated influenza vaccine and live attenuated influenza vaccine in the Vaccine Adverse Event Reporting System, 1990-2009. Am J Obstet Gynecol. 2011;204(2):146e1–7.
[Return to footnote 80 referrer](#fn80-rf)
Footnote 81
European Medicines Agency. Fifteenth pandemic pharmacovigilance update. http://www.ema.europa.eu/pdfs/influenza/21323810en.pdf. London: European Medicines Agency; 2010.
[Return to footnote 81 referrer](#fn81-rf)
Footnote 82
Simonsen L, Fukuda K, Schonberger LB, Cox NJ. The impact of influenza epidemics on hospitalizations. JInfectDis. 2000;181(3):831–7.
[Return to footnote 82 referrer](#fn82-rf)
Footnote 83
Schanzer DL, Tam TW, Langley JM, Winchester BT. Influenza-attributable deaths, Canada 1990-1999. EpidemiolInfect. 2007;135(7):1109–16.
[Return to footnote 83 referrer](#fn83-rf)
Footnote 84
Centers for Disease Control and P. Deaths related to 2009 pandemic influenza A (H1N1) among American Indian/Alaska Natives - 12 states, 2009. MMWR MorbMortalWklyRep. 2009;58(48):1341–4.
[Return to footnote 84 referrer](#fn84-rf)
Footnote 85
National Center for Education Statistics. Individuals, families and children in poverty. In: Status and trends in the education of American Indians and Alaska Natives. http://nces.ed.gov/pubs2008/nativetrends/ind\_1\_6.asp. Washington, DC: US Department of Education; 2008.
[Return to footnote 85 referrer](#fn85-rf)
Footnote 86
Indigenous and Northern Affairs Canada. Highlights from the report of the Royal Commission on Aboriginal Peoples - people to people, nation to nation [Internet]. Vol. 2016. 2010. Available from: https://www.rcaanc-cirnac.gc.ca/eng/1100100014597/1572547985018
[Return to footnote 86 referrer](#fn86-rf)
Footnote 87
Clark M, Riben P, Nowgesic E. The association of housing density, isolation and tuberculosis in Canadian First Nations communities. IntJEpidemiol. 2002;31(5):940–5.
[Return to footnote 87 referrer](#fn87-rf)
Footnote 88
Saxen H, Virtanen M. Randomized, placebo-controlled double blind study on the efficacy of influenza immunization on absenteeism of health care workers. PediatrInfectDisJ. 1999;18(9):779–83.
[Return to footnote 88 referrer](#fn88-rf)
Footnote 89
Wilde JA, McMillan JA, Serwint J, Butta J, O'Riordan MA, Steinhoff MC. Effectiveness of influenza vaccine in health care professionals: a randomized trial. JAMA. 1999;281(10):908–13.
[Return to footnote 89 referrer](#fn89-rf)
Footnote 90
Carman WF, Elder AG, Wallace LA, McAulay K, Walker A, Murray GD, et al. Effects of influenza vaccination of health-care workers on mortality of elderly people in long-term care: a randomised controlled trial. Lancet. 2000;355(9198):93–7.
[Return to footnote 90 referrer](#fn90-rf)
Footnote 91
Hayward AC, Harling R, Wetten S, Johnson AM, Munro S, Smedley J, et al. Effectiveness of an influenza vaccine programme for care home staff to prevent death, morbidity, and health service use among residents: cluster randomised controlled trial. BMJ. 2006;333(7581):1241.
[Return to footnote 91 referrer](#fn91-rf)
Footnote 92
Potter J, Stott DJ, Roberts MA, Elder AG, O'Donnell B, Knight PV, et al. Influenza vaccination of health care workers in long-term-care hospitals reduces the mortality of elderly patients. JInfectDis. 1997;175(1):1–6.
[Return to footnote 92 referrer](#fn92-rf)
Footnote 93
Lemaitre M, Meret T, Rothan-Tondeur M, Belmin J, Lejonc JL, Luquel L, et al. Effect of influenza vaccination of nursing home staff on mortality of residents: a cluster-randomized trial. JAmGeriatrSoc. 2009;57(9):1580–6.
[Return to footnote 93 referrer](#fn93-rf)
Footnote 94
Shugarman LR, Hales C, Setodji CM, Bardenheier B, Lynn J. The influence of staff and resident immunization rates on influenza-like illness outbreaks in nursing homes. JAmMedDirAssoc. 2006;7(9):562–7.
[Return to footnote 94 referrer](#fn94-rf)
Footnote 95
Kuster SP, Shah PS, Coleman BL, Lam PP, Tong A, Wormsbecker A, et al. Incidence of influenza in healthy adults and healthcare workers: a systematic review and meta-analysis. PLoS One. 2011;6(10):e26239.
[Return to footnote 95 referrer](#fn95-rf)
Footnote 96
Buchan SA, Kwong JC. Influenza immunization among Canadian health care personnel: a cross-sectional study. CMAJ Open. 2016;4(3):E479–88.
[Return to footnote 96 referrer](#fn96-rf)
Footnote 97
Hussain H, McGeer A, McNeil S, Katz K, Loeb M, Simor A, et al. Factors associated with influenza vaccination among healthcare workers in acute care hospitals in Canada. Influenza Other RespirViruses. 2018;12(3):319–25.
[Return to footnote 97 referrer](#fn97-rf)
Footnote 98
Public Health Agency of Canada. Vaccination Coverage Goals and Vaccine Preventable Disease Reduction Targets by 2025. [Internet]. Vol. 2019. 2019. Available from: https://www.canada.ca/en/public-health/services/immunization-vaccine-priorities/national-immunization-strategy/vaccination-coverage-goals-vaccine-preventable-diseases-reduction-targets-2025.html#det22.
[Return to footnote 98 referrer](#fn98-rf)
Footnote 99
Bish A, Yardley L, Nicoll A, Michie S. Factors associated with uptake of vaccination against pandemic influenza: a systematic review. Vaccine. 2011;29(38):6472–84.
[Return to footnote 99 referrer](#fn99-rf)
Footnote 100
Dini G, Toletone A, Sticchi L, Orsi A, Bragazzi NL, Durando P. Influenza vaccination in healthcare workers: A comprehensive critical appraisal of the literature. HumVaccin Immunother. 2018;14(3):772–89.
[Return to footnote 100 referrer](#fn100-rf)
Footnote 101
Hakim H, Gaur AH, McCullers JA. Motivating factors for high rates of influenza vaccination among healthcare workers. Vaccine. 2011;29(35):5963–9.
[Return to footnote 101 referrer](#fn101-rf)
Footnote 102
Lytras T, Kopsachilis F, Mouratidou E, Papamichail D, Bonovas S. Interventions to increase seasonal influenza vaccine coverage in healthcare workers: A systematic review and meta-regression analysis. HumVaccin Immunother. 2016;12(3):671–81.
[Return to footnote 102 referrer](#fn102-rf)
Footnote 103
Schmid P, Rauber D, Betsch C, Lidolt G, Denker ML. Barriers of Influenza Vaccination Intention and Behavior - A Systematic Review of Influenza Vaccine Hesitancy, 2005 - 2016. PLoS One. 2017;12(1):e0170550.
[Return to footnote 103 referrer](#fn103-rf)
Footnote 104
Vasilevska M, Ku J, Fisman D. Factors associated with healthcare worker acceptance of vaccination: a systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2014;35(6):699–708.
[Return to footnote 104 referrer](#fn104-rf)
Footnote 105
Accreditation Canada. Infection prevention and control standards. 9th ed. Ottawa: Accreditation Canada; 2013.
[Return to footnote 105 referrer](#fn105-rf)
Footnote 106
Grotto I, Mandel Y, Green MS, Varsano N, Gdalevich M, Ashkenazi I, et al. Influenza vaccine efficacy in young, healthy adults. ClinInfectDis. 1998;26(4):913–7.
[Return to footnote 106 referrer](#fn106-rf)
Footnote 107
Leighton L, Williams M, Aubery D, Parker SH. Sickness absence following a campaign of vaccination against influenza in the workplace. OccupMed(Lond). 1996;46(2):146–50.
[Return to footnote 107 referrer](#fn107-rf)
Footnote 108
Nichol KL, Lind A, Margolis KL, Murdoch M, McFadden R, Hauge M, et al. The effectiveness of vaccination against influenza in healthy, working adults. NEnglJMed. 1995;333(14):889–93.
[Return to footnote 108 referrer](#fn108-rf)
Footnote 109
Department of Health (UK). Flu vaccination for poultry workers. London: Department of Health; 2007.
[Return to footnote 109 referrer](#fn109-rf)
Footnote 110
Gray GC, Trampel DW, Roth JA. Pandemic influenza planning: shouldn't swine and poultry workers be included? Vaccine. 2007;25(22):4376–81.
[Return to footnote 110 referrer](#fn110-rf)
Footnote 111
Bridges CB, Lim W, Hu-Primmer J, Sims L, Fukuda K, Mak KH, et al. Risk of influenza A (H5N1) infection among poultry workers, Hong Kong, 1997-1998. JInfectDis. 2002;185(8):1005–10.
[Return to footnote 111 referrer](#fn111-rf)
Footnote 112
Puzelli S, Di Trani L, Fabiani C, Campitelli L, De Marco MA, Capua I, et al. Serological analysis of serum samples from humans exposed to avian H7 influenza viruses in Italy between 1999 and 2003. JInfectDis. 2005;192(8):1318–22.
[Return to footnote 112 referrer](#fn112-rf)
Footnote 113
Tweed SA, Skowronski DM, David ST, Larder A, Petric M, Lees W, et al. Human illness from avian influenza H7N3, British Columbia. EmergInfectDis. 2004;10(12):2196–9.
[Return to footnote 113 referrer](#fn113-rf)
Footnote 114
Skowronski DM, Li Y, Tweed SA, Tam TW, Petric M, David ST, et al. Protective measures and human antibody response during an avian influenza H7N3 outbreak in poultry in British Columbia, Canada. CMAJ. 2007;176(1):47–53.
[Return to footnote 114 referrer](#fn114-rf)
Footnote 115
Langley JM, Vanderkooi OG, Garfield HA, Hebert J, Chandrasekaran V, Jain VK, et al. Immunogenicity and safety of 2 dose levels of a thimersol-free trivalent seasonal influenza vaccine in children aged 6-35 months. J Ped Infect Dis. 2012;1(1):55–8.
[Return to footnote 115 referrer](#fn115-rf)
Footnote 116
Skowronski DM, Hottes TS, Chong M, De Serres G, Scheifele DW, Ward BJ, et al. Randomized controlled trial of dose response to influenza vaccine in children aged 6 to 23 months. Pediatrics. 2011;128(2):e276-89.
[Return to footnote 116 referrer](#fn116-rf)
Footnote 117
Pavia-Ruz N, Weber MAR, Lau YL, Nelson EAS, Kerdpanich A, Huang LM, et al. A randomized controlled study to evaluate the immunogenicity of a trivalent inactivated seasonal influenza vaccine at two dosages in children 6 to 35 month of age. Human Vaccines & Immunotherapeutics. 2013;9(9):1978–88.
[Return to footnote 117 referrer](#fn117-rf)
Footnote 118
Skowronski DM, Tweed SA, De Serres G. Rapid decline of influenza vaccine-induced antibody in the elderly: is it real, or is it relevant? JInfectDis. 2008;197(4):490–502.
[Return to footnote 118 referrer](#fn118-rf)
Footnote 119
Anema A, Mills E, Montaner J, Brownstein JS, Cooper C. Efficacy of influenza vaccination in HIV-positive patients: a systematic review and meta-analysis. HIVMed. 2008;9(1):57–61.
[Return to footnote 119 referrer](#fn119-rf)
Footnote 120
Cooper C, Hutton B, Fergusson D, Mills E, Klein MB, Boivin G, et al. A review of influenza vaccine immunogenicity and efficacy in HIV-infected adults. Can J Infect Dis Med Microbiol. 2008;19(6):419–23.
[Return to footnote 120 referrer](#fn120-rf)
Footnote 121
Scharpe J, Evenepoel P, Maes B, Bammens B, Claes K, Osterhaus AD, et al. Influenza vaccination is efficacious and safe in renal transplant recipients. AmJTransplant. 2008;8(2):332–7.
[Return to footnote 121 referrer](#fn121-rf)
Footnote 122
Manuel O, Humar A, Chen MH, Chernenko S, Singer LG, Cobos I, et al. Immunogenicity and safety of an intradermal boosting strategy for vaccination against influenza in lung transplant recipients. AmJTransplant. 2007;7(11):2567–72.
[Return to footnote 122 referrer](#fn122-rf)
Footnote 123
Buxton JA, Skowronski DM, Ng H, Marion SA, Li Y, King A, et al. Influenza revaccination of elderly travelers: antibody response to single influenza vaccination and revaccination at 12 weeks. JInfectDis. 2001;184(2):188–91.
[Return to footnote 123 referrer](#fn123-rf)
Footnote 124
Ljungman P, Nahi H, Linde A. Vaccination of patients with haematological malignancies with one or two doses of influenza vaccine: a randomised study. BrJHaematol. 2005;130(1):96–8.
[Return to footnote 124 referrer](#fn124-rf)
Footnote 125
Gross PA, Weksler ME, Quinnan GV J, Douglas RG J, Gaerlan PF, Denning CR. Immunization of elderly people with two doses of influenza vaccine. JClinMicrobiol. 1987;25(9):1763–5.
[Return to footnote 125 referrer](#fn125-rf)
Footnote 126
Mosca F, Tritto E, Muzzi A, Monaci E, Bagnoli F, Iavarone C, et al. Molecular and cellular signatures of human vaccine adjuvants. ProcNatlAcadSciUSA. 2008;105(30):10501–6.
[Return to footnote 126 referrer](#fn126-rf)
Footnote 127
Calabro S, Tortoli M, Baudner B, Pacitto A, Cortese M, O'Hagan D, et al. Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes. Vaccine. 2011;29(9):1812–23.
[Return to footnote 127 referrer](#fn127-rf)
Footnote 128
Seubert A, Monaci E, Pizza M, O'Hagan D, Wack A. The adjuvants aluminum hydroxide and MF59 induce monocyte and granulocyte chemoattractants and enhance monocyte differentiation toward dendritic cells. JImmunol. 2008;180(8):5402–12.
[Return to footnote 128 referrer](#fn128-rf)
Footnote 129
O'Hagan DT, Rappuoli R, De Gregorio E, Tsai T, Del Giudice G. MF59 adjuvant: the best insurance against influenza strain diversity. Expert RevVaccines. 2011;10(4):447–62.
[Return to footnote 129 referrer](#fn129-rf)
Footnote 130
Vesikari T, Knuf M, Wutzler P, Karvonen A, Kieninger-Baum D, Schmitt HJ, et al. Oil-in-water emulsion adjuvant with influenza vaccine in young children. NEnglJMed. 2011;365(Journal Article):1406–16.
[Return to footnote 130 referrer](#fn130-rf)
Footnote 131
Vesikari T, Groth N, Karvonen A, Borkowski A, Pellegrini M. MF59 (R)-adjuvanted influenza vaccine (FLUAD (R)) in children: Safety and immunogenicity following a second year seasonal vaccination. Vaccine. 2009;27(Journal Article):6291–5.
[Return to footnote 131 referrer](#fn131-rf)
Footnote 132
Vesikari T, Pellegrini M, Karvonen A, Groth N, Borkowski A, Hagan DT, et al. Enhanced immunogenicity of seasonal influenza vaccines in young children using MF59 adjuvant. PediatrInfectDisJ. 2009;28(Journal Article):563–71.
[Return to footnote 132 referrer](#fn132-rf)
Footnote 133
Della Cioppa G, Vesikari T, Sokal E, Lindert K, Nicolay U. Trivalent and quadrivalent MF59 (R)-adjuvanted influenza vaccine in young children: A dose- and schedule-finding study. Vaccine. 2011;29(Generic):8696–704.
[Return to footnote 133 referrer](#fn133-rf)
Footnote 134
Zedda L, Forleo-Neto E, Vertruyen A, Raes M, Marchant A, Jansen W, et al. Dissecting the immune response to MF59-adjuvanted and nonadjuvanted seasonal influenza vaccines in children less than three years of age. PediatrInfectDisJ. 2015;34(1):73–8.
[Return to footnote 134 referrer](#fn134-rf)
Footnote 135
Nolan T, Bravo L, Ceballos A, Mitha E, Gray G, Quiambao B, et al. Enhanced and persistent antibody response against homologous and heterologous strains elicited by a MF59-adjuvanted influenza vaccine in infants and young children. Vaccine. 2014;32(46):6146–56.
[Return to footnote 135 referrer](#fn135-rf)
Footnote 136
Vaarala O, Vuorela A, Partinen M, Baumann M, Freitag TL, Meri S, et al. Antigenic differences between AS03 adjuvanted influenza A (H1N1) pandemic vaccines: implications for pandemrix-associated narcolepsy risk. PLoS One. 2014;9(12):e114361.
[Return to footnote 136 referrer](#fn136-rf)
Footnote 137
Jain VK, Rivera L, Zaman K, Espos Jr. RA, Sirivichayakul C, Quiambao BP, et al. Vaccine for prevention of mild and moderate-to-severe influenza in children. NEnglJMed. 2013;369(26):2481–91.
[Return to footnote 137 referrer](#fn137-rf)
Footnote 138
Haber P, Moro PL, Lewis P, Woo EJ, Jankosky C, Cano M. Post-licensure surveillance of quadrivalent inactivated influenza (IIV4) vaccine in the United States, Vaccine Adverse Event Reporting System (VAERS), July 1, 2013− May 31, 2015. Vaccine. 2016;34(22):2507–12.
[Return to footnote 138 referrer](#fn138-rf)
Footnote 139
Eposito A, Nauta J, Lapini G, et. al. Efficacy and safety of a quadrivalent influenza vaccine in children aged 6–35 months: A global, multiseasonal, controlled, randomized Phase III study. Vaccine. 2022;40(18):2626–34.
[Return to footnote 139 referrer](#fn139-rf)
Footnote 140
Diaz Granados CA, Dunning AJ, Robertson CA, Talbot HK, Landolfi V, Greenberg DP. Efficacy and immunogenicity of high-dose influenza vaccine in older adults by age, comorbidities, and frailty. JAmGeriatrSoc. 2014;62(Journal Article):S37–8.
[Return to footnote 140 referrer](#fn140-rf)
Footnote 141
Izurieta HS, Thadani N, Shay DK, Lu Y, Maurer A, Foppa IM, et al. Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis. Lancet InfectDis. 2015;15(3):293–300.
[Return to footnote 141 referrer](#fn141-rf)
Footnote 142
Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. JInfectDis. 2009;200(2):172–80.
[Return to footnote 142 referrer](#fn142-rf)
Footnote 143
Couch RB, Winokur P, Brady R, Belshe R, Chen WH, Cate TR, et al. Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Vaccine. 2007;25(44):7656–63.
[Return to footnote 143 referrer](#fn143-rf)
Footnote 144
Keitel WA, Atmar RL, Cate TR, Petersen NJ, Greenberg SB, Ruben F, et al. Safety of high doses of influenza vaccine and effect on antibody responses in elderly persons. ArchInternMed. 2006;166(10):1121–7.
[Return to footnote 144 referrer](#fn144-rf)
Footnote 145
Sanofi Pasteur. Study of Fluzone® influenza virus vaccine 2011-2012 formulation (intramuscular route) among adults [Internet]. Vol. 2014. 2013. Available from: https://www.clinicaltrials.gov/ct2/show/study/NCT01430819
[Return to footnote 145 referrer](#fn145-rf)
Footnote 146
Tsang P, Gorse GJ, Strout CB, Sperling M, Greenberg DP, Ozol-Godfrey A, et al. Immunogenicity and safety of Fluzone intradermal and high-dose influenza vaccines in older adults >65 years of age: A randomized, controlled, phase II trial. Vaccine. 2014;32(21):2507–17.
[Return to footnote 146 referrer](#fn146-rf)
Footnote 147
Nace DA, Lin CJ, Ross TM, Saracco S, Churilla RM, Zimmerman RK. Randomized, controlled trial of high-dose influenza vaccine among frail residents of long-term care facilities. JInfectDis. 2015;211(12):1915–24.
[Return to footnote 147 referrer](#fn147-rf)
Footnote 148
DiazGranados CA, Dunning AJ, Jordanov E, Landolfi V, Denis M, Talbot HK. High-dose trivalent influenza vaccine compared to standard dose vaccine in elderly adults: safety, immunogenicity and relative efficacy during the 2009-2010 season. Vaccine. 2013;31(6):861–6.
[Return to footnote 148 referrer](#fn148-rf)
Footnote 149
DiazGranados CA, Dunning AJ, Kimmel M, Kirby D, Treanor J, Collins A, et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. NEnglJMed. 2014;371(7):635–45.
[Return to footnote 149 referrer](#fn149-rf)
Footnote 150
Sanofi Pasteur. Product Monograph: FLUZONE® High-Dose Quadrivalent [Internet]. 2019 [cited 2020 Sep 15]. Available from: Https://Health-Products.Canada.Ca/Dpd-Bdpp/Info.Do?Lang=En&Code=99020
[Return to footnote 150 referrer](#fn150-rf)
Footnote 151
Chang LJ, Meng Y, Janosczyk H, et. al. Safety and Immunogenicity of High-Dose Quadrivalent Influenza Vaccine in Adults ≥65 Years of Age: A Phase 3 Randomized Clinical Trial. Vaccine. 2019;37(39):5825–34.
[Return to footnote 151 referrer](#fn151-rf)
Footnote 152
Dunkle LM, Izikson R, Patriarca P, Goldenthal KL, Muse D, Callahan J, et al. Efficacy of Recombinant Influenza Vaccine in Adults 50 Years of Age or Older. N Engl J Med. 2017 Jun 22;376(25):2427–36.
[Return to footnote 152 referrer](#fn152-rf)
Footnote 153
Belongia EA, Levine MZ, Olaiya O, Gross FL, King JP, Flannery B, et al. Clinical trial to assess immunogenicity of high-dose, adjuvanted, and recombinant influenza vaccines against cell-grown A(H3N2) viruses in adults 65 to 74 years, 2017–2018. Vaccine. 2020 Mar;38(15):3121–8.
[Return to footnote 153 referrer](#fn153-rf)
Footnote 154
Shinde V, Cai R, Plested J, Cho I, Fiske J, Pham X, et al. Induction of Cross-Reactive Hemagglutination Inhibiting Antibody and Polyfunctional CD4+ T-Cell Responses by a Recombinant Matrix-M–Adjuvanted Hemagglutinin Nanoparticle Influenza Vaccine. Clinical Infectious Diseases. 2021;73(11):e4278–87.
[Return to footnote 154 referrer](#fn154-rf)
Footnote 155
Dunkle LM, Izikson R, Patriarca PA, Goldenthal KL, Muse D, Cox MMJ. Randomized Comparison of Immunogenicity and Safety of Quadrivalent Recombinant Versus Inactivated Influenza Vaccine in Healthy Adults 18–49 Years of Age. The Journal of Infectious Diseases. 2017 Dec 5;216(10):1219–26.
[Return to footnote 155 referrer](#fn155-rf)
Footnote 156
Wang W, Alvarado-Facundo E, Vassell R, Collins L, Colombo RE, Ganesan A, et al. Comparison of A(H3N2) Neutralizing Antibody Responses Elicited by 2018–2019 Season Quadrivalent Influenza Vaccines Derived from Eggs, Cells, and Recombinant Hemagglutinin. Clinical Infectious Diseases. 2021 Dec 6;73(11):e4312–20.
[Return to footnote 156 referrer](#fn156-rf)
Footnote 157
Cowling BJ, Perera RAPM, Valkenburg SA, Leung NHL, Iuliano AD, Tam YH, et al. Comparative Immunogenicity of Several Enhanced Influenza Vaccine Options for Older Adults: A Randomized, Controlled Trial. Clinical Infectious Diseases. 2020 Oct 23;71(7):1704–14.
[Return to footnote 157 referrer](#fn157-rf)
Footnote 158
Gouma S, Zost SJ, Parkhouse K, Branche A, Topham DJ, Cobey S, et al. Comparison of Human H3N2 Antibody Responses Elicited by Egg-Based, Cell-Based, and Recombinant Protein–Based Influenza Vaccines During the 2017–2018 Season. Clinical Infectious Diseases. 2020 Sep 12;71(6):1447–53.
[Return to footnote 158 referrer](#fn158-rf)
Footnote 159
Dawood FS, Naleway AL, Flannery B, Levine MZ, Murthy K, Sambhara S, et al. Comparison of the Immunogenicity of Cell Culture-Based and Recombinant Quadrivalent Influenza Vaccines to Conventional Egg-Based Quadrivalent Influenza Vaccines Among Healthcare Personnel Aged 18–64 Years: A Randomized Open-Label Trial. Clinical Infectious Diseases. 2021 Dec 6;73(11):1973–81.
[Return to footnote 159 referrer](#fn159-rf)
Footnote 160
European Medicines Agency (EMA). Assessment report: Supemtek [Internet]. Vol. 2021. 2020. Available from: https://www.ema.europa.eu/en/documents/assessment-report/supemtek-epar-public-assessment-report\_en.pdf
[Return to footnote 160 referrer](#fn160-rf)
Footnote 161
US Food and Drug Administration. Guidance for industry: Clinical data needed to support the licensure of seasonal inactivated influenza vaccines [Internet]. Vol. 2021. 2007. Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm091990.pdf
[Return to footnote 161 referrer](#fn161-rf)
Footnote 162
Woo EJ, Moro PL. Postmarketing safety surveillance of quadrivalent recombinant influenza vaccine: Reports to the vaccine adverse event reporting system. Vaccine. 2021 Mar;39(13):1812–7.
[Return to footnote 162 referrer](#fn162-rf)
Footnote 163
Cowling BJ, Thompson MG, Ng TWY, Fang VJ, Perera RAPM, Leung NHL, et al. Comparative Reactogenicity of Enhanced Influenza Vaccines in Older Adults. The Journal of Infectious Diseases. 2020 Sep 14;222(8):1383–91.
[Return to footnote 163 referrer](#fn163-rf)
Footnote 164
National Advisory Committee on Immunization. Recommendations on the use of live, attenuated influenza vaccine (FluMist®): supplemental statement on seasonal influenza vaccine 2011-2012. CanCommunDisRep. 2011;37(7):1–77.
[Return to footnote 164 referrer](#fn164-rf)
Footnote 165
Block SL, Falloon J, Hirschfield JA, Krilov LR, Dubovsky F, Yi T, et al. Immunogenicity and safety of a quadrivalent live attenuated influenza vaccine in children. PediatrInfectDisJ. 2012;31(7):745–51.
[Return to footnote 165 referrer](#fn165-rf)
Footnote 166
Block SL, Yi T, Sheldon E, Dubovsky F, Falloon J. A randomized, double-blind noninferiority study of quadrivalent live attenuated influenza vaccine in adults. Vaccine. 2011;29(50):9391–7.
[Return to footnote 166 referrer](#fn166-rf)
Footnote 167
MedImmune. A randomized, partially blind active controlled study to evaluate the immunogenicity of MEDI8662 in adults 18-49 years of age [Internet]. Vol. 2015. 2011. Available from: https://clinicaltrials.gov/ct2/show/results/NCT00952705?term=MEDI8662&rank=1
[Return to footnote 167 referrer](#fn167-rf)
Footnote 168
Public Health Agency of Canada. Recommendation on the Use of Live Attenuated Influenza Vaccine (LAIV) in HIV-Infected Individuals [Internet]. 2020. Available from: https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/live-attenuated-influenza-vaccine-hiv-infected-individuals.html
[Return to footnote 168 referrer](#fn168-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html&n=National%20Advisory%20Committee%20on%20Immunization%20(NACI)%20statement%3A%20Seasonal%20influenza%20vaccine%20for%202023-2024%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html&title=National%20Advisory%20Committee%20on%20Immunization%20(NACI)%20statement%3A%20Seasonal%20influenza%20vaccine%20for%202023-2024%20-%20Canada.ca)
* [Email](mailto:?subject=National%20Advisory%20Committee%20on%20Immunization%20(NACI)%20statement%3A%20Seasonal%20influenza%20vaccine%20for%202023-2024%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html&t=National%20Advisory%20Committee%20on%20Immunization%20(NACI)%20statement%3A%20Seasonal%20influenza%20vaccine%20for%202023-2024%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=National%20Advisory%20Committee%20on%20Immunization%20(NACI)%20statement%3A%20Seasonal%20influenza%20vaccine%20for%202023-2024%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html&title=National%20Advisory%20Committee%20on%20Immunization%20(NACI)%20statement%3A%20Seasonal%20influenza%20vaccine%20for%202023-2024%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html&t=National%20Advisory%20Committee%20on%20Immunization%20(NACI)%20statement%3A%20Seasonal%20influenza%20vaccine%20for%202023-2024%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html&media=&description=National%20Advisory%20Committee%20on%20Immunization%20(NACI)%20statement%3A%20Seasonal%20influenza%20vaccine%20for%202023-2024%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html&title=National%20Advisory%20Committee%20on%20Immunization%20(NACI)%20statement%3A%20Seasonal%20influenza%20vaccine%20for%202023-2024%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html&name=National%20Advisory%20Committee%20on%20Immunization%20(NACI)%20statement%3A%20Seasonal%20influenza%20vaccine%20for%202023-2024%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=National%20Advisory%20Committee%20on%20Immunization%20(NACI)%20statement%3A%20Seasonal%20influenza%20vaccine%20for%202023-2024%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html)
* [Whatsapp](https://api.whatsapp.com/send?text=National%20Advisory%20Committee%20on%20Immunization%20(NACI)%20statement%3A%20Seasonal%20influenza%20vaccine%20for%202023-2024%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=National%20Advisory%20Committee%20on%20Immunization%20(NACI)%20statement%3A%20Seasonal%20influenza%20vaccine%20for%202023-2024%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2023-06-28
| None | None |
7ebbf0203ce87391d158d4d5df602d55b834f52a | cma | COVID-19 for health professionals: Post COVID-19 condition (long COVID) | COVID-19 for health professionals: Post COVID-19 condition (long COVID)
On this page
About the condition
The World Health Organization (WHO) defines post COVID-19 condition (PCC) as occurring:
"in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time."
The WHO published a separate clinical case definition for post COVID-19 condition in children and adolescents. It recognizes the unique health considerations of this population. Of note, the WHO indicates:
"Post COVID-19 condition in children and adolescents occurs in individuals with a history of confirmed or probable SARS-CoV-2 infection, when experiencing symptoms lasting at least 2 months which initially occurred within 3 months of acute COVID-19. Current evidence suggests that symptoms more frequently reported in children and adolescents with post-COVID-19 condition compared with controls are fatigue, altered smell/anosmia and anxiety. Other symptoms have also been reported. Symptoms generally have an impact on everyday functioning such as changes in eating habits, physical activity, behaviour, academic performance, social functions (interactions with friends, peers, family) and developmental milestones. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. They may also fluctuate or relapse over time. Workup may reveal additional diagnoses, but this does not exclude the diagnosis of post COVID-19 condition. This can be applied to children of all ages, with age-specific symptoms and impact on everyday function taken into consideration."
Several studies have reported that long-term symptoms are more common in patients who had severe COVID-19, for example, those who:
- were hospitalized
- needed intensive care during the acute infection phase
However, the condition may also occur in people who experienced only mild to moderate symptoms of COVID-19.
People experiencing symptoms of post COVID-19 condition may not have been formally tested and diagnosed with COVID-19 using:
- nucleic acid-based testing
- polymerase chain reaction (PCR) testing
This may be due to limited testing capacity during the pandemic and a gradual shift towards self-testing kits.
Learn more about:
Symptoms
Post COVID-19 condition is associated with a wide variety of symptoms across multiple organ systems. They can impact or limit everyday activities, such as school, work and caregiving. Symptoms can fluctuate in intensity, and on occasion may disappear and later reappear. Notably, some patients report that mental and physical over-exertion can exacerbate the condition.
# Adults
The most commonly reported symptoms in adults include:
- fatigue
- sleep disturbances
- shortness of breath
- general pain and discomfort
- cognitive problems, such as:
- memory loss
- difficulty thinking or concentrating
- mental health symptoms, such as:
- anxiety
- depression
In October 2022, preliminary estimates from the Canadian COVID-19 Antibody Health Survey indicated that, of the adults who experienced longer-term COVID-19 symptoms:
- 47.3% experienced symptoms for 1 year or longer
- 21.3% reported that their symptoms often or always limited their daily activities
- 74.1% of those who were employed or attending school, missed work or school due to their symptoms
- this averaged out to an estimated 20 missed days
Learn more about:
# Children
Post COVID-19 condition typically appears in adults. However, emerging evidence shows that children may also develop chronic, persistent symptoms after COVID-19.
The most commonly reported symptoms in children include:
- fatigue
- headaches
- abdominal pain
- sleep problems
- shortness of breath
- cognitive problems, such as:
- difficulty thinking
- concentrating
- muscle aches and joint pains
More research is needed on the longer-term symptoms after a SARS-CoV-2 infection in children and adolescents. In September 2022, the Public Health Agency of Canada began a 2-year collaboration with the Canadian Paediatric Society to better understand post COVID-19 condition in children.
Learn more about:
# Mental health
Mental health symptoms, such as anxiety and depression, are commonly reported by individuals experiencing post COVID-19 condition. Encourage patients to talk to their health care provider if they think they may be experiencing symptoms of:
- anxiety
- depression
- posttraumatic stress disorder
Learn more about:
Prevalence
# Adults
There is still uncertainty about the prevalence of post COVID-19 condition. Several studies and systematic reviews were carried out in the initial phase of the pandemic (prior to the Omicron variant and roll out of vaccination campaigns). These found that about 30% to 40% of those not hospitalized still reported at least 1 symptom, whether it be mild or more severe, 12 or more weeks after having COVID-19.
In systematic reviews, prevalence estimates from individual studies vary widely, ranging from below 5% in some studies to around 80% in studies among those with severe initial illness. The variation in estimates is likely due to differences in:
- definitions used for the condition
- methods and timing of assessment of post COVID-19 condition-related symptoms
- characteristics of the study populations, such as those hospitalized for COVID-19 or outpatients
Early evidence now suggests that infection with Omicron variants may be less likely to lead to post COVID-19 condition compared to infection with other variants. This may be partially offset by the fact that Omicron variants have been more contagious than earlier strains, resulting in higher numbers of cases of COVID-19.
In October 2022, preliminary prevalence estimates from the Canadian COVID-19 Antibody Health Survey indicated that:
- 14.8% of adults with a confirmed or suspected COVID-19 infection experienced longer-term COVID-19 symptoms
- per Statistics Canada, this translates into about 1.4 million adults in Canada aged 18 years and older (4.6% of the Canadian population)
- a higher percentage of females (18%) reported prolonged symptoms compared with males (11.6%)
- the percentage of adults reporting prolonged symptoms did not differ significantly by age group
These Canadian prevalence estimates are consistent with current international estimates from similar populations, such as adults:
- with different vaccination status
- with a range of illness severity from COVID-19
- who contracted different variants of SARS-CoV-2
Learn more about:
# Children
The prevalence of post COVID-19 condition in children is not yet well established, with high variability in estimates based on a small number of studies. As more studies are conducted and new evidence emerges, these estimates will become more precise.
Risk factors
Anyone who has contracted SARS-CoV-2, the virus that causes COVID-19, can experience post COVID-19 condition, even people who had a mild SARS CoV-2 infection.
The studies reviewed by the Public Health Agency of Canada and collaborators show that these groups appear to be disproportionally impacted by the condition:
- females
- those who experienced severe acute COVID-19
- those who required hospitalization for their acute COVID-19 illness
Those with underlying chronic conditions may also be at greater risk.
Further studies are being closely watched for the potential impacts of the condition on different subpopulations, including:
1. those who did not get 2 or more doses of COVID-19 vaccine prior to infection with SARS-CoV-2
2. those who experience re-infections
Prevention
Currently, the best way to avoid post COVID-19 condition is to take measures to prevent SARS-CoV-2 infection. This includes measures like:
- staying home when sick
- wearing a well-fitted mask
- improving indoor ventilation
This can also protect people who are at risk of more severe disease.
Vaccination is one of the most effective ways to protect against severe COVID-19. Early evidence suggests that vaccination with 2 or more vaccine doses prior to infection with SARS-CoV-2 helps to reduce the risk of developing post COVID-19 condition.
In addition to vaccination, the Government of Canada has also taken measures to secure safe and effective COVID-19 therapies. When used properly, COVID-19 therapies can help reduce the severity of symptoms and improve outcomes for individuals who contract SARS-CoV-2.
The government has made efforts to secure a range of therapies so that people in Canada have access to the most effective treatments available. These efforts are part of a broader strategy to control the spread of COVID-19 and protect the health of people in Canada. While vaccination remains the best way to protect against severe outcomes of COVID-19, the availability of safe and effective therapies is an important tool to limit the spread of this disease.
Canada continues to monitor new developments to learn more about other preventive measures. Some international studies on post COVID-19 condition are exploring the potential use of already-approved drugs for the treatment or prevention of post COVID-19 condition. For example, nirmatrelvir combined with ritonavir will be assessed for its efficacy in treating patients with post-acute sequelae SARS-CoV-2 (PASC) or post COVID-19 condition. This is a therapy already approved for the treatment of mild to moderate COVID-19. At this time, there is insufficient rigorous evidence to guide clinical care decision making for post COVID-19 condition.
Learn more about:
Diagnosis and treatment
While clinical studies are underway in Canada and around the world, there are currently no regulator-level approved diagnostic tests and treatments for post COVID-19 condition. Ongoing research about what causes it, and how to diagnose and treat it, will help in the development of specific guidelines for health care professionals and patients.
The WHO, along with patients, researchers and others, developed a clinical case definition of post COVID-19 condition to assist clinicians in diagnosing the condition.
In September 2022, the WHO released living guidelines for the clinical management of COVID-19, which contain 16 new recommendations for the rehabilitation of adults with post COVID-19 condition. In the same month, the U.S. Centers for Disease Control and Prevention updated their guidance webpage for health professionals.
The provinces and territories are responsible for the management and delivery of health care services for their residents. This includes rehabilitation and treatment services for people with post COVID-19 condition. Public and private clinics that provide care to individuals with post COVID-19 condition have now opened in some provinces. These focus on interdisciplinary care, and some are connected with clinical research.
Learn more about:
+ see Chapter 24: Care of patients after acute illness, which focuses on the rehabilitation of adults of post COVID-19 condition
What Canada is doing
People in Canada with post COVID-19 condition who are unable to work because of their symptoms may be eligible for financial support.
The Government of Canada continues to conduct and support scientific activities, in collaboration with other partners, to learn more about:
- the burden of post COVID-19 condition in Canada
- how to prevent, manage and treat the condition
# Budget 2022
The Government of Canada provided funding in Budget 2022 to support research and generate more evidence about the impacts of post COVID-19 condition in Canada.
The funding package includes $9 million to the Public Health Agency of Canada over 3 years to fund the development, dissemination and evaluation of evidence-based guidelines and knowledge translation tools. The guidelines and tools will cover topics related to the full cycle of the condition to support patients, health professionals and caregivers.
The budget also includes $20 million over 5 years to the new Centre for Research on Pandemic Preparedness and Health Emergencies at the Canadian Institutes of Health Research, starting in 2022 to 2023. This funding will support a dedicated Canadian post COVID-19 condition research network that will study:
- long-term effects of COVID-19 on people in Canada
- the wider impacts of COVID-19 on health and health care systems
Learn more about:
# Canadian COVID-19 Antibody and Health Survey
The Public Health Agency of Canada also collaborated with Statistics Canada on the population-based Canadian COVID-19 Antibody and Health Survey. The survey was sent to 100,000 randomly selected people in Canada aged 18 years and older across the 10 provinces to:
- identify risk factors associated with developing longer-term symptoms
- gather information on symptoms, including severity, duration and impact on daily activities
- estimate the percentage of Canadian adults who are living with longer-term symptoms after a positive COVID-19 test or suspected infection
Final results from the survey are expected to be released in early 2023 and will further our knowledge about longer-term COVID-19 symptoms.
Learn more about:
# Task Force on Post COVID-19 Condition
At the request of the Minister of Health, Canada's Chief Science Advisor, Dr. Mona Nemer, convened the T Force on Post COVID-19 Condition in August 2022 to develop a framework to manage post COVID-19 condition. The executive summary and full report are currently available. These recommendations will be critical in informing future all-inclusive action in responding to the condition, and are currently being reviewed by officials.
Learn more about:
# Post COVID-19 Condition Secretariat
The Post COVID-19 Condition Secretariat, housed within the Public Health Agency of Canada, has been established to bring greater coordination and strategic direction to the on-going work relating to the condition. This includes coordinating a whole-of-government approach in taking action to address evidence and data gaps around the condition, along with supporting Canadians in managing and eventually recovering from it.
Related links
# Publications and information
# Patient resources
# Patient support groups |
COVID-19 for health professionals: Post COVID-19 condition (long COVID)
========================================================================
On this page
------------
* [About the condition](#a1)
* [Symptoms](#a2)
* [Prevalence](#b1)
* [Risk factors](#b2)
* [Prevention](#a3)
* [Diagnosis and treatment](#b3)
* [What Canada is doing](#a4)
About the condition
-------------------
The World Health Organization (WHO) defines post COVID-19 condition (PCC) as occurring:
>
> "[…]in individuals with a history of probable or confirmed SARS CoV-2 infection, usually **3 months** from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others and generally have an impact on everyday functioning. Symptoms may be **new onset** following initial recovery from an acute COVID-19 episode or **persist** from the initial illness. Symptoms may also **fluctuate** or relapse over time."
>
>
>
The WHO published a separate clinical case definition for post COVID-19 condition in children and adolescents. It recognizes the unique health considerations of this population. Of note, the WHO indicates:
>
> "Post COVID-19 condition in children and adolescents occurs in individuals with a history of confirmed or probable SARS-CoV-2 infection, when experiencing symptoms lasting at least 2 months which initially occurred within 3 months of acute COVID-19. Current evidence suggests that symptoms more frequently reported in children and adolescents with post-COVID-19 condition compared with controls are fatigue, altered smell/anosmia and anxiety. Other symptoms have also been reported. [...] Symptoms generally have an impact on everyday functioning such as changes in eating habits, physical activity, behaviour, academic performance, social functions (interactions with friends, peers, family) and developmental milestones. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. They may also fluctuate or relapse over time. Workup may reveal additional diagnoses, but this does not exclude the diagnosis of post COVID-19 condition. This can be applied to children of all ages, with age-specific symptoms and impact on everyday function taken into consideration."
>
>
>
Several studies have reported that long-term symptoms are more common in patients who had severe COVID-19, for example, those who:
* were hospitalized
* needed intensive care during the acute infection phase
However, the condition may also occur in people who experienced only mild to moderate symptoms of COVID-19.
People experiencing symptoms of post COVID-19 condition may not have been formally tested and diagnosed with COVID-19 using:
* nucleic acid-based testing
* polymerase chain reaction (PCR) testing
This may be due to limited testing capacity during the pandemic and a gradual shift towards self-testing kits.
Learn more about:
* [A clinical case definition of post COVID-19 condition by a Delphi consensus (World Health Organization)](https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1)
* [A clinical case definition for post COVID-19 condition in children and adolescents by expert consensus, 16 February 2023 (World Health Organization)](https://www.who.int/publications/i/item/WHO-2019-nCoV-Post-COVID-19-condition-CA-Clinical-case-definition-2023-1)
Symptoms
--------
Post COVID-19 condition is associated with a wide variety of symptoms across multiple organ systems. They can impact or limit everyday activities, such as school, work and caregiving. Symptoms can fluctuate in intensity, and on occasion may disappear and later reappear. Notably, some patients report that mental and physical over-exertion can exacerbate the condition.
### Adults
The most commonly reported symptoms in adults include:
* fatigue
* sleep disturbances
* shortness of breath
* general pain and discomfort
* cognitive problems, such as:
+ memory loss
+ difficulty thinking or concentrating
* mental health symptoms, such as:
+ anxiety
+ depression
In October 2022, preliminary estimates from the Canadian COVID-19 Antibody Health Survey indicated that, of the adults who experienced longer-term COVID-19 symptoms:
* 47.3% experienced symptoms for 1 year or longer
* 21.3% reported that their symptoms often or always limited their daily activities
* 74.1% of those who were employed or attending school, missed work or school due to their symptoms
+ this averaged out to an estimated 20 missed days
Learn more about:
* [Frequency and impact of longer-term symptoms following COVID-19 in Canadian adults](https://health-infobase.canada.ca/covid-19/post-covid-condition/)
### Children
Post COVID-19 condition typically appears in adults. However, emerging evidence shows that children may also develop chronic, persistent symptoms after COVID-19.
The most commonly reported symptoms in children include:
* fatigue
* headaches
* abdominal pain
* sleep problems
* shortness of breath
* cognitive problems, such as:
+ difficulty thinking
+ concentrating
* muscle aches and joint pains
More research is needed on the longer-term symptoms after a SARS-CoV-2 infection in children and adolescents. In September 2022, the Public Health Agency of Canada began a 2-year collaboration with the Canadian Paediatric Society to better understand post COVID-19 condition in children.
Learn more about:
* [Post-COVID-19 condition (long COVID) [Canadian Paediatric Surveillance Program]](http://cpsp.cps.ca/surveillance/study-etude/post-covid-19-condition)
### Mental health
Mental health symptoms, such as anxiety and depression, are commonly reported by individuals experiencing post COVID-19 condition. Encourage patients to talk to their health care provider if they think they may be experiencing symptoms of:
* anxiety
* depression
* posttraumatic stress disorder
Learn more about:
* [Wellness Together Canada: Mental Health and Substance Use Support](https://wellnesstogether.ca/en-CA)
* [How COVID-19 impacted mental health services in Canada (Canadian Institute for Health Information)](https://www.cihi.ca/en)
* [Mental health in long COVID: A resource for general practitioners (PDF, Provincial Health Services Authority of British Columbia)](http://www.phsa.ca/health-info-site/Documents/post_covid-19_Mental_Health_in_Long-COVID_for_GPs.pdf)
Prevalence
----------
### Adults
There is still uncertainty about the prevalence of post COVID-19 condition. Several studies and systematic reviews were carried out in the initial phase of the pandemic (prior to the Omicron variant and roll out of vaccination campaigns). These found that about 30% to 40% of those not hospitalized still reported at least 1 symptom, whether it be mild or more severe, 12 or more weeks after having COVID-19.
In systematic reviews, prevalence estimates from individual studies vary widely, ranging from below 5% in some studies to around 80% in studies among those with severe initial illness. The variation in estimates is likely due to differences in:
* definitions used for the condition
* methods and timing of assessment of post COVID-19 condition-related symptoms
* characteristics of the study populations, such as those hospitalized for COVID-19 or outpatients
Early evidence now suggests that infection with Omicron variants may be less likely to lead to post COVID-19 condition compared to infection with other variants. This may be partially offset by the fact that Omicron variants have been more contagious than earlier strains, resulting in higher numbers of cases of COVID-19.
In October 2022, preliminary prevalence estimates from the Canadian COVID-19 Antibody Health Survey indicated that:
* 14.8% of adults with a confirmed or suspected COVID-19 infection experienced longer-term COVID-19 symptoms
+ per Statistics Canada, this translates into about 1.4 million adults in Canada aged 18 years and older (4.6% of the Canadian population)
* a higher percentage of females (18%) reported prolonged symptoms compared with males (11.6%)
* the percentage of adults reporting prolonged symptoms did not differ significantly by age group
These Canadian prevalence estimates are consistent with current international estimates from similar populations, such as adults:
* with different vaccination status
* with a range of illness severity from COVID-19
* who contracted different variants of SARS-CoV-2
Learn more about:
* [Long-term symptoms in Canadian adults who tested positive for COVID-19 or suspected an infection, January 2020 to August 2022](https://www150.statcan.gc.ca/n1/daily-quotidien/221017/dq221017b-eng.htm)
### Children
The prevalence of post COVID-19 condition in children is not yet well established, with high variability in estimates based on a small number of studies. As more studies are conducted and new evidence emerges, these estimates will become more precise.
Risk factors
------------
Anyone who has contracted SARS-CoV-2, the virus that causes COVID-19, can experience post COVID-19 condition, even people who had a mild SARS CoV-2 infection.
The studies reviewed by the Public Health Agency of Canada and collaborators show that these groups appear to be disproportionally impacted by the condition:
* females
* those who experienced severe acute COVID-19
* those who required hospitalization for their acute COVID-19 illness
Those with underlying chronic conditions may also be at greater risk.
Further studies are being closely watched for the potential impacts of the condition on different subpopulations, including:
1. those who did not get 2 or more doses of COVID-19 vaccine prior to infection with SARS-CoV-2
2. those who experience re-infections
Prevention
----------
Currently, the best way to avoid post COVID-19 condition is to take measures to prevent SARS-CoV-2 infection. This includes measures like:
* staying home when sick
* wearing a well-fitted mask
* improving indoor ventilation
This can also protect people who are at risk of more severe disease.
Vaccination is one of the most effective ways to protect against severe COVID-19. Early evidence suggests that vaccination with 2 or more vaccine doses prior to infection with SARS-CoV-2 helps to reduce the risk of developing post COVID-19 condition.
In addition to vaccination, the Government of Canada has also taken measures to secure safe and effective COVID-19 therapies. When used properly, COVID-19 therapies can help reduce the severity of symptoms and improve outcomes for individuals who contract SARS-CoV-2.
The government has made efforts to secure a range of therapies so that people in Canada have access to the most effective treatments available. These efforts are part of a broader strategy to control the spread of COVID-19 and protect the health of people in Canada. While vaccination remains the best way to protect against severe outcomes of COVID-19, the availability of safe and effective therapies is an important tool to limit the spread of this disease.
Canada continues to monitor new developments to learn more about other preventive measures. Some international studies on post COVID-19 condition are exploring the potential use of already-approved drugs for the treatment or prevention of post COVID-19 condition. For example, nirmatrelvir combined with ritonavir will be assessed for its efficacy in treating patients with post-acute sequelae SARS-CoV-2 (PASC) or post COVID-19 condition. This is a therapy already approved for the treatment of mild to moderate COVID-19. At this time, there is insufficient rigorous evidence to guide clinical care decision making for post COVID-19 condition.
Learn more about:
* [COVID-19 treatments](/en/health-canada/services/drugs-health-products/covid19-industry/drugs-vaccines-treatments/treatments.html)
Diagnosis and treatment
-----------------------
While clinical studies are underway in Canada and around the world, there are currently no regulator-level approved diagnostic tests and treatments for post COVID-19 condition. Ongoing research about what causes it, and how to diagnose and treat it, will help in the development of specific guidelines for health care professionals and patients.
The WHO, along with patients, researchers and others, developed a clinical case definition of post COVID-19 condition to assist clinicians in diagnosing the condition.
In September 2022, the WHO released living guidelines for the clinical management of COVID-19, which contain 16 new recommendations for the rehabilitation of adults with post COVID-19 condition. In the same month, the U.S. Centers for Disease Control and Prevention updated their guidance webpage for health professionals.
The provinces and territories are responsible for the management and delivery of health care services for their residents. This includes rehabilitation and treatment services for people with post COVID-19 condition. Public and private clinics that provide care to individuals with post COVID-19 condition have now opened in some provinces. These focus on interdisciplinary care, and some are connected with clinical research.
Learn more about:
* [Post COVID-19 Condition: Guidance for Primary Care (PDF, Ontario Health)](https://www.ontariohealth.ca/sites/ontariohealth/files/2021-12/PostCovidConditionsClinicalGuidance_EN.pdf)
* [Post-COVID recovery care (Provincial Health Services Authority of British Columbia)](http://www.phsa.ca/health-professionals/clinical-resources/post-covid-19-care)
* [Clinical management of COVID-19: Living guideline (World Health Organization)](https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2023.1)
+ see Chapter 24: Care of patients after acute illness, which focuses on the rehabilitation of adults of post COVID-19 condition
* [Care Models for Long COVID: A Rapid Systematic Review (PDF, SPOR Evidence Alliance)](https://sporevidencealliance.ca/wp-content/uploads/2021/06/Care-Models-for-Long-COVID_Full-Report_2021.06.18.pdf)
* [A clinical case definition of post COVID-19 condition by a Delphi consensus (World Health Organization)](https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1)
* [Post-COVID conditions: Information for healthcare providers (U.S. Centers for Disease Control and Prevention)](https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html#tools-and-resources)
* [COVID-19 rapid guideline: Managing the long-term effects of COVID-19 (U.K. National Institute for Health and Care Excellence)](https://www.nice.org.uk/guidance/ng188)
What Canada is doing
--------------------
People in Canada with post COVID-19 condition who are unable to work because of their symptoms may be eligible for financial support.
The Government of Canada continues to conduct and support scientific activities, in collaboration with other partners, to learn more about:
* the burden of post COVID-19 condition in Canada
* how to prevent, manage and treat the condition
### Budget 2022
The Government of Canada provided funding in Budget 2022 to support research and generate more evidence about the impacts of post COVID-19 condition in Canada.
The funding package includes $9 million to the Public Health Agency of Canada over 3 years to fund the development, dissemination and evaluation of evidence-based guidelines and knowledge translation tools. The guidelines and tools will cover topics related to the full cycle of the condition to support patients, health professionals and caregivers.
The budget also includes $20 million over 5 years to the new Centre for Research on Pandemic Preparedness and Health Emergencies at the Canadian Institutes of Health Research, starting in 2022 to 2023. This funding will support a dedicated Canadian post COVID-19 condition research network that will study:
* long-term effects of COVID-19 on people in Canada
* the wider impacts of COVID-19 on health and health care systems
Learn more about:
* [Budget 2022: A Plan to Grow Our Economy and Make Life More Affordable](https://www.budget.canada.ca/2022/home-accueil-en.html)
### Canadian COVID-19 Antibody and Health Survey
The Public Health Agency of Canada also collaborated with Statistics Canada on the population-based Canadian COVID-19 Antibody and Health Survey. The survey was sent to 100,000 randomly selected people in Canada aged 18 years and older across the 10 provinces to:
* identify risk factors associated with developing longer-term symptoms
* gather information on symptoms, including severity, duration and impact on daily activities
* estimate the percentage of Canadian adults who are living with longer-term symptoms after a positive COVID-19 test or suspected infection
Final results from the survey are expected to be released in early 2023 and will further our knowledge about longer-term COVID-19 symptoms.
Learn more about:
* [Canadian COVID-19 Antibody and Health Survey](https://www.statcan.gc.ca/en/survey/household/5339)
### Task Force on Post COVID-19 Condition
At the request of the Minister of Health, Canada's Chief Science Advisor, Dr. Mona Nemer, convened the T[ask](https://www.ic.gc.ca/eic/site/063.nsf/eng/h_98027.html) Force on Post COVID-19 Condition in August 2022 to develop a framework to manage post COVID-19 condition. The executive summary and full report are currently available. These recommendations will be critical in informing future all-inclusive action in responding to the condition, and are currently being reviewed by officials.
Learn more about:
* [Task Force on Post COVID-19 Condition](https://www.ic.gc.ca/eic/site/063.nsf/eng/h_98027.html)
* [Post-COVID-19 Condition in Canada: What we know, what we don't know, and a framework for action](https://science.gc.ca/site/science/en/office-chief-science-advisor/initiatives-covid-19/post-covid-19-condition-canada-what-we-know-what-we-dont-know-and-framework-action)
### Post COVID-19 Condition Secretariat
The Post COVID-19 Condition Secretariat, housed within the Public Health Agency of Canada, has been established to bring greater coordination and strategic direction to the on-going work relating to the condition. This includes coordinating a whole-of-government approach in taking action to address evidence and data gaps around the condition, along with supporting Canadians in managing and eventually recovering from it.
Related links
-------------
* [COVID-19: Prevention and risks](/en/public-health/services/diseases/2019-novel-coronavirus-infection/prevention-risks.html)
* [COVID-19: Canadian Institutes of Health Research](https://cihr-irsc.gc.ca/e/51917.html)
* [After COVID-19: Resources for health professionals (Alberta Health Services)](https://www.albertahealthservices.ca/topics/Page17540.aspx)
* [Post COVID-19 condition: Clinical management tools (French only, Institut national d'excellence en santé et en services sociaux)](https://www.inesss.qc.ca/covid-19/affections-post-covid-19-covid-19-longue/outil-daide-a-la-prise-en-charge-affections-post-covid-19.html)
### Publications and information
* [Clinical long-term effects of COVID-19 (PDF, World Health Organization)](https://www.who.int/docs/default-source/coronaviruse/risk-comms-updates/update54_clinical_long_term_effects.pdf?sfvrsn=3e63eee5_8)
* [Report on Pan-Canadian Long COVID Impact Survey (PDF, COVID Long-Haulers)](https://imgix.cosmicjs.com/d8d3d3b0-c936-11eb-ba89-e7f98c8c358b-FINAL---Report-on-Long-Covid-Impact-Survey---June-8-2021.pdf)
* [Evidence brief on the association and safety of COVID-19 vaccination and post COVID-19 condition](/en/public-health/services/diseases/2019-novel-coronavirus-infection/canadas-reponse/summaries-recent-evidence/evidence-brief-associations-safety-covid-19-vaccination-post-condition.html)
* [Diagnosing post-COVID-19 condition (long COVID) in adults (PDF, Canadian Medical Association Journal)](https://www.cmaj.ca/content/cmaj/195/2/E78.full.pdf)
### Patient resources
* [Patient resources (CANCOV)](https://cancov.net/patient-resources/)
* [Canada Pension Plan Disability benefits](/en/employment-social-development/programs/pension-plan-disability-benefits.html)
* [Patient-Led Research Collaborative for Long COVID](https://patientresearchcovid19.com/)
* [Long COVID: Projet Co-Vie (Government of Quebec)](https://www.santemonteregie.qc.ca/en/west/long-covid)
* [Employment insurance (EI) sickness benefits program](/en/services/benefits/ei/ei-sickness.html)
* [Living with Post-COVID Symptoms (Provincial Health Services Authority of British Columbia)](http://www.phsa.ca/health-info/post-covid-19-care-recovery)
### Patient support groups
* [Survivor Corps](https://www.survivorcorps.com/)
* [Long Covid SOS](https://www.longcovidsos.org/)
* [Long COVID Kids](https://www.longcovidkids.org/)
* [Quebec Long Covid](https://www.facebook.com/groups/covidlongueqc/)
* [C19 Recovery Awareness](https://www.c19recoveryawareness.com/)
* [COVID Long-Haulers Canada](https://covidlonghaulcanada.com/)
* [Long COVID Resources Canada](https://longcovidcanada.ca/)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-03-15
| None | None |
ed59a2e3b0322a38813453224041341dbf0b0276 | cma | **Immunization of patients in health care institutions: Canadian Immunization Guide** | Immunization of patients in health care institutions: Canadian Immunization Guide
# Introduction
In both acute and long-term health care settings, it is important that immunization be part of organized care plans within each department, with clear accountability for program planning, implementation and evaluation. There is good evidence that the use of health care provider reminders and standing orders or medical directives, as well as evaluation of vaccine coverage with feedback to health care providers, improves vaccine uptake. Immunization programs or increased uptake of available vaccines has been associated with decreased antibiotic usage. Antibiotic usage reductions ranged from 5% to 10% in randomized controlled trials to relative reductions of 64% in observational studies.
Recommended vaccination schedules differ among the provinces and territories; therefore, immunization schedule differences may need to be considered when discharging a patient to another jurisdiction. When transferring a patient, information about the patient's immunization status should be provided to the receiving institution.
# Acute care institutions
Admission to hospital as well as visits to outpatient clinics or the emergency department provide important opportunities for health care providers to evaluate immunization status and to offer vaccination to patients of all ages. For patients without regular sources of health care or those followed in specialized clinics, the only opportunities for immunization may be during clinic visits or hospitalization.
In addition to routine practices, further infection control precautions may be indicated when administering live vaccines, such as varicella-containing, rotavirus, or live attenuated influenza virus (LAIV) vaccines in the hospital setting. For example, transmission of an attenuated virus through a rash occurring after immunization with a varicella-containing vaccine, or viral shedding following rotavirus vaccination could pose a risk to severely immunocompromised patients. Similarly, health care providers and other close contacts of severely immunocompromised patients should avoid contact with these patients for at least two weeks following vaccination with LAIV due to a theoretical risk of transmission. Consultation with the hospital's infection control experts is advised. Live vaccines are generally not administered to immunocompromised patients; refer to in Part 3 for information about vaccination of immunocompromised people.
Protocols for reporting adverse events following immunization should be in place in acute care institutions. Patients may be admitted to hospital for a serious adverse event following immunization, or patients who receive a vaccine in hospital, may experience an adverse event. Any adverse event following immunization that results in hospital admission or prolongs an existing hospitalization is considered a serious adverse event and should be reported without delay. Refer to in Part 2 for additional information about reporting adverse events following immunization.
## Pregnant women
The immunization status of any pregnant woman admitted to hospital should be assessed and arrangements should be made to optimize her immunization status. Refer to in Part 3 for additional information.
## Newborns and infants
Newborns of hepatitis B (HB) infected mothers should receive post-exposure prophylaxis with HB vaccine and HB immune globulin within 12 hours of birth. As well, administration of the first dose of HB vaccine to other newborns at high risk of exposure to HB virus may be considered before discharge. Refer to in Part 4 for additional information.
Neonatal intensive care units (NICU) should have immunization programs in place for infants who remain in the NICU for 2 months or longer. Refer to in Part 1 and in Part 3 for additional information.
Hospitalized infants who qualify for the anti-respiratory syncytial virus monoclonal antibody should receive the first dose at the onset of the RSV season. Qualifying infants who are discharged from hospital during the RSV season should receive their first dose before discharge home if possible. Refer to chapter in part 4 for more information.
## Post-partum women and other close contacts of newborns
Post-partum, women susceptible to pertussis, rubella or varicella should receive the relevant vaccine before discharge. Arrangements should be made for varicella-susceptible women to receive a second dose of univalent varicella vaccine at least 6 weeks after the first dose. During influenza season, women who did not receive influenza vaccination during pregnancy should also receive influenza vaccine before discharge. Arrangements should be made for household and other close contacts who anticipate having regular contact with the infant to optimize their immunization status. Refer to in Part 1 for additional information.
## Children and adolescents
Hospitalization may be an ideal opportunity to ensure catch up of routine childhood immunizations. Recommendations may need to be modified depending on the underlying condition leading to hospitalization. Refer to in Part 3 for additional information regarding children and adolescents who may be hospitalized with immunodeficiency disorders, or undergoing chemotherapy for malignant hematologic disorders. Refer to in Part 3 for additional information about hospitalized children and adolescents who have chronic conditions.
## Adults
There is an increasing number of vaccines recommended for adults; refer to in Part 3 for additional information. Despite the growing list of recommended adult immunizations, young and middle-aged adults, especially men, tend to have fewer contacts with the health care system than either children or the elderly; therefore, opportunistic immunization of adults during hospitalization is very important.
Many immunosuppressive or chronic disorders are associated with increased susceptibility to complications of vaccine preventable diseases in adults. Refer to in Part 3 for additional information on adults who may be hospitalized with HIV or other immunodeficiency disorders. Refer to in Part 3 for additional information on hospitalized adults who have chronic conditions.
## The elderly
The admission of elderly patients to hospital is an opportunity to optimize their immunization status. Effective programs to vaccinate elderly patients before discharge or while attending a clinic will guarantee that they do not miss influenza immunization in the community during the limited influenza vaccination period. It is also a useful time to assess whether tetanus and diphtheria toxoid-containing (Td) or Tdap, pneumococcal, and herpes zoster (shingles) vaccines are needed. Refer to in Part 3 for additional information on patients with chronic conditions.
# Long term care institutions
Residents of long-term care facilities, including children, should receive all routine immunizations, as appropriate for their age and risk status. The following vaccines are particularly important to consider: influenza, pneumococcal, and herpes zoster (for residents 50 years of age and older). Td vaccine is recommended every 10 years for adults. Immunization with Td vaccine provides an opportunity to immunize previously unimmunized or under-immunized individuals against polio or pertussis.
Annual seasonal influenza immunization is essential for adults of any age residing in a nursing home, chronic care, or continuing care facility. Programs and strategies should be implemented to ensure that annual influenza immunization occurs. Residents in long-term care facilities that have standing order programs for influenza are more likely to be immunized. Patients and their surrogate decision makers should be advised of the facility's immunization policy on admission and every effort made to obtain informed consent before the influenza season. |
**Immunization of patients in health care institutions: Canadian Immunization Guide**
=====================================================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-5-immunization-infants-born-prematurely.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html)
Notice
------
This CIG chapter has not been updated to contain any information regarding COVID-19 vaccines, refer to the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html).
Last partial content update (see [Table of updates](/en/public-health/services/canadian-immunization-guide/updates.html)): March 2023
March 2023: This chapter was updated to incorporate guidance from the National Advisory Committee on Immunization (NACI) statement: [Recommended use of palivizumab to reduce complications of respiratory syncytial virus infection in infants](/en/public-health/services/publications/vaccines-immunization/palivizumab-respiratory-syncitial-virus-infection-infants.html).
Last complete chapter revision: July 2015
On this page
------------
* [Introduction](#p3c5a1)
* [Acute care institutions](#p3c5a2)
+ [Pregnant women](#p3c5a1a)
+ [Newborns and infants](#p3c5a1b)
+ [Post-partum women and other close contacts of newborns](#p3c5a1c)
+ [Children and adolescents](#p3c5a1d)
+ [Adults](#p3c5a1e)
+ [The elderly](#p3c5a1f)
* [Long term care institutions](#p3c5a3)
* [Selected references](#p3c5a4)
### Introduction
In both acute and long-term health care settings, it is important that immunization be part of organized care plans within each department, with clear accountability for program planning, implementation and evaluation. There is good evidence that the use of health care provider reminders and standing orders or medical directives, as well as evaluation of vaccine coverage with feedback to health care providers, improves vaccine uptake. Immunization programs or increased uptake of available vaccines has been associated with decreased antibiotic usage. Antibiotic usage reductions ranged from 5% to 10% in randomized controlled trials to relative reductions of 64% in observational studies.
Recommended vaccination schedules differ among the provinces and territories; therefore, immunization schedule differences may need to be considered when discharging a patient to another jurisdiction. When transferring a patient, information about the patient's immunization status should be provided to the receiving institution.
### Acute care institutions
Admission to hospital as well as visits to outpatient clinics or the emergency department provide important opportunities for health care providers to evaluate immunization status and to offer vaccination to patients of all ages. For patients without regular sources of health care or those followed in specialized clinics, the only opportunities for immunization may be during clinic visits or hospitalization.
In addition to routine practices, further infection control precautions may be indicated when administering live vaccines, such as varicella-containing, rotavirus, or live attenuated influenza virus (LAIV) vaccines in the hospital setting. For example, transmission of an attenuated virus through a rash occurring after immunization with a varicella-containing vaccine, or viral shedding following rotavirus vaccination could pose a risk to severely immunocompromised patients. Similarly, health care providers and other close contacts of severely immunocompromised patients should avoid contact with these patients for at least two weeks following vaccination with LAIV due to a theoretical risk of transmission. Consultation with the hospital's infection control experts is advised. Live vaccines are generally not administered to immunocompromised patients; refer to [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for information about vaccination of immunocompromised people.
Protocols for reporting adverse events following immunization should be in place in acute care institutions. Patients may be admitted to hospital for a serious adverse event following immunization, or patients who receive a vaccine in hospital, may experience an adverse event. Any adverse event following immunization that results in hospital admission or prolongs an existing hospitalization is considered a serious adverse event and should be reported without delay. Refer to [Adverse events following immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) in Part 2 for additional information about reporting adverse events following immunization.
#### Pregnant women
The immunization status of any pregnant woman admitted to hospital should be assessed and arrangements should be made to optimize her immunization status. Refer to [Immunization in pregnancy and breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3 for additional information.
#### Newborns and infants
Newborns of hepatitis B (HB) infected mothers should receive post-exposure prophylaxis with HB vaccine and HB immune globulin within 12 hours of birth. As well, administration of the first dose of HB vaccine to other newborns at high risk of exposure to HB virus may be considered before discharge. Refer to [Hepatitis B vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for additional information.
Neonatal intensive care units (NICU) should have immunization programs in place for infants who remain in the NICU for 2 months or longer. Refer to [Recommended immunization schedules](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-13-recommended-immunization-schedules.html) in Part 1 and [Immunization of infants born prematurely](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-5-immunization-infants-born-prematurely.html) in Part 3 for additional information.
Hospitalized infants who qualify for the anti-respiratory syncytial virus monoclonal antibody should receive the first dose at the onset of the RSV season. Qualifying infants who are discharged from hospital during the RSV season should receive their first dose before discharge home if possible. Refer to [Respiratory syncytial virus](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/respiratory-syncytial-virus.html) chapter in part 4 for more information.
#### Post-partum women and other close contacts of newborns
Post-partum, women susceptible to pertussis, rubella or varicella should receive the relevant vaccine before discharge. Arrangements should be made for varicella-susceptible women to receive a second dose of univalent varicella vaccine at least 6 weeks after the first dose. During influenza season, women who did not receive influenza vaccination during pregnancy should also receive influenza vaccine before discharge. Arrangements should be made for household and other close contacts who anticipate having regular contact with the infant to optimize their immunization status. Refer to [Recommended immunization schedules](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-13-recommended-immunization-schedules.html) in Part 1 for additional information.
#### Children and adolescents
Hospitalization may be an ideal opportunity to ensure catch up of routine childhood immunizations. Recommendations may need to be modified depending on the underlying condition leading to hospitalization. Refer to [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional information regarding children and adolescents who may be hospitalized with immunodeficiency disorders, or undergoing chemotherapy for malignant hematologic disorders. Refer to [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional information about hospitalized children and adolescents who have chronic conditions.
#### Adults
There is an increasing number of vaccines recommended for adults; refer to [Immunization of adults](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-2-immunization-of-adults.html) in Part 3 for additional information. Despite the growing list of recommended adult immunizations, young and middle-aged adults, especially men, tend to have fewer contacts with the health care system than either children or the elderly; therefore, opportunistic immunization of adults during hospitalization is very important.
Many immunosuppressive or chronic disorders are associated with increased susceptibility to complications of vaccine preventable diseases in adults. Refer to [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional information on adults who may be hospitalized with HIV or other immunodeficiency disorders. Refer to [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional information on hospitalized adults who have chronic conditions.
#### The elderly
The admission of elderly patients to hospital is an opportunity to optimize their immunization status. Effective programs to vaccinate elderly patients before discharge or while attending a clinic will guarantee that they do not miss influenza immunization in the community during the limited influenza vaccination period. It is also a useful time to assess whether tetanus and diphtheria toxoid-containing (Td) or Tdap, pneumococcal, and herpes zoster (shingles) vaccines are needed. Refer to [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional information on patients with chronic conditions.
### Long term care institutions
Residents of long-term care facilities, including children, should receive all routine immunizations, as appropriate for their age and risk status. The following vaccines are particularly important to consider: influenza, pneumococcal, and herpes zoster (for residents 50 years of age and older). Td vaccine is recommended every 10 years for adults. Immunization with Td vaccine provides an opportunity to immunize previously unimmunized or under-immunized individuals against polio or pertussis.
Annual seasonal influenza immunization is essential for adults of any age residing in a nursing home, chronic care, or continuing care facility. Programs and strategies should be implemented to ensure that annual influenza immunization occurs. Residents in long-term care facilities that have standing order programs for influenza are more likely to be immunized. Patients and their surrogate decision makers should be advised of the facility's immunization policy on admission and every effort made to obtain informed consent before the influenza season.
Refer to [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) and [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional information on immunization recommendations for residents with specific disorders.
### Selected references
* Bardenheier BH, Shefer AM, Lu PJ et al. *Are standing order programs associated with influenza vaccination? NNHS, 2004*. J Am Med Dir Assoc 2010 Nov; 11 (9): 654 - 61.
* Centers for Disease Control and Prevention *Recommendations of the Advisory Committee on Immunization Practices: programmatic strategies to increase vaccination rates - assessment and feedback of provider-based vaccination coverage information*. MMWR Morb Mortal Wkly Rep 1996; 45 (10): 219 - 20.
* Task Force on Community Preventive Services. *The guide to community preventive services*. Accessed March 2015 at: http://www.thecommunityguide.org/
* Wilby KJ, Werry D. *A review of the effect of immunization programs on antimicrobial utilization*. Vaccine 2012; 30 (46): 6509-14.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-5-immunization-infants-born-prematurely.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-03-23
| None | None |
03e7f43093ac104482e380fe10320e9335476896 | cma | Reports of myocarditis and pericarditis after COVID-19 vaccination: Communiqué to health practitioners (June 3, 2021) | Reports of myocarditis and pericarditis after COVID-19 vaccination: Communiqué to health practitioners (June 3, 2021)
On this page
Background
In May 2021, of myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the lining around the heart) following vaccination with COVID-19 mRNA vaccines emerged, including from and the .
Available information indicates that:
- Cases were more commonly reported after the second dose
- Symptom onset was typically within several days after vaccination
- Cases were mainly adolescents and young adults
- Cases were more often males compared to females
- Cases experienced mild illness, responded well to conservative treatment and rest, and their symptoms improved quickly
Follow-up on these cases is ongoing. No clear association has been established between myocarditis/pericarditis and mRNA vaccines, and to date, no regulatory action has been taken in Canada or internationally.
Situation in Canada
As part of ongoing COVID-19 vaccine safety efforts, the Public Health Agency of Canada (PHAC) and Health Canada are closely monitoring myocarditis/pericarditis in passive and active Canadian safety surveillance systems, including the , the (CV), and the .
In Canada, there have been a small number of reports of , following vaccination with a COVID-19 mRNA vaccine, however it is important to note that adverse events occurring after vaccination are not necessarily related to the vaccine. Based on the few reports received in Canada, we are not currently seeing higher rates than would be expected in the general population. The Canadian provides updates on the latest numbers.
Diagnosis and reporting
Myocarditis and pericarditis both involve inflammation of the heart in response to an infection or some other trigger. Symptoms can include shortness of breath, chest pain, or the feeling of a rapid or abnormal heart rhythm.
Healthcare providers should consider myocarditis and pericarditis in evaluation of acute chest pain or pressure, arrhythmias, shortness of breath or other clinically compatible symptoms after vaccination. They should consider doing an electrocardiogram (ECG), troponins, and an echocardiogram, in consultation with a cardiologist. It would also be important to rule out other potential causes of myocarditis and pericarditis, as such, consultation with infectious disease and/or rheumatology is recommended, to assist in this evaluation, particularly for acute COVID-19 infection (e.g., PCR testing), prior SARS-CoV-2 infection (e.g., detection of SARS-CoV-2 nucleocapsid antibodies), and other viral etiologies (e.g., enterovirus PCR and comprehensive respiratory viral pathogen testing).
All cases of myocarditis or pericarditis following vaccination should be reported to the . Health Canada, PHAC, and the provincial and territorial health authorities will continue to closely monitor reports of myocarditis and/or pericarditis. Health Canada is also working closely with the manufacturers and international regulators to review information as it becomes available and will take appropriate action as needed. More information will be shared as it becomes available.
The benefits of the mRNA vaccines continue to outweigh their risks in the populations, as there are clear benefits of mRNA vaccines in reducing deaths and hospitalizations due to COVID-19 infections. |
Reports of myocarditis and pericarditis after COVID-19 vaccination: Communiqué to health practitioners (June 3, 2021)
======================================================================================================================
On this page
------------
* [Background](#a1)
* [Situation in Canada](#a2)
* [Diagnosis and reporting](#a3)
Background
----------
In May 2021, [international reports](https://www.who.int/news/item/26-05-2021-gacvs-myocarditis-reported-with-covid-19-mrna-vaccines) of myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the lining around the heart) following vaccination with COVID-19 mRNA vaccines emerged, including from [Israel](https://www.gov.il/en/departments/news/01062021-03) and the [United States](https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/myocarditis.html).
Available information indicates that:
* Cases were more commonly reported after the second dose
* Symptom onset was typically within several days after vaccination
* Cases were mainly adolescents and young adults
* Cases were more often males compared to females
* Cases experienced mild illness, responded well to conservative treatment and rest, and their symptoms improved quickly
Follow-up on these cases is ongoing. No clear association has been established between myocarditis/pericarditis and mRNA vaccines, and to date, no regulatory action has been taken in Canada or internationally.
Situation in Canada
-------------------
As part of ongoing COVID-19 vaccine safety efforts, the Public Health Agency of Canada (PHAC) and Health Canada are closely monitoring myocarditis/pericarditis in passive and active Canadian safety surveillance systems, including the [Canadian Adverse Events Following Immunization Surveillance System (CAEFISS)](/en/public-health/services/immunization/canadian-adverse-events-following-immunization-surveillance-system-caefiss.html), the [Canada Vigilance Program](/en/health-canada/services/drugs-health-products/medeffect-canada/canada-vigilance-program.html) (CV), [the Canadian National Vaccine Safety Network (CANVAS)](https://cirnetwork.ca/network/national-ambulatory-network/) and the [Canadian Immunization Monitoring Program ACTive (IMPACT)](https://www.cps.ca/impact).
In Canada, there have been a small number of reports of [pericarditis or myocarditis (PDF)](https://brightoncollaboration.us/wp-content/uploads/2021/05/Myocarditis-decision-tree_brief-format_DRAFT_24May2021.pdf), following vaccination with a COVID-19 mRNA vaccine, however it is important to note that adverse events occurring after vaccination are not necessarily related to the vaccine. Based on the few reports received in Canada, we are not currently seeing higher rates than would be expected in the general population. The Canadian [weekly online adverse events report](https://health-infobase.canada.ca/covid-19/vaccine-safety/) provides updates on the latest numbers.
Diagnosis and reporting
-----------------------
Myocarditis and pericarditis both involve inflammation of the heart in response to an infection or some other trigger. Symptoms can include shortness of breath, chest pain, or the feeling of a rapid or abnormal heart rhythm.
**Healthcare providers should consider myocarditis and pericarditis in evaluation of acute chest pain or pressure, arrhythmias, shortness of breath or other clinically compatible symptoms after vaccination.** They should consider doing an electrocardiogram (ECG), troponins, and an echocardiogram, **in consultation with a cardiologist**. **It would also be important to rule out other potential causes of myocarditis and pericarditis**, as such, consultation with infectious disease and/or rheumatology is recommended, to assist in this evaluation, particularly for acute COVID-19 infection (e.g., PCR testing), prior SARS-CoV-2 infection (e.g., detection of SARS-CoV-2 nucleocapsid antibodies), and other viral etiologies (e.g., enterovirus PCR and comprehensive respiratory viral pathogen testing).
**All cases of myocarditis or pericarditis following vaccination should be reported to the** [**local health authority**](/en/public-health/services/immunization/reporting-adverse-events-following-immunization/form.html). Health Canada, PHAC, and the provincial and territorial health authorities will continue to closely monitor reports of myocarditis and/or pericarditis. Health Canada is also working closely with the manufacturers and international regulators to review information as it becomes available and will take appropriate action as needed. More information will be shared as it becomes available.
The benefits of the mRNA vaccines continue to outweigh their risks in the [authorized](/en/health-canada/services/drugs-health-products/covid19-industry/drugs-vaccines-treatments/vaccines.html) populations, as there are clear benefits of mRNA vaccines in reducing deaths and hospitalizations due to COVID-19 infections.
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2021-06-14
| None | None |
e34705a6138c466deb2df74573baa8d3c2c1cd5a | cma | Canadian recommendations for the prevention and treatment of malaria | Canadian recommendations for the prevention and treatment of malaria
Overview
This guidance document is designed for Canadian health practitioners who prepare travellers to visit areas with a risk of malaria, and for those caring for ill travellers upon their return. The malaria guidelines aim to ensure appropriate prevention, diagnosis and management of this potentially life threatening infectious disease.
Who this guide is for
- Canadian health practitioners
In this guide
This guidance document consists of 8 chapters and 6 appendices. Chapters and appendices are updated as new evidence becomes available.
- Chapter 5: Malaria issues in special hosts |
Canadian recommendations for the prevention and treatment of malaria
=====================================================================
Related topics
--------------
* [Statement on Personal Protective Measures to Prevent Arthropod Bites](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2012-38/statement-on-personal-protective-measures-prevent-arthropod-bites.html)
* [Evidence Based Process for Developing Travel and Tropical Medicine Related Guidelines and Recommendations](/en/public-health/services/publications/diseases-conditions/evidence-based-process-developing-travel-tropical-medicine-guidelines-recommendations.html)
* [CATMAT statements and Recommendations](/en/public-health/services/catmat.html)
**An Advisory Committee Statement (ACS) from the
Committee to Advise on Tropical Medicine and Travel (CATMAT)**
**Updated:**
* [Chapter 5.2 - Issues in special hosts - pregnancy and breastfeeding](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-5-2-pregnancy-breastfeeding.html)
* [Chapter 7 - Treatment of malaria](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-7-treatment.html)
* [Chapter 8 - Drugs for the prevention and treatment of malaria](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-8-drugs.html)
Overview
--------
This guidance document is designed for Canadian health practitioners who prepare travellers to visit areas with a risk of malaria, and for those caring for ill travellers upon their return. The malaria guidelines aim to ensure appropriate prevention, diagnosis and management of this potentially life threatening infectious disease.
Who this guide is for
---------------------
* Canadian health practitioners
In this guide
-------------
This guidance document consists of 8 chapters and 6 appendices. Chapters and appendices are updated as new evidence becomes available.
Table of contents
-----------------
* [Executive Summary](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/executive-summary.html)
* [Acknowledgements](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/acknowledgements.html)
* [Chapter 1: Introduction](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-1-introduction.html)
* [Chapter 2: Prevention and risk assessment](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-2-prevention-risk-assessment.html)
* [Chapter 3: Prevention — bite protection measures and malaria education](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-3-prevention-bite-protection-measures.html)
* [Chapter 4: Prevention — chemoprophylaxis regimens](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-4-prevention-chemoprophylaxis-regimen.html)
* Chapter 5: Malaria issues in special hosts
+ [5.1 Prevention in special hosts — children](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-5-1-children.html)
+ [5.2 Prevention in special hosts — pregnancy and breastfeeding](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-5-2-pregnancy-breastfeeding.html)
+ [5.3 Prevention in special hosts — long term traveller or expatriate](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-5-3-long-term-travellor-expatriate.html)
+ [5.4 Prevention in special hosts — travellers with co-morbidities](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-5-4-travellers-co-morbidities.html)
+ [5.5 Migrant and those visiting friends and relatives (VFR)](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-5-5-migrants-visiting-friends-relatives.html)
* [Chapter 6: Malaria diagnosis](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-6-malaria-diagnosis.html)
* [Chapter 7: Treatment of malaria](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-7-treatment.html)
* [Chapter 8: Drugs for the prevention and treatment of malaria](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-8-drugs.html)
* [Appendix I: Malaria risk and recommended preventive measures by geographical area](/en/public-health/services/catmat/appendix-1-malaria-risk-recommended-chemoprophylaxis-geographic-area.html)
* [Appendix II: Pre-travel checklist for advising travellers to malarial areas](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/appendix-2-pre-travel-check-list.html)
* [Appendix III: Frequently asked questions about malaria](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/appendix-3-frequently-asked-questions.html)
* [Appendix IV: Strength and quality of evidence summary](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/appendix-4-strength-quality-evidence-summary.html)
* [Appendix V: Canadian malaria network accessing parenteral artesunate or quinine](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/appendix-5-canadian-malaria-network.html)
* [Appendix VI: Malaria card](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/appendix-6-malaria-card.html)
[Next Page](/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/executive-summary.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fcatmat%2Fcanadian-recommendations-prevention-treatment-malaria.html&n=Canadian%20recommendations%20for%20the%20prevention%20and%20treatment%20of%20malaria%20-%20CATMAT%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fcatmat%2Fcanadian-recommendations-prevention-treatment-malaria.html&title=Canadian%20recommendations%20for%20the%20prevention%20and%20treatment%20of%20malaria%20-%20CATMAT%20-%20Canada.ca)
* [Email](mailto:?subject=Canadian%20recommendations%20for%20the%20prevention%20and%20treatment%20of%20malaria%20-%20CATMAT%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fcatmat%2Fcanadian-recommendations-prevention-treatment-malaria.html%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fcatmat%2Fcanadian-recommendations-prevention-treatment-malaria.html&t=Canadian%20recommendations%20for%20the%20prevention%20and%20treatment%20of%20malaria%20-%20CATMAT%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=Canadian%20recommendations%20for%20the%20prevention%20and%20treatment%20of%20malaria%20-%20CATMAT%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fcatmat%2Fcanadian-recommendations-prevention-treatment-malaria.html%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fcatmat%2Fcanadian-recommendations-prevention-treatment-malaria.html&title=Canadian%20recommendations%20for%20the%20prevention%20and%20treatment%20of%20malaria%20-%20CATMAT%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fcatmat%2Fcanadian-recommendations-prevention-treatment-malaria.html&t=Canadian%20recommendations%20for%20the%20prevention%20and%20treatment%20of%20malaria%20-%20CATMAT%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fcatmat%2Fcanadian-recommendations-prevention-treatment-malaria.html&media=&description=Canadian%20recommendations%20for%20the%20prevention%20and%20treatment%20of%20malaria%20-%20CATMAT%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fcatmat%2Fcanadian-recommendations-prevention-treatment-malaria.html&title=Canadian%20recommendations%20for%20the%20prevention%20and%20treatment%20of%20malaria%20-%20CATMAT%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fcatmat%2Fcanadian-recommendations-prevention-treatment-malaria.html)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fcatmat%2Fcanadian-recommendations-prevention-treatment-malaria.html&name=Canadian%20recommendations%20for%20the%20prevention%20and%20treatment%20of%20malaria%20-%20CATMAT%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=Canadian%20recommendations%20for%20the%20prevention%20and%20treatment%20of%20malaria%20-%20CATMAT%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fcatmat%2Fcanadian-recommendations-prevention-treatment-malaria.html)
* [Whatsapp](https://api.whatsapp.com/send?text=Canadian%20recommendations%20for%20the%20prevention%20and%20treatment%20of%20malaria%20-%20CATMAT%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fcatmat%2Fcanadian-recommendations-prevention-treatment-malaria.html)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=Canadian%20recommendations%20for%20the%20prevention%20and%20treatment%20of%20malaria%20-%20CATMAT%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fcatmat%2Fcanadian-recommendations-prevention-treatment-malaria.html%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2020-01-16
| None | None |
bbbb8c90a08c78589f60c35a0fc2b1f7db274a1a | cma | Anaphylaxis and COVID-19: Summary information for health care professionals | Anaphylaxis and COVID-19: Summary information for health care professionals
Overview
Anaphylaxis is a severe allergic reaction and a medical emergency. As with any medicines and vaccines, allergic reactions are very rare but can occur. The estimated historical frequency of anaphylaxis is about 1.3 episodes per million doses of vaccine administered. Anaphylaxis can be easily recognized and prompt treatment improves outcomes.
Quick recognition and management can be life saving. The progression and severity can be difficult to predict. Every vaccine provider should be familiar with the signs and symptoms of anaphylaxis and be prepared to act quickly. should be readily available wherever vaccines are administered.
Advance preparation for emergency management of anaphylaxis is essential. It is recommended that vaccine providers develop, post, and regularly rehearse a written anaphylaxis emergency management protocol. Protocols should specify the necessary emergency equipment, drugs and dosages, and medical personnel necessary to safely and effectively manage anaphylaxis.
Symptoms of anaphylaxis
Symptoms of anaphylaxis can start within minutes of exposure to an allergen (such as a vaccine ingredient).
Symptoms vary from person to person. The same person can have different symptoms each time they have an allergic reaction.
Symptoms of a severe allergic reaction can include any of the following:
- Skin (most common): hives, swelling (face, lips, tongue, causing throat tightness, hoarse voice or trouble swallowing), itching, warmth, redness
- Respiratory: coughing, wheezing, shortness of breath, chest pain or tightness, nasal congestion or hay fever-like symptoms (runny, itchy nose and watery eyes, sneezing)
- Gastrointestinal: intense nausea, severe abdominal pain or cramps, vomiting, diarrhea
- Cardiovascular: rapid heart rate, low blood pressure, fainting, dizziness or light-headedness - shock and cardiac arrest are exceptionally rare
- Other: anxiety, sense of doom (the feeling that something bad is about to happen)
Anaphylaxis usually involves two or more body systems. Isolated respiratory or gastrointestinal symptoms are rare.
Symptoms of anaphylaxis in infants and young children
It may be challenging to identify anaphylaxis in infants and young children because they are unable to describe their symptoms. Behavioural changes (e.g. irritability and inconsolable crying) should be watched for. Infants may present with:
- Skin: hives, flushing, swelling of the face
+ For all children, including infants, skin symptoms are the most common overall of any body system affected.
- Respiratory: coughing, wheezing, dyspnea
- Gastrointestinal: Vomiting (including persistent vomiting)
- Cardiovascular: rapid heart rate
- Non-specific signs and symptoms:
+ Sudden quietness or sleepiness, drooling, incontinence and behavioural changes such as inconsolable crying and irritability. Behavioural symptoms can occur, such as those listed previously, however context is important as changes in behavior are non-specific and can be common in this age group.
Risk factors for severe anaphylaxis
Anaphylaxis is a rare, acute and severe allergic reaction that can be triggered by allergens such as food, medications, or vaccines. Risk factors for increased severity of anaphylactic events include:
- Very young or old age
- Pregnancy
- Severe or uncontrolled asthma
- Cardiovascular disease
- Chronic obstructive pulmonary disease
- Systemic mastocytosis (a condition resulting in a build up of mast cells in the body)
- Concurrent use of certain medications (e.g., angiotensin-converting enzyme inhibitors and beta-blockers)
How anaphylaxis should be managed
Steps for basic management of anaphylaxis in a community setting:
Death can occur within minutes. Rapid intervention, including administration of Epinephrine, is extremely important. Steps 1 to 4 should be done immediately and simultaneously.
1. Direct someone to call 9-1-1 (where available) or emergency medical services.
2. Assess airway, breathing, circulation, mental status, skin, and body weight. Secure an oral airway if necessary
- Airway: look specifically at lips, tongue and throat for swelling.
3. Place individual on his/her back and elevate lower extremities. The client should remain in this position. Exceptions include:
- If in respiratory distress, place in a position of comfort (elevate head and chest).
- If vomiting or unconscious, place lying on the patient's side.
- If pregnant, place lying down on their left side.
4. Inject epinephrine. There are no contraindications to the use of epinephrine for anyone.
- Dose: 0.01 mg/kg body weight of 1:1000 (1 mg/mL) solution, to a maximum total dose of 0.5 mg.
+ Weight is the preferred method for dose calculation. If unknown, age can be used as a guide (). This table should be included as part of the for use as a quick reference.
+ For infants weighing less than 5 kg, the dose of epinephrine should be determined by weight, if possible.
- Route: intramuscular (IM) in mid-anterolateral thigh.
- Repeat every 5-15 minutes if symptoms persist - most cases improve in 1-2 doses.
- Record the time of each dose.
- Stabilize and monitor client.
Vaccine anaphylaxis is not an indication to carry an epinephrine auto-injector (e.g. EpiPen, Allerject, Emerade) long term. However, if an epinephrine auto-injector is available, it can be used in place of a dose of injectable epinephrine.
Epinephrine is the only medication that reduces hospitalization and death, and it should be administered promptly following the onset of anaphylaxis.
What happens after a case of anaphylaxis is identified following vaccination
Anaphylaxis following vaccine administration must be reported to local public health authorities.
Provincial/territorial public health authorities will then remove all personal identifying information and forward reports to the Public Health Agency of Canada as part of the national vaccine surveillance program. |
Anaphylaxis and COVID-19: Summary information for health care professionals
============================================================================
On this page
------------
* [Overview](#a1)
* [Symptoms of anaphylaxis](#a2)
* [Symptoms of anaphylaxis in infants and young children](#a3)
* [Risk factors for severe anaphylaxis](#a4)
* [How anaphylaxis should be managed](#a5)
* [What happens after a case of anaphylaxis is identified following vaccination](#a6)
* [Additional resources](#a7)
+ [Anaphylaxis management](#a7.1)
+ [COVID-19 vaccines](#a7.2)
Overview
--------
Anaphylaxis is a severe allergic reaction and a medical emergency. As with any medicines and vaccines, allergic reactions are very rare but can occur. The estimated historical frequency of anaphylaxis is about 1.3 episodes per million doses of vaccine administered. Anaphylaxis can be easily recognized and prompt treatment improves outcomes.
Quick recognition and management can be life saving. The progression and severity can be difficult to predict. Every vaccine provider should be familiar with the signs and symptoms of anaphylaxis and be prepared to act quickly. [Anaphylaxis management kits](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html#t3) should be readily available wherever vaccines are administered.
Advance preparation for emergency management of anaphylaxis is essential. It is recommended that vaccine providers develop, post, and regularly rehearse a written anaphylaxis emergency management protocol. Protocols should specify the necessary emergency equipment, drugs and dosages, and medical personnel necessary to safely and effectively manage anaphylaxis.
Symptoms of anaphylaxis
-----------------------
Symptoms of anaphylaxis can start within minutes of exposure to an allergen (such as a vaccine ingredient).
Symptoms vary from person to person. The same person can have different symptoms each time they have an allergic reaction.
Symptoms of a severe allergic reaction can include any of the following:
* **Skin** (most common)**:** hives, swelling (face, lips, tongue, causing throat tightness, hoarse voice or trouble swallowing), itching, warmth, redness
* **Respiratory:** coughing, wheezing, shortness of breath, chest pain or tightness, nasal congestion or hay fever-like symptoms (runny, itchy nose and watery eyes, sneezing)
* **Gastrointestinal:** intense nausea, severe abdominal pain or cramps, vomiting, diarrhea
* **Cardiovascular:** rapid heart rate, low blood pressure, fainting, dizziness or light-headedness - shock and cardiac arrest are exceptionally rare
* **Other:** anxiety, sense of doom (the feeling that something bad is about to happen)
Anaphylaxis usually involves two or more body systems. Isolated respiratory or gastrointestinal symptoms are rare.
Symptoms of anaphylaxis in infants and young children
-----------------------------------------------------
It may be challenging to identify anaphylaxis in infants and young children because they are unable to describe their symptoms. Behavioural changes (e.g. irritability and inconsolable crying) should be watched for. Infants may present with:
* **Skin:** hives, flushing, swelling of the face
+ For all children, including infants, **skin symptoms are the most common overall** of any body system affected.
* **Respiratory:** coughing, wheezing, dyspnea
* **Gastrointestinal:** Vomiting (including persistent vomiting)
* **Cardiovascular:** rapid heart rate
* **Non-specific signs and symptoms:**
+ Sudden quietness or sleepiness, drooling, incontinence and behavioural changes such as inconsolable crying and irritability. Behavioural symptoms can occur, such as those listed previously, however context is important as changes in behavior are non-specific and can be common in this age group.
Risk factors for severe anaphylaxis
-----------------------------------
Anaphylaxis is a rare, acute and severe allergic reaction that can be triggered by allergens such as food, medications, or vaccines. Risk factors for increased severity of anaphylactic events include:
* Very young or old age
* Pregnancy
* Severe or uncontrolled asthma
* Cardiovascular disease
* Chronic obstructive pulmonary disease
* Systemic mastocytosis (a condition resulting in a build up of mast cells in the body)
* Concurrent use of certain medications (e.g., angiotensin-converting enzyme [ACE] inhibitors and beta-blockers)
How anaphylaxis should be managed
---------------------------------
Steps for basic management of anaphylaxis in a community setting:
Death can occur within minutes. Rapid intervention, including administration of Epinephrine, is extremely important. **Steps 1 to 4 should be done immediately and simultaneously**.
1. **Direct someone to call 9-1-1 (where available) or emergency medical services**.
2. **Assess airway, breathing, circulation, mental status, skin, and body weight**. Secure an oral airway if necessary
* Airway: look specifically at lips, tongue and throat for swelling.
3. **Place individual on his/her back and elevate lower extremities**. The client should remain in this position. Exceptions include:
* If in respiratory distress, place in a position of comfort (elevate head and chest).
* If vomiting or unconscious, place lying on the patient's side.
* If pregnant, place lying down on their left side.
4. **Inject epinephrine**. There are no contraindications to the use of epinephrine for anyone.
* Dose: 0.01 mg/kg body weight of 1:1000 (1 mg/mL) solution, to a maximum total dose of 0.5 mg.
+ Weight is the preferred method for dose calculation. If unknown, age can be used as a guide ([Table 4 in the Canadian Immunization Guide: Dosage of intramuscular epinephrine solution, by age or weight](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html#t4)). This table should be included as part of the [anaphylaxis management kit](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html#t3) for use as a quick reference.
+ For infants weighing less than 5 kg, the dose of epinephrine should be determined by weight, if possible.
* Route: intramuscular (IM) in mid-anterolateral thigh.
* Repeat every 5-15 minutes if symptoms persist - most cases improve in 1-2 doses.
* Record the time of each dose.
* Stabilize and monitor client.
Vaccine anaphylaxis is not an indication to carry an epinephrine auto-injector (e.g. EpiPen, Allerject, Emerade) long term. However, if an epinephrine auto-injector is available, it can be used in place of a dose of injectable epinephrine.
**Epinephrine is the only medication that reduces hospitalization and death, and it should be administered promptly following the onset of anaphylaxis.**
What happens after a case of anaphylaxis is identified following vaccination
----------------------------------------------------------------------------
Anaphylaxis following vaccine administration must be reported to local public health authorities.
Provincial/territorial public health authorities will then remove all personal identifying information and forward reports to the Public Health Agency of Canada as part of the national vaccine surveillance program.
Additional resources
--------------------
### Anaphylaxis management
* [Canadian Immunization Guide](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html)
* [Reporting Adverse Events Following Immunization (AEFI) in Canada](/en/public-health/services/immunization/reporting-adverse-events-following-immunization/user-guide-completion-submission-aefi-reports.html)
* Cardona et al. World Allergy Organization Journal (2020) 13:100472 http://doi.org/10.1016/j.waojou.2020.100472
* Your local or provincial/territorial public health authority
### COVID-19 vaccines
* [Vaccines for COVID-19](/en/public-health/services/diseases/coronavirus-disease-covid-19/vaccines.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fhealth-professionals%2Fvaccines%2Fanaphylaxis.html%3Futm_source%3Dpdf-link%26utm_medium%3Dvaccine-toolkit-healthcare-pro%26utm_content%3Den%26utm_campaign%3Dhc-sc-covid-21-22&n=Anaphylaxis%20and%20COVID-19%3A%20Summary%20information%20for%20health%20care%20professionals%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fhealth-professionals%2Fvaccines%2Fanaphylaxis.html%3Futm_source%3Dpdf-link%26utm_medium%3Dvaccine-toolkit-healthcare-pro%26utm_content%3Den%26utm_campaign%3Dhc-sc-covid-21-22&title=Anaphylaxis%20and%20COVID-19%3A%20Summary%20information%20for%20health%20care%20professionals%20-%20Canada.ca)
* [Email](mailto:?subject=Anaphylaxis%20and%20COVID-19%3A%20Summary%20information%20for%20health%20care%20professionals%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fhealth-professionals%2Fvaccines%2Fanaphylaxis.html%3Futm_source%3Dpdf-link%26utm_medium%3Dvaccine-toolkit-healthcare-pro%26utm_content%3Den%26utm_campaign%3Dhc-sc-covid-21-22%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fhealth-professionals%2Fvaccines%2Fanaphylaxis.html%3Futm_source%3Dpdf-link%26utm_medium%3Dvaccine-toolkit-healthcare-pro%26utm_content%3Den%26utm_campaign%3Dhc-sc-covid-21-22&t=Anaphylaxis%20and%20COVID-19%3A%20Summary%20information%20for%20health%20care%20professionals%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=Anaphylaxis%20and%20COVID-19%3A%20Summary%20information%20for%20health%20care%20professionals%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fhealth-professionals%2Fvaccines%2Fanaphylaxis.html%3Futm_source%3Dpdf-link%26utm_medium%3Dvaccine-toolkit-healthcare-pro%26utm_content%3Den%26utm_campaign%3Dhc-sc-covid-21-22%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fhealth-professionals%2Fvaccines%2Fanaphylaxis.html%3Futm_source%3Dpdf-link%26utm_medium%3Dvaccine-toolkit-healthcare-pro%26utm_content%3Den%26utm_campaign%3Dhc-sc-covid-21-22&title=Anaphylaxis%20and%20COVID-19%3A%20Summary%20information%20for%20health%20care%20professionals%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fhealth-professionals%2Fvaccines%2Fanaphylaxis.html%3Futm_source%3Dpdf-link%26utm_medium%3Dvaccine-toolkit-healthcare-pro%26utm_content%3Den%26utm_campaign%3Dhc-sc-covid-21-22&t=Anaphylaxis%20and%20COVID-19%3A%20Summary%20information%20for%20health%20care%20professionals%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fhealth-professionals%2Fvaccines%2Fanaphylaxis.html%3Futm_source%3Dpdf-link%26utm_medium%3Dvaccine-toolkit-healthcare-pro%26utm_content%3Den%26utm_campaign%3Dhc-sc-covid-21-22&media=&description=Anaphylaxis%20and%20COVID-19%3A%20Summary%20information%20for%20health%20care%20professionals%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fhealth-professionals%2Fvaccines%2Fanaphylaxis.html%3Futm_source%3Dpdf-link%26utm_medium%3Dvaccine-toolkit-healthcare-pro%26utm_content%3Den%26utm_campaign%3Dhc-sc-covid-21-22&title=Anaphylaxis%20and%20COVID-19%3A%20Summary%20information%20for%20health%20care%20professionals%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fhealth-professionals%2Fvaccines%2Fanaphylaxis.html%3Futm_source%3Dpdf-link%26utm_medium%3Dvaccine-toolkit-healthcare-pro%26utm_content%3Den%26utm_campaign%3Dhc-sc-covid-21-22)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fhealth-professionals%2Fvaccines%2Fanaphylaxis.html%3Futm_source%3Dpdf-link%26utm_medium%3Dvaccine-toolkit-healthcare-pro%26utm_content%3Den%26utm_campaign%3Dhc-sc-covid-21-22&name=Anaphylaxis%20and%20COVID-19%3A%20Summary%20information%20for%20health%20care%20professionals%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=Anaphylaxis%20and%20COVID-19%3A%20Summary%20information%20for%20health%20care%20professionals%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fhealth-professionals%2Fvaccines%2Fanaphylaxis.html%3Futm_source%3Dpdf-link%26utm_medium%3Dvaccine-toolkit-healthcare-pro%26utm_content%3Den%26utm_campaign%3Dhc-sc-covid-21-22)
* [Whatsapp](https://api.whatsapp.com/send?text=Anaphylaxis%20and%20COVID-19%3A%20Summary%20information%20for%20health%20care%20professionals%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fhealth-professionals%2Fvaccines%2Fanaphylaxis.html%3Futm_source%3Dpdf-link%26utm_medium%3Dvaccine-toolkit-healthcare-pro%26utm_content%3Den%26utm_campaign%3Dhc-sc-covid-21-22)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=Anaphylaxis%20and%20COVID-19%3A%20Summary%20information%20for%20health%20care%20professionals%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fhealth-professionals%2Fvaccines%2Fanaphylaxis.html%3Futm_source%3Dpdf-link%26utm_medium%3Dvaccine-toolkit-healthcare-pro%26utm_content%3Den%26utm_campaign%3Dhc-sc-covid-21-22%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2021-05-07
| None | None |
b1d8d5b290e8a02fd974049ad6cd4c46e028b2f0 | cma | Canadian Immunization Guide | Canadian Immunization Guide
Overview
Who this guide is for
This guide was developed for those with an interest in immunization, including:
- health professionals
- vaccine program decision makers
- other Canadian stakeholders
In this guide
This guide consists of 54 chapters organized into 4 parts. Chapters are updated as new evidence becomes available, and NACI and CATMAT statements are completed. Email updates are available through our mailing list.
Details and history
Updated: see
Part of topic(s):
For assistance
Did you find what you were looking for?
Yes
No
If not, tell us why:
What was wrong?
I can't find the information
The information is hard to understand
There was an error or something didn't work
Other reason
Please provide more details
You will not receive a reply. Telephone numbers and email addresses will be removed.
Maximum 300 characters
Submit
Thank you for your feedback
Date modified: |
Canadian Immunization Guide
============================
From [Public Health Agency of Canada](/en/public-health/corporate-old.html)
Important notices:
------------------
* For information regarding COVID-19 vaccines refer to the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html).
Related services
----------------
* [Table of updates](/en/public-health/services/canadian-immunization-guide/updates.html)
* [Immunization schedules](http://www.healthycanadians.gc.ca/healthy-living-vie-saine/immunization-immunisation/children-enfants/schedule-calendrier-eng.php)
Overview
--------
The Canadian Immunization Guide is a comprehensive resource on immunization. It was developed based on recommendations and statements of expert advisory committees, including the:
* [National Advisory Committee on Immunization (NACI)](http://www.phac-aspc.gc.ca/naci-ccni/index-eng.php)
* [Committee to Advise on Tropical Medicine and Travel (CATMAT)](/en/public-health/services/catmat.html)
Who this guide is for
---------------------
This guide was developed for those with an interest in immunization, including:
* health professionals
* vaccine program decision makers
* other Canadian stakeholders
In this guide
-------------
This guide consists of 54 chapters organized into 4 parts. Chapters are updated as new evidence becomes available, and NACI and CATMAT statements are completed. Email updates are available through our mailing list.
[Subscribe for updates](http://www.healthycanadians.gc.ca/healthy-living-vie-saine/immunization-immunisation/canadian-immunization-guide-canadien-immunisation/email-subscription-abonnement-courriel-eng.php)
* [Acknowledgments](/en/public-health/services/canadian-immunization-guide/acknowledgements.html)
* [Introduction](/en/public-health/services/canadian-immunization-guide/introduction.html)
* [Part 1: Key immunization information](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
+ [Immunization in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-2-immunization-in-canada.html)
+ [Benefits of immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-3-benefits-immunization.html)
+ [National guidelines for immunization practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-4-national-guidelines-immunization-practices.html)
+ [Communicating effectively about immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-5-communicating-effectively-immunization.html)
+ [Principles of combination vaccines](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-6-principles-combination-vaccines.html)
+ [Principles of vaccine interchangeability](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-7-principles-vaccine-interchangeability.html)
+ [Vaccine administration practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html)
+ [Storage and handling of immunizing agents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-9-storage-handling-immunizing-agents.html)
+ [Timing of vaccine administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html)
+ [Blood products, human immunoglobulin and timing of immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html)
+ [Immunization records](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-12-immunization-records.html)
+ [Recommended immunization schedules](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-13-recommended-immunization-schedules.html)
+ [Basic immunology and vaccinology](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-14-basic-immunology-vaccinology.html)
+ [Contents of immunizing agents authorized for use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html)
* [Part 2: Vaccine safety](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety.html)
+ [Vaccine safety and pharmacovigilance](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html)
+ [Contraindications and precautions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html)
+ [Anaphylaxis and other acute reactions following vaccination](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html)
+ [Adverse events following immunization (AEFI)](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html)
* [Part 3: Vaccination of specific populations](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations.html)
+ [Immunization of adults](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-2-immunization-of-adults.html)
+ [Immunization of persons with inadequate immunization records](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-3-immunization-persons-inadequate-immunization-records.html)
+ [Immunization in pregnancy and breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html)
+ [Immunization of infants born prematurely](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-5-immunization-infants-born-prematurely.html)
+ [Immunization of patients in health care institutions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-6-immunization-patients-health-care-institutions.html)
+ [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html)
+ [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html)
+ [Immunization of travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html)
+ [Immunization of persons new to Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-10-immunization-persons-new-canada.html)
+ [Immunization of workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html)
* [Part 4: Immunizing agents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
+ [Bacille Calmette-Guérin (BCG) vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-2-bacille-calmette-guerin-vaccine.html)
+ [Cholera and enterotoxigenic *Escherichia coli* (ETEC) travellers' diarrhea vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-3-cholera-enterotoxigenic-escherichia-coli-travellers-diarrhea-vaccine.html)
+ [COVID-19 vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html)
+ [Diphtheria toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-4-diphtheria-toxoid.html)
+ [*Haemophilus influenzae* type B (Hib) vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-5-haemophilus-influenzae-type-b-vaccine.html)
+ [Hepatitis A vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html)
+ [Hepatitis B vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html)
+ [Herpes zoster (shingles) vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-8-herpes-zoster-(shingles)-vaccine.html)
+ [Human papillomavirus (HPV) vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-9-human-papillomavirus-vaccine.html)
+ [Influenza vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html)
+ [Japanese encephalitis vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-11-japanese-encephalitis-vaccine.html)
+ [Measles vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html)
+ [Meningococcal vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-13-meningococcal-vaccine.html)
+ [Mumps vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-14-mumps-vaccine.html)
+ [Pertussis (whooping cough) vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-15-pertussis-vaccine.html)
+ [Pneumococcal vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html)
+ [Poliomyelitis (polio) vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-17-poliomyelitis-vaccine.html)
+ [Rabies vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-18-rabies-vaccine.html)
+ [Respiratory syncytial virus (RSV)](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/respiratory-syncytial-virus.html)
+ [Rotavirus vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-19-rotavirus-vaccine.html)
+ [Rubella vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-20-rubella-vaccine.html)
+ [Smallpox and mpox (monkeypox) vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-21-smallpox-vaccine.html)
+ [Tetanus toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html)
+ [Typhoid vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-23-typhoid-vaccine.html)
+ [Varicella (chickenpox) vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-24-varicella-chickenpox-vaccine.html)
+ [Yellow fever vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-25-yellow-fever-vaccine.html)
Details and history
-------------------
Updated: see [Table of updates](/en/public-health/services/canadian-immunization-guide/updates.html)
Part of topic(s): [Immunization and vaccines](/en/public-health/services/immunization-vaccines.html)
For assistance
--------------
If you have any comments or questions regarding the Canadian Immunization Guide, [contact the Public Health Agency of Canada](http://www.phac-aspc.gc.ca/contac-eng.php) (PHAC). PHAC does not provide medical advice regarding individuals or cases.
Did you find what you were looking for?
---------------------------------------
Yes
No
If not, tell us why:
What was wrong?
I can't **find** the information
The information is hard to **understand**
There was an error or something **didn't work**
Other reason
Please provide more details
**You will not receive a reply. Telephone numbers and email addresses will be removed.**
Maximum 300 characters
Submit
Thank you for your feedback
Date modified:
2023-08-04
| None | None |
3260d6f47bd181ae96922eecff87b4ff67084eb2 | cma | Interim guidance on infection prevention and control for suspect, probable or confirmed monkeypox within healthcare settings | Interim guidance on infection prevention and control for suspect, probable or confirmed monkeypox within healthcare settings
On November 28, 2022, the World Health Organization began using ‘mpox’ as the preferred term for monkeypox disease. We’ll be updating our content to reflect this change.
May 27 2022
On this page
Background
Monkeypox is a rare infectious disease caused by the monkeypox virus (genus orthopox). Monkeypox virus is related to, but distinct from, the viruses that cause smallpox (variola virus) and cowpox. Cases of monkeypox are usually found in central and western Africa and it is rare to find cases outside of that geographic area. There are two genetically distinct clades of monkeypox virus: West African clade monkeypox manifests with limited human-to-human transmission, and a case fatality of 1%, whereas the Congo Basin clade is associated with human-to-human transmission and case fatalities historically reported of 10%.
On 13 May 2022, WHO was notified of laboratory-confirmed human cases of monkeypox in the United Kingdom (UK). The UK has confirmed the West African clade of the monkeypox virus. It is unknown at this time if the virus has mutated, which may lead to a change in the modes of transmission, clinical presentation or severity of disease. Transmission risk to healthcare workers is considered low at this time.
On May 19, the Public Health Agency of Canada confirmed the first two human cases of monkeypox in Canada. Both cases were detected in Quebec and other suspected cases are under investigation. Confirmed and probable monkeypox cases have now been reported in many countries outside of Africa.
Person-to-person spread of monkeypox is uncommon. However, when spread does occur between people, the mode is through close contact with an infected person such as through direct contact with their body fluids, respiratory droplets, and/or monkeypox sores, or by sharing clothing, bedding or common items that have been contaminated with the infected person's body fluids or sores. Sexual transmission has not been previously identified as a mode of transmission, though sexual partners also have close direct contact. It is not known whether airborne transmission of monkeypox occurs, although it does not appear to be the primary mode of transmission. However, given evidence of airborne transmission with smallpox, there is a concern that monkeypox can also be transmitted by the airborne route. At this time, as more information is gathered, healthcare settings should implement droplet and contact precautions, in addition to airborne precautions until more information about the potential for aerosol transmission is known.
At this time, it is not known if a person can transmit the infection just before they develop fever or develop a rash.
If a case is suspected, immediately notify local public health authorities.
Transmission
A person can contract monkeypox when they come into close contact with an infected animal, infected person, or materials contaminated with the virus. The virus can enter the body through broken skin, the respiratory tract, or through mucous membranes. Transmission can occur via direct contact with monkeypox skin lesions, non-intact skin or scabs, indirect contact with clothing or linens used by an infected person, or close contact with the respiratory tract secretions of an individual with monkeypox.
Clinical progression and incubation period
- Incubation period is typically 6-13 days from time of exposure, with a range of 5-21 days.
- In previous clinical descriptions, the febrile stage lasts 1 to 4 days prior to the first eruption of skin lesions.
- In some recent cases it appears that the initial lesions may precede the development of the febrile stage.
- Lesions progress from macule, to papule, to vesicle, to pustule, which will then crust.
- The rash/skin lesion stage can last 2-4 weeks.
- The patient is contagious until the scab crusts have fallen off (about 3-4 weeks) and new skin has formed.
- Most infections last 2-to-4 weeks and self-resolve.
Infection prevention and control
Airborne, droplet, and contact precautions should be used for all suspect, probable, and confirmed cases of monkeypox. Precautions should be used when a patient presents with fever and vesicular/pustular rash (suspected case). Any lesions or respiratory secretions should be considered infectious material.
# Routine practices
Continue to follow routine practices including:
- Point of Care Risk Assessment (PCRA)
- Hand Hygiene
- Patient Placement
- Respiratory hygiene
- Personal Protective Equipment (PPE)
- Injection and Medication Safety
- Cleaning and Disinfection Procedures
- Waste Management
# Hand hygiene
Alcohol-based hand sanitizers and soap and water are acceptable methods for hand hygiene. When hands are visibly soiled, soap and water is the preferred method. Hand hygiene should always be performed after the removal of gloves.
Additional precautions
As the modes of transmission in this current outbreak are not well understood, airborne, droplet and contact precautions are recommended.
## Patient:
- Patient should perform hand hygiene
- Patient should wear a medical mask
- Suspect, probable and confirmed cases should be immediately placed into an Airborne Infection Isolation Room (AIIR) or single room with the door closed, for assessment upon entry to the healthcare setting.
- If the patient must leave the room, a medical mask should be worn, if medically able to tolerate or clinical condition allows.
- Skin lesions should be kept covered with a gown, clothes, sheet or bandage, except during examination.
- Room should be cleaned and disinfected after use (as per directions below).
## Health care worker - Personal Protective Equipment (PPE):
- Fit-tested and seal-checked N95 respirator
- Gown (cuffed, long sleeve)
- Gloves
- Eye protection (e.g., face shield or goggles)
All PPE (including respirators) must be discarded after each contact with the patient and hand hygiene performed. All PPE should be donned before entering the patient’s room. All PPE should be disposed of prior to leaving the isolation room except for the respirator, which should be removed, outside of the room once the door is closed, and hands should again be cleaned.
## Room selection/patient placement
Patient should be placed in an AIIR, when available.
If an AIIR is not available, the patient should be placed in a single room with the door closed. For inpatients, a dedicated patient bathroom is required and commode can be used if dedicated bathroom not available
Visitors should be restricted to those necessary for care or compassionate grounds.
Cleaning and disinfection
# Equipment
- Use standard housekeeping cleaning and disinfection protocols.
- Dedicate patient care equipment to a single patient.
- Clean and disinfect all reusable equipment with Health Canada approved disinfectants (with Drug Identification Numbers (DIN)), as per manufacturers’ recommendations immediately after use.
# Environmental surfaces
All patient contact surfaces should be cleaned and disinfected with Health Canada approved disinfectants (with Drug Identification Numbers (DIN)), as per manufacturers’ recommendations.)
Clean and disinfect all surfaces that could have been touched including chairs in the area and public bathrooms. Attention should be paid to frequently touched surfaces, such as doorknobs, call bell pulls, faucet handles and wall surfaces that may have been frequently touched by the patient.
Use standard housekeeping cleaning and disinfection protocols.
Learn more about .
# Laundry (such as linens, towels, clothing, bedding)
- Wear appropriate PPE (gloves, gown, fit-tested and seal-checked N95 respirator and eye protection) during collection and bagging of all linens at the point of use.
- The laundry materials should carefully be placed in a leak-proof bag, sealed or tied and placed inside an impermeable bag for transport to laundry area.
- In ambulatory care settings, standard medical laundry facilities should be used. If not available, the items may be washed in a standard washing machine using hot water (70 degrees Celsius) with detergent and must be completely dried in a commercial dryer.
- When handling soiled laundry (clothing, towels, bedding), care should be taken to avoid contact with the worker’s skin and clothing.
- Do not shake laundry, as it disperses contaminated infectious particles into the air and onto the surrounding surfaces.
Containment and disposal of contaminated waste
- Biomedical waste should be contained in impervious waste-holding bags or double bagged according to municipal/regional regulations.
- Contaminated disposable items should be discarded according to jurisdictional protocols.
Discharge environmental cleaning and disinfection
- For discharge environmental cleaning and disinfection:
+ HCW must wear a gown, gloves, fit-tested and seal-checked N95 respirator and eye protection during cleaning and disinfection.
+ Use standard housekeeping discharge cleaning and disinfection protocols.
+ All disposable items in the patient’s room should be discarded.
+ Privacy curtains must be changed.
+ Equipment/supplies that cannot be disinfected must be discarded.
Transportation of suspected monkeypox patients
If a patient with suspect, probable, or confirmed monkeypox requires transportation, the patient should not use public transportation. The patient should be masked and lesions covered during transport. If used, patient transport services should be informed that the patient has suspect, probable, or confirmed monkeypox. The receiving healthcare setting should be informed before the patient’s arrival of the diagnosis and need for airborne, droplet and contact precautions.
Occupational monkeypox exposures in healthcare settings: July 8, 2022
This section provides guidance in assessing a potential occupational exposure of monkeypox in the healthcare setting. The occupational risk assessment is essential in ensuring the workplace remains safe for staff and for the patients who require diagnosis and care to prevent further transmission of monkeypox.
# Background
Airborne, droplet, and contact precautions should be used for all suspect, probable, and confirmed cases of monkeypox. Any lesions, body fluids or respiratory secretions and contaminated materials, such as bedding, should be considered infectious. At the present time the risk of transmission to a HCW appears to be very low. It is unknown if aerosol transmission can occur, if risk of transmission is associated with the stage of illness (prodrome, rash, systemic symptoms) or if there are patient-related factors such as pregnancy, immune suppression, or young age that may be associated with how much virus a person excretes or if they are more likely to have transmissible virus in the upper respiratory tract.
# Exposure
If a healthcare worker (HCW) had contact with a patient who is diagnosed with monkeypox and was not wearing PPE consistent with airborne, droplet, and contact precautions, an assessment of the risk to the HCW should be conducted.
# Defining an exposure
The purposes of this section is to define the HCW exposures and mitigate the risk of transmission to patients.
When adequate PPE is not used (see below), an exposure can be defined as:
- HCW skin/mucosa to skin contact with a case
- HCW skin/mucosa contact with a case's biological fluids, secretions, skin lesions or scabs
- HCW skin/mucosa contact with surfaces or objects contaminated by a case's secretions, biological fluids, skin lesions or scabs
- Face-to-face interaction with a case
All exposures should be considered on a case-by-case basis to determine level of risk.
When assessing the level of risk exposure, consider the length of time (transient versus prolonged) and proximity to the patient, other patient factors (drooling, coughing, immune suppression), use of PPE and any skin/mucosa contact with the person or their environment in the assessment.
For the purposes of assessing risk of occupational exposures, adequate PPE would be defined, at a minimum, as a medical mask or N95 respirator, and gloves. Any bare skin of the HCW exposed to infectious material or fomites is an exposure and a risk assessment should consider length of time, and whether there are active lesions or non-intact skin of either the HCW or the patient. Any splash of potentially infectious material into a HCW mucous membrane is a higher risk exposure. If the HCW is wearing a medical mask and not an N95, this is not considered an exposure unless there is a high risk of aerosols.
The risk of exposure to potentially infectious aerosols should be considered in the risk assessment. This should include an assessment of coughing or suctioning, intubation, proximity to the person and length of exposure.
# Working post-exposure: Length of time and frequency of active symptom monitoring
A HCW may continue to work post-exposure, if they monitor for and stop working immediately should symptoms arise. All exposed HCW should wear a medical mask at all times while working.
Monitoring monkeypox depends on risk levels of exposure:
- For lower-risk exposures conduct passive monitoring (self-monitoring) of symptoms once a day and prior to any shift for 21 days since the last exposure to a person with monkeypox. Notify occupational health if symptoms develop. Example of a lower-risk exposure is:
+ Briefly touching a patient without gloves when both the patient’s skin and the HCW’s skin are completely intact
- For higher-risk exposures conduct active screening of symptoms, once a day with Occupational Health and prior to any shift for 21 days since the last exposure to a person with monkeypox. Notify occupational health if symptoms develop. Examples of a higher-risk exposures are:
+ Unprotected contact with a patient’s active skin lesions
+ A splash of excretions from a patient into a HCW unprotected eye while suctioning
HCW with higher-risk exposures should not care for those who are immunosuppressed, pregnant, giving birth, or children < 12 years of age for 21 days since the last high(er) risk exposure to a person with monkeypox.
# Management of exposed HCWs
In the event a HCW develops symptoms of monkeypox, they must stop work and immediately report to Occupational Health and Public Health. An investigation should be conducted to determine if the HCW case was healthcare or community acquired. A potentially healthcare acquired case would be considered a sentinel event and should be reported promptly to Public Health and investigated fully.
If any symptoms consistent with monkeypox develop Occupational Health should direct the healthcare worker for assessment and diagnostic testing for monkeypox. Please refer to your local testing guidance for monkeypox. Testing for monkeypox while asymptomatic is not recommended.
The HCW should be assessed regarding their risk of severe disease and treatment should be discussed with an infectious diseases specialist. HCWs with higher risk exposure should be discussed with Public Health authorities and considered for post-exposure prophylaxis with the smallpox vaccine.
# HCW with monkeypox
If a HCW subsequently is diagnosed with monkeypox, they must not return to work until all of the following criteria are met:
- person has no new lesions for 48 hours, and
- no skin or mucous membrane lesions, and
- all previous lesion scabs have dropped off and intact skin is underneath, and
- occupational health has deemed the person well enough to return to work
Occupational Health or Public Health must inform the HCW of the criteria for returning to work. |
Interim guidance on infection prevention and control for suspect, probable or confirmed monkeypox within healthcare settings
=============================================================================================================================
On November 28, 2022, the World Health Organization began using ‘mpox’ as the preferred term for monkeypox disease. We’ll be updating our content to reflect this change.
May 27 2022
On this page
------------
* [Background](#a1)
* [Transmission](#a2)
* [Clinical progression and incubation period](#a3)
* [Infection prevention and control](#a4)
* [Additional precautions](#a5)
* [Cleaning and disinfection](#a6)
* [Containment and disposal of contaminated waste](#a7)
* [Discharge environmental cleaning and disinfection](#a8)
* [Transportation of suspected Monkeypox patients](#a9)
* [Occupational monkeypox exposures in healthcare settings: July 8, 2022](#a10)
Background
----------
Monkeypox is a rare infectious disease caused by the monkeypox virus (genus orthopox). Monkeypox virus is related to, but distinct from, the viruses that cause smallpox (variola virus) and cowpox. Cases of monkeypox are usually found in central and western Africa and it is rare to find cases outside of that geographic area. There are two genetically distinct clades of monkeypox virus: **West African clade** monkeypox manifests with limited human-to-human transmission, and a case fatality of 1%, whereas the **Congo Basin clade** is associated with human-to-human transmission and case fatalities historically reported of 10%.
On 13 May 2022, WHO was notified of laboratory-confirmed human cases of monkeypox in the United Kingdom (UK). The UK has confirmed the **West African clade** of the monkeypox virus. It is unknown at this time if the virus has mutated, which may lead to a change in the modes of transmission, clinical presentation or severity of disease. Transmission risk to healthcare workers is considered low at this time.
On May 19, the Public Health Agency of Canada confirmed the first two human cases of monkeypox in Canada. Both cases were detected in Quebec and other suspected cases are under investigation. Confirmed and probable monkeypox cases have now been reported in many countries outside of Africa.
Person-to-person spread of monkeypox is uncommon. However, when spread does occur between people, the mode is through close contact with an infected person such as through direct contact with their body fluids, respiratory droplets, and/or monkeypox sores, or by sharing clothing, bedding or common items that have been contaminated with the infected person's body fluids or sores. Sexual transmission has not been previously identified as a mode of transmission, though sexual partners also have close direct contact. It is not known whether airborne transmission of monkeypox occurs, although it does not appear to be the primary mode of transmission. However, given evidence of airborne transmission with smallpox, there is a concern that monkeypox can also be transmitted by the airborne route. At this time, as more information is gathered, healthcare settings should implement droplet and contact precautions, in addition to airborne precautions until more information about the potential for aerosol transmission is known.
At this time, it is not known if a person can transmit the infection just before they develop fever or develop a rash.
If a case is suspected, immediately notify local public health authorities.
Transmission
------------
A person can contract monkeypox when they come into close contact with an infected animal, infected person, or materials contaminated with the virus. The virus can enter the body through broken skin, the respiratory tract, or through mucous membranes. Transmission can occur via direct contact with monkeypox skin lesions, non-intact skin or scabs, indirect contact with clothing or linens used by an infected person, or close contact with the respiratory tract secretions of an individual with monkeypox.
Clinical progression and incubation period
------------------------------------------
* Incubation period is typically 6-13 days from time of exposure, with a range of 5-21 days.
* In previous clinical descriptions, the febrile stage lasts 1 to 4 days prior to the first eruption of skin lesions.
* In some recent cases it appears that the initial lesions may precede the development of the febrile stage.
* Lesions progress from macule, to papule, to vesicle, to pustule, which will then crust.
* The rash/skin lesion stage can last 2-4 weeks.
* The patient is contagious until the scab crusts have fallen off (about 3-4 weeks) and new skin has formed.
* Most infections last 2-to-4 weeks and self-resolve.
Infection prevention and control
--------------------------------
**Airborne, droplet, and contact precautions** should be used for all suspect, probable, and confirmed cases of monkeypox. Precautions should be used when a patient presents with fever and vesicular/pustular rash (suspected case). Any lesions or respiratory secretions should be considered infectious material.
### Routine practices
Continue to follow routine practices including:
* Point of Care Risk Assessment (PCRA)
* Hand Hygiene
* Patient Placement
* Respiratory hygiene
* Personal Protective Equipment (PPE)
* Injection and Medication Safety
* Cleaning and Disinfection Procedures
* Waste Management
### Hand hygiene
Alcohol-based hand sanitizers and soap and water are acceptable methods for hand hygiene. When hands are visibly soiled, soap and water is the preferred method. Hand hygiene should always be performed after the removal of gloves.
Additional precautions
----------------------
As the modes of transmission in this current outbreak are not well understood, **airborne, droplet and contact precautions** are recommended.
#### Patient:
* Patient should perform hand hygiene
* Patient should wear a medical mask
* Suspect, probable and confirmed cases should be immediately placed into an Airborne Infection Isolation Room (AIIR) or single room with the door closed, for assessment upon entry to the healthcare setting.
* If the patient must leave the room, a medical mask should be worn, if medically able to tolerate or clinical condition allows.
* Skin lesions should be kept covered with a gown, clothes, sheet or bandage, except during examination.
* Room should be cleaned and disinfected after use (as per directions below).
#### Health care worker - Personal Protective Equipment (PPE):
* Fit-tested and seal-checked N95 respirator
* Gown (cuffed, long sleeve)
* Gloves
* Eye protection (e.g., face shield or goggles)
All PPE (including respirators) must be discarded after each contact with the patient and hand hygiene performed. All PPE should be donned before entering the patient’s room. All PPE should be disposed of prior to leaving the isolation room except for the respirator, which should be removed, outside of the room once the door is closed, and hands should again be cleaned.
#### Room selection/patient placement
Patient should be placed in an AIIR, when available.
If an AIIR is not available, the patient should be placed in a single room with the door closed. For inpatients, a dedicated patient bathroom is required and commode can be used if dedicated bathroom not available
Visitors should be restricted to those necessary for care or compassionate grounds.
Cleaning and disinfection
-------------------------
### Equipment
* Use standard housekeeping cleaning and disinfection protocols.
* Dedicate patient care equipment to a single patient.
* Clean and disinfect all reusable equipment with Health Canada approved disinfectants (with Drug Identification Numbers (DIN)), as per manufacturers’ recommendations immediately after use.
### Environmental surfaces
All patient contact surfaces should be cleaned and disinfected with Health Canada approved disinfectants (with Drug Identification Numbers (DIN)), as per manufacturers’ recommendations.)
Clean and disinfect all surfaces that could have been touched including chairs in the area and public bathrooms. Attention should be paid to frequently touched surfaces, such as doorknobs, call bell pulls, faucet handles and wall surfaces that may have been frequently touched by the patient.
Use standard housekeeping cleaning and disinfection protocols.
Learn more about [surface disinfectants for emerging viral pathogens](/en/health-canada/services/drugs-health-products/disinfectants/emerging-viral-pathogens.html).
### Laundry (such as linens, towels, clothing, bedding)
* Wear appropriate PPE (gloves, gown, fit-tested and seal-checked N95 respirator and eye protection) during collection and bagging of all linens at the point of use.
* The laundry materials should carefully be placed in a leak-proof bag, sealed or tied and placed inside an impermeable bag for transport to laundry area.
* In ambulatory care settings, standard medical laundry facilities should be used. If not available, the items may be washed in a standard washing machine using hot water (70 degrees Celsius) with detergent and must be completely dried in a commercial dryer.
* When handling soiled laundry (clothing, towels, bedding), care should be taken to avoid contact with the worker’s skin and clothing.
* Do not shake laundry, as it disperses contaminated infectious particles into the air and onto the surrounding surfaces.
Containment and disposal of contaminated waste
----------------------------------------------
* Biomedical waste should be contained in impervious waste-holding bags or double bagged according to municipal/regional regulations.
* Contaminated disposable items should be discarded according to jurisdictional protocols.
Discharge environmental cleaning and disinfection
-------------------------------------------------
* For discharge environmental cleaning and disinfection:
+ HCW must wear a gown, gloves, fit-tested and seal-checked N95 respirator and eye protection during cleaning and disinfection.
+ Use standard housekeeping discharge cleaning and disinfection protocols.
+ All disposable items in the patient’s room should be discarded.
+ Privacy curtains must be changed.
+ Equipment/supplies that cannot be disinfected must be discarded.
Transportation of suspected monkeypox patients
----------------------------------------------
If a patient with suspect, probable, or confirmed monkeypox requires transportation, the patient should not use public transportation. The patient should be masked and lesions covered during transport. If used, patient transport services should be informed that the patient has suspect, probable, or confirmed monkeypox. The receiving healthcare setting should be informed before the patient’s arrival of the diagnosis and need for airborne, droplet and contact precautions.
Occupational monkeypox exposures in healthcare settings: July 8, 2022
---------------------------------------------------------------------
This section provides guidance in assessing a potential occupational exposure of monkeypox in the healthcare setting. The occupational risk assessment is essential in ensuring the workplace remains safe for staff and for the patients who require diagnosis and care to prevent further transmission of monkeypox.
### Background
**Airborne, droplet, and contact precautions** should be used for all suspect, probable, and confirmed cases of monkeypox. Any lesions, body fluids or respiratory secretions and contaminated materials, such as bedding, should be considered infectious. At the present time the risk of transmission to a HCW appears to be very low. It is unknown if aerosol transmission can occur, if risk of transmission is associated with the stage of illness (prodrome, rash, systemic symptoms) or if there are patient-related factors such as pregnancy, immune suppression, or young age that may be associated with how much virus a person excretes or if they are more likely to have transmissible virus in the upper respiratory tract.
### Exposure
If a healthcare worker (HCW) had contact with a patient who is diagnosed with monkeypox and was not wearing PPE consistent with airborne, droplet, and contact precautions, an assessment of the risk to the HCW should be conducted.
### Defining an exposure
The purposes of this section is to define the HCW exposures and mitigate the risk of transmission to patients.
When adequate PPE is **not** used (see below), an **exposure** can be defined as:
* HCW skin/mucosa to skin contact with a case
* HCW skin/mucosa contact with a case's biological fluids, secretions, skin lesions or scabs
* HCW skin/mucosa contact with surfaces or objects contaminated by a case's secretions, biological fluids, skin lesions or scabs
* Face-to-face interaction with a case
All exposures should be considered on a case-by-case basis to determine level of risk.
When assessing the level of risk exposure, consider the length of time (transient versus prolonged) and proximity to the patient, other patient factors (drooling, coughing, immune suppression), use of PPE and any skin/mucosa contact with the person or their environment in the assessment.
For the purposes of assessing risk of occupational exposures, adequate PPE would be defined, at a minimum, as a medical mask or N95 respirator, and gloves. Any bare skin of the HCW exposed to infectious material or fomites is an exposure and a risk assessment should consider length of time, and whether there are active lesions or non-intact skin of either the HCW or the patient. Any splash of potentially infectious material into a HCW mucous membrane is a higher risk exposure. If the HCW is wearing a medical mask and not an N95, this is not considered an exposure unless there is a high risk of aerosols.
The risk of exposure to potentially infectious aerosols should be considered in the risk assessment. This should include an assessment of coughing or suctioning, intubation, proximity to the person and length of exposure.
### Working post-exposure: Length of time and frequency of active symptom monitoring
A HCW may continue to work post-exposure, if they monitor for [symptoms](/en/public-health/services/diseases/monkeypox/symptoms-management.html#a1) and stop working immediately should symptoms arise. All exposed HCW should wear a medical mask at all times while working.
Monitoring monkeypox depends on risk levels of exposure:
* For **lower-risk** exposures conduct passive monitoring (self-monitoring) of symptoms once a day and prior to any shift for 21 days since the last exposure to a person with monkeypox. Notify occupational health if symptoms develop. Example of a lower-risk exposure is:
+ Briefly touching a patient without gloves when both the patient’s skin and the HCW’s skin are completely intact
* For **higher-risk** exposures conduct active screening of symptoms, once a day with Occupational Health and prior to any shift for 21 days since the last exposure to a person with monkeypox. Notify occupational health if symptoms develop. Examples of a higher-risk exposures are:
+ Unprotected contact with a patient’s active skin lesions
+ A splash of excretions from a patient into a HCW unprotected eye while suctioning
Refer to the Management of exposed HCWs section below for further direction on higher-risk exposures.
HCW with higher-risk exposures should not care for those who are immunosuppressed, pregnant, giving birth, or children < 12 years of age for 21 days since the last high(er) risk exposure to a person with monkeypox.
### Management of exposed HCWs
In the event a HCW develops symptoms of monkeypox, they must stop work and immediately report to Occupational Health and Public Health. An investigation should be conducted to determine if the HCW case was healthcare or community acquired. A potentially healthcare acquired case would be considered a sentinel event and should be reported promptly to Public Health and investigated fully.
If any symptoms consistent with monkeypox develop Occupational Health should direct the healthcare worker for assessment and diagnostic testing for monkeypox. Please refer to your local testing guidance for monkeypox. Testing for monkeypox while asymptomatic is not recommended.
The HCW should be assessed regarding their risk of severe disease and treatment should be discussed with an infectious diseases specialist. HCWs with higher risk exposure should be discussed with Public Health authorities and considered for post-exposure prophylaxis with the smallpox vaccine.
### HCW with monkeypox
If a HCW subsequently is diagnosed with monkeypox, they must not return to work until all of the following criteria are met:
* person has no new lesions for 48 hours, and
* no skin or mucous membrane lesions, and
* all previous lesion scabs have dropped off and intact skin is underneath, and
* occupational health has deemed the person well enough to return to work
Occupational Health or Public Health must inform the HCW of the criteria for returning to work.
**Acknowledgements**
**NAC-IPC:** Molly Blake, Joanne Embree, Jennifer Happe, Suzy Hota, Jennie Johnstone, Anne Masters-Boyne, Matthew Muller, Patsy Rawding, Suzanne Rhodenizer Rose, Brian Sagar, Patrice Savard, Stephanie Smith, Nisha Thampi
**PHAC, Infectious Diseases Programs Branch**
**Office of the Vice President:** Marina Salvadori, Marianna Ofner
**Antimicrobial Resistance Division :** Maureen Carew, Natalie Bruce
**Healthcare Associated Infection Prevention and Control Section:** Toju Ogunremi, Ama Anne, Katherine Defalco, Steven Ettles, Amanda Graham, Maureen McGrath, Chatura Prematunge, Jennifer Selkirk, Karen Timmerman
Bibliography
------------
Alakunle, E., et al. (2020). “Monkeypox Virus in Nigeria: Infection Biology, Epidemiology, and Evolution.” Viruses vol. 12, 11 1257. 5 Nov.
British HIV Association. (2022). BHIVA rapid statement on monkeypox virus. Tuesday 17 May. BHIVA rapid statement on monkeypox virus. Accessed May 19, 2022.
Bunge, E.M., Hoet, B., Chen, L., Lienert, F., Weidenthaler, H., Baer LR, et al. (2022) The changing epidemiology of human monkeypox—A potential threat? A systematic review. PLoS Negl Trop Dis 16(2): e0010141. https://doi.org/10.1371/ journal.pntd.0010141
Butcher, W., Ulaeto, D. (2005). Contact inactivation of orthopoxvirues by household disinfectants. Journal of Applied Microbiology, 99(2): 279-284.
Centers for Disease Control and Prevention (CDC). Guide D - Specimen Collection and Transport Guidelines.
Centers for Disease Control and Prevention (CDC). (2003). Multistate outbreak of monkeypox-- Illinois, Indiana, and Wisconsin, 2003. MMWR. Morbidity and mortality weekly report vol. 52, 23: 537-40.
Centres for Disease Control and Prevention (CDC). Monkeypox. (2022). https://www.cdc.gov/poxvirus/monkeypox/index.html. Accessed May 20, 2022.
Erez, Noam et al. (2019). Diagnosis of Imported Monkeypox, Israel, 2018. Emerging infectious diseases vol. 25,5: 980-983.
Formenty, Pierre et al. (2010). Human monkeypox outbreak caused by novel virus belonging to Congo Basin clade, Sudan, 2005.” Emerging infectious diseases vol. 16,10: 1539-45.
Gelfand, H.M., Posch, J. (1971). The recent outbreak of smallpox in Meschede, West Germany, Am J Epidemiol; 93:234-7.
Government of UK. (2022). Monkeypox cases confirmed in England – latest updates. Monkeypox cases confirmed in England – latest updates - GOV.UK (www.gov.uk). Accessed May 20, 2022.
Heymann, D.L., Simpson, K. (2021). The Evolving Epidemiology of Human Monkeypox: Questions Still to Be Answered. J Infect Dis.; 223(11):1839-1841.
Hobson, Gemma et al. (2021). Family cluster of three cases of monkeypox imported from Nigeria to the United Kingdom, May 2021. Euro surveillance : bulletin Europeen sur les maladies transmissibles - European communicable disease bulletin vol. 26,32: 2100745.
Ihekweazu, Chikwe et al. (2020). Importance of epidemiological research of monkeypox: is incidence increasing? Expert review of anti-infective therapy vol. 18, 5: 389-392.
Jezek, Z et al. (1988). Human monkeypox: disease pattern, incidence and attack rates in a rural area of northern Zaire. Tropical and geographical medicine vol. 40, 2: 73-83.
Jezek, Z et al. (1987). Human monkeypox: clinical features of 282 patients. The Journal of infectious diseases vol. 156, 2: 293-8.
Likos, Anna M et al. (2005). A tale of two clades: monkeypox viruses. The Journal of general virology vol. 86,Pt 10: 2661-2672.
Mary, G., et al. (2019). Monkeypox re-emergence in Africa: a call to expand the concept and practice of One Health. Expert review of anti-infective therapy vol. 17,2: 129-139.
Nakazawa, Yoshinori et al. (2013). Phylogenetic and ecologic perspectives of a monkeypox outbreak, southern Sudan, 2005. Emerging infectious diseases vol. 19,2: 237-45.
Nolen, Leisha Diane et al. (2016). Extended Human-to-Human Transmission during a Monkeypox Outbreak in the Democratic Republic of the Congo. Emerging infectious diseases vol. 22,6: 1014-21.
Public Health Agency of Canada. (2016 revised). Infection control guidelines: Routine practices and additional precautions for preventing the transmission of infection in health care. https://www.canada.ca/content/dam/phac-aspc/documents/services/publications/diseases- conditions/routine-practices-precautions-healthcare-associated-infections/routine-practices - precautions-healthcare-associated-infections-2016-FINAL-eng.pdf
Public Health Agency of Canada. (2022). Public Health Agency of Canada Confirms 2 cases of Monkeypox. May 19, 2022. https://www.canada.ca/en/public-health/news/2022/05/public- health-agency-of-canada-confirms-2-cases-of-monkeypox.html Accessed: May 20, 2022.
Reed, Kurt D et al. (2004). The detection of monkeypox in humans in the Western Hemisphere. The New England journal of medicine vol. 350, 4: 342-50.
Rimoin, Anne W et al. (2010). Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo. Proceedings of the National Academy of Sciences of the United States of America vol. 107, 37: 16262-7.
Simpson K, Heymann D, Brown CS, et al. (2020). Human monkeypox - After 40 years, an unintended consequence of smallpox eradication. Vaccine; 38(33):5077-5081.
Vaughan, Aisling et al. (2018). Two cases of monkeypox imported to the United Kingdom, September 2018. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin vol. 23,38: 1800509.
Wehrle PF, Posch J, Richter KH, et al. (1970). An airborne outbreak of smallpox in a German hospital and its significance with respect to other recent outbreaks in Europe. Bull World Health Org 1970; 43:669-79.
Yinka-Ogunleye, Adesola et al. (2018). Reemergence of Human Monkeypox in Nigeria, 2017. Emerging infectious diseases vol. 24, 6.
Yong, Sarah Ee Fang et al. (2020). Imported Monkeypox, Singapore. Emerging infectious diseases vol. 26, 8: 1826-1830.
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2022-12-09
| None | None |
b72d670428d4b660135b192304d96dd0c9844510 | cma | Considerations for the use of nirmatrelvir/ritonavir (brand name Paxlovid) to treat COVID-19 | Considerations for the use of nirmatrelvir/ritonavir (brand name Paxlovid) to treat COVID-19
Last updated: June 22, 2022
On January 17, 2022, Health Canada authorized the antiviral drug nirmatrelvir to be used in combination with ritonavir (brand name Paxlovid) to treat mild to moderate COVID-19 in adults at high risk of progressing to serious disease. A limited, initial supply was immediately made available to provinces and territories.
In February 2022, to help ensure the initial supply of Paxlovid reached those who would benefit most, the Public Health Agency of Canada (PHAC) published a document entitled .
The supply of nirmatrelvir/ritonavir is no longer limited: shipments have continued to arrive and Canada expects to receive a total of 1.5 million treatment courses in 2022. As such, the document has been archived.
Clinicians should refer to their jurisdiction's guidelines for management of COVID-19, including eligibility criteria. In addition, the following health technology agencies have provided guidance and tools for healthcare providers to assist with prescribing Paxlovid for the treatment of COVID-19 in the outpatient setting:
- Canadian Agency for Drugs and Health Technologies (CADTH)
- Institut national d'excellence en santé et en services sociaux (INESSS)
Please refer to the CADTH Drug Implementation Advice document: . Tools published on March 23, 2022, by INESSS include a: |
Considerations for the use of nirmatrelvir/ritonavir (brand name Paxlovid) to treat COVID-19
=============================================================================================
**Last updated: June 22, 2022**
On January 17, 2022, Health Canada authorized the antiviral drug nirmatrelvir to be used in combination with ritonavir (brand name Paxlovid) to treat mild to moderate COVID-19 in adults at high risk of progressing to serious disease. A limited, initial supply was immediately made available to provinces and territories.
In February 2022, to help ensure the initial supply of Paxlovid reached those who would benefit most, the Public Health Agency of Canada (PHAC) published a document entitled [Considerations for the use of nirmatrelvir/ritonavir to treat COVID-19 in the context of limited supply](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/considerations-nirmatrelvir-ritonavir-paxlovid/archived.html).
The supply of nirmatrelvir/ritonavir is no longer limited: shipments have continued to arrive and Canada expects to receive a total of 1.5 million treatment courses in 2022. As such, the document has been archived.
Clinicians should refer to their jurisdiction's guidelines for management of COVID-19, including eligibility criteria. In addition, the following health technology agencies have provided guidance and tools for healthcare providers to assist with prescribing Paxlovid for the treatment of COVID-19 in the outpatient setting:
* Canadian Agency for Drugs and Health Technologies (CADTH)
* Institut national d'excellence en santé et en services sociaux (INESSS)
Please refer to the CADTH Drug Implementation Advice document: [Nirmatrelvir and Ritonavir (Paxlovid) for Mild to Moderate COVID-19](https://www.cadth.ca/nirmatrelvir-and-ritonavir-paxlovid-mild-moderate-covid-19). Tools published on March 23, 2022, by INESSS include a:
* [clinical guide (PDF, French only)](https://www.inesss.qc.ca/fileadmin/doc/INESSS/COVID-19/COVID_19_Outil_Paxlovid_VF.pdf)
* [algorithm (PDF, French only)](https://www.inesss.qc.ca/fileadmin/doc/INESSS/COVID-19/Algorithme_traitement_COVID_ambulatoire_VF.pdf)
* [webinar PowerPoint presentation (PDF, French only)](https://www.inesss.qc.ca/fileadmin/doc/INESSS/COVID-19/Webinaire_Nirmatrelvir_diapos_VF.pdf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2022-06-17
| None | None |
22187cfa53023d286394fbd1273b110968c82259 | cma | Planning guidance for immunization clinics for COVID-19 vaccines: Introduction | Planning guidance for immunization clinics for COVID-19 vaccines: Introduction
The purpose of this document is to assist in planning immunization clinics for COVID-19 vaccines during the COVID-19 pandemic. Once COVID-19 vaccines are approved and available for use in Canada, they will need to be administered as quickly as possible according to allocation plans. Although they are not the only means of offering COVID-19 vaccines, immunization clinics offer the ability to immunize large numbers of people over a short period of time. The primary target audience for this document is immunization program planners of local/regional and provincial/territorial (PT) public health departments and federal health departments with responsibility for immunization programs. This document should be read in conjunction with other relevant jurisdictional (federal, provincial/territorial (FPT) and/or local) immunization program legislation, regulations, policies and planning documents. This planning guidance is meant to complement existing jurisdictional immunization campaign and clinic plans, and provides ideas and suggestions for consideration which may or may not be appropriate in particular settings and contexts.
Implementing immunization clinics is a large-scale operation which requires detailed planning, coordination, collaboration and efficiency. Typically in immunization clinics a large number of clients are being immunized, so any inefficiency in the processes can significantly decrease the clinic's capacity to safely immunize the optimal number of people. Any major incident (e.g., major injury requiring emergency medical services or technological problem) at a clinic can delay the receipt of immunizations and negatively impact the clients' confidence in the process. Building public confidence in vaccines will be even more important during the COVID-19 immunization clinics with the rollout of new vaccines.
This document builds on Appendix B of the . In the current context of the COVID-19 pandemic, planning is required to prevent COVID-19 infection of clinic staff, volunteers and clients. Larger clinics with more Immunizers are generally more efficient at vaccinating higher numbers of clients, however, in the context of COVID-19 community transmission, the need to maintain physical distancing and prevent crowding will be very important in determining the size and flow of people within immunization clinics. This document incorporates the recommendations of the Public Health Agency of Canada's (PHAC) as applicable to COVID-19 immunization. It also builds on the National Advisory Committee on Immunization's (NACI) .
Although the focus of this guidance document is on immunization clinic planning, some information and resources are provided regarding alternate vaccine delivery methods. Issues related to vaccine availability and prioritization/eligibility are beyond the scope of this document, however it should be noted that COVID-19 vaccines are expected to be available progressively over time in a sequenced roll out and clinics may have specific eligibility criteria depending on vaccine availability. |
Planning guidance for immunization clinics for COVID-19 vaccines: Introduction
===============================================================================
* [Introduction](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/planning-immunization-clinics-covid-19-vaccines.html)
* [Clinic planning and operations](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/planning-immunization-clinics-covid-19-vaccines/clinic-planning-operations.html)
* [Sample information sheets, consent forms, after care sheets](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/planning-immunization-clinics-covid-19-vaccines/sample-information-sheets-consent-forms-after-care-sheets.html)
* [Vaccine product comparison and overview of key features](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/planning-immunization-clinics-covid-19-vaccines/vaccine-product-comparison-overview-key-features.html)
* [Managing vaccine administration errors or deviations](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/quick-reference-guide-covid-19-vaccines/managing-administration-errors-deviations.html)
* [Recommended schedules by age, health status and product](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/planning-immunization-clinics-covid-19-vaccines/recommended-schedules.html)
The purpose of this document is to assist in planning immunization clinics for COVID-19 vaccines during the COVID-19 pandemic. Once COVID-19 vaccines are approved and available for use in Canada, they will need to be administered as quickly as possible according to allocation plans. Although they are not the only means of offering COVID-19 vaccines, immunization clinics offer the ability to immunize large numbers of people over a short period of time. The primary target audience for this document is immunization program planners of local/regional and provincial/territorial (PT) public health departments and federal health departments with responsibility for immunization programs. This document should be read in conjunction with other relevant jurisdictional (federal, provincial/territorial (FPT) and/or local) immunization program legislation, regulations, policies and planning documents. This planning guidance is meant to complement existing jurisdictional immunization campaign and clinic plans, and provides ideas and suggestions for consideration which may or may not be appropriate in particular settings and contexts.
Implementing immunization clinics is a large-scale operation which requires detailed planning, coordination, collaboration and efficiency. Typically in immunization clinics a large number of clients are being immunized, so any inefficiency in the processes can significantly decrease the clinic's capacity to safely immunize the optimal number of people. Any major incident (e.g., major injury requiring emergency medical services or technological problem) at a clinic can delay the receipt of immunizations and negatively impact the clients' confidence in the process. Building public confidence in vaccines will be even more important during the COVID-19 immunization clinics with the rollout of new vaccines.
This document builds on Appendix B of the [Vaccine annex: Canadian Pandemic Influenza Preparedness: Planning Guidance for the Health Sector](/en/public-health/services/flu-influenza/canadian-pandemic-influenza-preparedness-planning-guidance-health-sector/vaccine-annex.html). In the current context of the COVID-19 pandemic, planning is required to prevent COVID-19 infection of clinic staff, volunteers and clients. Larger clinics with more Immunizers are generally more efficient at vaccinating higher numbers of clients, however, in the context of COVID-19 community transmission, the need to maintain physical distancing and prevent crowding will be very important in determining the size and flow of people within immunization clinics. This document incorporates the recommendations of the Public Health Agency of Canada's (PHAC) [Guidance for influenza vaccine delivery in the presence of COVID-19](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-influenza-vaccine-delivery-covid-19.html) as applicable to COVID-19 immunization. It also builds on the National Advisory Committee on Immunization's (NACI) [Recommendations on the Duration of the Post-vaccination Observation Period for Influenza Vaccination during the COVID-19 Pandemic](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/recommendations-duration-observation-period-post-influenza-vaccination-during-covid-19-pandemic.html).
Although the focus of this guidance document is on immunization clinic planning, some information and resources are provided regarding alternate vaccine delivery methods. Issues related to vaccine availability and prioritization/eligibility are beyond the scope of this document, however it should be noted that COVID-19 vaccines are expected to be available progressively over time in a sequenced roll out and clinics may have specific eligibility criteria depending on vaccine availability.
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-03-06
| None | None |
17e49539cca51b9d21759a92e4f1e77f58aa1f1b | cma | Family-centred maternity and newborn care: National guidelines | Family-centred maternity and newborn care: National guidelines
Overview
Who these guidelines are for
The guidelines are for those interested in maternal and newborn health, such as:
- health care providers
- other Canadians involved with maternal and newborn health
- those who plan, manage and decide on maternal and newborn health programs and services
For assistance |
Family-centred maternity and newborn care: National guidelines
===============================================================
From [Public Health Agency of Canada](/en/public-health/corporate-old.html)
Overview
--------
The Family-centred maternity and newborn care: National guidelines is a resource on maternal and newborn health. It includes the latest information and advice from Canadian experts.
Who these guidelines are for
----------------------------
The guidelines are for those interested in maternal and newborn health, such as:
* health care providers
* other Canadians involved with maternal and newborn health
* those who plan, manage and decide on maternal and newborn health programs and services
Table of contents
-----------------
[Fact sheets and infographics: Maternity and newborn care](/en/public-health/services/maternity-newborn-care-guidelines/fact-sheets-infographics.html)
* [Preface](/en/public-health/services/maternity-newborn-care-guidelines/preface.html)
* [Chapter 1: Family-centred maternity and newborn care in Canada: Underlying philosophy and principles](/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-1.html)
+ [Chapter 1 fact sheet: Principles of family-centred maternity and newborn care](/en/public-health/services/publications/healthy-living/principles-maternity-newborn-care-fact-sheet.html)
* [Chapter 2: Preconception care](/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-2.html)
+ [Chapter 2 fact sheet: Optimizing preconception health](/en/public-health/services/publications/healthy-living/optimizing-preconception-health-fact-sheet.html)
+ [Chapter 2 infographic: Preconception health](/en/public-health/services/publications/healthy-living/preconception-health-infographic.html)
* [Chapter 3: Care during pregnancy](/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-3.html)
+ [Chapter 3 fact sheet: Family-centred pregnancy experience](/en/public-health/services/publications/healthy-living/family-centred-pregnancy-fact-sheet.html)
+ [Chapter 3 infographic: Pregnancy in Canada](/en/public-health/services/publications/healthy-living/pregnancy-canada-infographic.html)
* [Chapter 4: Care during labour and birth](/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-4.html)
+ [Chapter 4 fact sheet: Family-centred labour and birth experience](/en/public-health/services/publications/healthy-living/labour-birth-fact-sheet.html)
+ [Chapter 4 infographic: Labour and birth in Canada](/en/public-health/services/publications/healthy-living/labour-birth-infographic.html)
* [Chapter 5: Postpartum care](/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-5.html)
+ [Chapter 5 fact sheet: Family-centred postpartum experience](/en/public-health/services/publications/healthy-living/factsheet-family-centred-postpartum-experience.html)
+ [Chapter 5 infographic: Postpartum health in Canada](/en/public-health/services/publications/healthy-living/infographic-postpartum-health-canada.html)
* [Chapter 6: Breastfeeding](/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-6.html)
+ [Chapter 6 fact sheet: Protecting, promoting and supporting breastfeeding: Canadian recommendation and the ten steps to successful breastfeeding](/en/public-health/services/publications/healthy-living/breastfeeding-fact-sheet.html)
+ [Chapter 6 infographic: Breastfeeding in Canada](/en/public-health/services/publications/healthy-living/breastfeeding-infographic.html)
* [Chapter 7: Loss and grief](/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-7.html)
+ [Chapter 7 fact sheet: Family-centred care for families who experience perinatal loss](/en/public-health/services/publications/healthy-living/factsheet-family-centred-care-families-experience-perinatal-loss.html)
+ [Chapter 7 infographic: Perinatal loss in Canada](/en/public-health/services/publications/healthy-living/infographic-perinatal-loss-canada.html)
* [Chapter 8: Organization of services](/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-8.html)
+ [Chapter 8 fact sheet: Family-centred focus to organization of services in maternity and newborn care](/en/public-health/services/publications/healthy-living/family-focus-organization-services-maternity-newborn.html)
* [Epilogue](/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-9.html)
For assistance
--------------
If you have comments or questions about the Family-centred maternity and newborn care: National guidelines, please [contact the Public Health Agency of Canada](https://health.canada.ca/en/public-health/corporate/contact-us.html). We do not give medical advice on individuals or cases.
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2022-08-10
| None | None |
f6d16d06980c8ebd4246303de93b97b20a37760e | cma | **Immunization in Canada: Canadian Immunization Guide** | Immunization in Canada: Canadian Immunization Guide
Introduction
The objectives of immunization programs are to prevent, control, eliminate or eradicate vaccine-preventable diseases by directly protecting vaccine recipients and indirectly protecting vulnerable individuals who may not respond to vaccines or for whom vaccines may be contraindicated. These objectives are dependent upon the epidemiology of the diseases, the effectiveness of available vaccines, and the ability to achieve . In Canada, the low incidence of vaccine-preventable diseases and their associated morbidity and mortality have been a result of comprehensive Federal, Provincial and Territorial (F/P/T) immunization policies, and the ongoing monitoring and evaluation of vaccines and immunization programs. Refer to the in Part 1 for information about the impact of immunization on the epidemiology of vaccine preventable diseases and the benefits of immunization.
This chapter provides an overview of immunization programming in Canada and discusses the various F/P/T immunization committees and mechanisms that support policy development. In doing so, it describes the National Immunization Strategy which serves as the principle framework that guides the work of F/P/T advisory bodies, stakeholders, networks and key decision-making processes.
Immunization policy and program development
In Canada, the responsibility for health care, including immunization, is shared by the F/P/T governments. While each jurisdiction has a distinct mandate and unique operating context, their activities are complementary and collaborative. Collaboration is a key component of immunization policy and program development as F/P/T governments benefit from sharing data, knowledge, expertise and best practices that help provide the necessary information for their respective programs.
# National Immunization Strategy
Since its adoption in 2003, the (NIS) has been a platform for collaboration between F/P/T stakeholders and has facilitated the development of consistent and equitable approaches to immunization planning, vaccine purchasing, program delivery and education. The NIS provides mechanisms for enhanced collaboration on issues such as vaccine safety, surveillance, immunization registries, research, vaccine supply and immunization program planning. The NIS enables collaboration of policy recommendations made at the national level with immunization program development at the provincial/territorial level. NIS priorities and developments in immunization were reviewed in 2016 in order to develop key objectives and activities to be carried out for the next five years. For more information, refer to .
# Key federal/provincial/territorial stakeholders
Through health departments, advisory bodies and other public authorities, all F/P/T governments engage in different aspects of immunization program planning, delivery and evaluation. Key stakeholders are described below.
Federal Government
The (PHAC) is the federal agency responsible for immunization activities such as the , , vaccine recommendations, , as well as . The Public Health Agency of Canada is also involved in the national monitoring and assessment of vaccine preventable diseases.
To help provide leadership, advice and support for timely vaccine recommendations and sustainable immunization programs, PHAC is supported by two scientific advisory committees whose members are recognized experts in multiple fields including pediatrics, infectious diseases, immunology, medical microbiology, internal medicine, nursing and public health.
National Advisory Committee on Immunization (NACI)
Created in 1964, the (NACI) provides PHAC with expert and evidence-based recommendations regarding the use of vaccines authorized for use in Canada, advises on the need for national vaccination strategies, and makes recommendations for vaccine development research. NACI's mandate was expanded incrementally from 2016-2019 to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels. NACI uses the EEFA Framework, a published and peer-reviewed framework that considers programmatic factors including: economics, ethics, equity, feasibility, and acceptability (EEFA) to ensure comprehensive and transparent immunization program decision-making. However, not all NACI Statements will require an in-depth analysis of all programmatic factors. For more details on the development and application of NACI's EEFA Framework, please refer to . NACI knowledge syntheses, analyses and recommendations on vaccine use in Canada are published in literature reviews, statements and updates. NACI recommendations are also published in the Canadian Immunization Guide. Refer to for additional information about the immunization guideline development process.
Committee to Advise on Tropical Medicine and Travel (CATMAT)
The (CATMAT) provides evidence-based recommendations relating to prevention and treatment of infectious diseases and other health hazards that may be encountered by Canadian travellers outside of Canada, suggests mechanisms for the widespread dissemination and utilization of such information, and advises on priorities for epidemiological research and other activities related to travel or tropical medicine. Some CATMAT recommendations for the use of authorized immunization products for travellers may extend beyond recommendations developed by NACI for Canada due to differences in disease prevalence internationally. Refer to for publications.
Health Canada
Other Federal Departments and Agencies
Other federal departments and bodies with immunization related interests and activities (that is, research, policy and operational considerations) include: , , , , , , , , , , , and .
Provincial and Territorial Governments
The provincial and territorial (P/T) governments are responsible for the administration and delivery of health care services, including immunization-related programs. Immunization policies and schedules are developed by P/T governments or their expert immunization advisory committees, based on jurisdiction-specific needs, other immunization recommendations (such as NACI), program resource availability and constraints, and identified priorities. In addition, P/T governments are responsible for: purchasing vaccines for publicly funded programs; the design and maintenance of immunization registries; disease and safety surveillance and program monitoring; and public and professional education and engagement (such as immunization campaigns, information services, and professional training, education and guidance). Each jurisdiction has its own process and mechanism for setting immunization targets and planning, designing, implementing and evaluating immunization programs. Evidence and recommendations developed by NACI are referenced by P/T governments to inform their local immunization policy and program decisions.
Pan-Canadian Public Health Network
The (PHN) was established by Canada's F/P/T Ministers of Health in 2005 as a key intergovernmental mechanism to:
- strengthen and enhance Canada's public health capacity,
- enable F/P/T governments to enhance day-to-day business of public health, and
- anticipate, prepare for, and respond to public health events and threats.
The work of the PHN is governed by a 17-member Pan-Canadian Public Health Network Council (PHNC) composed of senior F/P/T government officials responsible for public health, including the and senior government officials from all jurisdictions who are responsible for public health. The PHNC is accountable to the Conference of F/P/T Deputy Ministers of Health, which provides direction and approves public health policy priorities for Canada. The PHNC has three Steering Committees reporting under it: the Healthy People and Communities Steering Committee, the Public Health Infrastructure Steering Committee, and the Communicable and Infectious Diseases Steering Committee.
Canadian Immunization Committee
The Canadian Immunization Committee (CIC) was established in 2004 to provide a national forum to implement the objectives of the National Immunization Strategy (NIS), improve the effectiveness and efficiency of immunization programs, address emerging immunization issues, and foster F/P/T cooperation, collaboration and engagement of non-governmental stakeholders. Under the direction of the Communicable and Infectious Diseases Steering Committee of the PHNC, the CIC consists of F/P/T government representatives who review and provide strategic operational and technical advice and recommendations on issues related to immunization policies and programs.
Council of Chief Medical Officers of Health
The Council of Chief Medical Officers of Health (CCMOH) may provide further guidance and recommendations on technical issues relating to immunization. Its members are the Chief Medical Officers of Health from each P/T, the most senior public health physician of the of Indigenous Services Canada, and the Chief Public Health Officer of Canada. The CCMOH reports to the Conference of F/P/T Deputy Ministers of Health through the PHNC.
Development of recommendations by NACI
A new statement with recommendations will be developed when certain circumstances arise such as a new vaccine or indication, anticipated public health emergency or programmatic concerns for instance. For more information, refer to .
In developing recommendations, NACI relies on its working groups. The working groups consist of NACI members, liaison members, ex-officio representatives and other vaccine experts who systematically review and synthesize the available scientific and other technical information (i.e., disease burden, vaccine characteristics, unpublished study data) pertaining to specific questions or issues raised by NACI. Recommendations from other groups (e.g., , . NACI recommendations are summarized for easy use by vaccine providers in the (CIG).
Chapter revision process
The CIG Part 1 Working Group updated this chapter to include additional information on immunization programs in Canada and to reflect the current responsibilities of F/P/T immunization committees, advisory bodies, stakeholders, and networks in immunization policy and program development. |
**Immunization in Canada: Canadian Immunization Guide**
=======================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-3-benefits-immunization.html)
**Last complete chapter revision** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): July 2021
This chapter has been completely reviewed and updated to include additional information on immunization programs in Canada and the responsibilities of Federal, Provincial and Territorial immunization committees, advisory bodies, stakeholders, and networks in immunization policy and program development.
On this page
------------
* [Introduction](#intro)
* [Immunization policy and program development](#p1c1a1)
+ [National Immunization Strategy](#p1c1a2a)
+ [Key Federal/Provincial/Territorial Stakeholders](#p1c1a2b)
* [Development of recommendations by the National Advisory Committee on Immunization (NACI)](#p1c1a3)
* [Chapter revision process](#p1crp)
* [Acknowledgments](#p1ackno)
* [Selected References](#p1c1a4)
Introduction
------------
The objectives of immunization programs are to prevent, control, eliminate or eradicate vaccine-preventable diseases by directly protecting vaccine recipients and indirectly protecting vulnerable individuals who may not respond to vaccines or for whom vaccines may be contraindicated. These objectives are dependent upon the epidemiology of the diseases, the effectiveness of available vaccines, and the ability to achieve [immunization coverage goals](/en/public-health/services/immunization-vaccine-priorities/national-immunization-strategy/vaccination-coverage-goals-vaccine-preventable-diseases-reduction-targets-2025.html). In Canada, the low incidence of vaccine-preventable diseases and their associated morbidity and mortality have been a result of comprehensive Federal, Provincial and Territorial (F/P/T) immunization policies, and the ongoing monitoring and evaluation of vaccines and immunization programs. Refer to the [Benefits of immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-3-benefits-immunization.html) in Part 1 for information about the impact of immunization on the epidemiology of vaccine preventable diseases and the benefits of immunization.
This chapter provides an overview of immunization programming in Canada and discusses the various F/P/T immunization committees and mechanisms that support policy development. In doing so, it describes the National Immunization Strategy which serves as the principle framework that guides the work of F/P/T advisory bodies, stakeholders, networks and key decision-making processes.
Immunization policy and program development
-------------------------------------------
In Canada, the responsibility for health care, including immunization, is shared by the F/P/T governments. While each jurisdiction has a distinct mandate and unique operating context, their activities are complementary and collaborative. Collaboration is a key component of immunization policy and program development as F/P/T governments benefit from sharing data, knowledge, expertise and best practices that help provide the necessary information for their respective programs.
### National Immunization Strategy
Since its adoption in 2003, the [National Immunization Strategy](/en/public-health/services/immunization-vaccine-priorities/national-immunization-strategy.html) (NIS) has been a platform for collaboration between F/P/T stakeholders and has facilitated the development of consistent and equitable approaches to immunization planning, vaccine purchasing, program delivery and education. The NIS provides mechanisms for enhanced collaboration on issues such as vaccine safety, surveillance, immunization registries, research, vaccine supply and immunization program planning. The NIS enables collaboration of policy recommendations made at the national level with immunization program development at the provincial/territorial level. NIS priorities and developments in immunization were reviewed in 2016 in order to develop key objectives and activities to be carried out for the next five years. For more information, refer to [NIS objectives 2016-2021](/en/public-health/services/publications/healthy-living/national-immunization-strategy-objectives-2016-2021.html).
### Key federal/provincial/territorial stakeholders
Through health departments, advisory bodies and other public authorities, all F/P/T governments engage in different aspects of immunization program planning, delivery and evaluation. Key stakeholders are described below.
**Federal Government**
The [Public Health Agency of Canada](/en/public-health.html) (PHAC) is the federal agency responsible for immunization activities such as the [bulk procurement of publicly funded vaccines](/en/public-health/services/vaccine-supply.html), [vaccine safety monitoring](/en/public-health/services/immunization/vaccine-safety.html), vaccine recommendations, [vaccination coverage assessment](/en/public-health/services/immunization-vaccines/vaccination-coverage.html), as well as [immunization awareness and promotion](/en/public-health/services/immunization-vaccine-awareness-materials.html). The Public Health Agency of Canada is also involved in the national monitoring and assessment of vaccine preventable diseases.
To help provide leadership, advice and support for timely vaccine recommendations and sustainable immunization programs, PHAC is supported by two scientific advisory committees whose members are recognized experts in multiple fields including pediatrics, infectious diseases, immunology, medical microbiology, internal medicine, nursing and public health.
**National Advisory Committee on Immunization (NACI)**
Created in 1964, the [National Advisory Committee on Immunization](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci.html) (NACI) provides PHAC with expert and evidence-based recommendations regarding the use of vaccines authorized for use in Canada, advises on the need for national vaccination strategies, and makes recommendations for vaccine development research. NACI's mandate was expanded incrementally from 2016-2019 to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels. NACI uses the EEFA Framework, a published and peer-reviewed framework that considers programmatic factors including: economics, ethics, equity, feasibility, and acceptability (EEFA) to ensure comprehensive and transparent immunization program decision-making. However, not all NACI Statements will require an in-depth analysis of all programmatic factors. For more details on the development and application of NACI's EEFA Framework, please refer to [A framework for the systematic consideration of ethics, equity, feasibility, and acceptability in vaccine program recommendations](https://www.sciencedirect.com/science/article/pii/S0264410X20306964?via%3Dihub). NACI knowledge syntheses, analyses and recommendations on vaccine use in Canada are published in literature reviews, statements and updates. NACI recommendations are also published in the Canadian Immunization Guide. Refer to [Development of recommendations by NACI](#p1c1a3) for additional information about the immunization guideline development process.
**Committee to Advise on Tropical Medicine and Travel (CATMAT)**
The [Committee to Advise on Tropical Medicine and Travel](/en/public-health/services/catmat/terms-reference.html) (CATMAT) provides evidence-based recommendations relating to prevention and treatment of infectious diseases and other health hazards that may be encountered by Canadian travellers outside of Canada, suggests mechanisms for the widespread dissemination and utilization of such information, and advises on priorities for epidemiological research and other activities related to travel or tropical medicine. Some CATMAT recommendations for the use of authorized immunization products for travellers may extend beyond recommendations developed by NACI for Canada due to differences in disease prevalence internationally. Refer to [CATMAT Statements and Recommendations](/en/public-health/services/catmat.html) for publications.
**Health Canada**
[Health Canada](/en/health-canada.html) (HC) is the federal authority responsible for regulation of vaccines for human use under the [Food and Drugs Act](http://laws-lois.justice.gc.ca/eng/acts/F-27/index.html) and [Food and Drugs Regulations](http://laws-lois.justice.gc.ca/eng/regulations/C.R.C.%2C_c._870/). The [Biologic and Radiopharmaceutical Drugs Directorate](http://www.hc-sc.gc.ca/ahc-asc/branch-dirgen/hpfb-dgpsa/bgtd-dpbtg/index-eng.php) (BRDD), formerly called the Biologics and Genetic Therapies Directorate (BGTD), of HC reviews the clinical, quality, and manufacturing information submitted and if the benefits outweigh any risks, issues a Notice of Compliance indicating that the vaccine is authorized for sale in Canada. Following approval, PHAC together with the Marketed Health Products Directorate (MHPD) of HC, are responsible for monitoring vaccine safety and effectiveness throughout the life cycle of the product. Post-marketing surveillance is supported by: the [Canadian Adverse Events Following Immunization Surveillance System [CAEFISS]](/en/public-health/services/immunization/canadian-adverse-events-following-immunization-surveillance-system-caefiss.html#_Reporting_adverse_event) managed by PHAC and the [Canada Vigilance Program](/en/health-canada/services/drugs-health-products/medeffect-canada/canada-vigilance-program.html) under MHPD. For more information on the regulatory process and post-market surveillance, refer to [Regulating vaccines for human use in Canada](/en/health-canada/services/drugs-health-products/biologics-radiopharmaceuticals-genetic-therapies/activities/fact-sheets/regulation-vaccines-human-canada.html), and [Vaccine safety and pharmacovigilance](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) and [Adverse Events Following Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) in Part 2.
**Other Federal Departments and Agencies**
Other federal departments and bodies with immunization related interests and activities (that is, research, policy and operational considerations) include: [Immigration and Citizenship Canada](http://www.cic.gc.ca/english/index-can.asp), [Correctional Service Canada](http://www.csc-scc.gc.ca/index-eng.shtml), [National Defence and the Canadian Armed Forces](/en/department-national-defence.html), [Canada Border Services Agency](http://www.cbsa-asfc.gc.ca/menu-eng.html), [Public Services and Procurement Canada](http://www.tpsgc-pwgsc.gc.ca/comm/index-eng.html), [Global Affairs Canada](https://www.international.gc.ca/gac-amc/index.aspx?lang=eng), [Statistics Canada](http://www.statcan.gc.ca/start-debut-eng.html), [Veterans Affairs Canada](/en/veterans-affairs-canada.html), [Indigenous Services Canada](/en/indigenous-services-canada.html), [Canadian Institutes of Health Research](http://www.cihr-irsc.gc.ca/e/193.html), [National Research Council Canada](http://www.nrc-cnrc.gc.ca/eng/), and [Innovation, Science and Economic Development Canada](http://www.ic.gc.ca/eic/site/icgc.nsf/eng/home).
**Provincial and Territorial Governments**
The provincial and territorial (P/T) governments are responsible for the administration and delivery of health care services, including immunization-related programs. Immunization policies and schedules are developed by P/T governments or their expert immunization advisory committees, based on jurisdiction-specific needs, other immunization recommendations (such as NACI), program resource availability and constraints, and identified priorities. In addition, P/T governments are responsible for: purchasing vaccines for publicly funded programs; the design and maintenance of immunization registries; disease and safety surveillance and program monitoring; and public and professional education and engagement (such as immunization campaigns, information services, and professional training, education and guidance). Each jurisdiction has its own process and mechanism for setting immunization targets and planning, designing, implementing and evaluating immunization programs. Evidence and recommendations developed by NACI are referenced by P/T governments to inform their local immunization policy and program decisions.
**Pan-Canadian Public Health Network**
The [Pan-Canadian Public Health Network](https://www.phn-rsp.ca/en/about/index.html) (PHN) was established by Canada's F/P/T Ministers of Health in 2005 as a key intergovernmental mechanism to:
* strengthen and enhance Canada's public health capacity,
* enable F/P/T governments to enhance day-to-day business of public health, and
* anticipate, prepare for, and respond to public health events and threats.
The work of the PHN is governed by a 17-member Pan-Canadian Public Health Network Council (PHNC) composed of senior F/P/T government officials responsible for public health, including the [Chief Public Health Officer of Canada](/en/public-health/corporate/organizational-structure/canada-chief-public-health-officer.html) and senior government officials from all jurisdictions who are responsible for public health. The PHNC is accountable to the Conference of F/P/T Deputy Ministers of Health, which provides direction and approves public health policy priorities for Canada. The PHNC has three Steering Committees reporting under it: the Healthy People and Communities Steering Committee, the Public Health Infrastructure Steering Committee, and the Communicable and Infectious Diseases Steering Committee.
**Canadian Immunization Committee**
The Canadian Immunization Committee (CIC) was established in 2004 to provide a national forum to implement the objectives of the National Immunization Strategy (NIS), improve the effectiveness and efficiency of immunization programs, address emerging immunization issues, and foster F/P/T cooperation, collaboration and engagement of non-governmental stakeholders. Under the direction of the Communicable and Infectious Diseases Steering Committee of the PHNC, the CIC consists of F/P/T government representatives who review and provide strategic operational and technical advice and recommendations on issues related to immunization policies and programs.
**Council of Chief Medical Officers of Health**
The Council of Chief Medical Officers of Health (CCMOH) may provide further guidance and recommendations on technical issues relating to immunization. Its members are the Chief Medical Officers of Health from each P/T, the most senior public health physician of the [First Nations and Inuit Health Branch](https://www.sac-isc.gc.ca/eng/1569861171996/1569861324236) of Indigenous Services Canada, and the Chief Public Health Officer of Canada. The CCMOH reports to the Conference of F/P/T Deputy Ministers of Health through the PHNC.
Development of recommendations by NACI
--------------------------------------
A new statement with recommendations will be developed when certain circumstances arise such as a new vaccine or indication, anticipated public health emergency or programmatic concerns for instance. For more information, refer to [NACI’s current workplan](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/workplan.html).
In developing recommendations, NACI relies on its working groups. The working groups consist of NACI members, liaison members, ex-officio representatives and other vaccine experts who systematically review and synthesize the available scientific and other technical information (i.e., disease burden, vaccine characteristics, unpublished study data) pertaining to specific questions or issues raised by NACI. Recommendations from other groups (e.g., [World Health Organization](http://www.who.int/en/) [WHO], [Canadian Paediatric Society](http://www.cps.ca/), [Advisory Committee on Immunization Practices](http://www.cdc.gov/vaccines/acip/index.html) [United States]) are also considered. This information is then presented in the form of a draft statement or statement update to the full NACI committee for review, discussion and adoption. Detailed literature reviews may be published separately from the statement. Once adopted, NACI recommendations and the reviewed evidence are made available to P/T governments, to health professionals and to the general public in both official languages on the [NACI website](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci.html). NACI recommendations are summarized for easy use by vaccine providers in the [Canadian Immunization Guide](/en/public-health/services/canadian-immunization-guide.html) (CIG).
Chapter revision process
------------------------
The CIG Part 1 Working Group updated this chapter to include additional information on immunization programs in Canada and to reflect the current responsibilities of F/P/T immunization committees, advisory bodies, stakeholders, and networks in immunization policy and program development.
Acknowledgements
----------------
The Public Health Agency of Canada (PHAC) would like to acknowledge the Part 1 Working Group consisting of NACI Members S Smith (Working Group Chair), V Dubey and NACI Liaison Representatives D Moore and T Cole for their contributions to the revision of this chapter. PHAC participants on the Part 1 Working Group include O Baclic, L Coward, C Jensen, and N Mohamed.
Selected references
-------------------
Ismail SJ, Hardy K, Tunis MC, et al. A framework for the systematic consideration of ethics, equity, feasibility, and acceptability in vaccine program recommendations. Vaccine. 2020 Aug 10;38(36):5861,5876. doi: 10.1016/j.vaccine.2020.05.051.
Ismail SJ, Langley JM, Harris TM et al. Canada's National Advisory Committee on Immunization (NACI): Evidence-based decision-making on vaccines and immunization. Vaccine 2010;28S:A58-63. doi: 10.1016/j.vaccine.2010.02.035.
National Advisory Committee on Immunization. Evidence-based recommendations for immunization – Methods of the National Advisory Committee on Immunization. Can Commun Dis Rep [Internet]. 2009 Jan; [cited 2021 May 10]; (ACS-1):1-10. Available from: https://www.canada.ca/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2009-35/methods-national-advisory-committee-immunization.html
Public Health Agency of Canada (PHAC). National Immunization Strategy [Internet]. Ottawa (ON): PHAC; 2017 December 8 [cited 2021 May 10]. Available from: https://www.canada.ca/en/public-health/services/immunization-vaccine-priorities/national-immunization-strategy.html
Public Health Agency of Canada (PHAC). National Immunization Strategy: Objectives 2016-2021[Internet]. Ottawa (ON): PHAC; 2017 December 8 [cited 2021 May 10]. Available from:
https://www.canada.ca/en/public-health/services/publications/healthy-living/national-immunization-strategy-objectives-2016-2021.html
Public Health Agency of Canada (PHAC). Vaccination Coverage Goals and Vaccine Preventable Disease Reduction Targets by 2025 [Internet]. Ottawa (ON): PHAC; 2021 May 3 [cited 2021 May 10]. Available from: https://www.canada.ca/en/public-health/services/immunization-vaccine-priorities/national-immunization-strategy/vaccination-coverage-goals-vaccine-preventable-diseases-reduction-targets-2025.html
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-3-benefits-immunization.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2022-08-16
| None | None |
184d2d3aeaf576ad5ee466cf38a208f963cfd84f | cma | Respiratory syncytial virus (RSV): Canadian Immunization Guide | Respiratory syncytial virus (RSV): Canadian Immunization Guide
Key information
# What
- Respiratory syncytial virus (RSV) infection is a major cause of lower respiratory illness, particularly among infants, young children and older adults.
- In Canada, RSV causes yearly outbreaks of respiratory tract disease, usually starting in late fall and running through to early spring.
- Reinfections with RSV are common but illness is usually milder with subsequent infections.
- At present there is no vaccine available in Canada to prevent RSV. The only means of prevention is temporary passive protection with the monoclonal antibody preparation palivizumab (PVZ). PVZ contains antibody only against RSV.
# Who
- PVZ should be offered to:
+ infants born at less than 30 weeks gestational age (wGA) and less than 6 months of age at onset of or during the RSV season
+ children less than 24 months of age with chronic lung disease (CLD) of prematurity who require ongoing oxygen therapy within the 6 months preceding or during the RSV season
+ infants less than 12 months of age at the onset of the RSV season with haemodynamically significant congenital heart disease (hsCHD) and
+ infants born at less than 36 weeks gestational age and who are less than 6 months of age at onset of or during the RSV season and living in remote northern Inuit communities who would require air transport for hospitalization.
- PVZ may also be considered for:
+ infants born at 30 to less than 33 weeks gestational age and less than 3 months of age at onset of or during the RSV season and who are at high risk for exposure to RSV
+ select children less than 24 months of age with severe chronic lung disease due to cystic fibrosis (CF) or other etiology who require ongoing oxygen therapy or assisted ventilation in the 6 months preceding or during the RSV season
+ infants less than 12 months of age with haemodynamically significant chronic cardiopathy other than congenital
+ children 12 to 24 months of age awaiting heart transplant or having received a heart transplant within 6 months of onset of the RSV season
+ children less than 24 months of age who are severely immunocompromised
+ healthy full term infants less than 6 months of age at the onset of or during RSV season living in remote Inuit communities with very high rates of hospitalization for RSV among term infants
+ infants born at less than 36 weeks gestational age and less than 6 months of age living in other remote communities with high rates of hospitalization for RSV and where air transport would be required for hospitalization
+ controlling an outbreak of RSV in a neonatal intensive care unit (NICU) when all other control measures have failed
- PVZ has not been evaluated in children 2 years of age and older.
# How
- The first dose of PVZ should be given at the onset of the local RSV season.
- A second dose of PVZ should follow at 21 to 28 days and the interval between subsequent doses is 28 to 35 days.
- The usual maximum number of doses is four.
- An additional dose should be given after cardiac bypass or extracorporeal membrane oxygenation.
- An additional dose may be considered in remote northern areas where RSV outbreaks may continue longer than is usual elsewhere.
- PVZ may be co-administered with any other live or inactivated vaccines.
# Why
- RSV is the most common cause of bronchiolitis and pneumonia among infants and young children.
- PVZ is approximately 40 to 80% effective in preventing hospitalization, depending on age and underlying health condition.
Epidemiology
# Disease description
## Infectious agent
RSV is an enveloped single-stranded RNA virus of the genus Pneumovirus. RSV causes respiratory tract infections and is the most common cause of bronchiolitis and pneumonia among infants and young children.
## Reservoir
Humans are the only natural reservoir.
## Transmission
RSV is transmitted by direct and indirect contact with infectious respiratory tract secretions. Transmission occurs directly when droplets generated from coughs or sneezes of an infected person come into contact with the mucous membranes of the eyes, nose, mouth, or airway of another person. Indirect transmission occurs when people touch contaminated hands, surfaces and objects and inoculate themselves by touching their mucous membranes.
## Risk factors
RSV infects almost all infants by 2 years of age. Chronological age is an important risk factor for RSV hospitalization.
Prematurity is also a notable risk factor for RSV hospitalization. Indeed, infants born at less than 30 weeks gestation have RSV hospitalization rates of 7.7 to 13.6% in the first year of life. Also at higher risk of RSV hospitalization are young children with chronic respiratory or cardiac conditions, and immunocompromised individuals of any age. High rates of RSV lower respiratory tract infection have been observed among Inuit infants, particularly those less than 6 months of age. Other risk factors for more severe disease include exposure to cigarette smoke and family history of atopy. Factors that predispose to acquisition of RSV include the number of young children in the home, crowding in the home, attending day care or school, and lack of breastfeeding. Severe infection, including pneumonia, may develop among elderly patients with underlying respiratory or cardiac conditions.
Transmission occurs in health care settings and RSV is an important cause of healthcare associated infections in young children, immunocompromised individuals and the elderly.
## Seasonal and temporal patterns
In temperate climates in the Northern Hemisphere, annual outbreaks begin in the fall and continue to early spring. In Canada, the RSV season usually begins in October or November and lasts until April or May, with peaks in December through March.
## Spectrum of clinical illness
Most RSV infections are upper respiratory tract infections that present as nasal congestion, cough, low grade fever and loss of appetite and last approximately 1 to 2 weeks. Approximately 20 to 30% of infected infants develop bronchiolitis or pneumonia. Croup or otitis media may also occur. Recurrent infections occur throughout life, with subsequent infections usually less severe than the first. Older children and adults usually present with symptoms similar to the common cold. Severe pneumonia may occur in the elderly and in immunocompromised individuals of any age.
Mortality is rare among children receiving supportive care. The overall case-fatality rate of children hospitalized with RSV is estimated to be less than 0.5%, with most deaths occurring in children with comorbidities predisposing to more severe disease. Mortality is more common among the elderly hospitalized for RSV.
# Disease distribution
RSV occurs worldwide, with virtually all children infected by age two. Globally, RSV is an important cause of acute lower respiratory tract infection and a major cause of hospital admissions in young children, for whom it has been estimated that RSV is associated with about 28% of all episodes of acute lower respiratory tract infections. In Canada, approximately 1% of all infants are hospitalized with RSV in their first year of life. In some remote communities, RSV hospitalization rates have been as high as 20 to 50% of all live births.
Preparations authorized for use in Canada
- SYNAGIS® (palivizumab) (PVZ), is a humanized IgG1 monoclonal antibody directed to the RSV fusion protein). AstraZeneca Canada Inc.
- BEYFORTUSTM (nirsevimab) is a passive immunizing agent (human monoclonal antibody). AstraZeneca Canada Inc.
NACI has not yet deliberated on the use of nirsevimab. The Canadian Agency for Drugs and Technologies in Health (CADTH) will provide an initial assessment of nirsevimab. NACI will subsequently review this passive immunizing agent relative to other prophylactic strategies for RSV and update the chapter in due course.
For complete prescribing information, consult the product leaflet or information contained within Health Canada's authorized product monographs available through the .
Efficacy and effectiveness
PVZ has been evaluated only in children less than 2 years of age at risk of severe RSV infection.
Among all infants at risk of severe RSV infection, PVZ prophylaxis is associated with risk reductions of approximately 38 to 86% for RSV-associated hospital admissions. In infants born at 32 weeks gestation or earlier PVZ has been shown to reduce the risk of all-cause mortality.
The efficacy of PVZ varies according to the infant's underlying health condition and level of prematurity, with a higher benefit for those at a greater level of prematurity.
PVZ has been shown to reduce the risk of RSV-associated hospitalization in children with chronic lung disease of prematurity. The same protective effect of PVZ on hospitalization has not been definitively demonstrated in children with cystic fibrosis.
Studies of children with hsCHD have shown conflicting results, with PVZ reducing hospitalization risk in the larger studies.
Infants living in some remote northern communities are at very high risk of hospitalization for RSV. Data on PVZ effectiveness to prevent hospitalization in this group are very limited.
Recommendations for use
# High risk children
## Schedule
In general, the usual number of doses given in a season is four. The interval between the first and second doses is 21 to 28 days, and the interval between subsequent doses is 28 to 35 days. The first dose of PVZ is given at the onset of the RSV season, as determined by local epidemiology.
Infants born during the RSV season and who qualify for PVZ prophylaxis should receive their first dose 48 to 72 hours before discharge home if possible, or promptly after discharge. Administering the first dose before discharge avoids the need to visit a health care facility soon after discharge and may improve adherence.
An infant who has already begun PVZ prophylaxis earlier in the season and is re-hospitalized on a date when a dose is due should receive that dose as scheduled while in hospital, providing the admitting institution is able to supply PVZ when due. Keeping to the child's existing PVZ schedule avoids the need to reschedule appointments and may improve adherence.
PVZ should be discontinued for the season if a child is hospitalized because of RSV infection. Reported rates of second episodes of RSV hospitalization in the same season are very low.
# Additional doses
An additional, or fifth, dose is recommended after surgery requiring cardiac bypass or at conclusion of extracorporeal membrane oxygenation to maintain PVZ levels that may be decreased following these procedures. An additional, or fifth, dose may also be considered in remote northern areas where RSV outbreaks may continue longer than is usual elsewhere.
# Outbreak control
PVZ should not routinely be used to prevent health care-associated RSV infections or to control RSV hospital outbreaks. It may be considered when all other measures to control an RSV outbreak in a NICU have failed.
Vaccination of specific populations
# Preterm infants without congenital heart disease or chronic lung disease of prematurity
PVZ is recommended for all infants born at less than 30 weeks gestation and aged less than 6 months at the onset of or during the RSV season.
PVZ may be considered for infants born at 30 to less than 33 weeks gestation and aged less than 3 months at the onset of or during the RSV season if they are at high risk of exposure to RSV from day care attendance or presence of another preschool child or children in the home.
PVZ is not recommended for healthy premature infants born at or after 33 weeks gestation or for infants or siblings of multiple births who do not otherwise have an indication for prophylaxis.
# Chronic lung disease of prematurity and other chronic lung disease
PVZ is recommended for all infants with CLD of prematurity (infants born at less than or equal to 32 weeks gestational age and with need for supplemental oxygen (O2) greater than 21% for at least the first 28 days after birth) who are less than 24 months of age at the onset of the RSV season and have required ongoing supplemental O2 therapy or assisted ventilation in the 6 months prior to the onset of or during the RSV season.
PVZ may be considered for infants less than 24 months of age with severe chronic lung disease of other etiology (e.g., congenital cystic lung disease, chronic interstitial lung disease, congenital lung malformations, congenital airway abnormalities or neuromuscular conditions affecting ability to clear airway secretions) or who require home respiratory support (e.g., supplemental O2, mechanical ventilation, continuous positive airway pressure, tracheostomy) if requiring ongoing supplemental O2 or assisted ventilation in the 6 months prior to the onset of or during the RSV season.
PVZ is not routinely recommended for children less than 24 months of age with cystic fibrosis; however, PVZ may be considered for those less than 24 months of age with cystic fibrosis who have severe chronic lung disease as defined by the need for ongoing supplemental O2 in the 6 months prior to the onset of or during the RSV season.
PVZ is not recommended for the prevention of recurrent wheezing or asthma in the absence of other indications.
# Congenital heart disease and other chronic cardiopathy
PVZ should be offered to infants with hsCHD, as assessed by a paediatric cardiologist, who are less than one year of age at the onset of the RSV season.
PVZ may be considered for infants less than one year of age at the onset of the RSV season who have haemodynamically significant chronic cardiopathy (as assessed by a paediatric cardiologist) of other etiology.
PVZ may be considered for children 12 to 24 months of age at the onset of the RSV season if they are awaiting heart transplantation or have received a heart transplant in the previous 6 months.
For children with both haemodynamically significant heart disease and chronic lung disease, recommendations for chronic lung disease should be followed.
# Down syndrome
PVZ should be offered to children with Down syndrome who qualify for prophylaxis because of hsCHD, CLD, prematurity or immunodeficiency, but should not be routinely offered to all children less than 24 months of age with Down syndrome.
# Immunocompromised children
PVZ may be considered for children less than 24 months of age who are severely immunocompromised (e.g., primary immunodeficiency, cancer chemotherapy). Those with absolute lymphocyte counts of <100 / mm3 may be at higher risk of severe RSV disease.
PVZ prophylaxis has not been evaluated in immunocompromised children. Refer to in Part 3 for additional general information about vaccination of people who are immunocompromised.
# Children residing in remote communities
PVZ should be offered to infants less than 36 weeks gestational age and less than 6 months of age living in remote northern Inuit communities who would require air transport for hospitalization.
PVZ is not routinely recommended for healthy full term infants living in remote northern Inuit communities. PVZ may be considered for these infants if aged less than 6 months and living in a community with a very high RSV hospitalization rate, taking into consideration the burden of illness in the community and need for air transport if hospitalization or specialized ambulatory care is required.
PVZ may be considered for infants less than 36 weeks gestational age and less than 6 months of age living in other remote communities with documented high rates of hospitalization for RSV who would require air transport for hospitalization.
Administration practices
# Dose and route of administration
PVZ is given at a dose of 15 mg/kg of body weight by intramuscular injection.
# Simultaneous administration with other vaccines
PVZ is a passive immunizing agent directed specifically against RSV. It does not interfere with the immune response to other vaccines. PVZ can be administered at the same time, at a separate site, as other immunization products.
Storage requirements
PVZ is supplied as 50 mg/0.5 mL and 100 mg/1 mL single use vials for injection. It should be stored between 2° C and 8° C in its original container and must not be frozen.
PVZ should be administered immediately after drawing the dose into the syringe. If an entire vial (50 mg or 100 mg) is not required for one child, the residual may be used for another child if it is within 6 hours of opening the vial and if the recommended storage conditions have been met. Open vials containing product not used within 6 hours should be discarded. If feasible, clinics or appointments should be organized to facilitate PVZ vial sharing, to reduce costs and PVZ wastage.
Safety and adverse events
# Common and very common adverse events
The most common adverse events following administration of PVZ are injection site reactions, fever, nervousness or irritability, cough, rhinitis and diarrhea. In randomized control trials the rates of these common adverse events were similar for those receiving PVZ as for those receiving a placebo.
# Uncommon, rare and very rare adverse events
Serious adverse events following administration of PVZ, mostly hypersensitivity reactions, are rare at 1.3 to 3.4 per 10,000 doses administered. Anaphylaxis occurs in approximately 1 per 1 million doses.
# Other safety issues
Repeated injections of a humanized monoclonal antibody have raised concern for the development of immune mediated disease. However, studies have not shown an increased risk of autoimmune disease or atopy in children exposed to PVZ.
# Guidance on reporting adverse reactions following palivizumab administration
To ensure the ongoing safety monitoring of passive immunizing agents, like palivizumab, in Canada, reporting of adverse reactions by health care providers is critical.
When a serious or unexpected adverse reaction follows the administration of a passive immunizing agent such as PVZ, report the adverse drug reaction to the using the available on the program web page. The Canada Vigilance Program collects and assesses reports of suspected adverse reactions to health products, including biologics. If PVZ was given along with a routine active immunizing agent, the adverse event(s) should also be reported to the provincial or territorial immunization program.
# Contraindications and precautions
Significant hypersensitivity to PVZ or to any component of PVZ is a contraindication to use of this product. Known hypersensitivity to other humanized monoclonal antibodies is also a contraindication. Minor illnesses such as the common cold, with or without fever, are not contraindications to use of PVZ. Moderate to severe illness, with or without fever, is a reason to consider deferring PVZ to avoid inadvertently attributing possible adverse effects from PVZ to the underlying illness, or vice versa. The decision to delay administration of PVZ will depend on the severity and etiology of the underlying disease.
Chapter revision process
This chapter was developed based on current evidence and the National Advisory Committee on Immunization's (NACI) expert opinion. For supporting information, additional references, please refer the related NACI statement: Recommended use of palivizumab to reduce complications of respiratory syncytial virus infection in infants. Future updates to this chapter will follow NACI's review of new RSV immunizing agents when they are approved for use in Canada by Health Canada. |
Respiratory syncytial virus (RSV): Canadian Immunization Guide
===============================================================
**For health professionals**
Notice
------
Nirsevimab (Beyfortus) has been authorized for use in Canada. PHAC requested that the Canadian Agency for Drugs and Technologies in Health (CADTH) undertake an initial health technology assessment, and the [CADTH rapid implementation advice is now available(PDF)](https://www.cadth.ca/sites/default/files/hta-he/HC0059%20Nirsevimab%20for%20RSV%20prophylaxis-secured.pdf). NACI recommendations on RSV prophylaxis for infants are forthcoming, including further analysis of nirsevimab in relation to comparator interventions.
New chapter (see [Table of updates](/en/public-health/services/canadian-immunization-guide/updates.html)): March 2023
March 2023**:** This new chapter was developed based on the statement: [Recommended use of palivizumab to reduce complications of respiratory syncytial virus infection in infants](/en/public-health/services/publications/vaccines-immunization/palivizumab-respiratory-syncitial-virus-infection-infants.html) from the National Advisory Committee on Immunization (NACI). This chapter replaces the Respiratory syncytial virus monoclonal antibody section in the former Part 5 Passive Immunization.
On this page
------------
* [Key information](#a1)
* [Epidemiology](#a2)
* [Preparations authorized for use in Canada](#a3)
* [Efficacy and effectiveness](#a4)
* [Recommendations for use](#a5)
+ [High risk children](#a5.1)
+ [Additional doses](#a5.2)
+ [Outbreak control](#a5.3)
* [Vaccination of specific populations](#a6)
* [Administration practices](#a7)
* [Storage requirements](#a8)
* [Safety and adverse events](#a9)
* [Chapter revision process](#a10)
* [Acknowledgments](#a11)
* [Selected references](#a12)
Key information
---------------
### What
* Respiratory syncytial virus (RSV) infection is a major cause of lower respiratory illness, particularly among infants, young children and older adults.
* In Canada, RSV causes yearly outbreaks of respiratory tract disease, usually starting in late fall and running through to early spring.
* Reinfections with RSV are common but illness is usually milder with subsequent infections.
* At present there is no vaccine available in Canada to prevent RSV. The only means of prevention is temporary passive protection with the monoclonal antibody preparation palivizumab (PVZ). PVZ contains antibody only against RSV.
### Who
* PVZ should be offered to:
+ infants born at less than 30 weeks gestational age (wGA) and less than 6 months of age at onset of or during the RSV season
+ children less than 24 months of age with chronic lung disease (CLD) of prematurity who require ongoing oxygen therapy within the 6 months preceding or during the RSV season
+ infants less than 12 months of age at the onset of the RSV season with haemodynamically significant congenital heart disease (hsCHD) and
+ infants born at less than 36 weeks gestational age and who are less than 6 months of age at onset of or during the RSV season and living in remote northern Inuit communities who would require air transport for hospitalization.
* PVZ may also be considered for:
+ infants born at 30 to less than 33 weeks gestational age and less than 3 months of age at onset of or during the RSV season and who are at high risk for exposure to RSV
+ select children less than 24 months of age with severe chronic lung disease due to cystic fibrosis (CF) or other etiology who require ongoing oxygen therapy or assisted ventilation in the 6 months preceding or during the RSV season
+ infants less than 12 months of age with haemodynamically significant chronic cardiopathy other than congenital
+ children 12 to 24 months of age awaiting heart transplant or having received a heart transplant within 6 months of onset of the RSV season
+ children less than 24 months of age who are severely immunocompromised
+ healthy full term infants less than 6 months of age at the onset of or during RSV season living in remote Inuit communities with very high rates of hospitalization for RSV among term infants
+ infants born at less than 36 weeks gestational age and less than 6 months of age living in other remote communities with high rates of hospitalization for RSV and where air transport would be required for hospitalization
+ controlling an outbreak of RSV in a neonatal intensive care unit (NICU) when all other control measures have failed
* PVZ has not been evaluated in children 2 years of age and older.
### How
* The first dose of PVZ should be given at the onset of the local RSV season.
* A second dose of PVZ should follow at 21 to 28 days and the interval between subsequent doses is 28 to 35 days.
* The usual maximum number of doses is four.
* An additional dose should be given after cardiac bypass or extracorporeal membrane oxygenation.
* An additional dose may be considered in remote northern areas where RSV outbreaks may continue longer than is usual elsewhere.
* PVZ may be co-administered with any other live or inactivated vaccines.
### Why
* RSV is the most common cause of bronchiolitis and pneumonia among infants and young children.
* PVZ is approximately 40 to 80% effective in preventing hospitalization, depending on age and underlying health condition.
Epidemiology
------------
### Disease description
#### Infectious agent
RSV is an enveloped single-stranded RNA virus of the genus Pneumovirus. RSV causes respiratory tract infections and is the most common cause of bronchiolitis and pneumonia among infants and young children.
#### Reservoir
Humans are the only natural reservoir.
#### Transmission
RSV is transmitted by direct and indirect contact with infectious respiratory tract secretions. Transmission occurs directly when droplets generated from coughs or sneezes of an infected person come into contact with the mucous membranes of the eyes, nose, mouth, or airway of another person. Indirect transmission occurs when people touch contaminated hands, surfaces and objects and inoculate themselves by touching their mucous membranes.
#### Risk factors
RSV infects almost all infants by 2 years of age. Chronological age is an important risk factor for RSV hospitalization.
Prematurity is also a notable risk factor for RSV hospitalization. Indeed, infants born at less than 30 weeks gestation have RSV hospitalization rates of 7.7 to 13.6% in the first year of life. Also at higher risk of RSV hospitalization are young children with chronic respiratory or cardiac conditions, and immunocompromised individuals of any age. High rates of RSV lower respiratory tract infection have been observed among Inuit infants, particularly those less than 6 months of age. Other risk factors for more severe disease include exposure to cigarette smoke and family history of atopy. Factors that predispose to acquisition of RSV include the number of young children in the home, crowding in the home, attending day care or school, and lack of breastfeeding. Severe infection, including pneumonia, may develop among elderly patients with underlying respiratory or cardiac conditions.
Transmission occurs in health care settings and RSV is an important cause of healthcare associated infections in young children, immunocompromised individuals and the elderly.
#### Seasonal and temporal patterns
In temperate climates in the Northern Hemisphere, annual outbreaks begin in the fall and continue to early spring. In Canada, the RSV season usually begins in October or November and lasts until April or May, with peaks in December through March.
#### Spectrum of clinical illness
Most RSV infections are upper respiratory tract infections that present as nasal congestion, cough, low grade fever and loss of appetite and last approximately 1 to 2 weeks. Approximately 20 to 30% of infected infants develop bronchiolitis or pneumonia. Croup or otitis media may also occur. Recurrent infections occur throughout life, with subsequent infections usually less severe than the first. Older children and adults usually present with symptoms similar to the common cold. Severe pneumonia may occur in the elderly and in immunocompromised individuals of any age.
Mortality is rare among children receiving supportive care. The overall case-fatality rate of children hospitalized with RSV is estimated to be less than 0.5%, with most deaths occurring in children with comorbidities predisposing to more severe disease. Mortality is more common among the elderly hospitalized for RSV.
### Disease distribution
RSV occurs worldwide, with virtually all children infected by age two. Globally, RSV is an important cause of acute lower respiratory tract infection and a major cause of hospital admissions in young children, for whom it has been estimated that RSV is associated with about 28% of all episodes of acute lower respiratory tract infections. In Canada, approximately 1% of all infants are hospitalized with RSV in their first year of life. In some remote communities, RSV hospitalization rates have been as high as 20 to 50% of all live births.
Preparations authorized for use in Canada
-----------------------------------------
* **SYNAGIS®** (palivizumab) (PVZ), is a humanized IgG1 monoclonal antibody directed to the RSV fusion protein). AstraZeneca Canada Inc.
* **BEYFORTUSTM** (nirsevimab) is a passive immunizing agent (human monoclonal antibody). AstraZeneca Canada Inc.
NACI has not yet deliberated on the use of nirsevimab. The Canadian Agency for Drugs and Technologies in Health (CADTH) will provide an initial assessment of nirsevimab. NACI will subsequently review this passive immunizing agent relative to other prophylactic strategies for RSV and update the chapter in due course.
For complete prescribing information, consult the product leaflet or information contained within Health Canada's authorized product monographs available through the [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
Efficacy and effectiveness
--------------------------
PVZ has been evaluated only in children less than 2 years of age at risk of severe RSV infection.
Among all infants at risk of severe RSV infection, PVZ prophylaxis is associated with risk reductions of approximately 38 to 86% for RSV-associated hospital admissions. In infants born at 32 weeks gestation or earlier PVZ has been shown to reduce the risk of all-cause mortality.
The efficacy of PVZ varies according to the infant's underlying health condition and level of prematurity, with a higher benefit for those at a greater level of prematurity.
PVZ has been shown to reduce the risk of RSV-associated hospitalization in children with chronic lung disease of prematurity. The same protective effect of PVZ on hospitalization has not been definitively demonstrated in children with cystic fibrosis.
Studies of children with hsCHD have shown conflicting results, with PVZ reducing hospitalization risk in the larger studies.
Infants living in some remote northern communities are at very high risk of hospitalization for RSV. Data on PVZ effectiveness to prevent hospitalization in this group are very limited.
Recommendations for use
-----------------------
### High risk children
#### Schedule
In general, the usual number of doses given in a season is four. The interval between the first and second doses is 21 to 28 days, and the interval between subsequent doses is 28 to 35 days. The first dose of PVZ is given at the onset of the RSV season, as determined by local epidemiology.
Infants born during the RSV season and who qualify for PVZ prophylaxis should receive their first dose 48 to 72 hours before discharge home if possible, or promptly after discharge. Administering the first dose before discharge avoids the need to visit a health care facility soon after discharge and may improve adherence.
An infant who has already begun PVZ prophylaxis earlier in the season and is re-hospitalized on a date when a dose is due should receive that dose as scheduled while in hospital, providing the admitting institution is able to supply PVZ when due. Keeping to the child's existing PVZ schedule avoids the need to reschedule appointments and may improve adherence.
PVZ should be discontinued for the season if a child is hospitalized because of RSV infection. Reported rates of second episodes of RSV hospitalization in the same season are very low.
### Additional doses
An additional, or fifth, dose is recommended after surgery requiring cardiac bypass or at conclusion of extracorporeal membrane oxygenation to maintain PVZ levels that may be decreased following these procedures. An additional, or fifth, dose may also be considered in remote northern areas where RSV outbreaks may continue longer than is usual elsewhere.
### Outbreak control
PVZ should not routinely be used to prevent health care-associated RSV infections or to control RSV hospital outbreaks. It may be considered when all other measures to control an RSV outbreak in a NICU have failed.
Vaccination of specific populations
-----------------------------------
### Preterm infants without congenital heart disease or chronic lung disease of prematurity
PVZ is recommended for all infants born at less than 30 weeks gestation and aged less than 6 months at the onset of or during the RSV season.
PVZ may be considered for infants born at 30 to less than 33 weeks gestation and aged less than 3 months at the onset of or during the RSV season if they are at high risk of exposure to RSV from day care attendance or presence of another preschool child or children in the home.
PVZ is not recommended for healthy premature infants born at or after 33 weeks gestation or for infants or siblings of multiple births who do not otherwise have an indication for prophylaxis.
Refer to [Immunization of infants born prematurely](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-5-immunization-infants-born-prematurely.html) in Part 3 for additional information about vaccination of premature infants.
### Chronic lung disease of prematurity and other chronic lung disease
PVZ is recommended for all infants with CLD of prematurity (infants born at less than or equal to 32 weeks gestational age and with need for supplemental oxygen (O2) greater than 21% for at least the first 28 days after birth) who are less than 24 months of age at the onset of the RSV season and have required ongoing supplemental O2 therapy or assisted ventilation in the 6 months prior to the onset of or during the RSV season.
PVZ may be considered for infants less than 24 months of age with severe chronic lung disease of other etiology (e.g., congenital cystic lung disease, chronic interstitial lung disease, congenital lung malformations, congenital airway abnormalities or neuromuscular conditions affecting ability to clear airway secretions) or who require home respiratory support (e.g., supplemental O2, mechanical ventilation, continuous positive airway pressure, tracheostomy) if requiring ongoing supplemental O2 or assisted ventilation in the 6 months prior to the onset of or during the RSV season.
PVZ is not routinely recommended for children less than 24 months of age with cystic fibrosis; however, PVZ may be considered for those less than 24 months of age with cystic fibrosis who have severe chronic lung disease as defined by the need for ongoing supplemental O2 in the 6 months prior to the onset of or during the RSV season.
PVZ is not recommended for the prevention of recurrent wheezing or asthma in the absence of other indications.
Refer to [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional information about vaccination of people with chronic diseases.
### Congenital heart disease and other chronic cardiopathy
PVZ should be offered to infants with hsCHD, as assessed by a paediatric cardiologist, who are less than one year of age at the onset of the RSV season.
PVZ may be considered for infants less than one year of age at the onset of the RSV season who have haemodynamically significant chronic cardiopathy (as assessed by a paediatric cardiologist) of other etiology.
PVZ may be considered for children 12 to 24 months of age at the onset of the RSV season if they are awaiting heart transplantation or have received a heart transplant in the previous 6 months.
For children with both haemodynamically significant heart disease and chronic lung disease, recommendations for chronic lung disease should be followed.
### Down syndrome
PVZ should be offered to children with Down syndrome who qualify for prophylaxis because of hsCHD, CLD, prematurity or immunodeficiency, but should not be routinely offered to all children less than 24 months of age with Down syndrome.
### Immunocompromised children
PVZ may be considered for children less than 24 months of age who are severely immunocompromised (e.g., primary immunodeficiency, cancer chemotherapy). Those with absolute lymphocyte counts of <100 / mm3 may be at higher risk of severe RSV disease.
PVZ prophylaxis has not been evaluated in immunocompromised children. Refer to [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional general information about vaccination of people who are immunocompromised.
### Children residing in remote communities
PVZ should be offered to infants less than 36 weeks gestational age and less than 6 months of age living in remote northern Inuit communities who would require air transport for hospitalization.
PVZ is not routinely recommended for healthy full term infants living in remote northern Inuit communities. PVZ may be considered for these infants if aged less than 6 months and living in a community with a very high RSV hospitalization rate, taking into consideration the burden of illness in the community and need for air transport if hospitalization or specialized ambulatory care is required.
PVZ may be considered for infants less than 36 weeks gestational age and less than 6 months of age living in other remote communities with documented high rates of hospitalization for RSV who would require air transport for hospitalization.
Administration practices
------------------------
### Dose and route of administration
PVZ is given at a dose of 15 mg/kg of body weight by intramuscular injection.
Refer to [Vaccine administration practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for additional information about pre-vaccination and post-vaccination counselling, vaccine preparation and administration technique and infection prevention and control.
### Simultaneous administration with other vaccines
PVZ is a passive immunizing agent directed specifically against RSV. It does not interfere with the immune response to other vaccines. PVZ can be administered at the same time, at a separate site, as other immunization products.
Refer to [Blood products, human immunoglobulin and timing of immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) in Part 1 for additional information.
Storage requirements
--------------------
PVZ is supplied as 50 mg/0.5 mL and 100 mg/1 mL single use vials for injection. It should be stored between 2° C and 8° C in its original container and must not be frozen.
PVZ should be administered immediately after drawing the dose into the syringe. If an entire vial (50 mg or 100 mg) is not required for one child, the residual may be used for another child if it is within 6 hours of opening the vial and if the recommended storage conditions have been met. Open vials containing product not used within 6 hours should be discarded. If feasible, clinics or appointments should be organized to facilitate PVZ vial sharing, to reduce costs and PVZ wastage.
Safety and adverse events
-------------------------
### Common and very common adverse events
The most common adverse events following administration of PVZ are injection site reactions, fever, nervousness or irritability, cough, rhinitis and diarrhea. In randomized control trials the rates of these common adverse events were similar for those receiving PVZ as for those receiving a placebo.
### Uncommon, rare and very rare adverse events
Serious adverse events following administration of PVZ, mostly hypersensitivity reactions, are rare at 1.3 to 3.4 per 10,000 doses administered. Anaphylaxis occurs in approximately 1 per 1 million doses.
### Other safety issues
Repeated injections of a humanized monoclonal antibody have raised concern for the development of immune mediated disease. However, studies have not shown an increased risk of autoimmune disease or atopy in children exposed to PVZ.
### Guidance on reporting adverse reactions following palivizumab administration
To ensure the ongoing safety monitoring of passive immunizing agents, like palivizumab, in Canada, reporting of adverse reactions by health care providers is critical.
When a serious or unexpected adverse reaction follows the administration of a passive immunizing agent such as PVZ, report the adverse drug reaction to the [Canada Vigilance Program](/en/health-canada/services/drugs-health-products/medeffect-canada/canada-vigilance-program.html) using the [Side Effect Reporting Form](/content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/pdf/medeff/report-declaration/ser-des_form-eng.pdf) available on the program web page. The Canada Vigilance Program collects and assesses reports of suspected adverse reactions to health products, including biologics. If PVZ was given along with a routine active immunizing agent, the adverse event(s) should also be reported to the provincial or territorial immunization program.
Refer to [Vaccine Safety and Pharmacovigilance](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) and [Adverse Events Following Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) in Part 2 for additional information on vaccine safety. Refer to [Contents of immunizing agents available for use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for additional information on the components of PVZ.
### Contraindications and precautions
Significant hypersensitivity to PVZ or to any component of PVZ is a contraindication to use of this product. Known hypersensitivity to other humanized monoclonal antibodies is also a contraindication. Minor illnesses such as the common cold, with or without fever, are not contraindications to use of PVZ. Moderate to severe illness, with or without fever, is a reason to consider deferring PVZ to avoid inadvertently attributing possible adverse effects from PVZ to the underlying illness, or vice versa. The decision to delay administration of PVZ will depend on the severity and etiology of the underlying disease.
Chapter revision process
------------------------
This chapter was developed based on current evidence and the National Advisory Committee on Immunization's (NACI) expert opinion. For supporting information, additional references, please refer the related NACI statement: Recommended use of palivizumab to reduce complications of respiratory syncytial virus infection in infants. Future updates to this chapter will follow NACI's review of new RSV immunizing agents when they are approved for use in Canada by Health Canada.
Acknowledgements
----------------
This chapter was based on a NACI statement prepared by D Moore, A Sinilaite, R Stirling, and MW Yeung on behalf of the NACI RSV Working Group. The chapter was prepared by D Moore, F Crane, and C Jensen and reviewed by A Killikelly, W Siu and M Tunis.
NACI gratefully acknowledges the contribution of: M Laplante.
Selected references
-------------------
American Academy of Pediatrics. Respiratory Syncytial Virus. In: Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH (Eds). Redbook: 2021 Report of the Committee on Infectious Diseases. Itasca IL. American Academy of Pediatrics: 2021. (pp 628-636).
AstraZeneca Canada Inc. Product Monograph - SYNAGIS® July 9, 2021.
Centers for Disease Control and Prevention. Respiratory Syncytial Virus Infection (RSV). Last reviewed: October 28, 2022. Accessed November 25, 2022 from https://www.cdc.gov/rsv/
Health Canada. Canada Vigilance Program. Accessed: December 02, 2022 from https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/canada-vigilance-program.html
National Advisory Committee on Immunization. An Advisory Committee Statement: Recommended use of Palivizumab to Reduce Complications of Respiratory Syncytial Virus Infection in Infants. June 1, 2022. Accessed November 25, 2022 from https://www.canada.ca/content/dam/phac-aspc/documents/services/publications/vaccines-immunization/palivizumab-respiratory-syncitial-virus-infection-infants/palivizumab-resp-infection-infants-eng.pdf
Public Health Agency of Canada. Respiratory Viruses Detections in Canada. Accessed December 2022 from: https://www.canada.ca/en/public-health/services/surveillance/respiratory-virus-detections-canada.html
Schanzer DL, Saboui M, Lee L, Nwosu A, Bancej C. Burden of influenza, respiratory syncytial virus, and other respiratory viruses and the completeness of respiratory viral identification among respiratory inpatients, Canada, 2003-2014. Influenza Other Respi Viruses. 2017;00:1–9. https://doi.org/10.1111/irv.12497
Shi T, McAllister DA, O'Brien KL, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. The Lancet. 2017 Sep 2;390(10098):946-58. doi: 10.1016/S0140-6736(17)30938-8.
Shi T, Denouel A, Tietjen AK, et al. Global Disease Burden Estimates of Respiratory Syncytial Virus-Associated Acute Respiratory Infection in Older Adults in 2015: A Systematic Review and Meta-Analysis. J Infect Dis. 2020 Oct 7;222:S577-S583. doi: 10.1093/infdis/jiz059.
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-08-04
| None | None |
81c29aa149cd22be79aee2ce801a5c2301f29306 | cma | Supplemental Statement – Mammalian Cell Culture-Based Influenza Vaccines | Supplemental Statement – Mammalian Cell Culture-Based Influenza Vaccines
Preamble
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC’s Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Summary of the information contained in this NACI supplemental statement
The following highlights key information for immunization providers. Please refer to the remainder of the Statement for details.
1. What
Flucelvax® Quad is a mammalian cell culture-based, inactivated seasonal influenza vaccine that has recently been authorized for use in Canada in adults and children ≥9 years of age.
2. Who
This supplemental statement addresses the annual influenza vaccination of adults and children who do not have contraindications for the influenza vaccine.
3. How
Flucelvax® Quad may be considered among the quadrivalent influenza vaccines offered to adults and children ≥9 years of age for their annual influenza vaccination.
4. Why
Flucelvax® Quad is considered effective, immunogenic, and safe in adults and children ≥9 years of age, and has a comparable immunogenicity and safety profile to egg-based influenza vaccines already licensed in Canada and Flucelvax®, which is a trivalent cell culture-based influenza vaccine that has been licensed in the United States, but for which licensure has never been sought in Canada. Flucelvax® Quad can provide broader protection against influenza B viruses when compared with trivalent influenza vaccines.
I. Introduction
Influenza is a viral infection that is estimated to cause approximately 12,200 hospitalizations and 3,500 deaths in Canada annually. Influenza in humans is caused by two main types of influenza virus: A, which is classified into subtypes based on hemagglutinin (HA) and neuraminidase (NA) surface proteins, and B, which consists of two antigenically distinct lineages, B/Yamagata and B/Victoria. Seasonal influenza vaccines are either trivalent or quadrivalent formulations. Trivalent influenza vaccines contain two influenza A and one influenza B strain, and quadrivalent influenza vaccines contain the three strains included in trivalent vaccines and an additional influenza B strain from the other lineage of influenza B. Each year, the National Advisory Committee on Immunization (NACI) publishes a statement on seasonal influenza vaccines, which contains recommendations and guidance on the use of influenza vaccines for the upcoming influenza season.
Influenza vaccine production using mammalian cell culture-based technology is an innovative technique that may offer enhanced manufacturing scalability and sterility and, thus, a potentially valuable alternative to overcome some of the problems and vulnerabilities associated with egg-based production,,,. Cell culture systems are more rapid, and robust, and produce yields with higher purity and a lower risk of production failure compared to standard egg-based manufacturing. The production timeline for the manufacturing of cell culture-based vaccines is more flexible compared to egg-based production because cells are frozen and banked, and virus amplification relies primarily on the capacity of bioreactors,,. The use of cell-culture technology for the manufacturing of influenza vaccines offers the additional advantages of reduced microbial or chemical contamination due to a closed system of vaccine production. There is also potentially higher vaccine effectiveness relative to standard egg-based influenza vaccines due to insulation from egg-adaptive mutations changes, and there is potential for quicker large-scale production of vaccine,,,,. However, at the time of statement development, there is a lack of infrastructure and experience with the cell culture-based production platform for influenza vaccines and the resulting cost of these vaccines is typically greater compared to vaccines made using egg-based manufacturing.
Flucelvax® Quad (Seqirus, Inc.) is a mammalian cell culture-based quadrivalent inactivated, subunit influenza vaccine (IIV4-cc) that was authorized for use in Canada in adults and children 9 years of age and older on November 22, 2019. Flucelvax® Quad (also licensed as Flucelvax® Quadrivalent or Flucelvax® Tetra in other jurisdictions) is prepared from viruses propagated in mammalian cell lines adapted to grow freely in suspension in culture medium. The authorization of Flucelvax® Quad triggered the need for a supplemental NACI statement as it is the first and only available mammalian cell culture-based influenza vaccine in Canada, and NACI has not previously made a recommendation on cell culture-based influenza vaccines in any population.
Flucelvax® Quad builds on the clinical development of its trivalent predecessor, Flucelvax® (registered as Optaflu® in the European Union, Australia and Switzerland), a cell culture-grown, inactivated influenza vaccine developed by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus, Inc.). Flucelvax® was the first mammalian cell culture-derived inactivated influenza vaccine. It was approved for use in adults in Europe, under the trade name Optaflu®, from 2007 to 2017, and in the US under the trade name Flucelvax® since 2012. Originally, the same egg-derived candidate vaccine viruses (CVVs) used in egg-based manufacturing, but grown in cultured mammalian cells, were used in the production of Flucelvax®. On August 31, 2016, Seqirus, Inc. received approval from the US Food and Drug Administration (FDA) for the use of CVVs that had been isolated and propagated in MDCK cells for the manufacture of cell culture-based inactivated quadrivalent influenza vaccine. This approval enabled the production of completely cell-derived influenza vaccine viruses from the initial virus isolation through to the full manufacture of the vaccine. The Flucelvax® Quadrivalent vaccine (US product) for the 2017–2018 influenza season was the first vaccine to be manufactured from A(H3N2) CVVs produced exclusively using the cell-derived method, while the A(H1N1) and the B strain CVVs were egg-derived . For the 2018–2019 Flucelvax Quadrivalent vaccine, the A(H3N2) and B strain CVVs were derived from the mammalian cell line, while the A(H1N1) CVVs remained egg derived. The Flucelvax® quadrivalent formulation for the 2019–2020 influenza season was manufactured using CVVs for all four influenza viruses that were derived solely from mammalian cell lines. It has been hypothesized that propagation of CVVs in mammalian cells may improve vaccine effectiveness relative to licensed egg-based influenza vaccines by reducing the risk of antigenic drift and changes acquired in the HA of human influenza viruses during isolation, adaptation, and propagation in eggs,,.
Guidance Objective
The objective of this advisory committee supplemental statement is to review the evidence for efficacy, effectiveness, immunogenicity, and safety that is available for Flucelvax® Quad, and to provide guidance on its use in Canada in adults and children.
II. Methods
In brief, the broad stages in the preparation of a NACI Advisory Committee Statement are:
1. Knowledge synthesis of the whole body of evidence on benefits and harms, considering the quality of the evidence and magnitude of effects observed.
2. Translation of evidence into recommendations
Further information on NACI’s evidence-based methods is available in: .
A systematic literature review was conducted to accumulate evidence for NACI’s recommendations regarding the use of Flucelvax® Quad, which is licensed for adults and children ≥9 years of age in Canada. Mammalian cell culture-based influenza vaccines have been approved for use by the US FDA in adults and children 4 years or older since the 2013-2014 influenza season (6 years) and effectiveness, immunogenicity, and safety data is currently available for this age group. The systematic review methodology was developed with the NACI Influenza Working Group (IWG) and specified a priori in a written protocol that included review questions, search strategy, inclusion and exclusion criteria, and quality assessment.
# Research question
What are the vaccine efficacy, effectiveness, immunogenicity, and safety of Flucelvax® Quad in persons 4 years of age and older?
P (population):
Children and adults (≥4 years of age)
I (intervention):
Mammalian cell culture-based influenza vaccine
C (comparison):
Egg-based, standard-dose quadrivalent inactivated influenza vaccine (IIV4-SD), trivalent, standard dose inactivated influenza vaccine (IIV3-SD), high-dose (IIV3-HD) or adjuvanted trivalent inactivated influenza vaccine (IIV3-Adj), mammalian cell culture-based trivalent inactivated, subunit influenza vaccine (IIV3-cc), placebo, or no comparator
O (outcomes):
Efficacy, effectiveness, immunogenicity, safety
The search strategy was developed based on the research question and PICO illustrated above, in conjunction with a librarian from the Health Library of Health Canada and PHAC (search strategy available upon request). The EMBASE, MEDLINE, Scopus, ProQuest Public Health, and ClinicalTrials.gov, electronic databases were searched for primary research articles and case reports from inception until February 12, 2019. Registered clinical trials and grey literature from international public health authorities and National Immunization Technical Advisory Groups were also considered. Searches were restricted to articles published in English and French due to the language proficiencies of the reviewers. Additionally, hand-searching of the reference lists of included articles was performed by one reviewer to identify additional relevant publications. Two reviewers independently screened the titles and abstracts of records retrieved from the database searches for potential eligibility. The full-texts of records deemed potentially eligible were obtained and further reviewed by both reviewers for potential inclusion in the review. Refer to Appendix A for the PRISMA Flow Diagram.
One reviewer extracted data from the studies included for review into an evidence table using a piloted data abstraction template designed to capture information on study design, population and outcomes of interest. A second reviewer independently validated the abstracted data with any disagreements or discrepancies resolved by discussion and consensus. The level of evidence (i.e. study design) and methodological quality of included studies was assessed independently by two reviewers using the design-specific criteria outlined by Harris et al.(2001), which has been adopted by NACI for rating the internal validity of individual studies. Any disagreements or discrepancies in the data extraction and quality appraisal were resolved by discussion and consensus. The knowledge synthesis was performed by AS and JP, and was supervised by the Influenza Working Group (IWG).
Studies were included if they met the following criteria:
1. The study population or subpopulation consisted of individuals ≥4 years of age; and
2. Study assessed efficacy and effectiveness, immunogenicity, or safety of Flucelvax® Quad or safety of Flucelvax®
3. Primary research studies from peer-reviewed scientific literature
4. Case reports and case series
5. Registered clinical trials and grey literature from international public health authorities
6. Study is published in English or French
Studies were excluded if they met one or more of the following criteria:
1. The study did not present data on any of: the efficacy, effectiveness, immunogenicity, or safety of Flucelvax® Quad, or the safety of Flucelvax®;
2. The study is in a language other than English or French;
3. The study is a non-human or in vitro study;
4. The article is not a primary research study;
5. The article is an editorial, opinion, commentary or news report;
6. The article is an economic study, clinical practice guidelines, consensus conference, health technology assessment report; or
7. The article was a doctoral dissertation, master’s thesis, or conference summary
Flucelvax® Quad has overlapping composition with Flucelvax® (the trivalent formulation) and is produced using the same MDCK manufacturing platform,. Therefore, studies that assessed the safety of Flucelvax® were also included in this literature review post hoc to supplement the evidence base for the safety outcome. Specialty trivalent vaccines (i.e., high-dose trivalent inactivated influenza vaccine (IIV3-HD) and adjuvanted trivalent inactivated influenza vaccine (IIV3-Adj) were also added as comparator vaccines post hoc, since these comparisons would originally have been excluded as there is currently no comparable quadrivalent formulation of these vaccines.
# Development of Recommendations
Following critical appraisal of individual studies, summary tables with ratings of the quality of the evidence using NACI's methodological hierarchy ( and ) were prepared, and proposed recommendations for vaccine use were developed. The evidence and proposed recommendations were discussed by the IWG in July 2019 and the NACI Vaccine Safety Working Group in August 2019. The IWG Chair and the Public Health Agency of Canada (PHAC) technical advisor (AS) presented the evidence and proposed recommendations to NACI on September 25, 2019. Following thorough review of the evidence, NACI approved the recommendation contained in this statement on December 16, 2019. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the following sections.
III. Vaccine
# III.1 Mammalian Cell Culture-Based Influenza Vaccine Preparation Authorized for Use in Canada
Flucelvax® Quad is a subunit influenza vaccine prepared from CVVs isolated and propagated in a MDCK cell line. It is authorized for intramuscular (IM) injection and is available as a 0.5 mL single-dose, pre-filled syringe without a needle, and as a 5 mL multi-dose vial containing 10 doses (each dose is 0.5 mL). For more information on Flucelvax® Quad, refer to the product monograph.
Each dose may also contain residual amounts of:
# III.2 Vaccine Efficacy and Effectiveness
No efficacy studies for Flucelvax® Quad were identified and studies evaluating the efficacy of Flucelvax® were beyond the scope of this review.
Four studies, two peer-reviewed and two not peer-reviewed were identified that assessed the effectiveness of Flucelvax® Quad,,,. Of these four studies, two were of good quality,, while the quality of the other two studies,,, could not be assessed because they were published as conference abstracts or posters. Common concerns relating to the quality of evidence included potential residual or unmeasured confounding even after statistical adjustments,,, and exposure and outcome misclassification,,. The following section outlines the key effectiveness findings from all these studies; additional details regarding study characteristics and results are shown in .
## III.2.1 Effectiveness against Influenza Infection
Two studies assessed the vaccine effectiveness (VE) of IIV4-cc compared to egg-based IIV against laboratory-confirmed influenza infection during the 2017–2018 influenza season in the USA. The first was a peer-reviewed study by DeMarcus et al. (2019), which used test-negative case-control design and was conducted by the US Department of Defense Global Respiratory Pathogen Surveillance Program. The DeMarcus et al. (2019) study included Department of Defense (DoD) healthcare beneficiaries (excluding service members) 6 months–94 years of age (median age: 13 years) who presented to a military treatment facility with symptoms of influenza-like illness (ILI) and had a respiratory specimen collected between October 1st 2017–April 28 2018. Individuals testing positive for influenza by reverse transcription polymerase chain reaction (RT-PCR) or viral culture, were classified as cases, while influenza-negative individuals were classified as controls. The second study by Klein at al. (2018), which was not peer-reviewed, is a retrospective cohort analysis of VE against PCR-confirmed influenza A(H3N2) influenza virus infection among Kaiser Permanente Northern California members aged 4–64 years .
The results from the study by DeMarcus et al. (2019) indicated that the odds of having any laboratory-confirmed influenza infection were not statistically significantly different between individuals who had received IIV4-cc and those who received egg-based IIV (trivalent or quadrivalent formulation). The authors conducted sub-analyses by influenza subtype and by age group, and found that the odds of having influenza A(H1N1)pdm09 infection were higher overall for all DoD dependents (odds ratio . The odds of having influenza A(H3N2) infection appeared to be lower overall and for adults who received the IIV4-cc compared to egg-based IIV, but the results did not reach statistical significance. All other estimates showed no statistically significant difference between the two vaccine types.
The results from the study by Klein et al. indicated that both IIV4-cc and egg-based IIV . The adjusted absolute VE for subjects vaccinated with IIV4-cc was 30.2% (95% CI: 17.1–41.3%; P<0.0001) and 17.9% (95% CI: 12.1–23.3%; P<0.0001) for subjects vaccinated with either egg-based IIV4 or IIV3.
## III.2.2 Effectiveness against Influenza-Related Health Care Interactions
One study by Izurieta et al. (2018) assessed the VE of IIV4-cc compared to 4 other egg-based influenza vaccines (egg-based, standard-dose quadrivalent IIV (IIV4-SD), egg-based IIV3, egg-based IIV3-Adj, and egg-based IIV3-HD) in preventing influenza-related health care interactions (i.e. office visits and hospital encounters). Influenza-related office visits were defined as community-based visits to physicians’ offices and hospital outpatient visits in which a rapid influenza test was performed by the healthcare provider and a therapeutic course of oseltamivir (75 mg twice daily for 5 days) was prescribed within 2 days following the test. Hospital encounters were defined as inpatient hospitalizations and emergency department visits in which International Classification of Diseases (ICD), Tenth revision, Clinical Modification, code for influenza was listed. This retrospective cohort study made use of electronic medical records (EMRs) providing data on enrolment in fee-for-service Medicare parts A and B in the 6 months before vaccination, inpatient and outpatient care, physician office visits, and prescription drugs for Medicare beneficiaries ≥65 years of age who received an influenza vaccine during the 2017–2018 influenza season(16). Estimates were adjusted using inverse probability of treatment weighting, and weights were derived from propensity scores. Relative vaccine effectiveness (rVE) was defined as the difference in influenza-related hospital encounters between persons vaccinated with IIV4-cc versus egg-based vaccines.
In a 2-way comparison, IIV4-cc was statistically significantly more effective against office visits (rVE): 10.5%; 95% CI: 6.8%–14.0%) and hospital encounters (rVE: 10.0%; 95% CI: 7.0%–13.0%) than egg-based, IIV4-SD. In an analysis comparing this vaccine to four other egg-based formulations, IIV4-cc was statistically significantly (P≤0.05) more effective against office visits compared to egg-based IIV4-SD and IIV3-Adj, and against inpatient stays and hospital encounters, compared to egg-based IIV3-SD, IIV4-SD, and IIV3-Adj. In addition, IIV4-cc was statistically significantly more effective against office visits compared to egg-based IIV3-HD, but not against inpatient visits or hospital encounters.
## III.2.3 Effectiveness against Influenza-Like Illness
One study that was recently accepted for publication assessed the effectiveness of Flucelvax® Quadrivalent for the prevention of ILI. Boikos et al. (2018) conducted a retrospective cohort study in the US during the 2017–2018 influenza season to determine the relative VE (rVE) of Flucelvax® Quadrivalent to standard-dose quadrivalent egg-based inactivated influenza vaccines against ILI in individuals ≥4 years of age. The rVE estimates were based on real-world primary care data from the EMRs of individual patients 4 years of age and older who were vaccinated with either Flucelvax® Quadrivalent (n= 92,192) or egg-based IIV4-SD (n=1,255,983). Results demonstrated that Flucelvax® Quadrivalent was statistically significantly more effective than egg-based IIV4-SD in preventing ILI. The estimate for rVE against ILI was 36.2% (95% CI: 26.1–44.9%; P<0.001) after adjusting for differences in age, sex, health status, and geographic region between the two exposure groups. The result from a sensitivity analysis using propensity scores was consistent in terms of direction and statistical significance compared to the adjusted estimate (propensity-score matched rVE: 19.3%; 95% CI: 9.5–28.0%). When stratified by age, however, Flucelvax® Quadrivalent was statistically significantly more effective than egg-based IIV4-SD in preventing ILI in adults aged 18–64 years (propensity-score matched rVE: 26.8%; 95% CI: 14.1–37.6%; P<0.001), but did not reach statistical significance in children 4-17 years of age (propensity-score matched rVE: 18.8 %; 95% CI: -53.9-57.2%) or adults 65 years of age or older (propensity-score matched rVE: -7.3 %; 95% CI: -51.6-24.0%).
# III.3 Immunogenicity
Regulators in Canada, the US, and Europe accept non-inferiority immunogenicity trials that compare the hemagglutination inhibition (HI) antibody response of the new vaccine to that of an existing licensed vaccine, or placebo-controlled immunogenicity trials that assess the HI antibody response to the new vaccine. Non-inferiority and placebo-controlled immunogenicity trials are often considered sufficient by regulatory authorities when there are bridging data to correlate immunogenicity outcomes to clinical protection, or when the new vaccines are considered by the regulators to be very similar to vaccines already authorized. Serological assessments based on the geometric mean titres (GMTs) of HI antibody that are used by regulators are: GMT ratio, seroprotection rate, and seroconversion rate. The FDA has published definitions for these serological assessments and criteria for immunogenicity data necessary for influenza vaccine licensure. These definitions and currently used criteria are shown in . Correlates of protection that are not based on HI antibody titres have not been well established.
Two studies, that assessed the immunogenicity of Flucelvax® Quad compared to different IIV3-cc (Flucelvax, Seqirus, Inc.) formulations were identified in this review; one study by Bart et al. (2016) was conducted with adult subjects 18 years of age and older, while the other study by Hartvickson et al. (2015) focused on pediatric subjects 4 to 17 years of age. Additional details on the immunogenicity findings from these studies are shown in . The adult randomized controlled trial (RCT) was of good quality overall. One methodological concern identified was that the study did not examine the subjects’ vaccination history from previous seasons. The pediatric study was of fair quality, as subjects’ HI titre was measured at different times, depending on whether the subject had been vaccinated previously or not.
Although no studies that assessed the immunogenicity of Flucelvax® Quad compared to egg-based IIV (trivalent or quadrivalent) were identified, non-inferiority of its trivalent predecessor, Flucelvax®, compared to egg-based IIV3 has been established in adult and pediatric subjects,,,.
## III.3.1 Immunogenicity in Adults
Bart et al. (2016) conducted a Phase III, double-blind, RCT study to assess the immunogenicity of Flucelvax Quad compared to two IIV3-cc (Flucelvax®; Seqirus), which contained either an influenza B/Victoria or B/Yamagata lineage strain, in healthy adults ≥18 years of age. The study compared the GMT ratio, seroprotection rate, and seroconversion rate in the control and intervention groups 22 days after vaccination. Flucelvax® Quad demonstrated non-inferiority to the two IIV3-cc in the HI antibody responses against influenza A(H1N1), A(H3N2), and the B lineage contained in the trivalent vaccines, based on GMT ratio and seroconversion rates. Flucelvax Quad demonstrated superiority for the influenza B lineage that was not included in the IIV3-cc. In a sub-analysis, Flucelvax® Quad also met the threshold for non-inferiority based on seroprotection rate for adults 18–64 years of age and ≥65 years of age.
## III.3.2 Immunogenicity in Children
Hartvickson et al. (2015) conducted a RCT study comparing the immunogenicity of Flucelvax® Quad to two formulations of IIV3-cc (Flucelvax®), containing either an influenza B/Victoria or B/Yamagata strain, in healthy children 4–17 years of age. Children <9 years of age who were not previously vaccinated received two doses of influenza vaccine (n=694). The study compared the GMT, seroprotection rate, and seroconversion rate in the control and intervention groups on day 22 post-vaccination for those who had been previously vaccinated and on day 50 for those that had not been previously vaccinated. Flucelvax® Quad met non-inferiority criteria for all four influenza strains contained in the IIV3-cc vaccines in healthy children aged 4–17 years. Flucelvax® Quad also demonstrated superiority for both influenza B strains over the unmatched B lineage included in the comparator IIV3-cc. Flucelvax® Quad also met the threshold for seroprotection for all strains.
The immunogenicity for Flucelvax® Quad is supported by evidence from the clinical development program for Flucelvax® (trivalent formulation), which has been licensed in the US and produced using the same MDCK manufacturing platform ,,,. Flucelvax® has demonstrated non-inferiority to standard egg-based IIV3 comparators, including Agrippal® (Seqirus; marketed in Canada as Agriflu®) and Fluvirin® (GSK), for HI antibody responses overall to any strain in adults ≥18 years of age and for A(H1N1) and B strains specifically, but not A((H3N2), for persons 4 to 17 years of age, based on post-vaccination GMT ratios and seroconversion rates ,,,.
# III.4 Safety
This review identified two peer-reviewed studies, that assessed the safety of Flucelvax® Quad; both studies were RCTs with one focused on healthy adults and the other on healthy children. For both of these studies, the safety outcomes assessed included solicited local and systemic adverse events (AE) from day 1–7 post-vaccination, serious adverse events (SAE) through 6 months after the last vaccination, and unsolicited AEs from day 1–23 post-vaccination. No studies that assessed the safety of Flucelvax® Quad compared to egg-based IIV (trivalent or quadrivalent) were identified in this review.
Flucelvax® Quadrivalent has been licensed in the US for use in adults and children 4 years or older in since 2016. Since authorization, no safety signals have been identified through routine pharmacovigilance. AE that have been reported during post-licensure use of Flucelvax® Quadrivalent in the US include, allergic or acute hypersensitivity reactions, nervous system disorders (syncope, presyncope, paresthesia), generalized skin reactions (pruritus, urticaria or non-specific rash), and extensive swelling of injected limb. However, a reliable estimate of the frequency of these reactions is not available and no definitive causal link to vaccination with Flucelvax® Quadrivalent has been established.
In addition, six peer-reviewed clinical studies, ,,,,and one clinical review of cases that assessed the safety of Flucelvax® were included in this review, four of which assessed safety in adults and two of which assessed safety in children. The safety evidence for Flucelvax® (trivalent) was considered relevant, as although licensure for Flucelvax® has never been sought in Canada, Flucelvax® and Flucelvax® Quad have overlapping compositions and are produced using the same MDCK manufacturing platform. In addition to these six published studies, it should be noted that Flucelvax® has an established record of safety in other jurisdictions, and no new safety signals have been identified through routine pharmacovigilance in the USA or Europe where the vaccine has been licensed,,.
Additional details on the safety evidence presented in this review are shown in . No published clinical data pertaining to safety of vaccination with IIV4-cc or IIV3-cc during pregnancy is currently available to inform vaccine-associated risks.
## III.4.1 Adverse Events in Adults
Bart et al. (2015) assessed the safety of Flucelvax® Quadrivalent in healthy adults 18–64 years of age and older adults ≥65 years of age compared to two IIV3-cc produced using the same cell culture-based manufacturing process. Across the three vaccine groups, a similar proportion of adults reported at least one solicited AE. The reported solicited local and systemic AE were generally mild to moderate in intensity, self-limited, and did not precipitate sequelae. There were also no major differences in the percentages of all adults (≥18 years of age) who reported unsolicited AE . Subgroup analyses based on age, sex, and race or ethnicity did not reveal any major variations in the AE profiles of the three vaccine groups in this study.
### Solicited adverse events
Injection site pain was the most common solicited AE and was reported by 33.6% of adults in the IIV4-cc group, 27.8% in the IIV3-cc (B/Yamagata) group, and 29.4% in the IIV3-cc (B/Victoria) group. Although a slightly higher percentage of adults (0.2%) in the IIV4-cc group reported severe pain compared to the IIV3-cc groups (0.1%), the proportion of adults experiencing other solicited local AE was comparable between the different groups overall. Notably, one case of severe ecchymosis and one case of severe induration were identified after vaccination with IIV3-cc (B/Yamagata). Fatigue and headache were the most common solicited systemic AE experienced by adults in this study. Within the IIV4-cc group, 13.5% of subjects reported fatigue and 14.0% reported headaches. A similar proportion of adults in the IIV3-cc groups experienced fatigue (IIV3-cc (B/Yamagata): 16.3%; IIV3-cc (B/Victoria): 12.2%) and headaches (IIV3-cc (B/Yamagata): 13.4%; IIV3-cc (B/Victoria): 13.4%). The incidence of severe systemic AEs was very low (<1%) overall. Only 15 subjects across the three vaccine groups reported experiencing fever following vaccination; however, the fever did not exceed 40°C in any of these cases. Across studies that assessed the safety of IIV3-cc compared to egg-based IIV3 Agrippal® (marketed in Canada as Agriflu®), pain and redness at the injection site were the most common local adverse reactions, while headache, myalgia, malaise, and fatigue were the most common systemic adverse reactions observed across the different age groups,,. Overall, the local and systemic solicited reactions as well as unsolicited AE and SAE were comparable to those typically observed with other injectable influenza vaccines,,. None of the deaths or SAEs reported over the course of these IIV3-cc studies were assessed as vaccine related ,,.
### Unsolicited adverse events and serious adverse events
The percentages of unsolicited AEs and medically attended AEs in the Bart el. al study were somewhat higher in adults ≥65 years of age compared to adults 18–64 years of age; however, these two age groups demonstrated a similar incidence of possibly vaccine-related AEs. New onset of chronic diseases (NOCD), specifically metabolic and nutritional disorders, cardiac disorders, and musculoskeletal and connective tissue disorders, were reported by 4.4% of study participants; however, there were no significant differences between vaccine groups or age groups. No indication of new onset of neurologic disorders, increased frequency of specifically monitored SAEs, or other safety signals was identified among IIV4-cc recipients. Over the course of this study, 12 deaths were reported (5 in the IIV4-cc group and 7 in the IIV3-cc groups) . The proportion of participants who died during the course of the study was similar across vaccine groups in both the 18–64 age group (IIV4-cc: 0%; IIV3-cc (B/Yamagata): 0%; IIV3-cc (B/Victoria): 0.3%) and the ≥65 age group (IIV4-cc: 0.8%; IIV3-cc (B/Yamagata): 1.5%; IIV3-cc (B/Victoria): 0.3%). None of the SAEs orAEs leading to premature withdrawal or deaths were considered to be vaccine-related by the sponsor. The proportion of adults who experience unsolicited AEs and SAEs were comparable to those typically observed with other injectable influenza vaccines. This review also identified a case report of a 55-year-old woman with multiple comorbidities, who developed optic neuropathy and severe visual impairment in the right eye following vaccination with Flucelvax®. In this case, progressive unilateral optic neuritis occurred secondary to a systemic reaction involving a wide range of symptoms that began two days after influenza vaccination. However, it should be noted that there was no definitive link established between this very rare serious adverse reaction and vaccination with IIV3-cc.
A clinical review of post-licensure surveillance data from the Vaccine Adverse Event Reporting System (VAERS), which closely monitors anaphylaxis events related to newly licensed vaccines prerecommended for use in the US, found that the crude reporting rate for hypersensitivity reactions among reports of AEs in adults aged ≥18 years who were vaccinated with Flucelvax® (IIV3-cc) during the first two influenza seasons of distribution (2013–2014 and 2014–2015) was similar to or less than what has been observed for other influenza vaccines (12.7 cases per million doses distributed). Two reports of anaphylactic reactions were identified; one report met Brighton Collaboration criteria level 2, and the second report did not meet Brighton criteria but was diagnosed by the attending physician as an anaphylactic reaction. Notably, a causal association with IIV3-cc has not been established for these two anaphylaxis reports. The crude reporting rate for anaphylaxis over these 2 years was 0.4 per million doses distributed; however, estimates for crude reporting rates for hypersensitivity reactions and anaphylaxis should be interpreted with caution given the uncertainties regarding the completeness, quality, and consistency of the data reported to VAERS and the use of doses distributed as a denominator.
## III.4.2 Adverse Events in Children
Hartvickson et al. (2015) assessed the safety of Flucelvax® Quad in healthy children aged 4–18 years of age compared to two IIV3-cc (Flucelvax®): one containing an influenza B/Yamagata lineage and one containing a B/Victoria lineage. Most solicited adverse reactions among those receiving Flucelvax® Quad were mild in severity, and all resolved within a few days without sequelae. The rates and types of unsolicited AEs in children who received IIV4-cc or a comparator IIV3-cc were comparable to those typically seen with routine childhood vaccinations .
### Solicited adverse events
Across all vaccine groups in the Hartvickson et al. (2015) study, the most common solicited local AE was tenderness for children 4–5 years of age, and injection-site pain for children 6–8 and 9–17 years of age. The proportion of children who experienced solicited local AEs were similar for the intervention and control groups across all ages. The largest difference in proportion between vaccine groups was for children 4–5 years of age reporting local AEs; 53% of children in the IIV4-cc group reported unsolicited local AEs compared to 44% and 36% in the IIV3-cc (B/Yamagata) and IIV3-cc (B/Victoria) groups respectively. For children <9 years of age who received a second dose, the proportions of solicited local AEs were also similar across study groups. In general, of the children that received two doses, there was a higher proportion of local AEs after the first dose compared to the second. The most common solicited systemic AEs were sleepiness for children 4–5 years of age, fatigue for children 6–8 years of age, and headache for children 9–17 years of age across all vaccine groups. Among children 6–8 years of age, the proportion of children who reported solicited systemic AEs was generally higher after the first vaccination compared to the second vaccination. However, children 4–5 years of age demonstrated a 1–3% increase in the percentage of solicited systemic AEs after the second vaccine dose in each of the vaccine groups.
Two studies, that assessed the safety of IIV3-cc compared to a standard egg-based IIV3 (Fluvirin®; licensed in the US but not available in Canada) in healthy children were identified in this review. Vesikari et al. (2012) found that the most common local AE among children 3–8 and 9–17 years of age was injection site pain, and the most common systemic AE were myalgia and headache . Nolan et al. (2016) assessed the safety of IIV3-cc in healthy children and adolescents 4-17 years of age stratified into two cohorts (4–8 year-olds and 9–17 year-olds). Children 4-8 years of age who were not previously vaccinated received two doses of influenza vaccine. The proportion of children in the 4-8 year-old age group who were not previously vaccinated and experienced solicited local and systemic AEs was similar for the intervention and control groups after the second vaccination. For previously vaccinated children 4-17 years of age who received a single dose, the proportions of solicited local AEs were similar to not previously vaccinated children 4-8 years of age. Overall, no important differences in safety outcome were identified between children who had received the IIV3-cc and the egg-based IIV3 ,.
### Unsolicited adverse events and serious adverse events
The proportion of reported unsolicited AE was similar in the three vaccine groups in the Hartvickson et al. (2015) study, and ranged from 24–27%. Approximately 1% of children 4–17 years of age experienced any SAE in all study groups. New onset of chronic diseases was reported in 2% of study participants in each of the vaccine groups. No deaths were reported over the course of the study and none of the SAEs were considered to be related to the vaccine.
Vesikari et al. (2012) and Nolan et al. (2016) assessed the safety of IIV3-cc compared to egg-based IIV3 (Fluvirin). Unsolicited AEs occurred in 1-4% of subjects across age and vaccine groups in the Vesikari et al. (2012) study and 0 to <1% were considered at least possibly related to the study vaccines. There were no deaths reported over the course of Vesikari et al. (2012) study and none of the 28 SAEs (4 during the post-vaccination period, 24 during the 6-month safety follow-up period) documented in the study were assessed as vaccine related. No deaths or vaccine-related SAEs were reported in Nolan et al. (2016) study and one of the withdrawals from the study was due to a non-serious AE.
# IV. Discussion
The present systematic review examined studies investigating the effectiveness, immunogenicity, and safety of Flucelvax® Quad, the first mammalian cell culture-based seasonal influenza vaccine to be approved for adult and pediatric use in Canada. The peer-reviewed published evidence on the effectiveness of Flucelvax® Quad manufactured from CVVs produced solely using the cell-derived method is sparse. Four observational VE studies, two peer-reviewed and two not peer-reviewed, were identified in this review. There was some data indicating that Flucelvax® Quad may potentially offer improved protection against influenza compared to egg-based IIV4 or IIV3, particularly against A(H3N2) virus infection. However, interpretation of the data from these observational studies is limited as all the analyses were conducted using data only from the 2017–2018 influenza season in the US, which was influenza A(H3N2)-dominant. Furthermore, two of the retrospective studies,, evaluating VE utilized real-world primary care data from the EMRs of individual patients. This approach for influenza VE estimation has not yet been validated and the potential sources of bias and confounding still need to be further investigated.
Two RCTs conducted in adults and children 4 years of age and older, that specifically assessed the immunogenicity and safety of Flucelvax® Quad were identified in this review. However, both studies used Flucelvax® IIV3-cc (produced by Seqirus using the same cell culture-based manufacturing process) as the comparator and were conducted during the 2013–2014 influenza season, which was prior to the FDA’s supplemental approval for the use of CVVs that had been isolated and propagated in MDCK cells for the manufacture of cell culture-based influenza vaccines. In both studies, Flucelvax® Quad demonstrated non-inferiority, based on GMT ratio and seroconversion rates, and met the threshold for seroprotection for all influenza strains contained in the IIV3-cc vaccines. The immunogenicity evidence for Flucelvax® Quad builds on the clinical development program of Flucelvax® IIV3-cc, noting that authorization for Flucelvax® (trivalent) has never been sought in Canada. Flucelvax® has demonstrated non-inferiority to licensed egg-based IIV3 comparators in for all strains in adults ≥18 years of age and A/H1N1 and B strains but not the A/H3N2 influenza strain for persons 4 to 17 years of age. Notably, Flucelvax® IIV3-cc was manufactured using egg-derived CVVs prior to the implementation of manufacturing methods using CVVs solely derived from MDCK cells.
This review also examined studies, ,,,, that assessed the safety of Flucelvax®, which is a trivalent vaccine produced using the same cell culture-based manufacturing platform, to supplement the evidence base for safety. These studies found that IIV-cc are a safe, well-tolerated, and immunogenic alternative to conventional egg-based influenza vaccines for children and adults. There is a theoretical concern that inactivated influenza vaccines produced in canine kidney cells (MDCK 33016-PF) may cause adverse reactions in individuals with dog allergy. This issue has been investigated in two in vitro studies, which used biological assays to evaluate the potential allergenicity of MDCK cell-based vaccines ,. The results of these studies suggest that influenza vaccines produced in MDCK cells do not have the potential to trigger hypersensitivity reactions in individuals with documented allergies associated with dogs. In addition, there has been no signal of an elevated risk of severe allergic reactions as compared to egg-based influenza vaccines identified through IIV-cc clinical trials or post-market safety surveillance,.
Influenza vaccine production using mammalian cell culture-based technology may offer enhanced manufacturing scalability, sterility, timeliness, and flexibility compared to traditional egg-based manufacturing platforms. Implementation of cell culture-based influenza vaccine technologies and other alternatives to egg-based methods will also enable diversification of vaccine manufacturing platforms to overcome influenza vaccine supply vulnerabilities and improve vaccine-production capacity. Additionally, research has indicated that influenza A(H3N2) viruses can undergo changes that decrease antigenic relatedness to wild-type, circulating viruses when they are grown in eggs, and that certain egg-adaptive mutations may negatively affect the immunogenicity, efficacy, and effectiveness of standard egg-based influenza vaccines, especially during influenza A(H3N2)-dominant seasons,,,,,,. Cell culture-based influenza vaccines solely derived from cell culture-based CVVs are insulated from such egg-adaptive changes and have the potential to provide enhanced protection in some seasons compared to standard egg-based influenza vaccines,,. Nevertheless, adaptation in cell culture-based influenza vaccines needs to be further investigated given the potential for mutations in the genetic segments of HA and NA proteins resulting of serial passaging in MDCK cells ,.Therefore, ongoing monitoring of vaccine effectiveness, immunogenicity, and safety will be important to compare prior and future seasons, across influenza subtypes, and overall VE for each vaccine type. A more robust, comprehensive and consistent body of evidence, including data on comorbidities, pregnant women, health status, and other potential confounders, is also needed to evaluate the relative effectiveness and safety of Flucelvax® Quad compared to other injectable influenza vaccines.
# V. Recommendation
The following section outlines the recommendation that NACI has made regarding the use of Flucelvax® Quad in adults and children. Additional information on the strength of NACI recommendations and the grading of evidence is available in .
The following recommendation for Flucelvax® Quad supplements NACI’s overarching recommendation for influenza vaccination, which is available in the NACI Seasonal Influenza Vaccine Statement. The overarching NACI recommendation for influenza vaccination is that an age appropriate influenza vaccine should be offered annually to anyone 6 months of age and older (Strong NACI Recommendation), noting product-specific contraindications.
1. NACI recommends that Flucelvax® Quad may be considered among the IIV4 offered to adults and children ≥9 years of age (Discretionary NACI Recommendation)
- NACI concludes that there is fair evidence to recommend vaccination of adults and children ≥9 years of age with Flucelvax® Quad (Grade B Evidence).
## Summary of Evidence and Rationale
- There is fair evidence that Flucelvax® Quad is effective, safe, and has non-inferior immunogenicity to comparable vaccines, based on direct evidence in adults and children ≥9 years of age.
- There is limited peer-reviewed evidence on the effectiveness, immunogenicity, and safety of Flucelvax® Quad manufactured using fully cell-derived viruses.
- There is some evidence that, overall, Flucelvax® Quad may be more effective than egg-based trivalent or quadrivalent influenza vaccines against non-laboratory confirmed influenza-related outcomes but there is insufficient evidence for laboratory-confirmed outcomes. The clinical significance and directness of the evidence provided by influenza-related outcomes, which are surrogate measures of influenza activity, and the validity of observational studies using EMRs for influenza vaccine effectiveness estimation remain uncertain and need to be further evaluated
- Although some data suggests that IIV4-cc may be more effective against laboratory-confirmed influenza A(H3N2) virus infection than egg-based IIV, there was no consistent and statistically significant difference in effectiveness identified for adults or children vaccinated with IIV4-cc compared to egg-based IIV. Therefore, no firm conclusions can be drawn at this time, and NACI will continue to monitor this issue.
- All studies that assessed effectiveness were conducted in the US during the same season (2017–2018), which was influenza A(H3N2)-dominant. As influenza seasons can vary widely from year to year, further evidence on effectiveness gathered during influenza seasons with different circulating viruses is needed before a conclusion on the relative effectiveness can be made.
- NACI will continue to monitor the evidence related to cell-culture based influenza vaccines and will update this supplemental statement as needed and as data on Flucelvax® Quad from several different influenza seasons accumulates.
An updated summary of the characteristics of influenza vaccines available in Canada for the 2020–2021 influenza season can be found in Appendix B. For complete prescribing information, readers should consult the product monograph available through .
“*should/should not be- offered”
- Known/Anticipated advantages outweigh known/anticipated disadvantages (“should”),
OR Known/Anticipated disadvantages outweigh known/anticipated advantages (“should not”)
- Implication: A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present
“*may be- considered”- Known/Anticipated advantages closely balanced with known/anticipated disadvantages, OR uncertainty in the evidence of advantages and disadvantages exists
- Implication: A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable
General design specific criteria are outlined in Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, Atkins D. Current methods of the US Preventive Services Task Force: A review of the process. Am J Prev Med. 2001;20(3):21-35 .
- 2017–2018 influenza season
- Funded by US Department of Defense (DoD) Global Emerging Infections Surveillance (DoD-GEIS) Respiratory
Focus Area through the Department of Defense Global Respiratory
Pathogen Surveillance Program
- 80% of specimens were collected
from the US, 20% originated from Europe,
the Middle East, and the Pacific Region
- Mean age: 24 years
- Median age: 13 years
- Mode: 1 year old
- 57% female
(n = 2307)
- 1757 Cases (laboratory confirmed):
531 vaccinated
(192 (36.15%) received cell-derived vaccine
and 339 (63.84%) egg-derived vaccine)
- 2280 Controls:
977 vaccinated (314 (32.13%) received cell-derived vaccine (Flucelvax Quadrivalent®) and 663 (67.86%) received egg-derived vaccine (Flulaval® Tetra, Fluarix® Quadrivalent)
- Adjusted VE estimate (95% CI), %
- All dependents — IIV4-cc (subunit):
Influenza A2: 50 (37-61)
Influenza B: 40 (21-55)
Subtype A(H1N1) pdm09: 61 (38-76)
Subtype A(H3N2): 48 (30-61)
Overall3: 46 (33-56)
- All dependents — Egg-based (split virus):
Influenza A2: 54 (44-62)
Influenza B: 53 (41-63)
Subtype A(H1N1) pdm09: 86 (78-91)
Subtype A(H3N2): 35 (20-48)
Overall3: 53 (45-60)
- Children — IIV4-cc (subunit):
Influenza A2: 51 (26-67)
Influenza B: 22 (-17-47)
Subtype A(H1N1) pdm09: 56 (15-77)
Subtype A(H3N2): 47 (14-67)
Overall3: 36 (12-54)
- Children— Egg-based (split virus):
Influenza A2: 60 (49-69)
Influenza B: 49 (32-61)
Subtype A(H1N1) pdm09: 88 (80-93
Subtype A(H3N2): 40 (21-64)
Overall3: 55 (45-64
- Adults — IIV4-cc (subunit):
Influenza A2: 54 (37-67)
Influenza B: 54 (31-69)
Subtype A(H1N1) pdm09: 71 (44-85)
Subtype A(H3N2): 47 (25-63)
Overall3: 52 (36-64)
- Adults— Egg-based (split virus):
Influenza A2: 37 (15-53)
Influenza B: 61 (40-75)
Subtype A(H1N1) pdm09: 81 (56-92)
Subtype A(H3N2): 19 (-11-41)
Overall3: 51 (35-63)
- 1 To calculate VE, the odds of influenza-positive (cases) to influenza-negative (controls) patients were compared among vaccinated and unvaccinated individuals.2 Includes all influenza A specimens (A/unsubtyped, A(H1N1)pdm09, A(H3N2))3 Includes all influenza types and subtypes (A/unsubtyped, A(H1N1)pdm09, A(H3N2), B)
- Adjusted OR for individuals vaccinated with cell-derived vaccine (subunit) compared to egg-derived vaccine (split virus) stratified by subtype and beneficiary group:
- Adjusted OR (95% CI), %
- All dependents:
Influenza A1: 0.9 (0.6, 1.2)
Influenza B: 1.2 (0.9, 1.7)
Subtype A(H1N1) pdm09: 2 (1.1, 3.6)
Subtype A(H3N2): 0.7 (0.5, 1)
Overal2: 1 (0.8, 1.3)
- Children:
Influenza A1: 1 (0.6, 1.6)
Influenza B: 1.3 (0.8, 2)
Subtype A(H1N1) pdm09: 2.9 (1.3, 6.3)
Subtype A(H3N2): 0.7 (0.4, 1.2)
Overall2: 1.2 (0.8, 1.7)
- Adults:
Influenza A1: 0.8 (0.5, 1.1)
Influenza B : 1.1 (0.7, 1.9)
Subtype A(H1N1) pdm09 : 1.6 (0.6, 4.4)
Subtype A(H3N2) : 0.7 (0.5, 1)
Overall 2: 0.9 (0.6, 1.3)
- 1 Includes all influenza A specimens (A/unsubtyped, A(H1N1)pdm09, A(H3N2))
- 2 Includes all influenza types and subtypes (A/unsubtyped, A(H1N1)pdm09, A(H3N2), B)
- US
- 2017–2018 influenza season
- Funded by the US FDA
- 58.6% female
- IIV4-cc (Flucelvax Quadrivalent®):
n= 653,099)
- Egg-based IIV4-SD (Afluria® Tetra):
n=1,844,745
- Egg-based IIV3-SD:
n= 8,449,508
- IIV3-Adj (Fluad®):
n= 1,465,747
- IIV3-HD (Fluzone® High-Dose):
n= 1,007,082
- Office visits:10.5%; 95% CI: 6.8%–14.0%)
Hospital encounters:10.0%; 95% CI: 7.0%–13.0%)
- Pairwise, adjusted rVE estimates for influenza-related hospital encounters from a 5-way analysis:
- rVE \*\- (95% CI), %:
Egg-based IIV4-SD (split virus): 11.0 \*\*\- (7.9-14.0)
Egg-based IIV3-SD (split virus): 10.8\*\*\- (7.4-14.1)
IIV3-Adj (subunit): 7.5\*\*\- (4.1–10.7)
IIV3-HD (split virus): 2.3 (−0.8- 5.3)
- \- Hospital encounters were defined as inpatient hospitalizations and emergency department visits in which International Classification of Diseases, Tenth revision, Clinical Modification, code for influenza was listed.
\*\*Compared to persons vaccinated with IIV4-cc
\*\*\- Significant at p ≤ 0.05.
- Pairwise, adjusted rVE estimates for influenza-related office visits from a 5-way analysis:
- rVE\- (95% CI), %:
Egg-based IIV4-SD (split virus): 5.7 (1.9–9.4)\*
Egg-based IIV3-SD (split virus): 1.0 (−3.5 to 5.3)
IIV3-Adj (subunit): 11.5 (7.9–15.0)\*
IIV3-HD (split virus): 5.1 (1.6–8.4)
- \*Statistically significant at the P ≤.05 level
- Pairwise rVE estimates (IPTW-adjusted) for influenza-related inpatient stays from a 5 way analysis:
- rVE\- (95% CI), %:
Egg-based IIV4-SD (split virus): 9.5 (5.3–13.4)\*
Egg-based IIV3-SD (split virus): 11.4 (7.0–15.7)\*
IIV3-Adj (subunit): 7.1 (2.7–11.3)\*
IIV3-HD (split virus): −0.7 (−4.8 to 3.4)
- \*Statistically significant at the P ≤.05 level
- rVE was defined as the difference in influenza-related hospital encounters\- between persons vaccinated with IIV4-cc (subunit) versus egg-based vaccines
- 2017–2018 influenza season
- Funded by Seqirus, Inc.
- IIV4-cc group:
n=92,192;
median age: 59
- Egg-based IIV4 group:
n=1,255,983;
median age: 41
- rVE estimate (95% CI),%
Overall cohort: 36.2\*\- (26.1-44.9)
Subjects 4-17 years of age: 18.8 (-53.9-57.2)
Subjects 18-64 years of age: 26.8\*\- (14.1-37.6)
Subjects 65+ years of age: -7,3 (-51,6 à 24,0)
Total: 33.9\*\- (31.5-36.2)
Adjusted\*: 36.2\*\- (26.1-44.9)
- \*Adjusted for age, sex, health status, and geographic region
\*\- Significant with p<0.001
(Study recently accepted for peer-reviewed publication. At the time of writing, this study was only available as conference poster; unable to evaluate quality of evidence.)
- US
- 2017–2018 influenza season
- No funding declared
aged 4–64 years
IIV4-cc group (subunit):
n= 932,874
- egg-based IIV group:
n= 84,440
6.8% (11.2-21.9; P = 0.43)
- Adjusted VE (95% CI) against all laboratory-confirmed\- influenza:
- VE (95% CI), %:
IIV4-cc: 30.2 (17.1-41.3)
Egg-based IIV\*\*: 17.9 (12.1-23.3)
\- Positive by Polymerase chain reaction (PCR).
\*\- 86.2% received egg-based IIV3.
ClinicalTrials.gov *Safety and Immunogenicity of Three Influenza Vaccines Adults Ages 18 and Older*
- US
Multicentre (40 sites)
- 2013–2014 influenza season
- Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus, Inc.)
- 54.8% female
- Mean age: 57 years
- Group 1:
1335 adults
vaccinated with IIV4-cc (subunit)
- Group 2:
676 adults vaccinated with Flucelvax® (IIV3-cc, B/Yamagata) (subunit)
- Group 3:
669 adults vaccinated with Flucelvax® (IIV3-cc, B/Victoria) (subunit)
- Estimate (95% CI):
A(H1N1): 1.0 (0.9-1.1)
A(H3N2): 1.0 (0.9-1.1)
B/Yam: 0.9 (0.8-1.0)
B/Vic: 0.9 (0.8-1.0)
- Difference in seroconversion rate three weeks (day 22) post-vaccination (Group 2 or Group 3 –Group 1):
- Estimate (95% CI):
A(H1N1): -0.5 (-5.3-4.2)
A(H3N2): -2.7 (-7.2-1.9)
B/Yam: -1.8 (-6.2-2.8)
B/Vic: -4.4 (-8.9-0.2)
- HI antibody responses of IIV4-cc compared to IIV3-cc (B/Yam) and IIV3-cc (B/Vic) for the unmatched B strain, 22 days after vaccination in terms of the differences in percentages of subjects achieving seroconversion and the between group GMT ratios (FAS immunogenicity set):
- HI seroconversion rate three weeks (day 22) post-vaccination:
- Estimate (95% CI), % :
B/Yam: 39.7 (37.0-42.4)
B/Vic: 36.6 (34.0-39.3)
- Vaccine Group Diff (95% CI), %:
B/Yam: -21.7 (-25.5,-17.7)
B/Vic: -19.4 (-23.2,-15.5)
ClinicalTrial.gov *Safety and Immunogenicity of Three Influenza Vaccines in Children Aged 4 Years Old to Less than 18 Years Old*
- US
Multicentre
- November 2013 to
August 2014
- Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus, Inc.)
and ≥9 to <18 years.
- Within the ≥4 to <9 years cohort, subjects
were further stratified as previously vaccinated and not previously vaccinated.
- Group 1:
1159 children
vaccinated with Flucelvax Quadrivalent®
(819 previously vaccinated,
340 not previously vaccinated)
- 48% female
- Group 2:
593 children vaccinated with Flucelvax® IIV3-cc
(B/Victoria)
(420 previously vaccinated, 173 not previously vaccinated)
- 48% female
- Group 3:
581 children vaccinated with Flucelvax® IIV3-cc
(B/Yamagata)
(400 previously vaccinated, 181 not
previously vaccinated)
- 49% female
- Estimate (95% CI) – IIV4-cc (subunit):
B/Yam: 2.12 (1.91–2.37)
- Estimate (95% CI) – Matched IIV3-cc (subunit):
B/Vic: 2.38 (2.17–2.61)
B/Yam: 8.16 (7.56–8.82)
- Seroconversion rate in children aged 4-17 years, 3 weeks post-vaccination with last dose of vaccine:
- Estimate (95% CI) – IIV4-cc (subunit) :
A(H1N1): 73 (70–76)
A(H3N2): 47 (44–50)
B/Vic: 67 (64–70)
B/Yam: 73 (70–76)
- Estimate (95% CI) – Matched IIV3-cc\- (subunit):
A(H1N1): 74 (70–77)
A(H3N2): 51 (47–55)
B/Vic: 66 (61–69)
B/Yam: 72 (68–76)
- \*Data presented for influenza B strains is from the IIV3-cc containing the matched B lineage.
- Seroprotection rate in children aged 4-17 years, 3 weeks post-vaccination with last dose of vaccine:
- Estimate (95% CI) - IIV4-cc (subunit):
A(H1N1) : 99 (98–100)
A(H3N2) : 100 (99–100)
B/Vic : 92 (91–94)
B/Yam : 91 (89–93)
- Estimate (95% CI) - Matched IIV3-cc\- (subunit):
A(H1N1) : 99 (98–100)
A(H3N2) : 99 (98–100)
B/Vic : 93 (90–95)
B/Yam : 91 (88–93)
- \*Data presented for influenza B strains is from the IIV3-cc containing the matched B lineage.
- Difference in seroconversion rate (IIV3-cc – IIV4-cc)
in children aged 4-17 years, 3 weeks post-vaccination with last dose of vaccine:
- Estimate (95% CI) - IIV4-cc (subunit) :
B/Vic : 67 (64–70)
B/Yam : 73 (70–76)
- Estimate (95% CI) - Matched IIV3-cc\- (subunit):
B/Vic : 33 (29–37)
B/Yam : 26 (23–30)
- \*Data presented for influenza B strains is from the IIV3-cc containing the matched B lineage.
ClinicalTrials.gov *Safety and Immunogenicity of Three Influenza Vaccines Adults Ages 18 and Older*
- US
Multi-centre
- 2013–2014 influenza season
- Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus, Inc.)
- 54.8% female
- Mean age: 57 years
- Group 1:
1335 adults
vaccinated with IIV4-cc (subunit)
- Group 2:
676 adults vaccinated with
IIV3-cc (B/Yamagata) (subunit)
- Group 3:
669 adults vaccinated with
IIV3-cc (B/Victoria) (subunit)
- Injection site pain:
+ IIV4-cc: 33.6
+ IIV3-cc (B/Yam): 27.8
+ IIV3-cc (B/Vic): 29.4
- \*1 case of severe ecchymosis and 1 case of severe induration was identified in the TIV1c group
- Systemic AE:
- Fatigue:
+ IIV4-cc: 13.5
+ IIV3-cc (B/Yam): 16.3
+ IIV3-cc (B/Vic): 12.2
- Headache:
+ IIV4-cc: 14.0
+ IIV3-cc (B/Yam): 13.4
+ IIV3-cc (B/Vic): 13.4
- Reported solicited local and systemic AEs were generally mild to moderate in intensity. Across all 3 vaccine groups, a similar percentage of subjects reported at least one solicited AE.
Proportion (%) of adults reporting any solicited AEs by age:- 18-64 age group:
+ IIV4-cc: 61.8
+ IIV3-cc (B/Yam): 56.7
+ IIV3-cc (B/Vic): 59.6
- ≥65 age group:
+ IIV4-cc: 41.3
+ IIV3-cc (B/Yam): 39.1
+ IIV3-cc (B/Vic): 43.2
Proportion (%) reporting any solicited AEs by sex:- Female:
+ IIV4-cc: 57.9
+ IIV3-cc (B/Yam): 54.1
+ IIV3-cc (B/Vic): 54.2
- Male:
+ IIV4-cc: 43.9
+ IIV3-cc (B/Yam): 38.9
+ IIV3-cc (B/Vic): 47.1
- Overall, the rates of any solicited AEs did not differ among subjects from different ethnicities.
- Proportion (%) of adults ≥18 reporting any AE:
+ IIV4-cc: 16.1
+ IIV3-cc (B/Yam): 14.7
+ IIV3-cc (B/Vic): 16.5
Proportion (%) of adults 18-64 reporting unsolicited AEs (collected from day 1 through day 22; SAEs, medically attended AEs, AEs leading to withdrawal from the study, and new onset of chronic diseases were collected from day 1 through day 181):- Any AE:
+ IIV4-cc: 16.1
+ IIV3-cc (B/Yam): 14.7
+ IIV3-cc (B/Vic): 16.5
- Possibly or probably related AE:
+ IIV4-cc: 4.2
+ IIV3-cc (B/Yam): 2.7
+ IIV3-cc (B/Vic): 4.6
- Any SAE:
+ IIV4-cc: 1.7
+ IIV3-cc (B/Yam): 1.8
+ IIV3-cc (B/Vic): 1.5
- Possibly or probably related SAE:
+ IIV4-cc: 0
+ IIV3-cc (B/Yam): 0
+ IIV3-cc (B/Vic): 0
- AEs leading to premature withdrawal\*:
+ IIV4-cc: 0
+ IIV3-cc (B/Yam): 0
+ IIV3-cc (B/Vic): 0.3
- Medically attended AE:
+ IIV4-cc: 21.2
+ IIV3-cc (B/Yam): 17.6
+ IIV3-cc (B/Vic): 20.4
- New onset of chronic diseases:
+ IIV4-cc: 3.6
+ IIV3-cc (B/Yam): 3.0
+ IIV3-cc (B/Vic): 3.7
- Death:
+ IIV4-cc: 0
+ IIV3-cc (B/Yam): 0
+ IIV3-cc (B/Vic): 0.3
- \*One subject from the IIV3-cc (B/Vic) group withdrew from the study prematurely due to death.
Proportion (%) of adults ≥65 reporting unsolicited AEs (collected from day 1 through day 22; SAEs, medically attended AEs, AEs leading to withdrawal from the study, and new onset of chronic diseases were collected from day 1 through day 181):- Any AE:
+ IIV4-cc: 42.8
+ IIV3-cc (B/Yam): 45.2
+ IIV3-cc (B/Vic): 42.7
- Possibly or probably related AE:
+ IIV4-cc: 4.4
+ IIV3-cc (B/Yam): 3.8
+ IIV3-cc (B/Vic): 4.5
- Any SAE:
+ IIV4-cc: 6.2
+ IIV3-cc (B/Yam): 4.7
+ IIV3-cc (B/Vic): 4.7
- Possibly or probably related SAE:
+ IIV4-cc: 0
+ IIV3-cc (B/Yam): 0
+ IIV3-cc (B/Vic): 0
- AEs leading to premature withdrawal\*:
+ IIV4-cc: 0.3
+ IIV3-cc (B/Yam): 0.3
+ IIV3-cc (B/Vic): 0
- Medically attended AE:
+ IIV4-cc: 30.8
+ IIV3-cc (B/Yam): 33.3
+ IIV3-cc (B/Vic): 29.4
- New onset of chronic diseases:
+ IIV4-cc: 5.8
+ IIV3-cc (B/Yam): 4.4
+ IIV3-cc (B/Vic): 5.0
- Death:
+ IIV4-cc: 0.8
+ IIV3-cc (B/Yam): 1.5
+ IIV3-cc (B/Vic): 0.3
- \*One subject from the IIV4-cc group withdrew from the study due to acute myeloid leukemia and worsening of diabetes and one from the IIV3-cc (B/Yam) group due to death.
- 12 deaths were reported over the course of the study. None of the deaths or AEs leading to premature withdrawal were considered to be related to the study vaccine.
Proportion (%) of the most commonly reported unsolicited medically attended AEs by the MedDRA preferred Term:- Overall:
+ IIV4-cc: 26.0
+ IIV3-cc (B/Yam): 25.6
+ IIV3-cc (B/Vic): 25.0
- Sinusitis:
+ IIV4-cc: 1.8
+ IIV3-cc (B/Yam): 2.5
+ IIV3-cc (B/Vic): 2.4
- Bronchitis:
+ IIV4-cc: 2.2
+ IIV3-cc (B/Yam): 1.5
+ IIV3-cc (B/Vic): 0.9
Proportion (%) the most commonly reported unsolicited AEs by the MedDRA preferred Term deemed possibly or probably related:- Injection-site hemorrhage:
+ IIV4-cc: 0.8
+ IIV3-cc (B/Yam): 0.4
+ IIV3-cc (B/Vic): 0.5
- Fatigue:
+ IIV4-cc: 0.5
+ IIV3-cc (B/Yam): 0.4
+ IIV3-cc (B/Vic): 0.6
- Myalgia:
+ IIV4-cc: 0.5
+ IIV3-cc (B/Yam): 0.1
+ IIV3-cc (B/Vic): 0.5
Proportion (%) of the most commonly reported new onset of chronic disease by the MedDRA preferred Term:- Metabolism and nutritional disorders
+ IIV4-cc: 0.8
+ IIV3-cc (B/Yam): 0.7
+ IIV3-cc (B/Vic): 0.5
- Cardiac disorders:
+ IIV4-cc: 0.8
+ IIV3-cc (B/Yam): 0.6
+ IIV3-cc (B/Vic): 0.3
- Musculoskeletal and connective tissue disorders:
+ IIV4-cc: 0.8
+ IIV3-cc (B/Yam): 0.4
+ IIV3-cc (B/Vic): 0.3
- No significant differences were observed between vaccine groups or age groups in the proportion of subjects with new onset of chronic diseases.
Proportion (%) of study subjects reporting unsolicited AEs and medically attended AEs by sex:- Female:
+ Any: 32.7
+ Medically attended: 22.3
- Male:
+ Any: 40.5
+ Medically attended: 28.5
- There were no major differences in the unsolicited AE profiles of IIV4-cc, IIV3-cc (B/Yam), and IIV3-cc (B/Vic), by age cohorts, sex, and race/ethnicity.
- Lithuania Multi-centre
- 2005-2006 influenza season
- No funding declared
- 61.0% female
- Mean age:32.5
- Total participants: 1200
- IIV3-cc
(3 consecutive production lots: A,B,C): n=1028
- Egg-based IIV3
(Agrippal®, Seqirus, Inc.; marketed in Canada as Agriflu®):
n=171
+ IIV3-cc Lot A+B+C (subunit): 29
+ Egg-based IIV3 (subunit): 25
- P\*=0.35
- Ecchymosis:
+ IIV3-cc Lot A+B+C (subunit): 4
+ Egg-based IIV3 (subunit): 6
- P\*=0.26
- Erythema:
+ IIV3-cc Lot A+B+C (subunit): 20
+ Egg-based IIV3 (subunit): 18
- P\*=0.66
- Induration:
+ IIV3-cc Lot A+B+C (subunit): 11
+ Egg-based IIV3 (subunit): 11
- P\*=0.90
- Swelling:
+ IIV3-cc Lot A+B+C (subunit): 7
+ Egg-based IIV3 (subunit): 8
- P\*=0.96
- Pain:
+ IIV3-cc Lot A+B+C (subunit): 12
+ Egg-based IIV3 (subunit): 8
- P\*=0.19
- Total systemic reactions:
+ IIV3-cc Lot A+B+C (subunit): 25
+ Egg-based IIV3 (subunit): 23
- P\*=0.54
- Chills:
+ IIV3-cc Lot A+B+C (subunit): 6
+ Egg-based IIV3 (subunit): 7
- P\*=0.73
- Malaise:
+ IIV3-cc Lot A+B+C (subunit): 13
+ Egg-based IIV3 (subunit): 12
- P\*=0.79
- Myalgia:
+ IIV3-cc Lot A+B+C (subunit): 6
+ Egg-based IIV3 (subunit): 5
- P\*=0.73
- Arthralgia:
+ IIV3-cc Lot A+B+C (subunit): 3
+ Egg-based IIV3 (subunit): 1
- P\*=0.30
- Headache:
+ IIV3-cc Lot A+B+C (subunit): 14
+ Egg-based IIV3 (subunit): 12
- P\*=0.47
- Sweating:
+ IIV3-cc Lot A+B+C (subunit): 4
+ Egg-based IIV3 (subunit): 3
- P\*=0.41
- Fatigue:
+ IIV3-cc Lot A+B+C (subunit): 13
+ Egg-based IIV3 (subunit): 11
- P\*=0.55
- Fever(≥38°C):
+ IIV3-cc Lot A+B+C (subunit): 1
+ Egg-based IIV3 (subunit): 2
- P\*=0.44\*\*
- Total other indicators of reactogenicity:
+ IIV3-cc Lot A+B+C (subunit): 5
+ Egg-based IIV3 (subunit): 7
- P\*=0.17
- Stayed at home due to reaction:
+ IIV3-cc Lot A+B+C (subunit): 3
+ Egg-based IIV3 (subunit): 2
- P\*=1.00\*\*
- Analgesic/antipyretic medication used:
+ IIV3-cc Lot A+B+C (subunit): 3
+ Egg-based IIV3 (subunit): 6
- P\*=0.10
- \- value from Pearson’s chi-square test for vaccine group differences (IIV3-cc total versus egg-based IIV3).
\*\- If any expected cell count was 20% of the cells have an expected cell count <5, then the Fisher exact test was used.
- One death was reported during the 6-month safety follow-up period; 1 subject in the IIV3-cc group committed suicide. None of the deaths or SAEs reported over the course of the study were determined to be related to the IIV3-cc vaccine.
ClinicalTrials.gov *Safety and Immunogenicity of a Cell Culture-derived Influenza Vaccine in Healthy Adults and Elderly
- Poland Multi-centre
- 2004-2005 influenza season
- Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus Inc.)
+ 58.0% female
+ Mean age:
18-60 age group: 38.7
+ >60 age group: 69.1
- Total participants analyzed:
+ IIV3-cc:
+ 18-60 age group: n=652
+ >60 age group: n=
- Egg-based IIV3 (Agrippal®):
+ 18-60 age group: n=648
+ >60 age group: n=676
- Subjects ≥61years of age: 33
Proportion (%) participants reporting local and systemic reactions between day 1 through day 7 after vaccination by vaccine group:- Local reactions:
+ IIV3-cc (subunit): 32
+ Egg-based IIV3 (subunit): 31
- Systemic reactions:
+ IIV3-cc (subunit): 22
+ Egg-based IIV3 (subunit): 23
Proportion (%) of participants reporting injection pain site by age group between day 1 through day 7 after vaccination:- Subjects 18-60 years of age:
+ IIV3-cc (subunit): 22
+ Egg-based IIV3 (subunit): 17
- P <.05
- Subjects ≥61years of age:
+ IIV3-cc (subunit): 9
+ Egg-based IIV3 (subunit): 5
- P<.001
Proportion (%) adults 18-60 years of age reporting solicited local AEs in between day 1 through day 7 after vaccination:- Ecchymosis:
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 3
- P\*=0.51
- Erythema:
+ IIV3-cc (subunit): 14
+ Egg-based IIV3 (subunit): 16
- P\*=0.26
- Induration:
+ IIV3-cc (subunit): 6
+ Egg-based IIV3 (subunit): 6
- P\*=0.62
- Swelling:
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 4
- P\*=0.76
- Pain:
+ IIV3-cc (subunit): 22
+ Egg-based IIV3 (subunit): 17
- P\*=0.04\*\*
- \- Pearson X2 test for vaccine group differences.
- \*\- P <.001
Proportion (%) of adults 18-60 years of age reporting solicited systemic reactions in between day 1 through day 7 after vaccination:- Chills:
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 4
- P\*=0.56
- Malaise:
+ IIV3-cc (subunit): 11
+ Egg-based IIV3 (subunit): 11
- P\*=0.97
- Myalgia:
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 8
- P\*=0.65
- Arthralgia:
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 4
- P\*=0.61
- Headache:
+ IIV3-cc (subunit): 12
+ Egg-based IIV3 (subunit): 12
- P\*=0.90
- Sweating:
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 4
- P\*=0.91
- Fatigue:
+ IIV3-cc (subunit): 11
+ Egg-based IIV3 (subunit): 11
- P\*=0.97
- Fever:
+ IIV3-cc (subunit): <1
+ Egg-based IIV3 (subunit): 1
- P\*=0.29
- Pearson X2 test for vaccine group differences.
Proportion (%) adults 18-60 years of age reporting solicited local AEs in between day 1 through day 7 after vaccination:- Stayed at home due to reaction:
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 2
- P\*=0.69
- Analgesic/antipyretic medication used:
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 6
- P\*=0.67
- Pearson X2 test for vaccine group differences
Proportion adults ≥61 years of age reporting solicited local AEs in between day 1 through day 7 after vaccination:- Ecchymosis:
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 4
- P\*=0.89
- Erythema:
+ IIV3-cc (subunit): 11
+ Egg-based IIV3 (subunit): 11
- P\*=0.99
- Induration:
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 4
- P\*=0.32
- Swelling:
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 3
- P\*=0.34
- Pain:
+ IIV3-cc (subunit): 9
+ Egg-based IIV3 (subunit): 5
- P\*=0.001\*\*
- Pearson X2 test for vaccine group differences.
- \*\- P <.001
Proportion of adults ≥61 years of age reporting solicited systemic reactions in between day 1 through day 7 after vaccination:- Chills:
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 4
- P\*=0.65
- Malaise:
+ IIV3-cc (subunit): 10
+ Egg-based IIV3 (subunit): 11
- P\*=0.65
- Myalgia:
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 8
- P\*=0.25
- Arthralgia:
+ IIV3-cc (subunit): 6
+ Egg-based IIV3 (subunit): 7
- P\*=0.73
- Headache:
+ IIV3-cc (subunit): 10
+ Egg-based IIV3 (subunit): 10
- P\*=0.91
- Sweating:
+ IIV3-cc (subunit): 6
+ Egg-based IIV3 (subunit): 7
- P\*=0.66
- Fatigue:
+ IIV3-cc (subunit): 11
+ Egg-based IIV3 (subunit): 12
- P\*=0.34
- Fever:
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
- P\*=1.0
- \- Pearson X2 test for vaccine group differences.
Proportion (%) of adults ≥61 years of age reporting other solicited reactions in between day 1 through day 7 after vaccination:- Stayed at home due to reaction:
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 2
- P\*=0.38
- Analgesic/antipyretic medication used:
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 4
- P\*=0.53
- \- Pearson X2 test for vaccine group differences.
- There were no differences reported between vaccine groups in unsolicited AEs (reported by 13-15% of subjects among all groups).
Proportion (%) of subjects reporting AEs considered to be possibly or probably related to the vaccine:- Subjects 18-60 years of age:
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 4
- Subjects ≥61years of age:
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 2
- SAEs occurred in 1% of adult subjects 18-60 years of age and 3% of elderly subjects ≥61 years of age.
- The three deaths that occurred over the course of the study were all in elderly subjects ≥61 years of age (1 in the IIV3-cc group and 2 in the egg-based IIV3 group). None of the SAEs or deaths were assessed as vaccine
- Multicentre:
+ US
(18 sites)
+ Australia
(6 sites)
+ New Zealand
(2 sites
+ Philippines
(5 sites)
+ Thailand
(3 sites)
- 2013-2014 influenza season
- Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus Inc.)
- % female:
+ 4-8 age group: 52%
+ 9-17 age group: 50%
- Mean age:
+ 4-8 age group: 5.9 years
+ 9-17 age group: 12.3 years
- Total participants:
+ n=2055
+ IIV3-cc: n= 1372
+ Egg-based IIV3 (Fluvirin): n= 683
+ IIV3-cc (subunit): 61
+ Egg-based IIV3 (subunit): 63
- Local:
+ IIV3-cc (subunit): 48
+ Egg-based IIV3 (subunit): 43
- Systemic:
+ IIV3-cc (subunit): 34
+ Egg-based IIV3 (subunit): 32
Proportion (%) of participants aged 4-8 years reporting any solicited reactions within seven days after second dose:- Any:
+ IIV3-cc (subunit): 48
+ Egg-based IIV3 (subunit): 52
- Local:
+ IIV3-cc (subunit): 40
+ Egg-based IIV3 (subunit): 43
- Systemic:
+ IIV3-cc (subunit): 21
+ Egg-based IIV3 (subunit): 22
Proportion (%) of participants aged 4-17 years reporting solicited reactions within seven days after single dose:- Any:
+ IIV3-cc (subunit): 63
+ Egg-based IIV3 (subunit): 54
- Local:
+ IIV3-cc (subunit): 53
+ Egg-based IIV3 (subunit): 43
- Systemic:
+ IIV3-cc (subunit): 37
+ Egg-based IIV3 (subunit): 30
Proportion (%) of participants aged 4-8 years who reported any (severe\- in brackets) solicited local reactions within 7 days of vaccination:- Pain:
+ IIV3-cc (subunit): 56 (1)
+ Egg-based IIV3 (subunit): 55
- Erythema:
+ IIV3-cc (subunit): 22
+ Egg-based IIV3 (subunit): 17(<1)
- Induration:
+ IIV3-cc (subunit): 16
+ Egg-based IIV3 (subunit): 13
- Swelling:
+ IIV3-cc (subunit): 13
+ Egg-based IIV3 (subunit): 11
- Ecchymosis:
+ IIV3-cc (subunit): 10
+ Egg-based IIV3 (subunit): 9
Proportion (%) of participants aged 9-17 years who reported any (severe\- in brackets) solicited local reactions within 7 days of vaccination:- Pain:
+ IIV3-cc (subunit): 52(<1)
+ Egg-based IIV3 (subunit): 42
- Erythema:
+ IIV3-cc (subunit): 11(<1)
+ Egg-based IIV3 (subunit): 11)
- Induration:
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 10
- Swelling:
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 8
- Ecchymosis:
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 3
Proportion (%) of participants aged 4-8 years who reported any (severe\- in brackets) solicited systemic reactions occurring within 7 days of vaccination:- Malaise:
+ IIV3-cc (subunit): 16(1)
+ Egg-based IIV3 (subunit): 13(1)
- Myalgia:
+ IIV3-cc (subunit): 16(1)
+ Egg-based IIV3 (subunit): 12(<1)
- Headache:
+ IIV3-cc (subunit): 15(<1)
+ Egg-based IIV3 (subunit): 12(<1)
- Fatigue:
+ IIV3-cc (subunit): 13(1)
+ Egg-based IIV3 (subunit): 10(1)
- Loss of appetite:
+ IIV3-cc (subunit): 10(<1)
+ Egg-based IIV3 (subunit): 7(1)
- Nausea:
+ IIV3-cc (subunit): 8(1)
+ Egg-based IIV3 (subunit): 8(1)
- Chills:
+ IIV3-cc (subunit): 7(<1)
+ Egg-based IIV3 (subunit): 5(1)
- Sweating:
+ IIV3-cc (subunit): 6(<1)
+ Egg-based IIV3 (subunit): 6
- Arthralgia:
+ IIV3-cc (subunit): 6(<1)
+ Egg-based IIV3 (subunit): 5(<1)
- Body Temperature (>38C):
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 9
- Analgesic/antipyretic (preventive):
+ IIV3-cc (subunit): 9
+ Egg-based IIV3 (subunit): 9
- Analgesic/antipyretic (treatment):
+ IIV3-cc (subunit): 13
+ Egg-based IIV3 (subunit): 12
Proportion (%) of participants aged 9-17 years who reported any (severe\- in brackets) solicited systemic reactions occurring within 7 days of vaccination:- Malaise:
+ IIV3-cc (subunit): 15(<1)
+ Egg-based IIV3 (subunit): 14(<1)
- Myalgia:
+ IIV3-cc (subunit): 19
+ Egg-based IIV3 (subunit): 13(<1)
- Headache:
+ IIV3-cc (subunit): 16
+ Egg-based IIV3 (subunit): 16(<1)
- Fatigue:
+ IIV3-cc (subunit): 19(1)
+ Egg-based IIV3 (subunit): 17(<1)
- Loss of appetite:
+ IIV3-cc (subunit): 7(<1)
+ Egg-based IIV3 (subunit): 4
- Nausea:
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 5
- Chills:
+ IIV3-cc (subunit): 6(<1)
+ Egg-based IIV3 (subunit): 2(<1)
- Sweating:
+ IIV3-cc (subunit): 8(<1)
+ Egg-based IIV3 (subunit): 7
- Arthralgia:
+ IIV3-cc (subunit): 8(<1)
+ Egg-based IIV3 (subunit): 4
- Body Temperature (>38C):
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 1
- Analgesic/antipyretic (preventive):
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 3
- Analgesic/antipyretic (treatment):
+ IIV3-cc (subunit): 6
+ Egg-based IIV3 (subunit): 5
- \*Reactions were categorized as mild, moderate or severe, if they resulted in no limitation of, some limitation of, or inability to perform normal daily activities, respectively.
Proportion (%) of participants aged 4-8 years reporting unsolicited AEs after first dose:- Any AE:
+ IIV3-cc (subunit): 33
+ Egg-based IIV3 (subunit): 31
- At least possibly related AE:
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 6
- SAE:
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
- Medically attended AE:
+ IIV3-cc (subunit): 12
+ Egg-based IIV3 (subunit): 11
- NOCD:
+ IIV3-cc (subunit): 0.3
+ Egg-based IIV3 (subunit): 01
- For 4-8 year old participants who were not previously vaccinated against influenza, AEs were collected from Day 1 through 49; SAEs, medically attended AEs and new onsets of chronic diseases were collected through up to Day 213.
Proportion (%) of participants aged 4-8 years reporting unsolicited AEs after second dose:- Any AE:
+ IIV3-cc (subunit): 19
+ Egg-based IIV3 (subunit): 22
- At least possibly related AE:
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 4
- SAE:
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 2
- Medically attended AE:
+ IIV3-cc (subunit): 38
+ Egg-based IIV3 (subunit): 42
- NOCD:
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 2
- For 4-8 year old participants who were not previously vaccinated against influenza, AEs were collected from Day 1 through 49; SAEs, medically attended AEs and NOCD were collected through up to Day 213.
Proportion (%) of participants aged 9-17 years (PV) reporting unsolicited AEs after single dose:- Any AE:
+ IIV3-cc (subunit): 23
+ Egg-based IIV3 (subunit): 26
- At least possibly related AE:
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 6
- SAE:
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 3
- Medically attended AE:
+ IIV3-cc (subunit): 25
+ Egg-based IIV3 (subunit): 31
- NOCD:
+ IIV3-cc (subunit): 0.4
+ Egg-based IIV3 (subunit): 0.3
- For all 9-17 year old participants, AEs were collected from Day 1 through Day 28, SAEs, medically attended AEs and NOCD were collected up to Day 183
Proportion (%) of participants aged 3-8 years (NPV/PV) with unsolicited AEs by preferred term- Upper respiratory tract infection:
+ IIV3-cc (subunit): 11
+ Egg-based IIV3 (subunit): 12
- Nasopharyngitis:
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 3
- Viral infection:
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 3
- Cough:
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 4
- Pyrexia:
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 4
- Headache:
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
- Vomiting:
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 3
- Gastroenteritis:
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
- Rhinorrhoea:
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 2
- Oropharyngeal pain:
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 2
Proportion (%) of participants aged 9-17 (PV) with unsolicited AEs by preferred term:- Upper respiratory tract infection:
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 6
- Nasopharyngitis:
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 4
- Viral infection:
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
- Cough:
+ IIV3-cc (subunit): 0.6
+ Egg-based IIV3 (subunit): 0.3
- Pyrexia:
+ IIV3-cc (subunit): 0.3
+ Egg-based IIV3 (subunit): 0.6
- Headache:
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 1
- Vomiting:
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
- Gastroenteritis:
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 2
- Rhinorrhoea:
+ IIV3-cc (subunit): 0.3
+ Egg-based IIV3 (subunit): 1
- Oropharyngeal pain:
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
- No deaths or vaccine-related SAEs were reported over the course of the study. None of the withdrawals from the study were due to AEs.
ClinicalTrials.gov *Pediatric Safety and Immunogenicity Study of Cell-Culture Derived and Egg-based Subunit Influenza Vaccines in Healthy Children and Adolescents
- Multi-centre:
+ US (16 sites)
+ Finland (14 sites)
+ Croatia (9 sites)
+ Hungary (8 sites)
+ Lithuania (6 sites)
+ Italy (5 sites)
+ Romania (2 sites)
- October 2007 to July 2008
- Funded by in part with US Government federal funds from the Office of Public Health Emergency Preparedness, Office of Research and Development Coordination, under contract to Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus Inc.)
- Mean age: 7.4 years
- 48.5% female
- Total participants analyzed:
- IIV3-cc two doses (3-8 years): n=1599
- Egg-based IIV3 (Fluvirin) two doses (3-8 years):n= 1013
- IIV3-cc single dose (9-17 years): n=652
- Egg-based IIV3 (Fluvirin) single dose (9-17 years):
n=316
+ IIV3-cc (subunit): 38
+ Egg-based IIV3 (subunit): 35
- 2nd Dose:
+ IIV3-cc (subunit): 35
+ Egg-based IIV3 (subunit): 34
Proportion (%) of subjects 3-8 years of age reporting any systemic AEs between day 1 through day 7 after vaccination: - 1st Dose:
+ IIV3-cc (subunit): 23
+ Egg-based IIV3 (subunit): 26
- 2nd Dose:
+ IIV3-cc (subunit): 15
+ Egg-based IIV3 (subunit): 19
Proportion (%) of subjects 9-17 years of age reporting any AEs between day 1 through day 7 after vaccination:- Local:
+ IIV3-cc (subunit): 42
+ Egg-based IIV3 (subunit): 45
- Systemic:
+ IIV3-cc (subunit): 29
+ Egg-based IIV3 (subunit): 30
Proportion (%) of subjects 3-8 years of age reporting mild and severe (brackets) solicited local AEs at injection site between day 1 through day 7 after first vaccination:- Pain:
+ IIV3-cc (subunit): 28 (<1)
+ Egg-based IIV3 (subunit): 25 (<1)
- Erythema:
+ IIV3-cc (subunit): 12
+ Egg-based IIV3 (subunit): 14
- Induration:
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 4
- Ecchymosis:
+ IIV3-cc (subunit): 6
+ Egg-based IIV3 (subunit): 6
- Swelling:
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 5
Proportion (%) of subjects 3-8 years of age reporting mild and severe (brackets) solicited local AEs between day 1 through day 7 after second vaccination:- Pain:
+ IIV3-cc (subunit): 27 (<1)
+ Egg-based IIV3 (subunit): 27 (<1)
- Erythema:
+ IIV3-cc (subunit): 13
+ Egg-based IIV3 (subunit): 12
- Induration:
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 5
- Ecchymosis:
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 4
- Swelling:
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 5
Proportion (%) of subjects 3-8 years old reporting mild and severe (brackets) solicited systemic AEs between day 1 through day 7 after first vaccination:- Chills:
+ IIV3-cc (subunit): 3(<1)
+ Egg-based IIV3 (subunit): 5(<1)
- Malaise:
+ IIV3-cc (subunit): 6(1)
+ Egg-based IIV3 (subunit): 8(1)
- Myalgia:
+ IIV3-cc (subunit): 9(<1)
+ Egg-based IIV3 (subunit): 7(<1)
- Arthralgia:
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 1
- Headache:
+ IIV3-cc (subunit): 8(1)
+ Egg-based IIV3 (subunit): 10(<1)
- Sweating:
+ IIV3-cc (subunit): 2(<1)
+ Egg-based IIV3 (subunit): 2(<1)
- Fatigue:
+ IIV3-cc (subunit): 10(<1)
+ Egg-based IIV3 (subunit): 12(1)
- Fever(≥38°C):
+ IIV3-cc (subunit): 3(<1)
+ Egg-based IIV3 (subunit): 4(<1)
- Analgesic/antipyretic:
+ IIV3-cc (subunit): 9
+ Egg-based IIV3 (subunit): 10
- Stayed at home:
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 4
Proportion of subjects 3-8 years old reporting mild and severe (brackets) solicited systemic AEs between day 1 through day 7 after second vaccination:- Chills:
+ IIV3-cc (subunit): 2(<1)
+ Egg-based IIV3 (subunit): 3(<1)
- Malaise:
+ IIV3-cc (subunit): 5(1)
+ Egg-based IIV3 (subunit): 5(<1)
- Myalgia:
+ IIV3-cc (subunit): 6(<1)
+ Egg-based IIV3 (subunit): 7(<1)
- Arthralgia:
+ IIV3-cc (subunit): 2(<1)
+ Egg-based IIV3 (subunit): 2
- Headache:
+ IIV3-cc (subunit): 5(<1)
+ Egg-based IIV3 (subunit): 7(<1)
- Sweating:
+ IIV3-cc (subunit): 1(<1)
+ Egg-based IIV3 (subunit): 1
- Fatigue:
+ IIV3-cc (subunit): 6(1)
+ Egg-based IIV3 (subunit): 8(<1)
- Fever(≥38°C):
+ IIV3-cc (subunit): 2(<1)
+ Egg-based IIV3 (subunit): 2
- Analgesic/antipyretic:
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 6
- Stayed at home:
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 2
Proportion (%) of subjects 9-17 years of age reporting mild and severe (brackets) solicited local AEs between day 1 through day 7 after vaccination:- Pain:
+ IIV3-cc (subunit): 34(<1)
+ Egg-based IIV3 (subunit): 38(1)
- Erythema:
+ IIV3-cc (subunit): 14
+ Egg-based IIV3 (subunit): 14
- Induration:
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 9
- Ecchymosis:
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 3
- Swelling:
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 5
Proportion (%) of subjects 9-17 years old reporting mild and severe (brackets) solicited systemic AEs between day 1 through day 7 after vaccination- Chills:
+ IIV3-cc (subunit): 4(<1)
+ Egg-based IIV3 (subunit): 4(<1)
- Malaise:
+ IIV3-cc (subunit): 9(1)
+ Egg-based IIV3 (subunit): 11(1)
- Myalgia:
+ IIV3-cc (subunit): 15(<1)
+ Egg-based IIV3 (subunit): 9(1)
- Arthralgia:
+ IIV3-cc (subunit): 4(<1)
+ Egg-based IIV3 (subunit): 5
- Headache:
+ IIV3-cc (subunit): 14(<1)
+ Egg-based IIV3 (subunit): 14(1)
- Sweating:
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 1(<1)
- Fatigue:
+ IIV3-cc (subunit): 9(1)
+ Egg-based IIV3 (subunit): 13(1)
- Fever(≥38°C):
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
- Analgesic/antipyretic:
+ IIV3-cc (subunit): 6
+ Egg-based IIV3 (subunit): 10
- Stayed at home:
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 3
- Severe local and severe systemic solicited
reactions were reported rarely and were comparable across age and vaccine groups; ≤1% of any reaction classified as severe.
Proportion (%) of subjects 3-8 years of age reporting unsolicited AEs\- collected for the 50-day study period:- 1st Dose:
+ IIV3-cc (subunit): 32
+ Egg-based IIV3 (subunit): 34
- 2nd Dose:
+ IIV3-cc (subunit): 18
+ Egg-based IIV3 (subunit): 20
- \*5-8% were considered at least possibly related to the vaccine
- 19-20% of subjects 8-17 years of age reported unsolicited AEs during the 29-day study period; 3% of these were considered at least possibly related to the vaccine.
- Unsolicited AEs occurred in 1-4% of subjects across age and vaccine groups; 0 to <1% were considered at least possibly related to the study vaccines.
- 28 SAEs were reported over the course of the study (4 –month during the postvaccination period, 24 during the 6 safety follow-up period). None of these SAEs were assessed as vaccine related.
- No deaths were reported.
- Multi-centre:
- US
Finland
Poland
- 2007-2008 influenza season
- Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus Inc.)
- Mean age: 32.7-33.0 years
- 54-55% female
- Total participants analyzed (safety):
- IIV3-cc: n=3813
- Egg-based IIV3 (Agrippal®): n=3669
- Placebo: n=3894
Proportion (%) of participants reporting solicited local reactions at injection site between day 1 through day 7 after vaccination (not including SAEs) by the MedDRA Term:- Erythema:
+ IIV3-cc (subunit): 13.38
+ Egg-based IIV3 (subunit): 13.41
+ Placebo: 10.04
- Induration:
+ IIV3-cc (subunit): 6.27
+ Egg-based IIV3 (subunit): 5.64
+ Placebo: 2.59
- Pain:
+ IIV3-cc (subunit): 30.37
+ Egg-based IIV3 (subunit): 24.34
+ Placebo: 9.63
- Swelling:
+ IIV3-cc (subunit): 5.72
+ Egg-based IIV3 (subunit): 4.93
+ Placebo: 2.65
Proportion (%) of participants reporting solicited systemic reactions between day 1 through day 7 after vaccination (not including SAEs) by the MedDRA Term:- Chills:
+ IIV3-cc (subunit): 5.56
+ Egg-based IIV3 (subunit): 5.78
+ Placebo: 5.78
- Fatigue:
+ IIV3-cc (subunit): 10.23
+ Egg-based IIV3 (subunit): 11.01
+ Placebo: 9.91
- Malaise:
+ IIV3-cc (subunit): 7.61
+ Egg-based IIV3 (subunit): 7.09
+ Placebo: 6.11
- Myalgia:
+ IIV3-cc (subunit): 11.83
+ Egg-based IIV3 (subunit): 10.06
+ Placebo: 7.14
- Headache:
+ IIV3-cc (subunit): 14.98
+ Egg-based IIV3 (subunit): 15.10
+ Placebo: 15.33
- Possibly or probably related unsolicited AEs were reported by 1-2% of study participants on days 1-7 and by <1% of participants from days 8-23; no AEs were reported on days 23-181
- 4 deaths were reported over the course of the study; 2 within the group that received IIV3-cc and 1 in each of the IIV3 and placebo groups. The deaths were judged as unrelated to the study vaccine.
- 127 other SAEs were reported over the course of the study; 42 in the IIV3-cc group, 35 in the TIV group, and 38 in the placebo group; the SAEs were judged as unrelated to the study vaccines.
ClinicalTrial.gov *Safety and Immunogenicity of Three Influenza Vaccines in Children Aged 4 Years Old to Less than 18 Years Old
- US Multicentre
- 2013-2014 influenza season
- Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus Inc.)
+ 1159 children vaccinated with Flucelvax® IIV4-cc (819 previously vaccinated,<340 not previously vaccinated)
+ 48% female
- Group 2:
+ 593 children vaccinated with Flucelvax® IIV3-cc (B/Yamagata)
(420 previously vaccinated, 173 not previously vaccinated)
+ 48% female
- Group 3:
+ 581 children vaccinated with Flucelvax® IIV3-cc (B/Victoria) (400 previously vaccinated,181 not previously vaccinated)
+ 49% female
+ Any AE:
- IIV4-cc (subunit): 65
- IIV3-cc (B/Yam) (subunit): 58
- IIV3-cc (B/Vic) (subunit): 57
+ Local:
- IIV4-cc (subunit): 57
- IIV3-cc (B/Yam) (subunit): 56
- IIV3-cc (B/Vic) (subunit): 51
+ Systemic:
- IIV4-cc (subunit): 28
- IIV3-cc (B/Yam) (subunit): 20
- IIV3-cc (B/Vic) (subunit): 18
+ Others:
- IIV4-cc (subunit): 10
- IIV3-cc (B/Yam) (subunit): 5
- IIV3-cc (B/Vic) (subunit): 4
- Subjects 6-8 years of age:
+ Any AE:
- IIV4-cc (subunit): 69
- IIV3-cc (B/Yam) (subunit): 72
- IIV3-cc (B/Vic) (subunit): 69
+ Local:
- IIV4-cc (subunit): 64
- IIV3-cc (B/Yam) (subunit): 67
- IIV3-cc (B/Vic) (subunit): 62
+ Systemic:
- IIV4-cc (subunit): 31
- IIV3-cc (B/Yam) (subunit): 36
- IIV3-cc (B/Vic) (subunit): 35
+ Others:
- IIV4-cc (subunit): 9
- IIV3-cc (B/Yam) (subunit): 9
- IIV3-cc (B/Vic) (subunit): 9
- Subjects 9-18 years of age:
+ Any AE:
- IIV4-cc (subunit): 71
- IIV3-cc (B/Yam) (subunit): 68
- IIV3-cc (B/Vic) (subunit): 61
+ Local:
- IIV4-cc (subunit): 65
- IIV3-cc (B/Yam) (subunit): 60
- IIV3-cc (B/Vic) (subunit): 55
+ Systemic:
- IIV4-cc (subunit): 40
- IIV3-cc (B/Yam) (subunit): 41
- IIV3-cc (B/Vic) (subunit): 33
+ Others:
- IIV4-cc (subunit): 6
- IIV3-cc (B/Yam) (subunit): 8
- IIV3-cc (B/Vic) (subunit): 7
+ \- Data from the first vaccination includes both previously vaccinated and not previously vaccinated subjects for those 4-5 and 6-8 years of age.
+ \*\- Not previously vaccinated subjects 4-5 and 6-9 years of age received two vaccinations, and previously vaccinated subjects 4-5, 6-8, and 9-17 years of age received one vaccination.
Proportion (%) of children reporting solicited AEs (age-appropriate) within 7 days after vaccination after the 2nd dose:- Subjects 4-5 years of age\*:
+ Any AE:
- IIV4-cc (subunit): 60
- IIV3-cc (B/Yam) (subunit): 49
- IIV3-cc (B/Vic) (subunit): 43
+ Local:
- IIV4-cc (subunit): 53
- IIV3-cc (B/Yam) (subunit): 44
- IIV3-cc (B/Vic) (subunit): 36
+ Systemic:
- IIV4-cc (subunit): 31
- IIV3-cc (B/Yam) (subunit): 23
- IIV3-cc (B/Vic) (subunit): 19
+ Others:
- IIV4-cc (subunit): 4
- IIV3-cc (B/Yam) (subunit): 8
- IIV3-cc (B/Vic) (subunit): 2
- Subjects 6-8 years of age\*:
+ Any AE:
- IIV4-cc (subunit): 57
- IIV3-cc (B/Yam) (subunit): 63
- IIV3-cc (B/Vic) (subunit): 64
+ Local:
- IIV4-cc (subunit): 50
- IIV3-cc (B/Yam) (subunit): 57
- IIV3-cc (B/Vic) (subunit): 57
+ Systemic:
- IIV4-cc (subunit): 22
- IIV3-cc (B/Yam) (subunit): 27
- IIV3-cc (B/Vic) (subunit): 23
+ Others:
- IIV4-cc (subunit): 8
- IIV3-cc (B/Yam) (subunit): 7
- IIV3-cc (B/Vic) (subunit): 10
+ \*Not previously vaccinated subjects 4-5 and 6-9 years of age received two vaccinations, and previously vaccinated subjects 4-5, 6-8, and 9-17 years of age received one vaccination.
Across all vaccine groups, the most common solicited local AE was tenderness for children 4-5 years of age and injection-site pain for children 6-8 and 9-17 years of age. The most common solicited systemic AEs across all vaccine groups for children 4-5 years of age, 6-8 years of age, and 9-17 years of age were sleepiness, fatigue and headache, and headache respectively.
Proportion (%) of children reporting unsolicited AEs by group:- Any:
+ IIV4-cc (subunit): 24
+ IIV3-cc (B/Yam) (subunit): 24
+ IIV3-cc (B/Vic) (subunit): 27
- At least possibly related to vaccine:
+ IIV4-cc (subunit): 5
+ IIV3-cc (B/Yam) (subunit): 6
+ IIV3-cc (B/Vic) (subunit): 5
- SAE:
+ IIV4-cc (subunit): 1
+ IIV3-cc (B/Yam) (subunit): 1
+ IIV3-cc (B/Vic) (subunit): <1
- Medically attended:
+ IIV4-cc (subunit): 27
+ IIV3-cc (B/Yam) (subunit): 27
+ IIV3-cc (B/Vic) (subunit): 27
- New onset of chronic diseases:
+ IIV4-cc (subunit): 2
+ IIV3-cc (B/Yam) (subunit): 2
+ IIV3-cc (B/Vic) (subunit): 2
- No SAEs was judged by the study investigators as related to the study vaccine. No deaths were reported during the study.
- Germany Single-center
- 2013-2014 influenza season
- Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus Inc.)
+ Mean age: 53.8 years
+ 56% female
+ Total participants: n=126;
+ Adults aged 18 to ≤60 years: n=63
+ Adults aged ≥61 years: n=63
- Local\*: 51
- Pain at the injection site: 49
- Induration: 8
- Systemic\*\*: 27
- Headache : 17
- Fatigue: 16
- Malaise: 5
- Arthralgia: 5
\*Threshold for erythema, ecchymosis and induration: grade 0 (<10mm), any (≥10 mm)
\*\- Includes subjects with body temperature ≥38̊C irrespective of route of measurement
Proportion (%) of subjects aged ≥61 years with solicited AEs after vaccination with IIV3-cc:- Any: 35
- Local\*: 29
- Pain at the injection site: 29
- Induration: <2
- Systemic\*\*: 13
- Headache: 10
- Fatigue : N/A
- Malaise : N/A
- Arthralgia: 5
\*Threshold for erythema, ecchymosis and induration: grade 0 (<10mm), any (≥10 mm)
\*\- Includes subjects with body temperature ≥38̊C irrespective of route of measurement
Proportion (%) for all subjects with solicited AEs after vaccination with IIV3-cc:- Any: 46
- Local\*: 40
- Pain: 39
- Induration: 5
- Systemic\*\- : 20
- Headache : 14
- Fatigue : N/A
- Malaise : N/A
- Arthralgia: 5
\*Threshold for erythema, ecchymosis and induration: grade 0 (<10mm), any (≥10 mm)
\*\- Includes subjects with body temperature ≥38̊C irrespective of route of measurement
Proportion (%) of subjects aged 18 to ≤60 years with unsolicited AEs after vaccination with IIV3-cc:- Any AEs: 10
- At least possibly related AEs: 3
- Serious AEs: 2
- At least possibly related SAEs: 0
- Medically attended AEs: 6
- AEs leading to discontinuation: 0
- Death: 0
Proportion (%) of all subjects with unsolicited AEs after vaccination with IIV3-cc:- Any AEs: 8
- At least possibly related AEs: 2
- Serious AEs: 1
- At least possibly related SAEs: 0
- Medically attended AEs: 6
- AEs leading to discontinuation: 0
- Death: 0
Centers for Disease Control and Prevention and the US FDA
- 2013-2014 2014-2015 influenza seasons
- No external sources of funding
- Mean age: 18.5 years
- Range: 0.7–85 years
- Total reports reviewed: n= 629
- Reports with an AE: n= 309
- Reports during 2013–2014 influenza season: n= 389
- Reports during 2014–2015 influenza season: n=240
- administration site conditions: 49.20
- Immune system disorders: 23.60
- Anaphylaxis: 0.65
- Musculoskeletal and connective tissue: 11.90
- Nervous system disorders: 4.50
- Guillain-Barre syndrome: 1.30
- Bell’s palsy: 0.65
- Respiratory, thoracic and mediastinal disorders: 3.60
- Gastrointestinal disorders: 1.60
- Cardiac disorders: 1.60
- Skin and subcutaneous tissue disorders: 1.00
- Infections and infestations: 1.00
- Ear and labyrinth disorders: 0.60
- Other: 1.30
\*Each report was assigned a primary clinical category using MedDRA system organ classes (SOC)
19 (6.1%) of the 309 reports with an AE documented were serious.
313 reports of use in persons of inappropriate age (271 during the 2013–2014 initial season of IIV3-cc use); none of the 10 reports which described an AE were serious |
Supplemental Statement – Mammalian Cell Culture-Based Influenza Vaccines
=========================================================================
[Download the alternative format](/content/dam/phac-aspc/documents/services/immunization/national-advisory-committee-on-immunization-naci/mammalian-cell-culture-based-influenza-vaccines/naci-sppl-stmt-ammalian-cell-based-influenza-vaccines-en.pdf)
(PDF format, 2.6 MB, 71 pages)
**Organization:** [Public Health Agency of Canada](/en/public-health.html)
**Published:** 2020
**Cat. :** HP40-272-2020E-PDF
**ISBN :** 978-0-660-35644-0
**Pub. :** 200143
**An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)**
Table of contents
-----------------
* [Summary of information contained in this NACI statement](#sum)
* [I. Introduction](#a1)
* [II. Methods](#a2)
* [III. Vaccine](#a3)
+ [III.1 Mammalian Cell Culture-Based Influenza Vaccine Preparation Authorized For Use In Canada](#a3.1)
+ [III.2 Vaccine Efficacy and Effectiveness](#a3.2)
+ [III.3 Immunogenicity](#a3.3)
+ [III.4 Safety](#a3.4)
* [IV. Discussion](#a4)
* [V. Recommendation](#a5)
* [Tables](#a8)
* [List of abbreviations](#a9)
* [Acknowledgments](#a10)
* [References](#a11)
* [Appendix A: PRISMA Flow Diagram](#a12)
* [Appendix B: Characteristics of Inlfuenza Vaccines Available For Use in Canada, 2020–2021](#a13)
Preamble
--------
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC’s Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Summary of the information contained in this NACI supplemental statement
------------------------------------------------------------------------
The following highlights key information for immunization providers. Please refer to the remainder of the Statement for details.
1. **What**
Flucelvax® Quad is a mammalian cell culture-based, inactivated seasonal influenza vaccine that has recently been authorized for use in Canada in adults and children ≥9 years of age.
2. **Who**
This supplemental statement addresses the annual influenza vaccination of adults and children who do not have contraindications for the influenza vaccine.
3. **How**
Flucelvax® Quad may be considered among the quadrivalent influenza vaccines offered to adults and children ≥9 years of age for their annual influenza vaccination.
4. **Why**
Flucelvax® Quad is considered effective, immunogenic, and safe in adults and children ≥9 years of age, and has a comparable immunogenicity and safety profile to egg-based influenza vaccines already licensed in Canada and Flucelvax®, which is a trivalent cell culture-based influenza vaccine that has been licensed in the United States, but for which licensure has never been sought in Canada. Flucelvax® Quad can provide broader protection against influenza B viruses when compared with trivalent influenza vaccines.
I. Introduction
---------------
Influenza is a viral infection that is estimated to cause approximately 12,200 hospitalizations[Footnote 1](#fn1) and 3,500 deaths[Footnote 2](#fn2) in Canada annually. Influenza in humans is caused by two main types of influenza virus: A, which is classified into subtypes based on hemagglutinin (HA) and neuraminidase (NA) surface proteins, and B, which consists of two antigenically distinct lineages, B/Yamagata and B/Victoria. Seasonal influenza vaccines are either trivalent or quadrivalent formulations. Trivalent influenza vaccines contain two influenza A and one influenza B strain, and quadrivalent influenza vaccines contain the three strains included in trivalent vaccines and an additional influenza B strain from the other lineage of influenza B. Each year, the National Advisory Committee on Immunization (NACI) publishes a statement on seasonal influenza vaccines, which contains recommendations and guidance on the use of influenza vaccines for the upcoming influenza season.
Influenza vaccine production using mammalian cell culture-based technology is an innovative technique that may offer enhanced manufacturing scalability and sterility and, thus, a potentially valuable alternative to overcome some of the problems and vulnerabilities associated with egg-based production[Footnote 3](#fn3),[Footnote 4](#fn4),[Footnote 5](#fn5),[Footnote 6](#fn6). Cell culture systems are more rapid, and robust, and produce yields with higher purity and a lower risk of production failure compared to standard egg-based manufacturing. The production timeline for the manufacturing of cell culture-based vaccines is more flexible compared to egg-based production because cells are frozen and banked, and virus amplification relies primarily on the capacity of bioreactors[Footnote 3](#fn3),[Footnote 4](#fn4),[Footnote 5](#fn5). The use of cell-culture technology for the manufacturing of influenza vaccines offers the additional advantages of reduced microbial or chemical contamination due to a closed system of vaccine production. There is also potentially higher vaccine effectiveness relative to standard egg-based influenza vaccines due to insulation from egg-adaptive mutations changes, and there is potential for quicker large-scale production of vaccine[Footnote 3](#fn3),[Footnote 4](#fn4),[Footnote 5](#fn5),[Footnote 6](#fn6),[Footnote 7](#fn7). However, at the time of statement development, there is a lack of infrastructure and experience with the cell culture-based production platform for influenza vaccines and the resulting cost of these vaccines is typically greater compared to vaccines made using egg-based manufacturing.
Flucelvax® Quad (Seqirus, Inc.) is a mammalian cell culture-based quadrivalent inactivated, subunit influenza vaccine (IIV4-cc) that was authorized for use in Canada in adults and children 9 years of age and older on November 22, 2019[Footnote 8](#fn8). Flucelvax® Quad (also licensed as Flucelvax® Quadrivalent or Flucelvax® Tetra in other jurisdictions) is prepared from viruses propagated in mammalian cell lines [proprietary 33016-PF Madin-Darby Canine Kidney (MDCK) cell lines] adapted to grow freely in suspension in culture medium. The authorization of Flucelvax® Quad triggered the need for a supplemental NACI statement as it is the first and only available mammalian cell culture-based influenza vaccine in Canada, and NACI has not previously made a recommendation on cell culture-based influenza vaccines in any population.
Flucelvax® Quad builds on the clinical development of its trivalent predecessor, Flucelvax® (registered as Optaflu® in the European Union, Australia and Switzerland), a cell culture-grown, inactivated influenza vaccine developed by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus, Inc.). Flucelvax® was the first mammalian cell culture-derived inactivated influenza vaccine. It was approved for use in adults in Europe, under the trade name Optaflu®, from 2007 to 2017, and in the US under the trade name Flucelvax® since 2012. Originally, the same egg-derived candidate vaccine viruses (CVVs) used in egg-based manufacturing, but grown in cultured mammalian cells, were used in the production of Flucelvax®. On August 31, 2016, Seqirus, Inc. received approval from the US Food and Drug Administration (FDA) for the use of CVVs that had been isolated and propagated in MDCK cells for the manufacture of cell culture-based inactivated quadrivalent influenza vaccine[Footnote 9](#fn9). This approval enabled the production of completely cell-derived influenza vaccine viruses from the initial virus isolation through to the full manufacture of the vaccine. The Flucelvax® Quadrivalent vaccine (US product) for the 2017–2018 influenza season was the first vaccine to be manufactured from A(H3N2) CVVs produced exclusively using the cell-derived method, while the A(H1N1) and the B strain CVVs were egg-derived [Footnote 4](#fn4). For the 2018–2019 Flucelvax Quadrivalent vaccine, the A(H3N2) and B strain CVVs were derived from the mammalian cell line, while the A(H1N1) CVVs remained egg derived. The Flucelvax® quadrivalent formulation for the 2019–2020 influenza season was manufactured using CVVs for all four influenza viruses that were derived solely from mammalian cell lines. It has been hypothesized that propagation of CVVs in mammalian cells may improve vaccine effectiveness relative to licensed egg-based influenza vaccines by reducing the risk of antigenic drift and changes acquired in the HA of human influenza viruses during isolation, adaptation, and propagation in eggs[Footnote 4](#fn4),[Footnote 6](#fn6),[Footnote 10](#fn10).
**Guidance Objective**
The objective of this advisory committee supplemental statement is to review the evidence for efficacy, effectiveness, immunogenicity, and safety that is available for Flucelvax® Quad, and to provide guidance on its use in Canada in adults and children.
II. Methods
-----------
In brief, the broad stages in the preparation of a NACI Advisory Committee Statement are:
1. Knowledge synthesis of the whole body of evidence on benefits and harms, considering the quality of the evidence and magnitude of effects observed.
2. Translation of evidence into recommendations
Further information on NACI’s evidence-based methods is available in: [*Evidence-Based Recommendations for Immunization: Methods of the NACI, January 2009, CCDR*](http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/09vol35/acs-1/index-eng.php).
A systematic literature review was conducted to accumulate evidence for NACI’s recommendations regarding the use of Flucelvax® Quad, which is licensed for adults and children ≥9 years of age in Canada. Mammalian cell culture-based influenza vaccines have been approved for use by the US FDA in adults and children 4 years or older since the 2013-2014 influenza season (6 years) and effectiveness, immunogenicity, and safety data is currently available for this age group. The systematic review methodology was developed with the NACI Influenza Working Group (IWG) and specified a priori in a written protocol that included review questions, search strategy, inclusion and exclusion criteria, and quality assessment.
### Research question
What are the vaccine efficacy, effectiveness, immunogenicity, and safety of Flucelvax® Quad in persons 4 years of age and older?
P (population):
Children and adults (≥4 years of age)
I (intervention):
Mammalian cell culture-based influenza vaccine
C (comparison):
Egg-based, standard-dose quadrivalent inactivated influenza vaccine (IIV4-SD), trivalent, standard dose inactivated influenza vaccine (IIV3-SD), high-dose (IIV3-HD) or adjuvanted trivalent inactivated influenza vaccine (IIV3-Adj), mammalian cell culture-based trivalent inactivated, subunit influenza vaccine (IIV3-cc), placebo, or no comparator
O (outcomes):
Efficacy, effectiveness, immunogenicity, safety
The search strategy was developed based on the research question and PICO illustrated above, in conjunction with a librarian from the Health Library of Health Canada and PHAC (search strategy available upon request). The EMBASE, MEDLINE, Scopus, ProQuest Public Health, and ClinicalTrials.gov, electronic databases were searched for primary research articles and case reports from inception until February 12, 2019. Registered clinical trials and grey literature from international public health authorities and National Immunization Technical Advisory Groups were also considered. Searches were restricted to articles published in English and French due to the language proficiencies of the reviewers. Additionally, hand-searching of the reference lists of included articles was performed by one reviewer to identify additional relevant publications. Two reviewers independently screened the titles and abstracts of records retrieved from the database searches for potential eligibility. The full-texts of records deemed potentially eligible were obtained and further reviewed by both reviewers for potential inclusion in the review. Refer to Appendix A for the PRISMA Flow Diagram.
One reviewer extracted data from the studies included for review into an evidence table using a piloted data abstraction template designed to capture information on study design, population and outcomes of interest. A second reviewer independently validated the abstracted data with any disagreements or discrepancies resolved by discussion and consensus. The level of evidence (i.e. study design) and methodological quality of included studies was assessed independently by two reviewers using the design-specific criteria outlined by Harris et al.(2001)[Footnote 11](#fn11), which has been adopted by NACI for rating the internal validity of individual studies. Any disagreements or discrepancies in the data extraction and quality appraisal were resolved by discussion and consensus. The knowledge synthesis was performed by AS and JP, and was supervised by the Influenza Working Group (IWG).
Studies were included if they met the following criteria:
1. The study population or subpopulation consisted of individuals ≥4 years of age; and
2. Study assessed efficacy and effectiveness, immunogenicity, or safety of Flucelvax® Quad or safety of Flucelvax®
3. Primary research studies from peer-reviewed scientific literature
4. Case reports and case series
5. Registered clinical trials and grey literature from international public health authorities
6. Study is published in English or French
Studies were excluded if they met one or more of the following criteria:
1. The study did not present data on any of: the efficacy, effectiveness, immunogenicity, or safety of Flucelvax® Quad, or the safety of Flucelvax®;
2. The study is in a language other than English or French;
3. The study is a non-human or in vitro study;
4. The article is not a primary research study;
5. The article is an editorial, opinion, commentary or news report;
6. The article is an economic study, clinical practice guidelines, consensus conference, health technology assessment report; or
7. The article was a doctoral dissertation, master’s thesis, or conference summary
Flucelvax® Quad has overlapping composition with Flucelvax® (the trivalent formulation) and is produced using the same MDCK manufacturing platform[Footnote 12](#fn12),[Footnote 13](#fn13). Therefore, studies that assessed the safety of Flucelvax® were also included in this literature review post hoc to supplement the evidence base for the safety outcome. Specialty trivalent vaccines (i.e., high-dose trivalent inactivated influenza vaccine (IIV3-HD) and adjuvanted trivalent inactivated influenza vaccine (IIV3-Adj) were also added as comparator vaccines post hoc, since these comparisons would originally have been excluded as there is currently no comparable quadrivalent formulation of these vaccines.
### Development of Recommendations
Following critical appraisal of individual studies, summary tables with ratings of the quality of the evidence using NACI's methodological hierarchy ([Table 4](#t4) and [5](#t5)) were prepared, and proposed recommendations for vaccine use were developed. The evidence and proposed recommendations were discussed by the IWG in July 2019 and the NACI Vaccine Safety Working Group in August 2019. The IWG Chair and the Public Health Agency of Canada (PHAC) technical advisor (AS) presented the evidence and proposed recommendations to NACI on September 25, 2019. Following thorough review of the evidence, NACI approved the recommendation contained in this statement on December 16, 2019. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the following sections.
III. Vaccine
------------
### III.1 Mammalian Cell Culture-Based Influenza Vaccine Preparation Authorized for Use in Canada
Flucelvax® Quad is a subunit influenza vaccine prepared from CVVs isolated and propagated in a MDCK cell line. It is authorized for intramuscular (IM) injection and is available as a 0.5 mL single-dose, pre-filled syringe without a needle, and as a 5 mL multi-dose vial containing 10 doses (each dose is 0.5 mL). For more information on Flucelvax® Quad, refer to the product monograph[Footnote 8](#fn8).
Table 1. Characteristics of Flucelvax® Quad influenza vaccine
| Route of Administration | Dosage | Non-medicinal Ingredients |
| --- | --- | --- |
| Intramuscular | Each 0.5 mL dose contains 15 μg of hemagglutinin (HA) of each of the four influenza virus strains contained in the vaccine. | Disodium phosphate dihydrate, magnesium chloride hexahydrate, potassium chloride, potassium dihydrogen phosphate, sodium chloride, thimerosal (multi-dose vial only) and water for injection.
Each dose may also contain residual amounts of:
beta-propiolactone, cetyltrimethlyammonium bromide, polysorbate 80 |
### III.2 Vaccine Efficacy and Effectiveness
No efficacy studies for Flucelvax® Quad were identified and studies evaluating the efficacy of Flucelvax® were beyond the scope of this review.
Four studies, two peer-reviewed and two not peer-reviewed were identified that assessed the effectiveness of Flucelvax® Quad[Footnote 14](#fn14),[Footnote 15](#fn15),[Footnote 16](#fn16),[Footnote 17](#fn17). Of these four studies, two were of good quality[Footnote 15](#fn15),[Footnote 16](#fn16), while the quality of the other two studies[Footnote 14](#fn14),[Footnote 15](#fn15),[Footnote 16](#fn16),[Footnote 17](#fn17) could not be assessed because they were published as conference abstracts or posters. Common concerns relating to the quality of evidence included potential residual or unmeasured confounding even after statistical adjustments[Footnote 14](#fn14),[Footnote 15](#fn15),[Footnote 16](#fn16),[Footnote 17](#fn17) and exposure and outcome misclassification[Footnote 14](#fn14),[Footnote 15](#fn15),[Footnote 16](#fn16). The following section outlines the key effectiveness findings from all these studies; additional details regarding study characteristics and results are shown in [Table 6](#t6).
#### III.2.1 Effectiveness against Influenza Infection
Two studies assessed the vaccine effectiveness (VE) of IIV4-cc compared to egg-based IIV against laboratory-confirmed influenza infection during the 2017–2018 influenza season in the USA. The first was a peer-reviewed study by DeMarcus et al. (2019), which used test-negative case-control design and was conducted by the US Department of Defense Global Respiratory Pathogen Surveillance Program[Footnote 15](#fn15). The DeMarcus et al. (2019) study included Department of Defense (DoD) healthcare beneficiaries (excluding service members) 6 months–94 years of age (median age: 13 years) who presented to a military treatment facility with symptoms of influenza-like illness (ILI) and had a respiratory specimen collected between October 1st 2017–April 28 2018. Individuals testing positive for influenza by reverse transcription polymerase chain reaction (RT-PCR) or viral culture, were classified as cases, while influenza-negative individuals were classified as controls[Footnote 15](#fn15). The second study by Klein at al. (2018), which was not peer-reviewed, is a retrospective cohort analysis of VE against PCR-confirmed influenza A(H3N2) influenza virus infection among Kaiser Permanente Northern California members aged 4–64 years [Footnote 17](#fn7).
The results from the study by DeMarcus et al. (2019) indicated that the odds of having any laboratory-confirmed influenza infection were not statistically significantly different between individuals who had received IIV4-cc and those who received egg-based IIV (trivalent or quadrivalent formulation). The authors conducted sub-analyses by influenza subtype and by age group, and found that the odds of having influenza A(H1N1)pdm09 infection were higher overall for all DoD dependents (odds ratio [OR]: 2.0; 95% CI: 1.1–3.6 %) and for children (OR: 2.9; 95% CI: 1.3–6.3%) who received the IIV4-cc compared to those that received an egg-based IIV [Footnote 15](#fn15). The odds of having influenza A(H3N2) infection appeared to be lower overall and for adults who received the IIV4-cc compared to egg-based IIV, but the results did not reach statistical significance[Footnote 15](#fn15). All other estimates showed no statistically significant difference between the two vaccine types[Footnote 15](#fn15).
The results from the study by Klein et al. indicated that both IIV4-cc and egg-based IIV [trivalent (received by 86.2% of members) or quadrivalent formulation] had relatively low effectiveness with respect to the risk of laboratory-confirmed influenza during the 2017–2018 influenza season. The authors found no statistically significant difference in VE against laboratory-confirmed influenza A infection between individuals vaccinated with IIV4-cc versus egg-based IIV (adjusted rVE: 6.8%; 95% CI: -11.2–21.9%; P=0.43)[Footnote 17](#fn17). The adjusted absolute VE for subjects vaccinated with IIV4-cc was 30.2% (95% CI: 17.1–41.3%; P<0.0001) and 17.9% (95% CI: 12.1–23.3%; P<0.0001) for subjects vaccinated with either egg-based IIV4 or IIV3[Footnote 17](#fn17).
#### III.2.2 Effectiveness against Influenza-Related Health Care Interactions
One study by Izurieta et al. (2018) assessed the VE of IIV4-cc compared to 4 other egg-based influenza vaccines (egg-based, standard-dose quadrivalent IIV (IIV4-SD), egg-based IIV3, egg-based IIV3-Adj, and egg-based IIV3-HD) in preventing influenza-related health care interactions (i.e. office visits and hospital encounters). Influenza-related office visits were defined as community-based visits to physicians’ offices and hospital outpatient visits in which a rapid influenza test was performed by the healthcare provider and a therapeutic course of oseltamivir (75 mg twice daily for 5 days) was prescribed within 2 days following the test[Footnote 16](#fn16). Hospital encounters were defined as inpatient hospitalizations and emergency department visits in which International Classification of Diseases (ICD), Tenth revision, Clinical Modification, code for influenza was listed. This retrospective cohort study made use of electronic medical records (EMRs) providing data on enrolment in fee-for-service Medicare parts A and B in the 6 months before vaccination, inpatient and outpatient care, physician office visits, and prescription drugs for Medicare beneficiaries ≥65 years of age who received an influenza vaccine during the 2017–2018 influenza season(16). Estimates were adjusted using inverse probability of treatment weighting, and weights were derived from propensity scores[Footnote 16](#fn16). Relative vaccine effectiveness (rVE) was defined as the difference in influenza-related hospital encounters between persons vaccinated with IIV4-cc versus egg-based vaccines.
In a 2-way comparison, IIV4-cc was statistically significantly more effective against office visits (rVE): 10.5%; 95% CI: 6.8%–14.0%) and hospital encounters (rVE: 10.0%; 95% CI: 7.0%–13.0%) than egg-based, IIV4-SD[Footnote 16](#fn16). In an analysis comparing this vaccine to four other egg-based formulations, IIV4-cc was statistically significantly (P≤0.05) more effective against office visits compared to egg-based IIV4-SD and IIV3-Adj, and against inpatient stays and hospital encounters, compared to egg-based IIV3-SD, IIV4-SD, and IIV3-Adj[Footnote 16](#fn16). In addition, IIV4-cc was statistically significantly more effective against office visits compared to egg-based IIV3-HD, but not against inpatient visits or hospital encounters[Footnote 16](#fn16).
#### III.2.3 Effectiveness against Influenza-Like Illness
One study that was recently accepted for publication assessed the effectiveness of Flucelvax® Quadrivalent for the prevention of ILI[Footnote 14](#fn14). Boikos et al. (2018) conducted a retrospective cohort study in the US during the 2017–2018 influenza season to determine the relative VE (rVE) of Flucelvax® Quadrivalent to standard-dose quadrivalent egg-based inactivated influenza vaccines against ILI [as defined by the Armed Forces Health Surveillance Centre (AFHSC) ICD Code Set B][Footnote 18](#fn18) in individuals ≥4 years of age[Footnote 14](#fn14). The rVE estimates were based on real-world primary care data from the EMRs of individual patients 4 years of age and older who were vaccinated with either Flucelvax® Quadrivalent (n= 92,192) or egg-based IIV4-SD (n=1,255,983). Results demonstrated that Flucelvax® Quadrivalent was statistically significantly more effective than egg-based IIV4-SD in preventing ILI[Footnote 14](#fn14). The estimate for rVE against ILI was 36.2% (95% CI: 26.1–44.9%; P<0.001) after adjusting for differences in age, sex, health status, and geographic region between the two exposure groups[Footnote 14](#fn14). The result from a sensitivity analysis using propensity scores was consistent in terms of direction and statistical significance compared to the adjusted estimate (propensity-score matched rVE: 19.3%; 95% CI: 9.5–28.0%)[Footnote 14](#fn14). When stratified by age, however, Flucelvax® Quadrivalent was statistically significantly more effective than egg-based IIV4-SD in preventing ILI in adults aged 18–64 years (propensity-score matched rVE: 26.8%; 95% CI: 14.1–37.6%; P<0.001), but did not reach statistical significance in children 4-17 years of age (propensity-score matched rVE: 18.8 %; 95% CI: -53.9-57.2%) or adults 65 years of age or older (propensity-score matched rVE: -7.3 %; 95% CI: -51.6-24.0%)[Footnote 14](#fn14).
### III.3 Immunogenicity
Regulators in Canada, the US, and Europe accept non-inferiority immunogenicity trials that compare the hemagglutination inhibition (HI) antibody response of the new vaccine to that of an existing licensed vaccine, or placebo-controlled immunogenicity trials that assess the HI antibody response to the new vaccine. Non-inferiority and placebo-controlled immunogenicity trials are often considered sufficient by regulatory authorities when there are bridging data to correlate immunogenicity outcomes to clinical protection, or when the new vaccines are considered by the regulators to be very similar to vaccines already authorized. Serological assessments based on the geometric mean titres (GMTs) of HI antibody that are used by regulators are: GMT ratio, seroprotection rate, and seroconversion rate. The FDA has published definitions for these serological assessments and criteria for immunogenicity data necessary for influenza vaccine licensure[Footnote 19](#fn19). These definitions and currently used criteria are shown in [Table 2](#t2). Correlates of protection that are not based on HI antibody titres have not been well established.
Two studies[Footnote 20](#fn20),[Footnote 21](#fn21) that assessed the immunogenicity of Flucelvax® Quad compared to different IIV3-cc (Flucelvax, Seqirus, Inc.) formulations were identified in this review; one study by Bart et al. (2016) was conducted with adult subjects 18 years of age and older, while the other study by Hartvickson et al. (2015) focused on pediatric subjects 4 to 17 years of age. Additional details on the immunogenicity findings from these studies are shown in [Table 7](#Table_7). The adult randomized controlled trial (RCT) was of good quality overall. One methodological concern identified was that the study did not examine the subjects’ vaccination history from previous seasons. The pediatric study was of fair quality, as subjects’ HI titre was measured at different times, depending on whether the subject had been vaccinated previously or not.
Although no studies that assessed the immunogenicity of Flucelvax® Quad compared to egg-based IIV (trivalent or quadrivalent) were identified, non-inferiority of its trivalent predecessor, Flucelvax®, compared to egg-based IIV3 has been established in adult and pediatric subjects[Footnote 22](#fn22),[Footnote 23](#f23),[Footnote 24](#fn24),[Footnote 25](#fn25).
#### III.3.1 Immunogenicity in Adults
Bart et al. (2016) conducted a Phase III, double-blind, RCT study to assess the immunogenicity of Flucelvax Quad compared to two IIV3-cc (Flucelvax®; Seqirus), which contained either an influenza B/Victoria or B/Yamagata lineage strain, in healthy adults ≥18 years of age[Footnote 20](#fn20). The study compared the GMT ratio, seroprotection rate, and seroconversion rate in the control and intervention groups 22 days after vaccination[Footnote 20](#fn20). Flucelvax® Quad demonstrated non-inferiority to the two IIV3-cc in the HI antibody responses against influenza A(H1N1), A(H3N2), and the B lineage contained in the trivalent vaccines, based on GMT ratio and seroconversion rates. Flucelvax Quad demonstrated superiority for the influenza B lineage that was not included in the IIV3-cc[Footnote 20](#fn20). In a sub-analysis, Flucelvax® Quad also met the threshold for non-inferiority based on seroprotection rate for adults 18–64 years of age and ≥65 years of age[Footnote 20](#fn20).
#### III.3.2 Immunogenicity in Children
Hartvickson et al. (2015) conducted a RCT study comparing the immunogenicity of Flucelvax® Quad to two formulations of IIV3-cc (Flucelvax®), containing either an influenza B/Victoria or B/Yamagata strain, in healthy children 4–17 years of age[Footnote 21](#fn21). Children <9 years of age who were not previously vaccinated received two doses of influenza vaccine (n=694)[Footnote 21](#fn21). The study compared the GMT, seroprotection rate, and seroconversion rate in the control and intervention groups on day 22 post-vaccination for those who had been previously vaccinated and on day 50 for those that had not been previously vaccinated[Footnote 21](#fn21). Flucelvax® Quad met non-inferiority criteria for all four influenza strains contained in the IIV3-cc vaccines in healthy children aged 4–17 years[Footnote 21](#fn21). Flucelvax® Quad also demonstrated superiority for both influenza B strains over the unmatched B lineage included in the comparator IIV3-cc[Footnote 21](#fn21). Flucelvax® Quad also met the threshold for seroprotection for all strains[Footnote 21](#fn21).
The immunogenicity for Flucelvax® Quad is supported by evidence from the clinical development program for Flucelvax® (trivalent formulation), which has been licensed in the US and produced using the same MDCK manufacturing platform [Footnote 36](#fn36),[Footnote 37](#fn37),[Footnote 38](#fn38),[Footnote 39](#fn39). Flucelvax® has demonstrated non-inferiority to standard egg-based IIV3 comparators, including Agrippal® (Seqirus; marketed in Canada as Agriflu®) and Fluvirin® (GSK), for HI antibody responses overall to any strain in adults ≥18 years of age and for A(H1N1) and B strains specifically, but not A((H3N2), for persons 4 to 17 years of age, based on post-vaccination GMT ratios and seroconversion rates [Footnote 22](#fn22),[Footnote 23](#fn23),[Footnote 24](#fn24),[Footnote 25](#fn25).
### III.4 Safety
This review identified two peer-reviewed studies[Footnote 20](#fn20),[Footnote 21](#fn21) that assessed the safety of Flucelvax® Quad; both studies were RCTs with one focused on healthy adults[Footnote 20](#fn20) and the other on healthy children[Footnote 21](#fn21). For both of these studies, the safety outcomes assessed included solicited local and systemic adverse events (AE) from day 1–7 post-vaccination, serious adverse events (SAE) through 6 months after the last vaccination, and unsolicited AEs from day 1–23 post-vaccination. No studies that assessed the safety of Flucelvax® Quad compared to egg-based IIV (trivalent or quadrivalent) were identified in this review.
Flucelvax® Quadrivalent has been licensed in the US for use in adults and children 4 years or older in since 2016. Since authorization, no safety signals have been identified through routine pharmacovigilance. AE that have been reported during post-licensure use of Flucelvax® Quadrivalent in the US include, allergic or acute hypersensitivity reactions, nervous system disorders (syncope, presyncope, paresthesia), generalized skin reactions (pruritus, urticaria or non-specific rash), and extensive swelling of injected limb. However, a reliable estimate of the frequency of these reactions is not available and no definitive causal link to vaccination with Flucelvax® Quadrivalent has been established.
In addition, six peer-reviewed clinical studies[Footnote 3](#fn3), [Footnote 26](#fn26),[Footnote 27](#fn27),[Footnote 28](#fn28),[Footnote 29](#fn29),[Footnote 30](#fn30)and one clinical review of cases[Footnote 31](#fn31) that assessed the safety of Flucelvax® were included in this review, four of which assessed safety in adults and two of which assessed safety in children. The safety evidence for Flucelvax® (trivalent) was considered relevant, as although licensure for Flucelvax® has never been sought in Canada, Flucelvax® and Flucelvax® Quad have overlapping compositions and are produced using the same MDCK manufacturing platform. In addition to these six published studies, it should be noted that Flucelvax® has an established record of safety in other jurisdictions, and no new safety signals have been identified through routine pharmacovigilance in the USA or Europe where the vaccine has been licensed[Footnote 22](#fn22),[Footnote 23](#fn23),[Footnote 31](#fn31).
Additional details on the safety evidence presented in this review are shown in [Table 8](#t8). No published clinical data pertaining to safety of vaccination with IIV4-cc or IIV3-cc during pregnancy is currently available to inform vaccine-associated risks.
#### III.4.1 Adverse Events in Adults
Bart et al. (2015) assessed the safety of Flucelvax® Quadrivalent in healthy adults 18–64 years of age and older adults ≥65 years of age compared to two IIV3-cc produced using the same cell culture-based manufacturing process[Footnote 20](#fn20). Across the three vaccine groups, a similar proportion of adults reported at least one solicited AE. The reported solicited local and systemic AE were generally mild to moderate in intensity, self-limited, and did not precipitate sequelae. There were also no major differences in the percentages of all adults (≥18 years of age) who reported unsolicited AE [IIV4-cc: 16.1%; IIV3-cc (B/Yamagata): 14.7%; IIV3-cc (B/Victoria): 16.5%]. Subgroup analyses based on age, sex, and race or ethnicity did not reveal any major variations in the AE profiles of the three vaccine groups in this study.
##### Solicited adverse events
Injection site pain was the most common solicited AE and was reported by 33.6% of adults in the IIV4-cc group, 27.8% in the IIV3-cc (B/Yamagata) group, and 29.4% in the IIV3-cc (B/Victoria) group[Footnote 20](#fn20). Although a slightly higher percentage of adults (0.2%) in the IIV4-cc group reported severe pain compared to the IIV3-cc groups (0.1%), the proportion of adults experiencing other solicited local AE was comparable between the different groups overall[Footnote 20](#fn20). Notably, one case of severe ecchymosis and one case of severe induration were identified after vaccination with IIV3-cc (B/Yamagata)[Footnote 20](#fn20). Fatigue and headache were the most common solicited systemic AE experienced by adults in this study[Footnote 20](#fn20). Within the IIV4-cc group, 13.5% of subjects reported fatigue and 14.0% reported headaches. A similar proportion of adults in the IIV3-cc groups experienced fatigue (IIV3-cc (B/Yamagata): 16.3%; IIV3-cc (B/Victoria): 12.2%) and headaches (IIV3-cc (B/Yamagata): 13.4%; IIV3-cc (B/Victoria): 13.4%)[Footnote 20](#fn20). The incidence of severe systemic AEs was very low (<1%) overall[Footnote 20](#fn20). Only 15 subjects across the three vaccine groups reported experiencing fever following vaccination; however, the fever did not exceed 40°C in any of these cases[Footnote 20](#fn20). Across studies that assessed the safety of IIV3-cc compared to egg-based IIV3 Agrippal® (marketed in Canada as Agriflu®), pain and redness at the injection site were the most common local adverse reactions, while headache, myalgia, malaise, and fatigue were the most common systemic adverse reactions observed across the different age groups[Footnote 27](#fn27),[Footnote 28](#fn28),[Footnote 29](#fn29). Overall, the local and systemic solicited reactions as well as unsolicited AE and SAE were comparable to those typically observed with other injectable influenza vaccines[Footnote 27](#fn27),[Footnote 28](#fn28),[Footnote 29](#fn29). None of the deaths or SAEs reported over the course of these IIV3-cc studies were assessed as vaccine related [Footnote 27](#fn27),[Footnote 28](#fn28),[Footnote 29](#fn29).
##### Unsolicited adverse events and serious adverse events
The percentages of unsolicited AEs and medically attended AEs in the Bart el. al study were somewhat higher in adults ≥65 years of age compared to adults 18–64 years of age; however, these two age groups demonstrated a similar incidence of possibly vaccine-related AEs. New onset of chronic diseases (NOCD), specifically metabolic and nutritional disorders, cardiac disorders, and musculoskeletal and connective tissue disorders, were reported by 4.4% of study participants; however, there were no significant differences between vaccine groups or age groups[Footnote 20](#fn20). No indication of new onset of neurologic disorders, increased frequency of specifically monitored SAEs, or other safety signals was identified among IIV4-cc recipients[Footnote 20](#fn20). Over the course of this study, 12 deaths were reported (5 in the IIV4-cc group and 7 in the IIV3-cc groups) [Footnote 20](#fn20). The proportion of participants who died during the course of the study was similar across vaccine groups in both the 18–64 age group (IIV4-cc: 0%; IIV3-cc (B/Yamagata): 0%; IIV3-cc (B/Victoria): 0.3%) and the ≥65 age group (IIV4-cc: 0.8%; IIV3-cc (B/Yamagata): 1.5%; IIV3-cc (B/Victoria): 0.3%). None of the SAEs orAEs leading to premature withdrawal or deaths were considered to be vaccine-related by the sponsor[Footnote 20](#fn20). The proportion of adults who experience unsolicited AEs and SAEs were comparable to those typically observed with other injectable influenza vaccines[Footnote 20](#fn20). This review also identified a case report of a 55-year-old woman with multiple comorbidities, who developed optic neuropathy and severe visual impairment in the right eye following vaccination with Flucelvax®[Footnote 32](#fn232). In this case, progressive unilateral optic neuritis occurred secondary to a systemic reaction involving a wide range of symptoms that began two days after influenza vaccination[Footnote 32](#fn32). However, it should be noted that there was no definitive link established between this very rare serious adverse reaction and vaccination with IIV3-cc[Footnote 32](#fn32).
A clinical review of post-licensure surveillance data from the Vaccine Adverse Event Reporting System (VAERS), which closely monitors anaphylaxis events related to newly licensed vaccines prerecommended for use in the US, found that the crude reporting rate for hypersensitivity reactions among reports of AEs in adults aged ≥18 years who were vaccinated with Flucelvax® (IIV3-cc) during the first two influenza seasons of distribution (2013–2014 and 2014–2015) was similar to or less than what has been observed for other influenza vaccines (12.7 cases per million doses distributed)[Footnote 31](#fn31). Two reports of anaphylactic reactions were identified; one report met Brighton Collaboration criteria level 2, and the second report did not meet Brighton criteria but was diagnosed by the attending physician as an anaphylactic reaction. Notably, a causal association with IIV3-cc has not been established for these two anaphylaxis reports. The crude reporting rate for anaphylaxis over these 2 years was 0.4 per million doses distributed; however, estimates for crude reporting rates for hypersensitivity reactions and anaphylaxis should be interpreted with caution given the uncertainties regarding the completeness, quality, and consistency of the data reported to VAERS and the use of doses distributed as a denominator[Footnote 31](#fn31).
#### III.4.2 Adverse Events in Children
Hartvickson et al. (2015) assessed the safety of Flucelvax® Quad in healthy children aged 4–18 years of age compared to two IIV3-cc (Flucelvax®): one containing an influenza B/Yamagata lineage and one containing a B/Victoria lineage. Most solicited adverse reactions among those receiving Flucelvax® Quad were mild in severity, and all resolved within a few days without sequelae[Footnote 21](#fn21). The rates and types of unsolicited AEs in children who received IIV4-cc or a comparator IIV3-cc were comparable to those typically seen with routine childhood vaccinations [Footnote 21](#fn21).
##### Solicited adverse events
Across all vaccine groups in the Hartvickson et al. (2015) study, the most common solicited local AE was tenderness for children 4–5 years of age, and injection-site pain for children 6–8 and 9–17 years of age[Footnote 21](#fn21). The proportion of children who experienced solicited local AEs were similar for the intervention and control groups across all ages[Footnote 21](#fn21). The largest difference in proportion between vaccine groups was for children 4–5 years of age reporting local AEs; 53% of children in the IIV4-cc group reported unsolicited local AEs compared to 44% and 36% in the IIV3-cc (B/Yamagata) and IIV3-cc (B/Victoria) groups respectively[Footnote 21](#fn21). For children <9 years of age who received a second dose, the proportions of solicited local AEs were also similar across study groups[Footnote 21](#fn21). In general, of the children that received two doses, there was a higher proportion of local AEs after the first dose compared to the second[Footnote 21](#fn21). The most common solicited systemic AEs were sleepiness for children 4–5 years of age, fatigue for children 6–8 years of age, and headache for children 9–17 years of age across all vaccine groups[Footnote 21](#fn21). Among children 6–8 years of age, the proportion of children who reported solicited systemic AEs was generally higher after the first vaccination compared to the second vaccination. However, children 4–5 years of age demonstrated a 1–3% increase in the percentage of solicited systemic AEs after the second vaccine dose in each of the vaccine groups[Footnote 21](#fn21).
Two studies[Footnote 26](#fn26),[Footnote 30](#fn30) that assessed the safety of IIV3-cc compared to a standard egg-based IIV3 (Fluvirin®; licensed in the US but not available in Canada) in healthy children were identified in this review. Vesikari et al. (2012) found that the most common local AE among children 3–8 and 9–17 years of age was injection site pain, and the most common systemic AE were myalgia and headache [Footnote 26](#fn26). Nolan et al. (2016) assessed the safety of IIV3-cc in healthy children and adolescents 4-17 years of age stratified into two cohorts (4–8 year-olds and 9–17 year-olds)[Footnote 30](#fn30). Children 4-8 years of age who were not previously vaccinated received two doses of influenza vaccine[Footnote 30](#fn30). The proportion of children in the 4-8 year-old age group who were not previously vaccinated and experienced solicited local and systemic AEs was similar for the intervention and control groups after the second vaccination[Footnote 30](#fn30). For previously vaccinated children 4-17 years of age who received a single dose, the proportions of solicited local AEs were similar to not previously vaccinated children 4-8 years of age[Footnote 30](#fn30). Overall, no important differences in safety outcome were identified between children who had received the IIV3-cc and the egg-based IIV3 [Footnote 26](#fn26),[Footnote 30](#fn30).
##### Unsolicited adverse events and serious adverse events
The proportion of reported unsolicited AE was similar in the three vaccine groups in the Hartvickson et al. (2015) study, and ranged from 24–27%[Footnote 21](#fn21). Approximately 1% of children 4–17 years of age experienced any SAE in all study groups[Footnote 21](#fn21). New onset of chronic diseases was reported in 2% of study participants in each of the vaccine groups[Footnote 21](#fn21). No deaths were reported over the course of the study and none of the SAEs were considered to be related to the vaccine[Footnote 21](#fn21).
Vesikari et al. (2012) and Nolan et al. (2016) assessed the safety of IIV3-cc compared to egg-based IIV3 (Fluvirin). Unsolicited AEs occurred in 1-4% of subjects across age and vaccine groups in the Vesikari et al. (2012) study and 0 to <1% were considered at least possibly related to the study vaccines. There were no deaths reported over the course of Vesikari et al. (2012) study and none of the 28 SAEs (4 during the post-vaccination period, 24 during the 6-month safety follow-up period) documented in the study were assessed as vaccine related. No deaths or vaccine-related SAEs were reported in Nolan et al. (2016) study and one of the withdrawals from the study was due to a non-serious AE.
### IV. Discussion
The present systematic review examined studies investigating the effectiveness, immunogenicity, and safety of Flucelvax® Quad, the first mammalian cell culture-based seasonal influenza vaccine to be approved for adult and pediatric use in Canada. The peer-reviewed published evidence on the effectiveness of Flucelvax® Quad manufactured from CVVs produced solely using the cell-derived method is sparse. Four observational VE studies, two peer-reviewed and two not peer-reviewed, were identified in this review. There was some data indicating that Flucelvax® Quad may potentially offer improved protection against influenza compared to egg-based IIV4 or IIV3, particularly against A(H3N2) virus infection. However, interpretation of the data from these observational studies is limited as all the analyses were conducted using data only from the 2017–2018 influenza season in the US, which was influenza A(H3N2)-dominant. Furthermore, two of the retrospective studies[Footnote 14](#fn14),[Footnote 16](#fn16),[Footnote 16](#fn14) evaluating VE utilized real-world primary care data from the EMRs of individual patients. This approach for influenza VE estimation has not yet been validated and the potential sources of bias and confounding still need to be further investigated.
Two RCTs conducted in adults and children 4 years of age and older[Footnote 20](#fn20),[Footnote 21](#fn21) that specifically assessed the immunogenicity and safety of Flucelvax® Quad were identified in this review. However, both studies used Flucelvax® IIV3-cc (produced by Seqirus using the same cell culture-based manufacturing process) as the comparator and were conducted during the 2013–2014 influenza season, which was prior to the FDA’s supplemental approval for the use of CVVs that had been isolated and propagated in MDCK cells for the manufacture of cell culture-based influenza vaccines. In both studies, Flucelvax® Quad demonstrated non-inferiority, based on GMT ratio and seroconversion rates, and met the threshold for seroprotection for all influenza strains contained in the IIV3-cc vaccines. The immunogenicity evidence for Flucelvax® Quad builds on the clinical development program of Flucelvax® IIV3-cc, noting that authorization for Flucelvax® (trivalent) has never been sought in Canada. Flucelvax® has demonstrated non-inferiority to licensed egg-based IIV3 comparators in for all strains in adults ≥18 years of age and A/H1N1 and B strains but not the A/H3N2 influenza strain for persons 4 to 17 years of age. Notably, Flucelvax® IIV3-cc was manufactured using egg-derived CVVs prior to the implementation of manufacturing methods using CVVs solely derived from MDCK cells.
This review also examined studies[Footnote 3](#fn3), [Footnote 26](#fn26),[Footnote 27](#fn27),[Footnote 28](#fn28),[Footnote 29](#fn29),[Footnote 30](#fn30) that assessed the safety of Flucelvax®, which is a trivalent vaccine produced using the same cell culture-based manufacturing platform, to supplement the evidence base for safety. These studies found that IIV-cc are a safe, well-tolerated, and immunogenic alternative to conventional egg-based influenza vaccines for children and adults. There is a theoretical concern that inactivated influenza vaccines produced in canine kidney cells (MDCK 33016-PF) may cause adverse reactions in individuals with dog allergy. This issue has been investigated in two in vitro studies, which used biological assays to evaluate the potential allergenicity of MDCK cell-based vaccines [Footnote 33](#fn33),[Footnote 34](#fn34). The results of these studies suggest that influenza vaccines produced in MDCK cells do not have the potential to trigger hypersensitivity reactions in individuals with documented allergies associated with dogs. In addition, there has been no signal of an elevated risk of severe allergic reactions as compared to egg-based influenza vaccines identified through IIV-cc clinical trials or post-market safety surveillance[Footnote 33](#fn33),[Footnote 34](#fn34).
Influenza vaccine production using mammalian cell culture-based technology may offer enhanced manufacturing scalability, sterility, timeliness, and flexibility compared to traditional egg-based manufacturing platforms. Implementation of cell culture-based influenza vaccine technologies and other alternatives to egg-based methods will also enable diversification of vaccine manufacturing platforms to overcome influenza vaccine supply vulnerabilities and improve vaccine-production capacity. Additionally, research has indicated that influenza A(H3N2) viruses can undergo changes that decrease antigenic relatedness to wild-type, circulating viruses when they are grown in eggs, and that certain egg-adaptive mutations may negatively affect the immunogenicity, efficacy, and effectiveness of standard egg-based influenza vaccines, especially during influenza A(H3N2)-dominant seasons[Footnote 4](#fn34),[Footnote 10](#fn10),[Footnote 35](#fn35),[Footnote 36](#fn36),[Footnote 37](#fn37),[Footnote 38](#fn38),[Footnote 39](#fn39). Cell culture-based influenza vaccines solely derived from cell culture-based CVVs are insulated from such egg-adaptive changes and have the potential to provide enhanced protection in some seasons compared to standard egg-based influenza vaccines[Footnote 3](#fn3),[Footnote 6](#fn6),[Footnote 10](#fn10). Nevertheless, adaptation in cell culture-based influenza vaccines needs to be further investigated given the potential for mutations in the genetic segments of HA and NA proteins resulting of serial passaging in MDCK cells [Footnote 40](#fn40),[Footnote 41](#fn41).Therefore, ongoing monitoring of vaccine effectiveness, immunogenicity, and safety will be important to compare prior and future seasons, across influenza subtypes, and overall VE for each vaccine type. A more robust, comprehensive and consistent body of evidence, including data on comorbidities, pregnant women, health status, and other potential confounders[Footnote 42](#fn42), is also needed to evaluate the relative effectiveness and safety of Flucelvax® Quad compared to other injectable influenza vaccines.
### V. Recommendation
The following section outlines the recommendation that NACI has made regarding the use of Flucelvax® Quad in adults and children. Additional information on the strength of NACI recommendations and the grading of evidence is available in [Table 3](#t3).
The following recommendation for Flucelvax® Quad supplements NACI’s overarching recommendation for influenza vaccination, which is available in the NACI Seasonal Influenza Vaccine Statement. The overarching NACI recommendation for influenza vaccination is that an age appropriate influenza vaccine should be offered annually to anyone 6 months of age and older (Strong NACI Recommendation), noting product-specific contraindications.
1. **NACI recommends that Flucelvax® Quad may be considered among the IIV4 offered to adults and children ≥9 years of age (Discretionary NACI Recommendation)**
* **NACI concludes that there is fair evidence to recommend vaccination of adults and children ≥9 years of age with Flucelvax® Quad (Grade B Evidence).**
#### Summary of Evidence and Rationale
* There is fair evidence that Flucelvax® Quad is effective, safe, and has non-inferior immunogenicity to comparable vaccines, based on direct evidence in adults and children ≥9 years of age.
* There is limited peer-reviewed evidence on the effectiveness, immunogenicity, and safety of Flucelvax® Quad manufactured using fully cell-derived viruses.
* There is some evidence that, overall, Flucelvax® Quad may be more effective than egg-based trivalent or quadrivalent influenza vaccines against non-laboratory confirmed influenza-related outcomes but there is insufficient evidence for laboratory-confirmed outcomes. The clinical significance and directness of the evidence provided by influenza-related outcomes, which are surrogate measures of influenza activity, and the validity of observational studies using EMRs for influenza vaccine effectiveness estimation remain uncertain and need to be further evaluated
* Although some data suggests that IIV4-cc may be more effective against laboratory-confirmed influenza A(H3N2) virus infection than egg-based IIV, there was no consistent and statistically significant difference in effectiveness identified for adults or children vaccinated with IIV4-cc compared to egg-based IIV. Therefore, no firm conclusions can be drawn at this time, and NACI will continue to monitor this issue.
* All studies that assessed effectiveness were conducted in the US during the same season (2017–2018), which was influenza A(H3N2)-dominant. As influenza seasons can vary widely from year to year, further evidence on effectiveness gathered during influenza seasons with different circulating viruses is needed before a conclusion on the relative effectiveness can be made.
* NACI will continue to monitor the evidence related to cell-culture based influenza vaccines and will update this supplemental statement as needed and as data on Flucelvax® Quad from several different influenza seasons accumulates.
An updated summary of the characteristics of influenza vaccines available in Canada for the 2020–2021 influenza season can be found in Appendix B. For complete prescribing information, readers should consult the product monograph available through [Health Canada’s Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
Tables
------
Table 2. Serological Assay Definitions and Thresholds for Protection Specified by the United States Food and Drug Administration[Footnote 19](#fn19)
| Serological assay | Definition | Threshold |
| --- | --- | --- |
| *GMT ratio* | Ratio of GMT post-vaccination of licensed vaccine to GMT post-vaccination of new vaccine | Non-inferiority: The upper bound of the two-sided 95% CI on the ratio of the GMTs should not exceed 1.5. |
| *Seroprotection* | Proportion of subjects achieving an HI titre of ≥1:40 post-vaccination | Placebo-controlled: Lower limit of the two-sided 95% CI for the percent of subjects achieving seroprotection should meet or exceed 70% (for adults <65 and children) or 60% (for adults ≥65) |
| *Seroconversion* | Proportion of subjects achieving an increase from ≤1:10 HI titre pre-vaccination to ≥1:40 post-vaccination or achieving at least four-fold rise in HI titres | Non-inferiority: Upper limit of the two-sided 95% CI on the difference between the seroconversion rates (rate of licensed vaccine – rate of new vaccine) should not exceed 10 percentage points.
Placebo-controlled: Lower limit of the two-sided 95% CI for the percent of subjects achieving seroprotection should meet or exceed 40% (for adults <65 and children) or 30% (for adults ≥65) |
| **Abbreviations:** CI: confidence interval, GMT: geometric mean titre, HI: hemagglutination inhibition |
Table 3. NACI Recommendations: Strength of Recommendation and Grade of Evidence
| Strength of NACI Recommendation | Grade of Evidence |
| --- | --- |
| *Based on factors not isolated to strength of evidence (e.g. public health need)* | *Based on assessment of the body of evidence* |
| **Strong**
“*should/should not be* offered”
* Known/Anticipated advantages outweigh known/anticipated disadvantages (“should”),
OR Known/Anticipated disadvantages outweigh known/anticipated advantages (“should not”)
* Implication: A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present
| A - *good evidence* to recommend |
| B – *fair evidence* to recommend |
| C – *conflicting evidence*, however other factors may influence decision-making |
| D – *fair evidence* to recommend against |
| E – *good evidence* to recommend against |
| I – *insufficient evidence* (in quality or quantity), however other factors may influence decision-making |
| **Discretionary**
“*may be* considered”* Known/Anticipated advantages closely balanced with known/anticipated disadvantages, OR uncertainty in the evidence of advantages and disadvantages exists
* Implication: A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable
| A - *good evidence* to recommend |
| B – *fair evidence* to recommend |
| C – *conflicting evidence*, however other factors may influence decision-making |
| D – *fair evidence* to recommend against |
| E – *good evidence* to recommend against |
| I – *insufficient evidence* (in quality or quantity), however other factors may influence decision-making |
Table 4. Ranking Individual Studies: Levels of Evidence Based on Research Design
| Level | Description |
| --- | --- |
| I | Evidence from randomized controlled trial(s). |
| II-1 | Evidence from controlled trial(s) without randomization. |
| II-2 | Evidence from cohort or case-control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy. |
| II-3 | Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence. |
| III | Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees. |
Table 5. Ranking Individual Studies: Quality (internal validity) Rating of Evidence
| Quality Rating | Description |
| --- | --- |
| Good | A study (including meta-analyses or systematic reviews) that meets all design- specific criteria[Footnote \*](#fnt5*) well. |
| Fair | A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion[Footnote \*](#fnt5*) but has no known "fatal flaw". |
| Poor | A study (including meta-analyses or systematic reviews) that has at least one design-specific[Footnote \*](#fnt5*) "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations. |
|
Table 5 Footnotes
Footnote \*
General design specific criteria are outlined in Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, Atkins D. Current methods of the US Preventive Services Task Force: A review of the process. Am J Prev Med. 2001;20(3):21-35 [Footnote 10](#fn10).
[Return to footnote \* referrer](#fnt5*)
|
Table 6. Summary of Evidence Related to the Effectiveness of Flucelvax® Quad
| Study Details | Summary |
| --- | --- |
| Study | Vaccine | Study Design | Participants | Summary of Key Findings | Level of Evidence | Quality |
| **DeMarcus L, Shoubaki L, Federinko S.** *Comparing influenza vaccine effectiveness between cell-derived and egg-derived vaccines, 2017–2018 influenza season*. Vaccine. 2019 Jul 9;37(30):4015-4021. | IIV4-cc (subunit) | * Test-negative case-control study
* 2017–2018 influenza season
* Funded by US Department of Defense (DoD) Global Emerging Infections Surveillance (DoD-GEIS) Respiratory
Focus Area through the Department of Defense Global Respiratory
Pathogen Surveillance Program
* 80% of specimens were collected
from the US, 20% originated from Europe,
the Middle East, and the Pacific Region
| * United States DoD healthcare beneficiaries ≥6 months– ≤94 years of age (excluding service members) who presented to a military treatment facility with an outpatient encounter for ILI symptoms.
* Mean age: 24 years
* Median age: 13 years
* Mode: 1 year old
* 57% female
(n = 2307)
* 1757 Cases (laboratory confirmed):
531 vaccinated
(192 (36.15%) received cell-derived vaccine
and 339 (63.84%) egg-derived vaccine)
* 2280 Controls:
977 vaccinated (314 (32.13%) received cell-derived vaccine (Flucelvax Quadrivalent®) and 663 (67.86%) received egg-derived vaccine (Flulaval® Tetra, Fluarix® Quadrivalent)
| * Adjusted VE1 against laboratory-confirmed influenza infection estimates for individuals vaccinated with cell-derived vaccine or egg-derived vaccine compared to unvaccinated controls stratified by subtype and beneficiary group.
* Adjusted VE estimate (95% CI), %
* **All dependents — IIV4-cc (subunit):**
Influenza A2: 50 (37-61)
Influenza B: 40 (21-55)
Subtype A(H1N1) pdm09: 61 (38-76)
Subtype A(H3N2): 48 (30-61)
Overall3: 46 (33-56)
* **All dependents — Egg-based (split virus):**
Influenza A2: 54 (44-62)
Influenza B: 53 (41-63)
Subtype A(H1N1) pdm09: 86 (78-91)
Subtype A(H3N2): 35 (20-48)
Overall3: 53 (45-60)
* **Children — IIV4-cc (subunit):**
Influenza A2: 51 (26-67)
Influenza B: 22 (-17-47)
Subtype A(H1N1) pdm09: 56 (15-77)
Subtype A(H3N2): 47 (14-67)
Overall3: 36 (12-54)
* **Children— Egg-based (split virus):**
Influenza A2: 60 (49-69)
Influenza B: 49 (32-61)
Subtype A(H1N1) pdm09: 88 (80-93
Subtype A(H3N2): 40 (21-64)
Overall3: 55 (45-64
* **Adults — IIV4-cc (subunit):**
Influenza A2: 54 (37-67)
Influenza B: 54 (31-69)
Subtype A(H1N1) pdm09: 71 (44-85)
Subtype A(H3N2): 47 (25-63)
Overall3: 52 (36-64)
* **Adults— Egg-based (split virus):**
Influenza A2: 37 (15-53)
Influenza B: 61 (40-75)
Subtype A(H1N1) pdm09: 81 (56-92)
Subtype A(H3N2): 19 (-11-41)
Overall3: 51 (35-63)
* 1 To calculate VE, the odds of influenza-positive (cases) to influenza-negative (controls) patients were compared among vaccinated and unvaccinated individuals.2 Includes all influenza A specimens (A/unsubtyped, A(H1N1)pdm09, A(H3N2))3 Includes all influenza types and subtypes (A/unsubtyped, A(H1N1)pdm09, A(H3N2), B)
* Adjusted OR for individuals vaccinated with cell-derived vaccine (subunit) compared to egg-derived vaccine (split virus) stratified by subtype and beneficiary group:
* Adjusted OR (95% CI), %
* **All dependents:**
Influenza A1: 0.9 (0.6, 1.2)
Influenza B: 1.2 (0.9, 1.7)
Subtype A(H1N1) pdm09: 2 (1.1, 3.6)
Subtype A(H3N2): 0.7 (0.5, 1)
Overal2: 1 (0.8, 1.3)
* **Children:**
Influenza A1: 1 (0.6, 1.6)
Influenza B: 1.3 (0.8, 2)
Subtype A(H1N1) pdm09: 2.9 (1.3, 6.3)
Subtype A(H3N2): 0.7 (0.4, 1.2)
Overall2: 1.2 (0.8, 1.7)
* **Adults:**
Influenza A1: 0.8 (0.5, 1.1)
Influenza B : 1.1 (0.7, 1.9)
Subtype A(H1N1) pdm09 : 1.6 (0.6, 4.4)
Subtype A(H3N2) : 0.7 (0.5, 1)
Overall 2: 0.9 (0.6, 1.3)
* 1 Includes all influenza A specimens (A/unsubtyped, A(H1N1)pdm09, A(H3N2))
* 2 Includes all influenza types and subtypes (A/unsubtyped, A(H1N1)pdm09, A(H3N2), B)
| II-2 | Good |
| **Izurieta HS, Chillarige Y, Kelman J, Wei Y, Lu Y, Xu W, Lu M, Pratt D, Chu S, Wernecke M, MaCurdy T,Forshee R.** *Relative effectiveness of cell-cultured and egg-based influenza vaccines among elderly persons in the United States, 2017-18, 2017-18*. J Infect Dis. 2019 Sep 13; 220(8):1255-1264. | IIV4-cc (subunit) | * Retrospective cohort
* US
* 2017–2018 influenza season
* Funded by the US FDA
| * Medicare beneficiaries ≥65 years of age
* 58.6% female
* IIV4-cc (Flucelvax Quadrivalent®):
n= 653,099)
* Egg-based IIV4-SD (Afluria® Tetra):
n=1,844,745
* Egg-based IIV3-SD:
n= 8,449,508
* IIV3-Adj (Fluad®):
n= 1,465,747
* IIV3-HD (Fluzone® High-Dose):
n= 1,007,082
| * \*(subunit) rVE estimates from the 2-way comparison between IIV4-cc and IIV4-SD:
* Office visits:10.5%; 95% CI: 6.8%–14.0%)
Hospital encounters:10.0%; 95% CI: 7.0%–13.0%)
* Pairwise, adjusted rVE estimates for influenza-related hospital encounters from a 5-way analysis:
* **rVE \*\* (95% CI), %:**
Egg-based IIV4-SD (split virus): 11.0 \*\*\* (7.9-14.0)
Egg-based IIV3-SD (split virus): 10.8\*\*\* (7.4-14.1)
IIV3-Adj (subunit): 7.5\*\*\* (4.1–10.7)
IIV3-HD (split virus): 2.3 (−0.8- 5.3)
* \* Hospital encounters were defined as inpatient hospitalizations and emergency department visits in which International Classification of Diseases, Tenth revision, Clinical Modification, code for influenza was listed.
\*\*Compared to persons vaccinated with IIV4-cc
\*\*\* Significant at p ≤ 0.05.
* Pairwise, adjusted rVE estimates for influenza-related office visits from a 5-way analysis:
* **rVE\* (95% CI), %:**
Egg-based IIV4-SD (split virus): 5.7 (1.9–9.4)\*
Egg-based IIV3-SD (split virus): 1.0 (−3.5 to 5.3)
IIV3-Adj (subunit): 11.5 (7.9–15.0)\*
IIV3-HD (split virus): 5.1 (1.6–8.4)
* \*Statistically significant at the P ≤.05 level
* Pairwise rVE estimates (IPTW-adjusted) for influenza-related inpatient stays from a 5 way analysis:
* **rVE\* (95% CI), %:**
Egg-based IIV4-SD (split virus): 9.5 (5.3–13.4)\*
Egg-based IIV3-SD (split virus): 11.4 (7.0–15.7)\*
IIV3-Adj (subunit): 7.1 (2.7–11.3)\*
IIV3-HD (split virus): −0.7 (−4.8 to 3.4)
* \*Statistically significant at the P ≤.05 level
* rVE was defined as the difference in influenza-related hospital encounters\* between persons vaccinated with IIV4-cc (subunit) versus egg-based vaccines
| II-2 | Good |
| **Boikos C, Sylvester G, Sampalis J, Mansi J**.*Effectiveness of the Cell Culture-and Egg-Derived, Seasonal Influenza Vaccine during the 2017-2018 Northern Hemisphere Influenza Season*. Poster presented at: Canadian Immunization Conference (CIC) 2018; Dec 4-6, 2018 Ottawa, ON, Canada. | IIV4-cc (subunit) | * Retrospective cohort
* 2017–2018 influenza season
* Funded by Seqirus, Inc.
| * Patients ≥4 years of age from US electronic medical record (EMR) dataset
* IIV4-cc group:
n=92,192;
median age: 59
* Egg-based IIV4 group:
n=1,255,983;
median age: 41
| * Propensity-score matched rVE estimate forILI (as defined by the US AFHSC Code Source B) for persons vaccinated with IIV4-cc (subunit) versus egg-based IIV4:
* **rVE estimate (95% CI),%**
Overall cohort: 36.2\*\* (26.1-44.9)
Subjects 4-17 years of age: 18.8 (-53.9-57.2)
Subjects 18-64 years of age: 26.8\*\* (14.1-37.6)
Subjects 65+ years of age: -7,3 (-51,6 à 24,0)
Total: 33.9\*\* (31.5-36.2)
Adjusted\*: 36.2\*\* (26.1-44.9)
* \*Adjusted for age, sex, health status, and geographic region
\*\* Significant with p<0.001
| II-2 | * n/a
(Study recently accepted for peer-reviewed publication. At the time of writing, this study was only available as conference poster; unable to evaluate quality of evidence.)
|
| **Klein NP, Fireman B, Goddard K, Zerbo O, Asher J, Zhou J, King J, Lewis N.** *LB15. Vaccine Effectiveness of Flucelvax Relative to Inactivated Influenza Vaccine During the 2017–18 Influenza Season in Northern California*. Open Forum Infect Dis. 2018;5(Suppl 1):S764. | IIV4-cc
(subunit) | * Retrospective cohort
* US
* 2017–2018 influenza season
* No funding declared
| * Kaiser Permanente Northern California members
aged 4–64 years
IIV4-cc group (subunit):
n= 932,874
* egg-based IIV group:
n= 84,440
| * Adjusted rVE (95% CI) against laboratory-confirmed influenza A (H3N2) infection in individuals vaccinated with IIV4-cc versus egg-based IIV:
6.8% (11.2-21.9; P = 0.43)
* Adjusted VE (95% CI) against all laboratory-confirmed\* influenza:
* **VE (95% CI), %:**
IIV4-cc: 30.2 (17.1-41.3)
Egg-based IIV\*\*: 17.9 (12.1-23.3)
\* Positive by Polymerase chain reaction (PCR).
\*\* 86.2% received egg-based IIV3.
| II-2 | n/a
(Study published as conference poster; unable to evaluate quality of evidence) |
| **Abbreviations:** AFHSC; Armed Forces Health Surveillance Center; CI: confidence interval; HD: high-dose; IIV: inactivated influenza vaccine; IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV4-cc: cell-culture based quadrivalent inactivated influenza vaccine IIV3-cc: cell-culture based trivalent inactivated influenza vaccine; IIV3-HD: high-dose trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; ILI: influenza-like illness; IPTW: inverse probability of treatment weighting GMT: geometric mean titre; n/a: not applicable; OR: odds ratio; RCT: randomized controlled trial; rVE: relative vaccine effectiveness; US: United States. |
Table 7. Summary of Evidence Related to the Immunogenicity of Flucelvax® Quad
| Study Detials | Summary |
| --- | --- |
| Study | Vaccine | Study Design | Participants | Summary of Key Findings | Level of Evidence | Quality |
| **Bart S., Cannon K., Herrington D., Mills R., Forleo-Neto E., Lindert K.,Abdul MA**. *Immunogenicity and safety of a cell culture-based quadrivalent influenza vaccine in adults: A phase III, double-blind, multicenter, randomized, non-inferiority study*. Hum Vaccines Immunother. 2016;12(9):2278-88.
**ClinicalTrials.gov** *Safety and Immunogenicity of Three Influenza Vaccines Adults Ages 18 and Older*
NCT 01992094 | IIV4-cc
(subunit) | * RCT
* US
Multicentre (40 sites)
* 2013–2014 influenza season
* Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus, Inc.)
| * Healthy adults 18 years of age and older
* 54.8% female
* Mean age: 57 years
* Group 1:
1335 adults
vaccinated with IIV4-cc (subunit)
* Group 2:
676 adults vaccinated with Flucelvax® (IIV3-cc, B/Yamagata) (subunit)
* Group 3:
669 adults vaccinated with Flucelvax® (IIV3-cc, B/Victoria) (subunit)
| * GMT ratio 22 days post-vaccination (Group 2 or Group 3 divided by Group 1):
* **Estimate (95% CI):**
A(H1N1): 1.0 (0.9-1.1)
A(H3N2): 1.0 (0.9-1.1)
B/Yam: 0.9 (0.8-1.0)
B/Vic: 0.9 (0.8-1.0)
* Difference in seroconversion rate three weeks (day 22) post-vaccination (Group 2 or Group 3 –Group 1):
* **Estimate (95% CI):**
A(H1N1): -0.5 (-5.3-4.2)
A(H3N2): -2.7 (-7.2-1.9)
B/Yam: -1.8 (-6.2-2.8)
B/Vic: -4.4 (-8.9-0.2)
* HI antibody responses of IIV4-cc compared to IIV3-cc (B/Yam) and IIV3-cc (B/Vic) for the unmatched B strain, 22 days after vaccination in terms of the differences in percentages of subjects achieving seroconversion and the between group GMT ratios (FAS immunogenicity set):
* HI seroconversion rate three weeks (day 22) post-vaccination:
* **Estimate (95% CI), % :**
B/Yam: 39.7 (37.0-42.4)
B/Vic: 36.6 (34.0-39.3)
* **Vaccine Group Diff (95% CI), %:**
B/Yam: -21.7 (-25.5,-17.7)
B/Vic: -19.4 (-23.2,-15.5)
| I | Good |
| **Hartvickson R., Cruz M., Ervin J., Brandon D., Forleo-Neto E., Dagnew A.F., Chandra R., Lindert K.,Mateen A.A**. *Non-inferiority of mammalian cell-derived quadrivalent subunit influenza virus vaccines compared to trivalent* *subunit influenza virus vaccines in healthy children: A phase III randomized, multicenter, double-blind clinical trial*. Int J Infect Dis. 2015;41:65-72.
**ClinicalTrial.gov** *Safety and Immunogenicity of Three Influenza Vaccines in Children Aged 4 Years Old to Less than 18 Years Old*
NCT01992107 | IIV4-cc (subunit) | * RCT
* US
Multicentre
* November 2013 to
August 2014
* Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus, Inc.)
| * Healthy children ≥4 to <18 years; stratified into two age cohorts: ≥4 to <9 years
and ≥9 to <18 years.
* Within the ≥4 to <9 years cohort, subjects
were further stratified as previously vaccinated and not previously vaccinated.
* Group 1:
1159 children
vaccinated with Flucelvax Quadrivalent®
(819 previously vaccinated,
340 not previously vaccinated)
* 48% female
* Group 2:
593 children vaccinated with Flucelvax® IIV3-cc
(B/Victoria)
(420 previously vaccinated, 173 not previously vaccinated)
* 48% female
* Group 3:
581 children vaccinated with Flucelvax® IIV3-cc
(B/Yamagata)
(400 previously vaccinated, 181 not
previously vaccinated)
* 49% female
| * GMT ratio in children aged 4-18 years of age, 3 week post-vaccination with last dose of vaccine:
* **Estimate (95% CI) – IIV4-cc (subunit):**
B/Yam: 2.12 (1.91–2.37)
* **Estimate (95% CI) – Matched IIV3-cc (subunit):**
B/Vic: 2.38 (2.17–2.61)
B/Yam: 8.16 (7.56–8.82)
* Seroconversion rate in children aged 4-17 years, 3 weeks post-vaccination with last dose of vaccine:
* **Estimate (95% CI) – IIV4-cc (subunit) :**
A(H1N1): 73 (70–76)
A(H3N2): 47 (44–50)
B/Vic: 67 (64–70)
B/Yam: 73 (70–76)
* **Estimate (95% CI) – Matched IIV3-cc\* (subunit):**
A(H1N1): 74 (70–77)
A(H3N2): 51 (47–55)
B/Vic: 66 (61–69)
B/Yam: 72 (68–76)
* \*Data presented for influenza B strains is from the IIV3-cc containing the matched B lineage.
* Seroprotection rate in children aged 4-17 years, 3 weeks post-vaccination with last dose of vaccine:
* **Estimate (95% CI) - IIV4-cc (subunit):**
A(H1N1) : 99 (98–100)
A(H3N2) : 100 (99–100)
B/Vic : 92 (91–94)
B/Yam : 91 (89–93)
* **Estimate (95% CI) - Matched IIV3-cc\* (subunit):**
A(H1N1) : 99 (98–100)
A(H3N2) : 99 (98–100)
B/Vic : 93 (90–95)
B/Yam : 91 (88–93)
* \*Data presented for influenza B strains is from the IIV3-cc containing the matched B lineage.
* Difference in seroconversion rate (IIV3-cc – IIV4-cc)
in children aged 4-17 years, 3 weeks post-vaccination with last dose of vaccine:
* **Estimate (95% CI) - IIV4-cc (subunit) :**
B/Vic : 67 (64–70)
B/Yam : 73 (70–76)
* **Estimate (95% CI) - Matched IIV3-cc\* (subunit):**
B/Vic : 33 (29–37)
B/Yam : 26 (23–30)
* \*Data presented for influenza B strains is from the IIV3-cc containing the matched B lineage.
| I | Fair |
| **Abbreviations:** CI: confidence interval; GMT: geometric mean titre; n/a: not applicable; IIV: inactivated influenza vaccine; IIV3-cc: cell-culture based trivalent inactivated influenza vaccine; IIV4-cc: cell-culture based quadrivalent inactivated influenza vaccine; RCT: randomized controlled trial; US: United States |
Table 8. Summary of Evidence Related to the Safety of Flucelvax® Quad and Flucelvax®
| Study Detials | Summary |
| --- | --- |
| Study | Vaccine | Study Design | Participants | Summary of Key Findings | Level of Evidence | Quality |
| **Bart S., Cannon K., Herrington D., Mills R., Forleo-Neto E., Lindert K.,Abdul MA.** *Immunogenicity and safety of a cell culture-based quadrivalent influenza vaccine in adults: A phase III, double-blind, multicenter, randomized, non-inferiority study. Hum Vaccines Immunother. 2016;12(9):2278-88*.
**ClinicalTrials.gov** *Safety and Immunogenicity of Three Influenza Vaccines Adults Ages 18 and Older*
NCT 01992094 | IIV4-cc (subunit) | * RCT
* US
Multi-centre
* 2013–2014 influenza season
* Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus, Inc.)
| * Healthy adults 18 years of age and older
* 54.8% female
* Mean age: 57 years
* Group 1:
1335 adults
vaccinated with IIV4-cc (subunit)
* Group 2:
676 adults vaccinated with
IIV3-cc (B/Yamagata) (subunit)
* Group 3:
669 adults vaccinated with
IIV3-cc (B/Victoria) (subunit)
| Proportion (%) of the most commonly reported solicited local and systemic AEs in adults ≥18 years of age reporting between day 1 through day 7 after vaccination:* **Local\* AE:**
* Injection site pain:
+ IIV4-cc: 33.6
+ IIV3-cc (B/Yam): 27.8
+ IIV3-cc (B/Vic): 29.4
* \*1 case of severe ecchymosis and 1 case of severe induration was identified in the TIV1c group
* **Systemic AE:**
* Fatigue:
+ IIV4-cc: 13.5
+ IIV3-cc (B/Yam): 16.3
+ IIV3-cc (B/Vic): 12.2
* Headache:
+ IIV4-cc: 14.0
+ IIV3-cc (B/Yam): 13.4
+ IIV3-cc (B/Vic): 13.4
* Reported solicited local and systemic AEs were generally mild to moderate in intensity. Across all 3 vaccine groups, a similar percentage of subjects reported at least one solicited AE.
Proportion (%) of adults reporting any solicited AEs by age:* **18-64 age group:**
+ IIV4-cc: 61.8
+ IIV3-cc (B/Yam): 56.7
+ IIV3-cc (B/Vic): 59.6
* **≥65 age group:**
+ IIV4-cc: 41.3
+ IIV3-cc (B/Yam): 39.1
+ IIV3-cc (B/Vic): 43.2
Proportion (%) reporting any solicited AEs by sex:* **Female:**
+ IIV4-cc: 57.9
+ IIV3-cc (B/Yam): 54.1
+ IIV3-cc (B/Vic): 54.2
* **Male:**
+ IIV4-cc: 43.9
+ IIV3-cc (B/Yam): 38.9
+ IIV3-cc (B/Vic): 47.1
* Overall, the rates of any solicited AEs did not differ among subjects from different ethnicities.
* Proportion (%) of adults ≥18 reporting any AE:
+ IIV4-cc: 16.1
+ IIV3-cc (B/Yam): 14.7
+ IIV3-cc (B/Vic): 16.5
Proportion (%) of adults 18-64 reporting unsolicited AEs (collected from day 1 through day 22; SAEs, medically attended AEs, AEs leading to withdrawal from the study, and new onset of chronic diseases were collected from day 1 through day 181):* **Any AE:**
+ IIV4-cc: 16.1
+ IIV3-cc (B/Yam): 14.7
+ IIV3-cc (B/Vic): 16.5
* **Possibly or probably related AE:**
+ IIV4-cc: 4.2
+ IIV3-cc (B/Yam): 2.7
+ IIV3-cc (B/Vic): 4.6
* **Any SAE:**
+ IIV4-cc: 1.7
+ IIV3-cc (B/Yam): 1.8
+ IIV3-cc (B/Vic): 1.5
* **Possibly or probably related SAE:**
+ IIV4-cc: 0
+ IIV3-cc (B/Yam): 0
+ IIV3-cc (B/Vic): 0
* **AEs leading to premature withdrawal\*:**
+ IIV4-cc: 0
+ IIV3-cc (B/Yam): 0
+ IIV3-cc (B/Vic): 0.3
* **Medically attended AE:**
+ IIV4-cc: 21.2
+ IIV3-cc (B/Yam): 17.6
+ IIV3-cc (B/Vic): 20.4
* **New onset of chronic diseases:**
+ IIV4-cc: 3.6
+ IIV3-cc (B/Yam): 3.0
+ IIV3-cc (B/Vic): 3.7
* **Death:**
+ IIV4-cc: 0
+ IIV3-cc (B/Yam): 0
+ IIV3-cc (B/Vic): 0.3
* \*One subject from the IIV3-cc (B/Vic) group withdrew from the study prematurely due to death.
Proportion (%) of adults ≥65 reporting unsolicited AEs (collected from day 1 through day 22; SAEs, medically attended AEs, AEs leading to withdrawal from the study, and new onset of chronic diseases were collected from day 1 through day 181):* **Any AE:**
+ IIV4-cc: 42.8
+ IIV3-cc (B/Yam): 45.2
+ IIV3-cc (B/Vic): 42.7
* **Possibly or probably related AE:**
+ IIV4-cc: 4.4
+ IIV3-cc (B/Yam): 3.8
+ IIV3-cc (B/Vic): 4.5
* **Any SAE:**
+ IIV4-cc: 6.2
+ IIV3-cc (B/Yam): 4.7
+ IIV3-cc (B/Vic): 4.7
* **Possibly or probably related SAE:**
+ IIV4-cc: 0
+ IIV3-cc (B/Yam): 0
+ IIV3-cc (B/Vic): 0
* **AEs leading to premature withdrawal\*:**
+ IIV4-cc: 0.3
+ IIV3-cc (B/Yam): 0.3
+ IIV3-cc (B/Vic): 0
* **Medically attended AE:**
+ IIV4-cc: 30.8
+ IIV3-cc (B/Yam): 33.3
+ IIV3-cc (B/Vic): 29.4
* **New onset of chronic diseases:**
+ IIV4-cc: 5.8
+ IIV3-cc (B/Yam): 4.4
+ IIV3-cc (B/Vic): 5.0
* **Death:**
+ IIV4-cc: 0.8
+ IIV3-cc (B/Yam): 1.5
+ IIV3-cc (B/Vic): 0.3
* \*One subject from the IIV4-cc group withdrew from the study due to acute myeloid leukemia and worsening of diabetes and one from the IIV3-cc (B/Yam) group due to death.
* 12 deaths were reported over the course of the study. None of the deaths or AEs leading to premature withdrawal were considered to be related to the study vaccine.
Proportion (%) of the most commonly reported unsolicited medically attended AEs by the MedDRA preferred Term:* **Overall:**
+ IIV4-cc: 26.0
+ IIV3-cc (B/Yam): 25.6
+ IIV3-cc (B/Vic): 25.0
* **Sinusitis:**
+ IIV4-cc: 1.8
+ IIV3-cc (B/Yam): 2.5
+ IIV3-cc (B/Vic): 2.4
* **Bronchitis:**
+ IIV4-cc: 2.2
+ IIV3-cc (B/Yam): 1.5
+ IIV3-cc (B/Vic): 0.9
Proportion (%) the most commonly reported unsolicited AEs by the MedDRA preferred Term deemed possibly or probably related:* **Injection-site hemorrhage:**
+ IIV4-cc: 0.8
+ IIV3-cc (B/Yam): 0.4
+ IIV3-cc (B/Vic): 0.5
* **Fatigue:**
+ IIV4-cc: 0.5
+ IIV3-cc (B/Yam): 0.4
+ IIV3-cc (B/Vic): 0.6
* **Myalgia:**
+ IIV4-cc: 0.5
+ IIV3-cc (B/Yam): 0.1
+ IIV3-cc (B/Vic): 0.5
Proportion (%) of the most commonly reported new onset of chronic disease by the MedDRA preferred Term:* **Metabolism and nutritional disorders**
+ IIV4-cc: 0.8
+ IIV3-cc (B/Yam): 0.7
+ IIV3-cc (B/Vic): 0.5
* **Cardiac disorders:**
+ IIV4-cc: 0.8
+ IIV3-cc (B/Yam): 0.6
+ IIV3-cc (B/Vic): 0.3
* **Musculoskeletal and connective tissue disorders:**
+ IIV4-cc: 0.8
+ IIV3-cc (B/Yam): 0.4
+ IIV3-cc (B/Vic): 0.3
* No significant differences were observed between vaccine groups or age groups in the proportion of subjects with new onset of chronic diseases.
Proportion (%) of study subjects reporting unsolicited AEs and medically attended AEs by sex:* **Female:**
+ Any: 32.7
+ Medically attended: 22.3
* **Male:**
+ Any: 40.5
+ Medically attended: 28.5
* There were no major differences in the unsolicited AE profiles of IIV4-cc, IIV3-cc (B/Yam), and IIV3-cc (B/Vic), by age cohorts, sex, and race/ethnicity.
| I | Good |
| **Ambrozaitis A, Groth N, Bugarini R, Sparacio V, Podda A, Lattanzi M. A** *novel mammalian cell-culture technique for consistent production of a well-tolerated and immunogenic trivalent subunit influenza vaccine. Vaccine. 2009;27(43):6022-9* | IIV3-cc
(subunit) | * RCT
* Lithuania Multi-centre
* 2005-2006 influenza season
* No funding declared
| * Healthy adults 18-60 years of age
* 61.0% female
* Mean age:32.5
* Total participants: 1200
* IIV3-cc
(3 consecutive production lots: A,B,C): n=1028
* Egg-based IIV3
(Agrippal®, Seqirus, Inc.; marketed in Canada as Agriflu®):
n=171
| Proportion (%) of local and systemic reactions in adults 18-60 years of age reporting between day 1 through day 7 after vaccination:* **Total local reactions:**
+ IIV3-cc Lot A+B+C (subunit): 29
+ Egg-based IIV3 (subunit): 25
- P\*=0.35
* **Ecchymosis:**
+ IIV3-cc Lot A+B+C (subunit): 4
+ Egg-based IIV3 (subunit): 6
- P\*=0.26
* **Erythema:**
+ IIV3-cc Lot A+B+C (subunit): 20
+ Egg-based IIV3 (subunit): 18
- P\*=0.66
* **Induration:**
+ IIV3-cc Lot A+B+C (subunit): 11
+ Egg-based IIV3 (subunit): 11
- P\*=0.90
* **Swelling:**
+ IIV3-cc Lot A+B+C (subunit): 7
+ Egg-based IIV3 (subunit): 8
- P\*=0.96
* **Pain:**
+ IIV3-cc Lot A+B+C (subunit): 12
+ Egg-based IIV3 (subunit): 8
- P\*=0.19
* **Total systemic reactions:**
+ IIV3-cc Lot A+B+C (subunit): 25
+ Egg-based IIV3 (subunit): 23
- P\*=0.54
* **Chills:**
+ IIV3-cc Lot A+B+C (subunit): 6
+ Egg-based IIV3 (subunit): 7
- P\*=0.73
* **Malaise:**
+ IIV3-cc Lot A+B+C (subunit): 13
+ Egg-based IIV3 (subunit): 12
- P\*=0.79
* **Myalgia:**
+ IIV3-cc Lot A+B+C (subunit): 6
+ Egg-based IIV3 (subunit): 5
- P\*=0.73
* **Arthralgia:**
+ IIV3-cc Lot A+B+C (subunit): 3
+ Egg-based IIV3 (subunit): 1
- P\*=0.30
* **Headache:**
+ IIV3-cc Lot A+B+C (subunit): 14
+ Egg-based IIV3 (subunit): 12
- P\*=0.47
* **Sweating:**
+ IIV3-cc Lot A+B+C (subunit): 4
+ Egg-based IIV3 (subunit): 3
- P\*=0.41
* **Fatigue:**
+ IIV3-cc Lot A+B+C (subunit): 13
+ Egg-based IIV3 (subunit): 11
- P\*=0.55
* **Fever(≥38°C):**
+ IIV3-cc Lot A+B+C (subunit): 1
+ Egg-based IIV3 (subunit): 2
- P\*=0.44\*\*
* **Total other indicators of reactogenicity:**
+ IIV3-cc Lot A+B+C (subunit): 5
+ Egg-based IIV3 (subunit): 7
- P\*=0.17
* **Stayed at home due to reaction:**
+ IIV3-cc Lot A+B+C (subunit): 3
+ Egg-based IIV3 (subunit): 2
- P\*=1.00\*\*
* **Analgesic/antipyretic medication used:**
+ IIV3-cc Lot A+B+C (subunit): 3
+ Egg-based IIV3 (subunit): 6
- P\*=0.10
* \* value from Pearson’s chi-square test for vaccine group differences (IIV3-cc total versus egg-based IIV3).
\*\* If any expected cell count was <1 or if >20% of the cells have an expected cell count <5, then the Fisher exact test was used.
* One death was reported during the 6-month safety follow-up period; 1 subject in the IIV3-cc group committed suicide. None of the deaths or SAEs reported over the course of the study were determined to be related to the IIV3-cc vaccine.
| I | Good |
| **Szymczakiewicz-Multanowska A, Groth, N, Bugarini R, Lattanzi M, Casula D, Hilbert A, Tsai T, Podda A.** *Safety and Immunogenicity of a Novel Influenza Subunit Vaccine Produced in Mammalian Cell Culture. J Infect Dis. 2009;200(6): 841-8*
**ClinicalTrials.gov** *Safety and Immunogenicity of a Cell Culture-derived Influenza Vaccine in Healthy Adults and Elderly
NCT00492063* | IIV3-cc
(subunit) | * Phase III, observer blind RCT
* Poland Multi-centre
* 2004-2005 influenza season
* Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus Inc.)
| * Healthy adults 18 years of age and older
+ 58.0% female
+ Mean age:
18-60 age group: 38.7
+ >60 age group: 69.1
* Total participants analyzed:
+ IIV3-cc:
+ 18-60 age group: n=652
+ >60 age group: n=
* Egg-based IIV3 (Agrippal®):
+ 18-60 age group: n=648
+ >60 age group: n=676
| Proportion (%) of participants who received IIV3-cc or egg-based IIV3 reporting solicited local or systemic reactions by age group between day 1 through day 7 after vaccination:* Subjects 18-60 years of age: 40
* Subjects ≥61years of age: 33
Proportion (%) participants reporting local and systemic reactions between day 1 through day 7 after vaccination by vaccine group:* **Local reactions:**
+ IIV3-cc (subunit): 32
+ Egg-based IIV3 (subunit): 31
* **Systemic reactions:**
+ IIV3-cc (subunit): 22
+ Egg-based IIV3 (subunit): 23
Proportion (%) of participants reporting injection pain site by age group between day 1 through day 7 after vaccination:* **Subjects 18-60 years of age:**
+ IIV3-cc (subunit): 22
+ Egg-based IIV3 (subunit): 17
- P <.05
* **Subjects ≥61years of age:**
+ IIV3-cc (subunit): 9
+ Egg-based IIV3 (subunit): 5
- P<.001
Proportion (%) adults 18-60 years of age reporting solicited local AEs in between day 1 through day 7 after vaccination:* **Ecchymosis:**
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 3
- P\*=0.51
* **Erythema:**
+ IIV3-cc (subunit): 14
+ Egg-based IIV3 (subunit): 16
- P\*=0.26
* **Induration:**
+ IIV3-cc (subunit): 6
+ Egg-based IIV3 (subunit): 6
- P\*=0.62
* **Swelling:**
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 4
- P\*=0.76
* **Pain:**
+ IIV3-cc (subunit): 22
+ Egg-based IIV3 (subunit): 17
- P\*=0.04\*\*
* \* Pearson X2 test for vaccine group differences.
* \*\* P <.001
Proportion (%) of adults 18-60 years of age reporting solicited systemic reactions in between day 1 through day 7 after vaccination:* **Chills:**
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 4
- P\*=0.56
* **Malaise:**
+ IIV3-cc (subunit): 11
+ Egg-based IIV3 (subunit): 11
- P\*=0.97
* **Myalgia:**
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 8
- P\*=0.65
* **Arthralgia:**
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 4
- P\*=0.61
* **Headache:**
+ IIV3-cc (subunit): 12
+ Egg-based IIV3 (subunit): 12
- P\*=0.90
* **Sweating:**
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 4
- P\*=0.91
* **Fatigue:**
+ IIV3-cc (subunit): 11
+ Egg-based IIV3 (subunit): 11
- P\*=0.97
* **Fever:**
+ IIV3-cc (subunit): <1
+ Egg-based IIV3 (subunit): 1
- P\*=0.29
* Pearson X2 test for vaccine group differences.
Proportion (%) adults 18-60 years of age reporting solicited local AEs in between day 1 through day 7 after vaccination:* **Stayed at home due to reaction:**
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 2
- P\*=0.69
* **Analgesic/antipyretic medication used:**
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 6
- P\*=0.67
* Pearson X2 test for vaccine group differences
Proportion adults ≥61 years of age reporting solicited local AEs in between day 1 through day 7 after vaccination:* **Ecchymosis:**
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 4
- P\*=0.89
* **Erythema:**
+ IIV3-cc (subunit): 11
+ Egg-based IIV3 (subunit): 11
- P\*=0.99
* **Induration:**
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 4
- P\*=0.32
* **Swelling:**
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 3
- P\*=0.34
* **Pain:**
+ IIV3-cc (subunit): 9
+ Egg-based IIV3 (subunit): 5
- P\*=0.001\*\*
* Pearson X2 test for vaccine group differences.
* \*\* P <.001
Proportion of adults ≥61 years of age reporting solicited systemic reactions in between day 1 through day 7 after vaccination:* **Chills:**
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 4
- P\*=0.65
* **Malaise:**
+ IIV3-cc (subunit): 10
+ Egg-based IIV3 (subunit): 11
- P\*=0.65
* **Myalgia:**
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 8
- P\*=0.25
* **Arthralgia:**
+ IIV3-cc (subunit): 6
+ Egg-based IIV3 (subunit): 7
- P\*=0.73
* **Headache:**
+ IIV3-cc (subunit): 10
+ Egg-based IIV3 (subunit): 10
- P\*=0.91
* **Sweating:**
+ IIV3-cc (subunit): 6
+ Egg-based IIV3 (subunit): 7
- P\*=0.66
* **Fatigue:**
+ IIV3-cc (subunit): 11
+ Egg-based IIV3 (subunit): 12
- P\*=0.34
* **Fever:**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
- P\*=1.0
* \* Pearson X2 test for vaccine group differences.
Proportion (%) of adults ≥61 years of age reporting other solicited reactions in between day 1 through day 7 after vaccination:* **Stayed at home due to reaction:**
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 2
- P\*=0.38
* **Analgesic/antipyretic medication used:**
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 4
- P\*=0.53
* \* Pearson X2 test for vaccine group differences.
* There were no differences reported between vaccine groups in unsolicited AEs (reported by 13-15% of subjects among all groups).
Proportion (%) of subjects reporting AEs considered to be possibly or probably related to the vaccine:* **Subjects 18-60 years of age:**
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 4
* **Subjects ≥61years of age:**
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 2
* SAEs occurred in 1% of adult subjects 18-60 years of age and 3% of elderly subjects ≥61 years of age.
* The three deaths that occurred over the course of the study were all in elderly subjects ≥61 years of age (1 in the IIV3-cc group and 2 in the egg-based IIV3 group). None of the SAEs or deaths were assessed as vaccine
| I | Good |
| **Nolan T, Chotpitayasunondh T, Rasrio Capeding M, Carson S, David Senders S, Jaehnig P, de Rooij R, Chandra R.** *Safety and tolerability of a cell culture derived trivalent subunit inactivated influenza vaccine administered to healthy children and adolescents: A Phase III, randomized, multicenter, observer-blind study. Vaccine. 2016; 34:230-236* | IIV3-cc
(subunit) | * Phase III, observer blind RCT
* **Multicentre:**
+ US
(18 sites)
+ Australia
(6 sites)
+ New Zealand
(2 sites
+ Philippines
(5 sites)
+ Thailand
(3 sites)
* 2013-2014 influenza season
* Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus Inc.)
| * Healthy children and adolescents 4-17 years of age
* **% female:**
+ 4-8 age group: 52%
+ 9-17 age group: 50%
* **Mean age:**
+ 4-8 age group: 5.9 years
+ 9-17 age group: 12.3 years
* **Total participants:**
+ n=2055
+ IIV3-cc: n= 1372
+ Egg-based IIV3 (Fluvirin): n= 683
| Proportion (%) of participants aged 4-8 years (NPV) reporting any solicited reactions within seven days after first dose:* **Any:**
+ IIV3-cc (subunit): 61
+ Egg-based IIV3 (subunit): 63
* **Local:**
+ IIV3-cc (subunit): 48
+ Egg-based IIV3 (subunit): 43
* **Systemic:**
+ IIV3-cc (subunit): 34
+ Egg-based IIV3 (subunit): 32
Proportion (%) of participants aged 4-8 years reporting any solicited reactions within seven days after second dose:* **Any:**
+ IIV3-cc (subunit): 48
+ Egg-based IIV3 (subunit): 52
* **Local:**
+ IIV3-cc (subunit): 40
+ Egg-based IIV3 (subunit): 43
* **Systemic:**
+ IIV3-cc (subunit): 21
+ Egg-based IIV3 (subunit): 22
Proportion (%) of participants aged 4-17 years reporting solicited reactions within seven days after single dose:* **Any:**
+ IIV3-cc (subunit): 63
+ Egg-based IIV3 (subunit): 54
* **Local:**
+ IIV3-cc (subunit): 53
+ Egg-based IIV3 (subunit): 43
* **Systemic:**
+ IIV3-cc (subunit): 37
+ Egg-based IIV3 (subunit): 30
Proportion (%) of participants aged 4-8 years who reported any (severe\* in brackets) solicited local reactions within 7 days of vaccination:* **Pain:**
+ IIV3-cc (subunit): 56 (1)
+ Egg-based IIV3 (subunit): 55
* **Erythema:**
+ IIV3-cc (subunit): 22
+ Egg-based IIV3 (subunit): 17(<1)
* **Induration:**
+ IIV3-cc (subunit): 16
+ Egg-based IIV3 (subunit): 13
* **Swelling:**
+ IIV3-cc (subunit): 13
+ Egg-based IIV3 (subunit): 11
* **Ecchymosis:**
+ IIV3-cc (subunit): 10
+ Egg-based IIV3 (subunit): 9
Proportion (%) of participants aged 9-17 years who reported any (severe\* in brackets) solicited local reactions within 7 days of vaccination:* **Pain:**
+ IIV3-cc (subunit): 52(<1)
+ Egg-based IIV3 (subunit): 42
* **Erythema:**
+ IIV3-cc (subunit): 11(<1)
+ Egg-based IIV3 (subunit): 11)
* **Induration:**
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 10
* **Swelling:**
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 8
* **Ecchymosis:**
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 3
Proportion (%) of participants aged 4-8 years who reported any (severe\* in brackets) solicited systemic reactions occurring within 7 days of vaccination:* **Malaise:**
+ IIV3-cc (subunit): 16(1)
+ Egg-based IIV3 (subunit): 13(1)
* **Myalgia:**
+ IIV3-cc (subunit): 16(1)
+ Egg-based IIV3 (subunit): 12(<1)
* **Headache:**
+ IIV3-cc (subunit): 15(<1)
+ Egg-based IIV3 (subunit): 12(<1)
* **Fatigue:**
+ IIV3-cc (subunit): 13(1)
+ Egg-based IIV3 (subunit): 10(1)
* **Loss of appetite:**
+ IIV3-cc (subunit): 10(<1)
+ Egg-based IIV3 (subunit): 7(1)
* **Nausea:**
+ IIV3-cc (subunit): 8(1)
+ Egg-based IIV3 (subunit): 8(1)
* **Chills:**
+ IIV3-cc (subunit): 7(<1)
+ Egg-based IIV3 (subunit): 5(1)
* **Sweating:**
+ IIV3-cc (subunit): 6(<1)
+ Egg-based IIV3 (subunit): 6
* **Arthralgia:**
+ IIV3-cc (subunit): 6(<1)
+ Egg-based IIV3 (subunit): 5(<1)
* **Body Temperature (>38C):**
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 9
* **Analgesic/antipyretic (preventive):**
+ IIV3-cc (subunit): 9
+ Egg-based IIV3 (subunit): 9
* **Analgesic/antipyretic (treatment):**
+ IIV3-cc (subunit): 13
+ Egg-based IIV3 (subunit): 12
Proportion (%) of participants aged 9-17 years who reported any (severe\* in brackets) solicited systemic reactions occurring within 7 days of vaccination:* **Malaise:**
+ IIV3-cc (subunit): 15(<1)
+ Egg-based IIV3 (subunit): 14(<1)
* **Myalgia:**
+ IIV3-cc (subunit): 19
+ Egg-based IIV3 (subunit): 13(<1)
* **Headache:**
+ IIV3-cc (subunit): 16
+ Egg-based IIV3 (subunit): 16(<1)
* **Fatigue:**
+ IIV3-cc (subunit): 19(1)
+ Egg-based IIV3 (subunit): 17(<1)
* **Loss of appetite:**
+ IIV3-cc (subunit): 7(<1)
+ Egg-based IIV3 (subunit): 4
* **Nausea:**
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 5
* **Chills:**
+ IIV3-cc (subunit): 6(<1)
+ Egg-based IIV3 (subunit): 2(<1)
* **Sweating:**
+ IIV3-cc (subunit): 8(<1)
+ Egg-based IIV3 (subunit): 7
* **Arthralgia:**
+ IIV3-cc (subunit): 8(<1)
+ Egg-based IIV3 (subunit): 4
* **Body Temperature (>38C):**
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 1
* **Analgesic/antipyretic (preventive):**
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 3
* **Analgesic/antipyretic (treatment):**
+ IIV3-cc (subunit): 6
+ Egg-based IIV3 (subunit): 5
* \*Reactions were categorized as mild, moderate or severe, if they resulted in no limitation of, some limitation of, or inability to perform normal daily activities, respectively.
Proportion (%) of participants aged 4-8 years reporting unsolicited AEs after first dose:* **Any AE:**
+ IIV3-cc (subunit): 33
+ Egg-based IIV3 (subunit): 31
* **At least possibly related AE:**
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 6
* **SAE:**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
* **Medically attended AE:**
+ IIV3-cc (subunit): 12
+ Egg-based IIV3 (subunit): 11
* **NOCD:**
+ IIV3-cc (subunit): 0.3
+ Egg-based IIV3 (subunit): 01
* For 4-8 year old participants who were not previously vaccinated against influenza, AEs were collected from Day 1 through 49; SAEs, medically attended AEs and new onsets of chronic diseases were collected through up to Day 213.
Proportion (%) of participants aged 4-8 years reporting unsolicited AEs after second dose:* **Any AE:**
+ IIV3-cc (subunit): 19
+ Egg-based IIV3 (subunit): 22
* **At least possibly related AE:**
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 4
* **SAE:**
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 2
* **Medically attended AE:**
+ IIV3-cc (subunit): 38
+ Egg-based IIV3 (subunit): 42
* **NOCD:**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 2
* For 4-8 year old participants who were not previously vaccinated against influenza, AEs were collected from Day 1 through 49; SAEs, medically attended AEs and NOCD were collected through up to Day 213.
Proportion (%) of participants aged 9-17 years (PV) reporting unsolicited AEs after single dose:* **Any AE:**
+ IIV3-cc (subunit): 23
+ Egg-based IIV3 (subunit): 26
* **At least possibly related AE:**
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 6
* **SAE:**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 3
* **Medically attended AE:**
+ IIV3-cc (subunit): 25
+ Egg-based IIV3 (subunit): 31
* **NOCD:**
+ IIV3-cc (subunit): 0.4
+ Egg-based IIV3 (subunit): 0.3
* For all 9-17 year old participants, AEs were collected from Day 1 through Day 28, SAEs, medically attended AEs and NOCD were collected up to Day 183
Proportion (%) of participants aged 3-8 years (NPV/PV) with unsolicited AEs by preferred term* **Upper respiratory tract infection:**
+ IIV3-cc (subunit): 11
+ Egg-based IIV3 (subunit): 12
* **Nasopharyngitis:**
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 3
* **Viral infection:**
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 3
* **Cough:**
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 4
* **Pyrexia:**
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 4
* **Headache:**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
* **Vomiting:**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 3
* **Gastroenteritis:**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
* **Rhinorrhoea:**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 2
* **Oropharyngeal pain:**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 2
Proportion (%) of participants aged 9-17 (PV) with unsolicited AEs by preferred term:* **Upper respiratory tract infection:**
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 6
* **Nasopharyngitis:**
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 4
* **Viral infection:**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
* **Cough:**
+ IIV3-cc (subunit): 0.6
+ Egg-based IIV3 (subunit): 0.3
* **Pyrexia:**
+ IIV3-cc (subunit): 0.3
+ Egg-based IIV3 (subunit): 0.6
* **Headache:**
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 1
* **Vomiting:**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
* **Gastroenteritis:**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 2
* **Rhinorrhoea:**
+ IIV3-cc (subunit): 0.3
+ Egg-based IIV3 (subunit): 1
* **Oropharyngeal pain:**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
* No deaths or vaccine-related SAEs were reported over the course of the study. None of the withdrawals from the study were due to AEs.
| I | Fair |
| **Vesikari T, Block SL, Guerra F, Lattanzi M, Holmes S, Izu A, Gaitatzis N, Katrin Hilbert A, Groth N.***Immunogenicity, Safety and Reactogenicity of a Mammalian Cell-Culture-Derived Influenza Vaccine in Healthy Children and Adolescents Three to Seventeen Years of Age. Pediatr Infect Dis J. 2012; 31(5).494-500*
**ClinicalTrials.gov** *Pediatric Safety and Immunogenicity Study of Cell-Culture Derived and Egg-based Subunit Influenza Vaccines in Healthy Children and Adolescents
NCT00645411* | IIV3-cc | * Phase II/III, observer-blind RCT
* **Multi-centre:**
+ US (16 sites)
+ Finland (14 sites)
+ Croatia (9 sites)
+ Hungary (8 sites)
+ Lithuania (6 sites)
+ Italy (5 sites)
+ Romania (2 sites)
* October 2007 to July 2008
* Funded by in part with US Government federal funds from the Office of Public Health Emergency Preparedness, Office of Research and Development Coordination, under contract to Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus Inc.)
| * Healthy children and adolescents 3-17 years of age
* Mean age: 7.4 years
* 48.5% female
* Total participants analyzed:
* IIV3-cc two doses (3-8 years): n=1599
* Egg-based IIV3 (Fluvirin) two doses (3-8 years):n= 1013
* IIV3-cc single dose (9-17 years): n=652
* Egg-based IIV3 (Fluvirin) single dose (9-17 years):
n=316
| Proportion (%) of subjects 3-8 years of age reporting any local AEs between day 1 through day 7 after vaccination: * **1st Dose:**
+ IIV3-cc (subunit): 38
+ Egg-based IIV3 (subunit): 35
* **2nd Dose:**
+ IIV3-cc (subunit): 35
+ Egg-based IIV3 (subunit): 34
Proportion (%) of subjects 3-8 years of age reporting any systemic AEs between day 1 through day 7 after vaccination: * **1st Dose:**
+ IIV3-cc (subunit): 23
+ Egg-based IIV3 (subunit): 26
* **2nd Dose:**
+ IIV3-cc (subunit): 15
+ Egg-based IIV3 (subunit): 19
Proportion (%) of subjects 9-17 years of age reporting any AEs between day 1 through day 7 after vaccination:* **Local:**
+ IIV3-cc (subunit): 42
+ Egg-based IIV3 (subunit): 45
* **Systemic:**
+ IIV3-cc (subunit): 29
+ Egg-based IIV3 (subunit): 30
Proportion (%) of subjects 3-8 years of age reporting mild and severe (brackets) solicited local AEs at injection site between day 1 through day 7 after first vaccination:* **Pain:**
+ IIV3-cc (subunit): 28 (<1)
+ Egg-based IIV3 (subunit): 25 (<1)
* **Erythema:**
+ IIV3-cc (subunit): 12
+ Egg-based IIV3 (subunit): 14
* **Induration:**
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 4
* **Ecchymosis:**
+ IIV3-cc (subunit): 6
+ Egg-based IIV3 (subunit): 6
* **Swelling:**
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 5
Proportion (%) of subjects 3-8 years of age reporting mild and severe (brackets) solicited local AEs between day 1 through day 7 after second vaccination:* **Pain:**
+ IIV3-cc (subunit): 27 (<1)
+ Egg-based IIV3 (subunit): 27 (<1)
* **Erythema:**
+ IIV3-cc (subunit): 13
+ Egg-based IIV3 (subunit): 12
* **Induration:**
+ IIV3-cc (subunit): 4
+ Egg-based IIV3 (subunit): 5
* **Ecchymosis:**
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 4
* **Swelling:**
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 5
Proportion (%) of subjects 3-8 years old reporting mild and severe (brackets) solicited systemic AEs between day 1 through day 7 after first vaccination:* **Chills:**
+ IIV3-cc (subunit): 3(<1)
+ Egg-based IIV3 (subunit): 5(<1)
* **Malaise:**
+ IIV3-cc (subunit): 6(1)
+ Egg-based IIV3 (subunit): 8(1)
* **Myalgia:**
+ IIV3-cc (subunit): 9(<1)
+ Egg-based IIV3 (subunit): 7(<1)
* **Arthralgia:**
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 1
* **Headache:**
+ IIV3-cc (subunit): 8(1)
+ Egg-based IIV3 (subunit): 10(<1)
* **Sweating:**
+ IIV3-cc (subunit): 2(<1)
+ Egg-based IIV3 (subunit): 2(<1)
* **Fatigue:**
+ IIV3-cc (subunit): 10(<1)
+ Egg-based IIV3 (subunit): 12(1)
* **Fever(≥38°C):**
+ IIV3-cc (subunit): 3(<1)
+ Egg-based IIV3 (subunit): 4(<1)
* **Analgesic/antipyretic:**
+ IIV3-cc (subunit): 9
+ Egg-based IIV3 (subunit): 10
* **Stayed at home:**
+ IIV3-cc (subunit): 3
+ Egg-based IIV3 (subunit): 4
Proportion of subjects 3-8 years old reporting mild and severe (brackets) solicited systemic AEs between day 1 through day 7 after second vaccination:* **Chills:**
+ IIV3-cc (subunit): 2(<1)
+ Egg-based IIV3 (subunit): 3(<1)
* **Malaise:**
+ IIV3-cc (subunit): 5(1)
+ Egg-based IIV3 (subunit): 5(<1)
* **Myalgia:**
+ IIV3-cc (subunit): 6(<1)
+ Egg-based IIV3 (subunit): 7(<1)
* **Arthralgia:**
+ IIV3-cc (subunit): 2(<1)
+ Egg-based IIV3 (subunit): 2
* **Headache:**
+ IIV3-cc (subunit): 5(<1)
+ Egg-based IIV3 (subunit): 7(<1)
* **Sweating:**
+ IIV3-cc (subunit): 1(<1)
+ Egg-based IIV3 (subunit): 1
* **Fatigue:**
+ IIV3-cc (subunit): 6(1)
+ Egg-based IIV3 (subunit): 8(<1)
* **Fever(≥38°C):**
+ IIV3-cc (subunit): 2(<1)
+ Egg-based IIV3 (subunit): 2
* **Analgesic/antipyretic:**
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 6
* **Stayed at home:**
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 2
Proportion (%) of subjects 9-17 years of age reporting mild and severe (brackets) solicited local AEs between day 1 through day 7 after vaccination:* **Pain:**
+ IIV3-cc (subunit): 34(<1)
+ Egg-based IIV3 (subunit): 38(1)
* **Erythema:**
+ IIV3-cc (subunit): 14
+ Egg-based IIV3 (subunit): 14
* **Induration:**
+ IIV3-cc (subunit): 7
+ Egg-based IIV3 (subunit): 9
* **Ecchymosis:**
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 3
* **Swelling:**
+ IIV3-cc (subunit): 5
+ Egg-based IIV3 (subunit): 5
Proportion (%) of subjects 9-17 years old reporting mild and severe (brackets) solicited systemic AEs between day 1 through day 7 after vaccination* **Chills:**
+ IIV3-cc (subunit): 4(<1)
+ Egg-based IIV3 (subunit): 4(<1)
* **Malaise:**
+ IIV3-cc (subunit): 9(1)
+ Egg-based IIV3 (subunit): 11(1)
* **Myalgia:**
+ IIV3-cc (subunit): 15(<1)
+ Egg-based IIV3 (subunit): 9(1)
* **Arthralgia:**
+ IIV3-cc (subunit): 4(<1)
+ Egg-based IIV3 (subunit): 5
* **Headache:**
+ IIV3-cc (subunit): 14(<1)
+ Egg-based IIV3 (subunit): 14(1)
* **Sweating:**
+ IIV3-cc (subunit): 2
+ Egg-based IIV3 (subunit): 1(<1)
* **Fatigue:**
+ IIV3-cc (subunit): 9(1)
+ Egg-based IIV3 (subunit): 13(1)
* **Fever(≥38°C):**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 1
* **Analgesic/antipyretic:**
+ IIV3-cc (subunit): 6
+ Egg-based IIV3 (subunit): 10
* **Stayed at home:**
+ IIV3-cc (subunit): 1
+ Egg-based IIV3 (subunit): 3
* Severe local and severe systemic solicited
reactions were reported rarely and were comparable across age and vaccine groups; ≤1% of any reaction classified as severe.
Proportion (%) of subjects 3-8 years of age reporting unsolicited AEs\* collected for the 50-day study period:* **1st Dose:**
+ IIV3-cc (subunit): 32
+ Egg-based IIV3 (subunit): 34
* **2nd Dose:**
+ IIV3-cc (subunit): 18
+ Egg-based IIV3 (subunit): 20
* \*5-8% were considered at least possibly related to the vaccine
* 19-20% of subjects 8-17 years of age reported unsolicited AEs during the 29-day study period; 3% of these were considered at least possibly related to the vaccine.
* Unsolicited AEs occurred in 1-4% of subjects across age and vaccine groups; 0 to <1% were considered at least possibly related to the study vaccines.
* 28 SAEs were reported over the course of the study (4 –month during the postvaccination period, 24 during the 6 safety follow-up period). None of these SAEs were assessed as vaccine related.
* No deaths were reported.
| I | Fair |
| **Frey S, Vesikari T, Szymczakiewicz-Multanowska A, Lattanzi M, Izu A, Groth N, Holmes S.** *Clinical Efficacy of Cell Culture-Derived and Egg-Derived Inactivated Subunit Influenza Vaccines in Healthy Adults. Clin Infect Dis. 2010; 51(9):997-1004.*
**ClinicalTrials.gov** *Efficacy Study of Two Influenza Vaccines and Placebo in Healthy Adult Subjects NCT00630331* | IIV3-cc
(subunit) | * Observer-blind RCT
* Multi-centre:
* US
Finland
Poland
* 2007-2008 influenza season
* Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus Inc.)
| * Healthy adults 18-49 years of age
* Mean age: 32.7-33.0 years
* 54-55% female
* Total participants analyzed (safety):
* IIV3-cc: n=3813
* Egg-based IIV3 (Agrippal®): n=3669
* Placebo: n=3894
| The overall proportion of participants reporting solicited local and systemic reactions between day 1 through day 7 after vaccination (not including SAEs) by the MedDRA Term was 51.11% for the IIV3-cc group, 46.42 % for the egg-based IIV3 group, and 35.62% for the placebo group.
Proportion (%) of participants reporting solicited local reactions at injection site between day 1 through day 7 after vaccination (not including SAEs) by the MedDRA Term:* **Erythema:**
+ IIV3-cc (subunit): 13.38
+ Egg-based IIV3 (subunit): 13.41
+ Placebo: 10.04
* **Induration:**
+ IIV3-cc (subunit): 6.27
+ Egg-based IIV3 (subunit): 5.64
+ Placebo: 2.59
* **Pain:**
+ IIV3-cc (subunit): 30.37
+ Egg-based IIV3 (subunit): 24.34
+ Placebo: 9.63
* **Swelling:**
+ IIV3-cc (subunit): 5.72
+ Egg-based IIV3 (subunit): 4.93
+ Placebo: 2.65
Proportion (%) of participants reporting solicited systemic reactions between day 1 through day 7 after vaccination (not including SAEs) by the MedDRA Term:* **Chills:**
+ IIV3-cc (subunit): 5.56
+ Egg-based IIV3 (subunit): 5.78
+ Placebo: 5.78
* **Fatigue:**
+ IIV3-cc (subunit): 10.23
+ Egg-based IIV3 (subunit): 11.01
+ Placebo: 9.91
* **Malaise:**
+ IIV3-cc (subunit): 7.61
+ Egg-based IIV3 (subunit): 7.09
+ Placebo: 6.11
* **Myalgia:**
+ IIV3-cc (subunit): 11.83
+ Egg-based IIV3 (subunit): 10.06
+ Placebo: 7.14
* **Headache:**
+ IIV3-cc (subunit): 14.98
+ Egg-based IIV3 (subunit): 15.10
+ Placebo: 15.33
* Possibly or probably related unsolicited AEs were reported by 1-2% of study participants on days 1-7 and by <1% of participants from days 8-23; no AEs were reported on days 23-181
* 4 deaths were reported over the course of the study; 2 within the group that received IIV3-cc and 1 in each of the IIV3 and placebo groups. The deaths were judged as unrelated to the study vaccine.
* 127 other SAEs were reported over the course of the study; 42 in the IIV3-cc group, 35 in the TIV group, and 38 in the placebo group; the SAEs were judged as unrelated to the study vaccines.
| I | Fair |
| **Hartvickson R., Cruz M., Ervin J., Brandon D., Forleo-Neto E., Dagnew A.F., Chandra R., Lindert K.,Mateen A.A.** *Non-inferiority of mammalian cell-derived quadrivalent subunit influenza virus vaccines compared to trivalent subunit influenza virus vaccines in healthy children: A phase III randomized, multicenter, double-blind clinical trial. Int J Infect Dis. 2015;41:65-72*.
**ClinicalTrial.gov** *Safety and Immunogenicity of Three Influenza Vaccines in Children Aged 4 Years Old to Less than 18 Years Old
NCT01992107* | IIV4-cc
(subunit) | * RCT
* US Multicentre
* 2013-2014 influenza season
* Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus Inc.)
| Healthy children aged 4-17 years* **Group 1:**
+ 1159 children vaccinated with Flucelvax® IIV4-cc (819 previously vaccinated,<340 not previously vaccinated)
+ 48% female
* **Group 2:**
+ 593 children vaccinated with Flucelvax® IIV3-cc (B/Yamagata)
(420 previously vaccinated, 173 not previously vaccinated)
+ 48% female
* **Group 3:**
+ 581 children vaccinated with Flucelvax® IIV3-cc (B/Victoria) (400 previously vaccinated,181 not previously vaccinated)
+ 49% female
| Proportion (%)\* of children reporting solicited AEs (age-appropriate\*\*) within 7 days after vaccination after the 1st dose:* **Subjects 4-5 years of age:**
+ Any AE:
- IIV4-cc (subunit): 65
- IIV3-cc (B/Yam) (subunit): 58
- IIV3-cc (B/Vic) (subunit): 57
+ Local:
- IIV4-cc (subunit): 57
- IIV3-cc (B/Yam) (subunit): 56
- IIV3-cc (B/Vic) (subunit): 51
+ Systemic:
- IIV4-cc (subunit): 28
- IIV3-cc (B/Yam) (subunit): 20
- IIV3-cc (B/Vic) (subunit): 18
+ Others:
- IIV4-cc (subunit): 10
- IIV3-cc (B/Yam) (subunit): 5
- IIV3-cc (B/Vic) (subunit): 4
* **Subjects 6-8 years of age:**
+ Any AE:
- IIV4-cc (subunit): 69
- IIV3-cc (B/Yam) (subunit): 72
- IIV3-cc (B/Vic) (subunit): 69
+ Local:
- IIV4-cc (subunit): 64
- IIV3-cc (B/Yam) (subunit): 67
- IIV3-cc (B/Vic) (subunit): 62
+ Systemic:
- IIV4-cc (subunit): 31
- IIV3-cc (B/Yam) (subunit): 36
- IIV3-cc (B/Vic) (subunit): 35
+ Others:
- IIV4-cc (subunit): 9
- IIV3-cc (B/Yam) (subunit): 9
- IIV3-cc (B/Vic) (subunit): 9
* **Subjects 9-18 years of age:**
+ Any AE:
- IIV4-cc (subunit): 71
- IIV3-cc (B/Yam) (subunit): 68
- IIV3-cc (B/Vic) (subunit): 61
+ Local:
- IIV4-cc (subunit): 65
- IIV3-cc (B/Yam) (subunit): 60
- IIV3-cc (B/Vic) (subunit): 55
+ Systemic:
- IIV4-cc (subunit): 40
- IIV3-cc (B/Yam) (subunit): 41
- IIV3-cc (B/Vic) (subunit): 33
+ Others:
- IIV4-cc (subunit): 6
- IIV3-cc (B/Yam) (subunit): 8
- IIV3-cc (B/Vic) (subunit): 7
+ \* Data from the first vaccination includes both previously vaccinated and not previously vaccinated subjects for those 4-5 and 6-8 years of age.
+ \*\* Not previously vaccinated subjects 4-5 and 6-9 years of age received two vaccinations, and previously vaccinated subjects 4-5, 6-8, and 9-17 years of age received one vaccination.
Proportion (%) of children reporting solicited AEs (age-appropriate) within 7 days after vaccination after the 2nd dose:* **Subjects 4-5 years of age\*:**
+ Any AE:
- IIV4-cc (subunit): 60
- IIV3-cc (B/Yam) (subunit): 49
- IIV3-cc (B/Vic) (subunit): 43
+ Local:
- IIV4-cc (subunit): 53
- IIV3-cc (B/Yam) (subunit): 44
- IIV3-cc (B/Vic) (subunit): 36
+ Systemic:
- IIV4-cc (subunit): 31
- IIV3-cc (B/Yam) (subunit): 23
- IIV3-cc (B/Vic) (subunit): 19
+ Others:
- IIV4-cc (subunit): 4
- IIV3-cc (B/Yam) (subunit): 8
- IIV3-cc (B/Vic) (subunit): 2
* **Subjects 6-8 years of age\*:**
+ Any AE:
- IIV4-cc (subunit): 57
- IIV3-cc (B/Yam) (subunit): 63
- IIV3-cc (B/Vic) (subunit): 64
+ Local:
- IIV4-cc (subunit): 50
- IIV3-cc (B/Yam) (subunit): 57
- IIV3-cc (B/Vic) (subunit): 57
+ Systemic:
- IIV4-cc (subunit): 22
- IIV3-cc (B/Yam) (subunit): 27
- IIV3-cc (B/Vic) (subunit): 23
+ Others:
- IIV4-cc (subunit): 8
- IIV3-cc (B/Yam) (subunit): 7
- IIV3-cc (B/Vic) (subunit): 10
+ \*Not previously vaccinated subjects 4-5 and 6-9 years of age received two vaccinations, and previously vaccinated subjects 4-5, 6-8, and 9-17 years of age received one vaccination.
Across all vaccine groups, the most common solicited local AE was tenderness for children 4-5 years of age and injection-site pain for children 6-8 and 9-17 years of age. The most common solicited systemic AEs across all vaccine groups for children 4-5 years of age, 6-8 years of age, and 9-17 years of age were sleepiness, fatigue and headache, and headache respectively.
Proportion (%) of children reporting unsolicited AEs by group:* **Any:**
+ IIV4-cc (subunit): 24
+ IIV3-cc (B/Yam) (subunit): 24
+ IIV3-cc (B/Vic) (subunit): 27
* **At least possibly related to vaccine:**
+ IIV4-cc (subunit): 5
+ IIV3-cc (B/Yam) (subunit): 6
+ IIV3-cc (B/Vic) (subunit): 5
* **SAE:**
+ IIV4-cc (subunit): 1
+ IIV3-cc (B/Yam) (subunit): 1
+ IIV3-cc (B/Vic) (subunit): <1
* **Medically attended:**
+ IIV4-cc (subunit): 27
+ IIV3-cc (B/Yam) (subunit): 27
+ IIV3-cc (B/Vic) (subunit): 27
* **New onset of chronic diseases:**
+ IIV4-cc (subunit): 2
+ IIV3-cc (B/Yam) (subunit): 2
+ IIV3-cc (B/Vic) (subunit): 2
* No SAEs was judged by the study investigators as related to the study vaccine. No deaths were reported during the study.
| II-2 | Fair |
| **Loebermann M, Fritzsche C, Geerdes-Fenge H, Heijnen E, Kirby D, Reisinger EC.** *A phase III, open-label, single-arm, study to evaluate the safety and immunogenicity of a trivalent, surface antigen inactivated subunit influenza virus vaccine produced in mammalian cell culture (Optaflu®) in healthy adults. Infection. 2019; 47:105-109.*
**ClinicalTrial.gov** *Safety and Immunogenicity of a Cell Derived Subunit Trivalent Nonadjuvanted Influenza Study Vaccine in Adults Aged 18 Years and Above NCT01880697* | IIV3-cc
(subunit) | * Phase III open-label, single-arm, study
* Germany Single-center
* 2013-2014 influenza season
* Funded by Novartis Vaccines and Diagnostics, Inc. (currently operating as Seqirus Inc.)
| * Healthy adults18 to ≤60 years and ≥61 years of age
+ Mean age: 53.8 years
+ 56% female
+ Total participants: n=126;
+ Adults aged 18 to ≤60 years: n=63
+ Adults aged ≥61 years: n=63
| Proportion (%) of subjects aged 18 to ≤60 years with solicited AEs after vaccination with IIV3-cc:* Any: 57
* Local\*: 51
* Pain at the injection site: 49
* Induration: 8
* Systemic\*\*: 27
* Headache : 17
* Fatigue: 16
* Malaise: 5
* Arthralgia: 5
\*Threshold for erythema, ecchymosis and induration: grade 0 (<10mm), any (≥10 mm)
\*\* Includes subjects with body temperature ≥38̊C irrespective of route of measurement
Proportion (%) of subjects aged ≥61 years with solicited AEs after vaccination with IIV3-cc:* Any: 35
* Local\*: 29
* Pain at the injection site: 29
* Induration: <2
* Systemic\*\*: 13
* Headache: 10
* Fatigue : N/A
* Malaise : N/A
* Arthralgia: 5
\*Threshold for erythema, ecchymosis and induration: grade 0 (<10mm), any (≥10 mm)
\*\* Includes subjects with body temperature ≥38̊C irrespective of route of measurement
Proportion (%) for all subjects with solicited AEs after vaccination with IIV3-cc:* Any: 46
* Local\*: 40
* Pain: 39
* Induration: 5
* Systemic\*\* : 20
* Headache : 14
* Fatigue : N/A
* Malaise : N/A
* Arthralgia: 5
\*Threshold for erythema, ecchymosis and induration: grade 0 (<10mm), any (≥10 mm)
\*\* Includes subjects with body temperature ≥38̊C irrespective of route of measurement
Proportion (%) of subjects aged 18 to ≤60 years with unsolicited AEs after vaccination with IIV3-cc:* Any AEs: 10
* At least possibly related AEs: 3
* Serious AEs: 2
* At least possibly related SAEs: 0
* Medically attended AEs: 6
* AEs leading to discontinuation: 0
* Death: 0
Proportion (%) of all subjects with unsolicited AEs after vaccination with IIV3-cc:* Any AEs: 8
* At least possibly related AEs: 2
* Serious AEs: 1
* At least possibly related SAEs: 0
* Medically attended AEs: 6
* AEs leading to discontinuation: 0
* Death: 0
| II-3 | Fair |
| **Moro PL, Winiecki S, Lewis P, Shimabukuro TT, Cano M.** *Surveillance of adverse events after the first trivalent inactivated influenza vaccine produced in mammalian cell culture (Flucelvax) reported to the Vaccine Adverse Event Reporting System (VAERS), United States, 2013-2015.Vaccine. 2015; 33(45):6684-6688*. | IIV3-cc (subunit) | * Clinical review of cases identified through the Vaccine Adverse Event Reporting System (VAERS) co-managed by the US
Centers for Disease Control and Prevention and the US FDA
* 2013-2014 2014-2015 influenza seasons
* No external sources of funding
| Persons vaccinated with IIV3-cc during July 1, 2013 through March 31, 2015 (reports received by April 30, 2015); excluding non-US reports* 55.5% female
* Mean age: 18.5 years
* Range: 0.7–85 years
* Total reports reviewed: n= 629
* Reports with an AE: n= 309
* Reports during 2013–2014 influenza season: n= 389
* Reports during 2014–2015 influenza season: n=240
| Proportion (%) of participants reporting local and systemic reactions:* General disorders and
* administration site conditions: 49.20
* Immune system disorders: 23.60
* Anaphylaxis: 0.65
* Musculoskeletal and connective tissue: 11.90
* Nervous system disorders: 4.50
* Guillain-Barre syndrome: 1.30
* Bell’s palsy: 0.65
* Respiratory, thoracic and mediastinal disorders: 3.60
* Gastrointestinal disorders: 1.60
* Cardiac disorders: 1.60
* Skin and subcutaneous tissue disorders: 1.00
* Infections and infestations: 1.00
* Ear and labyrinth disorders: 0.60
* Other: 1.30
\*Each report was assigned a primary clinical category using MedDRA system organ classes (SOC)
19 (6.1%) of the 309 reports with an AE documented were serious.
313 reports of use in persons of inappropriate age (271 during the 2013–2014 initial season of IIV3-cc use); none of the 10 reports which described an AE were serious
Among the serious reports, 1 death occurred in a 77-year-old female with a history of diabetes, chronic obstructive pulmonary disease, arthritis, and depression who received IIV-cc. Cause of death was reported as cardiovascular disease secondary to diabetes | III | Good |
| **Abbreviations:** AE: adverse event; CI: confidence interval; MedDRA: Medical Dictionary for Regulatory Activities; n/a: not applicable; IIV4-cc: cell-culture based quadrivalent inactivated influenza vaccine; RCT: randomized controlled trial; SAE: serious adverse event; IIV3-cc: cell-culture based trivalent inactivated influenza vaccine; US: United States; VAERS: Vaccine Adverse Event Reporting System, NPV: Not Previously Vaccinated, PV: Previously Vaccinated |
List of abbreviations
---------------------
Abbreviation
**Term**
AE
Adverse event
CI
Confidence interval
CVV
Candidate vaccine virus
EMR
Electronic medical record
DoD
Department of Defense (US)
FDA
Food and Drug Administration (United States)
GMT
Geometric mean titre
HA
Hemagglutinin
HI
Hemagglutination inhibition
IIV
Inactivated influenza vaccine ki cc
IIV3
Trivalent inactivated influenza vaccine
IIV3-Adj
Adjuvanted trivalent inactivated influenza vaccine
IIV3-cc
Cell-culture based trivalent inactivated influenza vaccine
IIV3-HD
High-dose trivalent inactivated influenza vaccine
IIV3-SD
Standard-dose trivalent inactivated influenza vaccine
IIV4
Quadrivalent inactivated influenza vaccine
IIV4-cc
Cell-culture based quadrivalent inactivated influenza vaccine
IIV4-SD
Standard-dose quadrivalent inactivated influenza vaccine
ILI
Influenza-like illness
IM
Intramuscular
IWG
Influenza Working Group
LAIV
Live attenuated influenza vaccine
LAIV3
Trivalent live attenuated influenza vaccine
LAIV4
Quadrivalent live attenuated influenza vaccine
MDCK
Madin-Darby Canine Kidney
MedDRA
Medical Dictionary for Regulatory Activities
Medical Dictionary for Regulatory Activities
Not applicable
NA
Neuraminidase
NACI
National Advisory Committee on Immunization
NOCD
New onset of chronic diseases
OR
Odds ratio
PHAC
Public Health Agency of Canada
RCT
Randomized controlled trial
rVE
Relative vaccine effectiveness
SAE
Serious adverse event
US
United States
VAERS
Vaccine Adverse Event Reporting System (US)
VE
Vaccine effectiveness
Acknowledgments
---------------
**This supplemental statement was prepared by:** A Sinilaite, J Przepiorkowski, K Young, I Gemmill, R Harrison and approved by NACI.
**NACI gratefully acknowledges the contribution of** A House (Centre for Immunization and Respiratory Infectious Diseases [CIRID], PHAC), M Laplante (CIRID, PHAC), and K Merucci (Health Library, HC).
### NACI Influenza Working Group
**Members:** I Gemmill (Chair), L Cochrane, N Dayneka, R Harrison, K Klein, D Kumar, J Langley, J McElhaney, A McGeer, D Moore, S Smith, B Warshawsky.
**Liaison representative:**L Grohskopf (Centers for Disease Control and Prevention [CDC], United States).
**Ex-officio representatives:**C Bancej (CIRID, PHAC), P Wolfe-Roberge (First Nations and Inuit Health Branch [FNIHB], Indigenous Services Canada [ISC]), and J Xiong (Biologics and Genetic Therapies Directorate [BGTD], Health Canada [HC]).
### NACI
**Members:** C Quach (Chair), S Deeks (Vice-Chair), N Dayneka, P De Wals, V Dubey, R Harrison, K Hildebrand, K. Klein, J Papenburg, C Rotstein, B Sander and S Smith.
**Former NACI members:** M Salvadori and N Sicard.
**Liaison Representatives:** LM Bucci (Canadian Public Health Association), E Castillo (Society of Obstetricians and Gynaecologists of Canada), A Cohn (Centers for Disease Control and Prevention, United States), M Naus (Canadian Immunization Committee), J Emili (College of Family Physicians of Canada), D Moore (Canadian Paediatric Society), and A Pham-Huy (Association of Medical Microbiology and Infectious Disease Canada).
**Ex-Officio Representatives:** C. Rossi (National Defence and the Canadian Armed Forces), E Henry (CIRID, PHAC), J Gallivan (Marketed Health Products Directorate [MHPD], HC), M Lacroix (Public Health Ethics Consultative Group, PHAC), J Pennock (CIRID, PHAC), R Pless (Biologics and Genetic Therapies Directorate [BGTD], Health Canada [HC]), G Poliquin (National Microbiology Laboratory, PHAC), T Wong (First Nations and Inuit Health Branch [FNIHB], Indigenous Services Canada [ISC]).
**Former ex-officio representatives:** K Barnes (National Defence and the Canadian Armed Forces).
References
----------
### Footnotes
Footnote 1
Schanzer DL, Allison M, Kathleen M. Statistical estimates of respiratory admissions attributable to seasonal and pandemic influenza for Canada. Influenza and Other Respiratory Viruses. 2013; 7(5):799-808.
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
Schanzer DL, Sevenhuysen C, Winchester B, Mersereau T. Estimating influenza deaths in Canada, 1992–2009. PLOS ONE. 2013; 8(11):e80481.
[Return to footnote 2 referrer](#fn2-rf)
Footnote 3
Frey S, Vesikari T, Szymczakiewicz-Multanowska A, Lattanzi M, Izu A, Groth N, Holmes S. Clinical Efficacy of Cell Culture—Derived and Egg-Derived Inactivated Subunit Influenza Vaccines in Healthy Adults. Clinical Infectious Diseases. 2010 Nov 1;51(9):997-1004.
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
The Centers for Disease Control and Prevention (CDC) (US). Seasonal Influenza (Flu): Cell-Based Flu Vaccines. [Internet]. 2016. [cited 2019 July 15]. Available from: https://www.cdc.gov/flu/prevent/cell-based.htm
[Return to footnote 4 referrer](#fn4-rf)
Footnote 5
Gregersen JP, Schmitt HJ, Trusheim H, Broker M. Safety of MDCK cell culture-based influenza vaccines. Future Microbiol 2011 Feb;6(2):143-152.
[Return to footnote 5 referrer](#fn5-rf)
Footnote 6
Barr IG, Donis RO, Katz JM, McCauley JW, Odagiri T, Trusheim H, Tsai TF, Wentworth DE. Cell culture-derived influenza vaccines in the severe 2017–2018 epidemic season: A step towards improved influenza vaccine effectiveness. NPJ Vaccines. 2018; 3(1):44.
[Return to footnote 6 referrer](#fn6-rf)
Footnote 7
Hampson A, Barr I, Cox N, Donis RO, Siddhivinayak H, Jernigan D, Katz J, McCauley J, Motta F, Odagiri T, Tam JS. Improving the selection and development of influenza vaccine viruses–Report of a WHO informal consultation on improving influenza vaccine virus selection, Hong Kong SAR, China, 18–20 November 2015. Vaccine. 2017; 35(8):1104-9.
[Return to footnote 7 referrer](#fn7-rf)
Footnote 8
Seqirus UK Limited. Product monograph: Flucelvax® QUAD: Influenza Vaccine (surface antigen, inactivated, prepared in cell cultures). [Internet]. 2019. Available from: https://pdf.hres.ca/dpd\_pm/00054016.PDF.
[Return to footnote 8 referrer](#fn8-rf)
Footnote 9
US FDA, Department of Health and Human Services. Supplemental Approval BL 125408/174. [Internet]. 2016. [cited 2019 July 15]. Available from: https://www.fda.gov/media/100697/download
[Return to footnote 9 referrer](#fn9-rf)
Footnote 10
CDC (US). Advisory Committee on Immunization Practices Presentation Slides: June 2018 Meeting. [Internet]. 2018. [cited 2019 July 15]. Available from: https://www.cdc.gov/vaccines/acip/meetings/slides-2018-06.html
[Return to footnote 10 referrer](#fn10-rf)
Footnote 11
Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, Atkins D. Current methods of the US Preventive Services Task Force: A review of the process. Am J Prev Med. 2001;20(3):21-35.
[Return to footnote 11 referrer](#fn11-rf)
Footnote 12
Seqirus. Flucelvax Doctor Discussion Guide. [Internet] Holly Springs, NC: Seqirus; 2017. [cited 2019 July 15]. Available from: https://labeling.cslbehring.com/PRODUCT-DOCUMENT/US/Flucelvax/EN/Flucelvax-Doctor-Discussion-Guide.pdf
[Return to footnote 12 referrer](#fn12-rf)
Footnote 13
Seqirus. US Product Monograph: Flucelvax Quadrivalent. [Internet]. Holly Springs, NC: Seqirus ;2016. [ cited 2019 July 15]. Available from: http://labeling.seqirus.com/PI/US/Flucelvax/EN/Flucelax-Prescribing-Information.pdf
[Return to footnote 13 referrer](#fn13-rf)
Footnote 14
Boikos C, Sylvester G, Sampalis J, Mansi J. Effectiveness of the Cell Culture-and Egg-Derived, Seasonal Influenza Vaccine during the 2017-2018 Northern Hemisphere Influenza Season. Canadian Immunization Conference 2018. 2018 Dec 04-06; Ottawa, ON, Canada [poster presentation].
[Return to footnote 14 referrer](#fn14-rf)
Footnote 15
DeMarcus L, Shoubaki L, Federinko S. Comparing influenza vaccine effectiveness between cell-derived and egg-derived vaccines, 2017–2018 influenza season. Vaccine. 2019 Jul 9;37(30):4015-4021.
[Return to footnote 15 referrer](#fn15-rf)
Footnote 16
Izurieta HS, Chillarige Y, Kelman J, Wei Y, Lu Y, Xu W, Lu M, Pratt D, Chu S, Wernecke M, MaCurdy T, Forshee R. Relative effectiveness of cell-cultured and egg-based influenza vaccines among elderly persons in the United States, 2017-18, 2017-18. J Infect Dis. 2019 Sep 13; 220(8):1255-1264.
[Return to footnote 16 referrer](#fn16-rf)
Footnote 17
Klein NP, Fireman B, Goddard K, Zerbo O, Asher J, Zhou J, King J, Lewis N. LB15. Vaccine Effectiveness of Flucelvax Relative to Inactivated Influenza Vaccine During the 2017–18 Influenza Season in Northern California. Open Forum Infect Dis. 2018; 5(Suppl 1):S764.t
[Return to footnote 17 referrer](#fn17-rf)
Footnote 18
US Armed Forces, Armed Forces Health Surveillance Center. Influenza-Like Illness (ILI). [Internet]. 2015. [cited 2019 July 15]. Available from: https://www.health.mil/Reference-Center/Publications/2015/10/01/Influenza-Like-Illness
[Return to footnote 18 referrer](#fn18-rf)
Footnote 19
US Food and Drug Administration. Guidance for industry: Clinical data needed to support the licensure of seasonal inactivated influenza vaccines. [Internet]. 2007. [cited 2019 July 15]. Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm091990.pdf
[Return to footnote 19 referrer](#fn19-rf)
Footnote 20
Bart S., Cannon K., Herrington D., Mills R., Forleo-Neto E., Lindert K., Abdul MA. Immunogenicity and safety of a cell culture-based quadrivalent influenza vaccine in adults: A phase III, double-blind, multicenter, randomized, non-inferiority study. Hum Vaccines Immunother. 2016; 12(9):2278-88.
[Return to footnote 20 referrer](#fn20-rf)
Footnote 21
Hartvickson R., Cruz M., Ervin J., Brandon D., Forleo-Neto E., Dagnew A.F., Chandra R., Lindert K., Mateen A.A. Non-inferiority of mammalian cell-derived quadrivalent subunit influenza virus vaccines compared to trivalent subunit influenza virus vaccines in healthy children: A phase III randomized, multicenter, double-blind clinical trial. Int J Infect Dis. 2015; 41:65-72.
[Return to footnote 21 referrer](#fn21-rf)
Footnote 22
European Union European Medicines Agency. Assessment report for paediatric studies submitted according to Article 46 of the Regulation (EC) No 1901/2006. [Internet]. 2015. [cited 2019 July 15]. Available from: https://www.ema.europa.eu/en/documents/variation-report/optaflu-h-c-758-p46-0052-epar-assessment-report\_en.pdf.
[Return to footnote 22 referrer](#fn22-rf)
Footnote 23
European Union European Medicines Agency. Optaflu European Public Assessment Report: Scientific Discussion. [Internet]. 2007. [cited 2019 July 15]. Available from: https://www.ema.europa.eu/en/documents/scientific-discussion/optaflu-epar-scientific-discussion\_en.pdf.
[Return to footnote 23 referrer](#fn23-rf)
Footnote 24
US Food and Drug Administration. Flucelvax Quadrivalent. [Internet]. 2019. [cited 2019 July 15]. Available from: https://www.fda.gov/vaccines-blood-biologics/vaccines/flucelvax-quadrivalent
[Return to footnote 24 referrer](#fn24-rf)
Footnote 25
US Food and Drug Administration. FLUCELVAX - Seqirus, Inc. 1.14.1.3 US Package Insert. [Internet]. 2019. [cited 2019 July 15]. Available from: https://www.fda.gov/media/85322/download
[Return to footnote 25 referrer](#fn25-rf)
Footnote 26
Vesikari T, Block SL, Guerra F, Lattanzi M, Holmes S, Izu A, Gaitatzis N, Hilbert AK, Groth N. Immunogenicity, safety and reactogenicity of a mammalian cell-culture–derived influenza vaccine in healthy children and adolescents three to seventeen years of age. Pediatr Infect Dis J 2012 May; 31(5):494-500.
[Return to footnote 26 referrer](#fn26-rf)
Footnote 27
Ambrozaitis A, Groth N, Bugarini R, Sparacio V, Podda A, Lattanzi M. A novel mammalian cell-culture technique for consistent production of a well-tolerated and immunogenic trivalent subunit influenza vaccine. Vaccine. 2009; 27(43):6022-9.
[Return to footnote 27 referrer](#fn27-rf)
Footnote 28
Szymczakiewicz-Multanowska A, Groth, N, Bugarini R, Lattanzi M, Casula D, Hilbert A, Tsai T, Podda A. Safety and Immunogenicity of a Novel Influenza Subunit Vaccine Produced in Mammalian Cell Culture. J Infect Dis. 2009; 200(6): 841-8.
[Return to footnote 28 referrer](#fn28-rf)
Footnote 29
Loebermann M, Fritzsche C, Geerdes-Fenge H, Heijnen E, Kirby D, Reisinger EC. A phase III, open-label, single-arm, study to evaluate the safety and immunogenicity of a trivalent, surface antigen inactivated subunit influenza virus vaccine produced in mammalian cell culture (Optaflu®) in healthy adults. Infection. 2019; 47:105-109.
[Return to footnote 29 referrer](#fn29-rf)
Footnote 30
Nolan T, Chotpitayasunondh T, Rasrio Capeding M, Carson S, David Senders S, Jaehnig P, de Rooij R, Chandra R. Safety and tolerability of a cell culture derived trivalent subunit inactivated influenza vaccine administered to healthy children and adolescents: A Phase III, randomized, multicenter, observer-blind study. Vaccine. 2016; 34:230-236.
[Return to footnote 30 referrer](#fn30-rf)
Footnote 31
Moro PL, Winiecki S, Lewis P, Shimabukuro TT, Cano M. Surveillance of adverse events after the first trivalent inactivated influenza vaccine produced in mammalian cell culture (Flucelvax) reported to the Vaccine Adverse Event Reporting System (VAERS), United States, 2013-2015.Vaccine. 2015; 33(45):6684-6688.
[Return to footnote 31 referrer](#fn31-rf)
Footnote 32
Papke D., McNussen P.J., Rasheed M., Tsipursky M.S., Labriola L.T. A case of unilateral optic neuropathy following influenza vaccination. Semin Ophthalmol. 2017; 32(4):517-23.
[Return to footnote 32 referrer](#fn32-rf)
Footnote 33
Bencharitiwong R, Leonard S, Tsai T, Nowak-Wegrzyn A. In vitro assessment of the allergenicity of novel MF59-adjuvanted pandemic H1N1 influenza vaccine produced in dog kidney cells. Hum Vaccin Immunother. 2012 Jul;8(7):863-865.
[Return to footnote 33 referrer](#fn33-rf)
Footnote 3r
Wanich N, Bencharitiwong R, Tsai T, Nowak-Wegrzyn A. In vitro assessment of the allergenicity of a novel influenza vaccine produced in dog kidney cells in individuals with dog allergy. Ann Allergy Asthma Immunol. 2010 May;104(5):426-433.
[Return to footnote 34 referrer](#fn34-rf)
Footnote 35
Skowronski DM, Chambers C, De Serres G, Dickinson JA, Winter AL, Hickman R, Chan T, Jassem AN, Drews SJ, Charest H, Gubbay JB. Early season co-circulation of influenza A (H3N2) and B (Yamagata): interim estimates of 2017/18 vaccine effectiveness, Canada, January 2018. Eurosurveillance. 2018; 23(5).
[Return to footnote 35 referrer](#fn35-rf)
Footnote 36
Skowronski DM, Janjua NZ, De Serres G, Sabaiduc S, Eshaghi A, Dickinson JA, Fonseca K, Winter AL, Gubbay JB, Krajden M, Petric M. Low 2012–13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses. PloS one. 2014; 9(3):e92153.
[Return to footnote 36 referrer](#fn36-rf)
Footnote 37
Zost SJ, Parkhouse K, Gumina ME, Kim K, Perez SD, Wilson PC, Treanor JJ, Sant AJ, Cobey S, Hensley SE. Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains. Proceedings of the National Academy of Sciences. 2017; 114(47):12578-83.
[Return to footnote 37 referrer](#fn37-rf)
Footnote 38
Wu NC, Zost SJ, Thompson AJ, Oyen D, Nycholat CM, McBride R, Paulson JC, Hensley SE, Wilson IA. A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine. PLoS pathogens. 2017; 13(10):e1006682.
[Return to footnote 38 referrer](#fn38-rf)
Footnote 39
The Francis Crick Institute. Worldwide Influenza Centre: Annual and Interim Reports – February 2018 interim report. [Internet]. 2018. [cited 2019 July 15]. Available from: https://www.crick.ac.uk/research/worldwide-influenza-centre/annual-and-interim-reports/
[Return to footnote 39 referrer](#fn39-rf)
Footnote 40
Harding AT, Heaton NS. Efforts to improve the seasonal influenza vaccine. Vaccines. 2018; 6(19):1–12.
[Return to footnote 40 referrer](#fn40-rf)
Footnote 41
Lin Y, Wharton SA, Whittaker L, Dai M, Ermetal B, Lo J, Pontoriero A, Baumeister E, Daniels RS, McCauley JW Influenza Other Respir Viruses. 2017 May; 11(3):263-274.
[Return to footnote 41 referrer](#fn41-rf)
Footnote 42
Remschmidt C, Wichmann O, Harder T. Frequency and impact of confounding by indication and health vaccinee bias in observational studies assessing influenza vaccine effectiveness: a systematic review. BMC Infect Dis 2015; 15 (429).
[Return to footnote 42 referrer](#fn42-rf)
Appendix A: PRISMA Flow Diagram
-------------------------------
**Figure 1. Efficacy, effectiveness, immunogenicity, and safety of Flucelvax® Quad. February 12, 2019**
Figure 1 - Text description
Appendix A: PRISMA Flow Diagram
The PRISMA flow diagram describes the process by which articles were selected for the literature review. The process is broken down into four stages: Identification, Screening, Eligibility and Included.
**Stage 1: Identification**
* 816 records were identified through the February 12, 2019 database search and 11 records were identified through additional sources.
* 827 records remained after duplicates were removed.
**Stage 2: Screening**
* 827 records were then screened.
* Of these 827 records, 686 records were excluded.
**Stage 3: Eligibility**
* 141 full-text articles were assessed for eligibility.
* Of these 141 full-text articles, 128 were excluded. The exclusion breakdown is as follows: 31 were secondary research, 5 were editorials, 49 were no outcome of interest, 8 were duplicates; 1 was a doctoral dissertation, 26 did not report on Flucelvax Quadrivalent® or Flucelvax® and 8 had insufficient data.
**Stage 4: Included**
* 13 articles were included in the final synthesis: 8 clinical trials (7 RCT, 1 phase III open-label, single arm study), 4 observational studies and 1 clinical review.
Appendix B: Characteristics of Inlfuenza Vaccines Available For Use in Canada, 2020–2021[Footnote \*](#fnt9a)
--------------------------------------------------------------------------------------------------------------
Appendix B: Characteristics of Inlfuenza Vaccines Available For Use in Canada, 2020–2021\*
| Product name (manufacturer) | Vaccine Characteristic |
| --- | --- |
| Vaccine type | Route of administration | Authorized ages for use | Antigen content for each vaccine strain | Adjuvant | Formats available | Post-puncture shelf life for multi-dose vials | Thimerosal | Antibiotics (traces) | Production medium |
| Quadrivalent |
| Flulaval® Tetra (GSK) | IIV4-SD
(split virus) | IM | 6 months and older | 15 µg HA
/0.5 mL dose | None | 5 mL multi-dose vial
Single dose pre-filled syringe | 28 days | Yes
(multi-dose vial only) | None | Egg (Avian) |
| Fluzone® Quadrivalent (Sanofi Pasteur) | IIV4-SD
(split virus) | IM | 6 months and older | 15 µg HA
/0.5 mL dose | None | 5 mL multi-dose vial
Single dose vial
Single-dose pre-filled syringe without attached needle | Up to expiry date indicated on vial label | Yes
(multi-dose vial only) | None | Egg (Avian) |
| Afluria® Tetra (Seqirus) | IIV4-SD
(split virus) | IM | 5 years and older | 15 µg HA
/0.5 mL dose | None | 5 mL multi-dose vial
Single dose pre-filled syringe without attached needle | Up to expiry date indicated on vial label | Yes
(multi-dose vial only) | Neomycin and polymyxin B | Egg (Avian) |
| Influvac® Tetra (BGP Pharma ULC, operating as Mylan) | IIV4-SD
(subunit) | IM or deep subcutaneous injection | 3 years and older | 15 µg HA
/0.5 mL dose | None | Single dose pre-filled syringe with or without a needle | Not applicable | No | Gentamicin or neomycin and polymyxin B[Footnote §](#fnt9b) | Egg (Avian) |
| Flucelvax® Quad (Seqirus) | IIV4-cc (subunit) | IM | 9 years and older | 15 µg HA
/0.5 mL dose | None | 5 mL multi-dose vial
Single dose pre-filled syringe without attached needle | 28 days | Yes
(multi-dose vial only) | No | Cell (Mammalian) |
| FluMist® Quadrivalent (AstraZeneca) | LAIV4
(live attenuated) | Intranasal | 2–59 years | 106.5-7.5 FFU of live attenuated reassortants
/0.2 mL dose
(given as 0.1 mL in each nostril) | None | Single use pre-filled glass sprayer | Not applicable | No | Gentamicin | Egg (Avian) |
| Trivalent |
| Agriflu® (Seqirus) | IIV3-SD
(subunit) | IM | 6 months and older | 15 µg HA
/0.5 mL dose | None | 5 mL multi-dose vial
Single dose pre-filled syringe without attached needle | 28 days | Yes
(multi-dose vial only) | Kanamycin and neomycin | Egg (Avian) |
| Fluviral® (GSK) | IIV3-SD
(split virus) | IM | 6 months and older | 15 µg HA
/0.5 mL dose | None | 5 mL multi-dose vial | 28 days | Yes | None | Egg (Avian) |
| Fluzone® High-Dose (Sanofi Pasteur) | IIV3-HD
(split virus) | IM | 65 years and older | 60 µg HA
/0.5 mL dose | None | Single dose pre-filled syringe | Not applicable | No | None | Egg (Avian) |
| Fluad Pediatric® and Fluad® (Seqirus) | IIV3-Adj
(subunit) | IM | **Pediatric:**
6–23 months**Adult:**
65 years and older | **Pediatric:**
7.5 µg HA
/0.25 mL dose**Adult:**15 µg HA
/0.5 mL dose | MF59 | Single dose pre-filled syringe without a needle | Not applicable | No | Kanamycin and neomycin | Egg (Avian) |
| **Abbreviations:** FFU: fluorescent focus units; HA: hemagglutinin; IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-HD: high-dose trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-cc: cell-culture based quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; IM: intramuscular; LAIV4: quadrivalent live attenuated influenza vaccine; NA: neuraminidase.
Footnotes
Footnote \*
Full details of the composition of each vaccine authorized for use in Canada, including other non-medicinal ingredients, and a brief description of its manufacturing process can be found in the product monograph.
[Return to footnote \* referrer](#fnt9a-rf)
Footnote §
§ Neomycin and polymyxin B are only used if gentamicin cannot be used. No trace amounts of neomycin or polymyxin B are present if gentamicin was used.
[Return to footnote § referrer](#fnt9b-rf)
|
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2020-09-04
| None | None |
ccb838280f40e2830f586b51b71ae2d51c91a0a1 | cma | Recommendations on the Duration of the Post-vaccination Observation Period for Influenza Vaccination during the COVID-19 Pandemic | Recommendations on the Duration of the Post-vaccination Observation Period for Influenza Vaccination during the COVID-19 Pandemic
Preamble
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (hereafter referred to as PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
(PDF format, 41 pages)
Organization:
Publication Date: 2020-10-15
Related topics
Summary of the Information Contained in this NACI Statement
The following highlights key information for immunization providers. Please refer to the remainder of this statement for details.
# 1. What
- It is important to continue routine immunization programs during the COVID-19 pandemic, especially for the upcoming influenza season, which will prevent influenza-related morbidity and mortality and contribute to reducing the burden on the Canadian health care system. This is particularly important in anticipation of a potential resurgence in COVID-19 in the fall or winter months.
- During the COVID-19 pandemic, large crowds at influenza immunization clinics could contribute to increased SARS-CoV-2 transmission risks if not managed appropriately; therefore, may be required.
- In addition to other public health and infection prevention and control measures, reducing the post-vaccination observation period in post-vaccination observation areas provides an option to reduce crowding. Decreasing close interactions among vaccine recipients and between vaccine recipients and clinic staff may help to mitigate against potential SARS-CoV-2 transmission in clinic settings. Vaccine recipients who do not meet the criteria for a reduced post-vaccination observation period will also benefit from a less crowded post-vaccination waiting area. This intervention may also allow more individuals to be vaccinated in a given time period (increase vaccination setting "throughput").
# 2. Who
- Settings providing influenza vaccinations for the upcoming influenza season during the COVID-19 pandemic.
# 3. How
1. NACI recommends that the current post-vaccination observation period, as specified in the Canadian Immunization Guide , should be maintained for influenza vaccination settings that can adhere to appropriate public health and infection prevention and control measures to reduce SARS-CoV-2 transmission, particularly physical distancing (Strong NACI recommendation).
- NACI concludes that there is fair evidence to maintain a 15-minute post-vaccination observation period during the COVID-19 pandemic for individuals with no known history of severe allergic reactions (including anaphylaxis) to any component of the influenza vaccine being considered for administration or any history of other immediate post-vaccination reactions (e.g., syncope with or without seizure) (Grade B Evidence).
2. NACI recommends that a shorter post-vaccination observation period, between 5 to 15 minutes after influenza immunization, may be considered during the COVID-19 pandemic, but only during times when appropriate physical distancing in post-vaccination waiting areas cannot otherwise be maintained due to the volume of individuals seeking immunization, and only when specific conditions are met (Discretionary NACI recommendation).
- NACI concludes that there is insufficient evidence from retrospective, passive adverse event following immunization (AEFI) case series reports to support a reduced post-vaccination observation period. However, other factors may be taken into consideration to support a reduced post-vaccination observation period, if necessary for public health and infection prevention and control purposes (Grade I Evidence).
Endnotes \*
Endnotes \*
A shorter observation period may be considered only if the vaccine recipient meets the following conditions :
- Past history of receipt of influenza vaccine and no known history of severe allergic reactions (including anaphylaxis) to any component of the influenza vaccine being considered for administration (note that novel technology vaccine recipients should be exempt from reduced post-observation period eligibility) .
- No history of other immediate post-vaccination reactions (e.g., syncope with or without seizure) after receipt of any vaccines.
- The vaccine recipient is accompanied by a parent/guardian (in the case of a child) or responsible adult who will act as a chaperone to monitor the vaccine recipient for a minimum of 15 minutes post-vaccination. In the case of two responsible adults, both can be vaccine recipients for the purposes of this criterion, if both agree to monitor the other post-vaccination.
- The vaccine recipient will not be operating a motorized vehicle or self-propelled or motorized wheeled transportation (e.g., bicycle, skateboard, rollerblades, scooter), or machinery for a minimum of 15 minutes after vaccination.
- The vaccine recipient and the parent/guardian or responsible adult chaperone are aware of when and how to seek post-vaccination advice and given instructions on what to do if assistance and medical services are required.
- The vaccine recipient and the parent/guardian/responsible adult agree to remain in the post-vaccination waiting area for the post-vaccination observation period and to notify staff if the recipient feels or looks at all unwell before leaving. They should be informed that an individual exhibiting any symptom suggestive of an evolving AEFI at the end of the shortened post-observation period necessitates a longer period of observation in the clinic.
# 4. Why
- A vaccination clinic setting that is able to maintain recommended public health and infection prevention and control measures, such as physical distancing in post-vaccination areas, is unlikely to achieve significant additional reductions in the risk of SARS-CoV-2 transmission by implementing a shorter post-vaccination observation period.
- A vaccination clinic setting that at times is unable to maintain recommended physical distancing in post-vaccination areas may consider implementing a shorter post-vaccination observation period to reduce the risk of SARS-CoV-2 transmission under specified conditions.
- Serious adverse events in the minutes following immunization that may require medical intervention are relatively rare.
I. Introduction
A cluster of cases of pneumonia of unknown origin was reported from Wuhan, Hubei Province, China in December 2019. These cases were determined to be due to a novel coronavirus (SARS-CoV-2) that causes a disease now referred to as coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) characterized COVID-19 as a pandemic on March 11, 2020.
Canadian provinces and territories instituted a series of public health measures to limit SARS-CoV-2 transmission and to reduce the burden on the healthcare system, including the temporary deferral of non-essential medical services. Recognizing the need to continue routine immunization programs during the pandemic, the Public Health Agency of Canada (PHAC), with consultation from the National Advisory Committee on Immunization (NACI) and the Canadian Immunization Committee, released interim guidance on , as well as guidance on to reduce the risk of SARS-CoV-2 transmission in a variety of immunization clinic settings.
There are a variety of process modifications (administrative, environmental and engineering controls, and personal protective measures) that can be implemented in the vaccination clinic setting to prevent SARS-CoV-2 transmission, such as promoting physical distancing (at least two metres) among vaccine recipients, and staff and their co-workers. Another possible measure may be to reduce the post-vaccination observation period for rare, but serious AEFIs. Reducing the amount of time vaccine recipients spend in the vaccination clinic post-vaccination could reduce the opportunity for SARS-CoV-2 transmission from an unrecognized, infectious COVID-19 case. However, any consideration of a reduction in post-vaccination observation period must weigh the potential risk of delayed identification of an adverse event that may require immediate medical intervention against the potential benefits of reducing the risk of SARS-CoV-2 transmission and allowing more individuals to be vaccinated (increase vaccination clinic "throughput") in a given time period.
In Canada, it is recommended that vaccine recipients remain under observation for at least 15 minutes after vaccination, unless there is a specific concern about a possible vaccine allergy in which case a 30-minute post-vaccination observation period is considered a safer interval. Guidelines for post-vaccination observation in other countries vary . In April 2020, the Australian Technical Advisory Group on Immunization (ATAGI) released a recommendation that the post-vaccination observation period could be reduced from 15 minutes to 5 minutes in immunization clinics where adequate physical distancing was not possible, as long as specific criteria were met. The ATAGI guidance was based on a targeted review of the literature and expert opinion.
# Guidance objective
The objectives of this NACI statement are to review the evidence on the timing of onset of serious AEFIs (anaphylaxis, syncope with or without seizure). These data will be used to assess the potential impact of a reduction in the post-vaccination observation period on the risk of delayed identification of a serious adverse event that may require immediate medical intervention, balanced against the potential benefits of reducing SARS-CoV-2 transmission in influenza vaccination settings and allowing more individuals to be vaccinated in a given time period. The analysis will be used to provide guidance to provincial and territorial immunization programs and frontline clinicians on the duration of the post-vaccination observation period for influenza vaccination during the COVID-19 pandemic.
II. Methods
# Rapid literature review
In preparation for influenza vaccination clinics in fall 2020, a rapid review of literature was conducted to determine the likelihood of missing serious AEFIs (anaphylaxis, syncope with or without seizure) with shorter post-vaccination observation periods. The rapid review's search strategy was developed in conjunction with a federal Reference Librarian and was used to search a single electronic database for studies on the timing of serious AEFIs in children and adults (all ages and populations).
# Research question
What is the minimum observation period needed post-vaccination to observe serious AEFI?
P (population):
Individuals 6 months of age and older
I (intervention):
Observation period post-vaccination, any vaccine
C (comparison):
N/A
O (outcomes):
Time to onset of serious AEFI
The electronic database (EMBASE) was searched from inception to May 22, 2020 using the following search terms: seizure, syncope, anaphylaxis, adverse event, immunization, vaccination reaction, allergic reaction, and post-vaccination reaction. Searches were restricted to articles published in English and French. Two reviewers (NF, PDP) independently screened the titles and abstracts and full-text of eligible articles, but not in duplicate. The PRISMA Flow Diagram is shown in . The complete search strategy is available upon request.
Studies were included if they met the following criteria:
- The study recorded the specific time of onset of at least a subset of AEFIs and reported events that occurred within 30 minutes of vaccination; and
- The study assessed the incidence of the following serious AEFIs:
+ anaphylaxis, syncope with or without seizure.
Studies were excluded if they met one or more of the following criteria:
- The study was in a language other than English or French;
- The article was an editorial, opinion, conference abstract or news report;
- The minimum observation period for AEFIs was greater than 30 minutes; or
- The study did not report the time to onset of serious AEFIs.
The eligible studies that were identified were divided amongst three reviewers (NF, PDP, GC). The reviewers independently extracted data from their assigned studies into evidence tables and appraised the risk of bias of the studies. The data extraction and risk of bias assessments were not done in duplicate for any of the eligible studies.
The extracted data were used to summarize key study characteristics and to analyze the studies for risk of bias, using a modified Institute of Health Economics Tool (IHE), as all included studies were case reports or case series. A narrative synthesis of the extracted data was created to summarize the outcomes of interest (number of AEFIs, severity, time to onset, and incidence, if reported). As not all of the identified articles evaluated outcomes by severity, the number of serious reports identified were compiled from reports that were explicitly classified as serious, as well as from inference from stated sequelae of individual cases that would meet usual serious outcome definitions (e.g., death, life-threatening illness, hospitalization, prolonged hospitalization, permanent disability).
# Canadian Adverse Events Following Immunization Surveillance System
The Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) database was searched for AEFI reports of anaphylaxis, syncope, and afebrile seizure associated with a date of vaccine administration between 2014 and 2018. The Medical Dictionary for Regulatory Activities (MedDRA) terms used to code CAEFISS reports were used to search CAEFISS for reports for the three outcomes of interest. Reports of anaphylaxis had to meet the Brighton Collaboration definition for anaphylaxis and the individual in the report managed as such. CAEFISS uses the World Health Organization definition of a serious AEFI: an event that is life threatening, results in hospitalization or a prolongation of hospitalization, persistent or significant disability or where the outcome is a birth defect or death. Reports that did not include a time to onset of symptoms were excluded.
The time to symptom onset for each AEFI was summarized by 5-minute intervals within the first 15 minutes post-vaccination, if available; and the time of onset that includes 25%, 50%, 75%, 95%, and 100% of all reports. These summary measures were analyzed by age groups: less than 2 years, 2 to less than 7 years, 7 to less than 18 years, 18 to less than 50 years, 50 to less than 65 years, 65 years and older, all ages, and by all reports versus serious AEFI.
# Qualitative assessment of reducing the post-vaccination observation period
It is challenging to accurately quantify the impact of a reduction in the post-vaccination observation period on the risk for SARS-CoV-2 transmission in a vaccination setting. This is particularly the case because the clinic settings in Canada are diverse; community prevalence of SARS-CoV-2 varies between communities and fluctuates over time within communities; and because this measure would be one of several public health and infection prevention and control measures implemented to reduce the risk of transmission in these settings. Consequently, a qualitative assessment of this intervention was undertaken to weigh the potential risk of any potential delay in identifying serious AEFIs that may require immediate medical intervention against the potential benefit of reducing the risk of SARS-CoV-2 transmission and enhancing the ability to vaccinate more individuals during a given time period (increase vaccination clinic "throughput").
# Recommendation Development
The draft statement was developed through the NACI Influenza Working Group and in consultation with the NACI Vaccine Safety Working Group. These three analyses, outlined above, were then used by NACI to draft recommendations on whether to reduce the duration of post-vaccination observation period in the context of the COVID-19 pandemic. NACI critically appraised the available evidence and approved the final recommendation on August 13, 2020.
III.Onset of adverse events following immunization
Twenty-two studies on time to onset of serious AEFI were identified through the rapid review. All studies were evaluated for risk of bias using a modified IHE tool and all were deemed to be at serious risk of bias, except two studies, which were deemed to be at unclear risk of bias. Both studies with unclear risk of bias described the incidence of anaphylaxis after vaccine administration using a restricted set of ICD-9 codes to search a health care database, a process deemed to be more sensitive at identifying anaphylaxis episodes than relying on reports submitted to passive AEFI reporting systems. McNeil et al. used the same code set used by Bohlke et al., but supplemented their search with allergy codes combined with epinephrine-dispensing codes. The majority of the included articles used data from passive surveillance systems, and had limitations such as underreporting, insufficient information on cases reported, lack of denominators and inconsistent case definitions. For measurement of whether the intervention of interest was described, articles were considered to be of low bias if they reported the vaccine name and manufacturer and whether this was the first or subsequent immunization dose, if relevant. A visual summary of the risk of bias assessments is provided in .
The findings from the rapid review must be interpreted with caution in light of the findings of the risk of bias assessment for the articles identified in the rapid review and the inherent limitations of data obtained from retrospective case series studies that rely on passive AEFI surveillance systems. For example, the voluntary nature of reporting in most of these systems can lead to underreporting of AEFIs; the retrospective nature of these studies may make it difficult to obtain the necessary clinical data to verify outcomes and to determine that outcomes meet case definitions; the studies may also not have access to data on the sequelae for individuals in case reports, which may lead to an underestimation of the seriousness of some outcomes. There is often no access to denominator data (i.e., the number of vaccine doses distributed or ideally the number of doses administered) to estimate the incidence of outcomes. Also estimates of incidence based on relatively few case reports may be unreliable (i.e., relatively few additional case reports can significantly alter the calculated rate) and rates generated in heterogeneous populations may not be comparable.
# III.1 Anaphylaxis
## Rapid literature review
### Time to symptom onset of anaphylaxis
There were 16 articles (12 retrospective case series , 4 case reports ) identified in the rapid review that provide data on the timing of reports of anaphylaxis following vaccine administration. The retrospective case series primarily use AEFI surveillance systems to examine reports of anaphylaxis in vaccine recipients. Across all of the identified articles, 981 reports of anaphylactic reactions were described, with 816 (83%) reports assessed against the Brighton Collaboration definition of anaphylaxis and the criteria for the three levels of diagnostic certainty (level 1: 413 reports; level 2: 372; level 3: 14; other/level not reported: 17). Of the 981 reports of anaphylaxis, 729 (74%) of the reports were classified as serious.
Overall, 873 (89%) of the anaphylaxis reports had some time to symptom onset recorded, of which the majority (492/873, 56%) occurred within 30 minutes of vaccination. The majority of the data (735/873, 84%) came from a single study using reports from the US Department of Health and Human Service's Vaccine Adverse Events Reporting System (VAERS) database, which categorized onset times into relatively broad time intervals (within 30 minutes, 30-119 minutes, 2-4 hours, 4-8 hours and 8-24 hours).
There were 8 retrospective case series and 3 case reports that identified 55 reports that provided descriptions of or actual times to anaphylaxis symptom onset in intervals within the first 15 minutes post-vaccination. Of these 55 reports, 35 (64%) occurred between 0 and 5 minutes post-vaccination, 4 (7%) "within minutes" or "within a few minutes," 9 (16%) between 5 and 10 minutes, 1 (2%) between 10 and 15 minutes, and 6 (11%) within 5 to 15 minutes.
Three of the retrospective case series studies provided summary measures of the time to anaphylaxis symptom onset after vaccination. Baxter et al. evaluated the Australian Surveillance of Adverse Events following Vaccination in the Community (SAEFVIC) database for reports of anaphylaxis occurring within the first 60 minutes following immunization in preschool aged (<5 years) children. The study found all 12 identified anaphylaxis reports had a time of symptom onset of 0-40 minutes, with an average of 7.5 minutes and a median of 5 minutes. Su et al., using anaphylaxis case reports from VAERS from 1990-2016, found 828 case reports that occurred within 1 day post-vaccination. These reports had a median time of onset after vaccination of 20 minutes (ranging from <1 minute to 24 hours). And finally Pahud et al., examining serious, non-fatal adverse events reported to VAERS following receipt of 2009 H1N1 vaccine in children (<18 years of age) from October 2009-January 2010 found 12 true allergic reactions (i.e., not just reports of anaphylaxis) occurred within 3 hours of vaccination with a median of 30 minutes (range: 5 minutes-3 hours).
### Estimates of anaphylaxis incidence based on literature
There were 6 retrospective case series that had access to the data on the number of vaccine doses either distributed or administered during the period of the study; these data were used to calculate either overall or vaccine-specific estimates of anaphylaxis incidence during the study period.
The incidence of anaphylaxis was fairly consistent across studies, although there was some variation. The variation could be due to the small number of anaphylaxis case reports and the different denominators used to calculate incidence (doses distributed or doses administered). McNeil et al. reported an overall incidence of anaphylaxis in children and adults of 1.31 per 1,000,000 doses administered. Two other studies calculated the incidence of anaphylaxis in children <18 years of age; estimates ranged from 0.65 to 1.3 per 1,000,000 doses .
Four studies reported incidence estimates for specific vaccines that varied significantly by vaccine and by study (0.1 to 26 per 1,000,000 doses) . The highest reported incidence was from a study based on anaphylaxis reports submitted to the New South Wales Health Immunization Unit for human papillomavirus (HPV) vaccine and the lowest reported incidence was for influenza vaccine based on reports submitted to VAERS. Incidence of anaphylaxis estimates after administration of influenza vaccine was 0.1 to 1.8 per 1,000,000 doses (administered or distributed) .
## Canadian Adverse Events Following Immunization Surveillance System
### Time to symptom onset of anaphylaxis
Of the 136 reports of anaphylaxis identified, 112 (82%) were classified as serious. Just over half of all the anaphylaxis reports occurred in individuals 7 to less than 18 years of age (n=30, 22%) and 18 to less than 50 years of age (n=46, 34%). There were fewer numbers of AEFI reports in each of the other age groups (range: 9-20 AEFI reports per age group).
For all ages combined, 25% of anaphylaxis reports had onset within 5 minutes of vaccination, increasing to 50% of reported cases by 15 minutes post-vaccination, with an overall median time to symptom onset of 15 minutes (range: 1 minute to 48 hours). The proportion of individuals with symptom onset within the first 15 minutes post-vaccination did not vary significantly by age grouping, with the exception of children less than 2 years of age (6 minutes vs 15 minutes for all ages) and individuals 50 to less than 65 years of age (45 minutes vs 15 minutes) (). When comparing the time to symptom onset for all anaphylaxis reports compared to reports classified as serious, similar trends were found. For all ages combined, 29% of case reports had onset of symptoms by 5 minutes post-vaccination, 46% by 10 minutes post-vaccination and 54% by 15 minutes post-vaccination. These proportions did not differ significantly by age grouping, with the exception of children less than 2 years of age (50% by 5 minutes, 67% by 15 minutes) and individuals 50 to less than 65 years of age (8% by 5 minutes, 31% by 15 minutes) (data not shown), reflecting the differences in median time to symptom onset in these age groups ().
# III.2 Syncope and Seizure
As seizures may occur secondary to syncopal episodes, the two outcomes are considered together in this section.
## Rapid literature review
### Time to symptom onset of syncope or seizure
There were 8 articles (7 retrospective case series , 1 case report) identified in the rapid review that provide data on the outcomes of either syncope or seizure following vaccine administration. The retrospective case series studies all utilized AEFI surveillance systems to evaluate reports of syncope or seizure in vaccine recipients. In the 8 articles that identified reports of syncope or seizure, there were 1,180 reports of syncope alone (i.e., not associated with any reported seizure activity), 199 reports of seizures associated with syncopal episodes ("syncopal seizures"), and 16 reports of seizures alone (either afebrile or febrile) for a total of 1,395 reports. Of the 1,395 reports, 103 (7%) were considered serious (97 syncope alone, 1 syncopal seizure, and 5 febrile seizures).
Of the 1,180 reported cases of syncope alone, 453 (38%) had some indication of time to symptom onset. The range of reported onset times varied from within 5 minutes to 2 days; however, 340 (75%) of the syncopal case reports with a recorded time to symptom onset occurred within the first 15 minutes post-vaccination. Twenty-four (5%) of these reports were from four studies using retrospective case series data: 15 (63%) cases had onset from 0-5 minutes post-vaccination and 1 (4%) case with onset within 10-15 minutes. The time of onset of the remaining 8 cases were not provided in the same 5-minute time intervals: 4 (17%) occurred within 10 minutes of vaccination and 4 (17%) within 15 minutes of vaccination.
Among the studies identified, a fifth study also using retrospective case series data provided the largest number of syncopal case reports with symptom onset within the first 15 minutes post-vaccination. This study by Braun et al evaluated reports of syncope occurring within 12 hours of immunization submitted to VAERS and injury reports for syncope-related falls from the US National Vaccine Injury Compensation Program in individuals of any age from 1990-October 1995. Of the 571 reports that had a recorded time to symptom onset (81.9% of total reports), 323 (63.2%) occurred within 5 minutes of vaccination, increasing to 416 (81.4%) within 10 minutes, and 454 (88.8%) within 15 minutes of vaccination. Of the 454 syncopal episodes, 153 were associated with "tonic or clonic movements" ("syncopal seizures"): 138 (30. 4%) within 15 minutes of vaccination and 15 (12.8%) greater than 15 minutes after vaccination. Of note, 67 (9.6%) cases reported subsequent hospitalization. Six individuals sustained head injuries after syncope-induced falls, which included skull fractures, cerebral contusions, cerebral hematomata and one case of major cerebral hemorrhage. Three of the injuries necessitated neurosurgery to alleviate cerebral swelling or bleeding and 2 individuals still had significant neurologic deficits up to 2 years after the incidents. All 6 of these head injuries occurred from syncopal events within 15 minutes after vaccination.
In the study by Sutherland et al., there were 10 secondary injuries recorded among the 26 serious syncopal reports: head injuries after syncopal falls (n=9), including one death of a 15-year-old boy due to intracranial hemorrhage, and a motor vehicle incident after a loss of consciousness while driving (n=1). Seven (70%) of the injuries occurred within 15 minutes of vaccination.
A description of the time to symptom onset was available for 154 (77%) of the 199 reports of seizures associated with syncopal episodes ("syncopal seizures") and for all 16 (100%) reports of seizures alone. Two articles provided the data on syncopal seizure following vaccine administration . Braun et al. reported 153 syncopal reports with associated "tonic or clonic movements": 138 (90.2%) occurred within 15 minutes of vaccination and 15 (9.8%) occurred greater than 15 minutes after vaccination. The remaining case which was reported in the second study occurred at 0 minutes post-vaccination (i.e., immediately). The 16 cases of seizure alone were identified in two studies . Crawford et al analyzed detailed clinical information on SAEFVIC case reports of syncope and seizures after quadrivalent HPV vaccination in females 12-26 years of age vaccinated as part of the Australian National HPV Vaccination Program from May 2007-April 2009. The study identified 31 episodes of syncope with associated seizures, but the time to seizure onset was reported only for 3 reports of afebrile seizure, all in individuals with confirmed underlying epilepsy. There were no deaths reported in the study population, but there were 7 injuries reported: head injuries (n=5), mouth bleeding (n=1) and a T5/T6 vertebral fracture (n=1). The study by Milstien et al. identified 13 reports that met the US Food and Drug Administration (FDA) case definition for a potentially vaccine-associated convulsion, four afebrile convulsions and nine febrile convulsions. The time of onset for the afebrile convulsions was 30 minutes, 2 hours, 24 hours and 2 days after vaccination.
### Estimates of syncope and/or seizure incidence based on literature
There were 3 retrospective case series studies that had access to the data on the number of vaccine doses either distributed or administered during the period of the study, allowing for calculation of either overall or vaccine-specific syncope or seizure incidence during the study period .
In an analysis of SAEFVIC case reports of syncope and seizures after quadrivalent HPV vaccination as part of the Australian National HPV Vaccination Program, Crawford et al. estimated an incidence of 7.8 and 2.6 per 100,000 doses of vaccine distributed for syncope and syncopal seizures respectively.Subelj et al. estimated the incidence of syncope and seizures associated with syncope to be 13.4 and 3.4 per 100,000 doses, respectively, based on 4 years of data from mandatory reports to the National Institute of Public Health of a school-based four-valent HPV (HPV4) vaccine program targeting girls 11-14 years of age in Slovenia. Sutherland et al evaluated reports of "syncope" or "syncope vasovagal" occurring in individuals ≥5 years of age on the same day as vaccination submitted to the VAERS surveillance system from January 1, 2005-July 31, 2007 and compared the rates of syncopal events to the rate of VAERS reports received from 2002-2004. The rates of syncopal events per 1,000,000 doses of vaccines distributed in the US during the respective study periods was increased in 2005-2006 (0.31-0.54) compared to 2002-2004 (0.28-0.35), as were the proportion of reports from females (77.5% vs 61.6%) and persons 11-18 years of age (62.0% vs 47.3%).
## Canadian Adverse Events Following Immunization Surveillance System
### Time to symptom onset of syncope or seizure
Of the 52 reports of syncope, 20 (38%) were classified as serious. Individuals 7 to less than 18 years of age (n=33, 65%) and 18 to less than 50 years of age (n=8, 16%) accounted for the majority of all 52 reports. There were very few AEFI reports in each of the remaining age groups (N is between 2 and 4 for each).
For all ages combined, 25% of syncope reports had onset within 1 minute of vaccination, increasing to 50% of reported cases by 3 minutes post-vaccination and 75% within 15 minutes, with an overall median time to symptom onset of 3 minutes (range: 1 minute to 29 days) (). The proportions were similar for syncope reports classified as serious (data not shown).
There were 61 reports of afebrile seizure between 2014 and 2018, 50 (82%) of which were classified as serious. The majority (74%) of reports were in individuals less than 2 years of age. There were very few AEFI reports in the other age groups. For all ages combined, the median time to onset of afebrile seizure was 21 hours (range: 1 minute to 29 days). Only for the group of individuals 7 to less than 18 years were a significant proportion (25%) of afebrile seizures reported to have occurred within 2 minutes of vaccination, based on a small number of case reports (n=8).
# III.3 Risk-benefit assessment
The rationale for potentially considering a reduction in the post-vaccination observation period in influenza vaccination settings during the COVID-19 pandemic is to reduce the duration of time vaccine recipients spend together with others in post-vaccination areas and to potentially reduce the number of contacts recipients encounter in vaccination settings. This could then reduce the opportunity for SARS-CoV-2 transmission from an unrecognized, infectious COVID-19 case and allow more individuals to be vaccinated (increase vaccination clinic "throughput") in a given time period. However, it is very challenging to quantify the impact of a reduction in the post-vaccination observation period on the risk for SARS-CoV-2 transmission, independent of other public health and infection prevention and control measures (engineering, environmental and administrative controls, and personal protective equipment) that are likely to be implemented in influenza vaccination settings during the COVID-19 pandemic. In addition, there will be differences in the risk of transmission in various settings due to variability in disease prevalence at different locations and at different points in time. Any consideration of a reduction in post-vaccination observation period would be a deviation from the current standard practice in Canadian provinces and territories. The current standard of a 15-minute post-vaccination observation period is intended to identify serious AEFIs that may require immediate medical intervention. This must be weighed against the potential benefits of reducing risk of SARS-CoV-2 transmission and allowing more individuals to be vaccinated (increase vaccination clinic "throughput") in a given time period.
## Potential benefits of a reduced post-vaccination observation period
- Reduction in crowding within post-vaccination waiting areas of vaccination clinics will improve the likelihood of maintaining physical distancing among vaccine recipients and between vaccine recipients and clinic staff.
- Less waiting post-vaccination may encourage members of the public to attend vaccination clinics if there is perceived to be less risk of COVID-19 infection due to less crowding in the vaccination clinics areas and if there is less time overall required to get vaccinated. Perceptions of reduced risk of infection will be enhanced by the other infection prevention and control measures taken in the context of COVID-19 that will also reduce crowding within the vaccination clinic setting (e.g., scheduled vaccination appointments, arrival just in time for appointments, screening of clinic staff and attendees).
- A reduced number of individuals in the post-vaccination waiting areas would benefit vaccine recipients who do not meet the criteria for a reduced post-vaccination observation period, and may remain in the vaccination setting for the standard 15-minute observation period or a 30-minute observation period if there is a specific concern about possible vaccine allergy.
- A reduced post-vaccination period may allow more individuals to be vaccinated (increase vaccination clinic "throughput") in a given time period and also allow vaccine recipients to be in contact with fewer individuals.
## Potential risks of a reduced post-vaccination observation period
- There would be a small but potentially increased risk of delayed identification of an adverse event that may require immediate medical intervention (e.g., anaphylaxis and syncope with or without seizure).
- Reducing the post-vaccination observation period may have only a relatively modest, independent impact in reducing the risk of SARS-CoV-2 transmission in the vaccination clinic setting during the COVID-19 pandemic when compared with the other public health and infection prevention and control measures (e.g., environmental and engineering controls, administrative processes, personal protective equipment). The overall risk will also depend upon factors such as local disease prevalence at the time of the immunization clinics.
- The reduction in the post-vaccination observation period may be perceived as an action being taken primarily to improve clinic efficiency rather than an important infection prevention measure.
IV. Recommendations
Following a thorough review of the evidence summarized above, NACI has made two recommendations for public health program decision-making. These recommendations are based on currently available scientific evidence and expert opinion and are relevant only during the COVID-19 pandemic, after which the current guidance for the post-vaccination observation period as identified in Part 2 of the Canadian Immunization Guide should be followed.
In considering these recommendations and for the purposes of publicly funded program implementation, provinces and territories may take into account economic factors and other local operational factors (e.g. current immunization programs, resources). Recognizing that there are differences in operational contexts across Canada, jurisdictions are advised to refer to the local epidemiology of COVID-19 and additional PHAC guidance to determine the relative merits of modifying the post-vaccination observation period. NACI will continue to monitor the scientific literature for developments related to post-vaccination observation period and will update recommendations as evidence evolves, if required.
Please note:
- A *strong recommendation- applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
- A *discretionary recommendation- may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.
# IV.1 Recommendations for Public Health Program Level Decision-Making
1. NACI recommends that the current post-vaccination observation period, as specified in the Canadian Immunization Guide, should be maintained for influenza vaccination settings that can adhere to appropriate public health and infection prevention and control measures to reduce SARS-CoV-2 transmission, particularly physical distancing (Strong NACI recommendation).
- NACI concludes that there is fair evidence to maintain a 15-minute post-vaccination observation period during the COVID-19 pandemic for individuals with no known history of severe allergic reactions (including anaphylaxis) to any component of the influenza vaccine being considered for administration or any history of other immediate post-vaccination reactions (e.g., syncope with or without seizure) (Grade B Evidence).Evidence and Rationale
- A 15-minute post-vaccination observation period is the Canadian standard for individuals with no known history of prior severe allergic reaction or any other immediate post-vaccination reactions.
- A vaccination clinic setting that is able to maintain recommended public health and infection prevention and control measures, including physical distancing in post-vaccination areas, is unlikely to achieve significant additional reductions in the risk of SARS-CoV-2 transmission by implementing a shorter post-vaccination observation period.
2. NACI recommends that a shorter post-vaccination observation period, between 5 to 15 minutes after influenza immunization, may be considered during the COVID-19 pandemic, but only during times when appropriate physical distancing in post-vaccination waiting areas cannot otherwise be maintained due to the volume of individuals seeking immunization, and only when specific conditions are met (Discretionary NACI recommendation).
- NACI concludes that there is insufficient evidence from retrospective, passive adverse event following immunization (AEFI) case series reports to support a reduced post-vaccination observation period. However, other factors may be taken into consideration to support a reduced post-vaccination observation period, if necessary for public health and infection prevention and control purposes (Grade I Evidence).
Endnotes \*
Endnotes \*
A shorter observation period may be considered only if the vaccine recipient meets the following conditions :
- Past history of receipt of influenza vaccine and no known history of severe allergic reactions (including anaphylaxis) to any component of the influenza vaccine being considered for administration (note that novel technology vaccine recipients should be exempt from reduced post-observation period eligibility).
- No history of other immediate post-vaccination reactions (e.g., syncope with or without seizure) after receipt of any vaccines.
- The vaccine recipient is accompanied by a parent/guardian (in the case of a child) or responsible adult who will act as chaperone to monitor the vaccine recipient for a minimum of 15 minutes post-vaccination. In the case of two responsible adults, both can be vaccine recipients for the purposes of this criterion, if both agree to monitor the other post-vaccination.
- The vaccine recipient will not be operating a motorized vehicle or self-propelled or motorized wheeled transportation (e.g., bicycle, skateboard, rollerblades, scooter), or machinery for a minimum of 15 minutes after vaccination.
- The vaccine recipient and the parent/guardian or responsible adult chaperone are aware of when and how to seek post-vaccination advice and given instructions on what to do if assistance and medical services are required.
- The vaccine recipient and the parent/guardian/responsible adult agree to remain in the post-vaccination waiting area for the reduced post-vaccination observation period and to notify staff if the recipient feels or looks at all unwell before leaving the clinic. They should be informed that an individual exhibiting any symptom suggestive of an evolving AEFI at the end of the shortened post-observation period necessitates a longer period of observation in the clinic.
Evidence and Rationale
- Public health and infection prevention and control measures (i.e., engineering, environmental and administrative controls, and personal protective equipment) should be implemented to reduce the risk for SARS-CoV-2 transmission.
- A consideration to reduce the post-vaccination observation period must weigh the potential risk of any delay in identifying serious adverse events that may require immediate medical intervention against the potential benefits of reducing contacts with others and the associated risk of SARS-CoV-2 transmission; and potentially allowing more individuals to be vaccinated in a given time period. It is recognized that several factors may influence decision-making and applicability of recommendations:
+ The community levels of SARS-CoV-2 transmission at the time of vaccination clinics will influence the risk of SARS-CoV-2 transmission in the vaccination setting. This risk will vary by and within jurisdictions over time.
+ Unanticipated or unprecedented increases in the number of individuals presenting for immunization in clinic settings at a given time could temporarily overwhelm the other public health and infection prevention measures in place.
+ It is unknown how much a reduced post-vaccination observation period, independent of other public health and infection prevention and control measures, contributes to reducing the risk of SARS-CoV-2 transmission in the vaccination setting.
- The evidence from retrospective, passive AEFI case series reports is insufficient to support a reduced post-vaccination observation period.
+ Overall estimates of anaphylaxis incidence using retrospective case series data from passive AEFI surveillance systems varied, but were consistent with estimates of anaphylaxis incidence for commonly administered vaccines (1 per 100,000 to 1 per 1,000,000 doses) cited by the World Allergy Organization in its International Consensus statement on allergic reactions to vaccines.
+ Estimates for the incidence of syncope using passive case series data ranged widely, but were consistently much higher than for anaphylaxis.
+ The data from the rapid review indicate that a shortened post-vaccination observation period may still identify a majority of syncopal episodes, but not the majority of episodes of anaphylaxis.
- The study by Braun et al that evaluated the largest number of reports of syncope found 63.2% occurred within 5 minutes of vaccination, increasing to 416 (81.4%) within 10 minutes, and 454 (88.8%) within 15 minutes of vaccination. CAEFISS data, for all ages combined, found 25% of syncope reports had onset within 1 minute of vaccination, increasing to 50% of reported cases by 3 minutes post-vaccination and 75% within 15 minutes, with an overall median time to symptom onset of 3 minutes (range: 1 minute to 29 days).
- A little over half of all anaphylaxis reports with a recorded time of symptom onset occurred within 30 minutes of vaccination, but the proportion of those reports occurring during the first 15 minutes post-vaccination was not reported. From the case series containing the largest number of anaphylaxis reports, the median time to anaphylaxis onset after vaccination was 20 minutes (range: from <1 minute-24 hours). CAEFISS reports, for all ages combined, found 25% of anaphylaxis reports had onset within 5 minutes of vaccination, increasing to 50% of reported cases by 15 minutes post-vaccination, with an overall median time to symptom onset of 15 minutes (range: 1 minute to 48 hours). Similar trends were found for anaphylaxis reports classified as serious.
- Use of a shortened post-vaccination observation period should be accompanied by safeguards, as outlined in the recommendation, to minimize situations that would place the vaccine recipient at risk for unintended injury should an adverse event occur after the shortened observation period, but within the standard 15-minute post-vaccination observation period.
"should/should not be offered"- Known/Anticipated advantages outweigh known/anticipated disadvantages ("should"),
OR Known/Anticipated disadvantages outweigh known/anticipated advantages ("should not")
- Implication: A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present
"may be considered"- Known/Anticipated advantages closely balanced with known/anticipated disadvantages, OR uncertainty in the evidence of advantages and disadvantages exists
- Implication: A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable
General design specific criteria are outlined in Harris et al. (2001)..
Australia
SAEFVIC passive surveillance system
US
US
VAERS passive surveillance system
Australia
Australia
SAEFVIC passive surveillance system
Overall incidence following HPV4 vaccination was 7.8 per 100,000 doses distributed for syncope and 2.6 per 100,000 for syncopal seizures.
Of the 94 syncopal episodes, 67% (63/94) had syncope alone, and 33% (31/94) had associated seizure activity, of which 23% (7/31) had urinary incontinence. The HPV4 vaccine was given alone in 85% (82/97) of reports, with concomitant vaccines including: hepatitis B (6); diphtheria-tetanus-acellular pertussis (6); varicella (1); and varicella and hepatitis B vaccine (2).
US
Vaccine Injury Comensation Program
US
US
Two cases of anaphylactic-like reactions were reported. One case was in a 3-year-old boy who became pale and hypotensive and began to wheeze five minutes after vaccination. The other case was in a 4-year-old boy who became nauseated, pale, and bradycardia; circumoral cyanosis developed 20 minutes after vaccination. Both cases responded quickly to epinephrine and oxygen.
Syncope
Seven reports of syncope were identified, three that noted treatment with epinephrine and/or Benadryl. All but three episodes occurred within ten minutes of vaccination (others occurred at 30 minutes, 2 hours, and 24 hours). All episodes were in children 3 to 5 years of age.
Seizure
US
VAERS passive surveillance system
Finland
Passive surveillance system
30 suspected cases of anaphylaxis were identified, all of which appeared within 20 minutes of vaccination, except one case who developed symptoms several hours after vaccination.
Seizure
Switzerland
Passive surveillance system
US
VAERS passive surveillance system
Slovenia
8 syncope events, accounting for 3.8% of all AEFIs reported, were identified. Incidence was 13.4 per 100,000 HPV4 vaccine doses distributed. Two syncope episodes were deemed serious. One event had an immediate onset, and another occurred 5 minutes following vaccine administration.
Seizure
US
VAERS passive surveillance system
US
VAERS passive surveillance system
107 reports of syncope/presyncope and unintentional injury on the day of vaccination were identified. 100 of the reported injuries occurred within 20 minutes of vaccination. There were three reports of serious head injury, including one that was deemed fatal due to vasovagal syncope.
Following the third dose of hepatitis B vaccine, a 15-year-old boy with no antecedent of event or medical problems, experienced vasovagal syncope several minutes after vaccination. He fell backward and hit his head, momentarily lost consciousness, then complained of pain in the chest and arms. Then, he reportedly had convulsions and went into cardiopulmonary arrest.
Passive surveillance system database
Funding:
Funding:
Funding:
A 71-year-old women with documented allergies to red meat required emergency department treatment and epinephrine administration upon receipt of live attenuated herpes zoster virus vaccine containing the Oka VZV strain. The vaccine was administered in a local pharmacy and within minutes she had a sensation of mental clouding progressing to lightheadedness, wheezing, and throat tightness.
Funding:
Funding: |
Recommendations on the Duration of the Post-vaccination Observation Period for Influenza Vaccination during the COVID-19 Pandemic
==================================================================================================================================
An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)
-----------------------------------------------------------------------------------------
Preamble
--------
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (hereafter referred to as PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
[Download the alternative format](/content/dam/phac-aspc/images/services/immunization/national-advisory-committee-on-immunization-naci/recommendations-duration-observation-period-post-influenza-vaccination-during-covid-19-pandemic/NACI_Stmt_Post-Vacc%20Ob%20Period%20for%20Influenza_V12_EN_clean_PDF_updated%20ref.pdf)
(PDF format, 41 pages)
**Organization:** [Public Health Agency of Canada](/en/public-health.html)
**Publication Date:** 2020-10-15
Related topics
--------------
* [Vaccines and Immunization](/en/services/health/publications/vaccines-immunization.html)
Table of contents
-----------------
* [Summary of the Information Contained in this NACI Statement](#a1)
* [I. Introduction](#a2)
* [II. Methods](#a3)
* [III. Onset of adverse events following immunization](#a4)
+ [III.1 Anaphylaxis](#a4.1)
+ [III.2 Syncope and Seizure](#a4.2)
+ [III.3 Risk-benefit Assessment](#a4.3)
* [IV. Recommendations](#a5)
+ [IV.1 Recommendations for Public Health Program Level Decision-Making](#a5.1)
* [Tables and Figures](#a6)
* [List of Abbreviations](#a7)
* [Acknowledgments](#a8)
* [References](#a9)
Summary of the Information Contained in this NACI Statement
-----------------------------------------------------------
The following highlights key information for immunization providers. Please refer to the remainder of this statement for details.
### 1. What
* It is important to continue routine immunization programs during the COVID-19 pandemic, especially for the upcoming influenza season, which will prevent influenza-related morbidity and mortality and contribute to reducing the burden on the Canadian health care system. This is particularly important in anticipation of a potential resurgence in COVID-19 in the fall or winter months.
* During the COVID-19 pandemic, large crowds at influenza immunization clinics could contribute to increased SARS-CoV-2 transmission risks if not managed appropriately; therefore, [adjustments to regular immunization practices and clinic design](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-influenza-vaccine-delivery-covid-19.html) may be required.
* In addition to other public health and infection prevention and control measures, reducing the post-vaccination observation period in post-vaccination observation areas provides an option to reduce crowding. Decreasing close interactions among vaccine recipients and between vaccine recipients and clinic staff may help to mitigate against potential SARS-CoV-2 transmission in clinic settings. Vaccine recipients who do not meet the criteria for a reduced post-vaccination observation period will also benefit from a less crowded post-vaccination waiting area. This intervention may also allow more individuals to be vaccinated in a given time period (increase vaccination setting "throughput").
### 2. Who
* Settings providing influenza vaccinations for the upcoming influenza season during the COVID-19 pandemic.
### 3. How
1. NACI recommends that the current post-vaccination observation period, as specified in the Canadian Immunization Guide [Reference a](#fna), should be maintained for influenza vaccination settings that can adhere to appropriate public health and infection prevention and control measures [Reference b](#fnb) to reduce SARS-CoV-2 transmission, particularly physical distancing (Strong NACI recommendation).
* NACI concludes that there is fair evidence to maintain a 15-minute post-vaccination observation period during the COVID-19 pandemic for individuals with no known history of severe allergic reactions (including anaphylaxis) to any component of the influenza vaccine being considered for administration or any history of other immediate post-vaccination reactions (e.g., syncope with or without seizure) (Grade B Evidence).
2. NACI recommends that a shorter post-vaccination observation period, between 5 to 15 minutes after influenza immunization, may be considered during the COVID-19 pandemic, but only during times when appropriate physical distancing in post-vaccination waiting areas cannot otherwise be maintained due to the volume of individuals seeking immunization, and only when specific conditions are met[Endnotes \*](#ref*) (Discretionary NACI recommendation).
* NACI concludes that there is insufficient evidence from retrospective, passive adverse event following immunization (AEFI) case series reports to support a reduced post-vaccination observation period. However, other factors may be taken into consideration to support a reduced post-vaccination observation period, if necessary for public health and infection prevention and control purposes (Grade I Evidence).
Endnotes \*
Endnotes \*
A shorter observation period may be considered only if the vaccine recipient meets the following conditions [Reference c](#fnc):
* Past history of receipt of influenza vaccine and no known history of severe allergic reactions (including anaphylaxis) to any component of the influenza vaccine being considered for administration (note that novel technology vaccine recipients should be exempt from reduced post-observation period eligibility) [Reference d](#fnd).
* No history of other immediate post-vaccination reactions (e.g., syncope with or without seizure) after receipt of any vaccines.
* The vaccine recipient is accompanied by a parent/guardian (in the case of a child) or responsible adult who will act as a chaperone to monitor the vaccine recipient for a minimum of 15 minutes post-vaccination. In the case of two responsible adults, both can be vaccine recipients for the purposes of this criterion, if both agree to monitor the other post-vaccination.
* The vaccine recipient will not be operating a motorized vehicle or self-propelled or motorized wheeled transportation (e.g., bicycle, skateboard, rollerblades, scooter), or machinery for a minimum of 15 minutes after vaccination.
* The vaccine recipient and the parent/guardian or responsible adult chaperone are aware of when and how to seek post-vaccination advice and given instructions on what to do if assistance and medical services are required.
* The vaccine recipient and the parent/guardian/responsible adult agree to remain in the post-vaccination waiting area for the post-vaccination observation period and to notify staff if the recipient feels or looks at all unwell before leaving. They should be informed that an individual exhibiting any symptom suggestive of an evolving AEFI at the end of the shortened post-observation period necessitates a longer period of observation in the clinic.
[Return to Reference \* referrer](#fn*-rf)
### 4. Why
* A vaccination clinic setting that is able to maintain recommended public health and infection prevention and control measures, such as physical distancing in post-vaccination areas, is unlikely to achieve significant additional reductions in the risk of SARS-CoV-2 transmission by implementing a shorter post-vaccination observation period.
* A vaccination clinic setting that at times is unable to maintain recommended physical distancing in post-vaccination areas may consider implementing a shorter post-vaccination observation period to reduce the risk of SARS-CoV-2 transmission under specified conditions.
* Serious adverse events in the minutes following immunization that may require medical intervention are relatively rare.
I. Introduction
---------------
A cluster of cases of pneumonia of unknown origin was reported from Wuhan, Hubei Province, China in December 2019. These cases were determined to be due to a novel coronavirus (SARS-CoV-2) that causes a disease now referred to as coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) characterized COVID-19 as a pandemic on March 11, 2020[Footnote 1](#fn1).
Canadian provinces and territories instituted a series of public health measures to limit SARS-CoV-2 transmission and to reduce the burden on the healthcare system, including the temporary deferral of non-essential medical services. Recognizing the need to continue routine immunization programs during the pandemic, the Public Health Agency of Canada (PHAC), with consultation from the National Advisory Committee on Immunization (NACI) and the Canadian Immunization Committee, released interim guidance on [priority populations for immunization programs in Canada](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/interim-guidance-immunization-programs-during-covid-19-pandemic.html),[Footnote 2](#fn2) as well as guidance on [strategies and modifications of usual immunization clinic processes for the upcoming influenza season](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-influenza-vaccine-delivery-covid-19.html) to reduce the risk of SARS-CoV-2 transmission in a variety of immunization clinic settings[Footnote 3](#fn3).
There are a variety of process modifications (administrative, environmental and engineering controls, and personal protective measures) that can be implemented in the vaccination clinic setting to prevent SARS-CoV-2 transmission, such as promoting physical distancing (at least two metres) among vaccine recipients, and staff and their co-workers. Another possible measure may be to reduce the post-vaccination observation period for rare, but serious AEFIs. Reducing the amount of time vaccine recipients spend in the vaccination clinic post-vaccination could reduce the opportunity for SARS-CoV-2 transmission from an unrecognized, infectious COVID-19 case. However, any consideration of a reduction in post-vaccination observation period must weigh the potential risk of delayed identification of an adverse event that may require immediate medical intervention against the potential benefits of reducing the risk of SARS-CoV-2 transmission and allowing more individuals to be vaccinated (increase vaccination clinic "throughput") in a given time period.
In Canada, it is recommended that vaccine recipients remain under observation for at least 15 minutes after vaccination, unless there is a specific concern about a possible vaccine allergy in which case a 30-minute post-vaccination observation period is considered a safer interval[Footnote 4](#fn4). Guidelines for post-vaccination observation in other countries vary [Footnote 5](#fn5)[Footnote 6](#fn6)[Footnote 7](#fn7)[Footnote 8](#fn8). In April 2020, the Australian Technical Advisory Group on Immunization (ATAGI) released a recommendation that the post-vaccination observation period could be reduced from 15 minutes to 5 minutes in immunization clinics where adequate physical distancing was not possible, as long as specific criteria were met[Footnote 9](#fn9). The ATAGI guidance was based on a targeted review of the literature and expert opinion.
### Guidance objective
The objectives of this NACI statement are to review the evidence on the timing of onset of serious AEFIs (anaphylaxis, syncope with or without seizure). These data will be used to assess the potential impact of a reduction in the post-vaccination observation period on the risk of delayed identification of a serious adverse event that may require immediate medical intervention, balanced against the potential benefits of reducing SARS-CoV-2 transmission in influenza vaccination settings and allowing more individuals to be vaccinated in a given time period. The analysis will be used to provide guidance to provincial and territorial immunization programs and frontline clinicians on the duration of the post-vaccination observation period for influenza vaccination during the COVID-19 pandemic.
II. Methods
-----------
### Rapid literature review
In preparation for influenza vaccination clinics in fall 2020, a rapid review of literature was conducted to determine the likelihood of missing serious AEFIs (anaphylaxis, syncope with or without seizure) with shorter post-vaccination observation periods. The rapid review's search strategy was developed in conjunction with a federal Reference Librarian and was used to search a single electronic database for studies on the timing of serious AEFIs in children and adults (all ages and populations).
### Research question
What is the minimum observation period needed post-vaccination to observe serious AEFI?
**P (population):**
Individuals 6 months of age and older
**I (intervention):**
Observation period post-vaccination, any vaccine
**C (comparison):**
N/A
**O (outcomes):**
Time to onset of serious AEFI
The electronic database (EMBASE) was searched from inception to May 22, 2020 using the following search terms: seizure, syncope, anaphylaxis, adverse event, immunization, vaccination reaction, allergic reaction, and post-vaccination reaction. Searches were restricted to articles published in English and French. Two reviewers (NF, PDP) independently screened the titles and abstracts and full-text of eligible articles, but not in duplicate. The PRISMA Flow Diagram is shown in [Appendix A](#appendixa). The complete search strategy is available upon request.
Studies were included if they met the following criteria:
* The study recorded the specific time of onset of at least a subset of AEFIs and reported events that occurred within 30 minutes of vaccination; and
* The study assessed the incidence of the following serious AEFIs:
+ anaphylaxis, syncope with or without seizure.
Studies were excluded if they met one or more of the following criteria:
* The study was in a language other than English or French;
* The article was an editorial, opinion, conference abstract or news report;
* The minimum observation period for AEFIs was greater than 30 minutes; or
* The study did not report the time to onset of serious AEFIs.
The eligible studies that were identified were divided amongst three reviewers (NF, PDP, GC). The reviewers independently extracted data from their assigned studies into evidence tables and appraised the risk of bias of the studies. The data extraction and risk of bias assessments were not done in duplicate for any of the eligible studies.
The extracted data were used to summarize key study characteristics and to analyze the studies for risk of bias, using a modified Institute of Health Economics Tool (IHE)[Footnote 10](#fn10), as all included studies were case reports or case series. A narrative synthesis of the extracted data was created to summarize the outcomes of interest (number of AEFIs, severity, time to onset, and incidence, if reported). As not all of the identified articles evaluated outcomes by severity, the number of serious reports identified were compiled from reports that were explicitly classified as serious, as well as from inference from stated sequelae of individual cases that would meet usual serious outcome definitions (e.g., death, life-threatening illness, hospitalization, prolonged hospitalization, permanent disability).
### Canadian Adverse Events Following Immunization Surveillance System
The Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) database was searched for AEFI reports of anaphylaxis, syncope, and afebrile seizure associated with a date of vaccine administration between 2014 and 2018. The Medical Dictionary for Regulatory Activities (MedDRA) terms used to code CAEFISS reports were used to search CAEFISS for reports for the three outcomes of interest. Reports of anaphylaxis had to meet the Brighton Collaboration definition for anaphylaxis [Footnote 11](#fn11) and the individual in the report managed as such. CAEFISS uses the World Health Organization definition of a serious AEFI[Footnote 12](#fn12): an event that is life threatening, results in hospitalization or a prolongation of hospitalization, persistent or significant disability or where the outcome is a birth defect or death. Reports that did not include a time to onset of symptoms were excluded.
The time to symptom onset for each AEFI was summarized by 5-minute intervals within the first 15 minutes post-vaccination, if available; and the time of onset that includes 25%, 50%, 75%, 95%, and 100% of all reports. These summary measures were analyzed by age groups: less than 2 years, 2 to less than 7 years, 7 to less than 18 years, 18 to less than 50 years, 50 to less than 65 years, 65 years and older, all ages, and by all reports versus serious AEFI.
### Qualitative assessment of reducing the post-vaccination observation period
It is challenging to accurately quantify the impact of a reduction in the post-vaccination observation period on the risk for SARS-CoV-2 transmission in a vaccination setting. This is particularly the case because the clinic settings in Canada are diverse; community prevalence of SARS-CoV-2 varies between communities and fluctuates over time within communities; and because this measure would be one of several public health and infection prevention and control measures implemented to reduce the risk of transmission in these settings. Consequently, a qualitative assessment of this intervention was undertaken to weigh the potential risk of any potential delay in identifying serious AEFIs that may require immediate medical intervention against the potential benefit of reducing the risk of SARS-CoV-2 transmission and enhancing the ability to vaccinate more individuals during a given time period (increase vaccination clinic "throughput").
### Recommendation Development
The draft statement was developed through the NACI Influenza Working Group and in consultation with the NACI Vaccine Safety Working Group. These three analyses, outlined above, were then used by NACI to draft recommendations on whether to reduce the duration of post-vaccination observation period in the context of the COVID-19 pandemic. NACI critically appraised the available evidence and approved the final recommendation on August 13, 2020.
III.Onset of adverse events following immunization
--------------------------------------------------
Twenty-two studies on time to onset of serious AEFI were identified through the rapid review. All studies were evaluated for risk of bias using a modified IHE tool and all were deemed to be at serious risk of bias, except two studies, which were deemed to be at unclear risk of bias[Footnote 14](#fn14)[Footnote 19](#fn19). Both studies with unclear risk of bias described the incidence of anaphylaxis after vaccine administration using a restricted set of ICD-9 codes to search a health care database, a process deemed to be more sensitive at identifying anaphylaxis episodes than relying on reports submitted to passive AEFI reporting systems. McNeil et al.[Footnote 19](#fn19) used the same code set used by Bohlke et al.[Footnote 14](#fn14), but supplemented their search with allergy codes combined with epinephrine-dispensing codes. The majority of the included articles used data from passive surveillance systems, and had limitations such as underreporting, insufficient information on cases reported, lack of denominators and inconsistent case definitions. For measurement of whether the intervention of interest was described, articles were considered to be of low bias if they reported the vaccine name and manufacturer and whether this was the first or subsequent immunization dose, if relevant. A visual summary of the risk of bias assessments is provided in [Figure 2](#f2).
The findings from the rapid review must be interpreted with caution in light of the findings of the risk of bias assessment for the articles identified in the rapid review and the inherent limitations of data obtained from retrospective case series studies that rely on passive AEFI surveillance systems. For example, the voluntary nature of reporting in most of these systems can lead to underreporting of AEFIs; the retrospective nature of these studies may make it difficult to obtain the necessary clinical data to verify outcomes and to determine that outcomes meet case definitions; the studies may also not have access to data on the sequelae for individuals in case reports, which may lead to an underestimation of the seriousness of some outcomes. There is often no access to denominator data (i.e., the number of vaccine doses distributed or ideally the number of doses administered) to estimate the incidence of outcomes. Also estimates of incidence based on relatively few case reports may be unreliable (i.e., relatively few additional case reports can significantly alter the calculated rate) and rates generated in heterogeneous populations may not be comparable.
### III.1 Anaphylaxis
#### Rapid literature review
##### Time to symptom onset of anaphylaxis
There were 16 articles (12 retrospective case series [Footnote 13](#fn13) [Footnote 14](#fn14) [Footnote 15](#fn15) [Footnote 16](#fn16) [Footnote 17](#fn17) [Footnote 18](#fn18) [Footnote 19](#fn19) [Footnote 20](#fn20) [Footnote 21](#fn21) [Footnote 22](#fn22) [Footnote 23](#fn23) [Footnote 24](#fn24), 4 case reports[Footnote 25](#fn25) [Footnote 26](#fn26) [Footnote 27](#fn27) [Footnote 28](#fn28)) identified in the rapid review that provide data on the timing of reports of anaphylaxis following vaccine administration. The retrospective case series primarily use AEFI surveillance systems to examine reports of anaphylaxis in vaccine recipients. Across all of the identified articles, 981 reports of anaphylactic reactions were described, with 816 (83%) reports assessed against the Brighton Collaboration definition of anaphylaxis and the criteria for the three levels of diagnostic certainty (level 1: 413 reports; level 2: 372; level 3: 14; other/level not reported: 17). Of the 981 reports of anaphylaxis, 729 (74%) of the reports were classified as serious.
Overall, 873 (89%) of the anaphylaxis reports had some time to symptom onset recorded, of which the majority (492/873, 56%) occurred within 30 minutes of vaccination. The majority of the data (735/873, 84%) came from a single study using reports from the US Department of Health and Human Service's Vaccine Adverse Events Reporting System (VAERS) database, which categorized onset times into relatively broad time intervals (within 30 minutes, 30-119 minutes, 2-4 hours, 4-8 hours and 8-24 hours)[Footnote 23](#fn23).
There were 8 retrospective case series [Footnote 13](#fn13) [Footnote 14](#fn14) [Footnote 15](#fn15) [Footnote 16](#fn16) [Footnote 17](#fn17) [Footnote 19](#fn19) [Footnote 22](#fn22) [Footnote 24](#fn24) and 3 case reports [Footnote 25](#fn25) [Footnote 26](#fn26) [Footnote 28](#fn28) that identified 55 reports that provided descriptions of or actual times to anaphylaxis symptom onset in intervals within the first 15 minutes post-vaccination. Of these 55 reports, 35 (64%) occurred between 0 and 5 minutes post-vaccination, 4 (7%) "within minutes" or "within a few minutes," 9 (16%) between 5 and 10 minutes, 1 (2%) between 10 and 15 minutes, and 6 (11%) within 5 to 15 minutes.
Three of the retrospective case series studies [Footnote 13](#fn13) [Footnote 20](#fn20) [Footnote 23](#fn23) provided summary measures of the time to anaphylaxis symptom onset after vaccination. Baxter et al. evaluated the Australian Surveillance of Adverse Events following Vaccination in the Community (SAEFVIC) database for reports of anaphylaxis occurring within the first 60 minutes following immunization in preschool aged (<5 years) children. The study found all 12 identified anaphylaxis reports had a time of symptom onset of 0-40 minutes, with an average of 7.5 minutes and a median of 5 minutes[Footnote 13](#fn13). Su et al., using anaphylaxis case reports from VAERS from 1990-2016, found 828 case reports that occurred within 1 day post-vaccination. These reports had a median time of onset after vaccination of 20 minutes (ranging from <1 minute to 24 hours)[Footnote 23](#fn23). And finally Pahud et al., examining serious, non-fatal adverse events reported to VAERS following receipt of 2009 H1N1 vaccine in children (<18 years of age) from October 2009-January 2010 found 12 true allergic reactions (i.e., not just reports of anaphylaxis) occurred within 3 hours of vaccination with a median of 30 minutes (range: 5 minutes-3 hours)[Footnote 20](#fn20).
##### Estimates of anaphylaxis incidence based on literature
There were 6 retrospective case series [Footnote 13](#fn13) [Footnote 14](#fn14) [Footnote 15](#fn15) [Footnote 16](#fn16) [Footnote 18](#fn18) [Footnote 23](#fn23) that had access to the data on the number of vaccine doses either distributed or administered during the period of the study; these data were used to calculate either overall or vaccine-specific estimates of anaphylaxis incidence during the study period.
The incidence of anaphylaxis was fairly consistent across studies, although there was some variation. The variation could be due to the small number of anaphylaxis case reports and the different denominators used to calculate incidence (doses distributed or doses administered). McNeil et al. reported an overall incidence of anaphylaxis in children and adults of 1.31 per 1,000,000 doses administered[Footnote 18](#fn18). Two other studies calculated the incidence of anaphylaxis in children <18 years of age; estimates ranged from 0.65 to 1.3 per 1,000,000 doses[Footnote 13](#fn13) [Footnote 14](#fn14).
Four studies reported incidence estimates for specific vaccines that varied significantly by vaccine and by study (0.1 to 26 per 1,000,000 doses)[Footnote 15](#fn15) [Footnote 16](#fn16) [Footnote 18](#fn18) [Footnote 23](#fn23). The highest reported incidence was from a study based on anaphylaxis reports submitted to the New South Wales Health Immunization Unit for human papillomavirus (HPV) vaccine[Footnote 15](#fn15) and the lowest reported incidence was for influenza vaccine based on reports submitted to VAERS[Footnote 23](#fn23). Incidence of anaphylaxis estimates after administration of influenza vaccine was 0.1 to 1.8 per 1,000,000 doses (administered or distributed)[Footnote 18](#fn18) [Footnote 23](#fn23).
#### Canadian Adverse Events Following Immunization Surveillance System
##### Time to symptom onset of anaphylaxis
Of the 136 reports of anaphylaxis identified, 112 (82%) were classified as serious. Just over half of all the anaphylaxis reports occurred in individuals 7 to less than 18 years of age (n=30, 22%) and 18 to less than 50 years of age (n=46, 34%). There were fewer numbers of AEFI reports in each of the other age groups (range: 9-20 AEFI reports per age group).
For all ages combined, 25% of anaphylaxis reports had onset within 5 minutes of vaccination, increasing to 50% of reported cases by 15 minutes post-vaccination, with an overall median time to symptom onset of 15 minutes (range: 1 minute to 48 hours). The proportion of individuals with symptom onset within the first 15 minutes post-vaccination did not vary significantly by age grouping, with the exception of children less than 2 years of age (6 minutes vs 15 minutes for all ages) and individuals 50 to less than 65 years of age (45 minutes vs 15 minutes) ([Table 1](#tbl1)). When comparing the time to symptom onset for all anaphylaxis reports compared to reports classified as serious, similar trends were found. For all ages combined, 29% of case reports had onset of symptoms by 5 minutes post-vaccination, 46% by 10 minutes post-vaccination and 54% by 15 minutes post-vaccination. These proportions did not differ significantly by age grouping, with the exception of children less than 2 years of age (50% by 5 minutes, 67% by 15 minutes) and individuals 50 to less than 65 years of age (8% by 5 minutes, 31% by 15 minutes) (data not shown), reflecting the differences in median time to symptom onset in these age groups ([Table 1](#tbl1)).
Table 1. Onset times for anaphylaxis for all vaccines combined and administered from 2014-2018 by age group.
| Age group (years) | Number of cases (%) | Percentage of case reports by time to symptom onset |
| --- | --- | --- |
| 25% of cases | 50% of cases | 75% of cases | 95% of cases | 100% of cases | Median (range) |
| Less than 2 | 15 (11%) | 3 minutes | 6 minutes | 40 minutes | 3 hours | 3 hours | 6 minutes
(1 minute to 3 hours) |
| 2 to less than 7 | 20 (15%) | 5 minutes | 13 minutes | 32 minutes | 25 hours | 48 hours | 13 minutes
(1 minute to 48 hours) |
| 7 to less than 18 | 30 (22%) | 5 minutes | 15 minutes | 30 minutes | 60 minutes | 2 hours | 15 minutes
(1 minute to 2 hours) |
| 18 to less than 50 | 46 (34%) | 7 minutes | 15 minutes | 30 minutes | 6 hours | 19 hours | 15 minutes
(1 minute to 19 hours) |
| 50 to less than 65 | 16 (12%) | 17 minutes | 45 minutes | 7 hours | 48 hours | 48 hours | 45 minutes
(1 minute to 48 hours) |
| 65 and older | 9 (7%) | 6 minutes | 18 minutes | 25 minutes | 2 hours | 2 hours | 18 minutes
(5 minutes to 2 hours) |
| All Ages | 136 | 5 minutes | 15 minutes | 31 minutes | 7 hours | 48 hours | 15 minutes
(1 minute to 48 hours) |
### III.2 Syncope and Seizure
As seizures may occur secondary to syncopal episodes, the two outcomes are considered together in this section.
#### Rapid literature review
##### Time to symptom onset of syncope or seizure
There were 8 articles (7 retrospective case series [Footnote 19](#fn19) [Footnote 21](#fn21) [Footnote 29](#fn29) [Footnote 30](#fn30) [Footnote 31](#fn31) [Footnote 32](#fn32) [Footnote 33](#fn33), 1 case report[Footnote 34](#fn34)) identified in the rapid review that provide data on the outcomes of either syncope or seizure following vaccine administration. The retrospective case series studies all utilized AEFI surveillance systems to evaluate reports of syncope or seizure in vaccine recipients. In the 8 articles that identified reports of syncope or seizure, there were 1,180 reports of syncope alone (i.e., not associated with any reported seizure activity), 199 reports of seizures associated with syncopal episodes ("syncopal seizures"), and 16 reports of seizures alone (either afebrile or febrile) for a total of 1,395 reports. Of the 1,395 reports, 103 (7%) were considered serious (97 syncope alone, 1 syncopal seizure, and 5 febrile seizures).
Of the 1,180 reported cases of syncope alone, 453 (38%) had some indication of time to symptom onset. The range of reported onset times varied from within 5 minutes to 2 days; however, 340 (75%) of the syncopal case reports with a recorded time to symptom onset occurred within the first 15 minutes post-vaccination. Twenty-four (5%) of these reports were from four studies [Footnote 19](#fn19) [Footnote 21](#fn21) [Footnote 31](#fn31) [Footnote 32](#fn32) using retrospective case series data: 15 (63%) cases had onset from 0-5 minutes post-vaccination and 1 (4%) case with onset within 10-15 minutes. The time of onset of the remaining 8 cases were not provided in the same 5-minute time intervals: 4 (17%) occurred within 10 minutes of vaccination and 4 (17%) within 15 minutes of vaccination.
Among the studies identified, a fifth study[Footnote 29](#fn29) also using retrospective case series data provided the largest number of syncopal case reports with symptom onset within the first 15 minutes post-vaccination. This study by Braun et al evaluated reports of syncope occurring within 12 hours of immunization submitted to VAERS and injury reports for syncope-related falls from the US National Vaccine Injury Compensation Program in individuals of any age from 1990-October 1995. Of the 571 reports that had a recorded time to symptom onset (81.9% of total reports), 323 (63.2%) occurred within 5 minutes of vaccination, increasing to 416 (81.4%) within 10 minutes, and 454 (88.8%) within 15 minutes of vaccination. Of the 454 syncopal episodes, 153 were associated with "tonic or clonic movements" ("syncopal seizures"): 138 (30. 4%) within 15 minutes of vaccination and 15 (12.8%) greater than 15 minutes after vaccination. Of note, 67 (9.6%) cases reported subsequent hospitalization. Six individuals sustained head injuries after syncope-induced falls, which included skull fractures, cerebral contusions, cerebral hematomata and one case of major cerebral hemorrhage. Three of the injuries necessitated neurosurgery to alleviate cerebral swelling or bleeding and 2 individuals still had significant neurologic deficits up to 2 years after the incidents. All 6 of these head injuries occurred from syncopal events within 15 minutes after vaccination.
In the study by Sutherland et al., there were 10 secondary injuries recorded among the 26 serious syncopal reports: head injuries after syncopal falls (n=9), including one death of a 15-year-old boy due to intracranial hemorrhage, and a motor vehicle incident after a loss of consciousness while driving (n=1). Seven (70%) of the injuries occurred within 15 minutes of vaccination[Footnote 32](#fn32).
A description of the time to symptom onset was available for 154 (77%) of the 199 reports of seizures associated with syncopal episodes ("syncopal seizures") and for all 16 (100%) reports of seizures alone. Two articles provided the data on syncopal seizure following vaccine administration [Footnote 29](#fn29) [Footnote 31](#fn31). Braun et al.[Footnote 29](#fn29) reported 153 syncopal reports with associated "tonic or clonic movements": 138 (90.2%) occurred within 15 minutes of vaccination and 15 (9.8%) occurred greater than 15 minutes after vaccination. The remaining case which was reported in the second study occurred at 0 minutes post-vaccination (i.e., immediately)[Footnote 31](#fn31). The 16 cases of seizure alone were identified in two studies[Footnote 30](#fn30) [Footnote 19](#fn19). Crawford et al analyzed detailed clinical information on SAEFVIC case reports of syncope and seizures after quadrivalent HPV vaccination in females 12-26 years of age vaccinated as part of the Australian National HPV Vaccination Program from May 2007-April 2009.[Footnote 30](#fn30) The study identified 31 episodes of syncope with associated seizures, but the time to seizure onset was reported only for 3 reports of afebrile seizure, all in individuals with confirmed underlying epilepsy. There were no deaths reported in the study population, but there were 7 injuries reported: head injuries (n=5), mouth bleeding (n=1) and a T5/T6 vertebral fracture (n=1). The study by Milstien et al.[Footnote 19](#fn19) identified 13 reports that met the US Food and Drug Administration (FDA) case definition for a potentially vaccine-associated convulsion, four afebrile convulsions and nine febrile convulsions. The time of onset for the afebrile convulsions was 30 minutes, 2 hours, 24 hours and 2 days after vaccination.
##### Estimates of syncope and/or seizure incidence based on literature
There were 3 retrospective case series studies that had access to the data on the number of vaccine doses either distributed or administered during the period of the study, allowing for calculation of either overall or vaccine-specific syncope or seizure incidence during the study period[Footnote 30](#fn30) [Footnote 31](#fn31) [Footnote 32](#fn32).
In an analysis of SAEFVIC case reports of syncope and seizures after quadrivalent HPV vaccination as part of the Australian National HPV Vaccination Program, Crawford et al. estimated an incidence of 7.8 and 2.6 per 100,000 doses of vaccine distributed for syncope and syncopal seizures respectively[Footnote 30](#fn30).Subelj et al. estimated the incidence of syncope and seizures associated with syncope to be 13.4 and 3.4 per 100,000 doses, respectively, based on 4 years of data from mandatory reports to the National Institute of Public Health of a school-based four-valent HPV (HPV4) vaccine program targeting girls 11-14 years of age in Slovenia[Footnote 31](#fn31). Sutherland et al evaluated reports of "syncope" or "syncope vasovagal" occurring in individuals ≥5 years of age on the same day as vaccination submitted to the VAERS surveillance system from January 1, 2005-July 31, 2007 and compared the rates of syncopal events to the rate of VAERS reports received from 2002-2004[Footnote 32](#fn32). The rates of syncopal events per 1,000,000 doses of vaccines distributed in the US during the respective study periods was increased in 2005-2006 (0.31-0.54) compared to 2002-2004 (0.28-0.35), as were the proportion of reports from females (77.5% vs 61.6%) and persons 11-18 years of age (62.0% vs 47.3%).
#### Canadian Adverse Events Following Immunization Surveillance System
##### Time to symptom onset of syncope or seizure
Of the 52 reports of syncope, 20 (38%) were classified as serious. Individuals 7 to less than 18 years of age (n=33, 65%) and 18 to less than 50 years of age (n=8, 16%) accounted for the majority of all 52 reports. There were very few AEFI reports in each of the remaining age groups (N is between 2 and 4 for each).
Table 2. Onset times for syncope for all vaccines combined and administered between 2014-2018
|
Age group (years) | Number of cases (%) | Percentage of case reports by time to symptom onset |
| --- | --- | --- |
| 25% of cases | 50% of cases | 75% of cases | 95% of cases | 100% of cases | Median
(range) |
| Less than 2 | 2 (4%) | 5 days | 12 days | 18 days | 18 days | 18 days | 12 days
(5 to 18 days) |
| 2 to less than 7 | 2 (4%) | 4 minutes | 7 minutes | 10 minutes | 10 minutes | 10 minutes | 7 minutes
(4 to 10 minutes) |
| 7 to less than 18 | 33 (65%) | 1 minute | 2 minutes | 6 minutes | 20 minutes | 35 minutes | 2 minutes
(1 to 35 minutes) |
| 18 to less than 50 | 8 (16%) | 2 minutes | 63 minutes | 48 hours | 29 days | 29 days | 63 minutes
(1 minute to 29 days) |
| 50 to less than 65 | 2 (4%) | 1 minute | 31 minutes | 60 minutes | 60 minutes | 60 minutes | 31 minutes
(1 to 60 minutes) |
| 65 and older | 4 (8%) | 2 hours | 11 hours | 33 hours | 48 hours | 48 hours | 11 hours
(1 minute to 48 hours) |
| All Ages | 52 | 1 minute | 3 minutes | 15 minutes | 5 days | 29 days | 3 minutes
(1 minute to 29 days) |
For all ages combined, 25% of syncope reports had onset within 1 minute of vaccination, increasing to 50% of reported cases by 3 minutes post-vaccination and 75% within 15 minutes, with an overall median time to symptom onset of 3 minutes (range: 1 minute to 29 days) ([Table 2](#tbl2)). The proportions were similar for syncope reports classified as serious (data not shown).
There were 61 reports of afebrile seizure between 2014 and 2018, 50 (82%) of which were classified as serious. The majority (74%) of reports were in individuals less than 2 years of age. There were very few AEFI reports in the other age groups. For all ages combined, the median time to onset of afebrile seizure was 21 hours (range: 1 minute to 29 days). Only for the group of individuals 7 to less than 18 years were a significant proportion (25%) of afebrile seizures reported to have occurred within 2 minutes of vaccination, based on a small number of case reports (n=8).
### III.3 Risk-benefit assessment
The rationale for potentially considering a reduction in the post-vaccination observation period in influenza vaccination settings during the COVID-19 pandemic is to reduce the duration of time vaccine recipients spend together with others in post-vaccination areas and to potentially reduce the number of contacts recipients encounter in vaccination settings. This could then reduce the opportunity for SARS-CoV-2 transmission from an unrecognized, infectious COVID-19 case and allow more individuals to be vaccinated (increase vaccination clinic "throughput") in a given time period. However, it is very challenging to quantify the impact of a reduction in the post-vaccination observation period on the risk for SARS-CoV-2 transmission, independent of other public health and infection prevention and control measures (engineering, environmental and administrative controls, and personal protective equipment) that are likely to be implemented in influenza vaccination settings during the COVID-19 pandemic. In addition, there will be differences in the risk of transmission in various settings due to variability in disease prevalence at different locations and at different points in time. Any consideration of a reduction in post-vaccination observation period would be a deviation from the current standard practice in Canadian provinces and territories. The current standard of a 15-minute post-vaccination observation period is intended to identify serious AEFIs that may require immediate medical intervention. This must be weighed against the potential benefits of reducing risk of SARS-CoV-2 transmission and allowing more individuals to be vaccinated (increase vaccination clinic "throughput") in a given time period.
#### Potential benefits of a reduced post-vaccination observation period
* Reduction in crowding within post-vaccination waiting areas of vaccination clinics will improve the likelihood of maintaining physical distancing among vaccine recipients and between vaccine recipients and clinic staff.
* Less waiting post-vaccination may encourage members of the public to attend vaccination clinics if there is perceived to be less risk of COVID-19 infection due to less crowding in the vaccination clinics areas and if there is less time overall required to get vaccinated. Perceptions of reduced risk of infection will be enhanced by the other infection prevention and control measures taken in the context of COVID-19 that will also reduce crowding within the vaccination clinic setting (e.g., scheduled vaccination appointments, arrival just in time for appointments, screening of clinic staff and attendees).
* A reduced number of individuals in the post-vaccination waiting areas would benefit vaccine recipients who do not meet the criteria for a reduced post-vaccination observation period, and may remain in the vaccination setting for the standard 15-minute observation period or a 30-minute observation period if there is a specific concern about possible vaccine allergy.
* A reduced post-vaccination period may allow more individuals to be vaccinated (increase vaccination clinic "throughput") in a given time period and also allow vaccine recipients to be in contact with fewer individuals.
#### Potential risks of a reduced post-vaccination observation period
* There would be a small but potentially increased risk of delayed identification of an adverse event that may require immediate medical intervention (e.g., anaphylaxis and syncope with or without seizure).
* Reducing the post-vaccination observation period may have only a relatively modest, independent impact in reducing the risk of SARS-CoV-2 transmission in the vaccination clinic setting during the COVID-19 pandemic when compared with the other public health and infection prevention and control measures (e.g., environmental and engineering controls, administrative processes, personal protective equipment). The overall risk will also depend upon factors such as local disease prevalence at the time of the immunization clinics.
* The reduction in the post-vaccination observation period may be perceived as an action being taken primarily to improve clinic efficiency rather than an important infection prevention measure.
IV. Recommendations
-------------------
Following a thorough review of the evidence summarized above, NACI has made two recommendations for public health program decision-making. These recommendations are based on currently available scientific evidence and expert opinion and are relevant only during the COVID-19 pandemic, after which the current guidance for the post-vaccination observation period as identified in Part 2 of the Canadian Immunization Guide should be followed[Footnote 4](#fn4).
In considering these recommendations and for the purposes of publicly funded program implementation, provinces and territories may take into account economic factors and other local operational factors (e.g. current immunization programs, resources). Recognizing that there are differences in operational contexts across Canada, jurisdictions are advised to refer to the local epidemiology of COVID-19 and additional PHAC guidance[Footnote 3](#fn3) to determine the relative merits of modifying the post-vaccination observation period. NACI will continue to monitor the scientific literature for developments related to post-vaccination observation period and will update recommendations as evidence evolves, if required.
Please note:
* A *strong recommendation* applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
* A *discretionary recommendation* may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.
Refer to [Table 3](#tbl3) for a more detailed explanation of strength of NACI recommendations and grade of the body of evidence.
### IV.1 Recommendations for Public Health Program Level Decision-Making
1. **NACI recommends that the current post-vaccination observation period, as specified in the Canadian Immunization Guide[Endnote a](#fna), should be maintained for influenza vaccination settings that can adhere to appropriate public health and infection prevention and control measures [Endnote b](#fnb)to reduce SARS-CoV-2 transmission, particularly physical distancing (Strong NACI recommendation).**
* NACI concludes that there is fair evidence to maintain a 15-minute post-vaccination observation period during the COVID-19 pandemic for individuals with no known history of severe allergic reactions (including anaphylaxis) to any component of the influenza vaccine being considered for administration or any history of other immediate post-vaccination reactions (e.g., syncope with or without seizure) (Grade B Evidence).**Evidence and Rationale**
* A 15-minute post-vaccination observation period is the Canadian standard for individuals with no known history of prior severe allergic reaction or any other immediate post-vaccination reactions.
* A vaccination clinic setting that is able to maintain recommended public health and infection prevention and control measures, including physical distancing in post-vaccination areas, is unlikely to achieve significant additional reductions in the risk of SARS-CoV-2 transmission by implementing a shorter post-vaccination observation period.
2. **NACI recommends that a shorter post-vaccination observation period, between 5 to 15 minutes after influenza immunization, may be considered during the COVID-19 pandemic, but only during times when appropriate physical distancing in post-vaccination waiting areas cannot otherwise be maintained due to the volume of individuals seeking immunization, and only when specific conditions are met [Endnotes \*](#ref2*) (Discretionary NACI recommendation).**
* NACI concludes that there is insufficient evidence from retrospective, passive adverse event following immunization (AEFI) case series reports to support a reduced post-vaccination observation period. However, other factors may be taken into consideration to support a reduced post-vaccination observation period, if necessary for public health and infection prevention and control purposes (Grade I Evidence).
Endnotes \*
Endnotes \*
A shorter observation period may be considered only if the vaccine recipient meets the following **conditions** [Reference c](#fnc):
* Past history of receipt of influenza vaccine and no known history of severe allergic reactions (including anaphylaxis) to any component of the influenza vaccine being considered for administration (note that novel technology vaccine recipients should be exempt from reduced post-observation period eligibility)[Reference d](#fnd).
* No history of other immediate post-vaccination reactions (e.g., syncope with or without seizure) after receipt of any vaccines.
* The vaccine recipient is accompanied by a parent/guardian (in the case of a child) or responsible adult who will act as chaperone to monitor the vaccine recipient for a minimum of 15 minutes post-vaccination. In the case of two responsible adults, both can be vaccine recipients for the purposes of this criterion, if both agree to monitor the other post-vaccination.
* The vaccine recipient will not be operating a motorized vehicle or self-propelled or motorized wheeled transportation (e.g., bicycle, skateboard, rollerblades, scooter), or machinery for a minimum of 15 minutes after vaccination.
* The vaccine recipient and the parent/guardian or responsible adult chaperone are aware of when and how to seek post-vaccination advice and given instructions on what to do if assistance and medical services are required.
* The vaccine recipient and the parent/guardian/responsible adult agree to remain in the post-vaccination waiting area for the reduced post-vaccination observation period and to notify staff if the recipient feels or looks at all unwell before leaving the clinic. They should be informed that an individual exhibiting any symptom suggestive of an evolving AEFI at the end of the shortened post-observation period necessitates a longer period of observation in the clinic.
[Return to endnote \* referrer](#en*-rf)
**Evidence and Rationale**
* Public health and infection prevention and control measures (i.e., engineering, environmental and administrative controls, and personal protective equipment) should be implemented to reduce the risk for SARS-CoV-2 transmission.
* A consideration to reduce the post-vaccination observation period must weigh the potential risk of any delay in identifying serious adverse events that may require immediate medical intervention against the potential benefits of reducing contacts with others and the associated risk of SARS-CoV-2 transmission; and potentially allowing more individuals to be vaccinated in a given time period. It is recognized that several factors may influence decision-making and applicability of recommendations:
+ The community levels of SARS-CoV-2 transmission at the time of vaccination clinics will influence the risk of SARS-CoV-2 transmission in the vaccination setting. This risk will vary by and within jurisdictions over time.
+ Unanticipated or unprecedented increases in the number of individuals presenting for immunization in clinic settings at a given time could temporarily overwhelm the other public health and infection prevention measures in place.
+ It is unknown how much a reduced post-vaccination observation period, independent of other public health and infection prevention and control measures, contributes to reducing the risk of SARS-CoV-2 transmission in the vaccination setting.
* The evidence from retrospective, passive AEFI case series reports is insufficient to support a reduced post-vaccination observation period.
+ Overall estimates of anaphylaxis incidence using retrospective case series data from passive AEFI surveillance systems varied, but were consistent with estimates of anaphylaxis incidence for commonly administered vaccines (1 per 100,000 to 1 per 1,000,000 doses) cited by the World Allergy Organization in its International Consensus statement on allergic reactions to vaccines[Footnote 35](#fn35).
+ Estimates for the incidence of syncope using passive case series data ranged widely, but were consistently much higher than for anaphylaxis.
+ The data from the rapid review indicate that a shortened post-vaccination observation period may still identify a majority of syncopal episodes, but not the majority of episodes of anaphylaxis.
- The study by Braun et al[Footnote 29](#fn29) that evaluated the largest number of reports of syncope found 63.2% occurred within 5 minutes of vaccination, increasing to 416 (81.4%) within 10 minutes, and 454 (88.8%) within 15 minutes of vaccination. CAEFISS data, for all ages combined, found 25% of syncope reports had onset within 1 minute of vaccination, increasing to 50% of reported cases by 3 minutes post-vaccination and 75% within 15 minutes, with an overall median time to symptom onset of 3 minutes (range: 1 minute to 29 days).
- A little over half of all anaphylaxis reports with a recorded time of symptom onset occurred within 30 minutes of vaccination, but the proportion of those reports occurring during the first 15 minutes post-vaccination was not reported. From the case series containing the largest number of anaphylaxis reports, the median time to anaphylaxis onset after vaccination was 20 minutes (range: from <1 minute-24 hours). CAEFISS reports, for all ages combined, found 25% of anaphylaxis reports had onset within 5 minutes of vaccination, increasing to 50% of reported cases by 15 minutes post-vaccination, with an overall median time to symptom onset of 15 minutes (range: 1 minute to 48 hours). Similar trends were found for anaphylaxis reports classified as serious.
* Use of a shortened post-vaccination observation period should be accompanied by safeguards, as outlined in the recommendation, to minimize situations that would place the vaccine recipient at risk for unintended injury should an adverse event occur after the shortened observation period, but within the standard 15-minute post-vaccination observation period.
Tables and figures
------------------
Table 3. NACI Recommendations: Strength of Recommendation and Grade of Evidence
| STRENGTH OF NACI RECOMMENDATION | GRADE OF EVIDENCE |
| --- | --- |
| Based on factors not isolated to strength of evidence (e.g. public health need) | Based on assessment of the body of evidence |
| **Strong**
"should/should not be offered"* Known/Anticipated advantages outweigh known/anticipated disadvantages ("should"),
OR Known/Anticipated disadvantages outweigh known/anticipated advantages ("should not")
* Implication: A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present
| A - good evidence to recommend |
| B - fair evidence to recommend |
| C - conflicting evidence, however other factors may influence decision-making |
| D - fair evidence to recommend against |
| E - good evidence to recommend against |
| I - insufficient evidence (in quality or quantity), however other factors may influence decision-making |
| **Discretionary**
"may be considered"* Known/Anticipated advantages closely balanced with known/anticipated disadvantages, OR uncertainty in the evidence of advantages and disadvantages exists
* Implication: A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable
| A - good evidence to recommend |
| B - fair evidence to recommend |
| C - conflicting evidence, however other factors may influence decision-making |
| D - fair evidence to recommend against |
| E - good evidence to recommend against |
| I - insufficient evidence (in quality or quantity), however other factors may influence decision-making |
Table 4. Ranking Individual Studies: Levels of Evidence Based on Research Design
| Level | Description |
| --- | --- |
| I | Evidence from randomized controlled trial(s). |
| II-1 | Evidence from controlled trial(s) without randomization. |
| II-2 | Evidence from cohort or case-control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy. |
| II-3 | Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence. |
| III | Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees. |
Table 5. Ranking Individual Studies: Quality (internal validity) Rating of Evidence
| Quality Rating | Description |
| --- | --- |
| Good | A study (including meta-analyses or systematic reviews) that meets all design- specific criteria[Table 5 tablenote \*](#t5tn*) well. |
| Fair | A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion[Table 5 tablenote \*](#t5tn*) but has no known "fatal flaw". |
| Poor | A study (including meta-analyses or systematic reviews) that has at least one design-specific[Table 5 tablenote \*](#t5tn*) "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations. |
|
Table 5 Tablenotes
Table 5 tablenote \*
General design specific criteria are outlined in Harris et al. (2001).[Footnote 24](#fn24).
[Return to Table 5 tablenote \* referrer](#t5tn*-rf)
|
Table 6. Summary of evidence on the safety of post-vaccination observation time
| Study | Vaccine | Study Design | Participants | Summary of Key Findings | Level of Evidence | Quality |
| --- | --- | --- | --- | --- | --- | --- |
| Case Series |
| Baxter et al., 2018 | Any vaccine | Case Series
Australia
SAEFVIC passive surveillance system
July 2007 to June 2015 | Children less than 5 years of age | Anaphylaxis
The incidence of anaphylaxis was found to be 0.13 per 100,000 doses of vaccine. The time interval between vaccine dose and onset of anaphylaxis ranged from 0-40 minutes (n=12), with an average of 7.5 minutes and a median of 5 minutes. Ten cases (83%) developed symptoms of anaphylaxis within 5 minutes, two cases (17%) had delayed symptom onset with one at 20 minutes and another at 40 minutes following vaccine administration. For the majority of cases (68%), more than one vaccine was given prior to the onset of anaphylaxis. | III | Poor |
| Bohlke et al., 2003 | Any vaccine | Case Series
US
1991 to 1997 | Children 17 years of age or younger registered in one of 4 Health Maintenance Organizations participating in the US CDC Vaccine Safety Datalink project | Anaphylaxis
5 cases of potential vaccine-associated anaphylaxis were identified after administration of 7,644,049 vaccine doses. Incidence of anaphylaxis was 0.65 cases per 1,000,000 doses (95% CI: 0.21-1.53). None of the episodes resulted in death. Among the 5 cases identified, one (20%) happened within 5-10 minutes of vaccine administration and the other 4 (80%) cases happen more than 1 hour following administration. Of the 5 cases, only one case of anaphylaxis reaction happened following a single vaccine administration (MMR vaccine). | III | Poor |
| Braun et al., 1997 | Any vaccine | Case Series
US
VAERS passive surveillance system
1990 to 1995 | All children and adults (no age restriction) | Syncope
A total of 697 syncopal episodes were reported that occurred within 12 hours of vaccine administration. Hospitalization was reported in 9.6% of cases. Of the 571 (73.3%) syncope events with known time, 511 (89.5%) occurred 1 hour or less after vaccination. Of these, 323 (63.2%) occurred within 5 minutes or less, 93 (18.2%) occurred within 10 minutes and 38 (7.4%) occurred within 15 minutes of vaccine administration. Six patients suffered skull fractures, cerebral bleeding, or cerebral contusion after falls; 3 of these patients required neurosurgery. All the falls occurred 15 minutes or less after vaccination, in or near the clinic or office. | III | Poor |
| Brotherton et al., 2008 | HPV4 vaccine | Case Series
Australia
2007 | Female adults and children 12-26 years of age that received HPV4 vaccine through Australia National HPV Vaccination Program in either the school-based or primary care clinic setting | Anaphylaxis
12 cases of suspected anaphylaxis were identified. Of the 11 cases that provided consent to be included in the study, 8 (73%) cases fulfilled the Brighton case definition for anaphylaxis (Level 1; n=1 and Level 2; n=7). All cases were reported to have an onset within 15 minutes of receiving vaccination; 4 (50%) cases were within 5 minutes and 3 (37.5%) cases occurred between 5-10 minutes of vaccine administration. | III | Poor |
| Cheng et al., 2015 | Any vaccine | Case Series
Australia
SAEFVIC passive surveillance system
May 2007 to May 2013 | Children less than18 years of age | Anaphylaxis
25 cases were identified that met Brighton Collaboration criteria for anaphylaxis. Of these cases, 9 (26%) met level 1 diagnosis certainty, 15 (60%) level 2 and one level 3 (4%). The majority of cases had rapid symptom onset with 13 (52%) cases happening within 5 minutes, 18 (72%) cases within the first 15 minutes and 20 (80%) cases during the first 30 minutes of vaccination. Overall, 20% (5/25) of cases had their first symptoms of anaphylaxis developed ≥30 minutes after immunization. | III | Poor |
| Crawford et al., 2011 | HPV4 vaccine | Case Series | Female adult and children 12-26 years of age who received HPV4 vaccine through Australia National HPV Vaccination Program | Syncope and Seizure
Overall incidence following HPV4 vaccination was 7.8 per 100,000 doses distributed for syncope and 2.6 per 100,000 for syncopal seizures.
Of the 94 syncopal episodes, 67% (63/94) had syncope alone, and 33% (31/94) had associated seizure activity, of which 23% (7/31) had urinary incontinence. The HPV4 vaccine was given alone in 85% (82/97) of reports, with concomitant vaccines including: hepatitis B (6); diphtheria-tetanus-acellular pertussis (6); varicella (1); and varicella and hepatitis B vaccine (2).
Three patients were identified with afebrile seizures without syncope and all had a confirmed underlying epilepsy disorder. One patient had a generalized seizure 4 hours after the HPV4 vaccine (dose 2). Another had an exacerbation of complex partial seizures 4 hours after the HPV4 vaccine (dose 2). Another patient experienced a generalized tonic-clonic seizure 2 days after receiving HPV4 vaccine (dose 1). This resulted in a wedge fracture of spinal vertebrae, which was treated conservatively. A generalized epilepsy disorder was confirmed, and anticonvulsant medication commenced. | III | Poor |
| Johann-Liang et al., 2011 | Any vaccine | Case Series
US
Vaccine Injury Comensation Program
Jan 2000 to Dec 2009 | Adults and children of all ages | Anaphylaxis
53 unique cases alleging "anaphylaxis or anaphylactic shock" were identified through the Vaccine Injury Compensation Program, accounting for 3% of the total of 1,819 non-autism claims for the study period. Of those, 9 (17%) were defined as anaphylaxis. One case occurred from minutes to hour, 2 cases were within 5 minutes, one case had onset at 15 minutes, 2 cases were between 20 and 30 minutes and 3 cases occurred more than one hour after vaccine administration (one at 1 hour, one at 2 hours and one at 2-3 hours). | III | Poor |
| McNeil et al., 2016 | Any vaccine | Case Series
US
Jan 2009 to Dec 2011 | Adults and children of all ages enrolled in health plans at one of 9 Vaccine Safety Datalink participating sites | Anaphylaxis
76 cases of chart-confirmed anaphylaxis were identified that met Brighton Collaboration levels 1 and 2 criteria. Of these, 33 anaphylaxis cases [Brighton Collaboration level 1 (n=12; 36%) and level 2 (n=21; 64%)] were associated with vaccination and 43 were attributed to other causes. 29 cases (87.9%) of anaphylaxis had documented time to onset: 8 cases (24%) occurred within 30 minutes, 8 (24%) between 30 and 120 minutes, 10 (30%) from 2 to 4 hours and 3 cases (10%) occurred from 4 to 20 hours following vaccine administration. Only one case had specific reaction time which was an immediate reaction after multiple vaccine administration. | III | Poor |
| Milstien et al., 1987 | Hib vaccine | Case Series
US
Apr 1985 to May 1986 | Children 18 to 23 months of age at high risk of Hib and children 2 to 5 years of age who are not at high risk | Anaphylaxis
Two cases of anaphylactic-like reactions were reported. One case was in a 3-year-old boy who became pale and hypotensive and began to wheeze five minutes after vaccination. The other case was in a 4-year-old boy who became nauseated, pale, and bradycardia; circumoral cyanosis developed 20 minutes after vaccination. Both cases responded quickly to epinephrine and oxygen.
Syncope
Seven reports of syncope were identified, three that noted treatment with epinephrine and/or Benadryl. All but three episodes occurred within ten minutes of vaccination (others occurred at 30 minutes, 2 hours, and 24 hours). All episodes were in children 3 to 5 years of age.
Seizure
13 patients whose reactions met the case definitions for seizures were identified: four afebrile convulsions and nine febrile convulsions. Five patients with febrile convulsions were hospitalized. All reactions occurred more than 2 hours after vaccine administration, except one afebrile convulsion that occurred within 30 minutes. The mean time to onset of febrile convulsions after receipt of the vaccine was 24 hours (median: 12 hours). Two of the children had a prior history of febrile convulsions, and an additional three had a history of febrile convulsions in a sibling or a parent. | III | Poor |
| Pahud et al., 2013 | 2009 H1N1 monovalent influenza vaccine | Case Series
US
VAERS passive surveillance system
Oct 2009 to Jan 2010 | Children less than 18 years of age | Anaphylaxis
3928 reports and 214 (5.4%) were classified as having serious, nonfatal condition. 109 cases were referred for further review of which 99 cases had complete clinical information. Of the 99 cases, they found fifteen presumed allergic reactions. The reported diagnoses included anaphylaxis (n=5), hypersensitivity reaction (n=3), angioedema (n=3), hives (n=3) and allergic reaction (n=1). True anaphylaxis caused by a vaccine was present in 4 cases, urticaria or other skin manifestations of a true allergic reaction in 6 cases and allergic reaction to a vaccine with respiratory symptoms in 2 cases. Two cases were considered anxiety reactions and 1 was considered likely attributable to an independent viral infection. All anaphylaxis cases or true allergic reactions (n = 12) occurred within 3 hours of vaccination (median, 30 minutes; range, 5 minutes-3 hours). | III | Poor |
| Patja et al., 2000 | MMR vaccine | Case Series
Finland
Passive surveillance system
1982 to 1996 | Adults and children of all ages | Anaphylaxis
30 suspected cases of anaphylaxis were identified, all of which appeared within 20 minutes of vaccination, except one case who developed symptoms several hours after vaccination.
Seizure
52 vaccinees reported febrile seizures 12 hours to 15 days after vaccination. Apart from 3 children who were 3 to 6 years of age, all reports were in children less than 3 years of age. Undefined seizures were observed in four children 2 to 12 days post-vaccination. | III | Poor |
| Schumacher et al., 2010 | Any vaccine | Case Series
Switzerland
Passive surveillance system
1991 to 2001 | Adults and children of all ages | Anaphylaxis
There were 18 cases of non-fatal anaphylaxis reaction reported. Two occurred within minutes after immunization, five within 6 hours, four within 6-24 hours, and seven after an unknown time interval. Of the 7 (3.6%) serious AEFI that were assessed as very likely or certainly related to immunization, there were 5 cases of anaphylaxis reaction with time to symptom onset ranging from 1 minute to 1 hour post-vaccine administration. One case happened several minutes after DTP-based combination vaccine, one case after 1 minute after DTP-based combination vaccine, one case after 5 minutes of DTP-based combination, one case after 1h of DTP-based combination vaccine and one case following MMR vaccination without information on timing of onset. | III | Poor |
| Su et al., 2019 | Any vaccine | Case Series
US
VAERS passive surveillance system
Jan 1990 to Dec 2016 | Adults and children of all ages | Anaphylaxis
828 reports that either met the Brighton case definition or included a diagnosis of anaphylaxis by a physician described symptoms within 24 hours of receiving the vaccine. Of reports with time to onset of symptoms available, 77% described symptoms less than 2 hours after vaccination with a median time to onset after vaccination of 20 minutes (range; <1 minute to 24 hours). Moreover, 402 (49%) of the reports had time to onset of symptoms < 30 minutes after vaccination. Finally, the authors identified 8 reports of death. Of 7 reports with time to onset symptoms available, 3 (43%) cases happened within 5 minutes and 4 (57%) cases within 15 minutes following vaccination. The other report of death happened at 20 min, 258 min or on the same day of vaccine administration. | III | Poor |
| Subelj et al., 2016 | HPV4 vaccine | Case Series
Slovenia
Sept 2009 to Aug 2013 | Girls 11 to 14 years of age who received HPV4 vaccine as part of a school-based vaccination program | Syncope
8 syncope events, accounting for 3.8% of all AEFIs reported, were identified. Incidence was 13.4 per 100,000 HPV4 vaccine doses distributed. Two syncope episodes were deemed serious. One event had an immediate onset, and another occurred 5 minutes following vaccine administration.
Seizure
2 seizure events, accounting for 0.9% of all AEFIs reported, were identified. Incidence was 3.4 per 100,000 HPV4 vaccine doses distributed. One seizure was deemed serious and occurred immediately following vaccine administration. | III | Poor |
| Sutherland et al., 2008 | Any vaccine | Case Series
US
VAERS passive surveillance system
Jan 2002 to Dec 2004 and Jan 2005 to July 2007 | Adults and children 5 years of age or older | Syncope
26 (5.6%) of the 463 post-vaccination syncope reports during 2005-2007 were coded as serious, which was not substantially different from the 20 (9.9%) serious reports during 2002-2004. Among the 23 patients for whom times of vaccination and syncope onset were indicated, 12 (52.2%) occurred within 5 minutes of vaccination, and 16 (69.6%) occurred within 15 minutes. | III | Poor |
| Woo et al., 2005 | Any vaccine | Case Series
US
VAERS passive surveillance system
2000 to 2005 | Adults and children of all ages who experienced syncope/presyncope and accidental injury on the day of vaccination | Syncope
107 reports of syncope/presyncope and unintentional injury on the day of vaccination were identified. 100 of the reported injuries occurred within 20 minutes of vaccination. There were three reports of serious head injury, including one that was deemed fatal due to vasovagal syncope.
Following the third dose of hepatitis B vaccine, a 15-year-old boy with no antecedent of event or medical problems, experienced vasovagal syncope several minutes after vaccination. He fell backward and hit his head, momentarily lost consciousness, then complained of pain in the chest and arms. Then, he reportedly had convulsions and went into cardiopulmonary arrest.
A 21- year-old man experienced intracerebral bleeding after falling backwards onto the floor 3 minutes after hepatitis B vaccine, tetanus toxoid, and diphtheria vaccine. He reportedly recovered without sequelae. An 18-year-old woman was in a fatal motor vehicle collision after she "passed out while driving her car" approximately 7 hours after meningococcal polysaccharide vaccine; the 7-hour interval between vaccination and the collision makes vaccine-related vasovagal syncope unlikely. | III | Poor |
| Zafack et al., 2019 | Any vaccine | Case Series
Passive surveillance system database
Jan 1998 to Dec 2016 | 5,600 children and adults of all ages receiving additional doses of vaccine(s) previously temporally associated with an AEFI | Anaphylaxis
Of the 5,600 individuals identified who had experienced an AEFI, 18 patients had an anaphylaxis reaction, of which 14 (77.8%) had information regarding delay of onset following immunization. Among the 18 patients with reported anaphylaxis, 3 met the Brighton Collaboration level 1 of diagnostic certainty, 8 met level 2, 6 met level 3 and one did not have a description of signs and symptoms. Among the 14 patients with timing of symptom onset, 4 (28.6%) occurred by 5 minutes, 9 (64.3%) by 10 minutes and 10 (71.4%) patients had symptom onset within 30 minutes of vaccine administration. | III | Poor |
| **Case reports** |
| Poddighe et al., 2014 | HPV2 vaccine | Physician case report
Funding:
N/A | A 14-year old girl | Syncope
A 14-year-old girl reported an AE after the second dose of bivalent HPV vaccine. The patient experienced sudden onset of general malaise and other symptoms after the vaccine administration. She fainted around 60 minutes after intramuscular injection. The patient did not have any previous physical and/or psychiatric diseases or complaints. Upon further evaluation in the following days, the patient was diagnosed with a neuropsychiatric syndrome. | III | Poor |
| Stone et al., 2019 | MMR, Varicella, and DTaP/ IPV vaccine | Physician case report
Funding:
N/A | A 5-year-old male with a history of alpha-gal allergy | Anaphylaxis
Five minutes after receiving the vaccines, 5 year-old developed shortness of breath, wheezing, disseminated urticaria, and angioedema of the face and oropharynx, prompting an emergency room visit where he received epinephrine, diphenhydramine, prednisone and famotidine with relief of symptoms within ten minutes. He had no history of egg, latex, dairy, or gelatin allergies and had uneventfully received all prior childhood vaccinations. | III | Poor |
| Stone et al., 2017 | Live-attenuated herpes zoster vaccine | Physician case report
Funding:
N/A | A 71-year-old woman with documented history of allergy to red meat | Anaphylaxis
A 71-year-old women with documented allergies to red meat required emergency department treatment and epinephrine administration upon receipt of live attenuated herpes zoster virus vaccine containing the Oka VZV strain. The vaccine was administered in a local pharmacy and within minutes she had a sensation of mental clouding progressing to lightheadedness, wheezing, and throat tightness.
She self-administered 50 mg diphenhydramine five minutes after symptom onset. Thirty minutes after her vaccination, she sought emergency care at which point she was documented to be dyspneic, flushed, with facial, oral, and uvular angioedema and bilateral conjunctival infections with stable vital signs and blood pressure, without documented wheezing on pulmonary examination. Her symptoms resolved within 20-30 minutes. She was later diagnosed with alpha-gal and the event was attributed to the presence of mammalian products within the vaccine. | III | Poor |
| Turktas et al., 1999 | Whole-cell DTP vaccine | Physician case report
Funding:
N/A | A 6-month-old infant | Anaphylaxis
A 6-month-old infant experienced anaphylaxis following the third dose of the whole-cell DTP vaccine. The infant experienced drowsiness, followed by loss of consciousness, an urticarial rash throughout the body and swelling of the eyes. He was brought into a community hospital 20 minutes after vaccine administration and was then referred to the Department of Pediatrics within 2 hours of vaccination. During follow-up, the patient had mild monthly wheezing and cough episodes in winter, and perennial rhinitis throughout the year. | III | Poor |
| Worm et al., 2000 | Tick-borne encephalitis vaccine | Case report
Funding:
N/A | A 29-year-old woman | Anaphylaxis
Patient developed a generalized urticaria, dyspnea and hypotension a few minutes after the third immunization. She immediately received antihistamines and steroids intravenously and the symptoms resolved completely within 1 hour. | III | Poor |
| **Abbreviations:** AE: adverse events; AEFI: adverse event following immunization; DTP: Diphtheria, tetanus, pertussis; HPV: human papillomavirus; HPV4 vaccine: 4-valent human papillomavirus vaccine; MedDRA: Medical Dictionary for Regulatory Activities; MMR: Measles-mumps-rubella; SAEFVIC: Surveillance of Adverse Events following Vaccination in the Community; US: United States; VAERS: Vaccine Adverse Events Reporting System |
Appendix A: Rapid review PRISMA Flow Diagram
--------------------------------------------
**PRISMA flow diagram**
PRISMA flow diagram: Text description
The PRISMA flow diagram describes the process by which articles were selected for the literature review. The process is broken down into four stages: Identification, Screening, Eligibility and Included.
### Stage 1: Identification
* 964 records were identified through the May 28, 2020 database search.
* 945 records remained after duplicates were removed.
### Stage 2: Screening
* 945 records were then screened.
* Of these 945 records, 548 records were excluded.
### Stage 3: Eligibility
* 397 full-text articles were assessed for eligibility.
* Of these 397 full-text articles, 375 were excluded. The exclusion breakdown is as follows: No specific timing of AEFI: 170; Not outcome of interest: 18
* Editorial, opinion or abstract: 40; Not in English or French: 73; Full text not available: 32; Other: 42
### Stage 4: Included
* 22 articles were included in the final synthesis: 8 case series and 5 case reports.
**Figure 2. Risk of Bias Domains assessed (Modified IHE tool). Graphics were generated by robvis online risk-of-bias assessment visualization tool [Footnote 36](#fn36).**
Risk of Bias Domains assessed (Modified IHE tool): Text description
Figure 2 Long Description (EN)
| Study | Domain 1 | Domain 2 | Domain 3 | Domain 4 | Domain 5 | Domain 6 | Domain 7 | Domain 8 | Domain 9 | Domain 10 | Domain 11 | Domain 12 | Domain 13 | Domain 14 | Domain 15 | Overall |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Baxter et al., 2018 | Low | High | High | High | Low | High | Unclear | Unclear | Low | High | High | Low | No information | No information | Low | High |
| Bohlke et al, 2003 | Low | Unclear | Low | Low | Low | Low | Low | Low | Low | Low | Low | Low | No information | No information | Low | Unclear |
| Braun et al., 1997 | Low | High | High | High | Low | Unclear | Low | Unclear | Low | High | Unclear | High | Low | High | High | High |
| Brotherton et al., 2008 | Low | High | High | High | Low | Low | Low | No information | Low | High | Low | Low | No information | No information | Low | High |
| Cheng et al., 2015 | Low | High | High | High | Low | Low | Low | Low | Low | High | Unclear | Low | No information | Unclear | Low | High |
| Crawford et al., 2011 | Low | High | High | High | Low | Low | Low | Unclear | Low | Unclear | Unclear | Unclear | No information | No information | Low | High |
| Johann-Liang et al., 2011 | Unclear | High | High | High | Unclear | Low | Unclear | Low | Low | High | Unclear | Low | No information | No information | Unclear | High |
| McNeil et al., 2016 | Low | Unclear | Low | Low | Low | Low | Low | Low | Low | Low | Low | Low | No information | Unclear | Low | Unclear |
| Millstein et al., 1987 | Low | High | High | High | Low | Unclear | Unclear | No information | Low | High | High | Unclear | No information | No information | Low | High |
| Pahud et al., 2013 | Low | Unclear | High | High | Low | Unclear | Unclear | Unclear | Low | High | Low | Low | No information | No information | Low | High |
| Patja et al., 2000 | Low | Unclear | High | High | Unclear | Unclear | Unclear | No information | Low | High | Low | Low | No information | No information | Unclear | High |
| Schumacher et al., 2010 | Low | Unclear | Low | High | Low | Unclear | Unclear | Unclear | Low | High | Unclear | Unclear | No information | No information | High | High |
| Su et al., 2019 | Low | High | High | High | Low | Low | Unclear | Unclear | Low | Unclear | Low | Unclear | No information | Unclear | Unclear | High |
| Subelj et al., 2016 | Low | High | High | High | Low | Unclear | Low | Low | Low | High | Unclear | Low | No information | No information | Unclear | High |
| Sutherland et al., 2008 | Low | Unclear | High | High | Low | Unclear | Unclear | Unclear | Low | High | Low | Unclear | No information | No information | Unclear | High |
| Woo et al., 2005 | Low | High | Unclear | Unclear | Low | Unclear | Unclear | Unclear | High | Unclear | High | High | No information | No information | High | High |
| Zafack et al., 2019 | Low | High | High | High | Low | Low | Unclear | Low | Low | Low | Unclear | Low | Low | Low | Low | High |
| Poddighe et al., 2014 | Low | High | High | No information | Low | Low | Low | Low | Low | Low | Low | High | No information | No information | High | High |
| Stone et al., 2019 | Low | Unclear | High | No information | Low | Low | Low | Low | Low | Low | Low | High | No information | No information | Low | High |
| Stone et al., 2017 | Low | High | High | No information | Low | Unclear | Low | No information | Low | Low | Low | High | No information | No information | Unclear | High |
| Turktas et al., 1999 | Low | High | High | No information | Low | Unclear | Low | No information | Low | Low | Low | High | No information | No information | High | High |
| Worm et al. 2000 | Low | High | Unclear | Unclear | Low | Unclear | Low | No information | Low | Low | Low | High | No information | No information | High | High |
List of abbreviations
---------------------
| Abbreviation | Term |
| --- | --- |
| AE | Adverse events |
| AEFI | Adverse event following immunization |
| ATAGI | Australian Technical Advisory Group on Immunisation |
| CAEFISS | Canadian Adverse Event Following Immunization Surveillance System |
| DTP | Diphtheria, tetanus, pertussis |
| FDA | United States Food and Drug Administration |
| IHE | Institute of Health Economics |
| HPV | Human papillomavirus |
| HPV4 vaccine | 4-valent human papillomavirus vaccine |
| MedDRA | Medical Dictionary for Regulatory Activities |
| MMR | Measles-mumps-rubella |
| NACI | National Advisory Committee on Immunization |
| PHAC | Public Health Agency of Canada |
| SAEFVIC | Surveillance of Adverse Events following Vaccination in the Community |
| US | United States |
| VAERS | Vaccine Adverse Events Reporting System |
Acknowledgments
---------------
**This statement was prepared by:** R Stirling, P Doyon-Plourde, N Forbes, K Young, and R Harrison, on behalf of the NACI Influenza Working Group and was approved by NACI.
**NACI gratefully acknowledges the contribution of:** G Crichlow, H Anyoti, A House, K Johnson, M Laplante, A Sinilaite, M Tunis, and E Westhaver
### NACI Influenza Working Group
**Members:** R Harrison (Chair), N Dayneka, I Gemmill, K Klein, D Kumar, J Langley, J McElhaney, A McGeer, D Moore, S Smith, and B Warshawsky
**Liaison representatives:** L Grohskopf (Centers for Disease Control and Prevention [CDC], United States)
**Ex-officio representatives:** L Whitmore (Centre for Immunization and Respiratory Infectious Diseases [CIRID], PHAC), A Gartley (First Nations and Inuit Health Branch [FNIHB], Indigenous Services Canada [ISC]), and J Xiong (Biologic and Radiopharmaceutical Drugs Directorate [BRDD], Health Canada [HC]).
### NACI
**Members:** C Quach (Chair), S Deeks (Vice-Chair), J Bettinger, N Dayneka, P De Wals, E Dubé, V Dubey, S Gantt, R Harrison, K Hildebrand, K Klein, J Papenburg, B Sander, S Smith and S Wilson.
**Liaison representatives:** LM Bucci (Canadian Public Health Association), E Castillo (Society of Obstetricians and Gynaecologists of Canada), A Cohn (CDC, United States), L Dupuis (Canadian Nurses Association), J Emili (College of Family Physicians of Canada), D Fell (Canadian Association for Immunization Research Evaluation), M Lavoie (Council of Chief Medical Officers of Health), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), and A Pham-Huy (Association of Medical Microbiology and Infectious Disease Canada).
**Ex-officio representatives:** D Danoff (Marketed Health Products Directorate, HC), E Henry (CIRID, PHAC), M Lacroix (Public Health Ethics Consultative Group, PHAC), J Pennock (CIRID, PHAC), R Pless (BRDD, HC), G Poliquin (National Microbiology Laboratory, PHAC), V Beswick-Escanlar (National Defense and the Canadian Armed Forces), and T Wong (FNIHB, ISC).
References
----------
### References
Reference a
Vaccine recipients should be kept under observation for at least 15 minutes after immunization; 30 minutes is a safer interval when there is a specific concern about possible vaccine allergy.
[Return to Reference a referrer](#fna-rf)
Reference b
Appropriate public health and infection prevention and control measures are to be determined by the responsible public health authority in the jurisdiction of the vaccination clinic.
[Return to Reference b referrer](#fnb-rf)
Reference c
Adapted from the Australian Technical Advisory Group on Immunisation (ATAGI), "Statement on the duration of observation after vaccination in the context of minimizing risk of exposure to COVID-19 at health care facilities
[Return to Reference c referrer](#fnc-rf)
Reference d
Refer to the [NACI Statement on Mammalian cell-culture based influenza vaccines](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/mammalian-cell-culture-based-influenza-vaccines.html)
[Return to Reference d referrer](#fnd-rf)
### Footnotes
Footnote 1
WHO. Coronavirus disease 2019 (COVID-19) Situation Report - 51. [online] Available at: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200311-sitrep-51-covid-19.pdf?sfvrsn=1ba62e57\_10.
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
PHAC. Interim guidance on continuity of immunization programs during the COVID-19 pandemic. Updated May 13, 2020. [online] Available at: /content/canadasite/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/interim-guidance-immunization-programs-during-covid-19-pandemic.html
[Return to footnote 2 referrer](#fn2-rf)
Footnote 3
PHAC. Guidance for influenza vaccine delivery in the presence of COVID-19. [online] Available at: /content/canadasite/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-influenza-vaccine-delivery-covid-19.html
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
PHAC. Canadian Immunization Guide: Part 2 - Vaccine Safety. [online] Available at: /content/canadasite/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html
[Return to footnote 4 referrer](#fn4-rf)
Footnote 5
US CDC. 2017. General Best Practice Guidelines for Immunization: Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP). [online] Available at: https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/adverse-reactions.html
[Return to footnote 5 referrer](#fn5-rf)
Footnote 6
The Vaccine Administration Task Force. 2001. United Kingdom Guidance on Best Practice in Vaccine Administration [online] Available at: http://www.wales.nhs.uk/sitesplus/documents/861/UK%20best%20practice%20guidance%20vacc%20admin%202001.pdf
[Return to footnote 6 referrer](#fn6-rf)
Footnote 7
New Zealand Ministry of Health. 2018. Immunisation Handbook 2017 (2nd edn). Wellington: Ministry of Health. [online] Available at: https://www.health.govt.nz/system/files/documents/publications/immunisation-handbook-2017-2nd-edition-mar18-v9\_1.html
[Return to footnote 7 referrer](#fn7-rf)
Footnote 8
Australian Government Department of Health. 2019. Australian Immunisation Handbook. [online] Available at: https://immunisationhandbook.health.gov.au/vaccination-procedures/after-vaccination
[Return to footnote 8 referrer](#fn8-rf)
Footnote 9
Australian Technical Advisory Group on Immunisation (ATAGI). 2020. ATAGI Clinical Statement on Vaccination Observation Time. [online] Available at: https://www.health.gov.au/resources/publications/atagi-clinical-statement-on-vaccination-observation-time
[Return to footnote 9 referrer](#fn9-rf)
Footnote 10
Guo B, Moga C, Harstall C, Schopflocher D. A principal component analysis is conducted for a case series quality appraisal checklist. Journal of clinical epidemiology. 2016 Jan 1;69:199-207.footnote1text
[Return to footnote 10 referrer](#fn10-rf)
Footnote 11
Rüggeberg JU, Gold MS, Bayas JM, Blum MD, Bonhoeffer J, Friedlander S, de Souza Brito G, Heininger U, Imoukhuede B, Khamesipour A, Erlewyn-Lajeunesse M. Anaphylaxis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2007 Aug 1;25(31):5675-84.
[Return to footnote 11 referrer](#fn11-rf)
Footnote 12
PHAC. Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) [online] Available at: /content/canadasite/en/public-health/services/immunization/canadian-adverse-events-following-immunization-surveillance-system-caefiss.html
[Return to footnote 12 referrer](#fn12-rf)
Footnote 13
Baxter CM, Clothier HJ, Perrett KP. Potential immediate hypersensitivity reactions following immunization in preschool aged children in Victoria, Australia. Human Vaccines & Immunotherapeutics. 2018 Aug 3;14(8):2088-92.
[Return to footnote 13 referrer](#fn13-rf)
Footnote 14
Bohlke K, Davis RL, Marcy SM, Braun MM, DeStefano F, Black SB, Mullooly JP, Thompson RS. Risk of anaphylaxis after vaccination of children and adolescents. Pediatrics. 2003 Oct 1;112(4):815-20.
[Return to footnote 14 referrer](#fn14-rf)
Footnote 15
Brotherton JM, Gold MS, Kemp AS, McIntyre PB, Burgess MA, Campbell-Lloyd S. Anaphylaxis following quadrivalent human papillomavirus vaccination. Cmaj. 2008 Sep 9;179(6):525-33.
[Return to footnote 15 referrer](#fn15-rf)
Footnote 16
Cheng DR, Perrett KP, Choo S, Danchin M, Buttery JP, Crawford NW. Pediatric anaphylactic adverse events following immunization in Victoria, Australia from 2007 to 2013. Vaccine. 2015 Mar 24;33(13):1602-7.
[Return to footnote 16 referrer](#fn16-rf)
Footnote 17
Johann-Liang R, Josephs S, Dreskin SC. Analysis of anaphylaxis cases after vaccination: 10-year review from the National Vaccine Injury Compensation Program. Annals of Allergy, Asthma & Immunology. 2011 May 1;106(5):440-3.
[Return to footnote 17 referrer](#fn17-rf)
Footnote 18
McNeil MM, Weintraub ES, Duffy J, Sukumaran L, Jacobsen SJ, Klein NP, Hambidge SJ, Lee GM, Jackson LA, Irving SA, King JP. Risk of anaphylaxis after vaccination in children and adults. Journal of Allergy and Clinical Immunology. 2016 Mar 1;137(3):868-78.
[Return to footnote 18 referrer](#fn18-rf)
Footnote 19
Milstien JB, Gross TP, Kuritsky JN. Adverse reactions reported following receipt of Haemophilus influenzae type b vaccine: an analysis after 1 year of marketing. Pediatrics. 1987 Aug 1;80(2):270-4.
[Return to footnote 19 referrer](#fn19-rf)
Footnote 20
Pahud BA, Williams SE, Dekker CL, Halsey N, LaRussa P, Baxter RP, Klein NP, Marchant CD, Sparks RC, Jakob K, Aukes L. Clinical assessment of serious adverse events in children receiving 2009 H1N1 vaccination. The Pediatric infectious disease journal. 2013 Feb 1;32(2):163-8.
[Return to footnote 20 referrer](#fn20-rf)
Footnote 21
Patja A, Davidkin I, Kurki T, Kallio MJ, Valle M, Peltola H. Serious adverse events after measles-mumps-rubella vaccination during a fourteen-year prospective follow-up. The Pediatric infectious disease journal. 2000 Dec 1;19(12):1127-34.
[Return to footnote 21 referrer](#fn21-rf)
Footnote 22
Schumacher Z, Bourquin C, Heininger U. Surveillance for adverse events following immunization (AEFI) in Switzerland-1991-2001. Vaccine. 2010 May 28;28(24):4059-64.
[Return to footnote 22 referrer](#fn22-rf)
Footnote 23
Su JR, Moro PL, Ng CS, Lewis PW, Said MA, Cano MV. Anaphylaxis after vaccination reported to the Vaccine Adverse Event Reporting System, 1990-2016. Journal of Allergy and Clinical Immunology. 2019 Apr 1;143(4):1465-73.
[Return to footnote 23 referrer](#fn23-rf)
Footnote 24
Zafack JG, Toth E, Landry M, Drolet JP, Top KA, De Serres G. Rate of Recurrence of Adverse Events Following Immunization: Results of 19 Years of Surveillance in Quebec, Canada. The Pediatric infectious disease journal. 2019 Apr 1;38(4):377-83.
[Return to footnote 24 referrer](#fn24-rf)
Footnote 25
Stone CA, Commins SP, Choudhary S, Vethody C, Heavrin JL, Wingerter J, Hemler JA, Babe K, Phillips EJ, Norton AE. Anaphylaxis after vaccination in a pediatric patient: further implicating alpha-gal allergy. The Journal of Allergy and Clinical Immunology: In Practice. 2019 Jan 1;7(1):322-4.
[Return to footnote 25 referrer](#fn25-rf)
Footnote 26
Stone CA, Hemler JA, Commins SP, Schuyler AJ, Phillips EJ, Peebles RS, Fahrenholz JM. Anaphylaxis after zoster vaccine: Implicating alpha-gal allergy as a possible mechanism. Journal of Allergy and Clinical Immunology. 2017 May 1;139(5):1710-3./p>
[Return to footnote 26 referrer](#fn26-rf)
Footnote 27
Türktas I, Ergenekon E. Anaphylaxis following diphtheria-tetanus-pertussis vaccination-a reminder. European journal of pediatrics. 1999 Apr 1;158(5):434.
[Return to footnote 27 referrer](#fn27-rf)
Footnote 28
Worm M, Sterry W, Zuberbier T. Gelatin-induced urticaria and anaphylaxis after tick-borne encephalitis vaccine. Acta dermato-venereologica. 2000;80(3).
[Return to footnote 28 referrer](#fn28-rf)
Footnote 29
Braun MM, Patriarca PA, Ellenberg SS. Syncope after immunization. Archives of pediatrics & adolescent medicine. 1997 Mar 1;151(3):255-9.
[Return to footnote 29 referrer](#fn29-rf)
Footnote 30
Crawford NW, Clothier HJ, Elia S, Lazzaro T, Royle J, Buttery JP. Syncope and seizures following human papillomavirus vaccination: a retrospective case series. Medical journal of Australia. 2011 Jan;194(1):16-8.
[Return to footnote 30 referrer](#fn30-rf)
Footnote 31
Šubelj M, Učakar V, Kraigher A, Klavs I. Adverse events following school-based vaccination of girls with quadrivalent human papillomavirus vaccine in Slovenia, 2009 to 2013. Eurosurveillance. 2016 Apr 7;21(14):30187.
[Return to footnote 31 referrer](#fn31-rf)
Footnote 32
Sutherland A, Izurieta H, Ball R, Braun MM, Miller ER, KR Broder KR, Slade BA, Iskander JK, Kroger AT, Markowitz LE, Huang WT. Syncope after vaccination--United States, January 2005-July 2007. MMWR. Morbidity and mortality weekly report. 2008 May 2;57(17):457.
[Return to footnote 32 referrer](#fn32-rf)
Footnote 33
Woo EJ, Ball R, Braun MM. Fatal syncope-related fall after immunization. Archives of pediatrics & adolescent medicine. 2005 Nov 1;159(11):1083.
[Return to footnote 33 referrer](#fn33-rf)
Footnote 34
Poddighe D, Castelli L, Marseglia GL, Bruni P. A sudden onset of a pseudo-neurological syndrome after HPV-16/18 AS04-adjuvated vaccine: might it be an autoimmune/inflammatory syndrome induced by adjuvants (ASIA) presenting as a somatoform disorder?. Immunologic research. 2014 Dec 1;60(2-3):236-46.
[Return to footnote 34 referrer](#fn34-rf)
Footnote 35
Dreskin SC, Halsey NA, Kelso JM, Wood RA, Hummell DS, Edwards KM. International Consensus (ICON): Allergic reactions to vaccines. World Allergy Organ J. 2016; 9: 32.
[Return to footnote 35 referrer](#fn35-rf)
Footnote 36
McGuinness, LA, Higgins, JPT. Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments. Res Syn Meth. 2020; 1- 7. https://doi.org/10.1002/jrsm.1411
[Return to footnote 36 referrer](#fn36-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2020-10-14
| None | None |
71abd4ae37ed04a73c8e738bb3188648c59eb450 | cma | Blood products, human immunoglobulin and timing of immunization: Canadian Immunization Guide | Blood products, human immunoglobulin and timing of immunization: Canadian Immunization Guide
For health professionals
Notice
- This CIG chapter has not been updated to contain any information regarding COVID-19 vaccines, refer to the .
Last partial content update (see ): January 2020
This chapter was updated to align with changes made to -vaccine.html) Chapter in Part 4 based on NACI's .
Last complete chapter revision: December 2013
On this page
General considerations
Blood products of human origin contain significant amounts of antibodies to infectious agents that are prevalent in the general population, such as measles virus and *varicella zoster virus- (VZV); these antibodies are present either because of natural disease or following vaccination. Therefore, administration of Ig preparations and certain blood products can interfere with the immune response to parenteral live virus vaccines if given concomitantly with or shortly before or after the vaccine. The duration of the interference with the immune response to the vaccine is related to the amount of antibody in the Ig preparation or blood product. Exceptions are respiratory syncytial virus monoclonal antibody (RSVAb) and transfusion of washed red blood cells (which is infrequently used). These products do not interfere with live vaccines because RSVAb contains only antibody to respiratory syncytial virus and washed red blood cells contain a negligible amount of antibody.
There is minimal or no interaction between blood products or Ig preparations, and:
- inactivated vaccines
- live oral vaccines (rotavirus, oral typhoid vaccines)
- live intranasal vaccine (live attenuated influenza vaccine)
- Bacille Calmette-Guerin (BCG) vaccine
- yellow fever vaccine
These vaccines may be given concomitantly with, or at any time before or after, an Ig preparation or blood product has been administered. If a parenteral vaccine and intramuscular Ig are given concomitantly, administer the vaccine and Ig preparation at different anatomic injection sites, using separate needles and syringes.
Measles-mumps-rubella (MMR), measles-mumps-rubella-varicella (MMRV) and monovalent varicella vaccines
Guidelines for the interval between administration of Ig preparations or blood products and MMR, MMRV or monovalent varicella vaccines have been developed because of the potential for reduced effectiveness of the vaccine if Ig is administered with, or shortly before or after the vaccine; it should be noted that there are no additional safety concerns if Ig is inadvertently administered with, or shortly before or after the vaccine. For an optimum immune response to MMR, MMRV or monovalent varicella vaccine, the vaccine should be administered at least 14 days prior to administration of an Ig preparation or blood product, or the vaccine administration delayed until the antibodies in the Ig preparation or blood product have degraded (refer to ). If the interval between the administration of any of these vaccines and subsequent administration of an Ig preparation or blood product is less than 14 days, or if these vaccines are administered before the antibody has degraded, repeat the vaccine dose after the recommended interval. The recommended interval between administration of Ig preparation or blood product and subsequent vaccination varies, depending on the Ig preparation or blood product (refer to ). The recommended intervals between live parenteral vaccines should also be respected when repeating vaccine doses.
Individuals with chronic conditions requiring continuous subcutaneous Ig therapy should not be immunized with MMR, MMRV or monovalent varicella vaccine (refer to footnote 1 in ). Individuals who have undergone cardiac surgery with cardiopulmonary bypass would have received packed red blood cells and platelets and may have received frozen plasma. They may have received subsequent blood products in the ICU after their surgery. They should delay receiving MMR, MMRV or monovalent varicella vaccine until 7 months after the date they were discharged from the ICU.
Ig can also be administered subcutaneously (SCIg). SCIg is primarily indicated as life-long replacement therapy in patients with primary antibody deficiencies for whom immunization with live vaccines is contraindicated. However, potential alternative indications for SCIg therapy may result in temporary use and discontinuation of therapy. Because pharmacokinetic properties of Ig G following SCIg administration have been shown to resemble those following IVIg administration, the recommended interval between the administration of SCIg and MMR, MMRV or monovalent varicella vaccines should be considered equivalent to the recommended interval after the corresponding IVIg monthly dosing.
washed red blood cells are infrequently used
# Rh immunoglobulin (RhIg)
A risk-benefit assessment is needed for post-partum women who have received RhIg and require MMR or monovalent varicella vaccine. The risk of lowered vaccine efficacy due to potential interference from the RhIg needs to be weighed against the need for protection against the vaccine preventable disease. To optimize response to vaccine, rubella-, measles- or varicella-susceptible women who receive RhIg in the peri-partum period should generally wait 3 months before being vaccinated with MMR or varicella vaccine.
However, if there is a risk of: exposure to rubella, measles, or varicella; recurrent pregnancy in the 3 months post-partum period; or a risk that vaccines may not be received later, either MMR or monovalent varicella vaccine or both may be given prior to discharge. In this context, serologic testing for antibodies to the vaccine antigens should be done 3 months after vaccination and non-immune women should be revaccinated. In the event that a post-partum woman receives either MMR or varicella vaccine or both vaccines in the 14 days prior to receiving RhIg, serologic testing for MMR or varicella should be done 3 months later and the woman revaccinated if non-immune.
Herpes zoster vaccine
Although no safety or efficacy data are available for the administration of live herpes zoster (LZV) vaccine to individuals who have recently received Ig preparations or other blood products, LZV is known to be immunogenic in adults with pre-existing antibody to VZV. In theory, administration of Ig should not interfere with LZV response; therefore, some experts do not consider recent administration of Ig or blood products as a reason to delay the administration of live herpes zoster vaccine.
Yellow fever vaccine
The background antibody level for yellow fever is low in North America; therefore, an Ig or blood product produced from blood donated in Canada or the United States is unlikely to interfere with vaccination with yellow fever vaccine. |
Blood products, human immunoglobulin and timing of immunization: Canadian Immunization Guide
=============================================================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-12-immunization-records.html)
Notice
------
* This CIG chapter has not been updated to contain any information regarding COVID-19 vaccines, refer to the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html).
**Last partial content update** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): January 2020
This chapter was updated to align with changes made to [Herpes Zoster (Shingles) Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-8-herpes-zoster-(shingles)-vaccine.html) Chapter in Part 4 based on NACI's [Updated Recommendations on the Use of Herpes Zoster Vaccines](/en/services/health/publications/healthy-living/updated-recommendations-use-herpes-zoster-vaccines.html).
**Last complete chapter revision:** December 2013
On this page
------------
* [General considerations](#p1c10a1)
* [MMR, MMRV, and monovalent varicella vaccines](#p1c10a2)
+ [Table 1: Guidelines for the interval between administration of immunoglobulin (Ig) preparations or blood products and measles-mumps-rubella (MMR), measles-mumps-rubella-varicella (MMRV) or monovalent varicella vaccine to maximize immunization effectiveness](#p1c10t1)
* [Herpes zoster vaccine](#p1c10a3)
* [Yellow fever vaccine](#p1c10a4)
* [Selected references](#p1c10a5)
General considerations
----------------------
Blood products of human origin contain significant amounts of antibodies to infectious agents that are prevalent in the general population, such as measles virus and *varicella zoster virus* (VZV); these antibodies are present either because of natural disease or following vaccination. Therefore, administration of Ig preparations and certain blood products can interfere with the immune response to parenteral live virus vaccines if given concomitantly with or shortly before or after the vaccine. The duration of the interference with the immune response to the vaccine is related to the amount of antibody in the Ig preparation or blood product. Exceptions are respiratory syncytial virus monoclonal antibody (RSVAb) and transfusion of washed red blood cells (which is infrequently used). These products do not interfere with live vaccines because RSVAb contains only antibody to respiratory syncytial virus and washed red blood cells contain a negligible amount of antibody.
There is minimal or no interaction between blood products or Ig preparations, and:
* inactivated vaccines
* live oral vaccines (rotavirus, oral typhoid vaccines)
* live intranasal vaccine (live attenuated influenza vaccine)
* Bacille Calmette-Guerin (BCG) vaccine
* yellow fever vaccine
These vaccines may be given concomitantly with, or at any time before or after, an Ig preparation or blood product has been administered. If a parenteral vaccine and intramuscular Ig are given concomitantly, administer the vaccine and Ig preparation at different anatomic injection sites, using separate needles and syringes.
Refer to [vaccine specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information
Measles-mumps-rubella (MMR), measles-mumps-rubella-varicella (MMRV) and monovalent varicella vaccines
-----------------------------------------------------------------------------------------------------
Guidelines for the interval between administration of Ig preparations or blood products and MMR, MMRV or monovalent varicella vaccines have been developed because of the potential for reduced effectiveness of the vaccine if Ig is administered with, or shortly before or after the vaccine; it should be noted that there are no additional safety concerns if Ig is inadvertently administered with, or shortly before or after the vaccine. For an optimum immune response to MMR, MMRV or monovalent varicella vaccine, the vaccine should be administered at least 14 days prior to administration of an Ig preparation or blood product, or the vaccine administration delayed until the antibodies in the Ig preparation or blood product have degraded (refer to [Table 1](#p1c10t1)). If the interval between the administration of any of these vaccines and subsequent administration of an Ig preparation or blood product is less than 14 days, or if these vaccines are administered before the antibody has degraded, repeat the vaccine dose after the recommended interval. The recommended interval between administration of Ig preparation or blood product and subsequent vaccination varies, depending on the Ig preparation or blood product (refer to [Table 1](#p1c10t1)). The recommended intervals between live parenteral vaccines should also be respected when repeating vaccine doses.
Individuals with chronic conditions requiring continuous subcutaneous Ig therapy should not be immunized with MMR, MMRV or monovalent varicella vaccine (refer to footnote 1 in [Table 1](#p1c10t1)). Individuals who have undergone cardiac surgery with cardiopulmonary bypass would have received packed red blood cells and platelets and may have received frozen plasma. They may have received subsequent blood products in the ICU after their surgery. They should delay receiving MMR, MMRV or monovalent varicella vaccine until 7 months after the date they were discharged from the ICU.
Table 1: Guidelines for the interval between administration of immunoglobulin (Ig) preparations or blood products and measles-mumps-rubella (MMR), measles-mumps-rubella-varicella (MMRV) or monovalent varicella vaccine to maximize immunization effectiveness
| Immunoglobulin or blood product | Dose, route | Interval between receipt of Ig or blood product and subsequent administration of MMR, MMRV or monovalent varicella vaccine (months) |
| --- | --- | --- |
| Standard immunoglobulin (human)[Table 1 - Footnote 1](#p1c10t1fn1) |
| --- |
| Immunoglobulin (Ig) | 0.02 - 0.06 mL/kg, IM | 3 |
| 0.25 mL/kg, IM | 5 |
| 0.50 mL/kg, IM | 6 |
| Intravenous immunoglobulin (IVIg) | 300 - 400 mg/kg, IV | 8 |
| 1,000 mg/kg, IV | 10 |
| 2,000 mg/kg, IV | 11 |
| Blood transfusion products |
| Plasma and platelet products | 10 mL/kg, IV | 7 |
| Whole blood | 10 mL/kg, IV | 6 |
| Packed red blood cells | 10 mL/kg, IV | 5 |
| Reconstituted red blood cells | 10 mL/kg, IV | 3 |
| Washed red blood cells[Table 1 - Footnote 2](#p1c10t1fn2) | 10 mL/kg, IV | 0 |
| Specific immunoglobulin (human) |
| Cytomegalovirus immunoglobulin (CMVIg) | 150 mg/kg, IV | 6 |
| Hepatitis B immunoglobulin (HBIg) | 0.06 mL/kg, IM | 3 |
| Rabies immunoglobulin (RabIg) | 20 IU/kg, IM | 4 |
| Rh immunoglobulin (RhIg) | 300 mcg, IM | 3[Table 1 - Footnote 3](#p1c10t1fn3) |
| Tetanus immunoglobulin (TIg) | 250 units, IM | 3 |
| Varicella immunoglobulin (VarIg) | 125 IU/10 kg, IM | 5 |
| Specific immunoglobulin (humanized monoclonal antibody) |
| Respiratory syncytial virus monoclonal antibody (palivizumab) (RSVAb) | 15 mg/kg/4 weeks, IM | 0 |
|
Table 1 - Footnote 1
Ig can also be administered subcutaneously (SCIg). SCIg is primarily indicated as life-long replacement therapy in patients with primary antibody deficiencies for whom immunization with live vaccines is contraindicated. However, potential alternative indications for SCIg therapy may result in temporary use and discontinuation of therapy. Because pharmacokinetic properties of Ig G following SCIg administration have been shown to resemble those following IVIg administration, the recommended interval between the administration of SCIg and MMR, MMRV or monovalent varicella vaccines should be considered equivalent to the recommended interval after the corresponding IVIg monthly dosing.
[Return to footnote 1 referrer](#p1c10t1fn1-rf)
Table 1 - Footnote 2
washed red blood cells are infrequently used
[Return to footnote 2 referrer](#p1c10t1fn2-rf)
Table 1 - Footnote 3
refer to *[Rh immunoglobulin](#rhim)* for additional information
[Return to footnote 3 referrer](#p1c10t1fn3-rf)
|
#### Rh immunoglobulin (RhIg)
A risk-benefit assessment is needed for post-partum women who have received RhIg and require MMR or monovalent varicella vaccine. The risk of lowered vaccine efficacy due to potential interference from the RhIg needs to be weighed against the need for protection against the vaccine preventable disease. To optimize response to vaccine, rubella-, measles- or varicella-susceptible women who receive RhIg in the peri-partum period should generally wait 3 months before being vaccinated with MMR or varicella vaccine.
However, if there is a risk of: exposure to rubella, measles, or varicella; recurrent pregnancy in the 3 months post-partum period; or a risk that vaccines may not be received later, either MMR or monovalent varicella vaccine or both may be given prior to discharge. In this context, serologic testing for antibodies to the vaccine antigens should be done 3 months after vaccination and non-immune women should be revaccinated. In the event that a post-partum woman receives either MMR or varicella vaccine or both vaccines in the 14 days prior to receiving RhIg, serologic testing for MMR or varicella should be done 3 months later and the woman revaccinated if non-immune.
Herpes zoster vaccine
---------------------
Although no safety or efficacy data are available for the administration of live herpes zoster (LZV) vaccine to individuals who have recently received Ig preparations or other blood products, LZV is known to be immunogenic in adults with pre-existing antibody to VZV. In theory, administration of Ig should not interfere with LZV response; therefore, some experts do not consider recent administration of Ig or blood products as a reason to delay the administration of live herpes zoster vaccine.
Yellow fever vaccine
--------------------
The background antibody level for yellow fever is low in North America; therefore, an Ig or blood product produced from blood donated in Canada or the United States is unlikely to interfere with vaccination with yellow fever vaccine.
Selected references
-------------------
* Centers for Disease Control and Prevention. *General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP)*. MMWR Morb Mortal Wkly Rep 2011;60(RR-02):1-61.
* Centers for Disease Control and Prevention. *Health Information for International Travel 2012. The Yellow Book*. Accessed August 2012 at: http://wwwnc.cdc.gov/travel/page/yellowbook-2012-home.htm
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-12-immunization-records.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-11-blood-products-human-immune-globulin-timing-immunization.html&n=Blood%20products%2C%20human%20immunoglobulin%20and%20timing%20of%20immunization%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-11-blood-products-human-immune-globulin-timing-immunization.html&title=Blood%20products%2C%20human%20immunoglobulin%20and%20timing%20of%20immunization%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Email](mailto:?subject=Blood%20products%2C%20human%20immunoglobulin%20and%20timing%20of%20immunization%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-11-blood-products-human-immune-globulin-timing-immunization.html%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-11-blood-products-human-immune-globulin-timing-immunization.html&t=Blood%20products%2C%20human%20immunoglobulin%20and%20timing%20of%20immunization%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=Blood%20products%2C%20human%20immunoglobulin%20and%20timing%20of%20immunization%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-11-blood-products-human-immune-globulin-timing-immunization.html%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-11-blood-products-human-immune-globulin-timing-immunization.html&title=Blood%20products%2C%20human%20immunoglobulin%20and%20timing%20of%20immunization%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-11-blood-products-human-immune-globulin-timing-immunization.html&t=Blood%20products%2C%20human%20immunoglobulin%20and%20timing%20of%20immunization%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-11-blood-products-human-immune-globulin-timing-immunization.html&media=&description=Blood%20products%2C%20human%20immunoglobulin%20and%20timing%20of%20immunization%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-11-blood-products-human-immune-globulin-timing-immunization.html&title=Blood%20products%2C%20human%20immunoglobulin%20and%20timing%20of%20immunization%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-11-blood-products-human-immune-globulin-timing-immunization.html)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-11-blood-products-human-immune-globulin-timing-immunization.html&name=Blood%20products%2C%20human%20immunoglobulin%20and%20timing%20of%20immunization%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=Blood%20products%2C%20human%20immunoglobulin%20and%20timing%20of%20immunization%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-11-blood-products-human-immune-globulin-timing-immunization.html)
* [Whatsapp](https://api.whatsapp.com/send?text=Blood%20products%2C%20human%20immunoglobulin%20and%20timing%20of%20immunization%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-11-blood-products-human-immune-globulin-timing-immunization.html)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=Blood%20products%2C%20human%20immunoglobulin%20and%20timing%20of%20immunization%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-11-blood-products-human-immune-globulin-timing-immunization.html%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2022-09-16
| None | None |
d118177c5c6268d0721a62e35748a3f140b2d8c1 | cma | Statement on prevention of Japanese encephalitis | Statement on prevention of Japanese encephalitis
Preamble
The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.
Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.
Key Points/Messages
- Japanese encephalitis (JE) is a potentially fatal disease caused by a mosquito-transmitted virus. It is endemic through much of Asia and also occurs in parts of Oceania.
- Since 1973 there have been 66 cases of JE reported among Western travellers and expatriates including 2 cases among Canadian travellers. The overall risk of JE among travellers is estimated to be negligible, i.e. < 1 case/10,000,000 trips. Even allowing for 10-fold underreporting of JE cases, overall risk is estimated to be negligible, i.e. approximately 1 case/1,000,000 trips.
- The only JE vaccine (JEV) currently available in Canada is IXIARO®, an inactivated Vero cell culture-derived vaccine licenced for individuals aged 2 months of age and older.
- Following a systematic review of the literature, recommendations for use of JEV were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Assessment focused on benefits and harms of JEV, use of an accelerated vaccination schedule, and use of JEV in children.
- No evidence on the values and preferences of travellers or health care providers related to use of JEV were found. However, there is evidence to indicate that some patients (including travellers) will choose and pay for vaccine-based protection against rare (e.g. a risk of 1/100,000), but serious diseases. Based partly on this evidence, CATMAT used a per trip risk for a case of JE of 1/100,000 as the threshold at which the majority of travellers would accept the harms, cost and inconvenience of JEV vaccination.
- Because the overall per trip JE risk estimate (< 1 case/10,000,000 or approximately 1 case/1,000,000 with 10-fold underreporting) is substantially less than this threshold, we suggest that JEV not be routinely used for travel to endemic areas.
- In some circumstances, based on factors that are thought to increase risk (e.g., rural exposure, repeated travel to risk areas, longer cumulative duration of travel (e.g., > 30 days), travel in areas suffering an outbreak), JEV will be of relatively greater absolute benefit and more travellers will likely choose to receive it.
GRADE Recommendations
# When to use JEV
- CATMAT suggests that JEV (IXIARO®) not be routinely used for travel to endemic areas
(Conditional recommendation against ; moderate confidence in estimate of effect)
+ For the large majority of travellers, the likelihood of developing clinical JE in endemic areas (see Table 1) is negligible (overall per trip attack rate estimated at approximately 1/10,000,000) as is the estimated absolute benefit of JEV (moderate confidence, intermediate risk of bias due to possibility of unreported clinical cases). Balanced against cost, inconvenience and the potential risk of adverse effects, most travellers would choose not to receive JEV in this situation.
+ The relative likelihood of acquiring JE is likely elevated for some populations (e.g., long-term travel, exposure in rural areas, multiple trips to endemic areas and/or travel to an area suffering an outbreak) and more travellers would choose to receive vaccine in such circumstances (Risk factor evidence was not evaluated using GRADE, ).
+ Because this recommendation is conditional, there is a need for providers to discuss with the traveller the anticipated benefits and harms (including financial costs) associated with JEV to help the traveller reach a decision that is consistent with their own values and preferences. The discussion should include potential alternative and/or complementary strategies (e.g., use of personal protective methods against mosquito bites) to vaccination.
+ See Text Box 3 for a list factors that influence decision-making related to JE vaccine.
+ For more information on how CATMAT arrived at this recommendation, see "".
# Vaccine administration
The licensed primary adult schedule for JEV in Canada is 2 doses spaced 28 days apart.
- CATMAT suggests use of an accelerated (0 and 7 days) schedule for adults aged 18-65 if there is insufficient time to immunize travellers with the normal primary schedule (0 and 28 days)
(Conditional recommendation for; moderate confidence in estimate of effect)
+ This accelerated schedule has been approved for use in Canada and Europe.
+ The accelerated schedule elicited similar levels of seroconversion and adverse effects as the normal schedule.
- CATMAT suggests that JEV (normal schedule) can be used in children aged 2 months to <18 years
(Conditional recommendation for; moderate confidence in estimate of effect)
+ This normal schedule has been approved for use in children (2 months to <18 years) in Canada and is also approved in the United States.
+ Seroconversion rates and rates of adverse effects were found to be similar in adults and children.
+ Children aged 2 months to <3 years of age are recommended to receive a reduced dose of vaccine (0.25 ml) compared to older children and adults (0.5 ml).
+ While a normal schedule is preferred, an accelerated schedule can be considered (off-label) for children where there is not sufficient time to complete the normal schedule.
Basis of GRADE Recommendation for Vaccine Use
# Quality of the Evidence
Vaccine efficacy:
moderate confidence in estimate of effect
Vaccine harms:
moderate to high confidence in estimate of effect
Baseline risk of developing JE among travellers:
moderate confidence in estimate of risk
Risk factors for JE:
insufficient evidence to assess with GRADE
Values and Preference:
insufficient evidence to assess with GRADE
# Summary of Balance of Benefits and Harms
JEV (IXIARO®) is expected to provide a high level of protection (>95%) against JE (Figure 1). Further, it is a well-tolerated vaccine. In the pivotal safety trial, JEV had a similar AE profile to placebo, though minor AE, e.g., pain at injection site, are common (Appendix 1; moderate to high confidence in the estimates of effect). The exception was itching, which occurred less often (RR 0.52; 95% Confidence Interval 0.29 to 0.92) with JEV than compared to placebo.
However, as with other vaccines, rare but serious AE are possible. This last point becomes increasingly important with decreasing JE risk in that it increases the possibility that rare but serious AE will be more prevalent than JE cases averted through immunization.
There were 42 AE following JEV immunization reported to the US Vaccine Adverse Event Reporting System (VAERS) for the period of 2009-2012. The majority of these (25/42) were reported after a patient had received several immunizations including JEV. Using an estimated 275,848 doses of vaccine distributed, the overall AE rate was 15.2/100,000 doses; and the serious AE rate was 1.8/100,000 doses. The most commonly reported serious AE were hypersensitivity reactions (0.7/100,000 doses). No cases of anaphylaxis or death were reported. Recently VAERS published an update on AE events reported during the period 2012-2016. There were 119 AE reported following JEV immunization. Using the estimated 802,229 doses of vaccine distributed, the overall AE rate during this time period was 14.8/100,000 doses. There were 9 serious AE reported for a rate of 1.1/100,000 doses. Serious AE included 1 report of anaphylaxis and 1 death (cardiac death due to ischemic heart disease). Importantly, reports to VAERS do not necessarily imply causal relationships.
For most travellers to endemic areas, the likelihood of acquiring JE is negligible (estimated at approximately 1 clinical case/10 million trips) (Table 1) and the number needed to vaccinate (NNV) to prevent a case is correspondingly high, e.g., > 10,000,000 (see Tables 2 and 3). The median trip duration for travel to endemic areas was estimated to be approximately 2 weeks (see Figure 2).
At the estimated overall JE attack rate among Canadians traveling to endemic areas of 1 clinical case/11,650,000 (95% CI ) person trips (median trip duration estimated to be 15 days), the number needed to vaccinate (NNV) to prevent 1 clinical case of JE, 1 severe sequelae from JE or 1 JE related death is approximately 12 million, 33 million and 49 million, respectively (see Tables 2 and 3). At this same risk of disease, approximately 5 million mild AEs would be expected to occur.
We did not identify JEV-specific evidence on traveller values and preferences. However, there is evidence to indicate that some patients (including travellers) will choose and pay for vaccine-based protection against rare (e.g. a risk of 1/100,000), but serious diseases.
The risk threshold should take into account patient values and preferences, risk of JE, the effectiveness and safety profile for JEV, and cost and inconvenience associated with the vaccine. In the absence of JEV-specific evidence on patient values and preferences, the committee judged that most travellers would be willing to accept the harms, cost (currently several hundred dollars) and inconvenience of vaccination if JEV risk was 1/100,000 or higher, but not at lower risks. This threshold for vaccine use is several orders of magnitude higher than the overall risk estimate for JE. Thus, we recommend against routine use of JEV for travel to endemic areas.
Certain populations, e.g., long term travellers (e.g., >30 days), travellers who make multiple trips to endemic areas, persons staying for extended periods in rural areas, persons visiting an area suffering a JE outbreak area, are likely at relatively higher risk for JE (). Due to the severity of potential consequences of JE, and the absence of specific treatments, it is plausible that individuals who are so affected would be more likely to choose to receive JEV.
# Why is the recommendation a conditional recommendation?
The recommendation for use of JEV is conditional. This reflects, among other things, the poorly defined impact of risk factors such as destination, seasonality, travel itinerary and duration of stay on JE risk, and our belief that travellers could have divergent values and preferences (including willingness to pay) related to use of JEV. For a more detailed discussion of what a conditional recommendation means in the context of JE, see Text Box 2.
Interpretation of GRADE Recommendations
Text Box 1: GRADE-based recommendation categories used by CATMAT (adapted from reference)
The GRADE working group specifies that if a recommendation is "strong", then it is expected that 90% or more of informed individuals would choose (or not choose) the recommended course of action.
The GRADE working group specified that if a recommendation is "conditional", then it is expected that less than 90% of informed individuals would choose (or not choose) the recommended course of action. The term "conditional" is used by CATMAT, and is considered as equivalent to "weak" as is articulated in much of the GRADE literature. For conditional recommendations the wording "suggests" rather than "recommends" will be used.
# Text Box 2: What does a conditional recommendation mean in the context of JEV?
GRADE-based recommendations for JEV are "conditional". This means that the majority of well-informed travellers to endemic areas would choose the recommended course of action and not use JEV. However, it also means that some travellers would choose to receive JEV. Reasons for making recommendations conditional include the very low overall risk of travel-associated JE, the poorly defined impact of risk factors such as destination, seasonality, travel itinerary and duration of stay, and our belief that travellers could have divergent values and preferences related to use of JEV.
Applied to individual travellers, our recommendations could result in the following types of joint (traveller and clinician) decisions:
- Persons staying in urban areas of endemic countries for relatively short periods (e.g., < 1 month) are estimated to have an extremely low risk for developing JE. In this situation and given the cost and inconvenience of vaccination, very few travellers would choose to receive JEV.
- Persons staying for longer periods in urban areas of endemic countries and/or who have short-term (e.g., ≤ 1 week) exposure in rural areas are estimated to have a relatively higher, but still extremely low risk of developing JE. Very few travellers would choose to receive JEV in this situation.
- Persons staying for longer periods (e.g., > 30 days) in endemic areas with exposure in rural areas during the risk season are likely to have a relatively higher, but still very low risk of developing JE. However, there might be some individuals in this population for whom relative risk is substantially elevated, e.g., because they are staying in a highly endemic area for an extended period. In this situation, many more travellers would choose to receive JEV, but also that many, for example based on values and preferences, would choose not to receive the vaccine.
# Text Box 3: Points to consider when discussing JE vaccine (adapted from reference)
## Reasons that might increase likelihood that traveller would choose to be vaccinated
- analytic uncertainty, i.e. overall risk might be underestimated due to non-reporting of cases
- seriousness of disease, high case fatality rate and many survivors with serious sequelae
- relatively lower risk tolerance for "exotic" diseases
- travelling to known epidemic area
- longer duration stays, e.g., > 30 days in endemic areas with rural exposure
- extensive overnight exposure in rural environments
- repeated travel to risk areas (cumulative time)
- established safety profile for vaccine
- high level of vaccine efficacy
## Reasons that decrease likelihood that traveller would choose to be vaccinated
- very low overall risk for large majority of travellers
- relatively higher risk tolerance for "exotic" diseases
- relatively high cost of vaccine
- urban/short-term travel
- concern about adverse effects related to vaccination in general
- inconvenience of vaccination, including multiple doses
- availability of alternative interventions, e.g. bite prevention methods
Non-GRADE Recommendations
- For Canadians (adults and children) who remain at risk and desire vaccine-induced protection, CATMAT suggests that a single booster dose of JEV be administered 12-24 months after the primary series and that a second booster is not required for at least 10 years.
+ After a primary series, 80-95% of fully immunized vaccine recipients maintained an adequate immune response after 6 months and 58-83% maintained it at 12-15 months.
+ After receipt of a booster dose, there is evidence that an adequate immune response persists for an extended period among adults. CATMAT therefore suggests that additional booster doses are not necessary for at least 10 years after the initial booster in the situation where protection against JE is desired.
+ Among children, evidence of long term seroprotection is limited but does suggest that antibody responses are at least as persistent in children as in adults. For this reason CATMAT suggests that it is reasonable to follow the same recommended second booster approach for children (off-label) as for adults.
- In adults 65 years or older CATMAT suggests that a single booster dose of JEV be considered earlier (before 12 months) following the primary series.
+ JEV is generally well tolerated in older patients although seroconversion rates are lower than in younger adults.
+ Assessment of the precise timing of vaccine administration should be done on a case-by-case basis if the traveller remains at risk for JE and wishes to receive protection.
- CATMAT recommends that, if an adult traveller wishes to receive JEV and if there is insufficient time to provide a normal or accelerated schedule, then an additional dose of vaccine can be provided with the first dose (on day 0).
+ This is based on evidence showing that this approach achieves a seroconversion rate of approximately 60% by 10 days post-vaccination, compared to approximately 30% following a single dose. If this double dose approach is used, subsequent doses (if protection is still required) should be as per the normal schedule.
- CATMAT recommends that all travellers use personal protective measures (PPM) such as topical repellents, treated bed nets and/or treated clothing to prevent mosquitoes from biting.
+ Recommendations related to PPM are provided in the CATMAT statement on .
Introduction
Japanese encephalitis (JE) is caused by a flavivirus transmitted by *Culex- mosquitoes. It is one of the most important causes of viral encephalitis in Asia, with an estimated 70,000 cases and up to 20,000 deaths annually . Appendix 2 shows areas where JE is endemic, and Appendix 3 provides country-specific information related to risk areas and seasonality. There is no specific treatment for JE but a JE vaccine (IXIARO®) is licenced for adults in Canada. Immunization and/or use of personal protective measures (PPMs) against mosquito bites will provide substantial protection against disease .
Background
# Clinical and Epidemiological features
The likelihood of developing clinical disease after infection with JE virus is low (approximately 1/250). If clinical disease develops (after an incubation period of 5 to 15 days), the prognosis is poor. Approximately 20-30% of patients die and, among survivors, about 50% will develop long term neurological and/or psychological sequelae . In endemic areas without a vaccination program, disease often occurs in children; whereas older adults, perhaps because of immune senescence, seem to be at greatest risk for disease in countries/areas with robust and long-standing immunization programs.
JE virus is maintained in a zoonotic cycle involving *Culex- mosquitoes and wild birds with pigs sometimes acting as amplification hosts. Risk is primarily in rural areas, and transmission can be year round with rainy season peaks (subtropical/tropical areas), or constrained to warmer periods of the year when the mosquito vectors are active (temperate areas) . Appendix 3 summarizes transmission patterns in JE-endemic countries.
JE vaccine programs, changes in animal husbandry practices and/or increased urbanization has led to a substantial reduction in human cases of JE in some countries like Japan and Korea . However, JE still presents a risk to non-immune persons (e.g., travellers) in these countries because zoonotic transmission persists.
# Vaccine
The only JE vaccine currently available in Canada is IXIARO®, an inactivated Vero cell culture-derived vaccine marketed in Canada by Valneva Canada and licenced for individuals aged 2 months of age and older. It is important that the product monograph for IXIARO® be read by those who prescribe and/or inoculate this vaccine. Information regarding important features of IXIARO®is also summarized in the Canadian Immunization Guide.
Methods
# General
This statement was developed by a CATMAT working group (WG) of volunteers, none of whom declared a relevant conflict of interest. The WG, with support from the secretariat, was responsible for: literature retrieval, evidence synthesis and analysis; development of key questions and draft recommendations and writing of the statement. The final statement and recommendations were approved by CATMAT.
The GRADE process was used to formulate some of the recommendations in this statement. Other recommendations in this statement did not use GRADE, for example those related to boostering or use of personal protective measures to prevent mosquito bites. This did not reflect an absence of evidence on these topics, but rather a decision on the part of the WG and broader committee to focus resources on clinical questions that were judged most likely to benefit by a GRADE-based evidence appraisal. For non-GRADE recommendations, advice was based on a narrative review of the relevant literature evidence and expert opinion. For more information on the CATMAT approach to developing recommendations and guidelines, see the statement on .
The following summarizes the process used to develop this statement and recommendations:
# GRADE Recommendations
1. An analytic framework identifying clinical preventive actions (interventions) and risk factors for JE was developed (Appendix 4).
2. From the analytic framework, the working group framed key concepts in the form of a PICO question (Population of interest, Intervention, Comparison, and Outcome) in order to develop focused GRADE-based recommendations. Evidence on efficacy and harms of JEV was considered for each PICO question.
The following PICO questions were identified:
1. Among adult Canadian travellers, does use of JEV (normal schedule) decrease the risk of acquiring JE compared to no vaccine (placebo)?
2. Among adult Canadian travellers, does use of an accelerated (0, 7 days) JEV schedule achieve levels of protection similar to or greater than a normal JEV schedule (0, 28 days)?
3. Among Canadian children, does use of JEV achieve levels of protection similar to that observed in adult travellers, and is use of JEV associated with similar harms to adults?
3. Other concepts from the analytical framework were identified to support the GRADE assessment but were framed as non-PICO questions. The following contextual questions were identified:
1. What is the risk of clinical JE among Canadian travellers?
2. What are the important risk factors for JE among Canadian travellers (e.g., destination, duration of travel)?
3. What are the values and preferences of Canadian travellers regarding the magnitude of risk reduction in JE that would make use of JEV worthwhile given associated costs and inconvenience?
4. Evidence was retrieved by performing searches in electronic databases (Ovid MEDLINE, Embase, Global Health, and Scopus) and by manually searching in Google for grey literature. Time period for the search was from earliest available to June 2015. There were 2 literature searches: 1. JE vaccine (efficacy and harms) and travellers and 2. Baseline risk of and risk factors for developing JE among travellers. Details on search strategies and dates are provided in Appendix 5. The inclusion and exclusion criteria were applied by 2 WG members to the identified studies, based on an initial screening of titles and abstracts. Studies were excluded if they appeared to be irrelevant, were not published in English or French, or were duplicates.
5. From these searches, relevant literature was identified. If evidence specific to Canadian travellers was not available, then evidence derived from other Western populations or from other populations, in that order of preference, was extracted.
6. Quality assessments were performed for: vaccine efficacy and adverse events (AE); and, risk of developing JE among travellers. Results were collated into summary of findings tables (see Appendices 5-7 and 9). We decided that there was insufficient evidence to subject the other questions to the GRADE process.
7. Recommendations were developed taking into consideration:
1. CATMAT's confidence in the estimates of effect for efficacy and JEV-associated AE;
2. the balance of harms and benefits; and,
3. CATMAT's judgement on the likely values and preferences of travellers and health care providers related to use of JEV.
# Non-GRADE Recommendations
1. Additional questions were identified that were not selected for GRADE review by the working group. They were:
1. What is the appropriate boostering interval for JEV?
2. Among older (aged > 65 years) Canadian travellers, does use of JEV achieve levels of protection similar to adult travellers?
3. Does an additional dose of vaccine on day 0 achieve a higher seroconversion rate than a single dose?
4. Do personal protective measures provide protection against bites from the type(s) of mosquitoes that transmit JE?
2. Evidence relevant to these questions was identified through the previously-described literature search, or was extracted from existing CATMAT statements. Recommendations are based on a narrative review of the evidence and expert opinion.
Results
# General
The literature search on JE vaccine and travellers identified 423 studies of which 310 were excluded. The risk factors for JE search identified 131 studies of which 127 were excluded. The remaining 117 relevant articles addressed vaccine harms and/or benefits (N= 36), booster dose (N=10), accelerated schedule (N= 4), pediatric use (N=6) and risk factors (N=4). As well, 57 studies addressing burden of disease (incidence, morbidity, mortality, hospitalizations) among travellers, population-specific risk factors (e.g., age), itinerary-specific risk factors (e.g., destination, duration of travel), efficacy of preventive measures (e.g., personal protective measures), and/or disease treatment/management were retained. After the literature review was completed, an additional study on values and preferences was identified and included. In addition, in 2018 an updated IXIARO®product monograph was released with expanded recommendations for use in Canada, and was used as a reference.
# GRADE questions
## PICO questions
Among adult Canadian travellers, does use of JEV (normal schedule) decrease the risk of acquiring JE as compared to no vaccine (placebo)?
We did not identify evidence showing JEV reduces the incidence of JE (and associated harms) among travellers to endemic areas. Rather, efficacy is inferred from studies using serological correlates of protection. Efficacy of JEV (IXIARO®) was initially established through a non-inferiority comparison to inactivated mouse brain-derived JE vaccine (MBV), trade name JEVAX, which is no longer licenced in Canada. Protection was defined using seroconversion rate (SCR) as an endpoint, i.e. a PRNT50 titre 95% of recipients) (moderate confidence in the estimates of effect, downgraded for indirectness given seroconversion is a surrogate of protection). The vaccines were associated with similar rates of systemic adverse effects; however, local reactions were more common with MBV (high confidence in estimate of effect).
Additional studies, without a comparator, have consistently shown that 2 doses of JEV (days 0, 28) achieve high SCR . Results from these studies are summarized in Figure 1.
Data extracted from 9 studies .
Among adult Canadian travellers, does use of an accelerated (0, 7 days) JEV schedule achieve levels of protection similar to or greater than a normal JEV schedule (0, 28 days)?
In adults, an accelerated JEV schedule (first dose on day 0 and second dose on day 7) yielded similar SCR to the normal schedule (1 dose on each of days 0 and 28) (moderate confidence in the estimate of effect) (Appendix 7). Compared at a similar time point (10-14 days) after the initial dose, the accelerated schedule was associated with a significantly higher SCR (RR 3.95; 95% CI 3.16 to 4.92) than the normal schedule (low confidence in the estimate of effect). Safety profiles (Appendix 7) for the accelerated and normal schedule were similar (moderate to high confidence in the estimates of effect). This accelerated schedule has recently been approved for use in Canada for adults aged 18-65 years.
Among Canadian children, does use of JEV achieve levels of protection similar to that observed in adult travellers and is JEV use associated with similar harms to adults?
Through the literature review, GRADE assessments published in 2013 by the United States Advisory Committee on Immunization Practices (ACIP) were identified. This work specifically addressed the question "Should inactivated Vero cell culture-derived Japanese encephalitis vaccine (JE-VC) be recommended for use in children 2 months through 16 years of age at increased risk of travel-related exposure to Japanese encephalitis virus". Adults were included in the analyses as a comparator. We judged that the ACIP GRADE could be used to address our PICO question: "Among Canadian children, does use of JEV achieve levels of protection similar to that observed in adult travellers?" We did not identify additional and relevant evidence published since this review in our literature search.
The ACIP concluded that SCR (moderate confidence in the estimate of effect) and rates of serious (low confidence in the estimate of effect) or systemic (moderate confidence in estimate of effect) adverse effects were similar in adults and children (see Appendix 8). A complete explanation of the assessment of quality of evidence is available elsewhere. Briefly, downgrading of the quality of evidence was done because of indirectness (e.g., because efficacy was not directly measured and/or the evidence was primarily developed with adults) and potential sources of bias (e.g., lack of blinding). Use of JEV in children aged 2 months to <18 years has recently been approved in Canada.
Evidence supporting the use of an accelerated schedule in children was not identified and use of an accelerated schedule in children is not approved in Canada. Hence, the normal schedule for JEV should be used for children when possible. However, it appears reasonable to use an off-label accelerated schedule for children in the circumstance where time does not allow for the normal schedule to be used, especially in older children.
## Contextual questions
What is the risk of clinical JE among Canadian travellers?
Likelihood estimates for travel-related clinical JE are shown in Table 1. For calculations, the numerator reflects the number of published cases over a 10 year period (2006-2015). We used cases identified in data from a previous review published in 2010 and identified more recent reports by applying the same search strategy as is described in the review. To be included, published cases must have been for a traveller returning to Canada, the United States (US) or Europe. For the denominator, we used outbound travel statistics for Canada, the United States and Europe .
We estimate the likelihood of clinical JE as approximately 1/10,000,000 trips (moderate confidence in the estimate of effect) for Canada, the United States and Europe (Table 1). The quality of the body of evidence was downgraded due to risk of bias (Appendix 9), i.e. not all cases in travellers may have been reported in the literature. In this respect, while we cannot be certain of the degree to which cases are under-reported, it has been suggested that the majority are identified in the literature. Moreover, even if it was assumed that only 1 in 10 cases of JE disease in travellers were reported, the overall risk of JE would remain very low, i.e. approximately 1 case/1,000,000 trips.
Previous estimates for US and European travellers have also suggested a very low overall risk for JE.
What are the important risk factors for JE among Canadian travellers (e.g., destination, duration of travel)?
For the period of 2006-2015, we identified 18 published reports of JE, of which 17 were in travellers returning to Canada (1 case), the United States (5 cases) or Europe (11 cases). Including reports published before 2006 increased the total to 67 cases. Only 1 case identified was not in a traveller from the Western hemisphere and hence was excluded from the analysis. Overall, the case fatality rate was 20% (12/60) (outcome was unknown in 6 cases); most cases were in males (59%); the average age of cases was 39 years; and the mean duration of travel was 35 days (Figure 2). The countries to which exposure was most often ascribed were: were Thailand, Indonesia, China and the Philippines (Figure 3).
We estimate that travel-associated JE is rare, consistent with previous estimates. However, it also is widely accepted that certain subpopulations of travellers are at relatively higher risk for JE; examples include those travelling for an extended period and/or those spending substantial amounts of time in rural areas where vectors are more prevalent . We did not identify evidence (observational or randomized trials) that would allow robust estimates of the incremental impact of these factors on risk to be made, and for this reason did not assess this evidence with GRADE. Based on identified travel-related cases (N=66, see above) we nevertheless make the following observations:
- Among cases where age is available (N=57), there is not an obvious age associated trend, e.g., children aged 10 years or younger (5 cases) accounted for 9% of the total and adults aged 60 years or older (12 cases) accounted for 21% of the total.
- There is a trend towards increased likelihood of JE with longer duration travel. Specifically, median duration of travel for cases at 35 days (Figure 2) is approximately double the median duration (15 days) for all travel to endemic areas . There is not, however, a clear cut-off for travel duration below which risk is absent (cases have been reported in short-term travellers) or for a travel duration at which disease likelihood crosses a "threshold" that would prompt use of JEV.
- Itineraries that include rural exposure are often reported in association with published cases. However, rural activity is not a universal risk factor nor, in the situation where time is spent in rural and urban areas, can the rural component of travel be definitively ascribed as the exposing activity. Hence, while there is consensus that activities in rural areas are "riskier", the absolute magnitude of the risk increase is unknown. |
Statement on prevention of Japanese encephalitis
=================================================
Notice to reader
----------------
Updated in January 2023: Appendix 3. Country-specific notes on Japanese encephalitis for Australia
Table of content
----------------
* [Preamble](#a1)
* [Key Points/Messages](#a2)
* [GRADE Recommendations](#a3)
+ [When to use JEV](#a3.1)
+ [Vaccine administration](#a3.2)
* [Basis of GRADE Recommendation for Vaccine Use](#a4)
+ [Quality of the Evidence](#a4.1)
+ [Summary of Balance of Benefits and Harms](#a4.2)
+ [Why is the recommendation a conditional recommendation?](#a4.3)
* [Interpretation of GRADE Recommendations](#a5)
* [Non-GRADE Recommendations](#a6)
* [Introduction](#a7)
* [Background](#a8)
+ [Clinical and Epidemiological features](#a8.1)
+ [Vaccine](#a8.2)
* [Methods](#a9)
+ [General](#a9.1)
+ [GRADE Recommendations](#a9.2)
+ [Non-GRADE Recommendations](#a9.3)
* [Results](#a10)
+ [General](#a10.1)
+ [GRADE questions](#a10.2)
- [PICO questions](#a10.2.1)
- [Figure 1. Japanese Encephalitis vaccine seroconversion rate (SCR) in adults (95% confidence interval)](#a10.2.2)
- [Contextual questions](#a10.2.3)
- [Figure 2. Cumulative proportion of Japanese Encephalitis cases among travellers by duration of travel in days.](#a10.2.4)
- [Figure 3. Proportion of Japanese Encephalitis cases (N=66) among travellers by country of exposure](#a10.2.5)
- [Table 1: Estimated overall attack rate of clinical Japanese Encephalitis for 2006-2015. Based on Canadian travel statistics, the mean duration of travel to endemic areas was approximately 15 days.](#a10.2.6)
- [Table 2: Predicted JE event rates (clinical cases, long-term sequelae and deaths) with and without JEV if overall risk is 1 case/11.65 million trips. Expressed as attack rate per 10 million trips to endemic areas.](#a10.2.7)
- [Table 3: Number needed to vaccinate to prevent a case, long-term sequelae and death at our JEV recommendation threshold (1 case/100,000 trips) and at the estimated overall risk (1 case/11,650,000 trips) of JE for Canadian travellers1.](#a10.2.8)
+ [Non-GRADE questions](#a10.3)
* [Conclusions and Research Needs](#a11)
* [Acknowledgements](#a12)
* [Conflict of Interest](#a13)
* [References](#a14)
* [Appendix 1. Summary of findings for comparison of JEV to placebo: Adverse events (AE)](#appen_1)
* [Appendix 2. Geographic distribution of Japanese encephalitis](#appen_2)
* [Appendix 3. Country-specific1 notes on Japanese encephalitis](#appen_3)
* [Appendix 4. Analytic framework for Japanese encephalitis vaccine (JEV)](#appen_4)
* [Appendix 5. Sample search strategy](#appen_5)
+ [Japanese encephalitis vaccination in travellers](#appen_5.1)
+ [Japanese encephalitis: Risk factors for travellers](#appen_5.2)
* [Appendix 6. Summary of findings for comparison of JEV and inactivated mouse-brain derived vaccine (MBV): Seroconversion rate (SCR) and adverse events (AE)](#appen_6)
* [Appendix 7. Summary of findings for comparison of conventional immunization schedule for JEV (0, 28 days) to accelerated schedule (0, 7 days): Seroconversion rate (SCR) and adverse events (AE)](#appen_7)
* [Appendix 8. Summary of Advisory Committee on Immunization Practice (ACIP) GRADE results](#appen_8)
* [Appendix 9. Quality assessment for risk of Japanese encephalitis in travellers from Canada, the United States and Europe](#appen_9)
* [Appendix 10. Factors to consider when evaluating a traveller's risk for Japanese encephalitis (JE) virus exposure](#appen_10)
* [Appendix 11. Study summaries considered for inclusion in GRADE analysis](#appen_11)
Preamble
--------
The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.
Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.
Key Points/Messages
-------------------
* Japanese encephalitis (JE) is a potentially fatal disease caused by a mosquito-transmitted virus. It is endemic through much of Asia and also occurs in parts of Oceania.
* Since 1973 there have been 66 cases of JE reported among Western travellers and expatriates including 2 cases among Canadian travellers. The overall risk of JE among travellers is estimated to be negligible, i.e. < 1 case/10,000,000 trips. Even allowing for 10-fold underreporting of JE cases, overall risk is estimated to be negligible, i.e. approximately 1 case/1,000,000 trips.
* The only JE vaccine (JEV) currently available in Canada is IXIARO®, an inactivated Vero cell culture-derived vaccine licenced for individuals aged 2 months of age and older[Footnote 1](#fn1).
* Following a systematic review of the literature, recommendations for use of JEV were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Assessment focused on benefits and harms of JEV, use of an accelerated vaccination schedule, and use of JEV in children.
* No evidence on the values and preferences of travellers or health care providers related to use of JEV were found. However, there is evidence to indicate that some patients (including travellers) will choose and pay for vaccine-based protection against rare (e.g. a risk of 1/100,000), but serious diseases. Based partly on this evidence, CATMAT used a per trip risk for a case of JE of 1/100,000 as the threshold at which the majority of travellers would accept the harms, cost and inconvenience of JEV vaccination.
* Because the overall per trip JE risk estimate (< 1 case/10,000,000 or approximately 1 case/1,000,000 with 10-fold underreporting) is substantially less than this threshold, we suggest that JEV not be routinely used for travel to endemic areas.
* In some circumstances, based on factors that are thought to increase risk (e.g., rural exposure, repeated travel to risk areas, longer cumulative duration of travel (e.g., > 30 days), travel in areas suffering an outbreak), JEV will be of relatively greater absolute benefit and more travellers will likely choose to receive it.
GRADE Recommendations
---------------------
### When to use JEV
* **CATMAT suggests that JEV (IXIARO®) not be routinely used for travel to endemic areas
(Conditional recommendation against [see Text Boxes 1 and 2 for what CATMAT suggests this means]; moderate confidence in estimate of effect)**
+ For the large majority of travellers, the likelihood of developing clinical JE in endemic areas (see Table 1) is negligible (overall per trip attack rate estimated at approximately 1/10,000,000) as is the estimated absolute benefit of JEV (moderate confidence, intermediate risk of bias due to possibility of unreported clinical cases). Balanced against cost, inconvenience and the potential risk of adverse effects, most travellers would choose not to receive JEV in this situation.
+ The relative likelihood of acquiring JE is likely elevated for some populations (e.g., long-term travel, exposure in rural areas, multiple trips to endemic areas and/or travel to an area suffering an outbreak) and more travellers would choose to receive vaccine in such circumstances (Risk factor evidence was not evaluated using GRADE, [see below for explanation](#a10)).
+ Because this recommendation is conditional, there is a need for providers to discuss with the traveller the anticipated benefits and harms (including financial costs) associated with JEV to help the traveller reach a decision that is consistent with their own values and preferences. The discussion should include potential alternative and/or complementary strategies (e.g., use of personal protective methods against mosquito bites) to vaccination.
+ See Text Box 3 for a list factors that influence decision-making related to JE vaccine.
+ For more information on how CATMAT arrived at this recommendation, see "[Basis of GRADE Recommendation for Vaccine Use](#a4)".
### Vaccine administration
The licensed primary adult schedule for JEV in Canada is 2 doses spaced 28 days apart[Footnote 1](#fn1).
* **CATMAT suggests use of an accelerated (0 and 7 days) schedule for adults aged 18-65 if there is insufficient time to immunize travellers with the normal primary schedule (0 and 28 days)**
**(Conditional recommendation for; moderate confidence in estimate of effect)**
+ This accelerated schedule has been approved for use in Canada[Footnote 1](#fn1) and Europe[Footnote 2](#fn2).
+ The accelerated schedule elicited similar levels of seroconversion and adverse effects as the normal schedule.
* **CATMAT suggests that JEV (normal schedule) can be used in children aged 2 months to <18 years**
**(Conditional recommendation for; moderate confidence in estimate of effect)**
+ This normal schedule has been approved for use in children (2 months to <18 years) in Canada[Footnote 1](#fn1) and is also approved in the United States[Footnote 3](#fn3).
+ Seroconversion rates and rates of adverse effects were found to be similar in adults and children.
+ Children aged 2 months to <3 years of age are recommended to receive a reduced dose of vaccine (0.25 ml) compared to older children and adults (0.5 ml)[Footnote 1](#fn1)[Footnote 4](#fn4).
+ While a normal schedule is preferred, an accelerated schedule can be considered (off-label) for children where there is not sufficient time to complete the normal schedule.
Basis of GRADE Recommendation for Vaccine Use
---------------------------------------------
### Quality of the Evidence
Vaccine efficacy:
moderate confidence in estimate of effect
Vaccine harms:
moderate to high confidence in estimate of effect
Baseline risk of developing JE among travellers:
moderate confidence in estimate of risk
Risk factors for JE:
insufficient evidence to assess with GRADE
Values and Preference:
insufficient evidence to assess with GRADE
### Summary of Balance of Benefits and Harms
JEV (IXIARO®) is expected to provide a high level of protection (>95%) against JE (Figure 1). Further, it is a well-tolerated vaccine. In the pivotal safety trial[Footnote 5](#fn5), JEV had a similar AE profile to placebo, though minor AE, e.g., pain at injection site, are common (Appendix 1; moderate to high confidence in the estimates of effect). The exception was itching, which occurred less often (RR 0.52; 95% Confidence Interval [CI] 0.29 to 0.92) with JEV than compared to placebo.
However, as with other vaccines, rare but serious AE are possible. This last point becomes increasingly important with decreasing JE risk in that it increases the possibility that rare but serious AE will be more prevalent than JE cases averted through immunization.
There were 42 AE following JEV immunization reported to the US Vaccine Adverse Event Reporting System (VAERS) for the period of 2009-2012[Footnote 6](#fn6). The majority of these (25/42) were reported after a patient had received several immunizations including JEV. Using an estimated 275,848 doses of vaccine distributed, the overall AE rate was 15.2/100,000 doses; and the serious AE rate was 1.8/100,000 doses[Footnote 6](#fn6). The most commonly reported serious AE were hypersensitivity reactions (0.7/100,000 doses). No cases of anaphylaxis or death were reported. Recently VAERS published an update on AE events reported during the period 2012-2016. There were 119 AE reported following JEV immunization. Using the estimated 802,229 doses of vaccine distributed, the overall AE rate during this time period was 14.8/100,000 doses. There were 9 serious AE reported for a rate of 1.1/100,000 doses. Serious AE included 1 report of anaphylaxis and 1 death (cardiac death due to ischemic heart disease)[Footnote 7](#fn7). Importantly, reports to VAERS do not necessarily imply causal relationships.
For most travellers to endemic areas, the likelihood of acquiring JE is negligible (estimated at approximately 1 clinical case/10 million trips) (Table 1) and the number needed to vaccinate (NNV) to prevent a case is correspondingly high, e.g., > 10,000,000 (see Tables 2 and 3). The median trip duration for travel to endemic areas was estimated to be approximately 2 weeks (see Figure 2).
At the estimated overall JE attack rate among Canadians traveling to endemic areas of 1 clinical case/11,650,000 (95% CI [1/2,056,512 to 1/65,996,483]) person trips (median trip duration estimated to be 15 days), the number needed to vaccinate (NNV) to prevent 1 clinical case of JE, 1 severe sequelae from JE or 1 JE related death is approximately 12 million, 33 million and 49 million, respectively (see Tables 2 and 3). At this same risk of disease, approximately 5 million mild AEs would be expected to occur.
We did not identify JEV-specific evidence on traveller values and preferences. However, there is evidence to indicate that some patients (including travellers) will choose and pay for vaccine-based protection against rare (e.g. a risk of 1/100,000), but serious diseases[Footnote 8](#fn8)[Footnote 9](#fn9).
The risk threshold should take into account patient values and preferences, risk of JE, the effectiveness and safety profile for JEV, and cost and inconvenience associated with the vaccine[Footnote 10](#fn10). In the absence of JEV-specific evidence on patient values and preferences, the committee judged that most travellers would be willing to accept the harms, cost (currently several hundred dollars) and inconvenience of vaccination if JEV risk was 1/100,000 or higher, but not at lower risks. This threshold for vaccine use is several orders of magnitude higher than the overall risk estimate for JE. Thus, we recommend against routine use of JEV for travel to endemic areas.
Certain populations, e.g., long term travellers (e.g., >30 days), travellers who make multiple trips to endemic areas, persons staying for extended periods in rural areas, persons visiting an area suffering a JE outbreak area, are likely at relatively higher risk for JE ([see below section on risk factors](#a10)). Due to the severity of potential consequences of JE, and the absence of specific treatments, it is plausible that individuals who are so affected would be more likely to choose to receive JEV.
### Why is the recommendation a conditional recommendation?
The recommendation for use of JEV is conditional. This reflects, among other things, the poorly defined impact of risk factors such as destination, seasonality, travel itinerary and duration of stay on JE risk, and our belief that travellers could have divergent values and preferences (including willingness to pay) related to use of JEV. For a more detailed discussion of what a conditional recommendation means in the context of JE, see Text Box 2.
Interpretation of GRADE Recommendations
---------------------------------------
Text Box 1: GRADE-based recommendation categories used by CATMAT (adapted from reference[Footnote 10](#fn10))
| Category of GRADE-based recommendation | Implication for practitioners |
| --- | --- |
| Strong[Footnote \*](#fn1.1) recommendation for | The balance of risks and benefits are such that most travellers would choose the intervention. |
| Strong recommendation against | The balance of risks and benefits are such that most travellers would not choose the intervention. |
| Conditional[Footnote \*\*](#fn1.2) recommendation for | With a conditional recommendation different travellers may make different choices. Practitioners should present the risks and benefits of the intervention and help each traveller make a decision consistent with his/her values and preferences. |
| Conditional recommendation against | With a conditional recommendation different travellers may make different choices. Practitioners should present the risks and benefits of the intervention and help each traveller make a decision consistent with his/her values and preferences. |
|
Footnote \*
The GRADE working group specifies that if a recommendation is "strong", then it is expected that 90% or more of informed individuals would choose (or not choose) the recommended course of action.
[Return to footnote \* referrer](#fn1.1-rf)
Footnote \*\*
The GRADE working group specified that if a recommendation is "conditional", then it is expected that less than 90% of informed individuals would choose (or not choose) the recommended course of action. The term "conditional" is used by CATMAT, and is considered as equivalent to "weak" as is articulated in much of the GRADE literature. For conditional recommendations the wording "suggests" rather than "recommends" will be used.
[Return to footnote \*\* referrer](#fn1.2-rf)
|
### Text Box 2: What does a conditional recommendation mean in the context of JEV?
GRADE-based recommendations for JEV are "conditional". This means that the majority of well-informed travellers to endemic areas would choose the recommended course of action and not use JEV. However, it also means that some travellers would choose to receive JEV. Reasons for making recommendations conditional include the very low overall risk of travel-associated JE, the poorly defined impact of risk factors such as destination, seasonality, travel itinerary and duration of stay, and our belief that travellers could have divergent values and preferences related to use of JEV.
Applied to individual travellers, our recommendations could result in the following types of joint (traveller and clinician) decisions:
* Persons staying in urban areas of endemic countries for relatively short periods (e.g., < 1 month) are estimated to have an extremely low risk for developing JE. In this situation and given the cost and inconvenience of vaccination, very few travellers would choose to receive JEV.
* Persons staying for longer periods in urban areas of endemic countries and/or who have short-term (e.g., ≤ 1 week) exposure in rural areas are estimated to have a relatively higher, but still extremely low risk of developing JE. Very few travellers would choose to receive JEV in this situation.
* Persons staying for longer periods (e.g., > 30 days) in endemic areas with exposure in rural areas during the risk season are likely to have a relatively higher, but still very low risk of developing JE. However, there might be some individuals in this population for whom relative risk is substantially elevated, e.g., because they are staying in a highly endemic area for an extended period. In this situation, many more travellers would choose to receive JEV, but also that many, for example based on values and preferences, would choose not to receive the vaccine.
### Text Box 3: Points to consider when discussing JE vaccine (adapted from reference[Footnote 11](#fn11))
#### Reasons that might increase likelihood that traveller would choose to be vaccinated
* analytic uncertainty, i.e. overall risk might be underestimated due to non-reporting of cases
* seriousness of disease, high case fatality rate and many survivors with serious sequelae
* relatively lower risk tolerance for "exotic" diseases
* travelling to known epidemic area
* longer duration stays, e.g., > 30 days in endemic areas with rural exposure
* extensive overnight exposure in rural environments
* repeated travel to risk areas (cumulative time)
* established safety profile for vaccine
* high level of vaccine efficacy
#### Reasons that decrease likelihood that traveller would choose to be vaccinated
* very low overall risk for large majority of travellers
* relatively higher risk tolerance for "exotic" diseases
* relatively high cost of vaccine
* urban/short-term travel
* concern about adverse effects related to vaccination in general
* inconvenience of vaccination, including multiple doses
* availability of alternative interventions, e.g. bite prevention methods
Non-GRADE Recommendations
-------------------------
* **For Canadians (adults and children) who remain at risk and desire vaccine-induced protection, CATMAT suggests that a single booster dose of JEV be administered 12-24 months after the primary series and that a second booster is not required for at least 10 years.**
+ After a primary series, 80-95% of fully immunized vaccine recipients maintained an adequate immune response after 6 months and 58-83% maintained it at 12-15 months.
+ After receipt of a booster dose, there is evidence that an adequate immune response persists for an extended period among adults[Footnote 12](#fn12)[Footnote 13](#fn13). CATMAT therefore suggests that additional booster doses are not necessary for at least 10 years after the initial booster in the situation where protection against JE is desired.
+ Among children, evidence of long term seroprotection is limited but does suggest that antibody responses are at least as persistent in children as in adults[Footnote 14](#fn14). For this reason CATMAT suggests that it is reasonable to follow the same recommended second booster approach for children (off-label) as for adults.
* **In adults 65 years or older CATMAT suggests that a single booster dose of JEV be considered earlier (before 12 months) following the primary series.**
+ JEV is generally well tolerated in older patients although seroconversion rates are lower than in younger adults[Footnote 15](#fn15).
+ Assessment of the precise timing of vaccine administration should be done on a case-by-case basis if the traveller remains at risk for JE and wishes to receive protection.
* **CATMAT recommends that, if an adult traveller wishes to receive JEV and if there is insufficient time to provide a normal or accelerated schedule, then an additional dose of vaccine can be provided with the first dose (on day 0).**
+ This is based on evidence showing that this approach achieves a seroconversion rate of approximately 60% by 10 days post-vaccination, compared to approximately 30% following a single dose. If this double dose approach is used, subsequent doses (if protection is still required) should be as per the normal schedule.
* **CATMAT recommends that all travellers use personal protective measures (PPM) such as topical repellents, treated bed nets and/or treated clothing to prevent mosquitoes from biting**.
+ Recommendations related to PPM are provided in the CATMAT statement on [Personal Protective Measures to Prevent Arthropod Bites](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2012-38/statement-on-personal-protective-measures-prevent-arthropod-bites.html)[Footnote 16](#fn16).
Introduction
------------
Japanese encephalitis (JE) is caused by a flavivirus transmitted by *Culex* mosquitoes. It is one of the most important causes of viral encephalitis in Asia, with an estimated 70,000 cases and up to 20,000 deaths annually[Footnote 17](#fn17) [Footnote 18](#fn18). Appendix 2 shows areas where JE is endemic, and Appendix 3 provides country-specific information related to risk areas and seasonality. There is no specific treatment for JE[Footnote 4](#fn4) but a JE vaccine (IXIARO®) is licenced for adults in Canada[Footnote 1](#fn1). Immunization and/or use of personal protective measures (PPMs) against mosquito bites will provide substantial protection against disease[Footnote 4](#fn4) [Footnote 17](#fn17) [Footnote 19](#fn19) [Footnote 20](#fn20).
Background
----------
### Clinical and Epidemiological features
The likelihood of developing clinical disease after infection with JE virus is low (approximately 1/250)[Footnote 21](#fn21). If clinical disease develops (after an incubation period of 5 to 15 days), the prognosis is poor. Approximately 20-30% of patients die and, among survivors, about 50% will develop long term neurological and/or psychological sequelae[Footnote 19](#fn19) [Footnote 21](#fn21). In endemic areas without a vaccination program, disease often occurs in children[Footnote 22](#fn22); whereas older adults, perhaps because of immune senescence, seem to be at greatest risk for disease in countries/areas with robust and long-standing immunization programs[Footnote 21](#fn21).
JE virus is maintained in a zoonotic cycle involving *Culex* mosquitoes and wild birds with pigs sometimes acting as amplification hosts[Footnote 21](#fn21). Risk is primarily in rural areas, and transmission can be year round with rainy season peaks (subtropical/tropical areas), or constrained to warmer periods of the year when the mosquito vectors are active (temperate areas)[Footnote 17](#fn17) [Footnote 23](#fn23). Appendix 3 summarizes transmission patterns in JE-endemic countries.
JE vaccine programs, changes in animal husbandry practices and/or increased urbanization has led to a substantial reduction in human cases of JE in some countries like Japan and Korea[Footnote 17](#fn17) [Footnote 23](#fn23). However, JE still presents a risk to non-immune persons (e.g., travellers) in these countries because zoonotic transmission persists.
### Vaccine
The only JE vaccine currently available in Canada is IXIARO®, an inactivated Vero cell culture-derived vaccine marketed in Canada by Valneva Canada and licenced for individuals aged 2 months of age and older. It is important that the product monograph for IXIARO®[Footnote 1](#fn1) be read by those who prescribe and/or inoculate this vaccine. Information regarding important features of IXIARO®is also summarized in the Canadian Immunization Guide[Footnote 24](#fn24).
Methods
-------
### General
This statement was developed by a CATMAT working group (WG) of volunteers, none of whom declared a relevant conflict of interest. The WG, with support from the secretariat, was responsible for: literature retrieval, evidence synthesis and analysis; development of key questions and draft recommendations and writing of the statement. The final statement and recommendations were approved by CATMAT.
The GRADE process was used to formulate some of the recommendations in this statement. Other recommendations in this statement did not use GRADE, for example those related to boostering or use of personal protective measures to prevent mosquito bites. This did not reflect an absence of evidence on these topics, but rather a decision on the part of the WG and broader committee to focus resources on clinical questions that were judged most likely to benefit by a GRADE-based evidence appraisal. For non-GRADE recommendations, advice was based on a narrative review of the relevant literature evidence and expert opinion. For more information on the CATMAT approach to developing recommendations and guidelines, see the statement on [Evidence Based process for developing travel and tropical medicine related guidelines and recommendations](/en/public-health/services/publications/diseases-conditions/evidence-based-process-developing-travel-tropical-medicine-guidelines-recommendations.html)[Footnote 10](#fn10).
The following summarizes the process used to develop this statement and recommendations:
### GRADE Recommendations
1. An analytic framework identifying clinical preventive actions (interventions) and risk factors for JE was developed (Appendix 4).
2. From the analytic framework, the working group framed key concepts in the form of a PICO question (Population of interest, Intervention, Comparison, and Outcome) in order to develop focused GRADE-based recommendations. Evidence on efficacy and harms of JEV was considered for each PICO question.
The following PICO questions were identified:
1. Among adult Canadian travellers, does use of JEV (normal schedule) decrease the risk of acquiring JE compared to no vaccine (placebo)?
2. Among adult Canadian travellers, does use of an accelerated (0, 7 days) JEV schedule achieve levels of protection similar to or greater than a normal JEV schedule (0, 28 days)?
3. Among Canadian children, does use of JEV achieve levels of protection similar to that observed in adult travellers, and is use of JEV associated with similar harms to adults?
3. Other concepts from the analytical framework were identified to support the GRADE assessment but were framed as non-PICO questions. The following contextual questions were identified:
1. What is the risk of clinical JE among Canadian travellers?
2. What are the important risk factors for JE among Canadian travellers (e.g., destination, duration of travel)?
3. What are the values and preferences of Canadian travellers regarding the magnitude of risk reduction in JE that would make use of JEV worthwhile given associated costs and inconvenience?
4. Evidence was retrieved by performing searches in electronic databases (Ovid MEDLINE, Embase, Global Health, and Scopus) and by manually searching in Google for grey literature. Time period for the search was from earliest available to June 2015. There were 2 literature searches: 1. JE vaccine (efficacy and harms) and travellers and 2. Baseline risk of and risk factors for developing JE among travellers. Details on search strategies and dates are provided in Appendix 5. The inclusion and exclusion criteria were applied by 2 WG members to the identified studies, based on an initial screening of titles and abstracts. Studies were excluded if they appeared to be irrelevant, were not published in English or French, or were duplicates.
5. From these searches, relevant literature was identified. If evidence specific to Canadian travellers was not available, then evidence derived from other Western populations or from other populations, in that order of preference, was extracted.
6. Quality assessments were performed for: vaccine efficacy and adverse events (AE); and, risk of developing JE among travellers. Results were collated into summary of findings tables (see Appendices 5-7 and 9). We decided that there was insufficient evidence to subject the other questions to the GRADE process.
7. Recommendations were developed taking into consideration[Footnote 10](#fn10):
1. CATMAT's confidence in the estimates of effect for efficacy and JEV-associated AE;
2. the balance of harms and benefits; and,
3. CATMAT's judgement on the likely values and preferences of travellers and health care providers related to use of JEV.
### Non-GRADE Recommendations
1. Additional questions were identified that were not selected for GRADE review by the working group. They were:
1. What is the appropriate boostering interval for JEV?
2. Among older (aged > 65 years) Canadian travellers, does use of JEV achieve levels of protection similar to adult travellers?
3. Does an additional dose of vaccine on day 0 achieve a higher seroconversion rate than a single dose?
4. Do personal protective measures provide protection against bites from the type(s) of mosquitoes that transmit JE?
2. Evidence relevant to these questions was identified through the previously-described literature search, or was extracted from existing CATMAT statements. Recommendations are based on a narrative review of the evidence and expert opinion.
Results
-------
### General
The literature search on JE vaccine and travellers identified 423 studies of which 310 were excluded. The risk factors for JE search identified 131 studies of which 127 were excluded. The remaining 117 relevant articles addressed vaccine harms and/or benefits (N= 36), booster dose (N=10), accelerated schedule (N= 4), pediatric use (N=6) and risk factors (N=4). As well, 57 studies addressing burden of disease (incidence, morbidity, mortality, hospitalizations) among travellers, population-specific risk factors (e.g., age), itinerary-specific risk factors (e.g., destination, duration of travel), efficacy of preventive measures (e.g., personal protective measures), and/or disease treatment/management were retained. After the literature review was completed, an additional study on values and preferences was identified and included[Footnote 8](#fn8). In addition, in 2018 an updated IXIARO®product monograph[Footnote 1](#fn1) was released with expanded recommendations for use in Canada, and was used as a reference.
### GRADE questions
#### PICO questions
**Among adult Canadian travellers, does use of JEV (normal schedule) decrease the risk of acquiring JE as compared to no vaccine (placebo)?**
We did not identify evidence showing JEV reduces the incidence of JE (and associated harms) among travellers to endemic areas. Rather, efficacy is inferred from studies using serological correlates of protection. Efficacy of JEV (IXIARO®) was initially established through a non-inferiority comparison[Footnote 25](#fn25) to inactivated mouse brain-derived JE vaccine (MBV), trade name JEVAX, which is no longer licenced in Canada. Protection was defined using seroconversion rate (SCR) as an endpoint, i.e. a PRNT50 titre <10 at baseline and ≥10 post vaccination, or a 4-fold rise from a baseline titre of ≥10[Footnote 17](#fn17). The evidence from this trial[Footnote 25](#fn25), which included safety and immunogenicity outcomes, is summarized in Appendix 1 and 6. JEV and MBV performed similarly well in eliciting high SCR (> 95% of recipients) (moderate confidence in the estimates of effect, downgraded for indirectness given seroconversion is a surrogate of protection). The vaccines were associated with similar rates of systemic adverse effects; however, local reactions were more common with MBV (high confidence in estimate of effect).
Additional studies, without a comparator, have consistently shown that 2 doses of JEV (days 0, 28) achieve high SCR[Footnote 15](#fn15) [Footnote 26](#fn26) [Footnote 27](#fn27) [Footnote 28](#fn28) [Footnote 29](#fn29) [Footnote 30](#fn30) [Footnote 31](#fn31). Results from these studies are summarized in Figure 1.
**Figure 1. Japanese Encephalitis vaccine seroconversion rate (SCR) in adults (95% confidence interval)**
Data extracted from 9 studies[Footnote 12](#fn12) [Footnote 13](#fn13) [Footnote 15](#fn15) [Footnote 25](#fn25) [Footnote 26](#fn26) [Footnote 27](#fn27) [Footnote 28](#fn28) [Footnote 29](#fn29) [Footnote 30](#fn30).
**Among adult Canadian travellers, does use of an accelerated (0, 7 days) JEV schedule achieve levels of protection similar to or greater than a normal JEV schedule (0, 28 days)?**
In adults, an accelerated JEV schedule (first dose on day 0 and second dose on day 7) yielded similar SCR to the normal schedule (1 dose on each of days 0 and 28) (moderate confidence in the estimate of effect) (Appendix 7). Compared at a similar time point (10-14 days) after the initial dose[Footnote 26](#fn26), the accelerated schedule was associated with a significantly higher SCR (RR 3.95; 95% CI 3.16 to 4.92) than the normal schedule (low confidence in the estimate of effect). Safety profiles (Appendix 7) for the accelerated and normal schedule were similar (moderate to high confidence in the estimates of effect). This accelerated schedule has recently been approved for use in Canada for adults aged 18-65 years[Footnote 1](#fn1).
**Among Canadian children, does use of JEV achieve levels of protection similar to that observed in adult travellers and is JEV use associated with similar harms to adults?**
Through the literature review, GRADE assessments published in 2013 by the United States Advisory Committee on Immunization Practices (ACIP)[Footnote 32](#fn32) were identified. This work specifically addressed the question "Should inactivated Vero cell culture-derived Japanese encephalitis vaccine (JE-VC) be recommended for use in children 2 months through 16 years of age at increased risk of travel-related exposure to Japanese encephalitis virus". Adults were included in the analyses as a comparator. We judged that the ACIP GRADE could be used to address our PICO question: "Among Canadian children, does use of JEV achieve levels of protection similar to that observed in adult travellers?" We did not identify additional and relevant evidence published since this review in our literature search.
The ACIP concluded that SCR (moderate confidence in the estimate of effect) and rates of serious (low confidence in the estimate of effect) or systemic (moderate confidence in estimate of effect) adverse effects were similar in adults and children (see Appendix 8). A complete explanation of the assessment of quality of evidence is available elsewhere[Footnote 32](#fn32). Briefly, downgrading of the quality of evidence was done because of indirectness (e.g., because efficacy was not directly measured and/or the evidence was primarily developed with adults) and potential sources of bias (e.g., lack of blinding). Use of JEV in children aged 2 months to <18 years has recently been approved in Canada[Footnote 1](#fn1).
Evidence supporting the use of an accelerated schedule in children was not identified and use of an accelerated schedule in children is not approved in Canada[Footnote 1](#fn1). Hence, the normal schedule for JEV should be used for children when possible. However, it appears reasonable to use an off-label accelerated schedule for children in the circumstance where time does not allow for the normal schedule to be used, especially in older children.
#### Contextual questions
**What is the risk of clinical JE among Canadian travellers?**
Likelihood estimates for travel-related clinical JE are shown in Table 1. For calculations, the numerator reflects the number of published cases over a 10 year period (2006-2015). We used cases identified in data from a previous review[Footnote 33](#fn33) published in 2010 and identified more recent reports[Footnote 34](#fn34) [Footnote 35](#fn35) [Footnote 36](#fn36) [Footnote 37](#fn37) [Footnote 38](#fn38) [Footnote 39](#fn39) [Footnote 40](#fn40) [Footnote 41](#fn41) by applying the same search strategy as is described in the review. To be included, published cases must have been for a traveller returning to Canada, the United States (US) or Europe. For the denominator, we used outbound travel statistics for Canada, the United States and Europe [Footnote 42](#fn42) [Footnote 43](#fn43) [Footnote 44](#fn44).
We estimate the likelihood of clinical JE as approximately 1/10,000,000 trips (moderate confidence in the estimate of effect) for Canada, the United States and Europe (Table 1). The quality of the body of evidence was downgraded due to risk of bias (Appendix 9), i.e. not all cases in travellers may have been reported in the literature. In this respect, while we cannot be certain of the degree to which cases are under-reported, it has been suggested[Footnote 33](#fn33) that the majority are identified in the literature. Moreover, even if it was assumed that only 1 in 10 cases of JE disease in travellers were reported, the overall risk of JE would remain very low, i.e. approximately 1 case/1,000,000 trips.
Previous estimates for US and European travellers [Footnote 11](#fn11) [Footnote 45](#fn45) have also suggested a very low overall risk for JE.
**What are the important risk factors for JE among Canadian travellers (e.g., destination, duration of travel)?**
For the period of 2006-2015, we identified 18 published reports of JE, of which 17 were in travellers returning to Canada (1 case), the United States (5 cases) or Europe (11 cases). Including reports published before 2006 increased the total to 67 cases. Only 1 case identified was not in a traveller from the Western hemisphere and hence was excluded from the analysis. Overall, the case fatality rate was 20% (12/60) (outcome was unknown in 6 cases); most cases were in males (59%); the average age of cases was 39 years; and the mean duration of travel was 35 days (Figure 2). The countries to which exposure was most often ascribed were: were Thailand[Footnote 27](#fn27), Indonesia[Footnote 46](#fn46), China[Footnote 47](#fn47) and the Philippines[Footnote 48](#fn48) (Figure 3).
We estimate that travel-associated JE is rare, consistent with previous estimates[Footnote 11](#fn11). However, it also is widely accepted that certain subpopulations of travellers are at relatively higher risk for JE; examples include those travelling for an extended period and/or those spending substantial amounts of time in rural areas where vectors are more prevalent [Footnote 33](#fn33) [Footnote 45](#fn45) [Footnote 49](#fn49) [Footnote 50](#fn50) [Footnote 51](#fn51) [Footnote 52](#fn52) [Footnote 53](#fn53). We did not identify evidence (observational or randomized trials) that would allow robust estimates of the incremental impact of these factors on risk to be made, and for this reason did not assess this evidence with GRADE. Based on identified travel-related cases (N=66, see above) we nevertheless make the following observations:
* Among cases where age is available (N=57), there is not an obvious age associated trend, e.g., children aged 10 years or younger (5 cases) accounted for 9% of the total and adults aged 60 years or older (12 cases) accounted for 21% of the total.
* There is a trend towards increased likelihood of JE with longer duration travel. Specifically, median duration of travel for cases at 35 days (Figure 2) is approximately double the median duration (15 days) for all travel to endemic areas[Footnote 43](#fn43) [Footnote 44](#fn44). There is not, however, a clear cut-off for travel duration below which risk is absent (cases have been reported in short-term travellers) or for a travel duration at which disease likelihood crosses a "threshold" that would prompt use of JEV.
* Itineraries that include rural exposure are often reported in association with published cases[Footnote 33](#fn33). However, rural activity is not a universal risk factor nor, in the situation where time is spent in rural and urban areas, can the rural component of travel be definitively ascribed as the exposing activity. Hence, while there is consensus that activities in rural areas are "riskier", the absolute magnitude of the risk increase is unknown.
Appendix 10 describes how these and other factors might be used when undertaking a risk assessment for a person travelling to a JE risk area.
**Figure 2. Cumulative proportion of Japanese Encephalitis cases among travellers by duration of travel in days.**
**Figure 3. Proportion of Japanese Encephalitis cases (N=66) among travellers by country of exposure**
Table 1: Estimated overall attack rate of clinical Japanese Encephalitis for 2006-2015. Based on Canadian travel statistics, the mean duration of travel to endemic areas was approximately 15 days.
| Region of embarkation | Cases | Estimated travel volume (millions) 2006-2015 | Overall attack rate (cases/trips) for travellers (95% confidence interval) 2006-2015[Footnote 6](#fn2.6) |
| --- | --- | --- | --- |
| Canada | 1[Footnote 1](#fn2.1) | 11.65[Footnote 3](#fn2.3) | 1/11,650,000 (1/2,056,512 to 1/65,996,483) |
| United States | 5[Footnote 2](#fn2.2) | 55.4[Footnote 4](#fn2.4) | 1/11,078,000 (1/4,731859 to 1/25,935,276) |
| Europe | 11[Footnote 2](#fn2.2) | 150[Footnote 5](#fn2.5) | 1/13,636,363 (7,614,592 to 24,420,2750) |
|
Footnote 1
This was the only identified published case. Review of records from the National Microbiology Laboratory, which is the only entity in Canada performing confirmatory tests for JE, did not identify additional cases during the period in question (2006-2015).
[Return to footnote 1 referrer](#fn2.1-rf)
Footnote 2
Estimates based on published case reports and databases for outbound travel 2006-2015.
[Return to footnote 2 referrer](#fn2.2-rf)
Footnote 3
Source: Statistics Canada International Travel Survey[Footnote 43](#fn43). Countries included: China, India, Japan, Philippines, Thailand, Singapore, South Korea, Malaysia, Cambodia, Vietnam, Nepal, Taiwan, Pakistan, Indonesia, Sri Lanka, Laos, Burma, Brunei, Bangladesh, Papua New Guinea and Guam. Cumulative 10-yr country specific volumes extrapolated from estimates for 2014.
[Return to footnote 3 referrer](#fn2.3-rf)
Footnote 4
Source: U.S. Department of Commerce, National Travel and Tourism Office[Footnote 44](#fn44). Includes travel volumes to JE endemic countries that comprise Asian countries that comprise at least 0.3% of outbound traffic (China, India, Japan, Philippines, South Korea, Taiwan, Thailand, Vietnam and Singapore). Cumulative 10-yr country specific volumes extrapolated from estimates for 2014. This likely underestimates travel volume as travel to Asian destinations declined by approximately 15% from 2007-2014.
[Return to footnote 4 referrer](#fn2.4-rf)
Footnote 5
Source: Eurostat[Footnote 42](#fn42). Estimated as approximately 50% of the total (30 million) annual travel volume in 2014 between Europe and Asia. Estimate consistent with 2004 estimate of 17,000,000 trips to JE endemic countries[Footnote 11](#fn11).
[Return to footnote 5 referrer](#fn2.5-rf)
Footnote 6
Assumption: Travellers did not use Japanese Encephalitis vaccine.
[Return to footnote 6 referrer](#fn2.6-rf)
|
Table 2: Predicted JE event rates (clinical cases, long-term sequelae and deaths) with and without JEV if overall risk is 1 case/11.65 million trips. Expressed as attack rate per 10 million trips to endemic areas.[Footnote 1](#fn3.1)
| Group | Clinical JE (no vaccine) | Clinical JE (with vaccine) | JE sequelae (no vaccine) | JE sequelae (with vaccine) | Mortality (no vaccine) | Mortality (with vaccine) |
| --- | --- | --- | --- | --- | --- | --- |
| Attack rate (events/10,000,000 trips) |
| Canadian travellers to endemic areas | 0.858 | 0.043 | 0.322 | 0.016 | 0.215 | 0.011 |
|
Footnote 1
Assumptions: Vaccine efficacy = 95%, probability of serious sequelae among survivors = 50%, case fatality rate =25%.
[Return to footnote 1 referrer](#fn3.1-rf)
|
Table 3: Number needed to vaccinate to prevent a case, long-term sequelae and death at our JEV recommendation threshold (1 case/100,000 trips) and at the estimated overall risk (1 case/11,650,000 trips) of JE for Canadian travellers[Footnote 1](#fn4.1).
| Baseline risk (no vaccine) | Clinical JE | Severe sequelae | Death |
| --- | --- | --- | --- |
| 1/100,000 | 105,263 | 280,702 | 421,053 |
| 1/11,650,000 | 12,263,158 | 32,701,754 | 49,052,631 |
|
Footnote 1
Assumptions: Probability of serious sequelae among survivors = 50%, case fatality rate =25%.
[Return to footnote 1 referrer](#fn4.1-rf)
|
**What are the values and preferences of travellers regarding the magnitude of risk reduction in JE that would make use of JEV worthwhile given associated costs and inconvenience?**
Use of vaccines to prevent JE can be cost effective in endemic countries[Footnote 17](#fn17) [Footnote 54](#fn54) [Footnote 55](#fn55) [Footnote 56](#fn56) [Footnote 57](#fn57) [Footnote 58](#fn58). However, these represent scenarios where the burden of disease is relatively elevated and the cost of the intervention relatively reduced compared to the typical travel context. Further, cost-effectiveness might be moot for travellers as they often pay for travel-related vaccines. We did not identify evidence specific to the values and preferences of travellers related to JEV, including their Willingness to Pay (WTP) for vaccine-based protection.
For other immunizations against low likelihood but high hazard diseases (like JE), there is evidence that patients are sometimes willing to pay a modest sum to receive protection. For example, a discrete choice experiment[Footnote 9](#fn9) indicated that patients, on average, were willing to pay approximately 250-300 Australian dollars for the protection afforded by a meningococcal B vaccine that was: 90% effective; required a single primary dose; provided protection that lasted for 10 years: and, was without adverse effects. However, WTP decreased substantially if vaccine characteristics did not meet these performance standards, e.g., if effectiveness was < 90%, duration of protection was shorter, there were associated adverse effects and/or more than 1 injection was required. Similarly, a discrete choice study of traveller willingness to pay for hypothetical travel vaccines identified disease risk, severity and intervention cost as having the most important impacts on decision making[Footnote 8](#fn8). Moreover, the study respondents showed a significant bias towards not opting out of vaccination, up to a risk level of 1/100,000. Lower risk levels, e.g., as would typically be experienced for JE, were not evaluated in the study, nor were safety aspects of the hypothetical vaccines.
If WTP was influenced by similar factors for JEV, then some travellers might be willing to pay to receive immunization despite the low risk of disease. This would be tempered by vaccine characteristics perceived as suboptimal, which, in turn, would result in reduced WTP; for JEV, this would include the requirement for multiple doses and the relatively short duration of protection following primary vaccination.
### Non-GRADE questions
**What is the appropriate boostering interval for JEV?**
In clinical trials to date, a primary series of JEV induced protective antibody levels that declined gradually over time, with 80-95% of fully immunized vaccine recipients maintaining adequate antibodies after 6 months and 58-83% maintaining adequate levels at 12-15 months[Footnote 1](#fn1) [Footnote 13](#fn13) [Footnote 30](#fn30) [Footnote 60](#fn60). At 24 months following primary series the evidence is less clear, with a study indicating that only 48% maintained seroprotection levels[Footnote 59](#fn59) and another study showing that 82% maintained adequate SCR[Footnote 1](#fn1).
A phase 3 clinical study conducted with 198 subjects in Austria and Germany found that a booster provided at 15 months after the primary series increased SCR to 100% at 28 days and SCR remained at 99% 12 months after the booster dose[Footnote 13](#fn13). Longer term protection was demonstrated in an extension of the trial which followed a subset of the previous participants (N=67)[Footnote 12](#fn12). At month 76, 96% of participants had adequate SCR[Footnote 12](#fn12) (see Figure 1). Geometric mean titres (GMT) were examined stratified by age and sex and prior vaccinations. Differences were found by age, where participants older than 50 years (N=6) had statistically significantly lower GMT compared to participants less than 50 years of age, although the sample size was very small[Footnote 12](#fn12).
Data on immunogenicity of a booster vaccine in children remains limited. Data from a small study of children (N=18) from non-JE endemic areas indicted that although antibodies titres declined over time, SCR was still high (89%) 36 months after vaccination[Footnote 14](#fn14). A larger pediatric study of 149 children and adolescents from a JE-endemic area found similar results, with SCR over 80% in all age groups up to month 36[Footnote 14](#fn14). Though limited, the available evidence suggests that antibody responses are at least as persistent in children as in adults.
Early evidence from a mathematical model based on titres after primary immunization and 12 months after booster administration predicted that 50% of vaccine recipients would remain protected after 8 years[Footnote 13](#fn13). An updated modeling estimate based on data at 76 months indicates that a single booster may provide an even longer period of protection than previously estimated[Footnote 12](#fn12). Additional information is required on length of protection, stratified by population subgroups of interest.
Based on the available human data, it seems reasonable to administer a single booster dose of JEV if the primary series was administered more than 1 year previously. In 2011 ACIP stated that a booster dose may be given if the primary series was administered more than a year previously, and there is potential for JE virus exposure[Footnote 20](#fn20). In 2018 the Canadian product monograph for IXIARO®was updated[Footnote 1](#fn1) and now recommends that adults and children receive a booster dose 12-24 months after the primary series, prior to re-exposure[Footnote 1](#fn1).
A second booster dose is suggested by the Canadian product monograph for adults (aged 18-65), 10 years after the first booster[Footnote 1](#fn1) and prior to any re-exposure. A similar approach has been approved by the European Medicine Agency[Footnote 2](#fn2). Among children, evidence of long term seroprotection is limited but does suggest that antibody responses are at least as persistent in children as in adults. For this reason CATMAT suggests that it is reasonable to follow the same recommended second booster approach for children (off-label) as for adults.
**Among older (aged >65 years) Canadian travellers, does use of JEV achieve levels of protection similar to adult travellers?**
In general, older individuals are more likely to acquire infection and experience more severe disease, possibly due to immunosenescence, less robust physical barriers to infection, and medical comorbidities[Footnote 60](#fn60). It should be noted that only a tiny minority of the participants in the important JEV clinical trials that established safety and efficacy appear to have been over the age of 65[Footnote 13](#fn13) [Footnote 15](#fn15) [Footnote 25](#fn25) [Footnote 30](#fn30) [Footnote 31](#fn31) [Footnote 61](#fn61). Interestingly, 9.8% of travellers evaluated at Global TravEpiNet travel medicine clinics in the United States between 2009-2012 judged to be at risk for the acquisition of Japanese encephalitis were over the age of 65[Footnote 62](#fn62). This proportion may be increasing; from 2012 to 2015, the annual number of Canadian travellers aged 54 years and older visiting areas of JE risk has increased from approximately 600,000 to over 1 million[Footnote 43](#fn43). Fortunately, none of the 42 AEs following immunization with JEV in the United States reported to the Vaccine Adverse Event Reporting System between 2009-2012 occurred in individuals older than 60 years of age[Footnote 6](#fn6).
One open-label uncontrolled phase IV clinical trial of JEV was conducted in healthy adults aged > 65 years to evaluate safety and immunogenicity in this particular population[Footnote 15](#fn15). Of the 249 individuals screened at travel medicine clinics and clinical vaccine trial sites, 200 received the first dose, and 193 received a second dose 28 days later. Seroconversion was observed in 65% (95% CI 58 - 71%) at day 70; no significant differences were found in adults aged 65-74 and those over 75 years of age. These SCR appear to be substantially lower than those observed in previous trials enrolling younger adults[Footnote 25](#fn25). The authors postulated that duration of protection may also be much shorter in elderly individuals and recommended consideration of booster immunizations before 1 year after the primary series, though they did not specify exactly what the optimal booster interval should be. Only a small minority (24 of 200, 12%) were older than 75 years of age. Overall, 61% percent of participants experienced any AE, with 47% of participants having had an AE thought to be related to vaccine; no differences were observed between the different age groups. These rates may have been higher than AE following immunization rates observed in previous clinical trials enrolling younger adults[Footnote 31](#fn31). A third of participants reported local AEs within the first week after any dose of vaccine and 27% reported systemic AEs (72% of which were judged to be mild), most frequently headache and myalgia. There were no AEs found to be caused by the vaccine that were either serious or medically attended.
The new IXIARO®product monograph recommends that for adults 65 and older who remain at risk for re-exposure that an earlier booster dose may be considered, although the time period is not specified[Footnote 1](#fn1). ATMAT suggests that for adults aged > 65 a single booster dose of JEV be considered before 12 months following the primary series and assessment of the precise timing of vaccine administration should be done on a case-by-case basis**.**
**Does an additional dose of vaccine on day 0 achieve a higher SCR than a single dose?**
As noted previously, there are obvious advantages to abbreviating vaccination regimens. An initial dose-finding phase II study demonstrated that 22 of 23 (96%) healthy individuals recruited at the Walter Reed Army Institute of Research who received a double dose (12 μg) of JE-VC seroconverted at 1 month post-immunization[Footnote 28](#fn28). Unfortunately, a follow-up multicentre phase III study was not able to duplicate these results[Footnote 27](#fn27). Of 490 individuals screened in Germany and Northern Ireland, 374 were enrolled and randomized 1:1:1 to a single 12 μg dose, two 6 μg doses (standard regimen), and a single 6 μg dose. Only 66% (95% CI 57-74%) of those randomized to the single 12 μg-dose arm seroconverted at 28 days, which further decreased to 41% (95% CI 32-50%) at 56 days. This was obviously inferior to the standard 2x6 μg dose regimen, which was associated with a 97% (95% CI 94-100%) seroconversion rate at 56 days[Footnote 27](#fn27).
As a result, a single 12 μg-dose regimen cannot be routinely recommended. In certain specific scenarios, when the travel timeframe precludes administration of JEV using standard or accelerated schedules, vaccine providers may consider giving a 12 μg dose, as this would appear to elicit a superior immune response as compared to a single standard dose. These travellers should have their vaccine series completed when possible, should they remain at risk for JE acquisition in future.
**Do personal protective measures provide protection against bites from the type(s) of mosquitoes that transmit JE?**
Insect repellents[Footnote 63](#fn63) [Footnote 64](#fn64), permethrin-treated bed nets[Footnote 65](#fn65) [Footnote 66](#fn66) and permethrin-treated clothing[Footnote 67](#fn67) have efficacy against the types of mosquitoes (*Culex* species) that transmit JE virus. Hence, these interventions should be used to reduce exposure to the mosquito vectors of JE. For more detail on these interventions as well as other approaches to prevent the bites of arthropods, readers are referred to the CATMAT statement on personal protective measures to prevent insect bites[Footnote 16](#fn16).
Conclusions and Research Needs
------------------------------
Our recommendations are based on the supposition that likelihood of JE is negligible for the large majority of travellers (moderate confidence). However, we were unable to determine the magnitude of increased JE risk due to other factors, such as duration of travel, or rural exposure. Research to define the impact of such risk factors on the likelihood of developing travel-associated JE would allow for the development of more precise recommendations. Similarly, CATMAT's confidence in estimates of patient values and preferences, including WTP for JEV, was low. A greater focus on the development of evidence to define these parameters for JEV, as well as other travel-related interventions, would allow: guideline developers to elaborate more precise recommendations; and, practitioners to develop more targeted advice for individual patients.
Acknowledgements
----------------
**This statement was developed by the Japanese Encephalitis Working Group:** Schofield S (Lead), Brophy J, Pernica J and approved by CATMAT.
CATMAT would like to acknowledge the technical and administrative support from the Office of Border and Travel Health at the Public Health Agency of Canada for the development of this statement.
CATMAT members:
McCarthy A (Chair), Acharya A, Boggild A, Brophy J, Bui Y, Crockett M, Greenaway C, Libman M, Teitelbaum P and Vaughan S.
Liaison members:
Angelo K (United States Centers for Disease Control and Prevention), Audcent T (Canadian Paediatric Society) and Pernica J (Association of Medical Microbiology and Infectious Disease Canada).
Ex officio members:
Marion D (Canadian Forces Health Services Centre, Department of National Defence), McDonald P (Bureau of Medical Sciences, Health Canada), Rossi C (Medical Intelligence, Department of National Defence) and Schofield S (Pest Management Entomology, Department of National Defence).
Conflict of Interest
--------------------
None declared.
References
----------
Footnote 1
Valneva Austria GmbH. IXIARO Product Monograph. 2018.
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
European Medicines Agency. Ixiaro - Japanese-encephalitis vaccine (inactivated, adsorbed). 2016; Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000963/human\_med\_000862.jsp&mid=WC0b01ac058001d124.
[Return to footnote 2 referrer](#fn2-rf)
Footnote 3
US Food and Drug Administration. Approval Letter - IXIARO. May 17, 2013; Available at: https://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm353334.htm. Accessed April 11, 2017.
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
Centers for Disease Control and Prevention. Use of Japanese encephalitis vaccine in children: Recommendations of the advisory committee on immunization practices, 2013. MMWR Morb Mortal Wkly Rep 2013;62(45):898-900.
[Return to footnote 4 referrer](#fn4-rf)
Footnote 5
Tauber E, Kollaritsch H, Von Sonnenburg F, Lademann M, Jilma B, Firbas C, et al. Randomized, double-blind, placebo-controlled phase 3 trial of the safety and tolerability of IC51, an inactivated Japanese encephalitis vaccine. J Infect Dis 2008 15 Aug 2008;198(4):493-499.
[Return to footnote 5 referrer](#fn5-rf)
Footnote 6
Rabe IB, Miller ER, Fischer M, Hills SL. Adverse events following vaccination with an inactivated, Vero cell culture-derived Japanese encephalitis vaccine in the United States, 2009-2012. Vaccine 2015 Jan 29;33(5):708-712.
[Return to footnote 6 referrer](#fn6-rf)
Footnote 7
Walker WL, Hills SL, Miller ER, Fischer M, Rabe IB. Adverse events following vaccination with an inactivated, Vero cell culture-derived Japanese encephalitis vaccine in the United States, 2012-2016. Vaccine 2018 Jul 5;36(29):4369-4374.
[Return to footnote 7 referrer](#fn7-rf)
Footnote 8
Poulos C, Curran D, Anastassopoulou A, De Moerlooze L. German travelers' preferences for travel vaccines assessed by a discrete choice experiment. Vaccine 2018 Feb 8;36(7):969-978.
[Return to footnote 8 referrer](#fn8-rf)
Footnote 9
Marshall HS, Chen G, Clarke M, Ratcliffe J. Adolescent, parent and societal preferences and willingness to pay for meningococcal B vaccine: A Discrete Choice Experiment. Vaccine 2016 1/27;34(5):671-677.
[Return to footnote 9 referrer](#fn9-rf)
Footnote 10
Committee to Advise on Tropical Medicine and Travel (CATMAT). Evidence Based Process for developing travel and tropical medicine related guidelines and recommendations. 2017; Available at: https://www.canada.ca/en/public-health/services/publications/diseases-conditions/evidence-based-process-developing-travel-tropical-medicine-guidelines-recommendations.html. Accessed January 9 2018, 2018.
[Return to footnote 10 referrer](#fn10-rf)
Footnote 11
Hatz C, Werlein J, Mutsch M, Hufnagel M, Behrens RH. Japanese encephalitis: defining risk incidence for travelers to endemic countries and vaccine prescribing from the UK and Switzerland. Journal of Travel Medicine 2009;16(3):200-203.
[Return to footnote 11 referrer](#fn11-rf)
Footnote 12
Paulke-Korinek M, Kollaritsch H, Kundi M, Zwazl I, Seidl-Friedrich C, Jelinek T. Persistence of antibodies six years after booster vaccination with inactivated vaccine against Japanese encephalitis. Vaccine 2015;33(30):3600-3604.
[Return to footnote 12 referrer](#fn12-rf)
Footnote 13
Eder S, Dubischar-Kastner K, Firbas C, Jelinek T, Jilma B, Kaltenboeck A, et al. Long term immunity following a booster dose of the inactivated Japanese Encephalitis vaccine IXIARO(R), IC51. Vaccine 2011 Mar 21;29(14):2607-2612.
[Return to footnote 13 referrer](#fn13-rf)
Footnote 14
Valneva Austria GmbH. New Clinical Data for IXIARO®Japanese Encephalitis Vaccine, Inactivated, Adsorbed. 2016 February 24.
[Return to footnote 14 referrer](#fn14-rf)
Footnote 15
Cramer JP, Jelinek T, Paulke-Korinek M, Reisinger EC, Dieckmann S, Alberer M, et al. One-year immunogenicity kinetics and safety of a purified chick embryo cell rabies vaccine and an inactivated Vero cell-derived Japanese encephalitis vaccine administered concomitantly according to a new, 1-week, accelerated primary series. J Travel Med 2016 Mar 19;23(3):10.1093/jtm/taw011. Print 2016 Mar.
[Return to footnote 15 referrer](#fn15-rf)
Footnote 16
Committee to Advise on Tropical Medicine and Travel. Statement on personal protective measures to prevent arthropod bites. Can Commun Dis Rep 2012;38(ACS-3).
[Return to footnote 16 referrer](#fn16-rf)
Footnote 17
World Health Organization. Japanese Encephalitis Vaccines: WHO position paper - February 2015. Weekly Epidemiological Record 2015;9(90):69-88.
[Return to footnote 17 referrer](#fn17-rf)
Footnote 18
Campbell GL, Hills SL, Fischer M, Jacobson JA, Hoke CH, Hombach JM, et al. Estimated global incidence of Japanese encephalitis: a systematic review. Bull World Health Organ 2011;89(10):766-774.
[Return to footnote 18 referrer](#fn18-rf)
Footnote 19
Centers for Disease Control and Prevention. Japanese Encephalitis Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2010;59(RR01):1-27.
[Return to footnote 19 referrer](#fn19-rf)
Footnote 20
Centers for Disease Control and Prevention. Recommendations for use of a booster dose of inactivated vero cell culture-derived Japanese encephalitis vaccine: advisory committee on immunization practices, 2011. MMWR Morb Mortal Wkly Rep 2011;60(20):661-663.
[Return to footnote 20 referrer](#fn20-rf)
Footnote 21
Halstead SB, Jacobson J, Dubischar-Kastner K. Japanese encephaltis vaccines. In: Plotkin S, Orenstein WA, Offit P, editors. Vaccines. 6th ed. China: Elsevier Saunders; 2013. p. 312-351.
[Return to footnote 21 referrer](#fn21-rf)
Footnote 22
Solomon T, Nguyen MD, Kneen R, Gainsboroug M, Vaughn DW, Khanh VT. Japanese encephalitis. J Neurol Neurosurg Ps 2000;68:405-415.
[Return to footnote 22 referrer](#fn22-rf)
Footnote 23
Erlanger TE, Weiss S, Keiser J, Utzinger J, Wiedenmayer K. Past, Present, and Future of Japanese Encephalitis. Emerg Infect Dis 2009;15(1):1-7.
[Return to footnote 23 referrer](#fn23-rf)
Footnote 24
Public Health Agency of Canada. Canadian Immunization Guide: Part 4 - Active Vaccines. 2014; Available at: https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-11-japanese-encephalitis-vaccine.html.
[Return to footnote 24 referrer](#fn24-rf)
Footnote 25
Tauber E, Kollaritsch H, Korinek M, Rendi-Wagner P, Jilma B, Firbas C, et al. Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: a non-inferiority, phase III, randomised controlled trial. Lancet 2007;370(9602):1847-1853.
[Return to footnote 25 referrer](#fn25-rf)
Footnote 26
Jelinek T, Burchard GD, Dieckmann S, Bühler S, Paulke-Korinek M, Nothdurft HD, et al. Short-Term Immunogenicity and Safety of an Accelerated Pre-Exposure Prophylaxis Regimen With Japanese Encephalitis Vaccine in Combination With a Rabies Vaccine: A Phase III, Multicenter, Observer-Blind Study. Journal of Travel Medicine 2015.
[Return to footnote 26 referrer](#fn26-rf)
Footnote 27
Schuller E, Klade CS, Wölfl G, Kaltenböck A, Dewasthaly S, Tauber E. Comparison of a single, high-dose vaccination regimen to the standard regimen for the investigational Japanese encephalitis vaccine, IC51: A randomized, observer-blind, controlled Phase 3 study. Vaccine 2009;27(15):2188-2193.
[Return to footnote 27 referrer](#fn27-rf)
Footnote 28
Lyons A, Kanesa-thasan N, Kuschner RA, Eckels KH, Putnak R, Sun W, et al. A Phase 2 study of a purified, inactivated virus vaccine to prevent Japanese encephalitis. Vaccine 2007;25(17):3445-3453.
[Return to footnote 28 referrer](#fn28-rf)
Footnote 29
Kaltenböck A, Dubischar-Kastner K, Schuller E, Datla M, Klade CS, Kishore TSA. Immunogenicity and safety of IXIARO®(IC51) in a Phase II study in healthy Indian children between 1 and 3 years of age. Vaccine 2010;28(3):834-839.
[Return to footnote 29 referrer](#fn29-rf)
Footnote 30
Schuller E, Jilma B, Voicu V, Golor G, Kollaritsch H, Kaltenböck A, et al. Long-term immunogenicity of the new Vero cell-derived, inactivated Japanese encephalitis virus vaccine IC51. Six and 12 month results of a multicenter follow-up phase 3 study. Vaccine 2008;26(34):4382-4386.
[Return to footnote 30 referrer](#fn30-rf)
Footnote 31
Tauber E, Kollaritsch H, Von Sonnenburg F, Lademann M, Jilma B, Firbas C, et al. Randomized, double-blind, placebo-controlled phase 3 trial of the safety and tolerability of IC51, an inactivated Japanese encephalitis vaccine. J Infect Dis 2008;198(4):493-499.
[Return to footnote 31 referrer](#fn31-rf)
Footnote 32
Centers for Disease Control and Prevention. Grading of recommendations, assessment, development, and evaluation (GRADE) for use of inactivated Vero cell culture-derived Japanese encephalitis vaccine in children. 2014; Available at: http://www.cdc.gov/vaccines/acip/recs/grade/je-child.html. Accessed May 16, 2016.
[Return to footnote 32 referrer](#fn32-rf)
Footnote 33
Hills SL, Griggs AC, Fischer M. Japanese encephalitis in travelers from non-endemic countries, 1973-2008. Am J Trop Med Hyg 2010;82(5):930-936.
[Return to footnote 33 referrer](#fn33-rf)
Footnote 34
Hills S.L., Stoltey J., Martinez D., Kim P.Y., Sheriff H., Zangeneh A., et al. A case series of three US adults with Japanese encephalitis, 2010-2012. 2014;. Accessed 5, 21.
[Return to footnote 34 referrer](#fn34-rf)
Footnote 35
Lagarde S., Lagier J.-C., Charrel R., Querat G., Vanhomwegen J., Despres P., et al. Japanese encephalitis in a French traveler to Nepal. 2014;. Accessed 1, 20.
[Return to footnote 35 referrer](#fn35-rf)
Footnote 36
Chen L, Peek M, Stokich D, Todd R, Anderson M, Murphy FK, et al. Japanese encephalitis in two children-United States, 2010. Morb Mortal Weekly Rep 2011;60(9):276-278.
[Return to footnote 36 referrer](#fn36-rf)
Footnote 37
Langevin S, Libman M, Drebot MA, Laverdiere M. A case of Japanese encephalitis virus infection acquired during a trip in Thailand. Journal of Travel Medicine 2012 March-April 2012;19(2):127-129.
[Return to footnote 37 referrer](#fn37-rf)
Footnote 38
Werlinrud AM, Christiansen CB, Koch A. Japanese encephalitis in a Danish short-term traveler to Cambodia. Journal of Travel Medicine 2011;18(6):411-413. 10 ref.
[Return to footnote 38 referrer](#fn38-rf)
Footnote 39
Doti P, Castro P, Martinez MJ, Zboromyrska Y, Aldasoro E, Inciarte A, et al. A case of Japanese encephalitis in a 20 year-old Spanish sportsman, February 2013. Euro Surveill 2013 Aug 29;18(35):20573.
[Return to footnote 39 referrer](#fn39-rf)
Footnote 40
Tappe D, Nemecek A, Zipp F, Emmerich P, Gabriel M, Gunther S, et al. Two laboratory-confirmed cases of Japanese encephalitis imported to Germany by travelers returning from Southeast Asia. J Clin Virol 2012 Jul;54(3):282-285.
[Return to footnote 40 referrer](#fn40-rf)
Footnote 41
Jeurissen A, Strauven T. A case of aseptic meningitis due to Japanese encephalitis virus in a traveller returning from the Philippines. Acta Neurol Belg 2011 Jun;111(2):143-145.
[Return to footnote 41 referrer](#fn41-rf)
Footnote 42
Eurostat: Statistics Explained. File: Extra -EU-28 Transport of passengers in 2014. 2015; Available at: http://ec.europa.eu/eurostat/statistics-explained/index.php?title=File:Extra-EU-28\_transport\_of\_passengers\_in\_2014.jpg&direction=prev&oldid=314881. Accessed April 11, 2017.
[Return to footnote 42 referrer](#fn42-rf)
Footnote 43
Statistics Canada. International Travel Survey. Custom extract. 2014.
[Return to footnote 43 referrer](#fn43-rf)
Footnote 44
U.S. Department of Commerce. National Travel and Tourism Office: 2014 U.S. Resident Travel to Asia. 2014; Available at: http://travel.trade.gov/outreachpages/download\_data\_table/2014-US-to-Asia.pdf.
[Return to footnote 44 referrer](#fn44-rf)
Footnote 45
Fischer M, Lindsey N, Staples JE, Hills S, Centers for Disease Control and Prevention (CDC). Japanese encephalitis vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity & Mortality Weekly Report.Recommendations & Reports 2010;59(RR-1):1-27.
[Return to footnote 45 referrer](#fn45-rf)
Footnote 46
Artsob H, Spence L. Imported arbovirus infections in Canada, 1974-89. Can J Infect Dis 1991;2(3):95-100.
[Return to footnote 46 referrer](#fn46-rf)
Footnote 47
Boggild AK, Castelli F, Gautret P, Torresi J, von Sonnenburg F, Barnett ED, et al. Vaccine preventable diseases in returned international travelers: Results from the GeoSentinel Surveillance Network. Vaccine 2010;28(46):7389-7395.
[Return to footnote 47 referrer](#fn47-rf)
Footnote 48
Freedman DO, Weld LH, Kozarsky PE, Fisk T, Robins R, Von Sonnenburg F, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. New Engl J Med 2006;354(2):119-130.
[Return to footnote 48 referrer](#fn48-rf)
Footnote 49
World Health Organization. Japanese Encephalitis. International Travel and Health;2017.
[Return to footnote 49 referrer](#fn49-rf)
Footnote 50
World Health Organization. BACKGROUND PAPER ON JAPANESE ENCEPHALITIS VACCINES. International Health and Travel 2014.
[Return to footnote 50 referrer](#fn50-rf)
Footnote 51
Australian Government Department of Health. 4.8 Japanese encephalitis. THE AUSTRALIAN IMMUNISATION HANDBOOK 10TH EDITION; 2015. p. 261-270.
[Return to footnote 51 referrer](#fn51-rf)
Footnote 52
Direction générale de la Santé, Comité technique des vaccinations. Guide des vaccinations. Édition 2012. Saint-Denis : Inpes, France; 2012.
[Return to footnote 52 referrer](#fn52-rf)
Footnote 53
Institut de veille sanitaire: Bulletin epidemiologique hebdomadaire. Recommendations sanitaire pour les voyageurs 2014. 2014 3 juin;16-17.
[Return to footnote 53 referrer](#fn53-rf)
Footnote 54
Touch S, Suraratdecha C, Samnang C, Heng S, Gazley L, Huch C, et al. A cost-effectiveness analysis of Japanese encephalitis vaccine in Cambodia. Vaccine 2010 6/23;28(29):4593-4599.
[Return to footnote 54 referrer](#fn54-rf)
Footnote 55
Yin Z, Beeler Asay GR, Zhang L, Li Y, Zuo S, Hutin YJ, et al. An economic evaluation of the use of Japanese encephalitis vaccine in the expanded program of immunization of Guizhou province, China. Vaccine 2012 8/10;30(37):5569-5577.
[Return to footnote 55 referrer](#fn55-rf)
Footnote 56
Upreti SR, Janusz KB, Schluter WW, Bichha RP, Shakya G, Biggerstaff BJ, et al. Estimation of the impact of a Japanese encephalitis immunization program with live, attenuated SA 14-14-2 vaccine in Nepal. Am J Trop Med Hyg 2013 Mar;88(3):464-468.
[Return to footnote 56 referrer](#fn56-rf)
Footnote 57
GAVI Alliance. Japanese encephalitis vaccine. 2017; Available at: http://www.gavi.org/support/process/apply/.
[Return to footnote 57 referrer](#fn57-rf)
Footnote 58
Elias C, Okwo-Bele JM, Fischer M. A strategic plan for Japanese encephalitis control by 2015. Lancet Infect Dis 2009 Jan;9(1):7-3099(08)70290-1.
[Return to footnote 58 referrer](#fn58-rf)
Footnote 59
Dubischar-Kastner K, Eder S, Buerger V, Gartner-Woelfl G, Kaltenboeck A, Schuller E, et al. Long-term immunity and immune response to a booster dose following vaccination with the inactivated Japanese encephalitis vaccine IXIARO®, IC51. Vaccine 2010;28(32):5197-5202.
[Return to footnote 59 referrer](#fn59-rf)
Footnote 60
Liang SY. Sepsis and Other Infectious Disease Emergencies in the Elderly. Emerg Med Clin North Am 2016 8;34(3):501-522.
[Return to footnote 60 referrer](#fn60-rf)
Footnote 61
Erra EO, Askling HH, Yoksan S, Rombo L, Riutta J, Vene S, et al. Cross-protection elicited by primary and booster vaccinations against Japanese encephalitis: A two-year follow-up study. Vaccine 2013 12/17;32(1):119-123.
[Return to footnote 61 referrer](#fn61-rf)
Footnote 62
Deshpande BR, Rao SR, Jentes ES, Hills SL, Fischer M, Gershman MD, et al. Use of Japanese encephalitis vaccine in US travel medicine practices in Global TravEpiNet. Am J Trop Med Hyg 2014;91(4):694-698. 13 ref.
[Return to footnote 62 referrer](#fn62-rf)
Footnote 63
Croft AM. Malaria: prevention in travellers (non-drug interventions). Clinical Evidence 2014;2014.
[Return to footnote 63 referrer](#fn63-rf)
Footnote 64
Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011 Apr;64(4):401-406.
[Return to footnote 64 referrer](#fn64-rf)
Footnote 65
Moore SJ DM. History of insect repellents. In: Debboun M, Francis S, Strickman D, editor. Insect repellents: Principles, methods and uses: CRC Press; 2007. p. 3-29.
[Return to footnote 65 referrer](#fn65-rf)
Footnote 66
Pest Management Regulatory Agency. Homepage. 2011; Available at: http://www.hc-sc.gc.ca/ahc-asc/branch-dirgen/pmra-arla/index-eng.php.
[Return to footnote 66 referrer](#fn66-rf)
Footnote 67
United States Environmental Protection Agency. Office of Pesticide Programs. 2011; Available at: http://www.epa.gov/pesticides.
[Return to footnote 67 referrer](#fn67-rf)
Footnote 68
Centers for Disease Control and Prevention (CDC). Health Information for International Travellers, Yellow Book. Chapter 3 - Japanese Encephalitis.; 2018.
[Return to footnote 68 referrer](#fn68-rf)
Footnote 69
Schuller E, Klingler A, DubischarKastner K, Dewasthaly S, Muller Z. Safety profile of the Vero cell-derived Japanese encephalitis virus (JEV) vaccine IXIAROReg.. Vaccine 2011;29(47):8669-8676. 39 ref.
[Return to footnote 69 referrer](#fn69-rf)
Footnote 70
Kaltenböck A, Dubischar-Kastner K, Eder G, Jilg W, Klade C, Kollaritsch H, et al. Safety and immunogenicity of concomitant vaccination with the cell-culture based Japanese Encephalitis vaccine IC51 and the hepatitis A vaccine HAVRIX®1440 in healthy subjects: A single-blind, randomized, controlled Phase 3 study. Vaccine 2009;27(33):4483-4489.
[Return to footnote 70 referrer](#fn70-rf)
Footnote 71
Yun KW, Lee HJ, Kang JH, Eun BW, Kim Y, Kim K, et al. Safety and immunogenicity of a freeze-dried, Vero cell culture-derived, inactivated Japanese encephalitis vaccine (KD-287, ENCEVAC®) versus a mouse brain-derived inactivated Japanese encephalitis vaccine in children: a phase III, multicenter, double-blinded, randomized trial. BMC infectious diseases 2015;15(1):1.
[Return to footnote 71 referrer](#fn71-rf)
Footnote 72
Eder S, DubischarKastner K, Firbas C, Jelinek T, Jilma B, Kaltenboeck A, et al. Long term immunity following a booster dose of the inactivated Japanese Encephalitis vaccine IXIAROReg., IC51. Vaccine 2011;29(14):2607-2612. 27 ref.
[Return to footnote 72 referrer](#fn72-rf)
Appendix 1. Summary of findings for comparison of JEV to placebo: Adverse events (AE)
-------------------------------------------------------------------------------------
JEV compared to placebo: Adverse events (AE)
| Outcomes | Illustrative comparative risks[Footnote \*](#fn5.1) (95% CI) | Relative effect
(95% CI) | No of Participants
(studies) | Quality of the evidence
(GRADE) [Footnote ɫ](#fn5.2) | Comments |
| --- | --- | --- | --- | --- | --- |
| Assumed risk
Placebo (AE) | Corresponding risk
JEV |
| **Any SAEFI** | **Study population** | **RR 0.55**
(0.2 to 1.51) | 2650
(1 study) | ⊕⊕⊕⊝**moderatemoderate**[Footnote 1](#fn5.3) | None |
| **9 per 1000** | **5 per 1000**
(2 to 14) |
| **Any AEFI** | **Study population** | **RR 1.04**
(0.96 to 1.12) | 2650
(1 study) | ⊕⊕⊕⊕**high** | None |
| **566 per 1000** | **589 per 1000**
(544 to 634) |
| **Gastrointestinal** | **Study population** | **RR 1.06**
(0.81 to 1.39) | 2650
(1 study) | ⊕⊕⊕⊝**moderatemoderate**[Footnote 1](#fn5.3) | None |
| **94 per 1000** | **100 per 1000**
(76 to 131) |
| **Musculoskeletal** | **Study population** | **RR 0.99**
(0.82 to 1.19) | 2650
(1 study) | ⊕⊕⊕⊝**moderatemoderate**[Footnote 1](#fn5.3) | None |
| **183 per 1000** | **181 per 1000**
(150 to 217) |
| **Headache** | **Study population** | **RR 1.07**
(0.93 to 1.24) | 2656
(1 study) | ⊕⊕⊕⊝**moderatemoderate**[Footnote 1](#fn5.3) | None |
| **261 per 1000** | **279 per 1000**
(243 to 324) |
| **Rash** | **Study population** | **RR 0.86**
(0.42 to 1.77) | 2650
(1 study) | ⊕⊕⊕⊝**moderatemoderate**[Footnote 1](#fn5.3) | None |
| **15 per 1000** | **13 per 1000**
(6 to 27) |
| **Pain** | **Study population** | **RR 1.16**
(1 to 1.35) | 2650[Footnote 1](#fn1) | ⊕⊕⊕⊕**high** | None |
| **250 per 1000** | **290 per 1000**
(250 to 337) |
| **Itching** | **Study population** | **RR 0.52**
(0.29 to 0.92) | 2650
(1 study) | ⊕⊕⊕⊕**high** | None |
| **29 per 1000** | **15 per 1000**
(8 to 27) |
| **Tenderness** | **Study population** | **RR 1.21**
(1.06 to 1.38) | 2650
(1 study) | ⊕⊕⊕⊕**high** | None |
| **294 per 1000** | **355 per 1000**
(311 to 405) |
| **Hardness** | **Study population** | **RR 0.95**
(0.66 to 1.38) | 2650
(1 study) | ⊕⊕⊕⊝**moderate**[Footnote 1](#fn5.3) | None |
| **55 per 1000** | **52 per 1000**
(36 to 76) |
| **Swelling** | **Study population** | **RR 1.01**
(0.59 to 1.73) | 2650
(1 study) | ⊕⊕⊕⊝**moderate**[Footnote 1](#fn5.3) | None |
| **26 per 1000** | **26 per 1000**
(15 to 45) |
| **Redness** | **Study population** | **RR 1.23**
(0.85 to 1.79) | 2650
(1 study) | ⊕⊕⊕⊝**moderate**[Footnote 1](#fn5.3) | None |
| **50 per 1000** | **62 per 1000**
(43 to 90) |
|
Footnote \*
The basis for the **assumed risk** (e.g. the median control group risk across studies) is provided in footnotes. The **corresponding risk** (and its 95% confidence interval) is based on the assumed risk in the comparison group and the **relative effect** of the intervention (and its 95% CI).**CI:** Confidence interval; **RR:** Risk ratio
[Return to footnote \* referrer](#fn5.1-rf)
Footnote ɫ
GRADE's approach to rating quality of evidence uses ⊕ to denote rating up the quality and ⊝ to denote rating down the quality.
[Return to footnote ɫ referrer](#fn5.2-rf)
Footnote 1
Confidence intervals null effect and appreciable levels of benefits and harms.
Source: Tauber 2008[Footnote 31](#fn31)
[Return to footnote 1 referrer](#fn5.3-rf)
|
Appendix 2. Geographic distribution of Japanese encephalitis
------------------------------------------------------------
**U.S. Centers for Disease Control Yellow Book, Chapter 3 - Japanese encephalitis, 2018[Footnote 68](#fn68).**
Appendix 3. Country-specific[Footnote 1](#fn6.1) notes on Japanese encephalitis
-------------------------------------------------------------------------------
| COUNTRY | AFFECTED AREAS | TRANSMISSION SEASON | COMMENTS |
| --- | --- | --- | --- |
| Australia | * Rural areas surrounding the Murray River, near the border of Victoria and New South Wales.
* Outer Torres Strait islands
| December-May; all human cases reported February-April | * From 2021 to early 2022, a JE outbreak occurred in parts of Australia. In November 2022, JE virus was detected in pigs in the Murray River region, confirming risk of infection in humans.
* 1 human case reported from north Queensland mainland
|
| Bangladesh | Presumed widespread | Most human cases reported May-October | Sentinel surveillance has identified human cases in Chittagong, Dhaka, Khulna, Rajshahi, Ranjpur, and Sylhet Divisions; highest incidence reported from Rajshahi Division; outbreak reported from Tangail District, Dhaka Division, in 1977 |
| Bhutan | Very rare reports; probably endemic in nonmountainous areas | No data | Proximity to other endemic areas and presence of vectors suggests virus transmission is likely |
| Brunei | Presumed transmission in many areas for the country | Unknown; presumed year-round | Outbreak with laboratory confirmed cases occurred in October-December 2013 |
| Burma (Myanmar) | Limited data; presumed to be endemic countrywide | Unknown; most human cases reported May-October | Outbreaks of human disease documented in Shan and Rakhine States; antibodies documented in animals and humans in other areas |
| Cambodia | Presumed to be endemic countrywide | Year-round with peak season May-October | Sentinel surveillance has identified human cases in at least 15 of 23 provinces, including Phnom Penh, Takeo, Kampong Cham, Battambang, Svay Rieng, and Siem Reap; 1 case reported in 2010 in a traveller who visited Phnom Penh and Angkor Wat/Siem Reap only |
| China | Human cases reported from all provinces except Xizang (Tibet), Xinjiang, and Qinghai; JE virus isolated from mosquitoes in Tibet | Most human cases reported June-October | Highest rates reported from Guizhou, Shaanxi, Sichuan, and Yunnan provinces, and Chongqing City; vaccine not routinely recommended for travel limited to Beijing, Shanghai, Hong Kong City/Kowloon, Macau, or other major cities |
| India | Human cases reported from all states except Dadra, Daman, Diu, Gujarat, Himachal Pradesh, Jammu and Kashmir, Lakshadweep, Meghalaya, Nagar Haveli, Punjab, Rajasthan, and Sikkim | Most human cases reported May-October, especially in northern India; the season may be extended or year-round in some areas, especially in southern India | Highest rates of human disease reported from the states of Andhra Pradesh, Assam, Bihar, Goa, Haryana, Karnataka, Kerala, Tamil Nadu, Uttar Pradesh, and West Bengal |
| Indonesia | Presumed to be endemic countrywide | Year-round; peak season varies by island | Sentinel surveillance has identified human cases in Bali, Kalimantan, Java, Nusa Tenggara, Papua, and Sumatra; several traveller cases reported in recent years from Bali |
| Japan[Footnote 2](#fn6.2) | Rare sporadic human cases on all islands except Hokkaido; enzootic activity ongoing | Most human cases reported July-October | Large number of human cases reported until JE vaccination program introduced in late 1960s; most recent small outbreak reported from Chugoku district in 2002; enzootic transmission without human cases observed on Hokkaido; vaccine not routinely recommended for travel limited to Tokyo or other major cities |
| Korea, North | Limited data; presumed to be endemic countrywide | No data; proximity to South Korea suggests peak transmission is likely to be May-October | N/A |
| Korea, South[Footnote 2](#fn6.2) | Rare sporadic human cases countrywide; enzootic activity ongoing | Most human cases reported May-October | Large number of human cases reported until routine JE vaccination program introduced in mid-1980s; last major outbreak reported in 1982; vaccine not routinely recommended for travel limited to Seoul or other major cities |
| Laos | Limited data; presumed to be endemic countrywide | Year-round, with peak season June-September | Sentinel surveillance has identified human cases in north, central, and southern Laos |
| Malaysia | Endemic in Sarawak; sporadic cases reported from all other states; occasional outbreaks reported | Year-round; in Sarawak, peak season October-December | Most human cases from reported from Sarawak; vaccine not routinely recommended for travel limited to Kuala Lumpur or other major cities |
| Nepal | Endemic in southern lowlands (Terai); cases also reported from hill and mountain districts, including the Kathmandu valley | Most human cases reported June-October | Highest rates of human disease reported from western Terai districts, including Banke, Bardiya, Dang, and Kailali; vaccine not routinely recommended for those trekking in high-altitude areas |
| Pakistan | Limited data; human cases reported from around Karachi | Unknown | N/A |
| Papua New Guinea | Limited data; probably widespread | Unknown; probably year-round | Sporadic human cases reported from Western Province; serologic evidence of disease from Gulf and Southen Highland Provinces; a case of JE was reported from near Port Moresby in 2004 |
| Philippines | Human, animal and mosquito studies have indicated transmission in 32 provinces located in all regions of the country; presumed to be endemic countrywide | Year-round, with peak season June-September | Several traveller cases recently reported |
| Russia | Rare human cases reported from the Far Eastern maritime areas south of Khabarovsk | Most human cases reported July-September | Vaccine not routinely recommended |
| Singapore | Rare sporadic human cases reported | Year-round | Vaccine not routinely recommended |
| Sri Lanka | Endemic countrywide except in mountainous areas | Year-round with variable peaks based on monsoon rains | Highest rates of human disease reported from Anuradhapura, Gampaha, Kurunegala, Polonnaruwa, and Puttalam districts |
| Taiwan[Footnote 2](#fn6.2) | Rare sporadic human cases island-wide | Most human cases reported May-October | Large number of human cases reported until routine JE vaccination introduced in 1968; vaccine not routinely recommended for travel limited to Taipei or other major cities |
| Thailand | Endemic countrywide; seasonal epidemics in the northern provinces | Year-round with peak season May-October, especially in the north | Highest rates of human disease reported from the Chiang Mai Valley; several cases reported recently in travellers who visited resort or coastal areas of southern Thailand. |
| Timor-Leste | Sporadic human cases reported; presumed to be endemic countrywide | No data; cases reported year-round in neighboring West Timor | N/A |
| Vietnam | Endemic countrywide; seasonal epidemics in the northern provinces | Year-round with peak season May-October, especially in the north | Highest rates of disease in the northern provinces around Hanoi and northwestern and northeastern provinces bordering China |
| Western Pacific Islands | Outbreaks of human disease reported in Guam in 1947-1948 and Saipan in 1990 | Unknown; most human cases reported October-March | Outbreaks likely followed introduction of virus, with enzootic cycle not sustained; vaccine not recommended |
|
Footnote 1
Data are based on published reports and personal correspondence. Risk assessments should be performed cautiously, because risk can vary within areas and from year to year, and surveillance data regarding human cases and JE virus transmission are incomplete.
[Return to footnote 1 referrer](#fn6.1-rf)
Footnote 2
In some endemic areas, human cases among residents are limited because of natural immunity among older people or vaccination. However, because JE virus is maintained in an enzootic cycle between animals and mosquitoes, susceptible visitors to these areas still may be at risk for infection.
[Return to footnote 2 referrer](#fn6.2-rf)
|
Adapted from U.S. Centers for Disease Control Yellow Book, Chapter 3 - Japanese encephalitis, 2018 (68).
Appendix 4. Analytic framework for Japanese encephalitis vaccine (JEV)
----------------------------------------------------------------------
Appendix 5. Sample search strategy
----------------------------------
### Japanese encephalitis vaccination in travellers
Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE(R) and Ovid OLDMEDLINE(R) 1946 to June 22, 2015
| # | Searches | Results |
| --- | --- | --- |
| 1 | Encephalitis, Japanese/ep, mo, pc, px, sn, th | 1155 |
| 2 | [Footnote \*](#fn7.1)Encephalitis, Japanese/ | 1985 |
| 3 | [Footnote \*](#fn7.1)Encephalitis Virus, Japanese/ | 1417 |
| 4 | "Japanese encephalitis".tw,kw,kf. | 3739 |
| 5 | or/1-4 | 4188 |
| 6 | Japanese Encephalitis Vaccines/ad, ae, ct, im, st, tu, to [Administration & Dosage, Adverse Effects, Contraindications, Immunology, Standards, Therapeutic Use, Toxicity] | 334 |
| 7 | [Footnote \*](#fn7.1)Japanese Encephalitis Vaccines/ | 296 |
| 8 | Vaccination/ | 57681 |
| 9 | Immunization, Secondary/ or Immunization/ or Immunization Schedule/ | 56292 |
| 10 | (immuniz[Footnote \*](#fn7.1) or immunis[Footnote \*](#fn7.1) or vaccin[Footnote \*](#fn7.1)).tw. | 306066 |
| 11 | or/6-10 | 333811 |
| 12 | ("IC51" or "IC-51" or "IC 51" or Ixiaro).mp. | 41 |
| 13 | Travel/ | 20053 |
| 14 | (tourist[Footnote \*](#fn7.1) or travel[Footnote \*](#fn7.1)).tw. | 44184 |
| 15 | 13 or 14 | 53724 |
| 16 | 5 and 11 and (12 or 15) | 172 |
| 17 | exp Canada/ or (Canada or Canadian[Footnote \*](#fn7.1)).mp. | 162641 |
| 18 | (5 or 6 or 7) and 17 | 16 |
| 19 | 16 or 18 | 177 |
| 20 | animals/ not (humans/ and animals/) | 3968004 |
| 21 | letter/ or comment/ or editorial/ | 1418699 |
| 22 | 19 not (20 or 21) | 168 |
| 23 | remove duplicates from 22 | 165 |
Embase 1974 to June 22, 2015
| # | Searches | Results |
| --- | --- | --- |
| 1 | Japanese encephalitis/co, dt, ep, et, pc, th [Complication, Drug Therapy, Epidemiology, Etiology, Prevention, Therapy] | 430 |
| 2 | [Footnote \*](#fn7.1)Japanese encephalitis/ | 502 |
| 3 | [Footnote \*](#fn7.1)Japanese encephalitis virus/ | 1664 |
| 4 | "Japanese encephalitis".tw,kw. | 4291 |
| 5 | or/1-4 | 4601 |
| 6 | Japanese encephalitis vaccine/ae, ct, ad, it, dt, to [Adverse Drug Reaction, Clinical Trial, Drug Administration, Drug Interaction, Drug Therapy, Drug Toxicity] | 791 |
| 7 | [Footnote \*](#fn7.1)Japanese encephalitis vaccine/ | 478 |
| 8 | vaccination reaction/ or vaccination/ | 108357 |
| 9 | immunization/ | 82401 |
| 10 | (immuniz[Footnote \*](#fn7.1) or immunis[Footnote \*](#fn7.1) or vaccin[Footnote \*](#fn7.1)).tw. | 351057 |
| 11 | or/6-10 | 389810 |
| 12 | ("IC51" or "IC-51" or "IC 51" or Ixiaro).mp. | 124 |
| 13 | travel/ | 28902 |
| 14 | (tourist[Footnote \*](#fn7.1) or travel[Footnote \*](#fn7.1)).tw. | 54771 |
| 15 | or/13-14 | 65389 |
| 16 | 5 and 11 and (12 or 15) | 275 |
| 17 | exp Canada/ or (Canada or Canadian[Footnote \*](#fn7.1)).mp. | 213446 |
| 18 | 17 and (5 or 6 or 7) | 25 |
| 19 | 16 or 18 | 290 |
| 20 | animal/ not (human/ and animal/) | 1258280 |
| 21 | editorial/ or letter/ | 1363656 |
| 22 | 19 not (20 or 21) | 278 |
| 23 | remove duplicates from 22 | 276 |
Global Health 1973 to June 22, 2015
| # | Searches | Results |
| --- | --- | --- |
| 1 | Japanese encephalitis/ | 2266 |
| 2 | "Japanese encephalitis".tw,hw. | 4114 |
| 3 | Japanese encephalitis virus.od. | 3202 |
| 4 | or/1-3 | 4114 |
| 5 | vaccination/ | 46057 |
| 6 | immunization/ | 51546 |
| 7 | (immuniz[Footnote \*](#fn7.1) or immunis[Footnote \*](#fn7.1) or vaccin[Footnote \*](#fn7.1)).tw. | 104918 |
| 8 | or/5-7 | 104918 |
| 9 | ("IC51" or "IC-51" or "IC 51" or Ixiaro).mp. | 22 |
| 10 | exp travel/ or exp travel associated diseases/ | 4246 |
| 11 | (tourist[Footnote \*](#fn7.1) or travel[Footnote \*](#fn7.1)).tw. | 17930 |
| 12 | or/10-11 | 18052 |
| 13 | 4 and 8 and (9 or 12) | 162 |
| 14 | exp Canada/ or (Canada or Canadian[Footnote \*](#fn7.1)).mp. | 33670 |
| 15 | 14 and 4 | 14 |
| 16 | 13 or 15 | 171 |
| 17 | remove duplicates from 16 | 170 |
Footnote 1
denotes truncation; a technique used in developing literature search strategies that broadens the search to include various endings to the search term.
[Return to footnote 1 referrer](#fn7.1-rf)
SCOPUS to June 22, 2015
(((TITLE-ABS("Japanese encephalitis")) and (TITLE-ABS-KEY((immuniz\* or immunis\* or vaccin\*)))) and ((TITLE-ABS-KEY(("IC51" or "IC-51" or "IC 51" or Ixiaro))) or (TITLE-ABS-KEY((tourist\* or travel\*))))) or ((TITLE-ABS((Canada or Canadian\*))) and (TITLE-ABS("Japanese encephalitis"))) AND ( EXCLUDE(DOCTYPE,"le") OR EXCLUDE(DOCTYPE,"ch") OR EXCLUDE(DOCTYPE,"ed")) 214 Document results
Google Search, June 22, 2015
Centers for Disease Control and Prevention
CDC's Health Information for International Travel (Yellow Book)
http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/japanese-encephalitis.aspx
Use of Japanese Encephalitis Vaccine in Children: Recommendations of the Advisory Committee on Immunization Practices, 2013
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6245a3.htm
Novartis Product Monograph: https://www.ask.novartispharma.ca/download.htm?res=ixiaro\_patient\_e.pdf&resTitleId=462
Public Health Agency of Canada
https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html?page=11
U.S. Food and Drug Administration
http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm179132.htm
Japanese encephalitis: Risk factors for travellers
--------------------------------------------------
Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE(R) and Ovid OLDMEDLINE(R) 1946 to June 19, 2015
| # | Searches | Results |
| --- | --- | --- |
| 1 | Encephalitis, Japanese/ep, mo, pc, px, sn, th | 1155 |
| 2 | [Footnote \*](#fn8.1)Encephalitis, Japanese/ | 1985 |
| 3 | [Footnote \*](#fn8.1)Encephalitis Virus, Japanese/ | 1417 |
| 4 | (Japanese adj encephalitis).mp. | 3771 |
| 5 | or/1-4 | 4205 |
| 6 | Risk Factors/ | 603019 |
| 7 | ("risk factor[Footnote \*](#fn8.1)" or (risk[Footnote \*](#fn8.1) adj25 "japanese encephalitis")).tw. | 386859 |
| 8 | 6 or 7 | 792870 |
| 9 | Travel/ | 20052 |
| 10 | (travel[Footnote \*](#fn8.1) or tourist[Footnote \*](#fn8.1)).tw. | 44149 |
| 11 | or/9-10 | 53689 |
| 12 | 5 and 8 and 11 | 61 |
| 13 | animals/ not (humans/ and animals/) | 3967673 |
| 14 | letter/ or comment/ or editorial/ | 1417918 |
| 15 | 12 not (13 or 14) | 59 |
| 16 | remove duplicates from 15 | 58 |
Embase 1974 to June 19, 2015
| # | Searches | Results |
| --- | --- | --- |
| 1 | Japanese encephalitis/ | 957 |
| 2 | Japanese encephalitis virus/ | 2887 |
| 3 | (Japanese adj encephalitis).mp. | 5454 |
| 4 | or/1-3 | 5454 |
| 5 | risk factor/ | 685974 |
| 6 | ("risk factor[Footnote \*](#fn8.1)" or (risk[Footnote \*](#fn8.1) adj25 "japanese encephalitis")).tw. | 531075 |
| 7 | or/5-6 | 876042 |
| 8 | travel/ | 28870 |
| 9 | travel[Footnote \*](#fn8.1).tw. | 52460 |
| 10 | (travel[Footnote \*](#fn8.1) or tourist[Footnote \*](#fn8.1)).tw. | 54731 |
| 11 | 8 or 10 | 65347 |
| 12 | 4 and 7 and 11 | 85 |
| 13 | animal/ not (human/ and animal/) | 1258280 |
| 14 | letter/ or editorial/ | 1363439 |
| 15 | 12 not (13 or 14) | 85 |
Global Health 1973 to June 19, 2015
| # | Searches | Results |
| --- | --- | --- |
| 1 | Japanese encephalitis/ | 2266 |
| 2 | "Japanese encephalitis".tw,hw. | 4114 |
| 3 | Japanese encephalitis virus.od. | 3202 |
| 4 | or/1-3 | 4114 |
| 5 | risk factors/ | 134937 |
| 6 | ("risk factor[Footnote \*](#fn8.1)" or (risk[Footnote \*](#fn8.1) adj25 "japanese encephalitis")).tw. | 168829 |
| 7 | 5 or 6 | 168829 |
| 8 | exp travel/ | 4046 |
| 9 | (tourist[Footnote \*](#fn8.1) or travel[Footnote \*](#fn8.1)).tw. | 17930 |
| 10 | 8 or 9 | 18052 |
| 11 | 4 and 7 and 10 | 43 |
Footnote 1
denotes truncation; a technique used in developing literature search strategies that broadens the search to include various endings to the search term.
[Return to footnote 1 referrer](#fn8.1-rf)
Scopus to June 19, 2015
(TITLE("Japanese encephalitis") AND TITLE-ABS-KEY(risk\*)AND TITLE-ABS-KEY(travel\*)) AND ( LIMIT-TO(DOCTYPE,"ar") OR LIMIT-TO(DOCTYPE,"re"))
Appendix 6. Summary of findings for comparison of JEV and inactivated mouse-brain derived vaccine (MBV): Seroconversion rate (SCR) and adverse events (AE)
----------------------------------------------------------------------------------------------------------------------------------------------------------
MBV vs JEV: Seroconversion rate (SCR)
| Outcomes | Illustrative comparative risks[Footnote \*](#fn9.1) (95% CI) | Relative effect
(95% CI) | No of Participants
(studies) | Quality of the evidence
(GRADE) ɫ |
| --- | --- | --- | --- | --- |
| Assumed risk
MBV | Corresponding risk
JEV |
| **SCR** | **Study population** | **RR 1.03**
(1.01 to 1.06) | 725
(1 study) | ⊕⊕⊕⊝**moderate**[Footnote 1](#fn9.2) |
| **953 per 1000** | **982 per 1000**
(963 to 1000) |
|
Footnote 1
The basis for the **assumed risk** (e.g. the median control group risk across studies) is provided in footnotes. The **corresponding risk** (and its 95% confidence interval) is based on the assumed risk in the comparison group and the **relative effect** of the intervention (and its 95% CI).**CI:** Confidence interval; **RR:** Risk ratio
[Return to footnote \* referrer](#fn9.1-rf)
Footnote 1
Downgraded for indirectness; comparison based on serologic correlates of protection, not reduction in clinical incidence of disease.
Source: Tauber 2007[Footnote 25](#fn25)
[Return to footnote 1 referrer](#fn9.2-rf)
|
MBV vs JEV: Adverse events (AE)
| Outcomes | Illustrative comparative risks[Footnote \*](#fn10.1) (95% CI) | Relative effect
(95% CI) | No of Participants
(studies) | Quality of the evidence
(GRADE) [Footnote ɫ](#fn10.2) |
| --- | --- | --- | --- | --- |
| Assumed risk
MBV | Corresponding risk
JEV |
| **Headache** | **Study population** | **RR 0.92**
(0.74 to 1.14) | 863
(1 study) | ⊕⊕⊕⊕**high** |
| **287 per 1000** | **264 per 1000**
(213 to 328) |
| **ILI** | **Study population** | **RR 1**
(0.7 to 1.42) | 863
(1 study) | ⊕⊕⊕⊕**high** |
| **126 per 1000** | **126 per 1000**
(89 to 180) |
| **Myalgia** | **Study population** | **RR 1.3**
(0.97 to 1.72) | 863
(1 study) | ⊕⊕⊕⊕**high** |
| **159 per 1000** | **206 per 1000**
(154 to 273) |
| **Fatigue** | **Study population** | **RR 1.14**
(0.79 to 1.65) | 863
(1 study) | ⊕⊕⊕⊕**high** |
| **110 per 1000** | **126 per 1000**
(87 to 182) |
| **Redness** | **Study population** | **RR 0.09**
(0.03 to 0.24) | 863
(1 study) | ⊕⊕⊕⊕**high** |
| **106 per 1000** | **10 per 1000**
(3 to 25) |
| **Swelling** | **Study population** | **RR 0.13**
(0.04 to 0.44) | 863
(1 study) | ⊕⊕⊕⊕**high** |
| **53 per 1000** | **7 per 1000**
(2 to 23) |
| **Hardness** | **Study population** | **RR 0.16**
(0.06 to 0.46) | 863
(1 study) | ⊕⊕⊕⊕**high** |
| **57 per 1000** | **9 per 1000**
(3 to 26) |
|
Footnote \*
The basis for the **assumed risk** (e.g. the median control group risk across studies) is provided in footnotes. The **corresponding risk** (and its 95% confidence interval) is based on the assumed risk in the comparison group and the **relative effect** of the intervention (and its 95% CI).
[Return to footnote \* referrer](#fn10.1-rf)
Footnote ɫ
**CI:** Confidence interval; **RR:** Risk ratioGRADE's approach to rating quality of evidence uses ⊕ to denote rating up the quality and ⊝ to denote rating down the quality.
[Return to footnote ɫ referrer](#fn10.2-rf)
Footnote 1
Confidence intervals null effect and appreciable levels of benefits and harms.
Source: Tauber 2007[Footnote 25](#fn25)
[Return to footnote 1 referrer](#fn10.3-rf)
|
Appendix 7. Summary of findings for comparison of conventional immunization schedule for JEV (0, 28 days) to accelerated schedule (0, 7 days): Seroconversion rate (SCR) and adverse events (AE)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
JEV conventional vs accelerated schedule: Seroconversion rate (SCR)
| Outcomes | Illustrative comparative risks[Footnote \*](#fn11.1) (95% CI) | Relative effect
(95% CI) | No of Participants
(studies) | Quality of the evidence
(GRADE)ɫ | Comments |
| --- | --- | --- | --- | --- | --- |
| Assumed risk
Conventional | Corresponding risk
Accelerated |
| **SCR day 10-14** | **Study population** | **RR 3.95**
(3.16 to 4.92) | 441
(1 study) | ⊕⊕⊝⊝**low**[Footnote 1](#fn11.2),[Footnote 2](#fn11.3) | None |
| **252 per 1000** | **996 per 1000**
(797 to 1000) |
| **SCR 35** | **Study population** | **RR 0.99**
(0.97 to 1.01) | 410
(1 study) | ⊕⊕⊕⊝**moderate**[Footnote 2](#fn11.3) | None |
| **995 per 1000** | **985 per 1000**
(965 to 1000) |
|
Footnote \*
The basis for the **assumed risk** (e.g. the median control group risk across studies) is provided in footnotes. The **corresponding risk** (and its 95% confidence interval) is based on the assumed risk in the comparison group and the **relative effect** of the intervention (and its 95% CI).**CI:** Confidence interval; **RR:** Risk ratio
[Return to footnote \* referrer](#fn11.1-rf)
Footnote 1
Downgraded for risk of bias, evidence for conventional and accelerated schedules extracted from different studies.
[Return to footnote 1 referrer](#fn11.2-rf)
Footnote 2
Downgraded for indirectness; comparison based on serologic correlates of protection, not reduction in clinical incidence of disease.
Source: Jelinek 2015[Footnote 26](#fn26)
[Return to footnote 2 referrer](#fn11.3-rf)
|
JEV conventional vs accelerated schedule: Adverse events (AE)
| Outcomes | Illustrative comparative risks[Footnote \*](#fn12.1) (95% CI) | Relative effect
(95% CI) | No of Participants
(studies) | Quality of the evidence
(GRADE)[Footnote ɫ](#fn12.2) | Comments |
| --- | --- | --- | --- | --- | --- |
| Assumed risk
Control | Corresponding risk
IXIARO®accelerated AE |
| **Any AE** | **Study population** | **RR 1**
(0.91 to 1.09) | 383
(1 study) | ⊕⊕⊕⊕**high** | None |
| **831 per 1000** | **831 per 1000**
(757 to 906) |
| **Local** | **Study population** | **RR 0.99**
(0.88 to 1.11) | 383
(1 study) | ⊕⊕⊕⊕**high** | None |
| **753 per 1000** | **745 per 1000**
(663 to 836) |
| **Systemic** | **Study population** | **OR 1.28**
(0.84 to 1.94) | 383
(1 study) | ⊕⊕⊕⊝**moderate[Footnote 1](#fn12.3)** | None |
| **602 per 1000** | **660 per 1000**
(560 to 746) |
| **Other** | **Study population** | **OR 1.01**
(0.59 to 1.74) | 383
(1 study) | ⊕⊕⊕⊝**moderate[Footnote 1](#fn12.3)** | None |
| **169 per 1000** | **170 per 1000**
(107 to 261) |
|
Footnote \*
The basis for the **assumed risk** (e.g. the median control group risk across studies) is provided in footnotes. The **corresponding risk** (and its 95% confidence interval) is based on the assumed risk in the comparison group and the **relative effect** of the intervention (and its 95% CI).**CI:** Confidence interval; **RR:** Risk ratio; **OR:** Odds ratio
[Return to footnote \* referrer](#fn12.1-rf)
Footnote ɫ
GRADE's approach to rating quality of evidence uses ⊕ to denote rating up the quality and ⊝ to denote rating down the quality.
[Return to footnote ɫ referrer](#fn12.2-rf)
Footnote 1
Confidence intervals null effect and appreciable levels of benefits and harms.
Source: Jelinek 2015[Footnote 26](#fn26)
[Return to footnote 1 referrer](#fn12.3-rf)
|
Appendix 8. Summary of Advisory Committee on Immunization Practice (ACIP) GRADE results
---------------------------------------------------------------------------------------
Background:
* In 2009, ACIP at the Centers for Disease Control and Prevention (CDC) approved recommendations for use of inactivated Vero cell culture-derived Japanese encephalitis vaccine JEV for use in adults 17 years of age and older[Footnote 45](#fn45).
* In 2013 the ACIP performed a GRADE review for the use of JE-VC in children (4,32). The question was: Should inactivated Vero cell culture-derived Japanese encephalitis vaccine be recommended for used in children 2 months through 16 years of age at increased risk of travel-related exposure to Japanese encephalitis virus?
+ Population: children 2 months through 16 years
+ Intervention: JEV administered as a 2-dose primary series
+ Current option: No JEV recommended and available for use in children
* Benefits were seroprotection at 1 and 6 months after vaccination. Harms were systemic adverse effects (e.g. fever, rash, hypersensitivity or uticaria, neurologic and medically attended adverse effects) or serious adverse effects (Table A1).
Methods:
* Literature published from January 1 2006 to April 30 2013 was retrieved for review and inclusion/exclusion criteria are provided in the document (primary data, no case studies, FDA approved dose, human subjects, etc.).
+ 67 studies identified and 51 excluded
* Evidence for critical outcomes was assessed using GRADE criteria (Table A2).
Findings:
* JEV is effective using seroprotection as the endpoint and safe in children aged 2 months through 16 years. The workgroup proposed to extend the previous ACIP recommendations[Footnote 45](#fn45) for use of JEV in adults to include children ≥2 months of age; no other changes to the existing ACIP recommendations were proposed. Key factors considered in making the recommendation are summarized in Table A3.
Table A1. Evidence type for benefits and harms for JEV in children, adapted from CDC[Footnote 32](#fn32)
| Outcome | Design
(# studies)[Footnote 1](#ta1fn1) | Risk of bias | Inconsistency | Indirectness | Imprecision | Other[Footnote 2](#ta1fn2) | Evidence type[Footnote 3](#ta1fn3) |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Benefits |
| --- |
| Seroprotection at 1 month | RCT[Footnote 4](#ta1fn4) | No serious | No serious | Yes[Footnote 4](#ta1fn4) | No serious | None | 2 |
| Obs[Footnote 6](#ta1fn6) | No serious | No serious | No serious | No serious | None | 3 |
| Seroprotection at 6 months | RCT[Footnote 2](#ta1fn2) | No serious | No serious | Yes[Footnote 4](#ta1fn4) | No serious | None | 2 |
| Obs[Footnote 3](#ta1fn3) | No serious | No serious | No serious | No serious | None | 3 |
| Harms |
| Serious adverse events | RCT[Footnote 8](#fn8) | Yes[Footnote 5](#ta1fn5) | No serious | Yes[Footnote 6](#ta1fn6) | No serious | None | 3 |
| Obs[Footnote 5](#ta1fn5) | No serious | No serious | Yes[Footnote 6](#ta1fn6) | No serious | None | 4 |
| Systemic adverse events | RCT[Footnote 5](#ta1fn5) | Yes[Footnote 5](#ta1fn5) | No serious | No serious | No serious | None | 2 |
| Obs[Footnote 4](#ta1fn4) | No serious | No serious | No serious | No serious | None | 3 |
|
Footnote 1
RCT = Randomized controlled trial with JE-VC; Obs = Observational study, RCT without comparative data for the outcome measure, or post-marketing surveillance data.
[Return to footnote 1 referrer](#ta1fn1-rf)
Footnote 2
Publication bias, strength of association, dose response, or opposing plausible residual confounding.
[Return to footnote 2 referrer](#ta1fn2-rf)
Footnote 3
Evidence type: 1 = RCTs or overwhelming evidence from observational studies, 2 = RCTs with important limitations, or exceptionally strong evidence from observational studies, 3 = Observational studies, or RCTs with notable limitations,4 = Clinical experience and observations, observational studies with important limitations, or RCTs with several major limitations
[Return to footnote 3 referrer](#ta1fn3-rf)
Footnote 4
Indirectness due to different population (majority of data are in adults). No efficacy data are available but there is a well-established immunologic correlate of protection.
[Return to footnote 4 referrer](#ta1fn4-rf)
Footnote 5
Risk of bias due to inadequate blinding of study participants and personnel.
[Return to footnote 5 referrer](#ta1fn5-rf)
Footnote 6
Indirectness due to different population (majority of data are in adults).
[Return to footnote 6 referrer](#ta1fn6-rf)
|
Table A2. Overall quality of evidence for JEV in children, adapted from CDC[Footnote 32](#fn32)
| Outcome | Study design
(# studies)[Footnote 1](#fn13.1) | Finding | Evidence
Type[Footnote 2](#fn13.2),[Footnote 3](#fn13.3) | Overall quality
of evidence |
| --- | --- | --- | --- | --- |
| Seroprotection at 1 month | RCT[Footnote 4](#fn4) | High (>95%) at 1 month | 2 | 2 |
| Seroprotection at 6 months | RCT[Footnote 2](#fn2) | Maintained (85-90%) at 6 months | 2 |
| Serious adverse events | RCT[Footnote 8](#fn8) | Low incidence; similar to comparison vaccines | 3 |
| Systemic adverse events | RCT[Footnote 5](#fn5) | Similar to comparison vaccines | 2 |
|
Footnote 1
RCT = Randomized controlled trial.
[Return to footnote 1 referrer](#fn13.1-rf)
Footnote 2
Evidence type: 1 = RCTs or overwhelming evidence from observational studies, 2 = RCTs with important limitations, or exceptionally strong evidence from observational studies, 3 = Observational studies, or RCTs with notable limitations, 4 = Clinical experience and observations, observational studies with important limitations, or RCTs with several major limitations
[Return to footnote 2 referrer](#fn13.2-rf)
Footnote 3
Body of evidence for each outcome includes both RCTs and observational studies; the study design that provides higher quality of evidence was selected.
[Return to footnote 3 referrer](#fn13.3-rf)
|
Table A3. Considerations for formulating recommendations for use of JEV in children 2 months through 16 years of age at increased risk of travel-related exposure to Japanese encephalitis virus, adapted from CDC[Footnote 32](#fn32)
| Key factors | Comments |
| --- | --- |
| Evidence type for benefits and harms | * Overall evidence type 2 for vaccine safety and effectiveness using seroprotection as the endpoint
* Downgraded due to indirectness (majority of data in adults) and risk of bias (inadequate blinding of study participants and personnel)
|
| Balance between benefits and harms | * JE-VC provides high levels of seroprotection in children following a 2-dose primary series
* Serious adverse events are uncommon and rates are similar to those seen with comparison vaccines
* Systemic adverse events also occur at rates similar to comparison vaccines
|
| Value | * Prevent a serious disease with no treatment and poor outcomes
* Inform decisions about JE vaccination based on a traveller's planned itinerary
|
| Cost-effectiveness | * Not evaluated
* Low risk of disease and high vaccine cost
* Number of U.S. children who travel to Asia and have an itinerary that puts them at increased risk for JE is likely very low.
* Travel vaccines are usually paid for by the travellers themselves; JE-VC is not covered under the Vaccines for Children program or most insurance plans.
|
Appendix 9. Quality assessment for risk of Japanese encephalitis in travellers from Canada, the United States and Europe
------------------------------------------------------------------------------------------------------------------------
| Jurisdiction | Risk of bias[Footnote 1](#fn14.1) | Inconsistency | Indirectness | Imprecision | Other considerations | Estimated attack rate | Confidence in baseline estimate[Footnote ɫ](#fn14.5) |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Canada[Footnote 2](#fn14.2) |
| --- |
| Case reports against travel denominator
(2006-2015) | intermediate | no serious | no serious | none | none | 1/11,650,000 (95% CI 1/65,996,483; 1/2,056,512) | ⊕⊕⊕⊝
MODERATE |
| United States[Footnote 3](#fn14.3) |
| Case reports against travel denominator
(2006-2015) | intermediate | no serious | no serious | none | none | 1/11,078,000 (95% CI 1/25,935,276; 1/4,731859) | ⊕⊕⊕⊝
MODERATE |
| Europe[Footnote 4](#fn14.4) |
| Case reports against travel denominator
(2006-2015) | intermediate | no serious[Footnote i](#fn14.6) | no serious | none | none | 1/13,636,363 (95% CI 24,420,2750; 7,614,592) | ⊕⊕⊕⊝
MODERATE |
|
Footnote 1
For all destinations, serious risk of bias due to possible under-ascertainment of cases.
[Return to footnote 1 referrer](#fn14.1-rf)
Footnote 2
Source: Statistics Canada International Travel Survey[Footnote 43](#fn43). Countries included: China, India, Japan, Philippines, Thailand, Singapore, South Korea, Malaysia, Cambodia, Vietnam, Nepal, Taiwan, Pakistan, Indonesia, Sri Lanka, Laos, Burma, Brunei, Bangladesh, Papua New Guinea and Guam.
[Return to footnote 2 referrer](#fn14.2-rf)
Footnote 3
Source: U.S. Department of Commerce, National Travel and Tourism Office[Footnote 44](#fn44). Includes travel volumes to JE endemic countries that comprise Asian countries that comprise at least 0.3% of outbound traffic (China, India, Japan, Philippines, South Korea, Taiwan, Thailand, Vietnam and Singapore).
[Return to footnote 3 referrer](#fn14.3-rf)
Footnote 4
Source: Eurostat[Footnote 42](#fn42) Estimated as approximately 50% of the total (30 million) annual travel volume in 2014 between Europe and Asia.
[Return to footnote 4 referrer](#fn14.4-rf)
Footnote ɫ
GRADE's approach to rating quality of evidence uses ⊕ to denote rating up the quality and ⊝ to denote rating down the quality.
[Return to footnote ɫ referrer](#fn14.5-rf)
Footnote i
Confidence intervals null effect and appreciable levels of benefits and harms.
[Return to footnote i referrer](#fn14.6-rf)
|
Appendix 10. Factors to consider when evaluating a traveller's risk for Japanese encephalitis (JE) virus exposure
-----------------------------------------------------------------------------------------------------------------
Destination
JE occurs in areas throughout most of Asia and parts of the western Pacific. It is generally accepted that the likelihood of JE exposure is highest in rural agricultural areas.
Duration of travel
A longer duration of travel increases the likelihood that a traveller might be exposed to a JEV-infected mosquito.
Season
In most temperate areas of Asia, JEV transmission is seasonal, and human disease usually peaks in summer and fall. In the subtropics and tropics, JEV transmission patterns vary, and human disease can be sporadic or occur year-round. Appendix 2 provides country level information.
Activities
The mosquitoes that transmit JEV feed on humans most often in the outdoors, with peak feeding times usually being during the hours of darkness.
Extensive outdoor activities (e.g., camping, hiking, trekking, biking, fishing, hunting, or farming), especially during the evening or night, increase the risk of being exposed to a JEV-infected mosquito.
Accommodations with no air conditioning, screens, or bed nets increase the risk of exposure to mosquitoes that transmit JEV and other vector-borne diseases (e.g., dengue and malaria).
Use of Personal Protective Measures (PPM)
Use of PPMs, e.g. bed net, repellent, clothing treatment, are expected to provide substantial protection against the bites of the mosquito that transmits JE. The level of personal compliance with PPMs can significantly alter the risk of exposure to JE.
Appendix 11. Study summaries considered for inclusion in GRADE analysis
-----------------------------------------------------------------------
| Reference | Topic | Study design | Vaccine/comparator dose and schedule | Population | Demographic | Objectives | Comments |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Tauber 2008[Footnote 31](#fn31) | Safety | Randomized, double-blind, placebo-controlled, multicentre phase 3 trial. | JEV at 0, 28 days (6 μg of virus in 0.5 ml/dose) compared to PBS solution w/ aluminum hydroxide at 0,28 days (0.5 ml/dose). | 2,650 subjects. 1,993 received JEV and 657 received placebo. | Healthy male and female subjects aged 18 years and older and without history of JE vaccination. | Primary endpoint rate of SAEFI and MAEFI from first dose until 4 weeks after completion of vaccination. Secondary endpoint was local AEFI recoded in patient diary. | Included |
| Tauber 2007[Footnote 25](#fn25) | Immunogenicity and safety | Multicentre, observer-blinded, centrally randomised, controlled, non-inferiority phase 3 trial. | JEV at days 0, 28 (6 μg of virus in 0.5 ml/dose) and a placebo (0.5ml of aluminum hydroxide) at day 7 compared to JE-VAX at days 0, 7, 28 (1ml/dose). | 863 received study medication of 867 randomized. 428 received JEV and 435 received MBV. | Male and females aged 18 or older. No previous immunization for JE or YF. | Primary endpoint seroconversion, assessed on day 56. Secondary endpoint safety, assessed during visits and via patient diary. | Included |
| Schuller 2011[Footnote 69](#fn69) | Safety | Review article | 10 individual Phase 3 trials were examined | N/A | N/A | Reports on safety profiles derived from post marketing data and pooled analyses of clinical safety data | Excluded (review article) |
| Schuller 2009[Footnote 27](#fn27) | Safety and Immunogenicity | Randomized, controlled, observer-blind, parallel-group, multicentre phase 3 trial. | Single dose of JEV (6 μg/dose) at days 0, 28 compared to 2 doses of JEV (6 μg/dose) at day 0 compared to a single dose of JEV (6 μg/dose) at day 0. | 374 subjects. 124 received the single, high-dose (1x12 μg), 125 received the standard regimen (2x6 μg) and 125 received the single, standard dose (1x6 μg). | Healthy male and female subjects aged 18 years and older. No previous immunization for JE. | Primary endpoint seroconversion, assessed on days 10, 28, 35 and 56 after first vaccination. Secondary endpoint safety, assessed during visits and via patient diary. | Included |
| Kaltenböck 2009[Footnote 70](#fn70) | Safety and Immunogenicity | Multicentre, randomized, controlled, single-blind phase 3 trial. | JEV (6 μg/dose) at days 0,28 and placebo (0.5 ml) at day 0 compared to placebo (0.5 ml) at days 0,28 and HAV at day 0 compared to JEV (6 μg/dose) at days 0,28 and HAV at day 0 | 192 subjects. 65 received JEV + placebo, 65 received HAV + placebo and 62 received JEV + HAV. | Healthy male and female subjects 18 years of age or older. No previous immunization for JE, Yellow fever or hepatitis A. | Primary endpoint seroconversion for JEV (day 56). Secondary endpoint seroconversion compared JEV with concomitant JEV + HAV (day 56). Secondary endpoint safety, assessed during visits and via patient diary. | N/A |
| Dubischar-Kastner 2010[Footnote 59](#fn59) | Safety and Immunogenicity | Uncontrolled, multicentre, open-label, phase 3 follow-up study.
Extension of previously described study (Schuller et al., 2009). | Immunogenicity assessed in subjects from previous study at 6, 12 and 24 months after first vaccination. Subjects with a negative plaque reduction neutralization test (PRNT) result at 6 or 12 months received a booster dose of JEV (6 μg) at 11 or 23 months after. | 349 subjects. 206 received a booster at month 11, 43 received a booster at month 23 and 1 subject received a booster at months 11 and 23. | Healthy male and female subjects, 18 years and older, having previously participated in JEV study. | Primary endpoint seroconversion, assessed 24 months after first JEV vaccination.
Safety, assessed during visits and via patient diary. | Excluded (only related to booster) |
| Lyons 2007[Footnote 28](#fn28) | Safety and Immunogenicity | Randomized, open label, single center phase 2 trial. | JEV (6 μg/dose) at days 0, 28 compared to JEV (6 μg/dose) at days 0, 14, 28 compared to JEV (12 μg/dose) at days 0, compared to JE-Vax on days 0, 7, 28. | 94 subjects. 24 received JEV (2x6 μg), 24 received JEV (3x6 μg), 25 received (2x12 μg) and 21 received JE-Vax (3 doses). | Military or civilian subjects aged between 18 and 49 years old. Exclusions included previous exposure to dengue, JE, YF or TBE. | Primary endpoint seroconversion, assessed on days 28 and 56. Optional follow up at 6, 12, 18 and 24 months. Secondary endpoint safety, assessed during visits and via patient diary. | Included |
| Kaltenböck 2010[Footnote 29](#fn29) | Safety and Immunogenicity | Randomized, open-label, single center phase 2 trial. | JEV (3 μg /dose) compared to JEV (6 μg /dose) compared to JenceVac (0.5 ml/dose) | 60 subjects. 24 received JEV 3 μg, 24 received JEV 6 μg and 12 received JenceVac. | Healthy children of either sex between 1-3 years old. No previous immunization for JE, Yellow fever or Dengue. | Primary endpoint seroconversion, assessed on days 28 and 56.
Safety assessed during visits and via patient diary completed by proxy. | Included |
| Yun 2015[Footnote 71](#fn71) | N/A | Multicentre, double-blind, centrally randomised study with
ENCEVAC, not JEV. | N/A | N/A | N/A | N/A | Excluded (JEV was not used). |
| Jelinek 2015[Footnote 26](#fn26) | Safety and Immunogenicity | Phase 3, randomized, observer-blind, multicentre trial. | JEV (0.5 ml/dose) at days 0, 28 + rabies at days 0, 7 compared to
JEV (0.5 ml/dose) at days 0, 7 + rabies at days 0, 3 compared to
JEV (0.5 ml/dose) alone at days 0, 28. | 440 subjects. 167 received the standard JE + rabies regimen, 217 received the accelerated JE + rabies regimen and 56 received the standard JE regimen. | N/A | 440 healthy adults aged 18-65. Persons previously receiving JE vaccination.
Primary endpoint seroconversion, assessed 28 days after completion of series (day 35 or day 56). Secondary endpoint safety, assessed during visits and via patient diary. | N/A |
| Eder 2011[Footnote 72](#fn72) | Safety and Immunogenicity | Prospective, open-label, multi-center phase 3 extension study. Booster dose of JEV provided 15 months after the first dose of the primary series. | N/A | N/A | N/A | Healthy male and female subjects at least 18 YOA (198 subjects). Previously had completed JEV series.
Primary endpoint seroconversion, assessed 1, 6 and 12 months after booster. Secondary endpoint safety, assessed during visits and via patient diary. | N/A |
| Paulke-Korinek 2015[Footnote 12](#fn12) | Immunogenicity | Extension of previously described study (Eder et al 2011). | N/A | N/A | N/A | Blood draw at 76 months from 67 patients who participated in boostering study.
Primary endpoint seroconversion. | N/A |
| Schuller 2008[Footnote 30](#fn30) | Immunogenicity | Multi-centre phase 3 uncontrolled follow-up study.
JEV and MBV. | N/A | N/A | N/A | Of the 3258 subjects that completed previous phase 3 studies, 298 were enrolled.
Primary endpoint seroconversion, assessed at 6 (298 subjects) and 12 months (180 subjects). | N/A |
| ACIP 2013[Footnote 4](#fn4) | Safety and Immunogenicity | GRADE analysis for use of JEV in children. | N/A | N/A | N/A | Multiple studies included, includes unpublished evidence. | Include |
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-01-24
| None | None |
babf7bbe7abec26cc196d12210c045f3fd09a09b | cma | **Influenza vaccine: Canadian Immunization Guide** | Influenza vaccine: Canadian Immunization Guide
Key information
# What
- Influenza is a respiratory infection caused primarily by influenza A and B viruses.
- Seasonal influenza epidemics occur annually in Canada, generally in the late fall and winter months.
- Prior to the COVID-19 pandemic, influenza occurred globally with an annual attack rate estimated at 5% to 10% in adults and 20% to 30% in children.
- Common symptoms of influenza include fever, cough and myalgia. Most people will recover within a week to 10 days, but some people are at greater risk of complications, such as pneumonia.
- There are 10 influenza vaccines authorized and available for use in Canada: 8 inactivated influenza vaccines (IIV), a recombinant influenza vaccine (RIV), and a live attenuated influenza vaccine (LAIV). Some protect against 3 strains of influenza (i.e., trivalent) and others protect against 4 strains of influenza (i.e., quadrivalent).
- The influenza vaccines are safe and well-tolerated.
# Who
- Influenza vaccination should be offered annually to anyone 6 months of age and older who does not have contraindications to the vaccine.
- Influenza vaccination is particularly recommended for:
- people at high risk of severe disease, influenza-related complications, or hospitalization
- people capable of transmitting influenza to those at high risk
- people who provide essential community services
- people in direct contact with poultry infected with avian influenza during culling operations
# How
- Adults and children 9 years of age and older should receive 1 dose of influenza vaccine each year.
- Children 6 months to less than 9 years of age who have never received influenza vaccine in a previous influenza season should be given 2 doses of influenza vaccine in the current season.
- Children 6 months to less than 9 years of age who have been vaccinated with at least 1 dose of seasonal influenza vaccine in any previous season should receive 1 dose of influenza vaccine per season thereafter.
# Why
- Vaccination is the most effective way to prevent influenza and its complications that can lead to severe disease, hospitalization and death.
- Vaccination helps prevent the spread of influenza.
- Annual vaccination is required because influenza viruses are constantly evolving and the body's immune response to influenza vaccination may not persist beyond a year. A new vaccine is designed each year to target the changes in the circulating influenza viruses.
Epidemiology
# Disease description
## Infectious agent
There are 2 main types of influenza virus that cause seasonal epidemics in humans: A and B. Influenza A viruses are classified into subtypes based on 2 surface proteins: hemagglutinin (HA) and neuraminidase (NA). Three subtypes of HA (H1, H2, and H3) and 2 subtypes of NA (N1 and N2) are recognized among influenza A viruses as having caused widespread human disease.
There are 2 antigenically distinct lineages of influenza B viruses, B/Yamagata/16/88-like and B/Victoria/2/87-like viruses. Viruses from both lineages contribute variably to influenza illness each year.
Over time, antigenic variation (drift) of strains occurs within an influenza A subtype or a B lineage. Consequently, seasonal influenza vaccines need to be reformulated annually, to better match the circulating vaccine strains.
## Reservoir
The primary reservoir of most influenza A viruses is wild birds. In humans, currently only 3 type/subtype viruses , are circulating; for these, humans are the reservoir.
## Transmission
Influenza is primarily transmitted by aerosols and droplets spread through coughing or sneezing, and through direct or indirect contact with respiratory secretions. The incubation period is usually about 2 days but can range from 1 to 4 days. Adults may be able to spread influenza to others from 1 day before symptom onset to approximately 5 days after symptoms start. Children and people with weakened immune systems may be infectious longer.
## Risk factors
The people at greatest risk of influenza-related complications are adults and children with chronic health conditions, residents in long term care facilities, adults 65 years of age and older, children 0 to 59 months of age, individuals who are pregnant, and Indigenous Peoples.
## Seasonal and temporal patterns
Seasonal influenza activity in Canada begins to increase over the fall, and peaks in the winter months. The influenza season can last for many months, and more than 1 influenza strain typically circulates each season. Sporadic cases and occasional outbreaks may occur outside the typical influenza season.
## Spectrum of clinical illness
Influenza infection may be asymptomatic or present as mild disease; conversely, it can manifest as severe disease and result in death. Symptoms typically include the sudden onset of fever, cough, and myalgia. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week to 10 days. In some, influenza infection may lead to complications including pneumonia, respiratory failure, cardiovascular complications, or worsening of underlying chronic medical conditions. Influenza infection is also associated with an increased risk of myocardial infarction, stroke and Guillain-Barre syndrome (GBS).
## Disease distribution
Worldwide, annual epidemics result in approximately 1 billion cases of influenza, 3 to 5 million cases of severe illness, and 290,000 to 650,000 deaths. Historically, the global annual attack rate was estimated to be 5% to 10% in adults and 20% to 30% in children.
Together, influenza and pneumonia are among the top 10 leading causes of death in Canada. Prior to the COVID-19 pandemic, an average of 50,000 laboratory-confirmed cases of influenza were reported each year. This is an underestimate of the actual number of cases as most influenza infections go unreported. Although the burden of influenza-associated illness and death can vary from year to year, it is estimated that there are an average of 12,200 hospitalizations related to influenza and approximately 3,500 deaths attributable to influenza annually in Canada. Information on current influenza activity in Canada can be found on the
Preparations authorized for use in Canada
# Inactivated influenza vaccine (IIV)
## Standard-dose, egg-based, quadrivalent inactivated influenza vaccine (IIV4-SD)
- Afluria® Tetra, Seqirus Ltd. (IIV4)
- Flulaval® Tetra, GlaxoSmithKline Inc. (IIV4)
- Fluzone® Quadrivalent, Sanofi Pasteur Inc. (IIV4)
- Influvac® Tetra, BGP Pharma ULC. (IIV4)
## Standard-dose mammalian cell culture-based quadrivalent inactivated influenza vaccine (IIV-cc)
- Flucelvax® Quad, Seqirus Ltd. (IIV4-cc)
## Adjuvanted inactivated trivalent influenza vaccine (IIV-Adj)
- Fluad Pediatric®, (Pediatric dose ), Seqirus Ltd. (IIV3-Adj)
- Fluad®, Seqirus Ltd. (IIV3-Adj)
## High-dose inactivated influenza vaccine (IIV-HD)
- Fluzone®, (High-Dose ), Sanofi Pasteur Ltd. (IIV4-HD)
## Recombinant influenza vaccine (RIV)
- Supemtek™, Sanofi Pasteur Ltd. (RIV4)
## Live attenuated influenza vaccine (LAIV)
- FluMist® Quadrivalent, AstraZeneca Canada. (LAIV4)
Trivalent vaccines contain 1 A(H1N1) strain, 1 A(H3N2) strain, and 1 influenza B strain from 1 of 2 lineages, Victoria or Yamagata. Quadrivalent vaccines contain the strains in the trivalent vaccine plus an influenza B strain from the other lineage.
The antigenic characteristics of circulating influenza virus strains provide the basis for the . Manufacturers that distribute influenza vaccines in Canada ensure the vaccines for the upcoming influenza season contain the WHO's recommended antigenic strains for the Northern Hemisphere. Vaccine producers may also use antigenically equivalent strains. Not all influenza vaccines authorized for use in Canada are available in Canada.
A summary of the characteristics of influenza vaccines available in Canada during the 2023–2024 influenza season can be found in of the NACI Statement on Seasonal Influenza Vaccine. For complete prescribing information, consult the product monograph or information contained within Health Canada's authorized product monographs available through the . Refer to Table 1 in in Part 1 for a list of all vaccines authorized for use in Canada and their contents.
Immunogenicity, efficacy and effectiveness
# Immunogenicity
Antibody response after vaccination depends on several factors, including the age of the recipient, prior and subsequent exposure to antigens, and the presence of immune compromising conditions. Vaccine-induced immune response is not as robust in young children, older adults and persons with immune compromising conditions as it is in other people. Protective levels of humoral antibodies, which correlate with protection against influenza infection, are achieved approximately 2 weeks after vaccination; however, there may be some protection afforded before that time.
# Efficacy and effectiveness
Influenza vaccine has been shown to be efficacious in providing protection against influenza infection and illness; however, the effectiveness of the vaccine can vary from season to season and by influenza vaccine strain type and subtype. Influenza vaccine effectiveness depends on how well the vaccine strains match with circulating influenza viruses, the type and subtype of the circulating virus, as well as the health and age of the individual receiving the vaccine. Nevertheless, even when there is a less-than-ideal match or lower effectiveness against 1 strain, vaccine recipients, particularly people at high risk of influenza-related complications and hospitalization, are still more likely to be protected compared to those who are unvaccinated.
In general, influenza vaccination in consecutive seasons does not have a negative or positive effect on vaccine effectiveness in comparison to vaccination in the current season only.
Recommendations for use
# Routine schedule
Seasonal influenza vaccine should be offered annually to everyone 6 months of age and older who does not have contraindications to the vaccine, irrespective of vaccination in previous seasons. provides age group-specific recommendations. Any of the age-appropriate influenza vaccine types available for use may be considered for people without contraindications to the vaccine.
Influenza vaccines do not confer sufficient protection to make the vaccine useful in infants less than 6 months of age. Children 6 months to less than 9 years of age who have not previously received at least 1 dose of the seasonal influenza vaccine require 2 doses of influenza vaccine, with a minimum of 4 weeks between doses. Only 1 dose of influenza vaccine per season is recommended for everyone else.
Vaccination before the onset of the influenza season is strongly preferred, as delayed administration may result in lost opportunities to prevent infection from exposures that occur prior to vaccination. However, influenza vaccine may still be administered until the end of the season.
- IIV4-SD
- IIV4-cc
- IIV4-cc
- LAIV4
- LAIV4 may be given to children with:
+ stable, non-severe asthma
+ cystic fibrosis who are not being treated with immunosuppressive drugs (e.g., prolonged systemic corticosteroids)
+ stable HIV infection, i.e., if the child is currently being treated with ART (i.e., HAART) for at least 4 months and has adequate immune function
- LAIV should not be used in children or adolescents for whom it is contraindicated or for whom there are warnings and precautions such as those with:
+ severe asthma (defined as currently on oral or high-dose inhaled glucocorticosteroids or active wheezing)
+ medically attended wheezing in the 7 days prior to vaccination
+ current receipt of aspirin or aspirin-containing therapy
+ immune compromising conditions, with the exception of stable HIV infection, i.e., if the child is currently being treated with HAART for at least 4 months and has adequate immune function
+ pregnancy
- in pregnancy, IIV should be used instead
- IIV4-cc
- RIV4
- LAIV4
- IIV4-cc
- RIV4
- IIV4-SD
- IIV4-HD
- IIV4-cc
- RIV4
Vaccination of specific populations
To reduce the morbidity and mortality associated with influenza, immunization programs may focus on people at high risk of influenza-related complications (refer to ).
People at high risk of influenza-related complications or hospitalization* All children 6 to 59 months of age
- Adults and children with the following chronic health conditions:
+ Cardiac or pulmonary disorders (includes bronchopulmonary dysplasia, cystic fibrosis, and asthma)
+ Diabetes mellitus and other metabolic diseases
+ Cancer, immune compromising conditions (due to underlying disease, therapy, or both, such as solid organ transplant or hematopoietic stem cell transplant recipients)
+ Renal disease
+ Anemia or hemoglobinopathy
+ Neurologic or neurodevelopmental conditions (includes neuromuscular, neurovascular, neurodegenerative, and seizure disorders , but excludes migraines and psychiatric conditions without neurological conditions)
+ Morbid obesity (defined as BMI of 40 kg/m² and over)
+ Children 6 months to 18 years of age undergoing treatment for long periods with acetylsalicylic acid, because of the potential increase of Reye's syndrome associated with influenza
- All individuals who are pregnant
- People of any age who are residents of nursing homes and other chronic care facilities
- Adults 65 years of age and older
- Indigenous Peoples
- Household contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated:
- household contacts of individuals at high risk
- household contacts of infants less than 6 months of age, as these infants are at high risk but cannot receive influenza vaccine
- members of a household expecting a newborn during the influenza season
- Those providing regular child care to children 0 to 59 months of age, whether in or out of the home
- Those who provide services within closed or relatively closed settings to people at high risk (e.g., crew on a cruise ship)
Others* People who provide essential community services
- People who are in direct contact with poultry infected with avian influenza during culling operations
# Children 6 months to 59 months of age
Young children have a high burden of influenza-associated illness. The risk of serious infection and hospitalization is highest among the very young.
# Pregnant individuals
Pregnant individuals, at any stage of pregnancy, are recommended to receive any age-appropriate non-live influenza vaccine due to the increased risk of influenza associated morbidity in pregnancy and evidence of adverse neonatal outcomes associated with influenza infection during pregnancy. Moreover, vaccination of individuals who are pregnant protects their newborns from influenza and influenza-related hospitalization. It has also been shown to be protective against infants being born premature, small for gestational age, and low birth weight. To protect infants less than 6 months of age who are at high risk of influenza-related illness, the influenza vaccine should not only be offered to individuals who are pregnant, but to any household contacts and care providers of young infants.
# Older adults
Adults 65 years of age and older are at greater risk of more severe complications from influenza, and influenza-attributed mortality rates increase with age. High dose (IIV-HD) formulation is recommended for older adults as it provides better protection compared with the standard dose influenza vaccine in adults 65 years of age and older.
# Residents in nursing homes or other chronic care facilities
Residents of nursing homes and other chronic care facilities often have 1 or more chronic health conditions and live in institutional environments that may facilitate the spread of influenza.
# Persons with chronic health conditions
Certain chronic health conditions are associated with increased risk of influenza-related complications and hospitalization. Refer to . Influenza infection in individuals with certain chronic diseases can also lead to an exacerbation of the chronic condition.
# Immunocompromised persons
People who are immunocompromised have an increased risk of morbidity and mortality from influenza. All people 6 months of age and older who are immunocompromised are particularly recommended to receive an influenza vaccine every year. Although influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, vaccine effectiveness may be lower than in healthy individuals.
# Indigenous Peoples
Influenza vaccination is particularly recommended for Indigenous Peoples who tend to have higher rates of influenza-associated hospitalization and death. The increased risk of severe outcomes may be related to the presence of chronic health conditions and/or delays in accessing healthcare. Susceptibility to infection may also be increased due to living conditions that favour transmission.
# Health care workers, care providers and other workers
Influenza vaccination is recommended for health care workers (HCWs) and other care providers include regular visitors, emergency response workers, those who work in continuing care or long-term care facilities or residences, those who provide home care for people at high risk, and students of related health care services. HCWs and other care providers who are potentially capable of transmitting influenza to those at high risk should receive annual vaccination with any age appropriate non-live influenza vaccine, regardless of whether the high-risk individual has been vaccinated. Vaccination of HCWs and other care providers decreases the vaccinated person's risk of illness, as well as the risk of transmission of influenza to patients at high risk of influenza-associated complications. Vaccination of HCWs and residents of nursing homes is associated with decreased risk of influenza outbreaks. Annual influenza vaccination is considered an essential component of the standard of care for all HCWs.
To minimize the disruption of services during annual influenza epidemics, all people who provide essential community services should consider annual influenza vaccination, as it can decrease work absenteeism due to respiratory and related illnesses.
Seasonal influenza vaccination will not prevent avian influenza but it is recommended for those working in direct contact with poultry infected with avian influenza during culling operations, as these individuals may be at increased risk of exposure to avian influenza infection. Preventing infection with human influenza strains may reduce the theoretical potential for human-avian reassortment of genes, should such workers become co-infected with both human and avian influenza viruses.
# Travellers
Influenza occurs year-round in the tropics. In temperate northern and southern countries, influenza activity generally peaks during the winter season (November to March in the Northern Hemisphere and April to October in the Southern Hemisphere). Influenza vaccine should be offered to travellers.
Vaccines prepared specifically for use in the Southern Hemisphere are not available in Canada, and the extent to which recommended vaccine components for the Southern Hemisphere may overlap with those in available Canadian formulations will vary. A decision for or against revaccination of travellers to the Southern Hemisphere between April and October, if they had already been vaccinated in the preceding fall or winter with the Northern Hemisphere's vaccine, depends on individual risk assessment, the similarity between the Northern and Southern Hemisphere vaccines, the similarity between the Northern Hemisphere vaccine strains and currently circulating strains in the Southern Hemisphere, and the availability of a reliable and safe vaccine at the traveller's destination.
Serologic testing
Serologic testing is not necessary or recommended before or after receiving seasonal influenza vaccine.
Administration practices
# Dose and route of administration
The dose and route for influenza vaccines vary and are detailed in the product monographs.
- With the exception of IIV4-HD, most unadjuvanted IIVs are administered as a 0.5 mL intramuscular (IM) injection for everyone 6 months of age and older.
- The following IIVs are administered as a 0.5 mL IM injection but are only authorized or recommended for certain age groups: Afluria® Tetra (5 years and older), Influvac® Tetra (3 years and older), and Flucelvax® Quad (2 years and older).
- IIV4-HD (Fluzone® High-Dose Quadrivalent) is administered as a 0.7 mL IM injection for adults 65 years of age and older.
- Adjuvanted IIV3 (Fluad®) is administered as a 0.5 mL IM injection for adults 65 years of age and older. A pediatric formulation is also available (Fluad Pediatric®) and is administered as a 0.25 mL IM injection for children 6–23 months of age.
- RIV4 (Supemtek™) is administered as a 0.5 mL IM injection for adults 18 years of age and older.
- LAIV (FluMist® Quadrivalent) is administered as 0.2 mL given intranasal (0.1 mL in each nostril) for individuals 2 to 59 years of age.
# Concurrent administration with other vaccines
All influenza vaccines, including LAIV, may be given at the same time as, or at any time before or after administration of other live or inactivated vaccines, including COVID-19 vaccines for those aged 6 months and older.
# Interchangeability of vaccines
If a child aged less than 9 years requires 2 doses of influenza vaccine in the same influenza season, it is preferable to use the same type of vaccine for both doses. However, if the type of vaccine used for the first dose is not available for the second dose, a different type of influenza vaccine may be provided. For more information refer to in Part 1.
# Pre- and post-vaccination counselling
Storage requirements
Influenza vaccines should be stored at +2°C to +8°C and should not be frozen. For additional information, consult the product monographs available through Health Canada's . Refer to in Part 1 for additional information.
Safety and adverse events
# Common and very common adverse events
Common adverse events occur in 1% to less than 10% of vaccinees. Very common adverse events occur in 10% or more of vaccinees.
With IM-administered influenza vaccines, mild and transient injection site reactions e.g., soreness at the injection site lasting up to 2 days, are common. Any systemic reactions e.g., myalgia, headache, fatigue and malaise, are usually mild and short-lived. Influenza vaccines with adjuvant tend to produce more extensive injection site reactions than unadjuvanted, but these reactions are also generally mild and resolve within a few days. IIV-HD tends to induce higher rates of systemic reactions compared to IIV-SD, but most of these reactions are also mild and short-lived. The most common adverse reactions experienced by recipients of LAIV are nasal congestion and runny nose.
# Uncommon, rare and very rare adverse events
Uncommon adverse events occur in 0.1% to less than 1% of vaccinees. Rare and very rare adverse events occur, respectively, in 0.01% to less than 0.1% and less than 0.01% of vaccinees.
Serious adverse events are rare following influenza vaccination, and in most cases, data are insufficient to determine a causal association. Allergic responses to influenza vaccine are a rare consequence of hypersensitivity to some components of the vaccine or its container.
# Other reported adverse events and conditions
## Guillain-Barré syndrome
Studies suggest that the absolute risk of GBS in the period following seasonal and A(H1N1) pdm09 influenza vaccination is about 1 excess case per million vaccinations, and that the risk of GBS associated with influenza illness (about 17 cases per million influenza-coded health care encounters, which are a proxy for influenza illness) is higher than that associated with influenza vaccination.
Although the evidence considering influenza vaccination and GBS is inadequate to accept or reject a causal relation between GBS in adults and seasonal influenza vaccination, avoiding subsequent influenza vaccination of individuals known to have had GBS without other known etiology within 6 weeks of a previous influenza vaccination appears prudent at this time. However, the potential risk of GBS recurrence associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.
## Oculorespiratory syndrome
Oculorespiratory syndrome (ORS) consists of bilateral red eyes and 1 or more associated respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, or sore throat) that starts within 24 hours of vaccination, with or without facial oedema. ORS was first identified during the 2000 – 2001 influenza season. Since then, there have been far fewer cases per year. ORS is not considered to be an allergic response. People who have an occurrence or recurrence of ORS upon vaccination do not necessarily experience further episodes with future vaccinations. Individuals who have experienced ORS without lower respiratory tract symptoms may be safely revaccinated with influenza vaccine. Individuals who have experienced ORS with lower respiratory tract symptoms should seek medical advice.
# Guidance on reporting adverse events following immunization
To ensure the ongoing safety of vaccines in Canada, reporting of adverse events following immunization (AEFIs) by vaccine providers and other clinicians is critical, and in some jurisdictions, reporting is mandatory under the law.
Vaccine providers are asked to report AEFIs through officials and to check for specific AEFI reporting requirements in their province or territory. In general, any serious or unexpected adverse event felt to be temporally related to vaccination should be reported.
For influenza vaccines, the following AEFIs are of particular interest:
- ORS
- GBS within 6 weeks following vaccination
# Contraindications and precautions
Influenza vaccines are contraindicated in persons with a history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component, except egg, of the specific vaccine or its container. Refer to in Part 1 for a list of all vaccines authorized for use in Canada and their contents.
Safety data confirm that egg-allergic individuals may be vaccinated against influenza using any influenza vaccine, including egg-based vaccines and LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg and without any particular considerations, including vaccination setting.
Additional contraindications apply to the use of LAIV in people with certain health conditions:
- People with immune-compromising conditions due to underlying disease, therapy, or both, with the exception of children with stable HIV infection on anti-retroviral therapy (ART) and with adequate immune function
- People with severe asthma who are on oral or high dose inhaled glucocorticosteroids or have active wheezing or have medically attended wheezing in the 7 days of vaccination
- Children less than 24 months of age
- Children 2 to 17 years of age currently receiving aspirin or aspirin-containing therapy
- Pregnant individuals, because there is a lack of safety data at this time.
Precautions for the use of LAIV are as follows:
- LAIV should not be administered until 48 hours after antiviral agents active against influenza (e.g., oseltamivir, zanamivir) are stopped, and those antiviral agents, unless medically indicated, should not be administered until 2 weeks after receipt of LAIV so that the antiviral agents do not inactivate the replicating vaccine virus.
- If significant nasal congestion is present that might impede delivery of LAIV to the nasopharyngeal mucosa, IIV can be administered or LAIV can be deferred until resolution of the congestion.
- LAIV is not recommended for adults with the chronic health conditions identified in , IIV or RIV should be used instead.
- LAIV is not recommended for HCWs, IIV or RIV should be used instead.
- LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection.
- LAIV recipients who are less than 18 years of age should avoid the use of aspirin-containing products for at least 4 weeks after receipt of LAIV.
As a precaution, influenza vaccination should be avoided in people who have developed GBS within 6 weeks of a previous influenza vaccination. Medical advice may be sought to balance the potential risk of GBS recurrence associated with influenza vaccination against the risk of GBS associated with influenza infection itself, and the benefits of influenza vaccination.
ORS is usually transient, resolving within 48 hours of onset. The only associated precaution is when lower respiratory symptoms accompany ORS, in which case expert review is required prior to subsequent immunization.
Influenza vaccination should not be delayed because of minor or moderate acute illness, with or without fever; however, in people with serious acute illnesses it may be postponed until their symptoms have abated.
Other considerations
# Drug interactions
Although influenza vaccine can inhibit the clearance of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine. Statins have effects on the immune system in addition to their therapeutic cholesterol-lowering actions. Two published studies have found that adults who are regular statin users had an apparent decreased response to influenza vaccination as measured by reduced geometric mean titres (GMT) or reduced vaccine effectiveness against medically attended acute respiratory illness. Statins are widely used in the same adult populations who are also at-risk for influenza-related complications and hospitalizations. Therefore, if these preliminary findings are confirmed in future studies, concurrent statin use in adult populations could have implications for influenza vaccine effectiveness and how this use is assessed in the measurement of vaccine effectiveness.
Chapter creation process
This new chapter was developed based on the Statement on Seasonal Influenza Vaccine for 2023–2024 from the National Advisory Committee on Immunization (NACI). It incorporates key information from other recent NACI statements on influenza vaccines. |
**Influenza vaccine: Canadian Immunization Guide**
==================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-9-human-papillomavirus-vaccine.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-11-japanese-encephalitis-vaccine.html)
**New chapter** (see [Table of updates](/en/public-health/services/canadian-immunization-guide/updates.html)): May 2023
This chapter was developed based on the following statements from the National Advisory Committee on Immunization (NACI):
* May 31, 2023: [Statement on seasonal influenza vaccine for 2023-2024](/en/public-health/services/publications/vaccines-immunization/national-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html)
* February 21, 2023: [Recommendation on repeated seasonal influenza vaccination](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/recommendation-repeated-seasonal-influenza-vaccination.html)
On this page
------------
* [Key information](#a1)
* [Epidemiology](#a2)
* [Preparations authorized for use in Canada](#a3)
* [Immunogenicity, efficacy and effectiveness](#a4)
* [Recommendations for use](#a5)
+ [Routine schedule](#a5.1)
+ [Table 1: Recommendations for influenza vaccine type by age group](#a5.2)
* [Vaccination of specific populations](#a6)
+ [List 1: Groups for whom influenza vaccination is particularly recommended](#a6.1)
+ [Children 6 months to 59 months of age](#a6.2)
+ [Pregnant individuals](#a6.3)
+ [Older adults](#a6.4)
+ [Residents in nursing homes or other chronic care facilities](#a6.5)
+ [Persons with chronic health conditions](#a6.6)
+ [Immunocompromised persons](#a6.7)
+ [Indigenous persons](#a6.8)
+ [Health care workers, care providers and other workers](#a6.9)
+ [Travellers](#a6.10)
* [Serologic testing](#a7)
* [Administration practices](#a8)
* [Storage requirements](#a9)
* [Safety and adverse events](#a10)
* [Other considerations](#a11)
* [Chapter creation process](#a12)
* [Acknowledgments](#a13)
* [Selected references](#a14)
Key information
---------------
### What
* Influenza is a respiratory infection caused primarily by influenza A and B viruses.
* Seasonal influenza epidemics occur annually in Canada, generally in the late fall and winter months.
* Prior to the COVID-19 pandemic, influenza occurred globally with an annual attack rate estimated at 5% to 10% in adults and 20% to 30% in children.
* Common symptoms of influenza include fever, cough and myalgia. Most people will recover within a week to 10 days, but some people are at greater risk of complications, such as pneumonia.
* There are 10 influenza vaccines authorized and available for use in Canada: 8 inactivated influenza vaccines (IIV), a recombinant influenza vaccine (RIV), and a live attenuated influenza vaccine (LAIV). Some protect against 3 strains of influenza (i.e., trivalent) and others protect against 4 strains of influenza (i.e., quadrivalent).
* The influenza vaccines are safe and well-tolerated.
### Who
* Influenza vaccination should be offered annually to anyone 6 months of age and older who does not have contraindications to the vaccine.
* Influenza vaccination is particularly recommended for:
+ people at high risk of severe disease, influenza-related complications, or hospitalization
+ people capable of transmitting influenza to those at high risk
+ people who provide essential community services
+ people in direct contact with poultry infected with avian influenza during culling operations
### How
* Adults and children 9 years of age and older should receive 1 dose of influenza vaccine each year.
* Children 6 months to less than 9 years of age who have never received influenza vaccine in a previous influenza season should be given 2 doses of influenza vaccine in the current season.
* Children 6 months to less than 9 years of age who have been vaccinated with at least 1 dose of seasonal influenza vaccine in any previous season should receive 1 dose of influenza vaccine per season thereafter.
### Why
* Vaccination is the most effective way to prevent influenza and its complications that can lead to severe disease, hospitalization and death.
* Vaccination helps prevent the spread of influenza.
* Annual vaccination is required because influenza viruses are constantly evolving and the body's immune response to influenza vaccination may not persist beyond a year. A new vaccine is designed each year to target the changes in the circulating influenza viruses.
Epidemiology
------------
### Disease description
#### Infectious agent
There are 2 main types of influenza virus that cause seasonal epidemics in humans: A and B. Influenza A viruses are classified into subtypes based on 2 surface proteins: hemagglutinin (HA) and neuraminidase (NA). Three subtypes of HA (H1, H2, and H3) and 2 subtypes of NA (N1 and N2) are recognized among influenza A viruses as having caused widespread human disease.
There are 2 antigenically distinct lineages of influenza B viruses, B/Yamagata/16/88-like and B/Victoria/2/87-like viruses. Viruses from both lineages contribute variably to influenza illness each year.
Over time, antigenic variation (drift) of strains occurs within an influenza A subtype or a B lineage. Consequently, seasonal influenza vaccines need to be reformulated annually, to better match the circulating vaccine strains.
#### Reservoir
The primary reservoir of most influenza A viruses is wild birds. In humans, currently only 3 type/subtype viruses [A(H1N1), A(H3N2), and B], are circulating; for these, humans are the reservoir.
#### Transmission
Influenza is primarily transmitted by aerosols and droplets spread through coughing or sneezing, and through direct or indirect contact with respiratory secretions. The incubation period is usually about 2 days but can range from 1 to 4 days. Adults may be able to spread influenza to others from 1 day before symptom onset to approximately 5 days after symptoms start. Children and people with weakened immune systems may be infectious longer.
#### Risk factors
The people at greatest risk of influenza-related complications are adults and children with chronic health conditions, residents in long term care facilities, adults 65 years of age and older, children 0 to 59 months of age, individuals who are pregnant, and Indigenous Peoples.
#### Seasonal and temporal patterns
Seasonal influenza activity in Canada begins to increase over the fall, and peaks in the winter months. The influenza season can last for many months, and more than 1 influenza strain typically circulates each season. Sporadic cases and occasional outbreaks may occur outside the typical influenza season.
#### Spectrum of clinical illness
Influenza infection may be asymptomatic or present as mild disease; conversely, it can manifest as severe disease and result in death. Symptoms typically include the sudden onset of fever, cough, and myalgia. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week to 10 days. In some, influenza infection may lead to complications including pneumonia, respiratory failure, cardiovascular complications, or worsening of underlying chronic medical conditions. Influenza infection is also associated with an increased risk of myocardial infarction, stroke and Guillain-Barre syndrome (GBS).
#### Disease distribution
Worldwide, annual epidemics result in approximately 1 billion cases of influenza, 3 to 5 million cases of severe illness, and 290,000 to 650,000 deaths. Historically, the global annual attack rate was estimated to be 5% to 10% in adults and 20% to 30% in children.
Together, influenza and pneumonia are among the top 10 leading causes of death in Canada. Prior to the COVID-19 pandemic, an average of 50,000 laboratory-confirmed cases of influenza were reported each year. This is an underestimate of the actual number of cases as most influenza infections go unreported. Although the burden of influenza-associated illness and death can vary from year to year, it is estimated that there are an average of 12,200 hospitalizations related to influenza and approximately 3,500 deaths attributable to influenza annually in Canada. Information on current influenza activity in Canada can be found on the [FluWatch website.](/en/public-health/services/diseases/flu-influenza/influenza-surveillance.html)
Preparations authorized for use in Canada
-----------------------------------------
### Inactivated influenza vaccine (IIV)
#### Standard-dose, egg-based, quadrivalent inactivated influenza vaccine (IIV4-SD)
* **Afluria® Tetra,** Seqirus Ltd. (IIV4)
* **Flulaval® Tetra,** GlaxoSmithKline Inc. (IIV4)
* **Fluzone® Quadrivalent,** Sanofi Pasteur Inc. (IIV4)
* **Influvac® Tetra,** BGP Pharma ULC. (IIV4)
#### Standard-dose mammalian cell culture-based quadrivalent inactivated influenza vaccine (IIV-cc)
* **Flucelvax® Quad,** Seqirus Ltd. (IIV4-cc)
#### Adjuvanted inactivated trivalent influenza vaccine (IIV-Adj)
* **Fluad Pediatric®,** (Pediatric dose [7.5 µg HA per strain]), Seqirus Ltd. (IIV3-Adj)
* **Fluad®,** Seqirus Ltd. (IIV3-Adj)
#### High-dose inactivated influenza vaccine (IIV-HD)
* **Fluzone®,** (High-Dose [60 µg HA per strain]), Sanofi Pasteur Ltd. (IIV4-HD)
#### Recombinant influenza vaccine (RIV)
* **Supemtek™,** Sanofi Pasteur Ltd. (RIV4)
#### Live attenuated influenza vaccine (LAIV)
* **FluMist® Quadrivalent,** AstraZeneca Canada. (LAIV4)
Trivalent vaccines contain 1 A(H1N1) strain, 1 A(H3N2) strain, and 1 influenza B strain from 1 of 2 lineages, Victoria or Yamagata. Quadrivalent vaccines contain the strains in the trivalent vaccine plus an influenza B strain from the other lineage.
The antigenic characteristics of circulating influenza virus strains provide the basis for the [World Health Organization's (WHO) recommendations for the strains selected for inclusion in each season's vaccine](https://www.who.int/teams/global-influenza-programme/vaccines/who-recommendations). Manufacturers that distribute influenza vaccines in Canada ensure the vaccines for the upcoming influenza season contain the WHO's recommended antigenic strains for the Northern Hemisphere. Vaccine producers may also use antigenically equivalent strains. Not all influenza vaccines authorized for use in Canada are available in Canada.
A summary of the characteristics of influenza vaccines available in Canada during the 2023–2024 influenza season can be found in [Appendix A](/en/public-health/services/publications/vaccines-immunization/national-advisory-committee-immunization-statement-seasonal-influenza-vaccine-2023-2024.html#a8) of the NACI Statement on Seasonal Influenza Vaccine. For complete prescribing information, consult the product monograph or information contained within Health Canada's authorized product monographs available through the [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html). Refer to Table 1 in [Contents of Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for a list of all vaccines authorized for use in Canada and their contents.
Immunogenicity, efficacy and effectiveness
------------------------------------------
### Immunogenicity
Antibody response after vaccination depends on several factors, including the age of the recipient, prior and subsequent exposure to antigens, and the presence of immune compromising conditions. Vaccine-induced immune response is not as robust in young children, older adults and persons with immune compromising conditions as it is in other people. Protective levels of humoral antibodies, which correlate with protection against influenza infection, are achieved approximately 2 weeks after vaccination; however, there may be some protection afforded before that time.
### Efficacy and effectiveness
Influenza vaccine has been shown to be efficacious in providing protection against influenza infection and illness; however, the effectiveness of the vaccine can vary from season to season and by influenza vaccine strain type and subtype. Influenza vaccine effectiveness depends on how well the vaccine strains match with circulating influenza viruses, the type and subtype of the circulating virus, as well as the health and age of the individual receiving the vaccine. Nevertheless, even when there is a less-than-ideal match or lower effectiveness against 1 strain, vaccine recipients, particularly people at high risk of influenza-related complications and hospitalization, are still more likely to be protected compared to those who are unvaccinated.
In general, influenza vaccination in consecutive seasons does not have a negative or positive effect on vaccine effectiveness in comparison to vaccination in the current season only.
Recommendations for use
-----------------------
### Routine schedule
Seasonal influenza vaccine should be offered annually to everyone 6 months of age and older who does not have contraindications to the vaccine, irrespective of vaccination in previous seasons. [Table 1](#a5.2) provides age group-specific recommendations. Any of the age-appropriate influenza vaccine types available for use may be considered for people without contraindications to the vaccine.
Influenza vaccines do not confer sufficient protection to make the vaccine useful in infants less than 6 months of age. Children 6 months to less than 9 years of age who have not previously received at least 1 dose of the seasonal influenza vaccine require 2 doses of influenza vaccine, with a minimum of 4 weeks between doses. Only 1 dose of influenza vaccine per season is recommended for everyone else.
Vaccination before the onset of the influenza season is strongly preferred, as delayed administration may result in lost opportunities to prevent infection from exposures that occur prior to vaccination. However, influenza vaccine may still be administered until the end of the season.
Table 1: Recommendations for influenza vaccine type by age group| Recipient by age group | Vaccine types authorized for use | Recommendations |
| --- | --- | --- |
| 6 to 23 months | * IIV3-Adj
* IIV4-SD
* IIV4-cc
| A quadrivalent influenza vaccine should be used in infants and young children without contraindications to the vaccine. There is insufficient evidence to recommend Influvac Tetra (IIV4-SD) in children younger than 3 years of age. If a quadrivalent vaccine is not available, a trivalent vaccine licensed for this age group should be used. |
| 2 to 17 years | * IIV4-SD
* IIV4-cc
* LAIV4
| An age-appropriate quadrivalent influenza vaccine should be used in children without contraindications or precautions to the vaccine, including those with chronic health conditions. There is insufficient evidence to recommend Influvac Tetra (IIV4-SD) in children younger than 3 years of age.
* LAIV4 may be given to children with:
+ stable, non-severe asthma
+ cystic fibrosis who are not being treated with immunosuppressive drugs (e.g., prolonged systemic corticosteroids)
+ stable HIV infection, i.e., if the child is currently being treated with ART (i.e., HAART) for at least 4 months and has adequate immune function
* LAIV should not be used in children or adolescents for whom it is contraindicated or for whom there are warnings and precautions such as those with:
+ severe asthma (defined as currently on oral or high-dose inhaled glucocorticosteroids or active wheezing)
+ medically attended wheezing in the 7 days prior to vaccination
+ current receipt of aspirin or aspirin-containing therapy
+ immune compromising conditions, with the exception of stable HIV infection, i.e., if the child is currently being treated with HAART for at least 4 months and has adequate immune function
+ pregnancy
- in pregnancy, IIV should be used instead
|
| 18 to 59 years | * IIV4-SD
* IIV4-cc
* RIV4
* LAIV4
| Any of the available influenza vaccines authorized for this age group should be used in adults 18 to 59 years without contraindications or precautions to the vaccine. LAIV is not recommended for pregnant individuals, adults with any of the chronic health conditions identified in [List 1](/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html#List1), including immune compromising conditions, and health care workers. IIV or RIV should be used instead. |
| 60 to 64 years | * IIV4-SD
* IIV4-cc
* RIV4
| Any of the available influenza vaccines authorized for this age group should be used in adults 60 to 64 years without contraindications to the vaccine. |
| 65 years and older | * IIV3-Adj
* IIV4-SD
* IIV4-HD
* IIV4-cc
* RIV4
| If available, IIV-HD should be preferentially offered to adults 65 years and older as it provides better protection than IIV-SD in this age group. |
| **Abbreviations:** ART: antiretroviral therapy; HAART: highly active antiretroviral therapy; IIV: inactivated influenza vaccine; IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV4-cc: quadrivalent mammalian cell culture-based inactivated influenza vaccine; IIV4-HD: high-dose quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; RIV4: quadrivalent recombinant influenza vaccine; LAIV4: quadrivalent live attenuated influenza vaccine. |
Vaccination of specific populations
-----------------------------------
To reduce the morbidity and mortality associated with influenza, immunization programs may focus on people at high risk of influenza-related complications (refer to [List 1: Groups for whom influenza vaccination is particularly recommended](/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html#List1)).
| |
| --- |
| List 1: Groups for whom influenza vaccination is particularly recommended
**People at high risk of influenza-related complications or hospitalization*** All children 6 to 59 months of age
* Adults and children with the following chronic health conditions:
+ Cardiac or pulmonary disorders (includes bronchopulmonary dysplasia, cystic fibrosis, and asthma)
+ Diabetes mellitus and other metabolic diseases
+ Cancer, immune compromising conditions (due to underlying disease, therapy, or both, such as solid organ transplant or hematopoietic stem cell transplant recipients)
+ Renal disease
+ Anemia or hemoglobinopathy
+ Neurologic or neurodevelopmental conditions (includes neuromuscular, neurovascular, neurodegenerative, and seizure disorders [and, for children, includes febrile seizures and isolated developmental delay], but excludes migraines and psychiatric conditions without neurological conditions)
+ Morbid obesity (defined as BMI of 40 kg/m² and over)
+ Children 6 months to 18 years of age undergoing treatment for long periods with acetylsalicylic acid, because of the potential increase of Reye's syndrome associated with influenza
* All individuals who are pregnant
* People of any age who are residents of nursing homes and other chronic care facilities
* Adults 65 years of age and older
* Indigenous Peoples
|
| **People capable of transmitting influenza to those at high risk*** Health care workers and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk
* Household contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated:
+ household contacts of individuals at high risk
+ household contacts of infants less than 6 months of age, as these infants are at high risk but cannot receive influenza vaccine
+ members of a household expecting a newborn during the influenza season
* Those providing regular child care to children 0 to 59 months of age, whether in or out of the home
* Those who provide services within closed or relatively closed settings to people at high risk (e.g., crew on a cruise ship)
**Others*** People who provide essential community services
* People who are in direct contact with poultry infected with avian influenza during culling operations
|
### Children 6 months to 59 months of age
Young children have a high burden of influenza-associated illness. The risk of serious infection and hospitalization is highest among the very young.
### Pregnant individuals
Pregnant individuals, at any stage of pregnancy, are recommended to receive any age-appropriate non-live influenza vaccine due to the increased risk of influenza associated morbidity in pregnancy and evidence of adverse neonatal outcomes associated with influenza infection during pregnancy. Moreover, vaccination of individuals who are pregnant protects their newborns from influenza and influenza-related hospitalization. It has also been shown to be protective against infants being born premature, small for gestational age, and low birth weight. To protect infants less than 6 months of age who are at high risk of influenza-related illness, the influenza vaccine should not only be offered to individuals who are pregnant, but to any household contacts and care providers of young infants.
Refer to [Immunization in pregnancy and breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3 for additional information.
### Older adults
Adults 65 years of age and older are at greater risk of more severe complications from influenza, and influenza-attributed mortality rates increase with age. High dose (IIV-HD) formulation is recommended for older adults as it provides better protection compared with the standard dose influenza vaccine in adults 65 years of age and older.
### Residents in nursing homes or other chronic care facilities
Residents of nursing homes and other chronic care facilities often have 1 or more chronic health conditions and live in institutional environments that may facilitate the spread of influenza.
Refer to [Immunization of patients in health care institutions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-6-immunization-patients-health-care-institutions.html#p3c5a3) in Part 3 for additional information.
### Persons with chronic health conditions
Certain chronic health conditions are associated with increased risk of influenza-related complications and hospitalization. Refer to [List 1: Groups for whom influenza vaccination is particularly recommended](/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html#List1). Influenza infection in individuals with certain chronic diseases can also lead to an exacerbation of the chronic condition.
Refer to [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional information.
### Immunocompromised persons
People who are immunocompromised have an increased risk of morbidity and mortality from influenza. All people 6 months of age and older who are immunocompromised are particularly recommended to receive an influenza vaccine every year. Although influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, vaccine effectiveness may be lower than in healthy individuals.
Refer to [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional information.
### Indigenous Peoples
Influenza vaccination is particularly recommended for Indigenous Peoples who tend to have higher rates of influenza-associated hospitalization and death. The increased risk of severe outcomes may be related to the presence of chronic health conditions and/or delays in accessing healthcare. Susceptibility to infection may also be increased due to living conditions that favour transmission.
### Health care workers, care providers and other workers
Influenza vaccination is recommended for health care workers (HCWs) and other care providers include regular visitors, emergency response workers, those who work in continuing care or long-term care facilities or residences, those who provide home care for people at high risk, and students of related health care services. HCWs and other care providers who are potentially capable of transmitting influenza to those at high risk should receive annual vaccination with any age appropriate non-live influenza vaccine, regardless of whether the high-risk individual has been vaccinated. Vaccination of HCWs and other care providers decreases the vaccinated person's risk of illness, as well as the risk of transmission of influenza to patients at high risk of influenza-associated complications. Vaccination of HCWs and residents of nursing homes is associated with decreased risk of influenza outbreaks. Annual influenza vaccination is considered an essential component of the standard of care for all HCWs.
To minimize the disruption of services during annual influenza epidemics, all people who provide essential community services should consider annual influenza vaccination, as it can decrease work absenteeism due to respiratory and related illnesses.
Seasonal influenza vaccination will not prevent avian influenza but it is recommended for those working in direct contact with poultry infected with avian influenza during culling operations, as these individuals may be at increased risk of exposure to avian influenza infection. Preventing infection with human influenza strains may reduce the theoretical potential for human-avian reassortment of genes, should such workers become co-infected with both human and avian influenza viruses.
Refer to [Immunization of workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html) in Part 3 for additional information.
### Travellers
Influenza occurs year-round in the tropics. In temperate northern and southern countries, influenza activity generally peaks during the winter season (November to March in the Northern Hemisphere and April to October in the Southern Hemisphere). Influenza vaccine should be offered to travellers.
Vaccines prepared specifically for use in the Southern Hemisphere are not available in Canada, and the extent to which recommended vaccine components for the Southern Hemisphere may overlap with those in available Canadian formulations will vary. A decision for or against revaccination of travellers to the Southern Hemisphere between April and October, if they had already been vaccinated in the preceding fall or winter with the Northern Hemisphere's vaccine, depends on individual risk assessment, the similarity between the Northern and Southern Hemisphere vaccines, the similarity between the Northern Hemisphere vaccine strains and currently circulating strains in the Southern Hemisphere, and the availability of a reliable and safe vaccine at the traveller's destination.
Refer to [Immunization of travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html#a3) in Part 3 for additional general information.
Serologic testing
-----------------
Serologic testing is not necessary or recommended before or after receiving seasonal influenza vaccine.
Administration practices
------------------------
### Dose and route of administration
The dose and route for influenza vaccines vary and are detailed in the product monographs.
* With the exception of IIV4-HD, most unadjuvanted IIVs are administered as a 0.5 mL intramuscular (IM) injection for everyone 6 months of age and older.
* The following IIVs are administered as a 0.5 mL IM injection but are only authorized or recommended for certain age groups: Afluria® Tetra (5 years and older), Influvac® Tetra (3 years and older), and Flucelvax® Quad (2 years and older).
* IIV4-HD (Fluzone® High-Dose Quadrivalent) is administered as a 0.7 mL IM injection for adults 65 years of age and older.
* Adjuvanted IIV3 (Fluad®) is administered as a 0.5 mL IM injection for adults 65 years of age and older. A pediatric formulation is also available (Fluad Pediatric®) and is administered as a 0.25 mL IM injection for children 6–23 months of age.
* RIV4 (Supemtek™) is administered as a 0.5 mL IM injection for adults 18 years of age and older.
* LAIV (FluMist® Quadrivalent) is administered as 0.2 mL given intranasal (0.1 mL in each nostril) for individuals 2 to 59 years of age.
Refer to [Vaccine administration practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for additional information.
### Concurrent administration with other vaccines
All influenza vaccines, including LAIV, may be given at the same time as, or at any time before or after administration of other live or inactivated vaccines, including COVID-19 vaccines for those aged 6 months and older.
Refer to the [COVID-19 vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html#a8.3) chapter for latest guidance on concurrent administration of influenza vaccine with COVID-19 vaccines. For more information regarding vaccine timing, refer to [Timing of vaccine administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) in Part 1.
### Interchangeability of vaccines
If a child aged less than 9 years requires 2 doses of influenza vaccine in the same influenza season, it is preferable to use the same type of vaccine for both doses. However, if the type of vaccine used for the first dose is not available for the second dose, a different type of influenza vaccine may be provided. For more information refer to [Principles of vaccine interchangeability](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-7-principles-vaccine-interchangeability.html) in Part 1.
### Pre- and post-vaccination counselling
Refer to [Vaccine administration practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for information on pre- and post-vaccination counseling, vaccine preparation and administration technique, and infection prevention and control.
Storage requirements
--------------------
Influenza vaccines should be stored at +2°C to +8°C and should not be frozen. For additional information, consult the product monographs available through Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html). Refer to [Storage and handling of immunizing agents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-9-storage-handling-immunizing-agents.html) in Part 1 for additional information.
Safety and adverse events
-------------------------
### Common and very common adverse events
Common adverse events occur in 1% to less than 10% of vaccinees. Very common adverse events occur in 10% or more of vaccinees.
With IM-administered influenza vaccines, mild and transient injection site reactions e.g., soreness at the injection site lasting up to 2 days, are common. Any systemic reactions e.g., myalgia, headache, fatigue and malaise, are usually mild and short-lived. Influenza vaccines with adjuvant tend to produce more extensive injection site reactions than unadjuvanted, but these reactions are also generally mild and resolve within a few days. IIV-HD tends to induce higher rates of systemic reactions compared to IIV-SD, but most of these reactions are also mild and short-lived. The most common adverse reactions experienced by recipients of LAIV are nasal congestion and runny nose.
### Uncommon, rare and very rare adverse events
Uncommon adverse events occur in 0.1% to less than 1% of vaccinees. Rare and very rare adverse events occur, respectively, in 0.01% to less than 0.1% and less than 0.01% of vaccinees.
Serious adverse events are rare following influenza vaccination, and in most cases, data are insufficient to determine a causal association. Allergic responses to influenza vaccine are a rare consequence of hypersensitivity to some components of the vaccine or its container.
### Other reported adverse events and conditions
#### Guillain-Barré syndrome
Studies suggest that the absolute risk of GBS in the period following seasonal and A(H1N1) pdm09 influenza vaccination is about 1 excess case per million vaccinations, and that the risk of GBS associated with influenza illness (about 17 cases per million influenza-coded health care encounters, which are a proxy for influenza illness) is higher than that associated with influenza vaccination.
Although the evidence considering influenza vaccination and GBS is inadequate to accept or reject a causal relation between GBS in adults and seasonal influenza vaccination, avoiding subsequent influenza vaccination of individuals known to have had GBS without other known etiology within 6 weeks of a previous influenza vaccination appears prudent at this time. However, the potential risk of GBS recurrence associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.
#### Oculorespiratory syndrome
Oculorespiratory syndrome (ORS) consists of bilateral red eyes and 1 or more associated respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, or sore throat) that starts within 24 hours of vaccination, with or without facial oedema. ORS was first identified during the 2000 – 2001 influenza season. Since then, there have been far fewer cases per year. ORS is not considered to be an allergic response. People who have an occurrence or recurrence of ORS upon vaccination do not necessarily experience further episodes with future vaccinations. Individuals who have experienced ORS without lower respiratory tract symptoms may be safely revaccinated with influenza vaccine. Individuals who have experienced ORS with lower respiratory tract symptoms should seek medical advice.
### Guidance on reporting adverse events following immunization
To ensure the ongoing safety of vaccines in Canada, reporting of adverse events following immunization (AEFIs) by vaccine providers and other clinicians is critical, and in some jurisdictions, reporting is mandatory under the law.
Vaccine providers are asked to report AEFIs through [local public health](/en/public-health/services/immunization/federal-provincial-territorial-contact-information-aefi-related-questions.html) officials and to check for specific AEFI reporting requirements in their province or territory. In general, any serious or unexpected adverse event felt to be temporally related to vaccination should be reported.
For influenza vaccines, the following AEFIs are of particular interest:
* ORS
* GBS within 6 weeks following vaccination
Refer to [Vaccine safety and pharmacovigilance](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) and [Adverse Events Following Immunization (AEFI)](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) in Part 2 for additional information on vaccine safety and for definitions of AEFIs, and reporting of AEFIs to public health.
### Contraindications and precautions
Influenza vaccines are contraindicated in persons with a history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component, except egg, of the specific vaccine or its container. Refer to [Contents of immunizing agents authorized for use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for a list of all vaccines authorized for use in Canada and their contents.
Safety data confirm that egg-allergic individuals may be vaccinated against influenza using any influenza vaccine, including egg-based vaccines and LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg and without any particular considerations, including vaccination setting.
Additional contraindications apply to the use of LAIV in people with certain health conditions:
* People with immune-compromising conditions due to underlying disease, therapy, or both, with the exception of children with stable HIV infection on anti-retroviral therapy (ART) and with adequate immune function
* People with severe asthma who are on oral or high dose inhaled glucocorticosteroids or have active wheezing or have medically attended wheezing in the 7 days of vaccination
* Children less than 24 months of age
* Children 2 to 17 years of age currently receiving aspirin or aspirin-containing therapy
* Pregnant individuals, because there is a lack of safety data at this time.
Precautions for the use of LAIV are as follows:
* LAIV should not be administered until 48 hours after antiviral agents active against influenza (e.g., oseltamivir, zanamivir) are stopped, and those antiviral agents, unless medically indicated, should not be administered until 2 weeks after receipt of LAIV so that the antiviral agents do not inactivate the replicating vaccine virus.
* If significant nasal congestion is present that might impede delivery of LAIV to the nasopharyngeal mucosa, IIV can be administered or LAIV can be deferred until resolution of the congestion.
* LAIV is not recommended for adults with the chronic health conditions identified in [List 1](/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html#List1), IIV or RIV should be used instead.
* LAIV is not recommended for HCWs, IIV or RIV should be used instead.
* LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection.
* LAIV recipients who are less than 18 years of age should avoid the use of aspirin-containing products for at least 4 weeks after receipt of LAIV.
As a precaution, influenza vaccination should be avoided in people who have developed GBS within 6 weeks of a previous influenza vaccination. Medical advice may be sought to balance the potential risk of GBS recurrence associated with influenza vaccination against the risk of GBS associated with influenza infection itself, and the benefits of influenza vaccination.
ORS is usually transient, resolving within 48 hours of onset. The only associated precaution is when lower respiratory symptoms accompany ORS, in which case expert review is required prior to subsequent immunization.
Influenza vaccination should not be delayed because of minor or moderate acute illness, with or without fever; however, in people with serious acute illnesses it may be postponed until their symptoms have abated.
Refer to [Contraindications and precautions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html) in Part 2 for additional information.
Other considerations
--------------------
### Drug interactions
Although influenza vaccine can inhibit the clearance of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine. Statins have effects on the immune system in addition to their therapeutic cholesterol-lowering actions. Two published studies have found that adults who are regular statin users had an apparent decreased response to influenza vaccination as measured by reduced geometric mean titres (GMT) or reduced vaccine effectiveness against medically attended acute respiratory illness. Statins are widely used in the same adult populations who are also at-risk for influenza-related complications and hospitalizations. Therefore, if these preliminary findings are confirmed in future studies, concurrent statin use in adult populations could have implications for influenza vaccine effectiveness and how this use is assessed in the measurement of vaccine effectiveness.
Chapter creation process
------------------------
This new chapter was developed based on the Statement on Seasonal Influenza Vaccine for 2023–2024 from the National Advisory Committee on Immunization (NACI). It incorporates key information from other recent NACI statements on influenza vaccines.
Acknowledgements
----------------
This chapter was based on a NACI statement prepared by A Sinilaite and W Siu on behalf of the NACI Influenza Working Group. The chapter was prepared by F Crane and reviewed by J Papenburg, C Jensen and W Siu.
NACI gratefully acknowledges the contribution of: Nayla Haddad.
Selected references
-------------------
Anema A, Mills E, Montaner J, et al. Efficacy of Influenza Vaccination in HIV-Positive Patients: A Systematic Review and Meta-Analysis. HIV Med. 2008;9(1):57-61.
AstraZeneca Canada Product Monograph - FLUMIST® QUADRIVALENT April 13, 2022.
BGP Pharma ULC Product Monograph INFLUVAC® TETRA May 13, 2022.
Black S, Nicolay U, Del Giudice G, et al. Influence of Statins on Influenza Vaccine Response in Elderly Individuals. J Infect Dis. 2016;213(8):1224-8.
Carman WF, Elder AG, Wallace LA, et al. Effects of Influenza Vaccination of Health-Care Workers on Mortality of Elderly People in Long-Term Care: A Randomised Controlled Trial. Lancet. 2000;355(9198):93-7.
Centers for Disease Control and Prevention. Selecting Viruses for the Seasonal Influenza Vaccine. Atlanta (GA): CDC; (updated 2021-08-31; accessed 2021-08-30). https://www.cdc.gov/flu/prevent/vaccine-selection.html
GlaxoSmithKline Inc. Product Monograph - FLULAVAL® TETRA April 20, 2022.
Kwong JC, Vasa PP, Campitelli MA, et al. Risk of Guillain-Barré Syndrome after Seasonal Influenza Vaccination and Influenza Health-Care Encounters: A Self-Controlled Study. Lancet Infect Dis. 2013;13(9):769-76.
Lemaitre M, Meret T, Rothan-Tondeur M, et al. Effect of Influenza Vaccination of Nursing Home Staff on Mortality of Residents: A Cluster-Randomized Trial. J Am Geriatr Soc. 2009;57(9):1580-6.
Mclean HQ, Thompson MG, Sundaram ME, et al. Impact of Repeated Vaccination on Vaccine Effectiveness against Influenza A(H3N2) and B During 8 Seasons. Clin Infect Dis. 2014;59(10):1375-85.
Omer SB, Phadke VK, Bednarczyk RA, et al. Impact of Statins on Influenza Vaccine Effectiveness against Medically Attended Acute Respiratory Illness. J Infect Dis. 2016;213(8):1216-23.
Public Health Agency of Canada. National Advisory Committee on Immunization. Recommendation on repeated seasonal influenza vaccination. (February 21, 2023). Accessed February 21, 2023 at https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/recommendation-repeated-seasonal-influenza-vaccination.html
Public Health Agency of Canada. National Advisory Committee on Immunization. Statement on Seasonal Influenza Vaccine for 2023–2024 (May 31, 2023)
Public Health Agency of Canada. National Advisory Committee on Immunization. Guidance on the use of influenza vaccine in the presence of COVID-19 (February 6, 2023). Accessed February 10, 2023 at https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-use-influenza-vaccine-covid-19.html
Sanofi Pasteur Inc. Product Monograph - FLUZONE® Quadrivalent April 19, 2022.
Sanofi Pasteur Ltd. Product Monograph - FLUZONE® High-Dose Quadrivalent April 19, 2022.
Sanofi Pasture Ltd. Product Monograph - Supemtek™ May 10, 2022.
Seqirus Canada Inc. Product Monograph - AFLURIA® TETRA January 24, 2023.
Seqirus Canada Inc. Product Monograph - FLUCELVAX® QUAD January 23, 2023.
Seqirus Canada Inc. Product Monograph - FLUAD Pediatric™ and FLUAD® April 8, 2022.
Zaman K, Roy E, Arifeen SE, et al. Effectiveness of Maternal Influenza Immunization in Mothers and Infants. N Engl J Med. 2008;359(15):1555-64. 41. Fell DB, Sprague AE, Liu N, et al.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-9-human-papillomavirus-vaccine.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-11-japanese-encephalitis-vaccine.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-05-31
| None | None |
1a8355f913cfde6f0b2bd38bfecaa3947f50ea0d | cma | Meningococcal vaccine: Canadian Immunization Guide | Meningococcal vaccine: Canadian Immunization Guide
Key information
# What
- The majority of invasive meningococcal disease (IMD) is associated with *Neisseria meningitidis- serogroups A, B, C, Y and W
- IMD is endemic in Canada but occurs at low rates, with the incidence being highest in infants
- Persons at higher risk of IMD include:
+ those at risk due to underlying medical conditions:
- persons with functional or anatomic asplenia, sickle cell disease, or combined T and B cell immunodeficiencies
- persons with congenital complement, properdin, factor D or primary antibody deficiencies
- persons with acquired complement deficiency due to receipt of the terminal complement inhibitor eculizumab (Soliris™)
- HIV positive individuals, especially if HIV is congenitally acquired
and
+ those at risk due to exposure:
- travellers to areas with high rates of endemic meningococcal disease or transmission, including travellers to the meningitis belt of sub-Saharan Africa and pilgrims to the Hajj in Mecca, Saudi Arabia
- research, industrial and clinical laboratory personnel who may be at risk of exposure to *N. meningitidis*
- military personnel who are at increased risk of meningococcal disease
- close contacts of a case of IMD and for individuals at risk in an outbreak setting, if the disease is caused by a serogroup contained in the vaccine
- Meningococcal vaccines are initially highly effective but effectiveness wanes over time
# Who
- Healthy children: should be immunized with a monovalent conjugate C meningococcal (Men-C-C) vaccine routinely at 12 months of age; however, they may begin meningococcal immunization earlier, depending on provincial and territorial schedules. If not previously immunized as infants or toddlers, children less than 5 years of age should receive Men-C-C vaccine. It should also be considered for children 5 to 11 years of age. Additionally, a serogroup B meningococcal vaccine may be considered on an individual basis for children two months of age and older to protect against serogroup B strains expressing antigens covered by the vaccine.
- Healthy adolescents and young adults: either a Men-C-C or a quadrivalent conjugate meningococcal (Men-C-ACYW) vaccine, depending on local epidemiology and programmatic considerations, is recommended for adolescents routinely at 12 years of age, and young adults, even if they have previously been vaccinated as an infant or toddler. In addition, 4CMenB or bivalent, factor-H binding protein serogroup B meningococcal (MenB-fHBP) vaccine may be considered on an individual basis for those wishing to protect against IMD caused by relevant serogroup B strains.
- High risk individuals: Men-C-ACYW provided together with 4CMenB or MenB-fHBP vaccine is recommended for children and adults with increased risk of IMD.
- Post-exposure management: in addition to chemoprophylaxis that is recommended for close contacts, if the serogroup is vaccine-preventable, immunoprophylaxis should also be considered, depending on the exposure history.
# How
- Routine immunization:
+ Less than 12 months: give Men-C-C vaccine to healthy infants according to provincial and territorial schedules.
+ 12 months to 11 years of age: give one dose of Men-C-C vaccine at 12 to 23 months of age, routinely at 12 months, whether the child has been immunized as an infant or not. For previously unimmunized children less than 5 years of age, give one dose of Men-C-C vaccine. Consider one dose of Men-C-C vaccine in children aged 5 to 11 years who were previously unimmunized.
+ 12 to 24 years of age: give adolescents, routinely at 12 years of age, and young adults one dose of either Men-C-C or Men-C-ACYW vaccine, even if previously they have been vaccinated as an infant or toddler.
- High risk individuals: The choice of vaccine and recommended schedules vary with age. Immunization with periodic booster doses with Men-C-ACYW vaccine is recommended.
- Men-C-C, 4CMenB and Men-C-ACYW-CRM vaccine may be administered concomitantly with routine childhood vaccines, and Men-C-ACYW vaccine may be administered concomitantly with adolescent and adult age-appropriate vaccines.
- MenB-fHBP may be administered concomitantly with other vaccines in individuals 10 years of age and older.
- Vaccines administered concomitantly must be at different injection sites, using separate needles and syringes.
# Why
- IMD mortality is approximately 10%.
- Of IMD survivors, 10% to 20% have long term sequelae which may include hearing loss, neurologic disabilities, and digit or limb amputations.
Epidemiology
# Disease description
## Infectious agent
Meningococcal disease is caused by an aerobic encapsulated diplococcus, *N. meningitidis- (meningococcus). Meningococcal serogroups are classified according to the immunologic reactivity of the polysaccharide capsule. Almost all invasive meningococcal disease (IMD) is associated with serogroups A, B, C, Y, and W. Meningococcal serogroups A, B, and C cause the majority of disease worldwide and are responsible for most sporadic cases and outbreaks. For additional information about *Neisseria meningitidis,- refer to the .
## Reservoir
Humans are the only reservoir for *N. meningitidis*.
## Transmission
Meningococci are transmitted person-to-person by mucosal contact with respiratory droplets from the nose and throat of infected persons. Most people who are colonized with meningococci are asymptomatic carriers.
## Risk factors
In epidemiological studies, increased incidence of IMD has been observed in individuals with: complement, properdin or factor D deficiencies; functional or anatomic asplenia; sickle cell disease; certain genetic risk factors (e.g. polymorphisms in the genes for mannose-binding lectin and tumor necrosis factor); household exposure to an infected person; recent infection with influenza; household crowding; and active and passive smoking. Persons with HIV infection may be at increased risk for meningococcal disease, especially if HIV is congenitally acquired.
## Seasonal and temporal patterns
Although disease occurs year-round, there is seasonal variation, with the majority of cases occurring in the winter and spring period in temperate climates, and in the dry season in tropical climates. Most noteworthy is the "meningitis belt" of sub-Saharan Africa where the majority of cases occur from December to June. For further information, refer to the website.
## Spectrum of clinical illness
IMD is characterized by a short incubation period (2 to 10 days, usually 3 to 4 days) and usually presents as an acute febrile illness with rapid onset and features of meningitis or septicemia (meningococcemia), or both, and a characteristic non-blanching petechial or purpuric rash. Symptoms of meningitis include intense headache, fever, nausea, vomiting, photophobia and stiff neck. Meningococcemia is characterized by circulatory collapse, hemorrhagic skin rash and a high fatality rate. Overall mortality is approximately 10%, and 10% to 20% of survivors have long term sequelae which include hearing loss, neurologic disabilities, and digit or limb amputations.
# Disease distribution
IMD occurs sporadically worldwide and in focal epidemics. In Canada, IMD is endemic and reported year round with peaks in winter. Although people at any age can develop IMD, children younger than 5 are at the greatest risk, followed by people aged 15-19 years and 60 years and up. Serogroups B, C, W and Y are most commonly reported types in the country.
With the introduction of childhood immunization programs against serogroup C IMD in 2002, not unexpectedly, the incidence of serogroup C has decreased significantly over the years. While the incidence of serogroup B remains predominant, disease caused by serogroups W and Y have stabilized at relatively lower incidence rates.
For more information about distribution in Canada, refer to the PHAC website. Comprehensive updates on the epidemiology of IMD in Canada are published periodically in the Canada Communicable Disease Report (CCDR).
Preparations authorized for use in Canada
# Meningococcal vaccines
Monovalent conjugate meningococcal vaccines (Men-C-C)
- MENJUGATE Liquid (meningococcal group C oligosaccharide conjugated to CRM197 protein), GlaxoSmithKline Inc., (Men-C-C-CRM)
- NeisVac-C®Vaccine (meningococcal group C polysaccharide conjugated to tetanus toxoids), Pfizer Canada ULC, (Men-C-C-TT)
Quadrivalent conjugate meningococcal vaccines (Men-C-ACYW)
- Menactra® (meningococcal groups A, C, Y, and W polysaccharides conjugated to diphtheria toxoid protein), Sanofi Pasteur Limited, (Men-C-ACYW-DT)
- MENVEO (meningococcal groups A, C, Y and W oligosaccharides conjugated to CRM197 protein), GlaxoSmithKline Inc., (Men-C-ACYW-CRM)
- NIMENRIX® (meningococcal groups A, C, Y, and W polysaccharides conjugated to tetanus toxoid protein), Pfizer Canada ULC, (Men-C-ACYW-TT)
- MenQuadfi™ (meningococcal groups A, C, Y, and W polysaccharides conjugated to tetanus toxoid protein), Sanofi Pasteur Limited, (Men-C-ACYW-TT)\*
\- NACI has not yet deliberated on the use of MenQuadfi™. NACI will review this vaccine and update the chapter in due course. Refer to the product monograph available through Health Canada's (DPD) for additional information regarding the use of this vaccine.
Serogroup B meningococcal vaccines
- BEXSERO (meningococcal porin A , factor H binding protein , neisserial antigen 2091 , heparin binding antigen , neisserial antigen 1030 , and Neisserial adhesion A surface proteins), GlaxoSmithKline Inc., (4CMenB)
- Trumenba® (subfamily A and B factor-H binding protein ), Pfizer Canada ULC, (MenB-fHBP)
Preparations authorized for use in Canada may not be currently available for sale. Refer to Health Canada's for its drug status. Definitions of drug status can be found under .
For complete prescribing information, consult the product leaflet or information contained within Health Canada's authorized product monographs available through Health Canada's .
Immunogenicity, efficacy and effectiveness
# Immunogenicity
Men-C-C and Men-C-ACYW vaccines are immunogenic in infants and toddlers but those vaccinated in infancy show a waning immune response over time. Vaccination with conjugate meningococcal vaccine primes the immune system for memory and induces good anamnestic responses; however, anamnestic response may not be sufficient to prevent disease after exposure and circulating antibodies are thought to be essential. In comparison to polysaccharide meningococcal vaccine, conjugate meningococcal vaccines demonstrate greater immunogenicity and induce better immunologic memory. Conjugate meningococcal vaccines do not result in hyporesponsiveness and have been shown to overcome the hyporesponsiveness evident with polysaccharide meningococcal vaccine usage. In clinical trials, the 4CMenB vaccine has shown to be immunogenic in toddlers and children after at least two doses, and in adolescents and adults after one dose. In adolescents and adults, a more robust immune response has been observed in clinical trials following the use of a three-dose compared to a two-dose MenB-fHBP vaccine schedule.
# Efficacy and effectiveness
A study of Men-C-C vaccine demonstrated effectiveness in infants of 97% within one year of vaccination, decreasing to 68% after 1 year. Longer term vaccine effectiveness requires receipt of a booster dose in the second year of life for those immunized in infancy. Vaccine effectiveness of Men-C-ACYW-DT within 3 to 4 years of vaccination in adolescence is 80% to 85%; however, effectiveness wanes over time. There are no efficacy or effectiveness data available for Men-C-ACYW-CRM, Men-C-ACYW-TT, MenB-fHBP or 4CMenB vaccines. Vaccine effectiveness measured at the individual level may under-estimate the impact of the immunization programs on the burden of meningococcal disease in the community, due to the additional benefit conferred by herd immunity.
Recommendations for use
# Routine schedule
## Healthy infants and children (2 to 23 months of age)
Infants may receive Men-C-C vaccine beginning at 2 months of age, depending on the provincial and territorial schedule and the incidence of meningococcal serogroup C disease in their jurisdiction. One dose of Men-C-C vaccine is recommended for all children at 12 to 23 months of age, regardless of any doses given during the first year of life. Men-C-C is routinely given at 12 months of age if they have not previously been immunized as infants or toddlers. In addition, immunization with 4CMenB vaccine may be considered on an individual basis, depending on individual preferences, regional serogroup B epidemiology and strain susceptibility.
## Healthy adolescents and young adults (12 to 24 years of age)
Either Men-C-C or Men-C-ACYW vaccine, depending on local epidemiology and programmatic considerations, is recommended for adolescents, routinely at 12 years of age and young adults, even if they have previously been vaccinated as an infant or toddler. In addition, 4CMenB or MenB-fHBP vaccine may be considered on an individual basis, depending on the individual preferences, regional serogroup B epidemiology and strain susceptibility.
# Catch-up and accelerated schedules
# Healthy infants and children (2 to 11 years of age)
One dose of Men-C-C vaccine is recommended in unimmunized children less than 5 years of age. One dose of Men-C-C vaccine may be considered for children 5 to 11 years of age if they have not previously been immunized as infants or toddlers. Immunization with 4CMenB vaccine (2 years of age and older) or MenB-fHBP (10 years of age and older) may be considered on an individual basis, depending on individual preferences, regional serogroup B epidemiology and strain susceptibility.
# High risk individuals
Meningococcal vaccines are recommended for individuals with underlying medical conditions and those who are at increased risk of exposure to meningococcal disease.
## Underlying medical conditions
Individuals with increased risk of meningococcal disease because of underlying medical conditions include the following:
- persons with functional or anatomic asplenia, sickle cell disease, or combined T and B cell immunodeficiencies
- persons with congenital complement, properdin, factor D or primary antibody deficiencies
- persons with acquired complement deficiency due to receipt of the terminal complement inhibitor eculizumab (Soliris™)
- individuals with HIV, especially if it is congenitally acquired
## Increased risk of exposure
Individuals at increased risk of exposure to meningococcal disease include the following:
- travellers to areas with high rates of endemic meningococcal disease or transmission, including travellers to the meningitis belt of sub-Saharan Africa and pilgrims to the Hajj in Mecca, Saudi Arabia. Refer to section for additional information.
- research, industrial and clinical laboratory personnel who are potentially routinely exposed to *N. meningitidis*. Refer to section for additional information.
- military personnel during recruit training and on certain deployments. Refer to section for additional information.
Meningococcal vaccine is also recommended for most close contacts of a case of IMD and for outbreak control, if the disease is caused by a serogroup contained in the vaccine. Refer to and for additional information.
## Age considerations for choice of vaccine for high risk groups
### 2 to 23 months of age
Based on available published data in this age group, Men-C-ACWY-CRM should be used because it has been found to be safe and immunogenic. Routine meningococcal C conjugate vaccine does not need to be administered in addition to Men-C-ACWY-CRM. For toddlers and children who may be at increased high risk of IMD caused by serogroup B, 4CMenB vaccine should also be offered.
### 24 months to 9 years of age
Any of the Men-C-ACYW vaccines may be used. For individuals who are at high risk of IMD caused by serogroup B, 4CMenB vaccine should also be offered.
### 10 years of age and older
Any of the Men-C-ACYW vaccines may be used. For individuals who are at high risk of IMD caused by serogroup B, 4CMenB or MenB-fHBP vaccine should also be offered.
Refer, for recommended vaccination for certain travellers.
At high risk due to underlying medical conditions: refer to
A serogroup B meningococcal vaccine should be offered for the active immunization of individuals with underlying medical conditions that would put them at higher risk of meningococcal disease. 4CMenB vaccine is indicated for immunization of high risk individuals greater than or equal to two months of age; MenB-fHBP vaccine may be considered as an option for use in high-risk individuals 10 years of age and older.
A booster dose should be given every 3 to 5 years if vaccinated at 6 years of age or younger and every 5 years for those vaccinated at 7 years of age and older.
Depending on the age at which immunization is initiated, the manufacturer of 4CMenB recommends three doses for infants who begin primary immunization between the ages of 2 and 5 months, and two doses when the first dose is received between ages of 6 and 11 months.
Men-C-ACYW vaccines may be given a minimum of 4 weeks apart if accelerated immunization needed.
Serogroup B Meningococcal vaccines are not authorized for use in those 26 years of age and older and Men-C-ACYW vaccines are not authorized for use in those 56 years of age and older; however, based on limited evidence and expert opinion their use is considered appropriate above these authorized ages.
# Booster doses and re-immunization
Circulating antibodies are considered necessary to protect an individual against IMD. Re-vaccination is recommended as follows:
- For individuals at high risk of developing meningococcal disease due to underlying medical conditions, refer to . Re-vaccination with Men-C-ACYW is recommended every 3 to 5 years for those vaccinated at 6 years of age and younger and every 5 years for those vaccinated at 7 years of age and older.
- When travelling to areas where meningococcal vaccine is recommended or required, re-vaccination with Men-C-ACYW is recommended every 3 to 5 years for those vaccinated at 6 years of age and younger, and every 5 years for those vaccinated at 7 years of age and older. Previously vaccinated travellers are advised to check requirements for re-vaccination with meningococcal vaccines prior to travel to the Hajj as more frequent vaccination may be required (refer to and ).
- For military personnel who remain at risk due to travel or overcrowded conditions, a booster dose of Men-C-ACYW is recommended every 5 years if at ongoing risk.
- At the time of exposure for contacts of a case of IMD in some circumstances. Refer to .
- During a community outbreak of IMD in some circumstances. Refer to .
- For all laboratory personnel who are potentially routinely exposed to *N. meningitidis.- Booster doses of Men-C-ACYW should be given at routine 5 year intervals for those laboratory workers who remain at ongoing risk of exposure. Refer to .
People previously vaccinated with a polysaccharide meningococcal vaccine should be re-vaccinated with the appropriate conjugate or serogroup B meningococcal vaccine if they remain at ongoing risk for meningococcal disease. Conjugated meningococcal vaccine should be given at least 6 months following vaccination with polysaccharide meningococcal vaccine.
# Post-exposure management
## Contacts of cases
Close contacts of individuals with meningococcal infections have an increased risk of developing IMD; this risk is greatest for household contacts. The increased risk of disease for household contacts persists for up to 1 year after disease in the index case and beyond any protection from antibiotic chemoprophylaxis. In general, this prolonged risk is not seen in contacts who do not have ongoing exposure.
Chemoprophylaxis should be offered to all persons having close contact with a case of IMD from 7 days before onset of symptoms in the case to 24 hours after onset of effective treatment in the case, regardless of their immunization status. Refer to the PHAC for information about chemoprophylaxis in the management of close contacts of individuals with meningococcal infection.
Vaccination or re-vaccination of certain close contacts should be considered in addition to chemoprophylaxis when the serogroup is vaccine preventable, as it may further reduce the risk of subsequent meningococcal disease.
### Close contacts requiring chemoprophylaxis and consideration for immunoprophylaxis
The following individuals (regardless of immunization status) should receive chemoprophylaxis and, if the meningococcal serogroup identified in the case of IMD is vaccine preventable, should also be considered for immunoprophylaxis:
- Household contacts of a case of IMD
- Persons who share sleeping arrangements with a case of IMD
- Persons who have direct nose or mouth contamination with oral or nasal secretions of a case of IMD (e.g., kissing on the mouth, shared cigarettes, sharing bottles)
- Children and staff in contact with a case of IMD in child care or nursery school facilities
### Re-vaccination criteria for those previously vaccinated against IMD
The following provides criteria for the re-vaccination of previously vaccinated close contacts when the index case has a vaccine preventable IMD serogroup or there is a vaccine preventable outbreak of IMD:
- Those previously vaccinated with a serogroup that differs from the index case or outbreak strain should be vaccinated immediately with the appropriate vaccine (as outlined in );
- Those previously vaccinated with a serogroup that is the same as the index case or outbreak strain should be re-vaccinated with the appropriate vaccine (as outlined in );
+ If they were less than 1 year of age at last meningococcal vaccination and more than 4 weeks has passed since their last meningococcal vaccine;
+ If they have an underlying medical condition that puts them at risk for meningococcal disease and more than 4 weeks has passed since their last meningococcal vaccine;
+ If more than a year has passed since their last meningococcal vaccine, if they were not less than 1 year of age at the time of their last meningococcal vaccination and if they have no underlying medical condition that puts them at risk for meningococcal disease.
### Close contacts requiring chemoprophylaxis only
The following individuals should receive chemoprophylaxis only, immunoprophylaxis is not necessary:
- Health care workers who have had intensive unprotected contact (without wearing a mask) with infected patients (i.e., intubating, resuscitating or closely examining the oropharynx).
- Airline passengers sitting immediately on either side of the case (but not across the aisle) when the total time spent aboard the aircraft was at least 8 hours.
- Close contacts of a case of IMD due to serogroups not present in meningococcal vaccines, or when the serogroup in the index case has not been determined.
- Previously vaccinated close contacts who do not meet the criteria for re-vaccination as outline above.
# Outbreak control
## Outbreaks of meningococcal disease
Consultation with public health officials, experts in communicable disease, or both is important in the assessment and control of meningococcal disease outbreaks. Outbreaks may be controlled by the use of a conjugate meningococcal vaccine. The type of vaccine to use in an outbreak is dependent on the serogroup causing the outbreak and the age of those being vaccinated as outlined in . Re-vaccination criteria of previously vaccinated individuals are outlined above in
OR
- Men-C-ACYW
Previously vaccinated:* If previously vaccinated with only Men C-C, give Men-C-ACYW-CRM as for unvaccinated persons, regardless of when Men-C-C was previously given
- If previously vaccinated with Men-C-ACYW, then re-vaccinate with one dose of Men-C-ACYW-CRM if at least 4 weeks since last dose of Men-C-ACYW vaccine; then complete series
Previously vaccinated:* If previously vaccinated with only Men C-C, give Men-C-ACYW-CRM as for unvaccinated persons, regardless of when Men-C-C was previously given
- If previously vaccinated with Men-C-ACYW at less than 1 year of age OR person is at high risk for IMD due to underlying medical conditions, then re-vaccinate with one dose of Men-C-ACYW-CRM if at least 4 weeks since last dose of Men-C-ACYW; otherwise re-vaccinate with one dose of Men-C-ACYW-CRM if at least 1 year since last dose of Men-C-ACYW
Previously vaccinated:* If previously vaccinated with only Men C-C, give Men-C-ACYW as for unvaccinated persons, regardless of when Men-C-C was previously given
- If previously vaccinated with Men-C-ACYW at less than 1 year of age OR person is at high risk for IMD due to underlying medical conditions, then re-vaccinate with one dose of Men-C-ACYW if at least 4 weeks since last dose of Men-C-ACYW; otherwise re-vaccinate if at least 1 year since last dose
At high risk due to underlying medical conditions - refer to
In general, a minimum four week interval is recommended between doses of conjugate meningococcal vaccines; however, in an outbreak or to manage a close contact of a case of IMD, the second dose of conjugate meningococcal vaccine may be given as soon as indicated to provide protection to a close contact who is unvaccinated for the implicated serogroup.
Individuals at high risk due to underlying medical conditions routinely need two doses of Men-C-ACYW
Only for outbreak control of IMD caused by serogroup B strains that are predicted to be susceptible to the vaccine. Consultation with public health officials, experts in communicable disease or both is required for optimal management of meningococcal disease outbreaks.
During an outbreak, the vaccine should be provided as soon as possible after the identification of a serogroup B strain that is predicted to be susceptible to the vaccine.
Vaccination of specific populations
# Persons with inadequate immunization records
Children and adults lacking adequate documentation of immunization should be considered unimmunized and started on an immunization schedule appropriate for their age and risk factors. Conjugate meningococcal vaccine, as appropriate for age, may be given regardless of possible previous receipt of the vaccine, as adverse events associated with repeated immunization have not been demonstrated. Refer to in Part 3 for additional general information.
# Pregnancy and breastfeeding
Conjugate and serogroup B meningococcal vaccines have not been studied in pregnancy or breastfeeding. However, there is no theoretical reason to suspect that adverse events will occur and, in circumstances in which the benefits outweigh the risks (i.e. in high risk individuals due to exposure or underlying medical conditions), the use of conjugate and serogroup B meningococcal vaccines in pregnancy and breastfeeding may be considered. Refer to in Part 3 for additional information.
# Infants born prematurely
Premature infants in stable clinical condition should be immunized with conjugate meningococcal vaccine at the same chronological age and according to the same schedule as full-term infants. Infants born prematurely, especially those weighing less than 1,500 grams at birth are at higher risk of apnea and bradycardia following vaccination. Hospitalized premature infants should have continuous cardiac and respiratory monitoring for 48 hours after their first immunization. Refer to in Part 3 for additional general information.
# Persons/residents in health care institutions
Residents of long-term care facilities should receive meningococcal vaccine as appropriate for their risk factors. Refer to in Part 3 for additional general information.
# Persons with chronic diseases
## Asplenia
Two doses of Men-C-ACYW vaccine are recommended for persons with anatomic or functional asplenia, including sickle cell disease. When elective splenectomy is planned, all recommended vaccines should ideally be completed at least 2 weeks before surgery; if only one dose can be given before surgery, the second dose should be given 8 weeks after the first dose, with a minimum interval of 4 weeks. In the case of an emergency splenectomy, two doses of vaccine should ideally be given beginning 2 weeks after surgery but can be given earlier, before discharge, if the person might not return for vaccination after discharge. Persons one year of age and older with asplenia who have not received Men-C-ACYW vaccine should receive two doses administered 8 weeks apart, with a minimum interval of 4 weeks. In addition, 4CMenB or MenB-fHBP vaccine should be offered. Periodic booster doses with Men-C-ACYW vaccine are also recommended.
# Immunocompromised persons
Quadrivalent conjugate meningococcal vaccine provided with 4CMenB or MenB-fHBP vaccine is recommended for certain high risk individuals as outlined under above. People with conditions requiring the receipt of the terminal complement inhibitor eculizumab (Soliris™) should be vaccinated at least two weeks prior to receiving the first dose of eculizumab. When considering immunization of an immunocompromised person, consultation with the individual's attending physician may be of assistance in addition to the guidance provided below. For complex cases, referral to a physician with expertise in immunization or immunodeficiency is advised.
# Travellers
Travellers should be vaccinated with Men-C-ACYW vaccine alone or in combination with 4CMenB or MenB-fHBP vaccine, depending on the risk of meningococcal disease in the area of travel. Men-C-C vaccine alone is not appropriate for protection of travellers, as it does not protect against serogroup A, which is endemic in selected regions of the world (e.g. sub-Saharan Africa), or serogroup W disease. 4CMenB or MenB-fHBP vaccine is recommended for individuals travelling to an area with a hyperendemic strain or an outbreak that is known to be caused by a serotype B that can be prevented by the vaccine. Current is available from the WHO.
Proof of meningococcal immunization may be required by certain countries. For example, Saudi Arabia requires proof of immunization with a quadrivalent (ACYW) vaccine for travellers with the purpose of Umrah or pilgrimage (Hajj) or for seasonal work. Refer to the Saudi Arabia Ministry of Health website for information regarding vaccination requirements. Refer to in Part 3 for additional information.
Travellers to the Hajj should check recommendations for re-vaccination at: as more frequent re-vaccination may be required.
A booster dose of Men-C-ACYW should be given every 3 to 5 years if vaccinated at 6 years of age or younger and every 5 years for those vaccinated at 7 years of age and older.
Depending on the age at which immunization is initiated, the manufacturer of 4CMenB recommends two or three primary doses and a booster (2 + 1 schedule or 3 + 1 schedule) when the first dose is received between the ages of 2 and 5 months, and two primary doses and a booster (2 + 1 schedule) when the first dose is received between ages of 6 and 11 months. The booster dose should be administered in the second year of life.
Men-C-ACYW-CRM may be given a minimum of 4 weeks apart if accelerated immunization is needed.
Serogroup B Meningococcal vaccines are not authorized for use in those 26 years of age and older and Men-C-ACYW vaccines are not authorized for use in those 56 years of age and older; however, based on limited evidence and expert opinion their use is considered appropriate above these authorized ages.
# Persons new to Canada
Health care providers who see persons newly arrived in Canada should review the immunization status and update immunization for these individuals. Review of meningococcal vaccination status is particularly important for persons from areas of the world where sickle cell disease is present as persons with sickle cell disease are at risk of serious meningococcal infections. In many countries outside of Canada, conjugate meningococcal vaccines are in limited use. Information on can be found on the website. Refer to in Part 3 for additional general information.
# Workers
## Laboratory workers
Research, industrial and clinical laboratory personnel who are potentially routinely exposed to *N. meningitidis- should be offered one dose of Men-C-ACYW vaccine and two doses of 4CMenB vaccine given at least 4 weeks apart or two doses of MenB-fHBP vaccine given at least 6 months apart. Re-vaccination is generally recommended every 5 years for Men-C-ACYW. There are currently no booster dose recommendations for serogroup B meningococcal vaccines. Routine infection control precautions should be practiced at all times to minimize the risk of exposure in laboratory workers and post-exposure prophylaxis should be offered after recognized exposures. Refer to for additional information.
## Health care workers (HCW)
Nosocomial transmission of IMD is very uncommon. HCW are considered as close contacts only if they have had intensive, unprotected contact (without wearing a mask) with infected patients (e.g., intubating, resuscitating or closely examining the oropharynx). It is recommended that HCW use barrier precautions to avoid direct contact with respiratory secretions of patients with meningococcal disease until the patient has completed 24 hours of effective antibiotic therapy, according to provincial and territorial communicable disease control guidelines.
There is no evidence to recommend routine meningococcal immunization of HCW since the risk period for acquisition ends when contact with an untreated patient terminates, and antibiotic chemoprophylaxis should be sufficient in the high-risk situation described above.
## Military personnel
Military personnel may be at increased risk of IMD when accommodated in close quarters or through deployment to endemic or epidemic countries.
Serologic testing
Serologic testing is not recommended before or after receiving meningococcal vaccine.
Administration practices
# Dose and route of administration
## Dose
Each dose of meningococcal vaccine is 0.5 mL.
## Route of administration
Conjugate and serogroup B meningococcal vaccines should be administered intramuscularly (IM). Refer to in Part 1 for additional information.
# Interchangeability of vaccines
There are no published data regarding the interchangeability of Men-C-C vaccines, but the vaccines have been safely interchanged without a noticeable decrease in efficacy. When possible, the infant series should be completed with the same vaccine. Either Men-C-ACYW vaccine may be used for re-vaccination, regardless of which meningococcal vaccine was used for initial vaccination. The serogroup B meningococcal vaccines are not interchangeable as they contain different antigens and there are no published studies on the immunogenicity resulting from a vaccination series combining the two products. Therefore, the same vaccine product should be used for all doses in a vaccination series. If, in a person with an incomplete vaccination series, it is unknown what vaccine product they initially received, the initial dose(s) should be discounted and the vaccination series repeated using the same vaccine product for all doses in the new, repeated series.
# Simultaneous administration with other vaccines
Men-C-C and 4CMenB vaccine may be administered concomitantly with routine childhood vaccines, and Men-C-ACYW vaccine may be administered concomitantly with adolescent and adult age appropriate vaccines. MenB-fHBP can be given concomitantly with quadrivalent human papillomavirus vaccine; meningococcal serogroup A, C, Y, W conjugate vaccine; and tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed. The concomitant administration of MenB-fHBP has not been studied with other vaccines.
Men-C-ACYW-CRM can be administered with routine paediatric vaccines; however, further studies are needed with regard to concomitant administration with pneumococcal 13-valent conjugate vaccine. Co-administration of Men-C-ACYW-CRM and combined tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) may result in a lower immune response to the pertussis antigens than when Tdap vaccine is given alone; however, the clinical significance of this is unknown. Tdap vaccine given one month after Men-C-ACYW-CRM induces the strongest immunologic response to pertussis antigens.
If vaccines are to be administered concomitantly with another vaccine, a separate injection site and a different syringe must be used for each injection.
Storage requirements
Menactra®, NeisVac-C® Vaccine, Trumenba®: Store in a refrigerator at +2°C to +8°C. Do not freeze.
BEXSERO, MENJUGATE Liquid, MENVEO, NIMENRIX®: Store in a refrigerator at +2°C to +8°C. Do not freeze. Protect from light.
Safety and adverse events
# Common and local adverse events
## Conjugate meningococcal vaccines
### Men-C-ACYW vaccines
Injection site reactions occur in up to 59% of vaccinees. Fever is reported in up to 5% of recipients and systemic reactions, such as headache and malaise, are reported in up to 60% of recipients.
### Men-C-C vaccines
Mild reactions, including injection site reactions (redness, tenderness, and swelling), occur in up to 50% of vaccine recipients. Irritability occurs in up to 80% of infants and fever in up to 9% when other vaccines were administered. Headaches and malaise occur in up to 10% of older children and adults. These reactions last no more than a few days.
## Serogroup B Meningococcal vaccines
### 4CMenB vaccine
Solicited local and systemic reactions have been commonly reported in clinical trials and include injection site tenderness, induration, sleepiness and irritability. Higher rates of fever have been observed with simultaneous administration of 4CMenB vaccine and routine infant vaccines; therefore, routine prophylactic administration of acetaminophen or separating 4CMenB vaccination from routine vaccination schedule has been proposed for preventing fever in infants and children up to three years of age.
### MenB-fHBP vaccine
Solicited local and systemic reactions have been commonly reported in clinical trials and include injection site tenderness, induration and irritability.
# Less common and serious or severe adverse events
Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association.
# Guidance on reporting adverse events following immunization (AEFI)
To ensure the ongoing safety of vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in some jurisdictions, reporting is mandatory under the law.
Vaccine providers are asked to report AEFIs, through officials, and to check for specific AEFI reporting requirements in their province or territory. In general, any serious or unexpected adverse event felt to be temporally related to vaccination should be reported.
For additional information about AEFI reporting, please refer to . For general vaccine safety information, refer to in Part 2.
# Contraindications and precautions
Meningococcal vaccine is contraindicated in persons with a history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Refer to Table 1 in in Part 1 for lists of all vaccines available for use in Canada and their contents.
There are very few individuals who cannot receive meningococcal vaccines. In situations of suspected hypersensitivity or non-anaphylactic allergy to vaccine components, investigation is indicated, which may involve immunization in a controlled setting. Consultation with an allergist is advised.
Administration of meningococcal vaccine should be postponed in persons with moderate or severe acute illness. Persons with minor acute illness, with or without fever, may be vaccinated. |
Meningococcal vaccine: Canadian Immunization Guide
===================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-14-mumps-vaccine.html)
Notice
------
* Please note: The contents of this chapter are currently under consideration by NACI in context of recent changes to the following product monographs:
+ BEXSERO: 4CMenB vaccine dosage **for children aged 2 months to 11 months and 24 months to less than 10 years of age**
+ NIMENRIX®: Men-C-ACYW-TT vaccine indications and dosage **for children aged 6 weeks to 23 months.**
+ Trumenba®: booster dose of MenB-fHBP vaccine **for individuals at continued risk of invasive meningococcal disease**.
+ Use of MenQuadfi™ **for individuals 12 months of age and older**.
* For current product monographs please refer to Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
* Please [subscribe to our mailing list](https://health.canada.ca/en/health-canada/services/healthy-living/immunization-and-vaccines/canadian-immunization-guide/subscribe.html) to receive a notification when this chapter is updated.
**Last partial content update (see [Table of updates](/en/public-health/services/canadian-immunization-guide/updates.html)):** February 2020
**February 2020**: The chapter has been updated to align with the [National Advisory Committee on Immunization Statement (NACI): The Use of Bivalent Factor H Binding Protein Meningococcal Serogroup B (MenB-fHBP) Vaccine for the Prevention of Meningococcal B Disease](/en/public-health/services/publications/vaccines-immunization/bivalent-factor-h-binding-protein-meningococcal-serogroup-b-prevention-meningococcal-b-disease.html).
Updates include:
MenB-fHBP vaccine may be considered as an option for use in individuals 10 years of age and older in situations when a serogroup B meningococcal vaccine should be offered:
1. during serogroup B meningococcal disease outbreaks or with the emergence of hyperendemic *Neisseria meningitidis* strains that are predicted to be susceptible to the vaccine;
2. for individuals who are close contacts with a case of invasive meningococcal disease caused by serogroup B *Neisseria meningitidis*;
3. for individuals with underlying medical conditions that would put them at higher risk of meningococcal disease than the general population; or
4. for individuals at higher risk of exposure to serogroup B meningococcal isolates than the general population.
MenB-fHBP vaccine may be considered as an option for individuals 10–25 years of age who are not at higher risk of meningococcal disease than the general population, but who wish to reduce their risk of invasive serogroup B meningococcal disease.
**Last complete chapter revision:** May 2015
On this page
------------
* [Key information](#p4c12a1)
* [Epidemiology](#p4c12a2)
* [Preparations authorized for use in Canada](#p4c12a3)
* [Immunogenicity, efficacy and effectiveness](#p4c12a4)
* [Recommendations for use](#p4c12a5)
+ [Routine schedule](#routine)
+ [Catch-up and accelerated schedules](#catch)
+ [High risk individuals](#high)
- [Table 1: Recommended immunization for high risk individuals because of underlying medical conditions not previously immunized with meningococcal Men-C-ACYW or serogroup B meningococcal vaccine](#p4c12t1)
+ [Booster doses and re-immunization](#booster)
+ [Post-exposure management](#p4c12a5m)
+ [Outbreak control](#p4c12a5n)
- [Table 2: Recommended vaccination of close contacts for post-exposure management and for outbreak control](#p4c12t2)
* [Vaccination of specific populations](#p4c12a6)
+ [Table 3: Recommended immunization schedule for travellers to destinations where risk of meningococcal transmission is high, not previously immunized with quadrivalent conjugate meningococcal vaccines or serogroup B meningococcal vaccine](#p4c12t3)
* [Serologic testing](#sero)
* [Administration practices](#admin)
* [Storage requirements](#storage)
* [Safety and adverse events](#safety)
* [Selected references](#selected)
Key information
---------------
### What
* The majority of invasive meningococcal disease (IMD) is associated with *Neisseria meningitidis* serogroups A, B, C, Y and W
* IMD is endemic in Canada but occurs at low rates, with the incidence being highest in infants
* Persons at higher risk of IMD include:
+ those at risk due to underlying medical conditions:
- persons with functional or anatomic asplenia, sickle cell disease, or combined T and B cell immunodeficiencies
- persons with congenital complement, properdin, factor D or primary antibody deficiencies
- persons with acquired complement deficiency due to receipt of the terminal complement inhibitor eculizumab (Soliris™)
- HIV positive individuals, especially if HIV is congenitally acquired
**and**
+ those at risk due to exposure:
- travellers to areas with high rates of endemic meningococcal disease or transmission, including travellers to the meningitis belt of sub-Saharan Africa and pilgrims to the Hajj in Mecca, Saudi Arabia
- research, industrial and clinical laboratory personnel who may be at risk of exposure to *N. meningitidis*
- military personnel who are at increased risk of meningococcal disease
- close contacts of a case of IMD and for individuals at risk in an outbreak setting, if the disease is caused by a serogroup contained in the vaccine
* Meningococcal vaccines are initially highly effective but effectiveness wanes over time
### Who
* **Healthy children:** should be immunized with a monovalent conjugate C meningococcal (Men-C-C) vaccine routinely at 12 months of age; however, they may begin meningococcal immunization earlier, depending on provincial and territorial schedules. If not previously immunized as infants or toddlers, children less than 5 years of age should receive Men-C-C vaccine. It should also be considered for children 5 to 11 years of age. Additionally, a serogroup B meningococcal vaccine may be considered on an individual basis for children two months of age and older to protect against serogroup B strains expressing antigens covered by the vaccine.
* **Healthy adolescents and young adults:** either a Men-C-C or a quadrivalent conjugate meningococcal (Men-C-ACYW) vaccine, depending on local epidemiology and programmatic considerations, is recommended for adolescents routinely at 12 years of age, and young adults, even if they have previously been vaccinated as an infant or toddler. In addition, 4CMenB or bivalent, factor-H binding protein serogroup B meningococcal (MenB-fHBP) vaccine may be considered on an individual basis for those wishing to protect against IMD caused by relevant serogroup B strains.
* **High risk individuals:** Men-C-ACYW provided together with 4CMenB or MenB-fHBP vaccine is recommended for children and adults with increased risk of IMD.
* **Post-exposure management:** in addition to chemoprophylaxis that is recommended for close contacts, if the serogroup is vaccine-preventable, immunoprophylaxis should also be considered, depending on the exposure history.
### How
* **Routine immunization:**
+ **Less than 12 months:** give Men-C-C vaccine to healthy infants according to provincial and territorial schedules.
+ **12 months to 11 years of age:** give one dose of Men-C-C vaccine at 12 to 23 months of age, routinely at 12 months, whether the child has been immunized as an infant or not. For previously unimmunized children less than 5 years of age, give one dose of Men-C-C vaccine. Consider one dose of Men-C-C vaccine in children aged 5 to 11 years who were previously unimmunized.
+ **12 to 24 years of age:** give adolescents, routinely at 12 years of age, and young adults one dose of either Men-C-C or Men-C-ACYW vaccine, even if previously they have been vaccinated as an infant or toddler.
* **High risk individuals:** The choice of vaccine and recommended schedules vary with age. Immunization with periodic booster doses with Men-C-ACYW vaccine is recommended.
* Men-C-C, 4CMenB and Men-C-ACYW-CRM vaccine may be administered concomitantly with routine childhood vaccines, and Men-C-ACYW vaccine may be administered concomitantly with adolescent and adult age-appropriate vaccines.
* MenB-fHBP may be administered concomitantly with other vaccines in individuals 10 years of age and older.
* Vaccines administered concomitantly must be at different injection sites, using separate needles and syringes.
### Why
* IMD mortality is approximately 10%.
* Of IMD survivors, 10% to 20% have long term sequelae which may include hearing loss, neurologic disabilities, and digit or limb amputations.
Epidemiology
------------
### Disease description
#### Infectious agent
Meningococcal disease is caused by an aerobic encapsulated diplococcus, *N. meningitidis* (meningococcus). Meningococcal serogroups are classified according to the immunologic reactivity of the polysaccharide capsule. Almost all invasive meningococcal disease (IMD) is associated with serogroups A, B, C, Y, and W. Meningococcal serogroups A, B, and C cause the majority of disease worldwide and are responsible for most sporadic cases and outbreaks. For additional information about *Neisseria meningitidis,* refer to the [Pathogen Safety Data Sheet](/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/neisseria-meningitidis.html).
#### Reservoir
Humans are the only reservoir for *N. meningitidis*.
#### Transmission
Meningococci are transmitted person-to-person by mucosal contact with respiratory droplets from the nose and throat of infected persons. Most people who are colonized with meningococci are asymptomatic carriers.
#### Risk factors
In epidemiological studies, increased incidence of IMD has been observed in individuals with: complement, properdin or factor D deficiencies; functional or anatomic asplenia; sickle cell disease; certain genetic risk factors (e.g. polymorphisms in the genes for mannose-binding lectin and tumor necrosis factor); household exposure to an infected person; recent infection with influenza; household crowding; and active and passive smoking. Persons with HIV infection may be at increased risk for meningococcal disease, especially if HIV is congenitally acquired.
#### Seasonal and temporal patterns
Although disease occurs year-round, there is seasonal variation, with the majority of cases occurring in the winter and spring period in temperate climates, and in the dry season in tropical climates. Most noteworthy is the "meningitis belt" of sub-Saharan Africa where the majority of cases occur from December to June. For further information, refer to the [Committee to Advise on Tropical Medicine and Travel (CATMAT)](/en/public-health/services/catmat.html) website.
#### Spectrum of clinical illness
IMD is characterized by a short incubation period (2 to 10 days, usually 3 to 4 days) and usually presents as an acute febrile illness with rapid onset and features of meningitis or septicemia (meningococcemia), or both, and a characteristic non-blanching petechial or purpuric rash. Symptoms of meningitis include intense headache, fever, nausea, vomiting, photophobia and stiff neck. Meningococcemia is characterized by circulatory collapse, hemorrhagic skin rash and a high fatality rate. Overall mortality is approximately 10%, and 10% to 20% of survivors have long term sequelae which include hearing loss, neurologic disabilities, and digit or limb amputations.
### Disease distribution
IMD occurs sporadically worldwide and in focal epidemics. In Canada, IMD is endemic and reported year round with peaks in winter. Although people at any age can develop IMD, children younger than 5 are at the greatest risk, followed by people aged 15-19 years and 60 years and up. Serogroups B, C, W and Y are most commonly reported types in the country.
With the introduction of childhood immunization programs against serogroup C IMD in 2002, not unexpectedly, the incidence of serogroup C has decreased significantly over the years. While the incidence of serogroup B remains predominant, disease caused by serogroups W and Y have stabilized at relatively lower incidence rates.
For more information about [IMD](/en/public-health/services/immunization/vaccine-preventable-diseases/invasive-meningococcal-disease/health-professionals.html) distribution in Canada, refer to the PHAC website. Comprehensive updates on the epidemiology of IMD in Canada are published periodically in the Canada Communicable Disease Report (CCDR).
Preparations authorized for use in Canada
-----------------------------------------
### Meningococcal vaccines
**Monovalent conjugate meningococcal vaccines** (Men-C-C)
* **MENJUGATE Liquid** (meningococcal group C oligosaccharide conjugated to CRM197 protein), GlaxoSmithKline Inc., (Men-C-C-CRM)
* **NeisVac-C****®****Vaccine** (meningococcal group C polysaccharide conjugated to tetanus toxoids), Pfizer Canada ULC, (Men-C-C-TT)
**Quadrivalent conjugate meningococcal vaccines** (Men-C-ACYW)
* **Menactra®** (meningococcal groups A, C, Y, and W polysaccharides conjugated to diphtheria toxoid protein), Sanofi Pasteur Limited, (Men-C-ACYW-DT)
* **MENVEO** (meningococcal groups A, C, Y and W oligosaccharides conjugated to CRM197 protein), GlaxoSmithKline Inc., (Men-C-ACYW-CRM)
* **NIMENRIX****®** (meningococcal groups A, C, Y, and W polysaccharides conjugated to tetanus toxoid protein), Pfizer Canada ULC, (Men-C-ACYW-TT)
* **MenQuadfi™** (meningococcal groups A, C, Y, and W polysaccharides conjugated to tetanus toxoid protein), Sanofi Pasteur Limited, (Men-C-ACYW-TT)\*
\* NACI has not yet deliberated on the use of MenQuadfi™. NACI will review this vaccine and update the chapter in due course. Refer to the product monograph available through Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html) (DPD) for additional information regarding the use of this vaccine.
**Serogroup B meningococcal vaccines**
* **BEXSERO** (meningococcal porin A [PorA], factor H binding protein [fHBP], neisserial antigen 2091 [GNA2091], heparin binding antigen [NHBA], neisserial antigen 1030 [GNA1030], and Neisserial adhesion A [NadA] surface proteins), GlaxoSmithKline Inc., (4CMenB)
* **Trumenba****®** (subfamily A and B factor-H binding protein [fHBP]), Pfizer Canada ULC, (MenB-fHBP)
Preparations authorized for use in Canada may not be currently available for sale. Refer to Health Canada's [DPD](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html) for its drug status. Definitions of drug status can be found under [DPD Terminology](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/terminology.html).
For complete prescribing information, consult the product leaflet or information contained within Health Canada's authorized product monographs available through Health Canada's [DPD](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
Refer to [Contents of Immunizing Agents Available for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for a list of vaccines and passive immunizing agents authorized for use in Canada and their contents.
Immunogenicity, efficacy and effectiveness
------------------------------------------
### Immunogenicity
Men-C-C and Men-C-ACYW vaccines are immunogenic in infants and toddlers but those vaccinated in infancy show a waning immune response over time. Vaccination with conjugate meningococcal vaccine primes the immune system for memory and induces good anamnestic responses; however, anamnestic response may not be sufficient to prevent disease after exposure and circulating antibodies are thought to be essential. In comparison to polysaccharide meningococcal vaccine, conjugate meningococcal vaccines demonstrate greater immunogenicity and induce better immunologic memory. Conjugate meningococcal vaccines do not result in hyporesponsiveness and have been shown to overcome the hyporesponsiveness evident with polysaccharide meningococcal vaccine usage. In clinical trials, the 4CMenB vaccine has shown to be immunogenic in toddlers and children after at least two doses, and in adolescents and adults after one dose. In adolescents and adults, a more robust immune response has been observed in clinical trials following the use of a three-dose compared to a two-dose MenB-fHBP vaccine schedule.
### Efficacy and effectiveness
A study of Men-C-C vaccine demonstrated effectiveness in infants of 97% within one year of vaccination, decreasing to 68% after 1 year. Longer term vaccine effectiveness requires receipt of a booster dose in the second year of life for those immunized in infancy. Vaccine effectiveness of Men-C-ACYW-DT within 3 to 4 years of vaccination in adolescence is 80% to 85%; however, effectiveness wanes over time. There are no efficacy or effectiveness data available for Men-C-ACYW-CRM, Men-C-ACYW-TT, MenB-fHBP or 4CMenB vaccines. Vaccine effectiveness measured at the individual level may under-estimate the impact of the immunization programs on the burden of meningococcal disease in the community, due to the additional benefit conferred by herd immunity.
Recommendations for use
-----------------------
### Routine schedule
#### Healthy infants and children (2 to 23 months of age)
Infants may receive Men-C-C vaccine beginning at 2 months of age, depending on the provincial and territorial schedule and the incidence of meningococcal serogroup C disease in their jurisdiction. One dose of Men-C-C vaccine is recommended for all children at 12 to 23 months of age, regardless of any doses given during the first year of life. Men-C-C is routinely given at 12 months of age if they have not previously been immunized as infants or toddlers. In addition, immunization with 4CMenB vaccine may be considered on an individual basis, depending on individual preferences, regional serogroup B epidemiology and strain susceptibility.
#### Healthy adolescents and young adults (12 to 24 years of age)
Either Men-C-C or Men-C-ACYW vaccine, depending on local epidemiology and programmatic considerations, is recommended for adolescents, routinely at 12 years of age and young adults, even if they have previously been vaccinated as an infant or toddler. In addition, 4CMenB or MenB-fHBP vaccine may be considered on an individual basis, depending on the individual preferences, regional serogroup B epidemiology and strain susceptibility.
### Catch-up and accelerated schedules
### Healthy infants and children (2 to 11 years of age)
One dose of Men-C-C vaccine is recommended in unimmunized children less than 5 years of age. One dose of Men-C-C vaccine may be considered for children 5 to 11 years of age if they have not previously been immunized as infants or toddlers. Immunization with 4CMenB vaccine (2 years of age and older) or MenB-fHBP (10 years of age and older) may be considered on an individual basis, depending on individual preferences, regional serogroup B epidemiology and strain susceptibility.
### High risk individuals
Meningococcal vaccines are recommended for individuals with underlying medical conditions and those who are at increased risk of exposure to meningococcal disease.
#### Underlying medical conditions
Individuals with increased risk of meningococcal disease because of underlying medical conditions include the following:
* persons with functional or anatomic asplenia, sickle cell disease, or combined T and B cell immunodeficiencies
* persons with congenital complement, properdin, factor D or primary antibody deficiencies
* persons with acquired complement deficiency due to receipt of the terminal complement inhibitor eculizumab (Soliris™)
* individuals with HIV, especially if it is congenitally acquired
[Table 1](#p4c12t1) outlines the recommended schedule for vaccination of individuals who are at high risk due to underlying medical conditions. Refer to [Recommendations for use](#p4c12a5) for additional information.
#### Increased risk of exposure
Individuals at increased risk of exposure to meningococcal disease include the following:
* travellers to areas with high rates of endemic meningococcal disease or transmission, including travellers to the meningitis belt of sub-Saharan Africa and pilgrims to the Hajj in Mecca, Saudi Arabia. Refer to [Travellers](#travel) section for additional information.
* research, industrial and clinical laboratory personnel who are potentially routinely exposed to *N. meningitidis*. Refer to [Workers](#p4c12a5l) section for additional information.
* military personnel during recruit training and on certain deployments. Refer to [Military personnel](#military) section for additional information.
Meningococcal vaccine is also recommended for most close contacts of a case of IMD and for outbreak control, if the disease is caused by a serogroup contained in the vaccine. Refer to [Post-exposure management](#p4c12a5m) and [Outbreak control](#p4c12a5n) for additional information.
#### Age considerations for choice of vaccine for high risk groups
##### 2 to 23 months of age
Based on available published data in this age group, Men-C-ACWY-CRM should be used because it has been found to be safe and immunogenic. Routine meningococcal C conjugate vaccine does not need to be administered in addition to Men-C-ACWY-CRM. For toddlers and children who may be at increased high risk of IMD caused by serogroup B, 4CMenB vaccine should also be offered.
##### 24 months to 9 years of age
Any of the Men-C-ACYW vaccines may be used. For individuals who are at high risk of IMD caused by serogroup B, 4CMenB vaccine should also be offered.
##### 10 years of age and older
Any of the Men-C-ACYW vaccines may be used. For individuals who are at high risk of IMD caused by serogroup B, 4CMenB or MenB-fHBP vaccine should also be offered.
Refer, [Table 3](#p4c12t3) for recommended vaccination for certain travellers.
Table 1: Recommended immunization for high risk individuals because of underlying medical conditions [Table 1 - Footnote 1](#p4c12t3fn1) not previously immunized with Meningococcal Men-C-ACYW or Serogroup B Meningococcal [Table 1 - Footnote 2](#p4c12t3fn2) vaccine
| Age | Recommended vaccine(s) | Schedule |
| --- | --- | --- |
| 2 to 11 months of age | Men-C-ACYW-CRM[Table 1 - Footnote 3](#p4c12t3fn3) and 4CMenB | 2 or 3 doses[Table 1 - Footnote 4](#p4c12t3fn4) (given 8 weeks apart, with another dose between 12-23 months of age that is at least 8 weeks from the previous dose) |
| 12 to 23 months of age | Men-C-ACYW-CRM[Table 1 - Footnote 3](#p4c12t3fn3) and 4CMenB | 2 doses (given at least 8 weeks apart)[Table 1 - Footnote 5](#p4c12t3fn5) |
| 24 months to 9 years of age | Men-C-ACYW [Table 1 - Footnote 3](#p4c12t3fn3) and 4CMenB | 2 doses (given at least 8 weeks apart)[Table 1 - Footnote 5](#p4c12t3fn5) |
| 10 years of age and older[Table 1 - Footnote 6](#p4c12t3fn6) | Men-C-ACYW[Table 1 - Footnote 3](#p4c12t3fn3) and 4CMenB or MenB-fHBP | 2 doses of Men-C-ACYW (given 8 weeks apart)[Table 1 - Footnote 5](#p4c12t3fn5); 2 doses of 4CMenB (given at least 4 weeks apart) or 3 doses of MenB-fHBP (given 4 weeks apart, with another dose at least 4 months after dose two and at least 6 months after dose one) |
|
Table 1 - Footnote 1
At high risk due to underlying medical conditions: refer to [Underlying medical conditions](#p4c12a5c1)
[Return to footnote 1 referrer](#p4c12t3fn1-rf)
Table 1 - Footnote 2
A serogroup B meningococcal vaccine should be offered for the active immunization of individuals with underlying medical conditions that would put them at higher risk of meningococcal disease. 4CMenB vaccine is indicated for immunization of high risk individuals greater than or equal to two months of age; MenB-fHBP vaccine may be considered as an option for use in high-risk individuals 10 years of age and older.
[Return to footnote 2 referrer](#p4c12t3fn2-rf)
Table 1 - Footnote 3
A booster dose should be given every 3 to 5 years if vaccinated at 6 years of age or younger and every 5 years for those vaccinated at 7 years of age and older.
[Return to first footnote 3 referrer](#p4c12t3fn3-0-rf)
Table 1 - Footnote 4
Depending on the age at which immunization is initiated, the manufacturer of 4CMenB recommends three doses for infants who begin primary immunization between the ages of 2 and 5 months, and two doses when the first dose is received between ages of 6 and 11 months.
[Return to footnote 4 referrer](#p4c12t3fn4-rf)
Table 1 - Footnote 5
Men-C-ACYW vaccines may be given a minimum of 4 weeks apart if accelerated immunization needed.
[Return to footnote 5 referrer](#p4c12t3fn5-rf)
Table 1 - Footnote 6
Serogroup B Meningococcal vaccines are not authorized for use in those 26 years of age and older and Men-C-ACYW vaccines are not authorized for use in those 56 years of age and older; however, based on limited evidence and expert opinion their use is considered appropriate above these authorized ages.
[Return to footnote 6 referrer](#p4c12t3fn6-rf)
|
### Booster doses and re-immunization
Circulating antibodies are considered necessary to protect an individual against IMD. Re-vaccination is recommended as follows:
* For individuals at high risk of developing meningococcal disease due to underlying medical conditions, refer to [High risk individuals, Underlying medical conditions](#high). Re-vaccination with Men-C-ACYW is recommended every 3 to 5 years for those vaccinated at 6 years of age and younger and every 5 years for those vaccinated at 7 years of age and older.
* When travelling to areas where meningococcal vaccine is recommended or required, re-vaccination with Men-C-ACYW is recommended every 3 to 5 years for those vaccinated at 6 years of age and younger, and every 5 years for those vaccinated at 7 years of age and older. Previously vaccinated travellers are advised to check requirements for re-vaccination with meningococcal vaccines prior to travel to the Hajj as more frequent vaccination may be required (refer to http://www.moh.gov.sa/en/Hajj/Pages/default.aspx and [Travellers](#travel)).
* For military personnel who remain at risk due to travel or overcrowded conditions, a booster dose of Men-C-ACYW is recommended every 5 years if at ongoing risk.
* At the time of exposure for contacts of a case of IMD in some circumstances. Refer to [Post-exposure management](#p4c12a5m).
* During a community outbreak of IMD in some circumstances. Refer to [Post-exposure management](#p4c12a5m).
* For all laboratory personnel who are potentially routinely exposed to *N. meningitidis.* Booster doses of Men-C-ACYW should be given at routine 5 year intervals for those laboratory workers who remain at ongoing risk of exposure. Refer to [Workers](#p4c12a5l).
People previously vaccinated with a polysaccharide meningococcal vaccine should be re-vaccinated with the appropriate conjugate or serogroup B meningococcal vaccine if they remain at ongoing risk for meningococcal disease. Conjugated meningococcal vaccine should be given at least 6 months following vaccination with polysaccharide meningococcal vaccine.
### Post-exposure management
#### Contacts of cases
Close contacts of individuals with meningococcal infections have an increased risk of developing IMD; this risk is greatest for household contacts. The increased risk of disease for household contacts persists for up to 1 year after disease in the index case and beyond any protection from antibiotic chemoprophylaxis. In general, this prolonged risk is not seen in contacts who do not have ongoing exposure.
Chemoprophylaxis should be offered to all persons having close contact with a case of IMD from 7 days before onset of symptoms in the case to 24 hours after onset of effective treatment in the case, regardless of their immunization status. Refer to the PHAC [Guidelines for the Prevention and Control of Meningococcal Disease](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2005-31/guidelines-prevention-control-meningococcal-disease.html) for information about chemoprophylaxis in the management of close contacts of individuals with meningococcal infection.
Vaccination or re-vaccination of certain close contacts should be considered in addition to chemoprophylaxis when the serogroup is vaccine preventable, as it may further reduce the risk of subsequent meningococcal disease.
##### Close contacts requiring chemoprophylaxis and consideration for immunoprophylaxis
The following individuals (regardless of immunization status) should receive chemoprophylaxis and, if the meningococcal serogroup identified in the case of IMD is vaccine preventable, should also be considered for immunoprophylaxis:
* Household contacts of a case of IMD
* Persons who share sleeping arrangements with a case of IMD
* Persons who have direct nose or mouth contamination with oral or nasal secretions of a case of IMD (e.g., kissing on the mouth, shared cigarettes, sharing bottles)
* Children and staff in contact with a case of IMD in child care or nursery school facilities
Refer to [Table 2](#p4c12t2) for specific recommendations for immunoprophylaxis of close contacts of IMD cases according to the serogroup in the index case and the age and underlying conditions of the contact.
##### Re-vaccination criteria for those previously vaccinated against IMD
The following provides criteria for the re-vaccination of previously vaccinated close contacts when the index case has a vaccine preventable IMD serogroup or there is a vaccine preventable outbreak of IMD:
* Those previously vaccinated with a serogroup that differs from the index case or outbreak strain should be vaccinated immediately with the appropriate vaccine (as outlined in [Table 2](#p4c12t2));
* Those previously vaccinated with a serogroup that is the same as the index case or outbreak strain should be re-vaccinated with the appropriate vaccine (as outlined in [Table 2](#p4c12t2));
+ If they were less than 1 year of age at last meningococcal vaccination and more than **4 weeks** has passed since their last meningococcal vaccine;
+ If they have an underlying medical condition that puts them at risk for meningococcal disease and more than **4 weeks** has passed since their last meningococcal vaccine;
+ If more than **a year** has passed since their last meningococcal vaccine, if they were not less than 1 year of age at the time of their last meningococcal vaccination and if they have no underlying medical condition that puts them at risk for meningococcal disease.
##### Close contacts requiring chemoprophylaxis only
The following individuals should receive chemoprophylaxis only, immunoprophylaxis is not necessary:
* Health care workers who have had **intensive unprotected contact** (without wearing a mask) with infected patients (i.e., intubating, resuscitating or closely examining the oropharynx).
* Airline passengers sitting immediately on either side of the case (but not across the aisle) when the total time spent aboard the aircraft was at least 8 hours.
* Close contacts of a case of IMD due to serogroups not present in meningococcal vaccines, or when the serogroup in the index case has not been determined.
* Previously vaccinated close contacts who do not meet the criteria for re-vaccination as outline above.
### Outbreak control
#### Outbreaks of meningococcal disease
Consultation with public health officials, experts in communicable disease, or both is important in the assessment and control of meningococcal disease outbreaks. Outbreaks may be controlled by the use of a conjugate meningococcal vaccine. The type of vaccine to use in an outbreak is dependent on the serogroup causing the outbreak and the age of those being vaccinated as outlined in [Table 2](#p4c12t2). Re-vaccination criteria of previously vaccinated individuals are outlined above in [Re-vaccination criteria for those previously vaccinated against IMD.](#p4c12a5m1)
Table 2: Recommended vaccination of close contacts for post-exposure management and for outbreak control
| Group | Recommended vaccine(s) | Schedule |
| --- | --- | --- |
| Close contacts and outbreak control of serogroup C invasive meningococcal disease |
| --- |
| 2 months to less than 12 months of age | Men-C-C | **Unvaccinated:** 1 dose immediately after exposure then complete the routine series of Men-C-C
**Previously vaccinated:** If previously vaccinated then re-vaccinate with Men-C-C if at least **4 weeks have elapsed** since last dose, then complete the routine series of Men-C-C if necessary |
| 12 months - 10 years of age | Men-C-C | **Unvaccinated:** 1 dose immediately after exposure
**Previously vaccinated:** If previously vaccinated at less than 1 year of age OR person is at high risk for IMD due to underlying medical conditions[Table 2 - Footnote 1](#p4c12t2fn1), then re-vaccinate with one dose of Men-C-C if at least **4 weeks** since last dose; otherwise re-vaccinate if at least **1 year** since last dose |
| 11 years of age and older | * Men-C-C
OR
* Men-C-ACYW
| **Unvaccinated:** 1 dose immediately after exposure
**Previously vaccinated:** If previously vaccinated at less than 1 year of age OR person is at high risk for IMD due to underlying medical conditions[Table 2 - Footnote 1](#p4c12t2fn1), then re-vaccinate with one dose of vaccine of choice if at least **4 weeks** since last dose; otherwise re-vaccinate if at least **1 year** since last dose |
| Close contacts and outbreak control of serogroup A, Y, or W invasive meningococcal disease |
| --- |
| 2 months to less than 12 months of age | Men-C-ACYW-CRM | **Unvaccinated:** 2 or 3 doses given 8 weeks apart with another dose between 12 and 23 months and at least 8 weeks from the previous dose
**Previously vaccinated:*** If previously vaccinated with only Men C-C, give Men-C-ACYW-CRM as for unvaccinated persons, regardless of when Men-C-C was previously given[Table 2 - Footnote 2](#p4c12t2fn2)
* If previously vaccinated with Men-C-ACYW, then re-vaccinate with one dose of Men-C-ACYW-CRM if at least **4 weeks** since last dose of Men-C-ACYW vaccine; then complete series
|
| 12 to 23 months of age | Men-C-ACYW-CRM | **Unvaccinated:** 2 doses at least 8 weeks apart
**Previously vaccinated:*** If previously vaccinated with only Men C-C, give Men-C-ACYW-CRM as for unvaccinated persons, regardless of when Men-C-C was previously given[Table 2 - Footnote 2](#p4c12t2fn2)
* If previously vaccinated with Men-C-ACYW at less than 1 year of age OR person is at high risk for IMD due to underlying medical conditions[Table 2 - Footnote 1](#p4c12t2fn1), then re-vaccinate with one dose of Men-C-ACYW-CRM if at least **4 weeks** since last dose of Men-C-ACYW; otherwise re-vaccinate with one dose of Men-C-ACYW-CRM if at least **1 year** since last dose of Men-C-ACYW
|
| 2 years and older | Men-C-ACYW | **Unvaccinated:** 1 dose immediately after exposure[Footnote 3](#p4c12t2fn3)
**Previously vaccinated:*** If previously vaccinated with only Men C-C, give Men-C-ACYW as for unvaccinated persons, regardless of when Men-C-C was previously given[Table 2 - Footnote 2](#p4c12t2fn2)
* If previously vaccinated with Men-C-ACYW at less than 1 year of age OR person is at high risk for IMD due to underlying medical conditions[Table 2 - Footnote 1](#p4c12t2fn1), then re-vaccinate with one dose of Men-C-ACYW if at least **4 weeks** since last dose of Men-C-ACYW; otherwise re-vaccinate if at least **1 year** since last dose
|
| Close contacts and outbreak control of serogroup B invasive meningococcal disease[Table 2 - Footnote 4](#p4c12t2fn4) |
| 2 months to less than 6 months | 4CMenB | **Unvaccinated:** 1 dose immediately after exposure[Table 2 - Footnote 5](#p4c12t2fn5); then re-vaccinate with 2 more doses with at least a **4 week** interval between doses.
**Previously vaccinated:** 1 dose immediately after exposure[Table 2 - Footnote 5](#p4c12t2fn5) |
| 6 months to less than 10 years | 4CMenB | **Unvaccinated:** 1 dose immediately after exposure[Table 2 - Footnote 5](#p4c12t2fn5); then re-vaccinate with a single dose after at least **8 weeks**.
**Previously vaccinated:** 1 dose immediately after exposure[Table 2 - Footnote 5](#p4c12t2fn5) |
| 10 years and older | 4CMenB or MenB-fHBP | **Unvaccinated:** 1 dose immediately after exposure[Table 2 - Footnote 5](#p4c12t2fn5); then re-vaccinate with a single dose after at least **4 weeks** with 4CMenB or MenB-fHBP.
**Previously vaccinated:** 1 dose immediately after exposure[Table 2 - Footnote 5](#p4c12t2fn5) |
|
Table 2 - Footnote 1
At high risk due to underlying medical conditions - refer to [Underlying medical conditions](#p4c12a5c1)
[Return to footnote 1 referrer](#p4c12t2fn1-rf)
Table 2 - Footnote 2
In general, a minimum four week interval is recommended between doses of conjugate meningococcal vaccines; however, in an outbreak or to manage a close contact of a case of IMD, the second dose of conjugate meningococcal vaccine may be given as soon as indicated to provide protection to a close contact who is unvaccinated for the implicated serogroup.
[Return to footnote 2 referrer](#p4c12t2fn2-rf)
Table 2 - Footnote 3
Individuals at high risk due to underlying medical conditions routinely need two doses of Men-C-ACYW
[Return to footnote 3 referrer](#p4c12t2fn3-rf)
Table 2 - Footnote 4
Only for outbreak control of IMD caused by serogroup B strains that are predicted to be susceptible to the vaccine. Consultation with public health officials, experts in communicable disease or both is required for optimal management of meningococcal disease outbreaks.
[Return to footnote 4 referrer](#p4c12t2fn4-rf)
Table 2 - Footnote 5
During an outbreak, the vaccine should be provided as soon as possible after the identification of a serogroup B strain that is predicted to be susceptible to the vaccine.
[Return to footnote 5 referrer](#p4c12t2fn5-rf)
|
Vaccination of specific populations
-----------------------------------
### Persons with inadequate immunization records
Children and adults lacking adequate documentation of immunization should be considered unimmunized and started on an immunization schedule appropriate for their age and risk factors. Conjugate meningococcal vaccine, as appropriate for age, may be given regardless of possible previous receipt of the vaccine, as adverse events associated with repeated immunization have not been demonstrated. Refer to [Immunization of persons with inadequate immunization records](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-3-immunization-persons-inadequate-immunization-records.html) in Part 3 for additional general information.
### Pregnancy and breastfeeding
Conjugate and serogroup B meningococcal vaccines have not been studied in pregnancy or breastfeeding. However, there is no theoretical reason to suspect that adverse events will occur and, in circumstances in which the benefits outweigh the risks (i.e. in high risk individuals due to exposure or underlying medical conditions), the use of conjugate and serogroup B meningococcal vaccines in pregnancy and breastfeeding may be considered. Refer to [Immunization in Pregnancy and Breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3 for additional information.
### Infants born prematurely
Premature infants in stable clinical condition should be immunized with conjugate meningococcal vaccine at the same chronological age and according to the same schedule as full-term infants. Infants born prematurely, especially those weighing less than 1,500 grams at birth are at higher risk of apnea and bradycardia following vaccination. Hospitalized premature infants should have continuous cardiac and respiratory monitoring for 48 hours after their first immunization. Refer to [Immunization of Infants Born Prematurely](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-5-immunization-infants-born-prematurely.html) in Part 3 for additional general information.
### Persons/residents in health care institutions
Residents of long-term care facilities should receive meningococcal vaccine as appropriate for their risk factors. Refer to [Immunization of Patients in Health Care Institutions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-6-immunization-patients-health-care-institutions.html) in Part 3 for additional general information.
### Persons with chronic diseases
#### Asplenia
Two doses of Men-C-ACYW vaccine are recommended for persons with anatomic or functional asplenia, including sickle cell disease. When elective splenectomy is planned, all recommended vaccines should ideally be completed at least 2 weeks before surgery; if only one dose can be given before surgery, the second dose should be given 8 weeks after the first dose, with a minimum interval of 4 weeks. In the case of an emergency splenectomy, two doses of vaccine should ideally be given beginning 2 weeks after surgery but can be given earlier, before discharge, if the person might not return for vaccination after discharge. Persons one year of age and older with asplenia who have not received Men-C-ACYW vaccine should receive two doses administered 8 weeks apart, with a minimum interval of 4 weeks. In addition, 4CMenB or MenB-fHBP vaccine should be offered. Periodic booster doses with Men-C-ACYW vaccine are also recommended.
Refer to [Table 1](#p4c12t1) for vaccination recommendations of high risk individuals due to underlying conditions. Refer to [Booster doses and re-immunization](#booster) for additional information and [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional general information.
### Immunocompromised persons
Quadrivalent conjugate meningococcal vaccine provided with 4CMenB or MenB-fHBP vaccine is recommended for certain high risk individuals as outlined under [High risk individuals](#high) above. People with conditions requiring the receipt of the terminal complement inhibitor eculizumab (Soliris™) should be vaccinated at least two weeks prior to receiving the first dose of eculizumab. When considering immunization of an immunocompromised person, consultation with the individual's attending physician may be of assistance in addition to the guidance provided below. For complex cases, referral to a physician with expertise in immunization or immunodeficiency is advised.
Refer to [Booster doses and re-immunization](#booster) for additional information and [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional general information.
### Travellers
Travellers should be vaccinated with Men-C-ACYW vaccine alone or in combination with 4CMenB or MenB-fHBP vaccine, depending on the risk of meningococcal disease in the area of travel. Men-C-C vaccine alone is not appropriate for protection of travellers, as it does not protect against serogroup A, which is endemic in selected regions of the world (e.g. sub-Saharan Africa), or serogroup W disease. 4CMenB or MenB-fHBP vaccine is recommended for individuals travelling to an area with a hyperendemic strain or an outbreak that is known to be caused by a serotype B that can be prevented by the vaccine. Current [meningococcal disease outbreak information](http://www.who.int/csr/don/archive/disease/meningococcal_disease/en/) is available from the WHO.
Refer to [Table 3](#p4c12t3) for recommended immunization for travellers to destinations where risk of meningococcal transmission is high.
Proof of meningococcal immunization may be required by certain countries. For example, Saudi Arabia requires proof of immunization with a quadrivalent (ACYW) vaccine for travellers with the purpose of Umrah or pilgrimage (Hajj) or for seasonal work. Refer to the Saudi Arabia Ministry of Health website for information regarding vaccination requirements. Refer to [Immunization of Travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) in Part 3 for additional information.
Refer to the [CATMAT](/en/public-health/services/catmat.html) information on assessing a traveller's need for pre-travel vaccination.
Table 3: Recommended immunization schedule for travellers to destinations where risk of meningococcal transmission is high, not previously immunized with quadrivalent conjugate meningococcal vaccines or serogroup B meningococcal vaccine
| Age | Recommended vaccine(s) | Schedule[Table 3 - Footnote 1](#p4c12t1fn1)[Table 3- Footnote 2](#p4c12t1fn2) |
| --- | --- | --- |
| 2 to 11 months of age | Men-C-ACYW-CRM or 4CMenB | 2 or 3 doses[Table 3 - Footnote 3](#p4c12t1fn3) (given 8 weeks apart, with another dose between 12-23 months of age that is at least 8 weeks from the previous dose)[Table 3 - Footnote 4](#p4c12t1fn4) |
| 12 to 23 months of age | Men-C-ACYW-CRM or 4CMenB | 2 doses (given at least 8 weeks apart)[Table 3 - Footnote 4](#p4c12t1fn4) |
| 24 months to 9 years of age | Men-C-ACYW or 4CMenB | 1 dose of Men-C-ACYW; 2 doses of 4CMenB (given at least 8 weeks apart) |
| 10 years of age and older[Table 3 - Footnote 5](#p4c12t1fn5) | Men-C-ACYW or 4CMenB or MenB-fHBP | 1 dose of Men-C-ACYW; 2 doses of 4CMenB (given at least 4 weeks apart) or 2 doses of MenB-fHBP (given at least 6 months apart) or 3 doses of MenB-fHBP (given 4 weeks apart, with another dose at least 4 months after dose two) |
|
Table 3 - Footnote 1
Travellers to the Hajj should check recommendations for re-vaccination at: http://www.moh.gov.sa/en/Hajj/Pages/default.aspx as more frequent re-vaccination may be required.
[Return to footnote 1 referrer](#p4c12t1fn1-rf)
Table 3 - Footnote 2
A booster dose of Men-C-ACYW should be given every 3 to 5 years if vaccinated at 6 years of age or younger and every 5 years for those vaccinated at 7 years of age and older.
[Return to footnote 2 referrer](#p4c12t1fn2-rf)
Table 3 - Footnote 3
Depending on the age at which immunization is initiated, the manufacturer of 4CMenB recommends two or three primary doses and a booster (2 + 1 schedule or 3 + 1 schedule) when the first dose is received between the ages of 2 and 5 months, and two primary doses and a booster (2 + 1 schedule) when the first dose is received between ages of 6 and 11 months. The booster dose should be administered in the second year of life.
[Return to footnote 3 referrer](#p4c12t1fn3-rf)
Table 3 - Footnote 4
Men-C-ACYW-CRM may be given a minimum of 4 weeks apart if accelerated immunization is needed.
[Return to footnote 4 referrer](#p4c12t1fn4-rf)
Table 3 - Footnote 5
Serogroup B Meningococcal vaccines are not authorized for use in those 26 years of age and older and Men-C-ACYW vaccines are not authorized for use in those 56 years of age and older; however, based on limited evidence and expert opinion their use is considered appropriate above these authorized ages.
[Return to footnote 5 referrer](#p4c12t1fn5-rf)
|
### Persons new to Canada
Health care providers who see persons newly arrived in Canada should review the immunization status and update immunization for these individuals. Review of meningococcal vaccination status is particularly important for persons from areas of the world where sickle cell disease is present as persons with sickle cell disease are at risk of serious meningococcal infections. In many countries outside of Canada, conjugate meningococcal vaccines are in limited use. Information on [vaccination schedules in other countries](http://apps.who.int/immunization_monitoring/globalsummary) can be found on the [World Health Organization](http://www.who.int/vaccines/GlobalSummary/Immunization/ScheduleSelect.cfm) website. Refer to [Immunization of Persons New to Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-10-immunization-persons-new-canada.html) in Part 3 for additional general information.
### Workers
#### Laboratory workers
Research, industrial and clinical laboratory personnel who are potentially routinely exposed to *N. meningitidis* should be offered one dose of Men-C-ACYW vaccine and two doses of 4CMenB vaccine given at least 4 weeks apart or two doses of MenB-fHBP vaccine given at least 6 months apart. Re-vaccination is generally recommended every 5 years for Men-C-ACYW. There are currently no booster dose recommendations for serogroup B meningococcal vaccines. Routine infection control precautions should be practiced at all times to minimize the risk of exposure in laboratory workers and post-exposure prophylaxis should be offered after recognized exposures. Refer to [Booster doses and re-immunization](#booster) for additional information.
#### Health care workers (HCW)
Nosocomial transmission of IMD is very uncommon. HCW are considered as close contacts only if they have had intensive, unprotected contact (without wearing a mask) with infected patients (e.g., intubating, resuscitating or closely examining the oropharynx). It is recommended that HCW use barrier precautions to avoid direct contact with respiratory secretions of patients with meningococcal disease until the patient has completed 24 hours of effective antibiotic therapy, according to provincial and territorial communicable disease control guidelines.
There is no evidence to recommend routine meningococcal immunization of HCW since the risk period for acquisition ends when contact with an untreated patient terminates, and antibiotic chemoprophylaxis should be sufficient in the high-risk situation described above.
#### Military personnel
Military personnel may be at increased risk of IMD when accommodated in close quarters or through deployment to endemic or epidemic countries.
Refer to [Immunization of Workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html) in Part 3 for additional general information.
Serologic testing
-----------------
Serologic testing is not recommended before or after receiving meningococcal vaccine.
Administration practices
------------------------
### Dose and route of administration
#### Dose
Each dose of meningococcal vaccine is 0.5 mL.
#### Route of administration
Conjugate and serogroup B meningococcal vaccines should be administered intramuscularly (IM). Refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for additional information.
### Interchangeability of vaccines
There are no published data regarding the interchangeability of Men-C-C vaccines, but the vaccines have been safely interchanged without a noticeable decrease in efficacy. When possible, the infant series should be completed with the same vaccine. Either Men-C-ACYW vaccine may be used for re-vaccination, regardless of which meningococcal vaccine was used for initial vaccination. The serogroup B meningococcal vaccines are not interchangeable as they contain different antigens and there are no published studies on the immunogenicity resulting from a vaccination series combining the two products. Therefore, the same vaccine product should be used for all doses in a vaccination series. If, in a person with an incomplete vaccination series, it is unknown what vaccine product they initially received, the initial dose(s) should be discounted and the vaccination series repeated using the same vaccine product for all doses in the new, repeated series.
Refer to [Principles of Vaccine Interchangeability](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-7-principles-vaccine-interchangeability.html) in Part 1 for additional general information.
### Simultaneous administration with other vaccines
Men-C-C and 4CMenB vaccine may be administered concomitantly with routine childhood vaccines, and Men-C-ACYW vaccine may be administered concomitantly with adolescent and adult age appropriate vaccines. MenB-fHBP can be given concomitantly with quadrivalent human papillomavirus vaccine; meningococcal serogroup A, C, Y, W conjugate vaccine; and tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed. The concomitant administration of MenB-fHBP has not been studied with other vaccines.
Men-C-ACYW-CRM can be administered with routine paediatric vaccines; however, further studies are needed with regard to concomitant administration with pneumococcal 13-valent conjugate vaccine. Co-administration of Men-C-ACYW-CRM and combined tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) may result in a lower immune response to the pertussis antigens than when Tdap vaccine is given alone; however, the clinical significance of this is unknown. Tdap vaccine given one month after Men-C-ACYW-CRM induces the strongest immunologic response to pertussis antigens.
If vaccines are to be administered concomitantly with another vaccine, a separate injection site and a different syringe must be used for each injection.
Refer to [Timing of Vaccine Administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) in Part 1 for additional general information.
Storage requirements
--------------------
Menactra®, NeisVac-C® Vaccine, Trumenba®: Store in a refrigerator at +2°C to +8°C. Do not freeze.
BEXSERO, MENJUGATE Liquid, MENVEO, NIMENRIX®: Store in a refrigerator at +2°C to +8°C. Do not freeze. Protect from light.
Refer to [Storage and Handling of Immunizing Agents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-9-storage-handling-immunizing-agents.html) in Part 1 for additional general information.
Safety and adverse events
-------------------------
Refer to [Vaccine safety and pharmacovigilance](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) in Part 2 for additional general information.
### Common and local adverse events
#### Conjugate meningococcal vaccines
##### Men-C-ACYW vaccines
Injection site reactions occur in up to 59% of vaccinees. Fever is reported in up to 5% of recipients and systemic reactions, such as headache and malaise, are reported in up to 60% of recipients.
##### Men-C-C vaccines
Mild reactions, including injection site reactions (redness, tenderness, and swelling), occur in up to 50% of vaccine recipients. Irritability occurs in up to 80% of infants and fever in up to 9% when other vaccines were administered. Headaches and malaise occur in up to 10% of older children and adults. These reactions last no more than a few days.
#### Serogroup B Meningococcal vaccines
##### 4CMenB vaccine
Solicited local and systemic reactions have been commonly reported in clinical trials and include injection site tenderness, induration, sleepiness and irritability. Higher rates of fever have been observed with simultaneous administration of 4CMenB vaccine and routine infant vaccines; therefore, routine prophylactic administration of acetaminophen or separating 4CMenB vaccination from routine vaccination schedule has been proposed for preventing fever in infants and children up to three years of age.
##### MenB-fHBP vaccine
Solicited local and systemic reactions have been commonly reported in clinical trials and include injection site tenderness, induration and irritability.
### Less common and serious or severe adverse events
Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association.
### Guidance on reporting adverse events following immunization (AEFI)
To ensure the ongoing safety of vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in some jurisdictions, reporting is mandatory under the law.
Vaccine providers are asked to report AEFIs, through [local public health](/en/public-health/services/immunization/federal-provincial-territorial-contact-information-aefi-related-questions.html) officials, and to check for specific AEFI reporting requirements in their province or territory. In general, any serious or unexpected adverse event felt to be temporally related to vaccination should be reported.
For additional information about AEFI reporting, please refer to [Adverse events following immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html). For general vaccine safety information, refer to [Vaccine safety and pharmacovigilance](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) in Part 2.
### Contraindications and precautions
Meningococcal vaccine is contraindicated in persons with a history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Refer to Table 1 in [Contents of Immunizing Agents Available for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for lists of all vaccines available for use in Canada and their contents.
There are very few individuals who cannot receive meningococcal vaccines. In situations of suspected hypersensitivity or non-anaphylactic allergy to vaccine components, investigation is indicated, which may involve immunization in a controlled setting. Consultation with an allergist is advised.
Administration of meningococcal vaccine should be postponed in persons with moderate or severe acute illness. Persons with minor acute illness, with or without fever, may be vaccinated.
Refer to [Contraindications and Precautions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html) in Part 2 for additional general information.
Selected references
-------------------
* Canadian Immunization Committee. Supplement: Advice for Consideration of Quadrivalent (A, C, Y, W135) Meningococcal Conjugate Vaccine, for use by Provinces and Territories. Can Commun Dis Rep 2010;36(S2):1-35.
* Centers for Disease Control and Prevention. Laboratory-acquired meningococcemia - California and Massachusetts. MMWR Morb Mortal Wkly Rep 1991;40(3):46-7, 55.
* Centers for Disease Control and Prevention. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2005;54(RR-7):1-21.
* Centers for Disease Control and Prevention. Updated Recommendations for Use of Meningococcal Conjugate Vaccines - Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep 2011;60(03):72-76.
* Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on meningococcal vaccination for travellers. Can Commun Dis Rep 2009;35(ASC4):1-22.
* Meningococcal B Pilot Project Task Group. The Recommended Use of the Multicomponent Meningococcal B (4CMenB) Vaccine in Canada: Common Guidance Statement. Public Health Agency of Canada. March 2014 (Catalogue no. HP40-103/2014E-PDF).
* National Advisory Committee on Immunization. Statement on conjugate meningococcal vaccine for serogroups A, C, Y and W135. Can Commun Dis Rep 2007;33(ACS-3):1-24.
* National Advisory Committee on Immunization. Update on the Use of Quadrivalent Conjugate Meningococcal Vaccines. Can Commun Dis Rep 2013;39(ACS-1)
* National Advisory Committee on Immunization. Update on the Invasive Meningococcal Disease and Meningococcal Vaccine Conjugate Recommendations. Can Commun Dis Rep 2009;36(ACS-3):1-40.
* National Advisory Committee on Immunization (NACI). Update on quadrivalent meningococcal vaccines available in Canada. Public Health Agency of Canada. October 2014 (Catalogue no. HP40-125/2014E-PDF).
* GlaxoSmithKline Inc. Product Monograph – MENJUGATE Liquid. June 2019.
* GlaxoSmithKline Inc. Product Monograph – MENVEO. February 2019.
* GlaxoSmithKline Inc. Product Monograph – BEXSERO. February 2019.
* Sanofi Pasteur Limited. Product Monograph – Menactra®**.** November 2017.
* Pfizer Canada ULC. Product Monograph – NeisVac-C® Vaccine. May 2019.
* Pfizer Canada ULC. Product Monograph – NIMENRIX**®**. December 2018.
* Pfizer Canada ULC. Product Monograph – Trumenba® Vaccine. May 2019.
* PHLS Meningococcal Infections Working Group and Public Health Medicine Environmental Group. Control of meningococcal disease: guidance for consultants in communicable disease control. Commune Dis Rep CDR Rev 1995;5(13):R189-95.
* Public Health Agency of Canada. Guidelines for the prevention and control of meningococcal disease. Can Commun Dis Rep 2005;31(S1):1-26.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-14-mumps-vaccine.html)
### On this page
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-06-12
| None | None |
d8890fa586ea63445721170a2621d6499ad8dcd9 | cma | Polymerase chain reaction (PCR) and cycle threshold (Ct) values in COVID-19 testing | Polymerase chain reaction (PCR) and cycle threshold (Ct) values in COVID-19 testing
On this page
About cycle threshold (Ct) values
Most tests that detect the ribonucleic acid (RNA) or genetic fingerprint of the virus that causes COVID-19 (e.g., a polymerase chain reaction, or PCR test) use a process where specific bits of the genetic fingerprint are amplified using a temperature cycling reaction that repeats up to 45 times. These are called amplification cycles. The amount of genetic material doubles after each cycle. The number of amplification cycles required to create enough copies of the viral RNA to be detected is called the cycle threshold or Ct value.
The more RNA that is present in the patient sample, the fewer cycles are required for the signal to reach the detection threshold (low Ct value). The less RNA present in the clinical sample, the more cycles are required. So a low Ct value corresponds to a high viral load, while a high Ct value corresponds to a low viral load.
For an example of a real-time amplification curve on a logarithmic scale, see .
Curves can also be viewed on a linear scale, which will look different but does not change the Ct interpretation. Not all commercial real-time PCR assays provide Ct values or amplification curves for viewing by the user. In addition, some molecular assays are based on other technologies (e.g., flow cytometry), and hence, do not provide Ct values.
How Ct values are used
The Ct value is the cut-off that calls a test positive. This is defined by the manufacturer of the test or the laboratory during the validation process. It ensures that the PCR test is correctly detecting the presence of the virus and not false signals.
In certain circumstances, such as in patients with compromised immune systems, samples may need to be retested following recovery from COVID-19. Ct values can be used to monitor changes in the amount of virus present in a person’s samples over time. This can be complex and typically requires consultation between health care providers and laboratory specialists.
Ct values and infectiousness
A frequent question is whether Ct values can help determine whether an individual is infectious or not. It is not possible to directly translate a Ct value into degree or duration of infectiousness.
A person is deemed infectious if they shed virus particles that are intact and able to go on to infect others. PCR tests cannot distinguish viral genomic material coming from intact viral particles in persons who are infectious or viral particle fragments that are present in individuals who have recovered.
There is good evidence that when more than 35 cycles are required to detect virus, the virus concentration is so low that it is unlikely to grow the virus in the laboratory. However, the cells used in the laboratory to grow the virus are different from the cells in the back of the throat and nose (nasopharynx) or the lungs in people. So just because one can’t grow the virus in a laboratory that does not mean that it won’t transmit.
Many believe that with low viral RNA copy numbers (high Ct value) the virus is not likely to be transmitted. A recent study which followed patients who were symptomatic but did not require hospitalization showed that those with higher viral loads (lower Cts) infected a higher proportion of their immediate contacts. But we do not know how much virus is actually required to cause an infection in someone and there are other important factors that may influence infectiousness, including the health of the person exposed and the type of exposure that has happened.
Factors to consider when interpreting Ct values
# Ct values will depend on the stage of infection
Between exposure to the virus and symptom onset (e.g., incubation or pre-symptomatic period), the amount of virus in a person’s sample can be initially too low to be detectable (negative). A person with an initially negative result may progress to give a test with a high Ct value i.e. >30 (low viral load), then to a lower Ct value (increased viral load) dramatically within a couple of days. Laboratories across the country have seen many cases where the person is tested early during their course of infection and the initial sample had a very high Ct value ~35 (low virus RNA concentration) and the following day the Ct was approximately 14 (high virus RNA concentration).
# Ct values are affected by the type of the sample taken from the person
Nasopharyngeal swabs (those that go deep into the nose to swab the back of the upper throat) are the most sensitive specimen type for people who do not need admission to hospital. Throat/nasal swabs, and gargles/saliva may not have as much virus in them (so they would give a positive test with a higher Ct value). In people where COVID- 19 has infected their lungs, these samples from the nose/throat can be negative and a deeper sample like sputum is needed to detect the virus. In addition, the type of swabs used for collecting samples may also influence the Ct value.
# Ct values are affected by the quality of the sample taken from the person
The quality of the sample collected is very important. If you don’t get the best possible sample, less virus will be in it and this can lead to a sample with an artificially high Ct value in a person who could have a lot of virus in their system.
# Ct values cannot be compared between different PCR tests
There is no standard yet to be able to compare one test to another so the Ct range can greatly differ by the type of test used, that may use different signal detection methods. In fact, even when testing identical samples using different PCR tests, the results can differ by up to 8 Ct values (e.g., from 22 to 30). This has been observed in the laboratories from different jurisdictions (e.g., Ontario, British Columbia and Saskatchewan).
# The genetic fingerprint of the virus can be picked up long after the virus is no longer infectious
PCR can be positive for over 100 days or more after infection, usually with tests that have high Ct values but in most cases are unlikely to transmit to others beyond 10 days post symptom onset. This finding has been considered in the Infection Prevention and Control (IPAC) and public health practice that recommends patient isolation based on symptom onset, disease severity and the presence of any underlying, immunocompromising conditions instead of on PCR results alone both in some healthcare facilities and more so in the community setting.
# The impact of new variants on Ct values is not clear
Our current tests can detect the new COVID-19 variants of concern (VOCs) - B.1.1.7 (first detected in the United Kingdom), B.1.351 (first detected in South Africa) and P.1 (first detected in Brazil). It has been documented that B.1.1.7 and B.1.351 variants are more infectious, and patients with B.1.1.7 infections have lower Ct values (higher viral loads) compared with those infected with the originally circulating (non-variant) SARS-CoV-2 virus. B.1.351 and P.1 are undergoing further study. We are closely following the VOC-positive samples in Canada to better understand the impact of these variants on our laboratory tests.
Key points and recommendations
- Ct values can sometimes be used by practitioners, in combination with clinical and epidemiologic information, to make judgment-based decisions. Ct values should not be used alone to make concrete clinical or public health decisions.
- Not all nucleic acid amplification assays produce Ct values or an equivalent proxy measure of viral ‘RNA load’.
- High Ct values are not yet proven to be able to declare someone non-infectious, only that they are less likely to be infectious.
- As a result, it is not recommended that Ct values be routinely clinically reported with SARS-CoV-2 RT-PCR results.
- If a laboratory chooses to routinely report Ct values, it is recommended that clear language regarding uncertainty in interpretation be included in the report. It should also specify which authorities may need to be consulted for decision making. |
Polymerase chain reaction (PCR) and cycle threshold (Ct) values in COVID-19 testing
====================================================================================
On this page
------------
* [About Ct values](#a1)
* [How Ct values are used](#a2)
* [Ct values and infectiousness](#a3)
* [Factors to consider when interpreting Ct values](#a4)
* [Key points and recommendations](#a5)
* [References](#a6)
About cycle threshold (Ct) values
---------------------------------
Most tests that detect the ribonucleic acid (RNA) or genetic fingerprint of the virus that causes COVID-19 (e.g., a polymerase chain reaction, or PCR test) use a process where specific bits of the genetic fingerprint are amplified using a temperature cycling reaction that repeats up to 45 times. These are called amplification cycles. The amount of genetic material doubles after each cycle. The number of amplification cycles required to create enough copies of the viral RNA to be detected is called the cycle threshold or Ct value.
The more RNA that is present in the patient sample, the fewer cycles are required for the signal to reach the detection threshold (low Ct value). The less RNA present in the clinical sample, the more cycles are required. So a low Ct value corresponds to a high viral load, while a high Ct value corresponds to a low viral load.
For an example of a real-time amplification curve on a logarithmic scale, see [Figure 1 in Public Health Ontario: An Overview of Cycle Threshold Values and their Role in SARS-CoV-2 Real-Time PCR Test Interpretation](https://www.publichealthontario.ca/-/media/documents/ncov/main/2020/09/cycle-threshold-values-sars-cov2-pcr.pdf?la=en).
Curves can also be viewed on a linear scale, which will look different but does not change the Ct interpretation. Not all commercial real-time PCR assays provide Ct values or amplification curves for viewing by the user. In addition, some molecular assays are based on other technologies (e.g., flow cytometry), and hence, do not provide Ct values.
How Ct values are used
----------------------
The Ct value is the cut-off that calls a test positive. This is defined by the manufacturer of the test or the laboratory during the validation process. It ensures that the PCR test is correctly detecting the presence of the virus and not false signals.
In certain circumstances, such as in patients with compromised immune systems, samples may need to be retested following recovery from COVID-19. Ct values can be used to monitor changes in the amount of virus present in a person’s samples over time. This can be complex and typically requires consultation between health care providers and laboratory specialists.
Ct values and infectiousness
----------------------------
A frequent question is whether Ct values can help determine whether an individual is infectious or not. It is not possible to directly translate a Ct value into degree or duration of infectiousness.
A person is deemed infectious if they shed virus particles that are intact and able to go on to infect others. PCR tests cannot distinguish viral genomic material coming from intact viral particles in persons who are infectious or viral particle fragments that are present in individuals who have recovered.
There is good evidence that when more than 35 cycles are required to detect virus, the virus concentration is so low that it is unlikely to grow the virus in the laboratory. However, the cells used in the laboratory to grow the virus are different from the cells in the back of the throat and nose (nasopharynx) or the lungs in people. So just because one can’t grow the virus in a laboratory that does not mean that it won’t transmit.
Many believe that with low viral RNA copy numbers (high Ct value) the virus is not likely to be transmitted. A recent study which followed patients who were symptomatic but did not require hospitalization showed that those with higher viral loads (lower Cts) infected a higher proportion of their immediate contacts. But we do not know how much virus is actually required to cause an infection in someone and there are other important factors that may influence infectiousness, including the health of the person exposed and the type of exposure that has happened.
Factors to consider when interpreting Ct values
-----------------------------------------------
### Ct values will depend on the stage of infection
Between exposure to the virus and symptom onset (e.g., incubation or pre-symptomatic period), the amount of virus in a person’s sample can be initially too low to be detectable (negative). A person with an initially negative result may progress to give a test with a high Ct value i.e. >30 (low viral load), then to a lower Ct value (increased viral load) dramatically within a couple of days. Laboratories across the country have seen many cases where the person is tested early during their course of infection and the initial sample had a very high Ct value ~35 (low virus RNA concentration) and the following day the Ct was approximately 14 (high virus RNA concentration).
### Ct values are affected by the type of the sample taken from the person
Nasopharyngeal swabs (those that go deep into the nose to swab the back of the upper throat) are the most sensitive specimen type for people who do not need admission to hospital. Throat/nasal swabs, and gargles/saliva may not have as much virus in them (so they would give a positive test with a higher Ct value). In people where COVID- 19 has infected their lungs, these samples from the nose/throat can be negative and a deeper sample like sputum is needed to detect the virus. In addition, the type of swabs used for collecting samples may also influence the Ct value.
### Ct values are affected by the quality of the sample taken from the person
The quality of the sample collected is very important. If you don’t get the best possible sample, less virus will be in it and this can lead to a sample with an artificially high Ct value in a person who could have a lot of virus in their system.
### Ct values cannot be compared between different PCR tests
There is no standard yet to be able to compare one test to another so the Ct range can greatly differ by the type of test used, that may use different signal detection methods. In fact, even when testing identical samples using different PCR tests, the results can differ by up to 8 Ct values (e.g., from 22 to 30). This has been observed in the laboratories from different jurisdictions (e.g., Ontario, British Columbia and Saskatchewan).
### The genetic fingerprint of the virus can be picked up long after the virus is no longer infectious
PCR can be positive for over 100 days or more after infection, usually with tests that have high Ct values but in most cases are unlikely to transmit to others beyond 10 days post symptom onset. This finding has been considered in the Infection Prevention and Control (IPAC) and public health practice that recommends patient isolation based on symptom onset, disease severity and the presence of any underlying, immunocompromising conditions instead of on PCR results alone both in some healthcare facilities and more so in the community setting.
### The impact of new variants on Ct values is not clear
Our current tests can detect the new COVID-19 variants of concern (VOCs) - B.1.1.7 (first detected in the United Kingdom), B.1.351 (first detected in South Africa) and P.1 (first detected in Brazil). It has been documented that B.1.1.7 and B.1.351 variants are more infectious, and patients with B.1.1.7 infections have lower Ct values (higher viral loads) compared with those infected with the originally circulating (non-variant) SARS-CoV-2 virus. B.1.351 and P.1 are undergoing further study. We are closely following the VOC-positive samples in Canada to better understand the impact of these variants on our laboratory tests.
Key points and recommendations
------------------------------
* Ct values can sometimes be used by practitioners, in combination with clinical and epidemiologic information, to make judgment-based decisions. Ct values should not be used alone to make concrete clinical or public health decisions.
* Not all nucleic acid amplification assays produce Ct values or an equivalent proxy measure of viral ‘RNA load’.
* High Ct values are not yet proven to be able to declare someone non-infectious, only that they are less likely to be infectious.
* As a result, it is not recommended that Ct values be routinely clinically reported with SARS-CoV-2 RT-PCR results.
* If a laboratory chooses to routinely report Ct values, it is recommended that clear language regarding uncertainty in interpretation be included in the report. It should also specify which authorities may need to be consulted for decision making.
References
----------
1. An Overview of Cycle Threshold Values and their Role in SARS-CoV-2 Real-Time PCR Test Interpretation. https://www.publichealthontario.ca/-/media/documents/ncov/main/2020/09/cycle- threshold-values-sars-cov2-pcr.pdf?la=en
2. Basile K, McPhie K, Carter I, et al. Cell-based culture of SARS-CoV-2 informs infectivity and safe de-isolation assessments during COVID-19. *Clinical Infectious Diseases*, 2020 Oct. DOI: https://doi.org/10.1093/cid/ciaa1579
3. Ct Values: What They Are and How They Can Be Used. *Association of Public Health Laboratories.* 2020, November 9. Retrieved from: https://www.aphl.org/programs/preparedness/Crisis-Management/Documents/APHL-COVID19-Ct-Values.pdf#search=What%20They%20Are%20and%20How%20They%20Can%20be%20Used
4. Frequently Asked Questions about Coronavirus (COVID-19) for Laboratories, *CDC*. Retrieved from: https://www.cdc.gov/coronavirus/2019-ncov/lab/faqs.html#Interpreting-Results-of-Diagnostic-Tests
5. Marks A, Millat-Martinez P, Ouchi D, et al. Transmission of COVID-19 in 282 clusters in Catalonia, Spain: a cohort study - *The Lancet Infectious Diseases* 2021. Published Online February 2, 2021 https://doi.org/10.1016/S1473-3099(20)30985-3
6. Rhoads D, Peaper DR, She RC, Nolte F, Wojewoda C, Anderson N, Pritt BS, College of American Pathologists (CAP) Microbiology Committee Perspective: Caution Must Be Used in Interpreting the Cycle Threshold (Ct) Value, *Clinical Infectious Diseases*, 2020, ciaa1199, https://doi.org/10.1093/cid/ciaa1199
7. Singanayagam A, Patel M, Charlett A, Lopez Bernal J, Saliba V, Ellis J, Ladhani S, Zambon M, Gopal R .Duration of infectiousness and correlation with RT-PCR cycle threshold values in cases of COVID-19, England, January to May 2020. *Euro Surveill.* 2020 Aug; 25(32):2001483. DOI: https://doi.org/10.2807/1560-7917.ES.2020.25.32.2001483
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2021-06-10
| None | None |
00f5e662aa1d651cb9ef633a97edfc23b4105c7e | cma | Use of Measles-Mumps-Rubella (MMR) Vaccine for the Management of Mumps Outbreaks in Canada | Use of Measles-Mumps-Rubella (MMR) Vaccine for the Management of Mumps Outbreaks in Canada
Preamble
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's policy on conflict of interest, including yearly declaration of potential conflict of interest.
(PDF format, 714 KB, 51 pages)
Organization:
Publication Date 2021-07-27
Cat.: HP40-286/2021E-PDF
ISBN: 9780660384337
Pub.: 210041 |
Use of Measles-Mumps-Rubella (MMR) Vaccine for the Management of Mumps Outbreaks in Canada
===========================================================================================
An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI)
----------------------------------------------------------------------------------------
Preamble
--------
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's policy on conflict of interest, including yearly declaration of potential conflict of interest.
[Download the alternative format](/content/dam/phac-aspc/documents/services/publications/vaccines-immunization/use-measles-mumps-rubella-vaccine-management-outbreaks-canada/naci-mmr-vaccine-statement-eng.pdf)
(PDF format, 714 KB, 51 pages)
**Organization:** [Public Health Agency of Canada](/en/public-health.html)
**Publication Date** 2021-07-27
**Cat.:** HP40-286/2021E-PDF
**ISBN:** 9780660384337
**Pub.:** 210041
Table of contents
-----------------
1. [Summary of Information Contained in the NACI Statement](#summary)
2. [I. Introduction](#introduction)
1. [I.1 Objective of this Statement](#objective)
2. [I.2 Background on Mumps Immunization Programs and Recommendations in Canada](#background)
3. [II. Methods](#methods)
1. [II.1 Burden of Illness](#burden)
2. [II.2 NACI Literature Review (Effectiveness and Safety)](#naci)
4. [III. Epidemiology](#epidemiology)
1. [III.1 Disease Characteristics and Burden of Illness](#disease)
2. [III.2 Mumps Vaccination Coverage](#mumps)
3. [III.3 Description of Mumps Epidemiology in Canada between 2014 and 2018](#desc)
4. [III.4 Outbreaks in Canada](#outbreaks)
5. [III.5 Molecular Epidemiology of Canadian Outbreaks](#molecular)
6. [III.6 Summary of Recent International Outbreaks](#recent)
5. [IV. Vaccine](#vaccine)
1. [IV.1 Preparation(s) Authorized for use in Canada (e.g., Description, Composition)](#preparation)
2. [IV.2 Vaccine Effectiveness](#effectiveness)
3. [IV.3 Vaccine Safety](#safety)
7. [V. Discussion](#discussion)
8. [VI. Recommendations](#recommendations)
1. [VI.1 Recommendations for Public Health Program Level Decision-Making (i.e., Provinces/Territories Making Decisions for Publicly Funded Immunization Programs)](#decision)
10. [VII. Management Options](#management)
11. [VIII. Knowledge Gaps and Research Priorities](#knowledge)
12. [IX. Surveillance Issues](#surveillance)
13. [Tables](#tables)
14. [List of Abbreviations](#abbreviations)
15. [Acknowledgments](#acknowledgments)
16. [Appendix A: Summary of Effectiveness Findings](#appendix-a)
17. [Appendix B: Summary of Safety Findings (Adverse Events [AE] and Serious Adverse Events [SAE])](#appendix-b)
18. [References](#references)
Summary of Information Contained in this NACI Statement
-------------------------------------------------------
The following highlights key information for immunization providers. Please refer to the remainder of the Statement for details.
### 1. What
#### Mumps
Since 2016, there has been a substantial increase in the number of reported mumps outbreaks and outbreak-associated mumps cases in Canada. The majority of outbreak-related mumps cases in Canada in recent years have occurred in young adults aged 15-39 years. Geographically, outbreaks in northern Canadian communities have had higher attack rates. In addition, outbreaks among vaccinated individuals often occur in situations with increased risks for exposure to the virus and transmission may be facilitated through behavioural risk factors.
Complications such as orchitis and oophoritis are relatively frequent; permanent sequelae like deafness are rare. While complications of mumps infections are not always well characterized or reported, they are less common in the post-vaccine era and among those vaccinated.
Additional information about Mumps is available on the Government of Canada web site ([Vaccine-Preventable Diseases](/en/public-health/services/diseases.html?vaccine-preventable)).
#### Vaccine
Mumps vaccine is available as measles-mumps-rubella (MMR) or measles-mumps-rubella-varicella (MMRV) vaccine. Mumps vaccine effectiveness has been estimated at 62% to 91% for 1 dose and 76% to 95% for 2 doses. Somewhat lower vaccine effectiveness has been observed in outbreak settings, especially when exposures occurred in close-contact settings, as protection appears to wane over time. Waning vaccine effectiveness is likely due to decline in cellular immunity, antibody concentrations and avidity.
Reactions to mumps vaccine are generally mild and transient and include pain and redness at the injection site, fever, and rash.
### 2. Who
This Statement provides an evidence summary and recommendations on the topic of additional dose(s) of MMR vaccine provided in mumps outbreak settings, including the off-label administration of a third dose of MMR vaccine (MMR3) in individuals who were previously vaccinated with two valid doses, for consideration by public health programs.
### 3. How
In an outbreak setting, NACI recommends that implementation of an outbreak dose of MMR vaccine may be considered as a part of the broader outbreak management strategy. In addition, NACI recommends that MMR vaccine (up to a third dose) may be considered for close contacts following exposure to a case of mumps in an outbreak setting. However, due to the potential logistical challenges that are associated with program implementation (such as those related to vaccine supply and acquisition costs, vaccine uptake and virus susceptibility determination and the absence of immunization records or information on the exposures), it is important to promptly assess the outbreak characteristics and define the populations that have or may be exposed to the disease.
### 4. Why
Mumps occurs worldwide and outbreaks continue to occur. Complications of mumps disease are relatively frequent, although permanent sequelae are rare.
I. Introduction
---------------
### I.1 Objective of this Statement
In 2018, following a period of elevated mumps activity in Canada, Canadian provinces and territories signalled interest in a review of evidence on the use of additional doses of mumps-containing vaccine in outbreak settings. The United States Advisory Committee on Immunization Practices (ACIP) has recommended the use of a third dose of a mumps-containing vaccine during mumps outbreaks to improve protection against mumps disease and related complications[Footnote 1](#fn1). The primary objective of this statement is to review the evidence on the effectiveness and safety of additional dose(s) of MMR vaccine when provided in mumps outbreak settings, including the off-label administration of a third dose of MMR vaccine (MMR3) in individuals who were previously vaccinated with two valid doses. A literature and environmental evidence review was undertaken to develop recommendations for the use of additional dose(s) of MMR vaccine in mumps outbreak settings. In developing this guidance, NACI reviewed evidence relating to:
* Programmatic recommendations with consideration given to the number and timing of additional MMR vaccine dose(s) with the following objectives:
+ Primary: To control the scale of mumps outbreaks in Canada by limiting the number of cases; and
+ Secondary: To prevent complications from mumps (e.g., orchitis, oophoritis, meningitis, encephalitis, hearing loss).
* Individual recommendations with consideration given to the number and timing of additional doses in outbreak settings for the protection of individuals who are not covered by programmatic recommendations.
The vaccine recommendations and other information provided in this Statement are intended to complement and, where applicable, update the [Guidelines for the Prevention and Control of Mumps Outbreaks in Canada](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2010-36/guidelines-prevention-control-mumps-outbreaks-canada.html) published in 2010, which provide more detailed and comprehensive information on the principles of mumps outbreak management beyond immunization.
### I.2 Background on Mumps Immunization Programs and Recommendations in Canada
The recently updated national disease reduction target for mumps is to maintain less than 100 annual cases[Footnote 2](#fn2), based on a 5-year rolling average. However, given the observed waning of mumps immunity following the administration of two doses of MMR vaccine[Footnote 3](#fn3),[Footnote 4](#fn4),[Footnote 5](#fn5),[Footnote 6](#fn6),[Footnote 7](#fn7),[Footnote 8](#fn8), there is acknowledgment that this target may be difficult to achieve currently with routine schedule.
Immunization with MMR vaccine has been demonstrated to effectively prevent mumps, viral transmission and disease complications[Footnote 9](#fn9). For routine immunization of children, since 1996, NACI has recommended the administration of 2 doses of mumps-containing vaccine after a child's first birthday. The first dose of mumps-containing vaccine [MMR or Measles, Mumps, Rubella and Varicella (MMRV) vaccine] should be provided at 12 to 15 months of age and the second dose at 18 months of age or any time thereafter, but no later than school entry.
The current national immunization target is to achieve 95% vaccination coverage for receipt of two doses of mumps-containing vaccine by seven years of age[Footnote 2](#fn2).
Recommendations for adults vary from 0 to 2 doses, depending on the individual's age and risk of exposure. Two doses of measles-containing vaccine (which also includes mumps) are recommended for those who are at the greatest risk of mumps exposure (travellers to destinations outside of Canada, students in post-secondary educational settings born after 1970, and all health care workers and military personnel)[Footnote 10](#fn10). In outbreak settings, NACI recommends that an additional dose of mumps-containing vaccine be provided to adults born in or after 1970 who have not already received two doses of the MMR vaccine[Footnote 11](#fn11). Adults born before 1970 are generally presumed to have acquired natural immunity to mumps; however, some of these individuals may be susceptible[Footnote 12](#fn12).
While the exact cause of mumps outbreaks in highly vaccinated populations remains unknown, several factors have been proposed as possible contributors to breakthrough infections[Footnote 3](#fn3),[Footnote 4](#fn4),[Footnote 7](#fn7),[Footnote 13](#fn13),[Footnote 14](#fn14),[Footnote 15](#fn15),[Footnote 16](#fn16),[Footnote 17](#fn17),[Footnote 18](#fn18),[Footnote 19](#fn19):
* Waning of immunity following vaccination[Footnote 3](#fn3),[Footnote 5](#fn5),[Footnote 6](#fn6),[Footnote 7](#fn7),[Footnote 8](#fn8),[Footnote 20](#fn20); studies have shown differential humoral immunity for each of measles, mumps, and rubella, even though they are combined in the MMR vaccine. Mumps antibody levels have consistently shown to be lower compared to measles and rubella[Footnote 21](#fn21);
* Reduced vaccine effectiveness due to antigenic differences between circulating and vaccine virus strains[Footnote 3](#fn3),[Footnote 22](#fn22),[Footnote 23](#fn23),[Footnote 24](#fn24);
* High intensity of exposure to the virus in close-contact settings, coupled with behaviours that increase the risk of transmission[Footnote 3](#fn3),[Footnote 22](#fn22),[Footnote 23](#fn23),[Footnote 24](#fn24),[Footnote 25](#fn25),[Footnote 26](#fn26);
II. Methods
-----------
### II.1 Burden of Illness
In brief, the broad stages in the preparation of a NACI advisory committee statement are:
1. Knowledge synthesis;
2. Synthesis of the body of evidence of benefits and harms, considering the quality of the evidence and magnitude of effects observed; and
3. Translation of evidence into a recommendation.
Details regarding NACI's evidence-based process for developing a Statement are outlined in [Evidence-based Recommendations for Immunization − Methods of the National Advisory Committee on Immunization](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2009-35/methods-national-advisory-committee-immunization.html).
NACI reviewed the key questions for the literature review as proposed by the NACI MMRV Working Group (MMRV WG), including such considerations as the burden of illness and the target population(s); the safety and effectiveness of the vaccine; vaccine schedules; and other aspects of the overall immunization strategy. NACI also reviewed the national surveillance data for mumps, which is routinely reported to the Public Health Agency of Canada (PHAC) by provincial and territorial departments of health through the Canadian Notifiable Disease Surveillance System (CNDSS) [Footnote 27](#fn27). To complement these data, the provinces and territories were surveyed for information on mumps outbreaks occurring from January 2016 to August 2018.
The literature review and knowledge synthesis were performed by PHAC staff and supervised by the NACI MMRV WG. Following critical appraisal of individual studies, proposed recommendations for vaccine use were developed. The evidence and proposed recommendations were presented to NACI for deliberation on September 25, 2019 and February 6, 2020. NACI approved the recommendations on November 18, 2020, following thorough review of the evidence to assess the risk-benefit of the use of mumps-containing vaccine in outbreak settings. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the text.
### II.2 NACI Literature Review (Effectiveness and Safety)
The policy questions addressed in this statement are:
*Should an additional dose of mumps-containing vaccine be provided in an outbreak setting? If so, who should receive it?*
The literature search and data extraction conducted on January 2, 2019 used the following population, intervention, comparator and outcomes (PICO 1):
**Population**:
Persons, all ages, at risk of mumps infection due to outbreaks receiving an outbreak dose of MMR vaccine
**Intervention**:
Provision of MMR vaccine during a mumps outbreak
**Comparator**:
Persons, all ages, at risk of mumps infection due to an outbreak with documented MMR vaccination status who did not receive a dose of MMR vaccine during the outbreak
Persons, all ages, at risk of mumps infection due to an outbreak with documented MMR vaccination status who did not receive an outbreak dose
**Outcomes**:
Effectiveness and safety of MMR3
The supplementary literature search and data extraction conducted on July 16, 2019 used the following PICO 2:
**Population**:
Persons, all ages, receiving a dose of MMR vaccine within 7 days of exposure to mumps
**Intervention**:
Post exposure dose of MMR vaccine
**Comparator**:
Persons, all ages, who did not receive a post-exposure dose of MMR
**Outcomes**:
Effectiveness of a post-exposure dose of MMR
MEDLINE and EMBASE electronic databases were searched using search terms and strategies developed with the assistance of a Health Canada library specialist. The results of a systematic review conducted by the US Centre for Disease Control and Prevention (CDC) supporting the ACIP, assessing the use of a third dose of a mumps containing vaccine (MMR3) in outbreak settings, were also reviewed and used as a foundation for the NACI systematic review. NACI modified the CDC literature review strategy in order to integrate additional studies on "outbreak dose" of MMR vaccine, defined as an additional dose (defined as a catch-up dose, which could include a third dose) provided in an outbreak setting. In order to fully align with the NACI MMRV Working Group PICO 1, studies published between January 2000 and January 2, 2019 were retrieved and screened by title, abstract and full-text for potential eligibility by two reviewers. The same reviewers also conducted the additional data screening extraction for the NACI MMRV Working Group PICO 2, which was requested by the WG in order to determine the effectiveness of a mumps-containing vaccine when used post-exposure. PICO 2 included studies that were published between 1946 and July 16, 2019. Hand-searching of the reference lists of included articles was performed by one reviewer to identify additional relevant publications. One reviewer extracted data from the studies included for review into an evidence table using a piloted data abstraction template designed to capture information on study design, population and outcomes of interest. A second reviewer independently validated the abstracted data with any disagreements or discrepancies resolved by discussion and consensus. The level of evidence (i.e., study design) and methodological quality of included studies was assessed independently by the two reviewers using the design-specific criteria by Harris et al. (2001)[Footnote 28](#fn28) adopted by NACI for rating the internal validity of individual studies ([Table 1](#table-1), [Table 2](#table-2)).
III. Epidemiology
-----------------
### III.1 Disease Characteristics and Burden of Illness
Mumps virus, the causative agent of mumps infection, is an enveloped RNA virus that belongs to the genus Rubulavirus in the family Paramyxoviridae[Footnote 29](#fn29). Infection is spread through large droplet transmission over short distances of less than two meters or by direct contact with infected respiratory droplets or saliva, and symptoms occur after an incubation period between 12 and 25 days (average 16 to 18 days). Typically, mumps is a relatively mild disease with parotitis being the most frequently observed clinical manifestation. However, subclinical and asymptomatic infections are common[Footnote 29](#fn29),[Footnote 30](#fn30),[Footnote 31](#fn31),[Footnote 32](#fn32). In rare cases, mumps infection may have permanent sequelae: meningoencephalitis can result in paralysis, seizures, cranial nerve palsies, hydrocephalus and deafness, while orchitis and oophoritis can result in sterility[Footnote 33](#fn33),[Footnote 34](#fn34),[Footnote 35](#fn35). Infection during the first trimester of pregnancy has not been associated with congenital anomalies[Footnote 36](#fn36), but may increase the rate of spontaneous abortion. The risk and the severity of complications, such as orchitis, oophoritis, meningitis, encephalitis, hearing loss and pancreatitis, may be reduced in partially or fully immunized individuals [Footnote 9](#fn9),[Footnote 10](#fn10),[Footnote 37](#fn37),[Footnote 38](#fn38),[Footnote 39](#fn39),[Footnote 40](#fn40),[Footnote 41](#fn41),[Footnote 42](#fn42),[Footnote 43](#fn43). Complications are known to occur more frequently among post-pubertal youth and adults than children[Footnote 44](#fn44).
Although the mumps virus has been isolated from the saliva of persons infected with mumps 7 days before symptom onset to 9 days after, persons infected with mumps are considered most infectious between 2 days before to 5 days after symptom onset. Infected individuals who are asymptomatic can still transmit mumps to others[Footnote 45](#fn45).
During the pre-vaccine period, mumps was an endemic disease that primarily affected children 5 to 9 years of age. Following the authorization of the mumps vaccine in Canada in 1969 and the subsequent introduction of a routine two-dose MMR vaccination (MMR2) schedule in 1996/97, the number of reported mumps cases nationally decreased by more than 99%[Footnote 45](#fn45). However, mumps continues to be a cyclical disease in Canada, with outbreaks occurring every few years and otherwise low incidence rates[Footnote 44](#fn44). The cohort of individuals born between 1970 and 1990 represents a cohort vulnerable to mumps infection, as these individuals are less likely to have received two doses of mumps-containing vaccine or been alive when the wild virus circulated widely.
In the post-vaccine era, complications from mumps infections are rarely reported. An analysis of Canadian hospitalization data (excluding Quebec) from the Canadian Institute for Health Information (CIHI) was conducted for the calendar years 2014-2018. The number of hospitalizations with a primary diagnosis of mumps (ICD-10-CA code B26 including B26.0, B26.1, B26.2, B26.3, B26.8 and B26.9) was low, with <260 hospitalizations in the 5-year period. Almost half (42%) of the mumps-related hospitalizations were among individuals born before 1970. The number of mumps hospitalizations with severe mumps complications (meningitis and pancreatitis) was extremely low, at two and one cases, respectively, over the 5-year period with all 3 hospitalizations from the cohort born after 1990. Only seven hospitalizations for mumps-related orchitis were identified, with 6/7 hospitalizations from the cohort born after 1990. No information on vaccination status or previous immunity from wild mumps virus infection was available. Although these data support the literature in that severe mumps complications are rare, caution is needed when interpreting these data as this extraction was not validated; the data are not national; and only the hospitalizations with a primary code of mumps were extracted. Co-morbidities and outcomes were not assessed. Age-specific hospitalization data for mumps are not reflective of surveillance data and outbreak data, and this discrepancy should be explored further to better understand the data.
### III.2 Mumps Vaccination Coverage
The national vaccination coverage goals aim for 95% of children to have received one dose of measles, mumps and rubella containing vaccine by the age of two years, and 95% vaccination coverage with the recommended two doses of mumps-containing vaccine by seven years of age[Footnote 2](#fn2).
Immunization coverage with two doses of mumps containing vaccine varies across Canada's provinces and territories and comprehensive regional coverage data is not currently available. Information on national immunization coverage for mumps and other childhood vaccines in Canada is collected through the Childhood National Immunization Coverage Survey (CNICS). According to the 2017 CNICS, 90% of Canadian children received one dose of MMR vaccine by age two years, and 86% received two doses by age seven years.
In most instances, in Canada, adults born before 1970 are presumed to have acquired natural immunity to mumps. It is important to note that population-level immunity against mumps is not homogenous though, due in part to differences in jurisdictional vaccination strategies over time:
* (1) Routine one-dose vaccination against mumps was implemented across provinces and territories between 1970 and 1983, with second dose programs implemented between 1996 and 2001. Overall, individuals born between 1970 and 1996 may only have received one dose or no doses of mumps containing vaccine, and this age cohort may be broader, depending on the province or territory[Footnote 11](#fn11). Exceptions to this would be adults identified to be in high risk groups who may have received two lifetime doses of mumps containing vaccines.
* (2) Vaccination has been a common strategy to improve mumps immunity in those who were born in 1970 or later if they are deemed to be at higher risk of mumps or measles and so this would include travellers, health care workers, military personnel and students in post-secondary educational settings.
Additionally, immigrants and other newcomers to Canada may be a susceptible/under-immunized group because they may have received only one dose or no dose of mumps-containing vaccine, given that MMR vaccination is not universal[Footnote 46](#fn46).
### III.3 Description of Mumps Epidemiology in Canada Between 2014 and 2018
Mumps has been a nationally reportable disease since 1986[Footnote 47](#fn47),[Footnote 48](#fn48) and is currently endemic in Canada, with cyclical outbreaks occurring every two to five years[Footnote 49](#fn49). Detailed information
regarding the case definition and case classification can be found in the [Canada Communicable Disease Report (CCDR)](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2009-35/definitions-communicable-diseases-national-surveillance/mumps.html) section pertaining to mumps. Briefly, the current national definition for a
confirmed mumps case requires clinical illness and laboratory confirmation of infection in the absence of recent immunization with mumps-containing vaccine; or a mumps compatible clinical
illness in a person with an epidemiological link to a laboratory-confirmed case. A probable case is defined as mumps compatible clinical illness in the absence of appropriate laboratory tests or in the
absence of an epidemiological link to a laboratory-confirmed case.
The national surveillance data for mumps have numerous limitations, including timeliness, and limited availability of information on cases regarding vaccination status, disease severity, long-term
sequelae, and complications. Data on outbreaks in Canada are not routinely collected through national surveillance. Additionally, the lack of a national immunization registry or immunization
registries for all provinces and territories hinders the ability to determine vaccination status of individuals or populations.
With the introduction of current mumps vaccination schedules, the incidence rate of mumps declined from 251.2 cases per 100,000 population during the pre-vaccine era (i.e., prior to 1969) to
1.9 cases per 100,000 population from 2014-2018 ([Figure 1](#figure-1))[Footnote 49](#fn49).
**Figure 1: Number and incidence rate (per 100,000 population) of reported mumps cases[Footnote a](#f1fna) in Canada by year, 1950 to 2018, before and after introduction of mumps-containing vaccine.**
Figure 1: Number and incidence rate (per 100,000 population) of reported mumps cases[Footnote a](#f1fna) in Canada by year, 1950 to 2018, before and after introduction of mumps-containing vaccine. - Text description
Figure 1 shows the number and incidence rate (per 100,000 population) of reported mumps cases in Canada by year based on national surveillance data for mumps reported to PHAC by provincial and territorial departments of health through the Canadian Notifiable Disease Surveillance System (CNDSS). The main bar-line graph shows the reported cases of mumps as blue bars (primary vertical axis) and the incidence rate in cases per 100,000 population (secondary vertical axis) with respect to year (horizontal axis), from 1950 to 2018, plotted as a blue line. The blue rectangle extending from the years 1959 to 1985 indicates the period when mumps was removed from the list of nationally notifiable diseases and national surveillance data were not available.
The second graph is a red bar graph located in the top right corner showing the reported cases of mumps as light red bars (primary vertical axis) and the incidence rate in cases per 100,000 population (secondary vertical axis) with respect to year (horizontal axis), from 2014 to 2018, as dark red points. The bars represents the reported number of cases, and the dot points indicate the incidence rate.
The following information is depicted in this figure:
| Year | Reported cases | Incidence rate
(cases per 100,000 population) |
| --- | --- | --- |
| 1954 | 26,908 | 176.0 |
| 1955 | 27,193 | 173.2 |
| 1956 | 28,112 | 195.2 |
| 1957 | 22,386 | 166.1 |
| 1958 | 13,360 | 96.3 |
| 1959 | - | - |
| 1960 | - | - |
| 1961 | - | - |
| 1962 | - | - |
| 1963 | - | - |
| 1964 | - | - |
| 1965 | - | - |
| 1966 | - | - |
| 1967 | - | - |
| 1968 | - | - |
| 1969[Footnote b](#f1fnb) | - | - |
| 1970 | - | - |
| 1971 | - | - |
| 1972 | - | - |
| 1973 | - | - |
| 1974 | - | - |
| 1975 | - | - |
| 1976 | - | - |
| 1977 | - | - |
| 1978 | - | - |
| 1979 | - | - |
| 1980 | - | - |
| 1981 | - | - |
| 1982 | - | - |
| 1983 | - | - |
| 1984 | - | - |
| 1985 | - | - |
| 1986 | 836 | 3.2 |
| 1987 | 949 | 3.6 |
| 1988 | 792 | 3.0 |
| 1989 | 1,550 | 5.7 |
| 1990 | 535 | 1.9 |
| 1991 | 390 | 1.4 |
| 1992 | 330 | 1.2 |
| 1993 | 325 | 1.1 |
| 1994 | 356 | 1.2 |
| 1995 | 397 | 1.4 |
| 1996[Footnote c](#f1fnc) | 290 | 1.0 |
| 1997[Footnote c](#f1fnc) | 254 | 0.8 |
| 1998 | 114 | 0.4 |
| 1999 | 92 | 0.3 |
| 2000 | 81 | 0.3 |
| 2001 | 102 | 0.3 |
| 2002 | 200 | 0.6 |
| 2003 | 28 | 0.1 |
| 2004 | 33 | 0.1 |
| 2005 | 79 | 0.2 |
| 2006 | 42 | 0.1 |
| 2007 | 1,110 | 3.4 |
| 2008 | 748 | 2.2 |
| 2009 | 187 | 0.6 |
| 2010 | 768 | 2.3 |
| 2011 | 273 | 0.8 |
| 2012 | 48 | 0.1 |
| 2013 | 94 | 0.3 |
| 2014 | 40 | 0.1 |
| 2015 | 59 | 0.2 |
| 2016 | 365 | 1.0 |
| 2017 | 2,263 | 6.2 |
| 2018 | 808 | 2.2 |
|
Footnote a
Mumps was removed from the list of national notifiable diseases for the years 1959 to 1985
[Return to footnote a referrer](#f1fna-rf)
Footnote b
Introduction of the mumps vaccine in Canada
[Return to footnote b referrer](#f1fnb-rf)
Footnote c
Introduction of a routine two-dose MMR vaccination schedule
[Return to footnote c referrer](#f1fnc-rf)
|
From 2014 to 2018, a total of 3,535 cases of mumps were reported nationally. However, 64% of the cases occurred in 2017 and were likely a result of various outbreaks that started in late 2016 and continued into 2017. This resulted in a five-year median of 73 cases per year (range: 40-2,263 cases). The overall incidence for this period was 1.9 cases per 100,000 population, ranging from 0.1 to 6.2 cases per 100,000 (Figure 1). Adults aged 20 to 39 years old accounted for 53% of all mumps cases, with the highest incidence rates among the 20 to 24-year-old age group (3.8 cases per 100,000 population).
In 2017, a total of 2,263 cases were reported in Canada, with a corresponding incidence rate of 6.2 cases per 100,000 population. Although cases were observed in all age groups, incidence rates were highest in the adolescent and young adult population (between 15 and 29 years of age). Fifty-three percent of the cases were male and 90% of the cases were reported in Manitoba, Ontario and British-Columbia.
### III.4 Outbreaks in Canada
Outbreaks between 1996 and 2010 have been described in previously-published mumps outbreak guidelines[Footnote 11](#fn11). Since 2016, there has been a substantial increase in the number and size of mumps outbreaks. In 2017 and in 2018, the provinces and territories were surveyed to collect enhanced provincial and territorial data on recent mumps outbreaks occurring from January 2016 to February 2017 and from January 2017 to August 2018, respectively[Footnote 50](#fn50). The purpose of the survey was to provide an overview of mumps activity including public health actions across Canada. This survey was conducted for information sharing among provinces and territories and internally. At that time, provinces and territories were asked to report on outbreak related cases only. No standard definition for an outbreak was used. Information on mumps hospitalisations and complications has not been collected and is not available.
#### Combined 2017 and 2018 Mumps Outbreak Surveys Results
Using combined data from both surveys from the Provinces and Territories, from January 2016 to August 2018, a total of 881 cases was reported, excluding the Manitoba outbreak (see below), corresponding to 24 outbreaks[Footnote 50](#fn50)). The median outbreak size was 12.5 cases, ranging from 2 to 166 cases. Overall, the mean outbreak duration was 16.5 weeks, ranging from 1 week to 59 weeks. Mumps outbreak activity was reported in at least one jurisdiction from February 2016 to July 2018. Most outbreaks were reported during the first quarter of 2017, with nine outbreaks starting in four provinces and two ongoing outbreaks in two other jurisdictions.
Of the cases for which age information was available (n=814), 80.6% of the outbreak-related cases were between 15-39 years of age, with 25% of the cases occurring among the 20 to 24-year-old age group (n=217 cases) ([Figure 2](#figure-2)).
**Figure 2: Outbreak mumps case counts by age group, from January 2016 to August 2018, in Canada (n=814)**
Note: Does not include cases from two outbreaks in Saskatchewan (n=63) for which specific age information were not given.
Source: Vaccine Preventable Diseases, Surveillance and Epidemiology Division (SED), Center for Immunization and Respiratory Infectious Diseases (CIRID), Public Health Agency of Canada
Figure 2: Outbreak mumps case counts by age group, from January 2016 to August 2018, in Canada (n=814)
Figure 2 shows the reported number of cases of mumps (vertical axis) with respect to age groups (horizontal axis), from January 2016 to August 2018, in Canada (n=814). Cases from two outbreaks in Saskatchewan (n=63) for which specific age information were not given have not been included.
The following information is depicted in this figure:
| Age groups (years) | Number of cases |
| --- | --- |
| < 1 | 1 |
| 1-4 | 9 |
| 5-9 | 24 |
| 10-14 | 23 |
| 15-19 | 129 |
| 20-24 | 217 |
| 25-29 | 153 |
| 30-39 | 157 |
| 40-49 | 65 |
| 50-59 | 27 |
| ≥ 60 | 9 |
Source: Vaccine Preventable Diseases, Surveillance and Epidemiology Division (SED), Center for Immunization and Respiratory Infectious Diseases (CIRID), Public Health Agency of Canada
The most commonly reported exposure settings included community settings (30.8%), social gatherings (26.9%), post-secondary institutions (19.2%), and sports teams (19.2%). Other exposure settings that were reported (26.9%) include workplace locations, working or living in close quarters, household, and post-secondary settings. Overall, 9 outbreaks (37.5%) were travel related.
Among the cases for which sex information was available (n=816), the majority of cases were male (59%), which is consistent with the sex distribution in the national notifiable disease surveillance system. This is likely due to diagnostic bias as orchitis may be diagnosed more often than oophoritis. It might also be due to differential immunization of females, as they are more frequently screened for rubella and, if susceptible, vaccinated with a mumps-containing vaccine.
Of the outbreak-related cases with known immunization status (n=628), approximately half of cases had received two doses of mumps containing vaccine (49%), 30% had received 1 dose, and 20% were unvaccinated. The remainder (1%) had received 3 doses.
Although the enhanced provincial and territorial surveillance data provides valuable insight on the magnitude and context of recent mumps outbreak activity in Canada, there are several limitations and other relevant factors that should be carefully considered when interpreting these data. First, there is no standard national outbreak case definition and the categorization of cases as outbreak-related is left to the discretion of each jurisdiction. Additionally, the expected incidence of mumps in Canada has changed significantly over the years, which presents a challenge in establishing a common provincial and territorial threshold for an outbreak definition. Furthermore, challenges with associating cases to unique mumps outbreaks is difficult, especially when a higher than expected number of cases is observed in a community. At the time of the original 2017 provincial and territorial data request, there were no specified end-dates for the ongoing 2016 mumps outbreaks. Therefore, these outbreaks could have continued into 2017, leading to reporting of duplicate case counts. In addition, because only aggregate data were provided, more detailed and in-depth analyses of survey results could not be conducted, including determination of the interval between the last MMR dose and disease onset, the geographical distribution of cases and occurrence of mumps-related complications.
#### Manitoba Mumps Outbreak 2016-2018
Manitoba reported a major mumps outbreak starting in September 2016. Provincial public health officials conducted a survival analysis to assess the protection of vaccine-induced immunity from infection of mumps from September 2016 to September 2018 (51). Among northern residents during this study period, vaccine-induced immunity waned over time, and the impact of vaccination with 1 dose and with 2 doses on waning was assessed. By end of the provincial outbreak, 2,223 cases were counted, 51.7% of whom were male. The overall cumulative incidence was 1.6 cases per 1,000 population. The median age was 25 years and the highest incidence rate was among the 18 to 29-year-old age group (3.4 cases per 1,000). Although 70.4% (n=1,566) of all cases were from the northern region, the most rural region of Manitoba with a large number of isolated communities, the outbreak originated in the Winnipeg Regional Health Authority. The outbreak spread from the affected urban center to rural areas across the province. The two-dose coverage of mumps containing vaccine was about 70% in confirmed cases who had records in the provincial registry. Among cases vaccinated with at least two documented doses of mumps-containing vaccine, a median of 11 years had passed since individuals received their most recent dose, suggesting waning of vaccine-induced immunity against mumps. Analysis of cases from the northern region indicated that the number of doses of vaccine (one or two) had no significant impact on waning of immunity. Additionally, although vaccine-induced immunity provided protection from mumps infection for a number of years following receipt of the last dose, immunity waned rapidly after several years and was not associated with receipt of one versus two doses of MMR/MMRV.
#### Northern Ontario Mumps Outbreak 2017-2018:
A mumps outbreak occurred within two First Nations communities in northern and remote areas of Ontario over the period of December 2017 to June 2018[Footnote 52](#fn52)
. The outbreak resulted in a total of 70 cases (52 confirmed, 18 probable), with a crude attack rate of 22.3 per 1000. Attack rates were high for many age groups, including infants and adults. The lowest attack rate (8.5 per 1000) was observed among children 1 to < 7 years of age. The median age of cases was 24 years (range 10 months to 62 years). Complications were reported in 7% of cases (5/70) and included orchitis, oophoritis and neurological symptoms. There was one hospitalization and no deaths. At the start of the outbreak, immunization coverage of mumps-containing vaccine among all community members was 46% with two doses and 35% with one dose.
As one component of the public health response, an outbreak dose of mumps-containing vaccine was recommended for individuals aged 8 to 48 years of age (born 1970-2010), not having received MMR vaccine in the last 28 days (based on patient self-report) and no medical contraindications, in addition to opportunistic immunization of under-immunized community members. Among all community members ≥1 year of age at the start of the outbreak, 33% received at least one dose of mumps-containing vaccine during the outbreak period. Thirty-eight percent of those aged 8-48 years at the start of the outbreak received an outbreak dose, and this varied by the number of pre-outbreak vaccine doses (54% uptake among those with no prior doses, 48% among those with one pre-outbreak dose, 31% among those with two pre-outbreak doses, 25% among those with more than two pre-outbreak doses).
An evaluation of the outbreak dose intervention focused on community members who were age eligible for mumps-containing vaccine (at least one year of age) at the start of the outbreak and defined an outbreak dose as the receipt of any dose of mumps-containing vaccine over the outbreak period. The adjusted hazard ratio for mumps infection among those who did not receive a dose of mumps-containing vaccine during the outbreak was 2.7 (95% confidence interval 1.0-10.1,), after adjustment for age group, sex and time since last pre-outbreak dose of vaccine. The data also suggested a dose response relationship between the time since the last pre-outbreak dose and the risk of mumps infection, despite wide and non-significant confidence intervals.
### III.5 Molecular Epidemiology of Canadian Outbreaks
According to mumps molecular surveillance from the National Microbiology Lab (NML), all major outbreaks across Canada since 2006 were of genotype G, and nearly all were identical or highly similar to the MuVi/Sheffield.GBR/1.05 WHO reference sequence. This strain is likely endemic, not only in Canada but also elsewhere in North America and Europe. Mumps genotyping involves the sequencing of a small portion of the mumps genome, the small hydrophobic (SH) gene which is only 316 nucleotides in length. Since SH genotyping has been unable to differentiate between outbreaks in Canada in the last decade, sequencing the whole genome (approximately 15,430 nucleotides) may be more informative[Footnote 53](#fn53),[Footnote 54](#fn54)
.
### III.6 Summary of Recent International Outbreaks
Over the last decade, there has been an increase in the reporting of mumps outbreaks in countries with highly vaccinated populations. However, direct comparison between jurisdictions is limited by the differences in case definitions, routine immunization schedules, and epidemiological data collection and reporting. The table below summarizes a sample of reported outbreaks over the last decade.
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| **Country** | **Size of outbreak** | **Population affected** | **Age group** | **Length of outbreak(s)** | **Time frame** |
| **United States of America[Footnote 25](#fn25)** | Number of cases ranged from 20 to 485 cases per outbreak | Predominately college students and young adults in close contact settings
Nearly half the outbreaks (39%) were reported in highly vaccinated populations (coverage for 2 doses ≥85%). | 18-24-year-olds | Total of 23 outbreaks
1.5 to 8.5 months (median = 3 months) | July 2010 to December 2015 |
| **Europe (European Centre for Disease Prevention and Control)[Footnote 8](#fn8)** | 14,795 cases reported by 28 EU/EEA member states | Males more affected than females (57% of all cases) | Highest incidence in 15-19-year-olds (13.2 cases per 100,000 population)
Followed by:
10-14-year-olds (12.4 cases per 100,000 population). | | 2016 |
| **Israel[Footnote 55](#fn55)** | 5239 cases | Majority of cases fully vaccinated (two dose program, 1 and 6 years of age) for their age (78%). | Largest proportion of cases reported in 5-14-year-olds (48% of cases | 12 months | 2009-2010 |
The reported outbreaks affected largely adolescents and young adults in close contact with each other[Footnote 56](#fn56),[Footnote 57](#fn57). The higher proportion of adolescents and young adults infected compared to the pre-vaccine era (during which young children were most affected), was explained as a probable consequence of the under-vaccination of children and/or waning immunity in that age group. Close contact settings have also been hypothesized as a factor contributing to the high incidence of mumps among students, particularly in settings in which there is clustering of individuals with relatively low immunization coverage.
IV. Vaccine
-----------
### IV.1 Preparation(s) Authorized for Use in Canada (e.g., Description, Composition)
There is currently no single-component mumps-containing vaccine available in Canada. All vaccines licensed for the prevention of mumps (MMR and MMRV) in Canada contain the Jeryl Lynn attenuated mumps virus strain that belongs to genotype A:
* **M-M-R®II** (live attenuated combined measles, mumps and rubella vaccine), Merck Canada Inc. (MMR)
* **PRIORIX®** (live attenuated combined measles, mumps and rubella vaccine), GlaxoSmithKline Inc. (MMR)
* **PRIORIX-TETRA®** (live attenuated combined measles, mumps, rubella and varicella vaccine), GlaxoSmithKline Inc. (MMRV)
* **ProQuad®** (live attenuated combined measles, mumps, rubella and varicella vaccine), Merck Canada Inc. (MMRV)
For additional information about the mumps vaccines available for use in Canada, refer to the [Canadian Immunization Guide, Part 4, Mumps Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-14-mumps-vaccine.html)
All of these products have been authorized for a routine two-dose schedule beginning after a child's first birthday. If an early dose of MMR vaccine is provided before 12 months of age (e.g., for travel), then two additional doses are recommended in the product monographs and by NACI[Footnote 10](#fn10). Moreover, the product monograph for Merck's M-M-R®II vaccine states that "if concern also exists about immune status regarding mumps or rubella, revaccination with appropriate mumps- or rubella-containing vaccine should be considered"[Footnote 58](#fn58). The recommendation for a third dose in an outbreak setting is not explicitly mentioned in any product monograph. For outbreak response, MMR vaccine should be used as opposed to MMRV, as in outbreak settings, studies used MMR or monovalent mumps vaccine.
### IV.2 Vaccine Effectiveness
Effectiveness of a Jeryl Lynn strain containing MMR vaccine in preventing laboratory-confirmed mumps cases in children and adolescents is estimated to range from 62% to 91% for MMR1 and 76% to 95% for MMR2[Footnote 10](#fn10). Somewhat lower vaccine effectiveness has been observed in outbreak settings[Footnote 19](#fn19), especially when exposures occurred in close-contact settings[Footnote 59](#fn59) as protection appears to wane over time[Footnote 60](#fn60).
NACI reviewed vaccination outcome data following the provision of MMR vaccine, including use of MMR3, reported in 16 publications describing mumps outbreak management interventions in the US, United Kingdom, Israel, Mexico and Norway (see [Appendix A](#appendix-a)). None of the vaccine manufacturers reported any additional non-published information on the effectiveness of MMR vaccine for outbreak management or post-exposure prophylaxis.
Outcomes of interventions in which the MMR vaccine was provided to a defined population in a community were described in two studies. In a community outbreak in a religious community in the US, MMR3 was administered in schools to approximately 65% of 11-17-year-old children[Footnote 61](#fn61). About 98% of the children in the community attended the schools where the vaccine was provided. In the 21 days after the vaccination campaign, a greater than 95% reduction in the mumps attack rate was observed in the vaccinated age group. A statistically significant decline (72.9%) in mumps attack rates was also observed among 5-10-year-old children. Compared to the three weeks before the intervention, the attack rate in the community declined by 76% three weeks post-intervention (from 0.86% to 0.21%). The reported incremental vaccine effectiveness of MMR3 was estimated to be 88% (95%CI: -31.9%-98.9%) at more than three weeks post-immunization. In a similar campaign in the US territory of Guam, an MMR3 dose was administered in schools in which the attack rate was greater than 0.5% (7/64 schools on the island)[Footnote 62](#fn62). Over the course of the immunization campaign, over 1,000 children received MMR3 (approximately 5% of children 9-14 years of age living on the island). In this age group, the study authors reported a non-significant difference in attack rates between students that did (0.09%) and did not (0.23%) receive MMR3 (RR=0.4 [95%CI: 0.05-3.5]) at more than three weeks following the intervention.
In the published literature where outcomes were reported, most often MMR vaccine was provided as part of larger institutional outbreak management strategies. In a UK school with 710 students and staff, approximately one fifth of students received an outbreak dose of MMR vaccine (73% received MMR3)[Footnote 63](#fn63). The vaccination campaign was initiated one month following the identification of the first case, with the outbreak ending one month following immunization. At more than three weeks after the completion of the vaccination campaign, only two cases of mumps were identified, neither of whom had received an outbreak vaccine dose. In another school outbreak in the UK, MMR vaccine was provided to children who were found to be susceptible to mumps based on saliva antibody testing[Footnote 64](#fn64). Following the immunization of 28 of 33 susceptible children, no further cases were reported in the school.
One publication from the US CDC also reported an intervention in which 15% (73/541) of individuals with no record of MMR2 vaccination or physician-diagnosed mumps were immunized during an outbreak in a summer camp[Footnote 65](#fn65). At more than two weeks following vaccination, no further cases were reported among campers. In another publication from Mexico, MMR vaccine was provided to resident physicians of 4 hospital departments who did not have a history of mumps. Following an immunization campaign during which 50% to 75%[Footnote 66](#fn66) of residents received the vaccine, no further cases were reported among hospital staff despite an increase in the number of mumps cases in the community. In another publication that described the outcomes of control measures in a hospital setting, MMR vaccine was provided to 14 individuals with no history of mumps or MMR immunization shortly following their contact with an index case[Footnote 67](#fn67). None of these individuals developed mumps after vaccination.
Two publications also reported the outcomes of university-based immunization campaigns that were conducted in the US. During the year-long outbreak that occurred at the University of Illinois,[Footnote 68](#fn68) among 50,000 eligible students and staff members (i.e. those born during or after 1957), approximately 11,500 received MMR3. The vaccination campaign was initiated approximately 4.5 months following the initial case report and lasted until the end of the outbreak. Among 317 cases identified during the outbreak, 50 (16%) mumps patients had received MMR3, 232 (73%) received MMR2, 12 (4%) received MMR1, seven (2%) were unvaccinated, and 16 (5%) had unknown vaccination status. Among MMR3 recipients, there were 34 individuals who developed symptoms of mumps two or more weeks after receiving MMR3 and 5 that received MMR3 in years prior the outbreak. During a somewhat shorter (9 months) outbreak at the University of Iowa, MMR3 vaccine was provided to approximately 23% of students[Footnote 69](#fn69),[Footnote 70](#fn70) (n≈5,000) within three months of the initial case report. In the 5 months following the intervention, there was an observed three-fold decrease in cases compared to 5 months prior to the intervention. The study authors also reported an incremental MMR3 dose effectiveness (vs. MMR2) of 78% (95%CI: 61-88%). This estimate was somewhat lower (68%; 95%CI: 42.2-82.5%) when only cases that occurred after the campaign initiation were included in the analysis. Among 259 cases identified during the outbreak, 21 developed symptoms of mumps two or more weeks following the receipt of MMR3.
The use of MMR vaccine in confined military settings was also reported in two publications. As a part of the Israeli Defence Forces outbreak management strategy[Footnote 55](#fn55),[Footnote 71](#fn71), MMR vaccine was provided to all soldiers in affected units within one week of case identification. During the 2005 outbreak, the vaccine was provided primarily to individuals who had previously received fewer than 2 doses, while during the 2009/10 outbreak all soldiers received the vaccine, independent of their vaccination status. There were no cases identified following immunization during the first outbreak in 2005, and no secondary cases outside of a single incubation period in either of the outbreaks. Similar outcomes were also reported following a report of 10 cases in a Luxembourg military centre[Footnote 72](#fn72). MMR vaccine was offered to all personnel and trainees in the affected units, after which no further cases were reported.
The outcomes after interventions in which MMR vaccine was provided to contacts of a case were also described in the retrieved publications. In a US[Footnote 17](#fn17) study, MMR3 was provided to 28 household members of mumps cases within 5 days of the household index-case parotitis onset; no household members became infected with mumps. In another study, among 16 individuals who received MMR1 or MMR2, one adult with no immunization history was diagnosed with mumps during the first incubation period following the index-case onset[Footnote 17](#fn17). In comparison, 4 out of 77 individuals with a history of MMR2 who declined a post-exposure dose were diagnosed with mumps. In another outbreak management intervention that was conducted in Norway, a post-exposure MMR3 dose was provided to approximately 1,300 close contacts of cases[Footnote 73](#fn73). In total, only three individuals developed mumps following immunization. One publication describes an intervention in which MMR vaccine was given to contacts of a mumps case on a US naval base[Footnote 73](#fn73). Individuals who were considered vaccine and disease naïve based on their infection and laboratory history (mumps IgG antibody titer < 20.0 U/mL) were immunized within 5 days of exposure (8 out of 81). No secondary cases of mumps were observed in any of the exposed individuals after the intervention.
The literature search also identified two older studies that reported on post-immunization outcomes following the administration of a monovalent mumps vaccine containing the Jeryl Lynn strain in settings with significant disease circulation in the US. In one study conducted in 1986, the vaccine was provided to 53/178 previously unimmunized 9- to 12-year-old students during a school outbreak[Footnote 74](#fn74) In the three weeks following the intervention, cases were reported among both students who received the mumps vaccine (15/53) as well as unimmunized children (51/125). There were no cases reported among immunized students at more than 21 days after receiving the vaccine, compared to 8 cases amongst the unimmunized children. The second study was a randomized controlled study, in which the monovalent vaccine was provided to 502 first and second grade students, while 54 students received placebo.[Footnote 75](#fn75) The vaccination occurred during the field testing of a candidate vaccine in the late 1960's, a time period with significant circulation of the wild-type virus. During the first two weeks post vaccination, there were 28 cases of mumps among immunized students (28/502) and 4 among those who received placebo (4/54). After two weeks, the study authors reported 8 cases of mumps among students who received the vaccine (3 occurring on days 15-30 and 5 at more than 30 days post vaccination) and 16 in the placebo group.
In all of the retrieved publications describing outbreak control measures, MMR vaccination was used as a part of a comprehensive public health response in attempt to control the spread of the disease. In addition to immunization, almost all publications reported the use of case isolation, promotion of appropriate preventive hygiene practices and use of public/media information campaigns as complementary outbreak management measures. The majority of the outbreaks reported the G genotype of mumps virus.
### IV.3 Vaccine Safety
While safety outcomes were reported in 7 publications[Footnote 61](#fn61),[Footnote 62](#fn62),[Footnote 63](#fn63),[Footnote 68](#fn68),[Footnote 76](#fn76),[Footnote 77](#fn77), details of adverse events (AEs) following administration of MMR3 were described in only two studies. None of the studies reported serious AEs following immunization with MMR3. Manufacturers did not report having any additional, non-published, information on the safety of MMR3 vaccine administration.
Abedi et.al and Ogbuanu et al. reported safety outcomes of MMR3 following the vaccination of more than 1,750 students 11-17 years of age[Footnote 61](#fn61),[Footnote 77](#fn77). At least 1 local or systemic AE was reported within 14 days of MMR3 by 7.2% (n=115) of survey respondents. The most commonly reported AEs were injection site pain, redness, or swelling (3.6%); joint or muscle aches (1.8%); dizziness or light-headedness (1.7%); and fever of 38 degrees Celsius or greater (1.3%). In another publication by Nelson et al., the authors reported on the adverse event outcomes following MMR3 immunization of approximately 1,000 children 9-14 years of age. Six percent (32/533) of the survey respondents reported at least 1 local or systemic AEs[Footnote 62](#fn62). The most commonly reported AEs were joint aches (2.6%, 14/533), dizziness (2.4%, 13/533) and injection site reactions (2.4%).
Summaries of data from the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) and the US CDC Vaccine Adverse Event Reporting System (VAERS) were also reviewed. In CAEFISS, from more than 15,000 reports for which the dose number of MMR(V) vaccine was available, receipt of MMR3 was identified in only 60 reports (0.4%). Of these, only one AEFI was reported as serious, and concerned a 5-year-old child who was immunized in 2012. The reported AEFI was transverse myelitis lasting 57 days from onset and starting 4 days after immunization. The infectious disease investigation performed in the hospital yielded a positive test result for parainfluenza 2, which may have been related to the event. The child was reported to have fully recovered. In VAERS, out of approximately 60,000 reports for which the dose number of MMR vaccine was available, about 1,500 reports included MMR3. Of these, 65 (4.4%) AEFIs were reported as serious.
V. Discussion
-------------
Since 2016, there has been a substantial increase in the number of reported mumps outbreaks and outbreak-associated mumps cases in Canada. Waning vaccine effectiveness is likely due to decline in cellular immunity, antibody concentrations and avidity. In addition, outbreaks among vaccinated individuals often occur in situations with increased risks for exposure to the virus and transmission may be facilitated through behavioural risk factors.
Epidemiologically, mumps outbreaks can be difficult to characterize especially in community settings. Provincial and Territorial survey data regarding recent mumps outbreaks in Canada, revealed that when vaccination status data were available, roughly half of mumps cases had received at least 2 doses of a mumps containing vaccine. The majority of outbreak-related mumps cases in Canada in recent years have occurred in young adults aged 15-39 years. This contrasts with the pre-vaccine era in Canada when outbreak-related mumps cases occurred most often in children. Geographically, outbreaks in northern Canadian communities have had higher attack rates. While complications of mumps infections are not always well characterized or reported, they are less common in the post-vaccine era and among those vaccinated.
The NACI literature review identified 16 publications where an additional dose of MMR vaccine was used as a control measure in an outbreak setting. Three main immunization approaches were described in these studies: 1) vaccination of a specific population group (typically an age group with a high disease attack rate); 2) vaccination of a specific community within a defined geographical setting (i.e., university students and staff), and 3) vaccination of close contacts (post exposure immunization in closed settings). These studies described varied immunization strategies (e.g., time to vaccine program implementation, population, setting, additional outbreak control measure) with varied coverage. The quality of the studies ranged from fair to low. Overall, the evidence suggested that an additional MMR dose seemed likely to reduce disease burden, however, pooled estimates of vaccine effectiveness could not be determined due to heterogeneity in study designs.
At the population level, there was some evidence that administration of additional MMR doses is likely to affect transmission and consequently the duration and size of an outbreak, particularly if given early in the course of the outbreak and when a high vaccine uptake is achieved in the target group.
At an individual level, following the receipt of MMR vaccine in an outbreak setting, onset of symptomatic mumps disease was rarely observed more than two weeks post-immunization and rarely outside of a single incubation period. The results of a small number of studies that provided MMR3 vaccine to close contacts of a case suggested that a dose provided within a week post-exposure may be effective in preventing symptomatic disease and transmission. However, ideal timing of a post-exposure dose was not specified. Several studies also suggested that acceptability to receive additional doses of MMR vaccine is likely to be increased during outbreaks and among individuals who are perceived to be at higher risk of mumps and its complications.
Safety outcomes were reported in 7 publications identified in the literature review. These studies did not identify any associated serious AEs following a third dose of MMR vaccine in an outbreak setting. This was based on data following the administration of >14,000 MMR3 doses in the reviewed studies. These findings are consistent with previous observations of lower frequency and intensity of AEs with subsequent doses. No unexpected safety signals were identified. Most systemic and local adverse events, particularly among previously vaccinated individuals, were mild in intensity and short in duration (lasting 1-3 days).
More robust, comprehensive and consistent evidence is needed on the effectiveness of use of outbreak doses of mumps-containing vaccine in situations similar to those observed in Canada. Therefore, NACI will continue to monitor the body of evidence related to the effectiveness and safety of MMR vaccine when provided in mumps outbreak settings, including off-label administration of MMR3 for outbreak control, and will update this statement as needed.
VI. Recommendations
-------------------
Following the review of available evidence on the burden of illness from mumps disease and outbreaks in Canada, as well as the effectiveness and the safety of additional MMR vaccine doses in outbreak settings, NACI makes the following recommendations for public health level decision-making. The recommendations are consistent with national goals for mumps disease reduction and vaccination targets for mumps in order to maintain less than 100 annual cases[Footnote 2](#fn2), based on a 5-year rolling average.
A *strong recommendation* applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present. A *discretionary recommendation* may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable. Please see [Table 3](#table-3) for a more detailed explanation of strength of NACI recommendations and grade of the body of evidence.
### VI.1 Recommendations for Public Health Program Level Decision-Making (i.e., Provinces/Territories Making Decisions for Publicly Funded Immunization Programs)
In considering these recommendations and for the purposes of publicly funded immunization program implementation, provinces and territories may take into account multiple factors, such as cost-benefit evaluation, the local epidemiology of mumps, and other local programmatic and operational factors (e.g., current immunization programs, resources, outbreak control measures).
**Recommendation 1:** NACI recommends that an outbreak dose of MMR vaccine may be considered in an outbreak setting. (Discretionary Recommendation)
* NACI concludes there is fair evidence to recommend MMR vaccine use (including catch-up vaccination with or without MMR3) during outbreaks (Grade B Evidence)
**Summary of Evidence and Rationale**
* An outbreak dose of MMR vaccine is likely to be effective in reducing the size and duration of the outbreak.
* A third dose is recommended for those who have previously received 2 doses of mumps-containing vaccine after their first birthday, particularly if the last dose of MMR vaccine was received 10 years ago or more.
* For those with unknown immunization status, an outbreak dose can be provided. There is no evidence to support providing an additional dose if three doses have been previously received after the first birthday.
* Other factors beyond number of doses, such as the time since last dose may also be important factors when considering outbreak vaccination control measures.
* Decisions on when and in what context to implement an outbreak/third dose recommendation are complex and require additional input on mumps outbreak response. Refer to the management options table.
* A broad, non-discriminatory recommendation for an outbreak dose simplifies program implementation (e.g., vaccination status may not be easily determined) and increases coverage.
* Increasing immunizations during mumps outbreaks is consistent with the public health management approach taken for other vaccine preventable disease outbreaks.
* The vaccine effectiveness of an outbreak dose could not be determined based on the currently available evidence, in part due to differences in study designs.
* In the setting of a mumps outbreak, MMR vaccine should be provided (not MMRV since it has not been studied in an outbreak setting). Although product monographs for MMR vaccines do not explicitly indicate the use of a third dose in an outbreak setting, MMR3 has been used as a strategy for outbreak control in many jurisdictions outside of Canada and with formal recommendations from some immunization advisory committees. Furthermore, no vaccine safety concerns for MMR3 were identified in this review. Therefore, based on the balance of beneficence and non-maleficence, NACI considers this an appropriate intervention to prevent disease in an outbreak setting, despite the current wording of product monographs.
**Recommendation 2:** NACI recommends that providing MMR vaccine up to a third dose to close contacts following exposure to a case of mumps may be considered in an outbreak setting (Discretionary Recommendation)
* NACI concludes there is insufficient evidence for or against recommending a dose of mumps-containing vaccine to close contacts following exposure to a case of mumps (Grade I Evidence).
**Summary of Evidence and Rationale**
* Evidence for recommending MMR vaccine to close contacts following exposure to a case of mumps is of poor quality.
* MMR vaccine may prevent symptomatic disease if administered shortly following exposure. The time period by which a post-exposure dose needs to be provided to prevent infection when already exposed is not known.
* Providing MMR vaccine to close contacts may be considered as an intervention for disease control in the setting of sporadic (non-outbreak) cases, and/or as an opportunity to provide an outbreak dose to at-risk groups in outbreak settings.
* This use of MMR vaccine for close contacts is consistent with the use of vaccines for contacts of other vaccine preventable diseases, either as post-exposure prophylaxis or using contact follow-up as an opportunity to update immunizations.
VII. Management Options
-----------------------
Mumps is spread through direct contact with saliva by sharing drinks or kissing, or by large droplet transmission via coughing or sneezing. The incubation period for mumps ranges from 14 to 25 days. Once an individual is infected, mumps can be communicable from 2 days before to 5 days after the onset of parotitis[Footnote 78](#fn78). Mumps cases can also be asymptomatic but remain infectious to others.
The size, scope and duration of mumps outbreaks can be variable and their progression and peak is difficult to predict given delays in reporting, health seeking behaviours, and the relatively long incubation period for the mumps virus. Furthermore, circulation of mumps virus in highly immunized populations may be undetected and determining immunization status of cases and contacts may be challenging in many jurisdictions in Canada due to variability in the availability of comprehensive immunization registries. The public health response to mumps includes management of cases and contacts and identifying social networks to define the at-risk population when contact follow-up is not feasible; and maintaining/enhancing surveillance for further cases and disease outcomes (e.g., hospitalizations, complications). Generally, a mumps outbreak is controlled by:
* Defining the at-risk population(s) and transmission setting(s);
* Preventing further transmission through isolation of cases and contact education/ awareness;
* Vaccination of under-immunized groups; and
* Good risk communication[Footnote 11](#fn11).
In an outbreak setting, implementation of MMR immunization strategies may be considered as a part of outbreak management. The MMR vaccine is considered to be safe with the majority of systemic or local adverse events being mild in intensity and limited in duration (lasting 1-3 days), particularly in previously vaccinated individuals. Immunization in an outbreak setting leads to the boosting of humoral and cellular immunity which can assist with outbreak control.
Various options for the implementation of the NACI recommendation for an outbreak dose of MMR vaccine are available, including immunization according to time since last dose, setting and intensity of exposure, and age and risk of complications. Understanding the nature of the outbreak (person-place-time) as well as ease of access to the immunization history of individuals within the target group are important for informing the choice and delivery of the outbreak dose strategy, including whether the immunization strategy is operationalized as a focus on under-immunized groups (i.e. delivery of a first or second dose), immunizing with a third dose of mumps-containing vaccine (i.e. in outbreak settings with high two dose coverage), or whether it is operationalized as delivery of an outbreak dose in settings where access to individual vaccination status to determine eligibility for a specific dose number of MMR is challenging and/or when the population at risk includes both one and two dose vaccinated individuals.
Implementation of outbreak-related immunization strategies early during a mumps outbreak (during the time of rapidly increasing case counts) is important, as early vaccination is likely to be the most effective intervention to control the outbreak. While immunization in later stages of the outbreak (e.g., following the peak of the outbreak) may benefit individuals, its effect at the population-level is uncertain. In order to minimize logistical challenges at the local level, particularly in outbreaks occurring in isolated and hard to reach communities, early coordination with provincial/territorial immunization program contacts is recommended.
In individuals for whom immunization history can be verified, immunization according to time since last dose should be considered. Vaccine effectiveness has been observed to wane over time, likely due to the declines in cellular immunity, antibody concentrations and avidity. The risk of mumps in outbreak settings has been observed to increase starting at 2 years following the last MMR dose with significant increases at more than 10 years after last MMR vaccination. Therefore, individuals who received their last dose of MMR vaccine > 10 years ago are at greatest risk of mumps infection and should be prioritized for vaccination in outbreak settings, where this is feasible to operationalize.
In groups for whom the risk of exposure or exposure history can be determined, targeted immunization may simplify program delivery. The majority of outbreaks in Canada and internationally have been observed in close contact settings in which the level of exposure (duration and intensity) to the mumps virus is increased. These have typically included households, educational institutions, sports facilities, and smaller communities. An outbreak dose of MMR vaccine provided to individuals in a defined setting may be effective in reducing mumps incidence in the setting.
When determining vaccination status or exposure risk is challenging, immunization of age groups who are known to historically have the highest attack rates and risks of complications may be another option for rapid program implementation. Immunization of age specific groups has been effective in reducing both mumps incidence in specific age groups as well as the overall disease burden in the community. Based on surveillance data obtained from the Canadian Notifiable Disease Surveillance System (CNDSS), over the period of 2014-2018, the majority of cases were observed in the 20- to <40-year-old age group, with the highest incidence observed among adults 20-24 years (3.8 cases per 100,000 population).
The decision on which immunization strategy is most appropriate for a specific outbreak will depend on the considerations summarized above, which are further outlined in the table below and through future updates to PHAC's Mumps Outbreak Control guidance[Footnote 11](#fn11).
Management Options Table
| | **Considerations** | **Decision Points** |
| 1. Immunization according to time since last dose | * Vaccine effectiveness has been observed to wane over time, likely due to the declines in cellular immunity and antibody concentrations and avidity[Footnote 14](#fn14),[Footnote 16](#fn16),[Footnote 17](#fn17),[Footnote 20](#fn20).
* The risk of mumps outbreaks has been observed to increase starting at 2 years following the last MMR dose, and significantly increasing at more than 10 years after the last MMR vaccination [Footnote 70](#fn70),[Footnote 79](#fn79).
* Mathematical models suggest that up to 25% of vaccinated individuals may be susceptible to mumps within 7.9 years (95% CI, 4.7 to 14.7 years), and 50% within 19 years (95% CI, 11.2 to 35.4 years) following the last mumps-containing vaccine dose[Footnote 20](#fn20).
* Determining vaccination status may be challenging, as records might be missing or incomplete or not available. This can complicate the implementation of an outbreak dose strategy that requires knowledge of time since last dose, resulting in barriers in the delivery of an outbreak dose.
| * Individuals who have received the last dose of MMR vaccine > 10 years are at greatest risk of mumps and should be prioritized for vaccination.
* Implementation of an outbreak dose strategy that requires knowledge of time since last dose can be complicated and result in barriers in the timely delivery of immunization. In some settings this information may be difficult to obtain.
* The vaccine is immunogenic and safe with no associated serious adverse events reported in immunocompetent individuals.
|
| 2. Immunization according to setting and level of exposure | * The majority of outbreaks in Canada and internationally have been observed in closed contact settings in which the level of exposure (duration and intensity) to the mumps virus is increased. These have typically included households, educational institutions, sports facilities, and smaller communities.
* There is evidence that an outbreak dose of MMR vaccine provided to individuals in a defined setting may be effective in reducing the incidence of infection following the outbreak dose campaign[Footnote 80](#fn80).
* Immunization of individuals within a defined setting may simplify vaccine delivery.
| * Outbreak immunization strategies focused on a particular setting or level of exposure is likely to contribute to the reduction of the disease burden in the wider community.
* If a mumps outbreak is occurring in a defined setting; immunization of all individuals within the setting may simplify delivery.
|
| 3. Immunization according to age and risk of complications | * In Canada, based on surveillance data obtained from the Canadian Notifiable Disease Surveillance System (CNDSS), the majority of cases have been observed in the 20- to <40-year-old age group in recent years (2014-2018). During this time period, the highest incidence rates were reported in adults 20-24 years (3.8 cases per 100,000 population).
* Severity of disease and the risk of complications, [Footnote 80](#fn80) is typically higher among post-pubertal youth and adults, though reduced compared to pre-vaccine era.
* In outbreaks where there is no defined setting or exposure group (e.g., a community outbreak), vaccinating age cohorts that are at highest risk may be considered.
* Targeted immunization of age groups with the highest attack rates has shown to be effective in reducing the age group-specific and overall disease burden in the community.
| * In situations where vaccination or exposure status of affected individuals may not be readily known, provision of additional doses is safe and is likely to increase individual protection.
* In large community outbreaks, determination of exposure (contact tracing) and vaccination status may not be practical and may quickly overwhelm available public health resources[Footnote 81](#fn81).
* Outbreak immunization programs focusing on a particular population group, particularly those with highest observed attack rates, is likely to contribute to the reduction of the disease burden in the wider community.
* The acceptability of additional doses of MMR vaccine is likely to be increased during outbreaks and among individuals who perceive themselves to be at higher risk of mumps and its complications.
|
VIII. Knowledge Gaps and Research Priorities
--------------------------------------------
After careful review of available evidence, NACI has identified the need for further research to address current knowledge gaps where data are absent or limited. NACI recognizes that there are studies already in progress that may address many of these gaps, but the findings of these studies were not yet available at the time of review. Identified knowledge gaps include:
* Examining the cost of different public health measures to contain a mumps outbreak in different settings and evaluating the cost-effectiveness of various options for the implementation of an additional mumps outbreak dose strategy
* Modeling the effect of an additional dose of MMR vaccine on the burden of mumps during a mumps outbreak
* Obtaining more comprehensive/complete national data on the epidemiology of and response to mumps outbreaks
* The absolute effectiveness of immunization with an outbreak dose of mumps-containing vaccine in reducing disease burden
* A more thorough understanding of the duration of immunity and waning of immunity and how this is impacted by the administration of additional outbreak doses of mumps-containing vaccine
* The immunologic correlates of protection from disease and the impact of an additional outbreak dose of mumps-containing vaccine on the immunologic response
* The optimal timing of the outbreak dose
* The protection offered by the vaccine strain as compared to the circulating strain of mumps in Canada
IX. Surveillance Issues
-----------------------
The following issues relating to mumps outbreak surveillance in Canada have been identified:
* The national surveillance data for mumps has numerous limitations, including incomplete variables (age, gender, onset date), timeliness and limited availability of information on vaccination status, disease severity, including complications and long-term sequelae.
* Data on outbreaks in Canada is not routinely collected through national surveillance.
* Given that there is no standard national outbreak case definition, categorization of cases as outbreak-related is left to the discretion of each jurisdiction.
* Due to asymptomatic infection and non-specific symptoms, it is often challenging to identify the source of infection for cases, with limited detail on setting-specific acquisition information in surveillance data as a result.
* Ascertaining mumps genome sequencing to assist in outbreak characterization and transmission patterns.
Tables
------
Table 1: Ranking Individual Studies: Levels of Evidence Based on Research Design
| Level | Description |
| --- | --- |
| I | Evidence from randomized controlled trial(s). |
| II-1 | Evidence from controlled trial(s) without randomization. |
| II-2 | Evidence from cohort or case-control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy. |
| II-3 | Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence. |
| III | Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees. |
Table 2: Ranking Individual Studies: Quality (internal validity) Rating of Evidence
| Quality Rating | Description |
| --- | --- |
| Good | A study (including meta-analyses or systematic reviews) that meets all design-specific criteria[Footnote \*](#fn*) well. |
| Fair | A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion[Footnote \*](#fn*) but has no known "fatal flaw". |
| Poor | A study (including meta-analyses or systematic reviews) that has at least one design-specific[Footnote \*](#fn*) "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations. |
|
Footnotes
Tablenote \*
General design specific criteria are outlined in Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med 2001; 20: 21–35.
[Return to tablenote \* referrer](#fn*-rf)
|
### Table 3: NACI Recommendations: Strength of Recommendation and Grade of Evidence
#### Strength of NACI recommendation
Based on factors not isolated to strength of evidence (e.g., public health need)
##### Strong
"should/should not be offered"
* Known/Anticipated advantages outweigh known/anticipated disadvantages ("should"),
OR Known/Anticipated disadvantages outweigh known/anticipated advantages ("should not")
* Implication: A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present
##### Discretionary
"may be considered"
* Known/Anticipated advantages closely balanced with known/anticipated disadvantages, OR uncertainty in the evidence of advantages and disadvantages exists
* Implication: A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.
#### Grade of evidence
Based on assessment of the body of evidence
1. A: good evidence to recommend
2. B: fair evidence to recommend
3. C: conflicting evidence, however other factors may influence decision-making
4. D: fair evidence to recommend against
5. E: good evidence to recommend against
6. I: insufficient evidence (in quality or quantity), however other factors may influence decision-making
List of abbreviations
---------------------
ACIP
Advisory Committee on Immunization Practices
AE
Adverse Event
CI
Confidence of Interval
CDC
Centres for Disease Control and Prevention (Unites States)
CNDSS
Canadian Notifiable Disease Surveillance System
MMR
Measles-mumps-rubella vaccine
MMRV
Measles-mumps-rubella-varicella vaccine
MMR1
First dose of MMR vaccine
MMR2
Two-dose MMR vaccination
MMR3
Third dose of MMR vaccine
NACI
National Advisory Committee on Immunizations
PHAC
Public Health Agency of Canada
PT
Provinces and Territories
RCT
Randomized controlled trial
SAE
Serious adverse event
US
United States
VAERS
Vaccine Adverse Events Reporting System
WG
Working Group (NACI MMR)
Acknowledgments
---------------
**This statement was prepared by:** Dr. O Baclic, Dr. M Salvadori, Ms. A Sinilaite, Dr. L Zhao, Dr. V Dubey, and approved by NACI.
**NACI gratefully acknowledges the contribution of:** Ms. B Ho Mi Fane, Ms. S Kelly, Ms. D MacDonald, Mr. M Roy, Ms. M Saboui, Ms. S Squires, Dr. M Tunis, Lynda Gamble (Health Library, HC), Ms. C Tremblay.
**NACI Members:** Dr. C Quach (Chair), Dr. S Deeks (Vice-Chair), Dr. N Dayneka, Dr. P De Wals, Dr. V Dubey, Dr. R Harrison, Dr. K Hildebrand, Dr. J Papenburg, Dr. C Rotstein, Dr. B Sander, Ms. S Smith, Dr. S Wilson
**Liaison Representatives:** Dr. LM Bucci (Canadian Public Health Association), Dr. E Castillo (Society of Obstetricians and Gynaecologists of Canada), Dr. A Cohn (Centers for Disease Control and Prevention, United States), Ms. L Dupuis (Canadian Nurses Association), Dr. J Emili (College of Family Physicians of Canada), Dr. D Fell (Canadian Association for Immunization Research and Evaluation), Dr. M Lavoie (Council of Chief Medical Officers of Health), Dr. D Moore (Canadian Paediatric Society), Dr. M Naus (Canadian Immunization Committee), and Dr. A Pham-Huy (Association of Medical Microbiology and Infectious Disease Canada).
**Ex-Officio Representatives:** Dr. D Danoff (Marketed Health Products Directorate, HC), Ms. E Henry (Centre for Immunization and Respiratory Infectious Diseases [CIRID], PHAC), Ms. M Lacroix (Public Health Ethics Consultative Group, PHAC), Ms. J Pennock (CIRID, PHAC), Dr. R Pless (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada), Dr. G Poliquin (National Microbiology Laboratory, PHAC), Dr. V Beswick-Escanlar (National Defence and the Canadian Armed Forces), and Dr. T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada).
**NACI MMRV Working Group Members:** Dr. V Dubey (Chair), Dr. J Brophy, Dr. S Deeks, Dr. G De Serres, Mr. J Gallivan, Dr. I Gemmill, Dr. R Harrison, Dr. T Hilderman, Dr. M Marin, Dr. M Asbury Marlow, Dr. M Naus, Dr. A Pham Huy, Dr. A Severini, Dr. N Sicard, Dr. S Wilson
Appendix A: Summary of Effectiveness Findings
---------------------------------------------
Summary of effectiveness findings
| Study Details | Summary |
| --- | --- |
| Publication | Vaccine (dose provided), Strain | Study Design | Outbreak and study description | Summary of Key Findings | Level of Evidence | Quality |
| Aasheim ET, Inns T, Trindall A, Emmett L, Brown KE, Williams CJ, Reacher. M. Outbreak of mumps in a school setting, United Kingdom, 2013. Human Vaccines and Immunotherapeu-tics, 2014;10(8): 2446. | MMR1, MMR2, MMR3;
Jeryl Lynn strain | Case series | * Outbreak location: UK (East of England; exact school location not provided)
* Duration of outbreak: January 1 - April 13, 2013
* Size of outbreak: 28 cases; median age 14 years
* Population at risk: students 10-19 years of age (n=540) and staff (n=170) of an unnamed school
* Time of intervention: February 12-14, 2013
* Intervention group: 110 students 10-19 years of age whose parents approved the administration of an additional MMR dose
* Other: 84% of cases with history of MMR2; MMR schedule in UK: 12 months and 3-5 years of age
| Attack rates by age group:* students 15-16 years of age: 13.7%
* students 13-14 years of age: 8.5%
* students 14-15 years of age: 5%
Out of 103 students vaccinated in school, 76 received MMR3.
Out of 13 cases that were reported after the completion of the immunization campaign, only one occurred in a student that received an outbreak dose; symptom onset was less than 2 weeks after vaccination.
Because the majority of new cases (n=11/13) occurred within 3 weeks after the immunization campaign (during the typical disease incubation period), study authors were not able to make conclusions regarding the effectiveness of the intervention. | II-3 | Fair |
| Albertson Albertson JP, Clegg WJ, Reid HD, Arbise BS, Pryde J, Vaid A, Thompson-Brown R, Echols F 2016. Mumps Outbreak at a University and Recommendation for a Third Dose of Measles-Mumps-Rubella Vaccine - Illinois, 2015-2016. MMWR. Morbidity and mortality weekly report, 65(29): 731. | MMR3; Jeryl Lynn strain | Case series | * Outbreak location: US (University of Illinois at Urbana-Champaign, IL)
* Duration of outbreak: April 9, 2015 - May 27 2016
* Size of outbreak: 317 cases; median age, 20 years
* Population at risk: approximately 50,000 students and staff
* Time of intervention: vaccination provided in the summer (August 6 to 27, 2015), as well as during fall and spring (2016) semesters
* Intervention group: university students and staff born during or after 1957
* Other: 73% (n=232) of cases with history of MMR2; genotype G isolated from the tested samples (n=4)
| A total of 8,200 doses were administered at vaccination clinics on the university campus during the summer months, and 3,300 doses through the fall (2015) and spring (2016) semesters. Additional doses (number unknown) were provided to students and staff members living off campus during the summer.
Out of 45 cases who received MMR3 during the outbreak, 60% (n=27) received it >4 weeks prior to symptom onset. 5 cases received MMR3 in years prior the outbreak. | II-3 | Fair |
| Wharton M, Cochi SL, Hutcheson RH, Bistowish JM, Schaffner W. A large outbreak
of mumps in the postvaccine era. J Infect Dis. 1988 Dec; 158(6):1253-60. | Monovalent mumps vaccine | Cohort | * Outbreak location: US (Unnamed high school A)
* Duration of outbreak: 25 August to 14 November, 1986
* Size of outbreak: 332 cases
* Population at risk: 1,764 9-12 grade students
* Time of intervention: vaccine provided on October 6, 1986
* Intervention group: 414 students and staff not previously immunized with one dose of mumps vaccine
* Other: Peak of outbreak registered on September 30th
| 178 susceptible students (negative history of either mumps disease or mumps vaccination) were followed until the end of the outbreak. 53/178 students received mumps vaccine during the outbreak. 15/53 immunized and 51/125 unimmunized students developed mumps between one and 21 days after the immunization clinic. The majority (13/15) of mumps cases in immunized students occurred within 14 days of the immunization clinic. Among the remaining 112 students, no subsequent cases of mumps occurred >22 days following vaccine administration among the 38 immunized students, whereas 8/74 unimmunized students acquired mumps. Based on these findings, authors concluded that a dose of monovalent mumps vaccine has an impact on controlling the outbreak. | II-2 | Fair |
| Ramsay ME, Brown DW, Eastcott HR, Begg NT. Saliva antibody testing and vaccination in a mumps outbreak. CDR (Lond Engl Rev). 1991 Aug 16;1(9):R96-8 | MMR vaccine, not specified | Cohort | * Outbreak location: UK (Unnamed 2 elementary)
* Duration of outbreak: October 1988 to March 1989
* Size of outbreak: 29 cases
* Population at risk: 33 students who were deemed susceptible based on saliva antibody testing; overall student population in both schools - 368 children 5 - 9 years of age
* Time of intervention: vaccine provided to 28/33 children at 22-25 weeks post index case diagnosis
* Intervention group: students
* Other: Peak of outbreak occurred at 15 weeks post index case diagnosis
| No new cases of mumps were reported following the immunization of susceptible children | II-3 | Fair |
| Sugg WC, Finger JA, Levine RH, Pagano JS. Field evaluation of live virus mumps vaccine. J Pediatr. 1968 Apr;72(4):461-6 | Monovalent mumps vaccine; Jeryl Lynn strain | RCT | * Outbreak location: Forsyth County, North Carolina (US)
The study field tested the formulation of the Jeryl Lynn strain that is currently contained in the MMR vaccine.
The monovalent vaccine was administered to 2,965 children attending 1st and 2nd grade of elementary school; 329 children received placebo. | Cases 1-14 days post vaccination:* 28 immunized
* 4 placebo
* 14 unimmunized
Cases 15-30 days post vaccination:* 3 immunized
* 3 placebo
* 10 unimmunized
Cases >30 days post vaccination:* 5 immunized
* 13 placebo
* 45 unimmunized
| I | Fair |
| Fischer PR, Brunetti C, Welch V, Christenson JC. Nosocomial mumps: report of an outbreak and its control. Am J Infect Control. 1996 Feb;24(1):13-8. | MMR vaccine, not specified | Cohort | * Outbreak location: US (Shriners Hospital)
* Duration of outbreak: April 26, 1994 to May 22, 1994
* Size of outbreak: 4 cases
* Population at risk: Hospital patients and staff
* Time of intervention: MMR vaccine provided following exposure to index case
* Intervention group: vaccine provided to 14 individuals with no history of clinical mumps
| None of the immunized individuals developed mumps | II-3 | Fair |
| Pérez-Alba E, García-Ortiz A, Salazar-Montalvo RG, Hernández-Guedea MA,
Camacho-Ortiz A. Mumps outbreak with high complication rates among residents in a university teaching hospital. Am J Infect Control. 2019 Mar;47(3):337-339. | MMR vaccine, not specified | Cohort | * Outbreak location: Mexico (University Hospital)
* Duration of outbreak: October 2017 to April 2017
* Size of outbreak: 9 cases
* Population at risk: HCW >21 years of age without history of mumps
* Time of intervention: March 2017
* Intervention group: MMR vaccine offered to all medical residents
* Other: Coverage of at least 1 new dose was achieved in 75% of internal medicine residents, 51% of surgery residents, 67% of radiology residents and 66% of in pediatrics residents.
| No further cases occurred among hospital residents despite an increase in the number of community cases. | II-3 | Fair |
| Mossong J, Bonert C, Weicherding P, Opp M, Reichert P, Even J, Schneider F.
Mumps outbreak among the military in Luxembourg in 2008: epidemiology and evaluation of control measures. Euro Surveill. 2009 Feb 19;14(7). | Outbreak dose of MMR (Priorix) | Cohort | * Outbreak location: Luxembourg military centre
* Duration of outbreak: September 8 to November 02, 2008
* Size of outbreak: 10 cases
* Population at risk: not specified
* Time of intervention: 28 October, 2008
* Intervention group: personnel and trainees in units on the affected military site
* Other: Approximately half of vaccine recipients were IgG positive prior to the immunization campaign.
| While no clinical cases were observed at the military centre following immunization, clinical cases continued to be reported in the Luxembourg "civilian" population. | II-3 | Fair |
| Centers for Disease Control and Prevention (CDC). Mumps outbreak at a summer
camp-New York, 2005. MMWR Morb Mortal Wkly Rep. 2006 Feb 24;55(7):175-7 | MMR1/2 | Cohort | * Outbreak location: US
* Duration of outbreak: June 30 to August 18, 2005
* Size of outbreak: 31 cases
* Population at risk: 541 campers and staff members
* Time of intervention: August 2005
* Intervention group: 73 individuals with no record of immunization or with documented record of only one dose of MMR vaccine
* Other: Peak of outbreak occurred on July 20.
| No further clinical cases were reported following the intervention. | II-3 | Fair |
| Cardemil CV, Dahl RM, James L, Wannemuehler K, Gary HE, Shah M, Marin M, Riley J, Feikin DR, Patel M, Quinlisk P. 2017. Effectiveness of a third dose of MMR vaccine for mumps outbreak control. New England Journal of Medicine, 377(10): 947.
Shah M, Quinlisk P, Weigel A, Riley J, James L, Patterson J, Hickman C, Rota PA, Stewart R, Clemmons N, Kalas N, Cardemil C, et al. 2018. Mumps Outbreak in a Highly Vaccinated University-Affiliated Setting before and after a Measles-Mumps-Rubella Vaccination Campaign-Iowa, July 2015-May 2016. Clinical Infectious Diseases, 66(1): 81 | MMR1, MMR2, MMR3; Jeryl Lynn strain | Cohort | * Outbreak location: US (University of Iowa)
* Outbreak observation period: 24 August, 2015 - 13 May, 2016
* Affected population group: 20,496 university students and staff
* Size of outbreak: 259 cases; median age, 21 years
* Time of intervention: November 10 - 19, 2015
* Intervention group: students < 25 years of age
* Intervention setting: University of Iowa
* Other: 85% (n=221) of cases with history of MMR2
| A total of 4,783 received MMR3 (94% provided during the vaccination campaign)
Attack rates according to number of MMR doses:* students receiving MMR3: 0.67%
* students with MMR2: 1.45%
* students with MMR1: 3.28%
Attack rates according to the timing of MMR2 dose:* if <2 years: 0.16%
* if 3-12 years: 0.39%
* if 13-15 years: 1.13%
* if 16-23 years: 1.76%
Risk of mumps (HR) according to the time since MMR2 (reference: 0-2 years):
if 3-12 years: 3.1 (95% CI: 0.6-16.2)
if 13-15 years: 9.1 (95%CI: 2.2-36.9)
if 16-24 years: 14.3 (95%CI: 3.5-57.6)
Incremental VE (MMR3 vs. MMR2): ranged from 60.0% (95% CI, 38.4 -74.0%) at 7 days after vaccination to 78.1% (95% CI: 60.9- 87.8%) at 28 days after vaccination in
Out of 34 cases who received MMR3 during the outbreak, 35% (n=12) received it >4 weeks prior to symptom onset. | II-2 | Fair |
| Fiebelkorn AP, Lawler J, Curns AT, Brandeburg C, Wallace GS. Wallace 2013. Mumps postexposure prophylaxis with a third dose of measles-mumps-rubella vaccine, Orange County, New York, USA. Emerging Infectious Diseases, 19(9): 1411. | MMR1, MMR2, MMR3; Jeryl Lynn strain | Cohort | * Outbreak location: US (NY state, Orange County)
* Duration of outbreak: September 2009- June 2010
* Size of outbreak: 49 index case-patients
; median age, 9 years
* Population at risk: 239 household members of index- case-patients
* Time of intervention: February 24 - April 24, 2010
* Intervention group: household members of index case-patients if onset of disease was <5 days
* Comparison group: household members of cases who declined vaccination
| 28 household members received MMR3 and 16 received MMR1 or MMR2. 77 household members with MMR2 who declined MMR3 immunization were used as controls.
Attack rates (12-25 days after parotitis onset in the index-case) according to MMR3 status\*:* intervention group: 0% (0/28)
* control group: 5.2% (4/77)
\*difference between groups was not statistically significant (p = 0.57).
The median number of years since last MMR dose in the control group was 11 years (range 0-39).
Median interval between disease onset and last MMR vaccine dose for index-case patients was 3 years. | II-2 | Fair |
| Levine H, Rishpon S, Huerta-Hartal M, Davidovitch N. 2011. Preventing mumps outbreaks in confined settings: Comprehensive ring vaccination as a containment strategy. Human Vaccines, 7(12): 1389. | MMR2, MMR3; Jeryl Lynn strain | Epidemiological report | * Outbreak location: Israel
* Duration of outbreak: throughout 2005 (not defined) and September 2009 - August 2010
* Population at risk: Israel Defence Forces
* Intervention group: soldiers in affected military units
* Other: genotype G5 isolated from samples in both outbreaks
| During the two waves of the 2005 outbreak, over 1,000 soldiers were immunized within one week of index case-report. In the first wave, all individuals were vaccinated with an additional MMR dose. In the second wave, individuals who received MMR2 were excluded. In both events, no further cases were found on active surveillance.
During the 2009/10 outbreak, overall nearly 2,000 soldiers were vaccinated with an additional dose, independent of MMR vaccine status (>40 different events). Mumps infections only occurred within a single incubation period after the initiation of the vaccination campaign. | II-3 | Poor |
| Nelson GE, Aguon A, Valencia E, Oliva R, Guerrero ML, Reyes R, Lizama A, Diras D, Mathew A, Camacho EJ, Monforte MN, Chen TH, Mahamud A, Kutty PK, Hickman C, Bellini WJ, Seward JF, Gallagher K, Fiebelkorn AP. 2013. Epidemiology of a mumps outbreak in a highly vaccinated island population and use of a third dose of measles-mumps-rubella vaccine for outbreak control - Guam 2009 to 2010. Pediatric Infectious Disease Journal, 32(4): 374. | MMR3; Jeryl Lynn strain | Cohort | * Outbreak location: US (Guam)
* Duration of outbreak: December 1, 2009- December 31, 2010
* Population at risk: 180,000 island residents
* Size of outbreak: 505 cases; median age, 12 years
* Time of intervention: May 18 - 21, 2010
* Intervention group: 9-14 year-old students with MMR2
* Intervention setting: 7 schools (from a total of 64 schools in Guam) with an attack rate >5/1,000
* Other: genotype G identified as an outbreak strain; peak of outbreak occurred one month prior to intervention.
| Out of 3,364 eligible students 9-14 years old, 33% (n=1,068) received MMR3.
Attack rates in eligible schools according to MMR3 status\*:* received MMR3: 0.09%
* not received MMR3: 0.23%
\*difference between groups (RR=0.4 [95%CI: 0.05-3.5]) was not statistically significant (p=0.67).
Out of six students who were diagnosed with mumps in the post-intervention period, only one received MMR3.
Incremental VE (MMR3 vs. MMR2): 61% (95% CI, -250 -95%) 21 or more days after vaccination | II-2 | Poor |
| Ogbuanu IU, Kutty PK, Hudson JM, Blog D, Abedi GR, Goodell S, Lawler J, McLean HQ, Pollock L, Rausch-Phung E, Schulte C, Valure B, Armstrong GL, Gallagher K. 2012. Impact of a third dose of measles-mumps-rubella vaccine on a mumps outbreak. Pediatrics, 130(6): e1567. | MMR1, MMR2, MMR3; Jeryl Lynn strain | Cohort | * Outbreak location: US (NY state, Orange County)
* Duration of outbreak: September 1, 2009 - June 30, 2010
* Population at risk: 20,300 religious community members
* Size of outbreak: 790 cases in the community (72% 11-17 years of age)
* Intervention setting: school (3 of 4 schools in the village attended by 98% of village school children)
* Time of intervention: January 19 - February 2, 2010
* Intervention group: 11-17 year-old students
* Other: household size in the affected community above average (5.7 versus the US national average of 2.6); peak of outbreak occurred in Nov/Dec 2009.
| Out of 2,688 students 11-17 years of age, 1,723 received MMR3; a small number of students (n=87) received a catch-up dose of MMR1 or MMR2.
Attack rates in students 11-17 years of age:* 21 days prior to intervention: 4.93%
* 21 days following intervention: 1.55%
* 22-42 days following intervention: 0.13%
Incremental VE (MMR3 vs. MMR2): 88% (95% CI: -31.9%, 98.9%); broad CI intervals due to high rate of vaccine uptake and small number of cases >21 days post intervention (2 among the 413 unvaccinated students and 1 among the 1,723 vaccinated students)
Decline in the mumps attack rate in the community post intervention was also statistically significant in the 11-17 year-old (96%; 95%CI: 87-99) and 5-10 year-old (72.9%; 95%CI: 52-84) age groups. | II-2 | Fair |
| Salmón-Mulanovich G, Utz G, Lescano AG, Bentzel DE, Blazes DL. 2009. Rapid response to a case of mumps: implications for preventing transmission at a medical research facility. Salud publica de Mexico, 51(1): 34. | MMR1; Jeryl Lynn strain | Case series | * Outbreak location: US Naval Medical Research Center Detachment in Lima, Peru
* Size of outbreak: 1 case (index case)
* Intervention setting: medical research facility
* Intervention group: mumps virus naive employees (i.e., without disease or vaccination history and with undetectable antibody titre)
| Out of 81 exposed employees, 8 were found to be vaccine and disease naïve based on history of infection and antibody titre of <20.0 U/ml.
All eligible individuals received MMR vaccine within one week of exposure. No secondary cases of mumps were observed after the intervention. | II-3 | Fair |
| Veneti L, Borgen K, Borge KS, Danis K, Greve-Isdahl M, Konsmo K, Njølstad G, Nordbø SA, Øystese KS, Rykkvin R, Sagvik E, Riise ØR. 2018. Large outbreak of mumps virus genotype G among vaccinated students in Norway, 2015 to 2016. Euro Surveillance: Bulletin Européen sur les maladies transmissibles = European Communicable Disease Bulletin, 23(38). | MMR1, MMR2, MMR3; genotype A (Jeryl Lynn and RIT 4385) | Case series | * Outbreak location: Norway
* Duration of outbreak: 6 September, 2015 - 30 June, 2016
* Population at risk: Whole population
* Size of outbreak: 232 cases, median age 23 (>75% university students, 87% 19-28 years old)
* Time of intervention: October 1-4 (Trondheim) and November 1-8 (Bergen), 2015
* Intervention group: under vaccinated students (vaccinated with MMR1 or MMR2) and close contacts of cases (vaccinated with MMR3)
* Other: MMR schedule in Norway: dose provided at 15 months and 11-12 years of age; majority of tested samples (66/68) genotype G
| MMR3 provided to approximately 1,300 close contacts of cases, including household members.
Only 3 cases, all within 2 weeks of vaccination, were reported among individuals who received MMR3. | II-3 | Poor |
Appendix B: Summary of Safety Findings (Adverse Events [AE] and Serious Adverse Events [SAE])
---------------------------------------------------------------------------------------------
Summary of Safety Findings
| Study Details | Summary |
| --- | --- |
| Publication | Vaccine (dose provided), Strain | Study Design | Outbreak and study description | Summary of Key Findings | Level of Evidence | Quality |
| Aasheim ET, Inns T, Trindall A, Emmett L, Brown KE, Williams CJ, Reacher M. 2014. Outbreak of mumps in a school setting, United Kingdom, 2013. Human Vaccines and Immunotherapeu-tics, 10(8): 2446. | MMR1, MMR2, MMR3; Jeryl Lynn strain | Case series | N=76 students 10-19 years of age whose parents approved the administration of an additional MMR dose | No AEs were reported following vaccine administration. | II-3 | Fair |
| Abedi GR, Mutuc JD, Lawler J, Leroy ZC, Hudson JM, Blog DS, Schulte CR, Rausch-Phung E, Ogbuanu IU, Gallagher K, Kutty PK 2012. Adverse events following a third dose of measles, mumps, and rubella vaccine in a mumps outbreak. Vaccine, 30(49): 7052.
Ogbuanu IU, Kutty PK, Hudson JM, Blog D, Abedi GR, Goodell S, Lawler J, McLean HQ, Pollock L, Rausch-Phung E, Schulte C, Valure B, Armstrong GL, Gallagher K. 2012. Impact of a third dose of measles-mumps-rubella vaccine on a mumps outbreak. Pediatrics, 130(6): e1567. | MMR3; Jeryl Lynn strain | Case series | N= 1,597 students 11-17 years old | Out of 1,755 students 11-17 years of age that received MMR3, 91% (1,597) returned for follow-up survey.
AEs among survey respondents (student and parent reported):* 7.2% (115) reported at least 1 local or systemic AE within 14 days of MMR3 administration; most commonly reported AEs were injection site pain, redness, or swelling (3.6%); joint or muscle aches (1.8%); dizziness or light-headedness (1.7%); and fever of 38 degrees Celsius or greater (1.3%). 0.2 % (3) reported fainting at any time during the 2-week period following vaccination. There were no significant differences in AE reported based on age and gender.
* No SAEs were reported/identified in the 2 months following MMR3 vaccination either through the study survey, VAERS analysis (enhanced surveillance one year post intervention) or after contacting local primary health care providers.
* No differences were identified in the reporting of AE by grade or sex, for specific AE in the follow-up surveys.
| II-3 | Fair |
| Albertson JP, Clegg WJ, Reid HD, Arbise BS, Pryde J, Vaid A, Thompson-Brown R, Echols F. Echols 2016. Mumps Outbreak at a University and Recommendation for a Third Dose of Measles-Mumps-Rubella Vaccine - Illinois, 2015-2016. MMWR. Morbidity and mortality weekly report, 65(29): 731. | MMR1, MMR2, MMR3; Jeryl Lynn strain | Case series | N=>11,500 university students and staff born during or after 1957 | No SAEs were reported following vaccine administration. | II-3 | Fair |
| Levine H, Rishpon S, Huerta-Hartal M, Davidovitch N. 2011. Preventing mumps outbreaks in confined settings: Comprehensive ring vaccination as a containment strategy. Human Vaccines, 7(12): 1389. | MMR2, MMR3; Jeryl Lynn strain | Epidemiological report | N=>2,000 soldiers | No AEs were reported following immunization. | II-3 | Poor |
| Nelson GE, Aguon A, Valencia E, Oliva R, Guerrero ML, Reyes R, Lizama A, Diras D, Mathew A, Camacho EJ, Monforte MN, Chen TH, Mahamud A, Kutty PK, Hickman C, Bellini WJ, Seward JF, Gallagher K, Fiebelkorn AP. 2013. Epidemiology of a mumps outbreak in a highly vaccinated island population and use of a third dose of measles-mumps-rubella vaccine for outbreak control - Guam 2009 to 2010. Pediatric Infectious Disease Journal, 32(4): 374. | MMR3; Jeryl Lynn strain | Case series | N=533 children 9-14 years of age | AE data was collected through retrospective surveys. 6% (n=32) of students reported AEs in the 2 weeks following vaccination, with joint aches (2.6%), local pain/redness/swelling and dizziness (2.4%) being most common.
No SAEs were reported. | II-3 | Poor |
| Veneti L, Borgen K, Borge KS, Danis K, Greve-Isdahl M, Konsmo K, Njølstad G, Nordbø SA, Øystese KS, Rykkvin R, Sagvik E, Riise ØR. 2018. Large outbreak of mumps virus genotype G among vaccinated students in Norway, 2015 to 2016. Euro Surveillance: Bulletin européen sur les maladies transmissibles = European Communicable Disease Bulletin, 23(38). | MMR1, MMR2, MMR3; genotype A (Jeryl Lynn and RIT 4385) | Case series | N≈1,300 adults | No SAEs were reported. | II-3 | Fair |
References
----------
Footnote 1
Marin M, Marlow M, Moore KL, Patel M. Recommendation of the Advisory Committee on Immunization Practices for Use of a Third Dose of Mumps Virus-Containing Vaccine in Persons at Increased Risk for Mumps During an Outbreak. MMWR Morb Mortal Wkly Rep. 2018;67(1):33-8.
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
Vaccination coverage goals and vaccine preventable disease reduction targets by 2025 [Internet]. 2019 [updated 2019-05-08; ]. Available from: https://www.canada.ca/en/public-health/services/immunization-vaccine-priorities/national-immunization-strategy/vaccination-coverage-goals-vaccine-preventable-diseases-reduction-targets-2025.html.
[Return to footnote 2 referrer](#fn2-rf)
Footnote 3
Ramanathan R, Voigt E, Kennedy R, Poland G. Knowledge gaps persist and hinder progress in eliminating mumps. US National Library of Medicine. 2018;36(26):3721-6.
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
Lewnard JA, Grad YH. Vaccine waning and mumps re-emergence in the United Stated. Science Translation Medicine. 2018;10(433):1-11.
[Return to footnote 4 referrer](#fn4-rf)
Footnote 5
Cortese M, Jordan H, Cums A, Quinlan P, Ens K, Denning P, et al. Mumps vaccine performance among university students during a mumps outbreak. US National Library of Medicine. 2008;46(8):1.
[Return to footnote 5 referrer](#fn5-rf)
Footnote 6
Cohen C, White JM, Savage EJ, Glynn JR, Choi Y, Andrews N, et al. Vaccine Effectiveness Estimates, 2004-2005 Mumps Outbreak, England. US National Library of Medicine. 2007;13(1):12-7.
[Return to footnote 6 referrer](#fn6-rf)
Footnote 7
Seagle EE, Bednarczyk RA, Hill T, Fiebelkorn AP, Hickman CJ, Icenogle JP, et al. Measles, mumps, and rubella antibody patterns of persistence and rate of decline following the second dose of the MMR vaccine. Vaccine. 2018 1 February 2018;36(6):818-26.
[Return to footnote 7 referrer](#fn7-rf)
Footnote 8
Annual Epidemiological Report for 2016 Mumps. Surveillance Report. European Centre for Disease Prevention and Control; 2016.
[Return to footnote 8 referrer](#fn8-rf)
Footnote 9
Gouma S, Hahné SJM, Gijselaar DB, Koopmans MPG, van Binnendijk RS. Severity of mumps disease is related to MMR vaccination status and viral shedding. Vaccine. 2016 7 April 2016;34(16):1868-73.
[Return to footnote 9 referrer](#fn9-rf)
Footnote 10
Mumps vaccine: Canadian immunization guide [Internet].: Government of Canada; 2018 [updated 2019-07-26; ]. Available from: https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-14-mumps-vaccine.html.
[Return to footnote 10 referrer](#fn10-rf)
Footnote 11
CCDR. Supplement guidelines for the prevention and control of mumps outbreak in Canada. 2010;36(Supplement 1):1-49.
[Return to footnote 11 referrer](#fn11-rf)
Footnote 12
Yoshida N, Fujino M, Miyata A, Nagai T, Kamada M, Sakiyama H, et al. Mumps virus reinfection is not a rare event confirmed by reverse transcription loop-mediated isothermal amplification. J Med Virol. 2008 03/01;80:517-23.
[Return to footnote 12 referrer](#fn12-rf)
Footnote 13
Kennedy RB, Ovsyannikova IG, Thomas A, Larrabee BR, Rubin S, Poland GA. Differential durability of immune responses to measles and mumps following MMR vaccination. Vaccine. 2019 22 March 2019;37(13):1775-84.
[Return to footnote 13 referrer](#fn13-rf)
Footnote 14
Kontio M, Jokinen S, Paunio M, Peltola H, Davidkin I. Waning antibody levels and avidity: Implications for MMR vaccine-induced protection. The Journal of infectious diseases. 2012;206(10):1542-8.
[Return to footnote 14 referrer](#fn14-rf)
Footnote 15
Davidkin I, Jokinen S, Broman M, Leinikki P, Peltola H. Persistence of measles, mumps, and rubella antibodies in an MMR-vaccinated cohort: A 20-year follow-up. The Journal of infectious diseases. 2008;197(7):950-6.
[Return to footnote 15 referrer](#fn15-rf)
Footnote 16
LeBaron CW, Forghani B, Beck C, Brown C, Bi D, Cossen C, et al. Persistence of mumps antibodies after 2 doses of measles-mumps-rubella vaccine. The Journal of infectious diseases. 2009;199(4):552-60.
[Return to footnote 16 referrer](#fn16-rf)
Footnote 17
Mumps antibody response in young adults after a third dose of measles-mumps-rubella vaccine [Internet].: PubMed.gov; 2014 [updated 2014; ]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25734162.
[Return to footnote 17 referrer](#fn17-rf)
Footnote 18
Principi N, Esposito S. Mumps outbreaks: A problem in need of solutions. Journal of Infection. 2018 June 2018;76(6):503-6.
[Return to footnote 18 referrer](#fn18-rf)
Footnote 19
Dayan GH, Rubin S, Plotkin S. Mumps outbreak in vaccinated populations: are available mumps vaccines effective enough to prevent outbreaks? Clinical Infectious Diseases. 2008;47(11):1458-67.
[Return to footnote 19 referrer](#fn19-rf)
Footnote 20
Lewnard JA, Grad YH. Vaccine waning and mumps re-emergence in the United States. US National Library of Medicine. 2018;10(433):1-22.
[Return to footnote 20 referrer](#fn20-rf)
Footnote 21
Rasheed M, Hickman C, McGrew M, et al. Decreased humoral immunity to mumps in young adults immunized with MMR vaccine in childhood. Proc Natl Acad Sci U S A. 2019 2019 Sep 17;116(38):19071-6.
[Return to footnote 21 referrer](#fn21-rf)
Footnote 22
Homan EJ, Bremel RD. Are cases of mumps in vaccinated patients attributable to mismatches in both vaccine T-cell and B-cell epitopes?: An immunoinformatic analysis. Human vaccines & immunotherapeutics. 2014;10(2):290-300.
[Return to footnote 22 referrer](#fn22-rf)
Footnote 23
Nöjd J, Tecle T, Samuelsson A, Örvell C. Mumps virus neutralizing antibodies do not protect against reinfection with a heterologous mumps virus genotype. Vaccine. 2001 8 February 2001;19(13):1727-31.
[Return to footnote 23 referrer](#fn23-rf)
Footnote 24
Gouma S, Ten Hulscher HI, Schurink-van't Klooster TM, de Melker HE, Boland GJ, Kaaijk P, et al. Mumps-specific cross-neutralization by MMR vaccine-induced antibodies predicts protection against mumps virus infection. Vaccine. 2016 29 July 2016;34(35):4166-71.
[Return to footnote 24 referrer](#fn24-rf)
Footnote 25
Clemmons NS, Redd SB, Gustanaduy PA, Marin M, Patel M, Fiebelkorn AP. Characteristics of large mumps outbreaks in the United States, July 2010-December 2015. Clinical Infectious Diseases. 2019;68(10):1684-90.
[Return to footnote 25 referrer](#fn25-rf)
Footnote 26
Mumps Cases and Outbreaks [Internet].: Centers for Disease Control and Prevention; 2019 [updated July, 22, 2019; cited July 31, 2019]. Available from: https://www.cdc.gov/mumps/outbreaks.html.
[Return to footnote 26 referrer](#fn26-rf)
Footnote 27
Mump - Surveillance [Internet]. Canada: Government of Canada; 2014 [updated 2014/11/24; cited 2019/07/19]. Available from: https://www.canada.ca/en/public-health/services/immunization/vaccine-preventable-diseases/mumps/surveillance.html.
[Return to footnote 27 referrer](#fn27-rf)
Footnote 28
Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, Atkins D, et al. Current methods of the US Preventive Services Task Force: a review of the process. American journal of preventive medicine JID - 8704773.
[Return to footnote 28 referrer](#fn28-rf)
Footnote 29
Hviid A, Rubin S, Mühlemann K. Mumps. The Lancet. 2008 15-21 March 2008;371(9616):932-44.
[Return to footnote 29 referrer](#fn29-rf)
Footnote 30
Robertson SE. Control of Communicable Diseases manual. 18th Edition. American Public Health Association. 2004:376-9.
[Return to footnote 30 referrer](#fn30-rf)
Footnote 31
Atkinson W, Hamborsky J, McIntyre L, et.al.. Epidemiology and prevention of vaccine-preventable diseases. 10th ed. Centers for Disease Control and Prevention. 2007:149-58.
[Return to footnote 31 referrer](#fn31-rf)
Footnote 32
Dittrich S, Hahné S, van Lier A, Kohl R, Boot H, Koopmans M, et al. Assessment of serological evidence for mumps virus infection in vaccinated children. Vaccine. 2011 15 November 2011;29(49):9271-5.
[Return to footnote 32 referrer](#fn32-rf)
Footnote 33
Conly J, Johnstone B. Is mumps making a comeback? Adult Infectious Disease Notes. 2007;18(1):1-3.
[Return to footnote 33 referrer](#fn33-rf)
Footnote 34
Rubin SA. Paramyxoviruses: Mumps. Springer Link. 2014:553-7.
[Return to footnote 34 referrer](#fn34-rf)
Footnote 35
Rubin S, Eckhaus M, Rennick LJ, Bamford CG, Duprex WP. Molecular biology, pathogenesis and pathology of mumps virus. The Journal of Pathology. 2015;235(2):242-52.
[Return to footnote 35 referrer](#fn35-rf)
Footnote 36
Lozo S, Ahmed A, Chapnick E, O'Keefe M, Minkoff H. Presumed cases of mumps in pregnancy: clinical and infection control complications. Infectious Diseases in Obstetrics & Gynecology. 2011;2012:1-4.
[Return to footnote 36 referrer](#fn36-rf)
Footnote 37
Gouma S, Durand ML, van Binnendiijk RS. Mumps and other types of viral parotitis. In: Infections of the Ears, Nose Throat, and Sinuses. SpringerNature ed. Canada: Springer, Cham; 2018. p. 279-89.
[Return to footnote 37 referrer](#fn37-rf)
Footnote 38
Donahue M, Schneider A, Ukegbu U, Shah M, Riley J, Weigel A, et al. Notes from the Field: Complications of Mumps during a University Outbreak Among Students who had Received 2 Doses of Measles-Mumps-Rubella Vaccine --Iowa, July 2015-May 2016. Center for Disease Control and Prevention. 2017;66(14):390-1.
[Return to footnote 38 referrer](#fn38-rf)
Footnote 39
J R Coll Gen Pract. A retrospective survey of the complications of mumps. US National Library of Medicine. 1974;24(145):552-6.
[Return to footnote 39 referrer](#fn39-rf)
Footnote 40
Zamir CS, Schroeder H, Shoob H, Abramson N, Zentner G. Characteristics of a large mumps outbreak: clinical severity, complications and association with vaccination status of mumps outbreak cases. Human vaccines & Immunotherapeutics. 2014;11(6):1413-7.
[Return to footnote 40 referrer](#fn40-rf)
Footnote 41
Yung C, Andrews N, Bukasa A, Brown KE, Ramsay M. Mumps Complications and Effects of Mumps Vaccination, England and Wales, 2002-2006. Centers for Disease Control and Prevention. 2011;17(4):661-7.
[Return to footnote 41 referrer](#fn41-rf)
Footnote 42
Sane J, Gouma S, Koopmans M, de Melker H, Swaan C, van Binnendijk R, et al. Epidemic of Mumps among Vaccinated Persons, the Netherlands, 20019-2012. Centers for Disease Control and Prevention [Emerging Infectious Diseases]. 2014;20(4):643-8.
[Return to footnote 42 referrer](#fn42-rf)
Footnote 43
López-Perea N, Masa-Calles J, Torres de Mier, María de Viarce, Fernández-García A, Echevarría JE, De Ory F, et al. Shift within age-groups of mumps incidence, hospitalizations and severe complications in a highly vaccinated population. Spain, 1998-2014. Vaccine. 2017 3 August 2017;35(34):4339-45.
[Return to footnote 43 referrer](#fn43-rf)
Footnote 44
European Centre for Disease Prevention and Control - Facts about Mumps [Internet]. Europe: European Centre for Disease Prevention and Control; 2020 [cited 2020/01/14]. Available from: https://www.ecdc.europa.eu/en/mumps/facts.
[Return to footnote 44 referrer](#fn44-rf)
Footnote 45
Government of Canada. Guidelines: Mumps in Canada. CCDR. 2010;36(Supplement 1):1-49.
[Return to footnote 45 referrer](#fn45-rf)
Footnote 46
Immunization Coverage [Internet].: World Health Organization; 2019 [updated December 6, 2020; cited January 31, 2020]. Available from: https://www.who.int/news-room/fact-sheets/detail/immunization-coverage.
[Return to footnote 46 referrer](#fn46-rf)
Footnote 47
List of Nationally Notifiable Diseases [Internet]. Canada: Public Health Agency of Canada; 2018 [updated 2018/11/25; cited 2019/07/19]. Available from: http://diseases.canada.ca/notifiable/diseases-list.
[Return to footnote 47 referrer](#fn47-rf)
Footnote 48
Mumps: For Health Professionals [Internet]. Canada: Government of Canada; 2014 [updated 2014/12/23; cited 2019/08/13]. Available from: https://www.canada.ca/en/public-health/services/immunization/vaccine-preventable-diseases/mumps/health-professionals.html.
[Return to footnote 48 referrer](#fn48-rf)
Footnote 49
National Advisory Committee on Immunization (NACI). An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI)
STATEMENT ON MUMPS VACCINE. Ottawa, Ontario: Public Health Agency of Canada; 2007. Report No.: ACS 8.
[Return to footnote 49 referrer](#fn49-rf)
Footnote 50
Saboui M, Squires S. Mumps outbreaks across Canada, 2016 to 2018. Can Commun Dis Rep. 2020;46(11/12):427-31. https://doi.org/10.14745/ccdr.v46i1112a10.
[Return to footnote 50 referrer](#fn50-rf)
Footnote 51
Wei Y, Wilkinson K, Rusk R, Kadkhoda K, Loeppky C. Large community mumps outbreak in Manitoba, Canada, September 2016-December 2018. Canada communicable disease report = Relevé des maladies transmissibles au Canada JID - 9303729 PMC - PMC7145432 OTO - NOTNLM.
[Return to footnote 51 referrer](#fn51-rf)
Footnote 52
Rudnick W, Wilson S, Majerovich JA, Haavaldsrud M, Gatali M, Matsumoto CL, Deeks S. Effectiveness of an outbreak dose of mumps-containing vaccine in two First Nations communities in Northern Ontario, Canada. Research Square [Preprint]. 2020 Nov 6. Available from: https://www.researchsquare.com/article/rs-103431/v1
[Return to footnote 52 referrer](#fn52-rf)
Footnote 53
Stapleton PJ, Eshaghi A, Seo CY, Wilson S, Harris T, Deeks SL, et al. Evaluating the use of whole genome sequencing for the investigation of a large mumps outbreak in Ontario, Canada. Scientific Reports. 2019 08/30;9(1):12615.
[Return to footnote 53 referrer](#fn53-rf)
Footnote 54
Gardy JL, Naus M, Amlani A, Chung W, Kim H, Tan M, et al. Whole-Genome Sequencing of Measles Virus Genotypes H1 and D8 During Outbreaks of Infection Following the 2010 Olympic Winter Games Reveals Viral Transmission Routes. The Journal of infectious diseases JID - 0413675.
[Return to footnote 54 referrer](#fn54-rf)
Footnote 55
Anis E, Grotto I, Moerman L, Warshavsky B, Slater PE, Lev B. Mumps outbreak in Isreal's highly vaccinated society: are two doses enough? Epidemiol Infect. 2012(140):439-46.
[Return to footnote 55 referrer](#fn55-rf)
Footnote 56
Cordeiro E, Ferreira M, Rodrigues F, Palminha P, Vinagre E, Pimentel JP. Mumps outbreak among highly vaccinated teenagers and children in the central region of Portugal, 2012-2013.2015;28(4):435-41.
[Return to footnote 56 referrer](#fn56-rf)
Footnote 57
Braeye T, Linina I, De Roy R, Hutse V, Wauters M, Cox P, et al. Mumps increase in Flanders, Belgium, 2012-2013: Results from temporary mandatory notification and a cohort study among university students. Vaccine. 2014 31 July 2014;32(35):4393-8.
[Return to footnote 57 referrer](#fn57-rf)
Footnote 58
Merck Canada Inc. Product Monograph: M-M-R®II (measles, mumps and rubella virus vaccine, live, attenuated, Merck Std.). 2017. Available from: https://www.merck.ca/static/pdf/MMR\_II-PM\_E.pdf
[Return to footnote 58 referrer](#fn58-rf)
Footnote 59
Langwig KE, Gomes MGM, Clark MD, Kwitny M, Yamada, Steffany, Wargo, Andrew R., Lipsitch Marc. Limited available evidence supports theoretical predictions of reduced vaccine efficacy at higher exposure dose. Scientific Reports. 2019:1-6.
[Return to footnote 59 referrer](#fn59-rf)
Footnote 60
Beleni A, Borgmann S. Mumps in the Vaccination Age: Global Epidemiology and the Situation in Germany. MDPI. 2018;15(8).
[Return to footnote 60 referrer](#fn60-rf)
Footnote 61
Ogbuanu IU, Kutty PK, Hudson JM, Blog D, Abedi GR, Goodell S, et al. Impact of a third dose of measles-mumps-rubella vaccine on a mumps outbreak. US National Library of Medicine. 2012;130(6):1567-74.
[Return to footnote 61 referrer](#fn61-rf)
Footnote 62
Nelson G, Aguon A, Valencia E, Oliver R, Guerrero M, Reyes R, et al. Epidemiology of a mumps outbreak in a highly vaccinated island population and use of a third dose of measles-mumps-rubella- vaccine for outbreak control--Guam 2009-2010. US National Library of Medicine. 2013;32(4):374-80.
[Return to footnote 62 referrer](#fn62-rf)
Footnote 63
Aasheim E, Inns T, Trindall A, Emmett L, Brown K, Williams C, et al. Outbreaks of Mumps in a school setting, United Kingdom, 2013. US National Library of Medicine. 2014;10(8):2446-9.
[Return to footnote 63 referrer](#fn63-rf)
Footnote 64
Ramsay M, Brown D, Eastcott H, Begg N. Saliva antibody testing and vaccination in a mumps outbreak. US National Library of Medicine. 1991;1(9):96-8.
[Return to footnote 64 referrer](#fn64-rf)
Footnote 65
Centers for Disease Control and Prevention (CDC). Mumps Outbreak in a Summer Camp--New York, 2005. 2006;24(55):175-7.
[Return to footnote 65 referrer](#fn65-rf)
Footnote 66
Pérez-Alba E, García-Ortiz A, Salazar-Montalvo RG, Hernández-Guedea MA, Camacho-Ortiz A. Mumps outbreak with high complication rates among residents in a university teaching hospital. US National Library of Medicine. 2019;47(3):337-9.
[Return to footnote 66 referrer](#fn66-rf)
Footnote 67
Fischer PR, Brunetti C, Welch V, Christenson JC. Nosocomial mumps: report of an outbreak and its control. American journal of infection control JID - 8004854.
[Return to footnote 67 referrer](#fn67-rf)
Footnote 68
Albertson JP, Clegg WJ, Reid HD, Arbise BS, Pryde J, Vaid A, Thompson-Brown R, Echols F. Mumps Outbreak at a University and Recommendation for a Third Dose of Measles-Mumps-Rubella Vaccine-Illinois, 2015-2016. Centers for Disease Control and Prevention. 2016;65(29):731-4.
[Return to footnote 68 referrer](#fn68-rf)
Footnote 69
Shah M, Quinlisk P, Weigel A, Riley J, James L, Patterson J, et al. Mumps Outbreak in a Highly Vaccinated University-Affiliated Setting before and After Measles-Mumps-Rubella Vaccination Campaign-Iowa, July 2015-May 2016. 2018;66(1):81-8.
[Return to footnote 69 referrer](#fn69-rf)
Footnote 70
Cardemil C, Dahl R, James L, Wannemuehler K, Gary H, Shah M, et al. Effectiveness of a Third Dose of MMR Vaccine for Mumps Outbreak Control. US National Library of Medicine. 2017;377(10):947-56.
[Return to footnote 70 referrer](#fn70-rf)
Footnote 71
Levine H, Rishpon S, Huerta-Hartal M, Davidovitch N. Preventing mumps outbreaks in confined settings: comprehensive ring vaccination as a containment strategy. US National Library of Medicine. 2011;7(12):1389-93.
[Return to footnote 71 referrer](#fn71-rf)
Footnote 72
Mossong J, Bonert C, Weicherding P, Opp M, Reichert P, Even J, Schneider F. Mumps outbreak among the military in Luxembourg in 2008: epidemiology and evaluation of control measures. US National Library of Medicine. 2009;14(7).
[Return to footnote 72 referrer](#fn72-rf)
Footnote 73
Veneti L, Borgen K, Borge KS, Danis K, Greve-Isdahl M, Konsmo K, Njølstad G, Nordbø SA, Øystese KS, Rykkvin R, Sagvik E, Riise ØR. Large outbreak of mumps virus genotype G among Vaccinated students in Norway, 2015 to 2016. Eurosurveillance. 2018;23(38).
[Return to footnote 73 referrer](#fn73-rf)
Footnote 74
Wharton M, Cochi S, Hutcheson R, Bistowish J, Schaffiner W. A large outbreak of mumps in the postvaccine era. US National Library of Medicine. 1988;158(6):1253-60.
[Return to footnote 74 referrer](#fn74-rf)
Footnote 75
Sugg W, Finger J, Levine R, Pagano J. Field evaluation of live virus mumps vaccine. US National Library of Medicine. 1968;72(4):461-6.
[Return to footnote 75 referrer](#fn75-rf)
Footnote 76
Veneti L, Borgen K, Borge KS, Danis K, Greve-Isdahl M, Konsmo K, et al. Large outbreak of mumps virus genotype G among vaccinated students in Norway, 2015 to 2016. LID - 10.2807/1560-7917.ES.2018.23.38.1700642 [doi] LID - 1700642. Euro surveillance: bulletin Européen sur les maladies transmissibles = European communicable disease bulletin JID - 100887452. (1025-496; 1025-496).
[Return to footnote 76 referrer](#fn76-rf)
Footnote 77
Abedi GR, Mutuc JD, Lawler J, Leroy ZC, Hudson JM, Blog DS, Schulte CR, Rausch-Phung E, Ogbuanu IU, Gallagher K, Kutty PK. Adverse events following a third dose of measles, mumps, and rubella vaccine in a mumps outbreak. US National Library of Medicine. 2012;30(49):7052-8.
[Return to footnote 77 referrer](#fn77-rf)
Footnote 78
Updated recommendations for isolation of persons with mumps. MMWR. Morbidity and mortality weekly report JID - 7802429. (1545-861).
[Return to footnote 78 referrer](#fn78-rf)
Footnote 79
Vygen S, Fischer A, Meurice L, Mounchetrou Njoya I, Gregoris M, Ndiaye B, et al. Waning immunity against mumps in vaccinated young adults, France 2013. Eurosurveillance. 2016;21(10):1-8.
[Return to footnote 79 referrer](#fn79-rf)
Footnote 80
Barskey AE, Schulte C, Rosen JB, Handschur EF, Rausch-Phung E, Doll MK, et al. Mumps Outbreak in Orthodox Jewish Communities in the United States. The New England journal of medicine. 2012;367:1704-13.
[Return to footnote 80 referrer](#fn80-rf)
Footnote 81
Marin M, Kitzmann TL, James L, Quinlisk P, Aldous WK, Zhang J, et al. Cost of Public Health Response and Outbreak Control with a Third Dose of Measles-Mumps-Rubella Vaccine During a University Mumps Outbreak - Iowa, 2015-2016. Open Forum Infectious Diseases. 2018;5(10).
[Return to footnote 81 referrer](#fn81-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fuse-measles-mumps-rubella-vaccine-management-outbreaks-canada.html&n=Use%20of%20Measles-Mumps-Rubella%20(MMR)%20Vaccine%20for%20the%20Management%20of%20Mumps%20Outbreaks%20in%20Canada%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fuse-measles-mumps-rubella-vaccine-management-outbreaks-canada.html&title=Use%20of%20Measles-Mumps-Rubella%20(MMR)%20Vaccine%20for%20the%20Management%20of%20Mumps%20Outbreaks%20in%20Canada%20-%20Canada.ca)
* [Email](mailto:?subject=Use%20of%20Measles-Mumps-Rubella%20(MMR)%20Vaccine%20for%20the%20Management%20of%20Mumps%20Outbreaks%20in%20Canada%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fuse-measles-mumps-rubella-vaccine-management-outbreaks-canada.html%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fuse-measles-mumps-rubella-vaccine-management-outbreaks-canada.html&t=Use%20of%20Measles-Mumps-Rubella%20(MMR)%20Vaccine%20for%20the%20Management%20of%20Mumps%20Outbreaks%20in%20Canada%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=Use%20of%20Measles-Mumps-Rubella%20(MMR)%20Vaccine%20for%20the%20Management%20of%20Mumps%20Outbreaks%20in%20Canada%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fuse-measles-mumps-rubella-vaccine-management-outbreaks-canada.html%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fuse-measles-mumps-rubella-vaccine-management-outbreaks-canada.html&title=Use%20of%20Measles-Mumps-Rubella%20(MMR)%20Vaccine%20for%20the%20Management%20of%20Mumps%20Outbreaks%20in%20Canada%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fuse-measles-mumps-rubella-vaccine-management-outbreaks-canada.html&t=Use%20of%20Measles-Mumps-Rubella%20(MMR)%20Vaccine%20for%20the%20Management%20of%20Mumps%20Outbreaks%20in%20Canada%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fuse-measles-mumps-rubella-vaccine-management-outbreaks-canada.html&media=&description=Use%20of%20Measles-Mumps-Rubella%20(MMR)%20Vaccine%20for%20the%20Management%20of%20Mumps%20Outbreaks%20in%20Canada%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fuse-measles-mumps-rubella-vaccine-management-outbreaks-canada.html&title=Use%20of%20Measles-Mumps-Rubella%20(MMR)%20Vaccine%20for%20the%20Management%20of%20Mumps%20Outbreaks%20in%20Canada%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fuse-measles-mumps-rubella-vaccine-management-outbreaks-canada.html)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fuse-measles-mumps-rubella-vaccine-management-outbreaks-canada.html&name=Use%20of%20Measles-Mumps-Rubella%20(MMR)%20Vaccine%20for%20the%20Management%20of%20Mumps%20Outbreaks%20in%20Canada%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=Use%20of%20Measles-Mumps-Rubella%20(MMR)%20Vaccine%20for%20the%20Management%20of%20Mumps%20Outbreaks%20in%20Canada%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fuse-measles-mumps-rubella-vaccine-management-outbreaks-canada.html)
* [Whatsapp](https://api.whatsapp.com/send?text=Use%20of%20Measles-Mumps-Rubella%20(MMR)%20Vaccine%20for%20the%20Management%20of%20Mumps%20Outbreaks%20in%20Canada%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fuse-measles-mumps-rubella-vaccine-management-outbreaks-canada.html)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=Use%20of%20Measles-Mumps-Rubella%20(MMR)%20Vaccine%20for%20the%20Management%20of%20Mumps%20Outbreaks%20in%20Canada%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fuse-measles-mumps-rubella-vaccine-management-outbreaks-canada.html%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2021-07-27
| None | None |
2cd9bf918fccc53760b921fdba5ec553436f4a57 | cma | For immunization providers: Interim national vaccine storage, handling and transportation guidelines for ultra-low temperature and frozen temperature COVID-19 vaccines | For immunization providers: Interim national vaccine storage, handling and transportation guidelines for ultra-low temperature and frozen temperature COVID-19 vaccines
Posted April 14, 2021
On this page
About this document
The objective of the Interim National Vaccine Storage, Handling and Transportation Guidelines for Ultra-Low Temperature and Frozen Temperature COVID-19 Vaccines – 2021 is to supplement and update the guidance for storage, handling and transportation of ultra-low temperature and frozen temperature COVID-19 vaccines for immunization providers in Canada.
Vaccines must be stored in specific temperature conditions and handled with extreme care in order to maximize their shelf life, and to ensure their potency and efficacy. Specific guidelines for vaccine storage and handling procedures may vary among public health offices and immunization programs, therefore this document is meant to supplement existing jurisdictional policies and manufacturer instructions rather than to replace them. This document does not replace the and as such, the 2015 guidelines takes precedence over this policy document in the event that clarity is needed on any related subject. Individuals and companies that hold an establishment license from Health Canada who access information from these guidelines are still expected to meet all applicable requirements of the Food and Drugs Act and Food and Drug Regulations (FDR) as this document does not replace the requirements under the FDR as outlined in the .
# Key assumptions informing these guidelines
The information provided in these guidelines are based on the following assumptions:
1. The recommendations for storage, handling and transportation of the Health Canada authorized ultra-low temperature and frozen temperature COVID-19 vaccines is informed by stability, temperature and other studies carried out by the manufacturers at the time the version of the guidelines was issued.
2. These guidelines will be updated periodically as additional evidence, experience and knowledge of vaccine storage, handling and transportation practices for the authorized ultra-low temperature and frozen temperature COVID-19 vaccines become available.
List of acronyms used
CCE
Cold Chain Equipment
CSA
Canadian Standards Association
E2E
End-to-End
EOC
Emergency Operations Center
EPS
Expanded Polystyrene
FPTs
Federal, Provinces and Territories
IR
Infrared
IQ
Installation Qualification
ISC
Intelligent Supply Chain
LMIS
Logistics Management Information System
LSPs
Logistics Service Providers (note: in some jurisdictions, referred to as 3LP for Third Party Logistics Provider)
NOC
National Operations Center
OQ
Operational Qualification
PCM
Phase Change Material
PHAC
Public Health Agency of Canada
POD
Points of Distribution
PPE
Personal protective equipment
PQ
Performance Qualification
P/Ts or PTs
Provinces and Territories
UCC
Ultra-Cold Chain
ULT
Ultra-Low Temperature
VDS
Vaccine delivery site
WICs
Walk-In Cold Rooms
WIFs
Walk-In Freezer Rooms
Part 1: Ultra-low temperature vaccine(s)
The information provided below are general guidelines for the management of ultra-low temperature COVID-19 vaccines. Detailed instructions for can be found on the manufacturer’s website and supersedes any information captured below.
# Storage of ultra-low temperature COVID-19 vaccine(s)
## Storing conditions
The storage conditions of the product have been specified by the manufacturer, including minimum and maximum temperature conditions for the safe storage of the product based on clinical and stability studies data provided by the manufacturer.
## Storage equipment
Ultra-low temperature COVID-19 vaccines must be stored in appropriate cold chain equipment (CCE) that can maintain its ultra-low temperature. The manufacturer will indicate whether its vaccine(s) can be stored in the active CCE and/or passive CCE described below.
### Ultra-low temperature (ULT) freezers
Technology features: ULT freezers are active CCE that produce ultra-low temperatures to store vaccines requiring ultra-cold chain, with temperature requirement ranging from -80°C to -60°C. ULT freezers must be maintained at the temperature requirement of the particular vaccine provided by the manufacturer. Vials are stable at -80ºC to -60ºC until the expiration date on the vial and tray (6 months after manufacture). In addition to storing vaccines, ULT freezers can be used to freeze ultra-cold freezer packs (also known as phase change materials) to -80°C.
Power requirements: A reliable power supply is needed for optimal functionality of ULT freezers. If the building where the ULT freezer is kept provides less than the rated voltage, power voltage boosters may be required, depending on the type of ULT freezer. A back-up source of power supply is recommended, particularly if the building where the freezer will be stored is in an area with frequent power outages. A locking plug or a metal cage to prevent the freezer from being accidently unplugged from the electrical outlet/wall socket. All ULT freezers cause additional heat load and must be installed in an air-conditioned room to ensure working ambient temperature of <30°C.
Temperature monitoring: All ULT freezers should have data loggers to automate cold chain tracking. Data loggers for ULT freezers should have a data recording period of not less than 30 days at a data rate of not less than one data point per half hour. The data loggers should also have not less than 30 days of battery life and must have an integrated USB port for uploading data. It is also important that the computer requirements for uploading USB data is met.
Copyright: Fisher Scientific; PHC Corporation of North America; Sensitech
Left to right: An ultra-low temperature standing freezer, an ultra-low temperature chest freezer, a data logger shown at multiple angles, and a data logger connected with USB port.
### Thermal shippers
In the absence of ULT freezers, a thermal shipper/container can be used as passive CCE to store the vaccine temporarily at the clinic or vaccine delivery site. Thermal shippers require dry ice and maintain a temperature range of -90°C to -60°C. Thermal shippers have a capacity range of 3.4 to 6.2 liters and come with a vial rack system and a temperature data logger. In the event that thermal shipper does not contain a temperature data logger, arrangement should be made for the provision of data loggers to ensure proper monitoring of the cold chain. The duration and conditions for the use of thermal shippers as temporary storage for ultra-low temperature vaccines are available and can be obtained from the manufacturer*.*
### Active refrigerated devices
The manufacturer of ultra-low temperature COVID-19 vaccines will provide guidance on scenarios where their product can be stored in refrigerators as well as the specific duration and temperature of storage. In the event that refrigerators will be required, it is important to know the specific features of the device that can affect the storage of vaccines. For this reason, guidance has been provided on the refrigerators that are acceptable for vaccine storage and those that are not on pages 26-30 of the . Some refrigerators come as a fridge/freezer combination to enable the storage of different vaccines at their appropriate temperatures. The fridge compartment should maintain temperatures between 2°C and 8°C for vaccine storage, and it is advisable for fridges to be set at the temperature mid-range of about 5°C to provide the best safety margin for temperature fluctuations. A digital data logger should also be placed in each refrigerated device for continuous monitoring of the cold chain’s temperature. Refer to pages 24-35 of the for more information on refrigerators.
# Handling of ultra-low temperature COVID-19 vaccine(s)
## Personal protection measures for handling dry ice
It is important that appropriate protection is provided to personnel at vaccine delivery sites who will be handling dry ice. Jurisdictional occupational health and safety requirements, MSDS and federal laws on workplace safety should be referred to for information on potential hazards and how to work safely with dry ice. In the absence of an existing jurisdictional guidance, the requirements for safe handling of dry ice for individual protection are provided below:
Eye/face protection: Safety eyewear complying with current CSA standard Z94.3 should be used when a risk assessment indicates this is necessary to avoid exposure to liquid splashes, mists, gases or dusts. If contact is possible, safety glasses with side-shields or face shields should be worn, unless the assessment indicates a higher degree of protection is required.
Hand protection: Chemical-resistant, impervious and insulated gloves complying with jurisdictional standards should be worn at all times when handling dry ice. Gloves can be leather or nitrile, with fabric liner and cuffs. Ice scoops can also be used together with gloves to further prevent unintentional direct contact of dry ice with bare hands.
Body protection: Personal protective equipment (PPE) for the body such as aprons, or other similar PPE that meet jurisdictional standards, should be selected based on the task being performed and the risks involved before handling dry ice and related product, when a risk assessment indicates this is necessary. Apron, or other similar PPE, can be leather or canvas-type fabric.
Hygiene measures: Hands, forearms and face must be washed after handling dry ice, before eating, smoking, using the lavatory, and at the end of the working period.
Health and safety considerations: Dry ice must be handled in a well-ventilated area with ease of access to first aid kits.
Copyright: Fisher Scientific
Left to right: A face shield with an apron and gloves, tongs, and a scoop for dry ice handling.
## Disposal of used multi-dose vaccine vials/vial trays
Vials should be discarded in biomedical waste containers and in compliance with jurisdictional protocols. Vaccine vials should not be disposed of in sharps containers as vials are not considered a sharp and also because, sharps containers are not meant to store/have liquids. Therefore, vials containing vaccines should not be put in sharps containers or else they can leak if they are broken in the sharps container. Unlike the biomedical waste pails which are leak proof the sharps containers are not. Store empty COVID-19 vaccine vials in white and/or blue biomedical waste containers until they are ready for disposal. Incinerate the white and/or blue pharmaceutical waste containers. Do not autoclave and dispose of them in landfills since this poses a security risk for counterfeiting operations. Discard vial trays and all packaging associated with the vaccine so they cannot be reused and to prevent counterfeit efforts and any other potential criminal activities. Refer to jurisdictional and manufacturer instructions for more guidance on the disposal of ultra-low temperature COVID-19 vaccine.
# Transporting ultra-low temperature COVID-19 vaccine(s)
Ultra-low temperature COVID-19 vaccine(s) can be transported either ultra-frozen or thawed at refrigerator temperature for transport. Vaccine may be removed from a ULT freezer in a frozen state to thaw while in transport – however, the vaccine is considered to be “thawed” for the purpose of transportation guidelines and allowed storage time limits. When in the thawed state, the vaccine is susceptible to interfacial stresses and as such, it is important that it is handled with care and protected as much as possible from shocks, drops, vibration, etc. Portable vaccine refrigerator and freezer units that have built-in temperature regulation are considered the best options for vaccine transport. Expedited transportation service with an insulated container containing dry ice (for ultra-cold transport) / gel packs (for 2°C to 8°C transport) is required to ensure the vaccine is kept at the right temperature. Temperature tracking logs/devices should be put in place for full trays and separate vials during transfer activities, pack-out, repacking and redistribution. Detailed instructions for transportation of ultra-low temperature COVID-19 vaccine(s) in frozen or refrigerated state, including timing, is available and can be obtained from the manufacturer. Also refer to jurisdictional guidance, if available.
Part 2: Frozen temperature vaccine(s)
The information provided below are general guidelines for the management of frozen temperature COVID-19 vaccines. Detailed can be found on the manufacturer’s website and supersedes any information captured below.
# Storage of frozen temperature COVID-19 vaccine(s)
## Storing conditions
The storage conditions of the product have been specified by the manufacturer, including minimum and maximum temperature conditions for the safe storage of the product based on clinical and stability studies data provided by the manufacturer.
## Storage equipment
Frozen temperature COVID-19 vaccines must be stored in appropriate cold chain equipment (CCE) that can ensure maintenance of the vaccine cold chain. Frozen temperature COVID-19 vaccines can be stored in active and passive CCE; these types of equipment and when they should be used are described below.
### Stand-up freezers
Stand-up freezers are active CCE that can be used to store frozen temperature COVID-19 vaccines. They must be maintained at a temperature of –15°C or colder, depending on the temperature requirement of the particular frozen vaccine provided by the manufacturer. Many stand-up freezers come with a chart logger that contains spare charts and ink. A digital data logger must also be placed in each freezer for continuous monitoring of the cold chain’s temperature. The temperature in newly installed or newly repaired freezer unit may take 2 to 5 days to stabilize within the recommended range of –15°C or colder. Therefore, 2 to 5 days of twice daily freezer temperature recordings must be carried out before using the unit to store vaccines or as stipulated in jurisdictional guidance or recommended by the manufacturer. Freezer validation (installation qualification – IQ, operational qualification – OQ and performance qualification – PQ) is required when/where the freezer location is subject to good manufacturer practices regulations. Refer to pages 31-35 of the for more information on freezers.
Copyright: ThermoFisher Scientific
Left to right: A stand-up freezer, closed and open.
### Qualified transport containers
The frozen temperature COVID-19 vaccine can be transported in its frozen state using conditioned insulated containers that are qualified to maintain the vaccine at -18°C or colder for at least the duration of the intended transportation specified by the manufacturer(s) of the container. Molded expanded polystyrene (EPS) foam shippers, or hard plastic vacuum insulated shippers are qualified to hold the vaccine in the appropriate condition during transportation. The transport containers must be secured (strapped/braced) when being transported to prevent unnecessary movement. The container must be labeled prominently with “Fragile: Handle with Care, Do Not Drop” cautionary statements. A frozen digital data logger and an infrared thermometer (IR) should be placed in each qualified transport container for monitoring the temperature of the cold chain.
Copyright: Pelican Biothermal
Left to right: A qualified transport container for frozen state transportation, put together and in pieces.
### Active refrigerated devices
Frozen temperature COVID-19 vaccine while thawing, or after being thawed to refrigerator temperature, can be stored in a refrigerator qualified to maintain the vaccine at 2°C to 8°C for up to 30 days. It is advisable for refrigerators to be set at the temperature mid-range of about 5°C to provide the best safety margin for temperature fluctuations. Different refrigerators will have specific features that can affect the storage of vaccines. Refer to page 27 of the for a list of refrigerators that are appropriate for use and pages 24-30 of the same document for more information about refrigerators.
### Walk-in cold and freezer rooms
Walk-In Cold Rooms (WIC) and Walk-In Freezer Rooms (WIF) are refrigerated enclosures accessible via at least one door and large enough for a person to walk into, housed within existing buildings. Frozen temperature COVID-19 vaccines can be stored in WICs when thawed and during thawing and in WIFs in its frozen state per the temperature specifications of the vaccine manufacturer. WICs and WIFs are an important storage point in the temperature-controlled supply chain and usually used at the central depots at federal or provincial/territorial levels. The specifications listed in the table below are standard requirements for WICs and WIF:
Types of WICs and WIFs: There are two distinct WICs and WIFs models:
1. Plug-in model
A plug-in product has the controls, the compressor, the condenser and the evaporator as a complete unit, assembled and ready for installation. Each WIC/WIF is supplied with two complete plug-in refrigeration units to provide 100 per cent stand-by cooling. These are hung on the prefabricated panel walls of the WIC/WIF, or mounted on the ceiling panels.
2. Split-unit model
Unlike the Plug-in refrigeration units, the split unit refrigeration model consists of two main parts: the condensing component for installation outside the room where the WIC/WIF is installed, and the evaporator component installed inside the room. At the site of installation, these parts are linked with solid leak proof connection tubing between the evaporator and the condensing unit.
Power requirements for WICs and WIFs: The electric power supply should be maintained at least 8 hours per day for WIC/WIF to operate properly and maintain the appropriate temperature to safeguard the vaccines. Therefore, it is recommended that all central vaccine depots accommodating WICs and WIFs should be fitted with a standby generator with automatic start up, regardless of the reliability of the mains power supply. WICs and WIFs have electronic components and control systems which are susceptible to power fluctuations. Intermittent national grid power supply, as well as stand-by generators during start-up on heavy load pick-up and shut down, result in transients that contribute to system failure. This creates high surges that are detrimental to sensitive components and accessories, leading to their failure and consequently that of the WICs/WIFs. It is therefore recommended to equip WIC and WIF rooms with voltage stabilizers which only allow power to the system when pre-set conditions are met.
Temperature monitoring of WICs and WIFs: A temperature data logger with integral alarm and auto dialer is a standard requirement for WICs and WIFs. The data logger should have: a temperature sensor for specific locations within the
cold/freezer room; a door-open sensor for detecting whether door is open or closed; a power failure sensor; computer to store, display and print temperature and event reports; alarm sounder triggered whenever sensor records a temperature or event excursion outside programmed alarm settings; and an auto dialer which dials pre-programmed telephone numbers or sends E mails, SMS messages in case of alarm.
Another important temperature monitoring component that should be installed in the central depots accommodating WICs and WIFs is an alarm. Alarms should be mains operated and audible with battery back-up and automatic recharge, triggered in the event of mains failure or when cold/freezer room temperatures are outside set parameters.
Prefabrication of WIC and WIF rooms: Depending on the configuration of the WIC/WIF, the door position (on the long or short wall) should be in the middle, leaving a space of 2.5 – 3 meters in front of the door wall for easy access to the room, such as handling and possible repacking of stored goods. When planning the room lay-out, please note that the side and back of the room should be installed with a minimum distance of 100 mm from the existing building wall. As a prerequisite, installation of the WIC/WIF should be done on a levelled concrete floor. As rooms are made of prefabricated insulation panels, the levelling/base evenness requirements are maximum +/- 5 mm per 5 m. The door entrance to the installation area should be at least 900 mm wide to allow access for the prefabricated panels and other components.
# Handling frozen temperature COVID-19 vaccine(s)
Frozen temperature COVID-19 vaccine does not require any particular safe handling requirements other than the requirements outlined in the . However, if the manufacturer or local jurisdiction provides specific guidance for safe handling of frozen temperature COVID-19 vaccine, the advice contained in that document will take precedence over the *National Vaccine Storage and Handling Guidelines for Immunization Providers – 2015*.
# Transporting frozen temperature COVID-19 vaccine(s)
Frozen temperature COVID-19 vaccine should be transported in its frozen state, which is the preference of the manufacturer, however, there are certain circumstances were frozen state transportation is not feasible. In those situations, care must be taken to appropriately transport the product in the liquid state.
## Frozen state transport
Arrangements must be made by FPTs for transportation solutions to transport the vaccine(s) in its frozen state. Caution must be used to ensure that the passive CCE is within the desirable temperature range before transferring vaccine to the unit for transport – packs taken from a ULT may need to warm up to the proper temperature first. Otherwise, frozen vaccine may be exposed to temperatures that are too cold for their acceptable range. The monitoring of cold chain temperature must be carried out during transit and as such, it is important that data logging for temperature excursions be maintained. Specific instructions on the storage conditions and duration of transportation of the vaccine in this state is available and can be provided by the manufacturer. Also refer to jurisdictional guidance, if available.
## Liquid state transport
In the event that frozen state transport resources are not feasible, ability to transport the thawed vaccine at 2°C to 8°C may be required. Vaccine may be removed from a freezer in a frozen state to thaw while in transport – however, the vaccine is considered to be “thawed” for the purpose of transportation guidelines and allowed storage time limits. When in the thawed state, the vaccine is susceptible to interfacial stresses and as such, it is important that it is handled with care and protected as much as possible from shocks, drops, vibration, etc. The vaccine should be transported in a qualified transport container that is secured (strapped/braced) to prevent unnecessary movement. Care must be taken to ensure that the thawed vaccine does not re-freeze in transit or on arrival at its destination. Specifically, the thawed vaccine must not come into contact with any frozen packs added to maintain temperature, and the transport container must be labeled prominently with cautionary statements pertaining to prevention of re-freezing. Portable fridge units and qualified passive long-range vaccine carriers are other options for transporting the thawed vaccine at 2°C to 8°C. Specific instructions on the storage conditions and duration of transportation of the vaccine in the thawed state is available and can be provided by the manufacturer. Also refer to jurisdictional guidance, if available.
Part 3: General guidelines
The guidelines that will be provided in this part is not specific to any vaccine and is applicable only in the absence of manufacturer and local jurisdictional advice.
# Managing temperature excursions during storage
Heat or cold exposure can cause damage to COVID-19 vaccines in storage. It is important that, when they occur, the appropriate actions take place to preserve the integrity of the vaccines. When temperature excursions occur, the user at the vaccine delivery or storage site should follow the actions outlined on page 83 of the .
If the excursion occurred during initial delivery of vaccines to the FPTs, the user must follow jurisdictional processes to make sure the excursion is reported immediately to the national operations center (NOC) and contact the manufacturer or their designated third party agent for recommendations on the actions to be taken. Once the manufacturer has provided recommendations about the excursion, the user will carry out the advised actions needed to address the excursion including how to store the vaccines involved in the excursion incident that have been determined to be usable by the manufacturer. Local public health authorities and other designated sites must ensure proper documentation of all wastage in their respective information management system. Upon resolution of the excursion incident, the jurisdiction will report the outcome to the NOC using the format below.
Subject: FPT Delivery Temp Excursion Report
A. Date of Incident
B. VDS Location
C. Number of Doses in Question
D. Manufacturer Recommendations
E. Wastage (if any)
F. Impact on FPT
However, if the excursion did not occur during initial delivery of vaccines to the FPTs, the user will follow jurisdictional protocols on the actions to be taken until the situation is resolved. The vaccine delivery or storage site must also dispose of any unusable/wasted vaccine, based on jurisdictional guidance. Local public health authority must ensure proper documentation of all wastage in their respective information management system. Upon resolution of the excursion incident, the jurisdiction will report any wastage to the NOC using the format below.
Subject: FPT Temp Excursion Wastage Report
A. Date of Incident
B. VDS Location
C. Situation Surrounding Incident
D. Wastage
E. Impact on FPT
Jurisdictional procedure should be followed to contact the NOC through the following channels:
- email ()
- 24 hours line (1-613-952-0865)
- liaison (1-613-295-5491)
# Reporting vaccine wastage
Vaccine wastage is the sum of vaccines discarded, lost, damaged or destroyed. Accurately determining the wastage rate is essential to support the management of vaccine inventory, orders and deliveries and provides better understanding of the pace of administration and consumption. Accurate wastage reporting will enable PHAC and the NOC to target specific assistance to aid vaccine storage and administration at FPTs storage and vaccine delivery sites.
Two types of vaccine wastage should be reported:
- Closed Vial Wastage (wc): This wastage is primarily due to ineffective temperature control, temperature monitoring and stock management during storage and transportation. It may result from expiry, excess heat exposure, freezing, breakage, and missing inventory or discard following outreach sessions.
- Open Vial Wastage (wo): This wastage is attributable to immunization providers’ practices and discarding of unused doses of multi-dose vials.
Users must report all wastage to their local public health authorities based on their outlined jurisdictional documentation process. FPTs will then report all COVID-19 vaccine wastage (in exact numbers) to the NOC, by vaccine manufacturer, inventory, cumulative wastage numbers and their causes in the format below:
# Managing vaccine storage equipment breakdown
In order to ensure that COVID-19 vaccines maintain their efficacy, it is important to address cold chain breaks when they occur. If vaccine storage equipment stops working, first protect the vaccines and then check the cause of the problem. Guidance outlined by the jurisdiction/local public health office or immunization program for protecting the vaccines and addressing the equipment problem must be followed when cold chain breaks occur. It is advised that local public health units have a storage equipment breakdown plan in place so as to ensure that vaccine that might still be viable can either be safely moved to a suitable alternate storage location (e.g. fridge) or administered to as many individuals as possible to minimize wastage, if feasible (and only once confirmed with manufacturer that unacceptable temperature excursion has not occurred). Guidance has been provided on page 81 of the to support the response to cold chain breaks in the event that jurisdictional guidance is not available.
# Maintenance of vaccine storage equipment
In order to protect the vaccine cold chain, regular maintenance is important as it helps to ensure optimal functionality of cold chain equipment. This ensures that vaccines will continue to be stored at the required temperatures, and also helps to extend the useful life of the CCE. Two main types of maintenance are required as described below:
## Routine maintenance
Routine maintenance of CCE must be carried out at different frequencies; daily, monthly and quarterly by the end-user(s) at all levels of the cold chain. This is usually a do-it-yourself type of maintenance involving the use of simple instructional guides to complete outlined maintenance activities as scheduled. Routine maintenance also enables the identification of issues such as equipment breakdown or malfunctions that may require an expert-led repair response. Please see detailed the guidance on routine maintenance of CCE on pages 36-38 of the
## Planned preventive and corrective maintenance
Planned preventive maintenance of CCE involves the engagement of CCE technical expert(s) to conduct checks on CCE at specified intervals (quarterly or biannually). Corrective actions would be taken to repair any broken or malfunctioning cold chain equipment identified during these maintenance checks. Planned preventive and corrective maintenance can either be insourced or outsourced, and the decision for adopting either or both options is dependent on provincial/local preference and decision-making.
# Information management system for COVID-19 vaccine
A hallmark of effective supply chains is the end-to-end (E2E) visibility of supply data, its triangulation with demand information and its use in making decisions and taking effective action. A new information management system known as VaccineConnect will be deployed to support the COVID-19 vaccine rollout in Canada. VaccineConnect encompasses three key sets of functional capabilities, including the Intelligent Supply Chain (ISC) module, which will support the NOC in terms of executing all the functions associated with managing and distributing the Government of Canada procured vaccines. This comprises transportation and distribution, warehousing and handling, inventory control, logistics information management, security, reporting, and integration with other systems.
To ensure full visibility on the tracking and aggregation of essential information, the ISC module’s capabilities will coalesce data at each stage of the distribution, including vaccine ordering, processing and approval of orders, order fulfillment, distribution of order, and end user reporting. ISC capabilities will:
1. Provide the ability for provinces/territories to place orders for vaccine and the ability for PHAC to send approved orders to manufacturers and LSPs;
2. Track vaccines from manufacture to points of delivery through aggregating information from multiple LSPs and their tracking systems;
3. Provide supply chain management of short shelf-life vaccine products, including cold chain status, and end-to-end traceability and visibility of the demand, inventory, and distribution of the vaccines;
4. Integrate or capture information inputs from the LSPs and other entities involved in vaccines supply chain from manufacturer to the points of distribution/vaccine delivery sites (VDSs); and
5. Provide reporting and representative visual capabilities for pertinent aspects of the distribution system.
Developing and managing VaccineConnect is a federal responsibility to be handled by PHAC. FPTs will be responsible for integrating or inputting information into the VaccineConnect platform which will be interoperable with existing jurisdictional information management systems. FPTs can utilize the data on the VaccineConnect to make evidence-based decisions, consistent with the level of authorized access to the platform that they possess. In the event that a jurisdiction requires some functionalities of the VaccineConnect ISC module added to their information management system to aid vaccine rollout operations, PHAC should be notified by the FPT of the request. The request notification will formally initiate the definition of needs for the specific functionalities requested and the timelines for delivery to the FPTs.
# Accessing COVID-19 vaccines labelling information
Some COVID-19 vaccines will come with QR codes and barcodes on the secondary and tertiary packaging containers. The QR codes are intended to provide rapid access to important vaccine information for clinics, health care workers and information management systems. The QR code contains information on real-time shelf life, heat stability and information on the vaccines’ profiles. To obtain the labelling information for the authorized frozen temperature COVID-19 vaccine, scanning the QR code located on the vial or carton will direct the user to a website that contains the information. For the only authorized ultra-low temperature COVID-19 vaccine in Canada, the Canadian-specific labelling information can be accessed by scanning the QR code on the carton label. The vial and/or carton labels include the statements “For use under Emergency Use Authorization.” The US FDA specific information (e.g., Rx only, NDC) should be disregarded as this is not relevant to the Canadian authorization.
List of references and resources for additional information
The documents below provided the materials used to develop these guidelines. They can also be accessed to provide further guidance on COVID-19 vaccines and specifically, on their storage, handling and transportation.
- Health Canada (2020) –
- Health Canada (2020) –
- PHAC (2015) –
- Health Canada (2020) –
- NACI (2020) –
- NACI (2020) –
- Health Canada (2020) –
- Health Canada (2020) –
- Health Canada (2020) –
- Health Canada (2020) –
- Health Canada (2020) –
- PHAC (2020) – COVID-19 Vaccine Comprehensive Distribution Plan (Draft V2)
- PHAC (2021) – COVID-19 Vaccination Information Resources: Tool Kit for Health Care Providers
- Health Canada (2018) –
- Health Canada (2020) –
- Health Canada (2020) –
- Health Canada (2020) – Repackaging, Storage and Transport Requirements for Vaccines
- Pfizer-BioNTech Comirnaty –
- WHO (2013) –
- WHO (2016) –
- WHO (2019) –
- WHO/UNICEF (2020) –
- WHO (2020) – |
For immunization providers: Interim national vaccine storage, handling and transportation guidelines for ultra-low temperature and frozen temperature COVID-19 vaccines
========================================================================================================================================================================
Posted April 14, 2021
On this page
------------
* [About this document](#s1)
* [List of acronyms used](#s2)
* [Part 1: Ultra-low temperature vaccine(s)](#a1)
+ [Storage of ultra-low temperature COVID-19 vaccine(s)](#a1.1)
+ [Handling of ultra-low temperature COVID-19 vaccine(s)](#a1.2)
+ [Transporting ultra-low temperature COVID-19 vaccine(s)](#a1.3)
* [Part 2: Frozen temperature vaccine(s)](#a2)
+ [Storage of frozen temperature COVID-19 vaccine(s)](#a2.1)
+ [Handling frozen temperature COVID-19 vaccine(s)](#a2.2)
+ [Transporting frozen temperature COVID-19 vaccine(s)](#a2.3)
* [Part 3: General guidelines](#a3)
+ [Managing temperature excursions during storage](#a3.1)
+ [Reporting vaccine wastage](#a3.2)
+ [Managing vaccine storage equipment breakdown](#a3.3)
+ [Maintenance of vaccine storage equipment](#a3.4)
+ [Information management system for COVID-19 vaccine](#a3.5)
+ [Accessing COVID-19 vaccines labelling information](#a3.6)
* [List of references and resources for additional information](#a4)
* [Acknowledgments](#a5)
* [Contact us](#a6)
About this document
-------------------
The objective of the Interim National Vaccine Storage, Handling and Transportation Guidelines for Ultra-Low Temperature and Frozen Temperature COVID-19 Vaccines – 2021 is to supplement and update the guidance for storage, handling and transportation of ultra-low temperature and frozen temperature COVID-19 vaccines for immunization providers in Canada.
Vaccines must be stored in specific temperature conditions and handled with extreme care in order to maximize their shelf life, and to ensure their potency and efficacy. Specific guidelines for vaccine storage and handling procedures may vary among public health offices and immunization programs, therefore this document is meant to supplement existing jurisdictional policies and manufacturer instructions rather than to replace them. This document does not replace the [*National Vaccine Storage and Handling Guidelines for Immunization Providers – 2015*](/en/public-health/services/publications/healthy-living/national-vaccine-storage-handling-guidelines-immunization-providers-2015.html) and as such, the 2015 guidelines takes precedence over this policy document in the event that clarity is needed on any related subject. Individuals and companies that hold an establishment license from Health Canada who access information from these guidelines are still expected to meet all applicable requirements of the Food and Drugs Act and Food and Drug Regulations (FDR) as this document does not replace the requirements under the FDR as outlined in the [*Good Manufacturing Practices Guide for Drug Products (GUI-0001)*](/en/health-canada/services/drugs-health-products/compliance-enforcement/good-manufacturing-practices/guidance-documents/gmp-guidelines-0001/document.html) .
### Key assumptions informing these guidelines
The information provided in these guidelines are based on the following assumptions:
1. The recommendations for storage, handling and transportation of the Health Canada authorized ultra-low temperature and frozen temperature COVID-19 vaccines is informed by stability, temperature and other studies carried out by the manufacturers at the time the version of the guidelines was issued.
2. These guidelines will be updated periodically as additional evidence, experience and knowledge of vaccine storage, handling and transportation practices for the authorized ultra-low temperature and frozen temperature COVID-19 vaccines become available.
List of acronyms used
---------------------
CCE
Cold Chain Equipment
CSA
Canadian Standards Association
E2E
End-to-End
EOC
Emergency Operations Center
EPS
Expanded Polystyrene
FPTs
Federal, Provinces and Territories
IR
Infrared
IQ
Installation Qualification
ISC[Footnote 1](#fn1)
Intelligent Supply Chain
LMIS
Logistics Management Information System
LSPs
Logistics Service Providers (note: in some jurisdictions, referred to as 3LP for Third Party Logistics Provider)
NOC
National Operations Center
OQ
Operational Qualification
PCM
Phase Change Material
PHAC
Public Health Agency of Canada
POD
Points of Distribution
PPE
Personal protective equipment
PQ
Performance Qualification
P/Ts or PTs
Provinces and Territories
UCC
Ultra-Cold Chain
ULT
Ultra-Low Temperature
VDS
Vaccine delivery site
WICs
Walk-In Cold Rooms
WIFs
Walk-In Freezer Rooms
Part 1: Ultra-low temperature vaccine(s)
----------------------------------------
The information provided below are general guidelines for the management of ultra-low temperature COVID-19 vaccines. Detailed instructions for [storage, handling and transportation processes of authorized ultra-low temperature COVID-19 vaccine products in Canada (PDF)](https://www.pfizer.ca/sites/default/files/202102/Pfizer-BioNTech_COVID-19_Vaccine_PM_EN_248272_248628_08-Feb-2021.pdf) can be found on the manufacturer’s website and supersedes any information captured below.
### Storage of ultra-low temperature COVID-19 vaccine(s)
#### Storing conditions
The storage conditions of the product have been specified by the manufacturer, including minimum and maximum temperature conditions for the safe storage of the product based on clinical and stability studies data provided by the manufacturer.
#### Storage equipment
Ultra-low temperature COVID-19 vaccines must be stored in appropriate cold chain equipment (CCE) that can maintain its ultra-low temperature. The manufacturer will indicate whether its vaccine(s) can be stored in the active CCE[Footnote 2](#fn2) and/or passive CCE[Footnote 3](#fn3) described below.
##### Ultra-low temperature (ULT) freezers
**Technology features:** ULT freezers are active CCE that produce ultra-low temperatures to store vaccines requiring ultra-cold chain, with temperature requirement ranging from -80°C to -60°C. ULT freezers must be maintained at the temperature requirement of the particular vaccine provided by the manufacturer. Vials are stable at -80ºC to -60ºC until the expiration date on the vial and tray (6 months after manufacture). In addition to storing vaccines, ULT freezers can be used to freeze ultra-cold freezer packs (also known as phase change materials) to -80°C.
**Power requirements:** A reliable power supply is needed for optimal functionality of ULT freezers. If the building where the ULT freezer is kept provides less than the rated voltage, power voltage boosters may be required, depending on the type of ULT freezer. A back-up source of power supply is recommended, particularly if the building where the freezer will be stored is in an area with frequent power outages. A locking plug or a metal cage to prevent the freezer from being accidently unplugged from the electrical outlet/wall socket. All ULT freezers cause additional heat load and must be installed in an air-conditioned room to ensure working ambient temperature of <30°C.
**Temperature monitoring:** All ULT freezers should have data loggers to automate cold chain tracking. Data loggers for ULT freezers should have a data recording period of not less than 30 days at a data rate of not less than one data point per half hour. The data loggers should also have not less than 30 days of battery life and must have an integrated USB port for uploading data. It is also important that the computer requirements for uploading USB data is met.
**Figure 1. ULT freezers and data loggers**
Copyright: Fisher Scientific; PHC Corporation of North America; Sensitech
Figure 1 - Text description
Left to right: An ultra-low temperature standing freezer, an ultra-low temperature chest freezer, a data logger shown at multiple angles, and a data logger connected with USB port.
##### Thermal shippers
In the absence of ULT freezers, a thermal shipper/container can be used as passive CCE to store the vaccine temporarily at the clinic or vaccine delivery site. Thermal shippers require dry ice and maintain a temperature range of -90°C to -60°C. Thermal shippers have a capacity range of 3.4 to 6.2 liters and come with a vial rack system and a temperature data logger. In the event that thermal shipper does not contain a temperature data logger, arrangement should be made for the provision of data loggers to ensure proper monitoring of the cold chain. The duration and conditions for the use of thermal shippers as temporary storage for ultra-low temperature vaccines are available and can be obtained from the manufacturer*.*
##### Active refrigerated devices
The manufacturer of ultra-low temperature COVID-19 vaccines will provide guidance on scenarios where their product can be stored in refrigerators as well as the specific duration and temperature of storage. In the event that refrigerators will be required, it is important to know the specific features of the device that can affect the storage of vaccines. For this reason, guidance has been provided on the refrigerators that are acceptable for vaccine storage and those that are not on pages 26-30 of the [*National Vaccine Storage and Handling Guidelines for Immunization Providers – 2015*](/en/public-health/services/publications/healthy-living/national-vaccine-storage-handling-guidelines-immunization-providers-2015.html). Some refrigerators come as a fridge/freezer combination to enable the storage of different vaccines at their appropriate temperatures. The fridge compartment should maintain temperatures between 2°C and 8°C for vaccine storage, and it is advisable for fridges to be set at the temperature mid-range of about 5°C to provide the best safety margin for temperature fluctuations. A digital data logger should also be placed in each refrigerated device for continuous monitoring of the cold chain’s temperature. Refer to pages 24-35 of the [*National Vaccine Storage and Handling Guidelines for Immunization Providers – 2015*](/en/public-health/services/publications/healthy-living/national-vaccine-storage-handling-guidelines-immunization-providers-2015.html) for more information on refrigerators.
### Handling of ultra-low temperature COVID-19 vaccine(s)
#### Personal protection measures for handling dry ice
It is important that appropriate protection is provided to personnel at vaccine delivery sites who will be handling dry ice. Jurisdictional occupational health and safety requirements, MSDS[Footnote 4](#fn4) and federal laws on workplace safety should be referred to for information on potential hazards and how to work safely with dry ice. In the absence of an existing jurisdictional guidance, the requirements for safe handling of dry ice for individual protection are provided below:
**Eye/face protection:** Safety eyewear complying with current CSA standard Z94.3 should be used when a risk assessment indicates this is necessary to avoid exposure to liquid splashes, mists, gases or dusts. If contact is possible, safety glasses with side-shields or face shields should be worn, unless the assessment indicates a higher degree of protection is required.
**Hand protection:** Chemical-resistant, impervious and insulated gloves complying with jurisdictional standards should be worn at all times when handling dry ice. Gloves can be leather or nitrile, with fabric liner and cuffs. Ice scoops can also be used together with gloves to further prevent unintentional direct contact of dry ice with bare hands.
**Body protection:** Personal protective equipment (PPE) for the body such as aprons, or other similar PPE that meet jurisdictional standards, should be selected based on the task being performed and the risks involved before handling dry ice and related product, when a risk assessment indicates this is necessary. Apron, or other similar PPE, can be leather or canvas-type fabric.
**Hygiene measures:** Hands, forearms and face must be washed after handling dry ice, before eating, smoking, using the lavatory, and at the end of the working period.
**Health and safety considerations:** Dry ice must be handled in a well-ventilated area with ease of access to first aid kits.
**Figure 2. Dry ice safe handling equipment**
Copyright: Fisher Scientific
Figure 2 - Text description
Left to right: A face shield with an apron and gloves, tongs, and a scoop for dry ice handling.
#### Disposal of used multi-dose vaccine vials/vial trays
Vials should be discarded in biomedical waste containers and in compliance with jurisdictional protocols. Vaccine vials should not be disposed of in sharps containers as vials are not considered a sharp and also because, sharps containers are not meant to store/have liquids. Therefore, vials containing vaccines should not be put in sharps containers or else they can leak if they are broken in the sharps container. Unlike the biomedical waste pails which are leak proof the sharps containers are not. Store empty COVID-19 vaccine vials in white and/or blue biomedical waste containers until they are ready for disposal. Incinerate the white and/or blue pharmaceutical waste containers. Do not autoclave and dispose of them in landfills since this poses a security risk for counterfeiting operations. Discard vial trays and all packaging associated with the vaccine so they cannot be reused and to prevent counterfeit efforts and any other potential criminal activities. Refer to jurisdictional and manufacturer instructions for more guidance on the disposal of ultra-low temperature COVID-19 vaccine.
### Transporting ultra-low temperature COVID-19 vaccine(s)
Ultra-low temperature COVID-19 vaccine(s) can be transported either ultra-frozen or thawed at refrigerator temperature for transport. Vaccine may be removed from a ULT freezer in a frozen state to thaw while in transport – however, the vaccine is considered to be “thawed” for the purpose of transportation guidelines and allowed storage time limits. When in the thawed state, the vaccine is susceptible to interfacial stresses and as such, it is important that it is handled with care and protected as much as possible from shocks, drops, vibration, etc. Portable vaccine refrigerator and freezer units that have built-in temperature regulation are considered the best options for vaccine transport. Expedited transportation service with an insulated container containing dry ice (for ultra-cold transport) / gel packs (for 2°C to 8°C transport) is required to ensure the vaccine is kept at the right temperature. Temperature tracking logs/devices should be put in place for full trays and separate vials during transfer activities, pack-out, repacking and redistribution. Detailed instructions for transportation of ultra-low temperature COVID-19 vaccine(s) in frozen or refrigerated state, including timing, is available and can be obtained from the manufacturer. Also refer to jurisdictional guidance, if available.
Part 2: Frozen temperature vaccine(s)
-------------------------------------
The information provided below are general guidelines for the management of frozen temperature COVID-19 vaccines. Detailed [instructions for storage, handling and transportation processes of authorized frozen temperature COVID-19 vaccine products in Canada](https://www.modernacovid19global.com/ca/) can be found on the manufacturer’s website and supersedes any information captured below.
### Storage of frozen temperature COVID-19 vaccine(s)
#### Storing conditions
The storage conditions of the product have been specified by the manufacturer, including minimum and maximum temperature conditions for the safe storage of the product based on clinical and stability studies data provided by the manufacturer.
#### Storage equipment
Frozen temperature COVID-19 vaccines must be stored in appropriate cold chain equipment (CCE) that can ensure maintenance of the vaccine cold chain. Frozen temperature COVID-19 vaccines can be stored in active and passive CCE; these types of equipment and when they should be used are described below.
##### Stand-up freezers
Stand-up freezers are active CCE that can be used to store frozen temperature COVID-19 vaccines. They must be maintained at a temperature of –15°C or colder, depending on the temperature requirement of the particular frozen vaccine provided by the manufacturer. Many stand-up freezers come with a chart logger that contains spare charts and ink. A digital data logger must also be placed in each freezer for continuous monitoring of the cold chain’s temperature. The temperature in newly installed or newly repaired freezer unit may take 2 to 5 days to stabilize within the recommended range of –15°C or colder. Therefore, 2 to 5 days of twice daily freezer temperature recordings must be carried out before using the unit to store vaccines or as stipulated in jurisdictional guidance or recommended by the manufacturer. Freezer validation (installation qualification – IQ[Footnote 5](#fn5), operational qualification – OQ[Footnote 6](#fn6) and performance qualification – PQ[Footnote 7](#fn7)) is required when/where the freezer location is subject to good manufacturer practices regulations. Refer to pages 31-35 of the [*National Vaccine Storage and Handling Guidelines for Immunization Providers – 2015*](/en/public-health/services/publications/healthy-living/national-vaccine-storage-handling-guidelines-immunization-providers-2015.html) for more information on freezers.
**Figure 3. Stand-up freezer (closed and open)**
Copyright: ThermoFisher Scientific
Figure 3 - Text description
Left to right: A stand-up freezer, closed and open.
##### Qualified transport containers
The frozen temperature COVID-19 vaccine can be transported in its frozen state using conditioned insulated containers that are qualified to maintain the vaccine at -18°C or colder for at least the duration of the intended transportation specified by the manufacturer(s) of the container. Molded expanded polystyrene (EPS) foam shippers, or hard plastic vacuum insulated shippers are qualified to hold the vaccine in the appropriate condition during transportation. The transport containers must be secured (strapped/braced) when being transported to prevent unnecessary movement. The container must be labeled prominently with “Fragile: Handle with Care, Do Not Drop” cautionary statements. A frozen digital data logger and an infrared thermometer (IR) should be placed in each qualified transport container for monitoring the temperature of the cold chain.
**Figure 4. Qualified transport containers for frozen state transportation**
Copyright: Pelican Biothermal
Figure 4 - Text description
Left to right: A qualified transport container for frozen state transportation, put together and in pieces.
##### Active refrigerated devices
Frozen temperature COVID-19 vaccine while thawing, or after being thawed to refrigerator temperature, can be stored in a refrigerator qualified to maintain the vaccine at 2°C to 8°C for up to 30 days. It is advisable for refrigerators to be set at the temperature mid-range of about 5°C to provide the best safety margin for temperature fluctuations. Different refrigerators will have specific features that can affect the storage of vaccines. Refer to page 27 of the [*National Vaccine Storage and Handling Guidelines for Immunization Providers – 2015*](/en/public-health/services/publications/healthy-living/national-vaccine-storage-handling-guidelines-immunization-providers-2015.html) for a list of refrigerators that are appropriate for use and pages 24-30 of the same document for more information about refrigerators.
##### Walk-in cold and freezer rooms
Walk-In Cold Rooms (WIC) and Walk-In Freezer Rooms (WIF) are refrigerated enclosures accessible via at least one door and large enough for a person to walk into, housed within existing buildings. Frozen temperature COVID-19 vaccines can be stored in WICs when thawed and during thawing and in WIFs in its frozen state per the temperature specifications of the vaccine manufacturer. WICs and WIFs are an important storage point in the temperature-controlled supply chain and usually used at the central depots at federal or provincial/territorial levels. The specifications listed in the table below are standard requirements for WICs and WIF[Footnote 8](#fn8):
Table 1: Standard requirements for WICs and WIFs
| Specification | Requirement |
| --- | --- |
| Thermostat | Thermostat must be calibrated to ITS-90 (International Temperature Scale) and should be accurate to +/- 0.5°C |
| Hold-over time | The stated hold-over time (Temperature must remain above +2°C for cold climate zones, below +10°C for hot and temperate zones for WIC, and must not rise above -10°C for WIF) for at least 8 hours for both WIC and WIF |
| Lighting | Lighting must be internal ceiling mounted tungsten filament light fitting or LED with external switch and pilot light (fluorescent lighting must not be used) |
| Gas | CFC Free refrigerant gas must be used |
| Compressors | All compressors to be fitted with hour meter to record the running duration for each unit |
**Types of WICs and WIFs:** There are two distinct WICs and WIFs models:
**1. Plug-in model**
A plug-in product has the controls, the compressor, the condenser and the evaporator as a complete unit, assembled and ready for installation. Each WIC/WIF is supplied with two complete plug-in refrigeration units to provide 100 per cent stand-by cooling. These are hung on the prefabricated panel walls of the WIC/WIF, or mounted on the ceiling panels.
**2. Split-unit model**
Unlike the Plug-in refrigeration units, the split unit refrigeration model consists of two main parts: the condensing component for installation outside the room where the WIC/WIF is installed, and the evaporator component installed inside the room. At the site of installation, these parts are linked with solid leak proof connection tubing between the evaporator and the condensing unit.
**Power requirements for WICs and WIFs:** The electric power supply should be maintained at least 8 hours per day for WIC/WIF to operate properly and maintain the appropriate temperature to safeguard the vaccines. Therefore, it is recommended that all central vaccine depots accommodating WICs and WIFs should be fitted with a standby generator with automatic start up, regardless of the reliability of the mains power supply. WICs and WIFs have electronic components and control systems which are susceptible to power fluctuations. Intermittent national grid power supply, as well as stand-by generators during start-up on heavy load pick-up and shut down, result in transients that contribute to system failure. This creates high surges that are detrimental to sensitive components and accessories, leading to their failure and consequently that of the WICs/WIFs. It is therefore recommended to equip WIC and WIF rooms with voltage stabilizers which only allow power to the system when pre-set conditions are met.
**Temperature monitoring of WICs and WIFs:** A temperature data logger with integral alarm and auto dialer is a standard requirement for WICs and WIFs. The data logger should have: a temperature sensor for specific locations within the
cold/freezer room; a door-open sensor for detecting whether door is open or closed; a power failure sensor; computer to store, display and print temperature and event reports; alarm sounder triggered whenever sensor records a temperature or event excursion outside programmed alarm settings; and an auto dialer which dials pre-programmed telephone numbers or sends E mails, SMS messages in case of alarm.
Another important temperature monitoring component that should be installed in the central depots accommodating WICs and WIFs is an alarm. Alarms should be mains operated and audible with battery back-up and automatic recharge, triggered in the event of mains failure or when cold/freezer room temperatures are outside set parameters.
**Prefabrication of WIC and WIF rooms:** Depending on the configuration of the WIC/WIF, the door position (on the long or short wall) should be in the middle, leaving a space of 2.5 – 3 meters in front of the door wall for easy access to the room, such as handling and possible repacking of stored goods. When planning the room lay-out, please note that the side and back of the room should be installed with a minimum distance of 100 mm from the existing building wall. As a prerequisite, installation of the WIC/WIF should be done on a levelled concrete floor. As rooms are made of prefabricated insulation panels, the levelling/base evenness requirements are maximum +/- 5 mm per 5 m. The door entrance to the installation area should be at least 900 mm wide to allow access for the prefabricated panels and other components.
### Handling frozen temperature COVID-19 vaccine(s)
Frozen temperature COVID-19 vaccine does not require any particular safe handling requirements other than the requirements outlined in the [*National Vaccine Storage and Handling Guidelines for Immunization Providers – 2015*](/en/public-health/services/publications/healthy-living/national-vaccine-storage-handling-guidelines-immunization-providers-2015.html). However, if the manufacturer or local jurisdiction provides specific guidance for safe handling of frozen temperature COVID-19 vaccine, the advice contained in that document will take precedence over the *National Vaccine Storage and Handling Guidelines for Immunization Providers – 2015*.
### Transporting frozen temperature COVID-19 vaccine(s)
Frozen temperature COVID-19 vaccine should be transported in its frozen state, which is the preference of the manufacturer, however, there are certain circumstances were frozen state transportation is not feasible. In those situations, care must be taken to appropriately transport the product in the liquid state.
#### Frozen state transport
Arrangements must be made by FPTs for transportation solutions to transport the vaccine(s) in its frozen state. Caution must be used to ensure that the passive CCE is within the desirable temperature range before transferring vaccine to the unit for transport – packs taken from a ULT may need to warm up to the proper temperature first. Otherwise, frozen vaccine may be exposed to temperatures that are too cold for their acceptable range. The monitoring of cold chain temperature must be carried out during transit and as such, it is important that data logging for temperature excursions be maintained. Specific instructions on the storage conditions and duration of transportation of the vaccine in this state is available and can be provided by the manufacturer. Also refer to jurisdictional guidance, if available.
#### Liquid state transport
In the event that frozen state transport resources are not feasible, ability to transport the thawed vaccine at 2°C to 8°C may be required. Vaccine may be removed from a freezer in a frozen state to thaw while in transport – however, the vaccine is considered to be “thawed” for the purpose of transportation guidelines and allowed storage time limits. When in the thawed state, the vaccine is susceptible to interfacial stresses and as such, it is important that it is handled with care and protected as much as possible from shocks, drops, vibration, etc. The vaccine should be transported in a qualified transport container[Footnote 9](#fn9) that is secured (strapped/braced) to prevent unnecessary movement. Care must be taken to ensure that the thawed vaccine does not re-freeze in transit or on arrival at its destination. Specifically, the thawed vaccine must not come into contact with any frozen packs added to maintain temperature, and the transport container must be labeled prominently with cautionary statements pertaining to prevention of re-freezing. Portable fridge units and qualified passive long-range vaccine carriers are other options for transporting the thawed vaccine at 2°C to 8°C. Specific instructions on the storage conditions and duration of transportation of the vaccine in the thawed state is available and can be provided by the manufacturer. Also refer to jurisdictional guidance, if available.
Part 3: General guidelines
--------------------------
The guidelines that will be provided in this part is not specific to any vaccine and is applicable only in the absence of manufacturer and local jurisdictional advice.
### Managing temperature excursions during storage
Heat or cold exposure can cause damage to COVID-19 vaccines in storage. It is important that, when they occur, the appropriate actions take place to preserve the integrity of the vaccines. When temperature excursions occur, the user at the vaccine delivery or storage site should follow the actions outlined on page 83 of the [*National Vaccine Storage and Handling Guidelines for Immunization Providers – 2015*](/en/public-health/services/publications/healthy-living/national-vaccine-storage-handling-guidelines-immunization-providers-2015.html).
If the excursion occurred during initial delivery of vaccines to the FPTs, the user must follow jurisdictional processes to make sure the excursion is reported immediately to the national operations center (NOC) and contact the manufacturer or their designated third party agent for recommendations on the actions to be taken. Once the manufacturer has provided recommendations about the excursion, the user will carry out the advised actions needed to address the excursion including how to store the vaccines involved in the excursion incident that have been determined to be usable by the manufacturer. Local public health authorities and other designated sites must ensure proper documentation of all wastage in their respective information management system. Upon resolution of the excursion incident, the jurisdiction will report **the outcome** to the NOC using the format below.
Subject: FPT Delivery Temp Excursion Report
A. Date of Incident
B. VDS Location
C. Number of Doses in Question
D. Manufacturer Recommendations
E. Wastage (if any)
F. Impact on FPT
However, if the excursion did not occur during initial delivery of vaccines to the FPTs, the user will follow jurisdictional protocols on the actions to be taken until the situation is resolved. The vaccine delivery or storage site must also dispose of any unusable/wasted vaccine, based on jurisdictional guidance. Local public health authority must ensure proper documentation of all wastage in their respective information management system. Upon resolution of the excursion incident, the jurisdiction will report **any wastage** to the NOC using the format below.
Subject: FPT Temp Excursion Wastage Report
A. Date of Incident
B. VDS Location
C. Situation Surrounding Incident
D. Wastage
E. Impact on FPT
Jurisdictional procedure should be followed to contact the NOC through the following channels:
* email ([[email protected]](mailto:[email protected]))
* 24 hours line (1-613-952-0865)
* liaison (1-613-295-5491)
Refer to pages 82-83 of the [*National Vaccine Storage and Handling Guidelines for Immunization Providers – 2015*](/en/public-health/services/publications/healthy-living/national-vaccine-storage-handling-guidelines-immunization-providers-2015.html) for more guidance on managing temperature excursions.
### Reporting vaccine wastage
Vaccine wastage is the sum of vaccines discarded, lost, damaged or destroyed. Accurately determining the wastage rate is essential to support the management of vaccine inventory, orders and deliveries and provides better understanding of the pace of administration and consumption. Accurate wastage reporting will enable PHAC and the NOC to target specific assistance to aid vaccine storage and administration at FPTs storage and vaccine delivery sites.
Two types of vaccine wastage should be reported:
* Closed Vial Wastage (wc): This wastage is primarily due to ineffective temperature control, temperature monitoring and stock management during storage and transportation. It may result from expiry, excess heat exposure, freezing, breakage, and missing inventory or discard following outreach sessions.
* Open Vial Wastage (wo): This wastage is attributable to immunization providers’ practices and discarding of unused doses of multi-dose vials.
Users must report all wastage to their local public health authorities based on their outlined jurisdictional documentation process. FPTs will then report all COVID-19 vaccine wastage (in exact numbers) to the NOC, by vaccine manufacturer, inventory, cumulative wastage numbers and their causes in the format below:
| |
| --- |
| FPT: |
| Date: |
| Inventory (doses) | Closed vial wastage (doses) | Causes of closed vial wastage (percentage) | Open vial wastage (doses) | Causes of open vial wastage (percentage) |
| Vaccine A | | | | |
| Vaccine B | | | | |
| Sample vaccine | 1,500 | Freezing (75%); missing inventory (5%); heating (20%) | 300 | Discarding of unused multi-dose vial (100%) |
| Total | | | | |
### Managing vaccine storage equipment breakdown
In order to ensure that COVID-19 vaccines maintain their efficacy, it is important to address cold chain breaks when they occur. If vaccine storage equipment stops working, first protect the vaccines and then check the cause of the problem. Guidance outlined by the jurisdiction/local public health office or immunization program for protecting the vaccines and addressing the equipment problem must be followed when cold chain breaks occur. It is advised that local public health units have a storage equipment breakdown plan in place so as to ensure that vaccine that might still be viable can either be safely moved to a suitable alternate storage location (e.g. fridge) or administered to as many individuals as possible to minimize wastage, if feasible (and only once confirmed with manufacturer that unacceptable temperature excursion has not occurred). Guidance has been provided on page 81 of the [*National Vaccine Storage and Handling Guidelines for Immunization Providers – 2015*](/en/public-health/services/publications/healthy-living/national-vaccine-storage-handling-guidelines-immunization-providers-2015.html) to support the response to cold chain breaks in the event that jurisdictional guidance is not available.
### Maintenance of vaccine storage equipment
In order to protect the vaccine cold chain, regular maintenance is important as it helps to ensure optimal functionality of cold chain equipment. This ensures that vaccines will continue to be stored at the required temperatures, and also helps to extend the useful life of the CCE. Two main types of maintenance are required as described below:
#### Routine maintenance
Routine maintenance of CCE must be carried out at different frequencies; daily, monthly and quarterly by the end-user(s) at all levels of the cold chain. This is usually a do-it-yourself type of maintenance involving the use of simple instructional guides to complete outlined maintenance activities as scheduled. Routine maintenance also enables the identification of issues such as equipment breakdown or malfunctions that may require an expert-led repair response. Please see detailed the guidance on routine maintenance of CCE on pages 36-38 of the [*National Vaccine Storage and Handling Guidelines for Immunization Providers – 2015.*](/en/public-health/services/publications/healthy-living/national-vaccine-storage-handling-guidelines-immunization-providers-2015.html)
#### Planned preventive and corrective maintenance
Planned preventive maintenance of CCE involves the engagement of CCE technical expert(s) to conduct checks on CCE at specified intervals (quarterly or biannually). Corrective actions would be taken to repair any broken or malfunctioning cold chain equipment identified during these maintenance checks. Planned preventive and corrective maintenance can either be insourced or outsourced, and the decision for adopting either or both options is dependent on provincial/local preference and decision-making.
### Information management system for COVID-19 vaccine
A hallmark of effective supply chains is the end-to-end (E2E) visibility of supply data, its triangulation with demand information and its use in making decisions and taking effective action. A new information management system known as VaccineConnect will be deployed to support the COVID-19 vaccine rollout in Canada. VaccineConnect encompasses three key sets of functional capabilities, including the Intelligent Supply Chain (ISC) module, which will support the NOC in terms of executing all the functions associated with managing and distributing the Government of Canada procured vaccines. This comprises transportation and distribution, warehousing and handling, inventory control, logistics information management, security, reporting, and integration with other systems.
To ensure full visibility on the tracking and aggregation of essential information, the ISC module’s capabilities will coalesce data at each stage of the distribution, including vaccine ordering, processing and approval of orders, order fulfillment, distribution of order, and end user reporting. ISC capabilities will:
1. Provide the ability for provinces/territories to place orders for vaccine and the ability for PHAC to send approved orders to manufacturers and LSPs;
2. Track vaccines from manufacture to points of delivery through aggregating information from multiple LSPs and their tracking systems;
3. Provide supply chain management of short shelf-life vaccine products, including cold chain status, and end-to-end traceability and visibility of the demand, inventory, and distribution of the vaccines;
4. Integrate or capture information inputs from the LSPs and other entities involved in vaccines supply chain from manufacturer to the points of distribution/vaccine delivery sites (VDSs); and
5. Provide reporting and representative visual capabilities for pertinent aspects of the distribution system.
Developing and managing VaccineConnect is a federal responsibility to be handled by PHAC. FPTs will be responsible for integrating or inputting information into the VaccineConnect platform which will be interoperable with existing jurisdictional information management systems. FPTs can utilize the data on the VaccineConnect to make evidence-based decisions, consistent with the level of authorized access to the platform that they possess. In the event that a jurisdiction requires some functionalities of the VaccineConnect ISC module added to their information management system to aid vaccine rollout operations, PHAC should be notified by the FPT of the request. The request notification will formally initiate the definition of needs for the specific functionalities requested and the timelines for delivery to the FPTs.
### Accessing COVID-19 vaccines labelling information
Some COVID-19 vaccines will come with QR codes and barcodes on the secondary and tertiary packaging containers. The QR codes are intended to provide rapid access to important vaccine information for clinics, health care workers and information management systems. The QR code contains information on real-time shelf life, heat stability and information on the vaccines’ profiles. To obtain the labelling information for the authorized frozen temperature COVID-19 vaccine, scanning the QR code located on the vial or carton will direct the user to a website that contains the information. For the only authorized ultra-low temperature COVID-19 vaccine in Canada, the Canadian-specific labelling information can be accessed by scanning the QR code on the carton label. The vial and/or carton labels include the statements “For use under Emergency Use Authorization.” The US FDA specific information (e.g., Rx only, NDC) should be disregarded as this is not relevant to the Canadian authorization.
List of references and resources for additional information
-----------------------------------------------------------
The documents below provided the materials used to develop these guidelines. They can also be accessed to provide further guidance on COVID-19 vaccines and specifically, on their storage, handling and transportation.
* Health Canada (2020) – [Planning guidance for administration of COVID-19 vaccine](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/planning-guidance-administration-covid-19-vaccine.html#a3)
* Health Canada (2020) – [Planning guidance for immunization clinics for COVID-19 vaccines](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/planning-immunization-clinics-covid-19-vaccines.html#a2.8)
* PHAC (2015) – [National Vaccine Storage and Handling Guidelines for Immunization Providers](/en/public-health/services/publications/healthy-living/national-vaccine-storage-handling-guidelines-immunization-providers-2015.html)
* Health Canada (2020) – [Coronavirus disease (COVID-19): Guidance documents](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents.html)
* NACI (2020) – [Recommendations on the use of COVID-19 vaccines](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/recommendations-use-covid-19-vaccines.html)
* NACI (2020) – [Guidance on the prioritization of initial doses of COVID-19 vaccine(s)](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-prioritization-initial-doses-covid-19-vaccines.html)
* Health Canada (2020) – [Product Monograph- Pfizer-BioNTech Comirnaty COVID-19 Vaccine](https://www.pfizer.ca/sites/default/files/202102/Pfizer-BioNTech_COVID-19_Vaccine_PM_EN_248272_248628_08-Feb-2021.pdf)
* Health Canada (2020) – [Pfizer-BioNTech Comirnaty COVID-19 vaccine: What you should know](/en/health-canada/services/drugs-health-products/covid19-industry/drugs-vaccines-treatments/vaccines/pfizer-biontech.html)
* Health Canada (2020) – [Authorization of Pfizer-BioNTech Comirnaty COVID-19 Vaccine with English-only Carton and Vial Labels](https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2020/74541a-eng.php)
* Health Canada (2020) – [Product Monograph- Moderna Spikevax COVID-19 Vaccine](https://covid-vaccine.canada.ca/info/pdf/moderna-covid-19-vaccine-pm1.pdf)
* Health Canada (2020) – [Moderna Spikevax COVID-19 vaccine: What you should know](/en/health-canada/services/drugs-health-products/covid19-industry/drugs-vaccines-treatments/vaccines/moderna.html)
* PHAC (2020) – COVID-19 Vaccine Comprehensive Distribution Plan (Draft V2)
* PHAC (2021) – COVID-19 Vaccination Information Resources: Tool Kit for Health Care Providers
* Health Canada (2018) – [Good Manufacturing Practices Guide for Drug Products (GUI-0001)](/en/health-canada/services/drugs-health-products/compliance-enforcement/good-manufacturing-practices/guidance-documents/gmp-guidelines-0001.html)
* Health Canada (2020) – [Guidelines for environmental control of drugs during storage and transportation (GUI-0069)](/en/health-canada/services/drugs-health-products/compliance-enforcement/good-manufacturing-practices/guidance-documents/guidelines-temperature-control-drug-products-storage-transportation-0069.html)
* Health Canada (2020) – [Storage and handling of immunizing agents: Canadian Immunization Guide](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-9-storage-handling-immunizing-agents.html)
* Health Canada (2020) – Repackaging, Storage and Transport Requirements for Vaccines
* Pfizer-BioNTech Comirnaty – [Vaccination Storage & Dry Ice Safety Handling](https://www.cvdvaccine.ca/product-storage-and-dry-ice)
* WHO (2013) – [Effective Vaccine Management (EVM) Model Standard Operating Procedures: Consolidated version, with user guide](https://www.who.int/immunization/programmes_systems/supply_chain/EVM_model_SOP_manual_EN_June_2013_compact.pdf)
* WHO (2016) – [Global Ebola Vaccine Implementation Team (GEVIT): Practical guidance on the use of Ebola vaccine in an outbreak response](https://www.who.int/csr/resources/publications/ebola/gevit-guide/en/)
* WHO (2019) – [Revising global indicative wastage rates: a WHO initiative for better planning and forecasting of vaccine supply needs](https://www.who.int/immunization/programmes_systems/supply_chain/resources/Revising_Wastage_Concept_Note.pdf?ua=1)
* WHO/UNICEF (2020) – [Guidance on developing a national deployment and vaccination plan for COVID-19 vaccines](https://www.who.int/publications/i/item/WHO-2019-nCoV-Vaccine_deployment-2020.1)
* WHO (2020) – [PQS devices catalogue: Pre-qualified equipment for the Expanded Programme on Immunization (EPI)](https://apps.who.int/immunization_standards/vaccine_quality/pqs_catalogue/PdfCatalogue.aspx?cat_type=device)
Acknowledgments
---------------
The Public Health Agency of Canada would like to acknowledge the work of the Vaccine Logistics Task Group, the Vaccine Supply Working Group (VSWG) of the Canadian Immunization Committee (CIC), Health Canada and staff of the Public Health Agency of Canada in developing these guidelines.
Contact us
----------
For questions or clarification, please contact [[email protected]](mailto:[email protected]).
### Footnotes
Footnote 1
Please note that ISC is also commonly used to refer to Indigenous Services Canada in other documents.
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
CCE that use mechanical or electric systems, powered by an energy source, and combined with thermostatic control to maintain desired temperatures at optimal functionality.
[Return to footnote 2 referrer](#fn2-rf)
Footnote 3
CCE that do not produce cold but can maintain temperature for a limited time and are mainly used for keeping vaccines cold during transportation.
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
Material Safety Data Sheets – A document that contains information on the potential hazards of a chemical product and how to work safely with it.
[Return to footnote 4 referrer](#fn4-rf)
Footnote 5
IQ – verifies that the equipment has been properly delivered, installed and configured according to standards set by the manufacturer.
[Return to footnote 5 referrer](#fn5-rf)
Footnote 6
OQ – determines that equipment performance is consistent with the user requirement specification within the manufacturer-specified operating ranges.
[Return to footnote 6 referrer](#fn6-rf)
Footnote 7
PQ – verifies and documents that the equipment is working with reproducible results within a specific working range in simulated real-world conditions
[Return to footnote 7 referrer](#fn7-rf)
Footnote 8
WHO PQS Specifications - E001: Cold rooms, freezer rooms, and related equipment
[Return to footnote 8 referrer](#fn8-rf)
Footnote 9
Qualified transport containers are conditioned insulated containers that are qualified to maintain the vaccine at the manufacturer-approved temperature throughout the duration of the intended transportation.
[Return to footnote 9 referrer](#fn9-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-07-31
| None | None |
19cf0e504d6df5733997c9a1a0675cc238dbc183 | cma | Measles vaccine: Canadian Immunization Guide | Measles vaccine: Canadian Immunization Guide
Key Information (refer to text for details)
# What
- Measles occurs worldwide and is one of the most highly communicable diseases.
- Canada has imported cases and occasional outbreaks of measles.
- Measles vaccine is available as measles-mumps-rubella (MMR) or measles-mumps-rubella-varicella (MMRV) vaccine.
- MMR vaccine or human immunoglobulin (Ig) may be used for measles post-exposure immunization in susceptible persons.
- The efficacy of a single dose of measles vaccine given at 12 or 15 months of age is estimated to be 85% to 95%. With a second dose, efficacy is almost 100%.
- Reactions to MMR vaccine are generally mild and transient and include pain and redness at the injection site, fever less than 39°C, and rash. Reactions to MMRV vaccine include: pain and redness at the injection site and fever less than 39°C in 10% or more of vaccine recipients; measles-like, rubella-like or varicella-like rash, swelling at the injection site and fever greater than 39°C in less than 10% of vaccine recipients.
- When the first dose is administered to children 12 to 23 months of age as MMRV vaccine, there is a higher risk of fever and febrile seizures in the 7 to 10 days after vaccination when compared to separate administration of MMR and univalent varicella vaccine at the same visit. This risk is estimated at about 1 additional febrile seizure for every 2,300 to 2,800 doses of MMRV vaccine.
# Who
- Measles-containing vaccine is recommended for routine immunization of children and for immunization of children and adolescents who missed measles immunization on the routine schedule.
- Measles-containing vaccine is recommended for susceptible adults born in or after 1970.
- Adults born before 1970 can be presumed to have acquired natural immunity to measles; however, susceptible health care workers, travellers to destinations outside of Canada, and military personnel should receive MMR vaccine, regardless of year of birth.
# How
- Routine childhood immunization: 2 doses of any measles-containing (MMR or MMRV) vaccine. The first dose of measles-containing vaccine should be administered at 12 to 15 months of age and the second dose at 18 months of age or any time thereafter, but no later than around school entry.
- Children and adolescents who are previously unimmunized: 2 doses of measles-containing vaccine. MMRV vaccine may be used in healthy children aged 12 months to less than 13 years.
- Susceptible adults born in or after 1970: 1 dose of MMR vaccine. Those who are at the greatest risk of measles exposure (travellers to destinations outside of Canada, health care workers, students in post-secondary educational settings, and military personnel) should receive 2 doses of MMR vaccine.
- Susceptible health care workers and military personnel born before 1970: 2 doses of MMR vaccine.
- Susceptible travellers to destinations outside of Canada born before 1970: 1 dose of MMR vaccine.
- Susceptible students in post-secondary educational settings born before 1970: 1 dose of MMR vaccine should be considered.
# Why
- People who have not had measles disease or who have not been vaccinated are at risk of infection.
- Complications of measles disease occur in about 10% of measles cases.
Epidemiology
# Disease description
## Infectious agent
Measles (rubeola, red measles) is caused by measles virus, a member of the Paramyxoviridae family. For additional information about the measles virus, refer to the .
## Reservoir
Humans
## Transmission
Measles is one of the most highly communicable infectious diseases with greater than 90% secondary attack rates among susceptible persons. The virus is transmitted by the airborne route, respiratory droplets, or direct contact with nasal or throat secretions of infected persons. The incubation period is about 10 days (range, 7 to 18 days). The interval from exposure to appearance of rash averages 14 days. Cases are infectious from 4 days prior to rash onset to 4 days after rash onset. People who recover from measles have permanent immunity to the disease.
## Risk factors
People who have not had measles disease or who have not been vaccinated are at risk of infection. In Canada, adults born before 1970 are generally presumed to have acquired natural immunity to measles.
## Persons at greatest risk of exposure to measles
Adolescents and adults at greatest risk of exposure to measles include:
- travellers to destinations outside of Canada
- health care workers
- military personnel
- students in post-secondary educational settings
## Seasonal and temporal patterns
Historically, measles disease occurred primarily in late winter and spring in temperate zones. It is now restricted to sporadic cases and outbreaks.
## Spectrum of clinical illness
Symptoms of measles include prodromal fever, cough, coryza, conjunctivitis, Koplik spots (white spots on the inner lining of the mouth) and a rash that typically begins on the face, advances to the trunk and then to the arms and legs. Complications such as otitis media and bronchopneumonia occur in about 10% of reported cases, even more commonly in those who are poorly nourished and chronically ill, and in infants less than 1 year of age. Measles encephalitis occurs in approximately 1 of every 1,000 reported cases and may result in permanent brain damage. Measles infection can cause subacute sclerosing panencephalitis (SSPE), a rare but fatal disease. Measles during pregnancy results in a higher risk of premature labour, spontaneous abortion and low birth weight infants. Measles in an immunocompromised person may be severe.
# Disease distribution
Measles occurs worldwide and is one of the most highly communicable infectious diseases.
Measles has been eliminated in Canada since 1998; however, cases and outbreaks continue to occur as a result of importations. Comprehensive updates on the epidemiology of measles in Canada are published annually in the and weekly in the PHAC Measles & Rubella Monitoring Report.
Preparations Authorized for Use in Canada
# Measles-containing vaccines
- M-M-R®II (live attenuated combined measles, mumps and rubella vaccine), Merck Canada Inc. (MMR)
- PRIORIX® (live attenuated combined measles, mumps and rubella vaccine), GlaxoSmithKline Inc. (MMR)
- PRIORIX-TETRA® (live attenuated combined measles, mumps, rubella and varicella vaccine), GlaxoSmithKline Inc. (MMRV)
- ProQuad™ (live attenuated combined measles, mumps, rubella and varicella vaccine), Merck Canada Inc. (MMRV)
In Canada, measles vaccine is only available in combination with mumps and rubella vaccine (MMR) or mumps, rubella and varicella vaccine (MMRV). In some other countries, measles vaccine alone is given.
# Human immunoglobulin
- GamaSTAN® (immunoglobulin ), Grifols Therapeutics LLC. (Ig)
- Gammagard®(immunoglobulin ), Shire Pharma Canada Inc. (Ig)
- Gamunex®(immunoglobulin ), Grifols Therapeutics LLC. (Ig)
- IGIVnex (immunoglobulin ), Grifols Therapeutics LLC. (Ig)
- Privigen®(immunoglobulin ), CSL Behring Canada Inc. (Ig)
- Panzyga®(immunoglobulin ), Octapharma Pharmazeutika Produktionsges MBH. (Ig)
All Ig products are only available through the Canadian Blood Services (CBS). For complete prescribing information, consult the CBS website and the product leaflet or information contained within the product monograph available through Health Canada's .
Immunogenicity, Efficacy and Effectiveness
# Immunogenicity
In clinical studies a single injection of MMR vaccine induced measles antibodies in 95% of previously seronegative children.
In 12 month old children, a single dose of MMRV vaccine results in similar seroconversion rates as those achieved after concomitant administration of MMR vaccine and univalent varicella vaccine. A study of children receiving 2 doses of MMRV vaccine during the second year of life noted seropositivity for measles, mumps, rubella and varicella of 99%, 97.4%, 100% and 99.4% respectively by the third year post-vaccination.
# Efficacy and effectiveness
The efficacy of a single dose of measles-containing vaccine given at 12 or 15 months of age is estimated to be 85% to 95%. With a second dose, efficacy in children approaches 100%. However, measles outbreaks have occurred in populations with high immunization coverage rates. Due to the high infectivity of measles at least 95% of the population needs to be immunized to develop herd immunity.
There are no data regarding the long-term effectiveness of MMRV vaccine.
Recommendations for Use
# Healthy children (12 months to less than 18 years of age)
## Schedule
Routine schedule
Healthy children (12 months to less than 13 years of age)
For routine immunization of children aged 12 months to less than 13 years, 2 doses of measles-containing vaccine, using either MMR or MMRV vaccine, should be administered. The first measles-containing vaccine dose should be administered at 12 to 15 months of age and the second dose at 18 months of age or any time thereafter, but no later than around school entry.
Catch-up and accelerated schedules
Children (12 months to less than 13 years of age)
Two doses of measles-containing vaccine, using either MMR or MMRV vaccine, should be administered to children less than 13 years of age who were not immunized on the routine schedule. For preschool aged children, 2 doses of measles-containing vaccine should be administered before school entry (4 to 6 years of age). The minimum interval between doses of measles-containing vaccine is 4 weeks.
Adolescents (13 to less than 18 years of age)
Measles-susceptible adolescents (refer to for criteria for immunity) should receive 2 doses of MMR vaccine, given at least 4 weeks apart.
# Healthy adults (18 years of age and older)
Measles-susceptible adults (refer to for criteria for immunity) should receive 1 or 2 doses of MMR vaccine as appropriate for age and risk factors. If 2 doses are needed, MMR vaccine should be administered with a minimum interval of 4 weeks between doses.
## Routine immunization
Adults born before 1970 are generally presumed to have acquired natural immunity to measles; however, some of these individuals may be susceptible.
Adults without contraindications, born in or after 1970 who do not meet the definition of measles immunity (refer to for criteria for immunity) should be immunized with 1 dose of MMR vaccine.
+ Children 12 months to less than 18 years of age: 2 doses
+ Adults 18 years of age and older born in or after 1970: 1 dose,OR
- History of laboratory confirmed infectionOR
- Laboratory evidence of immunityOR
- Born before 1970
- History of laboratory confirmed infectionOR
- Laboratory evidence of immunity
+ If born in or after 1970: 2 doses
+ If born before 1970: 1 doseOR
- History of laboratory confirmed infectionOR
- Laboratory evidence of immunity
+ If born in or after 1970: 2 doses
+ If born before 1970: consider 1 dose if no documentation of receipt of measles-containing vaccineOR
- History of laboratory confirmed infectionOR
- Laboratory evidence of immunity
- History of laboratory confirmed infectionOR
- Laboratory evidence of immunity
Measles-containing vaccine
# Vaccination of specific populations
## Persons with inadequate immunization records
Children and adults who are susceptible to measles, including those lacking adequate documentation of immunization, should be started on an immunization schedule appropriate for their age and risk factors. Measles-containing vaccine may be given regardless of possible previous receipt of the vaccine because additional adverse events associated with repeated immunization have not been demonstrated. Refer to in Part 3 for additional information.
## Pregnancy and breastfeeding
Immunity to measles should be reviewed in women of reproductive age and vaccination should be recommended to susceptible non-pregnant women. Women should delay pregnancy by at least 4 weeks following vaccination with MMR vaccine.
MMR and MMRV vaccines are generally contraindicated in pregnancy because there is a theoretical risk to the fetus. However, there is no evidence to demonstrate a teratogenic risk from the vaccines and termination of pregnancy should not be recommended following inadvertent immunization with either of these vaccines on the basis of fetal risks following maternal immunization. In some situations, potential benefits of vaccination with MMR vaccine may outweigh risks such as during measles or rubella outbreaks, in which case vaccination may be considered based on recommendations from public health officials. Pregnant women who are susceptible to measles should have vaccination offered post-partum.
Susceptible women who are breastfeeding should be vaccinated with MMR vaccine.
## Patients in health care institutions
Susceptible residents of long-term care facilities should receive measles, mumps and rubella-containing vaccine as appropriate for their age and risk factors.
## Persons with chronic diseases
Age-appropriate measles-containing vaccine should routinely be provided to individuals with chronic diseases who are not immunocompromised.
## Immunocompromised persons
Individuals who are immunocompromised, either due to underlying conditions or immunosuppressive agents, are more susceptible to infections including measles. They may be more likely to experience more severe disease and complications. The safety and effectiveness of the measles vaccine is determined by the type of immunodeficiency and degree of immunosuppression. When considering immunization of an immunocompromised person with a live vaccine, approval from the individual's attending physician should be obtained before vaccination. For complex cases, referral to a physician with expertise in immunization or immunodeficiency is advised.
## Travellers
Protection against measles is especially important for people planning travel. Travellers to destinations outside of Canada, born in or after 1970, who do not meet the definition of measles immunity (refer to for criteria for immunity) should receive 2 doses of measles-containing vaccine.
Measles vaccines should be given at an earlier age than usual for children travelling outside of Canada where the disease is of concern or travelling to locations experiencing outbreaks. MMR vaccine may be given as early as 6 months of age; however, 2 additional doses of measles-containing vaccine must be administered after the child is 12 months old to ensure long lasting immunity to measles. Infants under 6 months of age are not considered for vaccination because the effectiveness and safety of the MMR vaccine has not been established in this age group.
Travellers to destinations outside of Canada, born before 1970, who do not meet the definition of measles immunity (refer to for criteria for immunity) should receive 1 dose of MMR vaccine.
Measles is endemic in many countries. Refer to the Public Health Agency of Canada's for information about measles outbreaks outside of Canada and to in Part 3 for additional information.
## Persons new to Canada
Health care providers who see persons newly arrived in Canada should review the immunization status and update immunization for these individuals as necessary. In many countries outside of Canada, mumps and rubella vaccines are in limited use and measles vaccine alone is given. A Canadian study showed that more than one-third of new immigrants and refugees, particularly women, were susceptible to measles, mumps, or rubella. Refer to for additional information.
## Workers
It is recommended that all health care workers be immune to measles. Health care workers, regardless of their year of birth, who do not meet the definition of measles immunity (refer to for criteria for immunity) should be vaccinated accordingly so that they have received 2 doses of MMR vaccine.
## Booster doses and re-immunization
Re-immunization with measles-containing vaccine after age and risk appropriate vaccination is not necessary.
# Post-exposure prophylaxis (PEP) and outbreak control
MMR vaccine or Ig may be used for measles post-exposure immunization in susceptible persons. In assessing the extent of measles exposure and deciding between MMR vaccine and Ig for post-exposure management, it is important to consider that Ig provides only short-term protection and requires postponing the administration of MMR vaccine. Long-term protection against measles is only provided following immunization with MMR vaccine. For a summary of measles PEP recommendations, refer to . For guidelines on the interval between administration of Ig preparations and MMR or MMRV refer to Table 1 in in Part 1.
Despite the use of MMR vaccine or Ig for post-exposure management, measles infection may occur. Exposed individuals should be counseled regarding: signs and symptoms of measles; avoiding contact with others should they become ill with symptoms compatible with measles; and the need to seek medical care, including advising health care workers of the possibility of measles before going to a health care setting so that appropriate precautions can be taken.
## Measles-Mumps-Rubella vaccine
Susceptible, immunocompetent individuals 6 months of age and older who are exposed to measles may be protected from measles disease if they are given measles-mumps-rubella (MMR) vaccine within 72 hours of their exposure. When MMR vaccine is provided prior to 12 months of age, 2 additional doses of measles-containing vaccine must be administered after the child is 12 months old (and at least 4 weeks after the previous dose) to ensure long lasting immunity. Infants under 6 months of age are not considered for vaccination because the effectiveness and safety of the MMR vaccine has not been established in this age group.
## Human immunoglobulin
Prophylactic use of human immunoglobulin (Ig) has been shown to be effective in modifying or preventing disease if administered within 6 days after exposure to measles; however, when indicated, it should be given as soon as possible after exposure. Ig should be considered for the following groups of individuals if they are contacts of measles:
- susceptible pregnant women
- susceptible individuals who are immunocompromised
- susceptible infants ˂ 6 months of age
- susceptible immunocompetent infants 6-11 months old who present between 73 hours and 6 days after exposure
Individuals receiving replacement IVIg (400 mg/kg of body weight or higher) are considered protected and do not require Ig if the last dose of IVIg was received within the three weeks prior to measles exposure.
## Intramuscular immunoglobulin
IMIg should be provided to susceptible infants at a dose of 0.5mL/kg, to a maximum dose of 15mL. For susceptible individuals who are pregnant or immunocompromised, IMIg can be provided at a dose of 0.5mL/kg understanding that those weighing 30 kg or more will not receive the measles antibody concentrations that are considered to be fully protective. Large volumes (greater than 2mL for children or 3-5 mL for adults) should be divided and injected at 2 or more sites. In cases where injection volume is a concern and for recipients weighing 30 kg or more, IVIg can be considered.
## Intravenous immunoglobulin
IVIg can be considered in susceptible individuals who are pregnant or immunocompromised and weigh 30 kg or more. IVIg can be considered for infants for whom Ig is indicated, but IMIg injection volume is a concern. IVIg administration requires in-hospital administration and active patient monitoring over several hours of infusion, performed by appropriately trained staff. Providers of IVIg should review the respective product monographs and CBS guidelines prior to IVIg administration.
or
or
Two additional doses of MMR vaccine provided after 12 months of age are required for long-term protection.
If injection volume is a major concern, IVIg can be provided at a dose of 400mg/kg.
Susceptible immunocompetent individuals 12 months of age and older are not a priority to receive Ig following measles exposure due to low risk of disease complications and the practical challenges of administration contact management.
Provide MMR vaccine series postpartum for future protection.
For individuals 30kg or more, IMIg will not provide complete protection but may prevent some symptoms.
In HIV-infected individuals, measles antibody titer is known to decline more rapidly over time as compared to those who are not HIV-infected. A dose of Ig should be considered in HIV-infected individuals with severe immunosuppression after a known exposure to confirmed measles, even with documented previous MMR immunization. Regardless of vaccination status pre-transplant, Ig should be considered for hematopoietic stem cell transplantation (HSCT) recipients, unless vaccinated post-HSCT and known to have an adequate measles antibody titre.
MMR vaccine will not provide PEP protection after 72 hours of exposure, however, starting and completing a two dose series should not be delayed to provide long term protection.
Two doses of measles-containing vaccine are still required after the first birthday for long-term protection.
Ig should only be provided within 6 days of measles exposure; unless it is contraindicated, individuals who receive Ig should receive measles-containing vaccine after a specified interval, once the measles antibodies administered passively have degraded. For more information, refer to in Part 1.
## Outbreak control
Immunization with MMR vaccine is an integral element of a comprehensive measles outbreak prevention and management strategy. In a measles outbreak, susceptible individuals 6 months of age and older may receive MMR vaccine. However, if given between 6 months and less than 12 months of age, 2 additional doses of measles-containing vaccine must be administered after the child is 12 months old (and at least 4 weeks after the previous dose) to ensure long lasting immunity to measles. For detailed information on outbreak control beyond vaccination and post-exposure prophylaxis strategies, refer to in the Canada Communicable Disease Report (CCDR).
Serologic Testing
Serological testing may be indicated to confirm the diagnosis of measles or to determine immune status. Serologic testing is not recommended before or after receiving measles-containing vaccine. If serology is inadvertently done subsequent to appropriate measles immunization and does not demonstrate immunity, measles re-immunization is not necessary.
Administration Practices
# Dose
Each dose of measles-containing vaccine is 0.5 mL.
# Route of administration
MMR vaccine should be administered subcutaneously (SC). MMRV vaccine should be administered according to the product monograph.
# Interchangeability of vaccines
On the basis of expert opinion, the MMR vaccines authorized in Canada may be used interchangeably. Refer to for information about interchangeability of MMRV vaccines. Refer to in Part 1 for additional general information.
# Concurrent administration with other vaccines
MMR vaccine may be administered concurrently with, or at any time before or after, non-live vaccines, live oral vaccines, or live intranasal influenza vaccine (LAIV). Refer to for additional information about concurrent administration of MMR vaccine with LAIV.
MMR vaccine may be administered concurrently with other routinely provided live parenteral vaccines. If not given concurrently, a minimum interval of 4 weeks is recommended between administration of MMR and other live parenteral vaccines. This recommendation is to address the risk of interference from the vaccine given first on the vaccine given later.
Different injection sites and separate needles and syringes must be used for concurrent parenteral injections. Refer to in Part 1 for additional information about concurrent administration of measles-containing vaccine with other vaccines.
Storage and Handling of Immunizing Agents
Safety and Adverse Events
# Common and local adverse events
## Measles-Mumps-Rubella vaccine
Adverse events following immunization with MMR vaccine occur less frequently and are less severe than those associated with natural disease. Adverse reactions are less frequent after the second dose of vaccine and tend to occur only in individuals not protected by the first dose. Six to 23 days after immunization with MMR vaccine, approximately 5% of immunized children experience malaise and fever (with or without rash) lasting up to 3 days. Parotitis, rash, lymphadenopathy, and joint symptoms also occur occasionally after immunization with MMR vaccine.
## Measles-Mumps-Rubella-Varicella vaccine
Pain and redness at the injection site or fever less than 39°C occur in 10% or more of vaccine recipients. Rash, including measles-like, rubella-like and varicella-like rash, as well as swelling at the injection site and fever greater than 39°C, occur in 1% to less than 10% of vaccine recipients. As varicella-like rashes that occur within the first 2 weeks after immunization may be caused by wild-type virus (varicella virus circulating in the community), health care providers should obtain specimens from the vaccine recipient to determine whether the rash is due to natural varicella infection or to the vaccine-derived strain.
## Rubella-containing vaccines
Acute transient arthritis or arthralgia may occur 1 to 3 weeks after immunization with rubella-containing vaccine, such as MMRV. It lasts for about 1 to 3 weeks, and rarely recurs. It is more common in post-pubertal females, among whom arthralgia develops in 25% and arthritis in 10% after immunization with rubella-containing vaccine. There is no evidence of increased risk of new onset chronic arthropathies.
## Human immunoglobulin
Injection site reactions following receipt of standard human Ig include tenderness, erythema and stiffness of local muscles, which may persist for several hours. Mild fever or malaise may occasionally occur.
# Less common and serious or severe adverse events
Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association. Anaphylaxis following vaccination with MMR or MMRV vaccine may occur but is very rare.
## Immune Thrombocytopenic Purpura
Rarely, Immune Thrombocytopenic Purpura (ITP) occurs within 6 weeks after immunization with MMR or MMRV vaccine. In most children, post-immunization thrombocytopenia resolves within 3 months without serious complications. In individuals who experienced ITP with the first dose of MMR or MMRV vaccine, serologic status may be evaluated to determine whether an additional dose of vaccine is needed for protection. The potential risk to benefit ratio should be carefully evaluated before considering vaccination in such cases.
## Encephalitis
Encephalitis has been reported in association with administration of measles vaccine in approximately 1 per million doses distributed in North America which is much lower than the incidence observed with natural measles disease (1 per 1,000 cases).
## Febrile seizures
When the first dose of measles-containing vaccine is administered to children 12 to 23 months as MMRV vaccine, there is a higher risk of fever and febrile seizures in the 7 to 10 days after vaccination when compared to separate administration of MMR and varicella vaccine at the same visit. This risk is estimated at about 1 additional febrile seizure for every 2,300 to 2,800 doses of MMRV vaccine.
## Human immunoglobulin
Less common side effects following receipt of standard human Ig include flushing, headache, chills and nausea. Urticaria, angioedema and anaphylactic reactions may occur rarely.
### Other reported adverse events and conditions
In the mid to late 1990s, researchers from the United Kingdom reported an association between MMR vaccine and inflammatory bowel disease, and MMR vaccine and autism. Rigorous scientific studies and reviews of the evidence have been done worldwide, and there is now considerable evidence to refute those claims. In 2010, the original study suggesting a link between the MMR vaccine and autism was found to be fraudulent and was retracted.
## Guidance on reporting Adverse Events Following Immunization
Vaccine providers are asked to report the following adverse events following immunization (AEFI) in particular, through local public health officials:
- Febrile seizures within 30 days after vaccination with MMR or MMRV vaccine.
- Varicella that is moderate (50 to 500 lesions) or severe (more than 500 vesicular lesions or associated complications or hospital admission) and occurs within 7 to 21 days after vaccination with MMRV vaccine.
- Any serious or unexpected adverse event temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.
# Contraindications and precautions
MMR and MMRV vaccines and Ig are contraindicated in persons with a history of anaphylaxis after previous administration of the product and in persons with proven immediate or anaphylactic hypersensitivity to any component of the product, with the exception of egg allergy for MMR and MMRV vaccines. Refer to in Part 1 for lists of vaccines and passive immunizing agents authorized in Canada and their contents.
Human Ig preparations should not be given to people with known isolated IgA deficiency unless the benefit outweighs the risk, in which case the product should be given with caution and under close observation.
In situations of suspected hypersensitivity or non-anaphylactic allergy to vaccine components, investigation is indicated which may involve immunization in a controlled setting. Consultation with an allergist is advised.
Although the measles and mumps components of MMR and MMRV vaccines are produced in chick embryo cell culture and may contain traces of residual egg and chicken protein, the trace amount of egg or chicken protein in the vaccine appears to be insufficient to cause an allergic reaction in egg-allergic individuals. Skin testing is not recommended prior to vaccination as it does not predict reaction to the vaccine. MMR or MMRV vaccine can be administered in the routine manner to people who have a history of anaphylactic hypersensitivity to hens' eggs. Prior egg ingestion is not a prerequisite for immunization with egg protein-containing vaccine. For all vaccines, immunization should always be performed by personnel with the capability and facilities to manage adverse events post-vaccination. Refer to in Part 2 for additional information.
Children with a known or suspected family history of congenital or hereditary immunodeficiency that is a contraindication to vaccination with live vaccine should not receive live vaccines unless their immune competence has been established.
MMRV vaccine can be contraindicated in persons with impaired immune function, including primary or secondary immunodeficiency disorders. Human Ig preparations should not be given to people with known isolated IgA deficiency unless the benefit outweighs the risk, in which case the product should be given with caution and under close observation. Refer to in Part 3 for more information. MMR and MMRV vaccines are generally contraindicated during pregnancy because of the theoretical risk to the fetus. Refer to in Part 3.
Measles-containing vaccines are contraindicated in individuals with active, untreated tuberculosis (TB) as a precautionary measure. Although TB may be exacerbated by natural measles infection, there is no evidence that measles-containing vaccines have such an effect. Nonetheless, anti-tuberculous therapy for active TB disease is advisable before administering measles-containing vaccines and it may be prudent to avoid live viral vaccines in those with active TB disease until treatment is underway. Consultation with an expert in infectious diseases is recommended.
A history of febrile seizures or a family history of seizures is not a contraindication for the use of MMRV vaccine.
Administration of MMR or MMRV vaccine should be postponed in persons with severe acute illness. Persons with a minor acute illness, with or without fever, may be vaccinated.
It is recommended to avoid the use of salicylates (medications derived from salicylic acid, such as acetylsalicylic acid ) for 6 weeks after immunization with MMRV vaccine because of an association between wild-type varicella, salicylate therapy and Reye's syndrome.
## Drug interactions
### Systemic antiviral therapy
Systemic antiviral therapy (such as acyclovir, valacyclovir, famciclovir) should be avoided in the peri-immunization period, as it may affect the reproduction of the vaccine virus and consequently may reduce the efficacy of varicella-containing vaccine, such as MMRV. On the basis of expert opinion, it is recommended that people taking long-term antiviral therapy should discontinue these drugs, if possible, from at least 24 hours before administration of MMRV vaccine and should not restart antiviral therapy until 14 days after vaccine administration.
### Tuberculin skin testing or Interferon Gamma Release Assay (IGRA)
The measles component in measles-containing vaccines can temporarily suppress tuberculin reactivity, resulting in false-negative results. If tuberculin skin testing or an IGRA test is required, it should be done on the same day as immunization or delayed for at least 4 weeks after measles vaccination. Vaccination with measles-containing vaccine may take place at any time after tuberculin skin testing has been performed and read.
## Human immunoglobulin or other blood products
Passive immunization with human Ig or receipt of most other blood products can interfere with the immune response to MMR, MMRV and univalent varicella vaccines. These vaccines should be given at least 14 days prior to administration of an immunoglobulin preparation or blood product, or delayed until the antibodies in the Ig preparation or blood product have degraded. Refer to in Part 1 for additional information. |
Measles vaccine: Canadian Immunization Guide
=============================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-11-japanese-encephalitis-vaccine.html "Japanese encephalitis vaccine: Canadian immunization guide")
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-13-meningococcal-vaccine.html "Meningococcal vaccine: Canadian immunization guide")
**Last partial content update** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): September 2020
**September 2020:** Updated recommendation:
The criterion for measles immunity was previously listed for travellers to destinations outside of North America. Due to the changes in global measles epidemiology, this criterion for measles immunity was changed to travellers to destinations outside of Canada.
**Last complete chapter revision:** April 2015
On this page
------------
* [Key Information](#p4c11a1)
* [Epidemiology](#p4c11a2)
* [Preparations Authorized for Use in Canada](#p4c11a3)
* [Immunogenicity, Efficacy and Effectiveness](#p4c11a4)
* [Recommendations for Use](#p4c11a5)
+ [Table 1: Criteria for measles immunity](#p4c11t1)
+ [Vaccination of specific populations](#vsp)
+ [Post-exposure prophylaxis (PEP) and outbreak control](#pep)
- [Table 2. Summary of updated measles PEP recommendations for susceptible contacts](#table2)
* [Serologic Testing](#p4c11a7)
* [Administration Practices](#p4c11a8)
* [Storage and Handling of Immunizing Agents](#p4c11a9)
* [Safety and Adverse Events](#p4c11a10)
+ [Common and local adverse events](#p4c11a10a)
+ [Contraindications and precautions](#p4c11a10e)
* [Selected References](#p4c11a11)
Key Information (refer to text for details)
-------------------------------------------
### What
* Measles occurs worldwide and is one of the most highly communicable diseases.
* Canada has imported cases and occasional outbreaks of measles.
* Measles vaccine is available as measles-mumps-rubella (MMR) or measles-mumps-rubella-varicella (MMRV) vaccine.
* MMR vaccine or human immunoglobulin (Ig) may be used for measles post-exposure immunization in susceptible persons.
* The efficacy of a single dose of measles vaccine given at 12 or 15 months of age is estimated to be 85% to 95%. With a second dose, efficacy is almost 100%.
* Reactions to MMR vaccine are generally mild and transient and include pain and redness at the injection site, fever less than 39°C, and rash. Reactions to MMRV vaccine include: pain and redness at the injection site and fever less than 39°C in 10% or more of vaccine recipients; measles-like, rubella-like or varicella-like rash, swelling at the injection site and fever greater than 39°C in less than 10% of vaccine recipients.
* When the first dose is administered to children 12 to 23 months of age as MMRV vaccine, there is a higher risk of fever and febrile seizures in the 7 to 10 days after vaccination when compared to separate administration of MMR and univalent varicella vaccine at the same visit. This risk is estimated at about 1 additional febrile seizure for every 2,300 to 2,800 doses of MMRV vaccine.
### Who
* Measles-containing vaccine is recommended for routine immunization of children and for immunization of children and adolescents who missed measles immunization on the routine schedule.
* Measles-containing vaccine is recommended for susceptible adults born in or after 1970.
* Adults born before 1970 can be presumed to have acquired natural immunity to measles; however, susceptible health care workers, travellers to destinations outside of Canada, and military personnel should receive MMR vaccine, regardless of year of birth.
### How
* **Routine childhood immunization:** 2 doses of any measles-containing (MMR or MMRV) vaccine. The first dose of measles-containing vaccine should be administered at 12 to 15 months of age and the second dose at 18 months of age or any time thereafter, but no later than around school entry.
* **Children and adolescents who are previously unimmunized:** 2 doses of measles-containing vaccine. MMRV vaccine may be used in healthy children aged 12 months to less than 13 years.
* **Susceptible adults born in or after 1970:** 1 dose of MMR vaccine. Those who are at the greatest risk of measles exposure (travellers to destinations outside of Canada, health care workers, students in post-secondary educational settings, and military personnel) should receive 2 doses of MMR vaccine.
* **Susceptible health care workers and military personnel born before 1970:** 2 doses of MMR vaccine.
* **Susceptible travellers to destinations outside of Canada born before 1970:** 1 dose of MMR vaccine.
* **Susceptible students in post-secondary educational settings born before 1970:** 1 dose of MMR vaccine should be considered.
### Why
* People who have not had measles disease or who have not been vaccinated are at risk of infection.
* Complications of measles disease occur in about 10% of measles cases.
Epidemiology
------------
### Disease description
#### Infectious agent
Measles (rubeola, red measles) is caused by measles virus, a member of the Paramyxoviridae family. For additional information about the measles virus, refer to the [Pathogen Safety Data Sheet](/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/measles-virus.html).
#### Reservoir
Humans
#### Transmission
Measles is one of the most highly communicable infectious diseases with greater than 90% secondary attack rates among susceptible persons. The virus is transmitted by the airborne route, respiratory droplets, or direct contact with nasal or throat secretions of infected persons. The incubation period is about 10 days (range, 7 to 18 days). The interval from exposure to appearance of rash averages 14 days. Cases are infectious from 4 days prior to rash onset to 4 days after rash onset. People who recover from measles have permanent immunity to the disease.
#### Risk factors
People who have not had measles disease or who have not been vaccinated are at risk of infection. In Canada, adults born before 1970 are generally presumed to have acquired natural immunity to measles.
#### Persons at greatest risk of exposure to measles
Adolescents and adults at greatest risk of exposure to measles include:
* travellers to destinations outside of Canada
* health care workers
* military personnel
* students in post-secondary educational settings
#### Seasonal and temporal patterns
Historically, measles disease occurred primarily in late winter and spring in temperate zones. It is now restricted to sporadic cases and outbreaks.
#### Spectrum of clinical illness
Symptoms of measles include prodromal fever, cough, coryza, conjunctivitis, Koplik spots (white spots on the inner lining of the mouth) and a rash that typically begins on the face, advances to the trunk and then to the arms and legs. Complications such as otitis media and bronchopneumonia occur in about 10% of reported cases, even more commonly in those who are poorly nourished and chronically ill, and in infants less than 1 year of age. Measles encephalitis occurs in approximately 1 of every 1,000 reported cases and may result in permanent brain damage. Measles infection can cause subacute sclerosing panencephalitis (SSPE), a rare but fatal disease. Measles during pregnancy results in a higher risk of premature labour, spontaneous abortion and low birth weight infants. Measles in an immunocompromised person may be severe.
### Disease distribution
Measles occurs worldwide and is one of the most highly communicable infectious diseases.
Measles has been eliminated in Canada since 1998; however, cases and outbreaks continue to occur as a result of importations. Comprehensive updates on the epidemiology of measles in Canada are published annually in the [Canadian Communicable Disease Report (CCDR)](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr.html) and weekly in the PHAC Measles & Rubella Monitoring Report.
Refer to [measles for health professionals](/en/public-health/services/diseases/measles/health-professionals-measles.html) for more information, including disease description, distribution and epidemiology.
Preparations Authorized for Use in Canada
-----------------------------------------
### Measles-containing vaccines
* **M-M-R®II** (live attenuated combined measles, mumps and rubella vaccine), Merck Canada Inc. (MMR)
* **PRIORIX®** (live attenuated combined measles, mumps and rubella vaccine), GlaxoSmithKline Inc. (MMR)
* **PRIORIX-TETRA®** (live attenuated combined measles, mumps, rubella and varicella vaccine), GlaxoSmithKline Inc. (MMRV)
* **ProQuad**™ (live attenuated combined measles, mumps, rubella and varicella vaccine), Merck Canada Inc. (MMRV)
In Canada, measles vaccine is only available in combination with mumps and rubella vaccine (MMR) or mumps, rubella and varicella vaccine (MMRV). In some other countries, measles vaccine alone is given.
### Human immunoglobulin
* **GamaSTAN®** (immunoglobulin [human]), Grifols Therapeutics LLC. (Ig)
* **Gammagard®**(immunoglobulin [human]), Shire Pharma Canada Inc. (Ig)
* **Gamunex®**(immunoglobulin [human]), Grifols Therapeutics LLC. (Ig)
* **IGIVnex** (immunoglobulin [human]), Grifols Therapeutics LLC. (Ig)
* **Privigen®**(immunoglobulin [human]), CSL Behring Canada Inc. (Ig)
* **Panzyga®**(immunoglobulin [human]), Octapharma Pharmazeutika Produktionsges MBH. (Ig)
All Ig products are only available through the Canadian Blood Services (CBS). For complete prescribing information, consult the CBS website and the product leaflet or information contained within the product monograph available through Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
Refer to [Contents of Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for lists of vaccines and passive immunizing agents authorized for use in Canada and their contents.
Immunogenicity, Efficacy and Effectiveness
------------------------------------------
### Immunogenicity
In clinical studies a single injection of MMR vaccine induced measles antibodies in 95% of previously seronegative children.
In 12 month old children, a single dose of MMRV vaccine results in similar seroconversion rates as those achieved after concomitant administration of MMR vaccine and univalent varicella vaccine. A study of children receiving 2 doses of MMRV vaccine during the second year of life noted seropositivity for measles, mumps, rubella and varicella of 99%, 97.4%, 100% and 99.4% respectively by the third year post-vaccination.
### Efficacy and effectiveness
The efficacy of a single dose of measles-containing vaccine given at 12 or 15 months of age is estimated to be 85% to 95%. With a second dose, efficacy in children approaches 100%. However, measles outbreaks have occurred in populations with high immunization coverage rates. Due to the high infectivity of measles at least 95% of the population needs to be immunized to develop herd immunity.
There are no data regarding the long-term effectiveness of MMRV vaccine.
Recommendations for Use
-----------------------
### Healthy children (12 months to less than 18 years of age)
#### Schedule
**Routine schedule**
Healthy children (12 months to less than 13 years of age)
For routine immunization of children aged 12 months to less than 13 years, 2 doses of measles-containing vaccine, using either MMR or MMRV vaccine, should be administered. The first measles-containing vaccine dose should be administered at 12 to 15 months of age and the second dose at 18 months of age or any time thereafter, but no later than around school entry.
**Catch-up and accelerated schedules**
Children (12 months to less than 13 years of age)
Two doses of measles-containing vaccine, using either MMR or MMRV vaccine, should be administered to children less than 13 years of age who were not immunized on the routine schedule. For preschool aged children, 2 doses of measles-containing vaccine should be administered before school entry (4 to 6 years of age). The minimum interval between doses of measles-containing vaccine is 4 weeks.
Adolescents (13 to less than 18 years of age)
Measles-susceptible adolescents (refer to [Table 1](#p4c11t1) for criteria for immunity) should receive 2 doses of MMR vaccine, given at least 4 weeks apart.
### Healthy adults (18 years of age and older)
Measles-susceptible adults (refer to [Table 1](#p4c11t1) for criteria for immunity) should receive 1 or 2 doses of MMR vaccine as appropriate for age and risk factors. If 2 doses are needed, MMR vaccine should be administered with a minimum interval of 4 weeks between doses.
#### Routine immunization
Adults **born before 1970** are generally presumed to have acquired natural immunity to measles; however, some of these individuals may be susceptible.
Adults without contraindications, **born in or after 1970** who do not meet the definition of measles immunity (refer to [Table 1](#p4c11t1) for criteria for immunity) should be immunized with 1 dose of MMR vaccine.
Table 1: Criteria for measles immunity | Routine immunization | Health care workers | Travellers to destinations outside of Canada | Students in post-secondary educational settings | Military personnel |
| --- | --- | --- | --- | --- |
| * Documentation of vaccination:
+ Children 12 months to less than 18 years of age: 2 doses[table 1 note 1](#p4c11t1fn1)
+ Adults 18 years of age and older born in or after 1970: 1 dose[table 1 note 1](#p4c11t1fn1),[table 1 note 2](#p4c11t1fn2)**OR**
* History of laboratory confirmed infection**OR**
* Laboratory evidence of immunity**OR**
* Born before 1970
| * Documentation of vaccination with 2 doses[table 1 note 1](#p4c11t1fn1) (regardless of year of birth)**OR**
* History of laboratory confirmed infection**OR**
* Laboratory evidence of immunity
| * Documentation of vaccination:
+ If born in or after 1970: 2 doses[table 1 note 1](#p4c11t1fn1)
+ If born before 1970: 1 dose[table 1 note 1](#p4c11t1fn1)**OR**
* History of laboratory confirmed infection**OR**
* Laboratory evidence of immunity
| * Documentation of vaccination:
+ If born in or after 1970: 2 doses[table 1 note 1](#p4c11t1fn1)
+ If born before 1970: consider 1 dose[table 1 note 1](#p4c11t1fn1) if no documentation of receipt of measles-containing vaccine**OR**
* History of laboratory confirmed infection**OR**
* Laboratory evidence of immunity
| * Documentation of vaccination with 2 doses[table 1 note 1](#p4c11t1fn1) (regardless of year of birth)**OR**
* History of laboratory confirmed infection**OR**
* Laboratory evidence of immunity
|
|
Table 1 notes
Table 1 note 1
Measles-containing vaccine
[Return to table 1 note 1 referrer](#p4c11t1fn1-rf)
Table 1 note 2
Refer to additional recommendations for [health care workers](#p4c11a6h), [travellers to destinations outside of Canada](#p4c11a6f), [students in post-secondary educational settings](#p4c11a5b1) and [military personnel](#p4c11a5b2).
[Return to table 1 note 2 referrer](#p4c11t1fn2-rf)
|
### Vaccination of specific populations
#### Persons with inadequate immunization records
Children and adults who are susceptible to measles, including those lacking adequate documentation of immunization, should be started on an immunization schedule appropriate for their age and risk factors. Measles-containing vaccine may be given regardless of possible previous receipt of the vaccine because additional adverse events associated with repeated immunization have not been demonstrated. Refer to [Immunization of Persons with Inadequate Immunization Records](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-3-immunization-persons-inadequate-immunization-records.html) in Part 3 for additional information.
#### Pregnancy and breastfeeding
Immunity to measles should be reviewed in women of reproductive age and vaccination should be recommended to susceptible non-pregnant women. Women should delay pregnancy by at least 4 weeks following vaccination with MMR vaccine.
MMR and MMRV vaccines are generally contraindicated in pregnancy because there is a theoretical risk to the fetus. However, there is no evidence to demonstrate a teratogenic risk from the vaccines and termination of pregnancy should not be recommended following inadvertent immunization with either of these vaccines on the basis of fetal risks following maternal immunization. In some situations, potential benefits of vaccination with MMR vaccine may outweigh risks such as during measles or rubella outbreaks, in which case vaccination may be considered based on recommendations from public health officials. Pregnant women who are susceptible to measles should have vaccination offered post-partum.
Susceptible women who are breastfeeding should be vaccinated with MMR vaccine.
Refer to [Post-exposure prophylaxis (PEP) and outbreak control](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html#pep) for additional information about the use of Ig in the management of susceptible pregnant women exposed to measles. Refer to [Blood Products, Human Immunoglobulin and Timing of Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) in Part 3 for information about measles vaccination of post-partum women who have received Rh immunoglobulin (RhIg). Refer to [Immunization in Pregnancy and Breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3 for additional information.
#### Patients in health care institutions
Susceptible residents of long-term care facilities should receive measles, mumps and rubella-containing vaccine as appropriate for their age and risk factors.
Refer to [Immunization of Patients in Health care Institutions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-6-immunization-patients-health-care-institutions.html) in Part 3 for additional information.
#### Persons with chronic diseases
Age-appropriate measles-containing vaccine should routinely be provided to individuals with chronic diseases who are not immunocompromised.
Refer to [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional general information about vaccination of people with chronic diseases.
#### Immunocompromised persons
Individuals who are immunocompromised, either due to underlying conditions or immunosuppressive agents, are more susceptible to infections including measles. They may be more likely to experience more severe disease and complications. The safety and effectiveness of the measles vaccine is determined by the type of immunodeficiency and degree of immunosuppression. When considering immunization of an immunocompromised person with a live vaccine, approval from the individual's attending physician should be obtained before vaccination. For complex cases, referral to a physician with expertise in immunization or immunodeficiency is advised.
Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 and [Post-exposure prophylaxis (PEP) and outbreak control](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html#pep) for more information.
#### Travellers
Protection against measles is especially important for people planning travel. Travellers to destinations outside of Canada, **born in or after 1970,** who do not meet the definition of measles immunity (refer to [Table 1](#p4c11t1) for criteria for immunity) should receive 2 doses of measles-containing vaccine.
Measles vaccines should be given at an earlier age than usual for children travelling outside of Canada where the disease is of concern or travelling to locations experiencing outbreaks. MMR vaccine may be given as early as 6 months of age; however, 2 additional doses of measles-containing vaccine must be administered after the child is 12 months old to ensure long lasting immunity to measles. Infants under 6 months of age are not considered for vaccination because the effectiveness and safety of the MMR vaccine has not been established in this age group.
Travellers to destinations outside of Canada, **born before 1970**, who do not meet the definition of measles immunity (refer to [Table 1](#p4c11t1) for criteria for immunity) should receive 1 dose of MMR vaccine.
Measles is endemic in many countries. Refer to the Public Health Agency of Canada's [Travel Health Notices](https://travel.gc.ca/travelling/health-safety/travel-health-notices) for information about measles outbreaks outside of Canada and to [Immunization of Travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) in Part 3 for additional information.
#### Persons new to Canada
Health care providers who see persons newly arrived in Canada should review the immunization status and update immunization for these individuals as necessary. In many countries outside of Canada, mumps and rubella vaccines are in limited use and measles vaccine alone is given. A Canadian study showed that more than one-third of new immigrants and refugees, particularly women, were susceptible to measles, mumps, or rubella. Refer to [Immunization of Persons New to Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-10-immunization-persons-new-canada.html) for additional information.
#### Workers
It is recommended that all health care workers be immune to measles. Health care workers, regardless of their year of birth, who do not meet the definition of measles immunity (refer to [Table 1](#p4c11t1) for criteria for immunity) should be vaccinated accordingly so that they have received 2 doses of MMR vaccine.
Refer to [Immunization of Workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html) in Part 3 for additional information.
#### Booster doses and re-immunization
Re-immunization with measles-containing vaccine after age and risk appropriate vaccination is not necessary.
### Post-exposure prophylaxis (PEP) and outbreak control
MMR vaccine or Ig may be used for measles post-exposure immunization in susceptible persons. In assessing the extent of measles exposure and deciding between MMR vaccine and Ig for post-exposure management, it is important to consider that Ig provides only short-term protection and requires postponing the administration of MMR vaccine. Long-term protection against measles is only provided following immunization with MMR vaccine. For a summary of measles PEP recommendations, refer to [Table 2](#table2). For guidelines on the interval between administration of Ig preparations and MMR or MMRV refer to Table 1 in [Blood Products, Human Immunoglobulin and Timing of Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html#p1c10t1) in Part 1.
Despite the use of MMR vaccine or Ig for post-exposure management, measles infection may occur. Exposed individuals should be counseled regarding: signs and symptoms of measles; avoiding contact with others should they become ill with symptoms compatible with measles; and the need to seek medical care, including advising health care workers of the possibility of measles before going to a health care setting so that appropriate precautions can be taken.
#### Measles-Mumps-Rubella vaccine
Susceptible, immunocompetent individuals 6 months of age and older who are exposed to measles may be protected from measles disease if they are given measles-mumps-rubella (MMR) vaccine within 72 hours of their exposure. When MMR vaccine is provided prior to 12 months of age, 2 additional doses of measles-containing vaccine must be administered after the child is 12 months old (and at least 4 weeks after the previous dose) to ensure long lasting immunity. Infants under 6 months of age are not considered for vaccination because the effectiveness and safety of the MMR vaccine has not been established in this age group.
#### Human immunoglobulin
Prophylactic use of human immunoglobulin (Ig) has been shown to be effective in modifying or preventing disease if administered within 6 days after exposure to measles; however, when indicated, it should be given as soon as possible after exposure. Ig should be considered for the following groups of individuals if they are contacts of measles:
* susceptible pregnant women
* susceptible individuals who are immunocompromised
* susceptible infants ˂ 6 months of age
* susceptible immunocompetent infants 6-11 months old who present between 73 hours and 6 days after exposure
Individuals receiving replacement IVIg (400 mg/kg of body weight or higher) are considered protected and do not require Ig if the last dose of IVIg was received within the three weeks prior to measles exposure.
#### Intramuscular immunoglobulin
IMIg should be provided to susceptible infants at a dose of 0.5mL/kg, to a maximum dose of 15mL. For susceptible individuals who are pregnant or immunocompromised, IMIg can be provided at a dose of 0.5mL/kg understanding that those weighing 30 kg or more will not receive the measles antibody concentrations that are considered to be fully protective. Large volumes (greater than 2mL for children or 3-5 mL for adults) should be divided and injected at 2 or more sites. In cases where injection volume is a concern and for recipients weighing 30 kg or more, IVIg can be considered.
#### Intravenous immunoglobulin
IVIg can be considered in susceptible individuals who are pregnant or immunocompromised and weigh 30 kg or more. IVIg can be considered for infants for whom Ig is indicated, but IMIg injection volume is a concern. IVIg administration requires in-hospital administration and active patient monitoring over several hours of infusion, performed by appropriately trained staff. Providers of IVIg should review the respective product monographs and CBS guidelines prior to IVIg administration.
Table 2. Summary of updated measles PEP recommendations for susceptible contacts | Populations | Time since exposure to measles[Footnote \*](#tb2fn*) |
| --- | --- |
| ≤ 72 hours | 73 hours - six days |
| Susceptible infants 0 to 6 months old [Footnote 8](#tb2fn8) | IMIg (0.5mL/kg)[Footnote 2](#tb2fn2) |
| Susceptible immunocompetent infants 6 to 12 months old | MMR vaccine[Footnote 1](#tb2fn1) | IMIg (0.5mL/kg) [Footnote 2](#tb2fn2)[Footnote 7](#tb2fn7)[Footnote 8](#tb2fn8) |
| Susceptible immunocompetent individuals 12 months and older | MMR vaccine series [Footnote 3](#tb2fn3)[Footnote 7](#tb2fn7) |
| Susceptible pregnant individuals[Footnote 4](#tb2fn4) | IVIg (400mg/kg)
or
IMIg (0.5mL/kg), limited protection if 30kg or more[Footnote 5](#tb2fn5) |
| Immunocompromised individuals 6 months and older | IVIg (400mg/kg)
or
IMIg (0.5mL/kg), limited protection if 30kg or more[Footnote 5](#tb2fn5)[Footnote 6](#tb2fn6) |
| Individuals with confirmed measles immunity | N/A |
|
Footnotes
Footnote 1
Two additional doses of MMR vaccine provided after 12 months of age are required for long-term protection.
[Return to footnote 1 referrer](#tb2fn1-rf)
Footnote 2
If injection volume is a major concern, IVIg can be provided at a dose of 400mg/kg.
[Return to footnote 2 referrer](#tb2fn2-rf)
Footnote 3
Susceptible immunocompetent individuals 12 months of age and older are not a priority to receive Ig following measles exposure due to low risk of disease complications and the practical challenges of administration contact management.
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
Provide MMR vaccine series postpartum for future protection.
[Return to footnote 4 referrer](#tb2fn4-rf)
Footnote 5
For individuals 30kg or more, IMIg will not provide complete protection but may prevent some symptoms.
[Return to footnote 5 referrer](#tb2fn5-rf)
Footnote 6
In HIV-infected individuals, measles antibody titer is known to decline more rapidly over time as compared to those who are not HIV-infected. A dose of Ig should be considered in HIV-infected individuals with severe immunosuppression after a known exposure to confirmed measles, even with documented previous MMR immunization. Regardless of vaccination status pre-transplant, Ig should be considered for hematopoietic stem cell transplantation (HSCT) recipients, unless vaccinated post-HSCT and known to have an adequate measles antibody titre.
[Return to footnote 6 referrer](#tb2fn6-rf)
Footnote 7
MMR vaccine will not provide PEP protection after 72 hours of exposure, however, starting and completing a two dose series should not be delayed to provide long term protection.
[Return to footnote 7 referrer](#tb2fn7-rf)
Footnote 8
Two doses of measles-containing vaccine are still required after the first birthday for long-term protection.
[Return to footnote 8 referrer](#tb2fn8-rf)
Footnote \*
Ig should only be provided within 6 days of measles exposure; unless it is contraindicated, individuals who receive Ig should receive measles-containing vaccine after a specified interval, once the measles antibodies administered passively have degraded. For more information, refer to [Blood Products, Human Immunoglobulin and Timing of Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) in Part 1.
[Return to footnote \* referrer](#tb2fn*-rf)
|
#### Outbreak control
Immunization with MMR vaccine is an integral element of a comprehensive measles outbreak prevention and management strategy. In a measles outbreak, susceptible individuals 6 months of age and older may receive MMR vaccine. However, if given between 6 months and less than 12 months of age, 2 additional doses of measles-containing vaccine must be administered after the child is 12 months old (and at least 4 weeks after the previous dose) to ensure long lasting immunity to measles. For detailed information on outbreak control beyond vaccination and post-exposure prophylaxis strategies, refer to [guidelines for measles outbreak in Canada](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2013-39/guidelines-prevention-control-measles-outbreaks-canada.html) in the Canada Communicable Disease Report (CCDR).
Serologic Testing
-----------------
Serological testing may be indicated to confirm the diagnosis of measles or to determine immune status. Serologic testing is not recommended before or after receiving measles-containing vaccine. If serology is inadvertently done subsequent to appropriate measles immunization and does not demonstrate immunity, measles re-immunization is not necessary.
Administration Practices
------------------------
### Dose
Each dose of measles-containing vaccine is 0.5 mL.
### Route of administration
MMR vaccine should be administered subcutaneously (SC). MMRV vaccine should be administered according to the product monograph.
Refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for additional information about pre-vaccination and post-vaccination counselling, vaccine preparation and administration technique, and infection prevention and control.
### Interchangeability of vaccines
On the basis of expert opinion, the MMR vaccines authorized in Canada may be used interchangeably. Refer to [Varicella Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-24-varicella-chickenpox-vaccine.html) for information about interchangeability of MMRV vaccines. Refer to [Principles of Vaccine Interchangeability](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-7-principles-vaccine-interchangeability.html) in Part 1 for additional general information.
### Concurrent administration with other vaccines
MMR vaccine may be administered concurrently with, or at any time before or after, non-live vaccines, live oral vaccines, or live intranasal influenza vaccine (LAIV). Refer to [Influenza Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html) for additional information about concurrent administration of MMR vaccine with LAIV.
MMR vaccine may be administered concurrently with other routinely provided live parenteral vaccines. If not given concurrently, a minimum interval of 4 weeks is recommended between administration of MMR and other live parenteral vaccines. This recommendation is to address the risk of interference from the vaccine given first on the vaccine given later.
Different injection sites and separate needles and syringes must be used for concurrent parenteral injections. Refer to [Timing of Vaccine Administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) in Part 1 for additional information about concurrent administration of measles-containing vaccine with other vaccines.
Storage and Handling of Immunizing Agents
-----------------------------------------
Refer to [Storage and Handling of Immunizing Agents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-9-storage-handling-immunizing-agents.html) in Part 1 for storage and handling recommendations for measles-containing vaccines.
Safety and Adverse Events
-------------------------
### Common and local adverse events
#### Measles-Mumps-Rubella vaccine
Adverse events following immunization with MMR vaccine occur less frequently and are less severe than those associated with natural disease. Adverse reactions are less frequent after the second dose of vaccine and tend to occur only in individuals not protected by the first dose. Six to 23 days after immunization with MMR vaccine, approximately 5% of immunized children experience malaise and fever (with or without rash) lasting up to 3 days. Parotitis, rash, lymphadenopathy, and joint symptoms also occur occasionally after immunization with MMR vaccine.
#### Measles-Mumps-Rubella-Varicella vaccine
Pain and redness at the injection site or fever less than 39°C occur in 10% or more of vaccine recipients. Rash, including measles-like, rubella-like and varicella-like rash, as well as swelling at the injection site and fever greater than 39°C, occur in 1% to less than 10% of vaccine recipients. As varicella-like rashes that occur within the first 2 weeks after immunization may be caused by wild-type virus (varicella virus circulating in the community), health care providers should obtain specimens from the vaccine recipient to determine whether the rash is due to natural varicella infection or to the vaccine-derived strain.
#### Rubella-containing vaccines
Acute transient arthritis or arthralgia may occur 1 to 3 weeks after immunization with rubella-containing vaccine, such as MMRV. It lasts for about 1 to 3 weeks, and rarely recurs. It is more common in post-pubertal females, among whom arthralgia develops in 25% and arthritis in 10% after immunization with rubella-containing vaccine. There is no evidence of increased risk of new onset chronic arthropathies.
#### Human immunoglobulin
Injection site reactions following receipt of standard human Ig include tenderness, erythema and stiffness of local muscles, which may persist for several hours. Mild fever or malaise may occasionally occur.
### Less common and serious or severe adverse events
Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association. Anaphylaxis following vaccination with MMR or MMRV vaccine may occur but is very rare.
#### Immune Thrombocytopenic Purpura
Rarely, Immune Thrombocytopenic Purpura (ITP) occurs within 6 weeks after immunization with MMR or MMRV vaccine. In most children, post-immunization thrombocytopenia resolves within 3 months without serious complications. In individuals who experienced ITP with the first dose of MMR or MMRV vaccine, serologic status may be evaluated to determine whether an additional dose of vaccine is needed for protection. The potential risk to benefit ratio should be carefully evaluated before considering vaccination in such cases.
#### Encephalitis
Encephalitis has been reported in association with administration of measles vaccine in approximately 1 per million doses distributed in North America which is much lower than the incidence observed with natural measles disease (1 per 1,000 cases).
#### Febrile seizures
When the first dose of measles-containing vaccine is administered to children 12 to 23 months as MMRV vaccine, there is a higher risk of fever and febrile seizures in the 7 to 10 days after vaccination when compared to separate administration of MMR and varicella vaccine at the same visit. This risk is estimated at about 1 additional febrile seizure for every 2,300 to 2,800 doses of MMRV vaccine.
#### Human immunoglobulin
Less common side effects following receipt of standard human Ig include flushing, headache, chills and nausea. Urticaria, angioedema and anaphylactic reactions may occur rarely.
### Other reported adverse events and conditions
In the mid to late 1990s, researchers from the United Kingdom reported an association between MMR vaccine and inflammatory bowel disease, and MMR vaccine and autism. Rigorous scientific studies and reviews of the evidence have been done worldwide, and there is now considerable evidence to refute those claims. In 2010, the original study suggesting a link between the MMR vaccine and autism was found to be fraudulent and was retracted.
#### Guidance on reporting Adverse Events Following Immunization
Vaccine providers are asked to report the following adverse events following immunization (AEFI) in particular, through local public health officials:
* Febrile seizures within 30 days after vaccination with MMR or MMRV vaccine.
* Varicella that is moderate (50 to 500 lesions) or severe (more than 500 vesicular lesions or associated complications or hospital admission) and occurs within 7 to 21 days after vaccination with MMRV vaccine.
* Any serious or unexpected adverse event temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.
Refer to [Reporting Adverse Events Following Immunization (AEFI) in Canada](/en/public-health/services/immunization/reporting-adverse-events-following-immunization/user-guide-completion-submission-aefi-reports.html) and [Adverse Events Following Immunization (AEFI)](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) in Part 2 for additional information about AEFI reporting.
### Contraindications and precautions
MMR and MMRV vaccines and Ig are contraindicated in persons with a history of anaphylaxis after previous administration of the product and in persons with proven immediate or anaphylactic hypersensitivity to any component of the product, with the exception of egg allergy for MMR and MMRV vaccines. Refer to [Contents of Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for lists of vaccines and passive immunizing agents authorized in Canada and their contents.
Human Ig preparations should not be given to people with known isolated IgA deficiency unless the benefit outweighs the risk, in which case the product should be given with caution and under close observation.
In situations of suspected hypersensitivity or non-anaphylactic allergy to vaccine components, investigation is indicated which may involve immunization in a controlled setting. Consultation with an allergist is advised.
Although the measles and mumps components of MMR and MMRV vaccines are produced in chick embryo cell culture and may contain traces of residual egg and chicken protein, the trace amount of egg or chicken protein in the vaccine appears to be insufficient to cause an allergic reaction in egg-allergic individuals. Skin testing is not recommended prior to vaccination as it does not predict reaction to the vaccine. MMR or MMRV vaccine can be administered in the routine manner to people who have a history of anaphylactic hypersensitivity to hens' eggs. Prior egg ingestion is not a prerequisite for immunization with egg protein-containing vaccine. For all vaccines, immunization should always be performed by personnel with the capability and facilities to manage adverse events post-vaccination. Refer to [Contraindications and Precautions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html) in Part 2 for additional information.
Children with a known or suspected family history of congenital or hereditary immunodeficiency that is a contraindication to vaccination with live vaccine should not receive live vaccines unless their immune competence has been established.
MMRV vaccine can be contraindicated in persons with impaired immune function, including primary or secondary immunodeficiency disorders. Human Ig preparations should not be given to people with known isolated IgA deficiency unless the benefit outweighs the risk, in which case the product should be given with caution and under close observation. Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for more information. MMR and MMRV vaccines are generally contraindicated during pregnancy because of the theoretical risk to the fetus. Refer to [Immunization in Pregnancy and Breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3.
Measles-containing vaccines are contraindicated in individuals with active, untreated tuberculosis (TB) as a precautionary measure. Although TB may be exacerbated by natural measles infection, there is no evidence that measles-containing vaccines have such an effect. Nonetheless, anti-tuberculous therapy for active TB disease is advisable before administering measles-containing vaccines and it may be prudent to avoid live viral vaccines in those with active TB disease until treatment is underway. Consultation with an expert in infectious diseases is recommended.
A history of febrile seizures or a family history of seizures is not a contraindication for the use of MMRV vaccine.
Administration of MMR or MMRV vaccine should be postponed in persons with severe acute illness. Persons with a minor acute illness, with or without fever, may be vaccinated.
It is recommended to avoid the use of salicylates (medications derived from salicylic acid, such as acetylsalicylic acid [ASA]) for 6 weeks after immunization with MMRV vaccine because of an association between wild-type varicella, salicylate therapy and Reye's syndrome.
Refer to [Contraindications and Precautions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html) in Part 2 for additional information.
#### Drug interactions
##### Systemic antiviral therapy
Systemic antiviral therapy (such as acyclovir, valacyclovir, famciclovir) should be avoided in the peri-immunization period, as it may affect the reproduction of the vaccine virus and consequently may reduce the efficacy of varicella-containing vaccine, such as MMRV. On the basis of expert opinion, it is recommended that people taking long-term antiviral therapy should discontinue these drugs, if possible, from at least 24 hours before administration of MMRV vaccine and should not restart antiviral therapy until 14 days after vaccine administration.
##### Tuberculin skin testing or Interferon Gamma Release Assay (IGRA)
The measles component in measles-containing vaccines can temporarily suppress tuberculin reactivity, resulting in false-negative results. If tuberculin skin testing or an IGRA test is required, it should be done on the same day as immunization or delayed for at least 4 weeks after measles vaccination. Vaccination with measles-containing vaccine may take place at any time after tuberculin skin testing has been performed and read.
#### Human immunoglobulin or other blood products
Passive immunization with human Ig or receipt of most other blood products can interfere with the immune response to MMR, MMRV and univalent varicella vaccines. These vaccines should be given at least 14 days prior to administration of an immunoglobulin preparation or blood product, or delayed until the antibodies in the Ig preparation or blood product have degraded. Refer to [Blood Products, Human Immunoglobulin and Timing of Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) in Part 1 for additional information.
Appendix A: List of abbreviations and acronyms
----------------------------------------------
AEFI
Adverse events following immunization
ASA
acetylsalicylic acid
CBS
Canadian blood services
IGRA
interferon gamma release assay
IMIg
Intramuscular immunoglobulin
ITP
immune thrombocytopenic purpura
IVIg
intravenous immunoglobulin
MMR
measles, mumps, rubella
MMRV
measles, mumps, rubella, varicella
PEP
post-exposure prophylaxis
TB
tuberculosis
Selected References
-------------------
* Advisory Committee on Epidemiology. Guidelines for control of measles outbreaks in Canada. Can Commun Dis Rep 1995;21:189-95.
* American Academy of Pediatrics. In: Pickering LK, Baker CJ, Kimberlin DW, et al. (editors). Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.
* Bell A, King A, Pielak K et al. Epidemiology of measles outbreak in British Columbia - February 1997. Can Commun Dis Rep 1997;23:49-51.
* Bellini WJ, Rota JS, Lowe LE et al. Subacute sclerosing panencephalitis: more cases of this fatal disease are prevented by measles immunization than was previously recognized. J Infect Dis 2005;192(10):1686-93.
* Centers for Disease Control and Prevention. The Yellow Book: CDC Health Information for International Travel 2014. Accessed June 2015 at: http://wwwnc.cdc.gov/travel/page/yellowbook-home-2014
* Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices Provisional Recommendations for Measles-Mumps-Rubella (MMR) 'Evidence of Immunity' Requirements for Healthcare Personnel. 2009.
* Centers for Disease Control and Prevention. The Pink Book: Epidemiology and Prevention of Vaccine Preventable Diseases. Updated 13th ed.; 2015. Accessed June 2015 at: http://www.cdc.gov/vaccines/pubs/pinkbook/index.html
* Centers for Disease Control and Prevention. Use of Combination Measles, Mumps, Rubella and Varicella Vaccine. Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 2010;59(03):1-12.
* Centers for Disease Control and Prevention. Update: recommendations from the Advisory Committee on Immunization Practices (ACIP) regarding administration of combination MMRV vaccine. MMWR Morb Mortal Wkly Rep 2008;57:258-60.
* De Serres G, Boulianne N, Meyer F et al. Measles vaccine efficacy during an outbreak in a highly vaccinated population: incremental increase in protection with age at vaccination up to 18 months. Epidemiol Infect 1995;115:315-23.
* De Serres G, Gay NJ, Paddy C et al. Epidemiology of transmissible diseases after elimination. Am J Epidemiol 2000;151(1):1039-48.
* De Serres G, Sciberras J, Naus M et al. Protection after two doses of measles vaccine is independent of interval between doses. J Infect Dis 1999;180:187-90.
* Gay NJ, De Serres G, Farrington CP et al. Elimination of measles from the United States: an assessment through basic surveillance data. J Infect Dis 2004;189(Suppl 1):S36-42.
* GlaxoSmithKline Inc. Product Monograph - PRIORIX-TETRA™. May 2010.
* GlaxoSmithKline Inc. Product Monograph - PRIORIX®. November 2008.
* Grifols Therapeutics LLC. Product Monograph - GamaSTAN®. March 2019.
* Halsey NA, Hyman SL. Measles-mumps-rubella vaccine and autistic spectrum disorder: report from the New Challenges in Childhood Immunizations Conference convened in Oak Brook, Illinois, June 12-13, 2000. Pediatrics 2001;107:E84.
* Institute of Medicine, Immunization Safety Review Committee (Stratton K, Gable A, Shetty P et al, eds.). Measles-mumps-rubella vaccine and autism. Washington DC: National Academy Press, 2001.
* Jadavji T, Scheifele D, Halperin S. Thrombocytopenia after immunization of Canadian children, 1992 to 2001. Pediatr Infect Dis J 2003;22(2):119-22.
* King A, Varughese P, De Serres G et al. Measles elimination in Canada. J Infect Dis 2004;189(Suppl 1):S236-42.
* Madse KM, Hviid A, Vestergaard M et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med 2002;347(19):1477-82.
* Mantadakis E, Farmaki E, Buchanan GR. Thrombocytopenic purpura after measles-mumps-rubella vaccination: a systematic review and guidance for management. J Pediatr 2010;156(4):623-8.
* Markowitz L, Albrecht P, Orenstein WA et al. Persistence of measles antibody after revaccination. J Infect Dis 1992;166:205-8.
* Merck Frosst Canada Ltd. Product Monograph - M-M-R®II. February 2009.
* Miller E, Andrews N, Grant A et al. No evidence of an association between MMR vaccine and gait disturbance. Arch Dis Child 2005;90(3):292-6.
* Murch SH, Anthony A, Casson DH et al. Retraction. Lancet 2004;363(4411):750.
* Nahirniak, S, Lazarus, A. immunoglobulin Products, in Clinical Guide to Transfusion. Canadian Blood Services 2016. Accessed July 2018 at : https://professionaleducation.blood.ca/en/transfusion/clinical-guide/immune-globulin-products
* National Advisory Committee on Immunization. Statement on measles-mumps-rubella-varicella vaccine. Can Commun Dis Rep 2010;36(ACS-9):1-22.
* National Advisory Committee on Immunization. Updated NACI recommendation for measles post-exposure prophylaxis. Can Comm Dis Rep. 2018 09 06; 44-9
* National Advisory Committee on Immunization. Updated recommendations for the use of varicella and MMR vaccines in HIV-infected individuals. Can Commun Dis Rep 2010;36(ACS-7):1-19.
* Ratnam S, West R, Gadag V et al. Immunity against measles in school aged children: implications for measles revaccination strategies. Can J Public Health 1996;87:407-10.
* Strauss B, Bigham M. Does measles-mumps-rubella (MMR) vaccination cause inflammatory bowel disease and autism? Can Commun Dis Rep 2001;27:65-72.
* Taylor B, Miller E, Lingam R et al. Measles, mumps and rubella vaccination and bowel problems or developmental regression in children with autism: population study. Br Med J 2002;324(7334):393-6.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-11-japanese-encephalitis-vaccine.html "Japanese encephalitis vaccine: Canadian immunization guide")
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-13-meningococcal-vaccine.html "Meningococcal vaccine: Canadian immunization guide")
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-06-21
| None | None |
eded60528498485b04df8c6361cb5885515ac49c | cma | Contents of immunizing agents authorized for use in Canada: Canadian Immunization Guide | Contents of immunizing agents authorized for use in Canada: Canadian Immunization Guide
Introduction
The following tables provide a comprehensive list of contents of immunizing agents authorized in Canada. lists contents of active vaccines and lists contents of passive immunizing agents. Vaccine providers should consult the product label, product leaflet, or product monograph for current product information. Manufacturers provide evidence of vaccine safety and efficacy and receive authorization for the immunizing agent only when it is used in accordance with the product monograph available through Health Canada's . Information about the vaccine manufacturer/distributor is available in in Part 4. For more information about immunoglobulins, refer to in Part 1.
Contents of immunizing agents
In addition to the active component (antigen or instructions for the antigen in case of vaccines or antibody in case of immunoglobulins), immunizing agents may contain additional ingredients such as adjuvants, preservatives, additives, and traces of other substances.
# Adjuvants
An adjuvant is a substance that is added to a vaccine to enhance the resulting immune response and to extend the duration of B and T cell activation. An adjuvant allows a reduction in the amount of antigen per dose or the total number of doses needed to achieve immunity, and helps to improve the immune response in individuals with some degree of immune suppression (for example, the elderly). The adjuvants used in vaccines currently marketed in Canada are:
- aluminum salts (aluminum hydroxide , aluminum phosphate , or amorphous aluminum hydroxyphosphate sulfate )
- AS01B (3-O-desacyl-4'-monophosphoryl lipid A , *Quillaja saponaria- Molina, fraction 21 , cholesterol, dioleoyl phosphatidylcholine , disodium phosphate anhydrous, potassium dihydrogen phosphate, sodium chloride, water for injection)
- AS03 (DL-alpha-tocopherol, squalene, polysorbate 80, phosphate buffered saline)
- AS04 (3-O-desacyl-4'-monophosphoryl lipid A adsorbed onto aluminum )
- Matrix-M adjuvant (cholesterol, disodium hydrogen phosphate dihydrate, phosphatidylcholine, potassium chloride, potassium dihydrogen phosphate, sodium chloride)
- MF59 (oil-in-water emulsion composed of squalene as the oil phase, stabilized with the surfactants polysorbate 80 and sorbitan trioleate, in citrate buffer).
# Preservatives
Chemicals (for example, thimerosal, phenol, 2-phenoxyethanol) may be added to vaccines to prevent serious infections which may result from bacterial or fungal contamination of the vaccine. Most vaccines authorized for use in Canada do not contain thimerosal.
# Other contents of immunizing agents
Other substances that may be found in immunizing agents include:
- Minute amounts of chemicals that are used during the production process, such as for the growth or purification of specific antigens or the inactivation of toxins. For example, antibiotics that prevent contamination during viral cell culture; egg or yeast proteins glycerol, serum, amino acids and enzymes that are needed for the growth of bacteria and viruses; and formaldehyde that is used to inactivate viruses and protein toxins.
- Small amounts of chemicals that support product stability. For example, additives such as potassium or sodium salts, lactose, and polysorbate help control product acidity (pH) and maintain the quality of vaccine antigens.
- Sucrose
- Trometamol
- d
- ap
- Glutaraldehyde
- d
- ap
- IPV
- Polymyxin B
- Streptomycin
- Polysorbate 80
- Formaldehyde
- Glutaraldehyde
- Water for injection
- Neomycin sulfate
- Polymixin B sulfate
- Thimerosal
- Calcium chloride
- Dibasic sodium phosphate (anhydrous)
- Hydrocortisone
- Monobasic potassium phosphate
- Monobasic sodium phosphate
- Potassium chloride
- Sodium chloride
- Sodium taurodeoxycholate
- Sucrose
- Water for injection
- Polysorbate 80
- Medium 199 Hanks
- Water for injection
- Formaldehyde
- Kanamycin (Residue)
- Sodium chloride
- Sucrose
- Water for injections
- d
- ap
- Glycine
- Sodium chloride
- Water for injection
- d
- ap
- IPV
- Polymyxin B
- Medium 199
- Sodium chloride
- Water for injection
- Sodium dihydrogen phosphate dihydrate
- Water for injection
- Tromethamine
- Tromethamine (hydrochloride)
- ALC-0159 = 2-[(polyethylene
glycol)-2000]-N,N-ditetradecylacetamide
- ALC-0315 = ((4-hydroxybutyl) azanediyl)bis
(hexane-6,1-diyl)bis(2-hexyldecanoate)
- Cholesterol
- Sodium chloride
- Sucrose
- Water for injection
- ALC-0159 = 2-[(polyethylene
glycol)-2000]-N,N-ditetradecylacetamide
- ALC-0315 = ((4-hydroxybutyl) azanediyl)bis
(hexane-6,1-diyl)bis(2-hexyldecanoate)
- Cholesterol
- Dibasic sodium phosphate dihydrate
- Monobasic potassium phosphate
- Potassium chloride
- Sodium chloride
- Sucrose
- Water for injection
- Kanamycin
- Polyethylene Glycol (PEG)
- Polysorbate 80
- Phosphate buffered saline
- Potassium phosphate monobasic anhydrous
- Sodium chloride
- Sodium phosphate dibasic anhydrous
- Squalene
- Water for injection
- Ecol
- Disodium hydrogen phosphate
- Raspberry flavor
- Saccharin sodium
- Sodium carbonate
- Sodium citrate
- Sodium chloride
- Sodium dihydrogen phosphate
- Sodium hydrogen carbonate
- Water for injection
- Sodium chloride
- Sodium dihydrogen phosphate dihydrate
- Water for injection
- Recombinant human serum albumin
- Sodium hydroxide
- Trace amounts of rice protein
- Trometamol buffer
- Water for injection
- Kanamycin
- Neomycin
- Polysorbate 80
- Cetyltrimethylammonium bromide
- Citric acid
- Disodium phosphate dihydrate
- Formaldehyde
- Hydrocortisone
- Magnesium chloride hexahydrate
- Potassium chloride
- Potassium dihydrogen phosphate
- Sodium chloride
- Sodium citrate
- Sorbitan trioleate
- Squalene
- Water for injection
- Thimerosal
- Cetyltrimethylammonium bromide
- Disodium phosphate dihydrate
- Magnesium chloride hexahydrate
- Potassium chloride
- Potassium dihydrogen phosphate
- Sodium chloride
- Water for injections
- Thimerosal
- Polysorbate 80
- Disodium hydrogen phosphate heptahydrate
- Ethanol
- Formaldehyde
- Potasium chloride
- Potassium dihydrogen phosphate
- Sodium chloride
- Sodium deoxycholate
- Sucrose
- Water for injection
- Egg protein
- Gelatin hydrolysate
- Gentamicin
- Monosodium glutamate
- Monobasic potassium phosphate
- Sucrose
- Thimerosal
- Polysorbate 80
- Disodium hydrogen phosphate heptahydrate
- Ethanol
- Formaldehyde
- Potassium chloride
- Potassium dihydrogen phosphate
- Sodium chloride
- Sodium deoxycholate
- Sucrose
- Water for injection
- Sodium phosphate-buffered isotonic sodium chloride solution
- Triton® X-100
- Thimerosal
- Sodium phosphate-buffered isotonic sodium chloride solution
- Triton® X-100
- Polysorbate 80
- Sodium borate
- Sodium chloride
- Disodium phosphate
- Formaldehyde
- Monopotassium phosphate
- Polysorbate 20
- Potassium chloride
- Sodium chloride
- Water for injection
- Polymyxin B
- Streptomycin
- Polysorbate 80
- Formaldehyde
- Medium 199 Hanks
- Phenol red
- Water for injection
- Bromobutyl rubber stopper
- Ciprofloxacin
- Gentamicin
- Residual host (egg) cell DNA and protein
- Trometamol
- Sodium chloride
- Tris-hydroxymethyl-amino methane
- Water for injection
- T
- aP
- HB
- IPV
- Hib
- Neomycin
- Polymyxin B
- M199
- Sodium chloride
- Water for injection
- T
- aP
- IPV
- Hib
- Polymixin sulphate
- Polysorbate 80
- Sodium chloride
- M199
- Water for injection
- Residual formaldehyde
- Potassium chloride
- Disodium phosphate
- Monopotassium phosphate
- Glycine
- Egg Material
- Gentamicin sulphate
- Neomycin sulphate
- Polymyxin B sulphate
- Polysorbate 80
- Cetyltrimethyl ammonium bromide
- Disodium phosphate dihydrate
- Formaldehyde
- Hydrocortisone
- Magnesium chloride hexahydrate
- Potassium chloride
- Potassium dihydrogen phosphate
- Sodium chloride
- Sodium citrate
- Sucrose
- Tylosine tartrate
- Water for injection
- Potassium dihydrogen phosphate
- Sodium chloride
- Water for injection
- Citric acid monohydrate
- Ethanol
- Hydrochloric acid
- Sodium chloride
- Sodium hydroxide
- Trisodium citrate dihydrate
- Water for injection
- Sodium phosphate dibasic (anhydrous)
- Sodium phosphate monobasic
- Water for injection
- Bromobutyl rubber stopper
- Sodium chloride
- Water for injection
- Sodium chloride
- Sterile water for injection
- Potassium dihydrogen phosphate
- Sodium chloride
- Sodium dihydrogen phosphate monohydrate
- Sucrose
- Water for injection
- Mumps
- Rub
- Phenol red
- Porcine gelatin
- Residual components of chick embryo cell cultures
- Medium 199 with Hank's salts
- Minimum essential medium (Eagle)
- Monosodium L-glutamate monohydrate
- Potassium phosphate dibasic (anhydrous)
- Potassium phosphate monobasic
- Recombinant human albumin
- Sodium bicarbonate
- Sodium phosphate dibasic (anhydrous)
- Sodium phosphate monobasic
- Sorbitol
- Sucrose
- Water for injection
- Trometamol
- Sodium chloride
- Water for injection
- Disodium hydrogen phosphate dihydrate
- Disodium hydrogen phosphate heptahydrate
- Hydrochloric acid
- Phosphatidylcholine
- Potassium chloride
- Potassium dihydrogen phosphate
- Sodium chloride
- Sodium dihydrogen phosphate monohydrate
- Sodium hydroxide
- Water for Injection
- T
- aP
- IPV
- Hib
- Polymyxin B
- Streptomycin
- Polysorbate 80
- Formaldehyde
- Glutaraldehyde
- Water for injection
- Hydrochloric acid
- Potassium chloride
- Potassium dihydrogen phosphate
- Sodium chloride
- Sodium hydroxide
- Water for injection
- Polysorbate 80
- Succinic acid
- Water for injection
- Succinic acid
- Water for injection
- Mumps
- Rub
- Neomycin
- Lactose
- Mannitol
- Sorbitol
- Water for injection
- Mumps
- Rub
- Var
- Neomycin
- Lactose
- Mannitol
- Sorbitol
- Water for injection
- Mumps
- Rub
- Var
- Neomycin
- Chicken protein
- Urea
- Sodium chloride
- Sorbitol
- Monosodium L-glutamate
- Sodium phosphate
- Human albumin
- T
- aP
- IPV
- Polymyxin B
- Polysorbate 80
- Formaldehyde
- Glutaraldehyde
- Chicken protein
- Chlortetracycline
- Neomycin
- Polygeline (gelatin)
- Egg protein
- Yeast protein
- Sodium borate
- Sodium chloride
- Water for injection
- DNA fragments from porcine circovirus 1
- Dulbecco's Modified Eagle Medium
- Sterile water
- Sucrose
- Fetal bovine serum
- Residual protein from cell culture
- Sodium citrate dihydrate
- Sodium hydroxide
- Sodium phosphate monobasic monohydrate
- Sucrose
- Sodium dihydrogen phosphate dihydrate
- Sucrose
- Water for injection
- Trometamol
- Trometamol (hydrochloride)
- Cholesterol
- DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine)
- Lipid SM-102
- PEG2000-DMG (1,2-dimyristoyl-racglycerol,
methoxy-polyethyleneglycol)
- Sodium acetate trihydrate
- Sucrose
- Water for injection
- Baculovirus and Spodoptera frugiperda cell proteins
- Dibasic sodium phosphate
- Monobasic sodium phosphate
- Sodium chloride
- Triton X-100
- Diphtheria toxoid carrier protein
- Tetanus toxoid carrier protein
- Non-typeable Haemophilus influenzae protein D carrier
protein
- Water for injection
- d
- Sodium chloride
- Water for injection
- Sodium chloride
- Water for injection
- HB
- Yeast protein
- Formaldehyde
- Polysorbate 20
- Sodium chloride
- Water for injection
- Neomycin
- DNA
- Formaldehyde
- Residual protein from cell culture
- Sodium borate
- Sodium chloride
- Water for injection
- Human albumin
- Lactose
- Polyalcohols
- Water for injection
- Porcine gelatin
- Monosodium L-glutamate
- Potassium chloride
- Potassium phosphate monobasic
- Residual protein from cell culture
- Sodium chloride
- Sodium phosphate dibasic
- Sucrose
- Urea
- Water for injection
- Sodium chloride
- Water for injection
- Ethanol
- L-Histidine
- L-Histidine hydrochloride monohydrate
- Magnesium chloride hexahydrate
- Sodium chloride
- Sucrose
- Water for injection
- Ascorbic acid
- Dibutyl phthalate
- Diethyl phthalate
- Erythrosine FD+C red 3
- Ethylene glycol
- Hydroxypropylcellulose-phthalate
- Lactose
- Magnesium stearate
- Red iron oxide
- Sucrose
- Titanium dioxide
- Yellow iron oxide
- Egg protein
- Gelatin
- Latex in stopper of diluent vial
- Sorbitol
Any component in a vaccine may be a potential allergen. This table identifies most common allergens; adjuvants and preservatives may be potential allergens, but this is extremely rare.
There is a potential of cross-reactive hypersensitivity between PEG and polysorbates. Therefore, individuals who are being administered a product that includes any one of these components as ingredients should be asked about any allergic reactions to either component.
Multi-dose presentation only.
Not present in COMIRNATY® (Original) and COMIRNATY® Original & Omicron BA.4/BA.5 vials with gray cap and label border (for 12 years of age and older).
IMVAMUNE® is not available for general use.
Only used if gentamicin cannot be used. If not used, not present.
# Abbreviations
## Route-
ID
intradermal
IM
intramuscular
IN
intranasal
SC
subcutaneous
## Immunogen-
aP
acellular pertussis
ap
acellular pertussis (reduced)
BCG
Bacillus Calmette-Guérin
Chol
cholera
D
diphtheria
d
diphtheria (reduced)
Ecol
enterotoxigenic Escherichia coli
Hib
Haemophilus influenzae type b
HA
hepatitis A
HB
hepatitis B
HPV
human papillomavirus
Inf
influenza
IPV
inactivated poliomyelitis
JE
Japanese encephalitis
Men
meningococcus
Men B
Neisseria meningitidis Serogroup B protein
Meas
measles
Mumps
mumps
Pneu
pneumococcus
Rab
rabies
Rot
rotavirus
Rub
rubella
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
T
tetanus
Typh
typhoid
Var
varicella
YF
yellow fever
ZEBOV
Zaire ebolavirus
## Adjuvant-
AAHS
amorphous aluminum hydroxyphosphate sulfate
Al(OH)3
Aluminum hydroxide
AlPO4
Aluminum phosphate
AS01B
3-O-desacyl-4'-monophosphoryl lipid A , *Quillaja saponaria- Molina, fraction 21 , cholesterol, dioleoyl phosphatidylcholine
sodium chloride, water for injection
AS04
3-O-desacyl-4'-monophosphoryl lipid A adsorbed onto aluminum (as hydroxide
salt)
MF59
squalene, polysorbate 80, sorbitan trioleate, sodium citrate, citric acid,
water for injection
## Preservative-
P
phenol
PE
2-phenoxyethanol
Tm
thimerosal
agents authorized for use in Canada
- Polysorbate 80
- Sucrose
- L-histidine
- L-histidine hydrochloride
- Sucrose
- Water for injection
- Sucrose
- Water for injection
- L-Histidine hydrochloride monohydrate
- Sucrose
- Water for injection
- Tri-n-butyl phosphate
- Triton®X-100
- Sodium hydroxide
- Water for injection
- Glycine
- Histidine
- Water for injection
- Human plasma protein
- Sodium chloride
- Sodium phosphate
- Tri-n-butyl phosphate
- Triton®X-100
Only available on an emergency basis by application to Health Canada's Special Access Programme (SAP) (). Public health should be contacted for assistance in obtaining these products. Information can also be obtained from the SAP website or by contacting the SAP office (telephone: 613-941-2108; fax: 613-941-3194; Available 24 hours a day, 7 days a week).
For further information refer to Health Canada: Botulism - Guide for healthcare professionals at
There is a potential of cross-reactive hypersensitivity between PEG and polysorbates. Therefore, individuals who are being administered a product that includes any one of these components as ingredients. should be asked about any allergic reactions to either component.
Should be used in consultation with a specialist in immunodeficiency.
# Abbreviations:
## Route-
IM
intramuscular
IV
intravenous
Local
local wound infiltration
## Protects against or treats-
B
botulism
CMV
cytomegalovirus
D
diphtheria
HA
hepatitis A
HB
hepatitis B
Meas
measles
Rub
rubella
Rab
rabies
RSV
respiratory syncytial virus
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
T
tetanus
Vac
vaccinia
Var
varicella
N/A
Not applicable
## Preservative-
P
phenol |
Contents of immunizing agents authorized for use in Canada: Canadian Immunization Guide
========================================================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
**Last partial content update** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): February 2023
This chapter was updated to align with changes made to:
* [Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2022-2023](/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html)
* [COVID-19 Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) chapter in Part 4
* [Pneumococcal Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html) chapter in Part 4
* The section on "Adjuvants" was updated to include two additional adjuvants: AS03 and Matrix M adjuvant used in COVIFENZ**®** AND NUVAXOVID**TM** COVID-19 vaccines, respectively
**Last complete chapter revision** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): April 2017
On this page
------------
* [Introduction](#a1)
* [Contents of immunizing agents](#a2)
* [Table 1: Types and contents of vaccines authorized for use in Canada](#a3)
* [Table 2: Types and contents of passive immunizing agents authorized for use in Canada](#a4)
Introduction
------------
The following tables provide a comprehensive list of contents of immunizing agents authorized in Canada. [Table 1](#a3) lists contents of active vaccines and [Table 2](#a4) lists contents of passive immunizing agents. Vaccine providers should consult the product label, product leaflet, or product monograph for current product information. Manufacturers provide evidence of vaccine safety and efficacy and receive authorization for the immunizing agent only when it is used in accordance with the product monograph available through Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html). Information about the vaccine manufacturer/distributor is available in [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4. For more information about immunoglobulins, refer to [Basic Immunology and Vaccinology](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-14-basic-immunology-vaccinology.html) in Part 1.
Contents of immunizing agents
-----------------------------
In addition to the active component (antigen or instructions for the antigen in case of vaccines or antibody in case of immunoglobulins), immunizing agents may contain additional ingredients such as adjuvants, preservatives, additives, and traces of other substances.
### Adjuvants
An adjuvant is a substance that is added to a vaccine to enhance the resulting immune response and to extend the duration of B and T cell activation. An adjuvant allows a reduction in the amount of antigen per dose or the total number of doses needed to achieve immunity, and helps to improve the immune response in individuals with some degree of immune suppression (for example, the elderly). The adjuvants used in vaccines currently marketed in Canada are:
* aluminum salts (aluminum hydroxide [Al(OH)₃], aluminum phosphate [AlPO4], or amorphous aluminum hydroxyphosphate sulfate [AAHS])
* AS01B (3-O-desacyl-4'-monophosphoryl lipid A [MPL], *Quillaja saponaria* Molina, fraction 21 [QS-21], cholesterol, dioleoyl phosphatidylcholine [DOPC], disodium phosphate anhydrous, potassium dihydrogen phosphate, sodium chloride, water for injection)
* AS03 (DL-alpha-tocopherol, squalene, polysorbate 80, phosphate buffered saline)
* AS04 (3-O-desacyl-4'-monophosphoryl lipid A adsorbed onto aluminum [as hydroxide salt])
* Matrix-M adjuvant (cholesterol, disodium hydrogen phosphate dihydrate, phosphatidylcholine, potassium chloride, potassium dihydrogen phosphate, sodium chloride)
* MF59 (oil-in-water emulsion composed of squalene as the oil phase, stabilized with the surfactants polysorbate 80 and sorbitan trioleate, in citrate buffer).
### Preservatives
Chemicals (for example, thimerosal, phenol, 2-phenoxyethanol) may be added to vaccines to prevent serious infections which may result from bacterial or fungal contamination of the vaccine. Most vaccines authorized for use in Canada do not contain thimerosal.
### Other contents of immunizing agents
Other substances that may be found in immunizing agents include:
* Minute amounts of chemicals that are used during the production process, such as for the growth or purification of specific antigens or the inactivation of toxins. For example, antibiotics that prevent contamination during viral cell culture; egg or yeast proteins glycerol, serum, amino acids and enzymes that are needed for the growth of bacteria and viruses; and formaldehyde that is used to inactivate viruses and protein toxins.
* Small amounts of chemicals that support product stability. For example, additives such as potassium or sodium salts, lactose, and polysorbate help control product acidity (pH) and maintain the quality of vaccine antigens.
Table 1: Types and contents of vaccines authorized for use in Canada
| Brand name | Route | Vaccine type
(live; non-live) | Immunogen | Adjuvant | Preservative | Potential allergens [Footnote 1](#fn1.1) | Other materials | Abbreviation |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| A dash [ - ] indicates that there are no materials under
that category in the product. |
| **Act-HIB®** | IM | non-live | * Hib
| - | - | * Tetanus toxoid carrier protein
| * Sodium chloride
* Sucrose
* Trometamol
| Hib |
| **ADACEL®** | IM | non-live | * T
* d
* ap
| AlPO4 | PE | - | * Formaldehyde
* Glutaraldehyde
| Tdap |
| **ADACEL® -POLIO** | IM | non-live | * T
* d
* ap
* IPV
| AlPO4 | PE | * Neomycin
* Polymyxin B
* Streptomycin
* Polysorbate 80 [Footnote 2](#fn1.2)
| * Bovine serum albumin
* Formaldehyde
* Glutaraldehyde
* Water for injection
| Tdap-IPV |
| **AFLURIA® TETRA** | IM | non-live | * Inf
| - | Tm[Footnote 3](#fn1.3) | * Egg protein
* Neomycin sulfate
* Polymixin B sulfate
* Thimerosal [Footnote 3](#fn1.3)
| * Beta-propiolactone
* Calcium chloride
* Dibasic sodium phosphate (anhydrous)
* Hydrocortisone
* Monobasic potassium phosphate
* Monobasic sodium phosphate
* Potassium chloride
* Sodium chloride
* Sodium taurodeoxycholate
* Sucrose
* Water for injection
| IIV4-SD |
| **AVAXIM®** | IM | non-live | HA | Al(OH)3 | * PE
| * Neomycin
* Polysorbate 80 [Footnote 2](#fn1.2)
| * Ethanol anhydrous
* Medium 199 Hanks
* Water for injection
* Formaldehyde
| HA |
| **BEXSERO®** | IM | non-live | Men B | Al(OH)3 | - | * Latex in tip cap of syringe
* Kanamycin (Residue)
| * Histidine
* Sodium chloride
* Sucrose
* Water for injections
| 4CMenB |
| **BOOSTRIX®** | IM | non-live | * T
* d
* ap
| Al(OH)3 | - | * Polysorbate 80 [Footnote 2](#fn1.2)
| * Formaldehyde
* Glycine
* Sodium chloride
* Water for injection
| Tdap |
| **BOOSTRIX® -POLIO** | IM | non-live | * T
* d
* ap
* IPV
| Al(OH)3, AlPO4 | - | * Neomycin
* Polymyxin B
| * Formaldehyde
* Medium 199
* Sodium chloride
* Water for injection
| Tdap-IPV |
| **CERVARIX®** | IM | non-live | HPV | AS04 | - | * Latex in plunger stopper of pre-filled syringe
| * Hydrated sodium chloride
* Sodium dihydrogen phosphate dihydrate
* Water for injection
| HPV2 |
| **COMIRNATY ® (Original) - Gray Vial Cap and Label Border** | IM | non-live | SARS-CoV-2 | - | - | * Polyethylene Glycol (PEG) [Footnote 2](#fn1.2)
* Tromethamine
* Tromethamine (hydrochloride)
| * 1,2-distearoyl-sn-glycero-3-phosphocholine
* ALC-0159 = 2-[(polyethylene
glycol)-2000]-N,N-ditetradecylacetamide
* ALC-0315 = ((4-hydroxybutyl) azanediyl)bis
(hexane-6,1-diyl)bis(2-hexyldecanoate)
* Cholesterol
* Sodium chloride [Footnote 4](#fn1.4)
* Sucrose
* Water for injection
| COVID-19 |
| **COMIRNATY ® (Original) - Orange Vial Cap and Label Border** |
| **COMIRNATY ® (Original) –Maroon Vial Cap and Label Border** |
| **COMIRNATY ® (Original) & Omicron BA.4/BA.5 – Gray Vial Cap and
Label Border** |
| **COMIRNATY ® (Original) & Omicron BA.4/BA.5 – Orange Vial Cap and
Label Border** |
| **COMIRNATY ® (Original) & Omicron BA.1** |
| **COMIRNATY ® (Original) - Purple Vial Cap and Label Border** | IM | non-live | SARS-CoV-2 | - | - | * Polyethylene Glycol (PEG) [Footnote 2](#fn1.2)
| * 1,2-distearoyl-sn-glycero-3-phosphocholine
* ALC-0159 = 2-[(polyethylene
glycol)-2000]-N,N-ditetradecylacetamide
* ALC-0315 = ((4-hydroxybutyl) azanediyl)bis
(hexane-6,1-diyl)bis(2-hexyldecanoate)
* Cholesterol
* Dibasic sodium phosphate dihydrate
* Monobasic potassium phosphate
* Potassium chloride
* Sodium chloride
* Sucrose
* Water for injection
| COVID-19 |
| **COVIFENZ® COVID-19 Vaccine** | IM | non-live | SARS-CoV-2 | AS03 | - | * Carbenicillin
* Kanamycin
* Polyethylene Glycol (PEG) [Footnote 2](#fn1.2)
* Polysorbate 80 [Footnote 2](#fn1.2)
| * DL-alpha-tocopherol
* Phosphate buffered saline
* Potassium phosphate monobasic anhydrous
* Sodium chloride
* Sodium phosphate dibasic anhydrous
* Squalene
* Water for injection
| COVID-19 |
| **DUKORAL®** | Oral | non-live | * Chol
* Ecol
| - | - | - | * Citric acid
* Disodium hydrogen phosphate
* Raspberry flavor
* Saccharin sodium
* Sodium carbonate
* Sodium citrate
* Sodium chloride
* Sodium dihydrogen phosphate
* Sodium hydrogen carbonate
* Water for injection
| Chol-Ecol-O |
| **ENGERIX® -B** | IM | non-live | HB | Al(OH)3 | - | * Yeast protein
| * Disodium phosphate dihydrate
* Sodium chloride
* Sodium dihydrogen phosphate dihydrate
* Water for injection
| HB |
| **ENGERIX® -B Pediatric dose** |
| **ERVEBO®** | IM | live | ZEBOV | - | - | * Benzonase
| * Hydrochloric acid
* Recombinant human serum albumin
* Sodium hydroxide
* Trace amounts of rice protein
* Trometamol buffer
* Water for injection
| EZV |
| **FLUAD®** | IM | non-live | Inf | MF59 | - | * Egg protein
* Kanamycin
* Neomycin
* Polysorbate 80 [Footnote 2](#fn1.2)
| * Calcium chloride dehydrate
* Cetyltrimethylammonium bromide
* Citric acid
* Disodium phosphate dihydrate
* Formaldehyde
* Hydrocortisone
* Magnesium chloride hexahydrate
* Potassium chloride
* Potassium dihydrogen phosphate
* Sodium chloride
* Sodium citrate
* Sorbitan trioleate
* Squalene
* Water for injection
| IIV3-Adj |
| **FLUAD****®****Pediatric** |
| **FLUCELVAX® QUAD** | IM | non-live | Inf | - | Tm [Footnote 3](#fn1.3) | * Polysorbate 80 [Footnote 2](#fn1.2)
* Thimerosal [Footnote 3](#fn1.3)
| * Beta-propiolactone
* Cetyltrimethylammonium bromide
* Disodium phosphate dihydrate
* Magnesium chloride hexahydrate
* Potassium chloride
* Potassium dihydrogen phosphate
* Sodium chloride
* Water for injections
| IIV4-cc |
| **FLULAVAL TETRA** | IM | non-live | Inf | - | Tm [Footnote 3](#fn1.3) | * Egg protein
* Thimerosal [Footnote 3](#fn1.3)
* Polysorbate 80 [Footnote 2](#fn1.2)
| * α-tocopheryl hydrogen succinate
* Disodium hydrogen phosphate heptahydrate
* Ethanol
* Formaldehyde
* Potasium chloride
* Potassium dihydrogen phosphate
* Sodium chloride
* Sodium deoxycholate
* Sucrose
* Water for injection
| IIV4-SD |
| **FLUMIST® QUADRIVALENT** | IN | live | Inf | - | - | * Arginine hydrochloride
* Egg protein
* Gelatin hydrolysate
* Gentamicin
| * Dibasic potassium phosphate
* Monosodium glutamate
* Monobasic potassium phosphate
* Sucrose
| LAIV4 |
| **FLUVIRAL®** | IM | non-live | Inf | - | Tm [Footnote 3](#fn1.3) | * Egg protein
* Thimerosal [Footnote 3](#fn1.3)
* Polysorbate 80 [Footnote 2](#fn1.2)
| * α-tocopheryl hydrogen succinate
* Disodium hydrogen phosphate heptahydrate
* Ethanol
* Formaldehyde
* Potassium chloride
* Potassium dihydrogen phosphate
* Sodium chloride
* Sodium deoxycholate
* Sucrose
* Water for injection
| IIV3-SD |
| **FLUZONE® High-Dose Quadrivalent** | IM | non-live | Inf | - | - | * Egg protein
| * Formaldehyde
* Sodium phosphate-buffered isotonic sodium chloride solution
* Triton® X-100
| IIV4-HD |
| **FLUZONE® Quadrivalent** | IM | non-live | Inf | - | Tm [Footnote 3](#fn1.3) | * Egg protein
* Thimerosal [Footnote 3](#fn1.3)
| * Formaldehyde
* Sodium phosphate-buffered isotonic sodium chloride solution
* Triton® X-100
| IIV4-SD |
| **GARDASIL® 9** | IM | non-live | HPV | AAHS | - | * Yeast protein
* Polysorbate 80 [Footnote 2](#fn1.2)
| * L-histidine
* Sodium borate
* Sodium chloride
| HPV9 |
| **HAVRIX®** | IM | non-live | HA | Al(OH)3 | - | * Neomycin
| * Amino acids
* Disodium phosphate
* Formaldehyde
* Monopotassium phosphate
* Polysorbate 20
* Potassium chloride
* Sodium chloride
* Water for injection
| HA |
| **HAVRIX® 720 JUNIOR** |
| **IMOVAX® Polio** | SC | non-live | IPV | - | PE | * Neomycin
* Polymyxin B
* Streptomycin
* Polysorbate 80 [Footnote 2](#fn1.2)
| * Bovine serum
* Formaldehyde
* Medium 199 Hanks
| IPV |
| **IMOVAX® Rabies** | IM | non-live | Rab | - | - | * Neomycin
* Phenol red
| * Human albumin
* Water for injection
| HDCV |
| **IMVAMUNE** **®** [Footnote 5](#fn1.5) | SC | live | Vaccinia | - | - | * Benzonase
* Bromobutyl rubber stopper
* Ciprofloxacin
* Gentamicin
* Residual host (egg) cell DNA and protein
* Trometamol
| * Hydrochloric acid
* Sodium chloride
* Tris-hydroxymethyl-amino methane
* Water for injection
| SMV |
| **INFANRIX hexa®** | IM | non-live | * D
* T
* aP
* HB
* IPV
* Hib
| Al(OH)3, AlPO4 | - | * Butyl in stopper
* Neomycin
* Polymyxin B
| * Lactose
* M199
* Sodium chloride
* Water for injection
| DTaP-HB-IPV-Hib |
| **INFANRIX® -IPV/Hib** | IM | non-live | * D
* T
* aP
* IPV
* Hib
| Al(OH)3 | - | * Neomycin sulphate
* Polymixin sulphate
* Polysorbate 80 [Footnote 2](#fn1.2)
| * Lactose
* Sodium chloride
* M199
* Water for injection
* Residual formaldehyde
* Potassium chloride
* Disodium phosphate
* Monopotassium phosphate
* Glycine
| DTaP-IPV-Hib |
| **INFLUVAC® TETRA** | SC/IM | non-live | Inf | - | - | * Chicken protein
* Egg Material
* Gentamicin sulphate
* Neomycin sulphate [Footnote 6](#fn1.6)
* Polymyxin B sulphate [Footnote 6](#fn1.6)
* Polysorbate 80 [Footnote 2](#fn1.2)
| * Calcium chloride dihydrate
* Cetyltrimethyl ammonium bromide
* Disodium phosphate dihydrate
* Formaldehyde
* Hydrocortisone
* Magnesium chloride hexahydrate
* Potassium chloride
* Potassium dihydrogen phosphate
* Sodium chloride
* Sodium citrate
* Sucrose
* Tylosine tartrate
* Water for injection
| IIV4-SD |
| **IXIARO®** | IM | non-live | JE | Al(OH)3 | - | - | * Disodium hydrogen phosphate
* Potassium dihydrogen phosphate
* Sodium chloride
* Water for injection
| JE |
| **JCOVDENTM COVID-19 VACCINE** | IM | non-live | SARS-CoV-2 | - | - | * Polysorbate 80 [Footnote 2](#fn1.2)
| * 2-hydroxypropyl-β-cyclodextrin (HBCD)
* Citric acid monohydrate
* Ethanol
* Hydrochloric acid
* Sodium chloride
* Sodium hydroxide
* Trisodium citrate dihydrate
* Water for injection
| COVID-19 |
| **Menactra®** | IM | non-live | Men | - | - | * Diphtheria toxoid carrier protein
| * Sodium chloride
* Sodium phosphate dibasic (anhydrous)
* Sodium phosphate monobasic
* Water for injection
| Men-C-ACYW-DT |
| **MENJUGATE Liquid** | IM | non-live | Men | Al(OH)3 | - | * Diphtheria CRM197 toxoid carrier protein
* Bromobutyl rubber stopper
| * Histidine
* Sodium chloride
* Water for injection
| Men-C-C-CRM |
| **MenQuadfiTM** | IM | non-live | Men | - | - | * Tetanus toxoid carrier protein
| * Sodium acetate
* Sodium chloride
* Sterile water for injection
| Men-C-ACYW-TT |
| **MenveoTM** | IM | non-live | Men | - | - | * Diphtheria CRM197 toxoid carrier protein
| * Disodium hydrogen phosphate bihydrate
* Potassium dihydrogen phosphate
* Sodium chloride
* Sodium dihydrogen phosphate monohydrate
* Sucrose
* Water for injection
| Men-C-ACYW-CRM |
| **M-M-R® II** | SC | live | * Meas
* Mumps
* Rub
| - | - | * Neomycin
* Phenol red
* Porcine gelatin
* Residual components of chick embryo cell cultures
| * Fetal bovine serum
* Medium 199 with Hank's salts
* Minimum essential medium (Eagle)
* Monosodium L-glutamate monohydrate
* Potassium phosphate dibasic (anhydrous)
* Potassium phosphate monobasic
* Recombinant human albumin
* Sodium bicarbonate
* Sodium phosphate dibasic (anhydrous)
* Sodium phosphate monobasic
* Sorbitol
* Sucrose
* Water for injection
| MMR |
| **NeisVac-C® Vaccine** | IM | non-live | Men | Al(OH)3 | - | * Tetanus toxoid carrier protein
| * Sodium chloride
| Men-C-C-TT |
| **NIMENRIX®** | IM | non-live | Men | - | - | * Tetanus toxoid carrier protein
| * Sucrose
* Trometamol
* Sodium chloride
* Water for injection
| Men-C-ACYW-TT |
| **NUVAXOVID****TM**
**COVID-19 Vaccine** | IM | non-live | SARS-CoV-2 | Matrix-M | - | * Polysorbate 80 [Footnote 2](#fn1.2)
| * Cholesterol
* Disodium hydrogen phosphate dihydrate
* Disodium hydrogen phosphate heptahydrate
* Hydrochloric acid
* Phosphatidylcholine
* Potassium chloride
* Potassium dihydrogen phosphate
* Sodium chloride
* Sodium dihydrogen phosphate monohydrate
* Sodium hydroxide
* Water for Injection
| COVID-19 |
| **PEDIACEL®** | IM | non-live | * D
* T
* aP
* IPV
* Hib
| AlPO4 | PE | * Neomycin
* Polymyxin B
* Streptomycin
* Polysorbate 80 [Footnote 2](#fn1.2)
| * Bovine serum albumin
* Formaldehyde
* Glutaraldehyde
| DTaP-IPV-Hib |
| **PNEUMOVAX® 23** | SC/IM | non-live | Pneu | - | P | - | * Sodium chloride
* Water for injection
| Pneu-P-23 |
| **PREHEVBRIOTM** | IM | non-live | HB | Al(OH)3 | - | - | * Disodium phosphate dodecahydrate
* Hydrochloric acid
* Potassium chloride
* Potassium dihydrogen phosphate
* Sodium chloride
* Sodium hydroxide
* Water for injection
| HB |
| **Prevnar® 13** | IM | non-live | Pneu | AlPO4 | - | * Diphtheria CRM197 toxoid carrier protein
* Polysorbate 80 [Footnote 2](#fn1.2)
| * Sodium chloride
* Succinic acid
* Water for injection
| Pneu-C-13 |
| **PREVNAR 20****TM** | IM | non-live | Pneu | AlPO4 | - | * Polysorbate 80 [Footnote 2](#fn1.2)
| * Sodium chloride
* Succinic acid
* Water for injection
| Pneu-C-20 |
| **PRIORIX®** | SC/IM | live | * Meas
* Mumps
* Rub
| - | - | * Egg protein
* Neomycin
| * Amino acids
* Lactose
* Mannitol
* Sorbitol
* Water for injection
| MMR |
| **PRIORIX-TETRA** | SC/IM | live | * Meas
* Mumps
* Rub
* Var
| - | - | * Egg protein
* Neomycin
| * Amino Acids
* Lactose
* Mannitol
* Sorbitol
* Water for injection
| MMRV |
| **PROQUADTM** | SC | live | * Meas
* Mumps
* Rub
* Var
| - | - | * Gelatin
* Neomycin
* Chicken protein
| * Sucrose
* Urea
* Sodium chloride
* Sorbitol
* Monosodium L-glutamate
* Sodium phosphate
* Human albumin
| MMRV |
| **QUADRACEL®** | IM | non-live | * D
* T
* aP
* IPV
| AlPO4 | PE | * Neomycin
* Polymyxin B
* Polysorbate 80 [Footnote 2](#fn1.2)
| * Bovine serum albumin
* Formaldehyde
* Glutaraldehyde
| DTaP-IPV |
| **RabAvert®** | IM | non-live | Rab | - | - | * Amphotericin B
* Chicken protein
* Chlortetracycline
* Neomycin
* Polygeline (gelatin)
* Egg protein
| * Human serum albumin
| PCECV |
| **RECOMBIVAX HB®** | IM | non-live | HB | AAHS | - | * Latex in vial stopper
* Yeast protein
| * Formaldehyde
* Sodium borate
* Sodium chloride
* Water for injection
| HB |
| **ROTARIX®** | Oral | live | Rot | - | - | - | * Disodium adipate
* DNA fragments from porcine circovirus 1
* Dulbecco's Modified Eagle Medium
* Sterile water
* Sucrose
| Rot-1 |
| **RotaTeq®** | Oral | live | Rot | - | - | * Polysorbate 80 [Footnote 2](#fn1.2)
| * DNA fragments from porcine circoviruses 1 and 2
* Fetal bovine serum
* Residual protein from cell culture
* Sodium citrate dihydrate
* Sodium hydroxide
* Sodium phosphate monobasic monohydrate
* Sucrose
| Rot-5 |
| **SHINGRIX** | IM | non-live | VZVgE | AS01B | - | * Polysorbate 80 [Footnote 2](#fn1.2)
| * Dipotassium phosphate
* Sodium dihydrogen phosphate dihydrate
* Sucrose
* Water for injection
| RZV |
| **SPIKEVAXTM Elasomeran mRNA vaccine – Red plastic cap**
**(0.20 mg/mL)** | IM | non-live | SARS-CoV-2 | - | - | * Polyethylene Glycol (PEG) [Footnote 2](#fn1.2)
* Trometamol
* Trometamol (hydrochloride)
| * Acetic acid
* Cholesterol
* DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine)
* Lipid SM-102
* PEG2000-DMG (1,2-dimyristoyl-racglycerol,
methoxy-polyethyleneglycol)
* Sodium acetate trihydrate
* Sucrose
* Water for injection
| COVID-19 |
| **SPIKEVAXTM Elasomeran mRNA vaccine – Royal blue plastic cap**
**(0.10 mg/mL)** |
| **SPIKEVAXTM Bivalent**
**(Original / Omicron BA.1)** |
| **SPIKEVAX Bivalent**
**(Original / Omicron BA.4/5)** |
| **SupemtekTM** | IM | non-live | Inf | - | - | * Polysorbate 20 [Footnote 2](#fn1.2)
| * Baculovirus and cellular DNA
* Baculovirus and Spodoptera frugiperda cell proteins
* Dibasic sodium phosphate
* Monobasic sodium phosphate
* Sodium chloride
* Triton X-100
| RIV4 |
| **SYNFLORIX®** | IM | non-live | Pneu | AlPO4 | - | * Latex in syringe components
* Diphtheria toxoid carrier protein
* Tetanus toxoid carrier protein
* Non-typeable Haemophilus influenzae protein D carrier
protein
| * Sodium chloride
* Water for injection
| Pneu-C-10 |
| **Td ADSORBED** | IM | non-live | * T
* d
| AlPO4 | PE | - | * Formaldehyde
* Sodium chloride
* Water for injection
| Td |
| **TRUMENBA®** | IM | non-live | Men B | AlPO4 | - | * Polysorbate 80 [Footnote 2](#fn1.2)
| * Histidine
* Sodium chloride
* Water for injection
| MenBf-HBP |
| **TWINRIX®** | IM | non-live | * HA
* HB
| Al(OH)3, AlPO4 | - | * Neomycin
* Yeast protein
| * Amino acids
* Formaldehyde
* Polysorbate 20
* Sodium chloride
* Water for injection
| HAHB |
| **TWINRIX® Junior** |
| **TYPHIM Vi®** | IM | non-live | Typh | - | P | - | * Isotonic buffer solution
| Typh-I |
| **VAQTA®** | IM | non-live | HA | AAHS | - | * Latex in vial stopper
* Neomycin
| * Bovine albumin
* DNA
* Formaldehyde
* Residual protein from cell culture
* Sodium borate
* Sodium chloride
* Water for injection
| HA |
| **VARILRIX®** | SC | live | Var | - | - | * Neomycin
| * Amino acids
* Human albumin
* Lactose
* Polyalcohols
* Water for injection
| Var |
| **VARIVAX® III** | SC | live | Var | - | - | * Neomycin
* Porcine gelatin
| * Fetal bovine serum
* Monosodium L-glutamate
* Potassium chloride
* Potassium phosphate monobasic
* Residual protein from cell culture
* Sodium chloride
* Sodium phosphate dibasic
* Sucrose
* Urea
* Water for injection
| Var |
| **VAXNEUVANCE** **®** | IM | non-live | Pneu | AlPO4 | - | * Polysorbate 20 [Footnote 2](#fn1.2)
| * L-histidine
* Sodium chloride
* Water for injection
| Pneu-C-15 |
| **VAXZEVRIATM** | IM | non-live | SARS-CoV-2 | - | - | * Polysorbate 80 [Footnote 2](#fn1.2)
| * Disodium edetate dihydrate (EDTA)
* Ethanol
* L-Histidine
* L-Histidine hydrochloride monohydrate
* Magnesium chloride hexahydrate
* Sodium chloride
* Sucrose
* Water for injection
| COVID-19 |
| **Vivotif®** | Oral | live | Typh | - | - | * Gelatin
| * Amino acid mixture
* Ascorbic acid
* Dibutyl phthalate
* Diethyl phthalate
* Erythrosine FD+C red 3
* Ethylene glycol
* Hydroxypropylcellulose-phthalate
* Lactose
* Magnesium stearate
* Red iron oxide
* Sucrose
* Titanium dioxide
* Yellow iron oxide
| Typh-O |
| **YF-VAX®** | SC | live | YF | - | - | * Chicken protein
* Egg protein
* Gelatin
* Latex in stopper of diluent vial
| * Sodium chloride
* Sorbitol
| YF |
|
Footnote 1
Any component in a vaccine may be a potential allergen. This table identifies most common allergens; adjuvants and preservatives may be potential allergens, but this is extremely rare.
[Return to footnote 1 referrer](#fn1.1-rf)
Footnote 2
There is a potential of cross-reactive hypersensitivity between PEG and polysorbates. Therefore, individuals who are being administered a product that includes any one of these components as ingredients should be asked about any allergic reactions to either component.
[Return to footnote 2 referrer](#fn1.2-rf)
Footnote 3
Multi-dose presentation only.
[Return to footnote 3 referrer](#fn1.3-rf)
Footnote 4
Not present in COMIRNATY® (Original) and COMIRNATY® Original & Omicron BA.4/BA.5 vials with gray cap and label border (for 12 years of age and older).
[Return to footnote 4 referrer](#fn1.4-rf)
Footnote 5
IMVAMUNE® is not available for general use.
[Return to footnote 5 referrer](#fn1.5-rf)
Footnote 6
Only used if gentamicin cannot be used. If not used, not present.
[Return to footnote 6 referrer](#fn1.6-rf)
|
### Abbreviations
#### Route-
ID
intradermal
IM
intramuscular
IN
intranasal
SC
subcutaneous
#### Immunogen-
aP
acellular pertussis
ap
acellular pertussis (reduced)
BCG
Bacillus Calmette-Guérin
Chol
cholera
D
diphtheria
d
diphtheria (reduced)
Ecol
enterotoxigenic Escherichia coli
Hib
Haemophilus influenzae type b
HA
hepatitis A
HB
hepatitis B
HPV
human papillomavirus
Inf
influenza
IPV
inactivated poliomyelitis
JE
Japanese encephalitis
Men
meningococcus
Men B
Neisseria meningitidis Serogroup B protein
Meas
measles
Mumps
mumps
Pneu
pneumococcus
Rab
rabies
Rot
rotavirus
Rub
rubella
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
T
tetanus
Typh
typhoid
Var
varicella
YF
yellow fever
ZEBOV
Zaire ebolavirus
#### Adjuvant-
AAHS
amorphous aluminum hydroxyphosphate sulfate
Al(OH)3
Aluminum hydroxide
AlPO4
Aluminum phosphate
AS01B
3-O-desacyl-4'-monophosphoryl lipid A [MPL], *Quillaja saponaria* Molina, fraction 21 [QS-21], cholesterol, dioleoyl phosphatidylcholine
[DOPC], disodium phosphate anhydrous, potassium dihydrogen phosphate,
sodium chloride, water for injection
AS04
3-O-desacyl-4'-monophosphoryl lipid A adsorbed onto aluminum (as hydroxide
salt)
MF59
squalene, polysorbate 80, sorbitan trioleate, sodium citrate, citric acid,
water for injection
#### Preservative-
P
phenol
PE
2-phenoxyethanol
Tm
thimerosal
Table 2: Types and contents of passive immunizing
agents authorized for use in Canada
| Brand name | Route | Passive immunizing agent type | Origin of antibodies | Protects against or treats | Preservative | Potential allergens | Other materials | Abbreviation |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| A dash [ - ] indicates that there are no materials under
that category in the product. |
| **Antidiphtheria serum**[Footnote 1](#fn2.1) | IV | Antitoxin | Horse serum or Horse plasma | D | Type varies with supplier | * Equine protein
| * Contents vary with supplier
| DAT |
| **BAT®** [Footnote 2](#fn2.2) | IV | Antitoxin | Horse plasma | B | - | * Equine protein
* Polysorbate 80 [Footnote 3](#fn2.3)
| * Maltose
| BAT |
| **Baby BIG®** [Footnote 1](#fn2.1)[Footnote 2](#fn2.2) | IV | Immunoglobulin | Human plasma | B | - | - | * Human albumin
* Sucrose
| BIG-IV |
| **BEYFORTUSTM
(nirsevimab)** | IM | Human monoclonal antibody | Recombinant DNA technology | RSV | - | * Polysorbate 80 [Footnote 3](#fn2.3)
| * L-arginine hydrochloride
* L-histidine
* L-histidine hydrochloride
* Sucrose
* Water for injection
| RSVAb |
| **Cytogam®** [Footnote 4](#fn2.4) | IV | Immunoglobulin | Human plasma | CMV | - | - | * Human albumin
* Sucrose
| CMVIg |
| **CNJ-016TM** | IV | Immunoglobulin | Human plasma | Vac | - | * Polysorbate 80 [Footnote 3](#fn2.3)
| * Maltose
* Water for injection
| VIG |
| **EVUSHELDTM** | IM | Anti-SARS-CoV-2 monoclonal antibodies | Recombinant DNA technology | SARS-CoV-2 | - | * Polysorbate 80 [Footnote 3](#fn2.3)
| * L-Histidine
* L-Histidine hydrochloride monohydrate
* Sucrose
* Water for injection
| - |
| **GamaSTAN® S/D** | IM | Immunoglobulin | Human plasma | HA
Meas | - | - | * Glycine
| Ig |
| **HepaGam B®** | IM/IV | Immunoglobulin | Human plasma | HB | - | * Polysorbate 80 [Footnote 3](#fn2.3)
| * Maltose
* Tri-n-butyl phosphate
* Triton®X-100
| HBIg |
| **HyperHEP B® S/D** | IM | Immunoglobulin | Human plasma | HB | - | - | * Glycine
| HBIg |
| **HYPERRAB®** | IM/ Local | Immunoglobulin | Human plasma | Rab | - | - | * Glycine
| RabIg |
| **HYPERTET® S/D** | IM | Immunoglobulin | Human plasma | Tet | - | - | * Glycine
| TIg |
| **KamRABTM** | IM/ Local | Immunoglobulin | Human plasma | Rab | - | - | * Glycine
* Sodium hydroxide
* Water for injection
| RabIg |
| **SYNAGIS® (palivizumab)** | IM | Humanized monoclonal antibody | Recombinant DNA technology | RSV | - | - | * Chloride
* Glycine
* Histidine
* Water for injection
| RSVAb |
| **VariZIG® TM** | IV/ IM | Immunoglobulin | Human plasma | Var | - | * Polysorbate 80 [Footnote 3](#fn2.3)
| * Glycine
* Human plasma protein
* Sodium chloride
* Sodium phosphate
* Tri-n-butyl phosphate
* Triton®X-100
| VarIg |
|
Footnote 1
Only available on an emergency basis by application to Health Canada's Special Access Programme (SAP) (https://www.canada.ca/en/health-canada/services/drugs-health-products/special-access/drugs.html). Public health should be contacted for assistance in obtaining these products. Information can also be obtained from the SAP website or by contacting the SAP office (telephone: 613-941-2108; fax: 613-941-3194; Available 24 hours a day, 7 days a week).
[Return to footnote 1 referrer](#fn2.1-rf)
Footnote 2
For further information refer to Health Canada: Botulism - Guide for healthcare professionals at https://www.canada.ca/en/health-canada/services/food-nutrition/legislation-guidelines/guidance-documents/botulism-guide-healthcare-professionals-2012.html
[Return to footnote 2 referrer](#fn2.2-rf)
Footnote 3
There is a potential of cross-reactive hypersensitivity between PEG and polysorbates. Therefore, individuals who are being administered a product that includes any one of these components as ingredients. should be asked about any allergic reactions to either component.
[Return to footnote 3 referrer](#fn2.3-rf)
Footnote 4
Should be used in consultation with a specialist in immunodeficiency.
[Return to footnote 4 referrer](#fn2.4-rf)
|
### Abbreviations:
#### Route-
IM
intramuscular
IV
intravenous
Local
local wound infiltration
#### Protects against or treats-
B
botulism
CMV
cytomegalovirus
D
diphtheria
HA
hepatitis A
HB
hepatitis B
Meas
measles
Rub
rubella
Rab
rabies
RSV
respiratory syncytial virus
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
T
tetanus
Vac
vaccinia
Var
varicella
N/A
Not applicable
#### Preservative-
P
phenol
Selected references
-------------------
* Keith LS, Jones DE, Chou C. Aluminum toxicokinetics regarding infant diet and vaccinations. Vaccine 2002;20:S13-17.
* Offit PA, Jew RK. Addressing parents' concerns: Do vaccines contain harmful preservatives, adjuvants, additives, or residuals? Pediatrics 2003;112:1394-97.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-07-06
| None | None |
33ca3df0d3bdce84867e33a718cf1d2277d6b612 | cma | Archived 47: Summary of National Advisory Committee on Immunization (NACI) updates of November 3, 2022: Recommendations on the use of Moderna Spikevax BA.4/5 bivalent mRNA (50 mcg) COVID-19 booster vaccine in adults | Archived 47: Summary of National Advisory Committee on Immunization (NACI) updates of November 3, 2022: Recommendations on the use of Moderna Spikevax BA.4/5 bivalent mRNA (50 mcg) COVID-19 booster vaccine in adults
Overview
- On November 3, 2022, Health Canada authorized the use of the Moderna Spikevax 50 mcg BA.4/5 bivalent COVID-19 vaccine as a booster dose in individuals 18 years of age and older.
- Health Canada has previously authorized similar bivalent booster doses containing Omicron BA.1 or BA.4/5 variants from Moderna (50 mcg) and Pfizer-BioNTech (30 mcg) in September and October of 2022.
- Available evidence suggests this new Moderna bivalent BA.4/5 formulation is comparable to other bivalent booster products already authorized and recommended for use as part of the fall 2022 COVID-19 booster program.
- NACI continues to recommend that bivalent Omicron-containing mRNA COVID-19 vaccines are the preferred booster products for the authorized age groups. (Strong NACI recommendation)
- Going forward, any of the bivalent Omicron-containing mRNA boosters are preferred over the original formulation boosters for authorized age groups (18 years of age and older for Moderna bivalent vaccines and 12 years of age and older for Pfizer-BioNTech bivalent vaccines).
- Bivalent Omicron-containing mRNA vaccines are expected to broaden the immune response and provide improved protection against the Omicron variant and subvariants compared to original mRNA COVID-19 vaccines, with a similar safety profile.
- Omicron is the most distinct variant of concern to date, with a number of key mutations distinguishing it from the original SARS-CoV-2 virus. The BA.4 and BA.5 Omicron subvariants are currently the dominant strains of the COVID-19 virus circulating in Canada.
- Health Canada and NACI are currently reviewing whether bivalent vaccines may also be an option for boosters in children 5 to 11 years of age this fall.
- There is currently no evidence to suggest any meaningful difference in protection between different bivalent booster vaccines targeting BA.1 versus BA.4/5, nor any clinical trials directly comparing the Moderna (50 mcg) and Pfizer-BioNTech (30 mcg) bivalent booster products. Vaccine effectiveness has not yet been established for the bivalent booster products.
- COVID-19 booster doses this fall are an important part of the ongoing pandemic response, contact your local public health department to learn where you can receive one.
For more information on the authorization of this new bivalent booster formulation, please refer to the .
For more information on NACI’s recommendations on the use of COVID-19 vaccines, please refer to the in the , as well as additional statements on the . |
Archived 47: Summary of National Advisory Committee on Immunization (NACI) updates of November 3, 2022: Recommendations on the use of Moderna Spikevax BA.4/5 bivalent mRNA (50 mcg) COVID-19 booster vaccine in adults
========================================================================================================================================================================================================================
[Download in PDF format](/content/dam/phac-aspc/documents/services/immunization/national-advisory-committee-on-immunization-naci/naci-summary-november-3-2022.pdf)
(823 KB, 3 pages)
**Organization:** [Public Health Agency of Canada](/en/public-health.html)
**Cat.:** HP5-148/2022E-PDF
**ISBN:** 978-0-660-46029-1
**Pub.:** 220546
**Published:** 2022-11-03
Publication date: November 3, 2022
Notice to reader
----------------
This is an archived version. Please refer to current COVID-19 vaccine pages:
* [NACI statements and publications](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci.html#covid-19)
* [COVID-19 vaccine: Canadian Immunization Guide](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html)
Overview
--------
* On November 3, 2022, Health Canada authorized the use of the Moderna Spikevax 50 mcg BA.4/5 bivalent COVID-19 vaccine as a booster dose in individuals 18 years of age and older.
* Health Canada has previously authorized similar bivalent booster doses containing Omicron BA.1 or BA.4/5 variants from Moderna (50 mcg) and Pfizer-BioNTech (30 mcg) in September and October of 2022.
* Available evidence suggests this new Moderna bivalent BA.4/5 formulation is comparable to other bivalent booster products already authorized and recommended for use as part of the fall 2022 COVID-19 booster program.
* **NACI continues to recommend that bivalent Omicron-containing mRNA COVID-19 vaccines are the preferred booster products for the authorized age groups. (Strong NACI recommendation)**
* Going forward, any of the bivalent Omicron-containing mRNA boosters are preferred over the original formulation boosters for authorized age groups (18 years of age and older for Moderna bivalent vaccines and 12 years of age and older for Pfizer-BioNTech bivalent vaccines).
* Bivalent Omicron-containing mRNA vaccines are expected to broaden the immune response and provide improved protection against the Omicron variant and subvariants compared to original mRNA COVID-19 vaccines, with a similar safety profile.
* Omicron is the most distinct variant of concern to date, with a number of key mutations distinguishing it from the original SARS-CoV-2 virus. The BA.4 and BA.5 Omicron subvariants are currently the dominant strains of the COVID-19 virus circulating in Canada.
* Health Canada and NACI are currently reviewing whether bivalent vaccines may also be an option for boosters in children 5 to 11 years of age this fall.
* There is currently no evidence to suggest any meaningful difference in protection between different bivalent booster vaccines targeting BA.1 versus BA.4/5, nor any clinical trials directly comparing the Moderna (50 mcg) and Pfizer-BioNTech (30 mcg) bivalent booster products. Vaccine effectiveness has not yet been established for the bivalent booster products.
* COVID-19 booster doses this fall are an important part of the ongoing pandemic response, contact your local public health department to learn where you can receive one.
For more information on the authorization of this new bivalent booster formulation, please refer to the [product monograph](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
For more information on NACI’s recommendations on the use of COVID-19 vaccines, please refer to the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) in the [Canadian Immunization Guide (CIG)](/en/public-health/services/canadian-immunization-guide.html), as well as additional statements on the [NACI web page](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci.html).
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-01-20
| None | None |
3bfb070777f37fcadce7a89b6d33a455c686dd8e | cma | Pan-Canadian COVID-19 Testing and Screening Guidance: Technical guidance and implementation plan | Pan-Canadian COVID-19 Testing and Screening Guidance: Technical guidance and implementation plan
(1 MB, 17 pages)
Organization:
Date published: August 2021
Cat.: H14-383/2021E-PDF
ISBN: 978-0-660-40219-2
Pub.: 210290
On this page
Background
The onset of the global COVID-19 pandemic in early 2020 triggered the need for coherent, pan-Canadian guidance on provincial and territorial testing. The federal, provincial and territorial Special Advisory Committee finalized and approved initial interim guidance on laboratory testing on April 16, 2020. The guidance focused on molecular polymerase chain reaction (PCR) as the sole laboratory test for accurately identifying SARS-CoV-2 in patients.
In May 2020, based on new evidence, the *National Laboratory Testing Indication Guidance for COVID-19- was updated to reflect developments in 4 areas:
1. expanded laboratory resources
2. viral transmission from asymptomatic individuals or those in the pre-symptomatic phase
3. outbreaks in congregate living and work settings
4. new testing modalities (molecular point-of-care and serological tests)
In October 2020, the guidance was updated to give a national perspective on testing and screening approaches. Recognizing that one size does not fit all, the guidance outlines approaches and tools that federal, provincial and territorial partners may adapt as the pandemic evolves.
Federal, provincial and territorial governments first endorsed this *Pan-Canadian Testing and Screening Guidance- in October 2020. This guidance outlines a portfolio approach that uses different testing technologies for diagnostic testing, screening and surveillance.
In addition, the Public Health Agency of Canada updated its in February 2021 to include information on novel RADT technologies. The update included details on performance and potential use cases including:
- routine outbreak monitoring
- monitoring in high-risk settings (for example, long-term care facilities)
- possible adaptation into mobile rapid testing in rural and remote communities
In May 2021, Health Canada approved the first self-test for use in Canada. The Lucira "Check It" COVID-19 Test Kit is a nucleic acid self-test. As of July 28, 2021, Health Canada has 77 COVID-19 testing devices (nucleic acid, antigen and serological). Authorized tests use various sample types, including saliva, nasal and nasopharyngeal. Thus far, there is no evidence of variants able to escape detection through existing testing technologies.
External expert advice has also helped to inform the approach to testing and screening. For instance, has published 5 reports to the Minister of Health on optimizing testing in Canada, long-term care, schools, borders and self-testing. The has published responses to the Expert Advisory Panel's reports on optimizing testing at borders. It has also published reports on the importance of task-shifting and the self-administration of tests in workplaces.
Since the publication of the initial *Pan-Canadian Testing and Screening Guidance*, much of Canada has experienced a significant third wave. Rapid tests have been procured and made available to provinces and territories in large numbers. Workplace screening programs have been developed and deployed. Highly effective vaccines have also been authorized and administered to many Canadians.
With rising vaccination rates, the incidence and rate of transmission of COVID-19 has decreased (see , ). Nevertheless, outbreaks continue to occur, with the vast majority among people who are , including those who may also face other health, social and economic barriers.
Some research indicates that vaccinated people who test positive for COVID-19 and do not carry the Delta variant are likely to have low viral loads (, ). There is also evidence that vaccination can greatly reduce rates of SARS-CoV-2 infections that have .
Emerging evidence for the Delta variant points to the possibility of high viral loads in some breakthrough cases in fully vaccinated people, which can be as high as in unvaccinated people. Preliminary data from the U.S. Centers for Disease Control and Prevention and from Public Health England indicate that levels of virus in fully vaccinated people who become infected with Delta may be similar to levels found in unvaccinated people, and therefore they may be as likely to transmit the virus. These new studies highlight the importance of monitoring and responding to the ever-evolving science.
With vaccination rates contributing to decreases in the incidence and prevalence of COVID-19, as outlined in , it is appropriate to consider how testing, screening and surveillance strategies should be adjusted. Strategies should reflect the changing dynamics of the pandemic as both vaccination and variant of concern rates increase.
The main objective of this guidance is to support the effective deployment of testing, screening and surveillance as public health tools. Considerations are provided for developing and implementing testing, screening and surveillance approaches where a majority of Canadians are now fully vaccinated.
Recognizing that testing regimes are within provincial and territorial jurisdiction, this guidance reflects the changing landscape of testing and screening. It also highlights the innovation and collaboration that have taken place within and among jurisdictions.
Principles-based testing approach
As more and more Canadians are vaccinated, the demand for testing and screening is expected to decrease. This is because of the protection that vaccination offers against COVID-19, and also because vaccinated individuals with COVID-19 are less likely to be symptomatic. However, there will still be a need to manage new waves and/or localized outbreaks, including testing of symptomatic individuals and close contacts of individuals who have tested positive, regardless of vaccination status. Close contacts of individuals who have tested positive should be tested as outlined in the . Individuals are also encouraged to consult local public health guidance related to isolation and self-monitoring. Meeting surges in testing and screening demand will require a shift, with the appropriate testing technology used for the situation (for instance, local vaccination rates and epidemiology).
Testing and screening strategies for public health purposes in a vaccinated population should consider the following 4 key variables:
1. community prevalence of COVID-19
2. community prevalence of variants of concern (VoCs)
3. presence of outbreaks
4. populations with vulnerabilities
Another goal of these strategies is to ensure there is sufficient capacity in place to respond to increases in cases and potential outbreaks. This approach will help protect those most at risk.
Community prevalence of COVID-19
Community prevalence is the proportion of a population with COVID-19 at a given time. Definitions for what constitutes high or low community prevalence should be developed by jurisdictions based on their broader community context.
Along with test sensitivity and specificity, the pre-test probability of disease affects test performance. All other things being equal, when community prevalence of disease is lower, the pre-test probability is also lower. A positive result is more likely to be a false positive when prevalence is low. A negative result is more likely to be a false negative when prevalence is high. Testing and screening are more effective when prevalence is higher.
Surveillance data will be needed to monitor community prevalence and inform testing and screening decisions. Data from the following sources can be used to track prevalence:
- sentinel surveillance sites
- health records
- illness and severe outcome surveillance (for example, emergency room data)
Confirming point-of-care rapid test results that are presumed to be positive using lab-based PCR will provide important surveillance information. Genome sequencing follow-up for VoCs will also be possible.
Wastewater surveillance also provides information about COVID-19 in the community.
# Community prevalence of variants of concern (VoCs)
A is a mutated SARS-CoV-2 virus. The mutations affect one or more characteristic that is responsible for increased transmissibility, increased virulence or change in clinical disease progression. The mutated virus may also decrease the effectiveness of available diagnostic tools or vaccines.
New VoCs are likely to emerge while the virus continues to circulate globally. If VoCs emerge that evade vaccine-mediated immunity, the community incidence of COVID-19 will likely increase. As well, if vaccine-escape VoCs develop, the pre-test probability of vaccinated populations will also likely increase because vaccinated populations will be more likely to test positive for COVID-19. This will necessitate a larger role for testing and screening.
Testing and screening may also play a larger role in helping to protect populations with vulnerabilities where VoCs are more easily transmissible or may seriously compromise the health of those infected.
# Presence of outbreaks
An outbreak occurs when there is uncontrolled transmission of the SARS-CoV-2 virus. In vulnerable or congregate settings, as few as 2 cases may be considered an outbreak.
In outbreak situations, testing and screening are critical to identify cases quickly in order to reduce transmission and prevent the infection from spreading further.
# Populations with vulnerabilities
Testing and screening are also critical for populations with vulnerabilities. People who benefit most from a targeted testing strategy are those who are:
- clinically vulnerable to more severe outcomes
- vulnerable to infection
In some settings, such as long-term care and acute care facilities, tolerance for outbreaks is much lower because the risk of severe illness from COVID-19 is higher. There are also settings that are vulnerable because cases are difficult to manage due to limited access to health care services (for example, rural and remote areas). The risk of transmission is also higher in congregate settings, high-density living arrangements and workplaces where people are in close contact. People who are not vaccinated are also more vulnerable than those who are vaccinated.
Testing, screening and surveillance technologies
Moving into the second half of 2021, we can expect to rely more on existing and new testing technologies, including the following:
- multiplex assays to test simultaneously for COVID-19 and other respiratory infections (such as respiratory syncytial virus, or RSV, and influenza)
- testing and genome sequencing for SARS-CoV-2 and its VoCs
- self-tests and emerging novel testing technologies, such as COVID-19 breathalyzer tests
Increasing the accessibility of testing technology, particularly to populations with vulnerabilities, and supporting large-scale surveillance to monitor community spread will continue to be important.
When using tests with good sensitivity and high specificity, the proportion of false positive results is lower among those testing positive in higher prevalence settings. These include areas where there are outbreaks or where a large proportion of the population is not vaccinated. Screening programs using rapid tests in such circumstances have proven successful and cost-effective.
Positive results from tests with high specificity (99.9% specific) are more likely to be in low prevalence settings, such as those where most or all are vaccinated.
When prevalence is very low, non-targeted asymptomatic rapid test screening may require many lab-based PCR tests to verify positive cases. The health, social and economic implications for those who receive false positive results are significant. The costs of false positives can be mitigated through confirmatory testing using a diagnostic test and provision of support strategies (for example, sick leave to offset loss of income).
detects viral genetic material
detects viral protein
- Slowest: up to 1 to 2 days turnaround time
- Can screen for known VoCs
- 70% to 90% sensitive and 95% to 99% specific when symptomatic
- 15 min to 1 h turnaround time
LAMP* Equally or slightly less accurate than lab-based PCR
- 15 min to 1 h turnaround time
- Low accuracy in asymptomatic people with low viral loads
- 15 to 30 min turnaround time
- Decouples testing from public health reporting system
- Up to 30 min turnaround time
- Decouples testing from public health reporting system
- 15 to 30 min turnaround time
# Lab-based molecular tests
Typically, a laboratory-based PCR test is suitable to diagnose people with symptoms and close contacts of individuals who have tested positive, and to confirm the results of rapid tests. This test can also be used to screen for known variants of concern by using genome sequencing to analyze samples in depth. When capacity is limited, the principles-based approach can help decide which groups and settings are priorities for lab-based molecular testing. is another method for saving time and reagents when testing capacity is limited.
# Point-of-care molecular tests
These tests may be suitable at a point-of-care setting because they are more sensitive and can detect infection when the patient has a low viral load. They are preferable to RADTs when definitive results are crucial, such as during an outbreak in a congregate setting. Point-of-care molecular tests can also be used in rural and remote communities.
# Rapid antigen detection tests (RADTs)
One found lower effectiveness of RADTs in breakthrough infections of vaccinated individuals. However, specific variants may result in higher viral loads, even in people who are vaccinated individuals. This would affect the performance of RADTs depending on the community context. The decision to use RADTs should be guided by the 4 key variables noted above, with the goal to protect populations with vulnerabilities, including in settings where a high proportion of people are not vaccinated or there are other risk factors. In these circumstances, it may be beneficial to test people who are vaccinated.
If the overall community vaccination rate is low, RADTs can also be used to identify paths of transmission. When used for screening, the regulatory guidance indicates RADTs should be used (for example, take the test twice over 2 or 3 days with at least 24 hours and no more than 36 hours between tests). Nevertheless, if community incidence is low and vaccination helps to reduce COVID-19 incidence, screening programs are less likely to be cost-effective (see , , , ). Confirmatory testing of positive results with more accurate tests may place burdens on public health systems, but would also provide a means of VoC screening/sequencing. It should be emphasized to those being screened with RADTs that a negative test result should not lead to a reduction in preventative measures.
# Multiplex tests
Multiplex tests can detect the presence of genetic material from multiple viruses/infectious agents using a single sample. For example, they can determine if a person in hospital with symptoms of respiratory illness is infected with SARS-CoV-2, influenza, both or neither.
Their use at sentinel surveillance sites can provide insight into the prevalence of COVID-19 and other respiratory viruses, such as influenza and RSV.
Multiplex tests may also be used to:
- inform treatment for immunocompromised people or those with severe illness in acute care settings
- identify the virus responsible in people living in congregate settings who present with symptoms
As these tests are more costly, priority should be for those at highest risk of severe outcomes, where test results can guide treatment and care, and where the results can contribute to overall respiratory viral surveillance.
# Wastewater surveillance
Data for wastewater testing could complement COVID-19 surveillance systems by providing readily accessible pooled community samples and data for communities where testing is not available or underutilized. Thus, it can complement COVID-19 surveillance systems. Protocols for using point-of-care molecular tests to analyze wastewater are being developed.
Testing, screening and surveillance framework
This framework is based on the evolving public health evidence, changing pandemic context and emerging technologies. The updated framework takes a broad approach that leverages and tailors technologies for testing, screening and surveillance while protecting and expanding the resilience of federal, provincial and territorial capacity. The intent is to target testing resources to the most relevant test in particular situations or use cases to address specific problems or purposes.
As the pandemic evolves, testing resources should support resurgence planning, outbreak management and re-opening while also:
- employing a right-sized and strategic approach focused on at-risk and vulnerable/congregate spaces
- ensuring flexibility to respond quickly and scale up efforts if needed
- being based, where applicable, on the program settings, scientific evidence and available and emerging testing technologies
Text Description: Figure 1
Testing:
- Focus on populations with vulnerabilities, employers and communities, and ensure readiness to respond to resurgence
- Maintain robust diagnostic capacity
- Consider multiplex testing to distinguish COVID-19 from other respiratory infectious diseases and prioritize for populations with vulnerabilities
Screening:
- Facilitate short-term broad access to rapid testing in areas such as schools and workplaces
- Maintain outbreak management capacity to rapidly shift testing and deploy to hotspots
- Focus on vulnerable and priority sectors as vaccination and epidemiology targets are met
Surveillance
- Maintain capacity to detect new VoCs, including through robust genomic surveillance with a focus on communities most at risk (for example, those with low rates of vaccination, populations with vulnerabilities)
- Ensure monitoring in low prevalence areas for early detection of cases as well as ongoing detection and characterization of VoCs
- Leverage established surveillance systems and expand early warning systems (for example, Fluwatch and wastewater surveillance, respectively)
Throughout the pandemic, significant diagnostic testing capacity has been established across Canada. Moving forward, it will be important to maintain a robust capacity and be able to ramp up quickly in hotspots and respond to outbreaks. As other respiratory viruses emerge alongside COVID-19, multiplex tests will be helpful to quickly distinguish COVID-19 from other respiratory diseases. A transition to more primary/ community-care settings for diagnostic testing will be important to focus on populations with vulnerabilities, employers and communities, and ensure readiness to respond to resurgence.
To date, rapid tests have been used to support widespread screening efforts to quickly identify cases in, for example, workplaces, community settings and schools. To support the shift from managing the pandemic to sustaining recovery and reopening, it will be important to:
- maintain the capacity to quickly deploy and scale screening capability
- focus our efforts on vulnerable and priority sectors
- support the rapid response to outbreaks
Partnerships with the private and not-for-profit sectors will be critical as well. Building on the lessons learned from workplace screening programs, these sectors can help us spread awareness about disease prevention and health promotion in the workplace. In addition, partnerships can be leveraged to facilitate data sharing and to fill data gaps on testing, screening and surveillance programs.
Monitoring low prevalence areas to detect COVID-19 cases early on as well as detect and characterize variants will also be critical. Efforts to enhance surveillance capacity (for example, by expanding wastewater and genomic surveillance) will be helpful in monitoring COVID-19 levels and VoCs in a community. Ongoing surveillance should also leverage established respiratory virus surveillance systems (for example, Fluwatch).
Five key foundational, interrelated pillars support the advancement of the framework:
- scientific integrity
- regulatory excellence
- procurement and deployment
- robust data and capacity
- strategic communication and partnerships
Continued updates to key guidance documents founded on rigorous scientific integrity will inform the evolution of testing approaches in Canada and support jurisdictions in the timely use of available technologies. Regulatory excellence will continue to be a focus, as it underpins the integrity of testing and screening strategies by assuring users that devices available in Canada meet stringent safety and efficacy standards. Procurement and deployment of tests will continue to focus on ensuring steady access to equipment and supplies for testing and screening wherever warranted. Furthering work in progress through the Pan-Canadian Health Data Strategy to ensure the availability of timely and comprehensive data will provide the evidence to underpin decision-making by governments.
Finally, in addition to strong federal, provincial and territorial partnerships, relationships with key partners in industry and the scientific community have been essential to the COVID-19 response. Ensuring rapid and effective progress is important, as is communicating what we know, what we are doing and what we are going to do. Strategic communications and partnerships are critical to informing people living in Canada of the continued importance and benefits of testing, screening and surveillance.
The continuous updating of this guidance will rely on strong federal, provincial and territorial partnerships and collaboration that leverage key governance bodies, including the Special Advisory Committee. The guidance will also capitalize on opportunities to leverage input and the capacity to mobilize knowledge in Canada and from around the world.
Looking forward
This guidance will evolve as the state of knowledge and risk management strategies continue to adapt to changing conditions. Guidance on current and emerging innovative testing and screening technologies will be adjusted to reflect new information concerning their performance in vaccinated context and how they meet the needs of various populations. As researchers and companies continue to innovate and develop new technologies and solutions, guidance will need to keep pace with, and take advantage of, these innovations.
Moving forward, testing and screening will continue to play a role in managing the pandemic. The epidemiology of the pandemic and the overall prevalence of COVID-19 will evolve based on factors such as the prevalence of COVID-19 and its VoCs, Canada's rates of vaccination and impacts of COVID-19 on populations with vulnerabilities. In vaccinated and unvaccinated populations, novel technologies including RADTs and self-tests will have ongoing uses for testing and screening, surveillance and outbreak responses.
Related links |
Pan-Canadian COVID-19 Testing and Screening Guidance: Technical guidance and implementation plan
=================================================================================================
[Download in PDF format](/content/dam/hc-sc/documents/services/drugs-health-products/covid19-industry/medical-devices/testing/pan-canadian-guidance/pan-canadian-guidance-eng.pdf)
(1 MB, 17 pages)
**Organization:** [Health Canada](/en/services/health.html)
**Date published:** August 2021
**Cat.:** H14-383/2021E-PDF
**ISBN:** 978-0-660-40219-2
**Pub.:** 210290
On this page
------------
* [Background](#a1)
* [Principles-based testing approach](#a2)
* [Community prevalence](#a3)
* [Testing, screening and surveillance technologies](#a4)
* [Testing, screening and surveillance framework](#a5)
* [Looking forward](#a6)
Background
----------
The onset of the global COVID-19 pandemic in early 2020 triggered the need for coherent, pan-Canadian guidance on provincial and territorial testing. The federal, provincial and territorial Special Advisory Committee finalized and approved initial interim guidance on laboratory testing on April 16, 2020. The guidance focused on molecular polymerase chain reaction (PCR) as the sole laboratory test for accurately identifying SARS-CoV-2 in patients.
In May 2020, based on new evidence, the *National Laboratory Testing Indication Guidance for COVID-19* was updated to reflect developments in 4 areas:
1. expanded laboratory resources
2. viral transmission from asymptomatic individuals or those in the pre-symptomatic phase
3. outbreaks in congregate living and work settings
4. new testing modalities (molecular point-of-care and serological tests)
In October 2020, the guidance was updated to give a national perspective on testing and screening approaches. Recognizing that one size does not fit all, the guidance outlines approaches and tools that federal, provincial and territorial partners may adapt as the pandemic evolves.
Federal, provincial and territorial governments first endorsed this *Pan-Canadian Testing and Screening Guidance* in October 2020. This guidance outlines a portfolio approach that uses different testing technologies for diagnostic testing, screening and surveillance.
In addition, the Public Health Agency of Canada updated its [Guidance on rapid antigen detection tests (RADTs)](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/use-rapid-antigen-detection-tests.html) in February 2021 to include information on novel RADT technologies. The update included details on performance and potential use cases including:
* routine outbreak monitoring
* monitoring in high-risk settings (for example, long-term care facilities)
* possible adaptation into mobile rapid testing in rural and remote communities
In May 2021, Health Canada approved the first self-test for use in Canada. The Lucira "Check It" COVID-19 Test Kit is a nucleic acid self-test. As of July 28, 2021, Health Canada has [authorized](/en/health-canada/services/drugs-health-products/covid19-industry/medical-devices/authorized/list.html) 77 COVID-19 testing devices (nucleic acid, antigen and serological). Authorized tests use various sample types, including saliva, nasal and nasopharyngeal. Thus far, there is no evidence of variants able to escape detection through existing testing technologies.
External expert advice has also helped to inform the approach to testing and screening. For instance, [Canada's COVID-19 Testing and Screening Expert Advisory Panel](/en/health-canada/services/drugs-health-products/covid19-industry/medical-devices/testing/content/canadasite/en/health-canada/services/drugs-health-products/covid19-industry/medical-devices/testing-screening-advisory-panel.html) has published 5 reports to the Minister of Health on optimizing testing in Canada, long-term care, schools, borders and self-testing. The [Industry Advisory Roundtable on COVID-19 Testing, Screening, Tracing and Data Management](/en/health-canada/services/drugs-health-products/covid19-industry/medical-devices/testing/content/canadasite/en/health-canada/services/drugs-health-products/covid19-industry/medical-devices/testing-outreach-collaboration/industry-advisory-roundtable.html) has published responses to the Expert Advisory Panel's reports on optimizing testing at borders. It has also published reports on the importance of task-shifting and the self-administration of tests in workplaces.
Since the publication of the initial *Pan-Canadian Testing and Screening Guidance*, much of Canada has experienced a significant third wave. Rapid tests have been procured and made available to provinces and territories in large numbers. Workplace screening programs have been developed and deployed. Highly effective vaccines have also been authorized and administered to many Canadians.
With rising vaccination rates, the incidence and rate of transmission of COVID-19 has decreased (see [eLife](https://elifesciences.org/articles/68808), [ECDC technical report](https://www.ecdc.europa.eu/sites/default/files/documents/Risk-of-transmission-and-reinfection-of-SARS-CoV-2-following-vaccination.pdf)). Nevertheless, outbreaks continue to occur, with the vast majority among people who are [not vaccinated](https://yukon.ca/en/health-and-wellness/covid-19-information/latest-updates-covid-19/chief-medical-officer-of-health-covid-19-updates), including those who may also face other health, social and economic barriers.
Some research indicates that vaccinated people who test positive for COVID-19 and do not carry the Delta variant are likely to have low viral loads ([Teran and others](https://www.cdc.gov/mmwr/volumes/70/wr/mm7017e1.htm?s_cid=mm7017e1_w), [Bailly and others](https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab446/6276392)). There is also evidence that vaccination can greatly reduce rates of SARS-CoV-2 infections that have [high viral shedding and symptoms](https://www.medrxiv.org/content/10.1101/2021.04.22.21255913v1.full).
Emerging evidence for the Delta variant points to the possibility of high viral loads in some breakthrough cases in fully vaccinated people, which can be as high as in unvaccinated people. Preliminary data from the U.S. Centers for Disease Control and Prevention and from Public Health England indicate that levels of virus in fully vaccinated people who become infected with Delta may be similar to levels found in unvaccinated people, and therefore they may be as likely to transmit the virus. These new studies highlight the importance of monitoring and responding to the ever-evolving science.
With vaccination rates contributing to decreases in the incidence and prevalence of COVID-19, as outlined in [Testing for COVID-19 in vaccinated populations](/en/public-health/services/diseases/coronavirus-disease-covid-19/testing-screening-contact-tracing/testing-vaccinated-populations.html), it is appropriate to consider how testing, screening and surveillance strategies should be adjusted. Strategies should reflect the changing dynamics of the pandemic as both vaccination and variant of concern rates increase.
The main objective of this guidance is to support the effective deployment of testing, screening and surveillance as public health tools. Considerations are provided for developing and implementing testing, screening and surveillance approaches where a majority of Canadians are now fully vaccinated.
Recognizing that testing regimes are within provincial and territorial jurisdiction, this guidance reflects the changing landscape of testing and screening. It also highlights the innovation and collaboration that have taken place within and among jurisdictions.
Principles-based testing approach
---------------------------------
As more and more Canadians are vaccinated, the demand for testing and screening is expected to decrease. This is because of the protection that vaccination offers against COVID-19, and also because vaccinated individuals with COVID-19 are less likely to be symptomatic. However, there will still be a need to manage new waves and/or localized outbreaks, including testing of symptomatic individuals and close contacts of individuals who have tested positive, regardless of vaccination status. Close contacts of individuals who have tested positive should be tested as outlined in the [national guidance on case and contact management](/en/public-health/services/diseases/2019-novel-coronavirus-infection/health-professionals/interim-guidance-cases-contacts.html). Individuals are also encouraged to consult local public health guidance related to isolation and self-monitoring. Meeting surges in testing and screening demand will require a shift, with the appropriate testing technology used for the situation (for instance, local vaccination rates and epidemiology).
Testing and screening strategies for public health purposes in a vaccinated population should consider the following 4 key variables:
1. community prevalence of COVID-19
2. community prevalence of variants of concern (VoCs)
3. presence of outbreaks
4. populations with vulnerabilities
Another goal of these strategies is to ensure there is sufficient capacity in place to respond to increases in cases and potential outbreaks. This approach will help protect those most at risk.
Community prevalence of COVID-19
--------------------------------
Community prevalence is the proportion of a population with COVID-19 at a given time. Definitions for what constitutes high or low community prevalence should be developed by jurisdictions based on their broader community context.
Along with test sensitivity and specificity, the pre-test probability of disease affects test performance. All other things being equal, when community prevalence of disease is lower, the pre-test probability is also lower. A positive result is more likely to be a false positive when prevalence is low. A negative result is more likely to be a false negative when prevalence is high. Testing and screening are more effective when prevalence is higher.
Surveillance data will be needed to monitor community prevalence and inform testing and screening decisions. Data from the following sources can be used to track prevalence:
* sentinel surveillance sites
* health records
* illness and severe outcome surveillance (for example, emergency room data)
Confirming point-of-care rapid test results that are presumed to be positive using lab-based PCR will provide important surveillance information. Genome sequencing follow-up for VoCs will also be possible.
Wastewater surveillance also provides information about COVID-19 in the community.
### Community prevalence of variants of concern (VoCs)
A [VoC](/en/public-health/services/diseases/2019-novel-coronavirus-infection/health-professionals/testing-diagnosing-case-reporting/sars-cov-2-variants-national-definitions-classifications-public-health-actions.html) is a mutated SARS-CoV-2 virus. The mutations affect one or more characteristic that is responsible for increased transmissibility, increased virulence or change in clinical disease progression. The mutated virus may also decrease the effectiveness of available diagnostic tools or vaccines.
New VoCs are likely to emerge while the virus continues to circulate globally. If VoCs emerge that evade vaccine-mediated immunity, the community incidence of COVID-19 will likely increase. As well, if vaccine-escape VoCs develop, the pre-test probability of vaccinated populations will also likely increase because vaccinated populations will be more likely to test positive for COVID-19. This will necessitate a larger role for testing and screening.
Testing and screening may also play a larger role in helping to protect populations with vulnerabilities where VoCs are more easily transmissible or may seriously compromise the health of those infected.
### Presence of outbreaks
An outbreak occurs when there is uncontrolled transmission of the SARS-CoV-2 virus. In vulnerable or congregate settings, as few as 2 cases may be considered an outbreak.
In outbreak situations, testing and screening are critical to identify cases quickly in order to reduce transmission and prevent the infection from spreading further.
### Populations with vulnerabilities
Testing and screening are also critical for populations with vulnerabilities. People who benefit most from a targeted testing strategy are those who are:
* clinically vulnerable to more severe outcomes
* vulnerable to infection
In some settings, such as long-term care and acute care facilities, tolerance for outbreaks is much lower because the risk of severe illness from COVID-19 is higher. There are also settings that are vulnerable because cases are difficult to manage due to limited access to health care services (for example, rural and remote areas). The risk of transmission is also higher in congregate settings, high-density living arrangements and workplaces where people are in close contact. People who are not vaccinated are also more vulnerable than those who are vaccinated.
Testing, screening and surveillance technologies
------------------------------------------------
Moving into the second half of 2021, we can expect to rely more on existing and new testing technologies, including the following:
* multiplex assays to test simultaneously for COVID-19 and other respiratory infections (such as respiratory syncytial virus, or RSV, and influenza)
* testing and genome sequencing for SARS-CoV-2 and its VoCs
* self-tests and emerging novel testing technologies, such as COVID-19 breathalyzer tests
Increasing the accessibility of testing technology, particularly to populations with vulnerabilities, and supporting large-scale surveillance to monitor community spread will continue to be important.
When using tests with good sensitivity and high specificity, the proportion of false positive results is lower among those testing positive in higher prevalence settings. These include areas where there are outbreaks or where a large proportion of the population is not vaccinated. Screening programs using rapid tests in such circumstances have proven successful and cost-effective.
Positive results from tests with high specificity (99.9% specific) are more likely to be [false positives](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850182/) in low prevalence settings, such as those where most or all are vaccinated.
When prevalence is very low, non-targeted asymptomatic rapid test screening may require many lab-based PCR tests to verify positive cases. The health, social and economic implications for those who receive false positive results are significant. The costs of false positives can be mitigated through confirmatory testing using a diagnostic test and provision of support strategies (for example, sick leave to offset loss of income).
Table 1: Characteristics of currently available testing technologies| Testing Technology | Nucleic acid
detects viral genetic material
most accurate | Antigen
detects viral protein
less accurate |
| --- | --- | --- |
| **Laboratory** performed by a trained person | **PCR*** Most sensitive/specific and used for diagnostic purposes
* Slowest: up to 1 to 2 days turnaround time
* Can screen for known VoCs
* 70% to 90% sensitive[Footnote 1](#tb1fn1) and 95% to 99% specific[Footnote 1](#tb1fn1) when symptomatic
| **N/A** |
| **Rapid Point-of-Care** performed or supervised by a trained person | **PCR*** Equally or slightly less accurate than lab-based PCR
* 15 min to 1 h turnaround time
**LAMP*** Equally or slightly less accurate than lab-based PCR
* 15 min to 1 h turnaround time
| **Rapid Antigen Detection Test (RADT)*** Less accurate than lab-based PCR
* Low accuracy in asymptomatic people with low viral loads
* 15 to 30 min turnaround time
|
| **Self-test****performed completely independently** | **LAMP*** Less accurate than laboratory-based PCR
* Decouples testing from public health reporting system
* Up to 30 min turnaround time
| **Rapid Antigen Detection Test (RADT)*** Least accurate vs lab-based PCR
* Decouples testing from public health reporting system
* 15 to 30 min turnaround time
|
|
Footnotes
Footnote 1
https://www.publichealthontario.ca/-/media/documents/lab/covid-19-lab-testing-faq.pdf?la=en
https://www.finddx.org/covid-19/sarscov2-eval-molecular/molecular-eval-results/
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202001700RR
[Return to footnote 1 referrer](#tb1fn1-rf)
|
### Lab-based molecular tests
Typically, a laboratory-based PCR test is suitable to diagnose people with symptoms and close contacts of individuals who have tested positive, and to confirm the results of rapid tests. This test can also be used to screen for known variants of concern by using genome sequencing to analyze samples in depth. When capacity is limited, the principles-based approach can help decide which groups and settings are priorities for lab-based molecular testing. [Sample pooling](https://www.nature.com/articles/s41598-021-82765-5) is another method for saving time and reagents when testing capacity is limited.
### Point-of-care molecular tests
These tests may be suitable at a point-of-care setting because they are more sensitive and can detect infection when the patient has a low viral load. They are preferable to RADTs when definitive results are crucial, such as during an outbreak in a congregate setting. Point-of-care molecular tests can also be used in rural and remote communities.
### Rapid antigen detection tests (RADTs)
One [study](https://www.nejm.org/doi/full/10.1056/NEJMoa2109072) found lower effectiveness of RADTs in breakthrough infections of vaccinated individuals. However, specific variants may result in higher viral loads, even in people who are vaccinated individuals. This would affect the performance of RADTs depending on the community context. The decision to use RADTs should be guided by the 4 key variables noted above, with the goal to protect populations with vulnerabilities, including in settings where a high proportion of people are not vaccinated or there are other risk factors. In these circumstances, it may be beneficial to test people who are vaccinated.
If the overall community vaccination rate is low, RADTs can also be used to identify paths of transmission. When used for screening, the regulatory guidance indicates RADTs should be used [serially](/en/health-canada/services/drugs-health-products/covid19-industry/medical-devices/testing/content/canadasite/en/health-canada/services/drugs-health-products/covid19-industry/medical-devices/testing/notice-rapid-antigen-serial-asymptomatic-individuals.html) (for example, take the test twice over 2 or 3 days with at least 24 hours and no more than 36 hours between tests). Nevertheless, if community incidence is low and vaccination helps to reduce COVID-19 incidence, screening programs are less likely to be cost-effective (see [testing in schools briefing](https://esnetwork.ca/briefings/covid-19-testing-strategies-in-schools/), [testing in business sectors briefing](https://esnetwork.ca/briefings/rapid-covid-19-testing-deployment-and-non-essential-business-sectors/), [Testing and Screening Expert Advisory Panel report](/en/health-canada/services/drugs-health-products/covid19-industry/medical-devices/testing-screening-advisory-panel/reports-summaries/priority-strategies.html), [Ontario Science Table report](https://covid19-sciencetable.ca/sciencebrief/routine-asymptomatic-sars-cov-2-screen-testing-of-ontario-long-term-care-staff-after-covid-19-vaccination/)). Confirmatory testing of positive results with more accurate tests may place burdens on public health systems, but would also provide a means of VoC screening/sequencing. It should be emphasized to those being screened with RADTs that a negative test result should not lead to a reduction in preventative measures.
### Multiplex tests
Multiplex tests can detect the presence of genetic material from multiple viruses/infectious agents using a single sample. For example, they can determine if a person in hospital with symptoms of respiratory illness is infected with SARS-CoV-2, influenza, both or neither.
Their use at sentinel surveillance sites can provide insight into the prevalence of COVID-19 and other respiratory viruses, such as influenza and RSV.
Multiplex tests may also be used to:
* inform treatment for immunocompromised people or those with severe illness in acute care settings
* identify the virus responsible in people living in congregate settings who present with symptoms
As these tests are more costly, priority should be for those at highest risk of severe outcomes, where test results can guide treatment and care, and where the results can contribute to overall respiratory viral surveillance.
### Wastewater surveillance
[Wastewater surveillance](https://www.sciencedirect.com/science/article/pii/S0048969720322816?casa_token=HKlKgaXrMhcAAAAA:qLbNayszuNnTbhgT6I51t2MNPHvil24TXmfO8Bs7hpY8aQFCiJyddahDCtjDXaa5oJRgAbF5H1g) can detect changes in COVID-19 at a community level. Wastewater is collected from treatment plants, pumping stations or other upstream community locations and the levels of SARS-CoV-2 and its VoCs are measured. PCR technology is used to test the samples. Wastewater samples can also be used for genome sequencing to detect existing and emerging VoCs in the population. [Wastewater surveillance for COVID-19](https://www.publichealthontario.ca/-/media/documents/ncov/phm/2021/04/public-health-measures-wastewater-surveillance.pdf?la=en) is still emerging in its development and use, and challenges remain when it comes to detecting SARS-CoV-2 in wastewater.
Data for wastewater testing could complement COVID-19 surveillance systems by providing readily accessible pooled community samples and data for communities where testing is not available or underutilized. Thus, it can complement COVID-19 surveillance systems. Protocols for using point-of-care molecular tests to analyze wastewater are being developed.
Testing, screening and surveillance framework
---------------------------------------------
This framework is based on the evolving public health evidence, changing pandemic context and emerging technologies. The updated framework takes a broad approach that leverages and tailors technologies for testing, screening and surveillance while protecting and expanding the resilience of federal, provincial and territorial capacity. The intent is to target testing resources to the most relevant test in particular situations or use cases to address specific problems or purposes.
As the pandemic evolves, testing resources should support resurgence planning, outbreak management and re-opening while also:
* employing a right-sized and strategic approach focused on at-risk and vulnerable/congregate spaces
* ensuring flexibility to respond quickly and scale up efforts if needed
* being based, where applicable, on the program settings, scientific evidence and available and emerging testing technologies
**Figure 1: Technology streams of a pan-Canadian framework for COVID-19 testing, screening and surveillance**
Text Description: Figure 1
Testing:
* Focus on populations with vulnerabilities, employers and communities, and ensure readiness to respond to resurgence
* Maintain robust diagnostic capacity
* Consider multiplex testing to distinguish COVID-19 from other respiratory infectious diseases and prioritize for populations with vulnerabilities
Screening:
* Facilitate short-term broad access to rapid testing in areas such as schools and workplaces
* Maintain outbreak management capacity to rapidly shift testing and deploy to hotspots
* Focus on vulnerable and priority sectors as vaccination and epidemiology targets are met
Surveillance
* Maintain capacity to detect new VoCs, including through robust genomic surveillance with a focus on communities most at risk (for example, those with low rates of vaccination, populations with vulnerabilities)
* Ensure monitoring in low prevalence areas for early detection of cases as well as ongoing detection and characterization of VoCs
* Leverage established surveillance systems and expand early warning systems (for example, Fluwatch and wastewater surveillance, respectively)
Throughout the pandemic, significant diagnostic testing capacity has been established across Canada. Moving forward, it will be important to maintain a robust capacity and be able to ramp up quickly in hotspots and respond to outbreaks. As other respiratory viruses emerge alongside COVID-19, multiplex tests will be helpful to quickly distinguish COVID-19 from other respiratory diseases. A transition to more primary/ community-care settings for diagnostic testing will be important to focus on populations with vulnerabilities, employers and communities, and ensure readiness to respond to resurgence.
To date, rapid tests have been used to support widespread screening efforts to quickly identify cases in, for example, workplaces, community settings and schools. To support the shift from managing the pandemic to sustaining recovery and reopening, it will be important to:
* maintain the capacity to quickly deploy and scale screening capability
* focus our efforts on vulnerable and priority sectors
* support the rapid response to outbreaks
Partnerships with the private and not-for-profit sectors will be critical as well. Building on the lessons learned from workplace screening programs, these sectors can help us spread awareness about disease prevention and health promotion in the workplace. In addition, partnerships can be leveraged to facilitate data sharing and to fill data gaps on testing, screening and surveillance programs.
Monitoring low prevalence areas to detect COVID-19 cases early on as well as detect and characterize variants will also be critical. Efforts to enhance surveillance capacity (for example, by expanding wastewater and genomic surveillance) will be helpful in monitoring COVID-19 levels and VoCs in a community. Ongoing surveillance should also leverage established respiratory virus surveillance systems (for example, Fluwatch).
Five key foundational, interrelated pillars support the advancement of the framework:
* scientific integrity
* regulatory excellence
* procurement and deployment
* robust data and capacity
* strategic communication and partnerships
Continued updates to key guidance documents founded on rigorous scientific integrity will inform the evolution of testing approaches in Canada and support jurisdictions in the timely use of available technologies. Regulatory excellence will continue to be a focus, as it underpins the integrity of testing and screening strategies by assuring users that devices available in Canada meet stringent safety and efficacy standards. Procurement and deployment of tests will continue to focus on ensuring steady access to equipment and supplies for testing and screening wherever warranted. Furthering work in progress through the Pan-Canadian Health Data Strategy to ensure the availability of timely and comprehensive data will provide the evidence to underpin decision-making by governments.
Finally, in addition to strong federal, provincial and territorial partnerships, relationships with key partners in industry and the scientific community have been essential to the COVID-19 response. Ensuring rapid and effective progress is important, as is communicating what we know, what we are doing and what we are going to do. Strategic communications and partnerships are critical to informing people living in Canada of the continued importance and benefits of testing, screening and surveillance.
The continuous updating of this guidance will rely on strong federal, provincial and territorial partnerships and collaboration that leverage key governance bodies, including the Special Advisory Committee. The guidance will also capitalize on opportunities to leverage input and the capacity to mobilize knowledge in Canada and from around the world.
Looking forward
---------------
This guidance will evolve as the state of knowledge and risk management strategies continue to adapt to changing conditions. Guidance on current and emerging innovative testing and screening technologies will be adjusted to reflect new information concerning their performance in vaccinated context and how they meet the needs of various populations. As researchers and companies continue to innovate and develop new technologies and solutions, guidance will need to keep pace with, and take advantage of, these innovations.
Moving forward, testing and screening will continue to play a role in managing the pandemic. The epidemiology of the pandemic and the overall prevalence of COVID-19 will evolve based on factors such as the prevalence of COVID-19 and its VoCs, Canada's rates of vaccination and impacts of COVID-19 on populations with vulnerabilities. In vaccinated and unvaccinated populations, novel technologies including RADTs and self-tests will have ongoing uses for testing and screening, surveillance and outbreak responses.
Related links
-------------
* [National polymerase chain reaction (PCR) testing indication guidance for COVID-19](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/national-laboratory-testing-indication.html)
* [Authorized medical devices for uses related to COVID-19: List of authorized testing devices](/en/health-canada/services/drugs-health-products/covid19-industry/medical-devices/authorized/list.html)
* [Interim guidance on the use of rapid antigen detection tests for the identification of SARS-CoV-2 infection](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/use-rapid-antigen-detection-tests.html)
* [COVID-19 Testing and Screening Expert Advisory Panel](/en/health-canada/services/drugs-health-products/covid19-industry/medical-devices/testing-screening-advisory-panel.html)
* [Testing in vaccinated populations](/en/public-health/services/diseases/coronavirus-disease-covid-19/testing-screening-contact-tracing/testing-vaccinated-populations.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fhealth-canada%2Fservices%2Fdrugs-health-products%2Fcovid19-industry%2Fmedical-devices%2Ftesting%2Fpan-canadian-guidance.html&n=Pan-Canadian%20COVID-19%20Testing%20and%20Screening%20Guidance%3A%20Technical%20guidance%20and%20implementation%20plan%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fhealth-canada%2Fservices%2Fdrugs-health-products%2Fcovid19-industry%2Fmedical-devices%2Ftesting%2Fpan-canadian-guidance.html&title=Pan-Canadian%20COVID-19%20Testing%20and%20Screening%20Guidance%3A%20Technical%20guidance%20and%20implementation%20plan%20-%20Canada.ca)
* [Email](mailto:?subject=Pan-Canadian%20COVID-19%20Testing%20and%20Screening%20Guidance%3A%20Technical%20guidance%20and%20implementation%20plan%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fhealth-canada%2Fservices%2Fdrugs-health-products%2Fcovid19-industry%2Fmedical-devices%2Ftesting%2Fpan-canadian-guidance.html%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fhealth-canada%2Fservices%2Fdrugs-health-products%2Fcovid19-industry%2Fmedical-devices%2Ftesting%2Fpan-canadian-guidance.html&t=Pan-Canadian%20COVID-19%20Testing%20and%20Screening%20Guidance%3A%20Technical%20guidance%20and%20implementation%20plan%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=Pan-Canadian%20COVID-19%20Testing%20and%20Screening%20Guidance%3A%20Technical%20guidance%20and%20implementation%20plan%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fhealth-canada%2Fservices%2Fdrugs-health-products%2Fcovid19-industry%2Fmedical-devices%2Ftesting%2Fpan-canadian-guidance.html%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fhealth-canada%2Fservices%2Fdrugs-health-products%2Fcovid19-industry%2Fmedical-devices%2Ftesting%2Fpan-canadian-guidance.html&title=Pan-Canadian%20COVID-19%20Testing%20and%20Screening%20Guidance%3A%20Technical%20guidance%20and%20implementation%20plan%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fhealth-canada%2Fservices%2Fdrugs-health-products%2Fcovid19-industry%2Fmedical-devices%2Ftesting%2Fpan-canadian-guidance.html&t=Pan-Canadian%20COVID-19%20Testing%20and%20Screening%20Guidance%3A%20Technical%20guidance%20and%20implementation%20plan%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fhealth-canada%2Fservices%2Fdrugs-health-products%2Fcovid19-industry%2Fmedical-devices%2Ftesting%2Fpan-canadian-guidance.html&media=&description=Pan-Canadian%20COVID-19%20Testing%20and%20Screening%20Guidance%3A%20Technical%20guidance%20and%20implementation%20plan%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fhealth-canada%2Fservices%2Fdrugs-health-products%2Fcovid19-industry%2Fmedical-devices%2Ftesting%2Fpan-canadian-guidance.html&title=Pan-Canadian%20COVID-19%20Testing%20and%20Screening%20Guidance%3A%20Technical%20guidance%20and%20implementation%20plan%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fhealth-canada%2Fservices%2Fdrugs-health-products%2Fcovid19-industry%2Fmedical-devices%2Ftesting%2Fpan-canadian-guidance.html)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fhealth-canada%2Fservices%2Fdrugs-health-products%2Fcovid19-industry%2Fmedical-devices%2Ftesting%2Fpan-canadian-guidance.html&name=Pan-Canadian%20COVID-19%20Testing%20and%20Screening%20Guidance%3A%20Technical%20guidance%20and%20implementation%20plan%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=Pan-Canadian%20COVID-19%20Testing%20and%20Screening%20Guidance%3A%20Technical%20guidance%20and%20implementation%20plan%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fhealth-canada%2Fservices%2Fdrugs-health-products%2Fcovid19-industry%2Fmedical-devices%2Ftesting%2Fpan-canadian-guidance.html)
* [Whatsapp](https://api.whatsapp.com/send?text=Pan-Canadian%20COVID-19%20Testing%20and%20Screening%20Guidance%3A%20Technical%20guidance%20and%20implementation%20plan%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fhealth-canada%2Fservices%2Fdrugs-health-products%2Fcovid19-industry%2Fmedical-devices%2Ftesting%2Fpan-canadian-guidance.html)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=Pan-Canadian%20COVID-19%20Testing%20and%20Screening%20Guidance%3A%20Technical%20guidance%20and%20implementation%20plan%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fhealth-canada%2Fservices%2Fdrugs-health-products%2Fcovid19-industry%2Fmedical-devices%2Ftesting%2Fpan-canadian-guidance.html%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2021-09-08
| None | None |
8ce81218d70f27f3c53a59a730dd000525a78907 | cma | Chapter 8: Organization of services | Chapter 8: Organization of services |
Chapter 8: Organization of services
====================================
* [Previous Chapter](/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-7.html)
* [Table of Contents](/en/public-health/services/maternity-newborn-care-guidelines.html)
* [Next Chapter](/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-9.html)
[Download in PDF format](/content/dam/phac-aspc/documents/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-8/maternity-newborn-care-guidelines-chapter-8.pdf)
(7.9 MB, 50 pages)
**Organization:** [Public Health Agency of Canada](/en/public-health.html)
**Date published:** 2022-08-10
Related Topics
--------------
* [Chapter 8 Fact sheet: Family-centred Focus to Organization of Services in Maternity and Newborn Care](/en/public-health/services/publications/healthy-living/family-focus-organization-services-maternity-newborn.html)
* [Family-Centred Maternity and Newborn Care: National Guidelines](/en/public-health/services/maternity-newborn-care-guidelines.html)
* [Fact sheets and infographics: Maternity and newborn care](/en/public-health/services/maternity-newborn-care-guidelines/fact-sheets-infographics.html)
Table of Contents
-----------------
* [Acknowledgements](#a0.1)
* [Introduction](#a0.2)
* [1. Regionalization of Maternity Services](#a1)
+ [1.1 Importance of Local Care](#a1.1)
+ [1.2 Out-of-Hospital Birth](#a1.2)
+ [1.3 Integration of Support](#a1.3)
+ [1.4 Tiers of Service](#a1.4)
* [2. Improving the System](#a2)
+ [2.1 Policies and Procedures](#a2.1)
+ [2.2 Education for Health Care Providers](#a2.2)
+ [2.3 Best Evidence and Clinical Practice Guidelines](#a2.3)
* [3. Service Delivery Level Accountabilities](#a3)
* [4. Personnel Requirements](#a4)
* [5. Interprofessional Care](#a5)
* [6. Transport](#a6)
+ [6.1 Regionalization and Transport System Structure](#a6.1)
+ [6.2 Essential Components of a Regional Referral and Transport Program](#a6.2)
+ [6.3 Decision Making for Maternal Transport](#a6.3)
+ [6.4 Maternal Transport Policies and Procedures](#a6.4)
+ [6.5 Neonatal Transport Policies and Procedures](#a6.5)
+ [6.6 Transport Personnel](#a6.6)
+ [6.7 Telemedicine](#a6.7)
* [7. Facilities and Equipment](#a7)
+ [7.1 Phases of Care](#a7.1)
+ [7.2 Design Principles and Design Process](#a7.2)
+ [7.3 Hospital births: Prenatal, Antepartum, Birth, and Postpartum Facilities](#a7.3)
+ [7.4 Home Births and Birthing Centres](#a7.4)
+ [7.5 Metrics for Facility Design Evaluation](#a7.5)
* [8. Implementing the Guidelines: Facilitating Change](#a8)
+ [8.1 Patient–client Engagement](#a8.1)
+ [8.2 Supporting the Culture of Family-Centred Maternity and Newborn Care](#a8.2)
* [9. Evaluation of Care](#a9)
+ [9.1 The Importance of Continuous Quality Improvement](#a9.1)
* [10. Planning for Pandemics](#a10)
+ [10.1 Pop-up Maternity Units](#a10.1)
+ [10.2 Considerations for Hospital-based Care](#a10.2)
+ [10.3 Health Care Provider Considerations](#a10.3)
+ [10.4 Patient–client Considerations](#a10.4)
* [Conclusion](#a11)
* [References](#a12)
Acknowledgments
---------------
Expand all
Collapse All
### Lead Writer
Jude Kornelsen, PhD
Associate Professor, Department of Family Practice,
University of British Columbia
Vancouver, British Columbia
### Contributing Authors
Carol Cameron, RM, MA
Executive Director, Alongside Midwifery Unit
Patient Care Director, Childbirth & Children's Services
Markham Stouffville Hospital
Markham, Ontario
Luisa Ciofani, RN, M.Sc.(A), IBCLC
Nurse and International Board Certified Lactation Consultant
Montreal, Quebec
Louise Hanvey, RN, BN, MHA
Senior Policy Analyst
Maternal and Child Health
Public Health Agency of Canada
Ottawa, Ontario
Lynn M. Menard, RN, BScN, MA
Team Leader
Maternal and Child Health
Public Health Agency of Canada
Ottawa, Ontario
Stephanie Redpath MBChB, FRCPCH (UK)
Assistant Professor of Neonatology
Division of Neonatology
Children's Hospital of Eastern Ontario
The Ottawa Hospital
Ottawa, ON
Diane Sawchuck, RN, PhD
Lead Evidence, Evaluation & Knowledge Translation
Research Department
Island Health
Victoria, British Columbia
Vicki Van Wagner RM, PhD
Associate Professor
Midwifery
Ryerson University
Toronto, ON
Lynne Wilson Orr, BID, M. Arch, OAA, FRAIC, ARIDO, IDC, EDAC
Principal
Parkin Architects Limited
Toronto, Ontario
### Reviewers
David Hancock, MHI, BTech, CBET(c), CET
Manager
Clinical Engineering
IWK Health Centre
Halifax, Nova Scotia
Carley Nicholson, RD, MPH
Policy Analyst
Maternal and Child Health
Public Health Agency of Canada
Ottawa, Ontario
Introduction
------------
The guiding principles of family-centred maternity and newborn care (FCMNC) provide the basis for national, provincial, regional, and local planning and organizing of maternal and newborn services. These principles state that pregnancy and birth are normal, healthy life events and family support, participation, and informed decision-making are central to all care. Care is organized in such a way that it responds to the physical, emotional, psychosocial, and spiritual needs of the woman, the newborn, and the family.
Care begins with attitudes and practices that value and respect women and trans or non-binary people, children, and families, and focuses on the many environments influencing the family, including the social, psychological, spiritual, and physical environments. Family-centred maternity and newborn care (FCMNC):
* Applies to all care environments;
* Recommends and enables care as close to home as possible;
* Encourages early parent–infant attachment as this is critical for newborn and child development and the growth of healthy families;
* Cares for the psychological needs of women and their families;
* Respects the diversity of people's lives and experiences;
* Recognizes the impact of racism on health and health care;
* Recognizes that discrimination against vulnerable families occurs;
* Incorporates informed decision-making;
* Functions within a system that incorporates ongoing evaluation.
To achieve these goals, the organization of services can take into account:
* All stakeholders when planning and providing care, including parents, community groups, community agencies, health care providers (HCPs), public health units, and hospitals;
* The pregnant women's health status (prior to and during pregnancy), and referral to the appropriate resources for care;
* Provision of accessible care, with consideration given to the family's geographical, demographic, and cultural conditions.
Responding to population needs, as informed by best available evidence, is vital in the planning and organization of care. Planning and organizing maternal and newborn services requires taking into account:
* Canada's size and low population density;
* The different needs of Indigenous communities;
* The shifting HCP mix through the attrition of family physicians providing maternity care and the growing contribution of midwives.
1. Regionalization of Maternity Services
----------------------------------------
The regionalization of health services in Canada took place in response to the persistent need to contain costs, a changing health care workforce, continued demands for services, and an aging population. Through regionalized health care, health planners anticipated meeting the more complex health care needs of rural residents in geographically proximal communities (regional referral centres) as opposed to large urban tertiary centres. The aim of this is to reduce the need to travel long distances and the associated disruptions. In addition, the policy objective of maternity care *closer to home* can be maximized for all aspects of care including preconception, the prenatal period, labour and birth, and the postpartum and newborn periods.
It is important to organize regionalized perinatal care so that women and families can access appropriate, safe and quality care as close to home as possible. The guiding imperatives behind regionalized perinatal care are decentralized services overseen by regionally defined governing bodies embedded in tiers of service that correspond to population needs. In this model, perinatal services without access to local caesarean birth function well in communities with a small number of births per year. In these communities, pregnant women are supported by both family physicians and midwives, and most of whom have uncomplicated pregnancies allowing for local birth. Also, in many rural settings in western and northern Canada, family physicians with enhanced surgical skills perform caesarean births, with the support of specialists in regional referral centres. Specialist involvement is required in larger populations where the absolute number of caesarean births is higher and complexity of care is also greater.
In a healthy, well-balanced system, the capacity of the maternity services aligns with the capacity of the site to appropriately care for the newborn. Case selection based on local resources is core to regionalized perinatal care, assuming that risk-associated triage is performed. Pregnant women with maternal or fetal risk factors are referred to facilities with more resources.
From a family-centred perspective, regionalized health care reduces the stress of having to relocate to a referral community for low-risk vaginal birth, improves outcomes, and begins to address the calls to action of the *Truth and Reconciliation Commission.* These calls to action have paved the way for actioning local birth as a cultural mandate and a part of the reconciliation process. [Footnote 1](#fn1)
Although the benefits of regionalized maternity care are built on the assumption that primary maternity care is available in or close to rural communities, the lack of stability of smaller maternity sites has made this difficult to achieve. This instability has been precipitated by difficulties in recruiting and retaining HCPs to work in low-volume sites that often have no local access to caesarean birth. Although maternity services without local access to caesarean birth are safe—assuming appropriate case selection for local birth, regional support of rural HCPs, and access to efficient transport, should it be needed—the last two decades have seen a worldwide lack of provider sustainability in low-volume sites.[Footnote 2](#fn2),[Footnote 3](#fn3),[Footnote 4](#fn4) A notable exception to this in Canada are services in the North, where provider levels have been maintained over many decades. [Footnote 5](#fn5)
Effective and efficient transportation is essential in those instances when greater levels of care are needed in a timely way. The Society of Obstetricians and Gynaecologists of Canada (SOGC) *Maternal Transport Policy* describes regional transport systems, including the equipment and personnel to facilitate safe and effective transfer if required, and the need for 24-hour availability of transport systems and reliable and accurate communication between referring hospitals and transport teams. [Footnote 6](#fn6)
Although clear transport protocols are relevant through all levels of tiers of service, the need is greatest for transport from sites with low levels of resources (e.g., without local access to caesarean birth or on-site specialist care). Across Canada, 40.5% of rural women experienced travel time to a hospital longer than an hour. [Footnote 7](#fn7)
Effective transport planning and implementation requires a holistic perspective, one that takes into account the health consequences of delayed access to appropriate levels of care and the impact of transport out of a local community or away from an expected location on the birthing family. Such transport often results in increased stress and anxiety, particularly when it is urgent and leads to separation of the family at a time of heightened vulnerability. When pregnant women need to leave their community prior to the onset of labour, they are often separated from partners and family for extended periods. This may be due to the limited capacity of emergency transport to accommodate a woman's chosen support and lack of financial resources for family members to travel privately. In some instances, family members may need to stay behind to work or look after other family members.
Transport with a supportive family member is both clinically and psychologically optimal for the birthing woman. A family-centred planning paradigm works to put in place structures that mitigate the effect of required travel from the home community (e.g., subsidized accommodation in the referral centre that can support family members; travel subsidies beyond those available through Indigenous Services Canada's Non-Insured Health Benefits Medical Transportation Policy Framework for eligible registered First Nations and recognized Inuit clients), keep families together, and facilitate timely return to their home environment.[Footnote 8](#fn8)
Planning regionalized maternity care is based on unique community needs and geography to reduce pregnancy complications that may occur due to travel when relocating for access to care services. Health care resources can be directed in ways that are most productive, under the organization and guidance of provincial and territorial ministries and departments of health. Well-functioning regional maternity care also promotes the participation of the community in making health services–related decisions.
### 1.1 Importance of Local Care
Regionalized perinatal care, underscored by the importance of responsiveness to community need, has not played out in all jurisdictions across Canada as originally intended. Many rural areas have seen maternity services centralized, as opposed to regionalized, and the dissolution of low-volume services in their community. *High outflow* maternity services, where more than two-thirds of the population leave the community for care, may lead to:[Footnote 9](#fn9),[Footnote 10](#fn10),[Footnote 11](#fn11),[Footnote 12](#fn12)
* The damaging cycle of fewer local births in an already low-volume setting, either because of clinical indications or because of maternal or family preferences;
* Diminished confidence of HCPs, which may reflect back to communities as lack of support for local birth, further encouraging patient–family outflow and challenging sustainability;
* A relationship between adverse maternal and newborn outcomes and distance to services;
* Health and psychosocial effects on pregnant women and their families, including in Indigenous communities where birthing on traditional land supported by extended family and community can be essential to care.
Appropriate care in the prenatal and postpartum periods also requires careful planning through a regional lens to ensure appropriate screening and triage for birthing women and newborns. Women with no complications of pregnancy can be comprehensively cared for by local HCPs or visiting primary care physicians or midwives. Referral to a specialist, if needed, can be facilitated through virtual care. But it is vital that women in communities without antepartum care have a plan to relocate either before or at the onset of labour and that they and their newborns have appropriate care in the postpartum period. All birthing families also need access to prenatal information and education. When in-person prenatal classes are not possible, virtual classes and written material can enhance family learning.
### 1.2 Out-of-Hospital Birth
An essential part of regionalized maternal and newborn care is support for out-of-hospital births attended by registered midwives. The SOGC recommends risk assessment using established criteria in either a home setting or a birthing centre, as both locations are suited for birthing women likely to proceed with a normal vaginal birth.[Footnote 13](#fn13) Recognizing and supporting out-of-hospital birth with a regulated HCP ensures that triage, referral, and transportation to a greater level of care are in place across the regionalized system should transfer be necessary.[Footnote 6](#fn6)
### 1.3 Integration of Support
A key determinant of safety in regionalized maternal and newborn care is the support for primary HCPs by other providers, such as specialists or sub-specialists.[Footnote 4](#fn4) Well-functioning, integrated tiers of services may be conceptualized as relationships, with sites with fewer resources depending on the backup and support of sites with more resources. The sites with more resources, in turn, offer support because they trust in the judgment of the services with fewer resources.[Footnote 14](#fn14)
Virtual communication has become increasingly important in health care with HCPs accessing on-demand consultation with other centres. For example, in British Columbia, four real-time virtual support (RTVS) pathways have been established using Zoom for Healthcare licences. One of the four pathways, MaBAL, for rural physicians with expertise in maternal and newborn care can be reached "24/7 through Zoom and by phone to provide guidance on urgent and non-urgent preconception, prenatal, antenatal, intrapartum, and postpartum presentations, for both moms and newborns".[Footnote 15](#fn15)
The concept of these networks is not new. They have historically characterized triage across rural Canada, but are now intentionally implemented to formalize and optimize referral and support pathways.[Footnote 16](#fn16)
### 1.4 Tiers of Service
Although maternity care is similar across many jurisdictions in Canada, the provincial/territorial mandate for health service delivery means that developing a national classification system for tiers of service is a challenge. The SOGC recently recommended "the adoption of one national standardized set of definitions to encompass all facilities providing maternity care for different levels of anticipated risk."[Footnote 17](#fn17) Currently, only British Columbia and Ontario have developed tiers of service for maternity care in Canada.[Footnote 18](#fn18),[Footnote 19](#fn19) The American College of Obstetricians and Gynecologists (ACOG) have refreshed their consensus statements on *Levels of Maternal Care*, and this framework could have applications to the Canadian context.[Footnote 20](#fn20)
Following the philosophical foundation of advancing tiers of service corresponding to population complexity, the SOGC consensus statement *Attendance at and Resources for Delivery of Optimal Maternity Care* describes levels of service and criteria of the various levels of care.[Footnote 17](#fn17)
British Columbia's *Tiers of Service* and Ontario's *Standardized Maternal and Newborn Levels of Care Definitions* further explain the levels of acuity and complexity that each level of service can safely support.[Footnote 18](#fn18),[Footnote 19](#fn19) Expanding capacity to support complex perinatal needs through generalist, specialist, and sub-specialist care maximizes efficiency in meeting anticipated local needs while centralized sub-specialist care aligns resources most effectively to address less common complexities. Research has shown that sub-specialist centres are not optimal for the care of birthing mothers who are at low risk.[Footnote 21](#fn21)
2. Improving the System
-----------------------
### 2.1 Policies and Procedures
An effective response to changing circumstances and emerging evidence is best achieved when policies and procedures towards a safe birthing environment are written, then regularly reviewed and updated. At a local level, all facility staff members should be able to easily refer to and provide input to these policies and procedures.
Written policies and procedures can be about:
* Communication about the care and support of women, infants, and families;
* Referral practices between agencies/services;
* Admission of women, infants, and families to hospitals and birthing centres;
* Assessment and criteria for discharge of women and babies from hospitals and birthing centres;
* Criteria for home birth;
* Referral to community services/supports;
* Identification and referral of women and/or infants in current or potentially abusive situations;
* Emergency transfer of mothers, babies, and support people, where possible, including the requirement for prior arrangements with a receiving health facility in the event of an emergency;
* Newborn resuscitation;
* Breastfeeding promotion, protection, and support;
* Maintenance of health records;
* Infection control and biohazard precautions including Level 4 pathogen and pandemic plans and responses;
* Storage of medications and emergency drugs;
* Hazardous materials and workplace safety practices;
* Responses to maternal/newborn emergencies;
* Evaluation of care and quality improvement;
* Internal disaster procedures, including in the case of fire;
* Cultural safety and health equity, including anti-racism and the elimination of discrimination against marginalized and vulnerable groups and people.
In addition, Accreditation Canada has developed Obstetrics Services standards to help organizations assess quality at the point of service delivery.[Footnote 22](#fn22) These standards are based on a culture of quality, safety, and family-centred care.
### 2.2 Education for Health Care Providers
Ongoing learning by HCPs is essential as new evidence for best practices continues to emerge. Oversight of professional development and skills maintenance is generally the combined responsibility of professional colleges and individual practitioners. Whereas some of the specific competencies and behaviours needed are delineated by professional colleges, others reflect the needs and standards of the clinical care unit or agency.
Optimal learning opportunities are multidisciplinary, with all care team members participating—that is, physicians, midwives, nurses, social workers, nutritionists, lactation consultants, respiratory therapists, perinatal psychologists, and others. Three principles outlined in Chapter 1 are important components of education for all health care professionals delivering FCMNC:[Footnote 23](#fn23)
* A holistic approach to maternal and newborn care (Principle 6);
* Collaboration between care providers (Principle 7);
* Consideration of maternal and newborn care best practices from global settings that may be relevant to a Canadian context (Principle 17).
Education topics—ideally identified at the team level—may include:
* New treatments;
* Clinical concerns;
* Research evidence or emergent situations that affect care;
* Cultural safety, anti-racism, and non-discriminatory, respectful, and psychosocially sensitive care education.
Opportunities for learning may include inter-disciplinary rounds, workshops, conferences, learning packages, formal undergraduate and graduate education programs, distance learning, self-study, or participation on new committees or in new projects or research. Regional administrators will want to consider the challenges that rural and remote HCPs may face if travel out of their community is difficult. Coordination of educational efforts through organized regional programs ensures consistency of information and reduces duplication of efforts. Increasingly, facilities and agencies are using virtual learning through online classes, conferences, and meetings.
### 2.3 Best Evidence and Clinical Practice Guidelines
HCPs can tailor guidelines to the needs of individual patient–clients.[Footnote 23](#fn23) Deciding about transport and referral is ideally based on "the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients."[Footnote 24](#fn24) In this way, care achieves the Institute for Healthcare Improvement Quadruple Aim: optimal patient–client outcomes, patient–client satisfaction, provider satisfaction with care, and cost efficiency.[Footnote 25](#fn25)
Beyond improving clinical quality, guidelines are an effective way to organize and present the increasing volume of evidence HCPs face.
3. Service Delivery Level Accountabilities
------------------------------------------
Although facility standards are provincially and territorially regulated across Canada, researchers and health planners increasingly recognize the need for a common framework to ensure quality of care and facilitate evaluation.[Footnote 26](#fn26) However, only British Columbia and Ontario have published expectations for capabilities in maternal–newborn care. These publications include guidelines defining maternal and newborn levels of care, human resource requirements, and diagnostic tests and treatments.[Footnote 27](#fn27),[Footnote 28](#fn28)
The commonalities between jurisdictional models align with consensus definitions such as those of the American College of Obstetricians and Gynecologists (ACOG) *Standards of Obstetric-Gynecologic Services*.[Footnote 29](#fn29) Recognizing the competencies required to safely support birth at home and in rural centres without local access to caesarean birth varies across Canada. Support for both these models of care is based on evidence on safety of care, an appreciation of Canada's vast geography and the recognition of the psychosocial consequences of relocating for birth.
The SOGC supports women with low-risk pregnancies giving birth in rural and remote communities. The Society states that "risk assessment is not a once-only measure but a process continuing throughout pregnancy and birth. Referral of the woman to a higher level of care may be required when signs of complications become apparent".[Footnote 30](#fn30) Despite a national endorsement of such services, rural Canada has seen a precipitous decline in local health care due to resourcing challenges.
Perinatal care in Canada is based on a regionalized system of service delivery for both maternal and newborn care. Hospitals with local caesarean birth capacity provide referral backup for those without such capacity, and larger centres provide increasingly specialized care based on population needs. In facilities that do not offer caesarean birth (that is, birth centres and level I hospitals), key preconditions to care include informed discussions about the limitations in emergency situations; transport and other potential consequences of limitations in emergency situations; established obstetrical backup should it be necessary; on-site availability of medications to manage obstetrical emergencies; and medication to treat postpartum hemorrhage.[Footnote 13](#fn13) Refer to the SOGC consensus statement *Attendance at and Resources for Delivery of Optimal Maternity* for expected capabilities by level of service.[Footnote 17](#fn17)
4. Personnel Requirements
-------------------------
Families in Canada receive intrapartum care from a variety of health practitioners, including obstetrician–gynecologists, family doctors, nurses or nurse practitioners, and midwives. According to the Vanier Institute, nurses make up the largest group of maternity care providers in Canada.[Footnote 31](#fn31) The 2018 *Perinatal Nursing Standards in Canada* articulated four standards to which perinatal nurses are expected to adhere.[Footnote 32](#fn32) These standards support and endorse the principles of FCMNC, including relationship-based care, interprofessional collaboration, quality and safety, and evidence-informed practice.
Staffing decisions affect clinical outcomes as well as provider satisfaction and retention.[Footnote 33](#fn33),[Footnote 34](#fn34) Evaluation of the impact of nurse staffing mandates on patient–client outcomes in California and on hospital outcomes in 15 European countries shows that lower nurse-to-patient ratios significantly affect surgical mortality and failure-to-rescue rates.[Footnote 35](#fn35),[Footnote 36](#fn36) However, models of staffing for surgical units may not be appropriate for perinatal units, as their staff-to-patient ratios are based on the different care needs.
Recommendations on minimum staffing levels are generally based on new mother–newborn care being without complications, but all mother–baby dyads do not need the same level of nursing care. Postpartum ratios in particular can range from 1:1 to 9:1, depending on the level of care required for any complications[Footnote 37](#fn37). The Association of Women's Health, Obstetric and Neonatal Nurses recommends the following patient-to-nurse ratios for perinatal care for healthy mother–newborn dyads:[Footnote 38](#fn38)
* One nurse to one woman for women labouring with minimal to no pharmacological pain relief or medical interventions;
* One nurse to one woman for women receiving oxytocin;
* One nurse to one woman with labour complications;
* Two nurses to one woman for vaginal and caesarean birth—one nurse for the mother and one nurse (with newborn resuscitation capabilities) for the baby;
* Two nurses up to 2 hours postpartum—one nurse for the mother and one nurse for the baby, or in the case of multiples, one nurse for each baby.
An indicator comparing nurse-to-patient ratios across Canada is currently not available. The Canadian Institute for Health Information (CIHI) is working to fill this gap by developing a nationally comparable, systematic method of measuring the number of patient–clients cared for per staff member.[Footnote 39](#fn39)
In addition to provider-to-patient ratios, the experience and skill mix of nurses is a key factor in perinatal staffing. Standardizing nurse-to-patient ratios in Canada might protect nurses from excessive workloads, but it might also prevent departments making independent decisions about staffing based on factors such as the availability of human resources and individual nursing skill and comfort levels.[Footnote 40](#fn40) In predicting personnel needs for births and postpartum care, factors to consider include different staffing models and patient–client needs in urban and rural hospitals. As noted earlier, mother–baby dyads in tertiary hospitals in urban centres are more likely to require higher levels of care than their counterparts in low-risk only birthing centres.[Footnote 37](#fn37) In small rural hospitals where resources are limited, the need for flexible staffing may not allow for the same nurse-to-patient ratios as implemented in higher-resource settings.[Footnote 41](#fn41)
Midwives are playing an increasingly important role in maternity care in Canada, offering a wide range of services and working with other medical professionals as needed. Care by a midwife of mothers and babies at low risk is cost effective and associated with shorter hospital stays and fewer interventions.[Footnote 42](#fn42) Also, midwifery-led care may improve birth outcomes for vulnerable women with low socioeconomic status.[Footnote 43](#fn43),[Footnote 44](#fn44)
Midwifery regulation and health care delivery vary significantly between jurisdictions in Canada.[Footnote 45](#fn45) Some provinces and territories have been regulating and funding midwifery for over 20 years, with the colleges of midwives the regulatory bodies that provide standards and guidelines for the profession.[Footnote 46](#fn46) In other jurisdictions, the profession remains unregulated and unfunded.[Footnote 46](#fn46)
Given that the perinatal period is characterized by significant biological and psychosocial changes, administrators will want to consider how staffing and coordinating allied health professionals and ancillary personnel can complement the work of primary HCPs to provide comprehensive and integrated family-centred care. The SOGC's *Attendance at and Resources for Delivery of Optimal Maternity Care* identifies appropriate resources, personnel, and facilities to encourage safe physiological birth in a family-centred environment in rural and urban communities. This consensus statement is built on an appreciation of birthing women's autonomy in making informed decisions "even in difficult situations when health care providers disagree with the choice."[Footnote 17](#fn17)
The consensus statement also recognizes the adverse psychological and sociocultural consequences of requiring birthing mothers to leave their community.[Footnote 17](#fn17) It urges HCPs to consider not only the health of the women and their babies but the psychosocial risks when selecting appropriate locations for birth. In addition, the statement calls for adopting a national, standardized set of definitions for all facilities providing maternity care based on their capacity to care for varying levels of risk. This would allow for a national framework for evaluation.
5. Interprofessional Care
-------------------------
Multidisciplinary collaborative maternity care teams are important in sustaining the overall availability of HCPs and improving access to and choice in maternity care in Canada.[Footnote 47](#fn47)
In 2006, the SOGC led the Multidisciplinary Collaborative Primary Maternity Care Project with the objective of developing guidelines, determining national standards, and increasing collaboration between professionals.[Footnote 48](#fn48) Recommendations included that decision makers and other key stakeholders commit to developing coordinated care, advocate for the resources required to support appropriate care, and reach a consensus on key strategies to establish, retain, or expand multidisciplinary collaborative maternity services.[Footnote 48](#fn48)
The project identified key principles to a collaborative model:[Footnote 48](#fn48)
* Quality, woman-centred maternity care, based on equity of access to and integration of services;
* Based on best evidence and practice guidelines;
* Professional competence with commitment to the collaborative model and mutual trust and respect;
* Shared values, goals, and visions, with honest, open, and continuous communication;
* Responsibility and accountability including the acceptance of the need to discuss financial issues;
* Effective, integrated regional provision of services to include locally based care with knowledge of available services.
This model aligns closely with FCMNC through common, articulated principles and through recognition of the importance of community consultation in developing locally-responsive models of care. The principles note specifically the unique challenges in low-volume rural settings: "In rural areas the challenge is less one of size and inter-relationships and more the enduring questions regarding access to and availability of care, and who provides that care. It is well known that the rural hospital closures and downsizing occurring across the country is placing new challenges on maternity care providers."[Footnote 48](#fn48),p.26
Since access to perinatal services varies across communities, many jurisdictions do not have standard protocols for sharing information about patient–clients with providers. This can result in missed referrals, inconsistent messaging, and a lack of coordinated care.
Two pilot communities in the Northern Health authority in British Columbia have established an integrated service model using practice support coaches and care process coaches to help bridge primary care practice with other services in the health authority. These communities have reported increased and improved access to primary care for prenatal service, including for vulnerable pregnant populations who subsequently receive evidence-based care for the remainder of their pregnancies and onwards.[Footnote 49](#fn49)
Other studies that evaluated integrated hospital and community models of perinatal care have reported increased screening for and treatment of perinatal mood and anxiety disorders (PMADs).[Footnote 50](#fn50),[Footnote 51](#fn51) Standardization of processes related to the coordination of perinatal care led to a reduction in risk factors across the social determinants of health and overall improved quality of care through clinical and professional integration.
The SOGC consensus statement *The Roles of Multidisciplinary Team Members in the Care of Pregnant Women* (2016) prioritizes the safety and interests of the patient–client while respecting their autonomy and maintaining respect for all team members.[Footnote 52](#fn52) The consensus statement highlights the importance of defined roles and responsibilities within teams and the importance of addressing barriers to successful collaborative care.
6. Transport
------------
The process of evacuating pregnant or birthing women from rural and remote areas was developed through the 1960s and 1970s, in response to a perceived lack of safety in low-resource settings. Efficient and timely access to emergency transport for women and their newborns is essential for safe regionalized care. However, the stress of separating from family and losing community connections and the potential for financial hardship on leaving the community can have deleterious effects.[Footnote 5](#fn5) The trauma of relocation has led to some women concealing pregnancy until they are in labour, often at the cost of access to prenatal care and screening.
Sensitivity to the family's view of transport together with strategies to meet acute clinical needs can lead to improved care. In many rural Indigenous communities, local birth has been reclaimed through community midwifery programs.[Footnote 53](#fn53),[Footnote 54](#fn54) Nevertheless, there are instances when higher levels of care are necessary, requiring culturally safe transportation.[Footnote 55](#fn55) In 2017, Indigenous Services Canada instituted funding for escorts for rural Indigenous birthing women, mitigating some of the effects of isolation due to relocation.[Footnote 56](#fn56)
If the health of the newborn is a concern, outcomes are better if the transport occurs during pregnancy.[Footnote 57](#fn57),[Footnote 58](#fn58),[Footnote 59](#fn59),[Footnote 60](#fn60) Despite the clinical advantages of caring for high-risk cases in appropriately resourced centres, the effect of transport on the family needs to be considered.[Footnote 61](#fn61) The stress of relocating from familiar settings, the loss of a known care provider, separation from supportive family and community members, and the financial costs of accommodation and travel are additional stresses for both the birthing mother and her family.[Footnote 62](#fn62) To this end, the most effective mitigation strategy is for HCPs to try to identify high-risk pregnancies and births early enough in the prenatal period to avoid urgent transport.
There are also times when, because of work or the need to care for other children, family escorts may not be available. This can result in the birthing mother feeling isolated and alone, which can further exacerbate her concerns for the health of her baby. The principles of FCMNC that underscore best practices are grounded in the importance of keeping families together through accompanied transport. Recognizing that there will be times when this is not possible, HCPs and administrators can work to mitigate the consequences of this stress.
Essential components of effective family-centred transport include:[Footnote 59](#fn59)
* Clear and honest communication about the health status, prognosis and anticipated interventions required to optimize the health of the birthing mother and her newborn;
* Presence of family members during stabilization and transport (if possible);
* Continuous, professional support given to the family;
* Including the family in care planning and decision-making;
* Ongoing communication from the referral site on the status of the mother and baby if the family is separated.
### 6.1 Regionalization and Transport System Structure
The regionalization of maternal and newborn care is based on maximizing access to and capacity of neonatal intensive care units (NICUs).[Footnote 61](#fn61) Two related goals of regionalized perinatal care include:
* Expedient identification of high-risk pregnancies to ensure birth at a hospital with the appropriate level of care;
* Speedy recognition of high risk not identified during prenatal care in order to efficiently transport infants to a more appropriate level of care.[Footnote 63](#fn63)
The key to successful regionalized perinatal care is therefore the identification and timely transport of at-risk pregnant women.
Best practices for efficient transport include a single access point and provincial/territorial coordination to prioritize needs based on clinical acuity and the integration of transport modalities (air and ground).[Footnote 64](#fn64) Single-call dispatch within a formalized network of patient–client transfer also increases provider satisfaction.[Footnote 65](#fn65),[Footnote 66](#fn66) In addition to streamlined access, transport systems need to be able to offer medical advice, rapidly dispatch transport teams, and identify a receiving hospital.[Footnote 59](#fn59) In line with FCMNC, after the necessary care in a tertiary centre, maternal transport services also repatriate the mother and newborn, and families to sites close to home, as soon as possible.
### 6.2 Essential Components of a Regional Referral and Transport Program
The first component of an effective transport system is to avoid unanticipated or urgent transport*.* Ideally, high-risk pregnancies are identified before the onset of labour and the optimal place of birth is chosen based on anticipated resource needs. This is predicated on comprehensive care during the prenatal period and the full inclusion of birthing mothers and families in decision making. Despite efforts to mitigate the need for perinatal transport, there will be instances when unanticipated and urgent transport is required.
Because of the jurisdictional nature of Canadian health care, emergency transport mechanisms vary widely in terms of processes and infrastructure. Minimum criteria start with a well-resourced system with the sustained investment in regional health authorities.[Footnote 67](#fn67) Standardization of equipment, education, clinical competencies, and quality indicators is also necessary.[Footnote 59](#fn59),[Footnote 68](#fn68)
Adverse outcome mitigation strategies for reducing non-tertiary deliveries include a perinatal telephone advice line to optimize in utero transfers, and perinatal outreach education to providers at non-specialty perinatal centers.[Footnote 68](#fn68),[Footnote 69](#fn69),[Footnote 70](#fn70)
Designated emergency medical service (EMS) vehicles may need to be specialized. For example, use of dedicated vehicles by the four specialized transport teams across Ontario have been shown to decrease complications and optimize the quality of care for sick newborn babies.[Footnote 71](#fn71) Transport equipment should meet occupational health and safety standards for crew and the communications infrastructure used in smart phone, satellite phone, or webcam communication should be encrypted.[Footnote 72](#fn72)
At a systems level, the value of a *no refusal policy* is identified as a key intervention for improving care. A "no refusal policy" means a facility cannot refuse or deny the transfer of a patient–client needing critical care. Although the policy was developed based on trauma care, this mechanism of enabling timely triage is transferable to maternity care.[Footnote 73](#fn73)
### 6.3 Decision Making for Maternal Transport
Maternal transport can occur for many reasons: preterm labour; preterm rupture of membranes; severe gestational hypertension or other hypertensive disorder; antepartum hemorrhage; intrauterine growth restriction; inadequate progress in labour; malpresentation; and maternal trauma.
Transport is contraindicated if:
* The mother's condition is insufficiently stable;
* The fetus' condition is unstable and threatening to deteriorate rapidly;
* Birth is imminent; or
* Weather conditions are hazardous for transport.
Canada's vast area and varied climate means that urgent transport from a rural community may not be feasible and that the dangers of immediate transport outweigh expected benefits. Situational assessment is a key part of the decision-making process. Such assessment requires attention to weather and road or flight conditions, the health status of the mother and baby, her stage in pregnancy, the likelihood of imminent birth, and the availability of skilled HCPs.[Footnote 72](#fn72)
The key principles that underscore transport decisions include:[Footnote 67](#fn67),[Footnote 72](#fn72)
* The need to consult with specialists to determine whether transport is indicated for a high-risk pregnancy or birth based on risk factors for the birthing mother, the baby, the stage and progress of labour, and potential conditions en route;
* Communication between all team members including the sending and receiving HCPs;
* Supporting rural sites that may not have the resources to stabilize infants for long periods;
* Minimizing the number of transfers for the birthing mother or her baby;
* Avoiding transfers that separate the mother and her baby;
* The family's preference for relocation given the loss of existing social support networks.
While no national guides exist to help in obstetrical and neonatal transport decisions, Alberta Health Services have developed an "Obstetrical Transport Decision Tree" as part of their guideline *Criteria to Support Appropriate Level of Obstetrical Care*.[Footnote 72](#fn72)
### 6.4 Maternal Transport Policies and Procedures
Maternal transport plays an important role in ensuring that mothers in all regions have equitable access to the appropriate level of care for best mother and baby outcomes.[Footnote 68](#fn68) Barriers to successful transport of pregnant women include:[Footnote 68](#fn68)
* Lack of expertise in triaging pregnant women at high risk;
* Limitations of screening in populations at low risk;
* Lack of maternal transport capacity;
* Inflexibility in the criteria applied to assess referrals.
There are no Canadian national guidelines specific to maternal transport, which emphasizes the need for institutions to have written policies to follow when transferring and receiving a pregnant woman. The policies should describe:[Footnote 72](#fn72)
* Transport team members, skills required and responsibilities of both the sending and receiving sites;
* Transportation and equipment requirements;
* Mechanisms to measure quality assurance and system improvements;
* Communication and record sharing protocols.
Effective policies also emphasize a family-centred approach and include:
* Ongoing and open communication with the woman and her family about their circumstances so that they can actively participate in decision making;
* Continuous, supportive care from qualified personnel;
* Effort to keep family members together, with mechanisms in place for them to communicate with each other if they do have to be separated.
### 6.5 Neonatal Transport Policies and Procedures
Although best outcomes are achieved when transport occurs antenatally, some infants will inevitably need to be transported. As with maternal transport, it is critical that both the sending and receiving sites have in place policies and procedures to do with the transfer of a newborn. These would include describing the necessary personnel and equipment, communication, documentation, and sharing of medical documents (records, ultrasounds, blood tests). Having dedicated neonatal retrieval teams for transfer improves outcomes.[Footnote 59](#fn59)
Whenever possible, the newborn should be stabilized in the referring hospital prior to transport.[Footnote 74](#fn74) For neonatal stabilization, the Canadian Paediatric Society recommends that providers use Acute Care of At-Risk Newborns (ACoRN), an eight-step clinically oriented framework to gather and organize information, establish priorities, and intervene appropriately.[Footnote 75](#fn75) When deciding on a mode of transport, it is important to consider the physical stressors on the newborn. Newborns are particularly vulnerable to vibrations, and these need to be minimized during transportation to reduce further stress.[Footnote 76](#fn76)
The Canadian Paediatric Society recommends the following tools to use when making decisions about neonatal transport:[Footnote 59](#fn59)
| Tool | Purpose |
| --- | --- |
| Mortality Index for Neonatal Transportation (MINT) | * Produces a mortality prediction score for infants based on the information given to a retrieval service
|
| Transport Risk Index of Physiological Stability (TRIPS) | * Used to predict mortality at 7 days and overall using four weighted items: temperature, blood pressure, respiratory status, and response to noxious stimuli
|
| Risk Score for Transport Patients (RSTP) | * Differentiates infants requiring interventions en route from those who do not need these
* Has been proposed to aid triage
|
| Situation, Background, Assessment, Recommendations, Read-back (SBARR) | * Enhances communication and reduces errors
* Intended for use in hand-overs
|
| Transport metrics recommended by the American Academy of Pediatrics and a Canadian initiative | * Proposes expected transport times (mobilization, response, stabilization), noting that transport time depends on weather, distance, and mode of transportation, factors that are often out of the control of the transport team
|
The Canadian Paediatric Society's position Statement, *The Interfacility Transport of Critically Ill Newborns*, identifies components of a neonatal transport team, skills and training, equipment and vehicles, and systems and processes, emphasizing the importance of a family-centred approach to transfer. Refer to *The Interfacility Transport of Critically Ill Newborns* for recommendations on the personnel, equipment and vehicles, systems and processes, and quality assurance required to transfer newborns.[Footnote 59](#fn59)
### 6.6 Transport Personnel
Transport personnel require the collective expertise, technical skills, and clinical judgment to provide supportive care for the wide variety of emergencies that can occur during transport. Team members can include physicians, nurses, respiratory therapists, and emergency medical services (EMS), consistent with the expected level of need of the woman or newborn being transported.
For most transfers between hospitals, paramedics are the appropriate clinical care provider, but there are scenarios where, for clinical, logistical, and/or general supportive reasons, a midwife, physician, or nurse should travel with the patient–client.
In the case of neonatal transport, members of the transportation team require additional training to be able to stabilize the infant. If the infant has significant life-threatening instability, a neonatologist may accompany the transport team to help stabilize the infant.[Footnote 77](#fn77) The Canadian Association of Pediatric Health Care Centres (CAPHC) *Competencies Profile - Interfacility Critical Care Transport of Maternal, Neonatal, and Paediatric Patients* lists detailed competencies that cover a broad spectrum of requirements for clinicians engaged in transport.[Footnote 78](#fn78)
Alberta Health Services *Criteria to Support Appropriate Level of Obstetrical Care* and the Canadian Paediatric Society's *Interfacility Transport of Critically Ill Newborns* position paper outline core competencies of HCPs in maternal and newborn transport:[Footnote 59](#fn59),[Footnote 72](#fn72)
* Ability to monitor women, fetuses and neonatal vital signs, and infants, and to assess and respond to changing conditions;
* Ability to perform neonatal resuscitation and cardiopulmonary resuscitation (CPR);
* Ability to initiate and administer intravenous (IV) therapy;
* Ability to conduct an emergency birth;
* Flexibility, critical thinking, timely judgment, and problem-solving skills;
* Independent thinking;
* Good leadership and interpersonal communication skills, and appropriate crisis resource management skills.
### 6.7 Telemedicine
Within a regionalized model of care, telemedicine can help reduce avoidable transfers by connecting specialists with patient–clients.[Footnote 79](#fn79),[Footnote 80](#fn80),[Footnote 81](#fn81) For example, telemedicine has been used to assess retinopathy of prematurity in very low birth-weight newborns; for fetal ultrasonography and echocardiography; and to support families and provide education.[Footnote 82](#fn82) Neonatologist consultations via telemedicine have resulted in fewer interfacility transfers compared to telephone consultations.[Footnote 80](#fn80) A majority (93%) of providers who piloted telemedicine technology reported improved patient–client safety or quality of care.[Footnote 83](#fn83)
These findings are particularly important for rural and remote community residents who may be able to avoid long distance transports to tertiary care centres as a result of increased integration of telemedicine into networks of care.
7. Facilities and Equipment
---------------------------
Although there are many ways to support FCMNC, the physical design of birthing facilities plays a key role. Birthing environments designed through a family-centred lens take into account the experiences and preferences of mothers and families. Facilities can meet the needs of women and families while achieving the overriding objective of safety for families and staff.
It is important to ensure, however, that the philosophy of care is primarily supported by the people who provide care. If changes to the physical facility are desired, they are best accompanied by efforts to support and sustain the practice of HCPs. Design decisions can impact teamwork in the context of care. The physical setting is as important as technology in facilitating communication. The culture of communication is supported by spatial transparency (the importance of seeing other employees); the creation of a collaborative and/or shared workspace; and *neutral zones*, that is, spaces that belong to everyone and neither create nor reinforce hierarchies (as is the case in doctors' rooms vs nurses' rooms).[Footnote 84](#fn84)
FCMNC principles are critical to consider when planning and organizing the physical facility. These principles recognize that birth is a celebration and, in most situations, a normal, healthy process. Women and families can be supported in a friendly, comfortable single-room environment, where they labour, give birth, spend time with their babies, and are cared for, together, without the disruption of moving from place to place or being separated from their newborn (known as single room maternity care, or SRMC).
The focus on maternal and newborn care has shifted towards improving quality of care.[Footnote 85](#fn85) This takes into account respectful and appropriate care and considers the family's satisfaction with their experience.[Footnote 85](#fn85),[Footnote 86](#fn86),[Footnote 87](#fn87) The provision of respectful maternity care is in accordance with a human rights–based approach to reducing maternal and neonatal morbidity and mortality. The World Health Organization (WHO) recommends:[Footnote 88](#fn88)
* Effective communication and engagement of all HCPs and administrators in response to women's needs and preferences;
* Interventions that aim to contribute to a respectful and dignified birthing experience.
This approach to dignified maternity care recognizes that:
* The central objective of care for women, babies, and families is to assist women in giving birth to healthy babies, with appropriate facilities and equipment;
* Caring for women is best done in the context of their families, and families can be comfortably accommodated in the environment and feel part of the process;
* When difficulties arise, a critical objective is to help families be together as much as possible;
* Technology needs to be used appropriately.
An integrated design process means involving the facility community in making decisions so that the priorities of the people using the facility–HCPs, staff, patient–clients–are at the centre of planning. This process is referred to as *social design*. Social design recognizes that families have diverse sociocultural needs, depending on the characteristics of the community and of the individual family.[Footnote 89](#fn89) Attention to diversity, through direct input, can lead to a tailored approach to the needs of the community. For many Indigenous communities, for example, birth is a collective experience supported by Elders and other family and community members during labour and after the birth. This requires enough space in the birthing room to respectfully welcome the woman's support people alongside HCPs.
Changing population characteristics can also factor into design decisions. A salient example is the rise in obesity rates in industrialized countries.[Footnote 90](#fn90) Design decisions that accommodate this trend include making sure an adequate number of beds, chairs, examination tables, blood pressure cuffs, and specialized equipment such as lifts are available to accommodate women living with obesity. Design should also consider the space required for women and their HCPs to navigate comfortably and safely and to accommodate other family members.
Ultimately, patient–clients value being met by "a welcoming homely space for themselves and their visitors that promotes health and wellbeing."[Footnote 91](#fn91)
Changing patterns in access to health care, namely the decreased length of hospital stay, also need to be taken into account when planning FCMNC.[Footnote 92](#fn92),[Footnote 93](#fn93) Design should reflect increased needs for antepartum and postpartum outpatient spaces. This may include private consultation or infant feeding locations near labour and birth units.
Although periods of new construction or major renovation are opportune for integrating family-centred processes and refreshing dated-looking facilities, existing spaces can also be improved using fewer resources. Examples include:
* Having showers for pain management instead of renovating to install birthing tubs;
* Using conventional hospitalbeds if no funds are available for special birthing beds;
* Using labour rooms for labour, birthing, and recovery;
* Expanding unit boundaries for walking during labour.
Other items, such as birthing balls, birth stools, rockers, sleeping chairs for partners, and decorative items that soften the environment, can be purchased at minimal expense. But design considerations extend beyond the birthing room to include continuous care, beginning with the birthing woman and family entering the facility.
Recognizing that FCMNC applies to all care environments, it is important to integrate family-centred design principles into all perinatal environments, including NICUs. In addition to meeting the newborn's physical needs, NICUs can support the psychosocial needs of the infant and their family.[Footnote 94](#fn94) In particular, design principles can help HCPs and families share the decision making and enable parents to be their baby's primary caregiver.[Footnote 95](#fn95) Single-family NICU rooms have a number of benefits, supporting families to make choices in the environment (by, for example, adjustinglighting, temperature, noise); improving rates of breastfeeding; and reducing parental stress and anxiety, particularly for those families that may be far from home for a prolonged hospital stay.[Footnote 95](#fn95)
Best practice standards for the design of a NICU also recommend a family library or education area, with information about NICU procedures, infant loss and grieving, and local resources.[Footnote 96](#fn96)
### 7.1 Phases of Care
Comprehensive maternal and newborn care encompasses a number of different phases. Facilities that incorporate such care can include a triage area for women who are not yet in active labour or are being observed to determine whether labour has begun. Some facilities will provide care for women requiring hospitalization during pregnancy, usually referred to as an antenatal unit.
According to guidelines established by Perinatal Services BC, the labour, birthing, and postpartum space is designed to avoid relocating the mother, utilizing SRMC. SRMC increases patient–client satisfaction, and can reduce infection rates, length of hospital stays, the number of staff positions, and direct costs.[Footnote 97](#fn97),[Footnote 98](#fn98),[Footnote 99](#fn99) Nurses have also expressed greater preference for single-room maternity care in terms of the physical settings, their ability to respond to family needs and teach families, the nursing practice environment, peer support, and perceived level of competency.[Footnote 100](#fn100) Their satisfaction was significantly higher than that of their colleagues in standard room settings. Although the goal of a complete hospital stay in a single room may not be possible for some existing buildings, reducing the number of relocations during a course of care could be achieved without infrastructural change.
If a caesarean birth is necessary, the woman is transferred to an operating room, and then returns to the same maternity/newborn unit.[Footnote 101](#fn101) Ideally, the operating room and recovery area are both within the maternal and newborn care area.
In the context of the COVID-19 pandemic, having a large number of single-family rooms in a NICU decreases the need for more restrictive parental presence policies, allowing families to stay together.[Footnote 102](#fn102)
### 7.2 Design Principles and Design Process
The functionality of space is determined by users or occupiers of that space. To enhance FCMNC, it is key to think about how women and families will experience the space. The following points are useful to consider:
* How do families find their way to the unit?
* What are the first impressions of families arriving at the hospital and on the unit?
* Is there adequate affordable parking next to the entrance? Is the walk-in entrance clearly marked?
* Does the unit have private areas where families can talk to staff, talk on the phone, or be together?
* Are there play areas for children?
* Is there a secure storage area for the family's belongings and dietary supplements (fridges, coffee/tea facilities)?
* Are there conference rooms, work areas, and lounges available for staff members?
* Are the surroundings warm and inviting? Is it clear that this is a place for families?
Mapping tools and three-dimensional (3D) modelling can maximize efficiencies in the design phase. Making a facility more family-centred without capital expenditure can be accomplished by carefully selecting interior colours, furnishings, finishes, and lighting to contribute to the comfort of the environment. In addition, facilities can incorporate relevant art work, murals, quilt work, and other decorative features that depict culturally diverse and inclusive representations of families. They may also offer services that promote FCMNC principles such as sibling tours and activities, nourishing snacks or meals as alternatives to food from the hospital kitchen, and personalized messages in families' rooms.[Footnote 103](#fn103)
**HSC Winnipeg Women’s Hospital**
The HSC Winnipeg Women's Hospital opened in December 2019 with a vision "to serve the unique and diverse health care needs of women through the life cycle, newborns and families on their journey of health, hope and healing." It also set out to "advance care through excellence in research and education to enable and support caregivers in their quest for safe, effective, innovative, compassionate and holistic care while being sensitive to women's lived experience" and to be a place "that is welcoming, respectful, calming and peaceful."[Footnote 104](#fn104)
Guiding principles included striving for safety, prioritizing patient–client experience, engaging in consultation, ensuring staff involvement, and striving for a high quality and healthy indoor environment and positive neighbourhood integration. Women and family-centred care were key guiding principles, with family-centred care emphasizing a "model that is about providing respectful, compassionate, culturally responsive care that meets the needs, values, and preferences of patients and their family members."[Footnote 104](#fn104)
The design process was an integrated one, based on collaboration and communication with a wide range of key stakeholders. This resulted in ensuring places for family respite, places for family at the bedside, places to gather and spiritual spaces.
Closely associated with a process for space design is the need for a *change management plan* to guide the transition from the existing space to the new environment and to encourage positive models of interaction between personnel and families in a new context. Although the physical layout of antenatal wards can encourage or hinder FCMNC, it is essential to recognize the influence of *culture* on such care and the importance of relationships as building blocks to a culture that encourages placing the birthing woman and her family at the centre of care.
### 7.3 Hospital Births: Prenatal, Antepartum, Birth, and Postpartum Facilities
Facilities that are 'patient-friendly' have easily accessible and usable layouts that allow for movement, communication, and connection between family members.[Footnote 91](#fn91) It is important to have adequate planning and space for independent and assisted wheelchair users throughout each of the antenatal, birth, and postpartum facilities.[Footnote 105](#fn105) Adequate storage space for handling aids, such as lifts and wheelchairs, is also needed.[Footnote 106](#fn106) Privacy is a very important aspect of care; it can be established and maintained through high levels of sound isolation and window drapes in all facilities.[Footnote 106](#fn106)
The International Health Facility Guidelines and the Canadian Health Care Facilities *CSA Z8000-18: Planning, Design and Construction* and other guidelines provide recommendations for the design and equipment in labour and birth units.[Footnote 106](#fn106),[Footnote 107](#fn107)
#### Recommendations for design and equipment
**Antepartum Inpatient Units and Home Care**
Women who need to be hospitalized during their pregnancy because of complications related to themselves or their babies are cared for in antepartum units.
Design recommendations for antepartum inpatient units include interventions to reduce sleep disturbance, for example, using a laminated door sign with sticky notes to write the mother's preferred wake time; and providing white noise machines, eye masks and ear plugs to facilitate sleep.[Footnote 108](#fn108)
Some jurisdictions provide antepartum home care for women with certain complications of pregnancy. A home care nurse visits regularly to conduct assessments and provide education based on the mother's needs. The goal of antepartum home care is to support families at home and reduce the number of hospital admissions.[Footnote 109](#fn109) Research out of BC Women's Hospital has shown that antepartum home care results in improved psychosocial outcomes and reduced costs for the system.[Footnote 110](#fn110)
**Entry/Reception Area**
An entry/reception area with a welcoming and informal atmosphere, public amenities and waiting areas for families is ideal. Clear access to admitting personnel is important.[Footnote 111](#fn111) The area should be monitored to prevent unrestricted access and to optimize safety.
**Triage/Early Labour Lounge**
WHO recommends delaying admission to a labour ward until active first stage. Such a delay decreases the likelihood of intervention to accelerate labour.[Footnote 112](#fn112) However, there may be instances when the risks of return travel outweigh the benefits of being at home, for example, if the labouring mother has far to go to get home and back again or if the weather makes travel unsafe. An early labour lounge provides a safe space for women and their families to be comfortable.
Design considerations for early labour lounges include handwashing stations, showers, areas for exercise and walking, a separate quiet lounge, and a nutrition station with light snacks and beverages.[Footnote 106](#fn106),[Footnote 113](#fn113)
**Labour/Birthing/Postpartum Room, or Single-room Maternity Care**
Ideally, women labour, birth, and stay in one room after the birth. This space may have multiple functions, for example, resuscitation, stabilization, observation, examination, etc., depending on the infant or mother's needs.
Regardless of the size of the room, the birthing mother should be supported in her choice of labouring position and mobility. A non-clinical ambience promotes relaxation, with the surroundings playing an important role in helping produce oxytocin during labour.[Footnote 106](#fn106),[Footnote 114](#fn114) Ideally, each room is equipped with a private toilet, shower/tub, and a window with an outside view.
The birth environment not only impacts the woman's birthing experience and her and her newborn's outcomes, it also affects the woman's birth supporters and maternity care staff.[Footnote 114](#fn114),[Footnote 115](#fn115),[Footnote 116](#fn116),[Footnote 117](#fn117) Control over the environment of the room (e.g., the lighting, temperature, freedom to close or open the door) and freedom of movement, in particular, promote the woman's and her family's overall comfort, suggesting that families could benefit from having a variety of options in how their room is set up and bring additional supplies from home to improve overall comfort.[Footnote 118](#fn118)
*CSA Z8000 Canadian Health Care Facilities – Planning, Design and Construction* includes a list of the equipment recommended for SRMC. Each birthing room needs:[Footnote 106](#fn106)
* Separate oxygen, air, and suctioning facilities; easily accessible gas outlets (which may include nitrous oxide); and wall-mounted equipment, although this may be covered;
* Natural and/or indirect lighting for labour and an adequate light source for medical procedures;
* An emergency power source;
* Smoke detectors;
* A telephone with an outside line;
* A nursing call system with data outlets and call buzzers near the bed and in the bathroom.
**Operative Birth Room**
The operative birth room is used for caesarean births, for situations of risk to the mother or baby, or when a complication is expected or in process. In keeping with infection control guidelines, operative birth rooms should be in a restricted area near to birthing rooms. Operative rooms should also be in close proximity to the NICU.[Footnote 119](#fn119)*CSA Z8000 Canadian Health Care Facilities – Planning, Design and Construction* includes a list of the equipment needed for an operative birth room, for example:[Footnote 106](#fn106)
* Each operative birth room should be at least 60 m2 in size, with an adjacent scrub area.
* Space for resuscitation and other care of the baby should be in a separate part of the operative birth room or in a room immediately adjacent (see "Infant Resuscitation Area").
* Any room functioning as an operative birth room should contain or have immediately available all the equipment necessary for the birth area.
* The room may have a bed with stirrups and retractable base, or a birthing bed.
* There should be separate wall suction and oxygen for mother and baby.
**Postpartum Mother/Baby Rooms**
If single-room care is not available, the mother and infant should still stay together after the birth. Design requirements for postpartum FCMNC include:
* A comfortable bed for the mother and a self-contained bassinet for her baby with capacity for a 24-hour supply of infant needs;
* A sleeping surface for a support person;[Footnote 106](#fn106)
* Handwashing facilities in each room, and a toilet and shower in or next to each room;
* A refrigerator and freezer to store expressed breastmilk;[Footnote 103](#fn103)
* An over-bed table and light, and a bedside cabinet;
* Storage space for supplies and laundry;
* A rocking chair;
* A telephone with an outside line;
* A television/monitor for educational purposes.[Footnote 103](#fn103)
**Infant Resuscitation Area**
A resuscitation area may be needed if a baby requires medical intervention or monitoring, as the importance of not separating mothers and babies is well established (WHO, 2018) and the mother and/or her partner should remain at the baby's side.[Footnote 112](#fn112)
While there are no Canadian guidelines, the American *Recommended Standards for Newborn ICU Design* recommends a resuscitation area of 13.0 m2 for each bassinet to accommodate the staff and equipment necessary for resuscitation and stabilization. A resuscitation area for two babies (at minimum) should be considered in order to accommodate multiple births.
Each resuscitation area requires the following:[Footnote 119](#fn119)
* A handwashing facility;
* A counter/workspace;
* Medical gas supply;
* Lights on separate switches;
* Privacy for each mother–baby dyad or family;
* Supplies and resuscitation equipment (these may be stored nearby);
* An overhead infant warmer.
**Neonatal Intensive Care Units (NICUs)**
Single-unit NICUs are optimal for providing families with the privacy and support they need.[Footnote 96](#fn96),[Footnote 120](#fn120) Separating mothers and babies is often the result of space limitations and habitual hospital practices. NICUs are increasingly being redesigned to move away from the open bay concept and towards single-room care with space to accommodate the parent(s) 24/7; this also lets parents provide a significant amount of care for their baby.
While there are no Canadian guidelines on NICUs, the American *Recommended Standards for Newborn ICU Design* recommends:[Footnote 119](#fn119)
* No less than 13.9 m2 [150 square feet] of clear floor area, excluding handwashing stations, columns, and aisles;
* A hands-free handwashing station;
* A design that gives the family privacy;
* An unobstructed adjacent aisle not less than 2.4 m (8 feet) wide for passage of personnel and movement of equipment;
* At minimum, a comfortable reclining chair to promote skin-to-skin contact, a desk or surface for writing or for a laptop, and no less than 0.17m3 (6 ft3) of storage space;
* Low sound levels in infant rooms.
### 7.4 Home Births and Birthing Centres
Increasing access to midwifery care across Canada since 1992 has led to an increase in the number of home or out-of-hospital births attended by registered midwives. Home birth is safe for low-risk women likely to have uncomplicated vaginal birth.[Footnote 121](#fn121),[Footnote 122](#fn122) For some women, birthing at home may be the epitome of FCMNC, as labour and birth occur in a familiar and intimate environment attuned to the needs of the woman and her family.
Although each jurisdictional midwifery association has requirements, set in guidelines, for a safe home birth, there are few restrictions on the size of the home beyond having enough room for the birthing woman to lie down and for midwives to be able to assist her and set up their equipment.[Footnote 123](#fn123) A midwife will visit the home during the prenatal period to make sure it is suitable for a home birth and to determine the distance to hospital services and the best access for emergency medical services (EMS).
In some jurisdictions, out-of-hospital births can take place at birthing centres. These regulated community-based health care facilities support birthing for women at low risk of needing specialist support. Birthing centres may be free-standing or part of a larger health care facility. They are generally staffed by midwives, although in some jurisdictions physicians may also play a role. Many birthing centres are designed with open or multi-use spaces to facilitate labour and birth as well as individual and group prenatal care and postpartum, breastfeeding, and educational groups.
Birthing room décor may vary from home-like environments with wood furniture and standard double beds to a more institutional style that has hospital-grade furniture and beds. Many birth centres offer water birth. The design of birth centres is specifically targeted to be a counter-point to institutional settings or traditional hospital care.
### 7.5 Metrics for Facility Design Evaluation
Design decisions affect costs, operations, and performance, and effective design of health care facilities incorporates a sociotechnical approach; that is, one that combines human with technical elements.[Footnote 124](#fn124),[Footnote 125](#fn125) In recent years, Lean principles have been adopted widely in hospital design in order to reduce waste and fully utilize the capabilities of personnel.[Footnote 124](#fn124),[Footnote 126](#fn126) The "Lean 3P" (production, preparation, process) takes into account people, products, and processes in the design of facilities.[Footnote 124](#fn124) Lean principles include "understanding user value, mapping value-streams, creating flow, developing pull processes and continuous improvement."[Footnote 84](#fn84), p.1 Two recent studies out of England applied these principles to the design of a new endoscopy unit and a new maternity ward.[Footnote 124](#fn124),[Footnote 127](#fn127) Both research teams found that 3P is an effective tool for developing facility designs that meet the requirements of multiple stakeholders.[Footnote 124](#fn124),[Footnote 127](#fn127)
The move towards evidence-based environmental design requires establishing metrics to evaluate the design. This includes tracking and evaluating the role of the physical design in clinical outcomes and improvements in indicators such as economic performance, employee productivity, and family satisfaction.[Footnote 128](#fn128) In addition to site-specific metrics, post-occupancy evaluations provide useful data to iteratively adapt the design to meet the needs of women and families.
Some jurisdictions are now mandating that health care redevelopment projects include a post-occupancy evaluation. Although such projects vary in terms of size, scale, location, and purpose, relevant evaluations can be standardized using toolkits.[Footnote 129](#fn129)
8. Implementing the Guidelines: Facilitating Change
---------------------------------------------------
Jurisdictions across Canada have shifted towards patient-and family-centred care as a way of increasing responsiveness to community needs in health care. Intended effects include improving measurable health outcomes, such as access to primary care; improving patient-client satisfaction with the care they receive; and reducing hospital wait times.[Footnote 130](#fn130),[Footnote 131](#fn131),[Footnote 132](#fn132) Explicit jurisdictional commitments to family-centred care is also taking place internationally.[Footnote 133](#fn133) These changes are supported by a restructuring process that prioritizes adapting the health care system to individuals' and communities' needs and preferences, rather than requiring people to adapt to the system. The core tenant is respect for people's values, preferences, and expressed needs.[Footnote 134](#fn134)
The following principles of family-centred care are particularly important to maternity care:
* Education and knowledge, on which care decisions can be made;
* Commitment to the family's full participation in decision making and in advocating for the birthing woman;
* Collaboration and team management to foster continuity through the care pathway;
* Sensitivity to cultural and spiritual dimensions of birth;
* Respect for patient–client needs and preferences to recognize individual values and beliefs;
* Access to information so that patient–clients participate in informed decision making;[Footnote 135](#fn135)
* An understanding that pregnancy and birth are normal physiological events that have the potential for pathologies and unexpected events;
* Recognition of the importance of meeting the psychological needs of women and their families throughout the childbearing year.
A culturally competent, family-centred care framework applies to three levels: the individual level, the hospital level, and the health care system level. The SRMC approach, for example, reflects best practices from the perspective of the mother and family. Prioritizing such *process* measures when evaluating care reinforces a family-centred perspective by re-framing the care pathway through the eyes of the mother and family.
### 8.1 Patient–client Engagement
Public engagement rooted in respect for patient–client voices in health care design and planning is one way to achieve family-centred care. Such engagement extends beyond capturing patient–clients' perceptions of care and involves the input of members of the public in strategic decisions about health services and policies.[Footnote 136](#fn136) Clear operational definitions of *public* and their role remains unclear. The public "wants input particularly in prioritisation processes across broad service areas, including development of the criteria on which funding decisions will ultimately be based", but there is a lack of a clarity of how citizens and patient–clients can contribute to this prioritization process and to transforming health care and improving maternity care.[Footnote 93](#fn93),[Footnote 137](#fn137),[Footnote 138](#fn138)
The widely used *IAP2 Spectrum of Public Participation* was developed to help define the public's role in any public participation process.[Footnote 139](#fn139) The continuum, representing categories of increasing impact on decision making, moves between activities to inform, consult, involve, collaborate, and empower citizens.
IAP2's Spectrum of Public Participation[Footnote 139](#fn139)| | Inform | Consult | Involve | Collaborate | Empower |
| --- | --- | --- | --- | --- | --- |
| **Public participation goal** | To provide the public with balanced and objective information to help them understand the problem, the alternatives, the opportunities, and/or the solutions. | To obtain public feedback on analysis alternatives and/or decisions. | To work directly with the public throughout the process to make sure that public concerns and aspirations are consistently understood and considered. | To partner with the public in each aspect of the decision making, including developing alternatives and choosing the preferred solution. | To place decision making in the hands of the public. |
| **Examples of methods of engagement** | * News releases
* Fact sheets
* Websites
* Open houses
* Ads/flyers
* Info hotlines
* Talk shows
| * Websites
* Focus groups
* Surveys
* Public/small groups meetings
| * Workshops
* Roundtables
* Deliberative polling
* Public/small group meetings
| * Advisory committees
* Partnerships
* Consensus building
* Participatory decision making
| * Citizen juries
* Ballots
* Delegated decisions
* Service contracts
|
Enhanced care and improved service delivery occur when the public is effectively engaged.[Footnote 140](#fn140),[Footnote 141](#fn141) The success of patient–client engagement processes relies in a large part on the effectiveness of the health care culture in shifting from a largely hierarchical and top-down model to one where power is shared or is neutral across patient–clients and providers.[Footnote 142](#fn142) Since such a shift requires considerable energy and time to implement, success also relies on it being well-supported within the organizational structure and culture of the health care setting.
### 8.2 Supporting the Culture of Family-Centred Maternity and Newborn Care
A supportive organizational culture is key to transforming a system.[Footnote 143](#fn143) Establishing and supporting a new paradigm for maternity care requires the sustained application of FCMNC principles and building on any initial structural changes made to the health care system. Once areas for positive change have been identified, the following strategies will help to create and sustain cultural and organizational change:
* Aligning vision and action: Connecting the vision and the action requires structural change through all levels of an organization (resource allocation plans, budget decisions).[Footnote 144](#fn144)
* Making incremental changes: Although system and policy-driven change provides the necessary framework to support widespread changes, small and incremental shifts can accrue, leading to significant, overarching improvements.[Footnote 145](#fn145)
* Fostering distributed leadership: System- or hospital-wide change is a "wicked problem," that is, a problem characterized as having no single solution or resisting resolution due to incomplete or contradictory viewpoints.[Footnote 146](#fn146) Practically, this means that health care system change is a problem that cannot be solved in organizational isolation, but requires shared leadership and responsibility and the commitment to shared decision models to reduce organizational fragmentation.[Footnote 147](#fn147)
* Promoting staff engagement: Sharing in the decision making by involving all levels of personnel through focus groups, unit-level improvement teams, brainstorming sessions, rapid results feedback of completed small-scale projects, on-site visits, teleconferences, and individual consultations.[Footnote 147](#fn147) Although time intensive, authentic outreach underscores meaningful solutions.
* Creating and fostering collaborative interpersonal relationships: At a hospital level, mechanisms to encourage collaboration among members of the health care team with different roles and responsibilities facilitate a culture of collaboration essential to sustaining necessary structural changes. Collaborative relationships are supported in many ways, such as "through the creation of task forces, problem-specific committees or learning groups that support collaborative action, with time allocation and reward structures that encourage participation from a broad range of stakeholders."
* Paying attention to context: System changes can elicit concern and even anxiety about professional livelihood. Processes are needed to support staff and sustain engagement in iterative feedback about the consequences of change, some of which may be unintended. It is essential to ensure policies are in place to respond to workers' concerns.[Footnote 148](#fn148)
9. Evaluation of Care
---------------------
The lack of consensus definitions and the organizational differences across provinces and territories have hindered pan-Canadian data analysis. While collecting national data is difficult, its dissemination and utilization can also be problematic. In particular, privacy concerns may constrain the analysis of subgroups of databases (for example, mothers requiring specialized or intensive care or NICU admissions). But such analyses are crucial towards effectively understanding the personal and clinical needs of higher-risk segments of the population. A balance needs to be achieved between privacy considerations and the effective provision of maternal and newborn care services (e.g., access to anonymous or aggregated data).
Successful implementation of FCMNC calls for an efficient, reliable and timely system that evaluates clinical care outcomes and also learns how women and their families perceive their maternity experiences.
Evaluation of care involves carefully documenting both process and outcome indicators. It also involves thoughtful review and analysis of the information within an anonymous reporting structure to ensure full disclosure in order to actualize improved care.
Evaluating maternal and newborn care is often considered the responsibility of regional and national organizations. Each unit and service provider, however, should participate in the evaluation to determine success in ensuring accessible, appropriate, and affordable care for mothers, babies, and families. Local multidisciplinary maternal and newborn committees fulfill this function. High-reliability organizations (HROs) are those that "achieve safety quality and efficiency goals by employing five central principles: (1) sensitivity to operations (i.e.,heightened awareness of the state of relevant systems and processes); (2) reluctance to simplify (i.e., the acceptance that work is complex, with the potential to fail in new and unexpected ways); (3) preoccupation with failure (i.e.,to view near misses as opportunities to improve, rather than proof of success); (4) deference to expertise (i.e.,to value insights from staff with the most pertinent safety knowledge over those with greater seniority); (5) and practicing resilience (i.e.,to prioritize emergency training for many unlikely, but possible, system failures)".[Footnote 149](#fn149)
Evaluation of care can include:
* Continuous quality improvement (CQI), which involves feedback and audit activities including goal-setting, determining appropriate measurement of goals, identifying gaps in care, incorporating patient–client feedback, and undertaking regular practice audits;
* Regularly reviewing policies and procedures based on current information;
* Staff training and education and parents' education and learning;
* Assessing outcomes, including reviewing maternal and newborn mortality, major morbidity, and significant incidents; and conducting epidemiologic analyses;
* Assessing use of hospital services and resources;
* Assessing the mother's and baby's integration into the community, including breastfeeding support;
* Requesting mothers' and families' feedback and assessing their satisfaction with their perinatal care;
* Assessing commonly used investigations or treatments and investigating the mechanisms of disease and/or prevention.
Each unit should have in place a written policy that describes the evaluation methods currently in use and a mechanism by which new evaluations may be approved for use.
### 9.1 The Importance of Continuous Quality Improvement
CQI in health care is a mechanism for thinking about the processes and outcomes of comprehensively assessed quality. A key attribute of CQI for FCMNC is the development of indicators or measures that are important to all key stakeholders—including women and families. Ensuring that these shared measures are valid and the outcomes useful for improving health care requires active engagement with women and families to learn about their experiences. CQI or evaluation frameworks can be developed on the basis of HCPs documenting these experiences of care.
Ideally, the process evolves iteratively as new data and new models of care are implemented, enabling system course correction as parts of the care pathway require adjustment. Since one size does not fit all, decision-makers will want to build flexibility into their CQI and evaluation frameworks, respecting the contextual differences between settings in terms of how FCMNC is implemented. The systematic application of site-specific, relevant, and family-informed measures leads to quality improvement processes that will guide the maturation of FCMNC in Canada.
Achieving family-centred care depends on authentically involving women and families who receive such care, and asking them to articulate what care is like and how to measure success in care. The resurgence of midwifery in Canada is an example of responding to patient–client care preferences–it attests to the fundamental tenet of informed decision-making and to the capacity of clients to create an environment that directly reflects their needs through home birth. In the hospital setting, the commitment to implementing FCMNC principles is growing, along with an openness towards this care being directed by those receiving it.
As a measure of quality of health care services, indicators can help to support improvement and accountability.[Footnote 150](#fn150),[Footnote 151](#fn151) A systematic literature review evaluating the provision of maternal and child health internationally identified 87 key indicators in categories such as preventive activities, diagnostic and/or screening tools, treatment activities, maternal mortality, maternal morbidity, child mortality, and child morbidity.[Footnote 151](#fn151) In Canada, perinatal health indicators (PHI) are grouped into four key health domains: health behaviours and practices, health services, maternal outcomes, and infant outcomes.[Footnote 152](#fn152)
The range of indicators applied both nationally and internationally underscores the contextual nature of markers of quality and safety in maternity care and emphasizes the importance of applying a nuanced approach when considering the social determinants of access to family-centred perinatal care. Furthermore, the broad range of maternal and health indicators in the literature underscores the importance of well-integrated, interprofessional collaboration including with those with expertise in mental health and diet/nutrition. This conclusion is supported by the Global Affairs Canada *Evaluation of the Maternal, Newborn and Child Health Initiative (2010-11 to 2017-18)*. This 2019 evaluation found that there is a need for "more emphasis on an integrated, multi-sectoral approach to further address determinants of health…".[Footnote 153](#fn153)
10. Planning for Pandemics
--------------------------
The principles of FCMNC can help inform decision making, practice, and policies during a pandemic. Adhering to the values of FCMNC is even more important when stressors are intensified and the need to feel connected and supported increases. However, certain pandemic-related hospital protocols, such as restricted access to visitation, pose barriers to family involvement during hospitalization. To address these challenges, it is essential to clearly explain the policies and mechanisms for nonphysical communication between family members.[Footnote 154](#fn154) The Institute for Patient- and Family-Centered Care recommends describing changes to policies using patient- and family-centred language. The language of partnership–including the tone, words used, and messages provided–helps communicate the essential role family members play.
If isolation becomes essential during labour and birth, hospitals can use virtual platforms to keep families informed about the mother and baby's progress. An impediment to this is a lack of adequate Internet access or the tools or resources for videoconferencing or long-distance calling. A workaround might be to issue patient–clients with a smartphone with low-cost or free Internet or prepaid calling cards. This would also allow patient–clients and family members to access translation services virtually.[Footnote 154](#fn154) At the same time, it is important to recognize the available capacity of HCPs to implement new tools/technology and to distribute limited resources.
In the past two decades alone, jurisdictions around the globe have contended with Severe Acute Respiratory Syndrome (SARS, 2003), novel H1N1 influenza virus (H1N1, 2009), Middle East Respiratory Syndrome coronavirus (MERS-CoV, 2013), the Ebola outbreak (2014-15), and the COVID-19 pandemics.[Footnote 155](#fn155) Global ecological conditions will give rise to more pandemics.[Footnote 156](#fn156) Common to all outbreaks is a surge in cases that require coordinated public health measures to reduce the burden of morbidity and mortality and avoid overwhelming health care resources.
Pandemics have implications across all population segments, including pregnant women and families, and a coordinated approach requires evidence-based planning.[Footnote 157](#fn157),[Footnote 158](#fn158),[Footnote 159](#fn159),[Footnote 160](#fn160),[Footnote 161](#fn161) Fundamental to any response is the development of clinical service models based on containing cross-infection.[Footnote 159](#fn159),[Footnote 160](#fn160),[Footnote 162](#fn162),[Footnote 163](#fn163),[Footnote 164](#fn164),[Footnote 165](#fn165) In maternity care, this can be accomplished in existing maternity wards and through temporary auxiliary maternity units to address hospital surge capacity.
Within the context of pandemic response, the psychological needs of the birthing mother and her family take on heightened importance. Isolation measures may increase the potential for intervention in labour and separation of newborns from their mothers (providing significant challenges to establishing breastfeeding). Potential effects on patient–client and family care can be mitigated by improving the focus on family supports during birth. This includes increasing the use of and access to midwives, allowing for even more women to give birth at home, away from hospital settings where such extreme restrictions are more likely to occur. As pandemics are predicted to be increasingly common in future, planning for them now is essential.
### 10.1 Pop-up Maternity Units
Although there are no Canadian guidelines on the use of pop-up maternity hospitals, the *Guidelines for Auxiliary Maternity Units* from the USA recommend expanding midwifery units (both in and out of hospital) to mitigate potential overloads in hospital capacity. The guidelinesdescribe the scope of services that such units could offer.[Footnote 162](#fn162) The *pop-up* units can be efficiently constructed to meet the needs of low-risk pregnant and labouring women who remain supported by a multidisciplinary leadership team (midwifery, obstetrics, neonatology and nursing).
Patient–client inclusion criteria are as follows:[Footnote 162](#fn162)
* Gestational age limited to between 36+0/7 and 42+0/7 weeks;
* Singleton pregnancy;
* Cephalic presentation;
* No hypertensive disorders, even if characterized as mild or controlled;
* No maternal or fetal/neonatal conditions that would exceed the capacities of the unit;
* Identification of patient–clients prior to the onset of birth.
In case patient–clients need greater levels of care, there should be in place:[Footnote 162](#fn162)
* A pre-arranged plan for the availability of obstetrical and neonatal telephone consultation and acute care services, 24/7;
* A pre-arranged plan for the emergent and non-emergent transfer of the mother and/or her newborn, 24/7.
Refer to the *Guidelines for Auxiliary Maternity Units* for specific requirements of temporary maternity units.[Footnote 162](#fn162)
10.2 Considerations for Hospital-based Care
-------------------------------------------
In terms of pandemic preparation, the most common challenges in maternity units tend to be high patient–client turnover, coordination of staff and supplies, ethical distribution of limited medical resources, and coordination with government agencies.[Footnote 158](#fn158),[Footnote 164](#fn164) All hospitals can plan for future pandemics and other emergencies by optimizing backup communications and their response to surge capacity, preparing for potential service degradation, and stockpiling and supply-line planning.[Footnote 158](#fn158) Other important considerations for hospital-based care include early identification of cases in the community to allow for isolation at home and appropriate triage to hospital care when necessary.[Footnote 159](#fn159) Whenever possible, hospital stays should be shortened and postpartum appointments offered by way of telemedicine [Footnote 158](#fn158).
Guidelines and recommendations during a pandemic are quick to change as patterns of infectious disease transmission evolve and research-based knowledge becomes available.[Footnote 166](#fn166) The public requires and deserves that new information about best practices for containment and treatment be provided as it becomes available to increase their awareness and change their behaviours and help prevent disease spread.[Footnote 167](#fn167)
### 10.3 Health Care Provider Considerations
It is particularly difficult for maternity care providers to prevent the spread of contagions because of their close contact with women in labour.[Footnote 161](#fn161) This may affect providers' mental wellbeing—along with the potentially increased workload despite reduced contact with patient–clients (because of shortened antenatal visits, increased use of virtual care, and reduced non-urgent consultation); shortages of personal protective equipment (PPE); and the physical discomfort of using such equipment.[Footnote 168](#fn168) HCPs may also experience increased emotional output because of their role in supporting labouring women in the absence of partners or other support people as a result of hospital restrictions. In addition, providers may feel anxious about spreading infection to their own family members and choose to self-isolate while in clinical practice. They may also be feeling the mental distress of emotionally and ethically fraught decision-making around resource allocation.[Footnote 169](#fn169)
Data from the 2003 Severe Acute Respiratory Syndrome (SARS) outbreak and early research from the COVID-19 pandemic support the claim of increased anxiety, stress, and fear among HCPs.[Footnote 168](#fn168) No doubt, supporting providers during a pandemic is vital for sustaining a healthy workforce. Ways to reduce burnout and support providers experiencing emotional distress include:
* Having psychologists on staff to mitigate stress and reduce burnout;
* Screening for mental health problems and providing psychoeducation[Footnote 169](#fn169);
* Leveraging technology for the delivery of psychosocial supports;[Footnote 168](#fn168)
* Amending policies to facilitate healthier lifestyles (getting enough sleep, exercise and eating a healthy diet);
* Facility-level supports for decompression (for example, on-site exercise rooms and self-care stations along with opportunities for debriefing).
### 10.4 Patient–client Considerations
Understanding the complex ways in which pandemics shape the experience of pregnancy, birth, and the postpartum period is fundamental to providing appropriate family-centred care. Larger society-wide stresses may be easily magnified for the birthing family. The fear of contracting the virus and what that would mean for the health of the mother, baby, and family, of potential separation of family members, of the mother labouring alone or of partner's grief about missing their child's birth affect the birthing experience. Early data from the COVID-19 pandemic point to high levels of stress and anxiety causing or amplifying mental health concerns because of the fear of contracting the disease and the impact of physical isolation on birth plans and the birthing experience.[Footnote 169](#fn169),[Footnote 170](#fn170) One-on-one, continuous support during labour can mitigate the stress and its effect on the health of mothers and babies.[Footnote 171](#fn171)
Reducing time in the hospital (extending early labouring at home) and the number of support people are strategies that could be adopted in the development and planning of care in future pandemics.
Finding a new provider proximal to where the family lives to minimize potential travel-related exposure would also be a consideration.[Footnote 172](#fn172) Women and their families need to understand all the options where they can give birth, and the risks and benefits associated with each given their specific circumstances. Keeping women and families safe during a pandemic is best achieved by balancing public health protocols with quality evidence-informed care and human rights agendas that adequately consider the concerns of the birthing mother and family.[Footnote 173](#fn173)
The autonomy of birthing women is the highest ethical principal in childbirth and fundamental to actualizing FCMNC.[Footnote 174](#fn174) This includes autonomy in decisions about where to give birth and choice of provider and supports. This core principle is challenged when public health emergencies make individual choice subservient to the safety of the population. In these instances, decision making is guided by the harm principle, or "the justification for a government, or government agency, to take action to restrict the liberty of an individual or group" to protect others.[Footnote 175](#fn175) Restricting liberties, when applied to maternity and newborn care in a pandemic, may include limiting support people in the birthing room, restricting ambulation in labour to a confined area, or unintentionally depersonalizing providers due to the need for PPE. Despite the difficulty of maintaining a family-centred focus while observing public health restrictions, reinforcing the normalcy of birth is essential. This involves ongoing, transparent communication with the birthing mother and family about protocols that may seem constricting, with an emphasis on the goal of a healthy mother, baby, and family.
Conclusion
----------
Over the past several decades, patient- and family-centred values and preferences have emerged as a guiding principle in maternity care and all health care in Canada. Organizing patient-centred care means health planners and providers can be more responsive by working in partnership with those they serve. This can be done at the individual level where birth is low risk, during acute situations where emergency protocols are in place to address an immediate clinical risk to the mother or baby, or where a larger societal risk exists, such as in a pandemic.
Such patient-centred thinking can be carried through the care pathway to mitigate the stress families in rural and remote areas may feel if they need emergency transport from their communities to a larger centre. Similarly, patient-centred care enhances the experience of Indigenous women and families by safely supporting the cultural practices of their choosing.
Patient-centred care can also be applied at the level of a facility by planning a physical environment that enhances principles of patient–client and family choice, autonomy, and respect. This can include, for example, single-room maternity care, the support of a partner's full involvement, and awareness of cultural inclusion in the surroundings. Introducing structural changes is only effective when these changes are also managed at a social level, by providing support for patient–clients, providers, and administrators when new practices are adopted.
At a psychological level, perinatal psychology as a profession could be developed to care for women and their families through normal pregnancies as well as when complications arise, and to support caregivers.
Health service planners can ensure that their institution's care delivery frameworks incorporate guidelines and protocols that reflect inclusivity and allow flexible application of FMCNC to safely meet the social and geographical needs of their patient-clients. At a society level, FCMNC requires that we foster a mindset based on partnerships between patient–clients, providers, and administrators in planning and evaluation, with evaluation using patient-identified metrics of quality care. Achieving a consensus that the right things are being measured is essential to success.
As reflected in many of the FCMNC principles outlined in the Preface and considered throughout the chapters, family-centered care requires that we consider all experiences of maternity care, including those of racialized and immigrant women and families, those who are gender non-conforming, those who have mental health concerns, and those who are disenfranchised through lack of stable housing or substance use. Their voices, and those of other vulnerable women such as those with chronic health conditions including obesity, are essential to include in service planning if we are to reduce health disparities. The principles of FCMNC may be particularly difficult to implement under extreme circumstances, but reconciling them with safe, culturally, and psychologically sensitive practices will enhance the care provided.
References
----------
Footnote 1
Truth and Reconciliation Commission of Canada. Honouring the truth, reconciling for the future: the final report of the Truth and Reconciliation Commission of Canada [Internet]. Winnipeg (MB): TRC; 2015 [cited 2021 June 17]. Available from: http://www.trc.ca/assets/pdf/Executive\_Summary\_English\_Web.pdf
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
Cameron PJ, Este DC, Worthington CA. Professional, personal and community: 3 domains of physician retention in rural communities. Can J Rural Med. 2012;17(2):47-55.
[Return to footnote 2 referrer](#fn2-rf)
Footnote 3
Dolea C, Stormont L, Braichet J. Evaluated strategies to increase attraction and retention of health workers in remote and rural areas. Bull World Health Organ. 2010;88(5):379-85.
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
Kornelsen J, McCartney K. The safety of rural maternity services without local access to cesarean section: an applied policy research unit review [Internet]. Vancouver (BC): Perinatal Services BC, BC Women's Hospital and Health Centre, University Centre for Rural Health, Australia; 2015 [cited 2021 June 17]. Available from: https://med-fom-crhr.sites.olt.ubc.ca/files/2015/11/apru\_the-safety-of-rural-maternity-services-without-local-access-to-c-section\_2015.pdf
[Return to footnote 4 referrer](#fn4-rf)
Footnote 5
Van Wagner V, Osepchook C, Harney E, Crosbie C, Tulugak M. Remote midwifery in Nunavik, Québec, Canada: outcomes of perinatal care for the Inuulitsivik Health Centre, 2000-2007. Birth. 2012;39(3):230-7.
[Return to footnote 5 referrer](#fn5-rf)
Footnote 6
Wilson AK, Martel M, Arsenault M, Cargill YM, Delaney M, Daniels S, et al. Maternal transport policy. J Obstet Gynaecol Can. 2005;27(10):956-63.
[Return to footnote 6 referrer](#fn6-rf)
Footnote 7
Canadian Institute for Health Information. Hospital births in Canada: a focus on women living in rural and remote areas. Ottawa (ON): CIHI; 2013.
[Return to footnote 7 referrer](#fn7-rf)
Footnote 8
Indigenous Services Canada. Non-insured health benefits (NIHB) medical transportation policy framework (Interim) [Internet]. Ottawa (ON): Government of Canada; 2019 [cited 2021 June 17]. Available from: https://www.sac-isc.gc.ca/eng/1579891130443/1579891286837
[Return to footnote 8 referrer](#fn8-rf)
Footnote 9
Nesbitt TS, Connell FA, Hart LG, Rosenblatt RA. Access to obstetric care in rural areas: effect on brith outcomes. Am J Public Health. 1990;80(7):814-8.
[Return to footnote 9 referrer](#fn9-rf)
Footnote 10
Grzybowski S, Stoll K, Kornelsen J. Distance matters: a population based study examining access to maternity services for rural women. BMC Health Serv Res. 2011;11(1):147.
[Return to footnote 10 referrer](#fn10-rf)
Footnote 11
Grzybowski S, Fahey J, Lai B, Zhang S, Aelicks N, Leung BM, et al. The safety of Canadian rural maternity services: a multi-jurisdictional cohort analysis. BMC Health Serv Res. 2015;15(1):410.
[Return to footnote 11 referrer](#fn11-rf)
Footnote 12
Kornelsen J, Grzybowski S. Safety and community: the maternity care needs of rural parturient women. J Obstet Gynaecol Can. 2005;27(6):554-61.
[Return to footnote 12 referrer](#fn12-rf)
Footnote 13
Campbell K, Carson G, Azzam H, Hutton E. No.372-Statement on planned homebirth. J Obstet Gynaecol Can. 2019;41(2):223-7.
[Return to footnote 13 referrer](#fn13-rf)
Footnote 14
Iglesias S, Kornelsen J, Woollard R, Caron N, Warnock G, Friesen R, et al. Joint position paper on rural surgery and operative delivery. Can J Rural Med. 2015;20(4):129-38.
[Return to footnote 14 referrer](#fn14-rf)
Footnote 15
Rural Coordination Centre of BC. MaBAL (Maternity and babies advice line) [Internet]. Vancouver (BC): RCCBC; 2021 [cited 2021 June 17]. Available from: https://rccbc.ca/rtvs/mabal/
[Return to footnote 15 referrer](#fn15-rf)
Footnote 16
Kornelsen J, Friesen R. Building rural surgical networks: an evidence-based approach to service delivery and evaluation. Healthcare policy. 2016;12(1):37-42.
[Return to footnote 16 referrer](#fn16-rf)
Footnote 17
Stirk L, Kornelsen J. No.379-Attendance at and resources for delivery of optimal maternity care. J Obstet Gynaecol Can. 2019;41(5):688-96.e4.
[Return to footnote 17 referrer](#fn17-rf)
Footnote 18
Perinatal Services BC. Maternal/fetal and neonatal services: setting the stage [Internet]. Vancouver (BC): Provincial Health Services Authority; 2020 [cited 2021 June 17]. Available from: http://www.perinatalservicesbc.ca/Documents/Resources/SystemPlanning/TiersOfService/Tier-of-service-setting-the-stage.pdf
[Return to footnote 18 referrer](#fn18-rf)
Footnote 19
Provincial Council for Maternal and Child Health. Standardized maternal and newborn levels of care definitions [Internet]. Ottawa (ON): PCMC; 2013 [cited 2021 June 17]. Available from: https://www.pcmch.on.ca/wp-content/uploads/2015/07/Level-of-Care-Guidelines-2011-Updated-August1-20131.pdf
[Return to footnote 19 referrer](#fn19-rf)
Footnote 20
Kilpatrick SJ, Menard MK, Zahn CM, Callaghan WM. Obstetric care consensus #9: levels of maternal care. Obstet Gynecol. 2019;221(6):B19-30.
[Return to footnote 20 referrer](#fn20-rf)
Footnote 21
Hemminki E, Heino A, Gissler M. Should births be centralised in higher level hospitals? Experiences from regionalised health care in Finland: should births be centralised in higher level hospitals? BJOG. 2011;118(10):1186-95.
[Return to footnote 21 referrer](#fn21-rf)
Footnote 22
Accreditation Canada. Obstetrics services [Internet]. Ottawa (ON): Accreditation Canada; 2021 [cited 2021 June 18]. Available from: https://store.accreditation.ca/products/obstetrics-services
[Return to footnote 22 referrer](#fn22-rf)
Footnote 23
Public Health Agency of Canada. Chapter 1: Family-centred maternity and newborn care in Canada: underlying philosophy and principles [Internet]. Ottawa (ON): PHAC; 2017 [cited 2021 June 18]. Available from: https://www.canada.ca/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-1.html
[Return to footnote 23 referrer](#fn23-rf)
Footnote 24
Sackett DL, Rosenberg WMC, Gray JAM, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn't. It's about integrating individual clinical expertise and the best external evidence. BMJ. 1996;312(7023):71-2.
[Return to footnote 24 referrer](#fn24-rf)
Footnote 25
Bodenheimer T, Sinsky C. From triple to quadruple aim: care of the patient requires care of the provider. Ann Fam Med. 2014;12(6):573-6.
[Return to footnote 25 referrer](#fn25-rf)
Footnote 26
World Health Organization. Standards for improving quality of maternal and newborn care in health facilities [Internet]. Geneva (CH): WHO; 2016 [cited 2021 June 18]. Available from: https://www.who.int/docs/default-source/mca-documents/advisory-groups/quality-of-care/standards-for-improving-quality-of-maternal-and-newborn-care-in-health-facilities.pdf
[Return to footnote 26 referrer](#fn26-rf)
Footnote 27
Perinatal Services BC. Guidelines and standards [Internet]. Vancouver (BC): Provincial Health Services Authority; 2021 [cited 2021 June 18]. Available from: http://www.perinatalservicesbc.ca/health-professionals/guidelines-standards
[Return to footnote 27 referrer](#fn27-rf)
Footnote 28
Provincial Council for Maternal and Child Health. Paediatric levels of care - PCMCH [Internet]. Ottawa (ON): PCMC; 2021 [cited 2021 June 18]. Available from: https://www.pcmch.on.ca/health-care-providers/paediatric-care/pcmch-strategies-and-initiatives/paediatric-levels-of-care/
[Return to footnote 28 referrer](#fn28-rf)
Footnote 29
American College of Obstetricians and Gynecologists. Standards of obstetric-gynecologic services. 7th ed. Washington (DC): ACOG; 1989.
[Return to footnote 29 referrer](#fn29-rf)
Footnote 30
Miller KJ, Couchie C, Ehman W, Graves L, Grzybowski S, Medves J. No. 282-Rural maternity care. J Obstet Gynaecol Can. 2017;39(12):e558-65.
[Return to footnote 30 referrer](#fn30-rf)
Footnote 31
Vanier Institute of the Family. In context: understanding maternity care in Canada [Internet]. Ottawa (ON): Vanier Institute; 2017 [cited 2021 June 18]. Available from: https://vanierinstitute.ca/in-context-understanding-maternity-care-in-canada/
[Return to footnote 31 referrer](#fn31-rf)
Footnote 32
Canadian Association of Perinatal and Women's Health Nurses. Perinatal nursing standards in Canada [Internet]. Ottawa (ON): CAPWHN; 2018 [cited 2021 June 18]. Available from: https://capwhn.ca/wp-content/uploads/2019/10/PERINATAL\_NURSING\_STANDARDS\_IN\_CANADA.pdf
[Return to footnote 32 referrer](#fn32-rf)
Footnote 33
Kane RL, Shamliyan TA, Mueller C, Duval S, Wilt TJ. The association of registered nurse staffing levels and patient outcomes: systematic review and meta-analysis. Med Care. 2007;45(12):1195-204.
[Return to footnote 33 referrer](#fn33-rf)
Footnote 34
Tellez M. Work satisfaction among California registered nurses: a longitudinal comparative analysis. Nurs Econ. 2012;30(2):73-81.
[Return to footnote 34 referrer](#fn34-rf)
Footnote 35
Aiken LH, Cerón C, Simonetti M, Lake ET, Galiano A, Garbarini A, et al. Hospital nurse staffing and patient outcomes. Revista Médica Clínica Las Condes. 2018;29(3):322-7.
[Return to footnote 35 referrer](#fn35-rf)
Footnote 36
Aiken LH, Sloane DM, Cimiotti JP, Clarke SP, Flynn L, Seago JA, et al. Implications of the California nurse staffing mandate for other states: implications of the California nurse staffing. Health Serv Res. 2010;45(4):904-21.
[Return to footnote 36 referrer](#fn36-rf)
Footnote 37
Raby C, Dowse T, Bennet L. Postpartum/newborn patients: who are they and do they all need the same amount of nursing care? J Nurs Manag. 2008;16(2):198-203.
[Return to footnote 37 referrer](#fn37-rf)
Footnote 38
Association of Women's Health, Obstetric & Neonatal Nursing. Guidelines for professional registered nurse staffing for perinatal units executive summary. J Obstet Gynecol Neonatal Nurs. 2011;40(1):131-4.
[Return to footnote 38 referrer](#fn38-rf)
Footnote 39
Singer J, Canadian Institute for Health Information, Negrello T, Rondeau A, Clussich A, Boyes C. A ratio of staff-to-patients – development of a new indicator [Internet]. Ottawa (ON): Canadian Health Workforce Network; 2016 [cited 2021 June 18]. Available from: http://www.hhr-rhs.ca/images/stories/J.Singer\_Presentation\_HWAO\_Abstract\_en.pdf
[Return to footnote 39 referrer](#fn39-rf)
Footnote 40
Canadian Nursing Association. How effective are nursing staff mix and nurse-to-patient ratio mechanisms in improving nurses' workloads? [Internet]. Ottawa (ON): CNA; 2006 [cited 2021 June 18]. Available from: https://www.cna-aiic.ca/-/media/cna/page-content/pdf-en/research\_summaries\_all\_e.pdf?la=en&hash=2CE778BA1506C447C21A7DAA4AE757DD1A58D627
[Return to footnote 40 referrer](#fn40-rf)
Footnote 41
MacKinnon K. We cannot staff for 'what ifs': the social organization of rural nurses' safeguarding work. Nurs Inq. 2012;19(3):259-69.
[Return to footnote 41 referrer](#fn41-rf)
Footnote 42
Koto PS, Fahey J, Meier D, LeDrew M, Loring S. Relative effectiveness and cost-effectiveness of the midwifery-led care in Nova Scotia, Canada: a retrospective, cohort study. Midwifery. 2019;77:144-54.
[Return to footnote 42 referrer](#fn42-rf)
Footnote 43
McRae DN, Muhajarine N, Stoll K, Mayhew M, Vedam S, Mpofu D, et al. Is model of care associated with infant birth outcomes among vulnerable women? A scoping review of midwifery-led versus physician-led care. SSM Popul Health. 2016;2:182-93.
[Return to footnote 43 referrer](#fn43-rf)
Footnote 44
McRae DN, Muhajarine N, Janssen PA. Improving birth outcomes for women who are substance using or have mental illness: A Canadian cohort study comparing antenatal midwifery and physician models of care for women of low socioeconomic position. BMC Pregnancy Childbirth. 2019;19(1):279.
[Return to footnote 44 referrer](#fn44-rf)
Footnote 45
Mattison CA, Lavis JN, Hutton EK, Dion ML, Wilson MG. Understanding the conditions that influence the roles of midwives in Ontario, Canada's health system: An embedded single-case study. BMC Health Serv Res. 2020;20(1):197.
[Return to footnote 45 referrer](#fn45-rf)
Footnote 46
Canadian Association of Midwives. Midwifery across Canada [Internet]. Montreal (QC): CAM; 2021 [cited 2021 June 21]. Available from: https://canadianmidwives.org/midwifery-across-canada/
[Return to footnote 46 referrer](#fn46-rf)
Footnote 47
Peterson WE, Medves JM, Davies BL, Graham ID. Multidisciplinary collaborative maternity care in Canada: easier said than done. J Obstet Gynaecol Can. 2007;29(11):880-6.
[Return to footnote 47 referrer](#fn47-rf)
Footnote 48
Multidisciplinary Collaborative Primary Maternity Care Project. Guidelines and implementation tools for multidisciplinary collaborative primary maternity care models [Internet]. Ottawa (ON): MCP2; 2006 [cited 2021 June 22]. Available from: https://www.homebirthsummit.org/wp-content/uploads/2013/09/Multidisciplinary-Collaborative-Primary-Maternity-Care-May\_Ottawa.pdf
[Return to footnote 48 referrer](#fn48-rf)
Footnote 49
Northern Health. Stories of integrated perinatal services in two northern communities [Internet]. Vancouver (BC): BCPSQC; 2015 [cited 2021 June 22]. Available from: https://bcpsqc.ca/quality-awards/winners/stories-of-integrated-perinatal-services-in-two-northern-communities/
[Return to footnote 49 referrer](#fn49-rf)
Footnote 50
Lomonaco-Haycraft KC, Hyer J, Tibbits B, Grote J, Stainback-Tracy K, Ulrickson C, et al. Integrated perinatal mental health care: a national model of perinatal primary care in vulnerable populations. Prim Health Care Res Dev. 2018;20:1-8.
[Return to footnote 50 referrer](#fn50-rf)
Footnote 51
Goedde D, Zidack A, Li Y, Arkava D, Mullette E, Mullowney Y, et al. Depression outcomes from a fully integrated obstetric mental health clinic: a 10-year examination. J Am Psychiatr Nurses Assoc. 2021;27(2):123-33.
[Return to footnote 51 referrer](#fn51-rf)
Footnote 52
Hutton, Eileen, RM, PhD, Farmer MJ, MD, Carson GD, MD. The roles of multidisciplinary team members in the care of pregnant women. J Obstet Gynaecol Can. 2016;38(11):1068-9.
[Return to footnote 52 referrer](#fn52-rf)
Footnote 53
Van Wagner V, Epoo B, Nastapoka J, Harney E. Reclaiming birth, health, and community: midwifery in the Inuit villages of Nunavik, Canada. J Midwifery Womens Health. 2007;52(4):384-91.
[Return to footnote 53 referrer](#fn53-rf)
Footnote 54
Epoo B, Stonier J, Wagner V Van, Harney E. Learning midwifery in Nunavik: community-based education for Inuit midwives. Primatisiwin A J Aborig Indig Community Heal. 2012;10:283–99.
[Return to footnote 54 referrer](#fn54-rf)
Footnote 55
Bowen A, Pratt C. Indigenous birth. In: Exner-Pirot H, Norbye B, Butler L, eds. Northern and Indigenous health care [Internet]. Saskatoon (SK): University of Saskatchewan; 2018 [cited 2021 June 22]. Available from: https://openpress.usask.ca/northernhealthcare/
[Return to footnote 55 referrer](#fn55-rf)
Footnote 56
Indigenous Services Canada. 2017–18 departmental results report [Internet]. Ottawa (ON): ISC; 2018 2018 [cited 2021 June 22]. Available from: https://www.sac-isc.gc.ca/eng/1538153575415/1538153630277
[Return to footnote 56 referrer](#fn56-rf)
Footnote 57
Stewart MJ, Smith J, Boland RA. Optimizing outcomes in regionalized perinatal care: Integrating maternal and neonatal emergency referral, triage, and transport. Curr Treat Options Pediatr. 2017;3:313-26.
[Return to footnote 57 referrer](#fn57-rf)
Footnote 58
Redpath S, Shah PS, Moore GP, Yang J, Toye J, Perreault T, et al. Do transport factors increase the risk of severe brain injury in outborn infants <33 weeks gestational age? J Perinatol. 2020;40(3):385-93.
[Return to footnote 58 referrer](#fn58-rf)
Footnote 59
Whyte HEA, Jefferies AL, Lacaze T, Newhook LA, Hendson L, Lemyre B, et al. The interfacility transport of critically ill newborns. Paediatr Child Health. 2015;20(5):265-9.
[Return to footnote 59 referrer](#fn59-rf)
Footnote 60
Harris Jr BA, Wirtschafter DD, Huddleston JF, Perlis HW. In utero versus neonatal transportation of high-risk perinates: a comparison. Obstet Gynaecol. 1981;57(4):496-9.
[Return to footnote 60 referrer](#fn60-rf)
Footnote 61
Lasswell SM, Barfield WD, Rochat RW, Blackmon L. Perinatal regionalization for very low-birth-weight and very preterm infants: a meta-analysis. JAMA. 2010;304(9):992-1000.
[Return to footnote 61 referrer](#fn61-rf)
Footnote 62
Mosher SL. The art of supporting families faced with neonatal transport. Nurs Womens Health. 2013;17(3):198-209.
[Return to footnote 62 referrer](#fn62-rf)
Footnote 63
Yu VYH, Dunn PM. Development of regionalized perinatal care. Semin Neonatol. 2004;9(2):89-97.
[Return to footnote 63 referrer](#fn63-rf)
Footnote 64
Newton, Scott M., DNP,RN, EMT-P., Fralic, Maryann, DrPH,RN, FAAN. Interhospital transfer center model: components, themes, and design elements. Air Med J. 2015;34(4):207-12.
[Return to footnote 64 referrer](#fn64-rf)
Footnote 65
Aguirre FV, Varghese JJ, Kelley MP, Lam W, Lucore CL, Gill JB, et al. Rural interhospital transfer of ST-elevation myocardial infarction patients for percutaneous coronary revascularization: the stat heart program. Circulation. 2008;117(9):1145-52.
[Return to footnote 65 referrer](#fn65-rf)
Footnote 66
Ahl E, Wold R. Defining and developing a specialty stroke transport team. Air Med J. 2009;28(3):133-8.
[Return to footnote 66 referrer](#fn66-rf)
Footnote 67
Perinatal Services BC. Provincial maternal newborn transfer network: principles and processes [Internet]. Vancouver (BC): Provincial Health Services Authority; 2004 [cited 2021 June 22]. Available from: http://www.perinatalservicesbc.ca/Documents/Guidelines-Standards/TransferProcess/MNTNPrinciplesProcessesApril2014.pdf
[Return to footnote 67 referrer](#fn67-rf)
Footnote 68
Lee K. Neonatal transport metrics and quality improvement in a regional transport service. Transl Pediatr. 2019;8(3):233-45.
[Return to footnote 68 referrer](#fn68-rf)
Footnote 69
Goh A, Browning Carmo K, Morris J, Berry A, Wall M, Abdel-Latif M. Outcomes of high-risk obstetric transfers in New South Wales and the Australian Capital Territory: the high-risk obstetric transfer study. Aust N Z J Obstet Gynaecol. 2015;55(5):434-39.
[Return to footnote 69 referrer](#fn69-rf)
Footnote 70
Binder S, Hill K, Meinzen-Derr J, Greenberg JM, Narendran V. Increasing VLBW deliveries at subspecialty perinatal centers via perinatal outreach. Obstet Gynecol Surv. 2011;66(6):331-2.
[Return to footnote 70 referrer](#fn70-rf)
Footnote 71
Sampaio TZAL, Wilson M, Aubertin C, Redpath S. Diagnosis discordance and neonatal transport: a single-center retrospective chart review. Am J Perinatol. 2019;36(5):522.
[Return to footnote 71 referrer](#fn71-rf)
Footnote 72
Alberta Health Services. Criteria to support appropriate level of obstetrical care [Internet]. Edmonton (AB): AHS; 2020 [cited 2021 June 22]. Available from: https://extranet.ahsnet.ca/teams/policydocuments/1/clp-womens-health-criteria-support-appropriate-level-obstetrical-care-gdl-hcs-201-01.pdf
[Return to footnote 72 referrer](#fn72-rf)
Footnote 73
Gagliardi AR, Nathens AB. Exploring the characteristics of high-performing hospitals that influence trauma triage and transfer. J Trauma Acute Care Surg. 2015;78(2):300-5.
[Return to footnote 73 referrer](#fn73-rf)
Footnote 74
Lupton BA, Pendray MR. Regionalized neonatal emergency transport. Semin Neonatol. 2004;9(2):125-33.
[Return to footnote 74 referrer](#fn74-rf)
Footnote 75
Canadian Paediatric Society. About ACoRN [Internet]. Ottawa (ON): CPS; 2019 [cited 2021 June 22]. Available from: https://www.cps.ca/en/acorn
[Return to footnote 75 referrer](#fn75-rf)
Footnote 76
Goswami I, Redpath S, Langlois RG, Green JR, Lee KS, Whyte HEA. Whole-body vibration in neonatal transport: a review of current knowledge and future research challenges. Early Hum Dev. 2020;146:105051.
[Return to footnote 76 referrer](#fn76-rf)
Footnote 77
Wright JD. Before the transport team arrives: neonatal stabilization. J Perinat Neonatal Nurs. 2000;13(4):87-107.
[Return to footnote 77 referrer](#fn77-rf)
Footnote 78
Canadian Association of Paediatric Health Centres. Competencies profile-interfacility critical care transport of maternal, neonatal, and paediatric patients [Internet]. Ottawa (ON): CAPHC; 2012 [cited 2021 June 22]. Available from: https://www.pcmch.on.ca/wp-content/uploads/2016/01/CAPHC-Transport-Systems-Competencies-Profile-Interfacility-Critical-Care-Transport-of-Maternal-Neonatal-and-Paediatric-Patients.pdf
[Return to footnote 78 referrer](#fn78-rf)
Footnote 79
Kyle E, Aitken P, Elcock M, Barneveld M. Use of telehealth for patients referred to a retrieval service: timing, destination, mode of transport, escort level and patient care. J Telemed Telecare. 2012;18(3):147-50.
[Return to footnote 79 referrer](#fn79-rf)
Footnote 80
Haynes SC, Dharmar M, Hill BC, Hoffman KR, Donohue LT, Kuhn-Riordon KM, et al. The impact of telemedicine on transfer rates of newborns at rural community hospitals. Acad Pediatr. 2020;20(5):636-41.
[Return to footnote 80 referrer](#fn80-rf)
Footnote 81
Mann S, McKay K, Brown H. The maternal health compact. N Engl J Med. 2017;376(14):1304-5.
[Return to footnote 81 referrer](#fn81-rf)
Footnote 82
Kim EW, Teague-Ross TJ, Greenfield WW, Keith Williams D, Kuo D, Hall RW. Telemedicine collaboration improves perinatal regionalization and lowers statewide infant mortality. J Perinatol. 2013;33(9):725-30.
[Return to footnote 82 referrer](#fn82-rf)
Footnote 83
Fang JL, Collura CA, Johnson RV, Asay GF, Carey WA, Derleth DP, et al. Emergency video telemedicine consultation for newborn resuscitations: the mayo clinic experience. Mayo Clin Proc. 2016;91(12):1735-43.
[Return to footnote 83 referrer](#fn83-rf)
Footnote 84
Becker F. Organizational ecology and knowledge networks. Calif Manage Rev. 2007;49(2):42-61.
[Return to footnote 84 referrer](#fn84-rf)
Footnote 85
Afulani PA, Moyer CA. Accountability for respectful maternity care. Lancet. 2019;394(10210):1692-3.
[Return to footnote 85 referrer](#fn85-rf)
Footnote 86
Bohren MA, Vogel JP, Hunter EC, Lutsiv O, Makh SK, Souza JP, et al. The mistreatment of women during childbirth in health facilities globally: a mixed-methods systematic review. PLoS Med. 2015;12(6):e1001847.
[Return to footnote 86 referrer](#fn86-rf)
Footnote 87
Miller S, Abalos E,Chamillard M, Ciapponi A, Colaci D, Comandé D, et al. Beyond too little, too late and too much, too soon: a pathway towards evidence-based, respectful maternity care worldwide. Lancet. 2016;388(10056):2176-92.
[Return to footnote 87 referrer](#fn87-rf)
Footnote 88
World Health Organization. The prevention and elimination of disrespect and abuse during facility-based childbirth [Internet]. Geneva (CH): WHO; 2014 [cited 2021 June 23]. Available from: https://www.who.int/docs/default-source/mca-documents/advisory-groups/quality-of-care/standards-for-improving-quality-of-maternal-and-newborn-care-in-health-facilities.pdf
[Return to footnote 88 referrer](#fn88-rf)
Footnote 89
Chen D, Cheng L, Hummels C, Koskinen I. Social design: an introduction. Int J Des. 2016;10(1):1-5.
[Return to footnote 89 referrer](#fn89-rf)
Footnote 90
Żukiewicz-Sobczak W, Wróblewska P, Zwoliński J, Chmielewska-Badora J, Adamczuk P, Krasowska E, et al. Obesity and poverty paradox in developed countries. Ann Agric Environ Med. 2014;21(3):590-4.
[Return to footnote 90 referrer](#fn90-rf)
Footnote 91
Douglas CH, Douglas MR. Patient-friendly hospital environments: exploring the patients' perspective. Health Expect. 2004;7(1):61-73.
[Return to footnote 91 referrer](#fn91-rf)
Footnote 92
Cegolon L, Maso G, Heymann WC, Bortolotto M, Cegolon A, Mastrangelo G. Determinants of length of stay after vaginal deliveries in the Friuli Venezia Giulia Region (North-Eastern Italy), 2005–2015. Sci Rep. 2020;10(1):5912.
[Return to footnote 92 referrer](#fn92-rf)
Footnote 93
Benahmed N, San Miguel L, Devos C, Fairon N, Christiaens W. Vaginal delivery: how does early hospital discharge affect mother and child outcomes? A systematic literature review. BMC Pregnancy Childbirth. 2017;17(1):289.
[Return to footnote 93 referrer](#fn93-rf)
Footnote 94
Saunders RP, Abraham MR, Crosby MJ, Thomas K, Edwards WH. Evaluation and development of potentially better practices for improving family-centered care in neonatal intensive care units. Pediatrics (Evanston). 2003;111(4):e437-49.
[Return to footnote 94 referrer](#fn94-rf)
Footnote 95
Public Health Agency of Canada. Chapter 5: Postpartum Care [Internet]. Ottawa (ON): PHAC; 2020 [cited 2021 June 23]. Available from: https://www.canada.ca/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-5.html
[Return to footnote 95 referrer](#fn95-rf)
Footnote 96
Gooding JS, Cooper LG, Blaine AI, Franck LS, Howse JL, Berns SD. Family support and family-centered care in the neonatal intensive care unit: origins, advances, impact. Semin Perinatol. 2011;35(1):20-8.
[Return to footnote 96 referrer](#fn96-rf)
Footnote 97
Janssen PA, Klein MC, Harris SJ, Soolsma J, Seymour LC. Single room maternity care and client satisfaction. Birth. 2000;27(4):235-43.
[Return to footnote 97 referrer](#fn97-rf)
Footnote 98
Harris SJ, Farren MD, Janssen PA, Klein MC, Lee SK. Single room maternity care: perinatal outcomes, economic costs, and physician preferences. J Obstet Gynaecol Can. 2004;26(7):633-40.
[Return to footnote 98 referrer](#fn98-rf)
Footnote 99
Ulrich R, Zimring C, Joseph A, Quan X, Choudhary R. The role of the physical environment in the hospital of the 21st century: a once-in-a-lifetime opportunity [Internet]. Concord (CA): The Center for Health Design; 2004 [cited 2021 June 23]. Available from: https://www.healthdesign.org/knowledge-repository/role-physical-environment-hospital-21st-century-once-lifetime-opportunity
[Return to footnote 99 referrer](#fn99-rf)
Footnote 100
Janssen PA, Harris SJ, Soolsma J, Klein MC, Seymour LC. Single room maternity care: the nursing response. Birth. 2001;28(3):173-9.
[Return to footnote 100 referrer](#fn100-rf)
Footnote 101
Halpern S. SOGC joint policy statement on normal childbirth. J Obstet Gynaecol Can. 2009;31(7):602-3.
[Return to footnote 101 referrer](#fn101-rf)
Footnote 102
Darcy Mahoney A, White RD, Velasquez A, Barrett TS, Clark RH, Ahmad KA. Impact of restrictions on parental presence in neonatal intensive care units related to coronavirus disease 2019. J Perinatol. 2020;40(Suppl 1):36-46.
[Return to footnote 102 referrer](#fn102-rf)
Footnote 103
Jenkinson, B., Josey N, Kruske S. BirthSpace: an evidence-based guide to birth environment design. [Internet]. Brisbane (AU): The Queensland Center for Mothers and Babies; 2014 [cited 2021 June 23]. Available from: https://www.researchgate.net/publication/278328878\_BirthSpace\_An\_evidence-based\_guide\_to\_birth\_environment\_design
[Return to footnote 103 referrer](#fn103-rf)
Footnote 104
Health Sciences Centre Winnipeg. HSC women's hospital update – January 2016 [Internet]. Winnipeg (MB): Health Sciences Centre; 2016 [cited 2021 June 23]. Available from: http://www.hsc.mb.ca/files/WRHPFAQsFINAL.pdf
[Return to footnote 104 referrer](#fn104-rf)
Footnote 105
Hignett S, Evans D. Spatial requirements in hospital shower and toilet rooms. Nurs Stand. 2006;21(3):43-8.
[Return to footnote 105 referrer](#fn105-rf)
Footnote 106
Canadian Standards Association. Canadian health care facilities CSA Z8000-18 : planning, design and construction : CSA standards. Ottawa (ON): CSA; 2018.
[Return to footnote 106 referrer](#fn106-rf)
Footnote 107
International Health Facility Guidelines. Part B – health facility briefing & design including functional planning units [Internet]. New South Wales (AU): TAHPI; 2017 [cited 2021 June 23]. Available from: http://healthfacilityguidelines.com/ViewPDF/ViewIndexPDF/iHFG\_part\_b\_complete
[Return to footnote 107 referrer](#fn107-rf)
Footnote 108
Lee KA, Gay CL. Improving sleep for hospitalized antepartum patients: a non-randomized controlled pilot study. J Clin Sleep Med. 2017;13(12):1445-53.
[Return to footnote 108 referrer](#fn108-rf)
Footnote 109
BC Women's Hospital and Health Centre. Antepartum care [Internet]. Vancouver (BC): Provincial Health Services Authority; 2021[cited 2021 June 23]. Available from: http://www.bcwomens.ca/our-services/pregnancy-prenatal-care/antepartum-care#At--Home
[Return to footnote 109 referrer](#fn109-rf)
Footnote 110
West C, Palmer L, Tier T. No place like home: an antepartum program at British Columbia's Women's Hospital has shown that women with complications of pregnancy do better and save the system money when they are cared for at home. Can Nurse. 2000;96:1–5.
[Return to footnote 110 referrer](#fn110-rf)
Footnote 111
United Kington Department of Health and Social Care. Children, young people and maternity Services. Health building note 09-02 [Internet]. London (UK): NBS; 2013 [cited 2021 June 23]. Available from: https://www.thenbs.com/PublicationIndex/documents/details?Pub=DHEFD&DocID=303357
[Return to footnote 111 referrer](#fn111-rf)
Footnote 112
World Health Organization. WHO recommendations Intrapartum care for a positive childbirth experience [Internet]. Geneva (CH): WHO; 2018 [cited 2021 June 24]. Available from: https://apps.who.int/iris/bitstream/handle/10665/272447/WHO-RHR-18.12-eng.pdf
[Return to footnote 112 referrer](#fn112-rf)
Footnote 113
Breman RB, Storr CL, Paul J, LeClair M, Johantgen M. Women's prenatal and labor experiences in a hospital with an early-labor lounge. Nurs Womens Health. 2019;23(4):299.
[Return to footnote 113 referrer](#fn113-rf)
Footnote 114
Lorentzen I, Andersen CS, Jensen HS, Fogsgaard A, Foureur M, Lauszus FF, et al. Study protocol for a randomised trial evaluating the effect of a "birth environment room" versus a standard labour room on birth outcomes and the birth experience. Contemp Clin Trials Commun. 2019;14:100336.
[Return to footnote 114 referrer](#fn114-rf)
Footnote 115
Hodnett ED, Stremler R, Weston JA, McKeever P. Re-conceptualizing the hospital labor room: The PLACE (Pregnant and Laboring in an Ambient Clinical Environment) pilot trial. Birth. 2009;36(2):159-66.
[Return to footnote 115 referrer](#fn115-rf)
Footnote 116
Singh D, Newburn M. Feathering the nest: what women want from the birth environment. RCM Midwives. 2006;9(7):266-9.
[Return to footnote 116 referrer](#fn116-rf)
Footnote 117
Hammond A, Foureur M, Homer CSE, Davis D. Space, place and the midwife: exploring the relationship between the birth environment, neurobiology and midwifery practice. Women Birth. 2013;26(4):277-81.
[Return to footnote 117 referrer](#fn117-rf)
Footnote 118
Hauck Y, Rivers C, Doherty K. Women's experiences of using a Snoezelen room during labour in Western Australia. Midwifery. 2008;24(4):460-70.
[Return to footnote 118 referrer](#fn118-rf)
Footnote 119
White RD, Smith JA, Shepley MM. Recommended standards for newborn ICU design, eighth edition. J Perinatol. 2013;33(1):S2-16.
[Return to footnote 119 referrer](#fn119-rf)
Footnote 120
Watson J, DeLand M, Gibbins S, York EM. Improvements in staff quality of work life and family satisfaction following the move to single-family room nicu design. Adv Neonatal Care. 2014;14(2):129-36.
[Return to footnote 120 referrer](#fn120-rf)
Footnote 121
Janssen PA, Saxell L, Page LA, Klein MC, Liston RM, Lee SK. Outcomes of planned home birth with registered midwife versus planned hospital birth with midwife or physician. CMAJ. 2009;181(6-7):377-83.
[Return to footnote 121 referrer](#fn121-rf)
Footnote 122
Hutton EK, Cappelletti A, Reitsma AH, Simioni J, Horne J, McGregor C, et al. Outcomes associated with planned place of birth among women with low-risk pregnancies. CMAJ. 2016;188(5):e80-90.
[Return to footnote 122 referrer](#fn122-rf)
Footnote 123
Association of Ontario Midwives. Home birth FAQ [Internet]. Toronto (ON): AOM; 2021 [cited 2021 June 24]. Available from: https://www.ontariomidwives.ca/home-birth-FAQ
[Return to footnote 123 referrer](#fn123-rf)
Footnote 124
Hicks C, McGovern T, Prior G, Smith I. Applying lean principles to the design of healthcare facilities. Int J Prod Econ. 2015;170:677-86.
[Return to footnote 124 referrer](#fn124-rf)
Footnote 125
Burack EH, Smith RD. Personnel management: a human resource systems approach. St. Paul (MN): Wiley & Sons; 1977.
[Return to footnote 125 referrer](#fn125-rf)
Footnote 126
Bowerman J, Fillingham D. Can lean save lives? Leadersh Health Serv. 2007;20(4):231-41.
[Return to footnote 126 referrer](#fn126-rf)
Footnote 127
Smith I. Operationalising the lean principles in maternity service design using 3P methodology. BMJ Qual Improv Rep. 2016;5(1):u208920.w5761.
[Return to footnote 127 referrer](#fn127-rf)
Footnote 128
Cesario SK. Designing health care environments: Part I. Basic concepts, principles, and issues related to evidence-based design. J Contin Educ Nurs. 2009;40(6):280-8.
[Return to footnote 128 referrer](#fn128-rf)
Footnote 129
Alvaro C, Kostovski D, Andrea Wilkinson A, Gallant S, Gardner P. A planning guide for post occupancy evaluation {Internet]. Toronto (ON): Methologica; 2015 [cited 2021 June 24]. Available from: http://methologi.ca/wp-content/uploads/2017/01/Methologica\_PlanningGuide\_Web\_PrintandFill\_Nov8.pdf
[Return to footnote 129 referrer](#fn129-rf)
Footnote 130
Ontario Ministry of Health. Patients first: a proposal to strengthen patient-centred health in Ontario [Internet]. Toronto (ON): Government of Ontario; 2015 [cited 2021 June 29]. Available from: http://www.health.gov.on.ca/en/news/bulletin/2015/docs/discussion\_paper\_20151217.pdf
[Return to footnote 130 referrer](#fn130-rf)
Footnote 131
Alberta Health Services. Strategic direction: defining our focus / measuring our progress [Internet]. Edmonton (AB): Alberta Health Services; 2012 [cited 2021 June 29]. Available from: https://docplayer.net/5964730-Strategic-direction-defining-our-focus-measuring-our-progress.html
[Return to footnote 131 referrer](#fn131-rf)
Footnote 132
Saskatchewan Ministry of Health. Patient first review update – the journey so far and the path forward [Internet]. Saskatoon (SK): Government of Saskatchewan; 2015 [cited 2021 June 29]. Available from: https://www.saskatchewan.ca/government/health-care-administration-and-provider-resources/saskatchewan-health-initiatives/patient-first-review
[Return to footnote 132 referrer](#fn132-rf)
Footnote 133
Villa S, Barbieri M, Lega F. Restructuring patient flow logistics around patient care needs: implications and practicalities from three critical cases. Health Care Manag Sci. 2009;12(2):155-65.
[Return to footnote 133 referrer](#fn133-rf)
Footnote 134
National Center for Interprofessional Practice and Education. Picker Institute's eight principles of patient-centered care [Internet]. Minneapolis (MN): University of Minnesota; 2015 [cited 2021 June 29]. Available from: https://nexusipe.org/informing/resource-center/picker-institute%E2%80%99s-eight-principles-person-centered-care
[Return to footnote 134 referrer](#fn134-rf)
Footnote 135
de Labrusse C, Ramelet A, Humphrey T, Maclennan SJ. Patient-centered care in maternity services: a critical appraisal and synthesis of the literature. Womens Health Issues. 2016;26(1):100-9.
[Return to footnote 135 referrer](#fn135-rf)
Footnote 136
Conklin A, Morris Z, Nolte E. What is the evidence base for public involvement in health‐care policy?: results of a systematic scoping review. Health Expect. 2015;18(2):153-65.
[Return to footnote 136 referrer](#fn136-rf)
Footnote 137
Usher S, Denis J, Préval J, Baker R, Chreim S, Kreindler S, et al. Learning from health system reform trajectories in seven Canadian provinces. Health Econ Policy Law. 2020:1-17.
[Return to footnote 137 referrer](#fn137-rf)
Footnote 138
Marsh S, Dunkley-Bent J, Jolly M. Implementing better births: a resource pack for local maternity systems [Internet]. London (UK): NHS; 2017 [cited 2021 June 29]. Available from: https://www.england.nhs.uk/wp-content/uploads/2017/03/nhs-guidance-maternity-services-v1.pdf
[Return to footnote 138 referrer](#fn138-rf)
Footnote 139
International Association for Public Participation (IAP2). IAP2 spectrum of public pParticipation [Internet]. Denver (CO: IAP2 International Federation; 2018 [cited 2021 June 29]. Available from: https://cdn.ymaws.com/www.iap2.org/resource/resmgr/pillars/Spectrum\_8.5x11\_Print.pdf
[Return to footnote 139 referrer](#fn139-rf)
Footnote 140
Bombard Y, Baker GR, Orlando E, Fancott C, Bhatia P, Casalino S, et al. Engaging patients to improve quality of care: a systematic review. Implement Sci. 2018;13(1):98.
[Return to footnote 140 referrer](#fn140-rf)
Footnote 141
Lofters A, Virani T, Grewal G, Lobb R. Using knowledge exchange to build and sustain community support to reduce cancer screening inequities. Prog Community Heal Partnerships Res Educ Action. 2015;9(3):379-87-387.
[Return to footnote 141 referrer](#fn141-rf)
Footnote 142
Acri M, Olin SS, Burton G, Herman RJ, Hoagwood KE. Innovations in the identification and referral of mothers at risk for depression: development of a peer-to-peer model. J Child Fam Stud. 2014;23(5):837-43.
[Return to footnote 142 referrer](#fn142-rf)
Footnote 143
Best A, Greenhalgh T, Lewis S, Saul JE, Carroll S, Bitz J. Large-system transformation in health care: a realist review. Milbank Q. 2012;90(3):421-56.
[Return to footnote 143 referrer](#fn143-rf)
Footnote 144
Lukas CV, Holmes SK, Cohen AB, Restuccia J, Cramer IE, Shwartz M, et al. Transformational change in health care systems: an organizational model. Health Care Manage Rev. 2007;32(4):309-20.
[Return to footnote 144 referrer](#fn144-rf)
Footnote 145
Buchanan DA, Addicott R, Fitzgerald L, Ferlie E, Baeza JI. Nobody in charge: distributed change agency in healthcare. Hum Relations. 2007;60(7):1065-89.
[Return to footnote 145 referrer](#fn145-rf)
Footnote 146
Buchanan R. Wicked problems in design thinking. Source Des Issues. 1992;8:5–21.
[Return to footnote 146 referrer](#fn146-rf)
Footnote 147
Willis CD, Best A, Riley B, Herbert CP, Millar J, Howland D. Systems thinking for transformational change in health. Evid Policy. 2014;10(1):113-26.
[Return to footnote 147 referrer](#fn147-rf)
Footnote 148
Austin MJ, Ciaassen J. Impact of organizational change on organizational culture: Implications for introducing evidence-based practice. J Evid Based Soc Work. 2008;5(1-2):321-59.
[Return to footnote 148 referrer](#fn148-rf)
Footnote 149
Veazie S, Peterson K, Bourne D. Evidence brief: implementation of high reliability organization principles. Washington (DC): Department of Veterans Affairs (US); 2019.
[Return to footnote 149 referrer](#fn149-rf)
Footnote 150
Saturno PJ, Martinez-Nicolas I, Robles-Garcia IS, López-Soriano F, Angel-García D. Development and pilot test of a new set of good practice indicators for chronic cancer pain management. Eur J Pain (United Kingdom). 2015;19(1):28-38.
[Return to footnote 150 referrer](#fn150-rf)
Footnote 151
Saturno-Hernández PJ, Martínez-Nicolás I, Moreno-Zegbe E, Fernández-Elorriaga M, Poblano-Verástegui O. Indicators for monitoring maternal and neonatal quality care: a systematic review. BMC Pregnancy Childbirth. 2019;19(1):25.
[Return to footnote 151 referrer](#fn151-rf)
Footnote 152
Public Health Agency of Canada. Perinatal health indicators (PHI) [Internet]. Ottawa (ON): PHAC; 2020 [cited 2021 June 29]. Available from: https://health-infobase.canada.ca/phi/
[Return to footnote 152 referrer](#fn152-rf)
Footnote 153
Global Affairs Canada. Final report: evaluation of the maternal, newborn and child health initiative 2010–11 to 2017–18 [Internet]. Ottawa (ON): GAC; 2019 [cited 2021 June 29]. Available from: https://www.international.gc.ca/gac-amc/publications/evaluation/2019/mnch-smne.aspx?lang=eng
[Return to footnote 153 referrer](#fn153-rf)
Footnote 154
Hart JL, Turnbull AE, Oppenheim IM, Courtright KR. Family-centered care during the COVID-19 era. J Pain Symptom Manage. 2020;60(2):e93-7.
[Return to footnote 154 referrer](#fn154-rf)
Footnote 155
World Health Organization. Past pandemics [Internet]. Geneva (CH): WHO; 2021 [cited 2021 June 29]. Available from: https://www.euro.who.int/en/health-topics/communicable-diseases/influenza/pandemic-influenza/past-pandemics
[Return to footnote 155 referrer](#fn155-rf)
Footnote 156
Daszak P, das Neves C, Amuasi J, Hayman D, Kuiken T, Roche B, et al. Workshop report on biodiversity and pandemics of the intergovernmental platform on biodiversity and ecosystem services [Internet]. Bonn (DE): IPBES; 2020 [cited 2021 June 29]. Available from: https://zenodo.org/record/4311798#.YPB-K-hKhPY
[Return to footnote 156 referrer](#fn156-rf)
Footnote 157
Beigi RH, Hodges J, Baldisseri M, English D, Magee-Womens Hospital Ethics Committee, the Magee-Womens Hospital Ethics Committee. Clinical review: considerations for the triage of maternity care during an influenza pandemic - one institution's approach. Crit Care. 2010;14(3):225.
[Return to footnote 157 referrer](#fn157-rf)
Footnote 158
Beigi R, Davis G, Hodges J, Akers A. Preparedness planning for pandemic influenza among large US maternity hospitals. Emerg Health Threats J. 2009;2(1):7079.
[Return to footnote 158 referrer](#fn158-rf)
Footnote 159
Capanna F, Haydar A, McCarey C, Bernini Carri E, Bartha Rasero J, Tsibizova V, et al. Preparing an obstetric unit in the heart of the epidemic strike of COVID-19: quick reorganization tips. J Matern Neonatal Med. 2020:1-7.
[Return to footnote 159 referrer](#fn159-rf)
Footnote 160
Chua M, Lee J, Sulaiman S, Tan H. From the frontline of COVID‐19 – how prepared are we as obstetricians? A commentary. BJOG. 2020;127(7):786-8.
[Return to footnote 160 referrer](#fn160-rf)
Footnote 161
Wilson AN, Ravaldi C, Scoullar MJL, Vogel JP, Szabo RA, Fisher JRW, et al. Caring for the carers: ensuring the provision of quality maternity care during a global pandemic. Women and Birth. 2021;34(3):206-9.
[Return to footnote 161 referrer](#fn161-rf)
Footnote 162
American Association of Birth Centers, Commission for the Accreditation of Birth Centers. Guidelines for auxiliary maternity units [Internet]. Perkiomenville (PA): AABC; 2020 [cited 2021 June 29]. Available from: https://cdn.ymaws.com/www.birthcenters.org/resource/resmgr/covid\_resources/guidelines\_for\_auxiliary\_mat.pdf
[Return to footnote 162 referrer](#fn162-rf)
Footnote 163
Dashraath P, Wong JLJ, Lim MXK, Lim LM, Li S, Biswas A, et al. Coronavirus disease 2019 (COVID-19) pandemic and pregnancy. Obstet Gynecol. 2020;222(6):521-31.
[Return to footnote 163 referrer](#fn163-rf)
Footnote 164
Odor PM, Neun M, Bampoe S, Clark S, Heaton D, Hoogenboom EM, et al. Anaesthesia and COVID-19: infection control. Br J Anaesth. 2020;125(1):16-24.
[Return to footnote 164 referrer](#fn164-rf)
Footnote 165
Ferrazzi EM, Frigerio L, Cetin I, Vergani P, Spinillo A, Prefumo F, et al. COVID-19 obstetrics task force, Lombardy, Italy: executive management summary and short report of outcome. Int J Obstet Gynaecol. 2020;149(3):377-8.
[Return to footnote 165 referrer](#fn165-rf)
Footnote 166
Rajan N, Joshi GP. COVID-19: role of ambulatory surgery facilities in this global pandemic. Anesth Analg. 2020;131(1):31-6.
[Return to footnote 166 referrer](#fn166-rf)
Footnote 167
Wong LP, Sam I. Public sources of information and information needs for pandemic influenza A(H1N1). J Community Health. 2010;35(6):676-82.
[Return to footnote 167 referrer](#fn167-rf)
Footnote 168
Wu PE, Styra R, Gold WL. Mitigating the psychological effects of COVID-19 on health care workers. CMAJ. 2020;192(17):E459-60.
[Return to footnote 168 referrer](#fn168-rf)
Footnote 169
Pfefferbaum B, North CS. Mental health and the Covid-19 pandemic. N Engl J Med. 2020;383(6):510-2.
[Return to footnote 169 referrer](#fn169-rf)
Footnote 170
Vazquez-Vazquez A, Dib S, Rougeaux E, Wells JC, Fewtrell MS. The impact of the Covid-19 lockdown on the experiences and feeding practices of new mothers in the UK: preliminary data from the COVID-19 new mum study. Appetite. 2021;156:104985.
[Return to footnote 170 referrer](#fn170-rf)
Footnote 171
Bohren MA, Hofmeyr GJ, Sakala C, Fukuzawa RK, Cuthbert A. Continuous support for women during childbirth. Cochrane Database Syst Rev. 2017;2017(7):CD003766.
[Return to footnote 171 referrer](#fn171-rf)
Footnote 172
Gildner TE, Thayer ZM. Birth plan alterations among American women in response to COVID‐19. Health Expect. 2020;23(4):969-71.
[Return to footnote 172 referrer](#fn172-rf)
Footnote 173
Renfrew MJ, Cheyne H, Craig J, Duff E, Dykes F, Hunter B, et al. Sustaining quality midwifery care in a pandemic and beyond. Midwifery. 2020;88:102759.
[Return to footnote 173 referrer](#fn173-rf)
Footnote 174
Kotaska A. Informed consent and refusal in obstetrics: a practical ethical guide. Birth. 2017;44(3):195-9.
[Return to footnote 174 referrer](#fn174-rf)
Footnote 175
Upshur REG. Principles for the justification of public health intervention. Can J Public Health. 2002;93(2):101-3.
[Return to footnote 175 referrer](#fn175-rf)
* [Previous Chapter](/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-7.html)
* [Table of Contents](/en/public-health/services/maternity-newborn-care-guidelines.html)
* [Next Chapter](/en/public-health/services/publications/healthy-living/maternity-newborn-care-guidelines-chapter-9.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fmaternity-newborn-care-guidelines-chapter-8.html&n=Chapter%208%3A%20Organization%20of%20services%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fmaternity-newborn-care-guidelines-chapter-8.html&title=Chapter%208%3A%20Organization%20of%20services%20-%20Canada.ca)
* [Email](mailto:?subject=Chapter%208%3A%20Organization%20of%20services%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fmaternity-newborn-care-guidelines-chapter-8.html%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fmaternity-newborn-care-guidelines-chapter-8.html&t=Chapter%208%3A%20Organization%20of%20services%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=Chapter%208%3A%20Organization%20of%20services%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fmaternity-newborn-care-guidelines-chapter-8.html%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fmaternity-newborn-care-guidelines-chapter-8.html&title=Chapter%208%3A%20Organization%20of%20services%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fmaternity-newborn-care-guidelines-chapter-8.html&t=Chapter%208%3A%20Organization%20of%20services%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fmaternity-newborn-care-guidelines-chapter-8.html&media=&description=Chapter%208%3A%20Organization%20of%20services%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fmaternity-newborn-care-guidelines-chapter-8.html&title=Chapter%208%3A%20Organization%20of%20services%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fmaternity-newborn-care-guidelines-chapter-8.html)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fmaternity-newborn-care-guidelines-chapter-8.html&name=Chapter%208%3A%20Organization%20of%20services%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=Chapter%208%3A%20Organization%20of%20services%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fmaternity-newborn-care-guidelines-chapter-8.html)
* [Whatsapp](https://api.whatsapp.com/send?text=Chapter%208%3A%20Organization%20of%20services%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fmaternity-newborn-care-guidelines-chapter-8.html)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=Chapter%208%3A%20Organization%20of%20services%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fmaternity-newborn-care-guidelines-chapter-8.html%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2022-08-10
| None | None |
e5de06e08616854a9ac42478b344472d5d0caf03 | cma | Basic immunology and vaccinology: Canadian Immunization Guide | Basic immunology and vaccinology: Canadian Immunization Guide
Introduction
Immunology is the study of the structure and function of the immune system. Vaccinology is the science of vaccine development and how the immune system responds to vaccines, as well as the ongoing evaluation of immunization programs, vaccine safety and effectiveness, and surveillance of the epidemiology of vaccine preventable diseases. This chapter provides a brief overview of some of the main concepts of immunology and vaccinology as they relate to immunization. A detailed review of immunology and vaccinology is beyond the scope of the Canadian Immunization Guide.
Human immune system
# Components of the immune system
An antigen is a substance that the body may recognize as foreign and that may trigger immune responses. The terms immunogen and antigen are often used interchangeably.
Antibodies are proteins that are produced in response to antigens introduced into the body. Antibodies protect the body from disease by:
- binding to the surface of the antigen to block its biological activity (neutralization)
- binding to the antigen that coats the surface of the infectious agent to make it more susceptible to clearance (phagocytosis) by phagocytes (opsonization)
- binding to specialized cells of the immune system, allowing them to recognize and respond to the antigen
- activation of the complement system to directly cause disintegration (lysis) of the infectious agent (pathogen) to enhance its phagocytosis, and to attract other immune cells towards the pathogen.
# Immune responses
Immunity is the ability of the human body to protect itself from infectious diseases. The human immune system is able to react to an enormous number and variety of foreign antigens and provides immunity through two complementary types of responses:
- Innate immunity is the body's initial defense mechanism that comes into play immediately or within hours of a pathogen's entry into the body. Innate immunity is made up of physical barriers (skin and mucous membranes); physiologic defenses (temperature, low pH and chemical mediators); evolutionarily-conserved pattern recognition receptors that react to protein signatures on microbes (i.e. pathogen associated molecular patterns), as well as phagocytic and humoral inflammatory responses. Innate immunity:
+ does not depend upon previous exposure to the pathogen
+ does not produce immunologic memory
+ does not improve with repeated exposure to the pathogen.
- Adaptive immunity is the body's second level of defense, which develops as a result of infection with a pathogen or following immunization. Adaptive immunity defends against a specific pathogen and takes several days to weeks to become protective. Adaptive immunity:
+ has the capacity for immunologic memory
+ provides long term immunity which may persist for a lifetime
+ increases in strength and precision each time it encounters a specific antigen.
The cells of the adaptive immune system include specialized white blood cells (B and T lymphocytes) which can contribute to either cell-mediated immunity or antibody-mediated (humoral) immunity:
- Cell-mediated immunity provides protection through the activation of T cells which can destroy infected host cells or stimulate other immune cells to directly destroy pathogens.
- Antibody-mediated (humoral) immunity provides protection through the activation of B cells which produce antibodies. The terms antibody and immunoglobulin (Ig) are often used interchangeably. There are five types (classes) of antibodies: IgA, IgD, IgE, IgG and IgM (IgA and IgG also have several subclasses). Each class of antibody has a different way of contributing to immunity.
Immunologic memory is the immune system's ability to remember its experience with an infectious agent, leading to effective and rapid immune response upon subsequent exposure to the same or similar infectious agents. Development of a complete immunologic memory requires participation of both B and T cells; memory B cell development is dependent on the presentation of antigens by T cells.
Immunizing agents
Immunization refers to the process by which a person becomes protected against a disease through exposure to immunizing agents. Immunizing agents are classified as active or passive, depending on the process by which they confer immunity; prevention of disease through the use of immunizing agents is called immunoprophylaxis.
Active immunization is the inherent production of antibodies against a specific agent after exposure to the antigen through vaccination. Active immunizing agents are typically referred to as vaccines. Refer to in Part 4 for information about active vaccines.
Passive immunization involves the transfer of pre-formed antibodies, from one person to another or from an animal product, to provide immediate, temporary protection from infection or to reduce the severity of illness caused by the infectious agent. Protection provided by passive immunization is temporary because the transferred antibodies degrade over time. Passive immunization can occur by transplacental transfer of maternal antibodies to the developing fetus, or it can be provided by systemic administration of a passive immunizing agent.
In addition to the active component (antigen in case of vaccines or antibody in case of immunoglobulins), immunizing agents may contain additional ingredients such as preservatives, additives, adjuvants and traces of other substances. Refer to for more information.
# Vaccines
Vaccines are complex biologic products designed to induce a protective immune response effectively and safely. An ideal vaccine is: safe with minimal adverse effects; effective in providing lifelong protection against disease after a single dose that can be administered at birth; inexpensive; stable during shipment and storage; and easy to administer. Some vaccines come closer to fulfilling these criteria than others. Although each vaccine has its own benefits and risks, and indications and contraindications, all vaccines offer protection against the disease for which they were created.
Vaccines are classified according to the type of active component (antigen) they contain and are most often categorized in two groups - live attenuated vaccines and non-live vaccines:
- Live attenuated vaccines contain whole, weakened bacteria or viruses. Since the agent replicates within the vaccine recipient, the stimulus to the immune system more closely resembles that associated with natural infection, resulting in longer lasting and broader immunity than can be achieved with other vaccine types. Because of the strong immunogenic response, live attenuated vaccines, except those administered orally, typically produce immunity in most recipients with one dose; however, a second dose helps to make sure that almost all vaccine recipients are protected, because some individuals may not respond to the first dose. Live vaccines require careful storage and handling to avoid inadvertent inactivation.
- Non-live vaccines contain whole inactivated (killed) bacteria or viruses, their parts, or products secreted by bacteria that are modified to remove their pathogenic effects (toxoids). Non-live vaccines cannot cause the disease they are designed to prevent. Because the immune response to non-live vaccines may be less than that induced by live organisms, they often require adjuvants and multiple doses. The initial doses prime the immune system and are called primary vaccination or the primary series. As protection following primary vaccination diminishes over time, periodic supplemental doses (booster doses) may be required to increase or boost antibody levels.
# Immunoglobulins
Passive immunization with immune globulins provides protection when vaccines for active immunization are unavailable or contraindicated, or in certain instances when unimmunized individuals have been exposed to the infectious agent and rapid protection is required (post-exposure immunoprophylaxis). Passive immunization also has a role in the management of immunocompromised people who may not be able to respond adequately to vaccines or for whom live vaccines may be contraindicated. The duration of the beneficial effects provided by passive immunizing agents is relatively short and protection may be incomplete.
There are two types of antibody preparations available:
- Standard immunoglobulin (Ig) of human origin – sometimes referred to as "immune serum globulin", "serum immune globulin" or "gamma globulin"
- Specific immunoglobulins of human or animal origin, or produced by recombinant DNA technology - containing high titres of specific antibodies against a particular microorganism or its toxin. Products of human origin are preferred over those of animal origin because of the high incidence of adverse reactions to animal sera and the longer lasting protection conferred by human immunoglobulins.
Standard Immunoglobulin (Human)
Standard human Ig, GamaSTAN®, is a sterile, concentrated solution for intramuscular (IM) injection containing 15% to 18% Ig. It is obtained from pooled human plasma from screened donors and contains mainly IgG with small amounts of IgA and IgM.
Subcutaneous (Sc) and intravenous (IV) Ig preparations are primarily used for continuous passive immunization for persons with selected congenital or acquired Ig deficiency states and as an immunomodulator in certain diseases.
Specific Immunoglobulins
Specific immunoglobulins are derived from the pooled sera of people with antibodies to specific infectious agents; antisera from horses that are hyper-immunized against a specific organism when human products are not available; or recombinant DNA technology. Immunoglobulins from human or animal sources are made by more than one B cell clone (polyclonal) and can bind to heterogeneous antigens. Antibodies produced through recombinant DNA technology originate from a single clone of B cells (monoclonal) and are specific to only one antigen. A monoclonal antibody product is available for the prevention of respiratory syncytial virus (RSV) infection. Because of the relatively high risk of a specific type of immunological reaction (known as serum sickness) following the use of animal products, human Ig should be used whenever possible.
Vaccine development
# How vaccines are developed
New vaccines undergo a very rigorous development process. The first steps in the development of a vaccine include the identification of the microorganism or toxin that causes a significant burden of disease in the population, and an understanding of the biological mechanisms occurring in the development of the disease (pathogenesis). Once the pathogen and pathogenesis are understood, research is initiated into the possibility of developing a vaccine to reduce the disease incidence, or severity, or both. Pre-clinical laboratory testing is carried out to ensure that the candidate vaccine produces the immune response needed to prevent disease and has no toxicities that would prevent its use in people. Clinical trials (human studies) then proceed through several phases involving progressively more study subjects. in Part 2 describes pre-clinical and clinical research throughout the vaccine life cycle and the accompanying regulatory requirements to ensure data and product quality.
How vaccines work
Vaccines work at an individual level to protect the immunized person against the specific disease, as well as at a population level to reduce the incidence of the disease in the population, thereby reducing exposure of susceptible persons and consequent illness. Although the primary measure of effectiveness occurs at an individual level, there is also interest in decreasing or even eliminating disease at a population level.
# How vaccines work at the individual level
Administration of a vaccine antigen triggers an inflammatory reaction that is initially mediated by the innate immune system and subsequently expands to involve the adaptive immune system through the activation of T and B cells. While the majority of vaccines provide protection through the induction of humoral immunity (primarily through B cells), some vaccines, such as BCG and live herpes zoster vaccines, act principally by inducing cell-mediated immunity (primarily though T cells). Many vaccines probably work through both, although humoral immunity is the basis most often used as a marker of how well a vaccine works.
Long-term immunity requires the persistence of antibodies, or the creation and maintenance of antigen-specific memory cells (priming) that can rapidly reactivate to produce an effective immune response upon subsequent exposure to the same or similar antigen.
# Markers of protection induced by vaccination
A correlate of protection is a specific immune response that is responsible for and statistically linked to protection against infection or disease. Following administration of most vaccines, prevention of infection has been shown to correlate predominantly with the production of antigen-specific antibodies. The quantity and functional activity of antibodies can be measured using serological assays such as the enzyme-linked immunosorbent assay (ELISA), serum bactericidal antibody assay (SBA), and the opsonophagocytic assay (OPA). In cases when a correlate of protection cannot be determined, a substitute (surrogate) immune marker is used. Surrogate markers may not be directly linked to protection against infection or disease. For example, vaccines against rotavirus produce both mucosal and serum antibodies. Whereas serum antibodies are not directly protective against rotavirus infection, they serve as a surrogate of protection since mucosal antibodies are difficult to measure.
Immunogenicity means the vaccine's ability to induce an immune response. Vaccine-induced seroconversion is the development of detectable antigen-specific antibodies in the serum as a result of vaccination; seroprotection is a predetermined antibody concentration as a result of vaccination, above which the probability of infection is low. The seroprotective antibody concentration differs depending on the vaccine.
# How vaccines work at the population-level
Vaccine efficacy refers to the vaccine's ability to prevent illness in people vaccinated in controlled studies. Vaccine effectiveness refers to the vaccine's ability to prevent illness in people in the "real world".
Herd immunity refers to the immunity of a population against a specific infectious disease. The resistance of that population to the spread of an infectious disease is based on the percentage of people who are immune and the probability that those who are still susceptible will come into contact with an infected person. The proportion of the population required to be immune to reach herd immunity depends on a number of factors, the most important one being the transmissibility of the infectious agent either from a symptomatically infected person or from an asymptomatically colonized person.
The reproduction number (R0), also called the basic reproductive rate, is defined as the average number of transmissions expected from a single primary case introduced into a totally susceptible population. Diseases that are highly infectious have a high R0 (for example, measles) and require higher immunization (vaccine) coverage to attain herd immunity than a disease with a lower R0 (for example, rubella, *Haemophilus influenzae- type b). Immunization coverage refers to the proportion of the population (either overall or for particular risk groups) that has been immunized against a disease. To stop transmission of a given disease, there needs to be at least a specified percentage (1 minus 1/R0) of the population immune to the disease. For example, measles has an estimated R0 of 15; therefore, at least 94% (1 minus 1/15 = 94%) of the population needs to be immune to prevent transmission of measles.
# Determinants of vaccine response in individuals
The strength and duration of the immune system's response to a vaccine is determined by a number of factors as outlined in .
- Non-live vaccines often require adjuvants to enhance antibody responses, usually require multiple doses to generate high and sustained antibody responses, and induce vaccine antibodies that decline over time below protective thresholds unless repeat exposure to the antigen reactivates immune memory. Pure polysaccharide vaccines induce limited immune response and do not induce immunologic memory.
- Conjugating (linking) a polysaccharide with a carrier protein (protein that is easily recognized by the immune system such as diphtheria or tetanus) leads to a significantly higher immune response.
- In general, antibody responses to vaccines received early in life decline rapidly for most, but not all (for example, hepatitis B) vaccines.
- In older age, immune responses decline (immunosenescence) and can result in a reduction in the strength and persistence of antibody responses to vaccines and in an increased incidence and severity of infectious diseases.
- The immune response to live vaccines will be influenced by passively transferred antibodies, such as after blood product transfusion or receipt of immunoglobulins. Refer to in Part 1 for additional information.
Epidemiology and immunization
Epidemiology provides data on the distribution and determinants of diseases. Epidemiology informs the first steps in vaccine development by describing the diseases caused by a pathogen in a particular population and indicating the need for vaccine development. As a vaccine is introduced into the population, epidemiology monitors the effect of the vaccine in the population by describing changes in the disease burden and the pathogens causing that disease. Epidemiology can also provide information regarding immunization coverage and vaccine safety.
Surveillance is the process of systematic collection, orderly analysis, evaluation and reporting of epidemiological data to inform disease control measures or policy decisions, or both. Surveillance of vaccine preventable diseases, including immunization coverage and vaccine safety, is needed to:
- identify and quantify risk factors to enable appropriate control of communicable diseases.
- assist in the investigation, containment and management of vaccine preventable disease outbreaks or a signal of adverse events following immunization.
- monitor progress toward the achievement of set goals and targets in disease control programs.
- provide up-to-date information to assist in the development of evidence-based guidelines.
Determining the burden of disease is important in setting immunization priorities. Burden of disease includes: the prevalence (total number of cases of a disease in a geographic area); the incidence (number of new cases of a disease in a geographic area over a specified period of time); the age or risk group that is most affected (for example, infants, children, adults, the elderly, immunocompromised persons); the severity of the disease (for example, as measured by time missed from work, hospitalization, complications or death); and the risk factors for disease that should be considered. These factors are particularly important when making vaccine recommendations regarding:
- populations who are susceptible to the disease and who require the direct protection of a vaccine; and
- populations who require indirect protection through herd immunity because they are susceptible to the disease but may not be the ideal target group to receive the vaccine.
Evaluation of vaccine programs is the systematic investigation of the structure, activities, or outcomes of public health programs. It explores whether or not activities are implemented as planned and outcomes have occurred as intended, and why. Evaluation can help to support program implementation and build on the program monitoring activities that immunization programs currently conduct to assess whether program objectives have been met.
Future of vaccinology
Ongoing scientific advances in biotechnology, genetics, immunology and virology are providing new tools for vaccine development. This knowledge provides the basis for improving the effectiveness of existing vaccines, as well as the development of new vaccines and vaccine delivery systems. These ongoing scientific advances in vaccine development need to be accompanied by scientific advances in epidemiological methods which can continue to inform the development and monitoring of new vaccines. The following are a few emerging areas in vaccinology, some form the foundation of basic research studies and some are already being tested in clinical trials around the world:
- Reverse vaccinology and bioinformatics: the broad sequencing of pathogen genomes allows the development of experimental vaccines for new candidate proteins/antigens that had not been previously identified.
- Viral or bacterial vector vaccines: a few genes coding for pathogen antigens can be inserted into a completely different benign virus or bacteria, which can then be used to infect the host and provide a safe active supply of the target antigens to promote strong immunity.
- DNA vaccines: DNA sequences coding for pathogen antigens can be stored on a bacterial plasmid, which is then taken into host cells upon injection of the DNA plasmid. The harmless vaccine antigens can then be actively produced by host cells.
- Recombinant subunit vaccines: several vaccines are currently produced in chicken eggs, but recombinant DNA technologies have been developed that allow vaccine proteins to be expressed by alternative cell types in controlled settings, including insect, plant, yeast, and mammalian cells. These provide good avenues for the rapid large-scale production of antigens to be used in vaccines.
- Personalized vaccinomics: different populations and individuals have different immune profiles, for example infants versus the elderly, and different adjuvant-vaccine combinations may be necessary to optimize individual vaccine responses. As new screening technologies are developed it may be possible to provide individuals with vaccines tailored to their immune system, thus improving vaccine immunogenicity or effectiveness, and preventing vaccine failure or adverse events.
- Adjuvant technologies: new adjuvants are being developed that can enhance the type of immune response (humoral versus cell-mediated) desired to eliminate specific pathogens; these adjuvants provide better immunity and can allow for a lower dose of antigen within the vaccine. Furthermore, new research into the innate immune system is informing the development of adjuvants that make better use of innate immune mechanisms to direct adaptive immunity.
For further information please see the selected references below. |
Basic immunology and vaccinology: Canadian Immunization Guide
==============================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-13-recommended-immunization-schedules.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html)
Notice
------
* This CIG chapter has not been updated to contain any information regarding COVID-19 vaccines, refer to the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html).
****Last partial content update**** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): January 2020
This chapter was updated to align with changes made to [Herpes Zoster (Shingles) Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-8-herpes-zoster-(shingles)-vaccine.html) Chapter in Part 4 based on NACI's [Updated Recommendations on the Use of Herpes Zoster Vaccines](/en/services/health/publications/healthy-living/updated-recommendations-use-herpes-zoster-vaccines.html).
**Last complete chapter revision** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html#t2015)): April 2017
On this page
------------
* [Introduction](#a1)
* [Human immune system](#a2)
* [Immunizing agents](#a3)
+ [Vaccines](#a9)
+ [Immunoglobulins](#a10)
* [Vaccine development](#a4)
* [How vaccines work](#a5)
+ [Table 1: Determinants of vaccine response in individuals](#t1)
* [Epidemiology and immunization](#a6)
* [Future of vaccinology](#a7)
* [Selected references](#a8)
Introduction
------------
Immunology is the study of the structure and function of the immune system. Vaccinology is the science of vaccine development and how the immune system responds to vaccines, as well as the ongoing evaluation of immunization programs, vaccine safety and effectiveness, and surveillance of the epidemiology of vaccine preventable diseases. This chapter provides a brief overview of some of the main concepts of immunology and vaccinology as they relate to immunization. A detailed review of immunology and vaccinology is beyond the scope of the Canadian Immunization Guide.
Human immune system
-------------------
### Components of the immune system
An antigen is a substance that the body may recognize as foreign and that may trigger immune responses. The terms immunogen and antigen are often used interchangeably.
Antibodies are proteins that are produced in response to antigens introduced into the body. Antibodies protect the body from disease by:
* binding to the surface of the antigen to block its biological activity (neutralization)
* binding to the antigen that coats the surface of the infectious agent to make it more susceptible to clearance (phagocytosis) by phagocytes (opsonization)
* binding to specialized cells of the immune system, allowing them to recognize and respond to the antigen
* activation of the complement system to directly cause disintegration (lysis) of the infectious agent (pathogen) to enhance its phagocytosis, and to attract other immune cells towards the pathogen.
### Immune responses
Immunity is the ability of the human body to protect itself from infectious diseases. The human immune system is able to react to an enormous number and variety of foreign antigens and provides immunity through two complementary types of responses:
* Innate immunity is the body's initial defense mechanism that comes into play immediately or within hours of a pathogen's entry into the body. Innate immunity is made up of physical barriers (skin and mucous membranes); physiologic defenses (temperature, low pH and chemical mediators); evolutionarily-conserved pattern recognition receptors that react to protein signatures on microbes (i.e. pathogen associated molecular patterns), as well as phagocytic and humoral inflammatory responses. Innate immunity:
+ does not depend upon previous exposure to the pathogen
+ does not produce immunologic memory
+ does not improve with repeated exposure to the pathogen.
* Adaptive immunity is the body's second level of defense, which develops as a result of infection with a pathogen or following immunization. Adaptive immunity defends against a specific pathogen and takes several days to weeks to become protective. Adaptive immunity:
+ has the capacity for immunologic memory
+ provides long term immunity which may persist for a lifetime
+ increases in strength and precision each time it encounters a specific antigen.
The cells of the adaptive immune system include specialized white blood cells (B and T lymphocytes) which can contribute to either cell-mediated immunity or antibody-mediated (humoral) immunity:
* Cell-mediated immunity provides protection through the activation of T cells which can destroy infected host cells or stimulate other immune cells to directly destroy pathogens.
* Antibody-mediated (humoral) immunity provides protection through the activation of B cells which produce antibodies. The terms antibody and immunoglobulin (Ig) are often used interchangeably. There are five types (classes) of antibodies: IgA, IgD, IgE, IgG and IgM (IgA and IgG also have several subclasses). Each class of antibody has a different way of contributing to immunity.
Immunologic memory is the immune system's ability to remember its experience with an infectious agent, leading to effective and rapid immune response upon subsequent exposure to the same or similar infectious agents. Development of a complete immunologic memory requires participation of both B and T cells; memory B cell development is dependent on the presentation of antigens by T cells.
Immunizing agents
-----------------
Immunization refers to the process by which a person becomes protected against a disease through exposure to immunizing agents. Immunizing agents are classified as active or passive, depending on the process by which they confer immunity; prevention of disease through the use of immunizing agents is called immunoprophylaxis.
Active immunization is the inherent production of antibodies against a specific agent after exposure to the antigen through vaccination. Active immunizing agents are typically referred to as vaccines. Refer to [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for information about active vaccines.
Passive immunization involves the transfer of pre-formed antibodies, from one person to another or from an animal product, to provide immediate, temporary protection from infection or to reduce the severity of illness caused by the infectious agent. Protection provided by passive immunization is temporary because the transferred antibodies degrade over time. Passive immunization can occur by transplacental transfer of maternal antibodies to the developing fetus, or it can be provided by systemic administration of a passive immunizing agent.
In addition to the active component (antigen in case of vaccines or antibody in case of immunoglobulins), immunizing agents may contain additional ingredients such as preservatives, additives, adjuvants and traces of other substances. Refer to [Contents of Immunizing Agents Available for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) for more information.
### Vaccines
Vaccines are complex biologic products designed to induce a protective immune response effectively and safely. An ideal vaccine is: safe with minimal adverse effects; effective in providing lifelong protection against disease after a single dose that can be administered at birth; inexpensive; stable during shipment and storage; and easy to administer. Some vaccines come closer to fulfilling these criteria than others. Although each vaccine has its own benefits and risks, and indications and contraindications, all vaccines offer protection against the disease for which they were created.
Vaccines are classified according to the type of active component (antigen) they contain and are most often categorized in two groups - live attenuated vaccines and non-live vaccines:
* Live attenuated vaccines contain whole, weakened bacteria or viruses. Since the agent replicates within the vaccine recipient, the stimulus to the immune system more closely resembles that associated with natural infection, resulting in longer lasting and broader immunity than can be achieved with other vaccine types. Because of the strong immunogenic response, live attenuated vaccines, except those administered orally, typically produce immunity in most recipients with one dose; however, a second dose helps to make sure that almost all vaccine recipients are protected, because some individuals may not respond to the first dose. Live vaccines require careful storage and handling to avoid inadvertent inactivation.
* Non-live vaccines contain whole inactivated (killed) bacteria or viruses, their parts, or products secreted by bacteria that are modified to remove their pathogenic effects (toxoids). Non-live vaccines cannot cause the disease they are designed to prevent. Because the immune response to non-live vaccines may be less than that induced by live organisms, they often require adjuvants and multiple doses. The initial doses prime the immune system and are called primary vaccination or the primary series. As protection following primary vaccination diminishes over time, periodic supplemental doses (booster doses) may be required to increase or boost antibody levels.
### Immunoglobulins
Passive immunization with immune globulins provides protection when vaccines for active immunization are unavailable or contraindicated, or in certain instances when unimmunized individuals have been exposed to the infectious agent and rapid protection is required (post-exposure immunoprophylaxis). Passive immunization also has a role in the management of immunocompromised people who may not be able to respond adequately to vaccines or for whom live vaccines may be contraindicated. The duration of the beneficial effects provided by passive immunizing agents is relatively short and protection may be incomplete.
There are two types of antibody preparations available:
* **Standard immunoglobulin (Ig) of human origin** – sometimes referred to as "immune serum globulin", "serum immune globulin" or "gamma globulin"
* **Specific immunoglobulins of human or animal origin, or produced by recombinant DNA technology** - containing high titres of specific antibodies against a particular microorganism or its toxin. Products of human origin are preferred over those of animal origin because of the high incidence of adverse reactions to animal sera and the longer lasting protection conferred by human immunoglobulins.
**Standard Immunoglobulin (Human)**
Standard human Ig, GamaSTAN®, is a sterile, concentrated solution for intramuscular (IM) injection containing 15% to 18% Ig. It is obtained from pooled human plasma from screened donors and contains mainly IgG with small amounts of IgA and IgM.
Subcutaneous (Sc) and intravenous (IV) Ig preparations are primarily used for continuous passive immunization for persons with selected congenital or acquired Ig deficiency states and as an immunomodulator in certain diseases.
**Specific Immunoglobulins**
Specific immunoglobulins are derived from the pooled sera of people with antibodies to specific infectious agents; antisera from horses that are hyper-immunized against a specific organism when human products are not available; or recombinant DNA technology. Immunoglobulins from human or animal sources are made by more than one B cell clone (polyclonal) and can bind to heterogeneous antigens. Antibodies produced through recombinant DNA technology originate from a single clone of B cells (monoclonal) and are specific to only one antigen. A monoclonal antibody product is available for the prevention of respiratory syncytial virus (RSV) infection. Because of the relatively high risk of a specific type of immunological reaction (known as serum sickness) following the use of animal products, human Ig should be used whenever possible.
Vaccine development
-------------------
### How vaccines are developed
New vaccines undergo a very rigorous development process. The first steps in the development of a vaccine include the identification of the microorganism or toxin that causes a significant burden of disease in the population, and an understanding of the biological mechanisms occurring in the development of the disease (pathogenesis). Once the pathogen and pathogenesis are understood, research is initiated into the possibility of developing a vaccine to reduce the disease incidence, or severity, or both. Pre-clinical laboratory testing is carried out to ensure that the candidate vaccine produces the immune response needed to prevent disease and has no toxicities that would prevent its use in people. Clinical trials (human studies) then proceed through several phases involving progressively more study subjects. [Adverse events following immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) in Part 2 describes pre-clinical and clinical research throughout the vaccine life cycle and the accompanying regulatory requirements to ensure data and product quality.
How vaccines work
-----------------
Vaccines work at an individual level to protect the immunized person against the specific disease, as well as at a population level to reduce the incidence of the disease in the population, thereby reducing exposure of susceptible persons and consequent illness. Although the primary measure of effectiveness occurs at an individual level, there is also interest in decreasing or even eliminating disease at a population level.
### How vaccines work at the individual level
Administration of a vaccine antigen triggers an inflammatory reaction that is initially mediated by the innate immune system and subsequently expands to involve the adaptive immune system through the activation of T and B cells. While the majority of vaccines provide protection through the induction of humoral immunity (primarily through B cells), some vaccines, such as BCG and live herpes zoster vaccines, act principally by inducing cell-mediated immunity (primarily though T cells). Many vaccines probably work through both, although humoral immunity is the basis most often used as a marker of how well a vaccine works.
Long-term immunity requires the persistence of antibodies, or the creation and maintenance of antigen-specific memory cells (priming) that can rapidly reactivate to produce an effective immune response upon subsequent exposure to the same or similar antigen.
### Markers of protection induced by vaccination
A correlate of protection is a specific immune response that is responsible for and statistically linked to protection against infection or disease. Following administration of most vaccines, prevention of infection has been shown to correlate predominantly with the production of antigen-specific antibodies. The quantity and functional activity of antibodies can be measured using serological assays such as the enzyme-linked immunosorbent assay (ELISA), serum bactericidal antibody assay (SBA), and the opsonophagocytic assay (OPA). In cases when a correlate of protection cannot be determined, a substitute (surrogate) immune marker is used. Surrogate markers may not be directly linked to protection against infection or disease. For example, vaccines against rotavirus produce both mucosal and serum antibodies. Whereas serum antibodies are not directly protective against rotavirus infection, they serve as a surrogate of protection since mucosal antibodies are difficult to measure.
Immunogenicity means the vaccine's ability to induce an immune response. Vaccine-induced seroconversion is the development of detectable antigen-specific antibodies in the serum as a result of vaccination; seroprotection is a predetermined antibody concentration as a result of vaccination, above which the probability of infection is low. The seroprotective antibody concentration differs depending on the vaccine.
### How vaccines work at the population-level
Vaccine efficacy refers to the vaccine's ability to prevent illness in people vaccinated in controlled studies. Vaccine effectiveness refers to the vaccine's ability to prevent illness in people in the "real world".
Herd immunity refers to the immunity of a population against a specific infectious disease. The resistance of that population to the spread of an infectious disease is based on the percentage of people who are immune and the probability that those who are still susceptible will come into contact with an infected person. The proportion of the population required to be immune to reach herd immunity depends on a number of factors, the most important one being the transmissibility of the infectious agent either from a symptomatically infected person or from an asymptomatically colonized person.
The reproduction number (R0), also called the basic reproductive rate, is defined as the average number of transmissions expected from a single primary case introduced into a totally susceptible population. Diseases that are highly infectious have a high R0 (for example, measles) and require higher immunization (vaccine) coverage to attain herd immunity than a disease with a lower R0 (for example, rubella, *Haemophilus influenzae* type b). Immunization coverage refers to the proportion of the population (either overall or for particular risk groups) that has been immunized against a disease. To stop transmission of a given disease, there needs to be at least a specified percentage (1 minus 1/R0) of the population immune to the disease. For example, measles has an estimated R0 of 15; therefore, at least 94% (1 minus 1/15 = 94%) of the population needs to be immune to prevent transmission of measles.
### Determinants of vaccine response in individuals
The strength and duration of the immune system's response to a vaccine is determined by a number of factors as outlined in [Table 1](#p1c13t1).
Table 1: Determinants of vaccine response in individuals| Determinants of vaccine response | Explanation |
| --- | --- |
| Vaccine type | The type of vaccine antigen and its immunogenicity directly influence the nature of the immune response that is induced to provide protection:* Live attenuated vaccines generally induce a significantly stronger and more sustained antibody response.
* Non-live vaccines often require adjuvants to enhance antibody responses, usually require multiple doses to generate high and sustained antibody responses, and induce vaccine antibodies that decline over time below protective thresholds unless repeat exposure to the antigen reactivates immune memory. Pure polysaccharide vaccines induce limited immune response and do not induce immunologic memory.
|
| Vaccine adjuvants and carrier proteins | * The addition of adjuvants to non-live vaccines enhances the immune response and extends the duration of B and T cell activation.
* Conjugating (linking) a polysaccharide with a carrier protein (protein that is easily recognized by the immune system such as diphtheria or tetanus) leads to a significantly higher immune response.
|
| Optimal dose of antigen | * Higher doses of inactivated antigens, up to a threshold, elicit higher antibody responses.
|
| Interval between doses | * The recommended interval between doses allows development of successive waves of antigen-specific immune system responses without interference, as well as the maturation of memory cells.
|
| Age of vaccine recipient | * In early life, the immune system is immature, resulting in limited immune responses to vaccines. For example, children less than 2 years of age do not respond to polysaccharide-based vaccines.
* In general, antibody responses to vaccines received early in life decline rapidly for most, but not all (for example, hepatitis B) vaccines.
* In older age, immune responses decline (immunosenescence) and can result in a reduction in the strength and persistence of antibody responses to vaccines and in an increased incidence and severity of infectious diseases.
|
| Pre-existent antibodies | * The immune response to vaccines received early in life may be influenced by the presence of maternal antibodies transferred across the placenta.
* The immune response to live vaccines will be influenced by passively transferred antibodies, such as after blood product transfusion or receipt of immunoglobulins. Refer to [Blood products, human immunoglobulin and timing of immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) in Part 1 for additional information.
|
| Status of the immune system | * Immune response to vaccines will be modified by the status of vaccine recipient's immune system. Refer to [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) and [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional information.
|
Epidemiology and immunization
-----------------------------
Epidemiology provides data on the distribution and determinants of diseases. Epidemiology informs the first steps in vaccine development by describing the diseases caused by a pathogen in a particular population and indicating the need for vaccine development. As a vaccine is introduced into the population, epidemiology monitors the effect of the vaccine in the population by describing changes in the disease burden and the pathogens causing that disease. Epidemiology can also provide information regarding immunization coverage and vaccine safety.
Surveillance is the process of systematic collection, orderly analysis, evaluation and reporting of epidemiological data to inform disease control measures or policy decisions, or both. Surveillance of vaccine preventable diseases, including immunization coverage and vaccine safety, is needed to:
* identify and quantify risk factors to enable appropriate control of communicable diseases.
* assist in the investigation, containment and management of vaccine preventable disease outbreaks or a signal of adverse events following immunization.
* monitor progress toward the achievement of set goals and targets in disease control programs.
* provide up-to-date information to assist in the development of evidence-based guidelines.
Determining the burden of disease is important in setting immunization priorities. Burden of disease includes: the prevalence (total number of cases of a disease in a geographic area); the incidence (number of new cases of a disease in a geographic area over a specified period of time); the age or risk group that is most affected (for example, infants, children, adults, the elderly, immunocompromised persons); the severity of the disease (for example, as measured by time missed from work, hospitalization, complications or death); and the risk factors for disease that should be considered. These factors are particularly important when making vaccine recommendations regarding:
* populations who are susceptible to the disease and who require the direct protection of a vaccine; and
* populations who require indirect protection through herd immunity because they are susceptible to the disease but may not be the ideal target group to receive the vaccine.
Evaluation of vaccine programs is the systematic investigation of the structure, activities, or outcomes of public health programs. It explores whether or not activities are implemented as planned and outcomes have occurred as intended, and why. Evaluation can help to support program implementation and build on the program monitoring activities that immunization programs currently conduct to assess whether program objectives have been met.
Future of vaccinology
---------------------
Ongoing scientific advances in biotechnology, genetics, immunology and virology are providing new tools for vaccine development. This knowledge provides the basis for improving the effectiveness of existing vaccines, as well as the development of new vaccines and vaccine delivery systems. These ongoing scientific advances in vaccine development need to be accompanied by scientific advances in epidemiological methods which can continue to inform the development and monitoring of new vaccines. The following are a few emerging areas in vaccinology, some form the foundation of basic research studies and some are already being tested in clinical trials around the world:
* Reverse vaccinology and bioinformatics: the broad sequencing of pathogen genomes allows the development of experimental vaccines for new candidate proteins/antigens that had not been previously identified.
* Viral or bacterial vector vaccines: a few genes coding for pathogen antigens can be inserted into a completely different benign virus or bacteria, which can then be used to infect the host and provide a safe active supply of the target antigens to promote strong immunity.
* DNA vaccines: DNA sequences coding for pathogen antigens can be stored on a bacterial plasmid, which is then taken into host cells upon injection of the DNA plasmid. The harmless vaccine antigens can then be actively produced by host cells.
* Recombinant subunit vaccines: several vaccines are currently produced in chicken eggs, but recombinant DNA technologies have been developed that allow vaccine proteins to be expressed by alternative cell types in controlled settings, including insect, plant, yeast, and mammalian cells. These provide good avenues for the rapid large-scale production of antigens to be used in vaccines.
* Personalized vaccinomics: different populations and individuals have different immune profiles, for example infants versus the elderly, and different adjuvant-vaccine combinations may be necessary to optimize individual vaccine responses. As new screening technologies are developed it may be possible to provide individuals with vaccines tailored to their immune system, thus improving vaccine immunogenicity or effectiveness, and preventing vaccine failure or adverse events.
* Adjuvant technologies: new adjuvants are being developed that can enhance the type of immune response (humoral versus cell-mediated) desired to eliminate specific pathogens; these adjuvants provide better immunity and can allow for a lower dose of antigen within the vaccine. Furthermore, new research into the innate immune system is informing the development of adjuvants that make better use of innate immune mechanisms to direct adaptive immunity.
For further information please see the selected references below.
Selected references
-------------------
* Andre FE, Booy R, Bock HL et al. Vaccination greatly reduces disease, disability, death and inequity worldwide. Bull World Health Organ 2008;86(2):140-6.
* BC Centre for Disease Control. Immunization Coverage. Accessed July 2015 at: http://www.bccdc.ca/imm-vac/BCImmunizationCov/default.htm.
* Canadian Paediatric Society in association with the Public Health Agency of Canada and Health Canada. Immunization Competencies Education Program. 2011.
* Centers for Disease Control and Prevention. Immunization: The Basics. Accessed December 2016 at http://www.cdc.gov/vaccines/vac-gen/imz-basics.htm.
* Loomis RJ and Johnson PR. Emerging Vaccine Technologies. Vaccines 2015; 3(2):429-47.
* Nabel GJ. Designing Tomorrow's Vaccines. N Eng J Med 2013;368(6): 551-60.
* Pasquale AD, Press S, Silva FT, Garcon N. Vaccine Adjuvants: from 1920 to 2015 and beyond. Vaccines 2015; 3(2):320-34.
* Plotkin SA. Correlates of protection induced by vaccination. Clin Vaccine Immunol 2010;17(7):1055-65.
* Plotkin SA. Correlates of vaccine-induced immunity. Clin Infect Dis 2008;47 (3):401-09.
* Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines. 5th ed. Philadelphia, PA: Elsevier Health Sciences; 2008.
* Poland GA, Kennedy RB, McKinney BA et al. Vaccinomics, adversomics, and the immune response network theory: individualized vaccinology in the 21stcentury. Semin Immunol 2013; 25(2):89-103.
* Public Health Agency of Canada. Immunization Competencies for Health Professionals. 2008. Accessed July 2015 at: http://healthycanadians.gc.ca/publications/healthy-living-vie-saine/immunization-competencies-competences-immunisation/index-eng.php
* Pulendran B, Ahmed R. Immunological mechanisms of vaccination. Nat Immunol 2011;12(6):509-17.
* Warrington R, Watson W, Kim HL et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol 2011;7 Suppl 1:S1.
* Weinberger B, Herndler-Brandstetter D, Schwanninger A et al. Biology of Immune Responses to Vaccines in Elderly Persons. Clin Infect Dis. 2008;46(7):1078-84.
* World Health Organization. Protocol for the Assessment of National Communicable Disease Surveillance and Response Systems, Annex 1.0 Surveillance Definitions. Accessed July 2015 at: http://www.who.int/csr/resources/publications/surveillance/whocdscsrisr20012.pdf.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-13-recommended-immunization-schedules.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-14-basic-immunology-vaccinology.html&n=Basic%20immunology%20and%20vaccinology%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-14-basic-immunology-vaccinology.html&title=Basic%20immunology%20and%20vaccinology%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Email](mailto:?subject=Basic%20immunology%20and%20vaccinology%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-14-basic-immunology-vaccinology.html%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-14-basic-immunology-vaccinology.html&t=Basic%20immunology%20and%20vaccinology%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=Basic%20immunology%20and%20vaccinology%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-14-basic-immunology-vaccinology.html%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-14-basic-immunology-vaccinology.html&title=Basic%20immunology%20and%20vaccinology%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-14-basic-immunology-vaccinology.html&t=Basic%20immunology%20and%20vaccinology%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-14-basic-immunology-vaccinology.html&media=&description=Basic%20immunology%20and%20vaccinology%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-14-basic-immunology-vaccinology.html&title=Basic%20immunology%20and%20vaccinology%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-14-basic-immunology-vaccinology.html)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-14-basic-immunology-vaccinology.html&name=Basic%20immunology%20and%20vaccinology%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=Basic%20immunology%20and%20vaccinology%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-14-basic-immunology-vaccinology.html)
* [Whatsapp](https://api.whatsapp.com/send?text=Basic%20immunology%20and%20vaccinology%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-14-basic-immunology-vaccinology.html)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=Basic%20immunology%20and%20vaccinology%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-1-key-immunization-information%2Fpage-14-basic-immunology-vaccinology.html%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2022-09-16
| None | None |
b52b8123bf766d24b33916d4b23ac325b3cc8261 | cma | Recommendation on Repeated Seasonal Influenza Vaccination | Recommendation on Repeated Seasonal Influenza Vaccination
Preamble
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Summary of the information contained in this NACI statement
The following highlights key information for immunization providers. Please refer to the remainder of the statement for details.
# 1. What
Influenza is a respiratory illness caused primarily by influenza A and B viruses. The burden of influenza varies from year to year. Prior to the COVID-19 pandemic, influenza was responsible for an estimated 12,200 hospitalizations and 3,500 deaths annually in Canada. Influenza vaccination is repeated annually due to waning immunity and the tendency of influenza viruses to frequently mutate, requiring changes in the vaccine formulation.
Some studies from different influenza seasons have suggested that receiving the seasonal influenza vaccine in one or more previous seasons may reduce the effectiveness of the vaccine against strains circulating in the current season, while other studies have not.
# 2. Who
This Statement applies to all individuals 6 months of age and older who are not contraindicated to receive the influenza vaccine.
# 3. How
The seasonal influenza vaccine should be offered to all individuals 6 months of age and older on an annual basis, regardless of whether they received a seasonal influenza vaccine in prior seasons.
# 4. Why
Annual influenza vaccination reduces the morbidity and mortality associated with influenza infection. Overall, the evidence shows no difference in the effectiveness of repeated influenza vaccination compared to vaccination in the current season only. Of all the seasons investigated across many studies, only during two influenza seasons was repeated vaccination across seasons associated with a reduced effectiveness against influenza A(H3N2), compared to vaccination in the current season only. Further evaluation of the effects of repeated influenza vaccination on vaccine effectiveness (VE) is needed as there is currently no predictable association that could inform vaccine program decisions from year to year. Also, repeated vaccination including the current season is consistently more effective than no vaccination in the current season.
I. Introduction
Influenza is a respiratory illness caused primarily by influenza A and B viruses. Prior to the COVID-19 pandemic, influenza was estimated to cause approximately 12,200 hospitalizations and 3,500 deaths annually in Canada. Although the epidemiology of influenza has changed during the course of the COVID-19 pandemic, seasonal influenza presents an ongoing disease burden in Canada during the fall and winter months, which varies from year to year. To reduce the morbidity and mortality associated with influenza, the National Advisory Committee on Immunization (NACI) recommends annual influenza vaccination for everyone 6 months of age and older who does not have contraindications to the vaccine. Influenza vaccination must be repeated annually due to waning of vaccine and infection-induced immunity against influenza over time and because influenza viruses frequently undergo antigenic drift. As a result, the World Health Organization (WHO) convenes twice a year to assess the currently circulating influenza strains and to recommend which strains should be used in the influenza vaccine for the upcoming Northern and Southern Hemisphere influenza seasons.
However, there is a growing body of evidence that explores the potential negative effects of repeated seasonal influenza vaccination on current season VE. This issue was first studied in the 1970s, and since then several studies have indicated a potential negative impact of prior influenza vaccination on current season influenza VE5
The primary objective of this overview of reviews is:
- To summarize the evidence from systematic reviews on the effects of repeated seasonal influenza vaccination on VE, vaccine efficacy and immunogenicity
II. Methods
# II.1 Research question
What are the effects of repeated seasonal influenza vaccination on VE, efficacy, and immunogenicity?
P (population): Adults and children
I (intervention): Seasonal influenza vaccination in prior season(s) and current season
C (comparison): Seasonal influenza vaccination in prior season(s) only OR in current season only OR unvaccinated in any season included in the study
O (outcome): VE, vaccine efficacy, or immunogenicity in the current season
S (study design): Systematic review and meta-analysis
An a priori search strategy was developed in collaboration with a federal reference librarian of the Health Library of Health Canada and PHAC that included search terms for "influenza", "repeated vaccination", "systematic review", and "meta-analysis". The complete search strategy can be found in . The search was limited to studies published in the English or French language and to a publication date of 2016 to June 2019. NACI was already aware of two systematic reviews that were published in 2017; therefore, the search was restricted to systematic reviews (SRs) and meta-analyses (MAs) published in 2016 or later to ensure that any additional recent and relevant SRs/MAs were captured. No limitation was placed on the types of primary study designs included in the SR/MA.
Inclusion criteria:
1. The study is a SR/MA;
2. The study assesses the effects of repeated influenza vaccination on VE, efficacy or immunogenicity.
Exclusion criteria:
1. The study only presents primary research;
2. The study is in language other than English or French;
3. The study only includes non-human studies;
4. The date of publication of the study is prior to 2016.
Abstracts and titles of records retrieved by the database search were loaded into DistillerSR (Evidence Partners, Ottawa, Canada) for screening. If the abstract and title met the inclusion criteria, or if it was not possible to determine eligibility based on the abstract and title alone, the full text was assessed for eligibility. Two reviewers independently screened titles, abstracts, and full texts for eligibility. Full texts that met all inclusion criteria were further assessed for the relevance of the SR/MA's PICO, as compared to the PICO formulated a priori by the NACI Influenza Working Group (outlined above) and for quality. SRs/MAs that were not considered sufficiently relevant for NACI's purposes or were not of sufficient quality were excluded from synthesis. This approach to the inclusion of systematic reviews into public health guidance was based on the methodology proposed within the Project on a Framework for Rating Evidence in Public Health (PRECEPT) and was initially developed by the United States Agency for Healthcare Research and Quality (AHRQ). The quality of the SRs/MAs were assessed using AMSTAR 2, which is a tool specifically designed to examine SR/MA quality. SRs/MAs for which reviewers had many serious concerns across AMSTAR 2 domains would be excluded.
Data from included SRs/MAs were extracted using a template with variables defined a priori. Extracted pooled effect estimates from SRs/MAs were assumed to represent pooled unadjusted estimates, unless otherwise specified. Quality assessment and data extraction were completed independently by two reviewers. Any disagreements during eligibility assessment, quality assessment, or data extraction were discussed until a consensus was reached. Results of subgroup analyses that included only one study were not extracted. Evidence was synthesized narratively, and estimates from all included SRs/MAs were discussed, regardless of primary study overlap.
III. Results
# III.1 Study characteristics
Through a comprehensive literature search performed on October 27, 2017 and updated on June 3, 2019, five SRs/MAs were identified as eligible for inclusion in the evidence synthesis; two through Medline, one through PROSPERO, and two that had previously been identified by experts. All five of the identified SRs/MAs sufficiently aligned with this overview's PICO (). No new or ongoing SRs/MAs eligible for inclusion were identified through additional PROSPERO search updates conducted through March 2022. A complete PRISMA flow diagram can be found in , and a full list of excluded studies and reason for exclusion is available upon request. None of the SRs/MAs included primary studies that assessed immunogenicity. Additional inclusion and exclusion criteria outlined for each SR/MA that were not specified by this overview's PICO are detailed in .
Yes: SR/MA's PICO aligns with this overview's PICO;
No: SR/MA's PICO does not align with this overview's PICO;
Partial: SR/MA's PICO partially, but not completely, aligns with this overview's PICO.
Results from the AMSTAR 2 quality assessment are presented in . For this review, none of the domains within AMSTAR 2 were highlighted as "critical". The SRs/MAs conducted by Bartoszko et al., Morimoto et al., and Ramsay et al. were similar in quality and had minor differences across domains. Importantly, The SR/MA conducted by Belongia et al. was judged to be of lower quality primarily due to the lack of a documented risk of bias (RoB) appraisal of included studies. None of the SRs/MAs included a list of excluded studies or reported the funding sources for included primary studies. In addition, none of the SRs/MAs provided a full investigation of heterogeneity within the results; however, most studies discussed important, non-measured factors that would impact VE in the discussion (e.g., history of natural infection). Two of the reviews searched the grey literature (i.e., trial registries), three assessed the quality of the included studies, and two assessed the likelihood of publication bias. The SR/MA conducted by Caspard et al. had a large number of serious concerns across almost all AMSTAR 2 domains. Of particular note, no evidence for a priori design was provided, study selection and data extraction were not performed in duplicate, no quality assessment was specified, and heterogeneity was not assessed. In addition, a fixed effects model was used to estimate the efficacy of the influenza vaccines, which, given the expected differences in estimates across seasons, would not be appropriate; a random effects model would be preferred and was used in all other included SRs/MAs. Due to the limitations of the Caspard et al. SR/MA regarding these AMSTAR 2 domains, this SR/MA was excluded from evidence synthesis.
Included: SR/MA explicitly states as inclusion criteria; Excluded: SR/MA explicitly states as exclusion criteria; Unknown: SR/MA does not explicitly state as inclusion/exclusion criteria; inclusion/exclusion criteria may or may not preclude from including/excluding studies.
The two studies that assessed the quality of included observational studies found that the RoB for included observational studies was low according to the Newcastle-Ottawa Scale. The evidence for laboratory confirmed influenza (LCI) infection from randomized controlled trials (RCTs) included by Bartoszko et al. was determined by the authors to have a serious RoB, according to Cochrane's RoB tool for RCTs, due to improper allocation concealment, loss to follow-up and private or unclear funding. Of the RCT studies included by Morimoto et al., the authors considered three to have a high RoB, two to have a low RoB, and three to have an unclear RoB. Belongia et al. did not perform a quality assessment of their included studies; however, the quality of all their included studies was examined in at least one other SR/MA (see ).
All four SRs/MAs that were included contained a systematic review and a meta-analysis of the effects of repeated influenza vaccination on vaccine efficacy or effectiveness, and analyzed findings from a total of 24 unique primary studies. There was substantial overlap in the primary studies included in the SRs/MAs, with findings from 24 of 48 primary studies (50%) assessed in more than one SR/MA. Details on primary study overlap among the included SRs/MAs can be seen in .
Only low risk of bias observational studies were included, sensitivity analysis was not possible.
Two of the SRs/MAs included primary studies with RCT and observational designs, one included only RCTs, and one included only observational studies. A test-negative case-control design was the most common type of observational study design of the included primary studies. The SR/MA conducted by Bartoszko et al. had the least restrictive study selection criteria and included the largest number of studies. Two SRs/MAs included only primary studies that confirmed influenza infection by RT-PCR. Bartoszko et al. included studies which confirmed influenza infection by RT-PCR or viral culture as the primary outcome, and by any laboratory method as a secondary outcome. A sensitivity analysis performed by the authors indicated that the inclusion of studies that did not confirm influenza infection by RT-PCR or viral culture did not significantly alter the effect estimates; therefore, the authors chose to include these studies in their final meta-analysis. Morimoto et al. also included studies that defined LCI as confirmed by RT-PCR and serology and/or culture; however, no sensitivity analysis for method of laboratory confirmation was performed.
All four SRs/MAs reported pooled effect estimates for vaccine efficacy or effectiveness of repeated influenza vaccination using a random effects model; however, each used a different method to combine primary study data. Belongia et al. calculated separately the pooled, unadjusted VE of vaccination in two consecutive seasons (i.e., the current and prior season), vaccination in the current season only, and vaccination in the prior season only, with no vaccination in both the current and prior seasons as a referent. Ramsay et al. pooled the differences in adjusted VE estimates for the different scenarios to control for within-study confounding. Bartoszko et al. calculated the unadjusted odds ratios (ORs) of medically-attended, LCI, comparing individuals with vaccination in two consecutive seasons to individuals with vaccination in the current season only. Morimoto et al. calculated the relative risk (RR) for medically-attended, LCI in individuals with vaccination in two consecutive seasons compared to individuals who were vaccinated in the current season only.
# III.2 Evidence for vaccine efficacy and effectiveness of repeated vaccination compared to vaccination in current season only
In general, influenza vaccination in two consecutive seasons did not have a negative or positive effect on VE in comparison to vaccination in the current season only; however, there were two circumstances in which a potential negative effect was demonstrated. One SR/MA demonstrated a pooled negative effect of vaccination in two consecutive seasons for VE against influenza A(H3N2) in the 2010–2011 influenza season and another SR/MA found a pooled negative effect for VE against influenza A(H3N2) in the 2014–2015 influenza season.
In addition, the odds of having medically-attended LCI were statistically significantly higher when the seasonal influenza vaccine was administered over multiple (three or more) consecutive seasons, compared to the current season only; however, data on this exposure were limited (refer to for further information).
## III.2.1 Vaccine effectiveness by influenza type and subtype
Three SRs/MAs reported pooled VE stratified by influenza type and subtype comparing participants vaccinated in the prior and current season with participants vaccinated in the current season only.
Influenza A(H1N1): All three SRs/MAs assessed the effect of repeated vaccination on VE against influenza A(H1N1). Belongia et al. excluded studies which reported current season VE for pre-2009 seasonal influenza; therefore, the estimates represent the VE against influenza A(H1N1)pdm09 specifically, whereas Ramsay et al. and Bartoszko et al. pooled estimates for VE against influenza A(H1N1) during any season. The meta-analyses conducted by Belongia et al. and Ramsay et al. assessed the effect of receiving seasonal influenza vaccine in the current and prior seasons, whereas the pooled estimates reported by Bartoszko et al. included estimates from studies which assessed the effect of receiving seasonal influenza vaccine in the current seasons and seasonal or monovalent pandemic vaccine in the prior season. None of the SRs/MAs showed differences in VE for those vaccinated in two consecutive seasons and those vaccinated in the current season only for influenza A(H1N1).
Bartoszko et al. found that the unadjusted odds of medically-attended, LCI A(H1N1) were statistically similar among participants vaccinated in two consecutive seasons and among participants vaccinated in the current season only. This result was consistent when the OR was calculated using estimates from RCTs found no statistically significant difference in adjusted VE against influenza A(H1N1) when influenza vaccination in two consecutive seasons was compared to vaccination in current season only (pooled VE difference: 3%, 95% CI: -8 to 13%, I2: 0%). Belongia et al. did not directly compare VE between the two groups; however, they reported similar (i.e., widely overlapping 95% CI) pooled estimates of unadjusted VE against influenza A(H1N1)pdm09 for participants who received influenza vaccine in two consecutive seasons (pooled VE: 67%, 95% CI: 53 to 78%, I2: 69%) and for participants who received influenza vaccine in the current season only (pooled VE: 58%, 95% CI: 48 to 67%, I2: 0%).
Influenza A(H3N2): All three SRs/MAs assessed the effect of repeated seasonal vaccination on VE against influenza A(H3N2). However, results from the SRs/MAs were inconsistent.
Similar to the findings for influenza A(H1N1), Bartoszko et al. did not find a statistically significant difference in the pooled unadjusted odds of having medically-attended, LCI A(H3N2) between participants who received an influenza vaccine in the current and prior season compared with participants who received the vaccine in the current season only .
Influenza B: All three SRs/MAs assessed the effect of repeated seasonal vaccination on VE against influenza B. The SRs/MAs had concordant results, demonstrating no apparent difference between vaccination in two consecutive seasons and vaccination in the current season only for influenza B. There were no statistically significant differences in the season specific estimates for adjusted VE against influenza B between vaccination in two consecutive seasons and vaccination in the current season only in the analyses by Ramsay et al., except for the overall seasons pooled VE estimate where the upper limit of the CI was close to the null (pooled VE difference: -11%, 95% CI: -20 to -2%, I2: 0%). Similarly, Bartoszko et al. did not find a statistical difference in the pooled ORs of influenza B infection, comparing vaccination in two consecutive seasons with vaccination in the current season only, derived from either RCT or observational study designs . Belongia et al. also reported similar VE against influenza B between vaccination in consecutive seasons and vaccination in the current season only (pooled VE: 61%, 95% CI: 43 to 74%, I2: NR). Belongia et al. was the only SR/MA that reported VE against the different influenza B lineages; the authors found similar pooled unadjusted VE between the two groups against influenza B/Yamagata and against B/Victoria .
## III.2.2 Vaccine effectiveness by influenza season where repeat effects were observed
Three of the four SRs/MAs examined VE stratified by influenza season. Belongia et al. assessed pooled VE against influenza A(H1N1)pdm09 in 2010–2011 and 2013–2014 and against influenza A(H3N2) in 2014–2015. Ramsay et al. assessed VE against influenza A(H1N1) and B in 2010–2011 to 2014–2015, and against influenza A(H3N2) in 2007–2008, 2011–2012, 2012–2013, and 2014–2015; however, not all analyses included data from more than one primary study. Bartoszko et al. assessed the effect of repeated vaccination on VE against influenza A(H3N2) during nine different influenza seasons (2008–2009 to 2016–2017), but only reported an effect estimate for the 2010–2011 season and narratively described the results for the other seasons. All estimates compared vaccination in two consecutive seasons to vaccination in the current season only.
None of the SRs/MAs found statistically significant differences in VE between vaccination in the current and prior season and vaccination in the current season only for influenza A(H1N1), A(H3N2), or B in any specific influenza season apart from the two listed below (data not shown, please refer to original studies for full details).
2010–2011: Bartoszko et al. completed a post-hoc subgroup meta-analysis of unadjusted estimates by season, and found that during the 2010–2011 influenza season, the odds of having medically-attended, LCI A(H3N2) were statistically significantly higher among those vaccinated with seasonal influenza vaccine over two consecutive seasons compared to those vaccinated in the current season only (OR: 1.98, 95% CI: 1.32 to 2.97%, I2: 0%) (I2 estimate received by request). Belongia et al. and Ramsay et al. did not have a VE estimate against influenza A(H3N2) for the 2010–2011 season.
2014–2015: Ramsay et al. found that repeated vaccination was statistically significantly less effective against influenza A(H3N2) in the 2014–2015 season than vaccination in the current season only (pooled adjusted VE difference: -54%, 95% CI: -88 to -20%, I2: 29%). Belongia et al. found that although the direction of the point estimates for vaccination in two consecutive seasons and for vaccination in the current season only differed, the CIs for the two estimates greatly overlapped, to the point that one estimate's CI completely encompassed the other's . As well, both CIs crossed zero, indicating that neither demonstrated statistically significant VE against medically-attended influenza A(H3N2) during the 2014–2015 season. Bartoszko et al. noted in their SR/MA that they did not observe a statistically significant difference in pooled unadjusted VE during 2014–2015 among repeated vaccinees compared to current season only vaccinees (OR: 1.34, 95% CI: 0.97 to 1.83, I2: 70%) (effect estimate received by request); however, the trend appeared to follow that shown in the other SRs/MAs.
## III.2.3 Vaccine effectiveness in individuals vaccinated over three or more consecutive seasons
Only the SR/MA by Bartoszko et al. assessed influenza VE over three or more consecutive seasons. The authors compared the current season VE of individuals vaccinated consecutively across three, four or more, and five or more influenza seasons compared with individuals vaccinated in the current season only, by pooling data from two RCTs (five estimates) and 3–4 observational studies (3–6 estimates). In observational studies, the pooled unadjusted odds of medically-attended, LCI among individuals vaccinated in three (OR: 1.97, 95% CI: 1.14 to 3.39%, I2: 60%), four or more (OR: 1.40, 95% CI: 1.03 to 1.88%, I2: 54%), and five or more (OR: 1.57, 95% CI: 1.23 to 2.02%, I2: 5%) consecutive seasons were higher relative to individuals vaccinated in the current season only. The pooled estimate from the two RCTs did not find a statistically significant difference in the unadjusted odds of having medically-attended, LCI among those with vaccination over three consecutive seasons compared with those with vaccination in the current season only (OR: 1.06, 95% CI: 0.65 to 1.75%, I2: 0%).
## III.2.4 Vaccine efficacy and effectiveness by vaccine type
Two studies examined vaccine efficacy or effectiveness stratified by type of seasonal influenza vaccine. Bartoszko et al. pooled data from four RCTs (eight estimates) and 27 observational studies (40 estimates) separately to assess the unadjusted VE of repeated vaccination compared with vaccination in the current season only for inactivated influenza vaccines (IIV). The authors found that the odds of having medically-attended, LCI were not statistically significantly different among participants with repeated IIV vaccination over two consecutive seasons and participants vaccinated with IIV in the current season only .
The authors also conducted a subgroup meta-analysis of two RCTs (two estimates) on the comparative VE for live attenuated influenza vaccine (LAIV) and did not find a statistically significant difference in the odds of having medically-attended, LCI between the two vaccination scenarios (OR: 1.16, 95% CI: 0.58 to 2.32%, I2: 69%).
Morimoto et al. assessed vaccine efficacy by vaccine type against medically-attended influenza infection in children (six estimates). The authors found that the risk of having medically-attended, LCI was not statistically significantly different among children who received IIV during two consecutive seasons compared to the current season only (matched cases: RR: 1.16, 95% CI: 0.28 to 4.76%, I2: 0%; mismatched cases: RR: 1.08, 95% CI: 0.27 to 4.37%, I2: 0%). Please refer to for Morimoto et al.'s definition of matched and mismatched cases. The same was true for matched cases of children who received LAIV (RR: 0.61, 95% CI: 0.24-1.57%, I2: 46.3%); however, children who received LAIV in two consecutive seasons and had a mismatched case of influenza had significantly higher risk of medically-attended, LCI infection (RR: 2.03, 95% CI: 1.20-3.41%, I2: 0%).
## III.2.5 Prior season vaccination with monovalent pandemic influenza vaccine
One SR/MA reported estimates involving prior vaccination with monovalent pandemic influenza vaccine. Bartoszko et al. pooled data from seven observational studies (number of estimates not reported) to examine the odds of having medically-attended, laboratory-confirmed seasonal influenza comparing participants who received monovalent pandemic influenza vaccine in the prior season and seasonal influenza vaccine in the current season relative to participants who received seasonal influenza vaccine in the current season alone. No difference in the pooled unadjusted odds was detected between either group (OR: 0.97, 95% CI: 0.59 to 1.60%, I2: NR). The authors did not report whether the pooled estimate included studies for which participants received an adjuvanted or unadjuvanted monovalent pandemic vaccine.
## III.2.6 Vaccine efficacy and effectiveness by age group
Two SRs/MAs assessed vaccine efficacy or effectiveness by age group. Overall, there appeared to be no significant difference in VE based on age group.
Two separate subgroup meta-analyses comparing VE by age group were completed by Bartoszko et al., which was the only SR/MA to report on VE stratified by age. One was a subgroup meta-analysis of 14 observational studies (20 estimates) that compared unadjusted VE of vaccination in consecutive seasons and vaccination in the current season only for children (17 years of age or younger), adults (18–64 years of age), and older adults (65 years of age and older) , while the other subgroup meta-analysis of four RCTs (eight estimates) compared unadjusted VE for the two vaccination scenarios in children and adults . Results from these subgroup meta-analyses showed that the odds of medically-attended LCI were not statistically significantly different between the two vaccination scenarios for any of the age groups assessed by pooled estimates from RCTs or observational studies.
Morimoto et al. assessed vaccine efficacy against any medically-attended influenza in children (six studies, six estimates) and in adults 30–60 years of age (one study, three estimates). The authors found that the risk of having medically-attended, LCI was not statistically significantly different among children or adults who had received influenza vaccination over two consecutive seasons compared to those that had received the vaccine in the current season only (children: RR: 1.31, 95% CI: 0.79 to 2.16%, I2: 37.6%; adults: RR:1.12, 95% CI: 0.65 to 1.92%, I2: 19.1%).
## III.2.7 Vaccine effectiveness by underlying comorbidity
A subgroup meta-analysis of 11 observational studies (12 estimates) conducted by Bartoszko et al. found that there was no statistically significant difference in the unadjusted odds of having medically-attended, LCI between vaccination in two consecutive seasons and vaccination in the current season only in subgroups with no reported comorbidities (OR: 1.06, 95% CI: 0.59 to 1.93%, I2: 81%) or in subgroups with one or more reported comorbidities (OR: 0.95, 95% CI: 0.69 to 1.54%, I2: 63%). There was substantial heterogeneity in both estimates. No other SRs/MAs assessed efficacy or effectiveness by underlying comorbidity.
## III.2.8 Vaccine efficacy and effectiveness by vaccine match
Bartoszko et al. conducted a subgroup meta-analysis of five RCTs (nine estimates) and a subgroup meta-analysis of 27 observational studies (39 estimates) to assess the comparative effectiveness of repeated influenza vaccination in scenarios where the circulating influenza strains in the current influenza season were a match to vaccine strains, and scenarios where they were a mismatch to vaccine strains. The odds of having medically-attended, LCI did not differ significantly between individuals vaccinated in consecutive seasons and individuals vaccinated in the current season only for influenza seasons when the vaccine matched the circulating strains or for when the vaccine was a mismatch for circulating strains . Vaccine match and mismatch were determined based on what had been reported in the primary study, and if not reported, were based on SR/MA author judgement. However, the authors did not report how vaccine match and mismatch were defined; therefore, these results should be interpreted with caution.
Morimoto et al. assessed vaccine efficacy by vaccine match in children and in adults. The authors defined cases as matched or mismatched to the vaccine strain based on antigenic characterization by hemagglutinin inhibition assay. The vaccine was considered to match the circulating strain if it was the same subtype (influenza A) or lineage (influenza B) and antigenically similar to the vaccine strain. Meta-analysis results showed that the risk of having medically-attended, LCI was not statistically significantly different between matched cases in children (RR: 0.64, 95% CI: 0.33 to 1.22%, I2: 17.3%) or mismatched cases in adults (RR: 1.35, 95% CI: 0.77 to 2.38%, I2: 0%); however, as reported in , children who had been vaccinated in two consecutive seasons were more at risk of influenza infection caused by an influenza virus not contained within the vaccine than those who had only been vaccinated in the current season (RR: 2.04, 95% CI: 1.29 to 3.22%, I2: 0%). No meta-analysis was conducted for matched cases in adults, as there was only one estimate available.
# III.3 Evidence for vaccine effectiveness of repeated vaccination compared to vaccination in prior season only
Two of the four SRs/MAs assessed VE of repeated vaccination compared to VE of vaccination in the prior season only. Ramsay et al. conducted three meta-analyses, stratified by influenza type, to examine the difference in adjusted VE between vaccination in the current and prior seasons and vaccination in the prior season only. For influenza A(H1N1), pooled data from 13 observational studies (16 estimates) showed statistically significantly higher adjusted VE among recipients vaccinated over the two most recent influenza seasons compared to vaccination in the prior season only (pooled VE difference: 25%, 95% CI: 14 to 35%, I2: 0%). Similar findings were also shown for influenza B, which were based on pooled data from 10 observational studies (13 estimates) (pooled VE difference: 18%, 95% CI: 3 to 33%, I2: 26%).
However, pooled data from 11 observational studies (14 estimates) found no statistically significant difference in adjusted VE against influenza A(H3N2) between the two vaccination scenarios (pooled VE difference: 7%, 95% CI: -7 to 21%, I2: 4%). VE estimates from the meta-analyses completed by Belongia et al. showed similar VE estimates for vaccination in consecutive seasons and for vaccination in the prior season only for influenza A(H1N1) , influenza A(H3N2) , and influenza B .
# III.4 Evidence for vaccine effectiveness of repeated vaccination compared to no vaccination
Two SRs/MAs reported VE of repeat vaccination compared to no vaccination. The SR/MA conducted by Belongia et al. reported the pooled VE of repeated influenza vaccination with reference to persons who were unvaccinated in both the current and prior season. Based on a meta-analysis of unadjusted estimates, vaccination in the current and prior season showed statistically significant VE against influenza A(H1N1) (pooled VE: 67%, 95% CI: 53 to 78%, I2: 69%) and influenza B (pooled VE: 55%, 95% CI: 38 to 67%, I2: NR). However, vaccination in the current and prior season did not produce statistically significant VE against influenza A(H3N2) (pooled VE: 17%, 95% CI: -10 to 37%, I2: 86%). A separate meta-analysis of three studies that assessed VE during specific influenza seasons found that repeated vaccination was not effective only during the 2014–2015 influenza season. Therefore, the authors concluded that the low VE during this season was driving the overall absence of statistically significant VE against influenza A(H3N2).
Bartoszko et al. concluded that, based on data pooled from five RCTs (nine estimates) and from 28 observational studies (40 estimates), vaccination in two consecutive seasons was statistically significantly effective against any influenza strain when no vaccination in either season was used as a reference .
IV. Discussion
For most estimates included in the SRs/MAs, there was no significant difference in vaccine efficacy or effectiveness between vaccination in two consecutive seasons and vaccination in the current season only. When stratified by season, the majority of estimates demonstrated that there was no significant difference in VE for vaccination in two consecutive seasons and vaccination in the current season only. However, there were some exceptions. Notably, two SRs/MAs demonstrated that repeated vaccination had a statistically significantly lower VE compared to vaccination in the current season only; one SR/MA found a lower VE against influenza A(H3N2) during 2010–2011, and the other SR/MA found a lower VE against influenza A(H3N2) during 2014–2015 and against influenza B, but only in the pooled overall estimate. During the 2014–2015 Northern Hemisphere influenza season, the influenza A(H3N2) component of the vaccine was unchanged from the 2013–2014 season and was mismatched with the circulating strain, a situation in which repeated vaccination is predicted by the antigenic distance hypothesis to negatively interfere with VE7,11. However, the authors of this study noted that their estimate was largely driven by the 2014–2015 season. The 2010–2011 influenza season was the first post-2009 pandemic season and also contained a different influenza A(H3N2) vaccine component than the 2009 Northern Hemisphere vaccine. Therefore, it is important to consider that factors besides vaccine virus components may be affecting VE estimates.
Vaccination in the current season appeared to offer the best protection against influenza, regardless of previous season's vaccination status, since vaccination in the current season only and vaccination in two consecutive seasons was consistently more effective than vaccination in the prior season only and no vaccination in either season. The only instance when vaccination in two consecutive seasons was not significantly more effective than vaccination in the prior season only was in 2014–2015 against influenza A(H3N2). Firm conclusions on the difference between vaccination in consecutive seasons and vaccination in the prior season only could not be drawn from the indirect comparisons, as many of the 95% CIs for these VE estimates were slightly overlapping.
The one SR/MA that assessed the effect of vaccination over three or more consecutive influenza seasons showed that, based on meta-analyses of observational studies, the odds of medically-attended, LCI was greater among those vaccinated in three, four or more, and five or more consecutive influenza seasons compared to those vaccinated in the current season only. However, these estimates were based on a small number of studies and were not adjusted for confounding, which may be important as there could be important underlying differences between individuals who receive the influenza vaccine annually and individuals who do not regularly receive the vaccine (e.g., individuals at high-risk of influenza infection may be more likely to receive the vaccine annually and to seek medical attention for influenza-like illness). Therefore, the current evidence is insufficient to draw firm conclusions on the effect of vaccination in three or more consecutive seasons. A recent study by Kwong et al., which was not captured by any of the included SRs/MAs due the recency of publication, assessed the effect of repeated influenza vaccination on older adults over 10 previous seasons in Canada. The authors of this study found a statistically significant trend towards decreasing VE for those vaccinated in the current season as the number of previous vaccinations increased. However, the opposite is true for those unvaccinated in the current season – as the number of previous vaccinations increased, protection in the current season also increased, which implies increasing residual protection from previous vaccinations. Regardless of the number of previous vaccinations however, vaccination in the current season provided some benefit, and was superior to remaining unvaccinated. This aligns with the findings presented in this overview for studies that assessed VE over a shorter period of time.
There was substantial heterogeneity for some of the pooled effect measures included in this overview, which indicates the presence of important underlying factors that may make meta-analysis of the data inappropriate. This was expected for estimates that pooled data across multiple influenza seasons, as VE is highly variable year to year. This was demonstrated by multiple SRs/MAs, as estimates from all SRs/MAs for specific influenza seasons tended to have little to no heterogeneity, suggesting that season-specific characteristics may account for most of the heterogeneity in other sub-analyses. However, despite seasonal differences explaining some of the heterogeneity present, further heterogeneity still exists. Some of this could be explained by differences in the local epidemiology, especially given that all SRs/MAs pooled estimates from multiple countries. Circulating influenza strains may differ by location, not just by hemisphere, and therefore estimates that pool data from many different countries could have substantial heterogeneity due to the varying contexts.
Influenza VE is also likely affected by many other factors, including vaccine strain match to circulating strains, initial exposure to influenza virus, egg-adaptive mutations in the vaccine viruses, and possibly other currently unknown factors. In addition, these factors likely have complex interactions with each other, as suggested in a recent article by Skowronski et al. The degree to which repeated vaccination and these other factors affect VE is not fully understood, and varies season to season, making it extremely difficult to predict far enough in advance of the next influenza season to make vaccine policy or administration practice changes. Therefore, a better understanding of the underlying immunological mechanisms and factors affecting the immune response to influenza vaccination are necessary to improve influenza vaccine development and programs.
Finally, addressing programmatic factors such as ethics, equity, feasibility and acceptability as future evidence emerges on this topic will remain important. Guidance on influenza immunization upholds the core ethical dimensions for public health by aiming to prevent future disease, but it must be given in the challenging context of parameters that vary from season to season and are very difficult to predict (such as vaccine to circulating strain match or mismatch, and variable clinical disease severity). It is also important to consider that the effectiveness of a vaccine may have a significant impact on vaccine acceptability, which in turn may affect the uptake and impact of an immunization program. Therefore, despite negative interference occurring inconsistently in the literature summarized, the potential for reduced VE is of concern. As new vaccine products are added and as evidence emerges, including new studies examining the effect of pre-existing immunity on influenza vaccine responses, NACI will continue to monitor the evidence for this phenomenon, and will issue new guidance as needed.
# IV.1 Limitations
This overview was designed to assess the effects of repeated influenza vaccination on VE, efficacy, and immunogenicity for the purpose of providing guidance on annual influenza vaccination. All SRs/MAs that were included contained a systematic review and a meta-analysis of the effects of repeated influenza vaccination on vaccine efficacy or effectiveness but did not provide an evaluation of immunogenicity. Through this lens, additional evidence is necessary for the outcomes in this overview to determine the effect of repeated vaccination over time and across multiple influenza seasons. However, pooling data across seasons and from different geographic locations, as done by the SRs/MAs included in this overview, is insufficient to determine the potential causes of and mechanisms behind the effect of repeated vaccination on VE, and is expected to give estimates with high heterogeneity, since VE is affected by variables that often change season to season (e.g., circulating strain, vaccine match, etc.).
The SRs/MAs included for review all had similar research questions, as well as inclusion and exclusion criteria; as a result, there was significant overlap (46%) in the primary studies included for evidence synthesis in the SRs/MAs. Therefore, we caution that, while the results appear to draw data from many studies and populations, the SRs/MAs used much of the same data to produce the pooled estimates. Despite the different methods used by the SRs/MAs to pool data across studies (VE, difference in VE, RR, and OR), the results and conclusions of the SRs/MAs were generally consistent with each other, strengthening the reliability of the conclusions drawn from this evidence synthesis. The SRs/MAs were of good quality based on AMSTAR 2. The primary studies included in the SRs/MAs were also generally of good quality; the RoB was low for observational studies, which formed the majority of the evidence base. However, authors noted a high RoB for RCTs. Separate meta-analyses were completed for estimates from RCTs and from observational studies. The findings for most outcomes were similar; therefore, it does not appear that the high RoB for the included RCTs significantly affected the results of the meta-analyses.
The SRs/MAs by Bartoszko et al. and Morimoto et al. included studies that confirmed influenza infection using RT-PCR, which is the gold standard for influenza virus detection due to its higher sensitivity and specificity, but also studies using influenza infection confirmed by laboratory methods other than RT-PCR. Bartoszko et al. included these studies after determining that their inclusion did not significantly alter effect estimates, which alleviates some of the concerns with including studies that detected influenza virus by other laboratory methods for their SR/MA. Of note, studies using laboratory methods other than RT-PCR represented a small proportion of the total number of included studies (14%).
This overview included SRs/MAs that presented pooled effect estimates for direct comparisons (pooled difference in VE, RR, OR) and indirect comparisons, such as comparing separate pooled VE estimates for different vaccination scenarios which used unvaccinated in either season as a reference. Since the purpose of this overview was to determine the effects of repeated vaccination compared to either vaccination in the current season only, vaccination in the prior season only, or no vaccination, an effect estimate from a direct comparison is more appropriate for answering this overview's research question than an indirect comparison, as estimates with slightly overlapping CIs could still be significantly different.
How some subgroups were assessed, and which subgroups were not assessed, presented particular limitations. Bartoszko et al. assessed influenza VE by vaccine match or mismatch, but did not specify how a match or mismatch had been defined, which presents difficulties for interpreting these findings. In addition, none of the SRs/MAs assessed the efficacy or effectiveness of adjuvanted, high dose, cell-based, or egg-based influenza vaccines, which are all different formulations of influenza vaccine authorized for use in Canada.
V. Recommendations
1. NACI continues to recommend that seasonal influenza vaccine should be offered annually to everyone 6 months of age and older who does not have contraindications to the vaccine, irrespective of previous seasons' influenza vaccination status. (Strong NACI Recommendation)
- NACI concludes that there is fair evidence to recommend annual influenza vaccination, irrespective of whether an individual received the seasonal influenza vaccine in previous seasons (Grade B Evidence).
Summary of evidence
- Repeated vaccination across seasons, including the current season, was consistently more effective than no vaccination in the current season.
- In general, the evidence shows no significant difference or predictable trend in vaccine efficacy or effectiveness between vaccinations in two consecutive seasons compared to vaccination in the current season only.
+ Of all the seasons investigated across many studies, only two influenza seasons indicated that VE of vaccination over consecutive seasons was statistically significantly lower than vaccination in the current season only. These notable seasons were influenza A(H3N2) in 2010–2011, and influenza A(H3N2) in 2014–2015. These findings were not statistically significant in all SRs/MAs which assessed VE in these two seasons; however, a trend towards lower VE for repeated vaccination was consistent for the 2014–2015 season across all studies.
- Evidence on the effects of repeated vaccination over three or more consecutive seasons was limited and is insufficient to draw firm conclusions at this point in time.
- Given the complex interplay between immune imprinting (such as previous exposures through vaccination and natural infection), circulating virus types, and individual characteristics, it is not currently feasible nor warranted to modify existing annual influenza vaccination programs to account for potential negative or positive interference effects related to repeated influenza vaccination across seasons.
VI. Research priorities
Research to address the following outstanding questions is encouraged:
New and emerging research priorities
Further evaluation of VE stratified by characteristics in addition to influenza strain type and subtype would allow for better identification of when the effects of repeated influenza vaccination should be considered and which specific populations may be affected.
- Further evaluation of the effects of long-term repeated influenza vaccination on VE over more than 2 consecutive seasons.
- Further evaluation of the effects of repeated influenza vaccination on VE stratified by age group and vaccine type.
- Investigation of the effects of repeated influenza vaccination on severe influenza-related outcomes, such as hospitalization and death.
- Evaluation of the effects of repeated influenza vaccination that accounts for previous influenza exposure through vaccination and/or natural infection.
- Further investigation of the immunological mechanisms underlying the effects of repeated influenza vaccination on VE, including the antigenic distance hypothesis and immunological imprinting. |
Recommendation on Repeated Seasonal Influenza Vaccination
==========================================================
[Download in PDF format](/content/dam/phac-aspc/documents/services/immunization/national-advisory-committee-on-immunization-naci/recommendation-repeated-seasonal-influenza-vaccination/recommendation-repeated-seasonal-influenza-vaccination.pdf)
(1.37 MB, 41 pages)
**Organization:** [Public Health Agency of Canada](/en/public-health.html)
**Published:** 2023-02-21
**An Advisory Committee Statement (ACS)**
**National Advisory Committee on Immunization (NACI)**
Preamble
--------
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Table of contents
-----------------
* [Summary of the information contained in this NACI statement](#sum)
* [I. Introduction](#a1)
* [II. Methods](#a2)
+ [II.1 Research question](#a2.1)
* [III. Results](#a3)
+ [III.1 Study characteristics](#a3.1)
+ [III.2 Evidence for vaccine efficacy and effectiveness of repeated vaccination compared to vaccination in current season only](#a3.2)
+ [III.3 Evidence for vaccine effectiveness of repeated vaccination compared to vaccination in prior season only](#a3.3)
+ [III.4 Evidence for vaccine effectiveness of repeated vaccination compared to no vaccination](#a3.4)
* [IV. Discussion](#a4)
+ [IV.1 Limitations](#a4.1)
* [V. Recommendations](#a5)
* [VI. Research priorities](#a6)
* [Additional tables](#a7)
* [List of abbreviations](#a8)
* [Acknowledgements](#a9)
* [Appendix A: Search strategies and results](#appa)
* [Appendix B: Flow diagram](#appb)
* [References](#a10)
Summary of the information contained in this NACI statement
-----------------------------------------------------------
The following highlights key information for immunization providers. Please refer to the remainder of the statement for details.
### 1. What
Influenza is a respiratory illness caused primarily by influenza A and B viruses. The burden of influenza varies from year to year. Prior to the COVID-19 pandemic, influenza was responsible for an estimated 12,200 hospitalizations and 3,500 deaths annually in Canada. Influenza vaccination is repeated annually due to waning immunity and the tendency of influenza viruses to frequently mutate, requiring changes in the vaccine formulation.
Some studies from different influenza seasons have suggested that receiving the seasonal influenza vaccine in one or more previous seasons may reduce the effectiveness of the vaccine against strains circulating in the current season, while other studies have not.
### 2. Who
This Statement applies to all individuals 6 months of age and older who are not contraindicated to receive the influenza vaccine.
### 3. How
The seasonal influenza vaccine should be offered to all individuals 6 months of age and older on an annual basis, regardless of whether they received a seasonal influenza vaccine in prior seasons.
### 4. Why
Annual influenza vaccination reduces the morbidity and mortality associated with influenza infection. Overall, the evidence shows no difference in the effectiveness of repeated influenza vaccination compared to vaccination in the current season only. Of all the seasons investigated across many studies, only during two influenza seasons was repeated vaccination across seasons associated with a reduced effectiveness against influenza A(H3N2), compared to vaccination in the current season only. Further evaluation of the effects of repeated influenza vaccination on vaccine effectiveness (VE) is needed as there is currently no predictable association that could inform vaccine program decisions from year to year. Also, repeated vaccination including the current season is consistently more effective than no vaccination in the current season.
I. Introduction
---------------
Influenza is a respiratory illness caused primarily by influenza A and B viruses. Prior to the COVID-19 pandemic, influenza was estimated to cause approximately 12,200 hospitalizations[Footnote 1](#fn1) and 3,500 deaths[Footnote 2](#fn2) annually in Canada. Although the epidemiology of influenza has changed during the course of the COVID-19 pandemic, seasonal influenza presents an ongoing disease burden in Canada during the fall and winter months, which varies from year to year. To reduce the morbidity and mortality associated with influenza, the National Advisory Committee on Immunization (NACI) recommends annual influenza vaccination for everyone 6 months of age and older who does not have contraindications to the vaccine[Footnote 3](#fn3). Influenza vaccination must be repeated annually due to waning of vaccine and infection-induced immunity against influenza over time and because influenza viruses frequently undergo antigenic drift. As a result, the World Health Organization (WHO) convenes twice a year to assess the currently circulating influenza strains and to recommend which strains should be used in the influenza vaccine for the upcoming Northern and Southern Hemisphere influenza seasons[Footnote 4](#fn4).
However, there is a growing body of evidence that explores the potential negative effects of repeated seasonal influenza vaccination on current season VE. This issue was first studied in the 1970s[Footnote 5](#fn5), and since then several studies have indicated a potential negative impact of prior influenza vaccination on current season influenza VE5
[Footnote 6](#fn6)[Footnote 7](#fn7)
[Footnote 8](#fn8)[Footnote 9](#fn9)
[Footnote 10](#fn10). The most prominent theory explaining this phenomenon is the antigenic distance hypothesis[Footnote 7](#fn7)[Footnote 11](#fn11). This hypothesis theorizes that influenza vaccination in the prior season may negatively interfere with the VE in the current season if the antigenic distance (difference) between the prior and current season's vaccine strain is small, but the antigenic distance between the prior season's vaccine strain and the current season's circulating strain is large[Footnote 7](#fn7). Furthermore, additional observations and theories suggest that immune "imprinting" for influenza responses can be linked to birth cohort and influenced by early exposures that happened in previous seasons, notably the first influenza virus exposure of life[Footnote 12](#fn12)[Footnote 13](#fn13). It is not yet well understood how repeated vaccination may impact influenza vaccine immune response. The current overview does not aim to address theories of how differences in VE due to repeated influenza vaccination may occur, but rather to determine the overall impact of this phenomenon and to provide an evidence base for population-level and individual-level vaccination decisions regarding annual influenza vaccination.
The primary objective of this overview of reviews is:
* To summarize the evidence from systematic reviews on the effects of repeated seasonal influenza vaccination on VE, vaccine efficacy and immunogenicity
II. Methods
-----------
### II.1 Research question
What are the effects of repeated seasonal influenza vaccination on VE, efficacy, and immunogenicity?
**P (population):** Adults and children
**I (intervention):** Seasonal influenza vaccination in prior season(s) and current season
**C (comparison):** Seasonal influenza vaccination in prior season(s) only OR in current season only OR unvaccinated in any season included in the study
**O (outcome):** VE, vaccine efficacy, or immunogenicity in the current season
**S (study design):** Systematic review and meta-analysis
An a priori search strategy was developed in collaboration with a federal reference librarian of the Health Library of Health Canada and PHAC that included search terms for "influenza", "repeated vaccination", "systematic review", and "meta-analysis". The complete search strategy can be found in [Appendix A](#appa). The search was limited to studies published in the English or French language and to a publication date of 2016 to June 2019. NACI was already aware of two systematic reviews that were published in 2017[Footnote 14](#fn14)[Footnote 15](#fn15); therefore, the search was restricted to systematic reviews (SRs) and meta-analyses (MAs) published in 2016 or later to ensure that any additional recent and relevant SRs/MAs were captured. No limitation was placed on the types of primary study designs included in the SR/MA.
Inclusion criteria:
1. The study is a SR/MA;
2. The study assesses the effects of repeated influenza vaccination on VE, efficacy or immunogenicity.
Exclusion criteria:
1. The study only presents primary research;
2. The study is in language other than English or French;
3. The study only includes non-human studies;
4. The date of publication of the study is prior to 2016.
Abstracts and titles of records retrieved by the database search were loaded into DistillerSR (Evidence Partners, Ottawa, Canada) for screening. If the abstract and title met the inclusion criteria, or if it was not possible to determine eligibility based on the abstract and title alone, the full text was assessed for eligibility. Two reviewers independently screened titles, abstracts, and full texts for eligibility. Full texts that met all inclusion criteria were further assessed for the relevance of the SR/MA's PICO, as compared to the PICO formulated a priori by the NACI Influenza Working Group (outlined above) and for quality. SRs/MAs that were not considered sufficiently relevant for NACI's purposes or were not of sufficient quality were excluded from synthesis. This approach to the inclusion of systematic reviews into public health guidance was based on the methodology proposed within the Project on a Framework for Rating Evidence in Public Health (PRECEPT)[Footnote 16](#fn16) and was initially developed by the United States Agency for Healthcare Research and Quality (AHRQ)[Footnote 17](#fn17). The quality of the SRs/MAs were assessed using AMSTAR 2[Footnote 18](#fn18), which is a tool specifically designed to examine SR/MA quality. SRs/MAs for which reviewers had many serious concerns across AMSTAR 2 domains would be excluded.
Data from included SRs/MAs were extracted using a template with variables defined a priori. Extracted pooled effect estimates from SRs/MAs were assumed to represent pooled unadjusted estimates, unless otherwise specified. Quality assessment and data extraction were completed independently by two reviewers. Any disagreements during eligibility assessment, quality assessment, or data extraction were discussed until a consensus was reached. Results of subgroup analyses that included only one study were not extracted. Evidence was synthesized narratively, and estimates from all included SRs/MAs were discussed, regardless of primary study overlap.
III. Results
------------
### III.1 Study characteristics
Through a comprehensive literature search performed on October 27, 2017 and updated on June 3, 2019, five SRs/MAs were identified as eligible for inclusion in the evidence synthesis; two through Medline[Footnote 19](#fn19)[Footnote 20](#fn20), one through PROSPERO[Footnote 21](#fn21), and two that had previously been identified by experts[Footnote 14](#fn14)[Footnote 15](#fn15). All five of the identified SRs/MAs sufficiently aligned with this overview's PICO ([Table 1](#t1)). No new or ongoing SRs/MAs eligible for inclusion were identified through additional PROSPERO search updates conducted through March 2022. A complete PRISMA flow diagram can be found in [Appendix B](#appb), and a full list of excluded studies and reason for exclusion is available upon request. None of the SRs/MAs included primary studies that assessed immunogenicity. Additional inclusion and exclusion criteria outlined for each SR/MA that were not specified by this overview's PICO are detailed in [Table 2](#t2).
Table 1: Alignment of SRs/MAs' inclusion and exclusion criteria with this overview's PICO[Table 1 Footnote a](#t1fna)
| PICO | Criteria | Ramsay et al. 2019[Footnote 15](#fn15) | Bartoszko et al. 2018[Footnote 21](#fn21) | Morimoto et al. 2018[Footnote 20](#fn20) | Belongia et al. 2017[Footnote 14](#fn14) | Caspard et al. 2016[Footnote 19](#fn19) |
| --- | --- | --- | --- | --- | --- | --- |
| **Population** | All ages included | Yes | Yes | Yes | Yes | Partial (studies on adults 18 years of age and older excluded) |
| **Intervention/ Comparison** | Seasonal influenza vaccination in the prior influenza season and in the current season | Yes | Yes | Yes | Yes | Yes |
| Seasonal influenza vaccination in the prior influenza season only | Yes | Yes | Yes | Yes | Yes |
| Seasonal influenza vaccination in the current influenza season only | Yes | Yes | Yes | Yes | Yes |
| Unvaccinated with influenza vaccination in both the prior influenza season and in the current season | Yes | Yes | No | Yes | Yes |
| Any seasonal influenza vaccine used for vaccination | Yes | Yes | Yes | Yes | No (only included studies on live attenuated influenza vaccine) |
| **Outcomes** | Studies investigating vaccine effectiveness or efficacy | Yes | Yes | Yes | Yes | Yes |
| Studies investigating immunogenicity | No | No | No | No | No |
|
Table 1 - Footnote a
Yes: SR/MA's PICO aligns with this overview's PICO;
No: SR/MA's PICO does not align with this overview's PICO;
Partial: SR/MA's PICO partially, but not completely, aligns with this overview's PICO.
[Return to Table 1 Footnote a referrer](#t1fna-rf)
|
Results from the AMSTAR 2 quality assessment are presented in [Table 3](#t3). For this review, none of the domains within AMSTAR 2 were highlighted as "critical". The SRs/MAs conducted by Bartoszko et al., Morimoto et al., and Ramsay et al. were similar in quality and had minor differences across domains. Importantly, The SR/MA conducted by Belongia et al. was judged to be of lower quality primarily due to the lack of a documented risk of bias (RoB) appraisal of included studies. None of the SRs/MAs included a list of excluded studies or reported the funding sources for included primary studies. In addition, none of the SRs/MAs provided a full investigation of heterogeneity within the results; however, most studies discussed important, non-measured factors that would impact VE in the discussion (e.g., history of natural infection). Two of the reviews searched the grey literature (i.e., trial registries)[Footnote 14](#fn14)[Footnote 21](#fn21), three assessed the quality of the included studies[Footnote 15](#fn15)[Footnote 20](#fn20)[Footnote 21](#fn21), and two assessed the likelihood of publication bias[Footnote 20](#fn20)[Footnote 21](#fn21). The SR/MA conducted by Caspard et al. had a large number of serious concerns across almost all AMSTAR 2 domains. Of particular note, no evidence for a priori design was provided, study selection and data extraction were not performed in duplicate, no quality assessment was specified, and heterogeneity was not assessed. In addition, a fixed effects model was used to estimate the efficacy of the influenza vaccines, which, given the expected differences in estimates across seasons, would not be appropriate; a random effects model would be preferred and was used in all other included SRs/MAs. Due to the limitations of the Caspard et al. SR/MA regarding these AMSTAR 2 domains, this SR/MA was excluded from evidence synthesis.
Table 2: Inclusion and exclusion criteria of included SRs/MAs identified as eligible that were not specified by this overview's PICOa[Table 2 Footnote a](#t2fna)
| PICO(T) | Criteria | Ramsay et al. 2019[Footnote 15](#fn15) | Bartoszko et al. 2018[Footnote 21](#fn21) | Morimoto et al. 2018[Footnote 20](#fn20) | Belongia et al. 2017[Footnote 14](#fn14) | Caspard et al. 2016[Footnote 19](#fn19) |
| --- | --- | --- | --- | --- | --- | --- |
| **Intervention/Comparison** | Also included studies with vaccination in 2 or more prior influenza seasons | Included
(Excluded from meta-analysis) | Included | Included | Excluded | Unknown
(Not excluded) |
| Vaccination with a monovalent pandemic influenza vaccine | Unknown
(Not excluded) | Not explicitly excluded | Excluded | Excluded | Unknown
(Not excluded) |
| **Outcomes** | Influenza infection defined as medically-attended and laboratory confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) | Included | Included | Included | Included | Unknown
(Not excluded) |
| Influenza infection defined as medically-attended and laboratory confirmed by any method | Unknown
(Not included) | Included | Included | Unknown
(Not included) | Unclear
(Method of laboratory confirmation not stated) |
| **Study design** | RCT | Unknown
(Not included) | Included | Included | Included | Included |
| Observational studies | Included | Included | Unknown
(Not included) | Partially included (includes only test-negative case-controls, case-controls, and cohort, others not included) | Excluded |
| Cost-effectiveness studies, review articles | Unknown
(Not included) | Unknown
(Not included) | Unknown
(Not included) | Excluded | Excluded |
| Conference abstract or proceeding | Excluded | Unknown
(Not excluded) | Unknown
(Not included) | Unknown
(Not excluded) | Unknown
(Not excluded) |
| Article is an interim VE report that was superseded by an end-of-season report | Excluded | Unknown
(Not excluded) | Unknown
(Not included) | Unknown
(Not excluded) | Unknown
(Not excluded) |
| Study did not apply standard symptom criteria for enrollment | Unknown
(Not excluded) | Unknown
(Not excluded) | Unknown
(Not excluded) | Excluded | Unknown
(Not excluded) |
| Study used a convenience sample of clinical diagnostic tests as opposed to predefined screening criteria | Unknown
(Not excluded) | Unknown
(Not excluded) | Unknown
(Not excluded) | Excluded | Unknown
(Not excluded) |
| **Timing** | Study reported current season VE for pre-2009 seasonal influenza | Unknown
(Not excluded) | Unknown
(Not excluded) | Unknown
(Not excluded) | Excluded | Unknown
(Not included) |
|
Table 2 - Footnote a
Included: SR/MA explicitly states as inclusion criteria; Excluded: SR/MA explicitly states as exclusion criteria; Unknown: SR/MA does not explicitly state as inclusion/exclusion criteria; inclusion/exclusion criteria may or may not preclude from including/excluding studies.
[Return to Table 2 Footnote a referrer](#t2fna-rf)
|
The two studies that assessed the quality of included observational studies found that the RoB for included observational studies was low according to the Newcastle-Ottawa Scale[Footnote 15](#fn15)[Footnote 21](#fn21). The evidence for laboratory confirmed influenza (LCI) infection from randomized controlled trials (RCTs) included by Bartoszko et al. was determined by the authors to have a serious RoB, according to Cochrane's RoB tool for RCTs, due to improper allocation concealment, loss to follow-up and private or unclear funding[Footnote 21](#fn21). Of the RCT studies included by Morimoto et al., the authors considered three to have a high RoB, two to have a low RoB, and three to have an unclear RoB[Footnote 20](#fn20). Belongia et al. did not perform a quality assessment of their included studies; however, the quality of all their included studies was examined in at least one other SR/MA[Footnote 14](#fn14) (see [Figure 1](#f1)).
All four SRs/MAs that were included contained a systematic review and a meta-analysis of the effects of repeated influenza vaccination on vaccine efficacy or effectiveness, and analyzed findings from a total of 24 unique primary studies. There was substantial overlap in the primary studies included in the SRs/MAs, with findings from 24 of 48 primary studies (50%) assessed in more than one SR/MA. Details on primary study overlap among the included SRs/MAs can be seen in [Figure 1](#f1).
**Figure 1: Overlap of primary studies included in the SRs/Mas**
Figure 1: Text description
Figure 1 shows a horizontal stacked bar graph providing details on the degree of primary study overlap among the included systematic reviews and meta-analyses. The following information is depicted:
| | Ramsay 2019 | Bartoszko 2018 | Morimoto 2018 | Belongia 2017 |
| --- | --- | --- | --- | --- |
| Overlapping | 20 | 21 | 2 | 17 |
| Unique | 0 | 18 | 6 | 0 |
| Total included in MA | 20 | 39 | 8 | 17 |
Table 3: Risk of bias of eligible SRs/MAs (AMSTAR 2)
| AMSTAR 2 criteria | Ramsay et al. 2019[Footnote 15](#fn15) | Bartoszko et al. 2018[Footnote 21](#fn21) | Morimoto et al. 2018[Footnote 20](#fn20) | Belongia et al. 2017[Footnote 14](#fn14) | Caspard et al. 2016[Footnote 19](#fn19) |
| --- | --- | --- | --- | --- | --- |
| 1. Did the research questions and inclusion criteria for the review include the components of PICO? | Yes | Yes | Yes | Yes | Yes |
| 2. Did the review rerort contain an explicit statement that the review methods were established prior to its conduct and did the report justify any significant deviations from the protocol? | Yes | Yes | No | No | No |
| 3. Did the review authors explain their selection of the study designs for inclusion in the review? | No | No | Yes | No | No |
| 4. Did the review authors use a comprehensive literature search strategy? | Partial Yes | Partial Yes | No | No | No |
| 5. Did the review authors perform study selection in duplicate? | Yes | Yes | Yes | No | No |
| 6. Did the review authors perform data extraction in duplicate? | Yes | Yes | Yes | Yes | No |
| 7. Did the review authors provide a list of excluded studies and justify the exclusions? | No | No | No | No | No |
| 8. Did the review authors describe the included studies in adequate detail? | Yes | Yes | Yes | Yes | Yes |
| 9. Did the review authors use a satisfactory technique for assessing the RoB in individual studies that were included in the review? | Yes | Yes | Yes | No | No |
| 10.Did the review authors report on the funding sources for the studies included in the review? | No | No | No | No | No |
| 11. If meta-analysis was performed, did the review authors use appropriate methods for statistical combination of results? | Yes | Yes | Yes | Yes | No |
| 12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis? | Yes[Table 3 Footnote a](#t3fna) | No | Yes | No | No |
| 13. Did the review authors account for RoB in individual studies when interpreting/discussing the review results? | Yes | Yes | No | No | No |
| 14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the review results? | No | No | No | No | No |
| 15. If they performed quantitative synthesis, did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the review results? | No | Yes | Yes | No | No |
| 16. Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review? | Yes | Yes | Yes | Yes | Yes |
| **Total (out of 16)** | **10.5** | **10.5** | **10** | **5** | **3** |
|
Table 3 - Footnote a
Only low risk of bias observational studies were included, sensitivity analysis was not possible.
[Return to Table 3 Footnote a referrer](#t3fna-rf)
|
Two of the SRs/MAs included primary studies with RCT and observational designs[Footnote 14](#fn14)[Footnote 21](#fn21), one included only RCTs[Footnote 20](#fn20), and one included only observational studies[Footnote 15](#fn15). A test-negative case-control design was the most common type of observational study design of the included primary studies. The SR/MA conducted by Bartoszko et al. had the least restrictive study selection criteria and included the largest number of studies. Two SRs/MAs included only primary studies that confirmed influenza infection by RT-PCR[Footnote 14](#fn14)[Footnote 15](#fn15). Bartoszko et al. included studies which confirmed influenza infection by RT-PCR or viral culture as the primary outcome, and by any laboratory method as a secondary outcome. A sensitivity analysis performed by the authors indicated that the inclusion of studies that did not confirm influenza infection by RT-PCR or viral culture did not significantly alter the effect estimates; therefore, the authors chose to include these studies in their final meta-analysis. Morimoto et al. also included studies that defined LCI as confirmed by RT-PCR and serology and/or culture; however, no sensitivity analysis for method of laboratory confirmation was performed.
All four SRs/MAs[Footnote 14](#fn14)[Footnote 15](#fn15)[Footnote 20](#fn20)[Footnote 21](#fn21) reported pooled effect estimates for vaccine efficacy or effectiveness of repeated influenza vaccination using a random effects model; however, each used a different method to combine primary study data. Belongia et al. calculated separately the pooled, unadjusted VE of vaccination in two consecutive seasons (i.e., the current and prior season), vaccination in the current season only, and vaccination in the prior season only, with no vaccination in both the current and prior seasons as a referent. Ramsay et al. pooled the differences in adjusted VE estimates for the different scenarios to control for within-study confounding. Bartoszko et al. calculated the unadjusted odds ratios (ORs) of medically-attended, LCI, comparing individuals with vaccination in two consecutive seasons to individuals with vaccination in the current season only. Morimoto et al. calculated the relative risk (RR) for medically-attended, LCI in individuals with vaccination in two consecutive seasons compared to individuals who were vaccinated in the current season only.
### III.2 Evidence for vaccine efficacy and effectiveness of repeated vaccination compared to vaccination in current season only
In general, influenza vaccination in two consecutive seasons did not have a negative or positive effect on VE in comparison to vaccination in the current season only; however, there were two circumstances in which a potential negative effect was demonstrated. One SR/MA demonstrated a pooled negative effect of vaccination in two consecutive seasons for VE against influenza A(H3N2) in the 2010–2011 influenza season[Footnote 21](#fn21) and another SR/MA found a pooled negative effect for VE against influenza A(H3N2) in the 2014–2015 influenza season[Footnote 15](#fn15).
In addition, the odds of having medically-attended LCI were statistically significantly higher when the seasonal influenza vaccine was administered over multiple (three or more) consecutive seasons[Footnote 21](#fn21), compared to the current season only; however, data on this exposure were limited (refer to [section III.2.3](#a3.2.3) for further information).
#### III.2.1 Vaccine effectiveness by influenza type and subtype
Three SRs/MAs reported pooled VE stratified by influenza type and subtype comparing participants vaccinated in the prior and current season with participants vaccinated in the current season only[Footnote 14](#fn14)[Footnote 15](#fn15)[Footnote 21](#fn21).
**Influenza A(H1N1):** All three SRs/MAs assessed the effect of repeated vaccination on VE against influenza A(H1N1). Belongia et al. excluded studies which reported current season VE for pre-2009 seasonal influenza; therefore, the estimates represent the VE against influenza A(H1N1)pdm09 specifically, whereas Ramsay et al. and Bartoszko et al. pooled estimates for VE against influenza A(H1N1) during any season. The meta-analyses conducted by Belongia et al. and Ramsay et al. assessed the effect of receiving seasonal influenza vaccine in the current and prior seasons, whereas the pooled estimates reported by Bartoszko et al. included estimates from studies which assessed the effect of receiving seasonal influenza vaccine in the current seasons and seasonal or monovalent pandemic vaccine in the prior season. None of the SRs/MAs showed differences in VE for those vaccinated in two consecutive seasons and those vaccinated in the current season only for influenza A(H1N1).
Bartoszko et al.[Footnote 21](#fn21) found that the unadjusted odds of medically-attended, LCI A(H1N1) were statistically similar among participants vaccinated in two consecutive seasons and among participants vaccinated in the current season only. This result was consistent when the OR was calculated using estimates from RCTs [OR: 0.86, 95% confidence interval (CI): 0.38 to 1.96%, I2: 0%] and from observational studies [OR: 0.87, 95% CI: 0.67 to 1.12%, I2: 46%]. Ramsay et al.[Footnote 15](#fn15) found no statistically significant difference in adjusted VE against influenza A(H1N1) when influenza vaccination in two consecutive seasons was compared to vaccination in current season only (pooled VE difference: 3%, 95% CI: -8 to 13%, I2: 0%). Belongia et al.[Footnote 14](#fn14) did not directly compare VE between the two groups; however, they reported similar (i.e., widely overlapping 95% CI) pooled estimates of unadjusted VE against influenza A(H1N1)pdm09 for participants who received influenza vaccine in two consecutive seasons (pooled VE: 67%, 95% CI: 53 to 78%, I2: 69%) and for participants who received influenza vaccine in the current season only (pooled VE: 58%, 95% CI: 48 to 67%, I2: 0%).
**Influenza A(H3N2):** All three SRs/MAs assessed the effect of repeated seasonal vaccination on VE against influenza A(H3N2). However, results from the SRs/MAs were inconsistent.
Similar to the findings for influenza A(H1N1), Bartoszko et al. did not find a statistically significant difference in the pooled unadjusted odds of having medically-attended, LCI A(H3N2) between participants who received an influenza vaccine in the current and prior season compared with participants who received the vaccine in the current season only [OR (RCTs): 0.71, 95% CI: 0.37 to 1.34%, I2: 0%; OR (observational): 1.09, 95% CI: 0.86 to 1.38%, I2: 70%]. The pooled VE results reported by Belongia et al. showed that, while influenza vaccination in the current season only produced statistically significant VE against influenza A(H3N2) infection (pooled VE: 39%, 95% CI: 16 to 55%, I2: 73%), influenza vaccination in two consecutive seasons did not (pooled VE: 17%, 95% CI: -10 to 37%, I2: 86%). Ramsay et al. also did find a statistically significant difference in the pooled adjusted VE against influenza A(H3N2) when vaccination in two consecutive seasons was compared to vaccination in the current season only (pooled VE difference: -20%, 95% CI: -36 to -4%, I2: 35%). The authors noted that this appeared to be driven by estimates from the 2014–2015 influenza season, whose results are discussed further in [Section III.2.2](#a3.2.2).
**Influenza B:** All three SRs/MAs assessed the effect of repeated seasonal vaccination on VE against influenza B. The SRs/MAs had concordant results, demonstrating no apparent difference between vaccination in two consecutive seasons and vaccination in the current season only for influenza B. There were no statistically significant differences in the season specific estimates for adjusted VE against influenza B between vaccination in two consecutive seasons and vaccination in the current season only in the analyses by Ramsay et al., except for the overall seasons pooled VE estimate where the upper limit of the CI was close to the null (pooled VE difference: -11%, 95% CI: -20 to -2%, I2: 0%). Similarly, Bartoszko et al. did not find a statistical difference in the pooled ORs of influenza B infection, comparing vaccination in two consecutive seasons with vaccination in the current season only, derived from either RCT or observational study designs [OR (RCTs): 0.85, 95% CI: 0.36 to 2.02%, I2: 15%; OR (observational): 1.13, 95% CI: 0.85 to 1.50%, I2: 52%]. Belongia et al. also reported similar VE against influenza B between vaccination in consecutive seasons [pooled VE: 55%, 95% CI: 38 to 67%, I2: not reported (NR)] and vaccination in the current season only (pooled VE: 61%, 95% CI: 43 to 74%, I2: NR). Belongia et al. was the only SR/MA that reported VE against the different influenza B lineages; the authors found similar pooled unadjusted VE between the two groups against influenza B/Yamagata [pooled VE (consecutive seasons): 57%, 95% CI: 47 to 65%, I2: NR; pooled VE (current season only): 62%, 95% CI: 46 to 73%, I2: NR] and against B/Victoria [pooled VE (consecutive seasons): 62%, 95% CI: 45 to 74%, I2: NR; pooled VE (current season only): 67%, 95% CI: 41 to 81%, I2: NR].
#### III.2.2 Vaccine effectiveness by influenza season where repeat effects were observed
Three of the four SRs/MAs examined VE stratified by influenza season. Belongia et al. assessed pooled VE against influenza A(H1N1)pdm09 in 2010–2011 and 2013–2014 and against influenza A(H3N2) in 2014–2015. Ramsay et al. assessed VE against influenza A(H1N1) and B in 2010–2011 to 2014–2015, and against influenza A(H3N2) in 2007–2008, 2011–2012, 2012–2013, and 2014–2015; however, not all analyses included data from more than one primary study. Bartoszko et al. assessed the effect of repeated vaccination on VE against influenza A(H3N2) during nine different influenza seasons (2008–2009 to 2016–2017), but only reported an effect estimate for the 2010–2011 season and narratively described the results for the other seasons. All estimates compared vaccination in two consecutive seasons to vaccination in the current season only.
None of the SRs/MAs found statistically significant differences in VE between vaccination in the current and prior season and vaccination in the current season only for influenza A(H1N1), A(H3N2), or B in any specific influenza season apart from the two listed below[Footnote 14](#fn14)[Footnote 15](#fn15)[Footnote 21](#fn21) (data not shown, please refer to original studies for full details).
**2010–2011:** Bartoszko et al. completed a post-hoc subgroup meta-analysis of unadjusted estimates by season, and found that during the 2010–2011 influenza season, the odds of having medically-attended, LCI A(H3N2) were statistically significantly higher among those vaccinated with seasonal influenza vaccine over two consecutive seasons compared to those vaccinated in the current season only (OR: 1.98, 95% CI: 1.32 to 2.97%, I2: 0%) (I2 estimate received by request). Belongia et al. and Ramsay et al. did not have a VE estimate against influenza A(H3N2) for the 2010–2011 season.
**2014–2015:** Ramsay et al. found that repeated vaccination was statistically significantly less effective against influenza A(H3N2) in the 2014–2015 season than vaccination in the current season only (pooled adjusted VE difference: -54%, 95% CI: -88 to -20%, I2: 29%). Belongia et al. found that although the direction of the point estimates for vaccination in two consecutive seasons and for vaccination in the current season only differed, the CIs for the two estimates greatly overlapped, to the point that one estimate's CI completely encompassed the other's [pooled VE (consecutive): -9%, 95% CI: -26 to 6%, I2: NR; pooled VE (current only): 36%, 95% CI: -32% to 69%, I2: NR]. As well, both CIs crossed zero, indicating that neither demonstrated statistically significant VE against medically-attended influenza A(H3N2) during the 2014–2015 season. Bartoszko et al. noted in their SR/MA that they did not observe a statistically significant difference in pooled unadjusted VE during 2014–2015 among repeated vaccinees compared to current season only vaccinees (OR: 1.34, 95% CI: 0.97 to 1.83, I2: 70%) (effect estimate received by request); however, the trend appeared to follow that shown in the other SRs/MAs.
#### III.2.3 Vaccine effectiveness in individuals vaccinated over three or more consecutive seasons
Only the SR/MA by Bartoszko et al. assessed influenza VE over three or more consecutive seasons. The authors compared the current season VE of individuals vaccinated consecutively across three, four or more, and five or more influenza seasons compared with individuals vaccinated in the current season only, by pooling data from two RCTs (five estimates) and 3–4 observational studies (3–6 estimates). In observational studies, the pooled unadjusted odds of medically-attended, LCI among individuals vaccinated in three (OR: 1.97, 95% CI: 1.14 to 3.39%, I2: 60%), four or more (OR: 1.40, 95% CI: 1.03 to 1.88%, I2: 54%), and five or more (OR: 1.57, 95% CI: 1.23 to 2.02%, I2: 5%) consecutive seasons were higher relative to individuals vaccinated in the current season only. The pooled estimate from the two RCTs did not find a statistically significant difference in the unadjusted odds of having medically-attended, LCI among those with vaccination over three consecutive seasons compared with those with vaccination in the current season only (OR: 1.06, 95% CI: 0.65 to 1.75%, I2: 0%).
#### III.2.4 Vaccine efficacy and effectiveness by vaccine type
Two studies examined vaccine efficacy or effectiveness stratified by type of seasonal influenza vaccine[Footnote 20](#fn20)[Footnote 21](#fn21). Bartoszko et al. pooled data from four RCTs (eight estimates) and 27 observational studies (40 estimates) separately to assess the unadjusted VE of repeated vaccination compared with vaccination in the current season only for inactivated influenza vaccines (IIV). The authors found that the odds of having medically-attended, LCI were not statistically significantly different among participants with repeated IIV vaccination over two consecutive seasons and participants vaccinated with IIV in the current season only [OR (RCTs): 0.87, 95% CI: 0.59 to 1.30%, I2: 28%; OR (observational): 1.14, 95% CI: 0.98 to 1.33%, I2: 63%].
The authors also conducted a subgroup meta-analysis of two RCTs (two estimates) on the comparative VE for live attenuated influenza vaccine (LAIV) and did not find a statistically significant difference in the odds of having medically-attended, LCI between the two vaccination scenarios (OR: 1.16, 95% CI: 0.58 to 2.32%, I2: 69%).
Morimoto et al. assessed vaccine efficacy by vaccine type against medically-attended influenza infection in children (six estimates). The authors found that the risk of having medically-attended, LCI was not statistically significantly different among children who received IIV during two consecutive seasons compared to the current season only (matched cases: RR: 1.16, 95% CI: 0.28 to 4.76%, I2: 0%; mismatched cases: RR: 1.08, 95% CI: 0.27 to 4.37%, I2: 0%). Please refer to [Section III.2.8](#a3.2.8) for Morimoto et al.'s definition of matched and mismatched cases. The same was true for matched cases of children who received LAIV (RR: 0.61, 95% CI: 0.24-1.57%, I2: 46.3%); however, children who received LAIV in two consecutive seasons and had a mismatched case of influenza had significantly higher risk of medically-attended, LCI infection (RR: 2.03, 95% CI: 1.20-3.41%, I2: 0%).
#### III.2.5 Prior season vaccination with monovalent pandemic influenza vaccine
One SR/MA reported estimates involving prior vaccination with monovalent pandemic influenza vaccine[Footnote 21](#fn21). Bartoszko et al. pooled data from seven observational studies (number of estimates not reported) to examine the odds of having medically-attended, laboratory-confirmed seasonal influenza comparing participants who received monovalent pandemic influenza vaccine in the prior season and seasonal influenza vaccine in the current season relative to participants who received seasonal influenza vaccine in the current season alone. No difference in the pooled unadjusted odds was detected between either group (OR: 0.97, 95% CI: 0.59 to 1.60%, I2: NR). The authors did not report whether the pooled estimate included studies for which participants received an adjuvanted or unadjuvanted monovalent pandemic vaccine.
#### III.2.6 Vaccine efficacy and effectiveness by age group
Two SRs/MAs assessed vaccine efficacy or effectiveness by age group[Footnote 20](#fn20)[Footnote 21](#fn21). Overall, there appeared to be no significant difference in VE based on age group.
Two separate subgroup meta-analyses comparing VE by age group were completed by Bartoszko et al., which was the only SR/MA to report on VE stratified by age. One was a subgroup meta-analysis of 14 observational studies (20 estimates) that compared unadjusted VE of vaccination in consecutive seasons and vaccination in the current season only for children (17 years of age or younger), adults (18–64 years of age), and older adults (65 years of age and older) [OR (children): 0.93, 95% CI: 0.51 to 1.69%, I2: 78%; OR (adults): 0.95, 95% CI: 0.75 to 1.21%, I2: 34%; OR (older adults): 0.78, 95% CI: 0.61 to 1.01%, I2: 0%], while the other subgroup meta-analysis of four RCTs (eight estimates) compared unadjusted VE for the two vaccination scenarios in children and adults [OR (children): 1.07, 95% CI: 0.63 to 1.80, I2: 59%; OR (adults): 0.79, 95% CI: 0.50 to 1.24%, I2: 0%]. Results from these subgroup meta-analyses showed that the odds of medically-attended LCI were not statistically significantly different between the two vaccination scenarios for any of the age groups assessed by pooled estimates from RCTs or observational studies.
Morimoto et al. assessed vaccine efficacy against any medically-attended influenza in children (six studies, six estimates) and in adults 30–60 years of age (one study, three estimates). The authors found that the risk of having medically-attended, LCI was not statistically significantly different among children or adults who had received influenza vaccination over two consecutive seasons compared to those that had received the vaccine in the current season only (children: RR: 1.31, 95% CI: 0.79 to 2.16%, I2: 37.6%; adults: RR:1.12, 95% CI: 0.65 to 1.92%, I2: 19.1%).
#### III.2.7 Vaccine effectiveness by underlying comorbidity
A subgroup meta-analysis of 11 observational studies (12 estimates) conducted by Bartoszko et al. found that there was no statistically significant difference in the unadjusted odds of having medically-attended, LCI between vaccination in two consecutive seasons and vaccination in the current season only in subgroups with no reported comorbidities (OR: 1.06, 95% CI: 0.59 to 1.93%, I2: 81%) or in subgroups with one or more reported comorbidities (OR: 0.95, 95% CI: 0.69 to 1.54%, I2: 63%). There was substantial heterogeneity in both estimates. No other SRs/MAs assessed efficacy or effectiveness by underlying comorbidity.
#### III.2.8 Vaccine efficacy and effectiveness by vaccine match
Bartoszko et al. conducted a subgroup meta-analysis of five RCTs (nine estimates) and a subgroup meta-analysis of 27 observational studies (39 estimates) to assess the comparative effectiveness of repeated influenza vaccination in scenarios where the circulating influenza strains in the current influenza season were a match to vaccine strains, and scenarios where they were a mismatch to vaccine strains. The odds of having medically-attended, LCI did not differ significantly between individuals vaccinated in consecutive seasons and individuals vaccinated in the current season only for influenza seasons when the vaccine matched the circulating strains [OR (RCTs): 0.73, 95% CI: 0.42 to 1.26%, I2: 0%; OR (observational): 1.00, 95% CI: 0.80 to 1.26%, I2: 46%] or for when the vaccine was a mismatch for circulating strains [OR (RCTs): 0.96, 95% CI: 0.61 to 1.51%, I2: 50%; OR (observational): 1.26, 95% CI: 1.00 to 1.58%, I2: 73%]. Vaccine match and mismatch were determined based on what had been reported in the primary study, and if not reported, were based on SR/MA author judgement. However, the authors did not report how vaccine match and mismatch were defined; therefore, these results should be interpreted with caution.
Morimoto et al. assessed vaccine efficacy by vaccine match in children and in adults. The authors defined cases as matched or mismatched to the vaccine strain based on antigenic characterization by hemagglutinin inhibition assay. The vaccine was considered to match the circulating strain if it was the same subtype (influenza A) or lineage (influenza B) and antigenically similar to the vaccine strain. Meta-analysis results showed that the risk of having medically-attended, LCI was not statistically significantly different between matched cases in children (RR: 0.64, 95% CI: 0.33 to 1.22%, I2: 17.3%) or mismatched cases in adults (RR: 1.35, 95% CI: 0.77 to 2.38%, I2: 0%); however, as reported in [Section III.2.4](#a3.2.4), children who had been vaccinated in two consecutive seasons were more at risk of influenza infection caused by an influenza virus not contained within the vaccine than those who had only been vaccinated in the current season (RR: 2.04, 95% CI: 1.29 to 3.22%, I2: 0%). No meta-analysis was conducted for matched cases in adults, as there was only one estimate available[Footnote 20](#fn20).
### III.3 Evidence for vaccine effectiveness of repeated vaccination compared to vaccination in prior season only
Two of the four SRs/MAs assessed VE of repeated vaccination compared to VE of vaccination in the prior season only. Ramsay et al. conducted three meta-analyses, stratified by influenza type, to examine the difference in adjusted VE between vaccination in the current and prior seasons and vaccination in the prior season only. For influenza A(H1N1), pooled data from 13 observational studies (16 estimates) showed statistically significantly higher adjusted VE among recipients vaccinated over the two most recent influenza seasons compared to vaccination in the prior season only (pooled VE difference: 25%, 95% CI: 14 to 35%, I2: 0%). Similar findings were also shown for influenza B, which were based on pooled data from 10 observational studies (13 estimates) (pooled VE difference: 18%, 95% CI: 3 to 33%, I2: 26%).
However, pooled data from 11 observational studies (14 estimates) found no statistically significant difference in adjusted VE against influenza A(H3N2) between the two vaccination scenarios (pooled VE difference: 7%, 95% CI: -7 to 21%, I2: 4%). VE estimates from the meta-analyses completed by Belongia et al. showed similar VE estimates for vaccination in consecutive seasons and for vaccination in the prior season only for influenza A(H1N1) [pooled VE (consecutive): 67%, 95% CI: 53 to 78%, I2: 69%; pooled VE (prior only): 46%, 95% CI: 29% to 59%, I2: 40%], influenza A(H3N2) [pooled VE (consecutive): 17%, 95% CI: -10 to 37%, I2: 86%; pooled VE (prior only): 9%, 95% CI: -10 to 25%, I2: 48%], and influenza B [pooled VE (consecutive): 55%, 95% CI: 38 to 67%, I2: NR; pooled VE (prior only): 25%, 95% CI: 4 to 42%, I2: NR].
### III.4 Evidence for vaccine effectiveness of repeated vaccination compared to no vaccination
Two SRs/MAs reported VE of repeat vaccination compared to no vaccination. The SR/MA conducted by Belongia et al. reported the pooled VE of repeated influenza vaccination with reference to persons who were unvaccinated in both the current and prior season. Based on a meta-analysis of unadjusted estimates, vaccination in the current and prior season showed statistically significant VE against influenza A(H1N1) (pooled VE: 67%, 95% CI: 53 to 78%, I2: 69%) and influenza B (pooled VE: 55%, 95% CI: 38 to 67%, I2: NR). However, vaccination in the current and prior season did not produce statistically significant VE against influenza A(H3N2) (pooled VE: 17%, 95% CI: -10 to 37%, I2: 86%). A separate meta-analysis of three studies that assessed VE during specific influenza seasons found that repeated vaccination was not effective only during the 2014–2015 influenza season. Therefore, the authors concluded that the low VE during this season was driving the overall absence of statistically significant VE against influenza A(H3N2).
Bartoszko et al. concluded that, based on data pooled from five RCTs (nine estimates) and from 28 observational studies (40 estimates), vaccination in two consecutive seasons was statistically significantly effective against any influenza strain when no vaccination in either season was used as a reference [pooled VE (RCTs): 71%, 95% CI: 62 to 78%, I2: NR; pooled VE (observational): 41%, 95% CI: 30 to 51%, I2: NR].
IV. Discussion
--------------
For most estimates included in the SRs/MAs, there was no significant difference in vaccine efficacy or effectiveness between vaccination in two consecutive seasons and vaccination in the current season only. When stratified by season, the majority of estimates demonstrated that there was no significant difference in VE for vaccination in two consecutive seasons and vaccination in the current season only. However, there were some exceptions. Notably, two SRs/MAs demonstrated that repeated vaccination had a statistically significantly lower VE compared to vaccination in the current season only; one SR/MA found a lower VE against influenza A(H3N2) during 2010–2011[Footnote 21](#fn21), and the other SR/MA found a lower VE against influenza A(H3N2) during 2014–2015 and against influenza B, but only in the pooled overall estimate[Footnote 15](#fn15). During the 2014–2015 Northern Hemisphere influenza season, the influenza A(H3N2) component of the vaccine was unchanged from the 2013–2014 season[Footnote 22](#fn22) and was mismatched with the circulating strain, a situation in which repeated vaccination is predicted by the antigenic distance hypothesis to negatively interfere with VE7,11. However, the authors of this study noted that their estimate was largely driven by the 2014–2015 season. The 2010–2011 influenza season was the first post-2009 pandemic season and also contained a different influenza A(H3N2) vaccine component than the 2009 Northern Hemisphere vaccine[Footnote 22](#fn22). Therefore, it is important to consider that factors besides vaccine virus components may be affecting VE estimates.
Vaccination in the current season appeared to offer the best protection against influenza, regardless of previous season's vaccination status, since vaccination in the current season only and vaccination in two consecutive seasons was consistently more effective than vaccination in the prior season only and no vaccination in either season. The only instance when vaccination in two consecutive seasons was not significantly more effective than vaccination in the prior season only was in 2014–2015 against influenza A(H3N2). Firm conclusions on the difference between vaccination in consecutive seasons and vaccination in the prior season only could not be drawn from the indirect comparisons, as many of the 95% CIs for these VE estimates were slightly overlapping[Footnote 23](#fn23).
The one SR/MA that assessed the effect of vaccination over three or more consecutive influenza seasons showed that, based on meta-analyses of observational studies, the odds of medically-attended, LCI was greater among those vaccinated in three, four or more, and five or more consecutive influenza seasons compared to those vaccinated in the current season only. However, these estimates were based on a small number of studies and were not adjusted for confounding, which may be important as there could be important underlying differences between individuals who receive the influenza vaccine annually and individuals who do not regularly receive the vaccine (e.g., individuals at high-risk of influenza infection may be more likely to receive the vaccine annually and to seek medical attention for influenza-like illness). Therefore, the current evidence is insufficient to draw firm conclusions on the effect of vaccination in three or more consecutive seasons. A recent study by Kwong et al., which was not captured by any of the included SRs/MAs due the recency of publication, assessed the effect of repeated influenza vaccination on older adults over 10 previous seasons in Canada[Footnote 21](#fn21). The authors of this study found a statistically significant trend towards decreasing VE for those vaccinated in the current season as the number of previous vaccinations increased. However, the opposite is true for those unvaccinated in the current season – as the number of previous vaccinations increased, protection in the current season also increased, which implies increasing residual protection from previous vaccinations. Regardless of the number of previous vaccinations however, vaccination in the current season provided some benefit, and was superior to remaining unvaccinated. This aligns with the findings presented in this overview for studies that assessed VE over a shorter period of time.
There was substantial heterogeneity for some of the pooled effect measures included in this overview, which indicates the presence of important underlying factors that may make meta-analysis of the data inappropriate. This was expected for estimates that pooled data across multiple influenza seasons, as VE is highly variable year to year. This was demonstrated by multiple SRs/MAs, as estimates from all SRs/MAs for specific influenza seasons tended to have little to no heterogeneity, suggesting that season-specific characteristics may account for most of the heterogeneity in other sub-analyses. However, despite seasonal differences explaining some of the heterogeneity present, further heterogeneity still exists. Some of this could be explained by differences in the local epidemiology, especially given that all SRs/MAs pooled estimates from multiple countries. Circulating influenza strains may differ by location, not just by hemisphere, and therefore estimates that pool data from many different countries could have substantial heterogeneity due to the varying contexts.
Influenza VE is also likely affected by many other factors, including vaccine strain match to circulating strains[Footnote 24](#fn24), initial exposure to influenza virus[Footnote 25](#fn25), egg-adaptive[Footnote 25](#fn25)[Footnote 26](#fn26) mutations in the vaccine viruses[Footnote 26](#fn26)[Footnote 27](#fn27), and possibly other currently unknown factors. In addition, these factors likely have complex interactions with each other, as suggested in a recent article by Skowronski et al.[Footnote 28](#fn28) The degree to which repeated vaccination and these other factors affect VE is not fully understood, and varies season to season, making it extremely difficult to predict far enough in advance of the next influenza season to make vaccine policy or administration practice changes. Therefore, a better understanding of the underlying immunological mechanisms and factors affecting the immune response to influenza vaccination are necessary to improve influenza vaccine development and programs.
Finally, addressing programmatic factors such as ethics, equity, feasibility and acceptability[Footnote 29](#fn29) as future evidence emerges on this topic will remain important. Guidance on influenza immunization upholds the core ethical dimensions for public health by aiming to prevent future disease, but it must be given in the challenging context of parameters that vary from season to season and are very difficult to predict (such as vaccine to circulating strain match or mismatch, and variable clinical disease severity). It is also important to consider that the effectiveness of a vaccine may have a significant impact on vaccine acceptability[Footnote 30](#fn30), which in turn may affect the uptake and impact of an immunization program. Therefore, despite negative interference occurring inconsistently in the literature summarized, the potential for reduced VE is of concern. As new vaccine products are added and as evidence emerges, including new studies examining the effect of pre-existing immunity on influenza vaccine responses[Footnote 31](#fn31)[Footnote 32](#fn32)[Footnote 33](#fn33), NACI will continue to monitor the evidence for this phenomenon, and will issue new guidance as needed.
### IV.1 Limitations
This overview was designed to assess the effects of repeated influenza vaccination on VE, efficacy, and immunogenicity for the purpose of providing guidance on annual influenza vaccination. All SRs/MAs that were included contained a systematic review and a meta-analysis of the effects of repeated influenza vaccination on vaccine efficacy or effectiveness but did not provide an evaluation of immunogenicity. Through this lens, additional evidence is necessary for the outcomes in this overview to determine the effect of repeated vaccination over time and across multiple influenza seasons. However, pooling data across seasons and from different geographic locations, as done by the SRs/MAs included in this overview, is insufficient to determine the potential causes of and mechanisms behind the effect of repeated vaccination on VE, and is expected to give estimates with high heterogeneity, since VE is affected by variables that often change season to season (e.g., circulating strain, vaccine match, etc.).
The SRs/MAs included for review all had similar research questions, as well as inclusion and exclusion criteria; as a result, there was significant overlap (46%) in the primary studies included for evidence synthesis in the SRs/MAs. Therefore, we caution that, while the results appear to draw data from many studies and populations, the SRs/MAs used much of the same data to produce the pooled estimates. Despite the different methods used by the SRs/MAs to pool data across studies (VE, difference in VE, RR, and OR), the results and conclusions of the SRs/MAs were generally consistent with each other, strengthening the reliability of the conclusions drawn from this evidence synthesis. The SRs/MAs were of good quality based on AMSTAR 2. The primary studies included in the SRs/MAs were also generally of good quality; the RoB was low for observational studies, which formed the majority of the evidence base. However, authors noted a high RoB for RCTs. Separate meta-analyses were completed for estimates from RCTs and from observational studies. The findings for most outcomes were similar; therefore, it does not appear that the high RoB for the included RCTs significantly affected the results of the meta-analyses.
The SRs/MAs by Bartoszko et al. and Morimoto et al. included studies that confirmed influenza infection using RT-PCR, which is the gold standard for influenza virus detection due to its higher sensitivity and specificity[Footnote 34](#fn34)[Footnote 35](#fn35), but also studies using influenza infection confirmed by laboratory methods other than RT-PCR. Bartoszko et al. included these studies after determining that their inclusion did not significantly alter effect estimates, which alleviates some of the concerns with including studies that detected influenza virus by other laboratory methods for their SR/MA. Of note, studies using laboratory methods other than RT-PCR represented a small proportion of the total number of included studies (14%).
This overview included SRs/MAs that presented pooled effect estimates for direct comparisons (pooled difference in VE, RR, OR) and indirect comparisons, such as comparing separate pooled VE estimates for different vaccination scenarios which used unvaccinated in either season as a reference. Since the purpose of this overview was to determine the effects of repeated vaccination compared to either vaccination in the current season only, vaccination in the prior season only, or no vaccination, an effect estimate from a direct comparison is more appropriate for answering this overview's research question than an indirect comparison, as estimates with slightly overlapping CIs could still be significantly different[Footnote 23](#fn23).
How some subgroups were assessed, and which subgroups were not assessed, presented particular limitations. Bartoszko et al. assessed influenza VE by vaccine match or mismatch, but did not specify how a match or mismatch had been defined, which presents difficulties for interpreting these findings. In addition, none of the SRs/MAs assessed the efficacy or effectiveness of adjuvanted, high dose, cell-based, or egg-based influenza vaccines, which are all different formulations of influenza vaccine authorized for use in Canada.
V. Recommendations
------------------
**1. NACI continues to recommend that seasonal influenza vaccine should be offered annually to everyone 6 months of age and older who does not have contraindications to the vaccine, irrespective of previous seasons' influenza vaccination status. (Strong NACI Recommendation)**
* NACI concludes that there is fair evidence to recommend annual influenza vaccination, irrespective of whether an individual received the seasonal influenza vaccine in previous seasons (Grade B Evidence).
**Summary of evidence**
* Repeated vaccination across seasons, including the current season, was consistently more effective than no vaccination in the current season.
* In general, the evidence shows no significant difference or predictable trend in vaccine efficacy or effectiveness between vaccinations in two consecutive seasons compared to vaccination in the current season only.
+ Of all the seasons investigated across many studies, only two influenza seasons indicated that VE of vaccination over consecutive seasons was statistically significantly lower than vaccination in the current season only. These notable seasons were influenza A(H3N2) in 2010–2011[Footnote 21](#fn21), and influenza A(H3N2) in 2014–2015[Footnote 15](#fn15). These findings were not statistically significant in all SRs/MAs which assessed VE in these two seasons; however, a trend towards lower VE for repeated vaccination was consistent for the 2014–2015 season across all studies[Footnote 14](#fn14)[Footnote 21](#fn21).
* Evidence on the effects of repeated vaccination over three or more consecutive seasons was limited and is insufficient to draw firm conclusions at this point in time.
* Given the complex interplay between immune imprinting (such as previous exposures through vaccination and natural infection), circulating virus types, and individual characteristics, it is not currently feasible nor warranted to modify existing annual influenza vaccination programs to account for potential negative or positive interference effects related to repeated influenza vaccination across seasons.
VI. Research priorities
-----------------------
Research to address the following outstanding questions is encouraged:
**New and emerging research priorities**
Further evaluation of VE stratified by characteristics in addition to influenza strain type and subtype would allow for better identification of when the effects of repeated influenza vaccination should be considered and which specific populations may be affected.
* Further evaluation of the effects of long-term repeated influenza vaccination on VE over more than 2 consecutive seasons.
* Further evaluation of the effects of repeated influenza vaccination on VE stratified by age group and vaccine type.
* Investigation of the effects of repeated influenza vaccination on severe influenza-related outcomes, such as hospitalization and death.
* Evaluation of the effects of repeated influenza vaccination that accounts for previous influenza exposure through vaccination and/or natural infection.
* Further investigation of the immunological mechanisms underlying the effects of repeated influenza vaccination on VE, including the antigenic distance hypothesis and immunological imprinting.
Additional tables
-----------------
Table 4. NACI recommendations: Strength of recommendation and grade of evidence
| Strength of NACI recommendation
Based on factors not isolated to strength of evidence (e.g. public health need) | Grade of evidence
Based on assessment of the body of evidence |
| --- | --- |
| **Strong**
“should/should not be offered”* Known/Anticipated advantages outweigh known/anticipated disadvantages ("should"),
OR Known/Anticipated disadvantages outweigh known/anticipated advantages ("should not")
* Implication: A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present
| * A – **good evidence** to recommend
* B – **fair evidence** to recommend
* C – **conflicting evidence**, however other factors may influence decision-making
* D – **fair evidence** to recommend against
* E – **good evidence** to recommend against
* I – **insufficient evidence** (in quality or quantity), however other factors may influence decision-making
|
| **Discretionary**
“may be considered”* Known/Anticipated advantages closely balanced with known/anticipated disadvantages,
OR uncertainty in the evidence of advantages and disadvantages exists
* Implication: A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable
| * A – **good evidence** to recommend
* B – **fair evidence** to recommend
* C – **conflicting evidence**, however other factors may influence decision-making
* D – **fair evidence** to recommend against
* E – **good evidence** to recommend against
* I – **insufficient evidence** (in quality or quantity), however other factors may influence decision-making
|
Table 5. Summary of evidence related to efficacy and effectiveness of repeated influenza vaccination
| Study details | Summary |
| --- | --- |
| Study | Vaccine | Study design | Participants | Summary of key findings | Level of evidence | Quality |
| Bartoszko JJ, McNamara IF, Aras OA, Hylton DA, Zhang YB, Malhotra D, Hyett SL, Morassut RE, Rudziak P, Loeb M. Does consecutive influenza vaccination reduce protection against influenza: A systematic review and meta-analysis. Vaccine. 2018 Jun 7;36(24):3434-44.[Footnote 21](#fn21) | Seasonal influenza vaccine | SR/MA
Random effects model
PICO: see [Tables 1](#t1) and [2](#t2)
Included: RCTs, quasi-RCTs, observational studies
Influenza seasons: 23 seasons between 1983–1994 and mid 2016–2017
Funding: Canadian Institute for Health Research Foundation Grant | Number of participants (RCTs): 11,987
Number of participants (observational): 28,627
Age range: all ages | Primary findings:
SR included a total of 5 RCTs (MA=5) and 39 observational studies (MA=34).
OR was assessed by determining the unadjusted odds of influenza infection, confirmed by any laboratory test, between vaccination in consecutive seasons and vaccination in the current season only.
**Any strain (RCT)**
OR: 0.88
95% CI: 0.62, 1.26
I2: 0.39
# of estimates (# of studies): 5 (9)
**Any strain (Obs)**
OR: 1.14
95% CI: 0.98, 1.32
I2: 0.63
# of estimates (# of studies): 40 (28)
**A(H1N1) (RCT)**
OR: 0.86
95% CI: 0.38, 1.96
I2: 0
# of estimates (# of studies): 3 (2)
**A(H1N1) (Obs)**
OR: 0.87
95% CI: 0.67, 1.12
I2: 0.46
# of estimates (# of studies): 15 (12)
**A(H3N2) (RCT)**
OR: 0.71
95% CI: 0.37, 1.34
I2: 0
# of estimates (# of studies): 3 (2)
**A(H3N2) (Obs)**
OR: 1.09
95% CI: 0.86, 1.38
I2: 0.7
# of estimates (# of studies): 18 (16)
**B (RCT)**
OR: 0.85
95% CI: 0.36, 2.02
I2: 0.15
# of estimates (studies): 4 (2)
**B (Obs)**
OR: 1.13
95% CI: 0.85, 1.50
I2: 0.52
# of estimates (# of studies): 11 (11)
The VE of repeated vaccination was also assessed by pooling the unadjusted VE against influenza infection, confirmed by any RT-PCR. Unvaccinated in the current and prior seasons was the reference category:
**Current and prior season (RCT)**
VE: 71%
95% CI: 62, 78
I2: NR
# of estimates (# of studies): 5 (9)
**Current and prior season (Obs)**
VE: 41%
95% CI: 30, 51
I2: NR
# of estimates (# of studies): 40 (28)
**Current season only (RCT)**
VE: 58%
95% CI: 48, 66
I2: NR
# of estimates (# of studies): 5 (9)
**Current season only (Obs)**
VE: 47%
95% CI: 39, 54
I2: NR
# of estimates (# of studies): 40 (28)
Subgroup meta-analyses:
Protection against any influenza strain by vaccine type:
**IIV (RCT)**
OR: 0.87
95% CI: 0.59, 1.30
I2: 28%
# of estimates (# of studies): 8 (4)
**IIV (Obs)**
OR: 1.14
95% CI: 0.98, 1.33
I2: 63%
# of estimates (# of studies): 40 (28)
**LAIV (RCT)**
OR: 1.16
95% CI: 0.58, 2.32
I2: 69%
# of estimates (# of studies): 2 (2)
Unadjusted odds of influenza infection, confirmed by any laboratory test, between vaccination with monovalent pandemic influenza vaccine in the prior season and seasonal influenza vaccine in the current season compared to vaccination in the current season only:
**Observational**
OR: 0.97
95% CI: 0.59, 1.60
I2: NR
# of estimates (# of studies): NR (7)
Protection against any influenza strain by age:
**Aged 17 years or younger (RCT)**
OR: 1.07
95% CI: 0.63, 1.80
I2: 59%
# of estimates (# of studies): 3 (3)
**Aged 17 years or younger (Obs)**
OR: 0.93
95% CI: 0.51, 1.69
I2: 78%
# of estimates (# of studies): 9 (8)
**Aged 18–64 years (RCT)**
OR: 0.79
95% CI: 0.50, 1.24
I2: 0%
# of estimates (# of studies): 5 (1)
**Aged 18–64 years (Obs)**
OR: 0.95
95% CI: 0.75, 1.21
I2: 34%
# of estimates (# of studies): 8 (7)
**Aged 65 years and older (Obs)**
OR: 0.78
95% CI: 0.61, 1.01
I2: 0%
# of estimates (# of studies): 3 (3)
Protection against any influenza strain by vaccine match:
**Match (RCT)**
OR: 0.73
95% CI: 0.42, 1.26
I2: 0%
# of estimates (# of studies): 4 (3)
**Match (Obs)**
OR: 1.00
95% CI: 0.80, 1.26
I2: 46%
# of estimates (# of studies): 18 (15)
**Mismatch (RCT)**
OR: 0.96
95% CI: 0.61, 1.51
I2: 50%
# of estimates (# of studies): 5 (3)
**Mismatch (Obs)**
OR: 1.26
95% CI: 1.00, 1.58
I2: 73%
# of estimates (# of studies): 21 (14)
Protection against any influenza strain by presence of underlying comorbidity:
**No reported comorbidities (Obs)**
OR: 1.06
95% CI: 0.59, 1.93
I2: 81%
# of estimates (# of studies): 9 (8)
**1 or more comorbidities reported (Obs)**
OR: 0.95
95% CI: 0.69, 1.54
I2: 63%
# of estimates (# of studies): 3 (3)
Protection against any influenza strain when vaccinated in three consecutive seasons compared to current season only:
**RCT**
OR: 1.06
95% CI: 0.65, 1.75
I2: 0%
# of estimates (# of studies): 5 (2)
**Obs**
OR: 1.97
95% CI: 1.14, 3.39
I2: 60%
# of estimates (# of studies): 6 (4)
Protection against any influenza strain when vaccinated in four or more consecutive seasons compared to current season only:
**Obs**
OR: 1.40
95% CI: 1.03, 1.88
I2: 54%
# of estimates (# of studies): 4 (4)
Protection against any influenza strain when vaccinated in five or more consecutive seasons compared to current season only:
**Obs**
OR: 1.57
95% CI: 1.23, 2.02
I2: 5%
# of estimates (# of studies): 3 (3)
Protection against influenza A(H3N2) in 2010–2011:
**Obs**
OR: 1.98
95% CI: 1.32, 2.97
I2: NR
# of estimates (# of studies): NR (NR)
The odds of influenza A(H3N2) infection were not statistically significantly different between repeated vaccination and vaccination in the current season only for any other specific influenza season. | SR/MA | See [Table 3](#t3). |
| **Morimoto N, Takeishi K.** Change in the efficacy of influenza vaccination after repeated inoculation under antigenic mismatch: A systematic review and meta-analysis.
Vaccine. 2018 Feb 8;36(7):949-57.[Footnote 20](#fn20) | Seasonal influenza vaccine | SR/MA
Random effects model
PICO: see [Tables 1](#t1) and [2](#t2)
Included: RCT
Influenza seasons (SR): 22 seasons between 1972-1973 and 2010-2011
Influenza seasons (MA): 9 seasons between 1973-1974 and 2009-2010
Funding: Study was not funded | Number of observations (MA): 4541
Age range: all ages | Primary findings:
SR included a total of 19 RCTs (MA=8).
Vaccine efficacy was assessed by calculating the relative risk (RR) of medically-attended influenza infection for vaccination in two consecutive seasons compared to vaccination in the current season only. Medically-attended influenza was defined as acute respiratory illness (defined as the presence of fever, cough, headache, myalgia, sore throat or other respiratory symptoms) plus laboratory confirmation of influenza virus. Influenza infection was confirmed by RT-PCR or serology and/or culture.
Vaccine efficacy against any medically-attended influenza:
**Children**
RR: 1.31
95% CI: 0.79-2.16
I2: 37.6%
# of estimates (# of studies): 6 (6)
**Adults**
RR: 1.12
95% CI: 0.65-1.92
I2: 19.1%
# of estimates (# of studies): 3 (1)
Subgroup meta-analyses:
Vaccine efficacy by vaccine match\* against any medically-attended influenza:
**Matched (Children)**
RR: 0.64
95% CI : 0.33-1.22
I2: 17.3%
# of estimates (# of studies): 5 (5)
**Matched (Adults)**
RR: 0.68
95% CI : 0.27-1.73
I2: N/A
# of estimates (# of studies): 1 (1)
**Mismatched (Children)**
RR: 2.04
95% CI : 1.29-3.22
I2: 0%
# of estimates (# of studies): 6 (6)
**Mismatched (Adults)**
RR: 1.35
95% CI : 0.77-2.38
I2: 0%
# of estimates (# of studies): 2 (1)
\* Antigenically matched is defined as a vaccine that was deemed to match circulating strains with the same subtype and were antigenically similar.
Vaccine efficacy by vaccine type and match\* against any medically-attended influenza in children\*\*:
**Matched (IIV)**
RR: 1.16
95% CI: 0.28-4.76
I2: 0%
# of estimates (# of studies): NR (NR)
**Matched (LAIV)**
RR: 0.61
95% CI: 0.24-1.57
I2: 46.3%
# of estimates (# of studies): NR (NR)
**Mismatched (IIV)**
RR: 1.08
95% CI: 0.27-4.37
I2: 0%
# of estimates (# of studies): NR (NR)
**Mismatched (LAIV)**
RR: 2.03
95% CI: 1.20-3.41
I2: 0%
# of estimates (# of studies): NR (NR)
\* Antigenically matched is defined as a vaccine that was deemed to match circulating strains with the same subtype and were antigenically similar.
\*\* Number of estimates included in analysis was not reported for this measure. | SR/MA | See [Table 3](#t3). |
| **Ramsay LC, Buchan SA, Stirling RG, Cowling BJ, Feng S, Kwong JC, Warshawsky BF**. The impact of repeated vaccination on influenza vaccine effectiveness: A systematic review and meta-analysis. BMC Med, 2019;17(1):9. Retraction of: Ramsay LC, Buchan SA, Stirling RG. The Impact of Repeated Vaccination on Influenza Vaccine Effectiveness: A Systematic Review and Meta-Analysis. BMC Med. 2017;15(1):159[Footnote 15](#fn15) | Seasonal influenza vaccine | SR/MA
Random effects model
PICO: see [Tables 1](#t1) and [2](#t2)
Included: observational studies
Influenza seasons:
2004–2005 to 2014–2015
Funding: study was not funded | Number of participants: NR
Age range: all ages | Primary findings:
SR included 26 observational studies (MA=20).
VE was assessed by determining the difference in adjusted VE against influenza infection, confirmed by any RT-PCR, between:
VE for vaccination in two consecutive seasons minus VE for vaccination in the current season only:
**A(H1N1)**
VE difference: 3%
95% CI: -8, 13
I2: 0%
# of estimates (# of studies): 16 (13)
**A(H3N2)**
VE difference: -20%
95% CI: -36, -4
I2: 35%
# of estimates (# of studies): 14 (11)
**B**
VE difference: -11%
95% CI: -20, -2
I2: 0%
# of estimates (# of studies): 14 (11)
VE for vaccination in two consecutive seasons minus VE for vaccination in the prior season only:
**A(H1N1)**
VE difference: 25%
95% CI: 14, 35
I2: 0%
# of estimates (# of studies): 16 (13)
**A(H3N2)**
VE difference: 7%
95% CI: -7, 21
I2: 4%
# of estimates (# of studies): 14 (11)
**B**
VE difference: 18%
95% CI: 3, 33
I2: 26%
# of estimates (# of studies): 13 (10)
Subgroup findings:
VE against A(H3N2) for vaccination in two consecutive seasons minus VE for vaccination in the current season only in 2014–2015
**A(H3N2)**
VE difference: -54%
95% CI: -88, -20
I2: 29%
# of estimates (# of studies): 3 (3)
Vaccination in two consecutive seasons was equally as effective as vaccination in current season only in all other season specific pooled analyses. | SR/MA | See [Table 3](#t3). |
| **Belongia EA, Skowronski DM, McLean HQ, Chambers C, Sundaram ME, De Serres G**. Repeated annual influenza vaccination and vaccine effectiveness: Review of evidence. Expert Rev Vaccines. 2017;16(7):723–36[Footnote 14](#fn14) | Seasonal influenza vaccine | SR/MA
Random effects model
PICO: see [Tables 1](#t1) and [2](#t2)
Included: test-negative case-control, case-control, cohort, RCTs
Influenza seasons:
2010–2011 to 2014–2015
Funding: study was not funded | Number of participants: NR
Age range: 2 years of age and older | Primary findings:
SR included 18 studies (MA=17).
VE was assessed by pooling the unadjusted VE against influenza infection, confirmed by any RT-PCR. Unvaccinated in the current and prior seasons was the reference category for all following scenarios:
VE for vaccination in two consecutive seasons:
**A(H1N1)pdm09**
VE: 67%
95% CI: 53, 78
I2: 69%
# of estimates (# of studies): 10 (10)
**A(H3N2)**
VE: 17%
95% CI: -10, 37
I2: 86%
# of estimates (# of studies): 7 (7)
**B**
VE: 55%
95% CI: 38, 67
I2: NR
# of estimates (# of studies): 5 (5)
**B/Yam**
VE: 57%
95% CI: 47, 65
I2: NR
# of estimates (# of studies): 6 (6)
**B/Vic**
VE: 62%
95% CI: 45, 74
I2: NR
# of estimates (# of studies): 3 (3)
VE for vaccination in current season only:
**A(H1N1)pdm09**
VE: 58%
95% CI: 48, 67
I2: 0%
# of estimates (# of studies): 10 (10)
**A(H3N2)**
VE: 39%
95% CI: 16, 55
I2: 73%
# of estimates (# of studies): 7 (7)
**B**
VE: 61%
95% CI: 43, 74
I2: NR
# of estimates (# of studies): 5 (5)
**B/Yam**
VE: 62%
95% CI: 46, 73
I2: NR
# of estimates (# of studies): 6 (6)
**B/Vic**
VE: 67%
95% CI: 41, 81
I2: NR
# of estimates (# of studies): 3 (3)
VE for vaccination in prior season only
**A(H1N1)pdm09**
VE: 46%
95% CI: 29, 59
I2: 40%
# of estimates (# of studies): 10 (10)
**A(H3N2)**
VE: 9%
95% CI: -10, 25
I2: 48%
# of estimates (# of studies): 7 (7)
**B**
VE: 25%
95% CI: 4, 42
I2: NR
# of estimates (# of studies): 5 (5)
**B/Yam**
VE: 42%
95% CI: 25, 55
I2: NR
# of estimates (# of studies): 6 (6)
**B/Vic**
VE: 45%
95% CI: -10, 72
I2: NR
# of estimates (# of studies): 3 (3) | SR/MA | See [Table 3](#t3). |
| **Abbreviations – CI:** confidence interval, **IIV:** inactivated influenza vaccine, **LAIV:** live attenuated influenza vaccine, **MA:** meta-analysis, **NR:** not reported, **obs.:** observational study, **OR:** odds ratio, **PICO:** population, intervention, comparator, and outcome, **RCT:** randomized controlled trial, **RR:** relative risk, **RT-PCR:** reverse-transcriptase polymerase chain reaction, **SR/MA:** systematic review and meta-analysis, **VE:** vaccine effectiveness |
List of abbreviations
---------------------
CI
Confidence interval
IIV
Inactivated influenza vaccine
LCI
Laboratory confirmed influenza
LAIV
Live attenuated influenza vaccine
MA
Meta-analysis
NACI
National Advisory Committee on Immunization
NR
Not reported
OR
Odds ratio
PHAC
Public Health Agency of Canada
PICO
Population, intervention, comparator, and outcome
RCT
Randomized controlled trial
RoB
Risk of Bias
RR
Relative risk
RT-PCR
Reverse transcriptase-polymerase chain reaction
SR
Systematic review
SR/MA
Systematic review and meta-analysis
VE
Vaccine effectiveness
Acknowledgments
---------------
**This NACI Statement was prepared by:** K Young, MK Doll, J Przepiorkowski, L Zhao, R Harrison, I Gemmill, J Papenburg, and A Sinilaite on behalf of NACI.
**NACI gratefully acknowledges the contribution of:** P Doyon-Plourde, A Gil, L Glandon (Health Library, HC), A House, SJ Ismail, M Laplante, R Stirling, C Tremblay, M Tunis, M Xi, L Glandon (Health Library, HC), A House, M Laplante, R Stirling, and M Tunis.
### NACI Influenza Working Group
**Members:** J Papenburg (Chair), P De Wals, D Fell, I Gemmill, R Harrison, J Langley, A McGeer, and D Moore.
**Former working group members:** N Dayneka, K Klein, D Kumar, M Lavoie, J McElhaney, S Smith, and B Warshawsky.
**Liaison representatives:** L Grohskopf (Centers for Disease Control and Prevention [CDC], United States).
**Ex-officio representatives:** C Bancej (Centre for Immunization and Respiratory Infectious Diseases [CIRID], PHAC), J Reiter (First Nations and Inuit Health Branch [FNIHB], Indigenous Services Canada [ISC]), and J Xiong (Biologics and Genetic Therapies Directorate [BGTD], Health Canada [HC]).
### NACI
**Members:** S Deeks (Chair), R Harrison (Vice-Chair), M Andrew, J Bettinger, N Brousseau, H Decaluwe, P De Wals, E Dubé, V Dubey, K Hildebrand, K Klein, J Papenburg, A Pham-Huy, B Sander, S Smith, and S Wilson.
**Former NACI members:** M Lavoie, C Quach, C Rotstein, M Salvadori and N Sicard
**Liaison representatives:** L Bill / M Nowgesic (Canadian Indigenous Nurses Association), LM Bucci (Canadian Public Health Association), E Castillo (Society of Obstetricians and Gynaecologists of Canada), A Cohn (Centers for Disease Control and Prevention, United States), L Dupuis (Canadian Nurses Association), D Fell (Canadian Association for Immunization Research and Evaluation), S Funnell (Indigenous Physicians Association of Canada), J Hu (College of Family Physicians of Canada), M Lavoie (Council of Chief Medical Officers of Health), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), and A Ung (Canadian Pharmacists Association).
**Former liaison representatives:** J Brophy (Canadian Association for Immunization Research and Evaluation), A Cohn (CDC, United States), J Emili (College of Family Physicians of Canada), K Klein (Council of Chief Medical Officers of Health), and A Pham-Huy (Association of Medical Microbiology and Infectious Disease Canada).
**Ex-Officio representatives:** V Beswick-Escanlar (National Defence and the Canadian Armed Forces), E Henry (Centre for Immunization and Respiratory Infectious Diseases (CIRID), PHAC), M Lacroix (Public Health Ethics Consultative Group, PHAC), C Lourenco (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada), D MacDonald (COVID-19 Epidemiology and Surveillance, PHAC), S Ogunnaike-Cooke (CIRID, PHAC), K Robinson (Marketed Health Products Directorate, HC), G Poliquin (National Microbiology Laboratory, PHAC), and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada).
**Former ex-officio representatives:** K Barnes (National Defence and the Canadian Armed Forces), J Gallivan (Marketed Health Products Directorate, HC), J Pennock (CIRID, PHAC), and R Pless (BGTD, HC).
Appendix A: Search strategy and results
---------------------------------------
Outlined below are the search terms formatted for the respective databases; this list was developed in collaboration with a librarian at the federal Health Library. Please note the Medline table for a breakdown of search concepts.
### OvidMEDLINE
Database(s): Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE and Versions(R)
Table 4: OvidMEDLINE Search Strategy
| ID | Searches | Results |
| --- | --- | --- |
| 1 | influenza vaccines/ or influenza, human/pc | 26844 |
| 2 | (influenza, human/ or exp influenzavirus a/ or exp influenzavirus b/) and (exp vaccines/ or exp vaccination/) | 18873 |
| 3 | ((influenza\* or flu or H?N?) adj5 (vaccin\* or immuni\* or inoculat\*)).tw,kf,kw. | 31281 |
| 4 | 1 or 2 or 3 | 40820 |
| 5 | (repeat\* or annual\* or yearly or consecutive\* or ((each or every) adj3 (year\* or season\*))).tw,kf,kw. | 1162272 |
| 6 | 4 and 5 | 4070 |
| 7 | limit 6 to (meta analysis or "review" or systematic reviews) | 763 |
| 8 | (meta analysis or "review" or systematic reviews).pt. | 2592121 |
| 9 | meta-analysis/ or systematic review/ or meta-analysis as topic/ or "meta analysis (topic)"/ or "systematic review (topic)"/ | 114346 |
| 10 | ((systematic\* adj3 (review\* or overview\*)) or (methodologic\* adj3 (review\* or overview\*)) or (quantitative adj3 (review\* or overview\* or synthes\*)) or (integrative adj3 (review\* or overview\*)) or (collaborative adj3 (review\* or overview\*)) or meta analy\* or metaanaly\*).tw,kf,kw. | 231991 |
| 11 | 8 or 9 or 10 | 2660082 |
| 12 | 6 and 11 | 708 |
| 13 | 7 or 12 | 773 |
| 14 | limit 13 to yr="2016 -Current" | 87 |
| 15 | limit 14 to (English or French) | 86 |
86 results
### EMBASE
Database: EMBASE 1974 to 2017 October 27
Table 5: EMBASE search strategy
| ID | Searches | Results |
| --- | --- | --- |
| 1 | influenza vaccine/ or influenza vaccination/ or exp influenza/pc or exp influenza virus/pc | 42496 |
| 2 | (exp influenza/ or exp influenza virus/) and (vaccine/ or virus vaccine/ or inactivated virus vaccine/ or vaccination/) | 12988 |
| 3 | ((influenza\* or flu or H?N?) adj5 (vaccin\* or immuni\* or inoculat\*)).tw,kw. | 35784 |
| 4 | 1 or 2 or 3 | 56476 |
| 5 | (repeat\* or annual\* or yearly or consecutive\* or ((each or every) adj3 (year\* or season\*))).tw,kw. | 1472575 |
| 6 | 4 and 5 | 5508 |
| 7 | limit 6 to (meta analysis or "systematic review" or "review") | 927 |
| 8 | (meta analysis or "systematic review" or "review").pt. | 2348984 |
| 9 | meta analysis/ or review/ or systematic review/ or "meta analysis (topic)"/ or "systematic review (topic)"/ | 2472401 |
| 10 | ((systematic\* adj3 (review\* or overview\*)) or (methodologic\* adj3 (review\* or overview\*)) or (quantitative adj3 (review\* or overview\* or synthes\*)) or (integrative adj3 (review\* or overview\*)) or (collaborative adj3 (review\* or overview\*)) or meta analy\* or metaanaly\*).tw,kw. | 268815 |
| 11 | 8 or 9 or 10 | 2663316 |
| 12 | 6 and 11 | 964 |
| 13 | 7 or 12 | 964 |
| 14 | limit 13 to yr="2016 -Current" | 114 |
| 15 | limit 14 to (English or French) | 110 |
110 results
### Cochrane Library (Wiley interface)
Table 6: Cochrane library search strategy
| ID | Searches | Results |
| --- | --- | --- |
| 1 | MeSH descriptor: [Influenza Vaccines] this term only | 1572 |
| 2 | MeSH descriptor: [Influenza, Human] this term only and with qualifier(s): [Prevention & control - PC] | 1198 |
| 3 | MeSH descriptor: [Influenza, Human] this term only | 1674 |
| 4 | MeSH descriptor: [Influenzavirus A] explode all trees | 895 |
| 5 | MeSH descriptor: [Influenzavirus B] explode all trees | 268 |
| 6 | MeSH descriptor: [Vaccines] explode all trees | 9061 |
| 7 | MeSH descriptor: [Vaccination] explode all trees | 2618 |
| 8 | (#3 or #4 or #5) and (#6 or #7) | 1298 |
| 9 | ((influenza\* or flu or H?N?) and (vaccin\* or immuni\* or inoculat\*)):ti,ab,kw (Word variations have been searched) | 3988 |
| 10 | #1 or #2 or #8 or #9 | 4145 |
| 11 | (repeat\* or annual\* or yearly or consecutive\* or ((each or every) near/3 (year\* or season\*))):ti,ab,kw (Word variations have been searched) | 103447 |
| 12 | #10 and #11 Publication Year from 2016 to 2017 | 78 |
78 results
### SCOPUS
( TITLE-ABS-KEY ( ( influenza\* OR flu OR h?n?) W/5 ( vaccin\* OR immuni\* OR inoculat\*))) AND ( TITLE-ABS-KEY ( repeat\* OR annual\* OR yearly OR consecutive\* OR ( ( each OR every) W/3 ( year\* OR season\*)))) AND ( TITLE-ABS-KEY ( ( systematic\* W/3 ( review\* OR overview\*)) OR ( methodologic\* W/3 ( review\* OR overview\*)) OR ( quantitative W/3 ( review\* OR overview\* OR synthes\*)) OR ( integrative W/3 ( review\* OR overview\*)) OR ( collaborative W/3 ( review\* OR overview\*)) OR meta AND analy\* OR metaanaly\*)) AND ( LIMIT-TO ( PUBYEAR, 2017) OR LIMIT-TO ( PUBYEAR, 2016))
18 results
### ProQUEST Public Health
Database: Public Health Database, narrowed by: Entered date: 2016 - 2017; source type: Scholarly Journals
TI,AB,SU((influenza\* or flu or H?N?) NEAR/5 (vaccin\* or immuni\* or inoculat\*)) AND TI,AB,SU(repeat\* or annual\* or yearly or consecutive\* or ((each or every) NEAR/3 (year\* or season\*))) AND ((systematic\* NEAR/3 (review\* or overview\*)) or (methodologic\* NEAR/3 (review\* or overview\*)) or (quantitative NEAR/3 (review\* or overview\* or synthes\*)) or (integrative NEAR/3 (review\* or overview\*)) or (collaborative NEAR/3 (review\* or overview\*)) or meta analy\* or metaanaly\*)Limits applied
81 results
### PROSPERO
(influenza\* or flu) and (vaccin\* or immuni\* or inoculat\*) and (repeat\* or annual\* or yearly or consecutive\* or "each year" or "every year" or "each season" or "every season")
25 results
Appendix B: Flow diagram
------------------------
**Effects of Repeated Seasonal Influenza Vaccination. October 27, 2017. Updated June 3, 2019**
Text description
The PRISMA flow diagram describes the process by which articles were selected for the literature review. The process is broken down into four stages: Identification, Screening, Eligibility and Included.
**Stage 1: Identification**
* 634 records were identified through a database search performed on October 27, 2017 and updated on June 3, 2019.
* 2 records had been previously identified through additional sources.
* 463 records remained after duplicates were removed.
**Stage 2: Screening**
* 463 records were then screened.
* Of these 463 records, 448 records were excluded.
**Stage 3: Eligibility**
* 15 full-text articles were assessed for eligibility.
* Of these 15 full-text articles, 10 were excluded. The exclusion breakdown is as follows: 5 were not a systematic review or meta-analysis; 4 were duplicates; 1 was incomplete.
* 5 full-text articles were assessed for quality.
* Of these 5 full-text articles, 1 was excluded due to insufficient quality.
**Stage 4: Included**
* 4 articles were included in the final synthesis.
References
----------
Footnote 1
Schanzer DL, McGeer A, Morris K. Statistical estimates of respiratory admissions attributable to seasonal and pandemic influenza for Canada. Influenza Other Respir Viruses. 2013 Sep;7(5):799–808.
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
Schanzer DL, Sevenhuysen C, Winchester B, Mersereau T. Estimating Influenza Deaths in Canada, 1992–2009. Nishiura H, editor. PLoS ONE. 2013 Nov 27;8(11):e80481.
[Return to footnote 2 referrer](#fn2-rf)
Footnote 3
National Advisory Committee on Immunization. Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2022–2023 [Internet]. Public Health Agency of Canada. 2022. Available from: https://www.canada.ca/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
World Health Organization. Influenza vaccine viruses and reagents [Internet]. Vol. 2017. [cited 2017 Nov 28]. Available from: http://www.who.int/influenza/vaccines/virus/en/
[Return to footnote 4 referrer](#fn4-rf)
Footnote 5
Hoskins TW, Davies JR, Smith AJ, Et. Al. Assessment of Inactivated Influenza-A Vaccine After Three Outbreaks of Influenza A at Christ's Hospital. The Lancet. 1979;313(8106):33–5.
[Return to footnote 5 referrer](#fn5-rf)
Footnote 6
Sullivan SG, Kelly H. Stratified Estimates of Influenza Vaccine Effectiveness by Prior Vaccination: Caution Required. Clin Infect Dis. 2013;57(3):474–6.
[Return to footnote 6 referrer](#fn6-rf)
Footnote 7
Skowronski DM, Chambers C, De Serres G, Et. Al. Serial Vaccination and the Antigenic Distance Hypothesis: Effects on Influenza Vaccine Effectiveness During A (H3N2) Epidemics in Canada, 2010–2011 to 2014–2015. J Infect Dis. 2017;215(7):1059–99.
[Return to footnote 7 referrer](#fn7-rf)
Footnote 8
McLean HQ, Thompson MG, Sundaram ME, Et. Al. Influenza Vaccine Effectiveness in the United States During 2012-2013: Variable Protection by Age and Virus Type. J Infect Dis. 2015;211(10):1529–40.
[Return to footnote 8 referrer](#fn8-rf)
Footnote 9
Puig-Barbera J, Burtseva E, Yu H, Et. Al. Influenza Epidemiology and Influenza Vaccine Effectiveness During the 2014-2015 Season: Annual Report from the Global Influenza Hospital Surveillance Network. BMC Public Health. 2016;16(Suppl 1):757.
[Return to footnote 9 referrer](#fn9-rf)
Footnote 10
Thompson MG, Naleway A, Fry AM, Et. Al. Effects of Repeated Annual Inactivated Influenza Vaccination among Healthcare Personnel on Serum Hemagglutinin Inhibition Antibody Response to A/Perth/16/2009 (H3N2)-like virus during 2010-11. Vaccine. 2016;34(7):981–8.
[Return to footnote 10 referrer](#fn10-rf)
Footnote 11
Smith DJ, Forrest S, Ackley DH, Et. Al. Variable Efficacy of Repeated Annual Influenza Vaccination. Proc Natl Acad Sci U S A. 1999;96(24):14001–6.
[Return to footnote 11 referrer](#fn11-rf)
Footnote 12
Flannery B, Smith C, Garten RJ, Et. Al. Influence of Birth Cohort on Effectiveness of 2015–2016 Influenza Vaccine Against Medically Attended Illness Due to 2009 Pandemic Influenza A(H1N1) Virus in the United States. J Infect Dis. 2018;218(2):189–96.
[Return to footnote 12 referrer](#fn12-rf)
Footnote 13
Gostic KM, Ambrose M, Worobey M, Et. Al. Potent Protection Against H5N1 and H7N9 Influenza via Childhood Hemagglutinin Imprinting. Science. 2016;354(6313):722–6.
[Return to footnote 13 referrer](#fn13-rf)
Footnote 14
Belongia EA, Skowronski DM, McLean HQ, Et. Al. Repeated Annual Influenza Vaccination and Vaccine Effectiveness: Review of Evidence. Expert Rev Vaccines. 2017;16(7):1–14.
[Return to footnote 14 referrer](#fn14-rf)
Footnote 15
Ramsay LC, Buchan SA, Stirling RG, Et. Al. The Impact of Repeated Vaccination on Influenza Vaccine Effectiveness: A Systematic Review and Meta-Analysis. BMC Med. 2019;17(1):9. Retraction of: Ramsay LC, Buchan SA, Stirling RG. The Impact of Repeated Vaccination on Influenza Vaccine Effectiveness: A Systematic Review and Meta-Analysis. BMC Med. 2017;15(1):159.
[Return to footnote 15 referrer](#fn15-rf)
Footnote 16
Harder T, Remschmidt C, Haller S, Et. Al. Use of Existing Systematic Reviews for Evidence Assessments in Infectious Disease Prevention: A Comparative Case Study. Syst Rev. 2016;5(1):171.
[Return to footnote 16 referrer](#fn16-rf)
Footnote 17
Robinson KA, Whitlock EP, Oneil ME, Et. Al. Integration of Existing Systematic Reviews into New Reviews: Identification of Guidance Needs. Syst Rev. 2014;3(1):60.
[Return to footnote 17 referrer](#fn17-rf)
Footnote 18
Shea BJ, Reeves BC, Wells G, Et. Al. AMSTAR 2: A Critical Appraisal Tool for Systematic Reviews that Include Randomised or Non-Randomised Studies of Healthcare Interventions, or Both. BMJ. 2017;358:j4008.
[Return to footnote 18 referrer](#fn18-rf)
Footnote 19
Caspard H., Heikkinen T., Belshe R.B., Et. Al. A Systematic Review of the Efficacy of Live Attenuated Influenza Vaccine upon Revaccination of Children. Hum Vaccines Immunother. 2016;12(7):1721–7.
[Return to footnote 19 referrer](#fn19-rf)
Footnote 20
Morimoto N, Takeishi K. Change in the Efficacy of Influenza Vaccination After Repeated Inoculation Under Antigenic Mismatch: A Systematic Review and Meta-Analysis. Vaccine. 2018;36(7):949–57.
[Return to footnote 20 referrer](#fn20-rf)
Footnote 21
Bartoszko JJ, McNamara IF, Aras OAZ, Et. Al. Does Consecutive Influenza Vaccination Reduce Protection Against Influenza: A Systematic Review and Meta-Analysis. Vaccine. 2018;36(24):3434–44.
[Return to footnote 21 referrer](#fn21-rf)
Footnote 22
World Health Organization. Recommended Composition of Influenza Virus Vaccines for Use in the 2021- 2022 Northern Hemisphere Influenza Season. Meet Rep [Internet]. 2021 [cited 2018 Mar 13]; Available from: https://cdn.who.int/media/docs/default-source/influenza/202102\_recommendation.pdf?sfvrsn=8639f6be\_3&download=true
[Return to footnote 22 referrer](#fn22-rf)
Footnote 23
Schenker N, Gentleman JF. On Judging the Significance of Differences by Examining the Overlap Between Confidence Intervals. Am Stat. 2001;55(3):182–6.
[Return to footnote 23 referrer](#fn23-rf)
Footnote 24
Belongia EA, Simpson MD, King JP, Et. Al. Variable Influenza Vaccine Effectiveness by Subtype: A Systematic Review and Meta-Analysis of Test-Negative Design Studies. Lancet Infect Dis. 2016;16(8):942–51.
[Return to footnote 24 referrer](#fn24-rf)
Footnote 25
Francis T. On the Doctrine of Original Antigenic Sin. Proc Am Philos Soc. 1960;104(6):572–8.
[Return to footnote 25 referrer](#fn25-rf)
Footnote 26
Zost S, Parkhouse K, Et. Al. Contemporary H3N2 Influenza Viruses have a Glycosylation Site that Alters Binding of Antibodies Elicited by Egg-Adapted Vaccine Strains. Proc Natl Acad Sci U A. 2017;114(47):12578–83.
[Return to footnote 26 referrer](#fn26-rf)
Footnote 27
Skowronski D, Janjua N, De Serres G. Low 2012-13 Influenza Vaccine Effectiveness Associated with Mutation in the Egg-Adapted H3N2 Vaccine Strain not Antigenic Drift in Circulating Viruses. PLoS One. 2014;9(3):e92153.
[Return to footnote 27 referrer](#fn27-rf)
Footnote 28
Skowronski D, Sabaiduc S, Leir S. Paradoxical Clade- and Age-Specific Vaccine Effectiveness during the 2018/19 Influenza A(H3N2) Epidemic in Canada: Potential Imprint-Regulated Effect of Vaccine (I-REV). Euro Surveill. 2019;24(46):1900585.
[Return to footnote 28 referrer](#fn28-rf)
Footnote 29
Ismail SJ, Hardy K, Tunis MC, Et. Al. A Framework for the Systematic Consideration of Ethics, Equity, Feasibility, and Acceptability in Vaccine Program Recommendations. Vaccine. 2020;38(36):5861–76.
[Return to footnote 29 referrer](#fn29-rf)
Footnote 30
Gates A, Gates M, Rahman S. A Systematic Review of Factors that Influence the Acceptability of Vaccines among Canadians. Vaccine. 2021;39(2):222–36.
[Return to footnote 30 referrer](#fn30-rf)
Footnote 31
Auladell M, Phuong H, Mai L. Influenza Virus Infection History Shapes Antibody Responses to Influenza Vaccination. Nat Med. 2022;28(2):363-372.
[Return to footnote 31 referrer](#fn31-rf)
Footnote 32
Moritzky S, Richards K, Glover M. The Negative Effect of Pre-Existing Immunity on Influenza Vaccine Responses Transcends the Impact of Vaccine Formulation Type and Vaccination History [published online ahead of print, 2022 Feb 24]. J Infect Dis. 2022;jiac068.
[Return to footnote 32 referrer](#fn32-rf)
Footnote 33
Snape N, Anderson G, Irving L. Vaccine Strain Affects Seroconversion after Influenza Vaccination in COPD Patients and Healthy Older People. NPJ Vaccines. 2022;7(1):8.
[Return to footnote 33 referrer](#fn33-rf)
Footnote 34
Centers for Disease Control and Prevention. Information on Rapid Molecular Assays, RT-PCR, and other Molecular Assays for Diagnosis of Influenza Virus Infection. Centers for Disease control and Prevention [Internet]. [cited 2018 Mar 13]. Available from: https://www.cdc.gov/flu/professionals/diagnosis/molecular-assays.htm
[Return to footnote 34 referrer](#fn34-rf)
Footnote 35
Merckx J, Wali R, Schiller I. Accuracy of Novel and Traditional Rapid Tests for Influenza Infection Compared with Reverse Transcriptase Polymerase Chain Reaction: A Systematic Review and Meta-Analysis. Ann Intern Med. 2017;167(6):394–409
[Return to footnote 35 referrer](#fn35-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-02-21
| None | None |
34e9ddc62b3902e331c55ef93e920d95570c59ff | cma | National polymerase chain reaction (PCR) testing indication guidance for COVID-19 | National polymerase chain reaction (PCR) testing indication guidance for COVID-19
Preamble
The first version of the *National laboratory testing indication guidance for COVID-19- document was developed at the onset of the COVID-19 pandemic. The original guidance document was finalized and approved by the Special Advisory Committee on April 16, 2020, and updated again in May 2020.
As part of the commitment to ongoing re-evaluation of testing guidance, an update was completed in September 2020. Distinct areas of testing requiring specific guidance were identified: (1) the core guidance for molecular, reverse transcription polymerase chain reaction (RT-PCR) testing is contained within the present document; (2) and guidance for the use of newer testing technologies (e.g., antigen tests) is presented in the document entitled *Interim Guidance on the Use of Rapid Antigen Detection Tests for the Identification of SARS-CoV-2 Infection*.
Purpose
To facilitate a consistent national approach to PCR testing, acknowledging regional variations in COVID-19 epidemiology and that testing requirements are expected to vary over time.
Objectives
- To outline the elements of a national approach to PCR testing for SARS-CoV-2 for consideration by Canadian provinces and territories (PTs);
- To support identification of triggers for public health actions.
Context
At present, the performance of a validated PCR test on a clinically appropriate sample (e.g., nasopharyngeal, lower respiratory tract sample obtained via bronchoalveolar lavage) collected by a trained health care provider is considered the gold standard for the diagnosis of SARS-CoV-2 infection.
The overall performance of SARS-CoV-2 PCR tests in distinguishing between individuals who do and do not have SARS-CoV-2 infection depends on both test attributes and epidemiological considerations.
Test attributes include the sensitivity (the ability of the test to correctly identify those who truly are infected with SARS-CoV-2) and the specificity (the ability of the test to correctly identify those who truly are not infected with SARS-CoV-2) at the time the clinical specimen was collected for laboratory analysis. Since the sensitivity and specificity of PCR testing for SARS-CoV-2 varies with viral load, test performance varies during the course of illness. False negative results can occur if the patient is not shedding sufficient virus at the time or at the site of specimen collection, or if the specimen is not collected properly. While rare, PCR tests can generate false positive results, such as when cross-contamination occurs during sample processing or in situations when there is non-specific amplification near the limit of detection. The observation of prolonged detection of SARS-CoV-2 RNA beyond the resolution of symptoms due to non-infectious viral fragments rather than infectious virus also complicates the interpretation of results showing a low viral load.
Epidemiological considerations include the pre-test likelihood of SARS-CoV-2 being truly present in a given population being considered for testing (prevalence). The proportion of false positive tests increases as the prevalence of SARS-CoV-2 in the population decreases, and any test result thought to be a false positive should be investigated further (e.g., sample tested again or lab processes checked for possible contamination). Interpreting a negative test result should be done with caution since, in situations where the clinical index of suspicion is high (high pre-test likelihood), a negative test does not rule out disease (due to the factors noted above). For those with a recent exposure, there is no defined time after exposure when a negative test excludes disease, since incubation can last for up to 14 days following contact with an infectious case.
It is recognized that there will be variation in how PTs implement this guidance, depending on resources, local epidemiology, and other considerations.
Approach
Overall, the recommended approach for PCR testing is to prioritize symptomatic individuals (including those with mild symptoms) for purposes of case identification, clinical treatment and contact tracing. This approach is consistent with the Infectious Diseases Society of America testing guidelines. Due to the non-specific nature of many COVID-19 symptoms, the set of symptoms used to determine the indication for testing will need to be considered in relation to local epidemiology, testing capacity and guidance from public health authorities. Yield of testing is highest in symptomatic individuals. The overall effectiveness of testing to identify SARS-CoV-2 infection is dependent on individuals who are likely to have been exposed to SARS-CoV-2 coming forward and being able to access the appropriately offered testing in a timely manner. Should testing resources become constrained, consideration for matching testing resources to public health objectives may become necessary.
# Consideration for PCR testing of individuals who are asymptomatic
It has been recognized that a significant proportion of SARS-CoV-2 infected patients can be asymptomatic. As a result, the value of broad-based asymptomatic testing has been a topic of frequent discussion in Canada. While the value of such programmes remain unclear, a number of pilot projects of testing asymptomatic people with no known exposure have been completed in Canada during the spring and summer of 2020. These have demonstrated low utility and limited yield so far, but this may change if community transmission increases significantly.
Furthermore, untargeted asymptomatic testing can displace capacity for the timely testing of symptomatic individuals, and this will likely become an even greater issue during the fall and winter seasons when colds, influenza, and other respiratory viral illnesses co-circulate. While there are limitations to asymptomatic testing, there are circumstances where it may be warranted and these are outlined below, with a distinction made between asymptomatic testing following a known exposure to a confirmed case and those who did not have an exposure.
# Testing individuals who are asymptomatic with known exposure to a confirmed case
The following groups of individuals without symptoms should be considered for testing for reasons of contact tracing or outbreak management:
- Close contacts of a case in the community;
- Health care workers and staff who work in health care facilities with reported outbreaks;
- Residents and workers in high-risk congregate living settings (e.g., long-term care facilities, correctional facilities, homeless shelters, other temporary shelters, single-room occupancy residences and work camps) with reported outbreaks;
- Work settings where physical distancing cannot be maintained (e.g., meat and poultry-processing facilities) and where there are reported outbreaks;
- Other outbreak or cluster investigations.
# Testing of individuals who are asymptomatic with no known exposure to a confirmed case
There is limited evidence regarding the utility of testing individuals who are asymptomatic with no known exposure to a case and is not generally recommended at this time. Evidence from a number of pilots suggests that the yield of asymptomatic testing is low in the context of limited community transmission. The utility of asymptomatic testing in the context of significant community transmission is unknown at this time. At present, testing of individuals who are asymptomatic with no known exposure to a case is best done in the context of research activities to generate the knowledge needed to make future evidence-informed decisions. As the epidemiology of COVID-19 and evidence evolves, the criteria for when asymptomatic testing adds value to the prevention and control of SARS-CoV-2 transmission will become clearer. Additionally, as new technologies, such as antigen testing, become available with good test performance characteristics, they may extend capacity into areas where asymptomatic testing using PCR methods is not feasible at present. Please see the *Interim Guidance on the Use of Rapid Antigen Detection Tests for the Identification of SARS-CoV-2 Infection- for further details.
PCR testing of asymptomatic individuals with no known exposure may be considered in certain limited situations, depending on local context and judgement by regional public health authorities, such as the following:
- Individuals upon admission to hospital in areas with high community prevalence of COVID-19 (note that individuals with symptoms or know exposure will be tested as per recommendations noted above);
- Immunocompromised individuals prior to admission to hospital, regardless of community prevalence of COVID-19;
- Individuals undergoing immunosuppressive procedures or major time-sensitive surgery that cannot be safely delayed;
- Travellers to certain remote locations, as defined by local public health authorities, where infection rates are low and where the capacity to deal with increased cases is especially limited;
- Deceased individuals with no known cause of death, but where COVID-19 is possible and where public health action would be taken if COVID-19 were the cause of death.
Previous versions of this guidance document had specific mention of testing asymptomatic workers and residents in both high risk (e.g., congregate living, correctional facilities) and vulnerable settings (e.g., long-term care facilities). The value of testing asymptomatic individuals prior to working in or admission to these settings using PCR is unknown but could be considered, particularly if there is significant community transmission and assessment of exposure risk is difficult. Repeat testing using NP swabs is of low yield in situations of low community transmission and consideration for the value of repeat testing using alternative technologies, such as antigen testing, is discussed in the *Interim Guidance on the Use of Rapid Antigen Detection Tests for the Identification of SARS-CoV-2 Infection.*
## Special considerations
- Asymptomatic pregnant women could be tested in the antepartum period according to local epidemiology, guidelines, and availability of testing, although little is known about the utility and yield of this approach at this time.
- Asymptomatic individuals who require testing prior to international travel. This requirement for testing is established by foreign national governments or international airline/travel organizations. At this time, the value of pre-travel testing is unknown and the mechanism to access this testing may vary by jurisdiction.
Other PCR testing modalities
Most PCR testing needs can be efficiently and effectively delivered by high throughput lab capacity, resulting in a turnaround time that enables timely public health action. While these laboratories are able to support remote, rural, isolated and/or Indigenous communities, the delays introduced due to sample shipment and transit times can increase turnaround time significantly. In these settings, the deployment of point-of-care (PoC) PCR testing is strongly recommended. PoC and other rapid tests will be useful in other situations where quick turnaround times are important, and the allocation of limited resources to locations where such devices will have the most beneficial impact is recommended. A variant of PCR, LAMP (loop-mediated isothermal amplification), is technology that may offer similar performance characteristics to PCR and can be considered using the same principles as outlined above.
In some situations, the inconvenience or intolerability of a nasopharyngeal swab (e.g., in children) may be a barrier to PCR testing. The development of alternative sampling methods, such as “swish/gargle” for saliva or sampling the anterior nares, will help improve overall access to and uptake of PCR tests, and may impact testing recommendations.
Forward planning
This guidance was created in collaboration with the provincial and territorial public health authorities and will continue to be reviewed and updated as necessary.
Endnotes
Hanson KE, Caliendo AM, Arias CA, et al. Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19. IDSA 2020. Accessed 8 September 2020. Available at: /.
An outbreak is defined according to local epidemiology and context, and may be a single case. |
National polymerase chain reaction (PCR) testing indication guidance for COVID-19
==================================================================================
On this page
------------
* [Preamble](#preamble)
* [Purpose](#purpose)
* [Objectives](#objectives)
* [Context](#context)
* [Approach](#approach)
+ [Consideration for PCR testing of individuals who are asymptomatic](#consideration_for_pcr)
+ [Testing individuals who are asymptomatic with known exposure to a confirmed case](#testing_individuals_who)
+ [Testing of individuals who are asymptomatic with no known exposure to a confirmed case](#testing_of_individuals)
* [Other PCR testing modalities](#other_pcr_testing)
* [Forward planning](#forward_planning)
* [Endnotes](#fn)
Preamble
--------
The first version of the *National laboratory testing indication guidance for COVID-19* document was developed at the onset of the COVID-19 pandemic. The original guidance document was finalized and approved by the Special Advisory Committee on April 16, 2020, and updated again in May 2020.
As part of the commitment to ongoing re-evaluation of testing guidance, an update was completed in September 2020. Distinct areas of testing requiring specific guidance were identified: (1) the core guidance for molecular, reverse transcription polymerase chain reaction (RT-PCR) testing is contained within the present document; (2) and guidance for the use of newer testing technologies (e.g., antigen tests) is presented in the document entitled *Interim Guidance on the Use of Rapid Antigen Detection Tests for the Identification of SARS-CoV-2 Infection*.
Purpose
-------
To facilitate a consistent national approach to PCR testing, acknowledging regional variations in COVID-19 epidemiology and that testing requirements are expected to vary over time.
Objectives
----------
* To outline the elements of a national approach to PCR testing for SARS-CoV-2 for consideration by Canadian provinces and territories (PTs);
* To support identification of triggers for public health actions.
Context
-------
At present, the performance of a validated PCR test on a clinically appropriate sample (e.g., nasopharyngeal, lower respiratory tract sample obtained via bronchoalveolar lavage) collected by a trained health care provider is considered the gold standard for the diagnosis of SARS-CoV-2 infection.
The overall performance of SARS-CoV-2 PCR tests in distinguishing between individuals who do and do not have SARS-CoV-2 infection depends on both test attributes and epidemiological considerations.
Test attributes include the sensitivity (the ability of the test to correctly identify those who truly are infected with SARS-CoV-2) and the specificity (the ability of the test to correctly identify those who truly are not infected with SARS-CoV-2) at the time the clinical specimen was collected for laboratory analysis. Since the sensitivity and specificity of PCR testing for SARS-CoV-2 varies with viral load, test performance varies during the course of illness. False negative results can occur if the patient is not shedding sufficient virus at the time or at the site of specimen collection, or if the specimen is not collected properly. While rare, PCR tests can generate false positive results, such as when cross-contamination occurs during sample processing or in situations when there is non-specific amplification near the limit of detection. The observation of prolonged detection of SARS-CoV-2 RNA beyond the resolution of symptoms due to non-infectious viral fragments rather than infectious virus also complicates the interpretation of results showing a low viral load.
Epidemiological considerations include the pre-test likelihood of SARS-CoV-2 being truly present in a given population being considered for testing (prevalence). The proportion of false positive tests increases as the prevalence of SARS-CoV-2 in the population decreases, and any test result thought to be a false positive should be investigated further (e.g., sample tested again or lab processes checked for possible contamination). Interpreting a negative test result should be done with caution since, in situations where the clinical index of suspicion is high (high pre-test likelihood), a negative test does not rule out disease (due to the factors noted above). For those with a recent exposure, there is no defined time after exposure when a negative test excludes disease, since incubation can last for up to 14 days following contact with an infectious case.
It is recognized that there will be variation in how PTs implement this guidance, depending on resources, local epidemiology, and other considerations.
Approach
--------
Overall, the recommended approach for PCR testing is to prioritize symptomatic individuals (including those with mild symptoms) for purposes of case identification, clinical treatment and contact tracing. This approach is consistent with the Infectious Diseases Society of America testing guidelines[Footnote 1](#fn1). Due to the non-specific nature of many COVID-19 symptoms, the set of symptoms used to determine the indication for testing will need to be considered in relation to local epidemiology, testing capacity and guidance from public health authorities. Yield of testing is highest in symptomatic individuals. The overall effectiveness of testing to identify SARS-CoV-2 infection is dependent on individuals who are likely to have been exposed to SARS-CoV-2 coming forward and being able to access the appropriately offered testing in a timely manner. Should testing resources become constrained, consideration for matching testing resources to public health objectives may become necessary.
### Consideration for PCR testing of individuals who are asymptomatic
It has been recognized that a significant proportion of SARS-CoV-2 infected patients can be asymptomatic. As a result, the value of broad-based asymptomatic testing has been a topic of frequent discussion in Canada. While the value of such programmes remain unclear, a number of pilot projects of testing asymptomatic people with no known exposure have been completed in Canada during the spring and summer of 2020. These have demonstrated low utility and limited yield so far, but this may change if community transmission increases significantly.
Furthermore, untargeted asymptomatic testing can displace capacity for the timely testing of symptomatic individuals, and this will likely become an even greater issue during the fall and winter seasons when colds, influenza, and other respiratory viral illnesses co-circulate. While there are limitations to asymptomatic testing, there are circumstances where it may be warranted and these are outlined below, with a distinction made between asymptomatic testing following a known exposure to a confirmed case and those who did not have an exposure.
### Testing individuals who are asymptomatic with known exposure to a confirmed case
The following groups of individuals without symptoms should be considered for testing for reasons of contact tracing or outbreak management:
* Close contacts of a case in the community;
* Health care workers and staff who work in health care facilities with reported outbreaks[Footnote 2](#fn2);
* Residents and workers in high-risk congregate living settings (e.g., long-term care facilities, correctional facilities, homeless shelters, other temporary shelters, single-room occupancy residences and work camps) with reported outbreaks;
* Work settings where physical distancing cannot be maintained (e.g., meat and poultry-processing facilities) and where there are reported outbreaks;
* Other outbreak or cluster investigations.
### Testing of individuals who are asymptomatic with no known exposure to a confirmed case
There is limited evidence regarding the utility of testing individuals who are asymptomatic with no known exposure to a case and is not generally recommended at this time. Evidence from a number of pilots suggests that the yield of asymptomatic testing is low in the context of limited community transmission. The utility of asymptomatic testing in the context of significant community transmission is unknown at this time. At present, testing of individuals who are asymptomatic with no known exposure to a case is best done in the context of research activities to generate the knowledge needed to make future evidence-informed decisions. As the epidemiology of COVID-19 and evidence evolves, the criteria for when asymptomatic testing adds value to the prevention and control of SARS-CoV-2 transmission will become clearer. Additionally, as new technologies, such as antigen testing, become available with good test performance characteristics, they may extend capacity into areas where asymptomatic testing using PCR methods is not feasible at present. Please see the *Interim Guidance on the Use of Rapid Antigen Detection Tests for the Identification of SARS-CoV-2 Infection* for further details.
PCR testing of asymptomatic individuals with no known exposure may be considered in certain limited situations, depending on local context and judgement by regional public health authorities, such as the following:
* Individuals upon admission to hospital in areas with high community prevalence of COVID-19 (note that individuals with symptoms or know exposure will be tested as per recommendations noted above);
* Immunocompromised individuals prior to admission to hospital, regardless of community prevalence of COVID-19;
* Individuals undergoing immunosuppressive procedures or major time-sensitive surgery that cannot be safely delayed;
* Travellers to certain remote locations, as defined by local public health authorities, where infection rates are low and where the capacity to deal with increased cases is especially limited;
* Deceased individuals with no known cause of death, but where COVID-19 is possible and where public health action would be taken if COVID-19 were the cause of death.
Previous versions of this guidance document had specific mention of testing asymptomatic workers and residents in both high risk (e.g., congregate living, correctional facilities) and vulnerable settings (e.g., long-term care facilities). The value of testing asymptomatic individuals prior to working in or admission to these settings using PCR is unknown but could be considered, particularly if there is significant community transmission and assessment of exposure risk is difficult. Repeat testing using NP swabs is of low yield in situations of low community transmission and consideration for the value of repeat testing using alternative technologies, such as antigen testing, is discussed in the *Interim Guidance on the Use of Rapid Antigen Detection Tests for the Identification of SARS-CoV-2 Infection.*
#### Special considerations
* Asymptomatic pregnant women could be tested in the antepartum period according to local epidemiology, guidelines, and availability of testing, although little is known about the utility and yield of this approach at this time.
* Asymptomatic individuals who require testing prior to international travel. This requirement for testing is established by foreign national governments or international airline/travel organizations. At this time, the value of pre-travel testing is unknown and the mechanism to access this testing may vary by jurisdiction.
Other PCR testing modalities
----------------------------
Most PCR testing needs can be efficiently and effectively delivered by high throughput lab capacity, resulting in a turnaround time that enables timely public health action. While these laboratories are able to support remote, rural, isolated and/or Indigenous communities, the delays introduced due to sample shipment and transit times can increase turnaround time significantly. In these settings, the deployment of point-of-care (PoC) PCR testing is strongly recommended. PoC and other rapid tests will be useful in other situations where quick turnaround times are important, and the allocation of limited resources to locations where such devices will have the most beneficial impact is recommended. A variant of PCR, LAMP (loop-mediated isothermal amplification), is technology that may offer similar performance characteristics to PCR and can be considered using the same principles as outlined above.
In some situations, the inconvenience or intolerability of a nasopharyngeal swab (e.g., in children) may be a barrier to PCR testing. The development of alternative sampling methods, such as “swish/gargle” for saliva or sampling the anterior nares, will help improve overall access to and uptake of PCR tests, and may impact testing recommendations.
Forward planning
----------------
This guidance was created in collaboration with the provincial and territorial public health authorities and will continue to be reviewed and updated as necessary.
Endnotes
--------
1
Hanson KE, Caliendo AM, Arias CA, et al. Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19. IDSA 2020. Accessed 8 September 2020. Available at: https://www.idsociety.org/practice-guideline/covid-19-guideline-diagnostics/.
[Return to footnote 1 referrer](#fn1-rf)
2
An outbreak is defined according to local epidemiology and context, and may be a single case.
[Return to footnote 2 referrer](#fn2-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fguidance-documents%2Fnational-laboratory-testing-indication.html&n=National%20polymerase%20chain%20reaction%20(PCR)%20testing%20indication%20guidance%20for%20COVID-19%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fguidance-documents%2Fnational-laboratory-testing-indication.html&title=National%20polymerase%20chain%20reaction%20(PCR)%20testing%20indication%20guidance%20for%20COVID-19%20-%20Canada.ca)
* [Email](mailto:?subject=National%20polymerase%20chain%20reaction%20(PCR)%20testing%20indication%20guidance%20for%20COVID-19%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fguidance-documents%2Fnational-laboratory-testing-indication.html%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fguidance-documents%2Fnational-laboratory-testing-indication.html&t=National%20polymerase%20chain%20reaction%20(PCR)%20testing%20indication%20guidance%20for%20COVID-19%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=National%20polymerase%20chain%20reaction%20(PCR)%20testing%20indication%20guidance%20for%20COVID-19%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fguidance-documents%2Fnational-laboratory-testing-indication.html%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fguidance-documents%2Fnational-laboratory-testing-indication.html&title=National%20polymerase%20chain%20reaction%20(PCR)%20testing%20indication%20guidance%20for%20COVID-19%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fguidance-documents%2Fnational-laboratory-testing-indication.html&t=National%20polymerase%20chain%20reaction%20(PCR)%20testing%20indication%20guidance%20for%20COVID-19%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fguidance-documents%2Fnational-laboratory-testing-indication.html&media=&description=National%20polymerase%20chain%20reaction%20(PCR)%20testing%20indication%20guidance%20for%20COVID-19%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fguidance-documents%2Fnational-laboratory-testing-indication.html&title=National%20polymerase%20chain%20reaction%20(PCR)%20testing%20indication%20guidance%20for%20COVID-19%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fguidance-documents%2Fnational-laboratory-testing-indication.html)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fguidance-documents%2Fnational-laboratory-testing-indication.html&name=National%20polymerase%20chain%20reaction%20(PCR)%20testing%20indication%20guidance%20for%20COVID-19%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=National%20polymerase%20chain%20reaction%20(PCR)%20testing%20indication%20guidance%20for%20COVID-19%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fguidance-documents%2Fnational-laboratory-testing-indication.html)
* [Whatsapp](https://api.whatsapp.com/send?text=National%20polymerase%20chain%20reaction%20(PCR)%20testing%20indication%20guidance%20for%20COVID-19%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fguidance-documents%2Fnational-laboratory-testing-indication.html)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=National%20polymerase%20chain%20reaction%20(PCR)%20testing%20indication%20guidance%20for%20COVID-19%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fdiseases%2F2019-novel-coronavirus-infection%2Fguidance-documents%2Fnational-laboratory-testing-indication.html%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2020-10-07
| None | None |
b9177cc09627b542c6267b12b5312ba753394b55 | cma | Anaphylaxis and other acute reactions following vaccination: Canadian Immunization Guide | Anaphylaxis and other acute reactions following vaccination: Canadian Immunization Guide
Introduction
This chapter is intended as a guide for the assessment and initial management of vaccine recipients who develop acute adverse reactions in a community setting (e.g., schools, public health clinics, health centres).
Two types of adverse events are most likely to present acutely:
- Anxiety-related adverse events following immunization (AEFI) including fainting (vasovagal syncope), hyperventilation and breath-holding
- Anaphylaxis or other immediate hypersensitivity reactions to vaccine components or the container (e.g., latex).
Management and implications for future immunization are markedly different for these events and it is important to distinguish one from the other as quickly as possible without delaying appropriate therapeutic interventions.
See for a side by side comparison of presenting features of anaphylaxis and vasovagal syncope.
Anxiety-related adverse events
# Breath-holding
Breath-holding episodes occur in some young children when they are upset and crying hard. The child suddenly becomes silent but remains agitated. Facial flushing and perioral cyanosis deepens as breath-holding continues. Some episodes end with resumption of crying, but others end with a brief period of unconsciousness during which breathing resumes. No treatment is required beyond reassurance of the child and parents.
# Hyperventilation
People experiencing anxiety may appear fearful, pale and diaphoretic. They may complain of lightheadedness, dizziness and numbness, as well as tingling of the face and extremities. Hyperventilation is usually evident. Treatment consists of reassurance and encouraging the individual to breathe slowly and deeply. Initiating a refocusing activity, such as asking the person to count to ten, may help. Should there be another condition causing the hyperventilation, such as asthma or heart attack, holding one's breath could worsen the condition.
# Vasovagal syncope (fainting)
Fainting itself has no adverse consequence but during a fall, severe head injuries could occur.
Fainting is common with at least one lifetime occurrence in about 3.5% of women and 3% of men. The exact frequency of fainting post-immunization is not known but the majority of syncope adverse event reports involve adolescents or adults. Fainting is rare in infants and children. Therefore, a sudden loss of consciousness in young children should be presumed to be anaphylaxis, especially if other clinical features of anaphylaxis are present.
Fainting usually occurs during immunization or within minutes of immunization. The individual may complain of feeling faint or light-headed, then suddenly become pale, lose consciousness and collapse to the ground. This may be accompanied by brief clonic seizure activity (i.e., rhythmic jerking of the limbs). As a general rule, the respiratory rate is normal and not laboured, but may be shallow. Cardiovascular signs include bradycardia and faint peripheral pulses but usually the carotid pulse is strong. In addition to pallor, the skin may be cool and clammy. There may be associated nausea and vomiting. Fainting is managed by placing the vaccinee in a supine (lying on their back) position and elevating the lower extremities. If vomiting has occurred or is imminent, position the vaccinee lying on one side. If the vaccinee is pregnant, position them lying on their left side. Recovery of consciousness and resolution of limb jerking usually occurs within a minute or two. The person may remain pale, diaphoretic and mildly hypotensive for several minutes. Continue monitoring and providing support to the vaccinee who has fainted until signs and symptoms have stabilized.
Adapted with permission from: Immunisation Section, South Australian Department for Health and Wellbeing.
For a more detailed list of system-specific manifestations of anaphylaxis, see .
For techniques to decrease anxiety and fainting, refer to in Part 1.
Anaphylaxis
Anaphylaxis is a serious, potentially life-threatening allergic reaction to foreign antigens; it has been proven to be causally associated with vaccines with an estimated frequency of 1.3 episodes per million doses of vaccine administered. Anaphylaxis is preventable in many cases and treatable in all. It should be anticipated in every vaccinee.
# Pre-vaccination screening
Prevention of anaphylaxis is critically important. Pre-vaccination screening includes screening for a history of anaphylaxis and identification of potential risk factors. It should include questions about possible allergy to any component or container of the scheduled vaccine(s) in order to identify if there is a contraindication to administration.
## Post-vaccination observation
Most instances of anaphylaxis to a vaccine begin within 30 minutes after administration of vaccine. Therefore, vaccine recipients should be kept under observation for at least 15 minutes after immunization; 30 minutes is a safer interval when there is a specific concern about possible vaccine allergy. In low-risk situations, observation can include asking vaccinees to watch for symptoms and return immediately for assessment if they feel unwell.
For information about reporting AEFI such as anaphylaxis, refer to (AEFI).
# Signs and symptoms of anaphylaxis
In anaphylaxis, signs and symptoms onset suddenly and progress rapidly over several minutes and involves two or more body systems. The most frequently involved systems are skin (80% to 90% of anaphylaxis cases), respiratory (up to 70% of cases) and less often cardiovascular and gastrointestinal (each up to 45% of cases). Up to 15% of cases may also manifest central nervous system changes of uneasiness, altered mental status, dizziness, or confusion. Features of severe anaphylaxis include obstructive swelling of the upper airway, marked bronchospasm and hypotension. Hypotension can progress to cause shock and collapse.
Reproduced with permission from: Cheng A; Canadian Paediatric Society, Acute Care Committee. Emergency treatment of anaphylaxis in infants and children. Paediatr Child Health 2011;16(1):35-40. Reaffirmed February 2018.
It may be challenging to identify anaphylaxis in infants and young children (0-2 years of age) as they are unable to describe their symptoms. Infants may present with respiratory distress (e.g., increased work of breathing, cough, wheeze, stridor) or tachycardia rather than hypotension. Non-specific signs and symptoms may include sudden quietness or sleepiness, drooling, incontinence and behavioural changes such as inconsolable crying and irritability - all of which are common in this age group. Generalized urticaria, flushing, vomiting (including persistent vomiting), and angioedema are typically observed in this age group. Specific or non-specific signs or symptoms in two or more body organ systems are required for a clinical diagnosis of anaphylaxis.
# Risk factors for severe anaphylaxis
Anaphylaxis is a rare complication of immunization. Risk factors for increased severity of anaphylactic events include:
- very young or old age,
- pregnancy,
- severe or uncontrolled asthma,
- cardiovascular disease,
- chronic obstructive pulmonary disease,
- systemic mastocytosis,
- concurrent use of certain medications (e.g., angiotensin-converting enzyme inhibitors and beta-blockers).
# Anaphylaxis management kits
Appropriate preparation is important for a good outcome in anaphylaxis. Anaphylaxis management kits should be readily available wherever vaccines are administered. EPINEPHrine in an autoinjector or in a vial may be used to treat anaphylaxis; however, vials of EPINEPHrine must be available for treatment of infants weighing less than 5 kg (refer to ). EPINEPHrine and other emergency supplies should be checked on a regular basis and replaced when outdated.
- EPINEPHrine dosage by weight and age
- Three extra 25 gauge needles of each different size: 5/8 inch, 1 or 1.25 inch, 1.5 inch
- Alcohol swabs
- Tongue depressors
- Pocket mask
- Wristwatch with second hand (for heart rate)
- Ready access to a phone to call emergency services
- Flashlight
- Oxygen and related equipment
- IV lines, fluids and related equipment
- Stethoscope
- Sphygmomanometer
All immunization sites should have the essential items. Optional items reflect variations in immunization sites some of which are equipped for advanced care.
TALLMAN lettering is a method of applying upper-case lettering to sections of look-alike/sound-alike name attributes in efforts to avoid drug name confusion and potential medication incidents.
# Management of anaphylaxis
Anaphylaxis is a medical emergency, and rapid recognition and management can be life-saving. Every vaccine provider should be familiar with the signs and symptoms of anaphylaxis and be prepared to act quickly. The rate of progression or the severity of the anaphylactic episode can be difficult to predict at the start of anaphylaxis; however, rapid development of anaphylaxis following vaccination indicates that a more severe reaction is likely. Death can occur within minutes. EPINEPHrine is the only medication that reduces hospitalization and death and should be administered promptly following the onset of anaphylaxis.
## Protocols
All immunization providers should be trained to recognize anaphylaxis, to administer intramuscular (IM) EPINEPHrine and to initiate basic life-support measures such as cardio-pulmonary resuscitation (CPR) if indicated.
Vaccinees with severe allergic reaction or anaphylaxis should be transported to a hospital as soon as possible. The establishment of intravenous (IV) access for fluid resuscitation may be necessary, and endotracheal intubation and other advanced life-support interventions may be required. These interventions generally do not take place in community settings but may at times be performed by competent and trained staff in safe and appropriate care settings.
Advance preparation for emergency management of anaphylaxis is essential. It is recommended that vaccine providers develop, post, and regularly rehearse a written anaphylaxis emergency management protocol. Protocols should specify the necessary emergency equipment, drugs and dosages, and medical personnel necessary to safely and effectively manage anaphylaxis.
## Steps for basic management of anaphylaxis in a community setting
Rapid intervention is of paramount importance. Steps 1, 2, 3 and 4 should be done promptly and simultaneously.
- 1. Direct someone to call 911 (where available) or emergency medical services.
- 2. Assess airway, breathing, circulation, mental status, skin, and body weight (mass). Secure an oral airway if necessary.
+ airway: look specifically at lips, tongue and throat for swelling; if appropriate, ask individual to say his/her name to assess glottic/peri-glottic swelling
- 3. Place individual on his/her back (supine) and elevate lower extremities. The vaccinee should remain in this position. Fatality can occur within seconds if the vaccinee stands or sits suddenly, due to empty vena cava/empty ventricle syndrome. Exceptions to the supine position:
+ if in respiratory distress, place in a position of comfort (elevate head and chest)
+ if vomiting or unconscious, place lying on his/her side
+ if pregnant, place lying on their left side
- 4. Inject EPINEPHrine:
+ Dose: 0.01 mg/kg body weight of 1:1000 (1 mg/mL) solution, MAX 0.5 mg (see for dosage by age or weight)
+ Route: INTRAMUSCULAR (IM) in mid-anterolateral thigh (*vastus lateralis- muscle)
+ Repeat every 5 minutes if symptoms persist (most patients improve in 1-2 doses)
+ Record the time of each dose
+ Stabilize and monitor patient (see steps & )
Weight is the preferred basis for dosage but if unknown, use age as a guide.
autoinjector dose
or
1 mg/mL
Adapted from: Australian Immunisation Handbook (ATAGI, confirmed June 2018). .
Adapted from: TREKK. Dec 2018. Pediatric anaphylaxis algorithm. Version 1.1. Accessed June 28, 2020 from: \_Anaphylaxis\_algorithm\_v\_1.1.pdf?1545083235
Cheng A; Canadian Paediatric Society, Acute Care Committee. Emergency treatment of anaphylaxis in infants and children. Paediatr Child Health 2011; 16(1):35-40.
Jensen J, Ryu J, Clifton H, Brown J. Impact of Pre-Arrival epinephrine in Emergency Department or Urgent Care pediatric anaphylaxis patients weighing < 15 kg, Poster P010, Ann Allergy Asthma Immunol 2018; 121: S22−S62.
As of October 2020, three EPINEPHrine autoinjectors were on the Canadian market: EpiPen®, Allerject® and EMERADE™.
In infants, it is recommended that EPINEPHrine be administered via a syringe rather than by an autoinjector. Needle lengths that are too long have a risk of intraosseous administration (due to the need to apply pressure in order to deploy the autoinjector). The depth of the needle is better controlled with the syringe administration rather than autoinjector.
Sicherer SH and FER Simons, Pediatrics 2007; 199:638-646.
- 5. Stabilize vaccinee: perform cardiopulmonary resuscitation if necessary, give oxygen and establish intravenous access if available
+ give supplemental oxygen (6 to 8 L/minute) by face mask or oropharyngeal airway (if available) to people with cyanosis, dyspnea or any other severe reaction requiring repeated doses of EPINEPHrine
+ if hypotensive, consider giving IV normal saline, 20 mL/kg if IV access established and if available.
- 6. Monitor vaccinee's blood pressure, cardiac rate and function, and respiratory status.
- 7. Transfer to hospital for observation. All vaccinees receiving emergency EPINEPHrine must be transported to hospital immediately for evaluation and observation. The symptoms of an anaphylactic reaction can reoccur after the initial reaction (biphasic anaphylaxis) in up to 23% of patients with anaphylaxis.
## EPINEPHrine treatment - additional information
Prompt intramuscular administration of EPINEPHrine is the priority and should not be delayed. EPINEPHrine is the treatment of choice for management of anaphylaxis in community and healthcare settings as it prevents and relieves upper airway swelling, hypotension and shock. In addition, it causes increased heart rate, increased force of cardiac contractions, increased bronchodilation, and decreased release of histamine and other mediators of inflammation. EPINEPHrine reaches peak plasma and tissue concentrations rapidly.
Failure to administer EPINEPHrine promptly may result in greater risk to the vaccinee with anaphylaxis than using EPINEPHrine improperly.
If uncertain, err on the side of treatment; there are no contraindications to the use of EPINEPHrine. If time is lost early in the treatment of an acute anaphylactic episode, subsequent management can become more difficult.
EPINEPHrine 0.01 mg/kg body weight of 1:1000 (1 mg/mL) solution (max 0.5 mg) should be administered into the mid-anterolateral aspect of the thigh (*vastus lateralis- muscle); the deltoid muscle of the arm should not be used as it is not as effective as the thigh in absorbing EPINEPHrine. Scissors may be needed to cut clothing to establish access. If scissors are not readily available, EPINEPHrine may be administered through clothing. Although there is a slightly increased risk of infection, timely administration of EPINEPHrine is the priority. The risk of infection can be addressed once the person has stabilized. For infants weighing less than 5 kg, the dose of EPINEPHrine should be determined by weight, if possible. For example, an infant weighing 4 kg (8.8 lb) should receive 0.04 mg of EPINEPHrine, which is 0.04 mL of a 1 mg/mL solution. However, if a vial is not available at the time of anaphylaxis, the 0.15 mg EPINEPHrine autoinjector device can be safely used. (Refer to for EPINEPHrine dosing guidelines). Mild and transient effects such as pallor, tremor, anxiety, palpitations, headache and dizziness occur within minutes after injection of a recommended dose of EPINEPHrine. These effects confirm that a therapeutic dose has been given.
# Antihistamines
Antihistamines (first generation and second generation) have no role in preventing or treating respiratory or cardiovascular symptoms of anaphylaxis in a community setting and should never be used in place of EPINEPHrine.
Swelling and urticarial rash at the injection site
Swelling and urticarial rash (i.e., hives) at the injection site can occur and may be the first indication of an evolving anaphylaxis. For this reason, while such reactions are not always caused by an allergic reaction, the individual should be observed for at least 30 minutes in order to ensure that the swelling or hives remain localized. Ice can be applied to the injection site for comfort. If the hives or swelling disappears and there is no evidence of any progression to other parts of the body and there are no other symptoms within the 30-minute observation period, no further observation is necessary. However, if any other symptoms arise, even if considered mild (e.g., sneezing, nasal congestion, tearing, coughing, facial flushing), or if there is evidence of any progression of the hives or swelling to other parts of the body during the 30-minute observation period, EPINEPHrine should be given (refer to the ).
A mild local reaction resolving by itself within a few minutes is not indicative of an allergic reaction and does not require special observation or specialized assessment prior to subsequent vaccination. |
Anaphylaxis and other acute reactions following vaccination: Canadian Immunization Guide
=========================================================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html)
Last partial content update (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): March 2021
March 2021 - This chapter has been updated with a minor change:* The addition of EMERADE™, an EPINEPHrine autoinjector, to [Table 4: Dosage of intramuscular EPINEPHrine 1:1000 (1mg/mL), by age or weight](#t4)
Last complete chapter revision (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): December 2020
On this page
------------
* [Introduction](#a1)
* [Anxiety-related adverse events](#a2)
+ [Breath-holding](#a3)
+ [Hyperventilation](#a4)
+ [Vasovagal syncope (fainting)](#a5)
- [Table 1. Key distinguishing features of anaphylaxis and vasovagal syncope](#t1)
* [Anaphylaxis](#a7)
+ [Pre-vaccination screening](#a8)
+ [Post-vaccination observation](#a9)
+ [Signs and symptoms of anaphylaxis](#a10)
- [Table 2. Signs and symptoms of anaphylaxis](#t2)
+ [Risk factors for severe anaphylaxis](#a13)
+ [Anaphylaxis management kits](#a14)
- [Table 3. Anaphylaxis management kits: recommended items](#t3)
+ [Management of anaphylaxis](#a16)
- [Protocols](#a17)
- [Steps for basic management of anaphylaxis in a community setting](#a18)
- [Table 4: Dosage of intramuscular EPINEPHrine 1:1000 (1 mg/mL) solution), by age or weight](#t4)
- [EPINEPHrine treatment - additional information](#a20)
+ [Antihistamines](#a21)
* [Swelling and urticarial rash at the injection site](#a22)
* [Selected references](#a23)
Introduction
------------
This chapter is intended as a guide for the assessment and initial management of vaccine recipients who develop acute adverse reactions in a community setting (e.g., schools, public health clinics, health centres).
Two types of adverse events are most likely to present acutely:
* **Anxiety-related** adverse events following immunization (AEFI) including fainting (vasovagal syncope), hyperventilation and breath-holding
* **Anaphylaxis** or other immediate hypersensitivity reactions to vaccine components or the container (e.g., latex).
Management and implications for future immunization are markedly different for these events and it is important to distinguish one from the other as quickly as possible without delaying appropriate therapeutic interventions.
See [Table 1](#t1) for a side by side comparison of presenting features of anaphylaxis and vasovagal syncope.
Anxiety-related adverse events
------------------------------
### Breath-holding
Breath-holding episodes occur in some young children when they are upset and crying hard. The child suddenly becomes silent but remains agitated. Facial flushing and perioral cyanosis deepens as breath-holding continues. Some episodes end with resumption of crying, but others end with a brief period of unconsciousness during which breathing resumes. No treatment is required beyond reassurance of the child and parents.
### Hyperventilation
People experiencing anxiety may appear fearful, pale and diaphoretic. They may complain of lightheadedness, dizziness and numbness, as well as tingling of the face and extremities. Hyperventilation is usually evident. Treatment consists of reassurance and encouraging the individual to breathe slowly and deeply. Initiating a refocusing activity, such as asking the person to count to ten, may help. Should there be another condition causing the hyperventilation, such as asthma or heart attack, holding one's breath could worsen the condition.
### Vasovagal syncope (fainting)
Fainting itself has no adverse consequence but during a fall, severe head injuries could occur.
Fainting is common with at least one lifetime occurrence in about 3.5% of women and 3% of men. The exact frequency of fainting post-immunization is not known but the majority of syncope adverse event reports involve adolescents or adults. Fainting is rare in infants and children. Therefore, a **sudden loss of consciousness in young children should be presumed to be anaphylaxis**, especially if other clinical features of anaphylaxis are present.
[Table 1](#t1) lists clinical features that differentiate fainting due to vasovagal syncope from anaphylaxis.
Fainting usually occurs during immunization or within minutes of immunization. The individual may complain of feeling faint or light-headed, then suddenly become pale, lose consciousness and collapse to the ground. This may be accompanied by brief clonic seizure activity (i.e., rhythmic jerking of the limbs). As a general rule, the respiratory rate is normal and not laboured, but may be shallow. Cardiovascular signs include bradycardia and faint peripheral pulses but usually the carotid pulse is strong. In addition to pallor, the skin may be cool and clammy. There may be associated nausea and vomiting. Fainting is managed by placing the vaccinee in a supine (lying on their back) position and elevating the lower extremities. If vomiting has occurred or is imminent, position the vaccinee lying on one side. If the vaccinee is pregnant, position them lying on their left side. Recovery of consciousness and resolution of limb jerking usually occurs within a minute or two. The person may remain pale, diaphoretic and mildly hypotensive for several minutes. Continue monitoring and providing support to the vaccinee who has fainted until signs and symptoms have stabilized.
**Table 1: Key distinguishing features of anaphylaxis and vasovagal syncope.**
| Clinical features | Anaphylaxis | Vasovagal syncope |
| --- | --- | --- |
| Onset from time of immunization | Within minutes up to 4 hours after injection; most within 2 hours | During or within minutes of injection |
| Skin | Urticaria, angioedema, pruritus, erythema | Generalized pallor, cold clammy skin |
| Respiratory | Cough, wheeze, stridor, respiratory distress, rhinorrhea, sneezing | Normal respiration – may be shallow but not laboured |
| Cardiac | Tachycardia | Bradycardia |
| Neurologic | Sense of severe anxiety and distress; loss of consciousness – no improvement once supine or in head down position | Sense of light-headedness; loss of consciousness – improves once supine or in head down position; may be transient jerking of the limbs and eye-rolling |
Adapted with permission from: Immunisation Section, South Australian Department for Health and Wellbeing.
For a more detailed list of system-specific manifestations of anaphylaxis, see [Table 2](#t2).
For techniques to decrease anxiety and fainting, refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1.
Anaphylaxis
-----------
Anaphylaxis is a serious, potentially life-threatening allergic reaction to foreign antigens; it has been proven to be causally associated with vaccines with an estimated frequency of 1.3 episodes per million doses of vaccine administered. Anaphylaxis is preventable in many cases and treatable in all. It should be anticipated in every vaccinee.
### Pre-vaccination screening
Prevention of anaphylaxis is critically important. Pre-vaccination screening includes screening for a history of anaphylaxis and identification of potential risk factors. It should include questions about possible allergy to any component or container of the scheduled vaccine(s) in order to identify if there is a contraindication to administration.
Refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html#t1) in Part 1 for a pre-vaccination administration checklist.
Refer to [Contents of Immunizing Agents Available in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for a list of potential allergens in immunizing agents.
#### Post-vaccination observation
Most instances of anaphylaxis to a vaccine begin within 30 minutes after administration of vaccine. Therefore, vaccine recipients should be kept under observation for at least 15 minutes after immunization; 30 minutes is a safer interval when there is a specific concern about possible vaccine allergy. In low-risk situations, observation can include asking vaccinees to watch for symptoms and return immediately for assessment if they feel unwell.
Refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for more information on post-vaccination counselling and observation.
For information about reporting AEFI such as anaphylaxis, refer to [Adverse Events Following Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) (AEFI).
### Signs and symptoms of anaphylaxis
In anaphylaxis, signs and symptoms onset suddenly and progress rapidly over several minutes and involves two or more body systems. The most frequently involved systems are skin (80% to 90% of anaphylaxis cases), respiratory (up to 70% of cases) and less often cardiovascular and gastrointestinal (each up to 45% of cases). Up to 15% of cases may also manifest central nervous system changes of uneasiness, altered mental status, dizziness, or confusion. Features of severe anaphylaxis include obstructive swelling of the upper airway, marked bronchospasm and hypotension. Hypotension can progress to cause shock and collapse.
**Table 2: Signs and symptoms of anaphylaxis**
| System | Signs and symptoms |
| --- | --- |
| General/CNS | Fussiness, irritability, drowsiness, lethargy, reduced level of consciousness, somnolence |
| Skin | Urticaria, pruritus, angioedema, flushing |
| Upper airway | Stridor, hoarseness, oropharyngeal or laryngeal edema, uvular edema, swollen lips/tongue, sneezing, rhinorrhea, upper airway obstruction |
| Lower airway | Coughing, dyspnea, bronchospasm, tachypnea, respiratory arrest |
| Cardiovascular | Tachycardia, hypotension, dizziness, syncope, arrhythmias, diaphoresis, pallor, cyanosis, cardiac arrest |
| Gastrointestinal | Nausea, vomiting, diarrhea, abdominal pain |
| *CNS Central nervous system* |
Reproduced with permission from: Cheng A; Canadian Paediatric Society, Acute Care Committee. Emergency treatment of anaphylaxis in infants and children. Paediatr Child Health 2011;16(1):35-40. Reaffirmed February 2018.
It may be challenging to identify anaphylaxis in infants and young children (0-2 years of age) as they are unable to describe their symptoms. Infants may present with respiratory distress (e.g., increased work of breathing, cough, wheeze, stridor) or tachycardia rather than hypotension. Non-specific signs and symptoms may include sudden quietness or sleepiness, drooling, incontinence and behavioural changes such as inconsolable crying and irritability - all of which are common in this age group. Generalized urticaria, flushing, vomiting (including persistent vomiting), and angioedema are typically observed in this age group. Specific or non-specific signs or symptoms in two or more body organ systems are required for a clinical diagnosis of anaphylaxis.
### Risk factors for severe anaphylaxis
Anaphylaxis is a rare complication of immunization. Risk factors for increased severity of anaphylactic events include:
* very young or old age,
* pregnancy,
* severe or uncontrolled asthma,
* cardiovascular disease,
* chronic obstructive pulmonary disease,
* systemic mastocytosis,
* concurrent use of certain medications (e.g., angiotensin-converting enzyme [ACE] inhibitors and beta-blockers).
### Anaphylaxis management kits
Appropriate preparation is important for a good outcome in anaphylaxis. **Anaphylaxis management kits should be readily available wherever vaccines are administered**. EPINEPHrine in an autoinjector or in a vial may be used to treat anaphylaxis; however, vials of EPINEPHrine must be available for treatment of infants weighing less than 5 kg (refer to [EPINEPHrine treatment - additional information](#a20)). EPINEPHrine and other emergency supplies should be checked on a regular basis and replaced when outdated.
**Table 3: Anaphylaxis management kits: recommended items [Footnote 1](#fn1)**
| Items | Essential | Optional |
| --- | --- | --- |
| Laminated documents | * Clear, concise summary of emergency management protocol
* EPINEPHrine dosage by weight and age
| N/A |
| Drugs | EPINEPHrine[Footnote 2](#fn2): three vials - 1:1000 (1 mg/mL) solution for IM injection[Footnote 3](#fn3) | N/A |
| Injection supplies[Footnote 4](#fn4) | * Two 1 cc syringes with attached 25 gauge needle (one - 1 inch; one 5/8 inch)
* Three extra 25 gauge needles of each different size: 5/8 inch, 1 or 1.25 inch, 1.5 inch
| EPINEPHrine[Footnote 2](#fn2) autoinjectors labelled by age and weight |
| Other | * Scissors
* Alcohol swabs
* Tongue depressors
* Pocket mask
* Wristwatch with second hand (for heart rate)
* Ready access to a phone to call emergency services
* Flashlight
| * 1 nasopharyngeal, 1 oropharyngeal airway for each age range anticipated in the clinic
* Oxygen and related equipment
* IV lines, fluids and related equipment
* Stethoscope
* Sphygmomanometer
|
|
Footnote 1
All immunization sites should have the essential items. Optional items reflect variations in immunization sites some of which are equipped for advanced care.
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
TALLMAN lettering is a method of applying upper-case lettering to sections of look-alike/sound-alike name attributes in efforts to avoid drug name confusion and potential medication incidents.
[Return to footnote 2 referrer](#fn2-rf)
Footnote 3
Refer to [Table 4](#t4) for recommended EPINEPHrine dosing information.
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
Refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for information on intramuscular injections and needle selection guidelines.
[Return to footnote 4 referrer](#fn4-rf)
|
### Management of anaphylaxis
Anaphylaxis is a medical emergency, and rapid recognition and management can be life-saving. Every vaccine provider should be familiar with the signs and symptoms of anaphylaxis and be prepared to act quickly. The rate of progression or the severity of the anaphylactic episode can be difficult to predict at the start of anaphylaxis; however, rapid development of anaphylaxis following vaccination indicates that a more severe reaction is likely. Death can occur within minutes. EPINEPHrine is the only medication that reduces hospitalization and death and should be administered promptly following the onset of anaphylaxis.
#### Protocols
All immunization providers should be trained to recognize anaphylaxis, to administer intramuscular (IM) EPINEPHrine and to initiate basic life-support measures such as cardio-pulmonary resuscitation (CPR) if indicated.
Vaccinees with severe allergic reaction or anaphylaxis should be transported to a hospital as soon as possible. The establishment of intravenous (IV) access for fluid resuscitation may be necessary, and endotracheal intubation and other advanced life-support interventions may be required. These interventions generally do not take place in community settings but may at times be performed by competent and trained staff in safe and appropriate care settings.
Advance preparation for emergency management of anaphylaxis is essential. It is recommended that vaccine providers develop, post, and regularly rehearse a written anaphylaxis emergency management protocol. Protocols should specify the necessary emergency equipment, drugs and dosages, and medical personnel necessary to safely and effectively manage anaphylaxis.
#### Steps for basic management of anaphylaxis in a community setting
Rapid intervention is of paramount importance. Steps 1, 2, 3 and 4 should be done promptly and simultaneously.
* 1. **Direct someone to call 911** (where available) **or emergency medical services**.
* 2. **Assess** airway, breathing, circulation, mental status, skin, and body weight (mass). Secure an oral airway if necessary.
+ airway: look specifically at lips, tongue and throat for swelling; if appropriate, ask individual to say his/her name to assess glottic/peri-glottic swelling
* 3. **Place** individual on his/her back (supine) and elevate lower extremities. The vaccinee should remain in this position. Fatality can occur within seconds if the vaccinee stands or sits suddenly, due to empty vena cava/empty ventricle syndrome. Exceptions to the supine position:
+ if in respiratory distress, place in a position of comfort (elevate head and chest)
+ if vomiting or unconscious, place lying on his/her side
+ if pregnant, place lying on their left side
* 4. **Inject EPINEPHrine**:
+ **Dose: 0.01 mg/kg body weight of 1:1000 (1 mg/mL) solution, MAX 0.5 mg** (see [Table 4](#t4) for dosage by age or weight)
+ **Route: INTRAMUSCULAR (IM) in mid-anterolateral thigh (*vastus lateralis* muscle)**
+ **Repeat** every 5 minutes if symptoms persist (most patients improve in 1-2 doses)
+ **Record the time of each dose**
+ Stabilize and monitor patient (see steps [5](#s5) & [6](#s6))
### Table 4: Dosage of intramuscular EPINEPHrine 1:1000 (1 mg/mL) solution, by age or weight[Footnote 1](#fnt4-1)
**Weight is the preferred basis for dosage but if unknown, use age as a guide.**
| Age[Footnote 1](#fnt4-1), [Footnote 2](#fnt4-2)
Use weight if available | Weight[Footnote 2](#fnt4-2) (kg) | **EPINEPHrine** dose
(1 mg/mL) ampoule/vial | EPINEPHrine
autoinjector dose[Footnote 5](#fn5)
Use only if measured dose by weight is unavailable |
| --- | --- | --- | --- |
| mg
or
mg/kg/dose | Volume
1 mg/mL
(mL) |
| Birth to less
5 kg | Less than 5 kg | 0.01**mg/kg/dose**[Footnote 3](#fnt4-3) **or**
0.1 mg [Footnote 3](#fnt4-3), [Footnote 4](#fnt4-4) | 0.01**mL/kg/dose****or**
0.1 mL [Footnote 3](#fnt4-3), [Footnote 4](#fnt4-4) | N/A |
| Greater than 5 kg **and** less than 2 years | 5 - 10 | 0.1 mg | 0.1 mL | 0.15 mg[Footnote 4](#fnt4-4), [Footnote 6](#fn6) |
| 2 to less than 4 years | 11 - 15 | 0.15 mg | 0.15 mL |
| 4 to less than 7 years | 16 - 20 | 0.2 mg | 0.2 mL |
| 21 - 25 | 0.25 mg | 0.25 mL | 0.3 mg [Footnote 2](#fnt4-2), [Footnote 7](#fn7) |
| 7 to less than 10 years | 26 - 30 | 0.3 mg | 0.3 mL |
| 31 - 35 | 0.35 mg | 0.35 mL |
| 10 to 12 years | 36 - 40 | 0.4 mg | 0.4 mL |
| 41 - 45 | 0.45 mg | 0.45 mL |
| Older than 12 years | 46 and above | 0.5 mg | 0.5 mL | 0.5 mg |
|
Footnote t4-1
Adapted from: Australian Immunisation Handbook (ATAGI, confirmed June 2018). https://immunisationhandbook.health.gov.au/resources/handbook-tables/doses-of-intramuscular-11000-adrenaline-for-anaphylaxis. [Accessed June 1, 2020]
[Return to footnote 1 referrer](#fnt4-1-rf)
Footnote t4-2
Adapted from: TREKK. Dec 2018. Pediatric anaphylaxis algorithm. Version 1.1. Accessed June 28, 2020 from: https://trekk.ca/system/assets/assets/attachments/339/original/2018-12-10\_Anaphylaxis\_algorithm\_v\_1.1.pdf?1545083235
[Return to footnote 2 referrer](#fnt4-2-rf)
Footnote t4-3
Cheng A; Canadian Paediatric Society, Acute Care Committee. Emergency treatment of anaphylaxis in infants and children. Paediatr Child Health 2011; 16(1):35-40.
[Return to footnote 3 referrer](#fnt4-3-rf)
Footnote t4-4
Jensen J, Ryu J, Clifton H, Brown J. Impact of Pre-Arrival epinephrine in Emergency Department or Urgent Care pediatric anaphylaxis patients weighing < 15 kg, Poster P010, Ann Allergy Asthma Immunol 2018; 121: S22−S62.
[Return to footnote 4 referrer](#fnt4-4-rf)
Footnote t4-5
As of October 2020, three EPINEPHrine autoinjectors were on the Canadian market: EpiPen®, Allerject® and EMERADE™.
[Return to footnote 5 referrer](#fn5-rf)
Footnote t4-6
In infants, it is recommended that EPINEPHrine be administered via a syringe rather than by an autoinjector. Needle lengths that are too long have a risk of intraosseous administration (due to the need to apply pressure in order to deploy the autoinjector). The depth of the needle is better controlled with the syringe administration rather than autoinjector.
[Return to footnote 6 referrer](#fn6-rf)
Footnote t4-7
Sicherer SH and FER Simons, Pediatrics 2007; 199:638-646.
[Return to footnote 7 referrer](#fn7-rf)
|
* 5. **Stabilize vaccinee:** perform cardiopulmonary resuscitation if necessary, give oxygen and establish intravenous access if available
+ give supplemental oxygen (6 to 8 L/minute) by face mask or oropharyngeal airway (if available) to people with cyanosis, dyspnea or any other severe reaction requiring repeated doses of EPINEPHrine
+ if hypotensive, consider giving IV normal saline, 20 mL/kg if IV access established and if available.
* 6. **Monitor** vaccinee's blood pressure, cardiac rate and function, and respiratory status.
* 7. **Transfer to hospital for observation.** All vaccinees receiving emergency EPINEPHrine must be transported to hospital immediately for evaluation and observation. The symptoms of an anaphylactic reaction can reoccur after the initial reaction (biphasic anaphylaxis) in up to 23% of patients with anaphylaxis.
#### EPINEPHrine treatment - additional information
**Prompt intramuscular administration of EPINEPHrine is the priority** and should not be delayed. EPINEPHrine is the treatment of choice for management of anaphylaxis in community and healthcare settings as it prevents and relieves upper airway swelling, hypotension and shock. In addition, it causes increased heart rate, increased force of cardiac contractions, increased bronchodilation, and decreased release of histamine and other mediators of inflammation. EPINEPHrine reaches peak plasma and tissue concentrations rapidly.
**Failure to administer EPINEPHrine promptly may result in greater risk to the vaccinee with anaphylaxis than using EPINEPHrine improperly.**
If uncertain, err on the side of treatment; **there are no contraindications to the use of EPINEPHrine**. If time is lost early in the treatment of an acute anaphylactic episode, subsequent management can become more difficult.
EPINEPHrine 0.01 mg/kg body weight of 1:1000 (1 mg/mL) solution (max 0.5 mg) should be administered into the mid-anterolateral aspect of the thigh (*vastus lateralis* muscle); the deltoid muscle of the arm should not be used as it is not as effective as the thigh in absorbing EPINEPHrine. Scissors may be needed to cut clothing to establish access. If scissors are not readily available, EPINEPHrine may be administered through clothing. Although there is a slightly increased risk of infection, timely administration of EPINEPHrine is the priority. The risk of infection can be addressed once the person has stabilized. For infants weighing less than 5 kg, the dose of EPINEPHrine should be determined by weight, if possible. For example, an infant weighing 4 kg (8.8 lb) should receive 0.04 mg of EPINEPHrine, which is 0.04 mL of a 1 mg/mL solution. However, if a vial is not available at the time of anaphylaxis, the 0.15 mg EPINEPHrine autoinjector device can be safely used. (Refer to [Table 4](#t4) for EPINEPHrine dosing guidelines). Mild and transient effects such as pallor, tremor, anxiety, palpitations, headache and dizziness occur within minutes after injection of a recommended dose of EPINEPHrine. These effects confirm that a therapeutic dose has been given.
### Antihistamines
Antihistamines (first generation and second generation) have no role in preventing or treating respiratory or cardiovascular symptoms of anaphylaxis in a community setting and should never be used in place of EPINEPHrine.
Swelling and urticarial rash at the injection site
--------------------------------------------------
Swelling and urticarial rash (i.e., hives) at the injection site can occur and may be the first indication of an evolving anaphylaxis. For this reason, while such reactions are not always caused by an allergic reaction, the individual should be observed for at least 30 minutes in order to ensure that the swelling or hives remain localized. Ice can be applied to the injection site for comfort. If the hives or swelling disappears and there is no evidence of any progression to other parts of the body and there are no other symptoms within the 30-minute observation period, no further observation is necessary. However, **if any other symptoms arise, even if considered mild (e.g., sneezing, nasal congestion, tearing, coughing, facial flushing), or if there is evidence of any progression of the hives or swelling to other parts of the body during the 30-minute observation period, EPINEPHrine should be given** (refer to the [Steps for basic management of anaphylaxis in a non-hospital setting](#a18)).
A mild local reaction resolving by itself within a few minutes is not indicative of an allergic reaction and does not require special observation or specialized assessment prior to subsequent vaccination.
Selected references
-------------------
* Alqurashi W, Ellis AK. Do Corticosteroids Prevent Biphasic Anaphylaxis? J allergy Clin Immunol Pract. 2017;5(5):1194-1205. doi:10.1016/j.jaip.2017.05.022
* Australian Technical Advisory Group on Immunisation (ATAGI). Australian Immunisation Handbook, Australian Government Department of Health, Canberra, 2018, immunisationhandbook.health.gov.au.
* Cheng A. Canadian Paediatric Society. Emergency treatment of anaphylaxis in infants and children. Paediatr Child Health 2011;16(1):35-40. Reaffirmed February 2018. https://www.cps.ca/en/documents/position/emergency-treatment-anaphylaxis
* Greenhawt M, Gupta RC, Meadows A, Pistiner M, Spergel JM, Camargo CA, Simons ER, Lieberman PL. Guiding Principles for the Recognition, Diagnosis, and Management of Infants with Anaphylaxis: An Expert Panel Consensus. J Allergy Clin Immunol Pract 2019;7 (4):1148-56.
* Halbrich M, Mack DP, Carr S, Watson W, Kim H. CSACI position statement: epinephrine autoinjectors and children less than 15 kg. Allergy, Asthma & Clinical Immunology (2015) 11:20.
* Jensen J, Ryu J, Clifton H, Brown J. Impact of Pre-Arrival epinephrine in Emergency Department or Urgent Care pediatric anaphylaxis patients weighing < 15 kg, Poster P010, Ann Allergy Asthma Immunol 2018; 121: S22−S62.
* Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. *The diagnosis and management of anaphylaxis: an updated practice parameter*. J Allergy Clin Immunol. 2005;115:S483-523.
* Kaleo, Inc. *Product Monograph - Allerject®.* November 2019.
* McNeil MM, Weintraub ES, Duffy J, et al. Risk of anaphylaxis after vaccination in children and adults. The Journal of allergy and clinical immunology. 2016;137(3):868-878. doi:10.1016/j.jaci.2015.07.048.
* Mylan Specialty Dey Pharma L.P. *Product Monograph - EpiPen®and EpiPen®Jr.* May 2017.
* Nilsson L, Brocknow K, Alm J et al. Vaccination and allergy: EAACI position paper, practical aspects. Pediatr Allergy Immunol. 2017;28:628-640.
* Sicherer SH, Simons FE and the Section on Allergy and Immunology. Self-injectable epinephrine for first-aid management of anaphylaxis. Pediatrics 2007; 199:638-646.
* Simons FE, Arudusso LR, Bilo MB et al. World Allergy Organization guidelines for the assessment and management of anaphylaxis. J Allergy Clin Immunol 2011;127(3):593e1-22.
* Simons FE, Ebisawa M, Sanchez-Borges M, et al. 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. World Allergy Organization Journal (2015) 8:32.
* Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: Intramuscular versus subcutaneous injection. J Allergy Clin Immunol. 2001; 108:5: 871- 873.
* Simons FE, Sampson HA. Anaphylaxis: Unique aspects of clinical diagnosis and management in infants (birth to age 2 years). J Allergy Clin Immunol, 2015; 135:1125-31.
* Translating Emergency Knowledge for Kids (TREKK). Bottom Line Recommendations: Anaphylaxis. December 2018, Version 1.2. Accessed July 9, 2019 from: https://trekk.ca/system/assets/assets/attachments/338/original/2018-12-14\_Anaphylaxis\_BLR\_version\_1.2.pdf?1545083199
* Translating Emergency Knowledge for Kids (TREKK). Pediatric anaphylaxis algorithm. Dec 2018. Version 1.1. Accessed June 28, 2020 from: https://trekk.ca/system/assets/assets/attachments/339/original/2018-12-10\_Anaphylaxis\_algorithm\_v\_1.1.pdf?1545083235
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-08-04
| None | None |
e4b8bd82d4ecf34c35318b506ea44de00189e3ed | cma | Zika Virus Prevention and Treatment Recommendations | Zika Virus Prevention and Treatment Recommendations
Key Points
- There has been a substantial reduction in the risk of Zika virus (ZIKV) infection among Canadian travellers. Accordingly, CATMAT no longer routinely recommends that pregnant travellers avoid travel to areas where Zika is known or suspected to occur, or that special precautions to prevent sexual transmission while abroad or upon return are necessary.
+ Some travellers, for example based on their values and preferences, might choose to follow recommendations for prevention of sexual or vertical (mother to fetus) transmission of ZIKV because Zika continues to present a low risk in many tropical and subtropical areas.
- Given the low risk of ZIKV infection, CATMAT recommends against routine testing of asymptomatic pregnant women. The poor positive predictive value, especially for screening serology tests, means a positive test has a high likelihood of being a false positive, which may have significant adverse consequences. The low population prevalence of infection means a negative test result is of negligible clinical utility.
- In a situation where testing is completed and ZIKV is confirmed CATMAT recommends:
+ women should wait at least 2 months after their return from a risk area or onset of symptoms (whichever occurs later) before trying to conceive/having unprotected sex.
+ men should wait at least 3 months after their return from a risk area or onset of symptoms (whichever occurs later) before trying to conceive with their partner or engaging in unprotected sex.
- In the case of a confirmed or symptomatic case with compatible symptoms of ZIKV infection in the male partner, CATMAT recommends that pregnant couples abstain from unprotected sex for the duration of the pregnancy.
- Travellers and health care providers should remain vigilant for emergent information related to ZIKV outbreaks. Should a significantly increased risk of ZIKV transmission be identified in a specific travel destination, pre- and post-travel advice should be modified accordingly. This would include consideration of avoiding travel to the outbreak area during pregnancy.
- Travel during pregnancy typically poses multiple health risks. The risk of ZIKV infection should be included in a broader discussion about infectious diseases and other potential complications when considering travel while pregnant.
Preamble
The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. The Agency acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.
Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.
Summary
There has been a substantial decrease in reported rates of Zika virus (ZIKV) related disease in countries (primarily in the Americas) that suffered from the outbreak that started in 2015 and a corresponding decline (>90%) in reports of ZIKV infection among travellers visiting these countries. Accordingly, CATMAT no longer routinely recommends that: pregnant travellers avoid travel to areas where Zika is known or suspected to occur, or that special precautions to prevent sexual transmission while abroad or upon return are necessary. Rather, CATMAT suggests that precautions for preventing ZIKV transmission be considered within the general context of the infectious and non-infectious risks travel may pose to a pregnant woman.
Introduction
Zika virus (ZIKV) infection is caused by a flavivirus transmitted through the bite of an infected Aedes mosquito, mainly *Aedes aegypti*. Although infections in humans have been known to occur for some time, ZIKV emerged on the global stage when it caused major outbreaks in many tropical and subtropical areas of the world, especially in the Americas ,. During these outbreaks, a previously unrecognized pattern of Zika-related adverse outcomes emerged. Pre-eminent among these were complications of pregnancy including major congenital anomalies. First identified through spatial and temporal clustering of ZIKV activity with an increased incidence of congenital microcephaly - is now known that these can be manifest as a constellation of fetal developmental problems that are collectively referred to as a congenital Zika syndrome (CZS) - The risk of CZS is substantial if infected while pregnant. For example, of 972 completed pregnancies enrolled in the US Zika Pregnancy Registry, 5% showed evidence of CZS (95% CI = 4%-7%). The greatest impact was observed when infection occurred during the first trimester (15% with CZS) . Similar results have been described for: affected US Territories, with a CZS rate of 5% among completed affected pregnancies and for French territories in the Americas where 7% (39/555) of fetuses and infants were identified as having suffered defects possibly associated with ZIKV infection. In this last study, effects were more common if infection occurred during the first trimester, but were also seen if infection occurred in the second (3.6%) or third (5.3%) trimesters . Recently, data have been described for Zika associated harms before and after birth in a population of children born to infected mothers in US territories and freely associated states . From a population of 1,450 children with follow-up care, 6% suffered from a Zika-associated birth defect(s), 9% had a neurodevelopmental abnormality(ies) possibly associated with congenital infection, and 1% had both.
Although disease is usually relatively benign in adults, ZIKV infection can cause neurologic sequelae such as Guillain-Barré syndrome (GBS) , , . A case control study done in French Polynesia estimated a 0.24 in 1,000 risk for developing GBS in persons infected with ZIKV. This is comparable to the GBS risk of 0.25 to 0.65/1,000 observed following Campylobacter jejuni infection. There are also reports of acute disseminated encephalomyelitis (ADEM) following ZIKV infection .
Complicating the picture for ZIKV epidemiology and prevention, the virus can be transmitted sexually, with most reported cases being from an infected male to a female, although female to male and male to male transmission have also been reported . The risk of such transmission remains difficult to quantify, though a significant proportion of symptomatic men shed viral RNA in their semen. For example, 22/36 (61%) of men in a US-based study had detectable viral RNA in their semen when tested within 30 days of illness onset . This dropped to < 10% at 3 - 4 months after illness, and approximately 1% at 5-6 months after illness. Importantly, recovery of infectious ZIKV was rarer, occurring in 3/78 (4%) samples with all positives being obtained within 30 days of illness onset , though the possibility of false negatives in this cohort cannot be ruled out. Complementing these observations, the median serial interval between onset of symptoms in couples where sexual transmission occurred was 12 days (interquartile range: 10-14.5 days) . Overall, these data suggest that the period during which sexual transmission (from a male) is likely to occur is much shorter than the period (often 6 months) for which sexual precautions had been previously recommended.
The purposes of this statement are to review current knowledge related to ZIKV infection and to provide guidelines for health care providers on prevention and management of ZIKV disease.
Methods
This statement was developed by a working group of the Committee to Advise on Tropical Medicine and Travel (CATMAT). Members of the working group were from CATMAT, the Public Health Agency of Canada (the Agency) and the Society of Obstetricians and Gynaecologists of Canada. Each member was a volunteer, and none declared a relevant conflict of interest. The working group was responsible for assessing available literature, synthesis and analysis of the evidence, drafting recommendations, and writing. Secretariat support was provided throughout the process by the Public Health Agency of Canada. The final statement was approved by the full CATMAT committee.
This guideline complements existing CATMAT statements including the and .
This document is an update to the CATMAT Zika statement published in February 2018. The most important changes are related to: the overall reduction in ZIKV transmission in many areas previously affected by the outbreak, the consequent significant reduction in risk for travellers (see Table 1); and, the availability of a systematic review related to sexual transmission .
Epidemiology
ZIKV was first isolated from monkeys in Uganda in 1947. Soon after, in 1952, human infections were detected in Uganda and Tanzania ,. However, human infections were rarely reported until 2007, when a large outbreak of ZIKV disease occurred on the island of Yap (Micronesia) . Between 2013 and 2015, additional outbreaks occurred on islands and archipelagos in the Pacific region - . In 2014, local transmission in the Americas was reported on Easter Island . Subsequently, ZIKV caused a large outbreak in the Americas as well as in other countries/regions. Since the outbreak peaked in 2016, the number of locally acquired reported cases in the majority of affected countries has decreased substantially ,, as has the number of travel-associated cases reported in Canada and the United States ,. For example, in the first 11 months of 2018, only 58 cases of travel-associated ZIKV infection had been reported in the continental United States , compared to almost 5,000 cases during the entirety of 2016 and 437 in 2017 . Similar decreases in travel-associated infections have been observed in Canada, with the number of cases reported dropping from 468 in 2016 to 74 in 2017, and then to 21 in 2018 and without a concomitant decrease in testing.
# Transmission
The mosquitoes associated with ZIKV tend to be more active during the day but can bite at night, with peak activity often occurring in the morning and later in the afternoon. In vertebrate hosts, the incubation period is usually 3 - 14 days , with blood viremia (the period when ZIKV is present in the blood) usually lasting for about 2 weeks - , but with the possibility of longer periods of viral detection in blood and other body fluids . Vertical transmission between mother and developing fetus presumably occurs during the viremic period ,. Other described routes of transmission include blood product transfusion and sexual transmission after symptomatic infection - . There is a report of sexual transmission from a symptomatic infected woman to a sexual partner , and another report of sexual transmission from an asymptomatically infected male to their partner ,.
Viral RNA has been detected in various biological fluids for prolonged periods, but isolation of infectious virus has only been documented at substantially lower rates and for shorter time intervals. Viral RNA has been detected in urine up to 6 weeks after illness onset; however, the median time until the loss of viral genome detection was determined to be 8 days . For individuals with detectable viral RNA in their serum the median time for loss of detection was 14 days, a small percentage of patients were reverse transcriptase polymerase chain reaction (RT-PCR) positive for more than a month . In particular, pregnant women carrying congenitally-infected fetuses may be symptomatically viremic for a prolonged period, thus, Zika should be considered in pregnant women with compatible exposure history and extended duration of fever, despite the typically short viremic phase of flaviviruses, in general ,.
Based on a cohort of symptomatic men followed in the US, a significant proportion (61%) had detectable viral RNA in their semen in the first month after illness onset . This decreases to 1% or less by 6 months after symptom onset. Duration of shedding increased modestly with increasing age, and with certain symptoms. Interestingly, persistence of RNA in semen was most strongly and inversely associated with frequency of ejaculation. For example, men who reported ejaculating 4 times per week were estimated to clear RNA 3 weeks earlier than men who reported ejaculating once per week. This raises the possibility of a modifiable risk factor for prolonged shedding. In this same study, infectious virus was isolated from 3/19 (16%) samples obtained within 30 days after illness onset but in none of the 59 samples that were obtained later. The 3 men in which infectious virus was isolated had relatively high (>7.0 log10) ZIKV RNA copies per milliliter of semen in their first sample which declined in subsequent samples to 5.8 (log10 copies/ml of semen), 3.1 (log10 copies/ml of semen), and undetectable, respectively. These follow-up samples were obtained at 38, 59 and 76 days following illness onset and infectious ZIKV was not detected in the two men who still had detectable ZIKV RNA . Nevertheless, it remains theoretically possible that some of the PCR positive but culture negative cases were contagious. To date the longest period after symptom onset at which replication-competent virus has been detected in semen was 69 days; this was reported in a single case report of a vasectomized man . ZIKV RNA has also been detected at lower concentrations in men who have undergone vasectomy, but at rates similar to men who have not had this procedure. Although not studied extensively, the persistent shedding of ZIKA RNA in semen is considered to be similar amongst infected symptomatic and asymptomatic men based on case reports of sexual transmission and on data from asymptomatic blood donors , , .
Neutralizing antibodies for ZIKV are detectable after infection, and by extrapolation from other flaviviruses that induce a humoral antibody response, post-infection immunity is presumed to be lifelong . Among couples where such data is available (n=15) the median time between onset of sexual partners' symptoms (serial interval) was 12 days (interquartile range: 10±14.5 days) while the maximum was 44 days . Based on RT-PCR data, the median duration of ZIKV positivity was 13.9 days (95% CI: 7.2-19.6) for any fluid in the female genital tract, with a maximum of 37 days. There were too few data available for analysis of viral culture specimens in female genital tract fluids .ZIKV RNA has been detected in breast milk; however, there have not been any unequivocally documented reports of transmission to infants through breastfeeding . At this time, the World Health Organization (WHO) considers that "the benefits of breastfeeding for the infant and mother outweigh any potential risk of Zika virus transmission through breast milk" . Until further evidence is available regarding transmission through breast milk, CATMAT suggests that potential benefits and harms of breastfeeding during acute ZIKV infection should be discussed with each patient and decisions be made on an individual basis.
# Clinical Manifestations
Approximately 20-25% (possibly as high as 50%) of persons infected with ZIKV will manifest symptoms, including fever, myalgia, pruritis, eye pain, and maculopapular rash , , .
Early clinical manifestations are similar to other arboviral infections including dengue and chikungunya ,. Thus, the differential diagnosis of a febrile returned traveller will likely include these arboviral infections, other viral illnesses ,, as well as .
Post-infectious neurologic complications, such as GBS, have been reported from many countries that were affected by the outbreak , , , . They include French Polynesia where a case-control study estimated that the odds of positive ZIKV serology was substantially greater in GBS cases compared to matched controls (OR 59.7; 95% CI 10.4 to ∞) . In the same study, and based on a ZIKV population seroprevalence of 0.66, the risk of GBS following ZIKV infection was estimated at approximately 0.25/ 1000. Other neurological manifestations have also been reported in association with ZIKV infection, e.g., acute myelitis, meningoencephalitis, acute disseminated encephalomyelitis, and reverse sensory polyneuropathy , , , suggesting that the neurological spectrum of sequelae associated with ZIKV is relatively broad.
Clinically relevant thrombocytopenia and subcutaneous hematomas have been reported in a small number of cases ,. Deaths from other causes have also been reported ,.
Over 30 countries have reported CZS . Common manifestations include microcephaly, cerebral atrophy, abnormal cortical development, callosal hypoplasia, and diffuse subcortical calcifications ,. Ocular abnormalities and other congenital malformations such as arthrogryposis and hydrops fetalis have also been described - .
Reviews of the epidemiology of ZIKV, as well as the causal association of ZIKV and microcephaly have been published .
Risk to travellers
There are multiple lines of evidence to indicate that the risk of ZIKV infection for travellers has decreased significantly. First, the number of cases reported in the epidemic regions of the Americas has decreased ,. For US territories specifically, more than 36,000 cases (presumed to be locally acquired) were reported in 2016, compared to 652 (98% decrease) cases reported in 2017 and 116 cases reported (as of December 4) in 2018 (> 99% decrease) ,. Second, the number of travel-related cases reported in Canada and the United States has decreased by approximately two orders of magnitude since 2016. In Canada, the overall decrease from 2016 to 2018 has been > 95% (468 cases in 2016 to 21 cases in 2018). A similar decrease has also occurred in the continental United States where 4,897 cases (travel-related) were reported in 2016, 437 in 2017 (91% reduction) and 34 cases reported (as of August 1) in 2018 (> 99% decrease); and, in the European Union where 2,121 cases were reported in 2016 and 198 cases (93% reduction) were reported in 2017 .
Set against the total travel volumes to countries affected by the outbreak, which exceeds 7 million annually for Canadians , the estimated risk of a traveller being confirmed with a ZIKV infection is currently very low, e.g., < 1 case/200,000 trips (14 cases in 2018, adjusted for surveillance period). While this is an underestimate of the true risk of infection, (the majority of infections are likely not reported), it nevertheless supports that ZIKV-infection among Canadian travellers has become a rare event. Accordingly, adverse outcomes associated with ZIKV-infection must be rare events in absolute terms, even with significant under-reporting. Indeed, from October 2015 - December 2018, a total of 4 sexually transmitted cases have been reported in Canada . During the same time period, 47 cases have been reported among pregnant women in Canada . From March 2017 to December 2018, CZS had been reported in ≤ 5 infants in Canada .
# Areas of risk
Transmission of ZIKV can occur in most areas of the world where *Aedes aegypti*, the principal vector, occurs. This means that there is the potential for transmission through much of the tropical and subtropical world and beyond. As described above, the risk of transmission to travellers is considered low.
Previously, CATMAT recommendations were linked to the WHO country classification scheme for ZIKV to determine areas of risk or potential risk. In July 2019, the WHO implemented a new approach for categorizing countries according to the presence or absence of current and historical reported ZIKV transmission. It should be noted that monitoring and reporting in some areas is suboptimal, and that this approach provides only an approximation of the areas of risk. Due to a general absence of laboratory and surveillance data from many countries/territories, it provides a conservative risk assessment (i.e. includes countries/territories where cases have been reported but also includes countries where there is a known historical risk but cases are not currently being reported).
Notwithstanding the above, travellers and health care providers should remain vigilant for emergent information related to ZIKV that might influence decision-making, for example evidence that indicates a significant outbreak is occurring in a travel destination. If this is the case, pre- and post-travel advice should be modified accordingly, including potentially recommending avoiding travel to the outbreak area during pregnancy.
Prevention - Decision to travel to areas of risk
# All travellers
Health care providers should discuss with travellers what is known and what is not known about ZIKV to help their patients make an informed choice about travel and precautions. Factors to consider include:
- The low absolute risk for ZIKV infection and consequent impact on travellers. Travel health providers should keep themselves informed of any evolving risks for transmission in destination regions, as with other endemic and potentially epidemic infectious risks.
- The potential for ZIKV infection during pregnancy to have a severe impact on the fetus.
- The possibility of serious sequelae such as post-infection neurologic complications (e.g., GBS, ADEM).
- The potential for sexual transmission, which is particularly relevant to couples who are actively trying to conceive.
- The potential for co-morbidities to predispose to more serious outcomes (there is little specific evidence in this regard, though it is reasonable to expect such impacts).
- Patients' values and preferences (including risk perception and risk tolerance).
- The potential impacts of following the recommendation on a couple's reproductive plans.
# Pregnant women and women who are planning a pregnancy
CATMAT no longer routinely recommends that pregnant women and those planning a pregnancy avoid travel to areas where Zika is known or suspected to occur.
Depending on individual values and preferences, including risk tolerance, some pregnant women or those planning a pregnancy might nevertheless choose to minimize risk by not travelling to these areas.
For pregnant travellers, there are many health considerations in addition to Zika. For more information in this regard, see the CATMAT .
Prevention of mosquito-borne transmission
CATMAT recommends that all travellers to areas of risk should be advised to adhere to recommendations for the use of personal protective measures (PPM) against mosquito bites (see below). Because the mosquitoes that transmit ZIKV often bite during daylight hours, PPM should be used through all hours of the day and night. In addition to ZIKV, PPM provide protection against other vector-associated diseases such as malaria, dengue, and chikungunya. Recommendations for PPM can be found in CATMAT's .
Prevention of sexual transmission
ZIKV RNA has been detected in semen 6 or more months after symptomatic infection. However, infectious (culturable) virus appears to be much less persistent , and mostly documented only for periods shorter than a month. At this time, all reported cases of sexual transmission have occurred within 41 days after illness onset in the source male partner, and the large majority have occurred within 20 days . Sexual transmission should be prevented by abstinence from exposure to semen, and minimized by proper condom use.
# Asymptomatic traveller
CATMAT no longer recommends routine use of measures to prevent sexual transmission from asymptomatic travellers while in or after returning from areas where Zika is known or suspected to occur. This applies to all travellers, including pregnant ones. The proportion of all travellers returning from tropical and subtropical areas who have been asymptomatically infected with ZIKV is considered to be negligible. Nevertheless, depending on individual values and preferences, including risk tolerance and the potential impact of an infection (e.g., during a pregnancy), travellers might still choose to minimize risk by using condoms and/or restricting sexual activity, and this should be discussed with each patient.
# Symptomatic traveller
## Compatible symptoms
CATMAT recommends that those with symptoms compatible with ZIKV infection, and no alternate diagnosis to explain their symptoms should discuss the likelihood of ZIKV infection (which will be low in most cases) with their health care provider when making the decision on whether to apply measures to prevent sexual transmission. Diagnostic testing can be considered after discussion of the risks of both false negative and false positive results.
## Confirmed case
CATMAT recommends that those who have confirmed ZIKV infection should follow recommendations for preventing sexual transmission. Based on current information on the incubation period and duration of viremia, and the unclear duration of viral persistence in tissues, travellers who choose to apply these recommendations should do so as follows:
- Women should wait at least 2 months after their return from an affected area or onset of symptoms (whichever occurs later) before trying to conceive/having unprotected sex.
- Men should wait at least 3 months after their return from an affected area or onset of symptoms (whichever occurs later) before trying to conceive with their partner or engaging in unprotected sex. In some circumstances, for example based on risk tolerance, men might wish to delay trying to conceive for up to 6 months, which represents the outer theoretical limit of the potentially contagious period.
In the case of a confirmed or symptomatic case with compatible symptoms of ZIKV infection in the male partner, CATMAT recommends that pregnant couples should abstain from unprotected sex for the duration of the pregnancy.
# Role of laboratory testing in transmission prevention or monitoring of pregnant women
Laboratory testing for ZIKV infection is fully described below. In theory, based on information from other similar viral infections, the absence of ZIKV-specific antibodies 2 weeks or more after the last possible exposure implies that the individual has never been infected, and is not contagious to sexual partners or to the fetus. Nevertheless, there are major limitations in the usefulness of ZIKV screening tests; neither serology nor molecular testing can ever be 100% sensitive. The absence of ZIKV RNA in a semen sample might indicate absence of contagiousness at that time, but intermittent shedding is possible and there are no data to support the use of this approach to defining a risk-free sexual contact. Of more concern, the current very low prevalence of ZIKV infection means that an increase in the false positive rate is to be expected, especially for serology when preliminary testing is carried out. As well, screening enzyme-linked immunosorbent assay (ELISA)s may detect cross reacting antibodies to related flaviviruses such as dengue viruses. Furthermore, in the context of previous travel, the presence of antibody (in the absence of detectable viral RNA) may indicate a remote / previous infection. These false positive results could result in significant anxiety, unnecessary delays in conception, and potentially inappropriate decisions regarding termination of pregnancy. Currently, testing in Canada is focused on symptomatic individuals coming from potentially endemic areas, and pregnant women. It has been observed that testing of asymptomatic individuals (men or non-pregnant women) has a very low yield of true positives. In addition to the poor specificity of a positive test (especially serologic screening tests), the very low population prevalence of infection means that a negative result is of negligible predictive utility. Therefore, routine testing of asymptomatic travellers and their partners is not recommended.
Laboratory Diagnosis
Molecular testing using RT-PCR and screening serology procedures are conducted by some provincial laboratories in Canada. The National Microbiology Laboratory (NML) provides RT-PCR, IgM and IgG ELISA serological testing support to provinces and territories, along with confirmatory plaque reduction neutralization test (PRNT) diagnostics. Sensitivity and specificity of molecular tests are presumed to be high during the initial few days of illness, since ZIKV appears to circulate in the blood for several days after onset of symptoms . ZIKV RNA may be present in urine for a week or more after symptom onset , . Information about NML's guidelines and testing recommendations are available on the .
Serologic testing for Zika has become increasingly problematic for several reasons. Specificity has always been relatively low due to cross reactivity with other related flaviviruses, and positive predictive value has fallen as prevalence has decreased in recent years. At the start of the epidemic, the presence of antibodies suggested recent exposure. At the present time, however, seropositivity may often represent remote exposure. In addition, data shows that IgM also may remain positive for over 2 years, thus limiting specificity for recent infection. Sensitivity and negative predictive value remain high when serology is performed at appropriate time intervals.
At the NML, screening serology is currently performed using a US CDC based in-house IgM ELISA and a commercial IgG ELISA. Serum samples identified as being positive by one or both of the ELISAs are then tested by a confirmatory ZIKV PRNT to determine if viral specific antibodies are present . IgM antibodies appear approximately 5 to 6 days after onset of symptoms, may persist for long periods as mentioned above, but also may wane as early as 3 months after exposure, affecting sensitivity as well as specificity. IgG antibodies are usually detected a few days later, with maximal sensitivity about 2 months after infection . For the acutely unwell patient with less than 10 days of symptoms, RT-PCR should be ordered. Serology can be requested to maximize sensitivity, but poor specificity typically limits the usefulness of this test. For the convalescent patient with symptom onset over 10 days ago, only serology should be requested, although again specificity for recent infection is a problem. Serum samples collected from exposed individuals several months after returning from ZIKV endemic areas may no longer be positive for IgM antibodies, however, IgG antibodies probably persist for years. Appropriate diagnostic specimens for RT-PCR testing include plasma/serum, urine, cerebrospinal fluid (CSF), amniotic fluid and placental tissue. Serology is usually only performed on serum; however, viral antibodies may be detected in CSF in some cases of neurological disease.
As stated previously ZIKV is a member of the Flaviviridae family, and serologic tests, including the IgM ELISA, may be cross-reactive with other flaviviruses such as dengue, West Nile, and Yellow Fever (including vaccine recipients) . Confirmation of ZIKV exposures therefore depends upon the amplification of viral RNA by RT-PCR, or by confirmatory PRNT serologic testing. Confirmatory testing generally requires neutralizing IgG production, which may appear later than IgM. The specificity of the IgM or IgG ELISAs is limited particularly during secondary flavivirus infections. Patients whose serum samples are IgM positive and have ZIKV-specific antibodies confirmed through PRNT are confirmed cases of viral infection. As previously noted individuals whose serum samples are IgG positive but negative for IgM and have PRNT documented ZIKV specific antibodies were most likely exposed several months before their serum sample(s) was collected, but estimating the timing of infection is usually difficult. Despite repeat testing, serological results may remain equivocal particularly in cases where the individual was previously infected with a related flavivirus. For secondary exposures an IgM positive result usually implies that a recent flavivirus infection is likely, but it may be unclear if this infection was due to Zika virus or a related virus such as dengue. This is because individuals previously infected with or vaccinated against non-Zika flaviviruses may also exhibit cross reactivity in PRNT tests making them difficult to interpret. It is also recommended for equivocal cases that acute and convalescent sera be collected 2 - 3 weeks apart to increase the likelihood of documenting a seroconversion or a diagnostic increase (four-fold or greater) in ZIKV specific neutralizing antibodies, which suggests recent infection when detected. As discussed above, a negative serology at least 2 weeks after the last possible exposure is presumed to indicate the absence of recent infection, although the precise sensitivity of currently available tests has not been determined. If a negative serological test result is being considered in order to support the discontinuation of transmission precautions, a careful risk assessment is required and collection of a second serum sample should also be considered at a later date to definitively rule out a ZIKV exposure.
In regions where the ZIKV outbreak has been extensive, positive serology (IgM, IgG and PRNT) may increasingly represent remote, rather than recent infection. As mentioned above, the declining incidence of transmission in most areas of the world will increase the false positive rates particularly for relatively non-specific tests such as IgM. Therefore, confirmation of recent infection, especially during pregnancy and for those with exposure in the past, now rests primarily on PCR.
PCR for ZIKV can be performed on amniotic fluid (when amniocentesis is technically feasible) to confirm infection of the fetus. At this time, the risk of adverse outcomes of pregnancy if the fetus is infected with ZIKV is at least 8% of adverse outcomes , so the risk of the procedure must be weighed against the clinical utility of this test result. A negative PCR result likely means that the fetus is not currently infected, but would not eliminate the possibility of previous infection. It is not known when ZIKV RNA would be expected to appear in amniotic fluid after infection, or how long it is likely to be detectable. There is some evidence that viral RNA may persist in amniotic fluid for months .
For postnatal diagnosis of congenital infection, PCR for ZIKV can be performed on placental tissue, umbilical cord blood or infant blood, and CSF for confirmation of congenital infection. It is possible, however, that infants or fetuses infected weeks prior to specimen sampling will no longer have detectable viral RNA.
Screening and Management
# Evaluation of non-pregnant travellers returning from countries with demonstrated or potential autochthonous Zika transmission
Testing for ZIKV infection using PCR should be considered in the diagnosis of any ill traveller with compatible epidemiologic and clinical history, when symptom onset is within 3 days after arrival in, to 14 days after departing from an area of risk as identified by the WHO. Testing for other similar viral infections and for malaria should also be done as appropriate.
Given the low incidence of infection in most regions, most testing should be limited to molecular techniques, performed within approximately 10 days of the onset of symptoms. It may often be appropriate to perform molecular tests for other similar arboviral infections on the same specimen, with the understanding that sensitivity wanes for all such assays as time elapses beyond the febrile period. For the convalescent patient later than 10 days after the onset of symptoms, there is currently no accurate diagnostic test available for Zika virus. Serology is no longer routinely recommended, due to its lack of specificity for diagnosing recent infection. Paired acute and convalescent serology may be informative, but PCR on the acute specimen is faster and easier to interpret..
Serologic testing could be considered in exceptional circumstances for male returned travellers from areas of risk whose clinically compatible illness has resolved, and are at least 2 weeks post exposure, and when it is impossible or dangerous to delay attempts at conception, in order to assess for potential contagiousness to sexual partners. It is always considered safer to delay conception until the period of potential viral shedding has passed, rather than depend on serologic testing. The high probability of false positive results must be considered and discussed with the patient, prior to testing.
Serological testing of male individuals with a history of travel to an area of risk, but no history of related symptoms is not recommended, given the extremely low risk of infection and high risk of false positive serology.
A negative test result for a symptomatic or asymptomatic patient, whether from an initial or follow-up serology (e.g., if the first test is equivocal) obtained over 2 weeks post potential exposure indicates that a recent ZIKV infection is very unlikely. However, the risk of false positive results, the time required for confirmatory serologic testing, and the relatively short period during which transmission prevention measures might be required all combine to limit the usefulness of such testing . The decision to test should be made in consultation with a health care provider, and should be set against the broader context of the likelihood of infection and patient values and preferences. Testing would only be appropriate when transmission prevention measures are planned during the testing period, which may take several weeks.
The potential for viremia or transmission following a second exposure is unknown. Given that neurologic disorders like GBS have occurred following ZIKV infection, returning travellers should be counselled to report any neurologic symptoms to their doctor. In the event of the diagnosis of GBS or other unusual neurologic syndrome, a travel history for the patient and any male sexual partners should be elicited. If ZIKV infection is thought to be potentially associated with the illness, a specialist should be consulted.
Evaluation in the context of pregnancy
# Evaluation of pregnant women with a travel history to an area of risk
Health care providers should take a travel history from their pregnant patients including relevant information related to the travel history of their partner(s). Any patient who indicates that they or their partner have recently travelled to areas of transmission should be further evaluated.
Screening of asymptomatic pregnant women with possible exposure during pregnancy or during the peri-conception period should be discussed on a case-by-case basis between the woman and her health care provider. The declining incidence of Zika transmission in most areas of the world means that infection rates in this population will be extremely low, and significantly lower than in a population with symptoms compatible with infection. The risk of false positive laboratory results, particularly for serology, would be correspondingly elevated in an asymptomatic population. False positive diagnoses would have important implications for adverse events related to unwarranted additional testing and anxiety, as well as resource utilization. The decision whether to screen should take into account intensity of the potential exposure, the use of prevention measures, the likelihood of remote infection, and the transmission trends at the location of potential exposure. In most cases, screening is NOT recommended. Exceptions could be considered when the risk of exposure is particularly high, and the psychological benefit of a negative result clearly outweighs the harms which could arise from a false positive result. Screening would be done as for the symptomatic pregnancy patient, see below. The decision to test should include consideration of how the results of the screening tests would be used to inform subsequent decisions. The likelihood of false negative, and especially false positive results in the absence of a recent infection always require careful discussion with the patient. Diagnosis and identification of poor fetal outcomes will allow for appropriate counselling.
Pregnant women and their partners may be justifiably concerned about the risk of ZIKV infection to their fetus and may want to receive counselling to decide the best course of action, including the question of termination. The risk of vertical infection (with clinical sequelae) in the setting of symptomatic or asymptomatic maternal infection appears highest in the first trimester . However severe sequelae have been reported after infection at all stages of pregnancy . This uncertainty makes pregnancy counselling a difficult prospect. Regardless, discussion and informed decision making regarding options for management of ZIKV infection in pregnancy (much like any other congenital infection or congenital anomaly) requires thorough consultation with a Maternal Fetal Medicine Specialist or another specialist familiar with reproductive infectious diseases.
# Evaluation of pregnant women with symptoms compatible with ZIKV infection
Testing should be offered to pregnant women with acute signs and symptoms compatible with ZIKV. Given the reports of longer periods of viremia in some pregnant women, for the patient with symptoms during the preceding 12 weeks, RT-PCR (on blood and urine) is the preferred testing modality. Serology is not recommended for routine testing and should only be requested very judiciously as it is not appropriate in most cases. A negative result has a high negative predictive value and serology at least 2 weeks after the last potential exposure provides reassurance if negative. However, the poor specificity must be clearly discussed and appreciated by the patient, and a clear and logical approach to a positive result should be established before ordering the test. The potential reassurance of a negative test must be weighed against the potentially important harms and likelihood of a false positive. Given the current epidemiology, it is reasonable to assume that for most women, a positive serology will NOT indicate exposure during the pregnancy. Exceptions would include the investigation of suspected congenital Zika syndrome. For the convalescent patient with symptom onset over 12 weeks ago, RT\_PCR will be of minimal value. Prolonged fever may be associated with persistent viremia and PCR testing is indicated in the investigation of these cases. Repeated ultrasound monitoring is indicated, unless the woman is found to be negative on appropriate laboratory testing, including negative serology at least 2 weeks after the last possible exposure. A woman whose fetus is suspected of having a congenital anomaly should also be offered testing if she or her partner has travelled to any location where ZIKV transmission may be occurring even at a low level.
Although measurements of head circumference and biparietal diameter may occur as early as 15 weeks, there is no defined gestational age by which microcephaly and other intracranial abnormalities can be ruled out. Serial monitoring by ultrasound with close attention to measurement trends over time is recommended. It is possible that changes in intracranial anatomy may not be elucidated until well into the third trimester, or later.
Counselling recommendations are as in the section on the asymptomatic woman, above.
# Evaluation of the fetus among pregnant women diagnosed with ZIKV infection
Serial ultrasounds (every 3 - 4 weeks) are recommended in pregnant women with confirmed or suspected (if testing results are pending or equivocal) ZIKV infection in pregnancy. Should CNS calcifications or fetal microcephaly be noted at ultrasonography of an asymptomatic pregnant returned traveller, then specific ZIKV testing of the fetus (e.g., amniocentesis), in addition to other investigations to elucidate alternate aetiologies, should be considered to help define the likely cause of the anomaly.
# Evaluation of the infant born to a woman diagnosed with ZIKV infection or with suspected congenital ZIKV infection or CZS
Infants born to women with confirmed or suspected ZIKV infection in pregnancy, or those with unexplained microcephaly, intracranial calcifications, ventriculomegaly or major structural central nervous system abnormalities or other symptoms of congenital ZIKV infection in whom the mother had potential exposure to the virus, should be tested. This testing should include serology, PCR of serum (umbilical cord or infant sample), and PCR of placenta; if CSF is sampled, this can also be sent for PCR and serology. Management is evolving and infants with suspected or confirmed CZS should also undergo further work-up including: routine lab tests (CBC and liver enzymes), head ultrasound, ophthalmologic examination, and hearing evaluation as outlined in current guidelines by the Canadian Paediatric Society (CPS) . Care should be taken to ensure a thorough work up for other important and treatable causes of congenital infections, such as cytomegalovirus and *Toxoplasma*. Infants with confirmed CZS should have neurodevelopmental monitoring throughout infancy to assess the potential for long-term sequelae.
Infants born to women with symptoms of active ZIKV infection around the time of delivery are at risk for perinatal transmission of the disease. In the limited number of reported cases to date, perinatally infected infants have exhibited either no or mild symptoms and laboratory findings (rash, thrombocytopenia) . Regardless, such infants should be monitored closely given the unclear spectrum of potential illness in this emerging infection. Testing with serology and serum PCR during acute illness is recommended. Long term follow-up with a pediatric infectious disease specialist is suggested.
Treatment
Currently there is no specific therapy for the treatment of ZIKV infection. Treatment is supportive with antipyretics (acetaminophen in pregnancy), hydration and rest. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided until dengue can be ruled out to reduce the risk of hemorrhage . Symptomatic disease typically lasts for up to 7 days. Urgent medical care is recommended for any symptoms associated with GBS, and treating health care providers should be made aware of recent travel to area with ZIKV circulation and/or symptoms of ZIKV infection.
If ZIKV infection is confirmed in the setting of pregnancy, referral to a Maternal Fetal Medicine Specialist or specialist familiar with Reproductive Infectious Diseases should be made. If microcephaly, intracranial calcifications or other abnormalities are identified, appropriate counselling by a Neonatologist and Pediatric Infectious Diseases Specialist on potential neurodevelopmental outcome should be offered to parents.
Summary of Recommendations for ZIKV
Discussion should occur around decision to travel, based on individual values and preferences, including risk of ZIKV infection. Some pregnant women or those planning a pregnancy may choose to minimize risk by:- not travelling to these areas or
- postponing travel until after pregnancy or
- postponing pregnancy until after travel.
If ZIKV infection is confirmed, CATMAT recommends:- women wait at least 2 months after their return from these areas or onset of symptoms (whichever occurs later) before trying to conceive and/or having unprotected sex;
- male partners wait at least 3 months after their return from these areas or onset of symptoms (whichever occurs later) before trying to conceive and/or having unprotected sex.
In the case of a confirmed or clinically compatible ZIKV infection in the male partner, couples planning a pregnancy might wish to delay conception for up to 6 months, depending on personal risk tolerance. The 6 months represents the outer theoretical limit of the potentially contagious period for a male partner.
As designated by the WHO |
Zika Virus Prevention and Treatment Recommendations
====================================================
**An Advisory Committee Statement (ACS)
Committee to Advise on Tropical Medicine and Travel (CATMAT)**
Table of contents
-----------------
* [Key Points](#s1)
* [Preamble](#s2)
* [Summary](#s3)
* [Introduction](#s4)
* [Methods](#s5)
* [Epidemiology](#s6)
+ [Transmission](#s6.1)
+ [Clinical Manifestations](#s6.2)
* [Risk to travellers](#s7)
+ [Areas of risk](#s7.1)
* [Prevention - Decision to travel to areas of risk](#s8)
+ [All travellers](#s8.1)
+ [Pregnant women and women who are planning a pregnancy](#s8.2)
* [Prevention of mosquito-borne transmission](#s9)
* [Prevention of sexual transmission](#s10)
+ [Role of laboratory testing in transmission prevention or monitoring of pregnant women](#s10.1)
* [Laboratory Diagnosis](#s11)
* [Screening and Management](#s12)
+ [Evaluation of non-pregnant travellers returning from countries with demonstrated or potential autochthonous Zika transmission](#s12.1)
* [Evaluation in the context of pregnancy](#s13)
+ [Evaluation of pregnant women with a travel history to an area of risk](#s13.1)
+ [Evaluation of pregnant women with symptoms compatible with ZIKV infection](#s13.2)
+ [Evaluation of the fetus among pregnant women diagnosed with ZIKV infection](#s13.3)
+ [Evaluation of the infant born to a woman diagnosed with ZIKV infection or with suspected congenital ZIKV infection or CZS](#s13.4)
* [Treatment](#s14)
* [Summary of Recommendations for ZIKV](#s15)
+ [Table 1a - Recommendations for Prevention of ZIKV](#table1a)
+ [Table 1b - Recommendations for Screening and Management of ZIKV](#table1b)
+ [Table 1c - Recommendations for Treatment of ZIKV](#table1c)
* [Additional resources and useful links](#s16)
* [Acknowledgements](#s17)
* [Conflict of Interest](#s18)
* [References](#s19)
Key Points
----------
* There has been a substantial reduction in the risk of Zika virus (ZIKV) infection among Canadian travellers. Accordingly, CATMAT **no longer routinely recommends** that pregnant travellers avoid travel to areas where Zika is known or suspected to occur, or that special precautions to prevent sexual transmission while abroad or upon return are necessary.
+ Some travellers, for example based on their values and preferences, might choose to follow recommendations for prevention of sexual or vertical (mother to fetus) transmission of ZIKV because Zika continues to present a low risk in many tropical and subtropical areas.
* Given the low risk of ZIKV infection, CATMAT **recommends against** routine testing of asymptomatic pregnant women. The poor positive predictive value, especially for screening serology tests, means a positive test has a high likelihood of being a false positive, which may have significant adverse consequences. The low population prevalence of infection means a negative test result is of negligible clinical utility.
* In a situation where testing is completed and ZIKV is **confirmed** CATMAT **recommends**:
+ women should wait at least **2 months** after their return from a risk area or onset of symptoms (whichever occurs later) before trying to conceive/having unprotected sex.
+ men should wait at least **3 months** after their return from a risk area or onset of symptoms (whichever occurs later) before trying to conceive with their partner or engaging in unprotected sex.
* In the case of a confirmed or symptomatic case with compatible symptoms of ZIKV infection in the male partner, CATMAT **recommends** that pregnant couples abstain from unprotected sex for the duration of the pregnancy.
* Travellers and health care providers should remain vigilant for emergent information related to ZIKV outbreaks. Should a significantly increased risk of ZIKV transmission be identified in a specific travel destination, pre- and post-travel advice should be modified accordingly. This would include consideration of avoiding travel to the outbreak area during pregnancy.
* Travel during pregnancy typically poses multiple health risks. The risk of ZIKV infection should be included in a broader discussion about infectious diseases and other potential complications when considering travel while pregnant.
Preamble
--------
The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. The Agency acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.
Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.
Summary
-------
There has been a substantial decrease in reported rates of Zika virus (ZIKV) related disease in countries (primarily in the Americas) that suffered from the outbreak that started in 2015 and a corresponding decline (>90%) in reports of ZIKV infection among travellers visiting these countries. Accordingly, CATMAT **no longer routinely recommends** that: pregnant travellers avoid travel to areas where Zika is known or suspected to occur, or that special precautions to prevent sexual transmission while abroad or upon return are necessary. Rather, CATMAT suggests that precautions for preventing ZIKV transmission be considered within the general context of the infectious and non-infectious risks travel may pose to a pregnant woman.
Introduction
------------
Zika virus (ZIKV) infection is caused by a flavivirus transmitted through the bite of an infected Aedes mosquito, mainly *Aedes aegypti*. Although infections in humans have been known to occur for some time, ZIKV emerged on the global stage when it caused major outbreaks in many tropical and subtropical areas of the world, especially in the Americas [Footnote 1](#fn1),[Footnote 2](#fn2). During these outbreaks, a previously unrecognized pattern of Zika-related adverse outcomes emerged. Pre-eminent among these were complications of pregnancy including major congenital anomalies. First identified through spatial and temporal clustering of ZIKV activity with an increased incidence of congenital microcephaly [Footnote 3](#fn3) - [Footnote 5](#fn5) is now known that these can be manifest as a constellation of fetal developmental problems that are collectively referred to as a congenital Zika syndrome (CZS)[Footnote 6](#fn6) - [Footnote 10](#fn10)The risk of CZS is substantial if infected while pregnant. For example, of 972 completed pregnancies enrolled in the US Zika Pregnancy Registry, 5% showed evidence of CZS (95% CI = 4%-7%). The greatest impact was observed when infection occurred during the first trimester (15% with CZS) [Footnote 11](#fn11). Similar results have been described for: affected US Territories, with a CZS rate of 5% among completed affected pregnancies [Footnote 12](#fn12) and for French territories in the Americas where 7% (39/555) of fetuses and infants were identified as having suffered defects possibly associated with ZIKV infection. In this last study, effects were more common if infection occurred during the first trimester, but were also seen if infection occurred in the second (3.6%) or third (5.3%) trimesters [Footnote 7](#fn7). Recently, data have been described for Zika associated harms before and after birth in a population of children born to infected mothers in US territories and freely associated states [Footnote 13](#fn13). From a population of 1,450 children with follow-up care, 6% suffered from a Zika-associated birth defect(s), 9% had a neurodevelopmental abnormality(ies) possibly associated with congenital infection, and 1% had both.
Although disease is usually relatively benign in adults, ZIKV infection can cause neurologic sequelae such as Guillain-Barré syndrome (GBS) [Footnote 4](#fn4), [Footnote 8](#fn8), [Footnote 14](#fn14). A case control study done in French Polynesia estimated a 0.24 in 1,000 risk for developing GBS in persons infected with ZIKV. This is comparable to the GBS risk of 0.25 to 0.65/1,000 observed following Campylobacter jejuni infection. There are also reports of acute disseminated encephalomyelitis (ADEM) following ZIKV infection [Footnote 9](#fn9).
Complicating the picture for ZIKV epidemiology and prevention, the virus can be transmitted sexually, with most reported cases being from an infected male to a female, although female to male and male to male transmission have also been reported [Footnote 15](#fn15). The risk of such transmission remains difficult to quantify, though a significant proportion of symptomatic men shed viral RNA in their semen. For example, 22/36 (61%) of men in a US-based study had detectable viral RNA in their semen when tested within 30 days of illness onset [Footnote 10](#fn10). This dropped to < 10% at 3 - 4 months after illness, and approximately 1% at 5-6 months after illness. Importantly, recovery of infectious ZIKV was rarer, occurring in 3/78 (4%) samples with all positives being obtained within 30 days of illness onset [Footnote 10](#fn10), though the possibility of false negatives in this cohort cannot be ruled out. Complementing these observations, the median serial interval between onset of symptoms in couples where sexual transmission occurred was 12 days (interquartile range: 10-14.5 days) [Footnote 15](#fn15). Overall, these data suggest that the period during which sexual transmission (from a male) is likely to occur is much shorter than the period (often 6 months) for which sexual precautions had been previously recommended.
The purposes of this statement are to review current knowledge related to ZIKV infection and to provide guidelines for health care providers on prevention and management of ZIKV disease.
Methods
-------
This statement was developed by a working group of the Committee to Advise on Tropical Medicine and Travel (CATMAT). Members of the working group were from CATMAT, the Public Health Agency of Canada (the Agency) and the Society of Obstetricians and Gynaecologists of Canada. Each member was a volunteer, and none declared a relevant conflict of interest. The working group was responsible for assessing available literature, synthesis and analysis of the evidence, drafting recommendations, and writing. Secretariat support was provided throughout the process by the Public Health Agency of Canada. The final statement was approved by the full CATMAT committee.
This guideline complements existing CATMAT statements including the [Statement on Personal Protective Measures to Prevent Arthropod bites](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2012-38/statement-on-personal-protective-measures-prevent-arthropod-bites.html) [Footnote 16](#fn16) and [the Statement on Pregnancy and Travel](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2010-36/canada-communicable-disease-report-7.html) [Footnote 17](#fn17).
This document is an update to the CATMAT Zika statement published in February 2018. The most important changes are related to: the overall reduction in ZIKV transmission in many areas previously affected by the outbreak, the consequent significant reduction in risk for travellers (see Table 1); and, the availability of a systematic review related to sexual transmission [Footnote 15](#fn15).
Epidemiology
------------
ZIKV was first isolated from monkeys in Uganda in 1947. Soon after, in 1952, human infections were detected in Uganda and Tanzania [Footnote 18](#fn18),[Footnote 19](#fn19). However, human infections were rarely reported until 2007, when a large outbreak of ZIKV disease occurred on the island of Yap (Micronesia) [Footnote 20](#fn20). Between 2013 and 2015, additional outbreaks occurred on islands and archipelagos in the Pacific region [Footnote 21](#fn21) - [Footnote 23](#fn23). In 2014, local transmission in the Americas was reported on Easter Island [Footnote 24](#fn24). Subsequently, ZIKV caused a large outbreak in the Americas [Footnote 25](#fn25) as well as in other countries/regions. Since the outbreak peaked in 2016, the number of locally acquired reported cases in the majority of affected countries has decreased substantially [Footnote 26](#fn26),[Footnote 27](#fn27), as has the number of travel-associated cases reported in Canada and the United States [Footnote 28](#fn28),[Footnote 29](#fn29). For example, in the first 11 months of 2018, only 58 cases of travel-associated ZIKV infection had been reported in the continental United States [Footnote 30](#fn30), compared to almost 5,000 cases during the entirety of 2016 and 437 in 2017 [Footnote 29](#fn29). Similar decreases in travel-associated infections have been observed in Canada, with the number of cases reported dropping from 468 in 2016 to 74 in 2017, and then to 21 in 2018 and without a concomitant decrease in testing.
### Transmission
The mosquitoes associated with ZIKV tend to be more active during the day but can bite at night, with peak activity often occurring in the morning and later in the afternoon. In vertebrate hosts, the incubation period is usually 3 - 14 days [Footnote 31](#fn31), with blood viremia (the period when ZIKV is present in the blood) usually lasting for about 2 weeks [Footnote 32](#fn32) - [Footnote 35](#fn35), but with the possibility of longer periods of viral detection in blood and other body fluids [Footnote 36](#fn36). Vertical transmission between mother and developing fetus presumably occurs during the viremic period [Footnote 37](#fn37),[Footnote 38](#fn38). Other described routes of transmission include blood product transfusion [Footnote 39](#fn39) and sexual transmission after symptomatic infection [Footnote 40](#fn40) - [Footnote 43](#fn43). There is a report of sexual transmission from a symptomatic infected woman to a sexual partner [Footnote 15](#fn15),[Footnote 44](#fn44) and another report of sexual transmission from an asymptomatically infected male to their partner [Footnote 15](#fn15),[Footnote 45](#fn45).
Viral RNA has been detected in various biological fluids for prolonged periods, but isolation of infectious virus has only been documented at substantially lower rates and for shorter time intervals. Viral RNA has been detected in urine up to 6 weeks after illness onset; however, the median time until the loss of viral genome detection was determined to be 8 days [Footnote 35](#fn35). For individuals with detectable viral RNA in their serum the median time for loss of detection was 14 days, a small percentage of patients were reverse transcriptase polymerase chain reaction (RT-PCR) positive for more than a month [Footnote 34](#fn34). In particular, pregnant women carrying congenitally-infected fetuses may be symptomatically viremic for a prolonged period, thus, Zika should be considered in pregnant women with compatible exposure history and extended duration of fever, despite the typically short viremic phase of flaviviruses, in general [Footnote 46](#fn46),[Footnote 47](#fn47).
Based on a cohort of symptomatic men followed in the US, a significant proportion (61%) had detectable viral RNA in their semen in the first month after illness onset [Footnote 10](#fn10). This decreases to 1% or less by 6 months after symptom onset. Duration of shedding increased modestly with increasing age, and with certain symptoms. Interestingly, persistence of RNA in semen was most strongly and inversely associated with frequency of ejaculation. For example, men who reported ejaculating 4 times per week were estimated to clear RNA 3 weeks earlier than men who reported ejaculating once per week. This raises the possibility of a modifiable risk factor for prolonged shedding. In this same study, infectious virus was isolated from 3/19 (16%) samples obtained within 30 days after illness onset but in none of the 59 samples that were obtained later. The 3 men in which infectious virus was isolated had relatively high (>7.0 log10) ZIKV RNA copies per milliliter of semen in their first sample which declined in subsequent samples to 5.8 (log10 copies/ml of semen), 3.1 (log10 copies/ml of semen), and undetectable, respectively. These follow-up samples were obtained at 38, 59 and 76 days following illness onset and infectious ZIKV was not detected in the two men who still had detectable ZIKV RNA [Footnote 10](#fn10). Nevertheless, it remains theoretically possible that some of the PCR positive but culture negative cases were contagious. To date the longest period after symptom onset at which replication-competent virus has been detected in semen was 69 days; this was reported in a single case report of a vasectomized man [Footnote 48](#fn48). ZIKV RNA has also been detected at lower concentrations in men who have undergone vasectomy, but at rates similar to men who have not had this procedure. Although not studied extensively, the persistent shedding of ZIKA RNA in semen is considered to be similar amongst infected symptomatic and asymptomatic men based on case reports of sexual transmission and on data from asymptomatic blood donors [Footnote 45](#fn45), [Footnote 49](#fn49), [Footnote 50](#fn50).
Neutralizing antibodies for ZIKV are detectable after infection, and by extrapolation from other flaviviruses that induce a humoral antibody response, post-infection immunity is presumed to be lifelong [Footnote 51](#fn51). Among couples where such data is available (n=15) the median time between onset of sexual partners' symptoms (serial interval) was 12 days (interquartile range: 10±14.5 days) while the maximum was 44 days [Footnote 15](#fn15). Based on RT-PCR data, the median duration of ZIKV positivity was 13.9 days (95% CI: 7.2-19.6) for any fluid in the female genital tract, with a maximum of 37 days. There were too few data available for analysis of viral culture specimens in female genital tract fluids [Footnote 15](#fn15).ZIKV RNA has been detected in breast milk; however, there have not been any unequivocally documented reports of transmission to infants through breastfeeding [Footnote 41](#fn41). At this time, the World Health Organization (WHO) considers that "the benefits of breastfeeding for the infant and mother outweigh any potential risk of Zika virus transmission through breast milk" [Footnote 52](#fn52). Until further evidence is available regarding transmission through breast milk, CATMAT suggests that potential benefits and harms of breastfeeding during acute ZIKV infection should be discussed with each patient and decisions be made on an individual basis.
### Clinical Manifestations
Approximately 20-25% (possibly as high as 50%) [Footnote 53](#fn53) of persons infected with ZIKV will manifest symptoms, including fever, myalgia, pruritis, eye pain, and maculopapular rash [Footnote 20](#fn20), [Footnote 54](#fn54), [Footnote 55](#fn55).
Early clinical manifestations are similar to other arboviral infections including dengue and chikungunya [Footnote 54](#fn54),[Footnote 56](#fn56). Thus, the differential diagnosis of a febrile returned traveller will likely include these arboviral infections, other viral illnesses [Footnote 57](#fn57),[Footnote 58](#fn58), as well as [malaria](http://www.publications.gc.ca/site/eng/463465/publication.html) [Footnote 59](#fn59).
Post-infectious neurologic complications, such as GBS, have been reported from many countries that were affected by the outbreak [Footnote 8](#fn8), [Footnote 33](#fn33), [Footnote 60](#fn60), [Footnote 61](#fn61). They include French Polynesia where a case-control study estimated that the odds of positive ZIKV serology was substantially greater in GBS cases compared to matched controls (OR 59.7; 95% CI 10.4 to ∞) [Footnote 62](#fn62). In the same study, and based on a ZIKV population seroprevalence of 0.66, the risk of GBS following ZIKV infection was estimated at approximately 0.25/ 1000. Other neurological manifestations have also been reported in association with ZIKV infection, e.g., acute myelitis, meningoencephalitis, acute disseminated encephalomyelitis, and reverse sensory polyneuropathy [Footnote 9](#fn9), [Footnote 51](#fn51), [Footnote 63](#fn63), [Footnote 64](#fn64) suggesting that the neurological spectrum of sequelae associated with ZIKV is relatively broad.
Clinically relevant thrombocytopenia and subcutaneous hematomas have been reported in a small number of cases [Footnote 65](#fn65),[Footnote 66](#fn66). Deaths from other causes have also been reported [Footnote 67](#fn67),[Footnote 68](#fn68).
Over 30 countries [Footnote 4](#fn4) have reported CZS [Footnote 69](#fn69). Common manifestations include microcephaly, cerebral atrophy, abnormal cortical development, callosal hypoplasia, and diffuse subcortical calcifications [Footnote 70](#fn70),[Footnote 71](#fn71). Ocular abnormalities and other congenital malformations such as arthrogryposis and hydrops fetalis have also been described [Footnote 72](#fn72) - [Footnote 74](#fn74).
Reviews of the epidemiology of ZIKV, as well as the causal association of ZIKV and microcephaly have been published [Footnote 75](#fn75).
Risk to travellers
------------------
There are multiple lines of evidence to indicate that the risk of ZIKV infection for travellers has decreased significantly. First, the number of cases reported in the epidemic regions of the Americas has decreased [Footnote 26](#fn26),[Footnote 27](#fn27). For US territories specifically, more than 36,000 cases (presumed to be locally acquired) were reported in 2016, compared to 652 (98% decrease) cases reported in 2017 [Footnote 29](#fn29) and 116 cases reported (as of December 4) in 2018 (> 99% decrease) [Footnote 15](#fn15),[Footnote 30](#fn30). Second, the number of travel-related cases reported in Canada and the United States has decreased by approximately two orders of magnitude since 2016. In Canada, the overall decrease from 2016 to 2018 has been > 95% (468 cases in 2016 to 21 cases in 2018). A similar decrease has also occurred in the continental United States [Footnote 29](#fn29) where 4,897 cases (travel-related) were reported in 2016, 437 in 2017 (91% reduction) and 34 cases reported (as of August 1) in 2018 (> 99% decrease); and, in the European Union where 2,121 cases were reported in 2016 and 198 cases (93% reduction) were reported in 2017 [Footnote 76](#fn76).
Set against the total travel volumes to countries affected by the outbreak, which exceeds 7 million annually for Canadians [Footnote 77](#fn77), the estimated risk of a traveller being confirmed with a ZIKV infection is currently very low, e.g., < 1 case/200,000 trips (14 cases in 2018, adjusted for surveillance period). While this is an underestimate of the true risk of infection, (the majority of infections are likely not reported), it nevertheless supports that ZIKV-infection among Canadian travellers has become a rare event. Accordingly, adverse outcomes associated with ZIKV-infection must be rare events in absolute terms, even with significant under-reporting. Indeed, from October 2015 - December 2018, a total of 4 sexually transmitted cases have been reported in Canada [Footnote 28](#fn28). During the same time period, 47 cases have been reported among pregnant women in Canada [Footnote 28](#fn28). From March 2017 to December 2018, CZS had been reported in ≤ 5 infants in Canada [Footnote 78](#fn78).
### Areas of risk
Transmission of ZIKV can occur in most areas of the world where *Aedes aegypti*, the principal vector, occurs. This means that there is the potential for transmission through much of the tropical and subtropical world and beyond. As described above, the risk of transmission to travellers is considered low.
Previously, CATMAT recommendations were linked to the WHO country classification scheme for ZIKV to determine areas of risk or potential risk[Footnote 79](#fn79). In July 2019, the WHO implemented a new approach for categorizing countries according to the presence or absence of current and historical reported ZIKV transmission[Footnote 80](#fn80). It should be noted that monitoring and reporting in some areas is suboptimal, and that this approach provides only an approximation of the areas of risk. Due to a general absence of laboratory and surveillance data from many countries/territories, it provides a conservative risk assessment (i.e. includes countries/territories where cases have been reported but also includes countries where there is a known historical risk but cases are not currently being reported).
Notwithstanding the above, travellers and health care providers should remain vigilant for emergent information related to ZIKV that might influence decision-making, for example evidence that indicates a significant outbreak is occurring in a travel destination. If this is the case, pre- and post-travel advice should be modified accordingly, including potentially recommending avoiding travel to the outbreak area during pregnancy.
Prevention - Decision to travel to areas of risk
------------------------------------------------
### All travellers
Health care providers should discuss with travellers what is known and what is not known about ZIKV to help their patients make an informed choice about travel and precautions. Factors to consider include:
* The low absolute risk for ZIKV infection and consequent impact on travellers. Travel health providers should keep themselves informed of any evolving risks for transmission in destination regions, as with other endemic and potentially epidemic infectious risks.
* The potential for ZIKV infection during pregnancy to have a severe impact on the fetus.
* The possibility of serious sequelae such as post-infection neurologic complications (e.g., GBS, ADEM).
* The potential for sexual transmission, which is particularly relevant to couples who are actively trying to conceive.
* The potential for co-morbidities to predispose to more serious outcomes (there is little specific evidence in this regard, though it is reasonable to expect such impacts).
* Patients' values and preferences (including risk perception and risk tolerance).
* The potential impacts of following the recommendation on a couple's reproductive plans.
### Pregnant women and women who are planning a pregnancy
CATMAT **no longer routinely recommends** that pregnant women and those planning a pregnancy avoid travel to areas where Zika is known or suspected to occur.
Depending on individual values and preferences, including risk tolerance, some pregnant women or those planning a pregnancy might nevertheless choose to minimize risk by not travelling to these areas.
For pregnant travellers, there are many health considerations in addition to Zika. For more information in this regard, see the CATMAT [Statement on Pregnancy and Travel](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2010-36/canada-communicable-disease-report-7.html) [Footnote 17](#fn17).
Prevention of mosquito-borne transmission
-----------------------------------------
CATMAT **recommends** that all travellers to areas of risk should be advised to adhere to recommendations for the use of personal protective measures (PPM) against mosquito bites (see below). Because the mosquitoes that transmit ZIKV often bite during daylight hours, PPM should be used through all hours of the day and night. In addition to ZIKV, PPM provide protection against other vector-associated diseases such as malaria, dengue, and chikungunya. Recommendations for PPM can be found in CATMAT's [Statement on Personal Protective Measures to Prevent Arthropod Bites](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2012-38/statement-on-personal-protective-measures-prevent-arthropod-bites.html) [Footnote 16](#fn16).
Prevention of sexual transmission
---------------------------------
ZIKV RNA has been detected in semen 6 or more months after symptomatic infection. However, infectious (culturable) virus appears to be much less persistent [Footnote 10](#fn10), and mostly documented only for periods shorter than a month. At this time, all reported cases of sexual transmission have occurred within 41 days after illness onset in the source male partner, and the large majority have occurred within 20 days [Footnote 10](#fn10). Sexual transmission should be prevented by abstinence from exposure to semen, and minimized by proper condom use.
### Asymptomatic traveller
CATMAT **no longer recommends** routine use of measures to prevent sexual transmission from asymptomatic travellers while in or after returning from areas where Zika is known or suspected to occur. This applies to all travellers, including pregnant ones. The proportion of all travellers returning from tropical and subtropical areas who have been asymptomatically infected with ZIKV is considered to be negligible. Nevertheless, depending on individual values and preferences, including risk tolerance and the potential impact of an infection (e.g., during a pregnancy), travellers might still choose to minimize risk by using condoms and/or restricting sexual activity, and this should be discussed with each patient.
### Symptomatic traveller
#### Compatible symptoms
CATMAT **recommends** that those with symptoms compatible with ZIKV infection, and no alternate diagnosis to explain their symptoms should discuss the likelihood of ZIKV infection (which will be low in most cases) with their health care provider when making the decision on whether to apply measures to prevent sexual transmission. Diagnostic testing can be considered after discussion of the risks of both false negative and false positive results.
#### Confirmed case
CATMAT **recommends** that those who have confirmed ZIKV infection should follow recommendations for preventing sexual transmission. Based on current information on the incubation period and duration of viremia, and the unclear duration of viral persistence in tissues, travellers who choose to apply these recommendations should do so as follows:
* Women should wait at least **2 months** after their return from an affected area or onset of symptoms (whichever occurs later) before trying to conceive/having unprotected sex.
* Men should wait at least **3 months** after their return from an affected area or onset of symptoms (whichever occurs later) before trying to conceive with their partner or engaging in unprotected sex. In some circumstances, for example based on risk tolerance, men might wish to delay trying to conceive for up to 6 months, which represents the outer theoretical limit of the potentially contagious period.
In the case of a confirmed or symptomatic case with compatible symptoms of ZIKV infection in the male partner, CATMAT **recommends** that pregnant couples should abstain from unprotected sex for the duration of the pregnancy.
### Role of laboratory testing in transmission prevention or monitoring of pregnant women
Laboratory testing for ZIKV infection is fully described below. In theory, based on information from other similar viral infections, the absence of ZIKV-specific antibodies 2 weeks or more after the last possible exposure implies that the individual has never been infected, and is not contagious to sexual partners or to the fetus. Nevertheless, there are major limitations in the usefulness of ZIKV screening tests; neither serology nor molecular testing can ever be 100% sensitive. The absence of ZIKV RNA in a semen sample might indicate absence of contagiousness at that time, but intermittent shedding is possible and there are no data to support the use of this approach to defining a risk-free sexual contact. Of more concern, the current very low prevalence of ZIKV infection means that an increase in the false positive rate is to be expected, especially for serology when preliminary testing is carried out. As well, screening enzyme-linked immunosorbent assay (ELISA)s may detect cross reacting antibodies to related flaviviruses such as dengue viruses. Furthermore, in the context of previous travel, the presence of antibody (in the absence of detectable viral RNA) may indicate a remote / previous infection. These false positive results could result in significant anxiety, unnecessary delays in conception, and potentially inappropriate decisions regarding termination of pregnancy. Currently, testing in Canada is focused on symptomatic individuals coming from potentially endemic areas, and pregnant women. It has been observed that testing of asymptomatic individuals (men or non-pregnant women) has a very low yield of true positives. In addition to the poor specificity of a positive test (especially serologic screening tests), the very low population prevalence of infection means that a negative result is of negligible predictive utility. Therefore, routine testing of asymptomatic travellers and their partners is not recommended.
Laboratory Diagnosis
--------------------
Molecular testing using RT-PCR and screening serology procedures are conducted by some provincial laboratories in Canada. The National Microbiology Laboratory (NML) provides RT-PCR, IgM and IgG ELISA serological testing support to provinces and territories, along with confirmatory plaque reduction neutralization test (PRNT) diagnostics. Sensitivity and specificity of molecular tests are presumed to be high during the initial few days of illness, since ZIKV appears to circulate in the blood for several days after onset of symptoms [Footnote 81](#fn81). ZIKV RNA may be present in urine for a week or more after symptom onset [Footnote 81](#fn81), [Footnote 82](#fn82). Information about NML's guidelines and testing recommendations are available on the [For health professionals: Zika virus webpage](/en/public-health/services/diseases/zika-virus/health-professionals.html)[Footnote 83](#fn83).
Serologic testing for Zika has become increasingly problematic for several reasons. Specificity has always been relatively low due to cross reactivity with other related flaviviruses, and positive predictive value has fallen as prevalence has decreased in recent years. At the start of the epidemic, the presence of antibodies suggested recent exposure. At the present time, however, seropositivity may often represent remote exposure. In addition, data shows that IgM also may remain positive for over 2 years, thus limiting specificity for recent infection[Footnote 84](#fn84). Sensitivity and negative predictive value remain high when serology is performed at appropriate time intervals.
At the NML, screening serology is currently performed using a US CDC based in-house IgM ELISA and a commercial IgG ELISA. Serum samples identified as being positive by one or both of the ELISAs are then tested by a confirmatory ZIKV PRNT to determine if viral specific antibodies are present [Footnote 25](#fn25). IgM antibodies appear approximately 5 to 6 days after onset of symptoms, may persist for long periods as mentioned above, but also may wane as early as 3 months after exposure, affecting sensitivity as well as specificity[Footnote 85](#fn85). IgG antibodies are usually detected a few days later, with maximal sensitivity about 2 months after infection [Footnote 33](#fn33). For the acutely unwell patient with less than 10 days of symptoms, RT-PCR should be ordered. Serology can be requested to maximize sensitivity, but poor specificity typically limits the usefulness of this test. For the convalescent patient with symptom onset over 10 days ago, only serology should be requested, although again specificity for recent infection is a problem. Serum samples collected from exposed individuals several months after returning from ZIKV endemic areas may no longer be positive for IgM antibodies, however, IgG antibodies probably persist for years. Appropriate diagnostic specimens for RT-PCR testing include plasma/serum, urine, cerebrospinal fluid (CSF), amniotic fluid and placental tissue. Serology is usually only performed on serum; however, viral antibodies may be detected in CSF in some cases of neurological disease.
As stated previously ZIKV is a member of the Flaviviridae family, and serologic tests, including the IgM ELISA, may be cross-reactive with other flaviviruses such as dengue, West Nile, and Yellow Fever (including vaccine recipients) [Footnote 1](#fn1). Confirmation of ZIKV exposures therefore depends upon the amplification of viral RNA by RT-PCR, or by confirmatory PRNT serologic testing. Confirmatory testing generally requires neutralizing IgG production, which may appear later than IgM. The specificity of the IgM or IgG ELISAs is limited particularly during secondary flavivirus infections. Patients whose serum samples are IgM positive and have ZIKV-specific antibodies confirmed through PRNT are confirmed cases of viral infection. As previously noted individuals whose serum samples are IgG positive but negative for IgM and have PRNT documented ZIKV specific antibodies were most likely exposed several months before their serum sample(s) was collected, but estimating the timing of infection is usually difficult. Despite repeat testing, serological results may remain equivocal particularly in cases where the individual was previously infected with a related flavivirus. For secondary exposures an IgM positive result usually implies that a recent flavivirus infection is likely, but it may be unclear if this infection was due to Zika virus or a related virus such as dengue. This is because individuals previously infected with or vaccinated against non-Zika flaviviruses may also exhibit cross reactivity in PRNT tests making them difficult to interpret. It is also recommended for equivocal cases that acute and convalescent sera be collected 2 - 3 weeks apart to increase the likelihood of documenting a seroconversion or a diagnostic increase (four-fold or greater) in ZIKV specific neutralizing antibodies, which suggests recent infection when detected. As discussed above, a negative serology at least 2 weeks after the last possible exposure is presumed to indicate the absence of recent infection, although the precise sensitivity of currently available tests has not been determined. If a negative serological test result is being considered in order to support the discontinuation of transmission precautions, a careful risk assessment is required and collection of a second serum sample should also be considered at a later date to definitively rule out a ZIKV exposure.
In regions where the ZIKV outbreak has been extensive, positive serology (IgM, IgG and PRNT) may increasingly represent remote, rather than recent infection. As mentioned above, the declining incidence of transmission in most areas of the world will increase the false positive rates particularly for relatively non-specific tests such as IgM. Therefore, confirmation of recent infection, especially during pregnancy and for those with exposure in the past, now rests primarily on PCR.
PCR for ZIKV can be performed on amniotic fluid (when amniocentesis is technically feasible) to confirm infection of the fetus. At this time, the risk of adverse outcomes of pregnancy if the fetus is infected with ZIKV is at least 8% of adverse outcomes [Footnote 12](#fn12), so the risk of the procedure must be weighed against the clinical utility of this test result. A negative PCR result likely means that the fetus is not currently infected, but would not eliminate the possibility of previous infection. It is not known when ZIKV RNA would be expected to appear in amniotic fluid after infection, or how long it is likely to be detectable. There is some evidence that viral RNA may persist in amniotic fluid for months [Footnote 86](#fn86).
For postnatal diagnosis of congenital infection, PCR for ZIKV can be performed on placental tissue, umbilical cord blood or infant blood, and CSF for confirmation of congenital infection. It is possible, however, that infants or fetuses infected weeks prior to specimen sampling will no longer have detectable viral RNA.
Screening and Management
------------------------
### Evaluation of non-pregnant travellers returning from countries with demonstrated or potential autochthonous Zika transmission
Testing for ZIKV infection using PCR should be considered in the diagnosis of any ill traveller with compatible epidemiologic and clinical history, when symptom onset is within 3 days after arrival in, to 14 days after departing from an area of risk as identified by the WHO. Testing for other similar viral infections and for malaria should also be done as appropriate.
Given the low incidence of infection in most regions, most testing should be limited to molecular techniques, performed within approximately 10 days of the onset of symptoms. It may often be appropriate to perform molecular tests for other similar arboviral infections on the same specimen, with the understanding that sensitivity wanes for all such assays as time elapses beyond the febrile period. For the convalescent patient later than 10 days after the onset of symptoms, there is currently no accurate diagnostic test available for Zika virus. Serology is no longer routinely recommended, due to its lack of specificity for diagnosing recent infection. Paired acute and convalescent serology may be informative, but PCR on the acute specimen is faster and easier to interpret.[Footnote 85](#fn85).
Serologic testing could be considered in exceptional circumstances for male returned travellers from areas of risk whose **clinically compatible illness has resolved**, and are at least 2 weeks post exposure, and when it is impossible or dangerous to delay attempts at conception, in order to assess for potential contagiousness to sexual partners. It is always considered safer to delay conception until the period of potential viral shedding has passed, rather than depend on serologic testing. The high probability of false positive results must be considered and discussed with the patient, prior to testing.
Serological testing of male individuals with a history of travel to an area of risk, but no history of related symptoms is not recommended, given the extremely low risk of infection and high risk of false positive serology.
A negative test result for a symptomatic or asymptomatic patient, whether from an initial or follow-up serology (e.g., if the first test is equivocal) obtained over 2 weeks post potential exposure indicates that a recent ZIKV infection is very unlikely. However, the risk of false positive results, the time required for confirmatory serologic testing, and the relatively short period during which transmission prevention measures might be required all combine to limit the usefulness of such testing [Footnote 85](#fn85). The decision to test should be made in consultation with a health care provider, and should be set against the broader context of the likelihood of infection and patient values and preferences. Testing would only be appropriate when transmission prevention measures are planned during the testing period, which may take several weeks.
The potential for viremia or transmission following a second exposure is unknown. Given that neurologic disorders like GBS have occurred following ZIKV infection, returning travellers should be counselled to report any neurologic symptoms to their doctor. In the event of the diagnosis of GBS or other unusual neurologic syndrome, a travel history for the patient and any male sexual partners should be elicited. If ZIKV infection is thought to be potentially associated with the illness, a specialist should be consulted.
Evaluation in the context of pregnancy
--------------------------------------
### Evaluation of pregnant women with a travel history to an area of risk
Health care providers should take a travel history from their pregnant patients including relevant information related to the travel history of their partner(s). Any patient who indicates that they or their partner have recently travelled to areas of transmission should be further evaluated.
Screening of asymptomatic pregnant women with possible exposure during pregnancy or during the peri-conception period should be discussed on a case-by-case basis between the woman and her health care provider. The declining incidence of Zika transmission in most areas of the world means that infection rates in this population will be extremely low, and significantly lower than in a population with symptoms compatible with infection. The risk of false positive laboratory results, particularly for serology, would be correspondingly elevated in an asymptomatic population. False positive diagnoses would have important implications for adverse events related to unwarranted additional testing and anxiety, as well as resource utilization. The decision whether to screen should take into account intensity of the potential exposure, the use of prevention measures, the likelihood of remote infection, and the transmission trends at the location of potential exposure. **In most cases, screening is NOT recommended**. Exceptions could be considered when the risk of exposure is particularly high, and the psychological benefit of a negative result clearly outweighs the harms which could arise from a false positive result. Screening would be done as for the symptomatic pregnancy patient, see below. The decision to test should include consideration of how the results of the screening tests would be used to inform subsequent decisions. The likelihood of false negative, and especially false positive results in the absence of a recent infection always require careful discussion with the patient. Diagnosis and identification of poor fetal outcomes will allow for appropriate counselling.
Pregnant women and their partners may be justifiably concerned about the risk of ZIKV infection to their fetus and may want to receive counselling to decide the best course of action, including the question of termination. The risk of vertical infection (with clinical sequelae) in the setting of symptomatic or asymptomatic maternal infection appears highest in the first trimester [Footnote 5](#fn5). However severe sequelae have been reported after infection at all stages of pregnancy [Footnote 87](#fn87). This uncertainty makes pregnancy counselling a difficult prospect. Regardless, discussion and informed decision making regarding options for management of ZIKV infection in pregnancy (much like any other congenital infection or congenital anomaly) requires thorough consultation with a Maternal Fetal Medicine Specialist or another specialist familiar with reproductive infectious diseases.
### Evaluation of pregnant women with symptoms compatible with ZIKV infection
Testing should be offered to pregnant women with acute signs and symptoms compatible with ZIKV. Given the reports of longer periods of viremia in some pregnant women, for the patient with symptoms during the preceding 12 weeks, RT-PCR (on blood and urine) is the preferred testing modality. Serology is not recommended for routine testing and should only be requested very judiciously as it is not appropriate in most cases. A negative result has a high negative predictive value and serology at least 2 weeks after the last potential exposure provides reassurance if negative. However, the poor specificity must be clearly discussed and appreciated by the patient, and a clear and logical approach to a positive result should be established before ordering the test. The potential reassurance of a negative test must be weighed against the potentially important harms and likelihood of a false positive. Given the current epidemiology, it is reasonable to assume that for most women, a positive serology will NOT indicate exposure during the pregnancy. Exceptions would include the investigation of suspected congenital Zika syndrome. For the convalescent patient with symptom onset over 12 weeks ago, RT\_PCR will be of minimal value. Prolonged fever may be associated with persistent viremia and PCR testing is indicated in the investigation of these cases. Repeated ultrasound monitoring is indicated, unless the woman is found to be negative on appropriate laboratory testing, including negative serology at least 2 weeks after the last possible exposure. A woman whose fetus is suspected of having a congenital anomaly should also be offered testing if she or her partner has travelled to any location where ZIKV transmission may be occurring [Footnote 88](#fn88) [Footnote 89](#fn89) even at a low level.
Although measurements of head circumference and biparietal diameter may occur as early as 15 weeks, there is no defined gestational age by which microcephaly and other intracranial abnormalities can be ruled out. Serial monitoring by ultrasound with close attention to measurement trends over time is recommended. It is possible that changes in intracranial anatomy may not be elucidated until well into the third trimester, or later.
Counselling recommendations are as in the section on the asymptomatic woman, above.
### Evaluation of the fetus among pregnant women diagnosed with ZIKV infection
Serial ultrasounds (every 3 - 4 weeks) are recommended in pregnant women with confirmed or suspected (if testing results are pending or equivocal) ZIKV infection in pregnancy. Should CNS calcifications or fetal microcephaly be noted at ultrasonography of an asymptomatic pregnant returned traveller, then specific ZIKV testing of the fetus (e.g., amniocentesis), in addition to other investigations to elucidate alternate aetiologies, should be considered to help define the likely cause of the anomaly.
### Evaluation of the infant born to a woman diagnosed with ZIKV infection or with suspected congenital ZIKV infection or CZS
Infants born to women with confirmed or suspected ZIKV infection in pregnancy, or those with unexplained microcephaly, intracranial calcifications, ventriculomegaly or major structural central nervous system abnormalities or other symptoms of congenital ZIKV infection in whom the mother had potential exposure to the virus, should be tested. This testing should include serology, PCR of serum (umbilical cord or infant sample), and PCR of placenta; if CSF is sampled, this can also be sent for PCR and serology. Management is evolving and infants with suspected or confirmed CZS should also undergo further work-up including: routine lab tests (CBC and liver enzymes), head ultrasound, ophthalmologic examination, and hearing evaluation as outlined in current guidelines by the Canadian Paediatric Society (CPS) [Footnote 90](#fn90). Care should be taken to ensure a thorough work up for other important and treatable causes of congenital infections, such as cytomegalovirus and *Toxoplasma*. Infants with confirmed CZS should have neurodevelopmental monitoring throughout infancy to assess the potential for long-term sequelae.
Infants born to women with symptoms of active ZIKV infection around the time of delivery are at risk for perinatal transmission of the disease. In the limited number of reported cases to date, perinatally infected infants have exhibited either no or mild symptoms and laboratory findings (rash, thrombocytopenia) [Footnote 37](#fn37). Regardless, such infants should be monitored closely given the unclear spectrum of potential illness in this emerging infection. Testing with serology and serum PCR during acute illness is recommended. Long term follow-up with a pediatric infectious disease specialist is suggested.
Treatment
---------
Currently there is no specific therapy for the treatment of ZIKV infection. Treatment is supportive with antipyretics (acetaminophen in pregnancy), hydration and rest. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided until dengue can be ruled out to reduce the risk of hemorrhage [Footnote 91](#fn91). Symptomatic disease typically lasts for up to 7 days. Urgent medical care is recommended for any symptoms associated with GBS, and treating health care providers should be made aware of recent travel to area with ZIKV circulation and/or symptoms of ZIKV infection.
If ZIKV infection is confirmed in the setting of pregnancy, referral to a Maternal Fetal Medicine Specialist or specialist familiar with Reproductive Infectious Diseases should be made. If microcephaly, intracranial calcifications or other abnormalities are identified, appropriate counselling by a Neonatologist and Pediatric Infectious Diseases Specialist on potential neurodevelopmental outcome should be offered to parents.
Summary of Recommendations for ZIKV
-----------------------------------
Table 1a - Recommendations for prevention of ZIKV
| Action | Group | Areas estimated to have a likelihood of travel-related infection and associated impacts including CZS[Footnote 1](#tfn1) |
| --- | --- | --- |
| Decision to travel to areas of risk | Pregnant women and women and couples who are planning a pregnancy | Risk of ZIKV is considered low. CATMAT **no longer routinely recommends** avoiding or postponing travel to any affected areas, however travellers and health care providers should remain vigilant of Zika virus activity in the area of travel.
Discussion should occur around decision to travel, based on individual values and preferences, including risk of ZIKV infection. Some pregnant women or those planning a pregnancy may choose to minimize risk by:* not travelling to these areas or
* postponing travel until after pregnancy or
* postponing pregnancy until after travel.
|
| Some countries in these ZIKV affected areas have a significant risk of malaria infection, e.g., Sub-Saharan Africa. As malaria infection during pregnancy is associated with substantial risk of maternal and fetal harm, pregnant travellers should avoid travel to these areas (for more information, see [CATMAT's Statement on pregnancy and travel](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2010-36/canada-communicable-disease-report-7.html)). |
| All other travellers | Low risk for ZIKV infection and consequent impact on travellers. Health care providers should discuss current knowledge about ZIKV, associated risks, and values and preferences with patients. |
| Prevention of mosquito borne transmission | All travellers | CATMAT **recommends** adherence to recommendations for the use of personal protective measures (PPM) against mosquito bites through all hours of the day and night. |
| Prevention of sexual transmission | All asymptomatic travellers (including pregnant women and women and couples who are planning a pregnancy) | Risk of ZIKV is considered low. CATMAT **no longer recommends** routine use of measures to prevent sexual transmission from asymptomatic travellers while in or after returning ZIKV affected areas.
Discussion should occur around individual values and preferences as travellers may still choose to minimize risk by using condoms and/or restricting sexual activity by following the recommendations below. |
| | All symptomatic travellers (including pregnant women and women and couples who are planning a pregnancy) | If **symptoms compatible** with ZIKV infection **are present** and no alternate explanation for symptoms is established, CATMAT **recommends** that discussion should occur around likelihood of ZIKV infection to inform decision to apply recommendations to prevent sexual transmission.
If ZIKV infection is **confirmed,** CATMAT **recommends**:* women wait at least **2 months** after their return from these areas or onset of symptoms (whichever occurs later) before trying to conceive and/or having unprotected sex;
* male partners wait at least **3 months** after their return from these areas or onset of symptoms (whichever occurs later) before trying to conceive and/or having unprotected sex.
In the case of a confirmed or clinically compatible ZIKV infection in the male partner, couples planning a pregnancy might wish to delay conception for up to 6 months, depending on personal risk tolerance. The 6 months represents the outer theoretical limit of the potentially contagious period for a male partner.
In the case of a confirmed or symptomatic case with compatible symptoms of ZIKV infection in the male partner, CATMAT **recommends** that pregnant couples abstain from unprotected sex for the duration of the pregnancy. |
|
Footnote 1
As designated by the WHO[Footnote 80](#fn80)
[Return to footnote 1 referrer](#tfn1-rf)
|
Table 1b - Recommendations for screening and management of ZIKV
| Risk group | Recommendations |
| --- | --- |
| All travellers | Testing should be considered for any ill traveller with compatible epidemiologic and clinical history (for areas designated by the WHO), when symptom onset is within 3 days after arrival in, to 14 days after departing from an area of risk.
Viral RNA testing in Canada is only recommended for symptomatic individuals or those that fulfill other routine testing criteria (see below). Serology is no longer routinely recommended, due to its lack of specificity for diagnosing recent infection. |
| **In the acutely unwell patient** with less than 10 days of symptoms, RT-PCR should be requested. Serology is generally not recommended due to lack of specificity. |
| **In the convalescent patient** with symptom onset over 10 days prior to presentation, only serology should be requested. However, lack of specificity makes serology difficult to interpret, and in most cases the test will have no practical utility. |
| Male partners | Serologic testing could be considered in exceptional circumstances for male returned travellers from areas of risk (as designated by the WHO) whose clinically compatible illness has resolved, and are at least 2 weeks post exposure, in order to help assess for potential contagiousness to sexual partners when it is impossible or dangerous to delay attempts at conception. |
| Serological testing of male individuals with a history of travel to an area of risk (as designated by the WHO) but no history of related symptoms is not recommended, given the extremely low risk of infection and high risk of false positive serology.
For those awaiting test results, and those who test positive, avoidance of pregnancy for 3 months after the last possible exposure is expected to reduce any risk to negligible levels. |
| Negative serology | A negative result for a symptomatic or asymptomatic traveller (male or female), whether from an initial or follow-up serology (e.g., if the first test is equivocal) obtained over 2 weeks post potential exposure indicates that a recent ZIKV infection is very unlikely. |
| All pregnant women | All pregnant patients with a travel history during the peri-conception period or pregnancy to an area of risk (as designated by the WHO) should receive an evaluation to assess whether increased levels of transmission have been reported around the time of possible exposure, as well as the likelihood of exposure to vectors. |
| Asymptomatic pregnant women | Asymptomatic pregnant women with a travel history to an area of risk (as designated by the WHO) should seek evaluation to determine whether increased levels of transmission were reported around the time of travel. If so, they should discuss the role of testing with their health care provider; in most cases, screening is NOT recommended. If recommended, testing would consist of RT-PCR, ideally within 10 days of potential exposure. Although sensitivity will decrease over time, PCR testing in pregnant women will sometimes detect virus in blood or urine up to 12 weeks after potential exposure and may be considered. Serology at least 2 weeks after the last potential exposure provides reassurance if negative, but must be weighed against the potentially important harms and likelihood of a false positive and is not routinely recommended. Consider fetal ultrasounds, at a frequency to be determined in consultation with the woman's obstetrician. |
| Symptomatic pregnant women | **Acutely unwell patient** within ≤12 weeks of symptom onset potentially exposed in an area of risk (as designated by the WHO), RT-PCR should be requested, as prolonged PCR positivity has been reported in some pregnant women. Serology at least 2 weeks after the last potential exposure provides reassurance if negative, but must be weighed against the potentially important harms and likelihood of a false positive and is not routinely recommended. |
| **Convalescent patient** with travel history to an area of risk (as designated by the WHO) and with symptom onset over 12 weeks prior RT\_PCR will be of minimal value. Serology may provide reassurance if negative, but must be weighed against the potentially important harms and likelihood of a false positive, and is not routinely recommended. Exceptions would include the investigation of suspected congenital Zika syndrome. RT-PCR can be considered if the patient continues to suffer from fever, regardless of symptom duration. |
| Repeated ultrasound monitoring is indicated, unless the woman found to be negative on appropriate laboratory testing, including negative serology at least 2 weeks after the last possible exposure. |
| Fetus of pregnant women with confirmed or suspected ZIKV infection | Pregnant women with confirmed or suspected ZIKV infection in pregnancy should receive serial ultrasounds (every 3 - 4 weeks). |
| Infant born to a woman with confirmed or suspected ZIKV infection or with suspected CZS | Infants born to women with confirmed or suspected ZIKV infection in pregnancy, or those with microcephaly, intracranial calcifications or other symptoms of CZS in whom the mother had potential exposure to the virus, should be tested.
This testing should include serology, PCR of serum (umbilical cord or infant sample), and PCR of placenta; if CSF is sampled, this can also be sent for PCR and serology. |
| Infants with suspected or confirmed congenital ZIKV infection/ syndrome | Infants with suspected or confirmed congenital ZIKV infection/syndrome should also undergo further work-up including routine lab tests (CBC and liver enzymes), head ultrasound, ophthalmologic examination, and hearing evaluation.
Those with confirmed CZS should have neurodevelopmental monitoring throughout infancy to assess the potential for long-term sequelae [Footnote 90](#fn90). |
Table 1c - Recommendations for treatment of ZIKV
| Risk group | Recommendations |
| --- | --- |
| Pregnant cases | Acetaminophen, hydration, and rest. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided until dengue can be ruled out. Urgent medical care is recommended for any symptoms associated with GBS or other neurologic syndromes. Referral to a maternal fetal medicine specialist or infectious diseases specialist should be made. If fetal abnormalities are identified, appropriate counselling should be offered. |
| All other cases | Antipyretics, hydration, and rest. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided until dengue can be ruled out. Urgent medical care is recommended for any symptoms associated with GBS or other neurologic syndromes. |
Additional resources and useful links:
--------------------------------------
Government of Canada - [For health professionals: Zika Virus](/en/public-health/services/diseases/zika-virus/health-professionals.html)
Government of Canada - Travel health notice: [Zika virus infection: Global Update](https://travel.gc.ca/travelling/health-safety/travel-health-notices/152)
Pan American Health Organization - [Zika Virus Infection](http://www.paho.org/hq/index.php?option=com_content&view=article&id=11585&Itemid=41688&lang=en)
World Health Organization - [Zika virus classification tables](http://www.who.int/emergencies/zika-virus/classification-tables/en/)
Committee to Advise on Tropical Medicine and Travel - [Travel Medicine Resources for Canadian Practitioners](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2015-41/ccdr-volume-41-05-may-7-2015/ccdr-volume-41-05-may-7-2015-3.html)
Acknowledgements
----------------
This statement was developed by the Zika Working Group: Libman M (chair), Boggild A, Bui Y, Drebot M, McCarthy A, Schofield S, Tataryn J, van Schalkwyk J, Wood H, Yudin M and approved by CATMAT.
CATMAT would like to acknowledge the technical and administrative support from the Office of Border and Travel Health at the Public Health Agency of Canada for the development of this statement.
**CATMAT members:** McCarthy A (Chair), Acharya A, Boggild A,, Bui Y, Crockett M, Greenaway C, Libman M, and Vaughan S.
**Liaison members:** Audcent T (Canadian Paediatric Society) and Pernica J (Association of Medical Microbiology and Infectious Disease Canada).
**Ex officio members:** Marion D (Canadian Forces Health Services Centre, Department of National Defence), McDonald P (Bureau of Medical Sciences, Health Canada), Rossi C (Medical Intelligence, Department of National Defence) and Schofield S (Pest Management Entomology, Department of National Defence).
Conflict of interest
--------------------
None declared.
References
----------
1
Hayes EB. Zika virus outside Africa. Emerg Infect Dis 2009;15(9):1347-1350.
[Return to first footnote 1 referrer](#fn1-1-rf)
2
Kraemer MU, Sinka ME, Duda KA, Mylne AQ, Shearer FM, Barker CM, et al. The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus. eLife 2015;4(e08347):1-18.
[Return to footnote 2 referrer](#fn2-rf)
3
Triunfol M. A new mosquito-borne threat to pregnant women in Brazil. Lancet Infect Dis 2016;16(2):156-157.
[Return to footnote 3 referrer](#fn3-rf)
4
World Health Organization. Surveillance for Zika virus infection, microcephaly and Guillain-Barré syndrome Interim guidance 7 April 2016. 2016; Available at: http://apps.who.int/iris/bitstream/10665/204897/1/WHO\_ZIKV\_SUR\_16.2\_eng.pdf?ua=1. Accessed April 12, 2016.
[Return to first footnote 4 referrer](#fn4-1-rf)
5
Cauchemez S, Besnard M, Bompard P, Dub T, Guillemette-Artur P, Eyrolle-Guignot D, et al. Association between Zika virus and microcephaly in French Polynesia, 2013-15: a retrospective study. Lancet 2016;ePub.
[Return to footnote 5 referrer](#fn5-rf)
6
Schuler-Faccini L. Possible Association Between Zika Virus Infection and Microcephaly-Brazil, 2015. Morb Mortal Wkly Rep 2016;65(3):59-62.
[Return to footnote 6 referrer](#fn6-rf)
7
Hoen B, Schaub B, Funk AL, Ardillon V, Boullard M, Cabie A, et al. Pregnancy Outcomes after ZIKV Infection in French Territories in the Americas. N Engl J Med 2018 Mar 15;378(11):985-994.
[Return to footnote 7 referrer](#fn7-rf)
8
European Centre for Disease Prevention and Control. Rapid risk assessment: Zika virus epidemic in the Americas: potential association with microcephaly and Guillain-Barré syndrome, 10 December 2015. 2015; Available at: http://ecdc.europa.eu/en/publications/Publications/zika-virus-americas-association-with-microcephaly-rapid-risk-assessment.pdf. Accessed Feb. 2, 2016.
[Return to first footnote 8 referrer](#fn8-1-rf)
9
Brito Ferreira ML. Neurologic Manifestations of Arboviruses in the Epidemic in Pernambuco, Brazil. American Academy of Neurology 68th Annual Meeting 2016.
[Return to first footnote 9 referrer](#fn9-1-rf)
10
Mead PS, Duggal NK, Hook SA, Delorey M, Fischer M, Olzenak McGuire D, et al. Zika Virus Shedding in Semen of Symptomatic Infected Men. N Engl J Med 2018 Apr 12;378(15):1377-1385.
[Return to first footnote 10 referrer](#fn10-1-rf)
11
Reynolds MR, Jones AM, Petersen EE, Lee EH, Rice ME, Bingham A, et al. Vital Signs: Update on Zika Virus-Associated Birth Defects and Evaluation of All U.S. Infants with Congenital Zika Virus Exposure - U.S. Zika Pregnancy Registry, 2016. MMWR Morb Mortal Wkly Rep 2017 Apr 7;66(13):366-373.
[Return to footnote 11 referrer](#fn11-rf)
12
Shapiro-Mendoza CK, Rice ME, Galang RR, Fulton AC, VanMaldeghem K, Prado MV, et al. Pregnancy Outcomes After Maternal Zika Virus Infection During Pregnancy - U.S. Territories, January 1, 2016-April 25, 2017. MMWR Morb Mortal Wkly Rep 2017 Jun 16;66(23):615-621.
[Return to first footnote 12 referrer](#fn12-1-rf)
13
Rice ME, Galang RR, Roth NM, et. al. Vital Signs: Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital zika virus infection - U.S. Territories and Freely Associated States. MMWR Morb Mortal Wkly Rep 2018 August 7, 2018;67:858-867.
[Return to footnote 13 referrer](#fn13-rf)
14
Boggild AK, Geduld J, Libman M, Yansouni CP, McCarthy AE, Hajek J, et al. Surveillance report of Zika virus among Canadian travellers returning from the Americas. CMAJ 2017 Mar 6;189(9):E334-E340.
[Return to footnote 14 referrer](#fn14-rf)
15
Counotte MJ, Kim CR, Wang J, Bernstien k, Deal CD, Broutet NJN, et al. Sexual transmission of Zika virus and other flaviviruses: A living systematic review. PLoS Med 2018;15(7).
[Return to footnote 15 referrer](#fn15-rf)
16
Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on Personal Protective Measures to Prevent Arthropod Bites. Can Commun Dis Rep 2012;38(ACS-3):1-18.
[Return to first footnote 16 referrer](#fn16-1-rf)
17
Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on Pregnancy and Travel. Can Commun Dis Rep 2010;36(ACS-2):1-44.
[Return to first footnote 17 referrer](#fn17-1-rf)
18
Dick GW. Epidemiological notes on some viruses isolated in Uganda; Yellow fever, Rift Valley fever, Bwamba fever, West Nile, Mengo, Semliki forest, Bunyamwera, Ntaya, Uganda S and Zika viruses. Trans R Soc Trop Med Hyg 1953;47(1):13-48.
[Return to footnote 18 referrer](#fn18-rf)
19
Dick GWA. Zika virus (II). Pathogenicity and physical properties. Trans R Soc Trop Med Hyg 1952;46(5):521-534.
[Return to footnote 19 referrer](#fn19-rf)
20
Duffy MR, Chen TH, Hancock WT, Powers AM, Kool JL, Lanciotti RS, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. New Engl J Med 2009;360(24):2536-2543.
[Return to first footnote 20 referrer](#fn20-1-rf)
21
Cao-Lormeau VM, Roche C, Teissier A, Robin E, Berry AL, Mallet HP, et al. Zika virus, French Polynesia, South Pacific, 2013. Emerg Infect Dis 2014;20(6):1085-1086.
[Return to footnote 21 referrer](#fn21-rf)
22
Musso D, Roche C, Nhan TX, Robin E, Teissier A, Cao-Lormeau VM. Detection of Zika virus in saliva. J Clin Virol 2015;68:53-55.
[Return to footnote 22 referrer](#fn22-rf)
23
World Health Organization. Zika virus infection - Cape Verde. 2015; Available at: http://www.who.int/csr/don/21-december-2015-zika-cape-verde/en/. Accessed Feb. 2, 2016.
[Return to footnote 23 referrer](#fn23-rf)
24
Tognarelli J, Ulloa S, Villagra E, Lagos J, Aguayo C, Fasce R, et al. A report on the outbreak of Zika virus on Easter Island, South Pacific, 2014. Arch Virol 2015;ePub.
[Return to footnote 24 referrer](#fn24-rf)
25
Pan American Health Organization. Countries and territories with autochthonous transmission in the Americas reported in 2015-2016. 2016; Available at: http://www.paho.org/hq/index.php?option=com\_content&view=article&id=11603%3Acountries-territories-zika-autochthonous-transmission-americas&catid=8424%3Acontents&Itemid=41696&lang=en. Accessed November 10, 2016.
[Return to first footnote 25 referrer](#fn25-1-rf)
26
Pan American Health Organization. Regional zika epidemiological update (Americas) Aug 25, 2017. 2017; Available at: https://www.paho.org/hq/index.php?option=com\_content&view=article&id=11599:regional-zika-epidemiological-update-americas&Itemid=41691&lang=en. Accessed August 27, 2018.
[Return to first footnote 26 referrer](#fn26-1-rf)
27
Caribbean Public Health Agency (CARPHA). CARPHA concludes risk of getting zika in the Caribbean low at this time. 2018; Available at: http://carpha.org/articles/ID/180/CARPHA-Concludes-Risk-of-Getting-Zika-in-the-Caribbean-Low-at-this-Time. Accessed August 27, 2018.
[Return to first footnote 27 referrer](#fn27-1-rf)
28
Government of Canada. Surveillance of Zika. 2018; Available at: https://www.canada.ca/en/public-health/services/diseases/zika-virus/health-professionals.html. Accessed October 12, 2018.
[Return to first footnote 28 referrer](#fn28-1-rf)
29
Centers for Disease Control and Prevention (CDC). Zika Cases in the United States. 2018; Available at: https://www.cdc.gov/zika/reporting/case-counts.html. Accessed October 12, 2018.
[Return to first footnote 29 referrer](#fn29-1-rf)
30
Centers for Disease Control and Prevention (CDC). 2018 Case Counts in the US. Provisional data as of December 4, 2018. 2018; Available at: https://www.cdc.gov/zika/reporting/2018-case-counts.html. Accessed December 12, 2018.
[Return to first footnote 30 referrer](#fn30-1-rf)
31
Krow-Lucal ER, Biggerstaff BJ, Staples JE. Estimated Incubation Period for Zika Virus Disease. Emerg Infect Dis 2017 May;23(5):841-845.
[Return to footnote 31 referrer](#fn31-rf)
32
Balm MN, Lee CK, Lee HK, Chiu L, Koay ES, Tang JW. A diagnostic polymerase chain reaction assay for Zika virus. J Med Virol 2012;84(9):1501-1505.
[Return to footnote 32 referrer](#fn32-rf)
33
European Centre for Disease Prevention and Control. Zika virus infection: Factsheet for health professionals. 2015; Available at: http://ecdc.europa.eu/en/healthtopics/zika\_virus\_infection/factsheet-health-professionals/Pages/factsheet\_health\_professionals.aspx. Accessed Jan. 22, 2016.
[Return to first footnote 33 referrer](#fn33-1-rf)
34
Lessler JT, Ott CT, Carcelen AC, Konikoff JM, Williamson J, Bi Q, Kucirka LM, Cummings DA, Reichd NG,Chaissona LH. Times to key events in the course of Zika infection and their implications: a systematic review and pooled analysis. Bull World Health Organ 2016.
[Return to footnote 34 referrer](#fn34-rf)
35
Paz-Bailey G, Rosenberg ES, Doyle K, Munoz-Jordan J, Santiago GA, Klein L, et al. Persistence of Zika Virus in Body Fluids - Preliminary Report. N Engl J Med 2017 Feb 14.
[Return to first footnote 35 referrer](#fn35-1-rf)
36
Murray KO, Gorchakov R, Carlson AR, Berry R, Lai L, Natrajan M, et al. Prolonged Detection of Zika Virus in Vaginal Secretions and Whole Blood. Emerg Infect Dis 2017 Jan;23(1):99-101.
[Return to footnote 36 referrer](#fn36-rf)
37
Besnard M, Lastère S, Teissier A, Cao-Lormeau VM, Musso D. Evidence of perinatal transmission of zika virus, French Polynesia, December 2013 and February 2014. Euro Surveill 2014;19(13):20751.
[Return to first footnote 37 referrer](#fn37-1-rf)
38
Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, Alves Sampaio S, Bispo De Filippis AM. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: Tip of the iceberg? Ultrasound Obstet Gynecol 2016;47(1):6-7.
[Return to footnote 38 referrer](#fn38-rf)
39
Musso D, Nhan T, Robin E, Roche C, Bierlaire D, Zisou K, et al. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveil 2014;19(14):20761.
[Return to footnote 39 referrer](#fn39-rf)
40
Musso D, Roche C, Robin E, Nhan T, Teissier A, Cao-Lormeau VM. Potential sexual transmission of Zika virus. Emerg Infect Dis 2015;21(2):359-361.
[Return to footnote 40 referrer](#fn40-rf)
41
Foy BD, Kobylinski KC, Chilson Foy JL, Blitvich BJ, Travassos da Rosa A, Haddow AD, et al. Probable non-vector-borne transmission of Zika virus, Colorado, USA. Emerg Infect Dis 2011;17(5):880-882.
[Return to footnote 41 referrer](#fn41-rf)
42
Dallas County Health and Human Services. DCHHS Reports First Zika Virus Case in Dallas County Acquired Through Sexual Transmission. 2016; Available at: http://www.dallascounty.org/department/hhs/press/documents/PR2-2-16DCHHSReportsFirstCaseofZikaVirusThroughSexualTransmission.pdf. Accessed Feb. 2, 2016.
[Return to footnote 42 referrer](#fn42-rf)
43
Hills SL, Russell K, Hennessey M, Williams C, Oster AM, Fischer M, et al. Transmission of Zika Virus Through Sexual Contact with Travelers to Areas of Ongoing Transmission - Continental United States, 2016. Morb Mortal Wkly Rep 2016;65(8):215-216.
[Return to footnote 43 referrer](#fn43-rf)
44
Davidson A, Slavinski S, Komoto K, Rakeman J, Weiss D. Suspected Female-to-Male Sexual Transmission of Zika Virus - New York City, 2016. MMWR Morb Mortal Wkly Rep 2016 Jul 22;65(28):716-717.
[Return to footnote 44 referrer](#fn44-rf)
45
Freour T, Mirallie S, Hubert B, Splingart C, Barriere P, Maquart M, et al. Sexual transmission of Zika virus in an entirely asymptomatic couple returning from a Zika epidemic area, France, April 2016. Euro Surveill 2016 Jun 9;21(23):10.2807/1560-7917.ES.2016.21.23.30254.
[Return to first footnote 45 referrer](#fn45-1-rf)
46
Schwartz KL, Chan T, Rai N, Murphy KE, Whittle W, Drebot MA, et al. Zika virus infection in a pregnant Canadian traveler with congenital fetal malformations noted by ultrasonography at 14-weeks gestation. Trop Dis Travel Med Vaccines 2018 Apr 4;4:2-018-0062-8. eCollection 2018.
[Return to footnote 46 referrer](#fn46-rf)
47
Suy A, Sulleiro E, Rodo C, Vazquez E, Bocanegra C, Molina I, et al. Prolonged Zika Virus Viremia during Pregnancy. N Engl J Med 2016 Dec 29;375(26):2611-2613.
[Return to footnote 47 referrer](#fn47-rf)
48
Arsuaga M, Bujalance SG, Diaz-Menendez M, Vazquez A, Arribas JR. Probable sexual transmission of Zika virus from a vasectomised man. Lancet Infect Dis 2016 Oct;16(10):1107-3099(16)30320-6. Epub 2016 Sep 19.
[Return to footnote 48 referrer](#fn48-rf)
49
Brooks RB, Carlos MP, Myers RA, White MG, Bobo-Lenoci T, Aplan D, et al. Likely Sexual Transmission of Zika Virus from a Man with No Symptoms of Infection - Maryland, 2016. MMWR Morb Mortal Wkly Rep 2016 Sep 2;65(34):915-916.
[Return to footnote 49 referrer](#fn49-rf)
50
Musso D, Richard V, Teissier A, Stone M, Lanteri MC, Latoni G, et al. Detection of Zika virus RNA in semen of asymptomatic blood donors. Clin Microbiol Infect 2017 Dec;23(12):1001.e1-1001.e3.
[Return to footnote 50 referrer](#fn50-rf)
51
Baud D, Gubler DJ, Schaub B, Lanteri MC, Musso D. An update on Zika virus infection. Lancet 2017 Jun 21.
[Return to first footnote 51 referrer](#fn51-1-rf)
52
World Health Organization. Breastfeeding in the context of Zika virus Interim Guidance 25 February 2016. 2016; Available at: http://apps.who.int/iris/bitstream/10665/204473/1/WHO\_ZIKV\_MOC\_16.5\_eng.pdf?ua=1. Accessed March 4, 2016.
[Return to footnote 52 referrer](#fn52-rf)
53
Gallian P, Cabié A, Richard P, Paturel L, Charrel RN, Pastorino B, et al. Zika virus in asymptomatic blood donors in Martinique. Blood 2017 American Society of Hematology;129(2):263-266.
[Return to footnote 53 referrer](#fn53-rf)
54
Ioos S, Mallet HP, Leparc Goffart I, Gauthier V, Cardoso T, Herida M. Current Zika virus epidemiology and recent epidemics. Med Mal Infect 2014;44(7):302-307.
[Return to first footnote 54 referrer](#fn54-1-rf)
55
Hamer DH, Barbre KA, Chen LH, Grobusch MP, Schlagenhauf P, Goorhuis A, et al. Travel-Associated Zika Virus Disease Acquired in the Americas Through February 2016: A GeoSentinel Analysis. Ann Intern Med 2017 Jan 17;166(2):99-108.
[Return to footnote 55 referrer](#fn55-rf)
56
Villamil-Gómez WE, González-Camargo O, Rodriguez-Ayubi J, Zapata-Serpa D, Rodriguez-Morales AJ. Dengue, chikungunya and Zika co-infection in a patient from Colombia. J Infect Public Health 2015;ePub.
[Return to footnote 56 referrer](#fn56-rf)
57
Committee to Advise on Tropical Medicine and Travel (CATMAT). Fever in the returning international traveller initial assessment guidelines. Can Commun Dis Rep 2011;37(ACS-2):1-24.
[Return to footnote 57 referrer](#fn57-rf)
58
Shinohara K, Kutsuna S, Takasaki T, Moi ML, Ikeda M, Kotaki A, et al. Zika fever imported from Thailand to Japan, and diagnosed by PCR in the urines. J Travel Med 2016;23(1):1-3.
[Return to footnote 58 referrer](#fn58-rf)
59
Committee to Advise on Tropical Medicine and Travel (CATMAT). Canadian Recommendations for the Prevention and Treatment of Malaria. 2014;140006.
[Return to footnote 59 referrer](#fn59-rf)
60
Oehler E, Watrin L, Larre P, Leparc-Goffart I, Lastãre S, Valour F, et al. Zika virus infection complicated by guillain-barré syndrome - case report, French Polynesia, December 2013. Euro Surveill 2014;19(9):20720.
[Return to footnote 60 referrer](#fn60-rf)
61
World Health Organization. Zika virus, Microcephaly and Guillain-Barré Syndrome Situation Report 26 February 2016. 2016; Available at: http://apps.who.int/iris/bitstream/10665/204491/1/zikasitrep\_26Feb2016\_eng.pdf?ua=1. Accessed March 4, 2016.
[Return to footnote 61 referrer](#fn61-rf)
62
Cao-Lormeau V, Blake A, Mons S, Lastere S, Roche C, Vanhomwegen J, et al. Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet 2016;ePub.
[Return to footnote 62 referrer](#fn62-rf)
63
Mécharles S, Herrmann C, Poullain P, Tran T, Deschamps N, Mathon G, et al. Acute myelitis due to Zika virus infection. Lancet 2016;ePub.
[Return to footnote 63 referrer](#fn63-rf)
64
Carteaux G, Maquart M, Bedet A, Contou D, Brugières P, Fourati S, et al. Zika Virus Associated with Meningoencephalitis. N Engl J Med 2016;ePub.
[Return to footnote 64 referrer](#fn64-rf)
65
Karimi O, Goorhuis A, Schinkel J, Codrington J, Vreden SGS, Vermaat JS, et al. Thrombocytopenia and subcutaneous bleedings in a patient with Zika virus infection. Lancet 2016;387:939-940.
[Return to footnote 65 referrer](#fn65-rf)
66
Zammarchi L, Stella G, Mantella A, Bartolozzi D, Tappe D, Günther S, et al. Zika virus infections imported to Italy: clinical, immunological and virological findings, and public health implications. J Clin Virol 2015;63:32-35.
[Return to footnote 66 referrer](#fn66-rf)
67
Baud D, Van Mieghem T, Musso D, Truttmann AC, Panchaud A, Vouga M. Clinical management of pregnant women exposed to Zika virus. Lancet Infect Dis 2016;16(5):523.
[Return to footnote 67 referrer](#fn67-rf)
68
Arzuza-Ortega L, Pérez-Tatis G, López-García H. Fatal Zika virus infection in girl with sickle cell disease, Colombia. Emerging Infect Dis 2016;22(5).
[Return to footnote 68 referrer](#fn68-rf)
69
World Health Organization. Zika Virus Microcephaly Guillian-Barré Syndrome 10 March 2017. 2017.
[Return to footnote 69 referrer](#fn69-rf)
70
Melo AS, Aguiar RS, Amorim MM, Arruda MB, Melo FO, Ribeiro ST, et al. Congenital Zika Virus Infection: Beyond Neonatal Microcephaly. JAMA Neurol 2016 Oct 3.
[Return to footnote 70 referrer](#fn70-rf)
71
de Araujo TV, Rodrigues LC, de Alencar Ximenes RA, de Barros Miranda-Filho D, Montarroyos UR, de Melo AP, et al. Association between Zika virus infection and microcephaly in Brazil, January to May, 2016: preliminary report of a case-control study. Lancet Infect Dis 2016 Sep 15.
[Return to footnote 71 referrer](#fn71-rf)
72
Ventura CV, Maia M, Bravo-Filho V, Góis AL, Belfort R. Zika virus in Brazil and macular atrophy in a child with microcephaly. Lancet 2016;387(10015):228.
[Return to footnote 72 referrer](#fn72-rf)
73
Costa F, Sarno M, Khouri R, de Paulo Freitas B, Siqueira I, Ribeiro GS, et al. Emergence of Congenital Zika Syndrome: Viewpoint From the Front Lines. Ann Intern Med 2016;ePub.
[Return to footnote 73 referrer](#fn73-rf)
74
Sarno M, Sacramento GA, Khouri R, do Rosário MS, Costa F, Archanjo G, et al. Zika Virus Infection and Stillbirths: A Case of Hydrops Fetalis, Hydranencephaly and Fetal Demise. PLOS Negl Trop Dis 2016;10(2):e0004517.
[Return to footnote 74 referrer](#fn74-rf)
75
Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika Virus and Birth Defects - Reviewing the Evidence for Causality. N Engl J Med 2016;ePub.
[Return to footnote 75 referrer](#fn75-rf)
76
European Centre for Disease Prevention and Control. Disease data from ECDC Surveillance Atlas - Zika virus disease. 2017:Available at: https://ecdc.europa.eu/en/zika-virus-infection/surveillance-and-disease-data/disease-data. Accessed July 16, 2018.
[Return to footnote 76 referrer](#fn76-rf)
77
Statistics Canada. International Travel Survey. Custom extract. 2015.
[Return to footnote 77 referrer](#fn77-rf)
78
Canadian Paediatric Surveillance Program, Canadian Paediatric Society. CPSP 2018 Results. Ottawa 2019.
[Return to footnote 78 referrer](#fn78-rf)
79
World Health Organization. Zika virus classification tables. 2018; Available at: http://www.who.int/emergencies/zika-virus/classification-tables/en/. Accessed October 12, 2018.
[Return to footnote 79 referrer](#fn79-rf)
80
World Health Organization. Zika virus transmission tables. 2019 (July 2, 2019): https://www.who.int/emergencies/diseases/zika/countries-with-zika-and-vectors-table.pdf.
[Return to first footnote 80 referrer](#fn80-1-rf)
81
European Centre for Disease Prevention and Control. Rapid risk assessment: Zika virus infection outbreak, French Polynesia, 14 February 2014. 2014; Available at: http://ecdc.europa.eu/en/publications/Publications/Zika-virus-French-Polynesia-rapid-risk-assessment.pdf. Accessed Feb. 2, 2016.
[Return to first footnote 81 referrer](#fn81-1-rf)
82
Centers for Disease Control and Prevention (CDC). Revised diagnostic testing for Zika, chikungunya, and dengue viruses in US Public Health Laboratories. 2016; Available at: http://www.cdc.gov/zika/pdfs/denvchikvzikv-testing-algorithm.pdf. Accessed March 3, 2016.
[Return to footnote 82 referrer](#fn82-rf)
83
Dimitrova K, Makowski K, Cunningham I, Holloway K, Giles E, Andonova M, et al. Zika virus in Canada. Can Commun Dis Rep 2016;42:101-104.
[Return to first footnote 83 referrer](#fn83-1-rf)
84
Griffin I, Martin SW, Fischer M, Chambers TV, Kosoy OL, Goldberg C, et al. Zika Virus IgM 25 Months after Symptom Onset, Miami-Dade County, Florida, USA. Emerg Infect Dis 2019 Dec;25(12):2264-2265.
[Return to first footnote 84 referrer](#fn84-1-rf)
85
Drebot M, for the National Microbiology Laboratory. Laboratory diagnosis. 2018 May 11.
[Return to footnote 85 referrer](#fn85-1-rf)
86
Calvet G, Aguiar RS, Melo AS, Sampaio SA, de Filippis I, Fabri A, et al. Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study. Lancet Infect Dis 2016;ePub.
[Return to footnote 86 referrer](#fn86-1-rf)
87
Brasil P, Pereira J,Jose P., Raja Gabaglia C, Damasceno L, Wakimoto M, Ribeiro Nogueira RM, et al. Zika Virus Infection in Pregnant Women in Rio de Janeiro — Preliminary Report. N Engl J Med 2016;ePub.
[Return to footnote 87 referrer](#fn87-rf)
88
World Health Organization. Zika virus situation reports. 2016; Available at: http://www.who.int/emergencies/zika-virus/situation-report/en/. Accessed October 4, 2016.
[Return to footnote 88 referrer](#fn88-rf)
89
Centers for Disease Control and Prevention (CDC). Advice for people living in or traveling to South Florida. 2016; Available at: http://www.cdc.gov/zika/intheus/florida-update.html. Accessed October 4, 2016.
[Return to first footnote 89 referrer](#fn89-1-rf)
90
Robinson JL. Zika virus: What does a physician caring for children in Canada need to know? Paediatr Child Health 2017 Mar;22(1):48-55.
[Return to footnote 90 referrer](#fn90-1-rf)
91
Centers for Disease Control and Prevention (CDC). Clinical Evaluation & Disease. 2016; Available at: http://www.cdc.gov/zika/hc-providers/clinicalevaluation.html. Accessed Feb. 5, 2016.
[Return to footnote 91 referrer](#fn91-1-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2020-03-25
| None | None |
a8bd37fadef4b497e2c605019e9226a610e3254e | cma | COVID-19 vaccine: Canadian Immunization Guide | COVID-19 vaccine: Canadian Immunization Guide
Key information (refer to text and tables for details)
# What
- Novel coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
- Anyone can be infected with SARS-CoV-2. However, some populations are at increased risk of exposure to the virus due to living or occupational settings and some populations are at increased risk of severe outcomes due to biological and/or social factors.
- Several vaccines for COVID-19 had been authorized for use in Canada since December 2020. These include messenger ribonucleic acid (mRNA) vaccines, protein subunit and virus-like particle (VLP) vaccines, and non-replicating viral vector vaccines. Refer to for more information.
- For all vaccines, some adverse events are reported to be very common (defined as 10% or more) among vaccine recipients. However, they are mild or moderate and transient, resolving within a few days. These side effects may include: pain, redness and swelling at the injection site, axillary (or groin) swelling or tenderness, fatigue, headache, muscle pain, chills, joint pain, and fever.
- Serious adverse events following immunization can occur very rarely. Refer to for more information.
# Who
- A complete primary series with an mRNA COVID-19 vaccine may be offered to children 6 months to less than 5 years of age and should be offered to children 5 to 11 years of age without contraindications to the authorized vaccine, with a dosing interval of at least 8 weeks between the first and second dose. Refer to for more information.
- A complete primary series, preferentially with an mRNA COVID-19 vaccine, should be offered to individuals 12 years of age and older without contraindications to the vaccine. Refer to and for more information.
- For recommendations for individuals 6 months of age and older who are moderately to severely immunocompromised, refer to , and .
- A first booster dose of mRNA COVID-19 vaccine should be offered to adults 18 years of age and older and select children and adolescents 5 to 17 years of age. A first booster of mRNA COVID-19 vaccine may also be offered to all other children and adolescents 5 to 17 years of age. Additional booster doses are recommended for select populations. Refer to for more information.
- It is recommended that mRNA COVID-19 vaccines should be offered to individuals 6 months of age and older with previous SARS-CoV-2 infection without contraindications to the vaccine. Refer to for more information, including recommended intervals.
- It is recommended that an authorized protein subunit COVID-19 vaccine (Novavax Nuvaxovid) should be offered to individuals in the authorized age groups without contraindications to the vaccine who are not able or willing to receive an mRNA COVID-19 vaccine.
- An authorized viral vector COVID-19 vaccine may be offered to individuals 18 years of age and over, without contraindications to the vaccine, when all other authorized COVID-19 vaccines are contraindicated.
# How
- Currently, for immunocompetent individuals, the Pfizer-BioNTech Comirnaty COVID-19 vaccine ).
- Bivalent mRNA COVID-19 vaccines are currently authorized only as booster doses. Refer to for more information.
- Prior to providing a COVID-19 vaccine informed consent should include discussion about frequently occurring minor adverse events and the risks and symptoms of potential rare severe adverse events.
- Serologic testing is not recommended before or after receipt of a COVID-19 vaccine to assess susceptibility to SARS-CoV-2 or immune response to the vaccine.
- For individuals 6 months of age and older, COVID-19 vaccines may be given concurrently with (i.e., same day), or at any time before or after, non-COVID-19 vaccines (including live and non-live vaccines).
- Regardless of vaccination status, individuals should continue to follow recommended public health measures for prevention and control of SARS-CoV-2 infection and transmission.
# Why
- The COVID-19 pandemic has caused significant morbidity and mortality, as well as social and economic disruption in Canada and worldwide.
- COVID-19 vaccines have been shown to be very effective at preventing severe disease, including hospitalization and death due to COVID-19.
Epidemiology
# Disease description
## Infectious agent
COVID-19 is caused by the SARS-CoV-2 virus, which was first recognized in Wuhan, China in December 2019.
## Transmission
Current evidence suggests that SARS-CoV-2 is spread through respiratory droplets and aerosols created when an infected person breathes, coughs, sneezes, sings, shouts, or talks. A person may be infectious for up to 3 days before showing symptoms and most people are considered no longer infectious 10 days from onset of symptoms (or first detection of infection if asymptomatic).
More information on the transmission of SARS-CoV-2 can be found on the Public Health Agency of Canada (PHAC) webpages for
## Variants of concern
Genetic mutations in the SARS-CoV-2 virus have led to the designation of variants of concern (VOCs) and these variants are more transmissible than the original strain. Mutations in VOCs may also affect the severity of disease and the level of protection offered by vaccines.
More information on the VOCs reported in Canada is available in the . The by the World Health Organization (WHO) provides a summary on the global distribution and emerging evidence on VOC and variants of interest (VOI). Differences between VOC and VOI are available from .
## Risk factors
Anyone can be infected with SARS-CoV-2. However, some populations are at increased risk of exposure to the virus (e.g., due to living or occupational settings), and some populations are at increased risk of severe disease and outcomes (e.g., hospitalization and death) due to biological factors (e.g., advanced age, pre-existing medical conditions, pregnancy) and social factors (e.g., socioeconomic status, belonging to a racialized population) that may intersect. Exposure and risk factors for severe disease may overlap, further increasing risk. Any combination of these factors, as well as varying access to health care services, has the potential for disproportionate consequences for specific populations characterized by increased rates of infection and disease, severe illness, hospitalizations, and/or deaths.
There is a spectrum of COVID-19 disease severity, ranging from asymptomatic to mild, moderate, severe and critical disease. Severe disease more often occurs in those with increasing age and those with underlying medical conditions, with the risk increasing with the number of underlying conditions. A list of can be found in .
There is limited evidence on clinical risk factors for severe COVID-19 disease in pediatric populations. Children at increased risk for severe outcomes may include children who are obese, children who are medically fragile/ have medical complexities, children with more than one comorbidity, children with neurological disorders, and children with immune dysregulation associated with Down syndrome (Trisomy 21) and other immunocompromising conditions.
## Spectrum of clinical illness and disease characteristics
The median incubation period (the time from exposure to symptom onset) for non-variant SARS-CoV-2 was estimated to be 4 to 7 days. For Omicron, the median incubation period is 2 to 4 days. The incubation period can range from 2 to 14 days.
Clinical presentation and symptoms of COVID-19 vary in frequency and severity, from asymptomatic to severe and fatal disease. To date, there is no list of symptoms that has been validated to have high specificity or sensitivity for COVID-19.
More information on the spectrum of clinical illness is available on the PHAC webpage for .
While most children and adolescents with COVID-19 have mild or no symptoms, some do experience severe disease. However, children and adolescents report fewer severe outcomes of COVID-19 (i.e., hospitalizations due to COVID-19, ICU admission, and deaths) compared to older age groups.
Children, adolescents and adults with SARS-CoV-2 infection are at risk of multisystem inflammatory syndrome (MIS), a rare but serious condition that can occur several weeks following SARS-CoV-2 infection. They are also at risk of post COVID-19 condition (PCC), a condition in which symptoms persist for more than 8 weeks and are present 12 or more weeks following acute infection with SARS-CoV-2. Refer to .
## Disease incidence
### Global
### National
Updated national, provincial and territorial-level data on COVID-19 cases and deaths in Canada over time is available from the PHAC webpage on .
Preparations authorized for use in Canada
When referring to COVID-19 vaccines throughout this chapter, only those currently authorized by Health Canada for use in Canada are included. Refer to for information regarding non-Health Canada authorized vaccines.
# mRNA vaccines
- ComirnatyTM (tozinameran, BNT162b2), Original, (formulations of 30 mcg, 10 mcg or 3 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus), Pfizer and BioNTech Manufacturing GmbH
+ Authorized as a primary series in those 12 years of age and older (30 mcg), children 5 to 11 years of age (10 mcg), and children 6 months of age to less than 5 years of age (3 mcg)
+ Authorized as a booster dose in children 5 to 11 years of age (10 mcg) and those 16 years of age and older (30 mcg)
- Comirnaty® Original & Omicron BA.4/BA.5, (Bivalent), Pfizer and BioNTech Manufacturing GmbH
+ Authorized as a booster dose only, in those 5 to 11 years of age (total 10 mcg of mRNA, with 5 mcg of mRNA encoding for the original SARS-CoV-2 virus and 5 mcg encoding for the Omicron BA.4/5 variant) and 12 years of age and older (total 30 mcg of mRNA, with 15 mcg of mRNA encoding for the original SARS-CoV-2 virus and 15 mcg encoding for the Omicron BA.4/5 variant)
- Comirnaty®Original & Omicron BA.1, (Bivalent, total 30 mcg of mRNA, with 15 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and 15 mcg encoding for the spike protein of the Omicron BA.1 variant), Pfizer and BioNTech Manufacturing GmbH
+ Authorized as a booster dose only, in those 12 years of age and older (30 mcg)
+ This formulation of Comirnaty was not distributed in Canada, so recommendations only refer to the BA.4/5 formulation throughout the rest of the chapter
- SpikevaxTM (elasomeran, mRNA-1273), Original, (formulations of 100 mcg, 50 mcg or 25 mcg of mRNA of mRNA encoding for the spike protein of the original SARS-CoV-2 virus), Moderna TX Inc.
+ Authorized as a primary series for use in those 12 years of age and older (100 mcg), children 6 to 11 years of age (50 mcg) and children 6 months to 5 years of age (25 mcg)
+ Authorized as a booster dose in those 12 years of age and older (50 mcg)
- Spikevax BivalentTM (elasomeran/imelasomeran) Original/Omicron BA. 4/BA.5 (Bivalent, total 50 mcg of mRNA or 25 mcg of mRNA, with half the dose of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and half encoding for the spike protein of the Omicron BA.4/5 variant), Moderna TX Inc.
+ Authorized as a booster dose only, in those 12 years of age and older (50 mcg) and in children 6 to 11 years of age (25 mcg)
- Spikevax BivalentTM (elasomeran/imelasomeran) Original/Omicron BA.1 (Bivalent, total 50 mcg of mRNA or 25 mcg of mRNA, with half the dose of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and half encoding for the spike protein of the Omicron BA.1 variant), Moderna TX Inc.
+ Authorized as a booster dose only, in those 12 years of age and older (50 mcg) and in children 6 to 11 years of age (25 mcg)
COVID-19 vaccines that use mRNA platforms contain modified nucleotides that code for the SARS-CoV-2 spike protein. The mRNA can encode for the spike protein from the original SARS-CoV-2 virus and/or from a variant of concern. A lipid nanoparticle formulation delivers the mRNA into the recipient's cells. Once inside the cytoplasm of a cell, the mRNA provides instructions to the cell's protein production machinery to produce the trans-membrane spike protein antigen that becomes anchored on the cell's external surface. The mRNA does not enter the nucleus of the cell and does not interact with, or alter, human DNA. The immune system is engaged by both the transmembrane spike protein and immune receptors carrying spike antigens to induce humoral and cellular immune responses. The mRNA, lipid nanoparticle, and spike protein are degraded or excreted within days to weeks from time of immunization. mRNA vaccines are not live vaccines and cannot cause infection in the host.
# Protein subunit vaccine
- NuvaxovidTM (SARS-CoV-2 recombinant spike protein of the original strain) with Matrix-M adjuvant, Novavax
+ Authorized for use as a primary series in those 12 years of age and older and a booster dose in those 18 years of age and older (5 mcg of recombinant protein)
Novavax Nuvaxovid consists of a purified full-length SARS-CoV-2 recombinant spike protein nanoparticle co-formulated with the adjuvant Matrix-M. Matrix-M is a novel saponin-based adjuvant that facilitates activation of the cells of the innate immune system, which enhances the magnitude of the spike protein-specific immune response. Matrix-M has been used in Novavax Nuvaxovid clinical trials and in pre-licensure studies targeting other pathogens, but has not previously been used in any licensed vaccine.
# Virus-like particle (VLP) vaccine
The Medicago Covifenz®COVID-19 vaccine was the first virus-like particle (VLP) COVID-19 vaccine authorized in Canada. Medicago Covifenz was authorized for use in adults 18 to 64 years of age as a primary series but was not marketed.
# Viral vector (non-replicating) vaccines
- Vaxzevria™ (ChAdOx1-S recombinant), AstraZeneca Canada Inc.
+ Authorized for use in those 18 years of age and older (5 x 1010 viral particles)
+ Vaxzevria is no longer available in Canada
- Jcovden COVID-19 vaccine (Ad26.COV2.S), Janssen Inc.
+ Authorized for use in those 18 years of age and older as a primary series and as a booster (5 x 1010 virus particles)
COVID-19 vaccines based on viral vector platforms use a modified virus to carry genes that encode SARS-CoV-2 spike proteins into the host cells. The vector virus is a type of adenovirus that has been modified to carry COVID-19 genes and to prevent replication of the adenovirus so that it does not cause disease. Once inside the cell, the SARS-CoV-2 spike protein genes are transcribed into mRNA in the nucleus and translated into proteins in the cytosol of the cell. The AstraZeneca Vaxzevria vaccine (and the version manufactured by the Serum Institute of India and marketed briefly in Canada as COVISHIELD) uses a modified chimpanzee adenovirus vector (ChAd) and the Janssen Jcovden vaccine uses a modified human adenovirus serotype 26 vector (Ad26).
# Anti-SARS-CoV-2 monoclonal antibodies authorized for pre-exposure prophylaxis of COVID-19
- EVUSHELD™ (tixagevimab and cilgavimab), AstraZeneca Canada Inc.
+ Authorized for use in those 12 years of age and older weighing at least 40 kg (300 mcg of tixagevimab and 300 mcg of cilgavimab administered in sequence)
Tixagevimab and cilgavimab are two recombinant human monoclonal antibodies with amino acid substitutions to extend antibody half-life and thus duration of protection, as well as minimize the potential risk of antibody-dependent enhancement of disease. In addition to authorization for pre-exposure prophylaxis, Evusheld has also been authorized to treat mild to moderate COVID-19.
Up to date information on alerts, including risk of treatment failure of specific anti-SARS-CoV-2 monoclonal antibodies as well as safety and recalls, is available from .
For complete prescribing information for any of the , consult the product leaflet or information contained within Health Canada's authorized product monographs available through the .
Immunogenicity, efficacy and effectiveness
# Immunogenicity
All COVID-19 vaccines induce humoral immune responses, including binding and neutralizing antibody responses. As well, all authorized COVID-19 vaccines have been shown to produce cellular immune responses in adult populations. The immune responses may vary depending on the product used, number of doses, interval between the doses, and the age and underlying medical conditions of the vaccine recipient. No immunological correlate of protection has been determined for SARS-CoV-2, and therefore the implications of differences in immune responses post-COVID-19 vaccination on protection against infection and severe disease, as well as on duration of protection, is uncertain.
# Efficacy and effectiveness
Efficacy and effectiveness of COVID-19 vaccines tends to be lowest against infection, somewhat higher against symptomatic disease and highest against severe disease. Vaccine effectiveness varies by variant. Clinical trials for original COVID-19 vaccines were conducted mostly when the original or Alpha VOC strains were circulating and prior to the emergence of Omicron. Compared to the original SARS-CoV-2 strain and earlier variants, COVID-19 vaccines have substantially lower vaccine effectiveness for Omicron sublineages when assessed against infection/symptomatic disease and also somewhat lower vaccine effectiveness against severe disease.
Vaccine effectiveness decreases over time since vaccination. Vaccine efficacy as determined by clinical trials was generally assessed within a few months of vaccination. Subsequent effectiveness studies have demonstrated waning over time, particularly against infection and symptomatic disease, and to a lesser extent against severe disease as well. Booster doses are intended to increase protection, particularly against severe disease, that may have decreased over time.
Similar to factors that impact the immune response, vaccine effectiveness may be affected by the vaccine product received, the interval between doses, the time since the most recent dose, the age and health status of the recipient and their prior SARS-CoV-2 infection history. Protection is higher in those with previous SARS-CoV-2 infection and vaccination (hybrid immunity) than in those who have only previously been vaccinated or infected. A recent Omicron sublineage infection combined with COVID-19 vaccination provides the best protection against future Omicron sublineage infection and severe disease. Bivalent vaccines offer similar or somewhat greater protection than original monovalent vaccines against Omicron infection/symptomatic disease, with limited evidence available with regard to severe disease.
Vaccine effectiveness against transmission is also measured in some studies. To the extent that COVID-19 vaccines protect against infection, they also prevent transmission as those who are not infected cannot spread infection to others. In addition, vaccination may offer additional protection against transmission even if infection is not prevented. This has been demonstrated particularly with a booster dose, although the duration of this protection against transmission remains uncertain.
## Efficacy of the primary series against symptomatic COVID-19 disease
In clinical trials, the original mRNA COVID-19 vaccines have been shown to be highly efficacious in the short term against confirmed symptomatic COVID-19 disease. There is similar efficacy in adults with 1 or more comorbidities, as well as in children (5 to 11 years), adolescents (12 to 17 years) and adults (18 years of age and older). There is some evidence of waning of immunogenicity and effectiveness over time that varies by age and vaccine interval.
Vaccine efficacy was assessed among children aged 6 months to 4 to 5 years following one and two doses of Moderna Spikevax (25 mcg) mRNA COVID-19 vaccine and three doses of Pfizer-BioNTech Comirnaty (3 mcg) mRNA COVID-19 vaccine, during a time when Omicron was the predominant variant of SARS-CoV-2. For Moderna Spikevax, efficacy against confirmed symptomatic infection starting 14 days after dose 2 among participants without evidence of prior SARS-CoV-2 infection was estimated at 50.6% among study participants aged 6 to 23 months with a median follow-up of 68 days and 36.8% among participants aged 2 to 5 years with a median follow-up of 72 days. For Pfizer-BioNTech Comirnaty, among children without prior infection, vaccine efficacy about 2 months following the third dose was estimated at 75.8% among children 6 to 23 months of age and 71.8% among children 2 through 4 years of age.
Clinical trial data available to date have shown that Novavax Nuvaxovid COVID-19 vaccine was highly efficacious (approximately 90% against Alpha and 80% against Delta) in preventing confirmed symptomatic COVID-19 disease in the short term during a time period when these variants predominated. However, efficacy was lower against the Beta variant in a study from South Africa (48.6%). A cohort study from Australia looking at vaccine effectiveness against Omicron infection (both symptomatic and asymptomatic), suggested a relatively higher effectiveness of original mRNA vaccines than viral vector and protein subunit vaccines.
The Janssen Jcovden COVID-19 vaccine demonstrated moderate efficacy against symptomatic confirmed moderate to severe COVID-19 infection from 14 days and 28 days post-vaccination of approximately 66% and 67% respectively in the primary analysis, prior to the emergence of SARS-CoV-2 variants. Estimates in the final analysis inclusive of variants prior to Omicron, against moderate to severe COVID-19 at least 14 days after vaccination with a median follow-up of 4 months was approximately 56%.
Decreased protection against infection/symptomatic disease over time has been noted to occur with mRNA vaccines, the protein subunit vaccine and the viral vector vaccines. Shorter intervals between the first and second dose of a 2-dose COVID-19 vaccine series result in lower initial titres that may result in protection that decreases sooner. Observational studies show a reduction in vaccine effectiveness against infection/symptomatic disease in immunocompromised adults when compared to the general population with a 2-dose vaccine series.
## Efficacy and effectiveness of the primary series against severe disease
The clinical trials of the authorized and available COVID-19 vaccines assessed efficacy against severe COVID-19 disease, but not all provided sufficient data to be able to assess the efficacy against hospitalizations or deaths.
Real world evidence suggests moderate to high vaccine effectiveness at preventing severe illness, such as hospitalization and death, which is sustained out to at least 6 months in most populations ages 12 years and older. There is some decline noted in older adults (such as those 80 years of age and over) and residents in long term care homes in overall effectiveness over time, although protection against severe outcomes appears to be more durable than protection against infection. Effectiveness estimates suggest the Pfizer-BioNTech Comirnaty (10 mcg) original vaccine in children 5 to 11 years of age for the primary series is similarly effective against severe disease due to Omicron as it is in older populations. Vaccine effectiveness against severe disease is unknown for Novavax Nuvaxovid as well as Moderna Spikevax original (50 mcg) vaccine in children 6 to 11 years. There were no deaths or cases of severe COVID-19 among trial participants 6 months to 5 years of age for the Moderna Spikevax original (25 mcg) vaccine. Therefore, efficacy against outcomes of severe COVID-19 could not be estimated. Similarly, efficacy against severe disease was not evaluated for Pfizer-BioNTech original (3 mcg) for children 6 months to 4 years of age due to very few events, including no deaths in the clinical trial.
## Effectiveness of the primary series against hospitalization due to MIS-C
Real world evidence suggests the Pfizer-BioNTech Comirnaty COVID-19 original vaccine has high vaccine effectiveness at preventing hospitalization due to multisystem inflammatory syndrome in children (MIS-C) among adolescents 12 to 18 years of age. Among children 5 to 11 years of age, a systematic review and meta-analysis of the efficacy and safety of mRNA COVID-19 vaccines found that 2-dose mRNA vaccination is associated with lower risks of asymptomatic and symptomatic SARS-CoV-2 infections as well as hospitalization and MIS-C.
There were no cases of MIS-C among trial participants 6 months to 5 years of age for the Moderna Spikevax original (25 mcg) vaccine; however, one case of MIS-C was reported in a placebo recipient after the data cut-off. In the Pfizer-BioNTech Comirnaty study for children 6 months to 4 years of age, there were no cases of MIS-C identified. Therefore, efficacy against MIS-C was not able to be evaluated in either of these studies of young children.
There are no results specific to other COVID-19 vaccines yet, however studies are ongoing.
## Effectiveness of vaccination against post-COVID-19 condition
Post COVID-19 condition (PCC) is a condition in which symptoms following a SARS-CoV-2 infection persist for more than 8 weeks and are present for 12 or more weeks following the acute phase. To the extent that vaccines prevent infection, they also prevent PCC as those who are not infected cannot develop PCC. Evidence suggests that receipt of 2 doses of COVID-19 vaccine prior to infection decreases the odds of PCC compared to those who are unvaccinated. The impact of a third dose prior to infection on preventing PCC after breakthrough disease is currently uncertain. Whether vaccination following SARS-CoV-2 infection can decrease the risk of PCC remains to be established. Research has not demonstrated a worsening of existing PCC symptoms with vaccination.
## Efficacy and effectiveness of the primary series against asymptomatic infection
Clinical trials for currently authorized COVID-19 vaccines were primarily designed to evaluate efficacy against symptomatic illness and conducted prior to the emergence of Omicron. While data on efficacy against asymptomatic infection remain limited, effectiveness studies have generally found that effectiveness against infection is somewhat lower than against symptomatic disease. Previous infection, particularly a previous Omicron infection, in combination with vaccination (hybrid immunity) improves protection against infection.
## Vaccine effectiveness of booster doses
Booster doses improve the immune response and vaccine effectiveness that has decreased over time. A booster dose achieved very high vaccine effectiveness (generally >90%) against the Delta variant for infection/symptomatic disease and severe disease. Against Omicron, a booster dose increased protection compared to pre-booster levels, however after a booster dose, protection against infection/symptomatic disease was approximately 60% (ranging from approximately 40 to 80%) and decreased over time. Protection against severe Omicron disease after a booster dose was higher at around 90%, and generally remained above 70% for approximately 6 months post booster dose. Subsequent booster doses raise protection again, but waning continues to occur, particularly against infection/symptomatic disease.
Several studies have shown that bivalent booster doses increase protection against symptomatic infection and severe disease compared to those who received original monovalent vaccine sometime in the past. These studies cannot determine if the increase in protection is due to receiving a booster dose or specifically due to the booster dose. Some studies have tried to more directly compare bivalent and original monovalent vaccines given at similar points in time, and have shown that the bivalent vaccine produces similar or somewhat higher protection against SARS-CoV-2 infection/symptomatic disease, but there is limited data with regard to severe disease.
Recommendations for use
# Children
## Recommendations for children 6 months to 4 years of age (not moderately to severely immunocompromised)
It is recommended that children 6 months to 4 years of age may be offered a primary series of an mRNA COVID-19 vaccine if they have no contraindications to the vaccine.
- For children who are not moderately to severely immunocompromised a primary series of Moderna Spikevax (25 mcg) consists of two doses for those 6 months to 5 years of age while a primary series of Pfizer-BioNTech Comirnaty (3 mcg) consists of three doses for those 6 months to 4 years of age, using an interval of at least 8 weeks between each dose for both products.
If readily available (i.e., easily available at the time of vaccination without delay or vaccine wastage), the same mRNA COVID-19 vaccine product should be offered for the subsequent dose in a vaccine series started with a specific mRNA COVID-19 vaccine.
If two different products are administered (i.e., a mixed schedule with at least one Moderna Spikevax and one Pfizer-BioNTech Comirnaty dose ), it is recommended that the 3-dose schedule be used. Either product can be used to complete the remaining dose of the 3-dose mixed schedule.
There are currently no recommendations for booster doses in those 6 months to 4 years of age and no product is authorized as a booster dose for this age group.
## Recommendations for children 6 months to 4 years of age who are moderately to severely immunocompromised
It is recommended that children 6 months to 4 years of age who are and do not have contraindications may be offered a primary series that consists of an additional dose of an mRNA COVID-19 vaccine compared to the age-based schedules noted above for non-immunocompromised children. Therefore, a primary series for children who are moderately to severely immunocompromised consists of three doses of the Moderna Spikevax (25 mcg) vaccine for those 6 months to 5 years of age or four doses of the Pfizer-BioNTech Comirnaty (3 mcg) for those 6 months to 4 years of age, using an interval of 4 to 8 weeks between each dose for both products.
Because there are fewer doses in the schedule and may be more acceptable and feasible, the Moderna Spikevax (25 mcg) is the recommended product for those who are moderately to severely immunocompromised, however, four doses of the Pfizer-BioNTech Comirnaty (3mcg) vaccine may be offered if the Moderna Spikevax (25 mcg) is not readily available.
If readily available (i.e., easily available at the time of vaccination without delay or vaccine wastage), the same mRNA COVID-19 vaccine product should be offered for the subsequent dose in a vaccine series started with a specific mRNA COVID-19 vaccine.
For mixed schedules consisting of at least one dose of Moderna Spikevax (25 mcg) and one dose of Pfizer-BioNTech Comirnaty (3 mcg), four doses given 4 to 8 weeks apart are recommended for those who are moderately to severely immunocompromised. Either mRNA product can be used to complete the remaining doses of the four-dose mixed schedule.
There are currently no recommendations for booster doses in those 6 months to 4 years of age and no product is authorized as a booster dose for this age group.
## Recommendations for children 5 to 11 years of age (not moderately to severely immunocompromised)
It is recommended that children who are 5 to 11 years of age should be offered a primary series of an mRNA COVID-19 vaccine if they have no contraindications to the vaccine.
For children 5 to 11 years of age who are not moderately to severely immunocompromised a primary series of an mRNA vaccine consists of 2-doses, with a dosing interval of at least 8 weeks between the first and second dose.
For children 5 to 11 years of age, the use of Pfizer-BioNTech Comirnaty original (10 mcg) COVID-19 vaccine is preferred to Moderna Spikevax original to start or continue the primary vaccine series, due to a potentially lower risk of myocarditis/pericarditis with the Pfizer-BioNTech product. However, Moderna Spikevax original (25 mcg at 5 years of age or 50 mcg from 6 to 11 years of age) vaccine may be offered as an alternative.
Children who have received Pfizer-BioNTech original (3 mcg) starting at 4 years of age and then turn 5 years of age prior to completing their primary series, should be offered three doses in the primary series, however any doses of Pfizer-BioNTech vaccine given at 5 years of age should be 10 mcg. Doses less than 10 mcg at 5 years of age are considered invalid and should be repeated. See PHAC's resource: Quick reference guide on the use of COVID-19 vaccines: .
Children who have received Moderna Spikevax original (25 mcg) for a previous dose at 5 years of age and turn 6 years of age prior to completing their primary series should be offered Moderna Spikevax original (50 mcg) to complete their 2-dose primary series. If the primary series was completed with Moderna Spikevax original (25 mcg) or with Pfizer-BioNTech Comirnaty original (10 mcg), the dose should be considered valid and the primary series complete.
Pfizer-BioNTech Comirnaty original (10 mcg) and Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (10 mcg) are authorized as a booster dose in those 5 to 11 years of age. Moderna Spikevax bivalent BA.1 (25 mcg) and Moderna Spikevax bivalent BA.4/5 (25 mcg) are authorized as a booster dose in those 6 to 11 years of age. A bivalent booster dose is preferred, and should be given ≥ 6 months after completion of a primary COVID-19 vaccine series or previous SARS-CoV-2 infection. It should be offered to children 5 to 11 years of age with an underlying medical condition that places them at high risk of severe illness due to COVID-19, and may also be offered to all other children in this age group.
Only one booster dose after the primary series for children 5 to 11 years of age is recommended. However, at the provider's discretion, a bivalent booster dose (as per recommended interval) could be offered to children considered at high risk of severe COVID-19 who have previously received a booster dose with the original Pfizer-BioNTech Comirnaty mRNA vaccine.
## Recommendations for children 5 to 11 years of age who are moderately to severely immunocompromised
It is recommended that children 5 to 11 years of age who are and do not have contraindications should be offered a primary series of three doses of an mRNA COVID-19 vaccine authorized for their age, using an interval of 4 to 8 weeks between each dose.
Pfizer-BioNTech Comirnaty is generally preferred as a primary series for those 5 to 11 years of age, however, indirect data from adult populations (≥18 years of age) on original mRNA COVID-19 vaccines suggest Moderna Spikevax original (100 mcg) may result in higher vaccine effectiveness after a 2-dose primary series compared to Pfizer-BioNTech Comirnaty original (30 mcg) and is associated with a higher seroconversion rate among adult immunocompromised patients. Given this potential benefit, administration of the Moderna Spikevax original (25 mcg at 5 years of age or 50 mcg at 6 to 11 years of age) vaccine as a 3-dose primary series may be considered for children 5 to 11 years of age who are .
Pfizer-BioNTech Comirnaty original (10 mcg) and Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (10 mcg) are authorized as a booster dose in those 5 to 11 years of age. Moderna Spikevax bivalent BA.1 (25 mcg) and Moderna Spikevax bivalent BA.4/5 (25 mcg) are authorized as a booster dose in those 6 to 11 years of age. A bivalent booster dose is preferred, and is recommended to be given ≥6 months after completion of a 3-dose primary COVID-19 vaccine series, or previous SARS-CoV-2 infection, to children 5 to 11 years of age who are moderately to severely immunocompromised.
Only one booster dose after the primary series for children 5 to 11 years of age is recommended. However, at the provider's discretion, a bivalent booster dose (as per recommended interval) could be offered to children considered at high risk of severe COVID-19 who have previously received a booster dose with the original Pfizer-BioNTech Comirnaty mRNA vaccine.
## Considerations
There is an identified risk of myocarditis or pericarditis with the Moderna Spikevax (50 mcg) original vaccine (Refer to ). The risk in children 6 to 11 years of age is unknown, given the limited use in this age group. However, in adolescents and young adults 12 years of age and older, the rare risk of myocarditis or pericarditis was higher with Moderna Spikevax original (100 mcg) than with Pfizer-BioNTech Comirnaty original (30 mcg) with a primary series. In younger children, vaccine safety surveillance data suggests the risk of myocarditis and/or pericarditis is lower than that of adolescents or young adults. Among children 5 to 11 years of age following vaccination with Pfizer-BioNTech Comirnaty original (10 mcg), only very rare cases of myocarditis/pericarditis were most often reported following the second dose and among males. Therefore, Pfizer-BioNTech Comirnaty original is the preferred product for the primary series in children 5 to 11 years of age.
# Adolescents
## Recommendations for adolescents 12 to 17 years of age (not moderately to severely immunocompromised)
It is recommended that a complete primary series consisting of two doses of an mRNA COVID-19 vaccine should be offered to adolescents 12 to 17 years of age who do not have contraindications to the vaccine.
- The use of Pfizer-BioNTech Comirnaty original (30 mcg) is preferred to Moderna Spikevax original (100 mcg) to start or continue the mRNA primary vaccine series due to a lower risk of myocarditis/pericarditis with the Pfizer-BioNTech product (Refer to ).
- For those who are not moderately to severely immunocompromised, the second dose of the 2-dose primary series of mRNA vaccine should be provided 8 weeks after the first dose.
Eleven year olds who receive the 10 mcg Pfizer-BioNTech Comirnaty original or 50 mcg Moderna Spikevax original for their first dose and who have turned 12 years of age by the time the second dose is due should receive the 30 mcg Pfizer-BioNTech Comirnaty original that is authorized for individuals aged 12 years and older to complete their primary series. The 100 mcg dose of Moderna Spikevax original is also authorized for those 12 years of age and older but Pfizer-BioNTech Comirnaty original is preferred for adolescents due to a lower risk of myocarditis/pericarditis. If the second dose of 10 mcg Pfizer-BioNTech Comirnaty original is given at 12 years of age, the dose is considered invalid. See PHAC's resource: Quick reference guide on the use of COVID-19 vaccines: . If the second dose is 50 mcg Moderna Spikevax original, the dose should still be considered valid and the series complete.
A bivalent booster dose should be offered to 12 to 17 year olds who are at increased risk of severe illness for COVID-19 and may be offered to other 12 to 17 year olds, with an interval of 6 months from the last dose of the primary series or COVID-19 infection. Pfizer-BioNTech Comirnaty bivalent BA.4/5 (30 mcg), Moderna Spikevax bivalent BA.1 (50 mcg) and Moderna Spikevax bivalent BA.4/5 (50 mcg) are authorized booster doses for this age group. Refer to for additional information on booster doses for adolescents 12 to 17 years of age.
It is recommended that a primary series of an authorized protein subunit COVID-19 vaccine (Novavax Nuvaxovid) should be offered to 12 to 17 year olds without contraindications to the vaccine who are not able or willing to receive an mRNA COVID-19 vaccine. Preference of mRNA over Novavax Nuvaxovid is due to the availability of more data with regard to the benefits and risks of mRNA vaccines compared to Novavax Nuvaxovid. Both mRNA vaccines and Novavax Nuvaxovid have been associated with a rare risk of myocarditis/pericarditis.
## Recommendations for adolescents 12 to 17 years of age who are moderately to severely immunocompromised
For adolescents 12 to 17 years of age without contraindications, it is recommended that a primary series of three doses of an mRNA vaccine should be offered with an interval of 4 to 8 weeks between doses.
Pfizer-BioNTech Comirnaty is generally preferred as a primary series for those 12 to 17 years of age, however, indirect data from adult populations (18 years of age and older) on original mRNA COVID-19 vaccines suggest Moderna Spikevax original (100 mcg) may result in higher vaccine effectiveness after a 2-dose primary series compared to Pfizer-BioNTech Comirnaty original (30 mcg) and is associated with a higher seroconversion rate among adult immunocompromised patients. Given this potential benefit, administration of the Moderna Spikevax original (100 mcg) vaccine as a 3-dose primary series may be considered for adolescents 12 to 17 years of age who are .
Pfizer-BioNTech Comirnaty bivalent BA.4/5 (30 mcg), Moderna Spikevax bivalent BA.1 (50 mcg) and Moderna Spikevax bivalent BA.4/5 (50 mcg) are authorized booster doses for this age group. Booster doses should be offered to 12 to 17 year olds who are moderately to severely immunocompromised with an interval of 6 months from the last dose of the primary series or COVID-19 infection.
Based on clinical discretion, Novavax Nuvaxovid should be offered as a 3 dose primary series to moderately to severely immunocompromised individuals 12 years of age and older who are not able or willing to receive an mRNA COVID-19 vaccine at a recommended interval of 4 to 8 weeks between doses. The safety and efficacy of Novavax Nuvaxovid has not been established in individuals who are immunocompromised due to disease or treatment. Informed consent for use of either vaccine type in these populations should include discussion that there is currently limited evidence on the use of Novavax Nuvaxovid in these populations, while there is evidence on the safety profile and effectiveness of mRNA COVID-19 vaccines in these populations based on real world use with large numbers of individuals.
## Considerations
The known risks of COVID-19 illness (including complications like myocarditis/pericarditis) outweigh the potential harms of having an adverse reaction following mRNA vaccination. The risk of myocarditis or pericarditis following mRNA vaccination is rare, relatively mild, and resolves quickly in most individuals. The use of the Pfizer-BioNTech Comirnaty original vaccine is preferred to the Moderna Spikevax original vaccine in individuals 12 to 17 years of age for a primary series because of a lower reported rate of myocarditis/pericarditis following the Pfizer-BioNTech Comirnaty original (30 mcg) compared to the Moderna Spikevax original (100 mcg) vaccine. Additionally, a longer interval between doses is associated with a somewhat higher vaccine effectiveness and potentially lower risk of myocarditis/pericarditis.
# Adults
## Recommendations for adults 18 years of age and older (not moderately to severely immunocompromised)
It is recommended that a complete primary series, preferentially with an mRNA COVID-19 vaccine, should be offered to individuals in the authorized age group without contraindications to the vaccine.
- For those who are not moderately to severely immunocompromised, the second dose of the 2-dose primary series of mRNA vaccine should be provided 8 weeks after the first dose.
There is a preferential recommendation for the use of mRNA COVID-19 vaccines in all authorized age groups due to greater effectiveness of mRNA vaccines and the rare risk of certain serious adverse events with viral vector vaccines, such as vaccine-induced immune thrombotic thrombocytopenia (VITT). Preference of mRNA over Novavax Nuvaxovid is due to the availability of more data with regard to the benefits and risks of mRNA vaccines compared to Novavax Nuvaxovid. Both mRNA vaccines and Novavax Nuvaxovid have a rare risk of myocarditis/pericarditis.
The known risks of COVID-19 illness (including complications like myocarditis/pericarditis) outweigh the potential harms of having an adverse reaction following mRNA vaccination, including the rare risk of myocarditis or pericarditis which despite hospitalization, is relatively mild and resolves quickly in most individuals.
For individuals aged 18 to 29 years receiving an mRNA COVID-19 vaccine primary series:
- The use of Pfizer-BioNTech Comirnaty original (30 mcg) is preferred to Moderna Spikevax original (100 mcg) to start or continue the mRNA primary vaccine series because of a lower reported rate of myocarditis/pericarditis following Pfizer-BioNTech Comirnaty original (30 mcg) compared to Moderna Spikevax original (100 mcg) for the mRNA primary vaccine series.
For adults aged 30 years or older receiving an mRNA COVID-19 vaccine primary series:
- Either of the mRNA COVID-19 vaccines (Moderna Spikevax original or Pfizer-BioNTech Comirnaty original ) should be used to start or continue the primary series given that this age group has a lower risk of vaccine-associated myocarditis/pericarditis.
It is recommended that a primary series of an authorized protein subunit COVID-19 vaccine (Novavax Nuvaxovid) should be offered to individuals 18 years of age and older without contraindications to the vaccine who are not able or willing to receive an mRNA COVID-19 vaccine.
A viral vector COVID-19 vaccine may be offered to individuals in the authorized age group without contraindications to the vaccine only when all other authorized COVID-19 vaccines are contraindicated.
At least one booster dose should be offered to all adults 18 years of age and over. Regardless of past booster doses, adults 65 years of age and over, as well as individuals 12 to 64 years of age who are at increased risk of severe illness from COVID-19 should be offered a COVID-19 booster dose if they have not received one since the start of fall 2022, and all others 12 to 64 years of age may be offered a booster dose. A bivalent mRNA booster dose is preferred. An additional booster dose may also be offered as of spring 2023 to specific groups. Refer to for more information.
The protein subunit COVID-19 vaccine (Novavax Nuvaxovid) containing spike protein from the original SARS-CoV-2 strain is authorized by Health Canada as a booster dose after a primary series with Novavax Nuvaxovid. A bivalent Novavax Nuvaxovid product is not currently available. Novavax Nuvaxovid should be offered to as a booster to adults who are not able or willing to receive an mRNA vaccine.
## Recommendations for adults 18 years of age and older who are moderately to severely immunocompromised
For moderately to severely immunocompromised adults 18 years of age and over, a primary series of three doses, preferentially with an mRNA vaccine, should be offered with intervals of 4 to 8 weeks between doses. Some immunocompromised individuals have a diminished immune response to the vaccines. Moderna Spikevax original (100 mcg) induces somewhat higher antibody levels compared to Pfizer-BioNTech Comirnaty original (30 mcg) and protection (against infection and severe disease) from a primary series with Moderna Spikevax original (100 mcg) may be more durable than Pfizer-BioNTech Comirnaty original (30 mcg).
Based on clinical discretion, Novavax Nuvaxovid should be offered as a 3 dose primary series, at a recommended interval of 4 to 8 weeks between doses, to moderately to severely immunocompromised individuals who are not able or willing to receive an mRNA COVID-19 vaccine. The safety and efficacy of Novavax Nuvaxovid has not been established in individuals who are immunocompromised due to disease or treatment. Informed consent for use of either vaccine type in these populations should include discussion that there is currently limited evidence on the use of Novavax Nuvaxovid in immunocompromised populations, while there is evidence on the safety profile and effectiveness of mRNA COVID-19 vaccines in these populations based on real world use with large numbers of individuals.
Booster doses should be offered to all adults 18 years of age and over who are moderately to severely immunocompromised. Regardless of past booster doses, adults 65 years of age and over, as well as individuals 12 to 64 years of age who are moderately to severely immunocompromised should be offered a COVID-19 booster dose if they have not received one since the start of fall 2022. An additional booster dose may also be offered as of spring 2023 to adults (18 years of age and older) who are moderately to severely immunocompromised. Bivalent vaccines are preferred for all booster doses.
# Schedule
In addition to the information contained in this section, a summary of recommendations, schedules and dosages for most available products can be found on .
## Primary series
For individuals 12 years of age and older, when the first dose in a COVID-19 vaccine series is an mRNA vaccine, the same mRNA vaccine product should be offered for the subsequent dose if readily available. When the same mRNA vaccine product is not readily available, or is unknown, another mRNA COVID-19 vaccine product recommended in that age group can be considered interchangeable and should be offered to complete the series.
For mixed COVID-19 vaccine schedules, the minimum interval between doses should be based on the minimum interval of the product used for the first dose.
Optimal intervals between doses of 8 weeks (or at least 8 weeks) are longer than the authorized intervals as longer intervals are likely to result in a more robust and potentially more durable immune response and potentially higher vaccine effectiveness. Data from adults also suggests an extended interval may be associated with a reduced risk of myocarditis/pericarditis following a second dose of an mRNA COVID-19 vaccine.
(see for those who are moderately to severely immunocompromised)
It is recommended that for moderately to severely immunocompromised individuals, a primary series consists of three doses, preferentially with an mRNA COVID-19 vaccine, noting that for children 6 months to 4 years of age who are moderately to severely immunocompromised and vaccinated with Pfizer-BioNTech Comirnaty (3 mcg), a primary series consists of four doses. Refer to for additional information on schedules and intervals for those who are moderately to severely immunocompromised.
There is evidence that longer intervals between the first and second doses of COVID-19 vaccines are likely to result in more robust and potentially more durable immune response and potentially higher vaccine effectiveness and a lower risk of myocarditis/pericarditis. Balancing this potential enhanced protection from a longer interval with simultaneously minimizing the time at risk of infection due to having protection from only 1 dose, for all COVID-19 vaccines in those who are not moderately to severely immunocompromised, an 8-week (or at least 8 week) interval is recommended.
The basis for this minimum interval is that the per-protocol design for the Pfizer-BioNTech Comirnaty COVID-19 vaccine clinical trial was 19 to 23 days.
The basis for this minimum interval is that the majority of participants in the Moderna Spikevax COVID-19 vaccine clinical trials received the second dose 21 to 42 days after the first, as per the pre-defined window.
The participants in the clinical trial received the second dose a minimum of 28 days after the first dose.
The basis for this minimum interval is that the majority of participants in the Novavax Nuvaxovid clinical trial received the second dose 21+7 days after the first, as per the pre-defined window.
## Moderately to severely immunocompromised individuals
The recommended interval between doses in the primary series for those who are moderately to severely immunocompromised is 4 to 8 weeks.
It is recommended that for moderately to severely immunocompromised individuals, a primary series consists of three doses, preferentially with an mRNA COVID-19 vaccine, noting that for children 6 months to 4 years of age who are moderately to severely immunocompromised and vaccinated with Pfizer-BioNTech Comirnaty (3 mcg), a primary series consists of four doses.
For immunocompromised individuals, providers should aim to provide each dose of the primary series 4 to 8 weeks apart from each other. An interval longer than 4 weeks between each dose is likely to result in a more robust and durable immune response, potentially higher vaccine effectiveness and a lower risk of myocarditis/pericarditis. However, if a longer interval is being considered, risk factors for exposure and risk of severe disease should also be taken into account.
For children 6 months to 4 years of age who are moderately to severely immunocompromised and vaccinated with Pfizer-BioNTech Comirnaty (3 mcg), a primary series consists of 4 doses, using an interval of 4 to 8 weeks between each dose. For children 6 months to 4 years of age who are moderately to severely immunocompromised, Moderna Spikevax original (25 mcg) is the preferred product because it has one fewer dose than Pfizer-BioNTech original (3 mcg) and so may be more acceptable and feasible for this group.
The basis for this minimum interval is that the per-protocol design for the Pfizer-BioNTech Comirnaty original COVID-19 vaccine clinical trial was 19 to 23 days.
The 30 mcg dose of Pfizer-BioNTech Comirnaty original COVID-19 vaccine is authorized for those 12 years of age and older. The 10 mcg dose of Pfizer-BioNTech Comirnaty original COVID-19 vaccine is authorized for those 5 to 11 years of age.
The 100 mcg dose of Moderna Spikevax original COVID-19 vaccine is authorized for those 12 years of age and older. The 50 mcg dose of Moderna Spikevax original COVID-19 vaccine is authorized for those 6 to 11 years of age.
The basis for this minimum interval is that the majority of participants in the Moderna Spikevax original COVID-19 vaccine clinical trials received the second dose 21 to 42 days after the first, as per the pre-defined window.
The participants in the clinical trial received the second dose a minimum of 28 days after the first dose.
mRNA COVID-19 vaccines are preferred and are authorized for a 3-dose primary series in moderately to severely immunocompromised individuals, while Novavax Nuvaxovid is not currently authorized as a 3-dose primary series in these populations. Based on clinical discretion, Novavax Nuvaxovid should be offered as a 3-dose primary series for moderately to severely immunocompromised individuals in the authorized age group who are not able or willing to receive an mRNA COVID-19 vaccine.
An initial or additional dose of a viral vector vaccine should only be considered for those in the authorized age group when all other authorized COVID-19 vaccines are contraindicated.
# Booster doses
All doses of COVID-19 vaccines after the primary series are described as booster doses. Note that for moderately to severely immunocompromised individuals, the primary series includes one additional dose that is not referred to as a booster dose.
Evidence suggests that protection against infection decreases with time from receipt of the last dose of vaccine. Booster doses provides additional protection, including against severe disease. However, the duration of protection is currently unknown, and the absolute benefit of additional booster doses will depend on the residual protection from the previous booster dose and on the level of circulating disease in the community. See for a summary of COVID-19 booster doses by age group.
An mRNA COVID-19 vaccine dose is preferred for the booster dose. Recipients of a viral vector vaccine series completed with only viral vector vaccines (AstraZeneca or Janssen Jcovden COVID-19 vaccine) should receive booster doses with an mRNA vaccine.
Bivalent vaccines are the preferred vaccine for booster doses among individuals in the authorized age groups, as, in addition to containing mRNA that encodes the spike protein of the original strain, they contain mRNA that encodes the spike protein of strains of the Omicron VOC.
Bivalent vaccines that encode for the BA.1 and BA.4/5 sublineages of Omicron are now available. Either type of vaccine can be used for the booster dose in authorized age groups.
## Timing of booster doses
The additional protection from a booster dose may be affected by the interval between doses. A longer time between doses may result in a better response after any subsequent dose, as this allows time for the immune response to mature in breadth and strength and minimizes interference from the response from one dose on the next dose. A longer interval may, however, also increase the chance of a period with waning (lower) protection while awaiting a next dose.
COVID-19 booster doses may be offered at an interval of 6 months after a previous COVID-19 vaccine dose (after completion of the primary series or previous booster dose) or SARS-CoV-2 infection (see ), regardless of the product offered.
- Post-market safety surveillance data to date indicate that the risk of myocarditis following a booster dose is lower compared to that following the second dose in the primary series, and current data do not show a product-specific difference in the risks of myocarditis and/or pericarditis after a booster dose of an mRNA COVID-19 vaccine. Adults can receive a booster dose with any available bivalent Omicron-containing mRNA COVID-19 vaccine.
For booster doses for adults 18 years of age and older who are not able or willing to receive an mRNA COVID-19 vaccine, a protein subunit COVID-19 vaccine (Novavax Nuvaxovid) should be offered to adults without contraindications to the vaccine. Janssen Jcovden COVID-19 vaccine may be offered as a first booster to individuals 18 years of age and older without contraindications to the vaccine only when all other COVID-19 vaccines are contraindicated.
- Adults 80 years of age and older
- Adult residents of long-term care homes and other congregate living settings for seniors or those with complex medical care needs
- Adults 18 years of age and older who are moderately to severely immunocompromised (due to an underlying condition or treatment)
- Adults 65 to 79 years of age, particularly if they do not have a known prior history of SARS-CoV-2 infection.
For individuals in authorized age groups who are not able or willing to receive a bivalent Omicron-containing mRNA COVID-19 vaccine, an original mRNA COVID-19 vaccine may be offered.
Pfizer-BioNTech Comirnaty bivalent BA.4/5 is authorized in individuals 5 years of age and older. Moderna Spikevax bivalent BA.1 is authorized in individuals 6 years of age and older. Moderna Spikevax bivalent BA.4/5 vaccine is authorized in individuals 6 years of age and older.
Vaccination of specific populations
# Pregnancy and breastfeeding
Compared to non-pregnant persons, SARS-CoV-2 infection in pregnancy is associated with increased risk of hospitalization and admission to an intensive care unit (ICU). SARS-CoV-2 infection during pregnancy is also associated with an increased risk in the neonate of preterm birth, low birth weight and admission to a neonatal intensive care unit (NICU).
## Recommendations
It is recommended that a complete vaccine series with an mRNA COVID-19 vaccine should be offered to individuals in the authorized age group who are pregnant or breastfeeding (Refer to section).
Booster recommendations for individuals at increased risk of severe illness from COVID-19 apply to people who are pregnant (see ). An individual may receive all doses for which they are eligible during the course of a pregnancy, regardless of the trimester of pregnancy.
An mRNA vaccine is preferred due to reassuring published data on the safety of these vaccines in pregnancy.
## Considerations
Pregnant or breastfeeding individuals were excluded from COVID-19 vaccine clinical trials. However, analysis of data collected through international COVID-19 immunization registries to date have not revealed any maternal or neonatal safety signals.
Informed consent should include discussion that there is real-world evidence on the safety profile and effectiveness of mRNA vaccination with large numbers of individuals who are pregnant or breastfeeding, but currently limited evidence on the use of the Novavax Nuvaxovid vaccine.
Rates of adverse effects are similar in people who are pregnant or breastfeeding and those who are not pregnant or breastfeeding. Studies have not found any impacts of mRNA COVID-19 vaccination on the infant/child being fed human milk or on milk production or excretion. Vaccination during pregnancy does not increase risk for adverse pregnancy/birth outcomes, including miscarriage, stillbirth, low birth weight, preterm birth and NICU admission.
Evidence suggests that COVID-19 mRNA vaccination during pregnancy results in comparable antibody titres to those generated in non-pregnant women. Maternal IgG humoral response to mRNA COVID-19 vaccines transfers across the placenta to the fetus, leading to a significant and potentially protective antibody titre in the neonatal bloodstream 1 week after the second dose. Infants of people who received the second dose of a primary series or a booster dose during pregnancy had a lower risk of hospitalization with COVID-19 (including Omicron) compared to infants born to individuals who were unvaccinated. The effect was greater with the booster dose than the second dose in a primary series and if the dose was given later in the pregnancy as opposed to earlier. The protection from maternal vaccination against infant hospitalization decreases over time since birth. Observational studies consistently show that both anti-spike IgG and IgA are present in breastmilk for at least 6 weeks after maternal vaccination with mRNA vaccines. The protection against disease as a result of breastfeeding is currently unknown.
Vaccine recipients and health care providers are encouraged to enroll patients who have received a COVID-19 vaccine during pregnancy in COVID-19 vaccine pregnancy registries (see ).
There is a , hosted at the University of British Columbia and supported by the COVID-19 Immunity Task Force (CITF) to assess the safety and effectiveness of COVID-19 vaccines.
# Individuals previously infected with SARS-CoV-2
The immune response due to prior infection may vary due to factors such as the severity of infection, age, presence of comorbidities, the SARS-CoV-2 variant causing the infection, time since the infection and vaccination history. People with both SARS-CoV-2 infection and COVID-19 vaccination are said to have "hybrid immunity" and have the highest vaccine effectiveness against SARS-CoV-2 infection and severe disease compared to either infection or vaccination alone.
## Recommendations
COVID-19 vaccines, with a preference for mRNA vaccines, should or may be offered to individuals 6 months of age and older with previous SARS-CoV-2 infection without contraindications to the vaccine based on the recommendation for their age and other risk factors (see section).
Safety and efficacy data in individuals previously infected with SARS-CoV-2 following vaccination with a protein subunit COVID-19 vaccine are not available.
Previous infection can be defined in different ways based on jurisdictional policies and access to testing. The following suggestion can be considered to define previous infection with SARS-CoV-2:
- Confirmed by a molecular (e.g., PCR) or Health Canada-approved antigen detection-based test; or
- Symptomatic disease compatible with COVID-19 AND household exposure to a confirmed COVID-19 case.
These suggested intervals are based on immunological principles and expert opinion, and may change as evidence on COVID-19, VOCs, and COVID-19 vaccines emerge. When considering whether or not to administer vaccine doses following the suggested intervals outlined in this table, biological and social risk factors for exposure (e.g., local epidemiology, circulating VOCs, living settings) and severe disease should also be taken into account. These intervals are a guide and clinical discretion is advised.
For individuals who have not had any previous doses, they may receive their first dose after acute symptoms of COVID-19 have resolved and they are no longer infectious, or they may follow these suggested intervals. Individual benefit/risk assessment and clinical discretion are advised as per footnote "b". Waiting until at least the infected person is no longer infectious is intended to minimize the risk of transmission of COVID-19 at an immunization venue and to enable monitoring for COVID-19 vaccine adverse events without potential confounding from symptoms of COVID-19.
The primary series is outlined in Recommendations for use. Note that for moderately to severely immunocompromised individuals who were immunized with a primary series that includes one additional dose, a booster dose would be subsequent to that additional dose.
## Considerations
Testing for previous SARS-CoV-2 infection is not needed prior to COVID-19 vaccination.
A longer interval between infection and vaccination may result in a better immune response from the infection as this allows time for this response to mature in breadth and strength, and for circulating antibodies from the infection to decrease, thus avoiding immune interference when the vaccine is administered.
Current evidence suggests protection is more robust and longer lasting with vaccination in previously infected individuals compared to immunity from SARS-CoV-2 infection alone.
COVID-19 vaccination in individuals previously infected with SARS-CoV-2 has a good safety profile and is well tolerated. Limited evidence suggests reactogenicity may be slightly increased in individuals previously infected with SARS-CoV-2 compared to those with no history of previous infection, however this evidence is limited to the primary series and variants prior to Omicron.
# Immunocompromised persons
## Recommendations
Those who are moderately to severely immunocompromised should receive an additional dose in the primary series and then subsequent booster doses as recommended following the primary series. Refer to for specific recommendations based on age for those who are moderately to severely immunocompromised.
## Considerations
Immunocompromised individuals, including those receiving immunosuppressive therapy, are at increased risk for prolonged infection and serious complications from SARS-CoV-2 infection. Numerous studies have shown that immunogenicity is substantially decreased in some immunocompromised individuals when compared to healthy vaccine recipients, although evidence is limited to studies in adolescent and adult populations. Observational studies in adults with complete 1 or 2 dose series, show lower vaccine effectiveness against SARS-CoV-2 infection and COVID-19 disease in immunocompromised adults when compared to the general population.
The minimum interval between the initial doses of the primary series and the additional dose should be 28 days but can up to 8 weeks. An interval longer than the minimum 28 days between doses is likely to result in a better immune response. However, moderately to severely immunocompromised individuals (after the initial 1- or 2- doses of the primary series) may still be susceptible during this time before the next dose is administered. If a longer interval between doses is being considered, then the need for earlier protection due to risk of exposure (including local transmission of SARS-CoV-2, circulation of VOC) and risk of severe disease (e.g., underlying high risk medical condition) should be taken into account.
A vaccine series should ideally be completed at least 2 weeks before initiation of immunosuppressive therapies where possible.
Moderately to severely immunocompromised includes individuals with the following conditions:
- Immunocompromised due to solid tumour or hematologic malignancies or treatments for these conditions
- Solid-organ transplant and taking immunosuppressive therapy
- Hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppression therapy)
- Immunocompromise due to chimeric antigen receptor (CAR) T cell therapy targeting lymphocytes
- Moderate to severe primary immunodeficiency with associated humoral and/or cell-mediated immunodeficiency or immune dysregulation
- HIV with AIDS-defining illness or TB diagnosis in last 12 months before starting vaccine series, or severe immune compromise with CD4<200 cells/uL or CD4%<15%, or without HIV viral suppression
- Recent treatment with the following categories of immunosuppressive therapies: anti-B cell therapies (monoclonal antibodies targeting CD19, CD20 and CD22), high-dose systemic corticosteroids, alkylating agents, antimetabolites, or tumor-necrosis factor (TNF) inhibitors and other biologic agents that are significantly immunosuppressive
- Chronic kidney disease on dialysis
A range of factors can impact the relative degree of immunocompromise and response to COVID-19 vaccines, and clinical and public health judgement should be applied. Jurisdictions may modify the list based on population considerations.
Novavax Nuvaxovid is not currently authorized as a 3-dose primary series and the safety and efficacy of Novavax Nuvaxovid has not been established in individuals who are immunocompromised due to disease or treatment. Based on clinical discretion, Novavax Nuvaxovid should be offered as a 3-dose primary series for moderately to severely immunocompromised individuals in the authorized age group who are not able or willing to receive an mRNA COVID-19 vaccine. Informed consent should include discussion that there is currently limited evidence on the use of Novavax Nuvaxovid in this population, while there is evidence on the safety profile and effectiveness of mRNA COVID-19 vaccines based on real world use with large numbers of individuals.
Evidence indicates that humoral immune responses increase in some individuals after a third dose of mRNA COVID-19 vaccine is administered as part of an extended primary series to adults with immunocompromising conditions, although the degree of increase varies between studies and according to the type of immunocompromising condition or treatment.
Studies assessing additional doses in immunocompromised individuals have primarily used mRNA vaccines, for both the initial and additional doses in the primary series, and are limited to studies in adult populations. Moderna Spikevax vaccines may produce a greater immune response in this population. Investigations are ongoing.
In observational studies and clinical trials, humoral and cellular immune responses were similar between fully vaccinated people living with HIV on antiretroviral therapy and those who were HIV-negative.
Based on observational studies, the frequency and severity of AEFIs with an mRNA COVID-19 vaccine in certain immunocompromised populations were comparable to those of non-immunosuppressed individuals. No worsening of underlying disease was reported after immunization.
# Travellers
Travellers should receive a complete series of COVID-19 vaccine and optimally should receive a booster dose, if they are eligible, at least 2 weeks prior to departure. Travellers should verify the travel requirements in place at their destination(s) and for their return to Canada. For more information, refer to the .
# Persons new to Canada
Based on a recommendation by PHAC to provinces and territories, people who are planning to live, work or study in Canada who have had only a complete or incomplete primary series of non-Health Canada authorized vaccines, should be offered an additional dose of an mRNA vaccine, unless they have already received 3 doses of a COVID-19 vaccine. They should receive booster doses when eligible.
Serologic testing
Serologic testing is not needed before or after immunization with COVID-19 vaccine.
Administration practices
# Dose and route of administration
## Dose
### Pfizer-BioNTech Comirnaty COVID-19 original vaccine (30 mcg)
This formulation has a grey cap and a grey label border and is authorized for use in individuals 12 years of age and older.
No dilution is required.
Each dose is 0.3 mL, containing 30 mcg of SARS-CoV-2 spike protein mRNA.
Special precaution should be taken to ensure the correct dose is taken from the multi-dose vial.
### Pfizer-BioNTech Comirnaty COVID-19 original vaccine (10 mcg, pediatric formulation)
This formulation has an orange vial cap and orange label border and is authorized for use in children 5 to 11 years of age.
Dilute with 1.3 mL 0.9% Sodium Chloride Injection, USP prior to use.
Each dose is 0.2 mL after dilution, containing 10 mcg of SARS-CoV-2 spike protein mRNA.
Special precaution should be taken to ensure the correct dose is taken from the multi-dose vial.
### Pfizer-BioNTech Comirnaty COVID-19 vaccine (3 mcg, pediatric formulation)
This formulation has a maroon vial cap and maroon label border and is authorized for use in children 6 months to 4 years of age.
Dilute with 2.2 mL 0.9% Sodium Chloride Injection, USP prior to use.
Each dose is 0.2 mL after dilution, containing 3 mcg of SARS-CoV-2 spike protein mRNA.
Special precaution should be taken to ensure the correct dose is taken from the multi-dose vial.
### Pfizer-BioNTech Comirnaty Original & Omicron BA.4/BA.5 COVID-19 vaccine (Bivalent)
There are two formulations of Pfizer-BioNTech Comirnaty bivalent BA.4/5 vaccine authorized for use.
- Vials with a gray cap and gray label border containing 30 mcg of mRNA (15 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and 15 mcg of mRNA encoding for the spike protein of the Omicron BA.4/BA.5 variant). This vaccine authorized for use in individuals 12 years of age and older. Each dose is 0.3 mL. No dilution is required.
- Vials with an orange cap and an orange label border containing 10 mcg of mRNA (5 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and 5 mcg of mRNA encoding for the spike protein of the Omicron BA.4/BA.5 variant). This vaccine authorized for use in individuals 5 to 11 years of age. Each dose is 0.2 mL after dilution with 1.3 mL sterile 0.9% Sodium Chloride Injection, USP prior to use.
### Moderna Spikevax original COVID-19 vaccine
There are two formulations of Moderna Spikevax original authorized for use in individuals 6 months of age and older.
- Vials with a red cap and light blue label border containing 0.20 mg/mL in a 5mL multidose vial
- Vials with a royal blue cap and a purple label border containing 0.10 mg/mL in a 2.5mL multidose vial
No dilution is required.
The volume (mL) required for primary series and booster dosing will be different depending on which presentation of the vaccine is being administered. Careful attention should be paid to the vial and carton label, vial cap colour, label border colour and corresponding dose volumes. See for primary series and booster doses of Moderna Spikevax by product and age.
### Moderna Spikevax Bivalent (Original & Omicron BA.1) COVID-19 vaccine
This formulation has a royal blue vial cap and a green label border and is authorized for use as a booster dose in individuals 6 years of age and older.
For individuals 6 to 11 years of age, the booster dose is 0.25 mL containing 25 mcg of mRNA (12.5 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and 12.5 mcg of mRNA encoding for the spike protein of the Omicron BA.1 variant).
For individuals 12 years of age and older, the booster dose is 0.5 mL containing 50 mcg of mRNA (25 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and 25 mcg of mRNA encoding for the spike protein of the Omicron BA.1 variant).
No dilution is required.
Vials contain 0.10 mg/mL in a 2.5 mL multidose vial.
Careful attention should be paid to the vial and carton label, vial cap colour and label border colour. See for booster doses of Moderna Spikevax by product and age.
### Moderna Spikevax Bivalent (Original & Omicron BA.4/5) COVID-19 vaccine
This formulation has a royal blue vial cap and a grey label border and is authorized for use as a booster dose in individuals 6 years of age and older.
For individuals 6 to 11 years of age, each booster dose is 0.25 mL, containing 25 mcg of mRNA (12.5 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and 12.5 mcg of mRNA encoding for the spike protein of the Omicron BA.4/5 variant).
For individuals 12 years of age and older, each booster dose is 0.5 mL, containing 50 mcg of mRNA (25 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and 25 mcg of mRNA encoding for the spike protein of the Omicron BA.4/5 variant).
No dilution is required.
Vials contain 0.10 mg/mL in a 2.5 mL multidose vial.
Careful attention should be paid to the vial and carton label, vial cap colour and label border colour. See for booster doses of Moderna Spikevax by product and age.
0.2 mg/mL
0.1 mg/mL
0.1 mg/mL
0.1 mg/mL
The 0.10 mg/mL presentation is not intended for preparation of the 100 mcg dose.
Moderna Spikevax COVID-19 vaccine (original) is authorized as a booster dose for individuals 12 years of age and older.
Bivalent products are preferred as booster doses for those in the authorized age groups.
The 0.20 mg/mL presentation is not intended for preparation of the 25 mcg dose.
### Novavax Nuvaxovid COVID-19 vaccine
Each dose is 0.5 mL, containing 5 mcg SARS-CoV-2 recombinant original strain spike protein. Vials contain 5 mcg/0.5 mL in a 5.0 mL multidose vial.
The product comes premixed with the Matrix-M adjuvant. No dilution or reconstitution is required.
### Janssen Jcovden COVID-19 vaccine
Each dose is 0.5 mL, containing 5 x 1010 viral particles of SARS-CoV-2 original strain spike protein. The vial contains 3.1 mL in a multidose vial.
No dilution is required.
## Route of administration
COVID-19 vaccines are given as an intramuscular (IM) injection. The deltoid muscle of the arm is the preferred injection site in adolescents and adults, unless the muscle mass is not adequate or vaccination in that site is not possible, in which case the anterolateral thigh can be used.
If an error in vaccine administration occurs, refer to for guidance.
# Interchangeability of vaccines
Regardless of which product is offered, the previous dose should be counted, and the series need not be restarted.
## mRNA COVID-19 vaccines
If readily available (i.e., easily available at the time of vaccination without delay or vaccine wastage), the same mRNA COVID-19 vaccine product should be offered for the subsequent dose in a vaccine series started with an mRNA COVID-19 vaccine. However, when the same mRNA COVID-19 vaccine product is not readily available, or is unknown, another mRNA COVID-19 vaccine product recommended for use in that age group can be considered interchangeable and should be offered to complete the vaccine series.
There are currently only limited data on the use of bivalent Omicron-containing mRNA COVID-19 vaccines as part of a primary series. A primary series with an original mRNA vaccine is recommended in all authorized age groups. If a bivalent vaccine is inadvertently used in the primary series, it is considered valid as long as a valid dosage was used. Refer to for guidance. Bivalent Omicron-containing mRNA vaccines are the preferred booster products for the authorized age groups; however, original strain mRNA vaccines used as a booster dose are considered valid.
## Novavax Nuvaxovid COVID-19 vaccine
Novavax Nuvaxovid should be used to start or complete a primary series, or used as a booster dose in a mixed prime-boost series, for individuals for whom mRNA COVID-19 vaccine is contraindicated, inaccessible, or has been refused.
Informed consent should include a discussion of the benefits and risks given the limited data available on mixed schedules with Novavax Nuvaxovid. There are currently no data on the use of Novavax Nuvaxovid in a mixed primary series with Moderna Spikevax original (100 mcg) or Janssen Jcovden COVID-19 vaccines. Clinical trial evidence for a heterologous booster dose is available from two randomized controlled trials where adults received a booster dose at least 12 weeks after a primary series with mRNA COVID-19 vaccines or viral vector COVID-19 vaccines. In one, humoral and cellular immune responses against original SARS-CoV-2 were lower compared to after Pfizer-BioNTech Comirnaty original or Moderna Spikevax original. In the other, humoral immune responses were similar to or slightly higher. In both trials Novavax Nuvaxovid was less reactogenic compared to mRNA COVID-19 vaccines. Evidence on immune responses against recent Omicron sub-lineages is also available from an observational study that showed that a heterologous booster dose of Novavax Nuvaxovid resulted in neutralizing antibody responses against BQ.1.1 and XBB.1 that were slightly lower (but not statistically significant) compared to responses after a bivalent mRNA booster dose.
## Mixed COVID-19 vaccine schedules
For mixed COVID-19 vaccine schedules, the minimum interval between doses should be based on the minimum interval of the product used for the first dose. When using mixed schedules, the suggested optimal interval between doses is 8 weeks (or at least 8 weeks) for those who are not moderately to severely immunocompromised based on considerations found in .
Evidence indicates that mixed COVID-19 viral vector, mRNA and protein subunit vaccine schedules with dosing intervals between 4 and 12 weeks have acceptable safety profiles.
Limited evidence suggests that a mixed schedule in which Novavax Nuvaxovid is administered following a partial or complete primary series of AstraZeneca Vaxzevria or Pfizer-BioNTech Comirnaty original COVID-19 vaccines may not be as immunogenic as continuing with Pfizer-BioNTech Comirnaty original or Moderna Spikevax original vaccines – despite it having an acceptable safety profile and immunogenicity.
# Concurrent administration with other vaccines
For individuals 6 months of age and older, COVID-19 vaccines may be given concurrently (i.e., same day), or at any time before or after, non-COVID-19 vaccines (including live and non-live vaccines).
It is recommended that COVID-19 vaccines may be concurrently administered with other vaccines among all vaccine eligible populations, as there is, to date, no evidence of safety concerns for concurrent administration. In addition, concurrent administration will reduce barriers to the provision of routine childhood immunizations and seasonal influenza immunization. Studies and surveillance activities to assess the safety and immunogenicity of concurrent administration of COVID-19 vaccines with other vaccines are ongoing.
If more than one type of vaccine is administered at a single visit, they should be administered at different injection sites using separate injection equipment. Preferably this is in different limbs, however if the same limb must be used, the injection sites should be separated by at least 2.5 cm (1 inch).
Informed consent should include a discussion of the benefits and risks given the limited data available on administration of COVID-19 vaccines at the same time as, or shortly before or after, other vaccines.
# Pre-vaccination counselling
Prophylactic oral analgesics or antipyretics (e.g., acetaminophen or ibuprofen) should not be routinely used before or at the time of vaccination, but their use is not a contraindication to vaccination. There is currently no evidence of benefit from administration of oral analgesics for the prevention of immunization injection pain or systemic reactions.
Prior to providing a COVID-19 vaccine, informed consent should include discussion about frequently occurring minor adverse events and the risks and symptoms of potential rare severe adverse events.
Anyone receiving a viral vector COVID-19 vaccine (Janssen Jcovden) should be informed of adverse events that may occur following vaccination with viral vector vaccines: Guillain-Barré syndrome (GBS), thrombosis with thrombocytopenia syndrome (TTS) including vaccine-induced immune thrombotic thrombocytopenia (VITT), capillary leak syndrome (CLS), venous thromboembolism (VTE), immune thrombocytopenia (ITP), Bell's palsy and anaphylaxis, and be advised to seek medical attention if they develop signs or symptoms suggestive of these conditions.
Anyone receiving any mRNA COVID-19 vaccine (Pfizer-BioNTech Comirnaty original or bivalent, or Moderna Spikevax original or bivalent) should be informed of the risks associated with mRNA COVID-19 vaccines: myocarditis/pericarditis, Bell's palsy and anaphylaxis, and be advised to seek medical attention if they develop signs or symptoms suggestive of these conditions.
Anyone receiving the Novavax Nuvaxovid vaccine should be informed of the risk of myocarditis/pericarditis and anaphylaxis and also be advised to seek medical attention if they develop signs or symptoms suggestive of these conditions.
# Post-vaccination counselling
Oral analgesics or antipyretics may be considered for the management of adverse events (e.g., pain or fever, respectively), if they occur after vaccination. Analgesics and antipyretics were used in clinical trials of COVID-19 vaccines for the management of pain and/or fever after vaccination.
All vaccine recipients should be instructed to seek medical care if they develop signs or symptoms of a serious adverse event or an allergic reaction following vaccination.
Storage requirements
For information on storage, handling and transport of frozen and thawed vaccine vials, refer to the .
For additional information, consult the product leaflet or information contained within the product monograph available through Health Canada's . Refer to in Part 1 for additional general information.
Safety and adverse events
Evidence on vaccine safety is available from COVID-19 clinical trials and ongoing international COVID-19 vaccine safety monitoring. The clinical trials solicited adverse events for defined lengths of time following a vaccine dose, as well as collecting unsolicited and serious events.
For reported side effects following COVID-19 vaccination in Canada, refer to the .
For individuals who develop AEFIs following COVID-19 vaccination, refer to the section for advice on future vaccinations.
# Very common and common adverse events
Common adverse events are defined as those that occur in 1% to less than 10% of vaccine recipients; very common adverse events occur in 10% or more of vaccine recipients.
## Local
Local adverse events were usually mild or moderate and resolved within a few days of vaccination in all age groups (6 months and older). Pain at the injection site was very common. Redness and swelling were common or very common after administration of any authorized COVID-19 vaccine. Localized axillary (or groin) swelling and tenderness (lymphadenopathy) was a solicited adverse event in the Moderna Spikevax original COVID-19 vaccine clinical trial and was very common after administration of that vaccine.
## Systemic
Systemic adverse events were usually mild or moderate and resolved within a few days of vaccination in all age groups (6 months and older). Fatigue, headache, muscle pain, chills, and joint pain were all either common or very common after the administration of any authorized COVID-19 vaccine.
The most frequent reactions reported for children aged 6 months to 2 years included irritability or crying, sleepiness, and loss of appetite. These reactions are common after childhood vaccination.
## Adverse events in individuals previously infected with SARS-CoV-2
Limited evidence suggests reactogenicity may be slightly increased in individuals previously infected with SARS-CoV-2 compared to those with no history of previous infection; however, this evidence is limited to the primary series and infection with variants prior to Omicron.
## Adverse events following bivalent Omicron- containing mRNA COVID-19 vaccines
Available clinical trial data show that Moderna Spikevax Bivalent BA.1 (50 mcg) administered as a second booster dose to individuals 18 years of age and older had a similar reactogenicity profile to that of Moderna Spikevax original (50 mcg) given as a second booster dose. Post licensure surveillance is ongoing.
There are no clinical safety data currently available for Pfizer-BioNTech Comirnaty Original & Omicron BA.4/5 (30 mcg) bivalent vaccine specifically; however, preliminary post-market safety surveillance data in individuals 12 years of age and older from Canada and the US suggest the BA.4/5 bivalent vaccines are well tolerated with a similar safety profile to the original mRNA COVID-19 vaccines when administered as booster doses.
# Uncommon, rare and very rare adverse events
Uncommon adverse events occur in 0.1% to less than 1% of vaccine recipients. Rare and very rare adverse events occur in 0.01% to less than 0.1% and less than 0.01% of vaccine recipients, respectively. The probability of detection of very rare adverse events in clinical trials is low given clinical trial sample sizes; therefore, ongoing pharmacovigilance is essential.
## Lymphadenopathy
Lymphadenopathy was an unsolicited event that was uncommonly reported after administration of the Pfizer-BioNTech Comirnaty original (both 10 mcg and 30 mcg formulations) and Janssen Jcovden COVID-19 vaccines in clinical trials. As noted above, lymphadenopathy was a solicited adverse event in the clinical trials for Moderna Spikevax original and was very commonly reported.
## Myocarditis or pericarditis following vaccination with an mRNA COVID-19 vaccine
Rare cases of myocarditis (inflammation of the heart muscle) and/or pericarditis (inflammation of the lining around the heart) have been reported following vaccination with COVID-19 mRNA vaccines.
Cases following mRNA COVID-19 vaccination are consistently reported to have occurred:
- More often after the second dose
- Usually within a week after vaccination
- More often in those 12 to 29 years of age
- More often in males
Analyses of primary series surveillance data in Canada, US and European Nordic countries suggests a higher rate of myocarditis/pericarditis cases reported after vaccination with Moderna Spikevax original (100 mcg) compared to Pfizer-BioNTech Comirnaty original (30 mcg) vaccine especially among 12 to 29 year old males following a second dose of vaccine.
Myocarditis unrelated to exposure to COVID-19 disease or COVID-19 vaccines is typically less common in younger children 5 to 11 years of age. Safety surveillance data from the US suggests that the risk of myocarditis or pericarditis may be lower in children aged 5 to 11 years following Pfizer-BioNTech original (10 mcg) vaccination compared to adolescents and young adults (who receive a 30 mcg Pfizer-BioNTech original dose). Among children 5 to 11 years of age following vaccination with Pfizer-BioNTech Comirnaty original (10 mcg), very rare cases were most often reported following dose 2 and among males. The risk of myocarditis or pericarditis with Moderna Spikevax original (50 mcg) in children 6 to 11 years of age is unknown. Post-market safety surveillance is ongoing.
Available post-market vaccine safety data from V-safe, Vaccine Safety Datalink (VSD) and Vaccine Adverse Event Reporting System (VAERS) in the US as of September 2022 show that the Moderna Spikevax (25 mcg) and Pfizer-BioNTech Comirnaty (3 mcg) mRNA COVID-19 vaccines are well tolerated among children aged 6 months to 5 years. No safety signals (including myocarditis) have been identified after administration of about 1.5 million vaccine doses.
Evidence from bivalent and original mRNA COVID-19 vaccines across different age groups show that the risk of myocarditis is lower following boosters compared to dose 2 of the primary series, and that no product-specific difference in the risk of myocarditis has been identified following a booster dose at this time. However, while these observations were also seen in adolescents 12 to 17 years of age, the use of Moderna Spikevax COVID-19 vaccines have been limited in those 5 to 17 years of age.
While long-term follow-up is ongoing, available data indicate that the majority of individuals who reported myocarditis/pericarditis after mRNA COVID-19 vaccination, though requiring hospitalization, have responded well to conservative therapy and tend to recover quickly.
Healthcare providers should consider myocarditis/pericarditis in their evaluation if the patient presents with clinically compatible symptoms (e.g., chest pain, shortness of breath, palpitations) after an mRNA COVID-19 vaccine regardless of timing from vaccination to symptoms onset. Investigations include electrocardiogram, serum troponins and echocardiogram. Abnormal electrocardiogram findings and elevated troponin levels have been frequently noted with myocarditis/pericarditis following mRNA vaccine.
Consultation with a cardiologist, infectious disease specialist, or internal medicine specialist may be advisable to assist in this evaluation, particularly to investigate the many potential causes of myocarditis and pericarditis. Investigations may include diagnostic testing for acute COVID-19 infection (e.g., PCR testing), prior SARS-CoV-2 infection and consideration of other potential infectious or non-infectious etiologies including auto-immune conditions.
## Myocarditis/pericarditis following vaccination with other COVID-19 vaccines
Cases of myocarditis/pericarditis have been rarely reported following the administration of Novavax Nuvaxovid. Australia's Therapeutic Goods Administration (TGA) reports that as of April 16, 2023, over 251,000 doses of Novavax Nuvaxovid had been administered in the country. Myocarditis was reported in approximately 3 to 4 in every 100,000 people who received a dose of this vaccine. Pericarditis was reported in 13 in every 100,000 people. A further breakdown of the rates of myocarditis/pericarditis after Novavax Nuvaxovid by age group (including among adolescents), sex and dose number are not available due to the relatively low number of doses given and reported cases. In Europe, over 345,000 doses of Novavax Nuvaxovid have been administered as of December 31, 2022 and myocarditis has been reported at a rate of 20.3 per million doses. In Japan, over 275,000 doses of Novavax Nuvaxovid have been administered as of December 31, 2022, with no reported cases of myocarditis. In Canada, there have been no reported cases of myocarditis or pericarditis following Novavax Nuvaxovid as of March 26, 2023 (following approximately 32,200 doses administered).
Reports of adverse events noted by the US FDA, suggest increased risks of myocarditis and pericarditis following vaccination with Janssen Jcovden, particularly within 7 days.
## Venous thromboembolism (VTE)
Venous thromboembolism (VTE) has been observed rarely following vaccination with the Janssen Jcovden COVID-19 Vaccine. In individuals with a pre-existing increased risk for thromboembolism, the possible increased risk of VTE with vaccine use should be considered. See the section if considering the use of Janssen Jcovden in an individual with a history of VTE.
## Guillain-Barré syndrome (GBS) following vaccination with viral vector COVID-19 vaccines
Guillain-Barré syndrome (GBS) is a rare but potentially serious immune-mediated neurologic disorder that results in numbness, muscle weakness and/or paralysis in severe cases, as well as pain, often in the back or legs. Most people fully recover from GBS but some have residual deficits or symptoms and rarely, fatal cases can occur. To date, no increased risk of GBS has been identified following vaccination with the mRNA COVID-19 vaccines (Pfizer-BioNTech Comirnaty original and Moderna Spikevax original). Investigations have identified an increased risk of GBS following vaccination with the viral vector COVID-19 vaccines (AstraZeneca Vaxzevria and Janssen Jcovden).
Symptoms of GBS may include:
- weakness or tingling sensations, especially in the upper or lower limbs, that worsens and spreads to other parts of the body
- coordination problems and unsteadiness
- difficulty walking
- weakness in the limbs, chest or face
- pain that can be severe, particularly at night
- difficulty with bladder control and bowel function
- double vision or difficulty moving eyes
- difficulty with facial movements, including swallowing, speaking, or chewing
Individuals should seek medical attention if they develop symptoms of GBS following vaccination. Healthcare providers should consider GBS in their evaluation if the patient presents with clinically compatible symptoms and exclude other potential causes.
See the section regarding individuals who developed GBS after COVID-19 vaccination for advice on re-vaccination.
## Bell's palsy
Very rare cases of Bell's palsy (typically temporary weakness or paralysis on one side of the face) have been reported following vaccination with Janssen Jcovden COVID-19 vaccine and COVID-19 mRNA vaccines (Pfizer-BioNTech Comirnaty original or Moderna Spikevax original) among individuals aged 12 years and older. Symptoms of Bell's palsy appear suddenly and generally start to improve after a few weeks. The exact cause is unknown. It's believed to be the result of swelling and inflammation of the nerve that controls muscles on the face.
Symptoms of Bell's palsy may include:
- uncoordinated movement of the muscles that control facial expressions, such as smiling, squinting, blinking or closing the eyelid
- loss of feeling in the face
- headache
- tearing from the eye
- drooling
- lost sense of taste on the front two-thirds of the tongue
- hypersensitivity to sound in the one ear
- inability to close an eye on one side of the face
Individuals should seek medical attention if they develop symptoms of Bell's palsy following receipt of COVID-19 vaccines. Healthcare providers should consider Bell's palsy in their evaluation if the patient presents with clinically compatible symptoms after a COVID-19 vaccine. Investigations should exclude other potential causes of facial paralysis.
## Multisystem inflammatory syndrome in children or in adults (MIS-C or MIS-A) following vaccination with an mRNA COVID-19 vaccine
During the manufacturer-led clinical trials for mRNA COVID-19 vaccines, no cases of MIS-C were reported among children or adolescents. However, any rare or very rare AE that occurs at a frequency less often than 1 in 10,000 would likely not be detected due to the limitations of the trial size.
Very rare cases of MIS-C or MIS-A have been reported following vaccination with COVID-19 mRNA vaccines in Canada and internationally among individuals aged 12 years and older. In October 2021, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (EMA-PRAC) issued a statement that there is currently insufficient evidence regarding a possible link between mRNA COVID-19 vaccines and very rare cases of MIS-C or MIS-A.
## Severe immediate allergic reactions (e.g., anaphylaxis) following vaccination with COVID-19 vaccines
Anaphylaxis is a very rare, severe, life-threatening allergic reaction typically with a rapid onset that involves multiple organ systems and can progress rapidly. Symptoms and signs of anaphylaxis may include but are not limited to generalized urticaria; wheezing; swelling of the mouth, tongue, and throat; difficulty breathing; vomiting; diarrhea; hypotension; decreased level of consciousness; and shock.
Very rare cases of severe immediate allergic reactions (e.g., anaphylaxis) have been reported following vaccination with mRNA COVID-19 vaccines. Most of the reported cases have occurred within 30 minutes of vaccination.
Individuals tend to recover quickly with appropriate treatment and there have been no fatalities nor long-term morbidity observed with any of these severe immediate allergic reactions in Canada.
Studies have shown that individuals with a severe immediate allergic reaction after a previous dose of mRNA vaccine can be re-vaccinated with the same vaccine or another mRNA COVID-19 vaccine following an appropriate medical assessment. In these studies, re-vaccination was safe and well tolerated with predominantly no, or mild, reactions after re-vaccination when provided in a controlled environment. Available evidence also suggests that most of the reported severe immediate allergic reactions following mRNA COVID-19 vaccines are likely not immunoglobulin E (IgE)-mediated and therefore have a low risk of recurrence following future vaccine doses. Refer to below for additional information.
## Thrombosis with thrombocytopenia syndrome (TTS) following vaccination with viral vector COVID-19 vaccines
Very rare cases of serious blood clots or thrombosis (at unusual sites such as cerebral venous sinus thrombosis, splanchnic vein thrombosis, as well as arterial thrombosis) associated with thrombocytopenia have been reported following vaccination with viral vector COVID-19 vaccines. The Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) uses the Brighton Collaboration case definition for TTS to detect and evaluate reported cases. In Canada, TTS cases that test positive for a biomarker, anti-PF4 (antibodies to platelet factor 4-polyanion complexes), represent a subset of events and are being referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT).
The exact mechanism by which the viral vector COVID-19 vaccines trigger this syndrome is still under investigation. Viral vector vaccines appear to trigger a presentation similar to spontaneous heparin-induced thrombosis (HIT)/autoimmune heparin-induced thrombosis, where antibodies to platelet factor 4 (PF4)-polyanion complexes induce platelet activation, which causes thrombosis and thrombocytopenia. Clots related to VITT can be very aggressive and challenging to treat. Please refer to . They cannot be managed the same way as clots related to oral contraceptives, immobility, or long-haul flights, and have an entirely different biologic pathophysiology.
Cases of TTS usually occur between 4 and 28 days after receipt of a viral vector COVID-19 vaccine, and patients should be monitored for symptoms up to 42 days. The rate of TTS after the first dose is estimated to be between 1 per 26,000 and 1 per 100,000 doses of AstraZeneca Vaxzevria COVID-19 vaccine administered and 1 per 300,000 doses of Janssen Jcovden COVID-19 vaccine administered. The frequency of TTS following a second dose of AstraZeneca Vaxzevria vaccine appears to be lower at about 1 per 520,000 doses administered. After the first dose, there was a higher reported incidence rate of TTS in the younger adults compared to the older adults. The reported incidence was also higher in women compared to men in some age groups. The case fatality rate ranges between 20 and 50%. Many cases have been reported to have serious long-term morbidity, including neurologic injury.
Anyone receiving a viral vector COVID-19 vaccine should be informed of the adverse event of TTS and advised to seek immediate medical attention if they develop symptoms following vaccination.
Symptoms of TTS may include the following, noting that some symptoms may be dependent on the location of the blood clot:
- shortness of breath
- chest pain
- leg swelling or pain
- persistent abdominal pain
- sudden onset of severe headaches
- persistent or worsening headaches
- blurred vision
- confusion or seizures
- skin bruising (other than at the site of vaccination) or petechiae
Healthcare professionals should be aware of TTS including how to diagnose and treat the condition (see ). People who developed TTS after a viral vector vaccine should not receive additional viral vector vaccines. Refer to the section.
## Capillary leak syndrome (CLS) following vaccination with viral vector COVID-19 vaccines
Very rare cases of CLS have been reported following immunization with the viral vector COVID-19 vaccines (AstraZeneca Vaxzevria and Janssen Jcovden). CLS is a very rare, serious condition that causes fluid leakage from small blood vessels (capillaries), resulting in swelling mainly in the arms and legs, low blood pressure, thickening of the blood and low blood levels of albumin (an important blood protein). Symptoms are often associated with feeling faint (due to low blood pressure).
The frequency of CLS has been estimated at less than 1 per million doses of viral vector vaccines administered. Some of those affected had a history of CLS. People with a history of CLS should not be offered viral vector vaccines. Refer to the section.
## Immune thrombocytopenia (ITP) following vaccination with viral vector COVID-19 vaccines
Cases of immune thrombocytopenia with very low platelet levels (<20,000 per uL) have been reported very rarely after vaccination with Janssen Jcovden and AstraZeneca Vaxzevria COVID-19 vaccines, usually within the first four weeks after vaccination. This included cases with bleeding and cases with fatal outcome. Some of these cases occurred in individuals with a history of immune thrombocytopenia (ITP). If an individual has a history of ITP, the risks of developing low platelet levels should be considered before vaccination with a viral vector vaccine, and platelet monitoring is recommended after vaccination.
# Guidance on reporting adverse events following immunization (AEFI)
Vaccine providers are asked to report AEFIs through local public health departments and to follow AEFI reporting requirements that are specific to their province or territory. In general, any serious (defined as resulting in hospitalization, permanent disability or death) or unexpected adverse event that is temporally related to vaccination should be reported. Refer to for additional information on the completion and submission of AEFI reports.
At the international level, the Brighton Collaboration has developed a list of Adverse Events of Special Interest (AESI). AESI are pre-specified medically significant events that have the potential to be causally associated with a vaccine product. Refer to for the list of AESIs and for case definitions of specific AEFIs.
# Contraindications and precautions
## Contraindications
### Thrombosis with thrombocytopenia syndrome (TTS) following vaccination
Patients who have experienced venous and/or arterial thrombosis with thrombocytopenia following vaccination with a viral vector COVID-19 vaccine should not receive a subsequent dose of a viral vector COVID-19 vaccine. They may receive further doses of mRNA COVID-19 vaccines following consultation with their clinical team which may include a hematologist.
### Capillary leak syndrome (CLS)
As a precautionary measure following the international cases that have been reported, individuals with a history of CLS (related or not to previous vaccination) should not receive viral vector COVID-19 vaccines.
## Precautions
### Hypersensitivity and allergies
Severe immediate allergic reaction (e.g., anaphylaxis) to a COVID-19 vaccine
In individuals with a history of a severe, immediate (4 hours or less following vaccination) allergic reaction after previous administration of an mRNA COVID-19 vaccine, re-vaccination may be offered with the same vaccine or the same platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Consultation with an allergist or other appropriate physician should be sought prior to re-vaccination. If re-vaccinated, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis. Individuals should be observed for at least 30 minutes after re-vaccination. For example, a longer period of observation is warranted for individuals exhibiting any symptom suggestive of an evolving AEFI at the end of the 30-minute observation period.
For those with a previous history of allergy to an mRNA vaccine where consultation with an allergist or other appropriate physician precludes further vaccination with an mRNA vaccine, vaccination with Novavax Nuvaxovid should be offered if the individual is in the authorized age group and does not have contraindications to the vaccine. They should also be observed for an extended period of at least 30 minutes after re-vaccination.
Confirmed allergies to a component of a COVID-19 vaccine
Ingredients of authorized COVID-19 vaccines that have been associated with allergic reactions in other products are: polyethylene glycol (PEG), tromethamine (trometamol or Tris) and polysorbate 80. There is a potential of cross-reactive hypersensitivity between PEG and polysorbate.
In individuals with a confirmed severe, immediate (≤4 hours following exposure) allergy (e.g., anaphylaxis) to a component of a specific COVID-19 vaccine (e.g., PEG), or its container, consultation with an allergist is recommended before receiving the specific COVID-19 vaccine. In individuals with a serious PEG allergy in whom mRNA vaccination is precluded based on a consultation with an allergist or other appropriate physician, vaccination with Novavax Nuvaxovid may be preferred for individuals in the authorized age group without contraindications to Novavax Nuvaxovid. Individuals with a known or suspected serious allergy to a component of a COVID-19 vaccine should be observed for at least 30 minutes after vaccination, if they receive a vaccine containing that component.
It is important to note that other, less serious ) and vaccination is not contraindicated in these cases.
Mild to moderate immediate allergic reactions to a COVID-19 vaccine or a vaccine excipient
In individuals with mild to moderate immediate allergic reactions (defined as limited in the scope of symptoms and involvement of organ systems or even localized to the site of administration) to a previous dose of mRNA COVID-19 vaccine or any of its components, re-vaccination may be offered with the same vaccine or the same platform (i.e., mRNA). Assessment by a physician or nurse with expertise in immunization may be warranted prior to re-immunization.
Most instances of anaphylaxis to a vaccine begin within 30 minutes after administration of the vaccine. Therefore, if re-vaccination is chosen, an extended period of observation post-vaccination of at least 30 minutes should be provided for the aforementioned individuals.
Other allergies
The following individuals may be routinely vaccinated with COVID-19 vaccines with the following recommended observation periods.
30 minute post-vaccination observation period:
- Those with a proven severe allergic reaction (e.g., anaphylaxis) to injectable therapy not related to a component of the COVID-19 vaccines (e.g., other intramuscular, intravenous, or subcutaneous vaccines or therapies)
- Those with a suspected but unproven allergy to a vaccine component (e.g., PEG)
15 minute post-vaccination observation period:
- Those with a history of allergy not related to a component of the COVID-19 vaccines or other injectable therapy (e.g., foods, oral drugs, insect venom or environmental allergens)
### Acute illness
Vaccination of individuals who may be currently infected with SARS-CoV-2 is not known to have a detrimental effect on the illness. However, vaccination should be deferred in individuals with confirmed or suspected SARS-CoV-2 infection, or those with respiratory symptoms, to minimize the risk of COVID-19 transmission at an immunization clinic/venue. If any person is identified with symptoms on arrival at the venue, they should not be immunized and should be instructed to seek medical and public health advice as appropriate and follow current local public health measures.
The recommended intervals between SARS-CoV-2 infection and COVID-19 vaccination are provided in .
### Bleeding disorders
In individuals with bleeding disorders, the condition should be managed prior to immunization to minimize the risk of bleeding. Individuals receiving long-term anticoagulation are not considered to be at higher risk of bleeding complications following immunization and may be safely immunized without discontinuation of their anticoagulation therapy.
### Immune thrombocytopenia (ITP)
If an individual has a history of ITP, the risks of developing low platelet levels should be considered before vaccination with a viral vector vaccine, and platelet monitoring is recommended after vaccination.
Individuals should seek immediate medical attention if they develop symptoms such as unexplained bleeding, unexplained bruising, or small purplish spots beyond the site of vaccination.
### Venous thromboembolism (VTE)
In individuals with a pre-existing increased risk for thromboembolism, the possible increased risk of VTE with the Janssen Jcovden COVID-19 vaccine should be considered. Along with the general preference for mRNA vaccines, mRNA vaccines would be a safer option for these individuals.
Individuals should seek immediate medical attention if they develop symptoms, such as shortness of breath, chest pain, leg pain, leg swelling, or persistent abdominal pain following vaccination.
### Thrombosis with thrombocytopenia syndrome (TTS)
There is no evidence that individuals with previous cerebral venous sinus thrombosis (CVST) with thrombocytopenia not related to a viral vector or people with previous heparin-induced thrombocytopenia (HIT) not related to a viral vector vaccine are at increased risk of vaccine-induced immune thrombotic thrombocytopenia (VITT) compared to other individuals after receiving a viral vector vaccine. However, similar to other individuals, an mRNA vaccine is preferred. Novavax Nuvaxovid should be used among individuals in the authorized age group without contraindications to the vaccine who are not able or willing to receive an mRNA vaccine.
### Myocarditis and/or pericarditis following vaccination
As a precautionary measure until more information is available, further doses of mRNA COVID-19 vaccines should be deferred among individuals who have experienced myocarditis and/or pericarditis within 6 weeks following a previous dose of an mRNA COVID-19 vaccine in most circumstances. This includes any person who had an abnormal cardiac investigation including ECG, elevated troponins, echocardiogram or cardiac MRI after a dose of an mRNA COVID-19 vaccine.
Those with a history compatible with pericarditis and who either had no cardiac workup or had normal cardiac investigations, can receive the next dose once they are symptom-free and at least 90 days have elapsed since vaccination.
Some individuals 5 years of age and older with confirmed myocarditis and/or pericarditis after a dose of an mRNA COVID-19 vaccine may choose to receive another dose of vaccine after discussing the risk and benefit with their healthcare provider. If another dose of vaccine is offered, it should be with a Pfizer-BioNTech Comirnaty COVID-19 vaccine product (original for the primary series or bivalent for the booster dose, at the age-appropriate dose) due to the lower reported rate of myocarditis and/or pericarditis following the Pfizer-BioNTech Comirnaty original (30 mcg) vaccine compared to the Moderna Spikevax original (100 mcg) vaccine among individuals 12 years of age and older. Informed consent should include discussion about the unknown risk of recurrence of myocarditis and/or pericarditis following receipt of additional doses of Pfizer-BioNTech Comirnaty original or bivalent vaccines in individuals with a history of confirmed myocarditis and/or pericarditis after a previous dose of mRNA COVID-19 vaccine, as well as the need to seek immediate medical assessment and care should symptoms develop.
There have been case reports of myocarditis and/or pericarditis following the administration of Novavax Nuvaxovid. Data from the clinical trials and global safety surveillance have suggested an increased risk.
Individuals who have a history of myocarditis unrelated to mRNA or protein subunit COVID-19 vaccination should consult their clinical team for individual considerations and recommendations. If the diagnosis is remote and they are no longer followed clinically for cardiac issues, they should receive the vaccine.
### Guillain-Barré syndrome
Individuals with past history of GBS unrelated to COVID-19 vaccination should receive an mRNA COVID-19 vaccine. When mRNA COVID-19 vaccines are contraindicated, Novavax Nuvaxovid should be considered or individuals may receive a viral vector COVID-19 vaccine after weighing the risks and benefits in consultation with their health care provider.
Individuals who developed GBS after a previous dose of a COVID-19 vaccine may receive an mRNA COVID-19 vaccine, after consultation with their health care provider if it is determined that the benefits outweigh the risk and informed consent is provided.
### Bell's palsy
Individuals should seek medical attention if they develop symptoms compatible with Bell's palsy following receipt of mRNA COVID-19 vaccines. Healthcare providers should consider Bell's palsy in their evaluation if the patient presents with clinically compatible symptoms after an mRNA COVID-19 vaccine. Investigations should exclude other potential causes of facial paralysis.
### Multisystem inflammatory syndrome in children or adults (MIS-C or MIS-A)
For children or adults with a previous history of MIS-C or MIS-A, vaccination or re-vaccination should be postponed until clinical recovery has been achieved or until it has been ≥ 90 days since diagnosis, whichever is longer (see ).
Other considerations
# Tuberculin skin testing (TST) or interferon gamma release assay (IGRA)
There is a theoretical risk that mRNA or viral vector vaccines could temporarily affect cell-mediated immunity, resulting in false-negative TST or IGRA test results. However, there is no direct evidence for this interaction. Therefore, in the absence of data and acknowledging the importance of both timely tuberculosis testing and immunization, vaccination with COVID-19 vaccines may take place at any time before, after or at the same visit as the TST or IGRA test. Repeat tuberculin skin testing or IGRA (at least 4 weeks post-COVID-19 immunization) of individuals with negative TST or IGRA results for whom there is high suspicion of latent tuberculosis infection may be considered in order to avoid missing persons with TB infection.
# Blood products, human immunoglobulin and timing of immunization
It is recommended that COVID-19 vaccines should not be given concurrently with anti-SARS-CoV-2 monoclonal antibodies.
Administration of these products concurrently may result in decreased effectiveness of the COVID-19 vaccine and/or anti-SARS-CoV-2 monoclonal antibodies. Anti-SARS-CoV-2 monoclonal antibodies have high affinity for the spike protein expressed by COVID-19 vaccines, which could prevent the production of antibodies stimulated by the vaccine, or binding of vaccine antigen to the monoclonal antibody may neutralize the monoclonal antibody.
# Pre-exposure prophylaxis for COVID-19 with anti-SARS-CoV-2 monoclonal antibodies
In some cases, anti-SARS-CoV-2 monoclonal antibodies may be given in addition to vaccination to some individuals with immunocompromising conditions, in consultation with clinical experts. Clinicians may consider the following factors when assessing the potential benefits or risks when recommending anti-SARS-CoV-2 monoclonal antibodies to their patients: the degree of immunocompromise, the presence of additional risk factors for severe COVID-19, the likelihood of not responding to COVID-19 vaccine, the risk of exposure to COVID-19 due to occupational or residential circumstances, as well as local circulation of variants with the potential for resistance to one or more of the anti-SARS-CoV-2 monoclonal antibodies, including some Omicron sublineages. Although anti-SARS-CoV-2 monoclonal antibodies could reduce humoral immune responses to a COVID-19 vaccine, cellular immune responses may not be impacted. Cellular immune responses to a COVID-19 vaccine are important for immunocompromised populations and, to sustain cellular immune responses, vaccination should be given to this group as recommended, whether or not their receive anti-SARS-CoV-2 monoclonal antibodies, noting the timing considerations below.
Implementation advice to inform decision-makers on the appropriate use of anti-SARS-CoV-2 monoclonal antibodies (e.g., patient prioritization) is available from the , and .
Up to date information on alerts including risk of treatment failure of specific anti-SARS-CoV-2 monoclonal antibodies as well as safety and recalls, is available from .
Guidance on anti-SARS-CoV-2 monoclonal antibodies may change as additional evidence emerges.
## Administration of anti-SARS-CoV-2 monoclonal antibodies following COVID-19 vaccines
To minimize interference, it is recommended that anti-SARS-CoV-2 monoclonal antibodies should be administered at least 2 weeks following COVID-19 vaccination.
## Administration of COVID-19 vaccines following anti-SARS-CoV-2 monoclonal antibodies
There is no evidence on which to base a specific minimum interval for COVID-19 vaccination following anti-SARS-CoV-2 monoclonal antibodies administration. Timing should be assessed in consultation with clinical experts on a case-by-case basis.
# Therapeutic management of COVID-19 with anti-SARS-CoV-2 monoclonal antibodies
Multiple products are authorized in Canada for therapeutic management of COVID-19. Expert clinical opinion should be sought on a case-by-case basis when deciding on the use of anti-SARS-CoV-2 monoclonal antibodies, as well as whether vaccination should be repeated if a therapeutic dose is given too close to vaccination.
Timing of administration of COVID-19 vaccines following administration of therapeutic anti-SARS-CoV-2 monoclonal antibodies should be assessed in consultation with clinical experts on a case-by-case basis.
For complete prescribing information, consult the product leaflet or information contained within the product monograph available through Health Canada's .
Chapter revision process
This chapter was updated to reflect guidance based on current evidence and the National Advisory Committee on Immunization's (NACI's) expert opinion since the last version of this chapter (March 22, 2023). Additional content changes may reflect changes to COVID-19 vaccine product monographs. Refer to the for additional information.
For supporting information on COVID-19 vaccine chapter updates, including additional references, refer to the and/or published on the NACI webpage under . |
COVID-19 vaccine: Canadian Immunization Guide
==============================================
Notice
------
This chapter has not yet been updated with the following statements from the National Advisory Committee on Immunization (NACI):
* July 11, 2023: [Guidance on the use of COVID-19 vaccines in the fall of 2023](/en/public-health/services/publications/vaccines-immunization/national-advisory-committee-immunization-guidance-use-covid-19-vaccines-fall-2023.html)
* June 9, 2023: [Interim guidance on the use of bivalent Omicron-containing COVID-19 vaccines for primary series](/en/public-health/services/publications/vaccines-immunization/national-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html)
**For health professionals**
**Last partial content update** (see [Table of updates](/en/public-health/services/canadian-immunization-guide/updates.html)): **June 27, 2023**
This chapter was updated based on the following guidance from the National Advisory Committee on Immunization (NACI):
* Recommendations on the use of Moderna bivalent BA.1 and BA.4/5 as a booster dose in individuals 6 to 17 years of age
* Recommendations on the use of Novavax Nuvaxovid COVID-19 vaccine as a primary series in adolescents (12 to 17 years of age)
* Update to previous recommendations on the use of Novavax Nuvaxovid COVID-19 vaccine as a primary series and as a booster dose in adults (18 years of age and older)
For more information, refer to [the Canadian Immunization Guide (CIG) Summary](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine/summary-updates-june-27-2023.html).
On this page
------------
* [Key information](#a1)
* [Epidemiology](#a2)
* [Preparations authorized for use in Canada](#a3)
* [Immunogenicity, efficacy and effectiveness](#a4)
* [Recommendations for use](#a5)
+ [Children](#a5.1)
+ [Adolescents](#a5.2)
+ [Adults](#a5.3)
+ [Schedule](#a5.4)
- [Table 1. Immunization schedule for a primary series, by COVID-19 vaccine](#t1)
- [Table 2. Immunization schedule and minimum intervals for a primary series for moderately to severely immunocompromised individuals, by COVID-19 vaccine](#t2)
+ [Booster doses](#a5.5)
- [Table 3. Summary table of mRNA COVID-19 booster doses by age group](#t3)
* [Vaccination of specific populations](#a6)
+ [Pregnancy and breastfeeding](#a6.1)
- [Table 4: Pregnancy registry information by vaccine product](#t4)
+ [Individuals previously infected with SARS-CoV-2](#a6.2)
- [Table 5. Suggested intervals between previous SARS-CoV-2 infection and COVID-19 vaccination](#t5)
+ [Immunocompromised persons](#a6.4)
+ [Travellers](#a6.5)
+ [Persons new to Canada](#a6.6)
* [Serologic testing](#a7)
* [Administration practices](#a8)
+ [Dose and route of administration](#a8.1)
- [Table 6. Dosing for Moderna Spikevax vaccines](#t6)
+ [Interchangeability of vaccines](#a8.2)
+ [Concurrent administration with other vaccines](#a8.3)
+ [Pre-vaccination counselling](#a8.4)
+ [Post-vaccination counselling](#a8.5)
* [Storage requirements](#a9)
* [Safety and adverse events](#a10)
+ [Very common and common adverse events](#a10.1)
+ [Uncommon, rare and very rare adverse events](#a10.2)
+ [Guidance on reporting adverse events following immunization (AEFI)](#a10.3)
+ [Contraindications and precautions](#a10.4)
- [Table 7. Vaccine products and potential allergens](#t7)
* [Other considerations](#a11)
+ [Tuberculin skin testing (TST) and interferon gamma release assay (IGRA)](#a11.2)
+ [Blood products, human immunoglobulin and timing of immunization](#a11.3)
* [Chapter revision process](#a12)
* [Acknowledgments](#a13)
* [Selected references](#a14)
Key information (refer to text and tables for details)
------------------------------------------------------
### What
* Novel coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
* Anyone can be infected with SARS-CoV-2. However, some populations are at increased risk of exposure to the virus due to living or occupational settings and some populations are at increased risk of severe outcomes due to biological and/or social factors.
* Several vaccines for COVID-19 had been authorized for use in Canada since December 2020. These include messenger ribonucleic acid (mRNA) vaccines, protein subunit and virus-like particle (VLP) vaccines, and non-replicating viral vector vaccines. Refer to [Preparations authorized for use in Canada](#a3) for more information.
* For all vaccines, some adverse events are reported to be very common (defined as 10% or more) among vaccine recipients. However, they are mild or moderate and transient, resolving within a few days. These side effects may include: pain, redness and swelling at the injection site, axillary (or groin) swelling or tenderness, fatigue, headache, muscle pain, chills, joint pain, and fever.
* Serious adverse events following immunization can occur very rarely. Refer to [Safety and adverse events](#a10) for more information.
### Who
* A complete primary series with an mRNA COVID-19 vaccine may be offered to children 6 months to less than 5 years of age and should be offered to children 5 to 11 years of age without contraindications to the authorized vaccine, with a dosing interval of at least 8 weeks between the first and second dose. Refer to [Recommendations for use, Children](#a5.1) for more information.
* A complete primary series, preferentially with an mRNA COVID-19 vaccine, should be offered to individuals 12 years of age and older without contraindications to the vaccine. Refer to [Recommendations for use, Adolescents](#a5.2) and [Adults](#a5.3) for more information.
* For recommendations for individuals 6 months of age and older who are moderately to severely immunocompromised, refer to [Children](#a5.1), [Adolescents](#a5.2) and [Adults](#a5.3).
* A first booster dose of mRNA COVID-19 vaccine should be offered to adults 18 years of age and older and select children and adolescents 5 to 17 years of age. A first booster of mRNA COVID-19 vaccine may also be offered to all other children and adolescents 5 to 17 years of age. Additional booster doses are recommended for select populations. Refer to [Recommendations for use, Booster doses](#a5.5) for more information.
* It is recommended that mRNA COVID-19 vaccines should be offered to individuals 6 months of age and older with previous SARS-CoV-2 infection without contraindications to the vaccine. Refer to [Individuals previously infected with SARS-CoV-2](#a6.2) for more information, including recommended intervals.
* It is recommended that an authorized protein subunit COVID-19 vaccine (Novavax Nuvaxovid) should be offered to individuals in the authorized age groups without contraindications to the vaccine who are not able or willing to receive an mRNA COVID-19 vaccine.
* An authorized viral vector COVID-19 vaccine may be offered to individuals 18 years of age and over, without contraindications to the vaccine, when all other authorized COVID-19 vaccines are contraindicated.
### How
* Currently, for immunocompetent individuals, the Pfizer-BioNTech Comirnaty COVID-19 vaccine [original] is administered as a 2-dose primary series for those 5 years of age and over and as a 3-dose primary series for those 6 months to less than 5 years of age; Moderna Spikevax [original] is administered as a 2-dose primary series for those 6 months of age and over; Novavax Nuvaxovid is administered as 2-dose primary series for those 12 years of age and over; and Janssen Jcovden is a one dose primary series for those 18 years of age and over. For those who are moderately to severely immunocompromised an additional dose is recommended to be added to the primary series (refer to [Table 2](#t2)).
* Bivalent mRNA COVID-19 vaccines are currently authorized only as booster doses. Refer to [Recommendations for use, Booster doses](#a5.5) for more information.
* Prior to providing a COVID-19 vaccine informed consent should include discussion about frequently occurring minor adverse events and the risks and symptoms of potential rare severe adverse events.
* Serologic testing is not recommended before or after receipt of a COVID-19 vaccine to assess susceptibility to SARS-CoV-2 or immune response to the vaccine.
* For individuals 6 months of age and older, COVID-19 vaccines may be given concurrently with (i.e., same day), or at any time before or after, non-COVID-19 vaccines (including live and non-live vaccines).
* Regardless of vaccination status, individuals should continue to follow recommended public health measures for prevention and control of SARS-CoV-2 infection and transmission.
### Why
* The COVID-19 pandemic has caused significant morbidity and mortality, as well as social and economic disruption in Canada and worldwide.
* COVID-19 vaccines have been shown to be very effective at preventing severe disease, including hospitalization and death due to COVID-19.
Epidemiology
------------
### Disease description
#### Infectious agent
COVID-19 is caused by the SARS-CoV-2 virus, which was first recognized in Wuhan, China in December 2019.
#### Transmission
Current evidence suggests that SARS-CoV-2 is spread through respiratory droplets and aerosols created when an infected person breathes, coughs, sneezes, sings, shouts, or talks. A person may be infectious for up to 3 days before showing symptoms and most people are considered no longer infectious 10 days from onset of symptoms (or first detection of infection if asymptomatic).
More information on the transmission of SARS-CoV-2 can be found on the Public Health Agency of Canada (PHAC) webpages for [COVID-19: Main modes of transmission.](/en/public-health/services/diseases/2019-novel-coronavirus-infection/health-professionals/main-modes-transmission.html)
#### Variants of concern
Genetic mutations in the SARS-CoV-2 virus have led to the designation of variants of concern (VOCs) and these variants are more transmissible than the original strain. Mutations in VOCs may also affect the severity of disease and the level of protection offered by vaccines.
More information on the VOCs reported in Canada is available in the [COVID-19 epidemiology update](https://health-infobase.canada.ca/covid-19/epidemiological-summary-covid-19-cases.html#VOC). The [COVID-19 Weekly Epidemiological Update](https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports) by the World Health Organization (WHO) provides a summary on the global distribution and emerging evidence on VOC and variants of interest (VOI). Differences between VOC and VOI are available from [SARS-CoV-2 variants: National definitions, classifications and public health actions](/en/public-health/services/diseases/2019-novel-coronavirus-infection/health-professionals/testing-diagnosing-case-reporting/sars-cov-2-variants-national-definitions-classifications-public-health-actions.html).
#### Risk factors
Anyone can be infected with SARS-CoV-2. However, some populations are at increased risk of exposure to the virus (e.g., due to living or occupational settings), and some populations are at increased risk of severe disease and outcomes (e.g., hospitalization and death) due to biological factors (e.g., advanced age, pre-existing medical conditions, pregnancy) and social factors (e.g., socioeconomic status, belonging to a racialized population) that may intersect. Exposure and risk factors for severe disease may overlap, further increasing risk. Any combination of these factors, as well as varying access to health care services, has the potential for disproportionate consequences for specific populations characterized by increased rates of infection and disease, severe illness, hospitalizations, and/or deaths.
There is a spectrum of COVID-19 disease severity, ranging from asymptomatic to mild, moderate, severe and critical disease. Severe disease more often occurs in those with increasing age and those with underlying medical conditions, with the risk increasing with the number of underlying conditions. A list of [underlying medical conditions associated with more severe COVID-19 disease](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/signs-symptoms-severity.html#a3) can be found in [COVID-19 signs, symptoms and severity of disease: A clinician guide](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/signs-symptoms-severity.html).
There is limited evidence on clinical risk factors for severe COVID-19 disease in pediatric populations. Children at increased risk for severe outcomes may include children who are obese, children who are medically fragile/ have medical complexities, children with more than one comorbidity, children with neurological disorders, and children with immune dysregulation associated with Down syndrome (Trisomy 21) and other immunocompromising conditions.
#### Spectrum of clinical illness and disease characteristics
The median incubation period (the time from exposure to symptom onset) for non-variant SARS-CoV-2 was estimated to be 4 to 7 days. For Omicron, the median incubation period is 2 to 4 days. The incubation period can range from 2 to 14 days.
Clinical presentation and symptoms of COVID-19 vary in frequency and severity, from asymptomatic to severe and fatal disease. To date, there is no list of symptoms that has been validated to have high specificity or sensitivity for COVID-19.
More information on the spectrum of clinical illness is available on the PHAC webpage for [COVID-19 signs, symptoms and severity of disease: A clinician guide](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/signs-symptoms-severity.html).
While most children and adolescents with COVID-19 have mild or no symptoms, some do experience severe disease. However, children and adolescents report fewer severe outcomes of COVID-19 (i.e., hospitalizations due to COVID-19, ICU admission, and deaths) compared to older age groups.
Children, adolescents and adults with SARS-CoV-2 infection are at risk of multisystem inflammatory syndrome (MIS), a rare but serious condition that can occur several weeks following SARS-CoV-2 infection. They are also at risk of post COVID-19 condition (PCC), a condition in which symptoms persist for more than 8 weeks and are present 12 or more weeks following acute infection with SARS-CoV-2. Refer to [Effectiveness of vaccination against post-COVID-19 condition](#a4.2.4).
#### Disease incidence
##### Global
[Updated international data on COVID-19 cases and deaths](https://health-infobase.canada.ca/covid-19/international/) are available.
[Weekly epidemiological updates highlighting key global, regional and country-level data on COVID-19 cases and deaths](https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports) are available from WHO.
##### National
Updated national, provincial and territorial-level data on COVID-19 cases and deaths in Canada over time is available from the PHAC webpage on [Coronavirus disease (COVID-19): Outbreak update](https://health-infobase.canada.ca/covid-19/epidemiological-summary-covid-19-cases.html).
Preparations authorized for use in Canada
-----------------------------------------
When referring to COVID-19 vaccines throughout this chapter, only those currently authorized by Health Canada for use in Canada are included. Refer to [Vaccination of specific populations, Persons new to Canada](#a6.6) for information regarding non-Health Canada authorized vaccines.
### mRNA vaccines
* **ComirnatyTM** (tozinameran, BNT162b2), Original, (formulations of 30 mcg, 10 mcg or 3 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus), Pfizer and BioNTech Manufacturing GmbH
+ Authorized as a primary series in those 12 years of age and older (30 mcg), children 5 to 11 years of age (10 mcg), and children 6 months of age to less than 5 years of age (3 mcg)
+ Authorized as a booster dose in children 5 to 11 years of age (10 mcg) and those 16 years of age and older (30 mcg)
* **Comirnaty® Original & Omicron BA.4/BA.5**, (Bivalent), Pfizer and BioNTech Manufacturing GmbH
+ Authorized as a booster dose only, in those 5 to 11 years of age (total 10 mcg of mRNA, with 5 mcg of mRNA encoding for the original SARS-CoV-2 virus and 5 mcg encoding for the Omicron BA.4/5 variant) and 12 years of age and older (total 30 mcg of mRNA, with 15 mcg of mRNA encoding for the original SARS-CoV-2 virus and 15 mcg encoding for the Omicron BA.4/5 variant)
* **Comirnaty®Original & Omicron BA.1**, (Bivalent, total 30 mcg of mRNA, with 15 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and 15 mcg encoding for the spike protein of the Omicron BA.1 variant), Pfizer and BioNTech Manufacturing GmbH
+ Authorized as a booster dose only, in those 12 years of age and older (30 mcg)
+ This formulation of Comirnaty was not distributed in Canada, so recommendations only refer to the BA.4/5 formulation throughout the rest of the chapter
* **SpikevaxTM** (elasomeran, mRNA-1273), Original, (formulations of 100 mcg, 50 mcg or 25 mcg of mRNA of mRNA encoding for the spike protein of the original SARS-CoV-2 virus), Moderna TX Inc.
+ Authorized as a primary series for use in those 12 years of age and older (100 mcg), children 6 to 11 years of age (50 mcg) and children 6 months to 5 years of age (25 mcg)
+ Authorized as a booster dose in those 12 years of age and older (50 mcg)
* **Spikevax BivalentTM** (elasomeran/imelasomeran) Original/Omicron BA. 4/BA.5 (Bivalent, total 50 mcg of mRNA or 25 mcg of mRNA, with half the dose of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and half encoding for the spike protein of the Omicron BA.4/5 variant), Moderna TX Inc.
+ Authorized as a booster dose only, in those 12 years of age and older (50 mcg) and in children 6 to 11 years of age (25 mcg)
* **Spikevax BivalentTM** (elasomeran/imelasomeran) Original/Omicron BA.1 (Bivalent, total 50 mcg of mRNA or 25 mcg of mRNA, with half the dose of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and half encoding for the spike protein of the Omicron BA.1 variant), Moderna TX Inc.
+ Authorized as a booster dose only, in those 12 years of age and older (50 mcg) and in children 6 to 11 years of age (25 mcg)
COVID-19 vaccines that use mRNA platforms contain modified nucleotides that code for the SARS-CoV-2 spike protein. The mRNA can encode for the spike protein from the original SARS-CoV-2 virus and/or from a variant of concern. A lipid nanoparticle formulation delivers the mRNA into the recipient's cells. Once inside the cytoplasm of a cell, the mRNA provides instructions to the cell's protein production machinery to produce the trans-membrane spike protein antigen that becomes anchored on the cell's external surface. The mRNA does not enter the nucleus of the cell and does not interact with, or alter, human DNA. The immune system is engaged by both the transmembrane spike protein and immune receptors carrying spike antigens to induce humoral and cellular immune responses. The mRNA, lipid nanoparticle, and spike protein are degraded or excreted within days to weeks from time of immunization. mRNA vaccines are not live vaccines and cannot cause infection in the host.
### Protein subunit vaccine
* **NuvaxovidTM** (SARS-CoV-2 recombinant spike protein of the original strain) with Matrix-M adjuvant, Novavax
+ Authorized for use as a primary series in those 12 years of age and older and a booster dose in those 18 years of age and older (5 mcg of recombinant protein)
Novavax Nuvaxovid consists of a purified full-length SARS-CoV-2 recombinant spike protein nanoparticle co-formulated with the adjuvant Matrix-M. Matrix-M is a novel saponin-based adjuvant that facilitates activation of the cells of the innate immune system, which enhances the magnitude of the spike protein-specific immune response. Matrix-M has been used in Novavax Nuvaxovid clinical trials and in pre-licensure studies targeting other pathogens, but has not previously been used in any licensed vaccine.
### Virus-like particle (VLP) vaccine
The Medicago Covifenz®COVID-19 vaccine was the first virus-like particle (VLP) COVID-19 vaccine authorized in Canada. Medicago Covifenz was authorized for use in adults 18 to 64 years of age as a primary series but was not marketed.
### Viral vector (non-replicating) vaccines
* **Vaxzevria™** (ChAdOx1-S recombinant), AstraZeneca Canada Inc.
+ Authorized for use in those 18 years of age and older (5 x 1010 viral particles)
+ Vaxzevria is no longer available in Canada
* **Jcovden** COVID-19 vaccine (Ad26.COV2.S), Janssen Inc.
+ Authorized for use in those 18 years of age and older as a primary series and as a booster (5 x 1010 virus particles)
COVID-19 vaccines based on viral vector platforms use a modified virus to carry genes that encode SARS-CoV-2 spike proteins into the host cells. The vector virus is a type of adenovirus that has been modified to carry COVID-19 genes and to prevent replication of the adenovirus so that it does not cause disease. Once inside the cell, the SARS-CoV-2 spike protein genes are transcribed into mRNA in the nucleus and translated into proteins in the cytosol of the cell. The AstraZeneca Vaxzevria vaccine (and the version manufactured by the Serum Institute of India and marketed briefly in Canada as COVISHIELD) uses a modified chimpanzee adenovirus vector (ChAd) and the Janssen Jcovden vaccine uses a modified human adenovirus serotype 26 vector (Ad26).
### Anti-SARS-CoV-2 monoclonal antibodies authorized for pre-exposure prophylaxis of COVID-19
* **EVUSHELD™** (tixagevimab and cilgavimab), AstraZeneca Canada Inc.
+ Authorized for use in those 12 years of age and older weighing at least 40 kg (300 mcg of tixagevimab and 300 mcg of cilgavimab administered in sequence)
Tixagevimab and cilgavimab are two recombinant human monoclonal antibodies with amino acid substitutions to extend antibody half-life and thus duration of protection, as well as minimize the potential risk of antibody-dependent enhancement of disease. In addition to authorization for pre-exposure prophylaxis, Evusheld has also been authorized to treat mild to moderate COVID-19.
Up to date information on alerts, including risk of treatment failure of specific anti-SARS-CoV-2 monoclonal antibodies as well as safety and recalls, is available from [Health Canada](https://recalls-rappels.canada.ca/en/alert-recall/evusheld-tixagevimab-and-cilgavimab-injection-risk-prophylaxis-or-treatment-failure-0?utm_source=gc-notify&utm_medium=email&utm_content=en&utm_campaign=hc-sc-rsa-22-23).
For complete prescribing information for any of the [Preparations authorized for use in Canada](#a3), consult the product leaflet or information contained within Health Canada's authorized product monographs available through the [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
Immunogenicity, efficacy and effectiveness
------------------------------------------
### Immunogenicity
All COVID-19 vaccines induce humoral immune responses, including binding and neutralizing antibody responses. As well, all authorized COVID-19 vaccines have been shown to produce cellular immune responses in adult populations. The immune responses may vary depending on the product used, number of doses, interval between the doses, and the age and underlying medical conditions of the vaccine recipient. No immunological correlate of protection has been determined for SARS-CoV-2, and therefore the implications of differences in immune responses post-COVID-19 vaccination on protection against infection and severe disease, as well as on duration of protection, is uncertain.
### Efficacy and effectiveness
Efficacy and effectiveness of COVID-19 vaccines tends to be lowest against infection, somewhat higher against symptomatic disease and highest against severe disease. Vaccine effectiveness varies by variant. Clinical trials for original COVID-19 vaccines were conducted mostly when the original or Alpha VOC strains were circulating and prior to the emergence of Omicron. Compared to the original SARS-CoV-2 strain and earlier variants, COVID-19 vaccines have substantially lower vaccine effectiveness for Omicron sublineages when assessed against infection/symptomatic disease and also somewhat lower vaccine effectiveness against severe disease.
Vaccine effectiveness decreases over time since vaccination. Vaccine efficacy as determined by clinical trials was generally assessed within a few months of vaccination. Subsequent effectiveness studies have demonstrated waning over time, particularly against infection and symptomatic disease, and to a lesser extent against severe disease as well. Booster doses are intended to increase protection, particularly against severe disease, that may have decreased over time.
Similar to factors that impact the immune response, vaccine effectiveness may be affected by the vaccine product received, the interval between doses, the time since the most recent dose, the age and health status of the recipient and their prior SARS-CoV-2 infection history. Protection is higher in those with previous SARS-CoV-2 infection and vaccination (hybrid immunity) than in those who have only previously been vaccinated or infected. A recent Omicron sublineage infection combined with COVID-19 vaccination provides the best protection against future Omicron sublineage infection and severe disease. Bivalent vaccines offer similar or somewhat greater protection than original monovalent vaccines against Omicron infection/symptomatic disease, with limited evidence available with regard to severe disease.
Vaccine effectiveness against transmission is also measured in some studies. To the extent that COVID-19 vaccines protect against infection, they also prevent transmission as those who are not infected cannot spread infection to others. In addition, vaccination may offer additional protection against transmission even if infection is not prevented. This has been demonstrated particularly with a booster dose, although the duration of this protection against transmission remains uncertain.
#### Efficacy of the primary series against symptomatic COVID-19 disease
In clinical trials, the original mRNA COVID-19 vaccines have been shown to be highly efficacious in the short term against confirmed symptomatic COVID-19 disease. There is similar efficacy in adults with 1 or more comorbidities, as well as in children (5 to 11 years), adolescents (12 to 17 years) and adults (18 years of age and older). There is some evidence of waning of immunogenicity and effectiveness over time that varies by age and vaccine interval.
Vaccine efficacy was assessed among children aged 6 months to 4 to 5 years following one and two doses of Moderna Spikevax (25 mcg) mRNA COVID-19 vaccine and three doses of Pfizer-BioNTech Comirnaty (3 mcg) mRNA COVID-19 vaccine, during a time when Omicron was the predominant variant of SARS-CoV-2. For Moderna Spikevax, efficacy against confirmed symptomatic infection starting 14 days after dose 2 among participants without evidence of prior SARS-CoV-2 infection was estimated at 50.6% among study participants aged 6 to 23 months with a median follow-up of 68 days and 36.8% among participants aged 2 to 5 years with a median follow-up of 72 days. For Pfizer-BioNTech Comirnaty, among children without prior infection, vaccine efficacy about 2 months following the third dose was estimated at 75.8% among children 6 to 23 months of age and 71.8% among children 2 through 4 years of age.
Clinical trial data available to date have shown that Novavax Nuvaxovid COVID-19 vaccine was highly efficacious (approximately 90% against Alpha and 80% against Delta) in preventing confirmed symptomatic COVID-19 disease in the short term during a time period when these variants predominated. However, efficacy was lower against the Beta variant in a study from South Africa (48.6%). A cohort study from Australia looking at vaccine effectiveness against Omicron infection (both symptomatic and asymptomatic), suggested a relatively higher effectiveness of original mRNA vaccines than viral vector and protein subunit vaccines.
The Janssen Jcovden COVID-19 vaccine demonstrated moderate efficacy against symptomatic confirmed moderate to severe COVID-19 infection from 14 days and 28 days post-vaccination of approximately 66% and 67% respectively in the primary analysis, prior to the emergence of SARS-CoV-2 variants. Estimates in the final analysis inclusive of variants prior to Omicron, against moderate to severe COVID-19 at least 14 days after vaccination with a median follow-up of 4 months was approximately 56%.
Decreased protection against infection/symptomatic disease over time has been noted to occur with mRNA vaccines, the protein subunit vaccine and the viral vector vaccines. Shorter intervals between the first and second dose of a 2-dose COVID-19 vaccine series result in lower initial titres that may result in protection that decreases sooner. Observational studies show a reduction in vaccine effectiveness against infection/symptomatic disease in immunocompromised adults when compared to the general population with a 2-dose vaccine series.
#### Efficacy and effectiveness of the primary series against severe disease
The clinical trials of the authorized and available COVID-19 vaccines assessed efficacy against severe COVID-19 disease, but not all provided sufficient data to be able to assess the efficacy against hospitalizations or deaths.
Real world evidence suggests moderate to high vaccine effectiveness at preventing severe illness, such as hospitalization and death, which is sustained out to at least 6 months in most populations ages 12 years and older. There is some decline noted in older adults (such as those 80 years of age and over) and residents in long term care homes in overall effectiveness over time, although protection against severe outcomes appears to be more durable than protection against infection. Effectiveness estimates suggest the Pfizer-BioNTech Comirnaty (10 mcg) original vaccine in children 5 to 11 years of age for the primary series is similarly effective against severe disease due to Omicron as it is in older populations. Vaccine effectiveness against severe disease is unknown for Novavax Nuvaxovid as well as Moderna Spikevax original (50 mcg) vaccine in children 6 to 11 years. There were no deaths or cases of severe COVID-19 among trial participants 6 months to 5 years of age for the Moderna Spikevax original (25 mcg) vaccine. Therefore, efficacy against outcomes of severe COVID-19 could not be estimated. Similarly, efficacy against severe disease was not evaluated for Pfizer-BioNTech original (3 mcg) for children 6 months to 4 years of age due to very few events, including no deaths in the clinical trial.
#### Effectiveness of the primary series against hospitalization due to MIS-C
Real world evidence suggests the Pfizer-BioNTech Comirnaty COVID-19 original vaccine has high vaccine effectiveness at preventing hospitalization due to multisystem inflammatory syndrome in children (MIS-C) among adolescents 12 to 18 years of age. Among children 5 to 11 years of age, a systematic review and meta-analysis of the efficacy and safety of mRNA COVID-19 vaccines found that 2-dose mRNA vaccination is associated with lower risks of asymptomatic and symptomatic SARS-CoV-2 infections as well as hospitalization and MIS-C.
There were no cases of MIS-C among trial participants 6 months to 5 years of age for the Moderna Spikevax original (25 mcg) vaccine; however, one case of MIS-C was reported in a placebo recipient after the data cut-off. In the Pfizer-BioNTech Comirnaty study for children 6 months to 4 years of age, there were no cases of MIS-C identified. Therefore, efficacy against MIS-C was not able to be evaluated in either of these studies of young children.
There are no results specific to other COVID-19 vaccines yet, however studies are ongoing.
#### Effectiveness of vaccination against post-COVID-19 condition
Post COVID-19 condition (PCC) is a condition in which symptoms following a SARS-CoV-2 infection persist for more than 8 weeks and are present for 12 or more weeks following the acute phase. To the extent that vaccines prevent infection, they also prevent PCC as those who are not infected cannot develop PCC. Evidence suggests that receipt of 2 doses of COVID-19 vaccine prior to infection decreases the odds of PCC compared to those who are unvaccinated. The impact of a third dose prior to infection on preventing PCC after breakthrough disease is currently uncertain. Whether vaccination following SARS-CoV-2 infection can decrease the risk of PCC remains to be established. Research has not demonstrated a worsening of existing PCC symptoms with vaccination.
#### Efficacy and effectiveness of the primary series against asymptomatic infection
Clinical trials for currently authorized COVID-19 vaccines were primarily designed to evaluate efficacy against symptomatic illness and conducted prior to the emergence of Omicron. While data on efficacy against asymptomatic infection remain limited, effectiveness studies have generally found that effectiveness against infection is somewhat lower than against symptomatic disease. Previous infection, particularly a previous Omicron infection, in combination with vaccination (hybrid immunity) improves protection against infection.
#### Vaccine effectiveness of booster doses
Booster doses improve the immune response and vaccine effectiveness that has decreased over time. A booster dose achieved very high vaccine effectiveness (generally >90%) against the Delta variant for infection/symptomatic disease and severe disease. Against Omicron, a booster dose increased protection compared to pre-booster levels, however after a booster dose, protection against infection/symptomatic disease was approximately 60% (ranging from approximately 40 to 80%) and decreased over time. Protection against severe Omicron disease after a booster dose was higher at around 90%, and generally remained above 70% for approximately 6 months post booster dose. Subsequent booster doses raise protection again, but waning continues to occur, particularly against infection/symptomatic disease.
Several studies have shown that bivalent booster doses increase protection against symptomatic infection and severe disease compared to those who received original monovalent vaccine sometime in the past. These studies cannot determine if the increase in protection is due to receiving a booster dose or specifically due to the booster dose. Some studies have tried to more directly compare bivalent and original monovalent vaccines given at similar points in time, and have shown that the bivalent vaccine produces similar or somewhat higher protection against SARS-CoV-2 infection/symptomatic disease, but there is limited data with regard to severe disease.
Recommendations for use
-----------------------
### Children
#### Recommendations for children 6 months to 4 years of age (not moderately to severely immunocompromised)
It is recommended that children 6 months to 4 years of age may be offered a primary series of an mRNA COVID-19 vaccine if they have no contraindications to the vaccine.
* For children who are not moderately to severely immunocompromised a primary series of Moderna Spikevax (25 mcg) consists of **two doses** for those 6 months to 5 years of age while a primary series of Pfizer-BioNTech Comirnaty (3 mcg) consists of **three doses** for those 6 months to 4 years of age, using an interval of at least 8 weeks between each dose for both products.
If readily available (i.e., easily available at the time of vaccination without delay or vaccine wastage), the same mRNA COVID-19 vaccine product should be offered for the subsequent dose in a vaccine series started with a specific mRNA COVID-19 vaccine.
If two different products are administered (i.e., a mixed schedule with at least one Moderna Spikevax [25 mcg] and one Pfizer-BioNTech Comirnaty dose [3 mcg]), it is recommended that the **3-dose** schedule be used. Either product can be used to complete the remaining dose of the 3-dose mixed schedule.
There are currently no recommendations for booster doses in those 6 months to 4 years of age and no product is authorized as a booster dose for this age group.
#### Recommendations for children 6 months to 4 years of age who are moderately to severely immunocompromised
It is recommended that children 6 months to 4 years of age who are [moderately to severely immunocompromised](#a6.4.considerations) and do not have contraindications may be offered a primary series that consists of an additional dose of an mRNA COVID-19 vaccine compared to the age-based schedules noted above for non-immunocompromised children. Therefore, a primary series for children who are moderately to severely immunocompromised consists of **three doses** of the Moderna Spikevax (25 mcg) vaccine for those 6 months to 5 years of age or **four doses** of the Pfizer-BioNTech Comirnaty (3 mcg) for those 6 months to 4 years of age, using an interval of 4 to 8 weeks between each dose for both products.
Because there are fewer doses in the schedule and may be more acceptable and feasible, the Moderna Spikevax (25 mcg) is the recommended product for those who are moderately to severely immunocompromised, however, **four doses** of the Pfizer-BioNTech Comirnaty (3mcg) vaccine may be offered if the Moderna Spikevax (25 mcg) is not readily available.
If readily available (i.e., easily available at the time of vaccination without delay or vaccine wastage), the same mRNA COVID-19 vaccine product should be offered for the subsequent dose in a vaccine series started with a specific mRNA COVID-19 vaccine.
For mixed schedules consisting of at least one dose of Moderna Spikevax (25 mcg) and one dose of Pfizer-BioNTech Comirnaty (3 mcg), **four doses** given 4 to 8 weeks apart are recommended for those who are moderately to severely immunocompromised. Either mRNA product can be used to complete the remaining doses of the four-dose mixed schedule.
There are currently no recommendations for booster doses in those 6 months to 4 years of age and no product is authorized as a booster dose for this age group.
#### Recommendations for children 5 to 11 years of age (not moderately to severely immunocompromised)
It is recommended that children who are 5 to 11 years of age should be offered a primary series of an mRNA COVID-19 vaccine if they have no contraindications to the vaccine.
For children 5 to 11 years of age who are not moderately to severely immunocompromised a primary series of an mRNA vaccine consists of **2-doses**, with a dosing interval of at least 8 weeks between the first and second dose.
For children 5 to 11 years of age, the use of Pfizer-BioNTech Comirnaty original (10 mcg) COVID-19 vaccine is preferred to Moderna Spikevax original to start or continue the primary vaccine series, due to a potentially lower risk of myocarditis/pericarditis with the Pfizer-BioNTech product. However, Moderna Spikevax original (25 mcg at 5 years of age or 50 mcg from 6 to 11 years of age) vaccine may be offered as an alternative.
Children who have received Pfizer-BioNTech original (3 mcg) starting at 4 years of age and then turn 5 years of age prior to completing their primary series, should be offered three doses in the primary series, however any doses of Pfizer-BioNTech vaccine given at 5 years of age should be 10 mcg. Doses less than 10 mcg at 5 years of age are considered invalid and should be repeated. See PHAC's resource: Quick reference guide on the use of COVID-19 vaccines: [Managing vaccine administration errors or deviations for additional guidance](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/quick-reference-guide-covid-19-vaccines/managing-administration-errors-deviations.html).
Children who have received Moderna Spikevax original (25 mcg) for a previous dose at 5 years of age and turn 6 years of age prior to completing their primary series should be offered Moderna Spikevax original (50 mcg) to complete their 2-dose primary series. If the primary series was completed with Moderna Spikevax original (25 mcg) or with Pfizer-BioNTech Comirnaty original (10 mcg), the dose should be considered valid and the primary series complete.
Pfizer-BioNTech Comirnaty original (10 mcg) and Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (10 mcg) are authorized as a booster dose in those 5 to 11 years of age. Moderna Spikevax bivalent BA.1 (25 mcg) and Moderna Spikevax bivalent BA.4/5 (25 mcg) are authorized as a booster dose in those 6 to 11 years of age. A bivalent booster dose is preferred, and should be given ≥ 6 months after completion of a primary COVID-19 vaccine series or previous SARS-CoV-2 infection. It should be offered to children 5 to 11 years of age with an underlying medical condition that places them at high risk of severe illness due to COVID-19, and may also be offered to all other children in this age group.
Only one booster dose after the primary series for children 5 to 11 years of age is recommended. However, at the provider's discretion, a bivalent booster dose (as per recommended interval) could be offered to children considered at high risk of severe COVID-19 who have previously received a booster dose with the original Pfizer-BioNTech Comirnaty mRNA vaccine.
Refer to [Booster doses](#a5.5) for additional information on booster doses for children 5 to 11 years of age.
#### Recommendations for children 5 to 11 years of age who are moderately to severely immunocompromised
It is recommended that children 5 to 11 years of age who are [moderately to severely immunocompromised](#a6.4.considerations) and do not have contraindications should be offered a primary series of **three doses** of an mRNA COVID-19 vaccine authorized for their age, using an interval of 4 to 8 weeks between each dose.
Pfizer-BioNTech Comirnaty is generally preferred as a primary series for those 5 to 11 years of age, however, indirect data from adult populations (≥18 years of age) on original mRNA COVID-19 vaccines suggest Moderna Spikevax original (100 mcg) may result in higher vaccine effectiveness after a 2-dose primary series compared to Pfizer-BioNTech Comirnaty original (30 mcg) and is associated with a higher seroconversion rate among adult immunocompromised patients. Given this potential benefit, administration of the Moderna Spikevax original (25 mcg at 5 years of age or 50 mcg at 6 to 11 years of age) vaccine as a 3-dose primary series may be considered for children 5 to 11 years of age who are [moderately to severely immunocompromised](#a6.4.considerations).
Pfizer-BioNTech Comirnaty original (10 mcg) and Pfizer-BioNTech Comirnaty BA.4/5 Bivalent (10 mcg) are authorized as a booster dose in those 5 to 11 years of age. Moderna Spikevax bivalent BA.1 (25 mcg) and Moderna Spikevax bivalent BA.4/5 (25 mcg) are authorized as a booster dose in those 6 to 11 years of age. A bivalent booster dose is preferred, and is recommended to be given ≥6 months after completion of a 3-dose primary COVID-19 vaccine series, or previous SARS-CoV-2 infection, to children 5 to 11 years of age who are moderately to severely immunocompromised.
Only one booster dose after the primary series for children 5 to 11 years of age is recommended. However, at the provider's discretion, a bivalent booster dose (as per recommended interval) could be offered to children considered at high risk of severe COVID-19 who have previously received a booster dose with the original Pfizer-BioNTech Comirnaty mRNA vaccine.
Refer to [Booster doses](#a5.5) for additional information on booster doses for children 5 to 11 years of age.
#### Considerations
There is an identified risk of myocarditis or pericarditis with the Moderna Spikevax (50 mcg) original vaccine (Refer to [Safety and adverse events, Myocarditis or pericarditis following vaccination with an mRNA COVID-19 vaccine](#a10.2.1)). The risk in children 6 to 11 years of age is unknown, given the limited use in this age group. However, in adolescents and young adults 12 years of age and older, the rare risk of myocarditis or pericarditis was higher with Moderna Spikevax original (100 mcg) than with Pfizer-BioNTech Comirnaty original (30 mcg) with a primary series. In younger children, vaccine safety surveillance data suggests the risk of myocarditis and/or pericarditis is lower than that of adolescents or young adults. Among children 5 to 11 years of age following vaccination with Pfizer-BioNTech Comirnaty original (10 mcg), only very rare cases of myocarditis/pericarditis were most often reported following the second dose and among males. Therefore, Pfizer-BioNTech Comirnaty original is the preferred product for the primary series in children 5 to 11 years of age.
### Adolescents
#### Recommendations for adolescents 12 to 17 years of age (not moderately to severely immunocompromised)
It is recommended that a complete primary series consisting of two doses of an mRNA COVID-19 vaccine should be offered to adolescents 12 to 17 years of age who do not have contraindications to the vaccine.
* The use of Pfizer-BioNTech Comirnaty original (30 mcg) is preferred to Moderna Spikevax original (100 mcg) to start or continue the mRNA primary vaccine series due to a lower risk of myocarditis/pericarditis with the Pfizer-BioNTech product (Refer to [Safety and adverse events, Myocarditis or pericarditis following vaccination with an mRNA COVID-19 vaccine](#a10.2.1)).
* For those who are not moderately to severely immunocompromised, the second dose of the 2-dose primary series of mRNA vaccine should be provided 8 weeks after the first dose.
Eleven year olds who receive the 10 mcg Pfizer-BioNTech Comirnaty original or 50 mcg Moderna Spikevax original for their first dose and who have turned 12 years of age by the time the second dose is due should receive the 30 mcg Pfizer-BioNTech Comirnaty original that is authorized for individuals aged 12 years and older to complete their primary series. The 100 mcg dose of Moderna Spikevax original is also authorized for those 12 years of age and older but Pfizer-BioNTech Comirnaty original is preferred for adolescents due to a lower risk of myocarditis/pericarditis. If the second dose of 10 mcg Pfizer-BioNTech Comirnaty original is given at 12 years of age, the dose is considered invalid. See PHAC's resource: Quick reference guide on the use of COVID-19 vaccines: [Managing vaccine administration errors or deviations for additional guidance](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/quick-reference-guide-covid-19-vaccines/managing-administration-errors-deviations.html). If the second dose is 50 mcg Moderna Spikevax original, the dose should still be considered valid and the series complete.
A bivalent booster dose should be offered to 12 to 17 year olds who are at increased risk of severe illness for COVID-19 and may be offered to other 12 to 17 year olds, with an interval of 6 months from the last dose of the primary series or COVID-19 infection. Pfizer-BioNTech Comirnaty bivalent BA.4/5 (30 mcg), Moderna Spikevax bivalent BA.1 (50 mcg) and Moderna Spikevax bivalent BA.4/5 (50 mcg) are authorized booster doses for this age group. Refer to [Booster doses](#a5.5) for additional information on booster doses for adolescents 12 to 17 years of age.
It is recommended that a primary series of an authorized protein subunit COVID-19 vaccine (Novavax Nuvaxovid) should be offered to 12 to 17 year olds without contraindications to the vaccine who are not able or willing to receive an mRNA COVID-19 vaccine. Preference of mRNA over Novavax Nuvaxovid is due to the availability of more data with regard to the benefits and risks of mRNA vaccines compared to Novavax Nuvaxovid. Both mRNA vaccines and Novavax Nuvaxovid have been associated with a rare risk of myocarditis/pericarditis.
#### Recommendations for adolescents 12 to 17 years of age who are moderately to severely immunocompromised
For [moderately to severely immunocompromised](#a6.4.considerations) adolescents 12 to 17 years of age without contraindications, it is recommended that a primary series of **three doses** of an mRNA vaccine should be offered with an interval of 4 to 8 weeks between doses.
Pfizer-BioNTech Comirnaty is generally preferred as a primary series for those 12 to 17 years of age, however, indirect data from adult populations (18 years of age and older) on original mRNA COVID-19 vaccines suggest Moderna Spikevax original (100 mcg) may result in higher vaccine effectiveness after a 2-dose primary series compared to Pfizer-BioNTech Comirnaty original (30 mcg) and is associated with a higher seroconversion rate among adult immunocompromised patients. Given this potential benefit, administration of the Moderna Spikevax original (100 mcg) vaccine as a 3-dose primary series may be considered for adolescents 12 to 17 years of age who are [moderately to severely immunocompromised](#a6.4.considerations).
Pfizer-BioNTech Comirnaty bivalent BA.4/5 (30 mcg), Moderna Spikevax bivalent BA.1 (50 mcg) and Moderna Spikevax bivalent BA.4/5 (50 mcg) are authorized booster doses for this age group. Booster doses should be offered to 12 to 17 year olds who are moderately to severely immunocompromised with an interval of 6 months from the last dose of the primary series or COVID-19 infection.
Based on clinical discretion, Novavax Nuvaxovid should be offered as a 3 dose primary series to moderately to severely immunocompromised individuals 12 years of age and older who are not able or willing to receive an mRNA COVID-19 vaccine at a recommended interval of 4 to 8 weeks between doses. The safety and efficacy of Novavax Nuvaxovid has not been established in individuals who are immunocompromised due to disease or treatment. Informed consent for use of either vaccine type in these populations should include discussion that there is currently limited evidence on the use of Novavax Nuvaxovid in these populations, while there is evidence on the safety profile and effectiveness of mRNA COVID-19 vaccines in these populations based on real world use with large numbers of individuals.
Refer to [Booster doses](#a5.5) for information on booster doses for adolescents 12 to 17 years of age who are moderately to severely immunocompromised.
#### Considerations
The known risks of COVID-19 illness (including complications like myocarditis/pericarditis) outweigh the potential harms of having an adverse reaction following mRNA vaccination. The risk of myocarditis or pericarditis following mRNA vaccination is rare, relatively mild, and resolves quickly in most individuals. The use of the Pfizer-BioNTech Comirnaty original vaccine is preferred to the Moderna Spikevax original vaccine in individuals 12 to 17 years of age for a primary series because of a lower reported rate of myocarditis/pericarditis following the Pfizer-BioNTech Comirnaty original (30 mcg) compared to the Moderna Spikevax original (100 mcg) vaccine. Additionally, a longer interval between doses is associated with a somewhat higher vaccine effectiveness and potentially lower risk of myocarditis/pericarditis.
### Adults
#### Recommendations for adults 18 years of age and older (not moderately to severely immunocompromised)
It is recommended that a complete primary series, preferentially with an mRNA COVID-19 vaccine, should be offered to individuals in the authorized age group without contraindications to the vaccine.
* For those who are not moderately to severely immunocompromised, the second dose of the 2-dose primary series of mRNA vaccine should be provided 8 weeks after the first dose.
There is a preferential recommendation for the use of mRNA COVID-19 vaccines in all authorized age groups due to greater effectiveness of mRNA vaccines and the rare risk of certain serious adverse events with viral vector vaccines, such as vaccine-induced immune thrombotic thrombocytopenia (VITT). Preference of mRNA over Novavax Nuvaxovid is due to the availability of more data with regard to the benefits and risks of mRNA vaccines compared to Novavax Nuvaxovid. Both mRNA vaccines and Novavax Nuvaxovid have a rare risk of myocarditis/pericarditis.
The known risks of COVID-19 illness (including complications like myocarditis/pericarditis) outweigh the potential harms of having an adverse reaction following mRNA vaccination, including the rare risk of myocarditis or pericarditis which despite hospitalization, is relatively mild and resolves quickly in most individuals.
For individuals aged 18 to 29 years receiving an mRNA COVID-19 vaccine primary series:
* The use of Pfizer-BioNTech Comirnaty original (30 mcg) is preferred to Moderna Spikevax original (100 mcg) to start or continue the mRNA primary vaccine series because of a lower reported rate of myocarditis/pericarditis following Pfizer-BioNTech Comirnaty original (30 mcg) compared to Moderna Spikevax original (100 mcg) for the mRNA primary vaccine series.
For adults aged 30 years or older receiving an mRNA COVID-19 vaccine primary series:
* Either of the mRNA COVID-19 vaccines (Moderna Spikevax original [100 mcg] or Pfizer-BioNTech Comirnaty original [30 mcg]) should be used to start or continue the primary series given that this age group has a lower risk of vaccine-associated myocarditis/pericarditis.
It is recommended that a primary series of an authorized protein subunit COVID-19 vaccine (Novavax Nuvaxovid) should be offered to individuals 18 years of age and older without contraindications to the vaccine who are not able or willing to receive an mRNA COVID-19 vaccine.
A viral vector COVID-19 vaccine may be offered to individuals in the authorized age group without contraindications to the vaccine only when all other authorized COVID-19 vaccines are contraindicated.
At least one booster dose should be offered to all adults 18 years of age and over. Regardless of past booster doses, adults 65 years of age and over, as well as individuals 12 to 64 years of age who are at increased risk of severe illness from COVID-19 should be offered a COVID-19 booster dose if they have not received one since the start of fall 2022, and all others 12 to 64 years of age may be offered a booster dose. A bivalent mRNA booster dose is preferred. An additional booster dose may also be offered as of spring 2023 to specific groups. Refer to [Table 3](#t3) for more information.
The protein subunit COVID-19 vaccine (Novavax Nuvaxovid) containing spike protein from the original SARS-CoV-2 strain is authorized by Health Canada as a booster dose after a primary series with Novavax Nuvaxovid. A bivalent Novavax Nuvaxovid product is not currently available. Novavax Nuvaxovid should be offered to as a booster to adults who are not able or willing to receive an mRNA vaccine.
Refer to [Booster doses](#a5.5) for information regarding booster doses for adults 18 years of age and older.
#### Recommendations for adults 18 years of age and older who are moderately to severely immunocompromised
For moderately to severely immunocompromised adults 18 years of age and over, a primary series of **three doses**, preferentially with an mRNA vaccine, should be offered with intervals of 4 to 8 weeks between doses. Some immunocompromised individuals have a diminished immune response to the vaccines. Moderna Spikevax original (100 mcg) induces somewhat higher antibody levels compared to Pfizer-BioNTech Comirnaty original (30 mcg) and protection (against infection and severe disease) from a primary series with Moderna Spikevax original (100 mcg) may be more durable than Pfizer-BioNTech Comirnaty original (30 mcg).
Based on clinical discretion, Novavax Nuvaxovid should be offered as a 3 dose primary series, at a recommended interval of 4 to 8 weeks between doses, to moderately to severely immunocompromised individuals who are not able or willing to receive an mRNA COVID-19 vaccine. The safety and efficacy of Novavax Nuvaxovid has not been established in individuals who are immunocompromised due to disease or treatment. Informed consent for use of either vaccine type in these populations should include discussion that there is currently limited evidence on the use of Novavax Nuvaxovid in immunocompromised populations, while there is evidence on the safety profile and effectiveness of mRNA COVID-19 vaccines in these populations based on real world use with large numbers of individuals.
Booster doses should be offered to all adults 18 years of age and over who are moderately to severely immunocompromised. Regardless of past booster doses, adults 65 years of age and over, as well as individuals 12 to 64 years of age who are moderately to severely immunocompromised should be offered a COVID-19 booster dose if they have not received one since the start of fall 2022. An additional booster dose may also be offered as of spring 2023 to adults (18 years of age and older) who are moderately to severely immunocompromised. Bivalent vaccines are preferred for all booster doses.
[Refer to Table 3 and to Booster doses for more information.](#a6.4.considerations)
### Schedule
In addition to the information contained in this section, a summary of recommendations, schedules and dosages for most available products can be found on [the Public Health Agency of Canada website](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/planning-immunization-clinics-covid-19-vaccines/recommended-schedules.html).
#### Primary series
For individuals 12 years of age and older, when the first dose in a COVID-19 vaccine series is an mRNA vaccine, the same mRNA vaccine product should be offered for the subsequent dose if readily available. When the same mRNA vaccine product is not readily available, or is unknown, another mRNA COVID-19 vaccine product recommended in that age group can be considered interchangeable and should be offered to complete the series.
[Table 1](#t1) provides the immunization schedule and minimum, authorized and optimal interval by product and age for those who are not moderately to severely immunocompromised. Doses administered at less than the minimum interval are considered invalid. See PHAC's resource: Quick reference guide on the use of COVID-19 vaccines: [Managing vaccine administration errors or deviations for additional guidance](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/quick-reference-guide-covid-19-vaccines/managing-administration-errors-deviations.html).
For mixed COVID-19 vaccine schedules, the minimum interval between doses should be based on the minimum interval of the product used for the first dose.
Optimal intervals between doses of 8 weeks (or at least 8 weeks) are longer than the authorized intervals as longer intervals are likely to result in a more robust and potentially more durable immune response and potentially higher vaccine effectiveness. Data from adults also suggests an extended interval may be associated with a reduced risk of myocarditis/pericarditis following a second dose of an mRNA COVID-19 vaccine.
[Table 2](#t2) provides the immunization schedule and minimum interval by product and age for those who are moderately to severely immunocompromised. For these individuals, providers should aim to administer each dose of the 3-dose series (or four doses for Pfizer-BioNTech Comirnaty [3 mcg]) for moderately to severely immunocompromised children 6 months to 4 years of age) 4 to 8 weeks apart from each other. An interval longer than 4 weeks between each dose is likely to result in a more robust and potentially more durable immune response and potentially higher vaccine effectiveness and may be associated with lower risk of myocarditis/pericarditis. However, if a longer interval between doses is being considered, then the need for earlier protection due to risk of exposure (including local transmission of SARS-CoV-2) and risk of severe disease (e.g., underlying high-risk medical condition) should be taken into account. Some moderately to severely immunocompromised individuals may still be susceptible after the initial first or second doses in the primary series, so their period of susceptibility until receipt of the additional dose will also increase if the interval between doses is increased. Some of these individuals will also remain susceptible after a third dose of COVID-19 vaccine.
Refer to [Table 5](#t5) for suggested intervals between previous SARS-CoV-2 infection and COVID-19 vaccination.
Table 1. Immunization schedule for a primary series, by COVID-19 vaccine for those who are not moderately to severely immunocompromised
(see [Table 2](#t2) for those who are moderately to severely immunocompromised)
| Vaccine product | Immunization schedule[Table 1 Footnote a](#t1fna) | Authorized age indication | Minimum interval | Authorized interval | Optimal interval[Table 1 Footnote b](#t1fnb) |
| --- | --- | --- | --- | --- | --- |
| Pfizer-BioNTech Comirnaty original (30 mcg) | 2-dose schedule | 12 years of age and older | 19 days[Table 1 Footnote c](#t1fnc) | 21 days | 8 weeks |
| Pfizer-BioNTech Comirnaty original (10 mcg, pediatric formulation) | 2-dose schedule | 5 to 11 years of age | 19 days | 21 days | At least 8 weeks |
| Pfizer-BioNTech Comirnaty original (3 mcg, pediatric formulation) | 3-dose schedule | 6 months to 4 years of age | 19 days[Table 1 Footnote c](#t1fnc) | First 2 doses, 21 days apart, 3rd dose at least 8 weeks after 2nd dose | At least 8 weeks between each dose |
| Moderna Spikevax original (100 mcg) | 2-dose schedule | 12 years of age and older | 21 days[Table 1 Footnote d](#t1fnd) | 28 days | 8 weeks |
| Moderna Spikevax original (50 mcg) | 2-dose schedule | 6 to 11 years of age | 21 days[Table 1 Footnote d](#t1fnd) | 28 days | At least 8 weeks |
| Moderna Spikevax original (25 mcg) | 2-dose schedule | 6 months to 5 years of age | 28 days[Table 1 Footnote e](#t1fne) | 28 days | At least 8 weeks |
| Novavax Nuvaxovid | 2-dose schedule | 12 years of age and older | 21 days[Table 1 Footnote f](#t1fnf) | 21 days | 8 weeks |
| Janssen Jcovden | 1-dose schedule | 18 years of age and older | N/A | N/A | N/A |
|
Table 1 Footnote a
It is recommended that for moderately to severely immunocompromised individuals, a primary series consists of three doses, preferentially with an mRNA COVID-19 vaccine, noting that for children 6 months to 4 years of age who are moderately to severely immunocompromised and vaccinated with Pfizer-BioNTech Comirnaty (3 mcg), a primary series consists of four doses. Refer to [Table 2](#t2) for additional information on schedules and intervals for those who are moderately to severely immunocompromised.
[Return Table 1 to footnote a referrer](#t1fna-rf)
Table 1 Footnote b
There is evidence that longer intervals between the first and second doses of COVID-19 vaccines are likely to result in more robust and potentially more durable immune response and potentially higher vaccine effectiveness and a lower risk of myocarditis/pericarditis. Balancing this potential enhanced protection from a longer interval with simultaneously minimizing the time at risk of infection due to having protection from only 1 dose, for all COVID-19 vaccines in those who are not moderately to severely immunocompromised, an 8-week (or at least 8 week) interval is recommended.
[Return Table 1 to footnote b referrer](#t1fnb-rf)
Table 1 Footnote c
The basis for this minimum interval is that the per-protocol design for the Pfizer-BioNTech Comirnaty COVID-19 vaccine clinical trial was 19 to 23 days.
[Return Table 1 to footnote c referrer](#t1fnc-rf)
Table 1 Footnote d
The basis for this minimum interval is that the majority of participants in the Moderna Spikevax COVID-19 vaccine clinical trials received the second dose 21 to 42 days after the first, as per the pre-defined window.
[Return Table 1 to footnote d referrer](#t1fnd-rf)
Table 1 Footnote e
The participants in the clinical trial received the second dose a minimum of 28 days after the first dose.
[Return Table 1 to footnote e referrer](#t1fne-rf)
Table 1 Footnote f
The basis for this minimum interval is that the majority of participants in the Novavax Nuvaxovid clinical trial received the second dose 21+7 days after the first, as per the pre-defined window.
[Return Table 1 to footnote f referrer](#t1fnf-rf)
|
#### Moderately to severely immunocompromised individuals
The recommended interval between doses in the primary series for those who are moderately to severely immunocompromised is 4 to 8 weeks.
Table 2. Immunization schedule and minimum intervals for a primary series for moderately to severely immunocompromised individuals, by COVID-19 vaccine
| Vaccine product | Immunization schedule[Table 2 Footnote a](#t2fna) | Minimum interval between the initial doses of a primary series[Table 2 Footnote b](#t2fnb) | Minimum interval between the previous dose and the additional dose in the primary series[Table 2 Footnote b](#t2fnb) |
| --- | --- | --- | --- |
| Pfizer-BioNTech Comirnaty original (3 mcg, pediatric formulation)[Table 2 Footnote c](#t2fnc) | 4-dose schedule | 19 days[Table 2 Footnote d](#t2fnd) | 28 days |
| Pfizer-BioNTech Comirnaty original (30 mcg) (10 mcg, pediatric formulation)[Table 2 Footnote e](#t2fnc) | 3-dose schedule | 19 days[Table 2 Footnote d](#t2fne) | 28 days |
| Moderna Spikevax original (100 mcg) (50 mcg)[Table 2 Footnote f](#t2fnf) | 3-dose schedule | 21 days[Table 2 Footnote g](#t2fnf) | 28 days |
| Moderna Spikevax original (25 mcg)[Table 2 Footnote c](#t2fnc) | 3-dose schedule | 28 days[Table 2 Footnote h](#t2fnh) | 28 days |
| Novavax Nuvaxovid[Table 2 Footnote i](#t2fni) | 3-dose schedule | 21 days | 28 days |
| Janssen Jcovden | 1-dose schedule[Table 2 Footnote j](#t2fnj) +1 mRNA | N/A | 28 days |
|
Table 2 Footnote a
It is recommended that for moderately to severely immunocompromised individuals, a primary series consists of three doses, preferentially with an mRNA COVID-19 vaccine, noting that for children 6 months to 4 years of age who are moderately to severely immunocompromised and vaccinated with Pfizer-BioNTech Comirnaty (3 mcg), a primary series consists of four doses.
[Table 2 Return to footnote a referrer](#t2fna-rf)
Table 2 Footnote b
For immunocompromised individuals, providers should aim to provide each dose of the primary series 4 to 8 weeks apart from each other. An interval longer than 4 weeks between each dose is likely to result in a more robust and durable immune response, potentially higher vaccine effectiveness and a lower risk of myocarditis/pericarditis. However, if a longer interval is being considered, risk factors for exposure and risk of severe disease should also be taken into account.
[Table 2 Return to footnote b referrer](#t2fnb-rf)
Table 2 Footnote c
For children 6 months to 4 years of age who are moderately to severely immunocompromised and vaccinated with Pfizer-BioNTech Comirnaty (3 mcg), a primary series consists of 4 doses, using an interval of 4 to 8 weeks between each dose. For children 6 months to 4 years of age who are moderately to severely immunocompromised, Moderna Spikevax original (25 mcg) is the preferred product because it has one fewer dose than Pfizer-BioNTech original (3 mcg) and so may be more acceptable and feasible for this group.
[Table 2 Return to footnote c referrer](#t2fnc-rf)
Table 2 Footnote d
The basis for this minimum interval is that the per-protocol design for the Pfizer-BioNTech Comirnaty original COVID-19 vaccine clinical trial was 19 to 23 days.
[Table 2 Return to footnote d referrer](#t2fnd-rf)
Table 2 Footnote e
The 30 mcg dose of Pfizer-BioNTech Comirnaty original COVID-19 vaccine is authorized for those 12 years of age and older. The 10 mcg dose of Pfizer-BioNTech Comirnaty original COVID-19 vaccine is authorized for those 5 to 11 years of age.
[Table 2 Return to footnote e referrer](#t2fne-rf)
Table 2 Footnote f
The 100 mcg dose of Moderna Spikevax original COVID-19 vaccine is authorized for those 12 years of age and older. The 50 mcg dose of Moderna Spikevax original COVID-19 vaccine is authorized for those 6 to 11 years of age.
[Table 2 Return to footnote f referrer](#t2fnf-rf)
Table 2 Footnote g
The basis for this minimum interval is that the majority of participants in the Moderna Spikevax original COVID-19 vaccine clinical trials received the second dose 21 to 42 days after the first, as per the pre-defined window.
[Table 2 Return to footnote g referrer](#t2fng-rf)
Table 2 Footnote h
The participants in the clinical trial received the second dose a minimum of 28 days after the first dose.
[Table 2 Return to footnote h referrer](#t2fnh-rf)
Table 2 Footnote i
mRNA COVID-19 vaccines are preferred and are authorized for a 3-dose primary series in moderately to severely immunocompromised individuals, while Novavax Nuvaxovid is not currently authorized as a 3-dose primary series in these populations. Based on clinical discretion, Novavax Nuvaxovid should be offered as a 3-dose primary series for moderately to severely immunocompromised individuals in the authorized age group who are not able or willing to receive an mRNA COVID-19 vaccine.
[Table 2 Return to footnote i referrer](#t2fni-rf)
Table 2 Footnote j
An initial or additional dose of a viral vector vaccine should only be considered for those in the authorized age group when all other authorized COVID-19 vaccines are contraindicated.
[Table 2 Return to footnote j referrer](#t2fnj-rf)
|
### Booster doses
All doses of COVID-19 vaccines after the primary series are described as booster doses. Note that for moderately to severely immunocompromised individuals, the primary series includes one additional dose that is not referred to as a booster dose.
Evidence suggests that protection against infection decreases with time from receipt of the last dose of vaccine. Booster doses provides additional protection, including against severe disease. However, the duration of protection is currently unknown, and the absolute benefit of additional booster doses will depend on the residual protection from the previous booster dose and on the level of circulating disease in the community. See [Table 3](#t3) for a summary of COVID-19 booster doses by age group.
An mRNA COVID-19 vaccine dose is preferred for the booster dose. Recipients of a viral vector vaccine series completed with only viral vector vaccines (AstraZeneca or Janssen Jcovden COVID-19 vaccine) should receive booster doses with an mRNA vaccine.
Bivalent vaccines are the preferred vaccine for booster doses among individuals in the authorized age groups, as, in addition to containing mRNA that encodes the spike protein of the original strain, they contain mRNA that encodes the spike protein of strains of the Omicron VOC.
Bivalent vaccines that encode for the BA.1 and BA.4/5 sublineages of Omicron are now available. Either type of vaccine can be used for the booster dose in authorized age groups.
#### Timing of booster doses
The additional protection from a booster dose may be affected by the interval between doses. A longer time between doses may result in a better response after any subsequent dose, as this allows time for the immune response to mature in breadth and strength and minimizes interference from the response from one dose on the next dose. A longer interval may, however, also increase the chance of a period with waning (lower) protection while awaiting a next dose.
COVID-19 booster doses may be offered at an interval of 6 months after a previous COVID-19 vaccine dose (after completion of the primary series or previous booster dose) or SARS-CoV-2 infection (see [Table 5](#t5)), regardless of the product offered.
Table 3. Summary table of COVID-19 booster doses by age group
| Population by age | Recommendation | Comments |
| --- | --- | --- |
| Adults ≥ 65 years of age[Table 3 Footnote a](#t3fna)[Table 3 Footnote b](#t3fnb) | Regardless of previous booster doses, a booster dose since the start of fall 2022 should be offered.
Bivalent Omicron-containing mRNA vaccines are preferred.[Table 3 Footnote c](#t3fnc) | * Data to date indicate that bivalent Omicron-containing mRNA COVID-19 vaccines have a similar safety profile to original mRNA COVID-19 vaccines.
* Post-market safety surveillance data to date indicate that the risk of myocarditis following a booster dose is lower compared to that following the second dose in the primary series, and current data do not show a product-specific difference in the risks of myocarditis and/or pericarditis after a booster dose of an mRNA COVID-19 vaccine. Adults can receive a booster dose with any available bivalent Omicron-containing mRNA COVID-19 vaccine.
|
| Adults 18 to 64 years of age who are at [increased risk of severe illness](#risk) from COVID-19 (including those who are immunocompromised and who received a 3-dose primary series)[Table 3 Footnote b](#t3fnb) | Regardless of previous booster doses, a booster dose since the start of fall 2022 should be offered.
Bivalent Omicron-containing mRNA vaccines are preferred.[Table 3 Footnote c](#t3fnc)[Table 3 Footnote d](#t3fnd) |
| All other adults 18 to 64 years of age[Table 3 Footnote a](#t3fna)[Table 3 Footnote b](#t3fnb) | At least one booster dose should be offered since the primary series. If a booster dose was received before the start of fall 2022, another booster dose may be offered since the start of fall 2022, with at least a 6-month interval since the previous dose.
Bivalent Omicron-containing mRNA vaccines are preferred.[Table 3 Footnote c](#t3fnc) |
| Adolescents 12 to 17 years of age who are at [increased risk of severe illness](#risk) from COVID-19 (including those who are immunocompromised and who received a 3-dose primary series) | Regardless of previous booster doses, a booster dose since the start of fall 2022 should be offered.
A bivalent Omicron-containing mRNA vaccine is preferred.[Table 3 Footnote d](#t3fnd) | - |
| All other adolescents 12 to 17 years of age | A booster dose since the start of fall 2022 may be offered.
A bivalent Omicron-containing mRNA vaccine is preferred.[Table 3 Footnote d](#t3fnd) |
| Children 5 to 11 years of age with an underlying medical condition that places them at high risk of severe illness due to COVID-19 (including those that are immunocompromised and who received an additional -dose in the primary series) | A booster dose should be offered.
A bivalent Omicron-containing mRNA vaccine is preferred.[Table 3 Footnote d](#t3fnd) | * Children 5 to 11 years of age who already received a booster dose with an original COVID-19 mRNA vaccine are not recommended to receive a bivalent Omicron-containing booster. However, at the provider's discretion, a bivalent booster dose could be offered to children considered at high risk of severe COVID-19 who have previously received a booster dose with the original Pfizer-BioNTech Comirnaty mRNA vaccine. There should be at least a 6-month interval since the previous dose.
|
| For all other children 5 to 11 years of age | A booster may be offered.
A bivalent Omicron-containing mRNA vaccine is preferred.[Table 3 Footnote d](#t3fnd) | - |
|
Table 3 Footnote a
For booster doses for adults 18 years of age and older who are not able or willing to receive an mRNA COVID-19 vaccine, a protein subunit COVID-19 vaccine (Novavax Nuvaxovid) should be offered to adults without contraindications to the vaccine. Janssen Jcovden COVID-19 vaccine may be offered as a first booster to individuals 18 years of age and older without contraindications to the vaccine only when all other COVID-19 vaccines are contraindicated.
[Table 3 Return to footnote a referrer](#t3fna-rf)
Table 3 Footnote b
[Starting in the spring of 2023, NACI recommends](/content/dam/phac-aspc/documents/services/publications/vaccines-immunization/national-advisory-committee-immunization-guidance-additional-covid-19-booster-dose-spring-2023-individuals-high-risk-severe-illness-due-covid-19/statement.pdf) that an additional booster dose may be offered as per the recommended interval to the following individuals who are at increased risk of severe illness from COVID-19:
* Adults 80 years of age and older
* Adult residents of long-term care homes and other congregate living settings for seniors or those with complex medical care needs
* Adults 18 years of age and older who are moderately to severely immunocompromised (due to an underlying condition or treatment)
* Adults 65 to 79 years of age, particularly if they do not have a known prior history of SARS-CoV-2 infection.
[Table 3 Return to footnote b referrer](#t3fnb-rf)
Table 3 Footnote c
For individuals in authorized age groups who are not able or willing to receive a bivalent Omicron-containing mRNA COVID-19 vaccine, an original mRNA COVID-19 vaccine may be offered.
[Table 3 Return to footnote c referrer](#t3fnc-rf)
Table 3 Footnote d
Pfizer-BioNTech Comirnaty bivalent BA.4/5 is authorized in individuals 5 years of age and older. Moderna Spikevax bivalent BA.1 is authorized in individuals 6 years of age and older. Moderna Spikevax bivalent BA.4/5 vaccine is authorized in individuals 6 years of age and older.
[Table 3 Return to footnote d referrer](#t3fnd-rf)
|
Vaccination of specific populations
-----------------------------------
### Pregnancy and breastfeeding
Compared to non-pregnant persons, SARS-CoV-2 infection in pregnancy is associated with increased risk of hospitalization and admission to an intensive care unit (ICU). SARS-CoV-2 infection during pregnancy is also associated with an increased risk in the neonate of preterm birth, low birth weight and admission to a neonatal intensive care unit (NICU).
#### Recommendations
It is recommended that a complete vaccine series with an mRNA COVID-19 vaccine should be offered to individuals in the authorized age group who are pregnant or breastfeeding (Refer to [Recommendations for use](#a5) section).
Booster recommendations for individuals at increased risk of severe illness from COVID-19 apply to people who are pregnant (see [Table 3](#t3)). An individual may receive all doses for which they are eligible during the course of a pregnancy, regardless of the trimester of pregnancy.
An mRNA vaccine is preferred due to reassuring published data on the safety of these vaccines in pregnancy.
#### Considerations
Pregnant or breastfeeding individuals were excluded from COVID-19 vaccine clinical trials. However, analysis of data collected through international COVID-19 immunization registries to date have not revealed any maternal or neonatal safety signals.
Informed consent should include discussion that there is real-world evidence on the safety profile and effectiveness of mRNA vaccination with large numbers of individuals who are pregnant or breastfeeding, but currently limited evidence on the use of the Novavax Nuvaxovid vaccine.
Rates of adverse effects are similar in people who are pregnant or breastfeeding and those who are not pregnant or breastfeeding. Studies have not found any impacts of mRNA COVID-19 vaccination on the infant/child being fed human milk or on milk production or excretion. Vaccination during pregnancy does not increase risk for adverse pregnancy/birth outcomes, including miscarriage, stillbirth, low birth weight, preterm birth and NICU admission.
Evidence suggests that COVID-19 mRNA vaccination during pregnancy results in comparable antibody titres to those generated in non-pregnant women. Maternal IgG humoral response to mRNA COVID-19 vaccines transfers across the placenta to the fetus, leading to a significant and potentially protective antibody titre in the neonatal bloodstream 1 week after the second dose. Infants of people who received the second dose of a primary series or a booster dose during pregnancy had a lower risk of hospitalization with COVID-19 (including Omicron) compared to infants born to individuals who were unvaccinated. The effect was greater with the booster dose than the second dose in a primary series and if the dose was given later in the pregnancy as opposed to earlier. The protection from maternal vaccination against infant hospitalization decreases over time since birth. Observational studies consistently show that both anti-spike IgG and IgA are present in breastmilk for at least 6 weeks after maternal vaccination with mRNA vaccines. The protection against disease as a result of breastfeeding is currently unknown.
Vaccine recipients and health care providers are encouraged to enroll patients who have received a COVID-19 vaccine during pregnancy in COVID-19 vaccine pregnancy registries (see [Table 4](#t4)).
There is a [Canadian COVID-19 Vaccine Registry for Pregnant and Lactating Individuals](https://covered.med.ubc.ca/), hosted at the University of British Columbia and supported by the COVID-19 Immunity Task Force (CITF) to assess the safety and effectiveness of COVID-19 vaccines.
Table 4: Pregnancy registry information by vaccine product
| Vaccine product | Registry information |
| --- | --- |
| Pfizer-BioNTech Comirnaty COVID-19 vaccine | Pfizer-BioNTech does not have a vaccine registry for pregnant persons. Individuals who are vaccinated with the Pfizer-BioNTech COVID-19 vaccine during pregnancy are encouraged to enroll into the [Canadian COVID-19 Vaccine Registry for Pregnant and Lactating Individuals](https://covered.med.ubc.ca/) described above. |
| Moderna Spikevax COVID-19 vaccines | There is a vaccine registry that monitors pregnancy outcomes in persons vaccinated with the Moderna COVID-19 vaccine during pregnancy. Individuals who are vaccinated with the Moderna COVID-19 vaccine during pregnancy are encouraged to enroll in the registry by calling 1-866-MODERNA (1-866-663-3762). |
| Janssen Jcovden COVID-19 vaccine | There is a vaccine registry that monitors pregnancy outcomes in persons vaccinated with Janssen Jcovden COVID-19 vaccine during pregnancy. Individuals who are vaccinated with Janssen Jcovden COVID-19 vaccine during pregnancy are encouraged to enroll in the registry by visiting [C-VIPER: COVID-19 Vaccines International Pregnancy Exposure Registry](https://c-viper.pregistry.com/). |
| Novavax Nuvaxovid COVID-19 vaccine | There is a vaccine registry that monitors pregnancy outcomes in persons vaccinated with NUVAXOVID during pregnancy. Individuals who are vaccinated with NUVAXOVID during pregnancy are encouraged to enroll in the registry by visiting [C-VIPER: COVID-19 Vaccines International Pregnancy Exposure Registry](https://c-viper.pregistry.com/) |
Refer to [Immunization in Pregnancy and Breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3 for additional general information.
### Individuals previously infected with SARS-CoV-2
The immune response due to prior infection may vary due to factors such as the severity of infection, age, presence of comorbidities, the SARS-CoV-2 variant causing the infection, time since the infection and vaccination history. People with both SARS-CoV-2 infection and COVID-19 vaccination are said to have "hybrid immunity" and have the highest vaccine effectiveness against SARS-CoV-2 infection and severe disease compared to either infection or vaccination alone.
#### Recommendations
COVID-19 vaccines, with a preference for mRNA vaccines, should or may be offered to individuals 6 months of age and older with previous SARS-CoV-2 infection without contraindications to the vaccine based on the recommendation for their age and other risk factors (see [Recommendations for use](#a5) section).
Safety and efficacy data in individuals previously infected with SARS-CoV-2 following vaccination with a protein subunit COVID-19 vaccine are not available.
Refer to [Table 5](#a5) for suggested intervals between previous infection and COVID-19 vaccination.
Table 5. Suggested intervals between previous SARS-CoV-2 infection[Table 5 Footnote a](#t5fna) and COVID-19 vaccination
| SARS-CoV-2 infection[Table 5 Footnote a](#t5fna) timing relative to COVID-19 vaccination | Population | Suggested interval between SARS-CoV-2 infection[Table 5 Footnote a](#t5fna) and vaccination (clinical discretion is advised)[Table 5 Footnote b](#t5fnb)[Table 5 Footnote c](#t5fnc) |
| --- | --- | --- |
| **Infection prior to completion or initiation**[Table 5 Footnote c](#t5fnc) **of primary vaccination series** | Individuals 6 months of age and older who are not considered moderately to severely immunocompromised and with no history of MIS-C or MIS-A | Receive the vaccine 8 weeks after symptom onset or positive test (if asymptomatic)[Table 5 Footnote b](#t5fnb) |
| Individuals 6 months of age and older who are moderately to severely immunocompromised and with no history of MIS-C or MIS-A | Receive the vaccine dose 4 to 8 weeks after symptom onset or positive test (if asymptomatic)[Table 5 Footnote b](#t5fnb) |
| Individuals 6 months of age and older with a history of MIS-C or MIS-A (regardless of immunocompromised status) | Receive the vaccine dose when clinical recovery has been achieved or ≥90 days since diagnosis of MIS-C or MIS-A, whichever is longer |
| **Infection after primary series**[Table 5 Footnote d](#t5fnd) **but before a booster dose, or after a booster dose but before a next booster dose** | Individuals 5 years of age and older currently eligible for a booster dose | 6 months since infection[Table 5 Footnote b](#t5fnb) |
|
Table 5 Footnote a
Previous infection can be defined in different ways based on jurisdictional policies and access to testing. The following suggestion can be considered to define previous infection with SARS-CoV-2:
* Confirmed by a molecular (e.g., PCR) or Health Canada-approved antigen detection-based test; or
* Symptomatic disease compatible with COVID-19 AND household exposure to a confirmed COVID-19 case.
[Table 5 Return to footnote a referrer](#t5fna-rf)
Table 5 Footnote b
These suggested intervals are based on immunological principles and expert opinion, and may change as evidence on COVID-19, VOCs, and COVID-19 vaccines emerge. When considering whether or not to administer vaccine doses following the suggested intervals outlined in this table, biological and social risk factors for exposure (e.g., local epidemiology, circulating VOCs, living settings) and severe disease should also be taken into account. These intervals are a guide and clinical discretion is advised.
[Table 5 Return to footnote b referrer](#t5fnb-rf)
Table 5 Footnote c
For individuals who have not had any previous doses, they may receive their first dose after acute symptoms of COVID-19 have resolved and they are no longer infectious, or they may follow these suggested intervals. Individual benefit/risk assessment and clinical discretion are advised as per footnote "b". Waiting until at least the infected person is no longer infectious is intended to minimize the risk of transmission of COVID-19 at an immunization venue and to enable monitoring for COVID-19 vaccine adverse events without potential confounding from symptoms of COVID-19.
[Table 5 Return to footnote c referrer](#t5fnc-rf)
Table 5 Footnote d
The primary series is outlined in Recommendations for use. Note that for moderately to severely immunocompromised individuals who were immunized with a primary series that includes one additional dose, a booster dose would be subsequent to that additional dose.
[Table 5 Return to footnote d referrer](#t5fnd-rf)
|
#### Considerations
Testing for previous SARS-CoV-2 infection is not needed prior to COVID-19 vaccination.
A longer interval between infection and vaccination may result in a better immune response from the infection as this allows time for this response to mature in breadth and strength, and for circulating antibodies from the infection to decrease, thus avoiding immune interference when the vaccine is administered.
Current evidence suggests protection is more robust and longer lasting with vaccination in previously infected individuals compared to immunity from SARS-CoV-2 infection alone.
COVID-19 vaccination in individuals previously infected with SARS-CoV-2 has a good safety profile and is well tolerated. Limited evidence suggests reactogenicity may be slightly increased in individuals previously infected with SARS-CoV-2 compared to those with no history of previous infection, however this evidence is limited to the primary series and variants prior to Omicron.
### Immunocompromised persons
#### Recommendations
Those who are moderately to severely immunocompromised should receive an additional dose in the primary series and then subsequent booster doses as recommended following the primary series. Refer to [Recommendations for use](#a5) for specific recommendations based on age for those who are moderately to severely immunocompromised.
#### Considerations
Immunocompromised individuals, including those receiving immunosuppressive therapy, are at increased risk for prolonged infection and serious complications from SARS-CoV-2 infection. Numerous studies have shown that immunogenicity is substantially decreased in some immunocompromised individuals when compared to healthy vaccine recipients, although evidence is limited to studies in adolescent and adult populations. Observational studies in adults with complete 1 or 2 dose series, show lower vaccine effectiveness against SARS-CoV-2 infection and COVID-19 disease in immunocompromised adults when compared to the general population.
The **minimum interval between the initial doses of the primary series and the additional dose should be 28 days but can up to 8 weeks**. An interval longer than the minimum 28 days between doses is likely to result in a better immune response. However, moderately to severely immunocompromised individuals (after the initial 1- or 2- doses of the primary series) may still be susceptible during this time before the next dose is administered. If a longer interval between doses is being considered, then the need for earlier protection due to risk of exposure (including local transmission of SARS-CoV-2, circulation of VOC) and risk of severe disease (e.g., underlying high risk medical condition) should be taken into account.
A vaccine series should ideally be completed at least 2 weeks before initiation of immunosuppressive therapies where possible.
Moderately to severely immunocompromised includes individuals with the following conditions:
* Immunocompromised due to solid tumour or hematologic malignancies or treatments for these conditions
* Solid-organ transplant and taking immunosuppressive therapy
* Hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppression therapy)
* Immunocompromise due to chimeric antigen receptor (CAR) T cell therapy targeting lymphocytes
* Moderate to severe primary immunodeficiency with associated humoral and/or cell-mediated immunodeficiency or immune dysregulation
* HIV with AIDS-defining illness or TB diagnosis in last 12 months before starting vaccine series, **or** severe immune compromise with CD4<200 cells/uL **or** CD4%<15%, **or** without HIV viral suppression
* Recent treatment with the following categories of immunosuppressive therapies: anti-B cell therapies (monoclonal antibodies targeting CD19, CD20 and CD22), high-dose systemic corticosteroids, alkylating agents, antimetabolites, or tumor-necrosis factor (TNF) inhibitors and other biologic agents that are significantly immunosuppressive
* Chronic kidney disease on dialysis
A range of factors can impact the relative degree of immunocompromise and response to COVID-19 vaccines, and clinical and public health judgement should be applied. Jurisdictions may modify the list based on population considerations.
Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for a suggested definition of high dose steroids and for guidance on vaccination with COVID-19 vaccines for individuals pre- and post-hematopoietic stem cell transplantation (HSCT) and for chimeric antigen receptor (CAR) T cell therapy recipients.
Novavax Nuvaxovid is not currently authorized as a 3-dose primary series and the safety and efficacy of Novavax Nuvaxovid has not been established in individuals who are immunocompromised due to disease or treatment. Based on clinical discretion, Novavax Nuvaxovid should be offered as a 3-dose primary series for moderately to severely immunocompromised individuals in the authorized age group who are not able or willing to receive an mRNA COVID-19 vaccine. Informed consent should include discussion that there is currently limited evidence on the use of Novavax Nuvaxovid in this population, while there is evidence on the safety profile and effectiveness of mRNA COVID-19 vaccines based on real world use with large numbers of individuals.
Evidence indicates that humoral immune responses increase in some individuals after a third dose of mRNA COVID-19 vaccine is administered as part of an extended primary series to adults with immunocompromising conditions, although the degree of increase varies between studies and according to the type of immunocompromising condition or treatment.
Studies assessing additional doses in immunocompromised individuals have primarily used mRNA vaccines, for both the initial and additional doses in the primary series, and are limited to studies in adult populations. Moderna Spikevax vaccines may produce a greater immune response in this population. Investigations are ongoing.
In observational studies and clinical trials, humoral and cellular immune responses were similar between fully vaccinated people living with HIV on antiretroviral therapy and those who were HIV-negative.
Based on observational studies, the frequency and severity of AEFIs with an mRNA COVID-19 vaccine in certain immunocompromised populations were comparable to those of non-immunosuppressed individuals. No worsening of underlying disease was reported after immunization.
Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for definitions and additional general information.
### Travellers
Travellers should receive a complete series of COVID-19 vaccine and optimally should receive a booster dose, if they are eligible, at least 2 weeks prior to departure. Travellers should verify the travel requirements in place at their destination(s) and for their return to Canada. For more information, refer to the [Committee to Advise on Tropical Medicine and Travel (CATMAT) Statement on COVID-19 and International Travel](/en/public-health/services/catmat/statement-covid-19-international-travel.html).
### Persons new to Canada
Based on a recommendation by PHAC to provinces and territories, people who are planning to live, work or study in Canada who have had only a complete or incomplete primary series of non-Health Canada authorized vaccines, should be offered an additional dose of an mRNA vaccine, unless they have already received 3 doses of a COVID-19 vaccine. They should receive booster doses when eligible.
Serologic testing
-----------------
Serologic testing is not needed before or after immunization with COVID-19 vaccine.
Administration practices
------------------------
### Dose and route of administration
#### Dose
##### Pfizer-BioNTech Comirnaty COVID-19 original vaccine (30 mcg)
This formulation has a grey cap and a grey label border and is authorized for use in individuals 12 years of age and older.
No dilution is required.
Each dose is 0.3 mL, containing 30 mcg of SARS-CoV-2 spike protein mRNA.
Special precaution should be taken to ensure the correct dose is taken from the multi-dose vial.
##### Pfizer-BioNTech Comirnaty COVID-19 original vaccine (10 mcg, pediatric formulation)
This formulation has an orange vial cap and orange label border and is authorized for use in children 5 to 11 years of age.
Dilute with 1.3 mL 0.9% Sodium Chloride Injection, USP prior to use.
Each dose is 0.2 mL after dilution, containing 10 mcg of SARS-CoV-2 spike protein mRNA.
Special precaution should be taken to ensure the correct dose is taken from the multi-dose vial.
##### Pfizer-BioNTech Comirnaty COVID-19 vaccine (3 mcg, pediatric formulation)
This formulation has a maroon vial cap and maroon label border and is authorized for use in children 6 months to 4 years of age.
Dilute with 2.2 mL 0.9% Sodium Chloride Injection, USP prior to use.
Each dose is 0.2 mL after dilution, containing 3 mcg of SARS-CoV-2 spike protein mRNA.
Special precaution should be taken to ensure the correct dose is taken from the multi-dose vial.
##### Pfizer-BioNTech Comirnaty Original & Omicron BA.4/BA.5 COVID-19 vaccine (Bivalent)
There are two formulations of Pfizer-BioNTech Comirnaty bivalent BA.4/5 vaccine authorized for use.
* Vials with a gray cap and gray label border containing 30 mcg of mRNA (15 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and 15 mcg of mRNA encoding for the spike protein of the Omicron BA.4/BA.5 variant). This vaccine authorized for use in individuals 12 years of age and older. Each dose is 0.3 mL. No dilution is required.
* Vials with an orange cap and an orange label border containing 10 mcg of mRNA (5 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and 5 mcg of mRNA encoding for the spike protein of the Omicron BA.4/BA.5 variant). This vaccine authorized for use in individuals 5 to 11 years of age. Each dose is 0.2 mL after dilution with 1.3 mL sterile 0.9% Sodium Chloride Injection, USP prior to use.
##### Moderna Spikevax original COVID-19 vaccine
There are two formulations of Moderna Spikevax original authorized for use in individuals 6 months of age and older.
* Vials with a red cap and light blue label border containing 0.20 mg/mL in a 5mL multidose vial
* Vials with a royal blue cap and a purple label border containing 0.10 mg/mL in a 2.5mL multidose vial
No dilution is required.
The volume (mL) required for primary series and booster dosing will be different depending on which presentation of the vaccine is being administered. Careful attention should be paid to the vial and carton label, vial cap colour, label border colour and corresponding dose volumes. See [Table 6](#t6) for primary series and booster doses of Moderna Spikevax by product and age.
##### Moderna Spikevax Bivalent (Original & Omicron BA.1) COVID-19 vaccine
This formulation has a royal blue vial cap and a green label border and is authorized for use as a booster dose in individuals 6 years of age and older.
For individuals 6 to 11 years of age, the booster dose is 0.25 mL containing 25 mcg of mRNA (12.5 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and 12.5 mcg of mRNA encoding for the spike protein of the Omicron BA.1 variant).
For individuals 12 years of age and older, the booster dose is 0.5 mL containing 50 mcg of mRNA (25 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and 25 mcg of mRNA encoding for the spike protein of the Omicron BA.1 variant).
No dilution is required.
Vials contain 0.10 mg/mL in a 2.5 mL multidose vial.
Careful attention should be paid to the vial and carton label, vial cap colour and label border colour. See [Table 6](#t6) for booster doses of Moderna Spikevax by product and age.
##### Moderna Spikevax Bivalent (Original & Omicron BA.4/5) COVID-19 vaccine
This formulation has a royal blue vial cap and a grey label border and is authorized for use as a booster dose in individuals 6 years of age and older.
For individuals 6 to 11 years of age, each booster dose is 0.25 mL, containing 25 mcg of mRNA (12.5 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and 12.5 mcg of mRNA encoding for the spike protein of the Omicron BA.4/5 variant).
For individuals 12 years of age and older, each booster dose is 0.5 mL, containing 50 mcg of mRNA (25 mcg of mRNA encoding for the spike protein of the original SARS-CoV-2 virus and 25 mcg of mRNA encoding for the spike protein of the Omicron BA.4/5 variant).
No dilution is required.
Vials contain 0.10 mg/mL in a 2.5 mL multidose vial.
Careful attention should be paid to the vial and carton label, vial cap colour and label border colour. See [Table 6](#t6) for booster doses of Moderna Spikevax by product and age.
Table 6. Dosing for Moderna Spikevax vaccines
| Presentation | Cap/label colour | Age | Vaccination | Dose | Dose volume |
| --- | --- | --- | --- | --- | --- |
| Original
0.2 mg/mL
Multidose vial (5 mL) | Red cap/light blue label border | 12+ years | primary series | 100 mcg[Table 6 Footnote a](#t6fna) | 0.5 mL |
| 12+ years | booster[Table 6 Footnote b](#t6fnb)[Table 6 Footnote c](#t6fnc) | 50 mcg | 0.25 mL |
| 6 to 11 years | primary series | 50 mcg | 0.25 mL |
| Original
0.1 mg/mL
Multidose vial (2.5 mL) | Royal blue cap/purple label border | 12+ years | booster[Table 6 Footnote c](#t6fnc) | 50 mcg[Table 6 Footnote c](#t6fnc) | 0.5 mL |
| 6 to 11 years | primary series | 50 mcg | 0.5 mL |
| 6 months to 5 years | primary series | 25 mcg[Table 6 Footnote d](#t6fnd) | 0.25 mL |
| Bivalent (Original & Omicron BA.1)
0.1 mg/mL
Multidose vial (2.5 mL) | Royal blue cap/green label border | 12+ years | booster | 50 mcg | 0.5 mL |
| 6 to 11 years | booster | 25 mcg | 0.25 mL |
| Bivalent (Original & Omicron BA.4/5)
0.1 mg/mL
Multidose vial (2.5 mL) | Royal blue cap/grey label border | 12+ years | booster | 50 mcg | 0.5 mL |
| 6 to 11 years | booster | 25 mcg | 0.25 mL |
|
Table 6 Footnote a
The 0.10 mg/mL presentation is not intended for preparation of the 100 mcg dose.
[Table 6 Return to footnote a referrer](#t6fna-rf)
Table 6 Footnote b
Moderna Spikevax COVID-19 vaccine (original) is authorized as a booster dose for individuals 12 years of age and older.
[Table 6 Return to footnote b referrer](#t6fnb-rf)
Table 6 Footnote c
Bivalent products are preferred as booster doses for those in the authorized age groups.
[Table 6 Return to footnote c referrer](#t6fnc-rf)
Table 6 Footnote d
The 0.20 mg/mL presentation is not intended for preparation of the 25 mcg dose.
[Table 6 Return to footnote d referrer](#t6fnd-rf)
|
Refer to [Booster doses](#a5.5) for additional information.
##### Novavax Nuvaxovid COVID-19 vaccine
Each dose is 0.5 mL, containing 5 mcg SARS-CoV-2 recombinant original strain spike protein. Vials contain 5 mcg/0.5 mL in a 5.0 mL multidose vial.
The product comes premixed with the Matrix-M adjuvant. No dilution or reconstitution is required.
##### Janssen Jcovden COVID-19 vaccine
Each dose is 0.5 mL, containing 5 x 1010 viral particles of SARS-CoV-2 original strain spike protein. The vial contains 3.1 mL in a multidose vial.
No dilution is required.
#### Route of administration
COVID-19 vaccines are given as an intramuscular (IM) injection. The deltoid muscle of the arm is the preferred injection site in adolescents and adults, unless the muscle mass is not adequate or vaccination in that site is not possible, in which case the anterolateral thigh can be used.
Refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for additional general information, including recommended routes of administration for children.
If an error in vaccine administration occurs, refer to [Managing COVID-19 vaccine administration errors or deviations](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/quick-reference-guide-covid-19-vaccines/managing-administration-errors-deviations.html) for guidance.
### Interchangeability of vaccines
Regardless of which product is offered, the previous dose should be counted, and the series need not be restarted.
#### mRNA COVID-19 vaccines
If readily available (i.e., easily available at the time of vaccination without delay or vaccine wastage), the same mRNA COVID-19 vaccine product should be offered for the subsequent dose in a vaccine series started with an mRNA COVID-19 vaccine. However, when the same mRNA COVID-19 vaccine product is not readily available, or is unknown, another mRNA COVID-19 vaccine product recommended for use in that age group can be considered interchangeable and should be offered to complete the vaccine series.
There are currently only limited data on the use of bivalent Omicron-containing mRNA COVID-19 vaccines as part of a primary series. A primary series with an original mRNA vaccine is recommended in all authorized age groups. If a bivalent vaccine is inadvertently used in the primary series, it is considered valid as long as a valid dosage was used. Refer to [Managing COVID-19 vaccine administration errors or deviations](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/quick-reference-guide-covid-19-vaccines/managing-administration-errors-deviations.html) for guidance. Bivalent Omicron-containing mRNA vaccines are the preferred booster products for the authorized age groups; however, original strain mRNA vaccines used as a booster dose are considered valid.
#### Novavax Nuvaxovid COVID-19 vaccine
Novavax Nuvaxovid should be used to start or complete a primary series, or used as a booster dose in a mixed prime-boost series, for individuals for whom mRNA COVID-19 vaccine is contraindicated, inaccessible, or has been refused.
Informed consent should include a discussion of the benefits and risks given the limited data available on mixed schedules with Novavax Nuvaxovid. There are currently no data on the use of Novavax Nuvaxovid in a mixed primary series with Moderna Spikevax original (100 mcg) or Janssen Jcovden COVID-19 vaccines. Clinical trial evidence for a heterologous booster dose is available from two randomized controlled trials where adults received a booster dose at least 12 weeks after a primary series with mRNA COVID-19 vaccines or viral vector COVID-19 vaccines. In one, humoral and cellular immune responses against original SARS-CoV-2 were lower compared to after Pfizer-BioNTech Comirnaty original or Moderna Spikevax original. In the other, humoral immune responses were similar to or slightly higher. In both trials Novavax Nuvaxovid was less reactogenic compared to mRNA COVID-19 vaccines. Evidence on immune responses against recent Omicron sub-lineages is also available from an observational study that showed that a heterologous booster dose of Novavax Nuvaxovid resulted in neutralizing antibody responses against BQ.1.1 and XBB.1 that were slightly lower (but not statistically significant) compared to responses after a bivalent mRNA booster dose.
#### Mixed COVID-19 vaccine schedules
For mixed COVID-19 vaccine schedules, the minimum interval between doses should be based on the minimum interval of the product used for the first dose. When using mixed schedules, the suggested optimal interval between doses is 8 weeks (or at least 8 weeks) for those who are not moderately to severely immunocompromised based on considerations found in [Table 2](#t2).
Evidence indicates that mixed COVID-19 viral vector, mRNA and protein subunit vaccine schedules with dosing intervals between 4 and 12 weeks have acceptable safety profiles.
Limited evidence suggests that a mixed schedule in which Novavax Nuvaxovid is administered following a partial or complete primary series of AstraZeneca Vaxzevria or Pfizer-BioNTech Comirnaty original COVID-19 vaccines may not be as immunogenic as continuing with Pfizer-BioNTech Comirnaty original or Moderna Spikevax original vaccines – despite it having an acceptable safety profile and immunogenicity.
### Concurrent administration with other vaccines
For individuals 6 months of age and older, COVID-19 vaccines may be given concurrently (i.e., same day), or at any time before or after, non-COVID-19 vaccines (including live and non-live vaccines).
It is recommended that COVID-19 vaccines may be concurrently administered with other vaccines among all vaccine eligible populations, as there is, to date, no evidence of safety concerns for concurrent administration. In addition, concurrent administration will reduce barriers to the provision of routine childhood immunizations and seasonal influenza immunization. Studies and surveillance activities to assess the safety and immunogenicity of concurrent administration of COVID-19 vaccines with other vaccines are ongoing.
If more than one type of vaccine is administered at a single visit, they should be administered at different injection sites using separate injection equipment. Preferably this is in different limbs, however if the same limb must be used, the injection sites should be separated by at least 2.5 cm (1 inch).
Informed consent should include a discussion of the benefits and risks given the limited data available on administration of COVID-19 vaccines at the same time as, or shortly before or after, other vaccines.
Refer to [Timing of Vaccine Administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) in Part 1 for additional general information on concurrent administration of other vaccines.
### Pre-vaccination counselling
Prophylactic oral analgesics or antipyretics (e.g., acetaminophen or ibuprofen) should not be routinely used before or at the time of vaccination, but their use is not a contraindication to vaccination. There is currently no evidence of benefit from administration of oral analgesics for the prevention of immunization injection pain or systemic reactions.
Prior to providing a COVID-19 vaccine, informed consent should include discussion about frequently occurring minor adverse events and the risks and symptoms of potential rare severe adverse events.
Anyone receiving a viral vector COVID-19 vaccine (Janssen Jcovden) should be informed of adverse events that may occur following vaccination with viral vector vaccines: Guillain-Barré syndrome (GBS), thrombosis with thrombocytopenia syndrome (TTS) including vaccine-induced immune thrombotic thrombocytopenia (VITT), capillary leak syndrome (CLS), venous thromboembolism (VTE), immune thrombocytopenia (ITP), Bell's palsy and anaphylaxis, and be advised to seek medical attention if they develop signs or symptoms suggestive of these conditions.
Anyone receiving any mRNA COVID-19 vaccine (Pfizer-BioNTech Comirnaty original or bivalent, or Moderna Spikevax original or bivalent) should be informed of the risks associated with mRNA COVID-19 vaccines: myocarditis/pericarditis, Bell's palsy and anaphylaxis, and be advised to seek medical attention if they develop signs or symptoms suggestive of these conditions.
Anyone receiving the Novavax Nuvaxovid vaccine should be informed of the risk of myocarditis/pericarditis and anaphylaxis and also be advised to seek medical attention if they develop signs or symptoms suggestive of these conditions.
Refer to [Safety and adverse events](#a10) for further information.
### Post-vaccination counselling
Oral analgesics or antipyretics may be considered for the management of adverse events (e.g., pain or fever, respectively), if they occur after vaccination. Analgesics and antipyretics were used in clinical trials of COVID-19 vaccines for the management of pain and/or fever after vaccination.
All vaccine recipients should be instructed to seek medical care if they develop signs or symptoms of a serious adverse event or an allergic reaction following vaccination.
Refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for additional information on pre- and post-vaccination counseling.
Storage requirements
--------------------
For information on storage, handling and transport of frozen and thawed vaccine vials, refer to the [Overview of key features of COVID-19 vaccines authorized in Canada](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/planning-immunization-clinics-covid-19-vaccines.html#app16).
For additional information, consult the product leaflet or information contained within the product monograph available through Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html). Refer to [Storage and Handling of Immunizing Agents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-9-storage-handling-immunizing-agents.html) in Part 1 for additional general information.
Safety and adverse events
-------------------------
Evidence on vaccine safety is available from COVID-19 clinical trials and ongoing international COVID-19 vaccine safety monitoring. The clinical trials solicited adverse events for defined lengths of time following a vaccine dose, as well as collecting unsolicited and serious events.
For reported side effects following COVID-19 vaccination in Canada, refer to the [PHAC AEFI report](https://health-infobase.canada.ca/covid-19/vaccine-safety/).
Refer to [Vaccine Safety and Pharmacovigilance](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) and [Adverse Events Following Immunization (AEFI)](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) in Part 2 for additional information on vaccine safety and for definitions of AEFIs, and reporting of AEFI to public health.
For individuals who develop AEFIs following COVID-19 vaccination, refer to the [Contraindications and precautions](#a10.4) section for advice on future vaccinations.
### Very common and common adverse events
Common adverse events are defined as those that occur in 1% to less than 10% of vaccine recipients; very common adverse events occur in 10% or more of vaccine recipients.
#### Local
Local adverse events were usually mild or moderate and resolved within a few days of vaccination in all age groups (6 months and older). Pain at the injection site was very common. Redness and swelling were common or very common after administration of any authorized COVID-19 vaccine. Localized axillary (or groin) swelling and tenderness (lymphadenopathy) was a solicited adverse event in the Moderna Spikevax original COVID-19 vaccine clinical trial and was very common after administration of that vaccine.
#### Systemic
Systemic adverse events were usually mild or moderate and resolved within a few days of vaccination in all age groups (6 months and older). Fatigue, headache, muscle pain, chills, and joint pain were all either common or very common after the administration of any authorized COVID-19 vaccine.
The most frequent reactions reported for children aged 6 months to 2 years included irritability or crying, sleepiness, and loss of appetite. These reactions are common after childhood vaccination.
#### Adverse events in individuals previously infected with SARS-CoV-2
Limited evidence suggests reactogenicity may be slightly increased in individuals previously infected with SARS-CoV-2 compared to those with no history of previous infection; however, this evidence is limited to the primary series and infection with variants prior to Omicron.
#### Adverse events following bivalent Omicron- containing mRNA COVID-19 vaccines
Available clinical trial data show that Moderna Spikevax Bivalent BA.1 (50 mcg) administered as a second booster dose to individuals 18 years of age and older had a similar reactogenicity profile to that of Moderna Spikevax original (50 mcg) given as a second booster dose. Post licensure surveillance is ongoing.
There are no clinical safety data currently available for Pfizer-BioNTech Comirnaty Original & Omicron BA.4/5 (30 mcg) bivalent vaccine specifically; however, preliminary post-market safety surveillance data in individuals 12 years of age and older from Canada and the US suggest the BA.4/5 bivalent vaccines are well tolerated with a similar safety profile to the original mRNA COVID-19 vaccines when administered as booster doses.
### Uncommon, rare and very rare adverse events
Uncommon adverse events occur in 0.1% to less than 1% of vaccine recipients. Rare and very rare adverse events occur in 0.01% to less than 0.1% and less than 0.01% of vaccine recipients, respectively. The probability of detection of very rare adverse events in clinical trials is low given clinical trial sample sizes; therefore, ongoing pharmacovigilance is essential.
#### Lymphadenopathy
Lymphadenopathy was an unsolicited event that was uncommonly reported after administration of the Pfizer-BioNTech Comirnaty original (both 10 mcg and 30 mcg formulations) and Janssen Jcovden COVID-19 vaccines in clinical trials. As noted above, lymphadenopathy was a solicited adverse event in the clinical trials for Moderna Spikevax original and was very commonly reported.
#### Myocarditis or pericarditis following vaccination with an mRNA COVID-19 vaccine
Rare cases of myocarditis (inflammation of the heart muscle) and/or pericarditis (inflammation of the lining around the heart) have been reported following vaccination with COVID-19 mRNA vaccines.
Cases following mRNA COVID-19 vaccination are consistently reported to have occurred:
* More often after the second dose
* Usually within a week after vaccination
* More often in those 12 to 29 years of age
* More often in males
Analyses of primary series surveillance data in Canada, US and European Nordic countries suggests a higher rate of myocarditis/pericarditis cases reported after vaccination with Moderna Spikevax original (100 mcg) compared to Pfizer-BioNTech Comirnaty original (30 mcg) vaccine especially among 12 to 29 year old males following a second dose of vaccine.
Myocarditis unrelated to exposure to COVID-19 disease or COVID-19 vaccines is typically less common in younger children 5 to 11 years of age. Safety surveillance data from the US suggests that the risk of myocarditis or pericarditis may be lower in children aged 5 to 11 years following Pfizer-BioNTech original (10 mcg) vaccination compared to adolescents and young adults (who receive a 30 mcg Pfizer-BioNTech original dose). Among children 5 to 11 years of age following vaccination with Pfizer-BioNTech Comirnaty original (10 mcg), very rare cases were most often reported following dose 2 and among males. The risk of myocarditis or pericarditis with Moderna Spikevax original (50 mcg) in children 6 to 11 years of age is unknown. Post-market safety surveillance is ongoing.
Available post-market vaccine safety data from V-safe, Vaccine Safety Datalink (VSD) and Vaccine Adverse Event Reporting System (VAERS) in the US as of September 2022 show that the Moderna Spikevax (25 mcg) and Pfizer-BioNTech Comirnaty (3 mcg) mRNA COVID-19 vaccines are well tolerated among children aged 6 months to 5 years. No safety signals (including myocarditis) have been identified after administration of about 1.5 million vaccine doses.
Evidence from bivalent and original mRNA COVID-19 vaccines across different age groups show that the risk of myocarditis is lower following boosters compared to dose 2 of the primary series, and that no product-specific difference in the risk of myocarditis has been identified following a booster dose at this time. However, while these observations were also seen in adolescents 12 to 17 years of age, the use of Moderna Spikevax COVID-19 vaccines have been limited in those 5 to 17 years of age.
While long-term follow-up is ongoing, available data indicate that the majority of individuals who reported myocarditis/pericarditis after mRNA COVID-19 vaccination, though requiring hospitalization, have responded well to conservative therapy and tend to recover quickly.
Healthcare providers should consider myocarditis/pericarditis in their evaluation if the patient presents with clinically compatible symptoms (e.g., chest pain, shortness of breath, palpitations) after an mRNA COVID-19 vaccine regardless of timing from vaccination to symptoms onset. Investigations include electrocardiogram, serum troponins and echocardiogram. Abnormal electrocardiogram findings and elevated troponin levels have been frequently noted with myocarditis/pericarditis following mRNA vaccine.
Consultation with a cardiologist, infectious disease specialist, or internal medicine specialist may be advisable to assist in this evaluation, particularly to investigate the many potential causes of myocarditis and pericarditis. Investigations may include diagnostic testing for acute COVID-19 infection (e.g., PCR testing), prior SARS-CoV-2 infection and consideration of other potential infectious or non-infectious etiologies including auto-immune conditions.
Refer to the [Contraindications and precautions](#a10.4) section for advice on re-vaccination of individuals who developed myocarditis/pericarditis after a COVID-19 vaccine.
#### Myocarditis/pericarditis following vaccination with other COVID-19 vaccines
Cases of myocarditis/pericarditis have been rarely reported following the administration of Novavax Nuvaxovid. Australia's Therapeutic Goods Administration (TGA) reports that as of April 16, 2023, over 251,000 doses of Novavax Nuvaxovid had been administered in the country. Myocarditis was reported in approximately 3 to 4 in every 100,000 people who received a dose of this vaccine. Pericarditis was reported in 13 in every 100,000 people. A further breakdown of the rates of myocarditis/pericarditis after Novavax Nuvaxovid by age group (including among adolescents), sex and dose number are not available due to the relatively low number of doses given and reported cases. In Europe, over 345,000 doses of Novavax Nuvaxovid have been administered as of December 31, 2022 and myocarditis has been reported at a rate of 20.3 per million doses. In Japan, over 275,000 doses of Novavax Nuvaxovid have been administered as of December 31, 2022, with no reported cases of myocarditis. In Canada, there have been no reported cases of myocarditis or pericarditis following Novavax Nuvaxovid as of March 26, 2023 (following approximately 32,200 doses administered).
Reports of adverse events noted by the US FDA, suggest increased risks of myocarditis and pericarditis following vaccination with Janssen Jcovden, particularly within 7 days.
#### Venous thromboembolism (VTE)
Venous thromboembolism (VTE) has been observed rarely following vaccination with the Janssen Jcovden COVID-19 Vaccine. In individuals with a pre-existing increased risk for thromboembolism, the possible increased risk of VTE with vaccine use should be considered. See the [Contraindications and precautions](#a10.4) section if considering the use of Janssen Jcovden in an individual with a history of VTE.
#### Guillain-Barré syndrome (GBS) following vaccination with viral vector COVID-19 vaccines
Guillain-Barré syndrome (GBS) is a rare but potentially serious immune-mediated neurologic disorder that results in numbness, muscle weakness and/or paralysis in severe cases, as well as pain, often in the back or legs. Most people fully recover from GBS but some have residual deficits or symptoms and rarely, fatal cases can occur. To date, no increased risk of GBS has been identified following vaccination with the mRNA COVID-19 vaccines (Pfizer-BioNTech Comirnaty original and Moderna Spikevax original). Investigations have identified an increased risk of GBS following vaccination with the viral vector COVID-19 vaccines (AstraZeneca Vaxzevria and Janssen Jcovden).
Symptoms of GBS may include:
* weakness or tingling sensations, especially in the upper or lower limbs, that worsens and spreads to other parts of the body
* coordination problems and unsteadiness
* difficulty walking
* weakness in the limbs, chest or face
* pain that can be severe, particularly at night
* difficulty with bladder control and bowel function
* double vision or difficulty moving eyes
* difficulty with facial movements, including swallowing, speaking, or chewing
Individuals should seek medical attention if they develop symptoms of GBS following vaccination. Healthcare providers should consider GBS in their evaluation if the patient presents with clinically compatible symptoms and exclude other potential causes.
See the [Contraindications and precautions](#a10.4) section regarding individuals who developed GBS after COVID-19 vaccination for advice on re-vaccination.
#### Bell's palsy
Very rare cases of Bell's palsy (typically temporary weakness or paralysis on one side of the face) have been reported following vaccination with Janssen Jcovden COVID-19 vaccine and COVID-19 mRNA vaccines (Pfizer-BioNTech Comirnaty original or Moderna Spikevax original) among individuals aged 12 years and older. Symptoms of Bell's palsy appear suddenly and generally start to improve after a few weeks. The exact cause is unknown. It's believed to be the result of swelling and inflammation of the nerve that controls muscles on the face.
Symptoms of Bell's palsy may include:
* uncoordinated movement of the muscles that control facial expressions, such as smiling, squinting, blinking or closing the eyelid
* loss of feeling in the face
* headache
* tearing from the eye
* drooling
* lost sense of taste on the front two-thirds of the tongue
* hypersensitivity to sound in the one ear
* inability to close an eye on one side of the face
Individuals should seek medical attention if they develop symptoms of Bell's palsy following receipt of COVID-19 vaccines. Healthcare providers should consider Bell's palsy in their evaluation if the patient presents with clinically compatible symptoms after a COVID-19 vaccine. Investigations should exclude other potential causes of facial paralysis.
#### Multisystem inflammatory syndrome in children or in adults (MIS-C or MIS-A) following vaccination with an mRNA COVID-19 vaccine
During the manufacturer-led clinical trials for mRNA COVID-19 vaccines, no cases of MIS-C were reported among children or adolescents. However, any rare or very rare AE that occurs at a frequency less often than 1 in 10,000 would likely not be detected due to the limitations of the trial size.
Very rare cases of MIS-C or MIS-A have been reported following vaccination with COVID-19 mRNA vaccines in Canada and internationally among individuals aged 12 years and older. In October 2021, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (EMA-PRAC) issued a statement that there is currently insufficient evidence regarding a possible link between mRNA COVID-19 vaccines and very rare cases of MIS-C or MIS-A.
#### Severe immediate allergic reactions (e.g., anaphylaxis) following vaccination with COVID-19 vaccines
Anaphylaxis is a very rare, severe, life-threatening allergic reaction typically with a rapid onset that involves multiple organ systems and can progress rapidly. Symptoms and signs of anaphylaxis may include but are not limited to generalized urticaria; wheezing; swelling of the mouth, tongue, and throat; difficulty breathing; vomiting; diarrhea; hypotension; decreased level of consciousness; and shock.
Very rare cases of severe immediate allergic reactions (e.g., anaphylaxis) have been reported following vaccination with mRNA COVID-19 vaccines. Most of the reported cases have occurred within 30 minutes of vaccination.
Individuals tend to recover quickly with appropriate treatment and there have been no fatalities nor long-term morbidity observed with any of these severe immediate allergic reactions in Canada.
Studies have shown that individuals with a severe immediate allergic reaction after a previous dose of mRNA vaccine can be re-vaccinated with the same vaccine or another mRNA COVID-19 vaccine following an appropriate medical assessment. In these studies, re-vaccination was safe and well tolerated with predominantly no, or mild, reactions after re-vaccination when provided in a controlled environment. Available evidence also suggests that most of the reported severe immediate allergic reactions following mRNA COVID-19 vaccines are likely not immunoglobulin E (IgE)-mediated and therefore have a low risk of recurrence following future vaccine doses. Refer to [Precautions](#a10.4) below for additional information.
Refer to [Anaphylaxis and other Acute Reactions Following Vaccination](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html) in Part 2 for information on the management of anaphylaxis post-vaccination.
Refer to the [Contraindications and precautions](#a10.4) section for advice on re-vaccination of individuals who had an anaphylactic reaction after vaccination and for vaccination advice for those allergic to components of the COVID-19 vaccines.
#### Thrombosis with thrombocytopenia syndrome (TTS) following vaccination with viral vector COVID-19 vaccines
Very rare cases of serious blood clots or thrombosis (at unusual sites such as cerebral venous sinus thrombosis, splanchnic vein thrombosis, as well as arterial thrombosis) associated with thrombocytopenia have been reported following vaccination with viral vector COVID-19 vaccines. The Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) uses the Brighton Collaboration case definition for TTS to detect and evaluate reported cases. In Canada, TTS cases that test positive for a biomarker, anti-PF4 (antibodies to platelet factor 4-polyanion complexes), represent a subset of events and are being referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT).
The exact mechanism by which the viral vector COVID-19 vaccines trigger this syndrome is still under investigation. Viral vector vaccines appear to trigger a presentation similar to spontaneous heparin-induced thrombosis (HIT)/autoimmune heparin-induced thrombosis, where antibodies to platelet factor 4 (PF4)-polyanion complexes induce platelet activation, which causes thrombosis and thrombocytopenia. Clots related to VITT can be very aggressive and challenging to treat. Please refer to [Thrombosis Canada guidance for clinical management of VITT](https://thrombosiscanada.ca/wp-uploads/uploads/2021/04/51.-Vaccine-induced-prothrobotic-immune-thrombcytopenia_26Apr21-Final.pdf). They cannot be managed the same way as clots related to oral contraceptives, immobility, or long-haul flights, and have an entirely different biologic pathophysiology.
Cases of TTS usually occur between 4 and 28 days after receipt of a viral vector COVID-19 vaccine, and patients should be monitored for symptoms up to 42 days. The rate of TTS after the first dose is estimated to be between 1 per 26,000 and 1 per 100,000 doses of AstraZeneca Vaxzevria COVID-19 vaccine administered and 1 per 300,000 doses of Janssen Jcovden COVID-19 vaccine administered. The frequency of TTS following a second dose of AstraZeneca Vaxzevria vaccine appears to be lower at about 1 per 520,000 doses administered. After the first dose, there was a higher reported incidence rate of TTS in the younger adults compared to the older adults. The reported incidence was also higher in women compared to men in some age groups. The case fatality rate ranges between 20 and 50%. Many cases have been reported to have serious long-term morbidity, including neurologic injury.
Anyone receiving a viral vector COVID-19 vaccine should be informed of the adverse event of TTS and advised to seek immediate medical attention if they develop symptoms following vaccination.
Symptoms of TTS may include the following, noting that some symptoms may be dependent on the location of the blood clot:
* shortness of breath
* chest pain
* leg swelling or pain
* persistent abdominal pain
* sudden onset of severe headaches
* persistent or worsening headaches
* blurred vision
* confusion or seizures
* skin bruising (other than at the site of vaccination) or petechiae
Healthcare professionals should be aware of TTS including how to diagnose and treat the condition (see [guidance from Thrombosis Canada](https://thrombosiscanada.ca/wp-uploads/uploads/2021/04/51.-Vaccine-induced-prothrobotic-immune-thrombcytopenia_26Apr21-Final.pdf)). People who developed TTS after a viral vector vaccine should not receive additional viral vector vaccines. Refer to the [Contraindications and precautions](#a10.4) section.
#### Capillary leak syndrome (CLS) following vaccination with viral vector COVID-19 vaccines
Very rare cases of CLS have been reported following immunization with the viral vector COVID-19 vaccines (AstraZeneca Vaxzevria and Janssen Jcovden). CLS is a very rare, serious condition that causes fluid leakage from small blood vessels (capillaries), resulting in swelling mainly in the arms and legs, low blood pressure, thickening of the blood and low blood levels of albumin (an important blood protein). Symptoms are often associated with feeling faint (due to low blood pressure).
The frequency of CLS has been estimated at less than 1 per million doses of viral vector vaccines administered. Some of those affected had a history of CLS. People with a history of CLS should not be offered viral vector vaccines. Refer to the [Contraindications and precautions](#a10.4) section.
#### Immune thrombocytopenia (ITP) following vaccination with viral vector COVID-19 vaccines
Cases of immune thrombocytopenia with very low platelet levels (<20,000 per uL) have been reported very rarely after vaccination with Janssen Jcovden and AstraZeneca Vaxzevria COVID-19 vaccines, usually within the first four weeks after vaccination. This included cases with bleeding and cases with fatal outcome. Some of these cases occurred in individuals with a history of immune thrombocytopenia (ITP). If an individual has a history of ITP, the risks of developing low platelet levels should be considered before vaccination with a viral vector vaccine, and platelet monitoring is recommended after vaccination.
### Guidance on reporting adverse events following immunization (AEFI)
Vaccine providers are asked to report AEFIs through local public health departments and to follow AEFI reporting requirements that are specific to their province or territory. In general, any serious (defined as resulting in hospitalization, permanent disability or death) or unexpected adverse event that is temporally related to vaccination should be reported. Refer to [Reporting AEFI in Canada](/en/public-health/services/immunization/reporting-adverse-events-following-immunization/form.html) for additional information on the completion and submission of AEFI reports.
At the international level, the Brighton Collaboration has developed a list of Adverse Events of Special Interest (AESI). AESI are pre-specified medically significant events that have the potential to be causally associated with a vaccine product. Refer to [Brighton Collaboration: COVID-19 resources and tools](https://brightoncollaboration.us/covid-19/) for the list of AESIs and for case definitions of specific AEFIs.
Refer to [Adverse Events Following Immunization (AEFI)](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) in Part 2 for additional information on definitions, reporting, investigating and managing, and causality assessments for AEFIs.
Refer to the [PHAC weekly report for reported adverse events](https://health-infobase.canada.ca/covid-19/vaccine-safety/summary.html) following COVID-19 vaccination in Canada.
### Contraindications and precautions
#### Contraindications
##### Thrombosis with thrombocytopenia syndrome (TTS) following vaccination
Patients who have experienced venous and/or arterial thrombosis with thrombocytopenia following vaccination with a viral vector COVID-19 vaccine should not receive a subsequent dose of a viral vector COVID-19 vaccine. They may receive further doses of mRNA COVID-19 vaccines following consultation with their clinical team which may include a hematologist.
##### Capillary leak syndrome (CLS)
As a precautionary measure following the international cases that have been reported, individuals with a history of CLS (related or not to previous vaccination) should not receive viral vector COVID-19 vaccines.
#### Precautions
##### Hypersensitivity and allergies
**Severe immediate allergic reaction (e.g., anaphylaxis) to a COVID-19 vaccine**
In individuals with a history of a severe, immediate (4 hours or less following vaccination) allergic reaction after previous administration of an mRNA COVID-19 vaccine, re-vaccination may be offered with the same vaccine or the same platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Consultation with an allergist or other appropriate physician should be sought prior to re-vaccination. If re-vaccinated, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis. Individuals should be observed for **at least** 30 minutes after re-vaccination. For example, a longer period of observation is warranted for individuals exhibiting any symptom suggestive of an evolving AEFI at the end of the 30-minute observation period.
For those with a previous history of allergy to an mRNA vaccine where consultation with an allergist or other appropriate physician precludes further vaccination with an mRNA vaccine, vaccination with Novavax Nuvaxovid should be offered if the individual is in the authorized age group and does not have contraindications to the vaccine. They should also be observed for an extended period of **at least** 30 minutes after re-vaccination.
**Confirmed allergies to a component of a COVID-19 vaccine**
Ingredients of authorized COVID-19 vaccines that have been associated with allergic reactions in other products are: polyethylene glycol (PEG), tromethamine (trometamol or Tris) and polysorbate 80. There is a potential of cross-reactive hypersensitivity between PEG and polysorbate.
Table 7. Vaccine products and potential allergens
| Vaccine product | Potential allergens |
| --- | --- |
| Polyethylene glycol (PEG) | Tromethamine (trometamol or Tris) | Polysorbate 80 | Others |
| Pfizer-BioNTech Comirnaty original (30 mcg, 12 years and older, gray vial cap and gray label border) | Yes | Yes | No | - |
| Pfizer-BioNTech Comirnaty original (10 mcg, 5 to 11 years of age, orange vial cap and orange label border) | Yes | Yes | No | - |
| Pfizer-BioNTech Comirnaty original (3mcg, 6 months to 4 years of age, maroon vial cap and maroon label border) | Yes | Yes | No | - |
| Pfizer-BioNTech Comirnaty Original & Omicron BA.4/5 (bivalent, 30 mcg, 12 years of age and older, gray vial cap and gray label border) | Yes | Yes | No | - |
| Pfizer-BioNTech Comirnaty Original & Omicron BA.4/5 (bivalent, 10 mcg, 5 to 11 years of age, orange vial cap and orange label border) | Yes | Yes | No | - |
| Moderna Spikevax original (0.20 mg/mL, red vial cap and light blue label border) | Yes | Yes | No | - |
| Moderna Spikevax original (0.10 mg/mL, royal blue cap and purple label border) | Yes | Yes | No | - |
| Moderna Spikevax Bivalent, Original & Omicron BA.4/5 (0.10mg/mL, royal blue cap and grey label border) | Yes | Yes | No | - |
| Moderna Spikevax Bivalent, Original & Omicron BA.1 (0.10 mg/mL, royal blue cap and green label border) | Yes | Yes | No | - |
| Janssen Jcovden | No | No | Yes | - |
| Novavax Nuvaxovid | No | No | Yes | - |
In individuals with a confirmed severe, immediate (≤4 hours following exposure) allergy (e.g., anaphylaxis) to a component of a specific COVID-19 vaccine (e.g., PEG), or its container, consultation with an allergist is recommended before receiving the specific COVID-19 vaccine. In individuals with a serious PEG allergy in whom mRNA vaccination is precluded based on a consultation with an allergist or other appropriate physician, vaccination with Novavax Nuvaxovid may be preferred for individuals in the authorized age group without contraindications to Novavax Nuvaxovid. Individuals with a known or suspected serious allergy to a component of a COVID-19 vaccine should be observed for at least 30 minutes after vaccination, if they receive a vaccine containing that component.
It is important to note that other, less serious [reactions may mimic allergic reactions (e.g., vasovagal syncope](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html#t1)) and vaccination is not contraindicated in these cases.
**Mild to moderate immediate allergic reactions to a COVID-19 vaccine or a vaccine excipient**
In individuals with mild to moderate immediate allergic reactions (defined as limited in the scope of symptoms and involvement of organ systems or even localized to the site of administration) to a previous dose of mRNA COVID-19 vaccine or any of its components, re-vaccination may be offered with the same vaccine or the same platform (i.e., mRNA). Assessment by a physician or nurse with expertise in immunization may be warranted prior to re-immunization.
Most instances of anaphylaxis to a vaccine begin within 30 minutes after administration of the vaccine. Therefore, if re-vaccination is chosen, an extended period of observation post-vaccination of **at least** 30 minutes should be provided for the aforementioned individuals.
**Other allergies**
The following individuals may be routinely vaccinated with COVID-19 vaccines with the following recommended observation periods.
30 minute post-vaccination observation period:
* Those with a proven severe allergic reaction (e.g., anaphylaxis) to injectable therapy not related to a component of the COVID-19 vaccines (e.g., other intramuscular, intravenous, or subcutaneous vaccines or therapies)
* Those with a suspected but unproven allergy to a vaccine component (e.g., PEG)
15 minute post-vaccination observation period:
* Those with a history of allergy not related to a component of the COVID-19 vaccines or other injectable therapy (e.g., foods, oral drugs, insect venom or environmental allergens)
##### Acute illness
Vaccination of individuals who may be currently infected with SARS-CoV-2 is not known to have a detrimental effect on the illness. However, vaccination should be deferred in individuals with confirmed or suspected SARS-CoV-2 infection, or those with respiratory symptoms, to minimize the risk of COVID-19 transmission at an immunization clinic/venue. If any person is identified with symptoms on arrival at the venue, they should not be immunized and should be instructed to seek medical and public health advice as appropriate and follow current local public health measures.
The recommended intervals between SARS-CoV-2 infection and COVID-19 vaccination are provided in [Table 5](#t5).
##### Bleeding disorders
In individuals with bleeding disorders, the condition should be managed prior to immunization to minimize the risk of bleeding. Individuals receiving long-term anticoagulation are not considered to be at higher risk of bleeding complications following immunization and may be safely immunized without discontinuation of their anticoagulation therapy.
##### Immune thrombocytopenia (ITP)
If an individual has a history of ITP, the risks of developing low platelet levels should be considered before vaccination with a viral vector vaccine, and platelet monitoring is recommended after vaccination.
Individuals should seek immediate medical attention if they develop symptoms such as unexplained bleeding, unexplained bruising, or small purplish spots beyond the site of vaccination.
##### Venous thromboembolism (VTE)
In individuals with a pre-existing increased risk for thromboembolism, the possible increased risk of VTE with the Janssen Jcovden COVID-19 vaccine should be considered. Along with the general preference for mRNA vaccines, mRNA vaccines would be a safer option for these individuals.
Individuals should seek immediate medical attention if they develop symptoms, such as shortness of breath, chest pain, leg pain, leg swelling, or persistent abdominal pain following vaccination.
##### Thrombosis with thrombocytopenia syndrome (TTS)
There is no evidence that individuals with previous cerebral venous sinus thrombosis (CVST) with thrombocytopenia not related to a viral vector or people with previous heparin-induced thrombocytopenia (HIT) not related to a viral vector vaccine are at increased risk of vaccine-induced immune thrombotic thrombocytopenia (VITT) compared to other individuals after receiving a viral vector vaccine. However, similar to other individuals, an mRNA vaccine is preferred. Novavax Nuvaxovid should be used among individuals in the authorized age group without contraindications to the vaccine who are not able or willing to receive an mRNA vaccine.
##### Myocarditis and/or pericarditis following vaccination
As a precautionary measure until more information is available, further doses of mRNA COVID-19 vaccines should be deferred among individuals who have experienced myocarditis and/or pericarditis within 6 weeks following a previous dose of an mRNA COVID-19 vaccine in most circumstances. This includes any person who had an abnormal cardiac investigation including ECG, elevated troponins, echocardiogram or cardiac MRI after a dose of an mRNA COVID-19 vaccine.
Those with a history compatible with pericarditis and who either had no cardiac workup or had normal cardiac investigations, can receive the next dose once they are symptom-free and at least 90 days have elapsed since vaccination.
Some individuals 5 years of age and older with confirmed myocarditis and/or pericarditis after a dose of an mRNA COVID-19 vaccine may choose to receive another dose of vaccine after discussing the risk and benefit with their healthcare provider. If another dose of vaccine is offered, it should be with a Pfizer-BioNTech Comirnaty COVID-19 vaccine product (original for the primary series or bivalent for the booster dose, at the age-appropriate dose) due to the lower reported rate of myocarditis and/or pericarditis following the Pfizer-BioNTech Comirnaty original (30 mcg) vaccine compared to the Moderna Spikevax original (100 mcg) vaccine among individuals 12 years of age and older. Informed consent should include discussion about the unknown risk of recurrence of myocarditis and/or pericarditis following receipt of additional doses of Pfizer-BioNTech Comirnaty original or bivalent vaccines in individuals with a history of confirmed myocarditis and/or pericarditis after a previous dose of mRNA COVID-19 vaccine, as well as the need to seek immediate medical assessment and care should symptoms develop.
There have been case reports of myocarditis and/or pericarditis following the administration of Novavax Nuvaxovid. Data from the clinical trials and global safety surveillance have suggested an increased risk.
Individuals who have a history of myocarditis unrelated to mRNA or protein subunit COVID-19 vaccination should consult their clinical team for individual considerations and recommendations. If the diagnosis is remote and they are no longer followed clinically for cardiac issues, they should receive the vaccine.
##### Guillain-Barré syndrome
Individuals with past history of GBS unrelated to COVID-19 vaccination should receive an mRNA COVID-19 vaccine. When mRNA COVID-19 vaccines are contraindicated, Novavax Nuvaxovid should be considered or individuals may receive a viral vector COVID-19 vaccine after weighing the risks and benefits in consultation with their health care provider.
Individuals who developed GBS after a previous dose of a COVID-19 vaccine may receive an mRNA COVID-19 vaccine, after consultation with their health care provider if it is determined that the benefits outweigh the risk and informed consent is provided.
##### Bell's palsy
Individuals should seek medical attention if they develop symptoms compatible with Bell's palsy following receipt of mRNA COVID-19 vaccines. Healthcare providers should consider Bell's palsy in their evaluation if the patient presents with clinically compatible symptoms after an mRNA COVID-19 vaccine. Investigations should exclude other potential causes of facial paralysis.
##### Multisystem inflammatory syndrome in children or adults (MIS-C or MIS-A)
For children or adults with a previous history of MIS-C or MIS-A, vaccination or re-vaccination should be postponed until clinical recovery has been achieved or until it has been ≥ 90 days since diagnosis, whichever is longer (see [Table 5](#t5)).
Other considerations
--------------------
### Tuberculin skin testing (TST) or interferon gamma release assay (IGRA)
There is a theoretical risk that mRNA or viral vector vaccines could temporarily affect cell-mediated immunity, resulting in false-negative TST or IGRA test results. However, there is no direct evidence for this interaction. Therefore, in the absence of data and acknowledging the importance of both timely tuberculosis testing and immunization, vaccination with COVID-19 vaccines may take place at any time before, after or at the same visit as the TST or IGRA test. Repeat tuberculin skin testing or IGRA (at least 4 weeks post-COVID-19 immunization) of individuals with negative TST or IGRA results for whom there is high suspicion of latent tuberculosis infection may be considered in order to avoid missing persons with TB infection.
### Blood products, human immunoglobulin and timing of immunization
It is recommended that COVID-19 vaccines should not be given concurrently with anti-SARS-CoV-2 monoclonal antibodies.
Administration of these products concurrently may result in decreased effectiveness of the COVID-19 vaccine and/or anti-SARS-CoV-2 monoclonal antibodies. Anti-SARS-CoV-2 monoclonal antibodies have high affinity for the spike protein expressed by COVID-19 vaccines, which could prevent the production of antibodies stimulated by the vaccine, or binding of vaccine antigen to the monoclonal antibody may neutralize the monoclonal antibody.
### Pre-exposure prophylaxis for COVID-19 with anti-SARS-CoV-2 monoclonal antibodies
In some cases, anti-SARS-CoV-2 monoclonal antibodies may be given in addition to vaccination to some individuals with immunocompromising conditions, in consultation with clinical experts. Clinicians may consider the following factors when assessing the potential benefits or risks when recommending anti-SARS-CoV-2 monoclonal antibodies to their patients: the degree of immunocompromise, the presence of additional risk factors for severe COVID-19, the likelihood of not responding to COVID-19 vaccine, the risk of exposure to COVID-19 due to occupational or residential circumstances, as well as local circulation of variants with the potential for resistance to one or more of the anti-SARS-CoV-2 monoclonal antibodies, including some Omicron sublineages. Although anti-SARS-CoV-2 monoclonal antibodies could reduce humoral immune responses to a COVID-19 vaccine, cellular immune responses may not be impacted. Cellular immune responses to a COVID-19 vaccine are important for immunocompromised populations and, to sustain cellular immune responses, vaccination should be given to this group as recommended, whether or not their receive anti-SARS-CoV-2 monoclonal antibodies, noting the timing considerations below.
Implementation advice to inform decision-makers on the appropriate use of anti-SARS-CoV-2 monoclonal antibodies (e.g., patient prioritization) is available from the [Canadian Agency for Drugs and Technologies in Health (CADTH)](https://www.cadth.ca/evusheld-tixagevimab-and-cilgavimab-pre-exposure-prophylaxis-covid-19-adults-and-adolescents-12), [the Institut national d'excellence en santé et en services sociaux (INESSS)](https://www.inesss.qc.ca/covid-19/traitements-specifiques-a-la-covid-19/tixagevimab-/-cilgavimab-evusheld-en-prophylaxie-preexposition.html) and [Ontario Health](https://www.ontariohealth.ca/sites/ontariohealth/files/2022-05/Information%20for%20health%20care%20providers%20-%20Evusheld.pdf).
Up to date information on alerts including risk of treatment failure of specific anti-SARS-CoV-2 monoclonal antibodies as well as safety and recalls, is available from [Health Canada](https://recalls-rappels.canada.ca/en/alert-recall/evusheld-tixagevimab-and-cilgavimab-injection-risk-prophylaxis-or-treatment-failure-0?utm_source=gc-notify&utm_medium=email&utm_content=en&utm_campaign=hc-sc-rsa-22-23).
Guidance on anti-SARS-CoV-2 monoclonal antibodies may change as additional evidence emerges.
#### Administration of anti-SARS-CoV-2 monoclonal antibodies following COVID-19 vaccines
To minimize interference, it is recommended that anti-SARS-CoV-2 monoclonal antibodies should be administered at least 2 weeks following COVID-19 vaccination.
#### Administration of COVID-19 vaccines following anti-SARS-CoV-2 monoclonal antibodies
There is no evidence on which to base a specific minimum interval for COVID-19 vaccination following anti-SARS-CoV-2 monoclonal antibodies administration. Timing should be assessed in consultation with clinical experts on a case-by-case basis.
### Therapeutic management of COVID-19 with anti-SARS-CoV-2 monoclonal antibodies
Multiple products are authorized in Canada for therapeutic management of COVID-19. Expert clinical opinion should be sought on a case-by-case basis when deciding on the use of anti-SARS-CoV-2 monoclonal antibodies, as well as whether vaccination should be repeated if a therapeutic dose is given too close to vaccination.
Timing of administration of COVID-19 vaccines following administration of therapeutic anti-SARS-CoV-2 monoclonal antibodies should be assessed in consultation with clinical experts on a case-by-case basis.
For complete prescribing information, consult the product leaflet or information contained within the product monograph available through Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
Chapter revision process
------------------------
This chapter was updated to reflect guidance based on current evidence and the National Advisory Committee on Immunization's (NACI's) expert opinion since the last version of this chapter (March 22, 2023). Additional content changes may reflect changes to COVID-19 vaccine product monographs. Refer to the [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html) for additional information.
For supporting information on COVID-19 vaccine chapter updates, including additional references, refer to the [Current](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine/summary-updates-june-23-2023.html) and/or [Previous summary of updates in the Canadian Immunization Guide](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci.html#covid-19) published on the NACI webpage under [COVID-19](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci.html#covid-19).
Acknowledgements
----------------
This chapter was prepared by SJ Ismail, K Young, MC Tunis, A Killikelly, O Baclic, J Zafack, MI Salvadori, N Forbes, L Coward, C Jensen, R Krishnan, NK Abraham, E Abrams, B Warshawsky, E Wong, J Montroy, R Pless, S Wilson, R Harrison, and S Deeks on behalf of NACI.
NACI gratefully acknowledges the contribution of: N Haddad, M Laplante, C Mauviel, K Ramotar, S Pierre, N Mohamed, E Tice.
Selected references
-------------------
* Abraham N, Spruin S, Rossi T, Fireman B, Zafack J, Blaser C, et al. Myocarditis and/or Pericarditis Risk After mRNA COVID-19 Vaccination: A Canadian Head to Head Comparison of BNT162b2 and mRNA-1273 Vaccines. JVAC-D-21-03106, Available at SSRN: https://ssrn.com/abstract=3988612
* AstraZeneca Canada Inc. Product monograph - Evusheld™. April 14, 2022.
* Brighton Collaboration. Interim case definition of Thrombosis with Thrombocytopenia Syndrome (TTS) [Internet]. Decatur (GA): The Task Force for Global Health; 2021 Nov 11. Available from: https://brightoncollaboration.us/wp-content/uploads/2021/11/TTS-Updated-Brighton-Collaboration-Case-Defintion-Draft-Nov-11-2021.pdf
* Janssen Inc. Product monograph - JCOVDEN™ COVID-19 vaccine. August 5, 2022.
* ModernaTX, Inc. Product monograph - SPIKEVAX™. July 14, 2022.
* ModernaTX, Inc. Product monograph - SPIKEVAX™ Bivalent. May 18, 2023
* National Advisory Committee on Immunization. COVID-19 vaccine statements. Accessed September 2022 from: https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci.html#covid-19
* Novavax, Inc. Product monograph - NUVAXOVID™. February 17, 2022.
* Pfizer Canada ULC. Product monograph - COMIRNATY® Original & Omicron BA.4/BA.5. December 9, 2022.
* Pfizer Canada ULC. Product monograph - COMIRNATY™. June 1, 2022.
* Public Health Ontario. Recommendations: Fourth COVID-19 vaccine dose for long-term care home residents and older adults in other congregate settings. December 29, 2021. Accessed February 2022 from: https://www.publichealthontario.ca/-/media/Documents/nCoV/Vaccines/2022/01/covid-19-oiac-4th-dose-recommendations-older-adults-ltc.pdf?sc\_lang=en
* Therapeutic Goods Administration (Australia). COVID-19 vaccine safety report - 04-05-23. https://www.tga.gov.au/news/covid-19-vaccine-safety-reports/covid-19-vaccine-safety-report-04-05-23
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-07-13
| None | None |
bea40181ecae4f0f105ccbb1b1409b6af2e8014b | cma | Interim guidance on the use of bivalent Omicron-containing COVID-19 vaccines for primary series | Interim guidance on the use of bivalent Omicron-containing COVID-19 vaccines for primary series
Preamble
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Background
Bivalent Omicron-containing mRNA COVID-19 vaccines are authorized as booster doses for those 5 years of age and older, but there is currently no bivalent vaccine authorized for a primary series in any age group or as a booster dose for those less than 5 years of age. Several regulatory submissions for the use of bivalent mRNA COVID-19 vaccines as a primary series are currently under review by Health Canada. Many original monovalent mRNA vaccines will no longer be available in the coming months, and PHAC has asked NACI to consider how jurisdictions can ensure COVID-19 product options for the primary series are available to all recommended populations. This includes consideration of off-label use of bivalent vaccines using age-based dosages that are different from those currently authorized for the primary series with the original mRNA COVID-19 vaccines. As regulatory submissions progress over the summer, vaccine schedules and/or dosages may change for some age groups. New formulations of COVID-19 vaccines that reflect changes in circulating Omicron subvariants may also become available in the fall of 2023.
Bivalent Omicron-containing mRNA COVID-19 vaccines have been recommended to be used as booster doses in Canada since September 1, 2022, when NACI published initial recommendations on their use. Currently, bivalent Omicron-containing vaccines are authorized as booster doses for individuals 5 years of age and older and NACI's recommendations cite a preference for their use over original mRNA vaccines for booster doses. For more information on COVID-19 booster doses, please refer to the of the Canadian Immunization Guide (CIG).
Since the initial authorization and recommendations of bivalent Omicron-containing COVID-19 vaccine booster doses:
- Although there are some fluctuations in COVID-19 transmission indicators (for example cases reported, hospitalizations, and deaths) and variations across provinces and territories, COVID-19 activity has been relatively stable with hospitalizations remaining at a relatively high level since the widespread circulation of Omicron in early 2022, with the highest hospitalization rates among older adults.
- Additional evidence has emerged on the performance and safety of bivalent vaccines as booster doses.
- Some limited direct evidence is now available on the use of bivalent Omicron-containing vaccines for the primary series.
NACI continues to monitor the rapidly evolving scientific data recognizing that the trajectory of the COVID-19 pandemic remains unclear.
NACI's recommendations remain aligned with the goals of the Canadian COVID-19 Pandemic Response that were last updated on :
- To minimize serious illness and death while minimizing societal disruption as a result of the COVID-19 pandemic
- To transition away from the crisis phase towards a more sustainable approach to long term management of COVID-19
Methods
On January 10, January 31, and April 4, 2023, the NACI COVID-19 Working Group (WG) reviewed the available epidemiology and evidence on vaccine safety and protection, including clinical trial results on bivalent Omicron-containing vaccines as the primary series and real-world evidence on bivalent Omicron-containing vaccines as booster doses. NACI also conducted an in-depth ethical analysis on this topic informed by the framework outlined by the Public Health Ethics Consultative Group (PHECG) . Equity, feasibility and acceptability factors were also considered according to NACI's published, peer-reviewed framework and evidence-informed tools to support systematic assessment of ethics, equity, feasibility, and acceptability (EEFA). On January 23, February 6, 7 and April 28, 2023, NACI reviewed the evidence presented to the COVID-19 WG and approved these recommendations on May 29, 2023.
These recommendations are interim and were made considering only the currently available bivalent Omicron-containing vaccines, which are not authorized for use as a primary series. Future recommendations will consider new product options as regulatory decisions are made.
For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to National Advisory Committee on Immunization (NACI): and the in the (CIG)
Further information on NACI's process and procedures is available elsewhere .
Overview of evidence
Information available as of May 11, 2023 is summarized below.
# Evolving epidemiology
- The evolutionary trajectory of SARS-CoV-2, including the emergence of novel variants of concern (VOCs), remains uncertain .
- Omicron XBB1.5 sub-lineage is currently the dominant strain circulating in Canada and has gradually replaced the previously dominant BA.5-related sub-lineages (e.g., BQ.1 and BQ.1.1). New XBB recombinant strains, such as XBB.1.16 and XBB.1.9, are also increasing nationally.
- Omicron is antigenically and genomically quite different from previous VOCs and hence is able to partially evade the immune response induced by COVID-19 vaccines formulated with only original SARS-CoV-2 and also previous pre-Omicron infections. Recently circulating sub-lineages of Omicron (e.g., BQ\*, XBB\*) are more immune evasive than previous Omicron sub-lineages (e.g., BA.2, BA.4/5) based on the ability of recent sub-lineages to more efficiently evade neutralizing antibodies elicited from vaccination and past infection .
- Rates of hospitalizations and deaths in Canada continue to be highest for adults 60 years of age and older, with risk increasing with age and highest among those 80 years of age and older and those who are unvaccinated, and lowest for those recently vaccinated and those with hybrid immunity, particularly if the previous infection was with an Omicron strain
- Seroepidemiologic studies demonstrate high levels of antibodies due to infection in the Canadian population overall (76.9%; 95% credible interval: 70.2 to 82.8%), with the estimates of seropositivity due to infection decreasing with increasing age.
- The proportion of individuals who have completed the primary series for COVID-19 is high in Canada among individuals 12 years of age and older (>85%). Uptake for the primary series has been low among children 5 to 11 years of age and 0 to 4 years of age (approximately 40% and 6% respectively).
- In Canada, hybrid immunity (resulting from ≥1 exposure(s) from vaccination and ≥1 exposure(s) from SARS-CoV-2 infection) also differs by age group. A greater proportion of older adults are protected by vaccination only and have not been infected, as compared to younger ages. Adolescents and young adults have the highest proportion of hybrid immunity.
# Summary of evidence on bivalent Omicron-containing vaccines for primary series
## Primary series of Moderna Spikevax bivalent BA.1 in children 6 months to 5 years of age
- The safety and immunogenicity of Moderna Spikevax bivalent BA.1 (25 mcg) as a primary series was evaluated in a Phase 3 open-label study in 179 unvaccinated children 6 months to 5 years of age. The vaccine contains equal parts (12.5 mcg each) of mRNA encoding for the spike protein of original SARS-CoV-2 and that of the Omicron BA.1 variant. Study participants were vaccinated with 2 doses 28 days apart. Neutralizing antibody responses and reactogenicity were compared to 6 month- to 5-year-old participants who had received a Moderna Spikevax original (25 mcg) primary series in an earlier study. Due to the different time frames for vaccination with each product, a substantially higher proportion of participants who received Moderna Spikevax bivalent BA.1 had serological evidence of prior SARS-CoV-2 infection compared to participants who received Moderna Spikevax original (63% vs. 8%).
- In all participants and the subset without evidence of prior SARS-CoV-2 infection, neutralizing antibody responses against BA.1 28 days after dose 2 of Moderna Spikevax bivalent BA.1 were superior compared to those after dose 2 in participants who received Moderna Spikevax original (geometric mean ratio of titres were 25.4 in all participants and 15.8 in the subgroup without prior infection). In all participants, neutralizing antibody responses against original SARS-CoV-2 were non-inferior after dose 2 of Moderna Spikevax bivalent BA.1 compared to dose 2 of Moderna Spikevax original (GMR 0.83 ). In the subgroup of participants without evidence of prior SARS-CoV-2 infection, neutralizing antibody responses against original SARS-CoV-2 did not meet non-inferiority criteria compared to responses after dose 2 of Moderna Spikevax original (GMR 0.4 ).
- Local and systemic reactogenicity after dose 1 and dose 2 of Moderna Spikevax bivalent BA.1 (25 mcg) were similar compared to those after dose 1 and dose 2 of Moderna Spikevax original (25 mcg). In an analysis conducted for Moderna Spikevax bivalent BA.1 recipients only, the frequency of fever was higher after dose 1 for those with prior SARS-CoV-2 infection compared to those without evidence of prior SARS-CoV-2 infection (12% vs. 2%). There were no reports of vaccine-related serious adverse events, myocarditis and/or pericarditis or deaths. Given the number of participants enrolled in the trial, it is unlikely that uncommon, rare or very rare adverse events would be detected. NACI will continue to monitor post-market safety surveillance data as it emerges.
# Effectiveness and safety of bivalent Omicron-containing mRNA vaccines
- While there is currently no clinical evidence on the safety, immunogenicity or efficacy of a primary series with bivalent BA.1-containing vaccines in individuals 6 years of age and older, and no data on the use of a primary series with bivalent BA.4/5 vaccines from either manufacturer in any age group, there is evidence on the safety and protection of bivalent BA.1 and BA.4/5 vaccines when used as a booster dose in individuals 5 years of age and older that has been described in NACI's . Briefly:
## Vaccine effectiveness
- Real-world effectiveness data from the United States (US) and Europe suggest that in children and adults, a booster dose of a bivalent BA.4/5 mRNA COVID-19 vaccine provides increased protection against infection, symptomatic disease and severe outcomes, compared to those who only received doses of original monovalent mRNA vaccines in the past . In some of the studies from the US, the relative vaccine effectiveness (VE) of the bivalent booster increased with increased time since the original vaccine group received their last dose, due to increased waning over time in this group. From most of these observational studies, it cannot be determined if the benefit is due to the recent receipt of a booster dose and/or specifically the receipt of a bivalent booster. For a more detailed description of some of these studies, please see NACI's .
- Preliminary data from Ontario demonstrate that short-term (<90 to 119 days) VE against severe outcomes in community dwelling adults 50 years of age and older was similar between those receiving original and bivalent mRNA vaccine booster doses and between the available vaccine products (Moderna Spikevax original or bivalent BA.1 and Pfizer-BioNTech Comirnaty original or bivalent BA.4/5) during a period when BA.5 was the predominant Omicron sub-lineage and BQ.1 was emerging.
- In studies where bivalent Omicron-containing booster recipients were compared to those who received an original booster dose in the same time period, the protection of a bivalent booster against symptomatic disease was similar to or slightly higher than that offered by original boosters against symptomatic disease.
+ A randomized clinical trial conducted by Moderna in the United Kingdom compared those 16 years of age and older randomized to receive a bivalent BA.1 booster to those randomized to receive an original monovalent booster. Although the primary endpoint was immunogenicity, exploratory analyses revealed that the efficacy against symptomatic disease was somewhat higher for the bivalent booster than the original booster against sub-lineages BA.2 (relative VE of bivalent booster compared to original booster vaccine of 32.6%; 95% CI: -15.1 to 60.5%) and BA.4 (41.6%; 95% CI: -5.1 to 67.5%), but not against BA.5 (4.4%; 95% CI: -27.2 to 28.2%).
+ A retrospective, observational study in France matched and compared those 60 years of age and older who had received a booster dose of Pfizer-BioNTech Comirnaty bivalent BA.4/5 with those who received a booster dose with an original COVID-19 vaccine (mostly Pfizer-BioNTech original) in the same time period. At a median of 77 days of follow-up, the bivalent booster offered minimal advantage over an original booster for protection against symptomatic disease (relative VE of bivalent booster compared to original booster of 8%; 95% CI: 0 to 16%). A sub-group analysis in participants without evidence of previous SARS-CoV-2 infection showed no significant difference between bivalent and original boosters (VE calculated using adjusted hazard ratio for infection was 4%; 95% CI: -6 to 12%).
- Preliminary data comparing bivalent BA.1 and BA.4/5 boosters are available from four Scandinavian countries using linked administrative data to evaluate the VE of original, bivalent BA.1 and bivalent BA.4/5 boosters. Bivalent BA.4/5 and BA.1 boosters (manufacturer not specified) were administered during the same time period and the bivalent BA.4/5 vaccine was associated with a somewhat lower relative risk of hospitalization compared to the bivalent BA.1 vaccine. However, this observation was based primarily on the comparative VE from Denmark. The VE estimate was not significant for Norway, and not estimable in the other two countries.
## Safety
- Available evidence from Canada and internationally show that overall, the safety profile of the bivalent mRNA COVID-19 vaccine boosters is comparable to that of original mRNA COVID-19 vaccine boosters among individuals 5 years of age and older .
- The safety profile appears to be similar in those with or without previous SARS-CoV-2 infections.
- Post-market surveillance data from Canada and the US indicates that the risk of myocarditis and/or pericarditis after mRNA COVID-19 vaccines (primary series or first booster) in children 5 to 11 years (who were predominantly vaccinated with Pfizer-BioNTech Comirnaty original .
- A possible association between Pfizer-BioNTech Comirnaty bivalent BA.4/5 booster and ischemic stroke in persons 65 years of age and older was identified by the US Vaccine Safety Datalink (VSD) in January 2023 . This potential safety signal has not been identified with the Moderna Spikevax bivalent BA.4/5 mRNA COVID-19 vaccine and has not been replicated in other surveillance systems used to monitor vaccine safety in the US or in other countries. To date, the totality of the US data suggests that it is very unlikely that the potential signal in VSD represents a true clinical risk . This is supported by international data including from Canada, Israel, Europe, and Singapore where a similar signal has not been identified. Monitoring of the potential safety signal is ongoing. NACI will update its recommendations as needed.
# Ethics, equity, feasibility, and acceptability (EEFA)
- NACI evaluated the following ethical considerations when making its recommendations: promoting well-being and minimizing risk of harm, maintaining trust, respect for persons and fostering autonomy, and promoting justice and equity. NACI considered the available evidence on bivalent, Omicron-containing mRNA vaccines used for primary series and accumulating real-world evidence on effectiveness and safety of bivalent Omicron-containing mRNA vaccine booster doses.
- It will not be feasible to continue using original monovalent mRNA vaccines for the primary series in Canada, as the supply of most original formulations is not expected to be available beyond summer 2023.
- Streamlining of products recommended for primary series and booster doses simplifies the storage and handling required for vaccination programs and reduces the risk of vaccine administration errors.
- Primary series recommendations are particularly important for infants who age into vaccine eligibility at 6 months and are less likely to be previously infected than older children and adults, and for young children for whom vaccine uptake has been low compared to individuals 12 years of age and older.
- Given the current prevalence of Omicron sub-lineages and preferential recommendation for bivalent Omicron-containing vaccines for booster doses, those who may be hesitant to receive an original monovalent mRNA vaccine for a primary series now have another option recommended by NACI.
- Despite the limited evidence on the use of bivalent vaccines as a primary series, the precautionary principle indicates that scientific uncertainty should not prevent decision makers from taking action to reduce risks associated with COVID-19.
- Informed consent of those receiving a bivalent vaccine as a primary series and clear communication on the rationale will be important given the limited direct evidence regarding use of the bivalent vaccines for the primary series compared to original mRNA vaccines, and limited product options for children 6 months to 4 years of age for whom only a bivalent Moderna Spikevax product can be administered at the appropriate dosage. The off-label use of the bivalent products for the primary series should also be included as part of the informed consent process.
- COVID-19 vaccines have evolved over the pandemic and will continue to change as science and research progresses. Recommendations will evolve as well to ensure equitable access to products that can be used for primary series for those who are unvaccinated.
Recommendations
NACI continues to recommend that unvaccinated individuals receive a primary series of COVID-19 vaccines as recommended in the of the Canadian Immunization Guide and current NACI . Regarding the product offered,
1. NACI recommends that when mRNA vaccines are used for the primary series, bivalent Omicron-containing vaccines can be used, as outlined in .
- Consistent with current NACI recommendations on vaccine interchangeability, regardless of which product is offered to start a primary series, the previous dose should be counted; the series should be continued and not restarted. If a primary series is started with an original mRNA vaccine, a bivalent Omicron-containing vaccine can be used to complete the series. If a primary series is started with a bivalent Omicron containing mRNA vaccine and the same product is not readily available to complete the series, another bivalent Omicron-containing mRNA vaccine may be used to complete the series. For more information on interchangeability with other COVID-19 vaccines, please refer to the in the Canadian Immunization Guide.
- The current recommendation for the primary series is for the bivalent vaccine products authorized to date, as these are the products currently available for use in Canada (see for more details). If there are changes to the authorized schedules and/or dosages or if new formulations of COVID-19 vaccines become available for the fall 2023 vaccination program, these interim recommendations will be reviewed and updated as appropriate.
- Please see the of the Canadian Immunization Guide and for information on recommended intervals and number of doses for the primary series for the and individuals who are .
# Additional considerations and rationale
- Moderna Spikevax bivalent 25 mcg (0.25 mL)
- Moderna Spikevax bivalent 50 mcg (0.5 mL)
Products referred to include Moderna Spikevax bivalent BA.1 or BA.4/5, and Pfizer-BioNTech Comirnaty bivalent BA.4/5.
There is no bivalent Pfizer-BioNTech product available in Canada to provide an appropriate dosage (3 mcg) for children 6 months to 4 years of age.
Individuals who are moderately to severely immunocompromised may benefit more from a primary series with Moderna Spikevax bivalent (50 mcg in ≥12 years of age and 25 mcg in 6 months to 11 years of age) compared to Pfizer-BioNTech Comirnaty bivalent BA.4/5 (30 mcg in ≥12 years of age and 10 mcg in 5 to 11 years of age).
- Omicron and its sub-lineages are antigenically distinct from the original SARS-CoV-2 virus. Recent and currently dominant strains circulating in Canada are some of the most antigenically distinct sub-lineages observed to date . Exposure to diverse antigens through vaccination and subsequent expansion of the immune repertoire against COVID-19 is expected to be beneficial in the long term, especially for unvaccinated individuals who have not been infected with SARS-CoV-2 (e.g., infection naïve young children who have not been vaccinated or infection naïve infants who are newly eligible for vaccination). Use of bivalent vaccines for the primary series primes naïve individuals with both Omicron and original SARS-CoV-2, which will help to maximize the breadth of immunity at the earliest opportunity.
- The safety profile of bivalent Omicron-containing vaccines as boosters has been observed to be similar to that of original mRNA vaccine boosters.
- Available evidence on the effectiveness of bivalent vaccines as boosters suggest they provide protection that is similar to, or somewhat better than that with original mRNA vaccines as boosters, particularly with regard to preventing SARS-CoV-2 infection or symptomatic disease. The limited available evidence assessing the immunogenicity of Moderna Spikevax bivalent BA.1 and original vaccines as a primary series in children 6 months to 5 years of age indicate a better immune response of the bivalent vaccine against the Omicron subvariant BA.1.
- Given the potential for substantial virus evolution and uncertainty about the emergence of future variants/subvariants, further modification of the strain composition of COVID-19 vaccines over time is anticipated and this is expected to increase the immune response and possibly also protection against divergent SARS-CoV-2 spike protein antigens.
## Rationale for the recommended bivalent Omicron-containing mRNA vaccines and dosages for the primary series (as described in ):
- Seroprevalence due to SARS-CoV-2 infection in Canada is high in adults (although somewhat lower in older adults), adolescents and school-aged children, but relatively lower in young children and infants who may not yet have been exposed to SARS-CoV-2. As such, the dosage of Moderna Spikevax bivalent BA.1 or BA.4/5 currently authorized for use as a booster dose (i.e., 50 mcg for adults and adolescents, 25 mcg for children 6 to 11 years of age) is expected to be sufficient for primary series doses with Moderna Spikevax bivalent vaccines for children 6 years of age and older, as well as adolescents and adults. The standard dose for Pfizer-BioNTech Comirnaty bivalent vaccines, according to age, is recommended for use in the primary series.
- Individuals with a decreased response to vaccination, such as those who are moderately to severely immunocompromised, may benefit from a primary series with Moderna Spikevax bivalent using the dosages outlined above (50 mcg in individuals 12 years of age and older, and 25 mcg in children 6 months to 11 years of age) compared to Pfizer-BioNTech Comirnaty bivalent BA.4/5 (30 mcg in individuals 12 years of age and older, and 10 mcg in children 5 to 11 years of age). For the original COVID-19 vaccines, NACI preferentially recommended the use of Moderna Spikevax original (25 mcg) for moderately to severely immunocompromised children 6 months to 4 years of age, as this product required one fewer dose than the Pfizer-BioNTech original (3 mcg) product and may therefore be more acceptable and feasible for this group.
- For individuals 12 to 29 years of age, Pfizer-BioNTech Comirnaty bivalent BA.4/5 is preferred to Moderna Spikevax bivalent BA.1 or BA.4/5 due to a lower risk of myocarditis and/or pericarditis observed after dose 1 and dose 2 of the primary series with Pfizer-BioNTech Comirnaty original (30 mcg) compared to Moderna Spikevax original (100 mcg) in this age group. For some moderately to severely immunocompromised individuals 12 to 29 years of age, administration of Moderna Spikevax bivalent (50 mcg) may be considered based on clinical judgement.
- NACI previously recommended the preferential use of Pfizer-BioNTech original (10 mcg) over Moderna Spikevax original (25 mcg or 50 mcg) in children 5 to 11 years of age based on the precautionary principle and limited data on the risk of myocarditis and/or pericarditis after COVID-19 vaccination that was available at the time for this age group. However, the risk of myocarditis and/or pericarditis after a primary series dose of an original mRNA COVID-19 vaccine in this age group is now known to be substantially lower compared to the risk following mRNA COVID-19 vaccines in individuals 12 to 29 years of age (in whom the risk of myocarditis and/or pericarditis is the highest) and individuals 30 to 49 years of age (in whom there is no preference between Pfizer-BioNTech Comirnaty original or Moderna Spikevax original for the primary series). Based on this, there is no preferred product between Pfizer-BioNTech Comirnaty bivalent BA.4/5 (10 mcg) and Moderna Spikevax bivalent BA.1 or BA.4/5 (25 mcg) for the primary series in children 5 to 11 years of age. It should be noted that the low rates of myocarditis and/or pericarditis with the primary series in children 5 to 11 years of age have been in the context of the predominant use of Pfizer-BioNTech Comirnaty original (10 mcg) in this age group.
- For children 6 months to 4 years of age, Moderna Spikevax bivalent BA.1 or BA.4/5 (25 mcg) is recommended for the primary series as:
+ It is not feasible to administer Pfizer-BioNTech Comirnaty bivalent BA.4/5 (3 mcg) with the products that are currently available in Canada.
+ There is a greater likelihood that children in this age group are immunologically naïve compared to older children. Thus, the same dose used for the primary series with Moderna Spikevax original is recommended for the primary series with Moderna Spikevax bivalent BA.1 or BA.4/5.
- None of the authorized bivalent mRNA COVID-19 vaccines in Canada are currently indicated for use as a primary series by Health Canada; they are currently authorized for booster doses. Regulatory review has been initiated for some products, but at this time all recommendations for use of bivalent mRNA vaccines for the primary series are considered off-label. NACI encourages manufacturers to submit modifications to current COVID-19 vaccine authorizations to the Canadian regulator in a timely manner.
Additional details on primary series vaccination for COVID-19 and bivalent Omicron-containing mRNA vaccines are available in the in the Canadian Immunization Guide and NACI .
NACI continues to monitor and assess the evidence as it emerges and will update its recommendations as needed.
Research priorities
1. Continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of COVID-19 vaccines, including bivalent mRNA vaccines for primary series and booster doses, through clinical trials and studies in real-world settings, including the degree and duration of protection conferred against circulating variants. The research should also consider the clinical implications of previous SARS-CoV-2 infection; repeated immunization; and the impacts of vaccination on outcomes after any infection such as multisystem inflammatory syndrome in children (MIS-C), post-COVID-19 condition/post-acute COVID syndrome (long COVID), or infection-induced myocarditis and/or pericarditis in older and younger adult, adolescent, and pediatric populations.
2. Ongoing monitoring of research related to any proposed change in the formulation for both the primary series and the booster doses.
3. Vigilant monitoring and reporting of adverse events of special interest to support the rapid identification of potential vaccine safety signals and accurately inform potential risks associated with any future primary series or booster doses. Global collaboration should be prioritized to enable data sharing so decision makers around the world can weigh benefits and risks of COVID-19 vaccines.
4. Continuous monitoring of COVID-19 epidemiology and vaccine effectiveness in special populations at high risk of severe outcomes or long-term consequences of infection with COVID-19, including but not limited to those with co-morbidities (including immunocompromising conditions) and pregnant populations.
5. Continuous monitoring of vaccine coverage in Canada, for COVID-19 vaccines and other routine vaccines, particularly in the context of COVID-19 vaccines for the primary series (particularly for children) and booster doses and including consideration of measures that may reduce the risk of disparities in vaccine confidence and uptake across different sub-populations. |
Interim guidance on the use of bivalent Omicron-containing COVID-19 vaccines for primary series
================================================================================================
[Download the alternative format](/content/dam/phac-aspc/documents/services/publications/vaccines-immunization/national-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series/naci-statement-bivalent-primary-series.pdf)
(PDF format, 637 KB, 19 pages)
**Organization:** [Public Health Agency of Canada](/en/public-health.html)
**Published:** 2023-06-09
**Cat.:** HP5-158/1-2023E-PDF
**ISBN:** 978-0-660-48930-8
**Pub.:** 230092
Publication date: June 9, 2023
On this page
------------
* [Preamble](#a1)
* [Background](#a2)
* [Methods](#a3)
* [Overview of evidence](#a4)
+ [Evolving epidemiology](#a4.1)
+ [Summary of evidence on bivalent Omicron-containing vaccines for primary series](#a4.2)
- [Primary series of Moderna Spikevax bivalent BA.1 in children 6 months to 5 years of age](#a4.2.1)
+ [Effectiveness and safety of bivalent Omicron-containing mRNA vaccines](#a4.3)
- [Vaccine effectiveness](#a4.3.1)
- [Safety](#a4.3.2)
+ [Ethics, equity, feasibility, and acceptability (EEFA)](#a4.4)
* [Recommendations](#a5)
+ [Additional considerations and rationale](#a5.1)
- [Table 1. Interim recommended bivalent Omicron-containing mRNA vaccines, dosages and schedules for primary series](#t1)
- [Rationale for the recommended bivalent Omicron-containing mRNA vaccines and dosages for the primary series](#a5.1.1)
* [Research priorities](#a6)
* [Acknowledgments](#a7)
* [References](#a8)
Preamble
--------
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Background
----------
Bivalent Omicron-containing mRNA COVID-19 vaccines are authorized as booster doses for those 5 years of age and older, but there is currently no bivalent vaccine authorized for a primary series in any age group or as a booster dose for those less than 5 years of age. Several regulatory submissions for the use of bivalent mRNA COVID-19 vaccines as a primary series are currently under review by Health Canada. Many original monovalent mRNA vaccines will no longer be available in the coming months, and PHAC has asked NACI to consider how jurisdictions can ensure COVID-19 product options for the primary series are available to all recommended populations. This includes consideration of off-label use of bivalent vaccines using age-based dosages that are different from those currently authorized for the primary series with the original mRNA COVID-19 vaccines. As regulatory submissions progress over the summer, vaccine schedules and/or dosages may change for some age groups. New formulations of COVID-19 vaccines that reflect changes in circulating Omicron subvariants may also become available in the fall of 2023.
Bivalent Omicron-containing mRNA COVID-19 vaccines have been recommended to be used as booster doses in Canada since September 1, 2022, when NACI published initial recommendations on their use. Currently, bivalent Omicron-containing vaccines are authorized as booster doses for individuals 5 years of age and older and NACI's recommendations cite a preference for their use over original mRNA vaccines for booster doses. For more information on COVID-19 booster doses, please refer to the [COVID-19 chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) of the Canadian Immunization Guide (CIG).
Since the initial authorization and recommendations of bivalent Omicron-containing COVID-19 vaccine booster doses:
* Although there are some fluctuations in COVID-19 transmission indicators (for example cases reported, hospitalizations, and deaths) and variations across provinces and territories, COVID-19 activity has been relatively stable with hospitalizations remaining at a relatively high level since the widespread circulation of Omicron in early 2022, with the highest hospitalization rates among older adults.
* Additional evidence has emerged on the performance and safety of bivalent vaccines as booster doses.
* Some limited direct evidence is now available on the use of bivalent Omicron-containing vaccines for the primary series.
NACI continues to monitor the rapidly evolving scientific data recognizing that the trajectory of the COVID-19 pandemic remains unclear.
NACI's recommendations remain aligned with the goals of the Canadian COVID-19 Pandemic Response that were last updated on [February 14, 2022](/en/public-health/news/2022/02/statement-from-the-council-of-chief-medical-officers-of-health-ccmoh-on-the-next-phase-of-the-covid-19-pandemic-response.html):
* To minimize serious illness and death while minimizing societal disruption as a result of the COVID-19 pandemic
* To transition away from the crisis phase towards a more sustainable approach to long term management of COVID-19
Methods
-------
On January 10, January 31, and April 4, 2023, the NACI COVID-19 Working Group (WG) reviewed the available epidemiology and evidence on vaccine safety and protection, including clinical trial results on bivalent Omicron-containing vaccines as the primary series and real-world evidence on bivalent Omicron-containing vaccines as booster doses. NACI also conducted an in-depth ethical analysis on this topic informed by the framework outlined by the Public Health Ethics Consultative Group (PHECG)[Footnote 1](#fn1) [Footnote 2](#fn2). Equity, feasibility and acceptability factors were also considered according to NACI's published, peer-reviewed framework and evidence-informed tools to support systematic assessment of ethics, equity, feasibility, and acceptability (EEFA)[Footnote 2](#fn2). On January 23, February 6, 7 and April 28, 2023, NACI reviewed the evidence presented to the COVID-19 WG and approved these recommendations on May 29, 2023.
**These recommendations are interim and were made considering only the currently available bivalent Omicron-containing vaccines, which are not authorized for use as a primary series.** Future recommendations will consider new product options as regulatory decisions are made.
For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to National Advisory Committee on Immunization (NACI): [Statements and publications](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci.html) and the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) in the [Canadian Immunization Guide](/en/public-health/services/canadian-immunization-guide.html) (CIG)
Further information on NACI's process and procedures is available elsewhere[Footnote 2](#fn2) [Footnote 3](#fn3).
Overview of evidence
--------------------
Information available as of May 11, 2023 is summarized below.
### Evolving epidemiology
* The evolutionary trajectory of SARS-CoV-2, including the emergence of novel variants of concern (VOCs), remains uncertain[Footnote 4](#fn4) [Footnote 5](#fn5).
* Omicron XBB1.5 sub-lineage is currently the dominant strain circulating in Canada and has gradually replaced the previously dominant BA.5-related sub-lineages (e.g., BQ.1 and BQ.1.1)[Footnote 6](#fn6). New XBB recombinant strains, such as XBB.1.16 and XBB.1.9, are also increasing nationally[Footnote 6](#fn6).
* Omicron is antigenically and genomically quite different from previous VOCs and hence is able to partially evade the immune response induced by COVID-19 vaccines formulated with only original SARS-CoV-2 and also previous pre-Omicron infections. Recently circulating sub-lineages of Omicron (e.g., BQ\*, XBB\*) are more immune evasive than previous Omicron sub-lineages (e.g., BA.2, BA.4/5) based on the ability of recent sub-lineages to more efficiently evade neutralizing antibodies elicited from vaccination and past infection[Footnote 5](#fn5) [Footnote 7](#fn7) [Footnote 8](#fn8) [Footnote 9](#fn9) [Footnote 10](#fn10) [Footnote 11](#fn11) [Footnote 12](#fn12) [Footnote 13](#fn13).
* Rates of hospitalizations and deaths in Canada continue to be highest for adults 60 years of age and older, with risk increasing with age and highest among those 80 years of age and older and those who are unvaccinated, and lowest for those recently vaccinated and those with hybrid immunity, particularly if the previous infection was with an Omicron strain[Footnote 14](#fn14) [Footnote 15](#fn15) [Footnote 16](#fn16)
* Seroepidemiologic studies demonstrate high levels of antibodies due to infection in the Canadian population overall (76.9%; 95% credible interval: 70.2 to 82.8%), with the estimates of seropositivity due to infection decreasing with increasing age[Footnote 17](#fn17).
* The proportion of individuals who have completed the primary series for COVID-19 is high in Canada among individuals 12 years of age and older (>85%). Uptake for the primary series has been low among children 5 to 11 years of age and 0 to 4 years of age (approximately 40% and 6% respectively)[Footnote 18](#fn18).
* In Canada, hybrid immunity (resulting from ≥1 exposure(s) from vaccination and ≥1 exposure(s) from SARS-CoV-2 infection) also differs by age group. A greater proportion of older adults are protected by vaccination only and have not been infected, as compared to younger ages. Adolescents and young adults have the highest proportion of hybrid immunity.
### Summary of evidence on bivalent Omicron-containing vaccines for primary series
#### Primary series of Moderna Spikevax bivalent BA.1 in children 6 months to 5 years of age
* The safety and immunogenicity of Moderna Spikevax bivalent BA.1 (25 mcg) as a primary series was evaluated in a Phase 3 open-label study in 179 unvaccinated children 6 months to 5 years of age. The vaccine contains equal parts (12.5 mcg each) of mRNA encoding for the spike protein of original SARS-CoV-2 and that of the Omicron BA.1 variant. Study participants were vaccinated with 2 doses 28 days apart. Neutralizing antibody responses and reactogenicity were compared to 6 month- to 5-year-old participants who had received a Moderna Spikevax original (25 mcg) primary series in an earlier study. Due to the different time frames for vaccination with each product, a substantially higher proportion of participants who received Moderna Spikevax bivalent BA.1 had serological evidence of prior SARS-CoV-2 infection compared to participants who received Moderna Spikevax original (63% vs. 8%)[Footnote 19](#fn19).
* In all participants and the subset without evidence of prior SARS-CoV-2 infection, neutralizing antibody responses against BA.1 28 days after dose 2 of Moderna Spikevax bivalent BA.1 were superior compared to those after dose 2 in participants who received Moderna Spikevax original (geometric mean ratio [GMR] of titres were 25.4 [95% confidence interval (CI): 20.1 to 32.1%] in all participants and 15.8 [95% CI: 11.4 to 21.9%] in the subgroup without prior infection). In all participants, neutralizing antibody responses against original SARS-CoV-2 were non-inferior after dose 2 of Moderna Spikevax bivalent BA.1 compared to dose 2 of Moderna Spikevax original (GMR 0.83 [95% CI: 0.67 to 1.02%]). In the subgroup of participants without evidence of prior SARS-CoV-2 infection, neutralizing antibody responses against original SARS-CoV-2 did not meet non-inferiority criteria compared to responses after dose 2 of Moderna Spikevax original (GMR 0.4 [95% CI: 0.3 to 0.5%]).
* Local and systemic reactogenicity after dose 1 and dose 2 of Moderna Spikevax bivalent BA.1 (25 mcg) were similar compared to those after dose 1 and dose 2 of Moderna Spikevax original (25 mcg). In an analysis conducted for Moderna Spikevax bivalent BA.1 recipients only, the frequency of fever was higher after dose 1 for those with prior SARS-CoV-2 infection compared to those without evidence of prior SARS-CoV-2 infection (12% vs. 2%). There were no reports of vaccine-related serious adverse events, myocarditis and/or pericarditis or deaths. Given the number of participants enrolled in the trial, it is unlikely that uncommon, rare or very rare adverse events would be detected. NACI will continue to monitor post-market safety surveillance data as it emerges.
### Effectiveness and safety of bivalent Omicron-containing mRNA vaccines
* While there is currently no clinical evidence on the safety, immunogenicity or efficacy of a primary series with bivalent BA.1-containing vaccines in individuals 6 years of age and older, and no data on the use of a primary series with bivalent BA.4/5 vaccines from either manufacturer in any age group, there is evidence on the safety and protection of bivalent BA.1 and BA.4/5 vaccines when used as a booster dose in individuals 5 years of age and older that has been described in NACI's [Guidance on an additional COVID-19 booster dose in the spring of 2023 for individuals at high risk of severe illness due to COVID-19](/en/public-health/services/publications/vaccines-immunization/national-advisory-committee-immunization-guidance-additional-covid-19-booster-dose-spring-2023-individuals-high-risk-severe-illness-due-covid-19.html). Briefly:
#### Vaccine effectiveness
* Real-world effectiveness data from the United States (US) and Europe suggest that in children and adults, a booster dose of a bivalent BA.4/5 mRNA COVID-19 vaccine provides increased protection against infection, symptomatic disease and severe outcomes, compared to those who only received doses of original monovalent mRNA vaccines in the past[Footnote 20](#fn20) [Footnote 21](#fn21) [Footnote 22](#fn22) [Footnote 23](#fn23) [Footnote 24](#fn24) [Footnote 25](#fn25) [Footnote 26](#fn26) [Footnote 27](#fn27) [Footnote 28](#fn28). In some of the studies from the US, the relative vaccine effectiveness (VE) of the bivalent booster increased with increased time since the original vaccine group received their last dose, due to increased waning over time in this group. From most of these observational studies, it cannot be determined if the benefit is due to the recent receipt of a booster dose and/or specifically the receipt of a bivalent booster. For a more detailed description of some of these studies, please see NACI's [Guidance on an additional COVID-19 booster dose in the spring of 2023 for individuals at high risk of severe illness due to COVID-19](/en/public-health/services/publications/vaccines-immunization/national-advisory-committee-immunization-guidance-additional-covid-19-booster-dose-spring-2023-individuals-high-risk-severe-illness-due-covid-19.html).
* Preliminary data from Ontario demonstrate that short-term (<90 to 119 days) VE against severe outcomes in community dwelling adults 50 years of age and older was similar between those receiving original and bivalent mRNA vaccine booster doses and between the available vaccine products (Moderna Spikevax original or bivalent BA.1 and Pfizer-BioNTech Comirnaty original or bivalent BA.4/5) during a period when BA.5 was the predominant Omicron sub-lineage and BQ.1 was emerging[Footnote 29](#fn29).
* In studies where bivalent Omicron-containing booster recipients were compared to those who received an original booster dose in the same time period, the protection of a bivalent booster against symptomatic disease was similar to or slightly higher than that offered by original boosters against symptomatic disease.
+ A randomized clinical trial conducted by Moderna in the United Kingdom compared those 16 years of age and older randomized to receive a bivalent BA.1 booster to those randomized to receive an original monovalent booster. Although the primary endpoint was immunogenicity, exploratory analyses revealed that the efficacy against symptomatic disease was somewhat higher for the bivalent booster than the original booster against sub-lineages BA.2 (relative VE of bivalent booster compared to original booster vaccine of 32.6%; 95% CI: -15.1 to 60.5%) and BA.4 (41.6%; 95% CI: -5.1 to 67.5%), but not against BA.5 (4.4%; 95% CI: -27.2 to 28.2%)[Footnote 30](#fn30).
+ A retrospective, observational study in France matched and compared those 60 years of age and older who had received a booster dose of Pfizer-BioNTech Comirnaty bivalent BA.4/5 with those who received a booster dose with an original COVID-19 vaccine (mostly Pfizer-BioNTech original) in the same time period. At a median of 77 days of follow-up, the bivalent booster offered minimal advantage over an original booster for protection against symptomatic disease (relative VE of bivalent booster compared to original booster of 8%; 95% CI: 0 to 16%). A sub-group analysis in participants without evidence of previous SARS-CoV-2 infection showed no significant difference between bivalent and original boosters (VE calculated using adjusted hazard ratio for infection was 4%; 95% CI: -6 to 12%)[Footnote 31](#fn31).
* Preliminary data comparing bivalent BA.1 and BA.4/5 boosters are available from four Scandinavian countries using linked administrative data to evaluate the VE of original, bivalent BA.1 and bivalent BA.4/5 boosters. Bivalent BA.4/5 and BA.1 boosters (manufacturer not specified) were administered during the same time period and the bivalent BA.4/5 vaccine was associated with a somewhat lower relative risk of hospitalization compared to the bivalent BA.1 vaccine. However, this observation was based primarily on the comparative VE from Denmark. The VE estimate was not significant for Norway, and not estimable in the other two countries[Footnote 24](#fn24).
#### Safety
* Available evidence from Canada and internationally show that overall, the safety profile of the bivalent mRNA COVID-19 vaccine boosters is comparable to that of original mRNA COVID-19 vaccine boosters among individuals 5 years of age and older[Footnote 32](#fn32) [Footnote 33](#fn33) [Footnote 34](#fn34) [Footnote 35](#fn35) [Footnote 36](#fn36) [Footnote 37](#fn37) [Footnote 38](#fn38).
* The safety profile appears to be similar in those with or without previous SARS-CoV-2 infections.
* Post-market surveillance data from Canada and the US indicates that the risk of myocarditis and/or pericarditis after mRNA COVID-19 vaccines (primary series or first booster) in children 5 to 11 years (who were predominantly vaccinated with Pfizer-BioNTech Comirnaty original [10 mcg]) is lower compared to adolescents and young adults who received Pfizer-BioNTech Comirnaty original (30 mcg) or Moderna Spikevax original (100 mcg)[Footnote 39](#fn39) [Footnote 40](#fn40) [Footnote 41](#fn41).
* A possible association between Pfizer-BioNTech Comirnaty bivalent BA.4/5 booster and ischemic stroke in persons 65 years of age and older was identified by the US Vaccine Safety Datalink (VSD) in January 2023[Footnote 42](#fn42) [Footnote 43](#fn43). This potential safety signal has not been identified with the Moderna Spikevax bivalent BA.4/5 mRNA COVID-19 vaccine and has not been replicated in other surveillance systems used to monitor vaccine safety in the US or in other countries. To date, the totality of the US data suggests that it is very unlikely that the potential signal in VSD represents a true clinical risk[Footnote 42](#fn42) [Footnote 43](#fn43) [Footnote 44](#fn44). This is supported by international data including from Canada, Israel, Europe, and Singapore where a similar signal has not been identified. Monitoring of the potential safety signal is ongoing. NACI will update its recommendations as needed.
### Ethics, equity, feasibility, and acceptability (EEFA)
* NACI evaluated the following ethical considerations when making its recommendations: promoting well-being and minimizing risk of harm, maintaining trust, respect for persons and fostering autonomy, and promoting justice and equity. NACI considered the available evidence on bivalent, Omicron-containing mRNA vaccines used for primary series and accumulating real-world evidence on effectiveness and safety of bivalent Omicron-containing mRNA vaccine booster doses.
* It will not be feasible to continue using original monovalent mRNA vaccines for the primary series in Canada, as the supply of most original formulations is not expected to be available beyond summer 2023.
* Streamlining of products recommended for primary series and booster doses simplifies the storage and handling required for vaccination programs and reduces the risk of vaccine administration errors.
* Primary series recommendations are particularly important for infants who age into vaccine eligibility at 6 months and are less likely to be previously infected than older children and adults, and for young children for whom vaccine uptake has been low compared to individuals 12 years of age and older.
* Given the current prevalence of Omicron sub-lineages and preferential recommendation for bivalent Omicron-containing vaccines for booster doses, those who may be hesitant to receive an original monovalent mRNA vaccine for a primary series now have another option recommended by NACI.
* Despite the limited evidence on the use of bivalent vaccines as a primary series, the precautionary principle indicates that scientific uncertainty should not prevent decision makers from taking action to reduce risks associated with COVID-19.
* Informed consent of those receiving a bivalent vaccine as a primary series and clear communication on the rationale will be important given the limited direct evidence regarding use of the bivalent vaccines for the primary series compared to original mRNA vaccines, and limited product options for children 6 months to 4 years of age for whom only a bivalent Moderna Spikevax product can be administered at the appropriate dosage. The off-label use of the bivalent products for the primary series should also be included as part of the informed consent process.
* COVID-19 vaccines have evolved over the pandemic and will continue to change as science and research progresses. Recommendations will evolve as well to ensure equitable access to products that can be used for primary series for those who are unvaccinated.
Recommendations
---------------
NACI continues to recommend that unvaccinated individuals receive a primary series of COVID-19 vaccines as recommended in the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) of the Canadian Immunization Guide and current NACI [statements and publications](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci.html). Regarding the product offered,
1. **NACI recommends that when mRNA vaccines are used for the primary series, bivalent Omicron-containing vaccines can be used, as outlined in [Table 1](#t1).**
* Consistent with current NACI recommendations on vaccine interchangeability, regardless of which product is offered to start a primary series, the previous dose should be counted; the series should be continued and not restarted. If a primary series is started with an original mRNA vaccine, a bivalent Omicron-containing vaccine can be used to complete the series. If a primary series is started with a bivalent Omicron containing mRNA vaccine and the same product is not readily available to complete the series, another bivalent Omicron-containing mRNA vaccine may be used to complete the series. For more information on interchangeability with other COVID-19 vaccines, please refer to the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html)in the Canadian Immunization Guide.
* The current recommendation for the primary series is for the bivalent vaccine products authorized to date, as these are the products currently available for use in Canada (see [Table 1](#t1) for more details). If there are changes to the authorized schedules and/or dosages or if new formulations of COVID-19 vaccines become available for the fall 2023 vaccination program, these interim recommendations will be reviewed and updated as appropriate.
* Please see the [COVID-19 chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) of the Canadian Immunization Guide and [Table 1](#t1) for information on recommended intervals and number of doses for the primary series for the [general population](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html#t1) and individuals who are [moderately to severely immunocompromised](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html#t2).
### Additional considerations and rationale
Table 1. Interim recommended bivalent Omicron-containing mRNA vaccines, dosages and schedules for primary series[Footnote a](#fna)| Population | Vaccine type and dosage | **Number of doses and optimal interval for individuals who are not moderately to severely immunocompromised** | **Number of doses and recommended intervals for individuals who are moderately to severely immunocompromised** |
| Children 6 months to 4 years of age | * Moderna Spikevax bivalent 25 mcg (0.25 mL)[Footnote b](#fnb)
| 2 doses at least 8 weeks apart | 3 doses 4 to 8 weeks apart |
| Children 5 to 11 years of age | * Pfizer-BioNTech Comirnaty bivalent 10 mcg (0.2 mL)
* Moderna Spikevax bivalent 25 mcg (0.25 mL)[Footnote c](#fnc)
| 2 doses at least 8 weeks apart | 3 doses 4 to 8 weeks apart |
| Individuals 12 years of age and older | * Pfizer-BioNTech Comirnaty bivalent 30 mcg (0.3 mL) (Preferred for those 12 to 29 years of age[Footnote c](#fnc))
* Moderna Spikevax bivalent 50 mcg (0.5 mL)[Footnote c](#fnc)
| 2 doses 8 weeks apart | 3 doses 4 to 8 weeks apart |
|
Footnote a
Products referred to include Moderna Spikevax bivalent BA.1 or BA.4/5, and Pfizer-BioNTech Comirnaty bivalent BA.4/5.
[Return to footnote a referrer](#fna-rf)
Footnote b
There is no bivalent Pfizer-BioNTech product available in Canada to provide an appropriate dosage (3 mcg) for children 6 months to 4 years of age.
[Return to footnote b referrer](#fnb-rf)
Footnote c
Individuals who are moderately to severely immunocompromised may benefit more from a primary series with Moderna Spikevax bivalent (50 mcg in ≥12 years of age and 25 mcg in 6 months to 11 years of age) compared to Pfizer-BioNTech Comirnaty bivalent BA.4/5 (30 mcg in ≥12 years of age and 10 mcg in 5 to 11 years of age).
[Return to footnote c referrer](#fnc-rf)
|
* Omicron and its sub-lineages are antigenically distinct from the original SARS-CoV-2 virus. Recent and currently dominant strains circulating in Canada are some of the most antigenically distinct sub-lineages observed to date[Footnote 5](#fn5) [Footnote 45](#fn45). Exposure to diverse antigens through vaccination and subsequent expansion of the immune repertoire against COVID-19 is expected to be beneficial in the long term, especially for unvaccinated individuals who have not been infected with SARS-CoV-2 (e.g., infection naïve young children who have not been vaccinated or infection naïve infants who are newly eligible for vaccination). Use of bivalent vaccines for the primary series primes naïve individuals with both Omicron and original SARS-CoV-2, which will help to maximize the breadth of immunity at the earliest opportunity.
* The safety profile of bivalent Omicron-containing vaccines as boosters has been observed to be similar to that of original mRNA vaccine boosters.
* Available evidence on the effectiveness of bivalent vaccines as boosters suggest they provide protection that is similar to, or somewhat better than that with original mRNA vaccines as boosters, particularly with regard to preventing SARS-CoV-2 infection or symptomatic disease. The limited available evidence assessing the immunogenicity of Moderna Spikevax bivalent BA.1 and original vaccines as a primary series in children 6 months to 5 years of age indicate a better immune response of the bivalent vaccine against the Omicron subvariant BA.1.
* Given the potential for substantial virus evolution and uncertainty about the emergence of future variants/subvariants, further modification of the strain composition of COVID-19 vaccines over time is anticipated and this is expected to increase the immune response and possibly also protection against divergent SARS-CoV-2 spike protein antigens.
#### Rationale for the recommended bivalent Omicron-containing mRNA vaccines and dosages for the primary series (as described in [Table 1](#t1)):
* Seroprevalence due to SARS-CoV-2 infection in Canada is high in adults (although somewhat lower in older adults), adolescents and school-aged children, but relatively lower in young children and infants who may not yet have been exposed to SARS-CoV-2. As such, the dosage of Moderna Spikevax bivalent BA.1 or BA.4/5 currently authorized for use as a booster dose (i.e., 50 mcg for adults and adolescents, 25 mcg for children 6 to 11 years of age) is expected to be sufficient for primary series doses with Moderna Spikevax bivalent vaccines for children 6 years of age and older, as well as adolescents and adults. The standard dose for Pfizer-BioNTech Comirnaty bivalent vaccines, according to age, is recommended for use in the primary series.
* Individuals with a decreased response to vaccination, such as those who are moderately to severely immunocompromised, may benefit from a primary series with Moderna Spikevax bivalent using the dosages outlined above (50 mcg in individuals 12 years of age and older, and 25 mcg in children 6 months to 11 years of age) compared to Pfizer-BioNTech Comirnaty bivalent BA.4/5 (30 mcg in individuals 12 years of age and older, and 10 mcg in children 5 to 11 years of age). For the original COVID-19 vaccines, NACI preferentially recommended the use of Moderna Spikevax original (25 mcg) for moderately to severely immunocompromised children 6 months to 4 years of age, as this product required one fewer dose than the Pfizer-BioNTech original (3 mcg) product and may therefore be more acceptable and feasible for this group.
* For individuals 12 to 29 years of age, Pfizer-BioNTech Comirnaty bivalent BA.4/5 is preferred to Moderna Spikevax bivalent BA.1 or BA.4/5 due to a lower risk of myocarditis and/or pericarditis observed after dose 1 and dose 2 of the primary series with Pfizer-BioNTech Comirnaty original (30 mcg) compared to Moderna Spikevax original (100 mcg) in this age group. For some moderately to severely immunocompromised individuals 12 to 29 years of age, administration of Moderna Spikevax bivalent (50 mcg) may be considered based on clinical judgement.
* NACI previously recommended the preferential use of Pfizer-BioNTech original (10 mcg) over Moderna Spikevax original (25 mcg or 50 mcg) in children 5 to 11 years of age based on the precautionary principle and limited data on the risk of myocarditis and/or pericarditis after COVID-19 vaccination that was available at the time for this age group. However, the risk of myocarditis and/or pericarditis after a primary series dose of an original mRNA COVID-19 vaccine in this age group is now known to be substantially lower compared to the risk following mRNA COVID-19 vaccines in individuals 12 to 29 years of age (in whom the risk of myocarditis and/or pericarditis is the highest) and individuals 30 to 49 years of age (in whom there is no preference between Pfizer-BioNTech Comirnaty original or Moderna Spikevax original for the primary series). Based on this, there is no preferred product between Pfizer-BioNTech Comirnaty bivalent BA.4/5 (10 mcg) and Moderna Spikevax bivalent BA.1 or BA.4/5 (25 mcg) for the primary series in children 5 to 11 years of age. It should be noted that the low rates of myocarditis and/or pericarditis with the primary series in children 5 to 11 years of age have been in the context of the predominant use of Pfizer-BioNTech Comirnaty original (10 mcg) in this age group.
* For children 6 months to 4 years of age, Moderna Spikevax bivalent BA.1 or BA.4/5 (25 mcg) is recommended for the primary series as:
+ It is not feasible to administer Pfizer-BioNTech Comirnaty bivalent BA.4/5 (3 mcg) with the products that are currently available in Canada.
+ There is a greater likelihood that children in this age group are immunologically naïve compared to older children. Thus, the same dose used for the primary series with Moderna Spikevax original is recommended for the primary series with Moderna Spikevax bivalent BA.1 or BA.4/5.
* None of the authorized bivalent mRNA COVID-19 vaccines in Canada are currently indicated for use as a primary series by Health Canada; they are currently authorized for booster doses. Regulatory review has been initiated for some products, but at this time all recommendations for use of bivalent mRNA vaccines for the primary series are considered off-label. NACI encourages manufacturers to submit modifications to current COVID-19 vaccine authorizations to the Canadian regulator in a timely manner.
Additional details on primary series vaccination for COVID-19 and bivalent Omicron-containing mRNA vaccines are available in the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) in the Canadian Immunization Guide and NACI [statements and publications](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci.html).
NACI continues to monitor and assess the evidence as it emerges and will update its recommendations as needed.
Research priorities
-------------------
1. Continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of COVID-19 vaccines, including bivalent mRNA vaccines for primary series and booster doses, through clinical trials and studies in real-world settings, including the degree and duration of protection conferred against circulating variants. The research should also consider the clinical implications of previous SARS-CoV-2 infection; repeated immunization; and the impacts of vaccination on outcomes after any infection such as multisystem inflammatory syndrome in children (MIS-C), post-COVID-19 condition/post-acute COVID syndrome (long COVID), or infection-induced myocarditis and/or pericarditis in older and younger adult, adolescent, and pediatric populations.
2. Ongoing monitoring of research related to any proposed change in the formulation for both the primary series and the booster doses.
3. Vigilant monitoring and reporting of adverse events of special interest to support the rapid identification of potential vaccine safety signals and accurately inform potential risks associated with any future primary series or booster doses. Global collaboration should be prioritized to enable data sharing so decision makers around the world can weigh benefits and risks of COVID-19 vaccines.
4. Continuous monitoring of COVID-19 epidemiology and vaccine effectiveness in special populations at high risk of severe outcomes or long-term consequences of infection with COVID-19, including but not limited to those with co-morbidities (including immunocompromising conditions) and pregnant populations.
5. Continuous monitoring of vaccine coverage in Canada, for COVID-19 vaccines and other routine vaccines, particularly in the context of COVID-19 vaccines for the primary series (particularly for children) and booster doses and including consideration of measures that may reduce the risk of disparities in vaccine confidence and uptake across different sub-populations.
Acknowledgments
---------------
**This statement was prepared by**: R Krishnan, B Warshawsky, J Zafack, N Forbes, E Wong, K Young, M Tunis, R Harrison, S Wilson, and S Deeks, on behalf of NACI.
**NACI gratefully acknowledges the contribution of**: K Ramotar, C Mauviel, M Salvadori, A Killikelly, SH Lim, S Ismail, S Collins, C Jensen, E Tice and the NACI Secretariat.
**NACI members:** S Deeks (Chair), R Harrison (Vice-Chair), M Andrew, J Bettinger, N Brousseau, H Decaluwe, P De Wals, E Dubé, V Dubey, K Hildebrand, K Klein, M O'Driscoll, J Papenburg, A Pham-Huy, B Sander, and S Wilson.
**Liaison representatives:** L Bill / M Nowgesic (Canadian Indigenous Nurses Association), LM Bucci (Canadian Public Health Association), S Buchan (Canadian Association for Immunization Research and Evaluation), E Castillo (Society of Obstetricians and Gynaecologists of Canada), J Comeau (Association of Medical Microbiology and Infectious Disease Canada), M Lavoie (Council of Chief Medical Officers of Health), J MacNeil (Centers for Disease Control and Prevention, United States), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), M Osmack (Indigenous Physicians Association of Canada), J Potter (College of Family Physicians of Canada), and A Ung (Canadian Pharmacists Association).
**Ex-officio representatives:** V Beswick-Escanlar (National Defence and the Canadian Armed Forces), E Henry (Centre for Immunization and Respiratory Infectious Diseases (CIRID), PHAC), M Lacroix (Public Health Ethics Consultative Group, PHAC), P Fandja (Marketed Health Products Directorate, Health Canada), M Su (COVID-19 Epidemiology and Surveillance, PHAC), S Ogunnaike-Cooke (CIRID, PHAC), C Pham (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada), M Routledge (National Microbiology Laboratory, PHAC), and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada).
### NACI COVID-19 Vaccine Working Group
**Members:** S Wilson (Chair), M Adurogbangba, M Andrew, M Baca-Estrada, Y-G Bui, H Decaluwe, P De Wals, V Dubey, S Hosseini-Moghaddam, M Miller, D Moore, S Oliver, and E Twentyman.
**PHAC Participants:** NK Abraham, E Abrams, O Baclic, L Coward, P Doyon-Plourde, N Forbes, M Hersi, N Islam, SJ Ismail, C Jensen, F Khan, A Killikelly, R Krishnan, SH Lim, R Neves Miranda, N Mohamed, J Montroy, S Pierre, R Pless, M Salvadori, A Stevens, E Tice, A Tuite, MC Tunis, B Warshawsky, E Wong, R Ximenes, MW Yeung, K Young, and J Zafack.
References
----------
Footnote 1
Framework For Ethical Deliberation And Decision-Making In Public Health [Internet]. Ottawa (ON): Public Health Agency of Canada; 2017 Mar [cited 2023 Apr 06]. Available from: https://www.canada.ca/content/dam/phac-aspc/documents/corporate/transparency/corporate-management-reporting/internal-audits/audit-reports/framework-ethical-deliberation-decision-making/pub-eng.pdf.
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
Ismail SJ, Hardy K, Tunis MC, Young K, Sicard N, Quach C. A framework for the systematic consideration of ethics, equity, feasibility, and acceptability in vaccine program recommendations. Vaccine. 2020 Aug 10;38(36):5861,5876. doi: 10.1016/j.vaccine.2020.05.051.
[Return to footnote 2 referrer](#fn2-rf)
Footnote 3
Ismail SJ, Langley JM, Harris TM, Warshawsky BF, Desai S, FarhangMehr M. Canada's National Advisory Committee on Immunization (NACI): Evidence-based decision-making on vaccines and immunization. Vaccine. 2010;28:A58,63. doi: 10.1016/j.vaccine.2010.02.035.
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
Cao Y, Jian F, Wang J, Yu Y, Song W, Yisimayi A, et al. Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution. Nature. 2023 Feb;614(7948):521,529. doi: 10.1038/s41586-022-05644-7.
[Return to footnote 4 referrer](#fn4-rf)
Footnote 5
Wang Q, Iketani S, Li Z, Liu L, Guo Y, Huang Y, et al. Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell. 2023 Jan 19;186(2):279,286.e8. doi:10.1016/j.cell.2022.12.018.
[Return to footnote 5 referrer](#fn5-rf)
Footnote 6
Public Health Agency of Canada. COVID-19 epidemiology update: Testing and variants. Data cut-off 2023 Apr 28 [Internet]. Ottawa (ON): Health Canada; 2023 Apr 28 [cited 2023 May 04]. Available from: https://health-infobase.canada.ca/covid-19/testing-variants.html.
[Return to footnote 6 referrer](#fn6-rf)
Footnote 7
Chalkias S, Whatley J, Eder F, Essink B, Khetan S, Bradley P, et al. Safety and Immunogenicity of Omicron BA.4/BA.5 Bivalent Vaccine Against Covid-19. medRxiv. 2022 Dec 13. https://doi.org/10.1101/2022.12.11.22283166.
[Return to footnote 7 referrer](#fn7-rf)
Footnote 8
Zou J, Kurhade C, Patel S, Kitchin N, Tompkins K, Cutler M, et al. Improved Neutralization of Omicron BA.4/5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 with Bivalent BA.4/5 Vaccine. bioRxiv. 2022 Nov 17. https://doi.org/10.1101/2022.11.17.516898.
[Return to footnote 8 referrer](#fn8-rf)
Footnote 9
Kurhade C, Zou J, Xia H, Liu M, Chang HC, Ren P, et al. Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1 and XBB.1 by parental mRNA vaccine or a BA.5 bivalent booster. Nat Med. 2022 Dec 6. doi: 10.1038/s41591-022-02162-x.
[Return to footnote 9 referrer](#fn9-rf)
Footnote 10
Davis-Gardner ME, Lai L, Wali B, Samaha H, Solis D, Lee M, et al. Neutralization against BA.2.75.2, BQ.1.1, and XBB from mRNA Bivalent Booster. N Engl J Med. 2023 Jan 12;388(2):183,185. doi: 10.1056/NEJMc2214293.
[Return to footnote 10 referrer](#fn10-rf)
Footnote 11
Arora P, Cossmann A, Schulz SR, Ramos GM, Stankov MV, Jäck H, et al. Neutralisation sensitivity of the SARS-CoV-2 XBB.1 lineage. Lancet Infect Dis. 2023 Feb;23(2):147,148. doi: 10.1016/S1473-3099(22)00831-3.
[Return to footnote 11 referrer](#fn11-rf)
Footnote 12
Uriu K, Ito J, Zahradnik J, Fujita S, Kosugi Y, Schreiber G, et al. Enhanced transmissibility, infectivity, and immune resistance of the SARS-CoV-2 omicron XBB.1.5 variant. Lancet Infect Dis. 2023 Jan 31:S1473-3099(23)00051-8. doi: 10.1016/S1473-3099(23)00051-8.
[Return to footnote 12 referrer](#fn12-rf)
Footnote 13
Qu P, Faraone JN, Evans JP, Zheng Y, Carlin C, Anghelina M, et al. Extraordinary Evasion of Neutralizing Antibody Response by Omicron XBB.1.5, CH.1.1 and CA.3.1 Variants. medRxiv. 2023 Jan 17. doi: https://doi.org/10.1101/2023.01.16.524244.
[Return to footnote 13 referrer](#fn13-rf)
Footnote 14
Surveillance and Epidemiology Division, Centre for Immunization and Respiratory Infectious Diseases, Infectious Disease Prevention and Control Branch. Data cut-off Dec 18, 2022. Ottawa (ON): Public Health Agency of Canada; 2022 Dec 18.
[Return to footnote 14 referrer](#fn14-rf)
Footnote 15
Carazo S, Skowronski DM, Brisson M, Barkati S, Sauvageau C, Brousseau N, et al. Protection against omicron (B.1.1.529) BA.2 reinfection conferred by primary omicron BA.1 or pre-omicron SARS-CoV-2 infection among health-care workers with and without mRNA vaccination: a test-negative case-control study. Lancet Infect Dis. 2023 Jan;23(1):45,55. doi: 10.1016/S1473-3099(22)00578-3.
[Return to footnote 15 referrer](#fn15-rf)
Footnote 16
Carazo S, Skowronski DM, Brisson M, Sauvageau C, Brousseau N, Fafard J, et al. Prior infection- and/or vaccine-induced protection against Omicron BA.1, BA.2 and BA.4/BA.5-related hospitalisations in older adults: a test-negative case-control study in Quebec, Canada. medRxiv. 2022 Dec 27. https://doi.org/10.1101/2022.12.21.22283740.
[Return to footnote 16 referrer](#fn16-rf)
Footnote 17
Seroprevalence in Canada. Data cut-off 2023 Mar 15 [Internet]. Montreal (QC): COVID-19 Immunity Task Force (CITF); 2023 Mar 15 [cited 2023 May 23]. Available from: https://www.covid19immunitytaskforce.ca/seroprevalence-in-canada/.
[Return to footnote 17 referrer](#fn17-rf)
Footnote 18
Public Health Agency of Canada. COVID-19 vaccination in Canada. Data cut-off 2023 Apr 23 [Internet]. Ottawa (ON): Health Canada; 2023 Apr 23 [cited 2023 Apr 23]. Available from: https://health-infobase.canada.ca/covid-19/vaccination-coverage/.
[Return to footnote 18 referrer](#fn18-rf)
Footnote 19
Moderna. Personal communication. 2023 Jan 31.
[Return to footnote 19 referrer](#fn19-rf)
Footnote 20
Tenforde MW, Weber ZA, Natarajan K, Klein NP, Kharbanda AB, Stenehjem E, et al. Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Emergency Department or Urgent Care Encounters and Hospitalizations Among Immunocompetent Adults - VISION Network, Nine States, September-November 2022. MMWR Morb Mortal Wkly Rep. 2022 Dec 30;71(5152):1616,1624. doi: 10.15585/mmwr.mm715152e1.
[Return to footnote 20 referrer](#fn20-rf)
Footnote 21
Surie D, DeCuir J, Zhu Y, Gaglani M, Ginde AA, Douin DJ, et al. Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Hospitalization Among Immunocompetent Adults Aged ≥65 Years - IVY Network, 18 States, September 8-November 30, 2022. MMWR Morb Mortal Wkly Rep. 2022 Dec 30;71(5152):1625,1630. doi: 10.15585/mmwr.mm715152e2.
[Return to footnote 21 referrer](#fn21-rf)
Footnote 22
Lin D, Xu Y, Gu Y, Zeng D, Wheeler B, Young H, et al. Effectiveness of Bivalent Boosters against Severe Omicron Infection. N Engl J Med. 2023 Feb 23. doi: 10.1056/NEJMc2215471.
[Return to footnote 22 referrer](#fn22-rf)
Footnote 23
Lin D, Xu Y, Gu Y, Zeng D, Wheeler B, Young H, et al. Effectiveness of Vaccination and Previous Infection Against Omicron Infection and Severe Outcomes in Children Under 12 Years of Age. medRxiv. 2023 Jan 19. https://doi.org/10.1101/2023.01.18.23284739.
[Return to footnote 23 referrer](#fn23-rf)
Footnote 24
Andersson NW, Thiesson EM, Baum U, Pihlström N, Starrfelt J, Faksová K, et al. Comparative effectiveness of the bivalent BA.4-5 and BA.1 mRNA-booster vaccines in the Nordic countries. medRxiv. 2023 Jan 19. https://doi.org/10.1101/2023.01.19.23284764.
[Return to footnote 24 referrer](#fn24-rf)
Footnote 25
Link-Gelles R, Ciesla AA, Roper LE, Scobie HM, Ali AR, Miller JD, et al. Early Estimates of Bivalent mRNA Booster Dose Vaccine Effectiveness in Preventing Symptomatic SARS-CoV-2 Infection Attributable to Omicron BA.5- and XBB/XBB.1.5-Related Sublineages Among Immunocompetent Adults - Increasing Community Access to Testing Program, United States, December 2022-January 2023. MMWR Morb Mortal Wkly Rep. 2023 Feb 3;72(5):119,124. doi: 10.15585/mmwr.mm7205e1.
[Return to footnote 25 referrer](#fn25-rf)
Footnote 26
Fabiani M, Mateo-Urdiales A, Sacco C, Fotakis EA, Rota MC, Petrone D, et al. Protection against severe COVID-19 after second booster dose of adapted bivalent (original/Omicron BA.4-5) mRNA vaccine in persons ≥ 60 years, by time since infection, Italy, 12 September to 11 December 2022. Euro Surveill. 2023 Feb;28(8):2300105. doi: 10.2807/1560-7917.ES.2023.28.8.2300105.
[Return to footnote 26 referrer](#fn26-rf)
Footnote 27
Huiberts AJ, de Gier B, Hoeve CE, de Melker HE, Hahné SJ, den Hartog G, et al. Effectiveness of bivalent mRNA booster vaccination against SARS-CoV-2 Omicron infection, the Netherlands, September to December 2022. Euro Surveill. 2023 Feb;28(7):2300087. doi: 10.2807/1560-7917.ES.2023.28.7.2300087.
[Return to footnote 27 referrer](#fn27-rf)
Footnote 28
Poukka E, Nohynek H, Goebeler S, Leino T, Baum U. Bivalent booster effectiveness against severe COVID-19 outcomes in Finland, September 2022 – March 2023. medRxiv. 2023 May 08. https://doi.org/10.1101/2023.03.02.23286561.
[Return to footnote 28 referrer](#fn28-rf)
Footnote 29
Grewal R, Sarah AB, Nguyen L, Nasreen S, Austin PC, Brown KA, et al. Effectiveness of mRNA COVID-19 monovalent and bivalent vaccine booster doses against Omicron severe outcomes among adults aged ≥50 years in Ontario, Canada. medRxiv. 2023 Apr 11. https://doi.org/10.1101/2023.04.11.23288403.
[Return to footnote 29 referrer](#fn29-rf)
Footnote 30
Lee IT, Cosgrove CA, Moore P, Bethune C, Nally R, Bula M, et al. A Randomized Trial Comparing Omicron-Containing Boosters with the Original Covid-19 Vaccine mRNA-1273. medRxiv. 2023 Feb 22. https://doi.org/10.1101/2023.01.24.23284869.
[Return to footnote 30 referrer](#fn30-rf)
Footnote 31
Auvigne V, Tamandjou C, Schaeffer J, Vaux S, Isabelle Parent dC. Protection against symptomatic SARS-CoV-2 BA.5 infection conferred by the Pfizer-BioNTech Original/BA.4-5 bivalent vaccine compared to the mRNA Original (ancestral) monovalent vaccines – a matched cohort study in France. medRxiv. 2023 Mar 17. https://doi.org/10.1101/2023.03.17.23287411.
[Return to footnote 31 referrer](#fn31-rf)
Footnote 32
Ischaemic stroke following mRNA bivalent COVID-19 vaccination Canada December 1, 2020 - January 6, 2023. [Unpublished]. Ottawa (ON): Public Health Agency of Canada (PHAC); 2023 Jan 18.
[Return to footnote 32 referrer](#fn32-rf)
Footnote 33
Lavery I. No 'elevated risk' of stroke from Pfizer's bivalent COVID shot, Health Canada says [Internet].: Global News; 2023 Jan 29 [cited 2023 Feb 02]. Available from: https://globalnews.ca/news/9443283/covid-pfizer-bivalent-booster-stroke-health-canada/.
[Return to footnote 33 referrer](#fn33-rf)
Footnote 34
Public Health Agency of Canada. Reported side effects following COVID-19 vaccination in Canada. Data cut-off Mar 3, 2023 [Internet]. Ottawa (ON): Health Canada; 2023 Mar 17 [cited 2023 Mar 17]. Available from: https://health-infobase.canada.ca/covid-19/vaccine-safety/.
[Return to footnote 34 referrer](#fn34-rf)
Footnote 35
Ontario Agency for Health Protection and Promotion (Public Health Ontario). Adverse Events Following Immunization (AEFIs) for COVID-19 in Ontario: December 13, 2020 to April 23, 2023. Data cut-off Apr 23, 2023 [Internet]. Toronto (ON): King's Printer for Ontario; 2023 Apr 23 [cited 2023 Apr 23]. Available from: https://www.publichealthontario.ca/-/media/Documents/nCoV/epi/covid-19-aefi-report.pdf?rev=d0854501b255400c927d32857c7b071a&sc\_lang=en.
[Return to footnote 35 referrer](#fn35-rf)
Footnote 36
Hause AM, Marquez P, Zhang B, Su JR, Myers TR, Gee J, et al. Safety Monitoring of Bivalent COVID-19 mRNA Vaccine Booster Doses Among Children Aged 5-11 Years - United States, October 12-January 1, 2023. MMWR Morb Mortal Wkly Rep. 2023 Jan 13;72(2):39,43. doi: 10.15585/mmwr.mm7202a5.
[Return to footnote 36 referrer](#fn36-rf)
Footnote 37
Hause AM, Marquez P, Zhang B, Myers TR, Gee J, Su JR, et al. Safety Monitoring of Bivalent COVID-19 mRNA Vaccine Booster Doses Among Persons Aged ≥12 Years - United States, August 31-October 23, 2022. MMWR Morb Mortal Wkly Rep. 2022 Nov 4;71(44):1401,1406. doi: 10.15585/mmwr.mm7144a3.
[Return to footnote 37 referrer](#fn37-rf)
Footnote 38
Andersson NW, Thiesson EM, Vinsløv Hansen J, Hviid A. Safety of bivalent omicron-containing mRNA-booster vaccines: a nationwide cohort study. medRxiv. 2023 Jan 22. https://doi.org/10.1101/2023.01.21.23284855.
[Return to footnote 38 referrer](#fn38-rf)
Footnote 39
Shimabukuro T. COVID-19 vaccine safety update: Primary series in young children and booster doses in older children and adults [slides presented at Advisory Committee on Immunization Practices (ACIP) meeting September 1, 2022] [Internet]. Atlanta (GA): Centers for Disease Control and Prevention (CDC); 2022 Sep 01 [cited 2022 Sep 07]. Available from: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-09-01/05-COVID-Shimabukuro-508.pdf.
[Return to footnote 39 referrer](#fn39-rf)
Footnote 40
Vaccine Safety Surveillance Division, Centre for Immunization Surveillance, Infectious Diseases and Vaccination Programs Branch. Date range from December 1, 2020 to February 3, 2023. Ottawa (ON): Public Health Agency of Canada; 2023.
[Return to footnote 40 referrer](#fn40-rf)
Footnote 41
Goddard K, Hanson KE, Lewis N, Weintraub E, Fireman B, Klein NP. Incidence of Myocarditis/Pericarditis Following mRNA COVID-19 Vaccination Among Children and Younger Adults in the United States. Ann Intern Med. 2022 Dec;175(12):1169,1771. doi: 10.7326/M22-2274.
[Return to footnote 41 referrer](#fn41-rf)
Footnote 42
Shimabukuro T, Klein, N. COVID-19 mRNA bivalent booster vaccine safety [slides presented at Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting January 26, 2023] [Internet]. Silver Spring (MD): Food and Drug Administration (FDA); 2023 Jan 26 [cited 2023 Feb 02]. Available from: https://www.fda.gov/media/164811/download.
[Return to footnote 42 referrer](#fn42-rf)
Footnote 43
CDC & FDA Identify Preliminary COVID-19 Vaccine Safety Signal for Persons Aged 65 Years and Older [Internet]. Atlanta (GA): Centers for Disease Control and Prevention (CDC); 2023 Jan 13 [cited 2023 Feb 02]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/bivalent-boosters.html.
[Return to footnote 43 referrer](#fn43-rf)
Footnote 44
Forshee R. Update on Original COVID-19 Vaccine and COVID-19 Vaccine, Bivalent Effectiveness and Safety [slides presented at Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting January 26, 2023] [Internet]. Silver Spring (MD): Food and Drug Administration (FDA); 2023 Jan 26 [cited 2023 Feb 02]. Available from: https://www.fda.gov/media/164815/download.
[Return to footnote 44 referrer](#fn44-rf)
Footnote 45
Interim statement on the composition of current COVID-19 vaccines [Internet]. Geneva (CH): World Health Organization (WHO); 2022 Jun 17 [cited 2022 Aug 10]. Available from: https://www.who.int/news/item/17-06-2022-interim-statement-on--the-composition-of-current-COVID-19-vaccines.
[Return to footnote 45 referrer](#fn45-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html&n=Interim%20guidance%20on%20the%20use%20of%20bivalent%20Omicron-containing%20COVID-19%20vaccines%20for%20primary%20series%3A%20NACI%2C%20June%2016%2C%202023%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html&title=Interim%20guidance%20on%20the%20use%20of%20bivalent%20Omicron-containing%20COVID-19%20vaccines%20for%20primary%20series%3A%20NACI%2C%20June%2016%2C%202023%20-%20Canada.ca)
* [Email](mailto:?subject=Interim%20guidance%20on%20the%20use%20of%20bivalent%20Omicron-containing%20COVID-19%20vaccines%20for%20primary%20series%3A%20NACI%2C%20June%2016%2C%202023%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html&t=Interim%20guidance%20on%20the%20use%20of%20bivalent%20Omicron-containing%20COVID-19%20vaccines%20for%20primary%20series%3A%20NACI%2C%20June%2016%2C%202023%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=Interim%20guidance%20on%20the%20use%20of%20bivalent%20Omicron-containing%20COVID-19%20vaccines%20for%20primary%20series%3A%20NACI%2C%20June%2016%2C%202023%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html&title=Interim%20guidance%20on%20the%20use%20of%20bivalent%20Omicron-containing%20COVID-19%20vaccines%20for%20primary%20series%3A%20NACI%2C%20June%2016%2C%202023%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html&t=Interim%20guidance%20on%20the%20use%20of%20bivalent%20Omicron-containing%20COVID-19%20vaccines%20for%20primary%20series%3A%20NACI%2C%20June%2016%2C%202023%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html&media=&description=Interim%20guidance%20on%20the%20use%20of%20bivalent%20Omicron-containing%20COVID-19%20vaccines%20for%20primary%20series%3A%20NACI%2C%20June%2016%2C%202023%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html&title=Interim%20guidance%20on%20the%20use%20of%20bivalent%20Omicron-containing%20COVID-19%20vaccines%20for%20primary%20series%3A%20NACI%2C%20June%2016%2C%202023%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html&name=Interim%20guidance%20on%20the%20use%20of%20bivalent%20Omicron-containing%20COVID-19%20vaccines%20for%20primary%20series%3A%20NACI%2C%20June%2016%2C%202023%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=Interim%20guidance%20on%20the%20use%20of%20bivalent%20Omicron-containing%20COVID-19%20vaccines%20for%20primary%20series%3A%20NACI%2C%20June%2016%2C%202023%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html)
* [Whatsapp](https://api.whatsapp.com/send?text=Interim%20guidance%20on%20the%20use%20of%20bivalent%20Omicron-containing%20COVID-19%20vaccines%20for%20primary%20series%3A%20NACI%2C%20June%2016%2C%202023%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=Interim%20guidance%20on%20the%20use%20of%20bivalent%20Omicron-containing%20COVID-19%20vaccines%20for%20primary%20series%3A%20NACI%2C%20June%2016%2C%202023%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fvaccines-immunization%2Fnational-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2023-07-05
| None | None |
ea004e828085db4de459f1b788403b57408e6c75 | cma | Contraindications and precautions: Canadian Immunization Guide | Contraindications and precautions: Canadian Immunization Guide
Introduction
Sometimes vaccines cannot be given or need to be delayed due to contraindications or precautions. Other times people have concerns that lead to hesitation or refusal to get vaccinated. It is important that vaccine providers correctly identify contraindications, distinguish them from precautions, and seek expert advice as needed.
Contraindications and precautions
A contraindication is a situation in which a drug, such as a vaccine, should not be used because the risk outweighs any potential therapeutic benefit.
A precaution is a condition that may increase the risk of an adverse reaction following immunization or that may compromise the ability of the vaccine to produce immunity. In general, vaccines are deferred when a precaution is present. However, there may be circumstances when the benefits of giving the vaccine outweigh any potential risks, or when reduced vaccine immunogenicity may still result in significant benefit to an immunocompromised host.
Contraindications and precautions are determined by a person's past immunization experience(s), known allergies, current health status (for example: acute illness, immunocompromised status, chronic disease, pregnancy and breastfeeding) and presence of close contacts who might be affected by the use of live attenuated vaccines.
Some precautions and contraindications depend on whether a vaccine is a live attenuated product or non-live product. For information on types of vaccines, refer to in Part 1. For complete vaccine-specific contraindications and precautions, consult the relevant in Part 4, the product leaflet, or information contained within the vaccine's product monograph available through Health Canada's .
Vaccine providers should question all clients about their past immunization experience(s), known allergies, current health, and any chronic conditions to identify contraindications and precautions to the vaccine before each dose of vaccine is given. Checklists and routine screening questions are useful and can be found in in Part 1.
The following is a general discussion of the key categories of events or underlying illness or conditions that may result in a contraindication and/or precaution to immunization. features a summary of the contraindications and precautions associated with conditions that may be present in vaccine candidates.
Contraindications and precautions associated with specific conditions
# Acute Illness
## Moderate to Severe Acute Illness
The risks and benefits of vaccinating a severely ill person need to be assessed. The benefits of protection in a high risk exposure situation or when the window of opportunity is short (i.e., when travel or use of immunocompromising medications are imminent) need to be assessed against the risks of a vaccine-related adverse event. It is possible that systemic adverse events may complicate the medical management of an acute illness or that events associated with the acute illness may be misperceived as vaccine-related adverse events. Expert opinion is recommended in this situation.
Situations with specific contraindications or precautions include:
- Gastroenteritis
+ Postpone oral typhoid, cholera and travellers' diarrhea vaccines until the illness has resolved.
+ Defer rotavirus vaccine until condition improves unless deferral results in scheduling the first dose beyond the recommended age limit.
- Inflammatory eye disease treated with steroids
+ Defer first-generation smallpox vaccine, if a non-outbreak situation, until condition resolves or course of steroids is completed.
- Measles
+ Delay varicella containing vaccine for 6 weeks (a minimum of 4 weeks delay can be applied if needed).
- Medically attended wheezing in the 7 days prior to vaccination
+ Live Attenuated Influenza Vaccine (LAIV) is contraindicated.
- Tuberculosis, active, untreated
+ Tuberculosis may be exacerbated by natural measles infection. Although there is no evidence that measles or varicella-containing vaccines have such an effect, measles-mumps-rubella (MMR), measles-mumps-rubella-varicella (MMRV), varicella, and live zoster vaccines (LZV) are contraindicated as a precautionary measure.
## Mild Acute illness
Mild illnesses, with or without fever (e.g., upper respiratory tract infection, otitis media) do not increase the risk of adverse events following immunization or interfere with the response to vaccines. There are no associated contraindications or precautions and these should not be used as a reason to withhold or delay immunization.
The single exception is when nasal congestion is present that could impede the delivery of LAIV to the nasopharyngeal mucosa. In such cases, non-live influenza vaccine can be offered.
# Adverse events following a previous immunization
There are numerous adverse events following a previous immunization that may lead to concern regarding subsequent immunization.
## Anaphylactic reaction to a vaccine or a component of a vaccine
A vaccine is contraindicated in a person with a documented history of confirmed anaphylaxis after previous administration of the same vaccine although exceptions may apply (i.e., Imvamune® and mRNA COVID-19 vaccines). Refer to the in Part 4 for more information. If there is uncertainty regarding the diagnosis of anaphylaxis or which vaccine or vaccine component may have triggered it, consultation with an expert is recommended.
## Febrile seizure following immunization
There are no contraindications or precautions associated with a history of a febrile seizure after a previous immunization. Children with a history of febrile seizures have no increased risk of developing a seizure disorder.
## Guillain-Barré syndrome (GBS) with onset within 6 weeks of immunization
Cases of GBS have been reported following immunization but the evidence only supports a causal association for two vaccines: influenza and tetanus toxoid-containing vaccines. For influenza vaccine, the evidence suggests that the absolute risk of GBS in the period following seasonal or A(H1N1)pdm09 influenza vaccination is about one excess case per 1 million vaccine doses. However, the risk is higher following wild type influenza infection with approximately 17 cases of GBS per million influenza coded health care encounters (proxy measure for influenza infection). Thus, the risk of GBS associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself.
The evidence for a causal association between tetanus toxoid-containing vaccines and GBS is informed by a single individual who developed GBS following each of three doses of tetanus toxoid given years apart. There are no confirmatory epidemiologic studies and, at most, it is a very rare event.
As a precaution, it is recommended that persons who develop GBS within 6 weeks of receipt of a tetanus or influenza vaccine should not receive further doses of that specific vaccine. If there is a history of both *Campylobacter- infection (which has been associated with GBS) and immunization within 6 weeks before the onset of GBS, consultation with an infectious disease specialist is advised. Those who develop GBS outside the 6-week interval may receive subsequent doses of the vaccine.
## Hypotonic-hyporesponsive episode (HHE) following immunization
HHE is the sudden onset of hypotonia, hyporesponsiveness and pallor or cyanosis that may follow immunization in the first 2 years of life. It is thought to be a pain response. There are no contraindications or precautions associated with a history of HHE. There is evidence that there are no adverse consequences to these events. The risk of recurrence with subsequent vaccinations is low (<5%).
## Persistent crying following immunization
There are no contraindications or precautions associated with a history of persistent crying following immunization. Such reactions, which may be accompanied by an unusual high-pitched cry, are likely to be responses to pain at the site of injection in young infants. There are no associated sequelae. For information on techniques to decrease injection site pain, refer to in Part 1.
## Oculorespiratory syndrome (ORS)
Oculorespiratory syndrome is defined as bilateral conjunctivitis plus one or more respiratory symptoms: cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness or sore throat, with or without facial edema that starts within 24 hours of influenza vaccination. It is usually transient, resolving within 48 hours of onset. The only associated precaution is when lower respiratory symptoms accompany ORS, in which case expert review is required prior to subsequent immunization. For more information, refer to in Part 4.
## Severe injection site reaction
Most injection site reactions are simply a normal inflammatory response to the vaccine. They are common and generally mild. These inflammatory reactions are not indicative of an allergy to the vaccine and patients can receive subsequent vaccinations.
An injection site reaction can be considered severe based on its size or location (e.g., ≥10cm, crossing the adjacent joint), duration (e.g., ≥4days) or impact on daily activities (e.g., required a consultation or hospitalization, prevented daily activities, resulted in missing work/school/daycare). There are specific types of severe injection site reactions like extensive limb swelling (ELS) or Arthus-type injection site reaction. A severe injection site reaction to one vaccine is not associated with an increased risk of injection site reactions to other vaccines. Repeating a dose of a vaccine that was previously associated with a large injection site reaction may result in a similar reaction; however, there is no increased risk of anaphylaxis. The presence of a large injection site reaction to a previous dose is not a contraindication to continuing the recommended schedule.
Severe Arthus-type injection site reactions are occasionally reported following receipt of diphtheria toxoid or tetanus toxoid-containing vaccines. There may be extensive painful swelling around the injection site, often involving the arm from shoulder to elbow and generally beginning 2 to 8 hours after injection. Persons who have experienced a previous Arthus-type injection site reaction should not receive further routine doses of Td/Tdap vaccine for at least 10 years. A pregnant person with a history of Arthus-type injection site reaction within the past 10 years should be referred to a specialist prior to re-vaccination with Tdap.
For information on wound prophylaxis following a tetanus-prone injury, refer to the section of the chapter in Part 4.
## Extensive limb swelling (ELS) following immunization
There are no contraindications or precautions associated with a history of ELS, which is defined as swelling with or without redness that extends at least to the joints immediately above and below the injection site and that may cross one or both joints or involve the entire limb where the vaccine was administered. The reaction is often painless. It is commonly (2-6%) seen in children receiving the 4th or 5th dose of DTaP containing vaccine and has also been reported after non-live influenza vaccination. For children who have had an episode of ELS, repeat episodes with the next dose of vaccine are very common (>10%). However, ELS resolves spontaneously within a few days, is not associated with any other complications, and repeat episodes are generally of less or the same intensity as the first episode.
## Syncope
There are no contraindications or precautions associated with a history of syncope (fainting) after a previous immunization. The likelihood of fainting can be reduced by measures that lower stress in those awaiting immunization, such as short waiting times, comfortable room temperature, preparation of vaccines out of view of recipients, and privacy during the procedure. People should be immunized while seated or lying down.
For more information, refer to .
# Allergies
A history of allergies is one of the most common concerns that people have about receiving vaccines. There are many types of allergic reactions and it is important to differentiate among them when considering implications for immunization.
Allergic reactions can be either immediate or delayed. Anaphylaxis is a serious, potentially life-threatening allergic reaction to foreign antigens; it has been causally associated with vaccines with an estimated frequency of 1.3 episodes per million doses of vaccine administered. In anaphylaxis, signs and symptoms have a sudden onset and progress rapidly over several minutes and involves two or more body systems. This immediate hypersensitivity reaction is IgE mediated (Type 1) and usually occurs within minutes up to 4 hours after injection; most within 2 hours.
The mechanisms of delayed reactions to vaccines are not fully understood. These may appear several hours to days after immunization. These reactions include an Arthus-type or Type 3 reaction (a local vasculitis due to deposition of IgG-based immune complexes in dermal blood vessels), a cell-mediated, delayed hypersensitivity or Type 4 reaction, or other unknown mechanisms.
On close questioning, it may become evident that people think they have an allergy to a vaccine or vaccine component but it is not a true allergy. People can be reassured that it is highly unlikely that they are allergic to a vaccine or vaccine component if they have a delayed, localized reaction.
People with a suspected moderate to severe hypersensitivity reaction, should seek expert advice. Suspected hypersensitivity should not be an ongoing reason to not administer vaccine. It should be investigated by an expert to clarify whether the person may proceed with vaccination or not. For more information, refer to .
## Allergy to a vaccine component or its container
Vaccine is contraindicated in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine (with the exception of ) or its container (e.g., latex). Assessment by an allergist is warranted if further vaccine doses are needed. There is general evidence that some individuals with proven immediate or anaphylactic hypersensitivity to vaccine component(s) or with immediate allergic reactions to vaccines can safely receive a subsequent dose of the same vaccine with low risk of a systemic reaction under the supervision of an allergist. For guidance on specific vaccine(s), consult the relevant in Part 4.
Precaution is warranted in situations of suspected hypersensitivity or non-anaphylactic allergy to a vaccine or its components. Investigation is indicated which may involve immunization in a controlled setting. Consultation with an expert may be advised. For guidance on specific vaccine(s), consult the relevant in Part 4.
People may report an allergy to a number of vaccine components including:
- Gelatin - Patients with a history of anaphylaxis to gelatin need to be assessed by skin testing to gelatin before vaccine with gelatin component is given. Most gelatin allergies are non-anaphylactic.
- Latex - Anaphylactic allergy to latex is very rare but if confirmed would pose a contraindication to the use of vaccines that come in vials with latex stoppers or that include syringes with latex components. For non-anaphylactic latex allergies (e.g., history of contact dermatitis to latex gloves), vaccines supplied in vials or syringes that contain dry natural rubber or natural rubber latex may be given.
- Neomycin - Neomycin allergy is most often a contact dermatitis (i.e., a delayed hypersensitivity reaction) which is not a contraindication for administration of vaccines containing neomycin.
- Thimerosal - Even if there is a documented history of a delayed hypersensitivity reaction to thimerosal (such as a large local reaction or contact dermatitis), immunization with thimerosal-containing vaccines can proceed. In the rare instance of individuals with proven delayed hypersensitivity to thimerosal, they should be advised that long-lasting local or systemic cutaneous reactions can occur. They should report any reaction of concern following immunization so that it can be managed appropriately.
For a list of potential allergens, refer to in Part 1.
## Egg allergy
Egg allergy is one of the most common food allergies of childhood, with a prevalence of approximately 2% in children. It is often associated with eczema in infants and asthma in young children. However, allergic diseases are not a contraindication to immunization with egg protein-containing vaccine.
As most children outgrow their egg allergy, the prevalence of egg allergy in adulthood is lower and is estimated at 0.7%. The most common egg allergy is to egg white. Anaphylaxis to egg is possible.
In Canada, there are several vaccines manufactured by processes involving hens' eggs or their derivatives, such as chick cell cultures. This manufacturing process may result in the following vaccines containing trace amounts of residual egg and chicken protein:
- measles-mumps-rubella (MMR) vaccines
- measles-mumps-rubella-varicella (MMRV) vaccines
- influenza vaccines grown in eggs or chick cell cultures
- RABAVERT® rabies vaccine
- yellow fever (YF) vaccine
- Imvamune® Smallpox Vaccine
Previous concerns about immunizing egg-allergic individuals with vaccines that contain egg protein have been allayed by several studies resulting in clear changes to expert recommendations for some, but not all, of the above vaccines. A known egg allergy is not a contraindication to MMR, MMRV, Imvamune® or influenza vaccines. Refer to in Part 4 for additional information.
## Measles and mumps-containing vaccine
MMR or MMRV vaccine can be administered in the routine manner to people who have a history of anaphylactic hypersensitivity to egg. Numerous studies of egg-allergic subjects have shown that there is no increased risk of allergic reaction to MMR vaccine in those with egg allergy. The trace amount of egg protein in both MMR and MMRV vaccines are insufficient to cause an allergic reaction in egg-allergic individuals. Skin testing is not recommended prior to vaccination as it does not predict reaction to the vaccine. Hypersensitivity reactions that do occur following MMR and MMRV vaccine are usually due to other components of the vaccine, such as gelatin or neomycin.
## Influenza vaccine
Studies have clearly demonstrated that egg-allergic persons can receive influenza vaccine. All egg-allergic individuals may be vaccinated against influenza using any of the vaccines authorized for use in Canada. Although the egg albumin (egg protein) content in influenza vaccines manufactured in eggs may vary from year to year, vaccines marketed in Canada are approved with a maximum allowable egg albumin content that is associated with low risk of adverse events.
The full recommended dose can be used and there is no need for a prior influenza vaccine skin test irrespective of a past severe reaction to egg. The vaccine may be given in any setting where vaccines are routinely administered. Refer to the Additional Vaccine Safety Considerations in the for safety data supporting this recommendation for inactivated influenza vaccine (IIV) and LAIV.
## Imvamune® vaccine
Imvamune® vaccine is prepared from virus grown in chicken embryo fibroblast cells. However, the risk associated with the trace amounts contained in the vaccine is thought to be low. The full recommended dose can be used and there is no need for a prior vaccine skin test irrespective of a past severe reaction to egg. The vaccine may be given in any setting where vaccines are routinely administered. Prolonged observation (30 minutes) may be considered.
## Rabies vaccine
RABAVERT® rabies vaccine is grown in chick embryo cell culture. Imovax® rabies vaccine is manufactured using human diploid cell cultures and therefore egg protein contamination is not an issue. For pre-exposure vaccination, Imovax® rabies vaccine should be given to persons with a history of hypersensitivity reactions to egg or egg products as a precautionary measure. For post-exposure prophylaxis, the use of Imovax® vaccine is preferred for persons with a history of hypersensitivity to egg. If Imovax® vaccine is not available, RABAVERT® vaccine should be administered with strict medical monitoring and facilities for emergency treatment of anaphylactic reactions readily available.
## Yellow fever vaccine
Yellow fever (YF) vaccine is prepared from virus grown in chick embryos and is the vaccine most likely to contain sufficient amounts of egg or chicken proteins to cause an allergic reaction in egg-allergic or chicken-allergic individuals. There have been several reports of anaphylactic reactions to YF vaccine in egg-allergic or chicken-allergic individuals; therefore, Yellow fever vaccine should not be routinely administered to egg-allergic or chicken-allergic individuals. Referral of egg-allergic or chicken-allergic individuals to an allergy specialist is recommended, as YF vaccination may be possible after careful evaluation, skin testing and graded challenge or desensitization.
## Individuals should be asked about allergies to egg or chicken prior to vaccination with Yellow fever or RABAVERT® rabies vaccines.
# Concurrent or recent medication including biologics
## Antibiotic therapy
Antibiotic therapy does not interfere with response to non-live vaccines or most live vaccines with the following exceptions:
- The Typh-O vaccine series should be finished at least 3 days before commencing, or initiated at least 3 days after completing, treatment with sulphonamides or other antibiotics active against *S. typhi*, or antimalarials. Exceptions include chloroquine, mefloquine and atovaquone/proguanil (Malarone®), as these antimalarials do not affect the immune response to Typh-O vaccine and can be administered at the same time as, or at any interval before or after Typh-O vaccine.
- Bacille Calmette-Guérin (BCG) vaccine should not be administered to individuals receiving drugs with anti-tuberculous activity, including fluoroquinolones.
## Anticoagulation
Individuals receiving long-term anticoagulation with either warfarin or heparin are not considered to be at higher risk of bleeding complications following immunization and may be immunized through either the intramuscular or subcutaneous route (as recommended for the vaccine product) without discontinuation of anticoagulation therapy. For intramuscular injection, use a small gauge needle (23 gauge or smaller) and apply firm pressure to the injection site for ≥ 2 minutes. There is a paucity of evidence on whether there is an increased risk of bleeding complications following immunization with the other types of anticoagulants, such as antiplatelet agents, but there is no reason to believe that persons receiving these anticoagulants need to be treated any differently from those receiving other anticoagulants.
## Antiviral therapy
Antiviral therapy does not interfere with response to non-live vaccines or most live vaccines with the following exceptions:
- Varicella vaccine and live herpes zoster (LZV) vaccine may have reduced effectiveness if given concurrently with antivirals active against varicella zoster virus (such as acyclovir, valacyclovir, famciclovir). People taking long-term antiviral therapy should discontinue these drugs, if possible, from at least 24 hours before administration of varicella or LZV vaccine and should not restart antiviral therapy until 14 days after vaccination.
- LAIV should not be administered until 48 hours after antiviral agents active against influenza (e.g., oseltamivir) are stopped, and antiviral agents should not be administered until at least 14 days after receipt of LAIV unless medically indicated. If antiviral agents are administered within this time frame (from 48 hours before to 14 days after LAIV), revaccination should take place at least 48 hours after the antivirals are stopped.
## Recent administration of blood products containing antibodies
Passive immunization with human immunoglobulin or receipt of most blood products can interfere with the immune response to MMR, MMRV and univalent varicella vaccines. Measles-containing or varicella vaccines should be given at least 14 days prior to administration of an immunoglobulin preparation or blood product, or delayed until the antibodies in the immunoglobulin preparation or blood product have degraded. Respiratory syncytial virus monoclonal antibody (RSVAb) does not interfere with live vaccines because RSVAb contains only antibody to respiratory syncytial virus. For more information, refer to Table 1 in in Part 1.
A risk-benefit assessment is needed for post-partum women who have received Rh immunoglobulin (RhIg) and require MMR or varicella vaccine. For more information, refer to in Part 1.
In adults with pre-existing antibody to varicella-zoster virus (VZV), in theory, administration of immunoglobulin should not interfere with the LZV response. For this reason, some experts do not consider recent administration of Ig or blood products as a reason to delay the administration of LZV. LZV should be considered only in cases where the recombinant zoster vaccine is contraindicated, unavailable or inaccessible.
## Salicylates
While it is generally safe to be immunized when taking salicylates (acetylsalicylic acid, aspirin, or ASA) there are some exceptions:
- LAIV is contraindicated in children and adolescents (2-17 years of age) currently receiving salicylates (e.g., ongoing treatment with aspirin-containing therapy) because of the association of Reye's syndrome with ASA and wild-type influenza infection. Non-live influenza vaccine should be used instead. ASA-containing products should be delayed for 4 weeks after receipt of LAIV in children aged 2 - 17 years, unless a risk assessment deems that the benefits outweigh the potential risks for the individual (e.g., treatment of Kawasaki disease).
- Varicella-containing vaccine manufacturers recommend avoidance of salicylate therapy for 6 weeks after varicella immunization because of an association between wild-type varicella, salicylate therapy and Reye's syndrome. Health care providers should weigh the theoretical risks associated with varicella vaccine against the known risks associated with wild-type varicella. Because adverse events have not been reported with the use of salicylates after varicella immunization, people with conditions requiring chronic salicylate therapy should be considered for immunization, with close subsequent monitoring.
# Other Situations, Underlying Condition or Illness
Chronic conditions with no contraindications or precautions are not included in the list below. However, it is important to ensure that individuals with chronic conditions are immunized appropriately since they are often at higher risk of complications due to vaccine-preventable diseases. For detailed recommendations on the use of live and non-live vaccines in individuals with asplenia or hyposplenia, endocrine/metabolic disease, heart disease, non-malignant hematologic disorders, inflammatory diseases, renal disease and dialysis, liver disease, lung disease and neurologic disorders, refer to in Part 3.
## Asthma, severe
Live attenuated influenza vaccine (LAIV) is contraindicated in individuals with severe asthma (defined as currently on oral or high dose inhaled glucocorticosteroids or active wheezing) or those with medically-attended wheezing in the 7 days prior to vaccination. LAIV can be used in stable, non-severe asthmatics.
## Bleeding disorders
People with bleeding disorders should receive all recommended immunizations according to routine schedules when appropriate safety measures have been taken. Control of bleeding disorders should be optimized prior to immunization. Vaccine providers should ensure that there are no symptoms or signs compatible with an undiagnosed bleeding disorder (e.g., unexplained bruising). If such indicators are present before immunization, a diagnosis should be established before commencing immunization. When administering a parenteral vaccine, consider the use of a small gauge needle (23 gauge or smaller) and apply firm pressure for ≥ 2 minutes after the immunization.
For more information, refer to in Part 3.
## Congenital malformation of gastrointestinal tract or history of intussusception
Rotavirus vaccine is contraindicated in infants with a history of intussusception or uncorrected congenital malformation of the gastrointestinal tract that would predispose for intussusception.
## Immunocompromised persons
For contraindications and precautions regarding immunization of individuals with primary immunodeficiencies, hematopoietic stem cell transplant candidates/recipients, solid organ transplant candidates/recipients and HIV-infected persons, refer to in Part 3. Contraindications and precautions are also provided for individuals slated for, or on, immunosuppressive therapy including infants of mothers treated during pregnancy.
## Positive Tuberculin skin test
BCG vaccine is contraindicated for individuals with a positive tuberculin skin test, although immunization of tuberculin reactors has occurred frequently without complications.
## Pregnancy and Breastfeeding
For contraindications and precautions regarding immunization during pregnancy and breastfeeding, refer to in Part 3.
## Preterm infants
Healthy preterm infants weighing 1,500 grams or more at birth generally tolerate immunizations well, with rates of adverse events similar to the low rates of full-term infants. Hospitalized premature infants should have continuous cardiac and respiratory monitoring for 48 hours after their first immunization. For more information, refer to in Part 3.
## Skin Disorders
Vaccines are generally safe for people with skin disorders. For comfort, administer vaccine into a non-affected area. Some smallpox vaccines and BCG are exceptions to this. Imvamune® vaccine can be safely administered in people with eczema (atopic dermatitis). BCG vaccine is contraindicated when there is extensive skin disease or burns.
For more information, refer to the and chapters in Part 4.
## Thymus disease
For individuals with a past history of thymus disease with abnormal immune function (e.g., thymoma, thymectomy, myasthenia gravis), Yellow fever vaccine is contraindicated because of an increased risk of viscerotropic disease.
Close Contacts of Immunocompromised or Pregnant Individuals
Vaccination provides protection at both an individual and population level. Some people may have conditions that preclude vaccination, but they can be protected by having the people around them vaccinated. Immunization of household contacts of immunosuppressed persons, pregnant women, and neonates provides important protection against transmission of disease in the household.
Up-to-date routine immunizations are recommended for household contacts of pregnant women, immunocompromised persons, and neonates with the following exceptions:
- Non-live influenza vaccine is preferred over LAIV for those in close contact with severely immunocompromised persons.
- Oral polio vaccine (OPV): OPV is not used in Canada but individuals may receive it in other countries. Household contacts who are vaccinated with OPV should not have contact with immunocompromised persons for six weeks after receipt of OPV.
- Following MMRV, varicella or LVZ vaccines, if a vaccine recipient develops a varicella-like rash, the rash should be covered and the vaccinee should avoid direct contact with the immunocompromised person for the duration of the rash.
- First-generation smallpox vaccine should not be administered to household contacts of an immunocompromised person in a non-emergency situation.
- First-generation smallpox vaccine: Vaccinees with household and other close contacts with active eczema or a history of eczema or other exfoliative skin conditions, immunosuppressive disorders, or with close contact with infants or pregnant women, should take special precautions in order to prevent viral transfer to these contacts.
Pre-exposure: use Imovax®
Post-exposure: Imovax® preferred but if unavailable administer RABAVERT® ensuring strict medical monitoring with readily available emergency treatment for anaphylaxis
Exceptions may apply (i.e., Imvamune® and mRNA COVID-19 vaccines).
Exceptions may apply (i.e., Imvamune® and mRNA COVID-19 vaccines).
2. Intermittent
2. Children and adolescents should avoid salicylates following :- LAIV for 4 weeks
- Varicella-containing vaccine for 6 weeks
OPV: avoid direct contact with immunocompromised person(s) for 6 weeks after receipt of OPV in another country
Varicella vaccine recipients with varicella-like rash: ensure that rash is covered and avoid direct contact with the immunocompromised person for the duration of the rash
Those who develop GBS outside the 6 week interval may receive subsequent doses of the vaccine.
Salicylates are avoided in these instances to decrease the risk of Reye's syndrome.
Severe asthma: defined as currently on oral or high dose inhaled glucocorticosteroids or active wheezing.
Because of an association between a history of thymus disease and acute viscerotropic disease.
Oral polio vaccine is neither recommended nor available in Canada.
BCG
Bacille Calmette-Guérin vaccine
ELS
extensive limb swelling
GBS
Guillain-Barré syndrome
HHE
hypotonic-hyporesponsive episode
HPV
human papillomavirus vaccine
Ig
immunoglobulin
LAIV
live attenuated influenza vaccine
LZV
live zoster vaccine
MMR
measles-mumps-rubella vaccine
MMRV
measles-mumps-rubella-varicella vaccine
OPV
-ral polio vaccine
ORS
-culorespiratory syndrome
RV
rotavirus vaccine
Tdap
tetanus toxoid, diphtheria toxoid (reduced), acellular pertussis (reduced) vaccine
VZV
varicella-zoster virus
YF
yellow fever
Chapter revision process
The CIG Part 2 Working Group members reviewed the chapter to ensure content was up-to-date with clinical practice and evidence based. The revised guidance on the pressure time post administration of a parenteral vaccine to persons with a bleeding disorder or on an anticoagulant were based on a review of the literature, a review of guidance provided by other National Immunization Technical Advisory Groups (NITAGs) and expert opinion. For persons with a history of thymus disease with abnormal immune function, guidance regarding YF vaccine administration was changed from "generally not recommended" to "contraindicated" following a literature review. Updated guidance on contraindications and precautions associated with allergies is based on the guidance on Imvamune vaccine in those with allergic/immunocompromising conditions from the Canadian Society of Allergy and Clinical Immunology (CSACI) as of November 1, 2022. |
Contraindications and precautions: Canadian Immunization Guide
===============================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html)
Notice
------
This CIG chapter has not been completely updated to contain information regarding COVID-19 vaccines. For more information, refer to the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html).
Last partial chapter revision (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): February 2023
**February 2023:** This chapter was updated with guidance on contraindications and precautions associated with allergies to a vaccine component or its container.
Last complete chapter revision: November 2021
On this page
------------
* [Introduction](#a1)
* [Contraindications and precautions](#a2)
* [Contraindications and precautions associated with specific conditions](#a3)
+ [Acute illness](#a4)
+ [Adverse events following a previous immunization](#a5)
+ [Allergies](#a6)
+ [Concurrent or recent medication including biologics](#a7)
+ [Other situations, underlying condition or illness](#a8)
* [Close contacts of immunocompromised or pregnant individuals](#a9)
* [Table 1: Contraindications and precautions associated with conditions that may be present in vaccine candidates](#tab1)
* [Chapter revision process](#a10)
* [Acknowledgements](#a11)
* [Selected References](#a12)
Introduction
------------
Sometimes vaccines cannot be given or need to be delayed due to contraindications or precautions. Other times people have concerns that lead to hesitation or refusal to get vaccinated. It is important that vaccine providers correctly identify contraindications, distinguish them from precautions, and seek expert advice as needed.
Contraindications and precautions
---------------------------------
A **contraindication** is a situation in which a drug, such as a vaccine, should **not** be used because the risk outweighs any potential therapeutic benefit.
A **precaution** is a condition that may increase the risk of an adverse reaction following immunization or that may compromise the ability of the vaccine to produce immunity. In general, vaccines are deferred when a precaution is present. However, there may be circumstances when the benefits of giving the vaccine outweigh any potential risks, or when reduced vaccine immunogenicity may still result in significant benefit to an immunocompromised host.
Contraindications and precautions are determined by a person's past immunization experience(s), known allergies, current health status (for example: acute illness, immunocompromised status, chronic disease, pregnancy and breastfeeding) and presence of close contacts who might be affected by the use of live attenuated vaccines.
Some precautions and contraindications depend on whether a vaccine is a live attenuated product or non-live product. For information on types of vaccines, refer to [Contents of Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1. For complete vaccine-specific contraindications and precautions, consult the relevant [vaccine-specific chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4, the product leaflet, or information contained within the vaccine's product monograph available through Health Canada's [Drug Product Database](https://health-products.canada.ca/dpd-bdpp/index-eng.jsp).
Vaccine providers should question all clients about their past immunization experience(s), known allergies, current health, and any chronic conditions to identify contraindications and precautions to the vaccine before each dose of vaccine is given. Checklists and routine screening questions are useful and can be found in [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1.
The following is a general discussion of the key categories of events or underlying illness or conditions that may result in a contraindication and/or precaution to immunization. [Table 1](#tab1) features a summary of the contraindications and precautions associated with conditions that may be present in vaccine candidates.
Contraindications and precautions associated with specific conditions
---------------------------------------------------------------------
### Acute Illness
#### Moderate to Severe Acute Illness
The risks and benefits of vaccinating a severely ill person need to be assessed. The benefits of protection in a high risk exposure situation or when the window of opportunity is short (i.e., when travel or use of immunocompromising medications are imminent) need to be assessed against the risks of a vaccine-related adverse event. It is possible that systemic adverse events may complicate the medical management of an acute illness or that events associated with the acute illness may be misperceived as vaccine-related adverse events. Expert opinion is recommended in this situation.
Situations with specific contraindications or precautions include:
* **Gastroenteritis**
+ Postpone oral typhoid, cholera and travellers' diarrhea vaccines until the illness has resolved.
+ Defer rotavirus vaccine until condition improves unless deferral results in scheduling the first dose beyond the recommended age limit.
* **Inflammatory eye disease treated with steroids**
+ Defer first-generation smallpox vaccine, if a non-outbreak situation, until condition resolves or course of steroids is completed.
* **Measles**
+ Delay varicella containing vaccine for 6 weeks (a minimum of 4 weeks delay can be applied if needed).
* **Medically attended wheezing** in the 7 days prior to vaccination
+ Live Attenuated Influenza Vaccine (LAIV) is contraindicated.
* **Tuberculosis, active, untreated**
+ Tuberculosis may be exacerbated by natural measles infection. Although there is no evidence that measles or varicella-containing vaccines have such an effect, measles-mumps-rubella (MMR), measles-mumps-rubella-varicella (MMRV), varicella, and live zoster vaccines (LZV) are contraindicated as a precautionary measure.
#### Mild Acute illness
Mild illnesses, with or without fever (e.g., upper respiratory tract infection, otitis media) do not increase the risk of adverse events following immunization or interfere with the response to vaccines. There are no associated contraindications or precautions and these should not be used as a reason to withhold or delay immunization.
The single exception is when nasal congestion is present that could impede the delivery of LAIV to the nasopharyngeal mucosa. In such cases, non-live influenza vaccine can be offered.
### Adverse events following a previous immunization
There are numerous adverse events following a previous immunization that may lead to concern regarding subsequent immunization.
#### Anaphylactic reaction to a vaccine or a component of a vaccine
A vaccine is contraindicated in a person with a documented history of confirmed anaphylaxis after previous administration of the same vaccine although exceptions may apply (i.e., Imvamune® and mRNA COVID-19 vaccines). Refer to the [vaccine-specific chapters](https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for more information. If there is uncertainty regarding the diagnosis of anaphylaxis or which vaccine or vaccine component may have triggered it, consultation with an expert is recommended.
#### Febrile seizure following immunization
There are no contraindications or precautions associated with a history of a febrile seizure after a previous immunization. Children with a history of febrile seizures have no increased risk of developing a seizure disorder.
#### Guillain-Barré syndrome (GBS) with onset within 6 weeks of immunization
Cases of GBS have been reported following immunization but the evidence only supports a causal association for two vaccines: influenza and tetanus toxoid-containing vaccines. For influenza vaccine, the evidence suggests that the absolute risk of GBS in the period following seasonal or A(H1N1)pdm09 influenza vaccination is about one excess case per 1 million vaccine doses. However, the risk is higher following wild type influenza infection with approximately 17 cases of GBS per million influenza coded health care encounters (proxy measure for influenza infection). Thus, the risk of GBS associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself.
The evidence for a causal association between tetanus toxoid-containing vaccines and GBS is informed by a single individual who developed GBS following each of three doses of tetanus toxoid given years apart. There are no confirmatory epidemiologic studies and, at most, it is a very rare event.
As a precaution, it is recommended that persons who develop GBS within 6 weeks of receipt of a tetanus or influenza vaccine should not receive further doses of that specific vaccine. If there is a history of both *Campylobacter* infection (which has been associated with GBS) and immunization within 6 weeks before the onset of GBS, consultation with an infectious disease specialist is advised. Those who develop GBS outside the 6-week interval may receive subsequent doses of the vaccine.
#### Hypotonic-hyporesponsive episode (HHE) following immunization
HHE is the sudden onset of hypotonia, hyporesponsiveness and pallor or cyanosis that may follow immunization in the first 2 years of life. It is thought to be a pain response. There are no contraindications or precautions associated with a history of HHE. There is evidence that there are no adverse consequences to these events. The risk of recurrence with subsequent vaccinations is low (<5%).
#### Persistent crying following immunization
There are no contraindications or precautions associated with a history of persistent crying following immunization. Such reactions, which may be accompanied by an unusual high-pitched cry, are likely to be responses to pain at the site of injection in young infants. There are no associated sequelae. For information on techniques to decrease injection site pain, refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1.
#### Oculorespiratory syndrome (ORS)
Oculorespiratory syndrome is defined as bilateral conjunctivitis plus one or more respiratory symptoms: cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness or sore throat, with or without facial edema that starts within 24 hours of influenza vaccination. It is usually transient, resolving within 48 hours of onset. The only associated precaution is when lower respiratory symptoms accompany ORS, in which case expert review is required prior to subsequent immunization. For more information, refer to [Influenza Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html) in Part 4.
#### Severe injection site reaction
Most injection site reactions are simply a normal inflammatory response to the vaccine. They are common and generally mild. These inflammatory reactions are not indicative of an allergy to the vaccine and patients can receive subsequent vaccinations.
An injection site reaction can be considered severe based on its size or location (e.g., ≥10cm, crossing the adjacent joint), duration (e.g., ≥4days) or impact on daily activities (e.g., required a consultation or hospitalization, prevented daily activities, resulted in missing work/school/daycare). There are specific types of severe injection site reactions like extensive limb swelling (ELS) or Arthus-type injection site reaction. A severe injection site reaction to one vaccine is not associated with an increased risk of injection site reactions to other vaccines. Repeating a dose of a vaccine that was previously associated with a large injection site reaction may result in a similar reaction; however, there is no increased risk of anaphylaxis. The presence of a large injection site reaction to a previous dose is not a contraindication to continuing the recommended schedule.
Severe Arthus-type injection site reactions are occasionally reported following receipt of diphtheria toxoid or tetanus toxoid-containing vaccines. There may be extensive painful swelling around the injection site, often involving the arm from shoulder to elbow and generally beginning 2 to 8 hours after injection. Persons who have experienced a previous Arthus-type injection site reaction should not receive further routine doses of Td/Tdap vaccine for at least 10 years. A pregnant person with a history of Arthus-type injection site reaction within the past 10 years should be referred to a specialist prior to re-vaccination with Tdap.
For information on wound prophylaxis following a tetanus-prone injury, refer to the [post-exposure prophylaxis](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html#p4c21a5l) section of the [Tetanus toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html) chapter in Part 4.
#### Extensive limb swelling (ELS) following immunization
There are no contraindications or precautions associated with a history of ELS, which is defined as swelling with or without redness that extends at least to the joints immediately above and below the injection site and that may cross one or both joints or involve the entire limb where the vaccine was administered. The reaction is often painless. It is commonly (2-6%) seen in children receiving the 4th or 5th dose of DTaP containing vaccine and has also been reported after non-live influenza vaccination. For children who have had an episode of ELS, repeat episodes with the next dose of vaccine are very common (>10%). However, ELS resolves spontaneously within a few days, is not associated with any other complications, and repeat episodes are generally of less or the same intensity as the first episode.
#### Syncope
There are no contraindications or precautions associated with a history of syncope (fainting) after a previous immunization. The likelihood of fainting can be reduced by measures that lower stress in those awaiting immunization, such as short waiting times, comfortable room temperature, preparation of vaccines out of view of recipients, and privacy during the procedure. People should be immunized while seated or lying down.
For more information, refer to [Anaphylaxis and other Acute Reactions following Vaccination](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html).
### Allergies
A history of allergies is one of the most common concerns that people have about receiving vaccines. There are many types of allergic reactions and it is important to differentiate among them when considering implications for immunization.
Allergic reactions can be either immediate or delayed. Anaphylaxis is a serious, potentially life-threatening allergic reaction to foreign antigens; it has been causally associated with vaccines with an estimated frequency of 1.3 episodes per million doses of vaccine administered. In anaphylaxis, signs and symptoms have a sudden onset and progress rapidly over several minutes and involves two or more body systems. This immediate hypersensitivity reaction is IgE mediated (Type 1) and usually occurs within minutes up to 4 hours after injection; most within 2 hours.
The mechanisms of delayed reactions to vaccines are not fully understood. These may appear several hours to days after immunization. These reactions include an Arthus-type or Type 3 reaction (a local vasculitis due to deposition of IgG-based immune complexes in dermal blood vessels), a cell-mediated, delayed hypersensitivity or Type 4 reaction, or other unknown mechanisms.
On close questioning, it may become evident that people think they have an allergy to a vaccine or vaccine component but it is not a true allergy. People can be reassured that it is highly unlikely that they are allergic to a vaccine or vaccine component if they have a delayed, localized reaction.
People with a suspected moderate to severe hypersensitivity reaction, should seek expert advice. Suspected hypersensitivity should not be an ongoing reason to not administer vaccine. It should be investigated by an expert to clarify whether the person may proceed with vaccination or not. For more information, refer to [Anaphylaxis and other Acute Reactions following Vaccination](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html).
#### Allergy to a vaccine component or its container
Vaccine is contraindicated in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine (with the exception of [egg allergy](https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html#egg)) or its container (e.g., latex). Assessment by an allergist is warranted if further vaccine doses are needed. There is general evidence that some individuals with proven immediate or anaphylactic hypersensitivity to vaccine component(s) or with immediate allergic reactions to vaccines can safely receive a subsequent dose of the same vaccine with low risk of a systemic reaction under the supervision of an allergist. For guidance on specific vaccine(s), consult the relevant [vaccine-specific chapter](https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4.
Precaution is warranted in situations of suspected hypersensitivity or non-anaphylactic allergy to a vaccine or its components. Investigation is indicated which may involve immunization in a controlled setting. Consultation with an expert may be advised. For guidance on specific vaccine(s), consult the relevant [vaccine-specific chapter](https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4.
People may report an allergy to a number of vaccine components including:
* Gelatin - Patients with a history of anaphylaxis to gelatin need to be assessed by skin testing to gelatin before vaccine with gelatin component is given. Most gelatin allergies are non-anaphylactic.
* Latex - Anaphylactic allergy to latex is very rare but if confirmed would pose a contraindication to the use of vaccines that come in vials with latex stoppers or that include syringes with latex components. For non-anaphylactic latex allergies (e.g., history of contact dermatitis to latex gloves), vaccines supplied in vials or syringes that contain dry natural rubber or natural rubber latex may be given.
* Neomycin - Neomycin allergy is most often a contact dermatitis (i.e., a delayed hypersensitivity reaction) which is not a contraindication for administration of vaccines containing neomycin.
* Thimerosal - Even if there is a documented history of a delayed hypersensitivity reaction to thimerosal (such as a large local reaction or contact dermatitis), immunization with thimerosal-containing vaccines can proceed. In the rare instance of individuals with proven delayed hypersensitivity to thimerosal, they should be advised that long-lasting local or systemic cutaneous reactions can occur. They should report any reaction of concern following immunization so that it can be managed appropriately.
For a list of potential allergens, refer to [Contents of Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1.
#### Egg allergy
Egg allergy is one of the most common food allergies of childhood, with a prevalence of approximately 2% in children. It is often associated with eczema in infants and asthma in young children. However, allergic diseases are not a contraindication to immunization with egg protein-containing vaccine.
As most children outgrow their egg allergy, the prevalence of egg allergy in adulthood is lower and is estimated at 0.7%. The most common egg allergy is to egg white. Anaphylaxis to egg is possible.
In Canada, there are several vaccines manufactured by processes involving hens' eggs or their derivatives, such as chick cell cultures. This manufacturing process may result in the following vaccines containing trace amounts of residual egg and chicken protein:
* measles-mumps-rubella (MMR) vaccines
* measles-mumps-rubella-varicella (MMRV) vaccines
* influenza vaccines grown in eggs or chick cell cultures
* RABAVERT® rabies vaccine
* yellow fever (YF) vaccine
* Imvamune® Smallpox Vaccine
Previous concerns about immunizing egg-allergic individuals with vaccines that contain egg protein have been allayed by several studies resulting in clear changes to expert recommendations for some, but not all, of the above vaccines. A known egg allergy is not a contraindication to MMR, MMRV, Imvamune® or influenza vaccines. Refer to [vaccine-specific chapters](https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
#### Measles and mumps-containing vaccine
**MMR or MMRV vaccine can be administered in the routine manner to people who have a history of anaphylactic hypersensitivity to egg.** Numerous studies of egg-allergic subjects have shown that there is no increased risk of allergic reaction to MMR vaccine in those with egg allergy. The trace amount of egg protein in both MMR and MMRV vaccines are insufficient to cause an allergic reaction in egg-allergic individuals. Skin testing is not recommended prior to vaccination as it does not predict reaction to the vaccine. Hypersensitivity reactions that do occur following MMR and MMRV vaccine are usually due to other components of the vaccine, such as gelatin or neomycin.
#### Influenza vaccine
**Studies have clearly demonstrated that egg-allergic persons can receive influenza vaccine. All egg-allergic individuals may be vaccinated against influenza using any of the vaccines authorized for use in Canada.** Although the egg albumin (egg protein) content in influenza vaccines manufactured in eggs may vary from year to year, vaccines marketed in Canada are approved with a maximum allowable egg albumin content that is associated with low risk of adverse events.
The full recommended dose can be used and there is no need for a prior influenza vaccine skin test irrespective of a past severe reaction to egg. The vaccine may be given in any setting where vaccines are routinely administered. Refer to the Additional Vaccine Safety Considerations in the [Statement on Seasonal Influenza Vaccine for 2018-2019](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2018-2019.html#4.4) for safety data supporting this recommendation for inactivated influenza vaccine (IIV) and LAIV.
#### Imvamune® vaccine
Imvamune® vaccine is prepared from virus grown in chicken embryo fibroblast cells. However, the risk associated with the trace amounts contained in the vaccine is thought to be low. The full recommended dose can be used and there is no need for a prior vaccine skin test irrespective of a past severe reaction to egg. The vaccine may be given in any setting where vaccines are routinely administered. Prolonged observation (30 minutes) may be considered.
#### Rabies vaccine
RABAVERT® rabies vaccine is grown in chick embryo cell culture. Imovax® rabies vaccine is manufactured using human diploid cell cultures and therefore egg protein contamination is not an issue. **For pre-exposure vaccination, Imovax® rabies vaccine should be given to persons with a history of hypersensitivity reactions to egg or egg products** as a precautionary measure. For post-exposure prophylaxis, the use of Imovax® vaccine is preferred for persons with a history of hypersensitivity to egg. If Imovax® vaccine is not available, RABAVERT® vaccine should be administered with strict medical monitoring and facilities for emergency treatment of anaphylactic reactions readily available.
#### Yellow fever vaccine
Yellow fever (YF) vaccine is prepared from virus grown in chick embryos and is the vaccine most likely to contain sufficient amounts of egg or chicken proteins to cause an allergic reaction in egg-allergic or chicken-allergic individuals. There have been several reports of anaphylactic reactions to YF vaccine in egg-allergic or chicken-allergic individuals; therefore, **Yellow fever vaccine should not be routinely administered to egg-allergic or chicken-allergic individuals.** Referral of egg-allergic or chicken-allergic individuals to an allergy specialist is recommended, as YF vaccination may be possible after careful evaluation, skin testing and graded challenge or desensitization.
#### Individuals should be asked about allergies to egg or chicken prior to vaccination with Yellow fever or RABAVERT® rabies vaccines.
### Concurrent or recent medication including biologics
#### Antibiotic therapy
Antibiotic therapy does not interfere with response to non-live vaccines or most live vaccines with the following exceptions:
* The Typh-O vaccine series should be finished at least 3 days before commencing, or initiated at least 3 days after completing, treatment with sulphonamides or other antibiotics active against *S. typhi*, or antimalarials. Exceptions include chloroquine, mefloquine and atovaquone/proguanil (Malarone®), as these antimalarials do not affect the immune response to Typh-O vaccine and can be administered at the same time as, or at any interval before or after Typh-O vaccine.
* Bacille Calmette-Guérin (BCG) vaccine should not be administered to individuals receiving drugs with anti-tuberculous activity, including fluoroquinolones.
#### Anticoagulation
Individuals receiving long-term anticoagulation with either warfarin or heparin are not considered to be at higher risk of bleeding complications following immunization and may be immunized through either the intramuscular or subcutaneous route (as recommended for the vaccine product) without discontinuation of anticoagulation therapy. For intramuscular injection, use a small gauge needle (23 gauge or smaller) and apply firm pressure to the injection site for ≥ 2 minutes. There is a paucity of evidence on whether there is an increased risk of bleeding complications following immunization with the other types of anticoagulants, such as antiplatelet agents, but there is no reason to believe that persons receiving these anticoagulants need to be treated any differently from those receiving other anticoagulants.
#### Antiviral therapy
Antiviral therapy does not interfere with response to non-live vaccines or most live vaccines with the following exceptions:
* Varicella vaccine and live herpes zoster (LZV) vaccine may have reduced effectiveness if given concurrently with antivirals active against varicella zoster virus (such as acyclovir, valacyclovir, famciclovir). People taking long-term antiviral therapy should discontinue these drugs, if possible, from at least 24 hours before administration of varicella or LZV vaccine and should not restart antiviral therapy until 14 days after vaccination.
* LAIV should not be administered until 48 hours after antiviral agents active against influenza (e.g., oseltamivir) are stopped, and antiviral agents should not be administered until at least 14 days after receipt of LAIV unless medically indicated. If antiviral agents are administered within this time frame (from 48 hours before to 14 days after LAIV), revaccination should take place at least 48 hours after the antivirals are stopped.
#### Recent administration of blood products containing antibodies
Passive immunization with human immunoglobulin or receipt of most blood products can interfere with the immune response to MMR, MMRV and univalent varicella vaccines. Measles-containing or varicella vaccines should be given at least 14 days prior to administration of an immunoglobulin preparation or blood product, or delayed until the antibodies in the immunoglobulin preparation or blood product have degraded. Respiratory syncytial virus monoclonal antibody (RSVAb) does not interfere with live vaccines because RSVAb contains only antibody to respiratory syncytial virus. For more information, refer to Table 1 in [Blood Products, Human Immunoglobulin and Timing of Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) in Part 1.
A risk-benefit assessment is needed for post-partum women who have received Rh immunoglobulin (RhIg) and require MMR or varicella vaccine. For more information, refer to [Blood Products, Human Immunoglobulin and Timing of Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) in Part 1.
In adults with pre-existing antibody to varicella-zoster virus (VZV), in theory, administration of immunoglobulin should not interfere with the LZV response. For this reason, some experts do not consider recent administration of Ig or blood products as a reason to delay the administration of LZV. LZV should be considered only in cases where the recombinant zoster vaccine is contraindicated, unavailable or inaccessible.
#### Salicylates
While it is generally safe to be immunized when taking salicylates (acetylsalicylic acid, aspirin, or ASA) there are some exceptions:
* LAIV is contraindicated in children and adolescents (2-17 years of age) currently receiving salicylates (e.g., ongoing treatment with aspirin-containing therapy) because of the association of Reye's syndrome with ASA and wild-type influenza infection. Non-live influenza vaccine should be used instead. ASA-containing products should be delayed for 4 weeks after receipt of LAIV in children aged 2 - 17 years, unless a risk assessment deems that the benefits outweigh the potential risks for the individual (e.g., treatment of Kawasaki disease).
* Varicella-containing vaccine manufacturers recommend avoidance of salicylate therapy for 6 weeks after varicella immunization because of an association between wild-type varicella, salicylate therapy and Reye's syndrome. Health care providers should weigh the theoretical risks associated with varicella vaccine against the known risks associated with wild-type varicella. Because adverse events have not been reported with the use of salicylates after varicella immunization, people with conditions requiring chronic salicylate therapy should be considered for immunization, with close subsequent monitoring.
Refer to [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional information.
### Other Situations, Underlying Condition or Illness
Chronic conditions with no contraindications or precautions are not included in the list below. However, it is important to ensure that individuals with chronic conditions are immunized appropriately since they are often at higher risk of complications due to vaccine-preventable diseases. For detailed recommendations on the use of live and non-live vaccines in individuals with asplenia or hyposplenia, endocrine/metabolic disease, heart disease, non-malignant hematologic disorders, inflammatory diseases, renal disease and dialysis, liver disease, lung disease and neurologic disorders, refer to [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3.
#### Asthma, severe
Live attenuated influenza vaccine (LAIV) is contraindicated in individuals with severe asthma (defined as currently on oral or high dose inhaled glucocorticosteroids or active wheezing) or those with medically-attended wheezing in the 7 days prior to vaccination. LAIV can be used in stable, non-severe asthmatics.
#### Bleeding disorders
People with bleeding disorders should receive all recommended immunizations according to routine schedules when appropriate safety measures have been taken. Control of bleeding disorders should be optimized prior to immunization. Vaccine providers should ensure that there are no symptoms or signs compatible with an undiagnosed bleeding disorder (e.g., unexplained bruising). If such indicators are present before immunization, a diagnosis should be established before commencing immunization. When administering a parenteral vaccine, consider the use of a small gauge needle (23 gauge or smaller) and apply firm pressure for ≥ 2 minutes after the immunization.
For more information, refer to [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3.
#### Congenital malformation of gastrointestinal tract or history of intussusception
Rotavirus vaccine is contraindicated in infants with a history of intussusception or uncorrected congenital malformation of the gastrointestinal tract that would predispose for intussusception.
#### Immunocompromised persons
For contraindications and precautions regarding immunization of individuals with primary immunodeficiencies, hematopoietic stem cell transplant candidates/recipients, solid organ transplant candidates/recipients and HIV-infected persons, refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3. Contraindications and precautions are also provided for individuals slated for, or on, immunosuppressive therapy including infants of mothers treated during pregnancy.
#### Positive Tuberculin skin test
BCG vaccine is contraindicated for individuals with a positive tuberculin skin test, although immunization of tuberculin reactors has occurred frequently without complications.
#### Pregnancy and Breastfeeding
For contraindications and precautions regarding immunization during pregnancy and breastfeeding, refer to [Immunization in Pregnancy and Breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3.
#### Preterm infants
Healthy preterm infants weighing 1,500 grams or more at birth generally tolerate immunizations well, with rates of adverse events similar to the low rates of full-term infants. Hospitalized premature infants should have continuous cardiac and respiratory monitoring for 48 hours after their first immunization. For more information, refer to [Immunization of Infants Born Prematurely](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-5-immunization-infants-born-prematurely.html) in Part 3.
#### Skin Disorders
Vaccines are generally safe for people with skin disorders. For comfort, administer vaccine into a non-affected area. Some smallpox vaccines and BCG are exceptions to this. Imvamune® vaccine can be safely administered in people with eczema (atopic dermatitis). BCG vaccine is contraindicated when there is extensive skin disease or burns.
For more information, refer to the [Smallpox Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-21-smallpox-vaccine.html) and [Bacille Calmette-Guerin Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-2-bacille-calmette-guerin-vaccine.html) chapters in Part 4.
#### Thymus disease
For individuals with a past history of thymus disease with abnormal immune function (e.g., thymoma, thymectomy, myasthenia gravis), Yellow fever vaccine is contraindicated because of an increased risk of viscerotropic disease.
Close Contacts of Immunocompromised or Pregnant Individuals
-----------------------------------------------------------
Vaccination provides protection at both an individual and population level. Some people may have conditions that preclude vaccination, but they can be protected by having the people around them vaccinated. Immunization of household contacts of immunosuppressed persons, pregnant women, and neonates provides important protection against transmission of disease in the household.
Up-to-date routine immunizations are recommended for household contacts of pregnant women, immunocompromised persons, and neonates with the following exceptions:
* Non-live influenza vaccine is preferred over LAIV for those in close contact with severely immunocompromised persons.
* Oral polio vaccine (OPV): OPV is not used in Canada but individuals may receive it in other countries. Household contacts who are vaccinated with OPV should not have contact with immunocompromised persons for six weeks after receipt of OPV.
* Following MMRV, varicella or LVZ vaccines, if a vaccine recipient develops a varicella-like rash, the rash should be covered and the vaccinee should avoid direct contact with the immunocompromised person for the duration of the rash.
* First-generation smallpox vaccine should not be administered to household contacts of an immunocompromised person in a non-emergency situation.
* First-generation smallpox vaccine: Vaccinees with household and other close contacts with active eczema or a history of eczema or other exfoliative skin conditions, immunosuppressive disorders, or with close contact with infants or pregnant women, should take special precautions in order to prevent viral transfer to these contacts.
Table 1: Contraindications and precautions associated with conditions that may be present in vaccine candidates
| Condition | Contraindication | Precaution | Comments |
| --- | --- | --- | --- |
| Acute illness |
| Gastrointestinal illness | None | **Oral typhoid, cholera and travellers' diarrhea vaccines**: postpone until illness has resolved
**Rotavirus vaccine**: if moderate to severe defer until condition improves unless deferral results in scheduling first dose beyond the recommended age limit. | Refer to the [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for more information. |
| Inflammatory eye disease treated with steroids | None | **First-generation smallpox vaccine**: in a non-outbreak situation defer until condition resolves or course of steroids completed. | Refer to [Smallpox Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-21-smallpox-vaccine.html) in Part 4. |
| Measles | None | **Varicella-containing vaccine**: delay vaccination for 6 weeks (a minimum of 4 weeks delay can be applied if needed). | Refer to [Varicella Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-24-varicella-chickenpox-vaccine.html) in Part 4. |
| Tuberculosis, active, untreated | **MMR, MMRV, univalent varicella, live herpes zoster vaccines** | None | Refer to the [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for more information. |
| Medically attended wheezing in the 7 days prior to vaccination | **LAIV** | None | Refer to [Influenza Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html) in Part 4. |
| Other moderate to severe acute illness | None | Consider risks and benefits. Expert opinion is recommended in such situations. | Refer to the [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for more information. |
| Minor illness with or without fever | None | **LAIV:** if significant nasal congestion is present that might impede delivery of LAIV to the nasopharyngeal mucosa non-live influenza vaccine can be administered instead. | Refer to [Influenza Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html) in Part 4. |
| Adverse events following previous immunization |
| Anaphylaxis | Receipt of the same vaccine is often contraindicated although exceptions may apply (i.e., Imvamune® and mRNA COVID-19 vaccines). Consult an allergist if further vaccine doses are needed. | None | Refer to [Anaphylaxis and Other Acute Reactions Following Vaccination](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html). |
| Febrile seizure | None | None | Refer to [Measles Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html) in Part 4. |
| GBS within 6 weeks of receiving influenza vaccine or tetanus toxoid | Generally contraindicated to receive the same vaccine | If there is a history of both *Campylobacter* infection and immunization within 6 weeks before the onset of GBS, consultation with an infectious disease specialist is advised.
**Influenza vaccine**: may need to balance the risk against that of GBS associated with influenza infection.[Footnote 1](#fn1) | Refer to [Tetanus Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html) and [Influenza Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html) in Part 4. |
| Hypotonic-hyporesponsive episode (HHE) | None | None | Refer to [Pertussis Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-15-pertussis-vaccine.html) in Part 4. |
| Oculorespiratory syndrome (ORS) | None | **Influenza vaccine**: need expert review if ORS episode involved lower respiratory tract. | Refer to [Influenza Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html) in Part 4. |
| Persistent crying | None | None | None |
| Extensive limb swelling (ELS) | None | None | Refer to [Tetanus Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html) in Part 4. |
| Arthus-type injection site reaction | None | **Tetanus-containing vaccines:** no further routine doses for at least 10 years. | Refer to [Tetanus Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html) in Part 4. |
| Syncope (fainting) | None | None but reduce likelihood by taking measures to lower stress while awaiting immunization and ensure individual is seated, or if at high risk, lying down during immunization. | Refer to [Anaphylaxis and Other Acute Reactions Following Vaccination](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html). |
| **Allergies** |
| Egg allergy - anaphylactic or other | None | **Rabies vaccination**:
Pre-exposure: use Imovax®
Post-exposure: Imovax® preferred but if unavailable administer RABAVERT® ensuring strict medical monitoring with readily available emergency treatment for anaphylaxis
**YF vaccine**: should not be routinely given to egg- or chicken-allergic individuals. If required, allergy specialist referral recommended. | Refer to [Rabies Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-18-rabies-vaccine.html) and [Yellow Fever Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-25-yellow-fever-vaccine.html) in Part 4. |
| Anaphylactic hypersensitivity to a specific component of the vaccine (other than egg) or its container (e.g., latex) | History of a confirmed reaction to a specific component of the vaccine or its container.
Exceptions may apply (i.e., Imvamune® and mRNA COVID-19 vaccines).
Refer to the [vaccine-specific chapters](https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for more information. | History of a suspected reaction; consultation with an expert is advised.
Exceptions may apply (i.e., Imvamune® and mRNA COVID-19 vaccines).
Refer to the [vaccine-specific chapters](https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for more information. | Refer to [Anaphylaxis and other Acute Reactions following Vaccination](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html).
Refer to [Contents of Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1. |
| Thimerosal - delayed hypersensitivity | None | Advise that long-lasting local or systemic cutaneous reactions can occur and should report any such reaction so appropriate management can be given. |
| Concurrent or recent medication including biologics |
| Antibiotic therapy | None | **Live oral typhoid vaccine**: delay until at least 3 days after last dose of antibiotic active against *Salmonella typhi*.
**BCG**: do not give while individuals are on anti-tuberculous drugs including fluoroquinolones. | Refer to [Typhoid Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-23-typhoid-vaccine.html) in Part 4.
Refer to [Bacille Calmette-Guérin Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-2-bacille-calmette-guerin-vaccine.html) in Part 4. |
| Antiviral therapy | None | **LAIV, varicella and live zoster vaccines (LZV)**: consider timing of administration if antiviral drug active against vaccine strain. | Refer to [Influenza Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html), [Herpes Zoster Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-8-herpes-zoster-(shingles)-vaccine.html) and [Varicella (Chickenpox) Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-24-varicella-chickenpox-vaccine.html) in Part 4. |
| Anti-coagulation | None | Intramuscular injections: use a 23 gauge or smaller needle; apply firm pressure to the injection site for ≥ 2 minutes. | Refer to [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3. |
| Blood products containing antibodies | None | **MMR, MMRV and univalent varicella vaccines**: should be given at least 14 days prior to blood product. If product already given recommended interval between blood product and these vaccines are vaccine and blood product specific
Risk benefit assessment is needed for post-partum women who have received Rh immunoglobulin (RhIg) and require MMR or varicella vaccine. | Refer to [Blood Products, Human Immunoglobulin and Timing of Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) in Part 1. Refer to [Immunization in Pregnancy and Breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3. |
| Salicylates1. Chronic
2. Intermittent
| 1. **LAIV**
2. None | 1. **Varicella-containing vaccine**: can be considered with close monitoring
2. Children and adolescents should avoid salicylates following [Footnote 2](#fn2):* **LAIV** for 4 weeks
* **Varicella-containing vaccine** for 6 weeks
Unless a risk assessment deems that the benefits outweigh the potential risks for the individual. | Refer to [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3.
Refer to [Influenza Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html) and [Varicella (Chickenpox) Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-24-varicella-chickenpox-vaccine.html) in Part 4. |
| Other situations, underlying condition or illness in vaccinee |
| Asthma, severe[Footnote 3](#fn3) | **LAIV** | None | Refer to [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3.
Refer to [Influenza Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html) in Part 4. |
| Bleeding disorder | None | Ensure optimal control of bleeding prior to immunization; use a 23 gauge or smaller needle and apply pressure for ≥ 2 minutes at the injection site after immunization. | Refer to [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3. |
| Congenital malformation of gastro-intestinal tract, uncorrected or history of intussusception | **Rotavirus vaccine** due to increased risk of intussusception | None | Refer to [Rotavirus Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-19-rotavirus-vaccine.html) in Part 4. |
| Immuno-compromised persons | **Live vaccines** contraindicated if severely immunocompromised. | Can give all non-live vaccines but should consider ability to mount an immune response to vaccine
For milder degrees of immunosuppression may consider live vaccines. | Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) |
| Positive tuberculin test | **BCG** | None | Refer to [Bacille Calmette-Guérin Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-2-bacille-calmette-guerin-vaccine.html) in Part 4. |
| Preterm infants | None | **Hepatitis B vaccine** for infants with a birth weight <1,500 grams
If hospitalized, continuous respiratory and cardiac monitoring for 48 hours after 1st immunization. | Refer to [Hepatitis B Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4. |
| Skin disorder | **First and second generation smallpox vaccines are** contraindicated in those with eczema (atopic dermatitis) in non-outbreak situation; Imvamune® (third generation) is not contraindicated and can be administered safely
**BCG vaccine** is contraindicated if extensive skin disease or burns | For comfort, administer vaccine into non-affected area. | Refer to [Bacille Calmette-Guérin Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-2-bacille-calmette-guerin-vaccine.html) and [Smallpox Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-21-smallpox-vaccine.html) in Part 4. |
| Thymus disease | **YF vaccine** is contraindicated in persons with a history of thymus disease with abnormal immune function (e.g., thymoma, thymectomy, myasthenia gravis)[Footnote 4](#fn4) | | Refer to [Yellow Fever Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-25-yellow-fever-vaccine.html) in Part 4. |
| Those in Close Contact of the Following Individuals |
| Immuno-compromised (severe) persons | **First-generation smallpox vaccine** is contraindicated in non-emergency situations
**OPV**[Footnote 5](#fn5) | **Influenza vaccine:** use non-live influenza vaccine rather than LAIV. LAIV recipients should avoid close contact for at least two weeks after immunization
**OPV:** avoid direct contact with immunocompromised person(s) for 6 weeks after receipt of OPV in another country
**Varicella vaccine recipients with varicella-like rash:** ensure that rash is covered and avoid direct contact with the immunocompromised person for the duration of the rash
**First-generation smallpox vaccine**: If required in an emergency situation must ensure isolation of vaccinee from affected household contacts until scab falls off. | Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3.
Refer to the [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for more information. |
| **Pregnant women, infants, eczema or other exfoliative skin condition** | | **First-generation smallpox vaccine**: Defer if non-outbreak situation. If required in an emergency situation must ensure isolation of vaccinee from affected household contacts until scab falls off. | Refer to [Smallpox Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-21-smallpox-vaccine.html) in Part 4. |
|
Footnote 1
Those who develop GBS outside the 6 week interval may receive subsequent doses of the vaccine.
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
Salicylates are avoided in these instances to decrease the risk of Reye's syndrome.
[Return to footnote 2 referrer](#fn2-rf)
Footnote 3
Severe asthma: defined as currently on oral or high dose inhaled glucocorticosteroids or active wheezing.
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
Because of an association between a history of thymus disease and acute viscerotropic disease.
[Return to footnote 4 referrer](#fn4-rf)
Footnote 5
Oral polio vaccine is neither recommended nor available in Canada.
[Return to footnote 5 referrer](#fn5-rf)
**Table 1 - Abbreviations**
BCG
Bacille Calmette-Guérin vaccine
ELS
extensive limb swelling
GBS
Guillain-Barré syndrome
HHE
hypotonic-hyporesponsive episode
HPV
human papillomavirus vaccine
Ig
immunoglobulin
LAIV
live attenuated influenza vaccine
LZV
live zoster vaccine
MMR
measles-mumps-rubella vaccine
MMRV
measles-mumps-rubella-varicella vaccine
OPV
oral polio vaccine
ORS
oculorespiratory syndrome
RV
rotavirus vaccine
Tdap
tetanus toxoid, diphtheria toxoid (reduced), acellular pertussis (reduced) vaccine
VZV
varicella-zoster virus
YF
yellow fever
|
Chapter revision process
------------------------
The CIG Part 2 Working Group members reviewed the chapter to ensure content was up-to-date with clinical practice and evidence based. The revised guidance on the pressure time post administration of a parenteral vaccine to persons with a bleeding disorder or on an anticoagulant were based on a review of the literature, a review of guidance provided by other National Immunization Technical Advisory Groups (NITAGs) and expert opinion. For persons with a history of thymus disease with abnormal immune function, guidance regarding YF vaccine administration was changed from "generally not recommended" to "contraindicated" following a literature review. Updated guidance on contraindications and precautions associated with allergies is based on the guidance on Imvamune vaccine in those with allergic/immunocompromising conditions from the Canadian Society of Allergy and Clinical Immunology (CSACI) as of November 1, 2022.
Acknowledgements
----------------
The Public Health Agency of Canada (PHAC) would like to acknowledge Part 2 Working Group members J Bettinger (Working Group Chair), N Dayneka, S Deeks, R Warrington, K Top, B Law, B Seifert, J Gallivan, D Moore, R Pless, D Danoff, G Lacuesta, and D Fell for their contributions to the revision of this chapter. PHAC participants on the Part 2 Working Group include C Jensen, J Zafack, O Baclic, E Abrams and R Krishnan.
Selected references
-------------------
* Canadian Society of Allergy and Clinical Immunology. IMVAMUNE (Monkeypox/Smallpox) vaccine in those with allergic/immunocompromising conditions: Guidance for allergists/immunologists from the CSACI. Accessed November 2022 at: https://canadiansocietyofallergyandclinicalimmunology.wildapricot.org/resources/CSACI%20Imvamune%20Statement.pdf
* Centers for Disease Control and Prevention. *Chart of Contraindications and Precautions to Commonly Used Vaccines*. Accessed February 2017 at: http://www.cdc.gov/vaccines/hcp/admin/contraindications-vacc.html
* Centers for Disease Control and Prevention. *The Pink Book: Epidemiology and Prevention of Vaccine Preventable Diseases*. 13th ed.; 2015.Accessed February 2017 at: http://www.cdc.gov/vaccines/pubs/pinkbook/genrec.html
* Clarke AE, Elliott SJ, St. Pierre Y, Soller L. La Vieille S, Ben-Shoshan M. Temporal trends in prevalence of food allergy in Canada. J Allergy Clin Immunol Pract 2019: 8(4): 1428-1430.e5.
* Committee to Advise on Tropical Medicine and Travel. Statement for yellow fever vaccine. Can Comm Dis Rep 2013;39(ACS-2). Accessed December 2019 at: https://www.canada.ca/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2013-39/statement-travellers-yellow-fever.html
* Crawford NW, McMinn A, Royle J, Lazzaro T, Danchin M, Perrett KP, Buttery J, Elia S, Orr K, Wood N. Recurrence risk of a hypotonic hyporesponsive episode in two Australian specialist immunisation clinics. Vaccine 36 (2018): 6152-6157.
* Dreskin et al Interantional Consensus (ICON): allergic reactions to vaccines World Allergy Organization J (2016) 9:32.
* Greenhawt M et al. The risk of allergic reaction to SARS-CoV-2 vaccines and recommended evaluation and management: A systematic review, meta-analysis, GRADE assessment, and international consensus approach. J Allergy Clin Immunol Pract 2021;9: 3546-3567.
* Kelso JM, Greenhawt M, Li JT. Task force report: Adverse reactions to vaccines practice parameter 2012 update. J Allergy Clin Immunol. 2012; 130 (1): 25-43.
* Kessel A et al. Safe administration of the Pfizer-BioNtTech COVID-19 vaccine following an immediate reaction to the first dose. Allergy 2021;76: 3538-3540 (PMID: 34370884).
* Khakoo GA, Lack G. *Recommendations for using MMR vaccine in children allergic to eggs.* Br Med J 2000;320:929-32.
* Krantz MS et al. Safety evaluation of the second dose of messenger RNA COVID-19 vaccines in patients with immediate reactions to the first dose. JAMA Intern Med 2021;181: 1530-1533 (PMID:34309623).
* Krantz MS et al. Anaphylaxis to the first dose of mRNA SARS-CoV-2 vaccines: Don't give up on the second dose! Allergy 2021;76: 2916-2920 (PMID:34028041).
* Kwong JC, Vasa PP, Campitelli MA, et al. Risk of Guillain-Barré syndrome after seasonal influenza vaccination and influenza health-care encounters: a self-controlled study. Lancet Infect Dis. 2013;13(9):769-76.
* National Advisory Committee on Immunization. *Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2018-2019.* Accessed December 2019 at: https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2018-2019.html
* Top KA, Billard M-N, Gariepy M-C, Rouleau I, Pernica JM, Pham-Huy A, Quach C, Tran D, Vaudry W, Dobson S, Boucher FD, Carignan A, Jadavji T, Mconnell A, McNeil SA, Halperin SA, DeSerres G. Immunizing patients with adverse events after immunization and potential contraindications to immunization. Pediatric Infectious Disease Journal. 2016;35:e384-e391.
* Zafack JG, DeSerres G, Kiely M et al. Risk of recurrence of adverse events following immunization: a systematic review. Pediatrics 2017; 140(3): e320163707.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-02-24
| None | None |
545522435ae7b04bd5aecfac07a91f3fd9a83d3a | cma | Immunization of persons with chronic diseases: Canadian Immunization Guide | Immunization of persons with chronic diseases: Canadian Immunization Guide
# Introduction
Chronic diseases may increase a person's risk of infection, or increase a person's risk of more severe disease should infection occur. There is also an increased risk of nosocomial exposure to vaccine-preventable diseases due the increased likelihood of prolonged hospitalization and frequent outpatient visits associated with chronic disease. Therefore, it is important that people with chronic diseases who are immunocompetent be immunized with both live and non-live (e.g., inactivated or recombinant) vaccines, according to routine immunization schedules. Vaccines may be less immunogenic in this population and additional vaccines, additional doses, or higher dosages of vaccines may be required to provide adequate protection.
Ideally, vaccination is best accomplished early in the disease when the response is likely to be similar to other persons of a similar age with no chronic medical condition. If a disease progresses and immunosuppressive therapy is required, vaccine requirements and recommendations may change.
In general, individuals with chronic disease are at higher risk of invasive pneumococcal disease, influenza and influenza-related complications, and should be immunized using the recommended vaccine and schedule.
COVID-19 vaccine is currently recommended for all individuals 6 months of age and older, including those with chronic conditions. This vaccine has not yet been added to Table 1, or to the text for chronic conditions other than autoimmune disease, pending recommendations for post-pandemic use.
For information about vaccination of people with immunodeficiencies, who are immunosuppressed or have HIV infection, refer to in Part 3.
# Chronic diseases
## Asplenia or hyposplenia
Asplenic or hyposplenic people have absent or defective splenic function. This condition can occur as a result of congenital absence of the spleen, surgical removal of the spleen, or medical conditions that result in poor or absent splenic function, such as sickle cell disease or thalassemia major, among others. All people, regardless of age, who have absent or defective splenic function, are at increased risk of fulminant bacteremia, which is associated with a high mortality rate. Risk is highest in the first 2 years following splenectomy but remains elevated for life.
Careful attention should be paid to immunization status when elective surgical splenectomy is planned so that all of the necessary vaccines are administered at least 2 weeks before surgery. In the case of an emergency splenectomy, vaccines are best given 2 weeks after the splenectomy for optimal vaccine responses. If a person is discharged earlier and there is a concern that she or he might not return, vaccines should be given before discharge.
Persons with asplenia or hyposplenia should receive all routine vaccinations, including annual influenza vaccine. In addition, particular attention should be paid to ensuring that all asplenic or hyposplenic individuals receive *Haemophilus influenzae- type b (Hib) regardless of age or previous immunization history, quadrivalent conjugate meningococcal vaccine, serogroup B meningococcal vaccine and both pneumococcal conjugate and polysaccharide vaccines, as these individuals are highly susceptible to infection with encapsulated bacteria. Hepatitis B vaccines are indicated for those who require repeat transfusions, such as individuals with sickle cell anemia or thalassemia.
## Autoimmune conditions
Autoimmune conditions (referred to in former versions of the CIG as inflammatory diseases) encompass a broad category of related diseases in which an individual's immune system attacks his or her own cells. The spectrum of autoimmune conditions is diverse. The relative degree of autoimmunity in individuals with autoimmune conditions is variable depending on the underlying condition, the severity and progression of disease, and the use of medications that impact immune function. Common autoimmune conditions include systemic inflammatory diseases such as systemic lupus erythematosus, systemic vasculitides, rheumatoid arthritis and juvenile arthritis; as well as organ-specific inflammatory conditions such as Crohn's disease and ulcerative colitis, Graves' disease, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, Goodpasture's syndrome, pemphigus vulgaris, psoriasis, idiopathic thrombocytopenic purpura and, autoimmune hemolytic anemia.
Infections are among the most common causes of morbidity, hospitalization and death in individuals with an autoimmune condition. An increased risk of infection and infection-related complications is thought to be due to both an altered immune response associated with the autoimmune condition itself and to the immunosuppressive nature of the treatments required to control the underlying inflammatory condition.
Individuals with autoimmune disease not being treated with immunosuppressive drugs are not considered significantly immunocompromised and can receive routine immunization, including live vaccines. Rheumatic disease modifying agents, such as hydroxychloroquine, sulfasalazine, or auranofin are not generally identified as immunosuppressive, nor are topically-administered non-absorbable formulations of steroids. For children receiving chronic salicylate therapy for autoimmune conditions, inactivated influenza vaccine (IIV) rather than live attenuated influenza vaccine (LAIV) should be used (refer to ).
Individuals with autoimmune conditions should receive, in addition to routine immunization, influenza vaccine annually. Vaccination status should be assessed promptly and routine immunizations updated if needed. Any indicated live vaccines should be given as early as possible, as immunosuppression may be required in the future and live vaccines may then be contraindicated. If immunosuppressive therapy is anticipated in the near future, pneumococcal conjugate and polysaccharide vaccines should be given. Because of immunodeficiencies associated with autoimmune inflammatory disease, some experts recommend giving these vaccines at diagnosis.
COVID-19 infection has been associated with the development of an intense inflammatory response, as well as autoimmune phenomena, in some people, though whether these occur more often in people with autoimmune conditions is unclear. There has been a theoretical concern that inflammation elicited by mRNA vaccines for COVID-19 could exacerbate existing autoimmune diseases, despite the fact that applications of mRNA technology for COVID-19 vaccines have been optimized to reduce this risk through modifications to the RNA and lipid constructs. Participants with autoimmune conditions who were not immunosuppressed were not excluded from clinical trials for mRNA COVID-19 vaccines, but they constituted a very small proportion of trial participants and represented a very narrow spectrum of autoimmune conditions. Data from observational studies in individuals with autoimmune conditions indicate that the frequency and severity of adverse events in this population is comparable to that of individuals without autoimmune conditions and to what was reported in clinical trials. The onset of new autoimmune disease or disease exacerbation following vaccination with mRNA COVID-19 vaccines has been rare or comparable to the background incidence of these events in the general population. NACI recommends that a complete vaccine series with an mRNA COVID-19 vaccine should be offered to individuals in the authorized age group with an autoimmune condition.
For individuals with dermatologic disorders, care should be taken not to administer vaccine into affected areas, as this procedure may exacerbate the condition. Bacille Calmette-Guérin (BCG) vaccine is contraindicated if there is extensive skin disease at or near the site of injection. Live replicating smallpox vaccine is contraindicated in a non-outbreak situation.
For individuals with chronic inflammatory diseases who are being treated with immunosuppressive therapies including biologic response modifiers, refer to in in Part 3.
## Cancer
People with cancer have a higher risk of contracting infectious diseases and a higher risk of developing complications because many cancers and their treatments affect the immune system. Therefore, it is important that children and adults with cancer receive protection from vaccine preventable diseases whenever possible.
Generally, cancer alone, if it is not hematologic, is not sufficient to cause immunosuppression to the extent that an individual cannot receive live vaccines. If chemotherapy is not required, all routine vaccines should be given. Influenza vaccine should be given annually. Other vaccines may be indicated, depending on which organs or systems are affected by the tumour. If chemotherapy is to be given, any immunizations required, as well as annual influenza vaccine, should be completed before beginning chemotherapy whenever possible.
For hematologic cancers or for people on immunosuppressive therapies, refer to in in Part 3.
## Cochlear implants
People who have received a cochlear implant are at increased risk for bacterial meningitis and for otitis media. In addition to all age appropriate vaccinations, people with cochlear implants and those who are receiving cochlear implants should receive annual influenza vaccine, pneumococcal conjugate and polysaccharide vaccines if age less than 18 years, or pneumococcal polysaccharide vaccine if 18 years of age or older, and Hib vaccine if 5 years of age or older regardless of Hib vaccination history.
## Endocrine and metabolic diseases
People with diabetes mellitus have defects in phagocytic and neutrophil function. In addition, they often have complications of diabetes such as cardiovascular, neurovascular, renal and other end-organ dysfunction and are at greater risk of complications from infection. Persons with other metabolic disorders, such as thyroid disorders, or morbid obesity (Body Mass Index of 40 or higher) are at high risk of influenza-related complications.
Routine immunization, including annual influenza vaccine, is recommended for persons with endocrine and metabolic disorders. In addition to routine immunization, people with diabetes should receive pneumococcal conjugate and polysaccharide vaccines if age less than 18 years or pneumococcal polysaccharide vaccine if 18 years of age or older. There is no evidence that vaccination interferes with glycemic control.
There is an association between yellow fever vaccine-associated viscerotropic disease and a history of thymus disease. Yellow fever vaccine is contraindicated in persons with a history of thymus disease associated with abnormal thymus function (e.g., thymoma, thymectomy or myasthenia gravis). If travelling to a yellow fever endemic or epidemic area, expert advice should be sought concerning the risks of exposure to yellow fever, the ability to adhere to mosquito protection measures, and the risk of vaccine-associated disease.
## Heart disease
In individuals with chronic heart disease, viral and bacterial infections may precipitate cardiac decompensation and lead to hospitalization. There is evidence that giving influenza vaccine to those with coronary artery disease has some protective effect on subsequent cardiac events.
People with cardiac disease should receive routine immunization, including annual influenza vaccine, as they are at high risk of influenza-related complications. Individuals with chronic heart disease should also receive pneumococcal conjugate vaccine and polysaccharide vaccine if less than 18 years or pneumococcal polysaccharide vaccine if 18 years of age or older.
Young children with certain chronic cardiac conditions are at high risk of respiratory syncytial virus (RSV) associated hospitalization. The monoclonal antibody preparation, palivizumab, is recommended to protect against severe infection in infants less than 12 months of age with haemodynamically significant congenital heart disease at the onset of the RSV season.
Live replicating smallpox vaccine is contraindicated in a non-outbreak situation for specific cardiac conditions (Table 2).
## Hematologic disorders (non-malignant)
Non-malignant hematologic disorders include different types of chronic anemia and hemoglobinopathy, as well as bleeding disorders. For further discussion on vaccines recommended for people with anemia due to sickle cell disease or other hemoglobinopathies associated with splenic dysfunction, refer to .
Some hematologic disorders require frequent or chronic administration of blood products. Recent administration of blood products may interfere with the antibody response to live vaccines, and receipt of plasma or immunoglobulin may result in false positive antibody tests. Refer to in Part 1 for additional information.
### Anemia and hemoglobinopathy
People with anemia may be at increased risk of complications from vaccine- preventable diseases. In addition to routine immunization, people with chronic anemia or hemoglobinopathy should receive influenza vaccine annually. If there is a need for repeated blood transfusions, hepatitis B vaccine is required. If there is splenic dysfunction, refer to .
### Bleeding disorders
People with bleeding disorders such as hemophilia may differ from the healthy population with respect to the potentially increased risk of infection as a result of exposure to blood products and the risk of hematoma formation from parenteral injections. In addition to routine immunization, people with hemophilia and other clotting factor disorders receiving repeated transfusions of blood or blood products should receive hepatitis B vaccines unless already infected or immune. Pre-immunization serologic testing for hepatitis B should be performed if they have already had repeated exposure to blood products. In addition, those receiving repeated infusions of plasma-derived clotting factors should receive hepatitis A vaccine.
Before beginning immunization of any child, vaccine providers should ensure that there are no symptoms or signs compatible with an undiagnosed bleeding disorder. If such indicators are present, a diagnosis should be established before commencing immunization. For example, in any child who has a history of an intramuscular (IM) hematoma following an IM injection, an undiagnosed bleeding disorder, such as hemophilia, should be considered. If a disorder is present, it should be optimally managed prior to immunization to minimize the risk of bleeding. Hemophiliacs may receive clotting factor concentrates to optimize their clotting factor level before they receive a parenteral vaccine or a passive immunizing agent.
Generally there is no evidence of increased risk of bleeding in those with bleeding disorders following IM versus subcutaneous injections. There is evidence to suggest that IM administration is safe when given with a small gauge needle (23 gauge or smaller) and when firm pressure is applied to the injection site for ≥ 2 minutes. There is also evidence that immunization by the subcutaneous route for vaccine intended for intramuscular administration may be associated with more local reactogenicity and a diminished immune response, compared to the IM route.
Individuals receiving long-term anticoagulation may also be safely immunized through either the IM or subcutaneous route as recommended for a specific vaccine, using the same precautions as for bleeding disorders, without discontinuation of their anticoagulation therapy.
## Kidney disease and patients on dialysis
Bacterial and viral infections are a major cause of morbidity and mortality in people with renal disease or who are undergoing chronic dialysis (hemodialysis or peritoneal dialysis). People with chronic kidney insufficiency and dialysis may have mild defects in T cell function, while in individuals with nephrotic syndrome, urinary loss of antibody may occur. Also, because these persons are also in frequent contact with the health care system, they are at greater risk of hospital-acquired infection from vaccine preventable diseases.
People with chronic renal disease or those who are undergoing dialysis should receive all routine vaccinations, including annual influenza vaccine. In addition to routine immunization, hepatitis B and pneumococcal vaccines (conjugate and polysaccharide vaccines if age less than 18 years, polysaccharide vaccine if 18 years of age or older) are recommended. Those with nephrotic syndrome should receive both the conjugate and the polysaccharide vaccines even if age 18 years or older. Since individuals with impaired renal function may experience a less than optimal response to immunization, higher vaccine doses and re-immunization may be required. Monitoring vaccine titers may be helpful.
For information about kidney transplant candidates and recipients, refer to in in Part 3.
## Liver disease
Chronic liver disease can impact innate and adaptive immune mechanisms. Splenic dysfunction may also occur if the liver disease is severe. Hepatic encephalopathy or chronic alcohol consumption may lead to aspiration pneumonia. Alcoholism is also a risk factor for invasive pneumococcal disease. Newly acquired hepatitis A or hepatitis B in persons who already have chronic liver disease from another cause could lead to more severe disease and rapid hepatic decompensation. Those with ascites have an altered immunoglobulin production and distribution.
People with chronic liver disease should receive all routine immunizations, including annual influenza vaccine, conjugate and polysaccharide pneumococcal vaccine if age less than 18 years or polysaccharide pneumococcal vaccine if age 18 years or older, as well as hepatitis A vaccine and hepatitis B vaccine if not already infected or immune. Vaccination should be completed early in the course of liver disease, as the immune response to vaccine is suboptimal in advanced liver disease. Since individuals with chronic liver disease may experience a less than optimal response to immunization, higher vaccine doses and re-immunization may be required.
## Lung disease
Individuals with chronic lung diseases such as bronchopulmonary dysplasia, cystic fibrosis, asthma or chronic obstructive pulmonary diseases (COPD) are at increased risk of complications of influenza and pneumococcal infection. Those with cystic fibrosis are also at increased risk of complications from varicella infection, which may cause a transient worsening of lung function. Young children with chronic lung disease of prematurity who require ongoing oxygen therapy are at high risk of respiratory syncytial virus (RSV) associated hospitalization. Many individuals with more severe chronic lung disease have bacterial colonization due to poor mucociliary clearance and bronchiectasis, pneumatoceles, or defects in pulmonary macrophage function.
People with chronic lung disorders should receive influenza vaccine annually in addition to other routine immunization. Live attenuated influenza vaccine (LAIV) is contraindicated for persons with current severe asthma (currently on oral or high dose inhaled glucocorticosteroids or active wheezing, or those with medically attended wheezing in the 7 days prior to immunization). In these situations, inactivated influenza vaccine (IIV) should be used. Pneumococcal vaccines are also recommended, including for those with asthma requiring medical care in the preceding 12 months. Conjugate and polysaccharide vaccines should be given if age less than 18 years, and pneumococcal polysaccharide vaccine if 18 years of age or older. The monoclonal antibody preparation, palivizumab, is recommended to protect against severe infection in children less than 24 months of age with chronic lung disease of prematurity who require ongoing oxygen therapy in the six months preceding or during the RSV season.
## Neurologic disorders
Persons with neurological disorders are at increased risk of hospitalization with influenza. Some studies suggest that influenza vaccine may decrease the risk of stroke.
In addition to all routine immunizations, people with neurological or neurodevelopmental conditions should receive annual influenza vaccine (with the exception of anyone who developed Guillain-Barre Syndrome within 6 weeks after a previous dose of influenza vaccine unless another cause was found). Some neurological conditions also predispose to pneumococcal infections. Pneumococcal vaccines are recommended for those with chronic cerebrospinal fluid (CSF) leak or difficulty handling respiratory secretions. Those less than 18 years of age should receive both pneumococcal conjugate and polysaccharide vaccines and those aged 18 years or older should receive polysaccharide vaccine.
Neurological conditions are generally not a contraindication to immunization. Some neurologic conditions, such as autism spectrum disorders, are diagnosed in childhood over the time period that routine vaccines are administered, causing concern that immunization may have caused the condition. Others that are present at birth or that begin during infancy, such as cerebral palsy, spina bifida, seizure disorders, neuromuscular diseases and inborn errors of metabolism, may have symptom onset before the receipt of the vaccines routinely recommended in infancy. There is no evidence that immunization causes or aggravates these conditions and these conditions are not reasons to delay or avoid vaccinations. On the contrary, patients with chronic neurological conditions benefit from optimal vaccination.
Certain neurologic disorders (e.g., multiple sclerosis), may be treated with immunosuppressive therapies. In this situation, recommendations for immunocompromised persons should be applied. For information, refer to in Part 3.
## Salicylate therapy in children
Individuals less than 18 years of age receiving low doses of salicylate therapy (e.g., acetylsalicylic acid ) require special consideration regarding live influenza and varicella vaccines because of an association between wild-type influenza or varicella infection, salicylate therapy and Reye's syndrome. Reye's syndrome, which causes damage to the brain and liver, is a rare complication that most commonly occurs in children taking ASA at the time of wild-type infection with these viruses.
Children and adolescents receiving chronic salicylate therapy are at high risk of influenza-related complications and should receive inactivated influenza vaccine annually (IIV). LAIV should not be administered to children currently receiving ASA.
Health care providers should weigh the theoretical risks associated with varicella vaccine against the known risks associated with wild-type varicella infection. Because adverse events have not been reported with the use of salicylates after varicella immunization, people with conditions requiring chronic salicylate therapy should be considered for immunization, with close subsequent monitoring.
# Co-morbidities
Guidance on immunization for those with more than one chronic condition is an emerging area of inquiry; evidence to support guidance on immunization of people with co-morbidities is lacking. There is some evidence that co-morbidities may have additive risk for complications from vaccine preventable diseases, such as influenza. As a general principle, when considering immunization of people with co-morbidities, all conditions and medications should be considered in relation to the indications, precautions and contraindications for each vaccine.
# Close contacts
Annual influenza vaccine and up-to-date routine immunizations are recommended for household members and other close contacts of people with chronic diseases, as well as for their health care workers.
There are no contraindications to family members receiving routine live vaccines.
Please note that the information in the text and tables is complementary and both should be used.
Consider optimizing control of bleeding disorders prior to receipt of parenteral injections. For people with sickle cell disease, refer to section.
Including asthma requiring medical care on the preceding 12 months.
People known to have developed GBS within 6 weeks of previously receiving a vaccine should not receive repeat doses of that vaccine unless an alternative cause for the GBS was identified.
May be considered in persons with chronic illnesses for whom there is an increased risk of serious consequences from travellers' diarrhea. Vaccine benefits have not been studied in these specific groups. Vaccine is of limited benefit and is not routinely recommended, except for high-risk travellers who are 2 years of age and older.
Given as combined vaccine (diphtheria, tetanus, pertussis; ± polio, Hib, hepatitis B depending on age and previous vaccine history).
Routine use: Follow routine immunization schedules with age-appropriate booster doses.
May be given as combined vaccine.
If age ≥ 5 yr, one dose regardless of previous Hib vaccine history to be given at least 1 yr after last dose if any dose(s) given before age 5 yr.
Vaccine recommended for conditions requiring repeated transfusions such as sickle cell disease or thalassemia major.
Higher dosage recommended; post-immunization serology recommended with re-immunization if hepatitis B surface antibody titre (anti-HBs) less than 10 IU/L; periodic monitoring of anti-HBs titre recommended. Initially annual monitoring of antibody levels may be considered. Optimal timing and frequency should be based on the severity of the clinical condition and the ongoing risk of acquisition of HB infection.
Vaccinate early in course of hepatic disease; for people with advanced liver disease, assess seroconversion and consider re-immunization with increased antigen content vaccine if anti-HBs less than 10 IU/L.
The recombinant zoster vaccine (not the live zoster vaccine) may be considered for immunocompromised adults 50 years of age and older based on a case-by-case assessment. Data on the use in immunocompromised individuals is limited, but based on the burden of zoster illness in this population and the general safety of inactivated vaccines, the benefits of vaccination are expected to outweigh the risks. Refer to and -vaccine.html) in Part 4.
Children (6 months to 17 years): Given the burden of influenza B disease, either IIV4 or LAIV should be used, including for those with non-immune compromising chronic health conditions. IIV4 should be used for children for whom LAIV4 is contraindicated. If IIV4 is not available and LAIV is not available or contraindicated, IIV3 should be used. Adults: Any available influenza vaccine should be used. IIV should be used for adults 18 – 59 years for whom LAIV is contraindicated or not recommended.
Annual influenza vaccine is recommended for everyone 6 months of age or older. "Recommended" here refers to groups for whom it is particularly recommended because of the high risk of complications from influenza.
Periodic re-immunization with quadrivalent conjugate meningococcal vaccine also recommended.
Either serogroup B meningococcal vaccine can be used; 4CMenB vaccine (for those 2 months of age and older) or MenB-fHBP (for those 10 years of age and older). The timing of booster doses has not yet been determined. Refer to in Part 4.
For those with chronic CSF leak or chronic neurologic conditions that may impair clearance of oral secretions, cochlear implant or for whom an implant is planned.
Abbreviations:
IIV: inactivated influenza vaccine
IIV3: trivalent inactivated influenza vaccine
IIV4: quadrivalent inactivated influenza vaccine
LAIV: live attenuated influenza vaccine
RZV: recombinant zoster vaccine
Please note that the information in the text and tables is complementary and both should be used.
LAIV may be used for children age 2-17 years:
LAIV may be used for children age 2-17 years:
LAIV may be used for children age 2-17 years:
LAIV may be used for children age 2-17 years:
LAIV may be used for children age 2-17 years if no immune suppression and not on chronic salicylate therapy, in which case IIV4 should be used.
LAIV may be used for children age 2-17 years:
LAIV may be used for children age 2-17 years:
LAIV may be used for children age 2-17 years and adults age 18-59 years
LAIV may be used for children age 2-17 years:
Consider optimizing control of bleeding disorders prior to receipt of parenteral injections. For people with sickle cell disease, refer to section.
Including asthma requiring medical care on the preceding 12 months.
People known to have developed GBS within 6 weeks of previously receiving a vaccine should not receive repeat doses of that vaccine unless an alternative cause for the GBS was identified.
When RZV is contraindicated, unavailable or inaccessible, LZV may be considered.
LAIV or IIV can be used in children above age 2 years with chronic conditions. A quadrivalent vaccine is preferred. IIV is recommended for adults with chronic conditions.
Annual influenza vaccine is recommended for everyone 6 months of age or older. "Recommended" here refers to groups for whom it is particularly recommended because of the high risk of complications from influenza.
Contraindicated for persons with current severe asthma (currently on oral or high dose inhaled glucocorticosteroids or active wheezing, those with medically attended wheezing in the 7 days prior to immunization), children and adolescents 2–17 years of age currently receiving aspirin or aspirin-containing therapy, and those with immune compromising conditions, excluding those with stable HIV infection on highly active antiretroviral therapy (HAART) and with adequate immune function – use IIV.
Contraindicated in uncorrected congenital malformation of gastrointestinal tract such as Meckel's diverticulum that could predispose to intussusception.
Diffuse vaccinia virus infection can occur in persons with acute atopic dermatitis or other widespread exfoliative skin disorders. Smallpox vaccine is contraindicated in people with known underlying heart disease or who have three or more known major cardiac risk factors (i.e., hypertension, diabetes, hypercholesterolemia, heart disease at age 50 years in a first-degree relative, and smoking). Persons with inflammatory eye disease may be at increased risk for inadvertent inoculation as a result of touching or rubbing the eye. Deferring vaccination is prudent for persons with inflammatory eye diseases requiring steroid treatment until the condition resolves and therapy is complete.
If typhoid vaccine is indicated, use the non-live vaccine.
Susceptible people with cystic fibrosis are a priority for varicella immunization.
There is an association between yellow fever vaccine-associated viscerotropic disease and a history of thymus disease. Yellow fever vaccine is contraindicated in persons with a history of thymus disease associated with abnormal thymus function (e.g., thymoma thymectomy or myasthenia gravis).
Abbreviations:
BCG: Bacille Calmette-Guérin vaccine
IIV: inactivated influenza vaccine
LAIV: live attenuated influenza vaccine
LZV: live zoster vaccine
MMRV: Measles, Mumps, Rubella, Varicella
RZV: recombinant zoster vaccine
# Chapter revision methodology
The Part 3 Working Group conducted a literature review on recommendations for yellow fever vaccination related to thymus function. The section on has been updated to clarify that yellow fever vaccine is contraindicated in persons with a history of thymus disease associated with abnormal thymus function (e.g., thymoma, thymectomy, myesthenia gravis). Previously, it was stated that YF vaccine was "not generally recommended" in this population.
The duration of injection site compression following immunization of individuals with and individuals receiving long-term anticoagulation was brought forward as guidance requiring further assessment. The previous recommendation was to apply pressure at the injection site for 5-10 minutes. A literature review was conducted for evidence to inform recommendations on the duration of pressure application following immunization in the identified groups. An independent and systematic search of Ovid MEDLINE, Embase, Scopus, and PubMed for studies or reports published between 1946 and 2020 using keywords which include "immunization", "vaccin\*", "anticoagulant", "bleeding disorder or blood-clotting disorder", "pressure", and "intramuscular injection" yielded 99 publications addressing the application of pressure to the injection site following immunization of individuals with bleeding disorders or individuals receiving anticoagulants. The search was limited to publications in English and human studies. Although primary evidence related to the topic was scarce, the majority of the publications provided recommendations that were based on expert opinion or findings from a primary research study by Evans et al. The study reported that following the use of a 23-gauge needle and 1 to 2 minutes of pressure applied to the injection site in children with hemophilia receiving the hepatitis B vaccine, only six of 153 IM injections (4%) resulted in bruising, and none of the children required treatment with clotting factor concentrates. Findings from the literature review and the proposed recommendation were circulated among WG members who agreed on the recommendation to apply firm pressure to the injection site for ≥ 2 minutes in the specified groups.
Publications pertaining to vaccination of persons with selected specific conditions were searched using the search strategy (vaccine OR vaccination OR immunization), AND (splenectomy OR asplenia OR hyposplenia OR "chronic inflammatory disease" OR rheumatic OR IBD OR, "renal disease" OR "kidney disease" OR nephrotic OR ESRD OR diabetes) This additional literature review conducted to identify changes in evidence or vaccine recommendations for persons with the aforementioned conditions did not lead to any new findings that would warrant further revisions to the corresponding sections.
The section on 'Asplenia or hyposplenia' was revised to state that there are other conditions of concern in addition to sickle cell disease or thalassemia major that are associated with splenic dysfunction.
The two tables in the chapter outlining recommendations for use of non-live and live attenuated vaccines for persons with chronic diseases were updated. These tables' contents reflect some of the information in the main text of the chapter and include extra details, and are intended to be used as a complementary resource with the text. The contents of the text and tables were extracted from the corresponding vaccine-specific chapters in of the CIG and from NACI statements. |
Immunization of persons with chronic diseases: Canadian Immunization Guide
===========================================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-6-immunization-patients-health-care-institutions.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html)
Notice
------
This chapter has not yet been updated with the following statement from the National Advisory Committee on Immunization (NACI):
* February 24, 2023: [Public health level recommendations on the use of pneumococcal vaccines in adults, including the use of 15-valent and 20-valent conjugate vaccines.](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/public-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html)
This CIG chapter has not been completely updated to contain information regarding COVID-19 vaccines. For this information, refer to the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html).
Last partial content update (see [Table of updates](/en/public-health/services/canadian-immunization-guide/updates.html)): March 2023
March 2023: This chapter was updated to incorporate guidance from the National Advisory Committee on Immunization (NACI) statement: [Recommended use of palivizumab to reduce complications of respiratory syncytial virus infection in infants](/en/public-health/services/publications/vaccines-immunization/palivizumab-respiratory-syncitial-virus-infection-infants.html). The amendments relate to very young children with haemodynamically significant congenital chronic heart disease and chronic lung disease of prematurity.
Last complete chapter revision: May 2022
On this page
------------
* [Introduction and general principles](#p3c6a1)
* [Chronic diseases](#p3c6a2)
+ [Asplenia or hyposplenia](#p3c6a2.1)
+ [Autoimmune conditions](#p3c6a2.2)
+ [Cancer](#p3c6a2.3)
+ [Cochlear implants](#p3c6a2.4)
+ [Endocrine and metabolic diseases](#p3c6a2.5)
+ [Heart disease](#p3c6a2.6)
+ [Hematologic disorders (non-malignant)](#p3c6a2.7)
- [Anemia and hemoglobinopathy](#p3c6a2.7.1)
- [Bleeding disorders](#p3c6a2.7.2)
+ [Kidney disease and patients on dialysis](#p3c6a2.8)
+ [Liver disease](#p3c6a2.9)
+ [Lung disease](#p3c6a2.10)
+ [Neurologic disorders](#p3c6a2.11)
+ [Salicylate therapy in children](#p3c6a2.12)
* [Co-morbidities](#p3c6a3)
* [Close contacts](#p3c6a4)
* [Table 1: Vaccination of persons with chronic diseases: Non-live vaccines](#p3c6t1)
* [Table 2: Vaccination of persons with chronic diseases: Live attenuated vaccines](#p3c6t2)
* [Chapter revision methodology](#p3c6a5)
* [Acknowledgments](#p3c6a6)
* [Selected references](#p3c6a7)
### Introduction
Chronic diseases may increase a person's risk of infection, or increase a person's risk of more severe disease should infection occur. There is also an increased risk of nosocomial exposure to vaccine-preventable diseases due the increased likelihood of prolonged hospitalization and frequent outpatient visits associated with chronic disease. Therefore, it is important that people with chronic diseases who are immunocompetent be immunized with both live and non-live (e.g., inactivated or recombinant) vaccines, according to routine immunization schedules. Vaccines may be less immunogenic in this population and additional vaccines, additional doses, or higher dosages of vaccines may be required to provide adequate protection.
Ideally, vaccination is best accomplished early in the disease when the response is likely to be similar to other persons of a similar age with no chronic medical condition. If a disease progresses and immunosuppressive therapy is required, vaccine requirements and recommendations may change.
In general, individuals with chronic disease are at higher risk of invasive pneumococcal disease, influenza and influenza-related complications, and should be immunized using the recommended vaccine and schedule.
COVID-19 vaccine is currently recommended for all individuals 6 months of age and older, including those with chronic conditions. This vaccine has not yet been added to Table 1, or to the text for chronic conditions other than autoimmune disease, pending recommendations for post-pandemic use.
For information about vaccination of people with immunodeficiencies, who are immunosuppressed or have HIV infection, refer to [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3.
### Chronic diseases
#### Asplenia or hyposplenia
Asplenic or hyposplenic people have absent or defective splenic function. This condition can occur as a result of congenital absence of the spleen, surgical removal of the spleen, or medical conditions that result in poor or absent splenic function, such as sickle cell disease or thalassemia major, among others. All people, regardless of age, who have absent or defective splenic function, are at increased risk of fulminant bacteremia, which is associated with a high mortality rate. Risk is highest in the first 2 years following splenectomy but remains elevated for life.
Careful attention should be paid to immunization status when elective surgical splenectomy is planned so that all of the necessary vaccines are administered at least 2 weeks before surgery. In the case of an emergency splenectomy, vaccines are best given 2 weeks after the splenectomy for optimal vaccine responses. If a person is discharged earlier and there is a concern that she or he might not return, vaccines should be given before discharge.
Persons with asplenia or hyposplenia should receive all routine vaccinations, including annual influenza vaccine. In addition, particular attention should be paid to ensuring that all asplenic or hyposplenic individuals receive *Haemophilus influenzae* type b (Hib) regardless of age or previous immunization history, quadrivalent conjugate meningococcal vaccine, serogroup B meningococcal vaccine and both pneumococcal conjugate and polysaccharide vaccines, as these individuals are highly susceptible to infection with encapsulated bacteria. Hepatitis B vaccines are indicated for those who require repeat transfusions, such as individuals with sickle cell anemia or thalassemia.
Refer to [Table 1](#p3c6t1), [Table 2](#p3c6t2) and to [Influenza vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html), [*Haemophilus influenzae* type B vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-5-haemophilus-influenzae-type-b-vaccine.html), [Meningococcal vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-13-meningococcal-vaccine.html), [Pneumococcal vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html), and [Hepatitis B](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) vaccine in Part 4 for additional information.
#### Autoimmune conditions
Autoimmune conditions (referred to in former versions of the CIG as inflammatory diseases) encompass a broad category of related diseases in which an individual's immune system attacks his or her own cells. The spectrum of autoimmune conditions is diverse. The relative degree of autoimmunity in individuals with autoimmune conditions is variable depending on the underlying condition, the severity and progression of disease, and the use of medications that impact immune function. Common autoimmune conditions include systemic inflammatory diseases such as systemic lupus erythematosus, systemic vasculitides, rheumatoid arthritis and juvenile arthritis; as well as organ-specific inflammatory conditions such as Crohn's disease and ulcerative colitis, Graves' disease, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, Goodpasture's syndrome, pemphigus vulgaris, psoriasis, idiopathic thrombocytopenic purpura and, autoimmune hemolytic anemia.
Infections are among the most common causes of morbidity, hospitalization and death in individuals with an autoimmune condition. An increased risk of infection and infection-related complications is thought to be due to both an altered immune response associated with the autoimmune condition itself and to the immunosuppressive nature of the treatments required to control the underlying inflammatory condition.
Individuals with autoimmune disease not being treated with immunosuppressive drugs are not considered significantly immunocompromised and can receive routine immunization, including live vaccines. Rheumatic disease modifying agents, such as hydroxychloroquine, sulfasalazine, or auranofin are not generally identified as immunosuppressive, nor are topically-administered non-absorbable formulations of steroids. For children receiving chronic salicylate therapy for autoimmune conditions, inactivated influenza vaccine (IIV) rather than live attenuated influenza vaccine (LAIV) should be used (refer to [Salicylate therapy in children](#p3c6a2.12)).
Individuals with autoimmune conditions should receive, in addition to routine immunization, influenza vaccine annually. Vaccination status should be assessed promptly and routine immunizations updated if needed. Any indicated live vaccines should be given as early as possible, as immunosuppression may be required in the future and live vaccines may then be contraindicated. If immunosuppressive therapy is anticipated in the near future, pneumococcal conjugate and polysaccharide vaccines should be given. Because of immunodeficiencies associated with autoimmune inflammatory disease, some experts recommend giving these vaccines at diagnosis.
COVID-19 infection has been associated with the development of an intense inflammatory response, as well as autoimmune phenomena, in some people, though whether these occur more often in people with autoimmune conditions is unclear. There has been a theoretical concern that inflammation elicited by mRNA vaccines for COVID-19 could exacerbate existing autoimmune diseases, despite the fact that applications of mRNA technology for COVID-19 vaccines have been optimized to reduce this risk through modifications to the RNA and lipid constructs. Participants with autoimmune conditions who were not immunosuppressed were not excluded from clinical trials for mRNA COVID-19 vaccines, but they constituted a very small proportion of trial participants and represented a very narrow spectrum of autoimmune conditions. Data from observational studies in individuals with autoimmune conditions indicate that the frequency and severity of adverse events in this population is comparable to that of individuals without autoimmune conditions and to what was reported in clinical trials. The onset of new autoimmune disease or disease exacerbation following vaccination with mRNA COVID-19 vaccines has been rare or comparable to the background incidence of these events in the general population. NACI recommends that a complete vaccine series with an mRNA COVID-19 vaccine should be offered to individuals in the authorized age group with an autoimmune condition.
For individuals with dermatologic disorders, care should be taken not to administer vaccine into affected areas, as this procedure may exacerbate the condition. Bacille Calmette-Guérin (BCG) vaccine is contraindicated if there is extensive skin disease at or near the site of injection. Live replicating smallpox vaccine is contraindicated in a non-outbreak situation.
For individuals with chronic inflammatory diseases who are being treated with immunosuppressive therapies including biologic response modifiers, refer to [Immunosuppressive therapy](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html#a25) in [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3.
Refer to [Table 1](#p3c6t1), [Table 2](#p3c6t2) and to [Pneumococcal vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html) and [Influenza vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html) in Part 4 for additional information.
#### Cancer
People with cancer have a higher risk of contracting infectious diseases and a higher risk of developing complications because many cancers and their treatments affect the immune system. Therefore, it is important that children and adults with cancer receive protection from vaccine preventable diseases whenever possible.
Generally, cancer alone, if it is not hematologic, is not sufficient to cause immunosuppression to the extent that an individual cannot receive live vaccines. If chemotherapy is not required, all routine vaccines should be given. Influenza vaccine should be given annually. Other vaccines may be indicated, depending on which organs or systems are affected by the tumour. If chemotherapy is to be given, any immunizations required, as well as annual influenza vaccine, should be completed before beginning chemotherapy whenever possible.
For hematologic cancers or for people on immunosuppressive therapies, refer to [Immunosuppressive therapy](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html#a25) in [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3.
#### Cochlear implants
People who have received a cochlear implant are at increased risk for bacterial meningitis and for otitis media. In addition to all age appropriate vaccinations, people with cochlear implants and those who are receiving cochlear implants should receive annual influenza vaccine, pneumococcal conjugate and polysaccharide vaccines if age less than 18 years, or pneumococcal polysaccharide vaccine if 18 years of age or older, and Hib vaccine if 5 years of age or older regardless of Hib vaccination history.
Refer to [Influenza vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html), [Pneumococcal vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html), and [*Haemophilus influenzae* type B vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-5-haemophilus-influenzae-type-b-vaccine.html) in Part 4 for additional information.
#### Endocrine and metabolic diseases
People with diabetes mellitus have defects in phagocytic and neutrophil function. In addition, they often have complications of diabetes such as cardiovascular, neurovascular, renal and other end-organ dysfunction and are at greater risk of complications from infection. Persons with other metabolic disorders, such as thyroid disorders, or morbid obesity (Body Mass Index of 40 or higher) are at high risk of influenza-related complications.
Routine immunization, including annual influenza vaccine, is recommended for persons with endocrine and metabolic disorders. In addition to routine immunization, people with diabetes should receive pneumococcal conjugate and polysaccharide vaccines if age less than 18 years or pneumococcal polysaccharide vaccine if 18 years of age or older. There is no evidence that vaccination interferes with glycemic control.
There is an association between yellow fever vaccine-associated viscerotropic disease and a history of thymus disease. Yellow fever vaccine is contraindicated in persons with a history of thymus disease associated with abnormal thymus function (e.g., thymoma, thymectomy or myasthenia gravis). If travelling to a yellow fever endemic or epidemic area, expert advice should be sought concerning the risks of exposure to yellow fever, the ability to adhere to mosquito protection measures, and the risk of vaccine-associated disease.
Refer to [Influenza vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html) and [Pneumococcal vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html) in Part 4 and [Table 1](#p3c6t1) for additional information.
#### Heart disease
In individuals with chronic heart disease, viral and bacterial infections may precipitate cardiac decompensation and lead to hospitalization. There is evidence that giving influenza vaccine to those with coronary artery disease has some protective effect on subsequent cardiac events.
People with cardiac disease should receive routine immunization, including annual influenza vaccine, as they are at high risk of influenza-related complications. Individuals with chronic heart disease should also receive pneumococcal conjugate vaccine and polysaccharide vaccine if less than 18 years or pneumococcal polysaccharide vaccine if 18 years of age or older.
Young children with certain chronic cardiac conditions are at high risk of respiratory syncytial virus (RSV) associated hospitalization. The monoclonal antibody preparation, palivizumab, is recommended to protect against severe infection in infants less than 12 months of age with haemodynamically significant congenital heart disease at the onset of the RSV season.
Live replicating smallpox vaccine is contraindicated in a non-outbreak situation for specific cardiac conditions (Table 2).
Refer to [Table 1](#p3c6t1), [Table 2](#p3c6t2) and to [Influenza vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html), [Pneumococcal vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html), and [Respiratory syncytial virus](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/respiratory-syncytial-virus.html) in Part 4 for additional information.
#### Hematologic disorders (non-malignant)
Non-malignant hematologic disorders include different types of chronic anemia and hemoglobinopathy, as well as bleeding disorders. For further discussion on vaccines recommended for people with anemia due to sickle cell disease or other hemoglobinopathies associated with splenic dysfunction, refer to [Asplenia or hyposplenia](#_Asplenia_or_hyposplenia).
Some hematologic disorders require frequent or chronic administration of blood products. Recent administration of blood products may interfere with the antibody response to live vaccines, and receipt of plasma or immunoglobulin may result in false positive antibody tests. Refer to [Blood products, human immunoglobulin and timing of immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) in Part 1 for additional information.
##### Anemia and hemoglobinopathy
People with anemia may be at increased risk of complications from vaccine- preventable diseases. In addition to routine immunization, people with chronic anemia or hemoglobinopathy should receive influenza vaccine annually. If there is a need for repeated blood transfusions, hepatitis B vaccine is required. If there is splenic dysfunction, refer to [Asplenia and hyposplenia](#_Asplenia_or_hyposplenia).
Refer to [Table 1](#p3c6t1), [Table 2](#p3c6t2) and to [Influenza vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html), and [Hepatitis B vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for additional information.
##### Bleeding disorders
People with bleeding disorders such as hemophilia may differ from the healthy population with respect to the potentially increased risk of infection as a result of exposure to blood products and the risk of hematoma formation from parenteral injections. In addition to routine immunization, people with hemophilia and other clotting factor disorders receiving repeated transfusions of blood or blood products should receive hepatitis B vaccines unless already infected or immune. Pre-immunization serologic testing for hepatitis B should be performed if they have already had repeated exposure to blood products. In addition, those receiving repeated infusions of plasma-derived clotting factors should receive hepatitis A vaccine.
Before beginning immunization of any child, vaccine providers should ensure that there are no symptoms or signs compatible with an undiagnosed bleeding disorder. If such indicators are present, a diagnosis should be established before commencing immunization. For example, in any child who has a history of an intramuscular (IM) hematoma following an IM injection, an undiagnosed bleeding disorder, such as hemophilia, should be considered. If a disorder is present, it should be optimally managed prior to immunization to minimize the risk of bleeding. Hemophiliacs may receive clotting factor concentrates to optimize their clotting factor level before they receive a parenteral vaccine or a passive immunizing agent.
Generally there is no evidence of increased risk of bleeding in those with bleeding disorders following IM versus subcutaneous injections. There is evidence to suggest that IM administration is safe when given with a small gauge needle (23 gauge or smaller) and when firm pressure is applied to the injection site for ≥ 2 minutes. There is also evidence that immunization by the subcutaneous route for vaccine intended for intramuscular administration may be associated with more local reactogenicity and a diminished immune response, compared to the IM route.
Individuals receiving long-term anticoagulation may also be safely immunized through either the IM or subcutaneous route as recommended for a specific vaccine, using the same precautions as for bleeding disorders, without discontinuation of their anticoagulation therapy.
Refer to [Table 1](#p3c6t1), [Table 2](#p3c6t2) and to [Influenza vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html), [Hepatitis A vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html) and [Hepatitis B vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for additional information.
#### Kidney disease and patients on dialysis
Bacterial and viral infections are a major cause of morbidity and mortality in people with renal disease or who are undergoing chronic dialysis (hemodialysis or peritoneal dialysis). People with chronic kidney insufficiency and dialysis may have mild defects in T cell function, while in individuals with nephrotic syndrome, urinary loss of antibody may occur. Also, because these persons are also in frequent contact with the health care system, they are at greater risk of hospital-acquired infection from vaccine preventable diseases.
People with chronic renal disease or those who are undergoing dialysis should receive all routine vaccinations, including annual influenza vaccine. In addition to routine immunization, hepatitis B and pneumococcal vaccines (conjugate and polysaccharide vaccines if age less than 18 years, polysaccharide vaccine if 18 years of age or older) are recommended. Those with nephrotic syndrome should receive both the conjugate and the polysaccharide vaccines even if age 18 years or older. Since individuals with impaired renal function may experience a less than optimal response to immunization, higher vaccine doses and re-immunization may be required. Monitoring vaccine titers may be helpful.
For information about kidney transplant candidates and recipients, refer to [Solid organ transplantation](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html#a21) in [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3.
Refer to [Table 1](#p3c6t1), [Table 2](#p3c6t2) and to [Influenza Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html), [Hepatitis B Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html), and [Pneumococcal Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html) in Part 4 for additional information.
#### Liver disease
Chronic liver disease can impact innate and adaptive immune mechanisms. Splenic dysfunction may also occur if the liver disease is severe. Hepatic encephalopathy or chronic alcohol consumption may lead to aspiration pneumonia. Alcoholism is also a risk factor for invasive pneumococcal disease. Newly acquired hepatitis A or hepatitis B in persons who already have chronic liver disease from another cause could lead to more severe disease and rapid hepatic decompensation. Those with ascites have an altered immunoglobulin production and distribution.
People with chronic liver disease should receive all routine immunizations, including annual influenza vaccine, conjugate and polysaccharide pneumococcal vaccine if age less than 18 years or polysaccharide pneumococcal vaccine if age 18 years or older, as well as hepatitis A vaccine and hepatitis B vaccine if not already infected or immune. Vaccination should be completed early in the course of liver disease, as the immune response to vaccine is suboptimal in advanced liver disease. Since individuals with chronic liver disease may experience a less than optimal response to immunization, higher vaccine doses and re-immunization may be required.
Refer to [Table 1](#p3c6t1), [Table 2](#p3c6t2) and to [Influenza vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html), [Pneumococcal vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html), [Hepatitis A vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html), and [Hepatitis B vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 for additional information.
#### Lung disease
Individuals with chronic lung diseases such as bronchopulmonary dysplasia, cystic fibrosis, asthma or chronic obstructive pulmonary diseases (COPD) are at increased risk of complications of influenza and pneumococcal infection. Those with cystic fibrosis are also at increased risk of complications from varicella infection, which may cause a transient worsening of lung function. Young children with chronic lung disease of prematurity who require ongoing oxygen therapy are at high risk of respiratory syncytial virus (RSV) associated hospitalization. Many individuals with more severe chronic lung disease have bacterial colonization due to poor mucociliary clearance and bronchiectasis, pneumatoceles, or defects in pulmonary macrophage function.
People with chronic lung disorders should receive influenza vaccine annually in addition to other routine immunization. Live attenuated influenza vaccine (LAIV) is contraindicated for persons with current severe asthma (currently on oral or high dose inhaled glucocorticosteroids or active wheezing, or those with medically attended wheezing in the 7 days prior to immunization). In these situations, inactivated influenza vaccine (IIV) should be used. Pneumococcal vaccines are also recommended, including for those with asthma requiring medical care in the preceding 12 months. Conjugate and polysaccharide vaccines should be given if age less than 18 years, and pneumococcal polysaccharide vaccine if 18 years of age or older. The monoclonal antibody preparation, palivizumab, is recommended to protect against severe infection in children less than 24 months of age with chronic lung disease of prematurity who require ongoing oxygen therapy in the six months preceding or during the RSV season.
Refer to [Table 1](#p3c6t1), [Table 2](#p3c6t2) and to [Influenza Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html), [Pneumococcal Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html), and [Respiratory syncytial virus](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/respiratory-syncytial-virus.html) in Part 4 for additional information. Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional information about vaccination of individuals receiving systemic steroids or other immunosuppressive therapy for their lung disease, as well for vaccination of lung transplant candidates and recipients.
#### Neurologic disorders
Persons with neurological disorders are at increased risk of hospitalization with influenza. Some studies suggest that influenza vaccine may decrease the risk of stroke.
In addition to all routine immunizations, people with neurological or neurodevelopmental conditions should receive annual influenza vaccine (with the exception of anyone who developed Guillain-Barre Syndrome [GBS] within 6 weeks after a previous dose of influenza vaccine unless another cause was found). Some neurological conditions also predispose to pneumococcal infections. Pneumococcal vaccines are recommended for those with chronic cerebrospinal fluid (CSF) leak or difficulty handling respiratory secretions. Those less than 18 years of age should receive both pneumococcal conjugate and polysaccharide vaccines and those aged 18 years or older should receive polysaccharide vaccine.
Neurological conditions are generally not a contraindication to immunization. Some neurologic conditions, such as autism spectrum disorders, are diagnosed in childhood over the time period that routine vaccines are administered, causing concern that immunization may have caused the condition. Others that are present at birth or that begin during infancy, such as cerebral palsy, spina bifida, seizure disorders, neuromuscular diseases and inborn errors of metabolism, may have symptom onset before the receipt of the vaccines routinely recommended in infancy. There is no evidence that immunization causes or aggravates these conditions and these conditions are not reasons to delay or avoid vaccinations. On the contrary, patients with chronic neurological conditions benefit from optimal vaccination.
Certain neurologic disorders (e.g., multiple sclerosis), may be treated with immunosuppressive therapies. In this situation, recommendations for immunocompromised persons should be applied. For information, refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html#a25) in Part 3.
Refer to [Table 1](#p3c6t1), [Table 2](#p3c6t2) and to [Influenza Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html) and [Pneumococcal Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html) in Part 4 for additional information.
#### Salicylate therapy in children
Individuals less than 18 years of age receiving low doses of salicylate therapy (e.g., acetylsalicylic acid [aspirin, ASA]) require special consideration regarding live influenza and varicella vaccines because of an association between wild-type influenza or varicella infection, salicylate therapy and Reye's syndrome. Reye's syndrome, which causes damage to the brain and liver, is a rare complication that most commonly occurs in children taking ASA at the time of wild-type infection with these viruses.
Children and adolescents receiving chronic salicylate therapy are at high risk of influenza-related complications and should receive inactivated influenza vaccine annually (IIV). LAIV should not be administered to children currently receiving ASA.
Health care providers should weigh the theoretical risks associated with varicella vaccine against the known risks associated with wild-type varicella infection. Because adverse events have not been reported with the use of salicylates after varicella immunization, people with conditions requiring chronic salicylate therapy should be considered for immunization, with close subsequent monitoring.
Refer to [Influenza vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html) and [Varicella (chickenpox) vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-24-varicella-chickenpox-vaccine.html) in Part 4 for additional information.
### Co-morbidities
Guidance on immunization for those with more than one chronic condition is an emerging area of inquiry; evidence to support guidance on immunization of people with co-morbidities is lacking. There is some evidence that co-morbidities may have additive risk for complications from vaccine preventable diseases, such as influenza. As a general principle, when considering immunization of people with co-morbidities, all conditions and medications should be considered in relation to the indications, precautions and contraindications for each vaccine.
### Close contacts
Annual influenza vaccine and up-to-date routine immunizations are recommended for household members and other close contacts of people with chronic diseases, as well as for their health care workers.
There are no contraindications to family members receiving routine live vaccines.
Refer to [Immunization of workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html) and [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional information.
### Table 1: Vaccination of persons with chronic diseases: Non-live vaccines
Please note that the information in the text and tables is complementary and both should be used.
Refer to [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information, especially concerning vaccine doses, schedules and boosters.
| Vaccine | Asplenia/
hyposplenia | Endocrine/
metabolic diseases | Heart disease | Hematologic disorders (non-malignant)[Table 1 footnote 1](#p3c6t1fn1) | Autoimmune conditions (including chronic salicylate therapy) | Kidneydisease/
dialysis | Liver disease | Lung disease[Table 1 footnote 2](#p3c6t1fn2) | Neurologic disorders[Table 1 footnote 3](#p3c6t1fn3) and Cochlear Implants |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| **Cholera and travellers' diarrhea** | Use if indicated | May be considered for diabetes mellitus[Table 1 footnote 4](#p3c6t1fn4)
Otherwise, use if indicated | May be considered if congestive heart failure[Table 1 footnote 4](#p3c6t1fn4) | Use if indicated | May be considered for inflammatory bowel disease[Table 1 footnote 4](#p3c6t1fn4)
Otherwise, use if indicated | May be considered for chronic renal failure[Table 1 footnote 4](#p3c6t1fn4) | Use if indicated | Use if indicated | Use if indicated |
| **Diphtheria**[Table 1 footnote 5](#p3c6t1fn5) | Routine use[Table 1 footnote 6](#p3c6t1fn6) | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use |
| ***Haemophilus Influenzae* type b (Hib)**[Table 1 footnote 5](#p3c6t1fn5),[Table 1 footnote 7](#p3c6t1fn7) | Recommended for all ages[Table 1 footnote 8](#p3c6t1fn8) | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | For cochlear implant recipients and those for whom implant is planned, recommended for all ages[Table 1 footnote 8](#p3c6t1fn8)
Otherwise, routine use |
| **Hepatitis A**[Table 1 footnote 7](#p3c6t1fn7) | Use if indicated | Use if indicated | Use if indicated | Recommended if receiving repeated replacement of plasma-derived clotting factors | Use if indicated | Use if indicated | Recommended | Use if indicated | Use if indicated |
| **Hepatitis B**[Table 1 footnote 5](#p3c6t1fn5),[Table 1 footnote 7](#p3c6t1fn7) | Routine use[Table 1 footnote 9](#p3c6t1fn9) | Routine use | Routine use | Recommended for hemophiliacs and others receiving repeated infusions of blood or blood products | Routine use | Recommended[Table 1 footnote 10](#p3c6t1fn10) | Recommended[Table 1 footnote 10](#p3c6t1fn10),[Table 1 footnote 11](#p3c6t1fn11) | Routine use | Routine use |
| **Herpes Zoster**[Table 1 footnote 12](#p3c6t1fn12) **(RZV)** | Routine use | Routine use | Routine use | Routine use | Routine use[Table 1 footnote 12](#p3c6t1fn12)
If immunocompromised, may be considered on a case-by-case basis | Routine use | Routine use | Routine use | Routine use |
| **HPV** | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use |
| **Influenza**[Table 1 footnote 13](#p3c6t1fn13) | Recommended annually | Recommended annually | Recommended annually | Recommended annually for people with anemia or hemoglobinopathy; otherwise Routine use[Table 1 footnote 14](#p3c6t1fn14) | Recommended annually if immunosuppressed or if age < 18 yr and receiving chronic salicylate therapy;
Otherwise Routine use[Table 1 footnote 14](#p3c6t1fn14) | Recommended annually | Routine use[Table 1 footnote 14](#p3c6t1fn14) | Recommended annually | Recommended annually[Table 1 footnote 3](#p3c6t1fn3) |
| **Japanese encephalitis** | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated |
| **Meningococcal quadrivalent conjugate** | Recommended for all over 2 months of age[Table 1 footnote 15](#p3c6t1fn15) | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use |
| **Meningococcal serogroup B** | Recommended for all over 2 months of age[Table 1 footnote 16](#p3c6t1fn16) | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated |
| **Pertussis**[Table 1 footnote 5](#p3c6t1fn5) | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use |
| **Pneumococcal conjugate 13-valent** | Recommended for all ages | Children: (age < 18 yr): recommended for diabetes mellitus, otherwise routine use | Children: (age < 18 yr): recommended | Hemoglobinopathy: Recommended for all ages if splenic dysfunction otherwise routine use | Recommended for all ages if immunosuppressed; otherwise routine use | Children (age < 18 yr): recommended
Adults: Recommended for nephrotic syndrome | Children (age < 18 yr): recommended | Children (age < 18 yr): recommended | Children (age < 18 yr): recommended for cochlear implant candidates and recipients and other specific conditions[Table 1 footnote 17](#p3c6t1fn17)
Otherwise, routine use |
| **Pneumococcal polysaccharide 23-valent** | Recommended for children 2 years of age and older, and adults | Recommended for children 2 years of age and older with diabetes and for adults with diabetes | Recommended for children 2 years of age and older and adults | Hemoglobinopathy: Recommended for children 2 years of age and older and adults if splenic dysfunction | Recommended for children 2 years of age and older, and adults, if immunosuppressed | Recommended for children 2 years of age and older, and adults | Recommended for children 2 years of age and older, and adults | Recommended for children 2 years of age and older, and adults | Recommended for children 2 years of age and older, and adults who are cochlear implant candidates or recipients and for those with other specific conditions[Table 1 footnote 17](#p3c6t1fn17)
Otherwise, routine use |
| **Polio (inactivated**[Table 1 footnote 5](#p3c6t1fn5)**)** | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use |
| **Rabies** | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated |
| **Tetanus**[Table 1 footnote 5](#p3c6t1fn5) | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use | Routine use[Table 1 footnote 3](#p3c6t1fn3) |
| **Typhoid (inactivated)** | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated |
|
Table 1 - Footnote 1
Consider optimizing control of bleeding disorders prior to receipt of parenteral injections. For people with sickle cell disease, refer to [Asplenia or hyposplenia](#p3c6a2.1) section.
[Return to Table 1 Footnote 1 referrer](#p3c6t1fn1-rf)
Table 1 - Footnote 2
Including asthma requiring medical care on the preceding 12 months.
[Return to Table 1 Footnote 2 referrer](#p3c6t1fn2-rf)
Table 1 - Footnote 3
People known to have developed GBS within 6 weeks of previously receiving a vaccine should not receive repeat doses of that vaccine unless an alternative cause for the GBS was identified.
[Return to Table 1 Footnote 3 referrer](#p3c6t1fn3-rf)
Table 1 - Footnote 4
May be considered in persons with chronic illnesses for whom there is an increased risk of serious consequences from travellers' diarrhea. Vaccine benefits have not been studied in these specific groups. Vaccine is of limited benefit and is not routinely recommended, except for high-risk travellers who are 2 years of age and older.
[Return to Table 1 Footnote 4 referrer](#p3c6t1fn4-rf)
Table 1 - Footnote 5
Given as combined vaccine (diphtheria, tetanus, pertussis; ± polio, Hib, hepatitis B depending on age and previous vaccine history).
[Return to Table 1 Footnote 5 referrer](#p3c6t1fn5-rf)
Table 1 - Footnote 6
Routine use: Follow routine immunization schedules with age-appropriate booster doses.
[Return to Table 1 Footnote 6 referrer](#p3c6t1fn6-rf)
Table 1 - Footnote 7
May be given as combined vaccine.
[Return to Table 1 Footnote 7 referrer](#p3c6t1fn7-rf)
Table 1 - Footnote 8
If age ≥ 5 yr, one dose regardless of previous Hib vaccine history to be given at least 1 yr after last dose if any dose(s) given before age 5 yr.
[Return to Table 1 Footnote 8 referrer](#p3c6t1fn8-rf)
Table 1 - Footnote 9
Vaccine recommended for conditions requiring repeated transfusions such as sickle cell disease or thalassemia major.
[Return to Table 1 Footnote 9 referrer](#p3c6t1fn9-rf)
Table 1 - Footnote 10
Higher dosage recommended; post-immunization serology recommended with re-immunization if hepatitis B surface antibody titre (anti-HBs) less than 10 IU/L; periodic monitoring of anti-HBs titre recommended. Initially annual monitoring of antibody levels may be considered. Optimal timing and frequency should be based on the severity of the clinical condition and the ongoing risk of acquisition of HB infection.
[Return to Table 1 Footnote 10 referrer](#p3c6t1fn10-rf)
Table 1 - Footnote 11
Vaccinate early in course of hepatic disease; for people with advanced liver disease, assess seroconversion and consider re-immunization with increased antigen content vaccine if anti-HBs less than 10 IU/L.
[Return to Table 1 Footnote 11 referrer](#p3c6t1fn11-rf)
Table 1 - Footnote 12
The recombinant zoster vaccine (not the live zoster vaccine) may be considered for immunocompromised adults 50 years of age and older based on a case-by-case assessment. Data on the use in immunocompromised individuals is limited, but based on the burden of zoster illness in this population and the general safety of inactivated vaccines, the benefits of vaccination are expected to outweigh the risks. Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) and [Herpes Zoster (shingles) vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-8-herpes-zoster-(shingles)-vaccine.html) in Part 4.
[Return to Table 1 Footnote 12 referrer](#p3c6t1fn12-rf)
Table 1 - Footnote 13
Children (6 months to 17 years): Given the burden of influenza B disease, either IIV4 or LAIV should be used, including for those with non-immune compromising chronic health conditions. IIV4 should be used for children for whom LAIV4 is contraindicated. If IIV4 is not available and LAIV is not available or contraindicated, IIV3 should be used. Adults: Any available influenza vaccine should be used. IIV should be used for adults 18 – 59 years for whom LAIV is contraindicated or not recommended.
[Return to Table 1 Footnote 13 referrer](#p3c6t1fn13-rf)
Table 1 - Footnote 14
Annual influenza vaccine is recommended for everyone 6 months of age or older. "Recommended" here refers to groups for whom it is particularly recommended because of the high risk of complications from influenza.
[Return to Table 1 Footnote 14 referrer](#p3c6t1fn14-rf)
Table 1 - Footnote 15
Periodic re-immunization with quadrivalent conjugate meningococcal vaccine also recommended.
[Return to Table 1 Footnote 15 referrer](#p3c6t1fn15-rf)
Table 1 - Footnote 16
Either serogroup B meningococcal vaccine can be used; 4CMenB vaccine (for those 2 months of age and older) or MenB-fHBP (for those 10 years of age and older). The timing of booster doses has not yet been determined. Refer to [Meningococcal Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-13-meningococcal-vaccine.html) in Part 4.
[Return to Table 1 Footnote 16 referrer](#p3c6t1fn16-rf)
Table 1 - Footnote 17
For those with chronic CSF leak or chronic neurologic conditions that may impair clearance of oral secretions, cochlear implant or for whom an implant is planned.
[Return to Table 1 Footnote 17 referrer](#p3c6t1fn17-rf)
**Abbreviations:**
**IIV:** inactivated influenza vaccine
**IIV3:** trivalent inactivated influenza vaccine
**IIV4:** quadrivalent inactivated influenza vaccine
**LAIV:** live attenuated influenza vaccine
**RZV:** recombinant zoster vaccine
|
### Table 2: Vaccination of persons with chronic diseases: Live attenuated vaccines
Please note that the information in the text and tables is complementary and both should be used.
Refer to [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) for additional information, especially concerning vaccine doses, schedules and boosters.
| Vaccine | Asplenia/
hyposplenia | Endocrine/
metabolic diseases | Heart disease | Hematologic disorders (non-malignant)[Table 2 footnote 1](#p3c6t2fn1) | Autoimmune conditions (including chronic salicylate therapy) | Kidney Renal disease/
dialysis | Liver disease | Lung disease[Table 2 footnote 2](#p3c6t2fn2) | Neurologic disorders[Table 2 footnote 3](#p3c6t2fn3) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| **BCG** | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated if no immune suppression.
Contraindicated if extensive skin disease at or near the site of injection | Use if indicated | Use if indicated | Use if indicated | Use if indicated |
| **Herpes zoster (LZV)**[Table 2 footnote 4](#p3c6t2fn4) | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated if no immune suppression | Use if indicated | Use if indicated | Use if indicated | Use if indicated |
| **Influenza (LAIV)**[Table 2 footnote 5](#p3c6t2fn5) | Influenza vaccine recommended annually
LAIV may be used for children age 2-17 years:
LAIV should not be used for children < 2 years of age or for adults (use IIV, see Table 1) | Influenza vaccine recommended annually
LAIV may be used for children age 2-17 years:
LAIV should not be used for children < 2 years of age or for adults (use IIV, see Table 1) | Influenza vaccine recommended annually
LAIV may be used for children age 2-17 years:
LAIV should not be used for children < 2 years of age or for adults (use IIV, see Table 1) | Influenza vaccine recommended annually for people with anemia or hemoglobinopathy, otherwise Routine use[Table 2 footnote 6](#p3c6t2fn6)
LAIV may be used for children age 2-17 years:
LAIV should not be used for children < 2 years of age or for adults (use IIV, see Table 1) | Routine use[Table 2 footnote 6](#p3c6t2fn6)
LAIV may be used for children age 2-17 years if no immune suppression and not on chronic salicylate therapy, in which case IIV4 should be used.
LAIV should not be used for children < 2 years of age or for adults (use IIV, see Table 1). | Influenza vaccine recommended annually
LAIV may be used for children age 2-17 years:
LAIV should not be used for children < 2 years of age or for adults (use IIV, see Table 1) | Routine use[Table 2 footnote 6](#p3c6t2fn6)
LAIV may be used for children age 2-17 years:
LAIV should not be used for children < 2 years of age or for adults (use IIV, see Table 1) | Influenza vaccine recommended annually
LAIV may be used for children age 2-17 years and adults age 18-59 years[Table 2 footnote 7](#p3c6t2fn7)
LAIV should not be used for children < 2 years of age (use IIV, see Table 1) | Influenza vaccine recommended annually
LAIV may be used for children age 2-17 years:
LAIV should not be used for children < 2 years of age or for adults (use IIV, see Table 1) |
| **Measles-mumps-rubella** | Routine use | Routine use | Routine use | Routine use | Routine use if no immune suppression | Routine use | Routine use | Routine use | Routine use |
| **MMRV** | Routine use | Routine use | Routine use | Routine use | Routine use if no immune suppression | Routine use | Routine use | Routine use | Routine use |
| **Rotavirus**[Table 2 footnote 8](#p3c6t2fn8) | Routine use | Routine use | Routine use | Routine use | Routine use if no immune suppression | Routine use | Routine use | Routine use | Routine use |
| **Smallpox**[Table 2 footnote 9](#p3c6t2fn9)**(live replicating)** | Use if indicated | Use if indicated | Contraindicated in non-outbreak situation | Use if indicated | Contraindicated in non-outbreak situation for people with immune suppression, dermatologic conditions or inflammatory eye disease[Table 2 footnote 9](#p3c6t2fn9) | Use if indicated | Use if indicated | Use if indicated | Use if indicated |
| **Typhoid (live)** | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated if no immune suppression, no acute gastrointestinal condition and no active chronic inflammatory bowel disease[Table 2 footnote 10](#p3c6t2fn10) | Use if indicated | Use if indicated | Use if indicated | Use if indicated |
| **Varicella (univalent)** | Routine use | Routine use | Routine use | Routine use | Routine use if no immune suppression
If age < 18 yr and receiving chronic salicylate therapy, consider for immunization, with close monitoring | Routine use | Routine use | Routine use[Table 2 footnote 11](#p3c6t2fn11) | Routine use |
| **Yellow fever**[Table 2 footnote 12](#p3c6t2fn12) | Use if indicated | Use if indicated[Table 2 footnote 12](#p3c6t2fn12) | Use if indicated | Use if indicated | Use if indicated if no immune suppression | Use if indicated | Use if indicated | Use if indicated | Use if indicated |
|
Table 2 - Footnote 1
Consider optimizing control of bleeding disorders prior to receipt of parenteral injections. For people with sickle cell disease, refer to [Asplenia or hyposplenia](#p3c6a2.1) section.
[Return to Table 2 Footnote 1 referrer](#p3c6t2fn1-rf)
Table 2 - Footnote 2
Including asthma requiring medical care on the preceding 12 months.
[Return to Table 2 Footnote 2 referrer](#p3c6t2fn2-rf)
Table 2 - Footnote 3
People known to have developed GBS within 6 weeks of previously receiving a vaccine should not receive repeat doses of that vaccine unless an alternative cause for the GBS was identified.
[Return to Table 2 Footnote 3 referrer](#p3c6t2fn3-rf)
Table 2 - Footnote 4
When RZV is contraindicated, unavailable or inaccessible, LZV may be considered.
[Return to Table 2 Footnote 4 referrer](#p3c6t2fn4-rf)
Table 2 - Footnote 5
LAIV or IIV can be used in children above age 2 years with chronic conditions. A quadrivalent vaccine is preferred. IIV is recommended for adults with chronic conditions.
[Return to Table 2 Footnote 5 referrer](#p3c6t2fn5-rf)
Table 2 - Footnote 6
Annual influenza vaccine is recommended for everyone 6 months of age or older. "Recommended" here refers to groups for whom it is particularly recommended because of the high risk of complications from influenza.
[Return to Table 2 Footnote 6 referrer](#p3c6t2fn6-rf)
Table 2 - Footnote 7
Contraindicated for persons with current severe asthma (currently on oral or high dose inhaled glucocorticosteroids or active wheezing, those with medically attended wheezing in the 7 days prior to immunization), children and adolescents 2–17 years of age currently receiving aspirin or aspirin-containing therapy, and those with immune compromising conditions, excluding those with stable HIV infection on highly active antiretroviral therapy (HAART) and with adequate immune function – use IIV.
[Return to Table 2 Footnote 7 referrer](#p3c6t2fn7-rf)
Table 2 - Footnote 8
Contraindicated in uncorrected congenital malformation of gastrointestinal tract such as Meckel's diverticulum that could predispose to intussusception.
[Return to Table 2 Footnote 8 referrer](#p3c6t2fn8-rf)
Table 2 - Footnote 9
Diffuse vaccinia virus infection can occur in persons with acute atopic dermatitis or other widespread exfoliative skin disorders. Smallpox vaccine is contraindicated in people with known underlying heart disease or who have three or more known major cardiac risk factors (i.e., hypertension, diabetes, hypercholesterolemia, heart disease at age 50 years in a first-degree relative, and smoking). Persons with inflammatory eye disease may be at increased risk for inadvertent inoculation as a result of touching or rubbing the eye. Deferring vaccination is prudent for persons with inflammatory eye diseases requiring steroid treatment until the condition resolves and therapy is complete.
[Return to Table 2 Footnote 9 referrer](#p3c6t2fn9-rf)
Table 2 - Footnote 10
If typhoid vaccine is indicated, use the non-live vaccine.
[Return to Table 2 Footnote 10 referrer](#p3c6t2fn10-rf)
Table 2 - Footnote 11
Susceptible people with cystic fibrosis are a priority for varicella immunization.
[Return to Table 2 Footnote 11 referrer](#p3c6t2fn11-rf)
Table 2 - Footnote 12
There is an association between yellow fever vaccine-associated viscerotropic disease and a history of thymus disease. Yellow fever vaccine is **contraindicated** in persons with a history of thymus disease associated with abnormal thymus function (e.g., thymoma thymectomy or myasthenia gravis).
[Return to Table 2 Footnote 12 referrer](#p3c6t2fn12-rf)
**Abbreviations:**
**BCG:** Bacille Calmette-Guérin vaccine
**IIV:** inactivated influenza vaccine
**LAIV:** live attenuated influenza vaccine
**LZV:** live zoster vaccine
**MMRV:** Measles, Mumps, Rubella, Varicella
**RZV:** recombinant zoster vaccine
Refer to text and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 and to [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) for additional information.
|
### Chapter revision methodology
The Part 3 Working Group conducted a literature review on recommendations for yellow fever vaccination related to thymus function. The section on [Endocrine and metabolic diseases](#p3c6a2.5) has been updated to clarify that yellow fever vaccine is contraindicated in persons with a history of thymus disease associated with abnormal thymus function (e.g., thymoma, thymectomy, myesthenia gravis). Previously, it was stated that YF vaccine was "not generally recommended" in this population.
The duration of injection site compression following immunization of individuals with [bleeding disorders](#p3c6a2.7.2) and individuals receiving long-term anticoagulation was brought forward as guidance requiring further assessment. The previous recommendation was to apply pressure at the injection site for 5-10 minutes. A literature review was conducted for evidence to inform recommendations on the duration of pressure application following immunization in the identified groups. An independent and systematic search of Ovid MEDLINE, Embase, Scopus, and PubMed for studies or reports published between 1946 and 2020 using keywords which include "immunization", "vaccin\*", "anticoagulant", "bleeding disorder or blood-clotting disorder", "pressure", and "intramuscular injection" yielded 99 publications addressing the application of pressure to the injection site following immunization of individuals with bleeding disorders or individuals receiving anticoagulants. The search was limited to publications in English and human studies. Although primary evidence related to the topic was scarce, the majority of the publications provided recommendations that were based on expert opinion or findings from a primary research study by Evans et al. The study reported that following the use of a 23-gauge needle and 1 to 2 minutes of pressure applied to the injection site in children with hemophilia receiving the hepatitis B vaccine, only six of 153 IM injections (4%) resulted in bruising, and none of the children required treatment with clotting factor concentrates. Findings from the literature review and the proposed recommendation were circulated among WG members who agreed on the recommendation to apply firm pressure to the injection site for ≥ 2 minutes in the specified groups.
Publications pertaining to vaccination of persons with selected specific conditions were searched using the search strategy (vaccine OR vaccination OR immunization), AND (splenectomy OR asplenia OR hyposplenia OR "chronic inflammatory disease" OR rheumatic OR IBD OR, "renal disease" OR "kidney disease" OR nephrotic OR ESRD OR diabetes) This additional literature review conducted to identify changes in evidence or vaccine recommendations for persons with the aforementioned conditions did not lead to any new findings that would warrant further revisions to the corresponding sections.
The section on 'Asplenia or hyposplenia' was revised to state that there are other conditions of concern in addition to sickle cell disease or thalassemia major that are associated with splenic dysfunction.
The two tables in the chapter outlining recommendations for use of non-live and live attenuated vaccines for persons with chronic diseases were updated. These tables' contents reflect some of the information in the main text of the chapter and include extra details, and are intended to be used as a complementary resource with the text. The contents of the text and tables were extracted from the corresponding vaccine-specific chapters in [Part 4](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) of the CIG and from NACI statements.
### Acknowledgements
The Public Health Agency of Canada (PHAC) would like to acknowledge the Part 3 Working Group, consisting of D Moore (Working Group Chair); NACI Members R Harrison, K Hildebrand, and Susan Smith; and NACI Liaison Representative A Pham-Huy and external expert Deepali Kumar, for their contributions to the revision of this chapter. PHAC participants on the Part 3 Working Group include C Jensen, N Mohamed, O Baclic, E Abrams and L Coward.
### Selected references
#### General references
American Academy of Pediatrics. Immunization in special clinical circumstances. In: Kimberlin DW, Brady MT, Jackson MA, Long SS (eds) Red Book: 2018 Report of the Committee on Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics; 2018. pp 67-111.
Committee to Advise on Tropical Medicine and Travel. The immunocompromised traveller. Can Commun Dis Rep 2007;33(ACS-4):1-24. Accessed June 28, 2021
Crawford NW, Bines JE, Royle J et al. Optimizing immunization in pediatric special risk groups. Expert Rev Vaccines 2011;10:175-86.
Kroger A, Bahta L, Hunter PKroger AT, Duchin J, Vázquez M. General best practice guidelines for immunization. Best practices guidance of the Advisory Committee on Immunization Practices (ACIP). Updated May 4, 2021.https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html Accessed May 21, 2021
Lail J, Fields E, Schoettker PJ. Quality improvement strategies for population management of children with medical complexity. Pediatrics. 2017;140(3):e20170484
Lobermann et al. Immunization in the adult immunocompromised host. Autoimmunity Reviews 2012;11:212-218
Lopez et al. Vaccination recommendations for the adult immunosuppressed patient: A systematic review and comprehensive field synopsis. J. Autoimmunity 2017: 80:10-27.
#### Asplenia, hyposplenia
Di Sabatino A, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic states. Lancet 2011; 378: 86–97.
Kuchar E, Miskiewicz K, Karlikowska M. A review of guidance on immunization in persons with defective or deficient splenic function. Br J Haemat 2015;171:683–694.
Simons MD, Scott-Sheldon LAJ, Risech-Neyman Y et al. Celiac disease and increased risk of pneumococcal infection: A systematic review and meta-analysis. Am J Med 2018;131:83–89.
Theilacker C, Ludewig K, Serr A. Overwhelming postsplenectomy infection: A prospective multicenter cohort study. Clin Infect Dis. 2016 62(7):871-878.
Tjernberg AR, Bonnedahl J, Inghammar M. Coeliac disease and invasive pneumococcal disease: a population-based cohort study. Epidemiol. Infect. (2017), 145, 1203–1209.
#### Autoimmune conditions
Bombardier C, Hazlewood GS, Akhavan P, et al. Canadian Rheumatology Association recommendations for the pharmacological management of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs: Part II. Safety. J Rheumatol 2012 Aug;39(8):1583-602.
Chaudrey K, Salvaggio M, Ahmed A, Mahmood S, Ali T. Updates in vaccination: recommendations for adult inflammatory bowel disease patients. World J Gastroenterol 2015; 21(11): 3184-3196.
Furer V, Rondaan C, Heijstek MW et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases Ann Rheum Dis. 2020 Jan;79(1):39-52.
Groot N, Heijstek MW, Wulffraat NM. Vaccinations in paediatric rheumatology: an update on current developments. Curr Rheumatol Rep. 2015 Jul;17(7):46. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449376/pdf/11926\_2015\_Article\_519.pdf Accessed May 21 2021.
Heijstek MW, Ott de Bruin LM, Bijl M, EULAR recommendations for vaccination in paediatric patients with rheumatic diseases. Ann Rheum Dis 2011;70:1704–1712.
Kantso B, Simonsen J,Hoffmann S.Inflammatory bowel disease patients are at increased risk of invasive pneumococcal disease: A nationwide Danish cohort study 1977–2013. Am J Gastroenterol 2015; 110:1582–1587
Luijten RKMAC, Cuppen BVJ, Bijlsma JWJ, Derksen RHWM. Serious infections in systemic lupus erythematosus with a focus on pneumococcal infections. Lupus (2014) 23, 1512–1516.
McCarthy EM, Azeez MA, Fitzpatrick FM et al. Knowledge, Attitudes and clinical practice of rheumatologists in vaccination of the at risk rheumatology patient population. J Clin Rheum 2012;18:237-41.
Morin MP, Quach C, Fortin E et al. Vaccination coverage in children with juvenile idiopathic arthritis followed at a paediatric tertiary care centre. Rheumatology 2012;276-90.
#### Bleeding disorders
Bauman ME, Hawkes M, Bruce A, Siddons S, Massicotte P. Immunizations in children requiring warfarin therapy. J Pediatr Hematol Oncol 2016;38:e329–e332.
Casajuana J, Iglesias B, Fabregas M et al. Safety of intramuscular influenza vaccine in patients receiving oral anticoagulation therapy: a single blinded multi-centre randomized controlled clinical trial. BMC Blood Disord 2008;8:1-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423363/
Evans D I K, Shaw A. Safety of intramuscular injection of hepatitis B vaccine in haemophiliacs. BMJ 1990;300:1694-5
Kroger A, Bahta L, Hunter P. General Best Practice Guidelines for Immunization. Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP). Vaccinating Persons with Increased Bleeding Risk p159-160. [www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf]. Accessed on May 21, 2021
Raj G, Kumar R, McKinney WP. Safety of intramuscular influenza immunization among patients receiving long-term warfarin anticoagulation therapy. Arch Intern Med.1995;155:1529-1531
van Aalsburg R, van Genderen PJ. Vaccination in patients on anticoagulants. Travel Med Infect Dis 2011;9: 310-11.
#### Kidney disease
Esposito S, Mastrolia MV, Prada E, Pietrasanta C, Principi N. Vaccine administration in children with chronic kidney disease. Vaccine. 2014 Nov 20;32(49):6601-6.
Mathew R, Mason D, Kennedy JS. Vaccination issues in patients with chronic kidney disease.Expert Rev Vaccines. 2014 Feb;13(2):285-98.
Soni R, Horowitz B, Unruh M. Immunization in end-stage renal disease: opportunity to improve outcomes. Semin Dial. 2013 Jul-Aug;26(4):416-26.
#### Other conditions
Centers for Disease Control and Prevention. Use of hepatitis B vaccination for adults with diabetes mellitus: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR, 2011;60(50):1709-1711.
Centers for Disease Control and Prevention. Clinical guidance for smallpox vaccine use in a postevent vaccination program. MMWR 2015;64(RR2):1-26
Langer-Gould A, Qian L, Tartof SY. Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases JAMA Neurol. 2014;71(12):1506-1513
Natarajan P, Cannon CP. Myocardial infarction vaccine? Evidence supporting the influenza vaccine for secondary prevention. Eur Heart J 2011;32:1701-03.
Schanzer DL, Langley JM, Tam TW. Co-morbidities associated with influenza-attributed mortality, 1994-2000, Canada. Vaccine. 2008 Aug 26;26(36):4697-703.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-6-immunization-patients-health-care-institutions.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-03-23
| None | None |
8ee3fd43f7977294df034396bb9caa31df081b44 | cma | Smallpox and mpox (monkeypox) vaccine: Canadian Immunization Guide | Smallpox and mpox (monkeypox) vaccine: Canadian Immunization Guide
Key information
# What
- Smallpox is a systemic viral illness with a characteristic rash that can have a 15% to 45% or higher mortality rate in an unimmunized population.
- Naturally occurring smallpox disease was eradicated by 1977 through a worldwide vaccination program.
- Remaining variola virus (causative agent of smallpox) stocks are kept in two World Health Organization (WHO) reference laboratories.
- The monkeypox virus is an orthopoxvirus that is genetically related to the variola virus.
- Since May 2022, cases of mpox (monkeypox) have been reported and transmission has occurred in a number of countries where it was not previously reported, including Canada.
- Smallpox vaccine provides cross-protection against all orthopoxviruses and can be used to protect individuals at risk against these viruses.
# Who
- Routine immunization of the general Canadian population with smallpox (vaccinia virus) vaccine is not recommended.
- Vaccination is recommended for individuals at risk of exposure to vaccinia or other replicative orthopoxviruses (including laboratory workers in research settings).
- In the event of a suspect case of smallpox, vaccination of public health and health care personnel involved in the case investigation and clinical management is indicated.
- Once a case of smallpox is confirmed, vaccination of contacts of cases and those living in the immediate vicinity (ring vaccination) is indicated. Vaccination of public health staff and health care workers, as well as first responders, such as police officers, firefighters, ambulance attendants, the military and others may also be indicated.
- Because of the relatively long incubation period for smallpox, historical data collected during the smallpox eradication program using the first generation vaccine showed that vaccination within 2 to 3 days of exposure may protect against clinical disease, and if given within 4 to 5 days, may decrease the risk of death.
- In the event of an outbreak involving other orthopoxviruses (e.g., monkeypox virus), vaccination of individuals at risk of infection is recommended. Vaccination can be offered as post-exposure prophylaxis as soon as possible, ideally within 4 days (but up to 14 days) after the last exposure, and can also be offered as pre-exposure vaccination for groups at highest risk of mpox.
# How
- Should a smallpox case be suspected, immediate telephone communication with local or provincial/territorial public health officials is required; the Public Health Agency of Canada (PHAC) should then be notified.
- Smallpox vaccine can be obtained by contacting PHAC's Centre for Emergency Preparedness and Response.
- For outbreak management guidance involving immunization against orthropoxviruses, the most recent National Advisory Committee on Immunization (NACI) statement should be consulted.
# Why
- To protect individuals at risk from monkeypox virus infection and other orthopoxvirus infections.
- To prevent the re-emergence and spread of smallpox, a severe and frequently fatal disease that has been eradicated by vaccination.
- A case of smallpox anywhere in the world constitutes a global health emergency.
- Under the International Health Regulations, it is the responsibility of PHAC to notify the WHO if a case of smallpox is suspected.
The Canadian Smallpox Contingency Plan provides recommendations for actions to be taken if smallpox occurs in Canada or elsewhere in the world. For additional information, refer to NACI's (PDF format).
Epidemiology
# Disease description
## Infectious agent
Smallpox is a systemic viral disease caused by the variola virus, a species of the *Poxviridae- family, belonging to the genus of *Orthopoxvirus*. For additional information about the variola virus, refer to the .
Mpox is a systemic viral disease caused by the monkeypox virus, a species of the *Poxviridae- family, belonging to the genus of *Orthopoxvirus*. For additional information about the monkeypox virus, refer to the .
## Reservoir
The reservoir for variola virus is exclusively humans. There are no animal reservoirs of variola virus and the last human case occurred in 1978. Currently, the virus is maintained in two designated laboratories.
The reservoir for monkeypox virus is not fully understood, but is believed to be rodents. Hosts include humans, squirrels, non-human primates, black-tailed prairie dogs, African brush-tailed porcupines, rats, and shrews. The virus is endemic in West and Central Africa.
## Transmission
Smallpox is spread by droplets from the respiratory tract or by direct or indirect contact with the virus shed from skin lesions. Airborne spread is thought to be less frequent, but transmission over significant distances has been documented, including transmission through a hospital stairwell. In addition, the virus is stable in dried form for months and has been transmitted by fomites such as bed linen.
The incubation period for smallpox is from 7 to 19 days, typically 10 to 14 days to the onset of illness and 2 to 4 more days to the onset of the rash. Infectivity can occur at any time from the development of the rash to the disappearance of all scabs - approximately 3 weeks. Infectivity is highest early in the clinical disease.
Monkeypox virus is spread from infected animals through a bite or scratch via direct contact with the infected animal's blood, body fluids, or lesions, or by preparing or eating meat or using products from an infected animal. It can also be spread from human-to-human, by direct contact with an infected person or their body fluids, including during sexual activity, by direct contact with virus-contaminated objects, and less frequently via respiratory droplets.
Mpox has a typical incubation period of 6-13 days from exposure, but can range from 5-21 days.
## Risk factors
Canadians born in 1972 or later have not been routinely immunized against smallpox and are therefore considered susceptible to orthopoxvirus infections. Discontinuation of vaccination for travel was recommended by the WHO in 1980 and was no longer required by any country by 1982. Individuals who have been vaccinated in the past against smallpox may have partial immunity to other orthopoxviruses.
## Spectrum of clinical illness
Early symptoms of smallpox include the sudden onset of high fever, malaise, headache, fatigue, severe backache, and occasional abdominal pain and vomiting. After 2 to 4 days the fever subsides and there is a characteristic rash consisting of deep-seated lesions first appearing on the face and extremities, including the palms and soles, and subsequently on the trunk. The rash progresses through all the phases of macules, papules, vesicles, pustules and then crusted scabs that fall off 3 to 4 weeks after the appearance of the rash. There are two strains of the smallpox virus, each with a different clinical course. *Variola minor- has a case fatality rate of less than 1%; *Variola major- has a case fatality rate among unvaccinated populations ranging from 15% to 45% or higher. Rates may vary depending up the virulence of the specific variola virus strain that circulates, and the vulnerability of the population it attacks. The case fatality rate is higher in pregnant women and in young children.
Mpox disease is usually self-limiting and resolves within 14 to 28 days. For information on the clinical manifestations of monkeypox virus infection, refer to the . The duration of communicability for monkeypox virus may be up to 2 to 4 weeks, based on limited evidence of polymerase chain reaction (PCR) detection of monkeypox virus in the upper respiratory tract, and people are considered infectious until all the lesions have scabbed, fallen off and been replaced with healed skin.
# Disease distribution
## Incidence/prevalence
### Global
The last known case of naturally occurring smallpox occurred in Somalia in 1977; two cases of smallpox occurred in England in 1978 as a result of a laboratory accident. In December 1979, the WHO officially declared that smallpox had been eradicated globally and in 1980 the World Health Assembly recommended all countries cease routine smallpox immunization programs. Remaining variola virus stocks are kept in two WHO reference laboratories in the United States (US) and Russia for research purposes.
With the breakup of the Soviet Union and the subsequent loss of safety and security controls over their biological weapon stockpiles, there has been a concern that there could be an accidental release of variola virus. In the US, a smallpox vaccination program was initiated in the military in December 2002. Subsequent smallpox vaccination programs were conducted in some health care workers in the US and the United Kingdom.
Due to its current eradication yet potential use as a biological weapon, the occurrence of a single case of smallpox anywhere in the world constitutes a global health emergency.
Mpox is endemic in Central and West Africa, but there have been cases and outbreaks in non-endemic countries due to international travel or the importation of infected animals from affected areas. There are two distinct clades of monkeypox virus: the Congo Basin (Central African) clade (now referred to as Clade I) and the West African clade (now referred to as Clade II). The Congo Basin clade has caused more severe illness. The 2022 multi-country monkeypox outbreak represented the first incidence of broader community transmission in a number of countries outside of certain regions of Africa. The international outbreak has primarily affected men who identify as gay, bisexual men or other men who have sex with men (gbMSM).
### National
Concerted vaccination campaigns were successful in eliminating endemic smallpox from Canada by 1946. Nova Scotia had a suspected case in 1949; with rigid quarantine, the disease did not spread. The final laboratory-confirmed case in Canada in 1962 involved an adolescent who returned to Toronto from Brazil.
Canada has been one of the countries affected by the 2022 multi-country mpox outbreak.
Preparations authorized for use in Canada
PHAC has a stock of three types of smallpox (vaccinia virus) vaccine (Sma):
- lyophilized (freeze-dried) vaccine - Smallpox Vaccine (dried) (Sanofi Pasteur Ltd.)
- frozen liquid formulation vaccine - Smallpox Vaccine (frozen-liquid) (Sanofi Pasteur Ltd).
- Imvamune® - Smallpox and Mpox (monkeypox) Vaccine (live-attenuated, non-replicating) (Bavarian Nordic A/S ), (Progress Therapeutics Inc. )
The lyophilized smallpox vaccine is an authorized product to vaccinate laboratory workers working with orthopoxviruses. The frozen liquid smallpox vaccine could be released in emergency situations (e.g., in response to a smallpox case) through Health Canada's Special Access Program. Both vaccines are prepared from live, vaccinia virus. Vaccinia virus is a member of the *Orthopoxvirus- family and confers immunity against variola (smallpox) and other orthopoxviruses through cross-reactivity.
Imvamune® , is a non-replicating, third generation smallpox vaccine manufactured by Bavarian Nordic. Imvamune® was initially authorized for use in Canada on November 21, 2013 as an Extraordinary Use New Drug Submission (EUNDS) for use by the Government of Canada in an emergency situation for active immunization against smallpox infection and disease in persons 18 years of age and older who have a contraindication to the first or second generation smallpox vaccines. It was subsequently approved under a supplement to the EUNDS on November 5, 2020 for active immunization against smallpox, monkeypox virus and related orthopoxvirus infections and disease in adults 18 years of age and older determined to be at high risk for exposure.
PHAC provides smallpox vaccine to laboratory staff working with vaccinia virus or other orthopoxviruses and would also provide vaccine to provinces/territories in the event of a smallpox case or orthopoxvirus outbreaks. In the context of the ongoing mpox outbreaks, Imvamune® is currently being provided to provinces and territories for post-exposure and pre-exposure vaccination to individuals/groups considered at high risk of mpox. Imvamune® is not available for general use.
For emergency (suspected or confirmed smallpox cases) or non-emergency situations, contact the Centre of Emergency Preparedness and Response, Health Portfolio Operations Centre, PHAC by telephone: 1-800-545-7661 or 613-952-7940 or e-mail: .
# Vaccinia immune globulin
Vaccinia Immune Globulin Intravenous (Human) (VIG) is a solution of gamma globulin from the serum of individuals recently immunized with smallpox vaccine. It is used to treat severe smallpox vaccine-associated adverse events. The Canadian Smallpox Contingency Plan indicates that VIG would be sent to the provinces/territories at the same time as smallpox vaccine and related supplies if smallpox occurs in Canada.
Immunogenicity, efficacy and effectiveness
In the early 1970s before smallpox was eradicated, a retrospective study conducted in West Pakistan showed a mortality rate of 52% among those who had never been vaccinated, 1.7% among those who had been vaccinated within 10 years, and 11% among those who had been vaccinated 20 or more years earlier.
The specific mechanisms that result in immunity to smallpox following vaccination have not been well characterized. Studies conducted in the 1970s suggest that both antibody and cell-mediated immunity are stimulated by smallpox vaccination. A more recent study showed that more than 95% of primary vaccinees had detectable neutralizing antibody within 1 to 2 weeks after immunization and strong increases in vaccinia-specific CD8+ cytotoxic T lymphocytes and interferon-gamma-producing T cells.
There is very little data indicating the efficacy or effectiveness of Imvamune vaccination against monkeypox virus infection or mpox disease in the context of pre-exposure or post-exposure vaccination, although efforts are underway to determine the effectiveness of the vaccine during the current mpox outbreak. The majority of clinical data for Imvamune pre-exposure vaccination are limited to clinical immunogenicity or indirect protection from vaccinia (the virus used for first or second generation smallpox vaccines). Indirect clinical immunological evidence showed that Imvamune was able to generate immune responses by week two after a first dose, and comparable immune responses to previous generation smallpox vaccines after two doses by week six.
Recommendations for use
Given that naturally occurring smallpox has been eradicated worldwide and smallpox vaccination is associated with the risk of significant morbidity and even mortality, the overall risk benefit analysis supports the recommendation to not routinely immunize the general Canadian population against smallpox. As a result, smallpox vaccination is highly restricted.
# Outbreak control
## Smallpox
The Canadian Smallpox Contingency Plan includes actions to be taken if a case of smallpox occurs in Canada or elsewhere. A single case of smallpox is considered an outbreak. In general terms, cases should be isolated immediately, preferably at home. If hospitalization is required, cases should be admitted to rooms under negative pressure equipped with high efficiency particulate air-filtration (HEPA) filters (airborne infection isolation rooms). Contacts and those living in the immediate vicinity of the identified case should be immunized immediately (ring vaccination) and placed under observation in quarantine. Vaccination is indicated for face-to-face contacts (less than 6 feet or 2 meters), household contacts, personnel involved in the medical care, public health evaluation or transportation of confirmed or suspected smallpox cases, laboratory personnel involved in the collection or processing of clinical specimens from confirmed or suspected smallpox cases, and persons who have a high likelihood of exposure to infectious materials (e.g., those responsible for medical waste disposal, linen disposal or disinfection) of smallpox cases.
Vaccine can be given after exposure with beneficial effect as smallpox has a relatively long incubation period. Historical data collected during the smallpox eradication program using first generation vaccine showed that vaccination within 2 to 3 days of exposure may protect against clinical disease, and if given within 4 to 5 days, may decrease the risk of death.
## Mpox (monkeypox)
In the context of an active mpox outbreak, vaccination using Imvamune should be offered to individuals/groups considered at high-risk of mpox.
Post-exposure vaccination using a single dose of Imvamune may be offered to individuals with high risk exposures to a probable or confirmed case of mpox, or within a setting where transmission is happening. Post-exposure vaccination should be offered as soon as possible, ideally within 4 days (but up to 14 days) of last exposure. A second dose may be offered after 28 days from the first dose if an assessment indicates an ongoing risk of exposure or if the individual is in a high-risk group for whom pre-exposure vaccination is recommended.
During the 2022 outbreak, the following individuals/groups have been considered for pre-exposure vaccination with Imvamune:
- Men who have sex with men (MSM), and individuals who have sex with MSM, and who meet at least one of the following criteria:
+ Having two or more sexual partners or being in a relationship where at least one of the partners has other sexual partners
+ Having had a confirmed sexually transmitted infection acquired in the last year
+ Engaging in sexual contact in sex-on-premises venues
- Individuals who self-identify as sex workers regardless of self- identified sex/gender
- Staff or volunteers in sex-on-premises venues where workers may have contact with fomites potentially contaminated with monkeypox virus without the use of personal protective equipment
Individuals receiving pre-exposure vaccination should be offered Imvamune as a two-dose primary series, with at least 28 days between first and second 0.5 mL sub-cutaneous doses. Individuals considered moderately to severely immunocompromised and eligible for pre-exposure vaccination should be prioritized to receive two doses of Imvamune administered at the authorized interval (28 days between doses).
Neither post-exposure nor pre-exposure vaccination should be offered to individuals with a prior documented history of monkeypox virus infection or those who are symptomatic and meet the definition of suspect, probable or confirmed mpox case.
Immunocompetent individuals recommended for Imvamune pre-exposure or post-exposure vaccination should receive a single dose if they have previously been vaccinated with a live replicating first or second generation smallpox vaccine (i.e., as a booster dose). However, individuals considered moderately to severely immunocompromised should receive two doses, regardless of previous smallpox vaccination.
In situations where there is ongoing mpox outbreak activity and limited vaccine supply, dose sparing strategies should be considered for pre-exposure vaccination of immunocompetent individuals in order to expand coverage to a broader population. These strategies may include extending the interval between doses and intradermal fractional dose administration. Intradermal administration (ID) can be used among immunocompetent adults when given as a second dose following a first dose given subcutaneously, provided dose sparing and safe administration practices are feasible. In situations where individuals received a first dose of Imvamune using an ID route, then the dose should be considered valid. Individuals who are <18 years of age, at risk of keloid scars, or moderately to severely immunocompromised should be offered Imvamune using the subcutaneous route of administration with a full dose only. For additional details, refer to .
# Vaccinia immune globulin
PHAC's Centre for Emergency Preparedness and Response has a supply of VIG based on a requirement of 1 dose of VIG for every 10,000 doses of first and second generation smallpox vaccines. VIG is indicated to treat severe smallpox vaccine-associated adverse events: eczema vaccinatum, progressive vaccinia, severe or recurrent generalized vaccinia, and extensive lesions resulting from accidental implantation (transfer of vaccinia virus from the primary vaccination site to other parts of the body). VIG is ineffective in the treatment of post-vaccinial encephalitis and has no role in the treatment or prevention of smallpox.
# Booster doses and re-immunization
For both first and second generation smallpox vaccines, booster doses should be given every 10 years for laboratory workers with ongoing risk of exposure.
Imvamune may be offered to personnel working with replicating orthopoxviruses that pose a risk to human health (vaccinia or monkeypox virus) in laboratory settings and who are at high risk of occupational exposure. If Imvamune is used, two doses should be given at least 28 days apart. A booster dose may be offered after 2 years if the risk of exposure extends beyond that time.
For immunocompetent individuals who have received a live replicating first or second generation smallpox vaccine in the past and who are at high risk for occupational exposure, a single dose of Imvamune may be offered (i.e., as a booster dose), rather than the two-dose primary vaccine series. This single Imvamune dose should be given at least two years after the latest live replicating smallpox vaccine dose.
Vaccination of Specific Populations
# Workers
Smallpox vaccine, including Imvamune, may be indicated for certain workers at high risk of exposure, such as laboratory workers who handle vaccinia or other replicating orthopoxviruses (including monkeypox virus and recombinant vaccinia vaccine products) in specialized reference or research facilities.
In the event of a suspect case of smallpox, vaccination of public health and health care personnel involved in the case investigation and clinical management is indicated. Once a case is confirmed, vaccination of public health staff and health care workers, as well as first responders such as police officers, firefighters, ambulance attendants, the military and others may also be indicated.
Serologic testing
Serologic testing is not recommended before or after receiving smallpox vaccine.
Administration Practices
# Dose, route of administration and schedule
Both first and second generation smallpox vaccines are administered by scarification into the epidermis, usually in the deltoid area of the non-dominant arm, by using the multiple-puncture technique with a bifurcated needle, packaged with the vaccine and diluent. According to the product labelling, 15 punctures are recommended for vaccination. A trace of blood should appear at the vaccination site after 15 to 20 seconds; if no trace of blood is visible, additional insertions should be made by using the same bifurcated needle without reinserting the needle into the vaccine vial. If alcohol is used to cleanse the skin before immunization, the skin must be allowed to dry thoroughly before the vaccine is administered, to prevent inactivation of the vaccine by alcohol.
Other methods of administration, such as multiple pressure method are possible in case bifurcated needles are not readily available. Refer to the product label for detailed instructions.
When vaccinia virus is inoculated into the epidermis the virus induces an immune reaction that is termed "a take". There is often no visible reaction for the first few days. On day 3 to 4 a papule appears and progresses to a vesicle with surrounding erythema. Typically, one week or so after vaccination, the centre of the vesicle umbilicates and pustulates. After about 2 weeks, the pustule crusts and a dark brown or black scab forms. After 3 weeks, the scab detaches leaving a scar. The vaccination site should be inspected 6 to 8 days after vaccination to ensure that a take has occurred. If there is no evidence of papules or vesicles and erythema, the person should be vaccinated again.
Optimal infection-control practices and appropriate vaccination site care should be used. Gloves should be worn by the vaccine provider when administering smallpox vaccine due to the increased risk of autoinoculation from the use of a bifurcated needle. Each vaccinee and anyone caring for the vaccination site should wash their hands thoroughly after touching the site or handling bandages used to cover the site. Contaminated bandages and scabs should be placed in sealed plastic bags before disposal in the garbage. The vaccinee should avoid rubbing or scratching the site.
A sterile piece of porous bandage (e.g., gauze) should be used to loosely cover the vaccination site until the scab falls off in order to deter the vaccinee from touching the scab, to prevent inadvertent self-inoculation or inoculation of others, and to contain the scab so it is not lost. Preferably, a semi-permeable dressing should be placed over the gauze and not directly on the site; occlusive dressings should not be used. Dressings used to cover the site should be changed frequently to prevent accumulation of exudates and consequent maceration. Frequent dressing changes are particularly important for vaccinees who have close contact with children or people at high risk for vaccinia complications.
Health care workers providing direct patient care should keep their vaccination sites covered with gauze in combination with a semipermeable membrane dressing to absorb exudates and to provide a barrier for containment of vaccinia virus to minimize the risk of transmission; the dressing should also be covered by a layer of clothing. Similar precautions should be used for vaccinated persons in close contact with children or other persons at high risk of serious complications of vaccinia.
Imvamune is administered as 0.5 mL subcutaneously (SC) using a two-dose schedule with a minimum interval of 28 days between doses. In cases of limited vaccine supply, Imvamune can also be administered using a fractional second dose (1/5th of SC dose) administered intradermally.
For information on the management of Imvamune administration errors, refer to the .
# Vaccinia immune globulin
VIG should be given intravenously through a dedicated infusion line at a rate of 2 mL/min; VIG is compatible with sodium chloride 0.9%. Parenteral products should be inspected visually for particulate matter and discoloration prior to administration; it should not be used if the solution is turbid. The vial should not be shaken as it may cause foaming.
VIG should be administered at a dose of 6,000 units/kg as soon as symptoms appear and are judged to be due to a severe vaccinia-related complication. Two exceptions to this are vaccinia keratitis and encephalitis. VIG should not be given for vaccinia keratitis due to the potential of increased corneal scarring, and should not be given for encephalitis due to lack of efficacy. For other VIG-treated complications, consideration may be given to repeat dosing, depending on the severity of the symptoms and response to treatment; however, clinical data on repeat doses are lacking. The administration of an additional dose of 9,000 units/kg may be considered in the event that the person does not respond to the initial 6,000 units/kg dose.
# Concurrent administration with other vaccines
In non-emergency situations (i.e., non-outbreaks), both first and second generation smallpox vaccines can be administered concurrently with any inactivated vaccine. To avoid confusion in ascertaining which vaccine might have caused post-vaccination skin lesions or other adverse events, varicella (chickenpox) vaccine should not be administered concurrently with smallpox vaccine; there must be an interval of at least 4 weeks between administration of varicella vaccine and smallpox vaccine. Smallpox vaccine can be administered simultaneously concurrently with other live parenteral vaccines; if not administered concurrently, there must be an interval of at least 4 weeks between smallpox vaccine and other live parenteral vaccines.
Currently, no data exist on the concurrent administration of Imvamune with other vaccines. If concurrent administration with another vaccine is indicated, immunization should be done in different limbs.
To minimize the potential risk of interactions or erroneous attribution of an adverse event following immunization (AEFI) to a particular vaccine, it is recommended to administer non-live vaccines more than 2 weeks and live vaccines at least 4 weeks before or after administration of Imvamune.
First and second generation orthopoxvirus vaccines and mRNA COVID-19 vaccines both have a potential risk of cardiac adverse events (myocarditis). Risk for myo- or pericarditis with the newer generation non-replicating attenuated virus vaccine Imvamune is still unknown. It would be prudent to wait for a period of at least 4 weeks before or after the administration of mRNA COVID-19 vaccine in order to prevent erroneous attribution of an adverse event following immunization (AEFI) to one particular vaccine or the other. This suggested minimum waiting period between vaccines is precautionary at this time. Protection from monkeypox virus exposure should be prioritized and recent mRNA vaccine receipt should not delay Imvamune pre-exposure vaccination or post-exposure vaccination if protection is urgent.
# Post-vaccination counselling
All vaccine and VIG recipients should be instructed to seek medical care if they develop signs or symptoms of a serious adverse event or an allergic reaction following immunization.
Storage requirements
Lyophilized smallpox vaccine should be stored in a refrigerator at +2°C to +8°C and reconstituted before use. The frozen liquid smallpox vaccine is frozen for long-term storage and thawed for shipping; the thawed vaccine should be maintained between +2°C and +8°C. Open vaccine vials should be used within 24 hours.
Imvamune should be stored frozen at -20°C ± 5°C or -50°C ± 10°C or -80°C ± 10°C. After thawing, the vaccine should be used immediately or can be stored at +2°C to +8°C for up to 2 weeks prior to use. Do not refreeze a vial once it has been thawed. Store in the original package to protect from light.
Safety and adverse events
Common adverse events occur in 1% to less than 10% of vaccinees. Very common adverse events occur in 10% or more of vaccinees.
Uncommon adverse events occur in 0.1% to less than 1% of vaccinees. Rare and very rare adverse events occur, respectively, in 0.01% to less than 0.1% and less than 0.01% of vaccinees.
# First and second generation smallpox vaccines and immunoglobulin safety and adverse events
## Common and local adverse events
In a UK study of 200 health care workers, 142 (71%) of vaccinees reported pain at the injection site, of which 25% considered it to be moderate or severe; 32 vaccinees (16%) recorded a temperature of greater than 37.7°C, two of which exceeded 39°C. Other, mainly minor, adverse events were common; local itching was reported in 72%, erythema at the injection site in 27%, axillary pain or lymphadenopathy in 38%, malaise or influenza-like symptoms in 40% and headache in 23%. The incidences of minor adverse events were lower in re-vaccinees, compared with primary vaccine recipients. The study used a single dose of the Swiss Serum Institute (SSI) vaccine, containing the Elstree/Lister strain of vaccinia virus.
Bacterial infection of the vaccination site can occur.
## Less common and serious or severe adverse events
### Inadvertent inoculation
Inadvertent inoculation is the transfer of the virus from the site of immunization to other body sites or other persons resulting in vaccinia lesions. The most susceptible areas are the eye, mouth, nose, face and genitalia. Children are most susceptible to inadvertent inoculation. Inadvertent inoculation is the most common (significant) adverse reaction, with rates approaching 600 cases per million doses administered. Most ensuing lesions heal spontaneously. There are case reports of secondary and tertiary vaccinia arising in sexual contacts of a person recently vaccinated; these cases were severe enough to require VIG to manage vaccinia-related complications. When a secondary case of vaccinia is diagnosed, contract tracing is indicated to ascertain whether there are additional secondary or tertiary cases.
### Generalized vaccinia
Generalized vaccinia may occur within a week after vaccination. Lesions appear on unimmunized skin and are thought to arise from viremia. Lesions are similar to those associated with the vaccination site but are usually smaller and evolve to scarring more rapidly, often within a week. In healthy individuals this is a benign complication of primary vaccination that needs to be differentiated from progressive vaccinia. Individuals with underlying and unsuspected immunosuppressive illnesses may develop a serious reaction.
### Progressive vaccinia (Vaccinia Necrosum)
Progressive vaccinia is a severe complication of smallpox vaccination. It often occurs because of an immune defect, especially T cell deficiencies. It is characterized by progressive necrosis at the site of immunization and, in the presence of viremia, leads to implants in distant skin sites and multiple organs. Progression is slow, persistent and resistant to treatment. In those with profound T cell defects, it is nearly always fatal.
### Eczema vaccinatum
Eczema vaccinatum occurs in vaccinees or their unvaccinated contacts with active or healed eczema lesions or other exfoliative skin conditions. Vaccinial skin lesions appear on skin that is currently or was previously affected by eczema. Usually the illness is mild and self-limited, but it can be severe and fatal.
### Vaccinia keratitis
Vaccinia keratitis can threaten eyesight through corneal abrasions, ulcerations and subsequent corneal clouding. If this occurs, consultation with an ophthalmologist is strongly recommended. VIG is contraindicated because of the potential of increased corneal scarring.
### Post-vaccinial encephalitis
Post-vaccinial encephalitis is a rare but serious complication that can develop 7 to 14 days after vaccination. There are no known predictors of susceptibility, but the incidence is somewhat higher among infants less than 1 year of age. Approximately, 25% of cases with encephalitis develop permanent sequelae (both motor and/or intellectual impairment) and up to 35% die. VIG is not recommended due to lack of efficacy.
### Acute myopericarditis
During a smallpox vaccination program for US military personnel which started in 2002, a previously unreported adverse event, acute myopericarditis, was recognized. Most of the affected vaccinees experienced chest pain and returned to normal activities within 7 to 10 days, and all recovered. It is unclear whether these events were adverse outcomes of smallpox vaccination. The smallpox vaccine (Dryvax, Wyeth Laboratories) containing the New York City Board of Health strain of vaccinia was used in this program.
VIG is available to treat certain smallpox vaccine-associated adverse events. Refer to for additional information.
# Third generation smallpox vaccine safety and adverse events
## Common adverse events
Most adverse events develop within a few days after receiving the vaccine.
The most common local adverse events following Imvamune immunization are pain, erythema, induration and swelling at the site of injection. The most common systemic adverse reactions observed after subcutaneous vaccination with Imvamune are fatigue, headache, myalgia, and nausea. Most of these reactions are mild to moderate intensity and resolve within the first seven days following vaccination.
## Less common and serious or severe adverse events
In clinical trials, cardiac adverse events of special interest (AESI) were reported to occur in 1.4% (91/6,640) of Imvamune recipients, 0.2% (3/1,206) of placebo recipients who were smallpox vaccine-naïve and 2.1% (16/762) of Imvamune recipients who were smallpox vaccine-experienced. Among the cardiac AESIs reported, 6 cases were considered to be causally related to Imvamune vaccination. The events reported included tachycardia, electrocardiogram T wave inversion, abnormal electrocardiogram, electrocardiogram ST segment elevation, abnormal electrocardiogram T wave, and palpitations. None of the 6 events considered vaccine-related were considered serious.
No trends have been identified which suggest the occurrence of any particular unexpected adverse reaction or classes of adverse reactions following vaccination. To date, myocarditis has not been determined to be causally associated with Imvamune, but monitoring is ongoing.
# Guidance on reporting Adverse Events Following Immunization (AEFI)
To ensure the ongoing safety of vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical.
Vaccine providers are asked to report, through officials, any serious or unexpected adverse event thought to be temporally related to smallpox vaccination, including any case of secondary or tertiary vaccinia. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.
# Contraindications and precautions
## First and second generation smallpox vaccines
Contraindications to smallpox vaccines are only applicable if the variola (smallpox) virus has not been introduced into the environment. In an outbreak situation, if smallpox cases are occurring and a risk of infection exists for an individual, there are no absolute contraindications to immunization.
The product leaflet lists the following contraindications in a non-emergency setting. For people at higher risk of vaccinia complications, potential risks and benefits must be weighed, including VIG availability. A third generation smallpox vaccine would be a better choice for these individuals, if available.
### Persons less than 18 years of age
Smallpox vaccination is contraindicated for children and adolescents because they are more likely to suffer from adverse reactions and cause inadvertent self-reinoculation and inoculation of others.
### Hypersensitivity or anaphylaxis
Smallpox vaccines are contraindicated in people with a history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Refer to in Part 1 for lists of all vaccines and passive immunizing agents authorized for use in Canada and their contents. For smallpox vaccines, potential allergens include: streptomycin, neomycin and latex in the stopper of vial.
### Immunodeficiency or immunocompromised
Smallpox vaccination is contraindicated for people who are immunocompromised such as those with leukemia, lymphoma, or a systemic malignancy; persons on immunocompromising therapies; persons with some hereditary immune deficiency disorders; and persons with HIV/AIDS. It is generally contraindicated pre/post solid organ transplant and hematopoietic stem cell transplant (HCST). Refer to in Part 3 for additional information.
### Atopic dermatitis and other widespread skin disorders
Diffuse vaccinia virus infection can occur in the presence of acute atopic dermatitis and other widespread exfoliative skin disorders.
### Pregnancy and breastfeeding
Smallpox vaccine is generally contraindicated in pregnant women in non-emergency situations although it is not known to cause congenital malformations. It can very rarely lead to fetal vaccinia after primary immunization during pregnancy, resulting in stillbirth or neonatal death. Women of childbearing age should be asked before vaccination if they are pregnant or intend to become pregnant during the next 4 weeks. If a woman becomes pregnant within 4 weeks after smallpox vaccination she should be counselled regarding concern for the fetus.
Breastfeeding mothers should not receive the smallpox vaccine in non-emergency situations. The close physical contact that occurs during breastfeeding increases the chance of inadvertent inoculation of the baby. It is not known whether vaccine virus or antibodies are excreted in human milk. A breastfeeding woman should only be immunized if she has been exposed to smallpox and a third generation vaccine is not available; in that case breastfeeding and other close contact should be delayed until after the vaccination scab has separated from the vaccination site.
### Heart disease and cardiac risk factors
Smallpox vaccine is contraindicated in people with known underlying heart disease (with or without symptoms), or who have three or more known major cardiac risk factors (i.e., hypertension, diabetes, hypercholesterolemia, heart disease at age 50 years or younger in a first-degree relative, and smoking). A risk assessment needs to be done in an emergency situation such as exposure to a case of smallpox.
The product monograph lists the following precautions:
Ocular or periorbital disease
Persons with inflammatory eye disease may be at increased risk for inadvertent inoculation as a result of touching or rubbing the eye. Therefore, deferring vaccination is prudent for persons with inflammatory eye diseases requiring steroid treatment until the condition resolves and the course of therapy is complete.
Close contacts
Generally, smallpox vaccine should not be administered to household contacts of an immunocompromised person in a non-emergency situation. If vaccination is required in an outbreak situation, precautions should be taken for unvaccinated household and other close contacts. Vaccinees with household and other close contacts with active eczema or a history of eczema or other exfoliative skin conditions, immunocompromising conditions, or with close contact with infants or pregnant women, should take special precautions in order to prevent viral transfer to these contacts. Such precaution can include isolation of the vaccinee from their higher risk household contacts until the vaccine scab falls off.
## Third generation smallpox vaccine
Contraindications to Imvamune include hypersensitivity to this vaccine. Individuals with suspected severe hypersensitivity reactions (e.g., anaphylaxis) after receiving the first dose of the vaccine should consult an . There is evidence that some individuals with immediate allergic reactions to vaccines in general (although less data are available for Imvamune) can safely receive a subsequent dose of the same vaccine with low risk of a systemic reaction under the supervision of an allergist. Individuals with confirmed or suspected hypersensitivity to the potential allergens contained in the vaccine components (egg, tromethamine, or antibiotics) can receive the vaccine without expert consultation; prolonged observation (30 minutes) may be considered.
Data on Imvamune are limited in people who are pregnant, lactating or <18 years of age, requiring an assessment of the benefits vs. the risks in these populations.
## Vaccinia immune globulin
The most common adverse events related to VIG are headache, nausea, rigors and dizziness.
Relative contraindications to VIG include:
- a history of systemic allergic reactions to human immune globulin products
- isolated vaccinia keratitis due to the potential of increased corneal scarring
- selective immunoglobulin A deficiency with antibodies against IgA and a history of IgA hypersensitivity (because VIG contains trace amounts of IgA)
It is not known whether VIG can cause fetal harm when given to pregnant women. Counselling based on an individual risk benefit assessment is indicated. VIG should not be withheld if a pregnant woman experiences a condition for which VIG is needed.
Other Considerations
# Drug interactions
There is some evidence for tuberculin skin test (TST) suppression following the administration of live, attenuated virus vaccines; a TST can be done on the same day as immunization or delayed until 4 weeks after administering a first or second generation smallpox vaccine.
Chapter revision process
This chapter was updated to reflect guidance based on current evidence and NACI's expert opinion on the use of Imvamune in the context of mpox outbreaks in Canada. |
Smallpox and mpox (monkeypox) vaccine: Canadian Immunization Guide
===================================================================
For health professionals
* [Previuous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-20-rubella-vaccine.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html)
**Last partial content update** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): June 2023
**June 2023** - The chapter was revised to align with the World Health Organization's preferred term of 'mpox' for monkeypox disease. Additionally, the "Safety and adverse events" section was updated to expand on the safety of Imvamune vaccine based on data from clinical trials.
**Last complete chapter revision: January 2014**
On this page
------------
* [Key information](#a1)
* [Epidemiology](#a2)
* [Preparations authorized for use in Canada](#a3)
* [Immunogenicity, efficacy and effectiveness](#a4)
* [Recommendations for use](#a5)
+ [Outbreak control](#a5.1)
- [Smallpox](#a5.1.1)
- [Mpox (monkeypox](#a5.1.2))
+ [Booster doses and re-immunization](#a5.2)
* [Vaccination of specific populations](#a6)
* [Serologic testing](#a7)
* [Administration practices](#a8)
* [Storage requirements](#a9)
* [Safety and adverse events](#a10)
* [Other considerations](#a11)
* [Chapter revision process](#a12)
* [Acknowledgements](#a13)
* [Selected references](#a14)
Key information
---------------
### What
* Smallpox is a systemic viral illness with a characteristic rash that can have a 15% to 45% or higher mortality rate in an unimmunized population.
* Naturally occurring smallpox disease was eradicated by 1977 through a worldwide vaccination program.
* Remaining variola virus (causative agent of smallpox) stocks are kept in two World Health Organization (WHO) reference laboratories.
* The monkeypox virus is an orthopoxvirus that is genetically related to the variola virus.
* Since May 2022, cases of mpox (monkeypox) have been reported and transmission has occurred in a number of countries where it was not previously reported, including Canada.
* Smallpox vaccine provides cross-protection against all orthopoxviruses and can be used to protect individuals at risk against these viruses.
### Who
* Routine immunization of the general Canadian population with smallpox (vaccinia virus) vaccine is not recommended.
* Vaccination is recommended for individuals at risk of exposure to vaccinia or other replicative orthopoxviruses (including laboratory workers in research settings).
* In the event of a suspect case of smallpox, vaccination of public health and health care personnel involved in the case investigation and clinical management is indicated.
* Once a case of smallpox is confirmed, vaccination of contacts of cases and those living in the immediate vicinity (ring vaccination) is indicated. Vaccination of public health staff and health care workers, as well as first responders, such as police officers, firefighters, ambulance attendants, the military and others may also be indicated.
* Because of the relatively long incubation period for smallpox, historical data collected during the smallpox eradication program using the first generation vaccine showed that vaccination within 2 to 3 days of exposure may protect against clinical disease, and if given within 4 to 5 days, may decrease the risk of death.
* In the event of an outbreak involving other orthopoxviruses (e.g., monkeypox virus), vaccination of individuals at risk of infection is recommended. Vaccination can be offered as post-exposure prophylaxis as soon as possible, ideally within 4 days (but up to 14 days) after the last exposure, and can also be offered as pre-exposure vaccination for groups at highest risk of mpox.
### How
* Should a smallpox case be suspected, immediate telephone communication with local or provincial/territorial public health officials is required; the Public Health Agency of Canada (PHAC) should then be notified.
* Smallpox vaccine can be obtained by contacting PHAC's Centre for Emergency Preparedness and Response.
* For outbreak management guidance involving immunization against orthropoxviruses, the most recent National Advisory Committee on Immunization (NACI) statement should be consulted.
### Why
* To protect individuals at risk from monkeypox virus infection and other orthopoxvirus infections.
* To prevent the re-emergence and spread of smallpox, a severe and frequently fatal disease that has been eradicated by vaccination.
* A case of smallpox anywhere in the world constitutes a global health emergency.
* Under the International Health Regulations, it is the responsibility of PHAC to notify the WHO if a case of smallpox is suspected.
The Canadian Smallpox Contingency Plan provides recommendations for actions to be taken if smallpox occurs in Canada or elsewhere in the world. For additional information, refer to NACI's [Statement on smallpox vaccination](https://publications.gc.ca/collections/Collection/H12-21-2-28-1.pdf) (PDF format).
Epidemiology
------------
### Disease description
#### Infectious agent
Smallpox is a systemic viral disease caused by the variola virus, a species of the *Poxviridae* family, belonging to the genus of *Orthopoxvirus*. For additional information about the variola virus, refer to the [Smallpox Pathogen Safety Data Sheet](/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/variola-virus.html).
Mpox is a systemic viral disease caused by the monkeypox virus, a species of the *Poxviridae* family, belonging to the genus of *Orthopoxvirus*. For additional information about the monkeypox virus, refer to the [Monkeypox Virus Pathogen Safety Data Sheet](/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/monkeypox-virus.html).
#### Reservoir
The reservoir for variola virus is exclusively humans. There are no animal reservoirs of variola virus and the last human case occurred in 1978. Currently, the virus is maintained in two designated laboratories.
The reservoir for monkeypox virus is not fully understood, but is believed to be rodents. Hosts include humans, squirrels, non-human primates, black-tailed prairie dogs, African brush-tailed porcupines, rats, and shrews. The virus is endemic in West and Central Africa.
#### Transmission
Smallpox is spread by droplets from the respiratory tract or by direct or indirect contact with the virus shed from skin lesions. Airborne spread is thought to be less frequent, but transmission over significant distances has been documented, including transmission through a hospital stairwell. In addition, the virus is stable in dried form for months and has been transmitted by fomites such as bed linen.
The incubation period for smallpox is from 7 to 19 days, typically 10 to 14 days to the onset of illness and 2 to 4 more days to the onset of the rash. Infectivity can occur at any time from the development of the rash to the disappearance of all scabs - approximately 3 weeks. Infectivity is highest early in the clinical disease.
Monkeypox virus is spread from infected animals through a bite or scratch via direct contact with the infected animal's blood, body fluids, or lesions, or by preparing or eating meat or using products from an infected animal. It can also be spread from human-to-human, by direct contact with an infected person or their body fluids, including during sexual activity, by direct contact with virus-contaminated objects, and less frequently via respiratory droplets.
Mpox has a typical incubation period of 6-13 days from exposure, but can range from 5-21 days.
#### Risk factors
Canadians born in 1972 or later have not been routinely immunized against smallpox and are therefore considered susceptible to orthopoxvirus infections. Discontinuation of vaccination for travel was recommended by the WHO in 1980 and was no longer required by any country by 1982. Individuals who have been vaccinated in the past against smallpox may have partial immunity to other orthopoxviruses.
#### Spectrum of clinical illness
Early symptoms of smallpox include the sudden onset of high fever, malaise, headache, fatigue, severe backache, and occasional abdominal pain and vomiting. After 2 to 4 days the fever subsides and there is a characteristic rash consisting of deep-seated lesions first appearing on the face and extremities, including the palms and soles, and subsequently on the trunk. The rash progresses through all the phases of macules, papules, vesicles, pustules and then crusted scabs that fall off 3 to 4 weeks after the appearance of the rash. There are two strains of the smallpox virus, each with a different clinical course. *Variola minor* has a case fatality rate of less than 1%; *Variola major* has a case fatality rate among unvaccinated populations ranging from 15% to 45% or higher. Rates may vary depending up the virulence of the specific variola virus strain that circulates, and the vulnerability of the population it attacks. The case fatality rate is higher in pregnant women and in young children.
Mpox disease is usually self-limiting and resolves within 14 to 28 days. For information on the clinical manifestations of monkeypox virus infection, refer to the [PHAC webpage](/en/public-health/services/diseases/mpox/health-professionals.html#a4). The duration of communicability for monkeypox virus may be up to 2 to 4 weeks, based on limited evidence of polymerase chain reaction (PCR) detection of monkeypox virus in the upper respiratory tract, and people are considered infectious until all the lesions have scabbed, fallen off and been replaced with healed skin.
### Disease distribution
#### Incidence/prevalence
##### Global
The last known case of naturally occurring smallpox occurred in Somalia in 1977; two cases of smallpox occurred in England in 1978 as a result of a laboratory accident. In December 1979, the WHO officially declared that smallpox had been eradicated globally and in 1980 the World Health Assembly recommended all countries cease routine smallpox immunization programs. Remaining variola virus stocks are kept in two WHO reference laboratories in the United States (US) and Russia for research purposes.
With the breakup of the Soviet Union and the subsequent loss of safety and security controls over their biological weapon stockpiles, there has been a concern that there could be an accidental release of variola virus. In the US, a smallpox vaccination program was initiated in the military in December 2002. Subsequent smallpox vaccination programs were conducted in some health care workers in the US and the United Kingdom.
Due to its current eradication yet potential use as a biological weapon, the occurrence of a single case of smallpox anywhere in the world constitutes a global health emergency.
Mpox is endemic in Central and West Africa, but there have been cases and outbreaks in non-endemic countries due to international travel or the importation of infected animals from affected areas. There are two distinct clades of monkeypox virus: the Congo Basin (Central African) clade (now referred to as Clade I) and the West African clade (now referred to as Clade II). The Congo Basin clade has caused more severe illness. The 2022 multi-country monkeypox outbreak represented the first incidence of broader community transmission in a number of countries outside of certain regions of Africa. The international outbreak has primarily affected men who identify as gay, bisexual men or other men who have sex with men (gbMSM).
##### National
Concerted vaccination campaigns were successful in eliminating endemic smallpox from Canada by 1946. Nova Scotia had a suspected case in 1949; with rigid quarantine, the disease did not spread. The final laboratory-confirmed case in Canada in 1962 involved an adolescent who returned to Toronto from Brazil.
Canada has been one of the countries affected by the 2022 multi-country mpox outbreak.
Preparations authorized for use in Canada
-----------------------------------------
PHAC has a stock of three types of smallpox (vaccinia virus) vaccine (Sma):
* lyophilized (freeze-dried) vaccine - Smallpox Vaccine (dried) (Sanofi Pasteur Ltd.)
* frozen liquid formulation vaccine - Smallpox Vaccine (frozen-liquid) (Sanofi Pasteur Ltd).
* Imvamune® - Smallpox and Mpox (monkeypox) Vaccine (live-attenuated, non-replicating) (Bavarian Nordic A/S [manufacturer]), (Progress Therapeutics Inc. [distributor])
The lyophilized smallpox vaccine is an authorized product to vaccinate laboratory workers working with orthopoxviruses. The frozen liquid smallpox vaccine could be released in emergency situations (e.g., in response to a smallpox case) through Health Canada's Special Access Program. Both vaccines are prepared from live, vaccinia virus. Vaccinia virus is a member of the *Orthopoxvirus* family and confers immunity against variola (smallpox) and other orthopoxviruses through cross-reactivity.
Imvamune® [also called Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN)], is a non-replicating, third generation smallpox vaccine manufactured by Bavarian Nordic. Imvamune® was initially authorized for use in Canada on November 21, 2013 as an Extraordinary Use New Drug Submission (EUNDS) for use by the Government of Canada in an emergency situation for active immunization against smallpox infection and disease in persons 18 years of age and older who have a contraindication to the first or second generation smallpox vaccines. It was subsequently approved under a supplement to the EUNDS on November 5, 2020 for active immunization against smallpox, monkeypox virus and related orthopoxvirus infections and disease in adults 18 years of age and older determined to be at high risk for exposure.
PHAC provides smallpox vaccine to laboratory staff working with vaccinia virus or other orthopoxviruses and would also provide vaccine to provinces/territories in the event of a smallpox case or orthopoxvirus outbreaks. In the context of the ongoing mpox outbreaks, Imvamune® is currently being provided to provinces and territories for post-exposure and pre-exposure vaccination to individuals/groups considered at high risk of mpox. Imvamune® is not available for general use.
For emergency (suspected or confirmed smallpox cases) or non-emergency situations, contact the Centre of Emergency Preparedness and Response, Health Portfolio Operations Centre, PHAC by telephone: 1-800-545-7661 or 613-952-7940 or e-mail: [[email protected]](mailto:[email protected]).
### Vaccinia immune globulin
Vaccinia Immune Globulin Intravenous (Human) (VIG) is a solution of gamma globulin from the serum of individuals recently immunized with smallpox vaccine. It is used to treat severe smallpox vaccine-associated adverse events. The Canadian Smallpox Contingency Plan indicates that VIG would be sent to the provinces/territories at the same time as smallpox vaccine and related supplies if smallpox occurs in Canada.
Refer to [Contents of Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for a list of vaccines and passive immunizing agents authorized for use in Canada and their contents.
Immunogenicity, efficacy and effectiveness
------------------------------------------
In the early 1970s before smallpox was eradicated, a retrospective study conducted in West Pakistan showed a mortality rate of 52% among those who had never been vaccinated, 1.7% among those who had been vaccinated within 10 years, and 11% among those who had been vaccinated 20 or more years earlier.
The specific mechanisms that result in immunity to smallpox following vaccination have not been well characterized. Studies conducted in the 1970s suggest that both antibody and cell-mediated immunity are stimulated by smallpox vaccination. A more recent study showed that more than 95% of primary vaccinees had detectable neutralizing antibody within 1 to 2 weeks after immunization and strong increases in vaccinia-specific CD8+ cytotoxic T lymphocytes and interferon-gamma-producing T cells.
There is very little data indicating the efficacy or effectiveness of Imvamune vaccination against monkeypox virus infection or mpox disease in the context of pre-exposure or post-exposure vaccination, although efforts are underway to determine the effectiveness of the vaccine during the current mpox outbreak. The majority of clinical data for Imvamune pre-exposure vaccination are limited to clinical immunogenicity or indirect protection from vaccinia (the virus used for first or second generation smallpox vaccines). Indirect clinical immunological evidence showed that Imvamune was able to generate immune responses by week two after a first dose, and comparable immune responses to previous generation smallpox vaccines after two doses by week six.
Recommendations for use
-----------------------
Given that naturally occurring smallpox has been eradicated worldwide and smallpox vaccination is associated with the risk of significant morbidity and even mortality, the overall risk benefit analysis supports the recommendation to not routinely immunize the general Canadian population against smallpox. As a result, smallpox vaccination is highly restricted.
### Outbreak control
#### Smallpox
The Canadian Smallpox Contingency Plan includes actions to be taken if a case of smallpox occurs in Canada or elsewhere. A single case of smallpox is considered an outbreak. In general terms, cases should be isolated immediately, preferably at home. If hospitalization is required, cases should be admitted to rooms under negative pressure equipped with high efficiency particulate air-filtration (HEPA) filters (airborne infection isolation rooms). Contacts and those living in the immediate vicinity of the identified case should be immunized immediately (ring vaccination) and placed under observation in quarantine. Vaccination is indicated for face-to-face contacts (less than 6 feet or 2 meters), household contacts, personnel involved in the medical care, public health evaluation or transportation of confirmed or suspected smallpox cases, laboratory personnel involved in the collection or processing of clinical specimens from confirmed or suspected smallpox cases, and persons who have a high likelihood of exposure to infectious materials (e.g., those responsible for medical waste disposal, linen disposal or disinfection) of smallpox cases.
Vaccine can be given after exposure with beneficial effect as smallpox has a relatively long incubation period. Historical data collected during the smallpox eradication program using first generation vaccine showed that vaccination within 2 to 3 days of exposure may protect against clinical disease, and if given within 4 to 5 days, may decrease the risk of death.
#### Mpox (monkeypox)
In the context of an active mpox outbreak, vaccination using Imvamune should be offered to individuals/groups considered at high-risk of mpox.
Post-exposure vaccination using a single dose of Imvamune may be offered to individuals with high risk exposures to a probable or confirmed case of mpox, or within a setting where transmission is happening. Post-exposure vaccination should be offered as soon as possible, ideally within 4 days (but up to 14 days) of last exposure. A second dose may be offered after 28 days from the first dose if an assessment indicates an ongoing risk of exposure or if the individual is in a high-risk group for whom pre-exposure vaccination is recommended.
During the 2022 outbreak, the following individuals/groups have been considered for pre-exposure vaccination with Imvamune:
* Men who have sex with men (MSM), and individuals who have sex with MSM, and who meet at least one of the following criteria:
+ Having two or more sexual partners or being in a relationship where at least one of the partners has other sexual partners
+ Having had a confirmed sexually transmitted infection acquired in the last year
+ Engaging in sexual contact in sex-on-premises venues
* Individuals who self-identify as sex workers regardless of self- identified sex/gender
* Staff or volunteers in sex-on-premises venues where workers may have contact with fomites potentially contaminated with monkeypox virus without the use of personal protective equipment
Individuals receiving pre-exposure vaccination should be offered Imvamune as a two-dose primary series, with at least 28 days between first and second 0.5 mL sub-cutaneous doses. Individuals considered moderately to severely immunocompromised and eligible for pre-exposure vaccination should be prioritized to receive two doses of Imvamune administered at the authorized interval (28 days between doses).
Neither post-exposure nor pre-exposure vaccination should be offered to individuals with a prior documented history of monkeypox virus infection or those who are symptomatic and meet the definition of suspect, probable or confirmed mpox case.
Immunocompetent individuals recommended for Imvamune pre-exposure or post-exposure vaccination should receive a single dose if they have previously been vaccinated with a live replicating first or second generation smallpox vaccine (i.e., as a booster dose). However, individuals considered moderately to severely immunocompromised should receive two doses, regardless of previous smallpox vaccination.
In situations where there is ongoing mpox outbreak activity and limited vaccine supply, dose sparing strategies should be considered for pre-exposure vaccination of immunocompetent individuals in order to expand coverage to a broader population. These strategies may include extending the interval between doses and intradermal fractional dose administration. Intradermal administration (ID) can be used among immunocompetent adults when given as a second dose following a first dose given subcutaneously, provided dose sparing and safe administration practices are feasible. In situations where individuals received a first dose of Imvamune using an ID route, then the dose should be considered valid. Individuals who are <18 years of age, at risk of keloid scars, or moderately to severely immunocompromised should be offered Imvamune using the subcutaneous route of administration with a full dose only. For additional details, refer to [NACI's Rapid Response: Updated interim guidance on Imvamune in the context of ongoing monkeypox outbreaks](/en/public-health/services/publications/vaccines-immunization/rapid-response-updated-interim-guidance-imvamune-monkeypox-outbreaks.html).
### Vaccinia immune globulin
PHAC's Centre for Emergency Preparedness and Response has a supply of VIG based on a requirement of 1 dose of VIG for every 10,000 doses of first and second generation smallpox vaccines. VIG is indicated to treat severe smallpox vaccine-associated adverse events: eczema vaccinatum, progressive vaccinia, severe or recurrent generalized vaccinia, and extensive lesions resulting from accidental implantation (transfer of vaccinia virus from the primary vaccination site to other parts of the body). VIG is ineffective in the treatment of post-vaccinial encephalitis and has no role in the treatment or prevention of smallpox.
### Booster doses and re-immunization
For both first and second generation smallpox vaccines, booster doses should be given every 10 years for laboratory workers with ongoing risk of exposure.
Imvamune may be offered to personnel working with replicating orthopoxviruses that pose a risk to human health (vaccinia or monkeypox virus) in laboratory settings and who are at high risk of occupational exposure. If Imvamune is used, two doses should be given at least 28 days apart. A booster dose may be offered after 2 years if the risk of exposure extends beyond that time.
For immunocompetent individuals who have received a live replicating first or second generation smallpox vaccine in the past and who are at high risk for occupational exposure, a single dose of Imvamune may be offered (i.e., as a booster dose), rather than the two-dose primary vaccine series. This single Imvamune dose should be given at least two years after the latest live replicating smallpox vaccine dose.
Vaccination of Specific Populations
-----------------------------------
### Workers
Smallpox vaccine, including Imvamune, may be indicated for certain workers at high risk of exposure, such as laboratory workers who handle vaccinia or other replicating orthopoxviruses (including monkeypox virus and recombinant vaccinia vaccine products) in specialized reference or research facilities.
In the event of a suspect case of smallpox, vaccination of public health and health care personnel involved in the case investigation and clinical management is indicated. Once a case is confirmed, vaccination of public health staff and health care workers, as well as first responders such as police officers, firefighters, ambulance attendants, the military and others may also be indicated.
Serologic testing
-----------------
Serologic testing is not recommended before or after receiving smallpox vaccine.
Administration Practices
------------------------
### Dose, route of administration and schedule
Both first and second generation smallpox vaccines are administered by scarification into the epidermis, usually in the deltoid area of the non-dominant arm, by using the multiple-puncture technique with a bifurcated needle, packaged with the vaccine and diluent. According to the product labelling, 15 punctures are recommended for vaccination. A trace of blood should appear at the vaccination site after 15 to 20 seconds; if no trace of blood is visible, additional insertions should be made by using the same bifurcated needle without reinserting the needle into the vaccine vial. If alcohol is used to cleanse the skin before immunization, the skin must be allowed to dry thoroughly before the vaccine is administered, to prevent inactivation of the vaccine by alcohol.
Other methods of administration, such as multiple pressure method are possible in case bifurcated needles are not readily available. Refer to the product label for detailed instructions.
When vaccinia virus is inoculated into the epidermis the virus induces an immune reaction that is termed "a take". There is often no visible reaction for the first few days. On day 3 to 4 a papule appears and progresses to a vesicle with surrounding erythema. Typically, one week or so after vaccination, the centre of the vesicle umbilicates and pustulates. After about 2 weeks, the pustule crusts and a dark brown or black scab forms. After 3 weeks, the scab detaches leaving a scar. The vaccination site should be inspected 6 to 8 days after vaccination to ensure that a take has occurred. If there is no evidence of papules or vesicles and erythema, the person should be vaccinated again.
Optimal infection-control practices and appropriate vaccination site care should be used. Gloves should be worn by the vaccine provider when administering smallpox vaccine due to the increased risk of autoinoculation from the use of a bifurcated needle. Each vaccinee and anyone caring for the vaccination site should wash their hands thoroughly after touching the site or handling bandages used to cover the site. Contaminated bandages and scabs should be placed in sealed plastic bags before disposal in the garbage. The vaccinee should avoid rubbing or scratching the site.
A sterile piece of porous bandage (e.g., gauze) should be used to loosely cover the vaccination site until the scab falls off in order to deter the vaccinee from touching the scab, to prevent inadvertent self-inoculation or inoculation of others, and to contain the scab so it is not lost. Preferably, a semi-permeable dressing should be placed over the gauze and not directly on the site; occlusive dressings should not be used. Dressings used to cover the site should be changed frequently to prevent accumulation of exudates and consequent maceration. Frequent dressing changes are particularly important for vaccinees who have close contact with children or people at high risk for vaccinia complications.
Health care workers providing direct patient care should keep their vaccination sites covered with gauze in combination with a semipermeable membrane dressing to absorb exudates and to provide a barrier for containment of vaccinia virus to minimize the risk of transmission; the dressing should also be covered by a layer of clothing. Similar precautions should be used for vaccinated persons in close contact with children or other persons at high risk of serious complications of vaccinia.
Imvamune is administered as 0.5 mL subcutaneously (SC) using a two-dose schedule with a minimum interval of 28 days between doses. In cases of limited vaccine supply, Imvamune can also be administered using a fractional second dose (1/5th of SC dose) administered intradermally.
For information on the management of Imvamune administration errors, refer to the [Managing vaccine administration errors or deviations](/en/public-health/services/diseases/mpox/health-professionals/vaccination-clinic-resources/managing-administrations-errors-deviations.html).
### Vaccinia immune globulin
VIG should be given intravenously through a dedicated infusion line at a rate of 2 mL/min; VIG is compatible with sodium chloride 0.9%. Parenteral products should be inspected visually for particulate matter and discoloration prior to administration; it should not be used if the solution is turbid. The vial should not be shaken as it may cause foaming.
VIG should be administered at a dose of 6,000 units/kg as soon as symptoms appear and are judged to be due to a severe vaccinia-related complication. Two exceptions to this are vaccinia keratitis and encephalitis. VIG should not be given for vaccinia keratitis due to the potential of increased corneal scarring, and should not be given for encephalitis due to lack of efficacy. For other VIG-treated complications, consideration may be given to repeat dosing, depending on the severity of the symptoms and response to treatment; however, clinical data on repeat doses are lacking. The administration of an additional dose of 9,000 units/kg may be considered in the event that the person does not respond to the initial 6,000 units/kg dose.
### Concurrent administration with other vaccines
In non-emergency situations (i.e., non-outbreaks), both first and second generation smallpox vaccines can be administered concurrently with any inactivated vaccine. To avoid confusion in ascertaining which vaccine might have caused post-vaccination skin lesions or other adverse events, varicella (chickenpox) vaccine should not be administered concurrently with smallpox vaccine; there must be an interval of at least 4 weeks between administration of varicella vaccine and smallpox vaccine. Smallpox vaccine can be administered simultaneously concurrently with other live parenteral vaccines; if not administered concurrently, there must be an interval of at least 4 weeks between smallpox vaccine and other live parenteral vaccines.
Currently, no data exist on the concurrent administration of Imvamune with other vaccines. If concurrent administration with another vaccine is indicated, immunization should be done in different limbs.
To minimize the potential risk of interactions or erroneous attribution of an adverse event following immunization (AEFI) to a particular vaccine, it is recommended to administer non-live vaccines more than 2 weeks and live vaccines at least 4 weeks before or after administration of Imvamune.
First and second generation orthopoxvirus vaccines and mRNA COVID-19 vaccines both have a potential risk of cardiac adverse events (myocarditis). Risk for myo- or pericarditis with the newer generation non-replicating attenuated virus vaccine Imvamune is still unknown. It would be prudent to wait for a period of at least 4 weeks before or after the administration of mRNA COVID-19 vaccine in order to prevent erroneous attribution of an adverse event following immunization (AEFI) to one particular vaccine or the other. This suggested minimum waiting period between vaccines is precautionary at this time. Protection from monkeypox virus exposure should be prioritized and recent mRNA vaccine receipt should not delay Imvamune pre-exposure vaccination or post-exposure vaccination if protection is urgent.
### Post-vaccination counselling
All vaccine and VIG recipients should be instructed to seek medical care if they develop signs or symptoms of a serious adverse event or an allergic reaction following immunization.
Refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for additional information on pre- and post-vaccination counseling.
Storage requirements
--------------------
Lyophilized smallpox vaccine should be stored in a refrigerator at +2°C to +8°C and reconstituted before use. The frozen liquid smallpox vaccine is frozen for long-term storage and thawed for shipping; the thawed vaccine should be maintained between +2°C and +8°C. Open vaccine vials should be used within 24 hours.
Imvamune should be stored frozen at -20°C ± 5°C or -50°C ± 10°C or -80°C ± 10°C. After thawing, the vaccine should be used immediately or can be stored at +2°C to +8°C for up to 2 weeks prior to use. Do not refreeze a vial once it has been thawed. Store in the original package to protect from light.
Refer to [Storage and Handling of Immunizing Agents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-9-storage-handling-immunizing-agents.html) in Part 1 for additional general information.
Safety and adverse events
-------------------------
Common adverse events occur in 1% to less than 10% of vaccinees. Very common adverse events occur in 10% or more of vaccinees.
Uncommon adverse events occur in 0.1% to less than 1% of vaccinees. Rare and very rare adverse events occur, respectively, in 0.01% to less than 0.1% and less than 0.01% of vaccinees.
Refer to [Vaccine Safety and pharmacovigilance](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) Part 2 for additional general information.
### First and second generation smallpox vaccines and immunoglobulin safety and adverse events
#### Common and local adverse events
In a UK study of 200 health care workers, 142 (71%) of vaccinees reported pain at the injection site, of which 25% considered it to be moderate or severe; 32 vaccinees (16%) recorded a temperature of greater than 37.7°C, two of which exceeded 39°C. Other, mainly minor, adverse events were common; local itching was reported in 72%, erythema at the injection site in 27%, axillary pain or lymphadenopathy in 38%, malaise or influenza-like symptoms in 40% and headache in 23%. The incidences of minor adverse events were lower in re-vaccinees, compared with primary vaccine recipients. The study used a single dose of the Swiss Serum Institute (SSI) vaccine, containing the Elstree/Lister strain of vaccinia virus.
Bacterial infection of the vaccination site can occur.
#### Less common and serious or severe adverse events
##### Inadvertent inoculation
Inadvertent inoculation is the transfer of the virus from the site of immunization to other body sites or other persons resulting in vaccinia lesions. The most susceptible areas are the eye, mouth, nose, face and genitalia. Children are most susceptible to inadvertent inoculation. Inadvertent inoculation is the most common (significant) adverse reaction, with rates approaching 600 cases per million doses administered. Most ensuing lesions heal spontaneously. There are case reports of secondary and tertiary vaccinia arising in sexual contacts of a person recently vaccinated; these cases were severe enough to require VIG to manage vaccinia-related complications. When a secondary case of vaccinia is diagnosed, contract tracing is indicated to ascertain whether there are additional secondary or tertiary cases.
##### Generalized vaccinia
Generalized vaccinia may occur within a week after vaccination. Lesions appear on unimmunized skin and are thought to arise from viremia. Lesions are similar to those associated with the vaccination site but are usually smaller and evolve to scarring more rapidly, often within a week. In healthy individuals this is a benign complication of primary vaccination that needs to be differentiated from progressive vaccinia. Individuals with underlying and unsuspected immunosuppressive illnesses may develop a serious reaction.
##### Progressive vaccinia (Vaccinia Necrosum)
Progressive vaccinia is a severe complication of smallpox vaccination. It often occurs because of an immune defect, especially T cell deficiencies. It is characterized by progressive necrosis at the site of immunization and, in the presence of viremia, leads to implants in distant skin sites and multiple organs. Progression is slow, persistent and resistant to treatment. In those with profound T cell defects, it is nearly always fatal.
##### Eczema vaccinatum
Eczema vaccinatum occurs in vaccinees or their unvaccinated contacts with active or healed eczema lesions or other exfoliative skin conditions. Vaccinial skin lesions appear on skin that is currently or was previously affected by eczema. Usually the illness is mild and self-limited, but it can be severe and fatal.
##### Vaccinia keratitis
Vaccinia keratitis can threaten eyesight through corneal abrasions, ulcerations and subsequent corneal clouding. If this occurs, consultation with an ophthalmologist is strongly recommended. VIG is contraindicated because of the potential of increased corneal scarring.
##### Post-vaccinial encephalitis
Post-vaccinial encephalitis is a rare but serious complication that can develop 7 to 14 days after vaccination. There are no known predictors of susceptibility, but the incidence is somewhat higher among infants less than 1 year of age. Approximately, 25% of cases with encephalitis develop permanent sequelae (both motor and/or intellectual impairment) and up to 35% die. VIG is not recommended due to lack of efficacy.
##### Acute myopericarditis
During a smallpox vaccination program for US military personnel which started in 2002, a previously unreported adverse event, acute myopericarditis, was recognized. Most of the affected vaccinees experienced chest pain and returned to normal activities within 7 to 10 days, and all recovered. It is unclear whether these events were adverse outcomes of smallpox vaccination. The smallpox vaccine (Dryvax, Wyeth Laboratories) containing the New York City Board of Health strain of vaccinia was used in this program.
VIG is available to treat certain smallpox vaccine-associated adverse events. Refer to [vaccinia immune globulin](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-21-smallpox-vaccine.html#p4c20a6c) for additional information.
### Third generation smallpox vaccine safety and adverse events
#### Common adverse events
Most adverse events develop within a few days after receiving the vaccine.
The most common local adverse events following Imvamune immunization are pain, erythema, induration and swelling at the site of injection. The most common systemic adverse reactions observed after subcutaneous vaccination with Imvamune are fatigue, headache, myalgia, and nausea. Most of these reactions are mild to moderate intensity and resolve within the first seven days following vaccination.
#### Less common and serious or severe adverse events
In clinical trials, cardiac adverse events of special interest (AESI) were reported to occur in 1.4% (91/6,640) of Imvamune recipients, 0.2% (3/1,206) of placebo recipients who were smallpox vaccine-naïve and 2.1% (16/762) of Imvamune recipients who were smallpox vaccine-experienced. Among the cardiac AESIs reported, 6 cases were considered to be causally related to Imvamune vaccination. The events reported included tachycardia, electrocardiogram T wave inversion, abnormal electrocardiogram, electrocardiogram ST segment elevation, abnormal electrocardiogram T wave, and palpitations. None of the 6 events considered vaccine-related were considered serious.
No trends have been identified which suggest the occurrence of any particular unexpected adverse reaction or classes of adverse reactions following vaccination. To date, myocarditis has not been determined to be causally associated with Imvamune, but monitoring is ongoing.
### Guidance on reporting Adverse Events Following Immunization (AEFI)
To ensure the ongoing safety of vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical.
Vaccine providers are asked to report, through [local public health](/en/public-health/services/immunization/federal-provincial-territorial-contact-information-aefi-related-questions.html) officials, any serious or unexpected adverse event thought to be temporally related to smallpox vaccination, including any case of secondary or tertiary vaccinia. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.
Refer to [Adverse events following immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) in Part 2 and the [User Guide to completion and submission of the AEFI reports](/en/public-health/services/immunization/reporting-adverse-events-following-immunization/user-guide-completion-submission-aefi-reports.html) for additional information about AEFI reporting. The [Brighton case definitions](https://brightoncollaboration.us/category/pubs-tools/case-definitions/) are also available.
### Contraindications and precautions
#### First and second generation smallpox vaccines
Contraindications to smallpox vaccines are only applicable if the variola (smallpox) virus has not been introduced into the environment. In an outbreak situation, if smallpox cases are occurring and a risk of infection exists for an individual, there are no absolute contraindications to immunization.
The product leaflet lists the following contraindications in a non-emergency setting. For people at higher risk of vaccinia complications, potential risks and benefits must be weighed, including VIG availability. A third generation smallpox vaccine would be a better choice for these individuals, if available.
##### Persons less than 18 years of age
Smallpox vaccination is contraindicated for children and adolescents because they are more likely to suffer from adverse reactions and cause inadvertent self-reinoculation and inoculation of others.
##### Hypersensitivity or anaphylaxis
Smallpox vaccines are contraindicated in people with a history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Refer to [Contents of immunizing agents authorized for use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for lists of all vaccines and passive immunizing agents authorized for use in Canada and their contents. For smallpox vaccines, potential allergens include: streptomycin, neomycin and latex in the stopper of vial.
##### Immunodeficiency or immunocompromised
Smallpox vaccination is contraindicated for people who are immunocompromised such as those with leukemia, lymphoma, or a systemic malignancy; persons on immunocompromising therapies; persons with some hereditary immune deficiency disorders; and persons with HIV/AIDS. It is generally contraindicated pre/post solid organ transplant and hematopoietic stem cell transplant (HCST). Refer to [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional information.
##### Atopic dermatitis and other widespread skin disorders
Diffuse vaccinia virus infection can occur in the presence of acute atopic dermatitis and other widespread exfoliative skin disorders.
##### Pregnancy and breastfeeding
Smallpox vaccine is generally contraindicated in pregnant women in non-emergency situations although it is not known to cause congenital malformations. It can very rarely lead to fetal vaccinia after primary immunization during pregnancy, resulting in stillbirth or neonatal death. Women of childbearing age should be asked before vaccination if they are pregnant or intend to become pregnant during the next 4 weeks. If a woman becomes pregnant within 4 weeks after smallpox vaccination she should be counselled regarding concern for the fetus.
Breastfeeding mothers should not receive the smallpox vaccine in non-emergency situations. The close physical contact that occurs during breastfeeding increases the chance of inadvertent inoculation of the baby. It is not known whether vaccine virus or antibodies are excreted in human milk. A breastfeeding woman should only be immunized if she has been exposed to smallpox and a third generation vaccine is not available; in that case breastfeeding and other close contact should be delayed until after the vaccination scab has separated from the vaccination site.
##### Heart disease and cardiac risk factors
Smallpox vaccine is contraindicated in people with known underlying heart disease (with or without symptoms), or who have three or more known major cardiac risk factors (i.e., hypertension, diabetes, hypercholesterolemia, heart disease at age 50 years or younger in a first-degree relative, and smoking). A risk assessment needs to be done in an emergency situation such as exposure to a case of smallpox.
The product monograph lists the following precautions:
**Ocular or periorbital disease**
Persons with inflammatory eye disease may be at increased risk for inadvertent inoculation as a result of touching or rubbing the eye. Therefore, deferring vaccination is prudent for persons with inflammatory eye diseases requiring steroid treatment until the condition resolves and the course of therapy is complete.
**Close contacts**
Generally, smallpox vaccine should not be administered to household contacts of an immunocompromised person in a non-emergency situation. If vaccination is required in an outbreak situation, precautions should be taken for unvaccinated household and other close contacts. Vaccinees with household and other close contacts with active eczema or a history of eczema or other exfoliative skin conditions, immunocompromising conditions, or with close contact with infants or pregnant women, should take special precautions in order to prevent viral transfer to these contacts. Such precaution can include isolation of the vaccinee from their higher risk household contacts until the vaccine scab falls off.
#### Third generation smallpox vaccine
Contraindications to Imvamune include hypersensitivity to this vaccine. Individuals with suspected severe hypersensitivity reactions (e.g., anaphylaxis) after receiving the first dose of the vaccine should consult an [allergist](https://www.csaci.ca/imvamune-statement/). There is evidence that some individuals with immediate allergic reactions to vaccines in general (although less data are available for Imvamune) can safely receive a subsequent dose of the same vaccine with low risk of a systemic reaction under the supervision of an allergist. Individuals with confirmed or suspected hypersensitivity to the potential allergens contained in the vaccine components (egg, tromethamine, or antibiotics) can receive the vaccine without expert consultation; prolonged observation (30 minutes) may be considered.
Data on Imvamune are limited in people who are pregnant, lactating or <18 years of age, requiring an assessment of the benefits vs. the risks in these populations.
#### Vaccinia immune globulin
The most common adverse events related to VIG are headache, nausea, rigors and dizziness.
Relative contraindications to VIG include:
* a history of systemic allergic reactions to human immune globulin products
* isolated vaccinia keratitis due to the potential of increased corneal scarring
* selective immunoglobulin A deficiency with antibodies against IgA and a history of IgA hypersensitivity (because VIG contains trace amounts of IgA)
It is not known whether VIG can cause fetal harm when given to pregnant women. Counselling based on an individual risk benefit assessment is indicated. VIG should not be withheld if a pregnant woman experiences a condition for which VIG is needed.
Refer to [Contraindications and Precautions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html) in Part 2 for additional general information.
Other Considerations
--------------------
### Drug interactions
There is some evidence for tuberculin skin test (TST) suppression following the administration of live, attenuated virus vaccines; a TST can be done on the same day as immunization or delayed until 4 weeks after administering a first or second generation smallpox vaccine.
Chapter revision process
------------------------
This chapter was updated to reflect guidance based on current evidence and NACI's expert opinion on the use of Imvamune in the context of mpox outbreaks in Canada.
Acknowledgements
----------------
This chapter update was prepared by A Killikelly, N Forbes, O Baclic, M Plamondon, R Krishnan, M Salvadori, B Warshawsky, P Doyon-Plourde, R Garno, F Khan, L Zhao, MY Yeung, N Brousseau, R Harrison, S Deeks, and MC Tunis, on behalf of the NACI's High Consequence Infectious Disease Working group.
NACI gratefully acknowledges the contribution of: C Jensen, L Coward, M Laplante and C Mauviel.
Selected references
-------------------
Auckland C. Cowlishaw A. Morgan D et al. *Reactions to smallpox vaccine in naïve and previously-vaccinated individuals*. Vaccine 2005;23(32):4185-7.
Bavarian Nordic. Product monograph – Imvamune. November 26, 2021.
Canadian Society of Allergy and Clinical Immunology. IMVAMUNE (Monkeypox/Smallpox) vaccine in those with allergic/immunocompromising conditions: Guidance for allergists/immunologists from the CSACI. Accessed November 2022 at: https://canadiansocietyofallergyandclinicalimmunology.wildapricot.org/resources/CSACI%20Imvamune%20Statement.pdf (PDF format)
Centers for Disease Control and Prevention. *Secondary and Tertiary Transmission of Vaccinia Virus After Sexual Contact with a Smallpox Vaccinee - San Diego, California, 2012*. MMWR Morb Mortal Wkly Rep 2013;62(08);145-7.
Centers for Disease Control and Prevention. *Smallpox Vaccine Adverse Events Monitoring and Response System for the first stage of the smallpox vaccination program.* MMWR Morb Mortal Wkly Rep 2003;52(5):88-9, 99.
Cohen J. *Bioterrorism. Smallpox vaccinations: how much protection remains?* Science 2001;294(5544):985.
Cono J, Casey CG, Bell DM. Centers for Disease Control and Prevention. *Smallpox vaccination and adverse reactions. Guidance for clinicians.* MMWR Recomm Rep 2003;52(RR-4):1-28.
De Vries RRP et al. *In vitro immune responsiveness to vaccinia virus and HLA*. NEJM, 1977;297:692-696.
Ennis FA et al. *Primary induction of CD8+ cytotoxic T lymphcytes and IFN-gamma-producing T cells after small pox vaccination*. J Infect Dis 2002;185:1657-1659.
Fenner F et al. *Smallpox and its eradication*. Geneva: WHO, 1988.
Fillmore GL, Ward TP, Bower KS et al. *Ocular complications in the Department of Defense Smallpox Vaccination Program.* Ophthalmology 2004;111(11):2086-93.
Fulginiti VA, Papier A, Lane JM et al. *Smallpox vaccination: a review, part I. Background, vaccination technique, normal vaccination and revaccination, and expected normal reactions.* Clin Infect Dis 2003;37(2):241-50.
Fulginiti VA, Papier A, Lane JM et al. *Smallpox vaccination: a review, part II. Adverse events.* Clin Infect Dis. 2003;37(2):251-71.
Grabenstein JD, Winkenwerder W. *US military smallpox vaccination program experience.* JAMA 2003;289:3278-82.
Health Canada. *Smallpox vaccination of laboratory workers*. Can Comm Dis Rep 2004;30(19):167-9.
Mack TM, Thomas DB, Ali A et al. *Epidemiology of small pox in West Pakistan. 1. Acquired immunity and the distribution of disease*. Am J Epidemiol 1972;95:157-68.
McIntyre JW, Houston, S. *Smallpox and its control in Canada. CMAJ 1999;161(12).*
Moller-Larsen A, Haahr S. *Humoral and cell-mediated immune responses in humans before and after revaccination with vaccinia virus*. Infect Immun 1978;19:34-39.
National Advisory Committee on Immunization. NACI Rapid Response: Updated interim guidance on Imvamune in the context of ongoing monkeypox outbreaks. September 23, 2022. Accessed September 2022 from: https://www.canada.ca/en/public-health/services/publications/vaccines-immunization/rapid-response-updated-interim-guidance-imvamune-monkeypox-outbreaks.html
National Advisory Committee on Immunization. NACI Rapid Response: Interim guidance on the use of Imvamune in the context of ongoing monkeypox outbreaks. June 10, 2022. Accessed September 2022 from: https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-imvamune-monkeypox.html
National Advisory Committee on Immunization. *Statement on smallpox vaccination*. Can Comm Dis Rep 2002;28(ACS-1):1-12.
Peter G. Napolitano PG, Ryan MA et al. *Pregnancy discovered after smallpox vaccination: Is vaccinia immune globulin appropriate?* Am J Ob Gyn 2004; 191:1863-7.
Rao AR. *Small Pox.* The Kothari Book Depot, Bombay-12. 1972.
Wharton M, Strikas RA, Harpaz R et al. Healthcare Infection Control Practices Advisory Committee. *Recommendations for using smallpox vaccine in a pre-event vaccination program. Supplemental recommendations of the Advisory Committee on Immunization Practices (ACIP) and the Healthcare Infection Control Practices Advisory Committee (HICPAC).*MMWR Recomm Rep 2003:52(RR-7):1-16.
Wiser I, Balicer RD, Cohen D. *An update on smallpox vaccine candidates and their role in bioterrorism related vaccination strategies.* Vaccine 2007;25(6):976-84.
* [Previuous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-20-rubella-vaccine.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-21-smallpox-vaccine.html&n=Smallpox%20and%20mpox%20(monkeypox)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-21-smallpox-vaccine.html&title=Smallpox%20and%20mpox%20(monkeypox)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Email](mailto:?subject=Smallpox%20and%20mpox%20(monkeypox)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-21-smallpox-vaccine.html%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-21-smallpox-vaccine.html&t=Smallpox%20and%20mpox%20(monkeypox)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=Smallpox%20and%20mpox%20(monkeypox)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-21-smallpox-vaccine.html%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-21-smallpox-vaccine.html&title=Smallpox%20and%20mpox%20(monkeypox)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-21-smallpox-vaccine.html&t=Smallpox%20and%20mpox%20(monkeypox)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-21-smallpox-vaccine.html&media=&description=Smallpox%20and%20mpox%20(monkeypox)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-21-smallpox-vaccine.html&title=Smallpox%20and%20mpox%20(monkeypox)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-21-smallpox-vaccine.html)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-21-smallpox-vaccine.html&name=Smallpox%20and%20mpox%20(monkeypox)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=Smallpox%20and%20mpox%20(monkeypox)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-21-smallpox-vaccine.html)
* [Whatsapp](https://api.whatsapp.com/send?text=Smallpox%20and%20mpox%20(monkeypox)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-21-smallpox-vaccine.html)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=Smallpox%20and%20mpox%20(monkeypox)%20vaccine%3A%20Canadian%20Immunization%20Guide%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fpublications%2Fhealthy-living%2Fcanadian-immunization-guide-part-4-active-vaccines%2Fpage-21-smallpox-vaccine.html%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2023-06-27
| None | None |
b2450b14ac48c7c2c8016cc30bccf866a72346fe | cma | Interim guidance on continuity of immunization programs during the COVID-19 pandemic | Interim guidance on continuity of immunization programs during the COVID-19 pandemic
Preamble
As a public health emergency of international concern, the coronavirus disease 2019 (COVID-19) pandemic (caused by the novel SARS-CoV-2 virus) has already impacted many aspects of healthcare delivery. Within Canada, all provinces and territories have initiated a range of public health measures to mitigate the transmission of SARS-CoV-2 and reduce the impact of the outbreak on healthcare systems; in some cases, this includes deferral of non-essential medical visits. Immunizations, particularly in infants and toddlers, are essential. If capacity is not sufficient to maintain all routine programs, emphasis should be put on the and booster doses for children aged less than two years.
Disruption of immunization services, even for short periods, will result in an accumulation of susceptible individuals, and a higher likelihood of vaccine-preventable disease (VPD) outbreaks. Such outbreaks may result in VPD-related deaths and an increased burden on healthcare systems already strained by the response to the COVID-19 outbreak. Moreover, once COVID-19 public health measures are relaxed and international borders are re-opened, risk for VPDs may increase as people start to travel or congregate again in settings where diseases are readily transmitted.
There is evidence that some individuals who miss routine immunizations at the scheduled time might not catch up later. Those who do seek catch-up immunization will add to increased volumes and pressures on the healthcare system during extended pandemic recovery phases, when other clinic visits will be resuming more actively. In addition, those seeking catch-up immunization could be subject to prolonged wait times and vaccine availability issues.
Some of the risks of COVID-19 transmission at immunization visits can be mitigated by to protect both healthcare providers and the public. These include child and parent screening prior to visits, for parents, physical distancing between patients at the clinic, scheduling considerations, and personal protective equipment for healthcare providers in ambulatory settings according to provincial, territorial or national guidelines which may change with transmission risk over the course of the pandemic. Immunization clinics for healthy individuals can occur early in the day, before appointments for sick patients, or having healthy child and sick child visits at separate locations. Vaccines should not be administered by health professionals without training, as this could result in immunization errors.
This guidance was prepared by the Public Health Agency of Canada in consultation with the National Advisory Committee on Immunization and the Canadian Immunization Committee, and should be considered in concert with provincial and territorial policies on continuity of immunization programs during the COVID-19 pandemic, and as routine services begin to resume.
Defer immunizations in symptomatic individuals
Immunization settings should consider COVID-19 screening prior to appointments in order to reduce risks to healthcare providers and other patients.
# Those with symptoms of an acute respiratory infection:
During the COVID-19 pandemic, individuals with symptoms of acute respiratory infection, including minor symptoms such as sore throat or runny nose, should defer routine immunization until they have recovered because they can pose an unnecessary risk to the public and healthcare providers if they have COVID-19.
# Individuals with suspected, probable or confirmed COVID-19
Individuals with suspected, probable, or confirmed COVID-19, and those who are close contacts of a case, should not attend scheduled immunization appointments during their period of isolation. Please visit the updated guidance on discontinuation of isolation specific to your province or territory.
Post-exposure prophylaxis (PEP) for VPDs
If PEP with vaccine or antibody products is required (e.g., measles, hepatitis A, hepatitis B, rabies, meningococcus, varicella), it should be given without delay. If PEP is required for someone with suspected, probable, or confirmed COVID-19, or a close contacts of a case, this should be given without delay using appropriate .
Infants and toddlers
Prioritize primary immunization series: Infants and toddlers without symptoms of acute respiratory infection should continue to receive their routine vaccines on schedule as recommended by their province or territory. While some jurisdictions may defer the 18-month visit based on their COVID-19 epidemiological situation, PHAC suggests that immunizations given at 18 months of age-month still be provided when possible.
Children
All children who have not completed their primary series and who do not have symptoms of acute respiratory infection should be prioritized for immunization.
The 4-6-year boosters can be deferred within this age range. However, the administration should be prioritized before school entry. School entry may vary depending on the epidemiological situation and pandemic public health measures across the country.
School-based immunization programs
Many provinces and territories are currently implementing extended school closures in order to prevent the spread of COVID-19. When school-based immunization programs are restarted, students can either initiate or complete their immunizations at that time. Re-starting a series is never necessary for routine immunization programs. Eligibility criteria should ensure that students who missed immunizations due to COVID-19 school closures remain eligible for the recommended vaccines.
Adolescent immunizations
In general, routine adolescent vaccines (e.g. Tdap, HPV, Hepatitis B, MenC-ACYW) can be deferred until full health care services are available, and/or when schools re-open.
Reminders for Deferred Immunizations
If doses have been deferred, a reminder, recall, or documentation process should be in place to ensure the child, student or adolescent receives the immunizations when full healthcare and/or school resumes.
Immunizations during pregnancy
Prenatal care is critically important, and many prenatal visits will still occur in-person. NACI currently recommends that Tdap vaccine is provided during every pregnancy, ideally between 27-32 weeks’ gestation. During the pandemic this should continue during one of the routine in-person prenatal visits or through a public health clinic, pharmacy or family physician office. If not feasible to combine with another visit, a unique visit would still be justified and recommended during the pandemic.
NACI currently recommends that influenza vaccine is provided during every pregnancy, at any gestational age. In the fall, influenza vaccine should also be given during pregnancy (see below).
Adult and older adult immunizations
Older adults are particularly susceptible to severe outcomes of COVID-19 and are at high risk for VPDs such as invasive pneumococcal disease, influenza, and herpes zoster. Local COVID-19 community transmission risk should be considered when making the decision to have an older adult come to a clinic only for a immunization during the pandemic. It would be preferable to offer immunization when it can be combined with another medical visit, and offering multiple vaccines if required, to minimize the risk of acquiring COVID-19 and to reduce the number of health care encounters.
For adults over 50 years of age who have received the first dose of recombinant zoster vaccine, the second dose can be deferred until the 6-12 month interval (doses are typically recommended 2-6 months apart, and may be considered up to 12 months apart) assuming that COVID-19 risk will be lower by that time. If an interval longer than 6-12 months after the first dose has elapsed, the vaccine series does not need to be restarted; the decision when to complete the series should take into consideration the local COVID-19 community transmission risk, recognizing that individuals may remain at risk of herpes zoster during a longer than recommended interval between doses 1 and 2.
Special populations
Individuals who are immunocompromised, including solid organ and stem cell transplant recipients, and those with chronic conditions, may be particularly susceptible to severe outcomes of COVID-19. Vulnerable populations should not attend clinics solely for the purpose of immunization in regions with ongoing community transmission of COVID-19. However, these populations remain priority populations for immunization against VPDs, and jurisdictions should consider alternative strategies to ensure opportunities for immunization in settings where these populations are followed for their medical care.
Immunization of workers
Immunization of workers in sectors at increased risk of exposure to VPDs (e.g. healthcare workers, laboratory workers) should proceed routinely according to the .
Travellers
Those individuals who must need to be aware of the health risks at their destination as well as any or required immunizations for entry, and should still be immunized according to recommended schedules. Should a traveller require post-exposure prophylaxis (PEP) following exposure during travel (e.g., rabies PEP, measles PEP), this remains a high priority for care.
Seasonal influenza programs
Seasonal influenza presents an ongoing disease burden in Canada during the fall and winter months. Influenza vaccine is the most effective way to prevent influenza illness and influenza-related complications, and will be an important component of managing health care system capacity during the next influenza season in the context of an ongoing COVID-19 pandemic.
Traditional influenza vaccine delivery strategies (e.g., indoor mass immunization clinics) will likely need to be adjusted to incorporate additional infection prevention and control measures to prevent the transmission of COVID-19. It would be preferable to offer immunization when it can be combined with another medical visit, and offering multiple vaccines if required, to minimize the risk of acquiring COVID-19 and reduce the number of health care encounters. Countries in the southern hemisphere (e.g. Australia) are currently exploring alternative influenza vaccine delivery solutions such as outdoor and drive-through vaccine clinics, and their experiences may be instructive for Canada.
Specific guidance on influenza immunization in the context of COVID-19 will be issued as needed.
Resuming normal immunization activities
As the pandemic progresses, provinces and territories continue to closely monitor the COVID-19 epidemiological situation. Vaccine providers should follow advice from their provincial/territorial jurisdiction and the Public Health Agency of Canada on when to relax physical distancing measures and how to resume usual provision of healthcare activities in their local region. At that time, a careful assessment of missed doses will be important to ensure that the pandemic does not leave a long-lasting immunization gap in any Canadian communities. |
Interim guidance on continuity of immunization programs during the COVID-19 pandemic
=====================================================================================
**Last updated: May 13, 2020**
On this page
------------
* [Preamble](#a1)
* [Defer immunizations in symptomatic individuals](#a2)
* [Post-exposure prophylaxis (PEP) for VPDs](#a3)
* [Infants and toddlers](#a4)
* [Children](#a5)
* [School-based immunization programs](#a6)
* [Adolescent immunizations](#a7)
* [Reminders for Deferred Immunizations](#a8)
* [Immunizations during pregnancy](#a9)
* [Adult and older adult immunizations](#a10)
* [Special populations](#a11)
* [Immunization of workers](#a12)
* [Travellers](#a13)
* [Seasonal influenza programs](#a14)
* [Resuming normal immunization activities](#a15)
Preamble
--------
As a public health emergency of international concern, the coronavirus disease 2019 (COVID-19) pandemic (caused by the novel SARS-CoV-2 virus) has already impacted many aspects of healthcare delivery. Within Canada, all provinces and territories have initiated a range of public health measures to mitigate the transmission of SARS-CoV-2 and reduce the impact of the outbreak on healthcare systems; in some cases, this includes deferral of non-essential medical visits. Immunizations, particularly in infants and toddlers, are essential. If capacity is not sufficient to maintain all routine programs, emphasis should be put on the [primary series](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-13-recommended-immunization-schedules.html#p1c12a2) and booster doses for children aged less than two years.
Disruption of immunization services, even for short periods, will result in an accumulation of susceptible individuals, and a higher likelihood of vaccine-preventable disease (VPD) outbreaks. Such outbreaks may result in VPD-related deaths and an increased burden on healthcare systems already strained by the response to the COVID-19 outbreak. Moreover, once COVID-19 public health measures are relaxed and international borders are re-opened, risk for VPDs may increase as people start to travel or congregate again in settings where diseases are readily transmitted.
There is evidence that some individuals who miss routine immunizations at the scheduled time might not catch up later. Those who do seek catch-up immunization will add to increased volumes and pressures on the healthcare system during extended pandemic recovery phases, when other clinic visits will be resuming more actively. In addition, those seeking catch-up immunization could be subject to prolonged wait times and vaccine availability issues.
Some of the risks of COVID-19 transmission at immunization visits can be mitigated by [basic precautions](/en/public-health/services/infectious-diseases/nosocomial-occupational-infections/routine-practices-additional-precautions-preventing-transmission-infection-healthcare-settings.html) to protect both healthcare providers and the public. These include child and parent screening prior to visits, [masks](/en/public-health/services/diseases/2019-novel-coronavirus-infection/prevention-risks/about-non-medical-masks-face-coverings.html) for parents, physical distancing between patients at the clinic, scheduling considerations, and personal protective equipment for healthcare providers in ambulatory settings according to provincial, territorial or national guidelines which may change with transmission risk over the course of the pandemic. Immunization clinics for healthy individuals can occur early in the day, before appointments for sick patients, or having healthy child and sick child visits at separate locations. Vaccines should not be administered by health professionals without training, as this could result in immunization errors.
This guidance was prepared by the Public Health Agency of Canada in consultation with the National Advisory Committee on Immunization and the Canadian Immunization Committee, and should be considered in concert with provincial and territorial policies on continuity of immunization programs during the COVID-19 pandemic, and as routine services begin to resume.
Defer immunizations in symptomatic individuals
----------------------------------------------
Immunization settings should consider COVID-19 screening prior to appointments in order to reduce risks to healthcare providers and other patients.
### Those with symptoms of an acute respiratory infection:
During the COVID-19 pandemic, individuals with symptoms of acute respiratory infection, including minor symptoms such as sore throat or runny nose, should defer routine immunization until they have recovered because they can pose an unnecessary risk to the public and healthcare providers if they have COVID-19.
### Individuals with suspected, probable or confirmed COVID-19
Individuals with suspected, probable, or confirmed COVID-19, and those who are close contacts of a case, should not attend scheduled immunization appointments during their period of isolation. Please visit the [provincial and territorial COVID-19 resources online](/en/public-health/services/diseases/2019-novel-coronavirus-infection/symptoms/provincial-territorial-resources-covid-19.html) updated guidance on discontinuation of isolation specific to your province or territory.
Post-exposure prophylaxis (PEP) for VPDs
----------------------------------------
If PEP with vaccine or antibody products is required (e.g., measles, hepatitis A, hepatitis B, rabies, meningococcus, varicella), it should be given without delay. If PEP is required for someone with suspected, probable, or confirmed COVID-19, or a close contacts of a case, this should be given without delay using appropriate [personal protective equipment for healthcare providers](/en/public-health/services/diseases/2019-novel-coronavirus-infection/health-professionals/infection-prevention-control-covid-19-second-interim-guidance.html#a8.7).
Infants and toddlers
--------------------
**Prioritize primary immunization series:** Infants and toddlers without symptoms of acute respiratory infection should continue to receive their routine vaccines on schedule as recommended by their province or territory. While some jurisdictions may defer the 18-month visit based on their COVID-19 epidemiological situation, PHAC suggests that immunizations given at 18 months of age-month still be provided when possible.
Children
--------
All children who have not completed their primary series and who do not have symptoms of acute respiratory infection should be prioritized for immunization.
The 4-6-year boosters can be deferred within this age range. However, the administration should be prioritized before school entry. School entry may vary depending on the epidemiological situation and pandemic public health measures across the country.
School-based immunization programs
----------------------------------
Many provinces and territories are currently implementing extended school closures in order to prevent the spread of COVID-19. When school-based immunization programs are restarted, students can either initiate or complete their immunizations at that time. Re-starting a series is never necessary for routine immunization programs. Eligibility criteria should ensure that students who missed immunizations due to COVID-19 school closures remain eligible for the recommended vaccines.
Adolescent immunizations
------------------------
In general, routine adolescent vaccines (e.g. Tdap, HPV, Hepatitis B, MenC-ACYW) can be deferred until full health care services are available, and/or when schools re-open.
Reminders for Deferred Immunizations
------------------------------------
If doses have been deferred, a reminder, recall, or documentation process should be in place to ensure the child, student or adolescent receives the immunizations when full healthcare and/or school resumes.
Immunizations during pregnancy
------------------------------
Prenatal care is critically important, and many prenatal visits will still occur in-person. NACI currently recommends that Tdap vaccine is provided during every pregnancy, ideally between 27-32 weeks’ gestation. During the pandemic this should continue during one of the routine in-person prenatal visits or through a public health clinic, pharmacy or family physician office. If not feasible to combine with another visit, a unique visit would still be justified and recommended during the pandemic.
NACI currently recommends that influenza vaccine is provided during every pregnancy, at any gestational age. In the fall, influenza vaccine should also be given during pregnancy (see below).
Adult and older adult immunizations
-----------------------------------
Older adults are particularly susceptible to severe outcomes of COVID-19 and are at high risk for VPDs such as invasive pneumococcal disease, influenza, and herpes zoster. Local COVID-19 community transmission risk should be considered when making the decision to have an older adult come to a clinic only for a immunization during the pandemic. It would be preferable to offer immunization when it can be combined with another medical visit, and offering multiple vaccines if required, to minimize the risk of acquiring COVID-19 and to reduce the number of health care encounters.
For adults over 50 years of age who have received the first dose of recombinant zoster vaccine, the second dose can be deferred until the 6-12 month interval (doses are typically recommended 2-6 months apart, and may be considered up to 12 months apart) assuming that COVID-19 risk will be lower by that time. If an interval longer than 6-12 months after the first dose has elapsed, the vaccine series does not need to be restarted; the decision when to complete the series should take into consideration the local COVID-19 community transmission risk, recognizing that individuals may remain at risk of herpes zoster during a longer than recommended interval between doses 1 and 2.
Special populations
-------------------
Individuals who are immunocompromised, including solid organ and stem cell transplant recipients, and those with chronic conditions, may be particularly susceptible to severe outcomes of COVID-19. Vulnerable populations should not attend clinics solely for the purpose of immunization in regions with ongoing community transmission of COVID-19. However, these populations remain priority populations for immunization against VPDs, and jurisdictions should consider alternative strategies to ensure opportunities for immunization in settings where these populations are followed for their medical care.
Immunization of workers
-----------------------
Immunization of workers in sectors at increased risk of exposure to VPDs (e.g. healthcare workers, laboratory workers) should proceed routinely according to the [recommended schedules](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html).
Travellers
----------
Those individuals who must [travel outside of Canada](https://travel.gc.ca/travel-covid/travelling-outside-canada) need to be aware of the health risks at their destination as well as any [recommended immunizations](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) or required immunizations for entry, and should still be immunized according to recommended schedules. Should a traveller require post-exposure prophylaxis (PEP) following exposure during travel (e.g., rabies PEP, measles PEP), this remains a high priority for care.
Seasonal influenza programs
---------------------------
Seasonal influenza presents an ongoing disease burden in Canada during the fall and winter months. Influenza vaccine is the most effective way to prevent influenza illness and influenza-related complications, and will be an important component of managing health care system capacity during the next influenza season in the context of an ongoing COVID-19 pandemic.
Traditional influenza vaccine delivery strategies (e.g., indoor mass immunization clinics) will likely need to be adjusted to incorporate additional infection prevention and control measures to prevent the transmission of COVID-19. It would be preferable to offer immunization when it can be combined with another medical visit, and offering multiple vaccines if required, to minimize the risk of acquiring COVID-19 and reduce the number of health care encounters. Countries in the southern hemisphere (e.g. Australia) are currently exploring alternative influenza vaccine delivery solutions such as outdoor and drive-through vaccine clinics, and their experiences may be instructive for Canada.
Specific guidance on influenza immunization in the context of COVID-19 will be issued as needed.
Resuming normal immunization activities
---------------------------------------
As the pandemic progresses, provinces and territories continue to closely monitor the COVID-19 epidemiological situation. Vaccine providers should follow advice from their provincial/territorial jurisdiction and the Public Health Agency of Canada on when to relax physical distancing measures and how to resume usual provision of healthcare activities in their local region. At that time, a careful assessment of missed doses will be important to ensure that the pandemic does not leave a long-lasting immunization gap in any Canadian communities.
References
----------
* Bogler, Tali. Interim schedule for pregnant women and children during the COVID-19 pandemic. [Internet]. Toronto (ON): College of Family Physicians; [modified 2020 Mar 25; cited 2020 Apr 28]. Available from: https://www.cfp.ca/news/2020/03/25/3-24
* British Columbia Centre for Disease Control. Continuity, Prioritization and Safe Delivery of Immunization Services during COVID-19 Response. [Internet]. Vancouver (BC): BC Ministry of Health; [modified 2020 Apr 9; cited 2020 Apr 29]. Available from: http://www.bccdc.ca/resource-gallery/Documents/Guidelines%20and%20Forms/Guidelines%20and%20Manuals/Epid/CD%20Manual/Chapter%202%20-%20Imms/Continuity\_of\_Immunization\_Services\_During\_COVID-19.pdf
* Centres for Disease Control and Prevention. Information for Healthcare Professionals about Coronavirus (COVID-19). [Internet]. Atlanta (GA): Department of Health and Human Services; [modified 2020 Apr 23; cited 2020 Apr 29]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/healthcare-facilities/index.html
* Office of the Chief Medical Officer of Health. Guidance for Immunization Service Providers during COVID-19. [Internet]. Toronto (ON): Ontario Ministry of Health and Long Term Care; [modified 2020 Apr 19; cited 2020 Apr 29]. Available from:https://www.toronto.ca/wp-content/uploads/2020/04/94f3-Immunization-Guidance-April-19-2020-E2.pdf
* Government of New Brunswick. Novel Coronavirus (COVID-19) Guidance for Primary Care Providers in a Community Setting. [Internet]. Fredericton (NB): Government of New Brunswick; [modified 2020 Mar 27; cited 2020 Apr 28]. Available from:https://www.vitalitenb.ca/sites/default/files/covid-19\_guidance\_for\_primary\_care\_providers\_in\_a\_community\_setting\_march\_27\_revmar29.pdf
* Ontario College of Family Physicians. Considerations for Family Physicians. [Internet]. Toronto (ON): Ontario College of Family Physicians; [modified 2020 Mar 26; cited 2020 Apr 28]. Available from:https://www.ontariofamilyphysicians.ca/tools-resources/timely-trending/novel-coronavirus-2019-ncov/ocfp-guidance-in-person-visits.pdf
* Quebec Immunization Committee. Should vaccination activities be continued in the context of the pandemic? [Internet]. Quebec (QC): Government of Quebec; [modified 2020 Mar 18; cited 2020 Apr 29]. Available from: https://www.inspq.qc.ca/publications/avis-ciq-covid-2019-2020
* Toronto Public Health. Guidance for Immunization Services during COVID-19. [Internet]. Toronto (ON): Toronto Public Health; [modified 2020 Apr 23; cited 2020 Apr 29]. Available from:https://www.toronto.ca/wp-content/uploads/2020/04/97ea-tph-immunization-duringcovid19-2020-04-23.pdf
* World Health Organization. Guiding principles for immunization activities during the COVID-19 Pandemic. Interim Guidance [Internet]. Geneva: World Health Organization; [modified 2020 Mar 26; cited 2020 Apr 29]. Available from: https://apps.who.int/iris/bitstream/handle/10665/331590/WHO-2019-nCoV-immunization\_services-2020.1-eng.pdf
* Word Health Organization Europe. Guidance on routine immunization services during COVID-19 pandemic in the WHO European Region. [Internet]. Copenhagen: WHO Regional Office for Europe; [modified 2020 Mar 20; cited 2020 Apr 29]. Available from: http://www.euro.who.int/\_\_data/assets/pdf\_file/0004/433813/Guidance-routine-immunization-services-COVID-19-pandemic.pdf
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2020-05-13
| None | None |
a80ccc4cff28235b7defb37acce6fd02dc6f714d | cma | Adverse events following immunization (AEFI): Canadian Immunization Guide | Adverse events following immunization (AEFI): Canadian Immunization Guide
Introduction
Evidence regarding vaccine safety generated throughout the vaccine life cycle helps to inform the risk-benefit discussion between immunization providers and potential vaccine recipients or their caregivers. Knowing about proven vaccine associations helps healthcare providers to assess clients who present with an illness in the post-immunization interval. Evidence addressing specific vaccine-associated adverse events (AEs) is discussed in . describes the types of studies that inform vaccine safety and that can establish or refute that an event is caused by vaccine.
Vaccinees and/or their parents/caregivers should be advised to notify their public health authority, vaccine provider or other healthcare provider about any concerns that arise following immunization. The provider can then assess these concerns and, if appropriate, complete an adverse event report.
Adverse Events Following Immunization (AEFI) definitions
The definitions below align with those used by the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS).
AEFI general definition: any untoward medical occurrence which follows administration of an active immunizing agent and which does not necessarily have a causal relationship with the use of a vaccine. The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, symptom or disease. The general definition of AEFI specifies that the event is not necessarily due to the vaccine. An AEFI can be classified by the following cause specific categories:
- Vaccine product-related reaction: an AEFI that is caused or precipitated by a vaccine due to one or more of the inherent properties of the vaccine product (examples include vaccination site pain, fever and anaphylaxis).
- Vaccine quality defect-related reaction: an AEFI that is caused or precipitated by a vaccine that is due to one or more quality defects of the vaccine product, including its administration device as provided by the manufacturer. Quality defect is defined as any deviation of the vaccine product as manufactured from its set quality specifications. (Example: failure to inactivate polio virus in some Salk vaccine lots prepared by Cutter laboratories in 1955 resulting in poliovirus infection among some vaccinees.)
- Immunization error-related reaction: an AEFI that is caused by inappropriate usage and, therefore, by its nature is preventable. Inappropriate usage is defined as vaccine handling, prescribing and/or administration other than what is authorized and recommended in a given jurisdiction based on scientific evidence or expert recommendation. (Example: inappropriate administration of live measles vaccine to immunocompromised persons resulting in measles encephalitis or pneumonia.)
- Immunization triggered stress response: an AEFI arising from anxiety about the immunization (examples include syncope or hyperventilation).
- Coincidental event: an AEFI that is caused by something other than the vaccine product, immunization error, or immunization anxiety but where a temporal association with immunization exists. (Example: meningitis that occurs within days of MMR vaccination that upon investigation is shown to be caused by *Streptococcus pneumoniae- )
Serious AEFI: an AEFI that meets one or more of the following criteria: life-threatening, results in hospitalization, prolongation of an existing hospitalization, persistent or significant disability/incapacity, is a congenital anomaly/birth defect, fatal outcome. Any medical event which requires intervention to prevent one of the outcomes listed above may also be considered as serious.
Unexpected AEFI: An adverse event whose nature, severity, or outcome is not consistent with the term or description used in the approved Product Monograph should be considered unexpected.
When and how to report an AEFI
Timely AEFI reporting is essential to detect possible changes to the safety profile of all vaccines. The key criteria for reporting an AEFI are temporal association and has no other clear cause at the time of reporting. A causal relationship does not need to be proven.
Vaccine providers contribute to vaccine safety by reporting AEFI which allows further investigation of adverse events, but does not mean that an observed event was caused by either vaccine or immunization. It is important that all serious AEFI are reported without delay. It is also important to report unexpected AEFI. Expected common events such as vaccination site reactions or fever do not need to be reported.
Providers should follow local or provincial public health protocols and submit reports to the appropriate jurisdictional authority. In most jurisdictions (Ontario, Quebec, Nova Scotia, Manitoba, New Brunswick, Saskatchewan, Prince Edward Island and Northwest Territories, BC, Alberta and Nunavut) AEFI reporting is a legislated requirement. While all provinces and territories collect information similar to that in the national , some have developed their own unique reporting form as well as supplementary forms for specific AEFI: these forms should be used for reporting.
When supplementary or follow-up information becomes available after an AEFI report has been submitted, it can be provided using the same AEFI report form (specifying that it is a follow-up), and submitted by the same route.
Given the importance of serious AEFI reporting, all such reports are referred by provincial/territorial public health authorities to PHAC within 15 days of becoming aware of the event and processed at the national level within 2 working days. Market authorization holders are required to report serious events to Health Canada within the same 15 day timeframe.
Jurisdiction-specific information on the AEFI reporting requirements can be obtained by contacting the appropriate .
Reporting adverse reactions following administration of a passive immunizing agent
To ensure the ongoing safety monitoring of passive immunizing agents in Canada, reporting of adverse reactions by health care providers is critical. When a serious or unexpected adverse reaction follows the administration of a passive immunizing agent, report the adverse drug reaction to the using the available on the program web page. The Canada Vigilance Program collects and assesses reports of suspected adverse reactions to health products, including biologics. If the passive immunizing agent was administered concurrently with an active immunizing agent, the adverse event should also be reported to the local or provincial public health immunization program in following local protocols.
Investigating and managing AEFI
It is important to use standard case definitions for AEFI investigation and reporting. The Canadian Adverse Event Following Immunization Surveillance System (CAEFISS) AEFI report form has been structured to facilitate establishing whether or not reported events meet standard case definitions for AEFIs considered to be of special public health importance (e.g., anaphylaxis, hypotonic-hyporesponsive episode, febrile seizure, intussusception).
It is also important to consider and investigate coincidental causes of an AEFI. This can be done after the initial report with additional relevant information provided at a later date. Establishing that an adverse event was actually coincidental and not causal is important for making appropriate decisions about future immunizations for a given individual. For more information, refer to the WHO’s
The Canadian Immunization Guide provides specific information on management of selected AEFI and/or special populations. Additional guidance may be found through Federal/Provincial/Territorial immunization program authorities, and, in several provinces, AEFI expert assessment is available via the Canadian Immunization Research Network’s . For more information on AEFI management, refer to SIC Network’s
Proof of causal association
The goal of adverse event investigation and reporting is to determine whether these events are associated with the vaccine or immunization. Vaccine attributable risk is defined as the difference between the frequency of the event in the vaccinated compared to the unvaccinated population. Determination of vaccine attributable risk is primarily done through research studies.
A placebo-controlled randomized control trial is the most rigorous study design, especially those using a cross-over design. An elegant example of such a design is a Finnish study involving 581 twin pairs where one twin of each pair was first given the measles-mumps-rubella (MMR) vaccine and 3 weeks later given a placebo. The other twin in the pair first received placebo and 3 weeks later the MMR vaccine. This was done in a double-blinded fashion (i.e., neither the researchers nor the subject caretakers knew whether a given injection was MMR vaccine or placebo). Adverse events were monitored for 21 days after immunization. The results of this classic study are shown in Table 3 and demonstrate two key points. First, fever is a common childhood event affecting 16% to 18% of the placebo group – i.e., a temporally associated coincidental event, related neither to vaccine nor to immunization. Secondly, the risk of fever attributable to MMR vaccine is 2% to 6% and occurs in the interval from 7 to 12 days after immunization.
Calculated from data presented in Table II in Peltola H, Heinonen OP. *Frequency of true adverse reactions to measles-mumps-rubella vaccine.- Reprinted with permission from Elsevier Science. Lancet 1986;1(8487):939-42.
An epidemiologic cohort design is another way to measure vaccine attributable risk (or risk difference). In Canada, this type of design was used to study the frequency of adverse events among a cohort of children given three successive doses of hepatitis B vaccine. The measured outcomes were the number of illnesses or clinical symptoms compatible with any adverse event recorded during one week intervals from 4 weeks before to 3 weeks after each vaccine dose. Recorded adverse events increased in the week after hepatitis B immunization but returned to pre-vaccination levels thereafter. The attributable increase in adverse events due to hepatitis B vaccine was limited to the first week after immunization and was 44%, 26% and 38% after doses 1, 2 and 3 respectively.
The self-controlled case series design is a powerful method for determining vaccine attributable risk for very rare adverse events. The risk of an event occurring during a defined period following vaccine exposure is compared to the risk of the event occurring in the same individual during intervals of similar length but without vaccine exposure. This technique has been successfully applied to address vaccine safety controversies (e.g., lack of causal link between MMR or thimerosal-containing vaccines and autism) as well as to quantify the attributable risk for some rare events that have been causally linked to vaccine such as thrombocytopenia following measles containing vaccines.
Individual case causality assessment of AEFI
It is nearly impossible to assess causality without a thorough investigation, near to the time an event occurs. This is especially important for serious as well as unexpected AEFI, and it underscores the important role that immunization and other healthcare providers have in managing AEFI.
The WHO guidelines for individual case assessment are an important tool for determining causality based on standardized case definitions that are provided by the Brighton Collaboration.
The stepwise algorithm provided in the guidelines takes into consideration evidence for known vaccine product-related reactions as well as individual case history and other details which may point to anxiety, immunization error or coincidental root cause for the AEFI. In addition to helping identify actions that are needed to rule out coincidental causes of an AEFI and make decisions about the safety of repeated immunization in individuals, these guidelines can also be used by program administrators to guide the investigation of AEFI clusters, and identify possible new vaccine – adverse event associations which may require further study.
In addition, challenge – dechallenge – rechallenge events may also be used to establish causality. This applies much more frequently to drugs than to vaccines. An example would be drug-associated rashes which appear after starting a drug (challenge), disappear after stopping the drug (dechallenge), and reappear upon re-exposure to the same drug (rechallenge). Given the immunologic properties of vaccines, dechallenge is difficult to achieve. The American Health and Medicine Division has accepted challenge – rechallenge events as mechanistic evidence that tetanus toxoid may cause Guillain-Barré Syndrome. This was based on a single case report of a man who developed GBS within 2 weeks following exposure to tetanus toxoid vaccine on three separate occasions.
While individual case investigation may be able to establish a vaccine – adverse event causal association, it cannot determine vaccine attributable risk. |
Adverse events following immunization (AEFI): Canadian Immunization Guide
==========================================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety.html)
* [Next Page](#)
Last partial content update (see [Table of updates](/en/public-health/services/canadian-immunization-guide/updates.html)): March 2023
March 2023: This chapter was updated to include guidance for reporting adverse reactions following administration of passive immunizing agents including monoclonal antibody preparations such as the anti-respiratory syncytial virus (RSV) monoclonal antibody, palivizumab (PVZ).
Last complete chapter revision (see [Table of updates](/en/public-health/services/canadian-immunization-guide/updates.html)): December 2019
Learn how to manage an Adverse Event Following Immunization (AEFI) including investigation as well as when and how to report.
On this page
------------
* [Introduction](#i)
* [Adverse Events Following Immunization (AEFI) definitions](#a)
* [When and how to report an AEFI](#w)
* [Reporting adverse reactions following administration of a passive immunizing agent](#rep)
* [Investigating and managing AEFI](#in)
* [Proof of casual association](#p)
+ [Table 1: Placebo-controlled randomized cross-over design to determine proportion of fever attributable to MMR vaccine](#t1)
* [Individual case causality assessment of AEFI](#ind)
* [Selected references](#s)
Introduction
------------
Evidence regarding vaccine safety generated throughout the vaccine life cycle helps to inform the risk-benefit discussion between immunization providers and potential vaccine recipients or their caregivers. Knowing about proven vaccine associations helps healthcare providers to assess clients who present with an illness in the post-immunization interval. Evidence addressing specific vaccine-associated adverse events (AEs) is discussed in [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html). [Proof of causal association](#p) describes the types of studies that inform vaccine safety and that can establish or refute that an event is caused by vaccine.
Vaccinees and/or their parents/caregivers should be advised to notify their public health authority, vaccine provider or other healthcare provider about any concerns that arise following immunization. The provider can then assess these concerns and, if appropriate, complete an adverse event report.
Adverse Events Following Immunization (AEFI) definitions
--------------------------------------------------------
The definitions below align with those used by the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS).
**AEFI general definition:** any untoward medical occurrence which follows administration of an active immunizing agent and which does not necessarily have a causal relationship with the use of a vaccine. The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, symptom or disease. The general definition of AEFI specifies that the event is not necessarily due to the vaccine. An AEFI can be classified by the following cause specific categories:
* **Vaccine product-related reaction:** an AEFI that is caused or precipitated by a vaccine due to one or more of the inherent properties of the vaccine product (examples include vaccination site pain, fever and anaphylaxis).
* **Vaccine quality defect-related reaction:** an AEFI that is caused or precipitated by a vaccine that is due to one or more quality defects of the vaccine product, including its administration device as provided by the manufacturer. Quality defect is defined as any deviation of the vaccine product as manufactured from its set quality specifications. (Example: failure to inactivate polio virus in some Salk vaccine lots prepared by Cutter laboratories in 1955 resulting in poliovirus infection among some vaccinees.)
* **Immunization error-related reaction:** an AEFI that is caused by inappropriate usage and, therefore, by its nature is preventable. Inappropriate usage is defined as vaccine handling, prescribing and/or administration other than what is authorized and recommended in a given jurisdiction based on scientific evidence or expert recommendation. (Example: inappropriate administration of live measles vaccine to immunocompromised persons resulting in measles encephalitis or pneumonia.)
* **Immunization triggered stress response:** an AEFI arising from anxiety about the immunization (examples include syncope or hyperventilation).
* **Coincidental event:** an AEFI that is caused by something other than the vaccine product, immunization error, or immunization anxiety but where a temporal association with immunization exists. (Example: meningitis that occurs within days of MMR vaccination that upon investigation is shown to be caused by *Streptococcus pneumoniae* )
**Serious AEFI:** an AEFI that meets one or more of the following criteria: life-threatening, results in hospitalization, prolongation of an existing hospitalization, persistent or significant disability/incapacity, is a congenital anomaly/birth defect, fatal outcome**.** Any medical event which requires intervention to prevent one of the outcomes listed above may also be considered as serious.
**Unexpected AEFI**: An adverse event whose nature, severity, or outcome is not consistent with the term or description used in the approved Product Monograph should be considered unexpected.
When and how to report an AEFI
------------------------------
Timely AEFI reporting is essential to detect possible changes to the safety profile of all vaccines. The key criteria for reporting an AEFI are temporal association and has no other clear cause at the time of reporting. A causal relationship does not need to be proven.
Vaccine providers contribute to vaccine safety by reporting AEFI which allows further investigation of adverse events, but does not mean that an observed event was caused by either vaccine or immunization. It is important that all **serious AEFI** are reported without delay. It is also important to report **unexpected AEFI. Expected common events** such as vaccination site reactions or fever do not need to be reported.
Providers should follow local or provincial public health protocols and submit reports to the appropriate jurisdictional authority. In most jurisdictions (Ontario, Quebec, Nova Scotia, Manitoba, New Brunswick, Saskatchewan, Prince Edward Island and Northwest Territories, BC, Alberta and Nunavut) AEFI reporting is a legislated requirement. While all provinces and territories collect information similar to that in the national [Adverse Events Following Immunization Report Form](/en/public-health/services/immunization/reporting-adverse-events-following-immunization/form.html), some have developed their own unique reporting form as well as supplementary forms for specific AEFI: these forms should be used for reporting.
When supplementary or follow-up information becomes available after an AEFI report has been submitted, it can be provided using the same AEFI report form (specifying that it is a follow-up), and submitted by the same route.
Given the importance of serious AEFI reporting, all such reports are referred by provincial/territorial public health authorities to PHAC within 15 days of becoming aware of the event and processed at the national level within 2 working days. Market authorization holders are required to report serious events to Health Canada within the same 15 day timeframe.
Jurisdiction-specific information on the AEFI reporting requirements can be obtained by contacting the appropriate [Federal/Provincial/Territorial immunization program authority](/en/public-health/services/immunization/federal-provincial-territorial-contact-information-aefi-related-questions.html).
Reporting adverse reactions following administration of a passive immunizing agent
----------------------------------------------------------------------------------
To ensure the ongoing safety monitoring of passive immunizing agents in Canada, reporting of adverse reactions by health care providers is critical. When a serious or unexpected adverse reaction follows the administration of a passive immunizing agent, report the adverse drug reaction to the [Canada Vigilance Program](/en/health-canada/services/drugs-health-products/medeffect-canada/canada-vigilance-program.html) using the [Side Effect Reporting Form](/content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/pdf/medeff/report-declaration/ser-des_form-eng.pdf) available on the program web page. The Canada Vigilance Program collects and assesses reports of suspected adverse reactions to health products, including biologics. If the passive immunizing agent was administered concurrently with an active immunizing agent, the adverse event should also be reported to the local or provincial public health immunization program in following local protocols.
Investigating and managing AEFI
-------------------------------
It is important to use standard case definitions for AEFI investigation and reporting. The Canadian Adverse Event Following Immunization Surveillance System (CAEFISS) AEFI report form has been structured to facilitate establishing whether or not reported events meet standard case definitions for AEFIs considered to be of special public health importance (e.g., anaphylaxis, hypotonic-hyporesponsive episode, febrile seizure, intussusception).
It is also important to consider and investigate coincidental causes of an AEFI. This can be done after the initial report with additional relevant information provided at a later date. Establishing that an adverse event was actually coincidental and not causal is important for making appropriate decisions about future immunizations for a given individual. For more information, refer to the WHO’s [Causality assessment of an adverse event following immunization (AEFI).](http://www.who.int/vaccine_safety/publications/gvs_aefi/en/)
The Canadian Immunization Guide provides specific information on management of selected AEFI and/or special populations. Additional guidance may be found through Federal/Provincial/Territorial immunization program authorities, and, in several provinces, AEFI expert assessment is available via the Canadian Immunization Research Network’s [Special Immunization Clinic Network](http://cirnetwork.ca/network/special-immunization/). For more information on AEFI management, refer to SIC Network’s [Managing Adverse Events Following Immunization: Resource for Public Health](http://cirnetwork.ca/wp-content/uploads/2019/01/SIC-AEFI-Management-Resource-for-PH_16Jan19-FINAL-1.pdf)
Proof of causal association
---------------------------
The goal of adverse event investigation and reporting is to determine whether these events are associated with the vaccine or immunization. Vaccine attributable risk is defined as the difference between the frequency of the event in the vaccinated compared to the unvaccinated population. Determination of vaccine attributable risk is primarily done through research studies.
A **placebo-controlled randomized control trial** is the most rigorous study design, especially those using a cross-over design. An elegant example of such a design is a Finnish study involving 581 twin pairs where one twin of each pair was first given the measles-mumps-rubella (MMR) vaccine and 3 weeks later given a placebo. The other twin in the pair first received placebo and 3 weeks later the MMR vaccine. This was done in a double-blinded fashion (i.e., neither the researchers nor the subject caretakers knew whether a given injection was MMR vaccine or placebo). Adverse events were monitored for 21 days after immunization. The results of this classic study are shown in Table 3 and demonstrate two key points. First, fever is a common childhood event affecting 16% to 18% of the placebo group – i.e., a temporally associated coincidental event, related neither to vaccine nor to immunization. Secondly, the risk of fever attributable to MMR vaccine is 2% to 6% and occurs in the interval from 7 to 12 days after immunization.
Table 1: Placebo-controlled randomized cross-over design to determine proportion of fever attributable to MMR vaccine[Footnote 1](#fn1)
| | Days after injection |
| 1 - 6 | 7 - 8 | 9 - 10 | 11 - 12 | 13 - 21 |
| MMR vaccine | 17.2% | 20.3% | 24.0% | 19.9% | 16.2% |
| Placebo | 17.0% | 18.0% | 17.9% | 17.5% | 16.5% |
| Difference or attributable risk | 0.2% | 2.3% | 6.1% | 2.4% | −0.3% |
|
Footnote 1
Calculated from data presented in Table II in Peltola H, Heinonen OP. *Frequency of true adverse reactions to measles-mumps-rubella vaccine.* Reprinted with permission from Elsevier Science. Lancet 1986;1(8487):939-42.
[Return to footnote 1 referrer](#fn1-rf)
|
An **epidemiologic cohort design** is another way to measure vaccine attributable risk (or risk difference). In Canada, this type of design was used to study the frequency of adverse events among a cohort of children given three successive doses of hepatitis B vaccine. The measured outcomes were the number of illnesses or clinical symptoms compatible with any adverse event recorded during one week intervals from 4 weeks before to 3 weeks after each vaccine dose. Recorded adverse events increased in the week after hepatitis B immunization but returned to pre-vaccination levels thereafter. The attributable increase in adverse events due to hepatitis B vaccine was limited to the first week after immunization and was 44%, 26% and 38% after doses 1, 2 and 3 respectively.
The **self-controlled case series design** is a powerful method for determining vaccine attributable risk for very rare adverse events. The risk of an event occurring during a defined period following vaccine exposure is compared to the risk of the event occurring in the same individual during intervals of similar length but without vaccine exposure. This technique has been successfully applied to address vaccine safety controversies (e.g., lack of causal link between MMR or thimerosal-containing vaccines and autism) as well as to quantify the attributable risk for some rare events that have been causally linked to vaccine such as thrombocytopenia following measles containing vaccines.
Individual case causality assessment of AEFI
--------------------------------------------
It is nearly impossible to assess causality without a thorough investigation, near to the time an event occurs. This is especially important for serious as well as unexpected AEFI, and it underscores the important role that immunization and other healthcare providers have in managing AEFI.
The WHO guidelines for individual case assessment are an important tool for determining causality based on standardized case definitions that are provided by the Brighton Collaboration.
The stepwise algorithm provided in the guidelines takes into consideration evidence for known vaccine product-related reactions as well as individual case history and other details which may point to anxiety, immunization error or coincidental root cause for the AEFI. In addition to helping identify actions that are needed to rule out coincidental causes of an AEFI and make decisions about the safety of repeated immunization in individuals, these guidelines can also be used by program administrators to guide the investigation of AEFI clusters, and identify possible new vaccine – adverse event associations which may require further study.
In addition, challenge – dechallenge – rechallenge events may also be used to establish causality. This applies much more frequently to drugs than to vaccines. An example would be drug-associated rashes which appear after starting a drug (challenge), disappear after stopping the drug (dechallenge), and reappear upon re-exposure to the same drug (rechallenge). Given the immunologic properties of vaccines, dechallenge is difficult to achieve. The American Health and Medicine Division has accepted challenge – rechallenge events as mechanistic evidence that tetanus toxoid may cause Guillain-Barré Syndrome. This was based on a single case report of a man who developed GBS within 2 weeks following exposure to tetanus toxoid vaccine on three separate occasions.
While individual case investigation may be able to establish a vaccine – adverse event causal association, it cannot determine vaccine attributable risk.
Selected references
-------------------
* De Serres G. et al. *Importance of attributing risk in monitoring adverse events after immunization: hepatitis B vaccination in children*. Am J Public Health 2001;91(2): 313-15.
* Health Canada. Canada Vigilance Program. Dated 2022-06-1. Accessed December 23, 2022: https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/canada-vigilance-program.html Canada Vigilance Program - Canada.ca
* ICH Expert Working Group. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Post-approval safety data management: Definitions and standards for expedited reporting E2D. Dated 12 November 2003. Accessed July 15, 2019: www.ich.org/fileadmin/Public\_Web\_Site/ICH\_Products/Guidelines/Efficacy/E2D/Step4/ E2D\_Guideline.pdf
* Peltola H, Heinonen OP. *Frequency of true adverse reactions to measles-mumps-rubella vaccine.* Lancet 1986;1(8487): 939-42.
* World Health Organization. *Causality assessment of an adverse event following immunization (AEFI).* Geneva: WHO, 2018.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-4-early-vaccine-reactions-including-anaphylaxis.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety.html)
* [Next Page](#)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-08-04
| None | None |
861db3918724f28204a7c281f8eb87e0c6e9d414 | cma | Recommendations on fractional influenza vaccine dosing | Recommendations on fractional influenza vaccine dosing
Preamble
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
On this page
Summary of the Information Contained in this NACI Supplemental Statement
The following highlights key information for immunization providers. Please refer to the remainder of this supplemental statement for details.
# 1. What
Influenza vaccination in Canada is provided annually through provincial and territorial seasonal influenza vaccine programs. Due to the rapid timelines required for vaccine production each year, any significant impact to the manufacturing process may cause delays in influenza vaccine delivery or decrease the overall number of doses produced, potentially resulting in vaccine shortages for a season. A significant and unexpected increase in demand for the influenza vaccine may also lead to insufficient supply, as the number of doses available is based on orders made primarily in the spring months. A strategy for the administration of fractional influenza vaccine doses (i.e., less than a full dose) might be considered in these situations, as the use of fractional doses would provide vaccine programs the ability to vaccinate a larger number of people with the amount of vaccine that is available.
# 2. Who
This supplemental statement provides an evidence summary and recommendations on the topic of fractional influenza vaccine doses for consideration by public health programs during a significant influenza vaccine shortage.
# 3. How
In the event of a significant population-level shortage of the currently available influenza vaccine products, NACI recommends that full dose influenza vaccine should continue to be used and existing vaccine supply should be prioritized for those considered to be at high risk or capable of transmitting to those at high risk of influenza-related complications or hospitalizations. NACI recommends against the use of fractional doses of influenza vaccines in any population.
# 4. Why
There is some, but still insufficient, evidence that fractional doses of influenza vaccine provided via the intramuscular (IM) route are effective and immunogenic in healthy individuals. Although there is some evidence on the use of fractional intradermal (ID) doses in adults ≥65 years of age, including those with chronic health conditions, that demonstrates that lower doses may be immunogenic in this population, there is no evidence regarding the use of fractional dosing in other adult high-risk groups. Moreover, administering influenza vaccines through the ID route, while using regular syringes, has been determined to not be feasible.
Since many of those at high risk of influenza (e.g., adults 65 years of age and older, individuals with specific underlying chronic health conditions) may have a lower immune response to influenza vaccination already (due to immunosenescence in older adults or a condition that alters immune function), it is important to ensure that those at high risk continue to receive the full dose of influenza vaccine.
There is fair evidence that fractional doses of influenza vaccine administered via the IM and ID routes do not result in a significant difference with regard to severe systemic adverse events (AEs) post-influenza vaccination; however, ID administration of influenza vaccine will likely result in a higher proportion of individuals who experience local AEs.
There are feasibility issues when considering fractional dosing of current influenza immunizations or administration of ID doses of influenza vaccines. Pre-filled syringes cannot be used for fractional dosing. ID administration of vaccine requires a different gauge needle than IM administration, and training and skill in ID administration that not all vaccinators will have. The volume of vaccine to be administered is high, requiring two ID injections if regular needles and syringes are used. The majority of studies of administration of influenza vaccine by the ID route used micro-needle injectors for administration. The use of fractional doses is not covered within influenza vaccine product monographs and would therefore require a novel communication and consent plan for any off-label dosing if it were adopted. Moreover, implementation of such an ID immunization program would require monitoring for any potential modification to a seasonal influenza vaccine program running low on vaccine supply and thus would be a challenge without significant advanced planning.
I. Introduction
Influenza is a viral infection that is estimated to cause approximately 12,200 hospitalizations and 3,500 deaths in Canada annually. All provinces and territories in Canada have implemented seasonal influenza vaccination programs, with the aim of reducing morbidity and mortality caused by influenza-associated illness. Although influenza programs vary across the country, all programs cover individuals who are at high risk of severe outcomes due to influenza and individuals that are capable of transmitting influenza to those at high risk (e.g., household members, healthcare workers).
Influenza vaccine for use in publicly funded programs in Canada is coordinated by the federal government's Public Services and Procurement Canada, and vaccine orders are completed in the spring in advance of the next influenza season. The schedule for finalizing influenza vaccine orders is generally consistent for all countries in the Northern Hemisphere, as vaccine manufacturers must follow strict timelines to produce influenza vaccine with the recommended strain composition for the next season. The strain composition for the upcoming Northern Hemisphere
season is announced by the World Health Organization annually in February . Significant changes to the amount of influenza vaccine ordered are, therefore, difficult once the influenza season has begun. In addition, unforeseen influenza vaccine production issues or an unexpected increase in demand for influenza vaccine could result in a delay or decrease in vaccine available for Canadians. In the event that a significant shortage of influenza vaccine were to occur in Canada, guidance on appropriate strategies for fractional dosing, or dose sparing, would be needed. However, significant global influenza vaccine shortages are extremely rare, given the variety of influenza vaccine products available on the market, with any issues that do arise typically being isolated to only one vaccine product or manufacturer.
In Canada, influenza vaccines are currently authorized for IM administration only, apart from the live-attenuated influenza vaccine (LAIV), which is administered intranasally. The stated dose of an influenza vaccine is based on the hemagglutinin (HA) content within the vaccine. Standard dose influenza vaccines contain 15 mcg of HA per strain and are delivered in 0.5 mL volume. Therefore, the total amount of HA in standard dose trivalent vaccines is 45 mcg, and the total amount of HA in standard dose quadrivalent vaccines is 60 mcg. Fractional dosing strategies are those where less than the standard amount of HA antigen and thus less volume of vaccine is administered during influenza vaccination, increasing the overall number of doses available. For the purposes of these recommendations, NACI considered two different strategies:
1. Fractional intramuscular (IM) administration of influenza vaccine
2. Fractional intradermal (ID) administration of influenza vaccine
# Guidance Objective
The objective of this advisory committee supplemental statement is to review the available evidence for efficacy, effectiveness, immunogenicity, and safety of fractional influenza vaccine dosing, and to provide guidance on potential fractional dosing strategies in the event of a significant influenza vaccine shortage in Canada.
II. Methods
In brief, the broad stages in the preparation of a NACI Advisory Committee Statement are:
1. Knowledge synthesis - individual studies were retrieved and key data abstracted, and the level (i.e., study design) and quality of the evidence assessed. This information is summarized in Summary of Evidence Tables.
2. Synthesis of the body of evidence of benefits and harms, considering the quality of the evidence and magnitude of effects observed.
3. Translation of evidence into recommendations.
Further information on NACI's evidence-based methods is available in: .
In preparation for this Statement, two reviews were conducted to gather evidence to inform NACI's recommendations regarding the use of fractional dosing strategies. The review methodologies were developed in collaboration with the Methods and Applications Group for Indirect Comparisons (MAGIC) through the Drug Safety and Effectiveness Network (DSEN). The methods were specified *a priori- in a written protocol that included the research questions, search strategy, inclusion and exclusion criteria, and quality assessment. The reviews were completed by MAGIC, with additional data extraction (notably immunogenicity outcomes as indirect evidence for effectiveness for IM administration of fractional doses) completed by PHAC.
# Research question #1
What is the safety and effectiveness of using fractional dosing strategies to deliver IM seasonal influenza vaccines?
# Research question #2
What is the safety and effectiveness of using fractional dosing strategies to deliver seasonal influenza vaccine by ID administration?
The search strategies were developed based on the research questions and pre-defined PICOST, in conjunction with an experienced librarian. For both reviews, EMBASE and MEDLINE electronic databases were searched for research articles, with the review of IM studies looking at publications in the last 20 years and the review of ID studies looking at publications in the last 10 years. The Cochrane library, the Cochrane Central Register of Controlled Trials, and international clinical trial registries were also searched for additional studies. Searches were restricted to articles published in English. Additionally, hand-searching of the reference lists of included articles and relevant systematic reviews were performed.
Screening of citations and full-text articles were completed using a standard form based on study eligibility criteria. The forms were pilot-tested between two reviewers until 70% or greater agreement was reached, after which screening was completed by one reviewer.
One reviewer extracted data from the studies included for review into an evidence table using a piloted data abstraction template designed to capture information on study design, vaccine characteristics, population and outcomes of interest. A second reviewer independently validated the abstracted data.
For the review of ID administration of fractional influenza vaccine, the DSEN MAGIC team conducted all data extraction and performed a meta-analysis for effectiveness, immunogenicity, and safety outcomes. The risk of bias for the studies included as part of the ID review was assessed using the Cochrane Tool for Risk of Bias in Randomized Controlled Studies.
For the IM fractional dose review, the DSEN MAGIC team extracted and narratively summarized the data for effectiveness and safety, and provided PHAC with a list of studies that assessed immunogenicity outcomes. PHAC then extracted the immunogenicity data from the studies provided, and summarized the evidence narratively. The level of evidence (i.e., study design) and methodological quality of studies included in the IM review were assessed independently by two reviewers with PHAC using the design-specific criteria outlined by Harris et al.(2001), which has been adopted by NACI for rating the internal validity of individual studies.
# Development of Recommendations
Following critical appraisal of individual studies, summary tables (Tables 9, 10, and 11) were prepared with ratings of the quality of the evidence using NACI's methodological hierarchy, and proposed recommendations for vaccine use were developed. The evidence and proposed recommendations were discussed by the NACI Influenza Working Group (IWG) and considered the
Ethics, Equity, Feasibility, and Acceptability (EEFA) framework . Following a thorough review of the evidence, NACI approved the recommendation contained in this statement on November 2, 2020. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the following sections.
III. Fractional Influenza Vaccine doses
# Intramuscular fractional dosing
Thirteen studies were identified through the DSEN MAGIC team review on IM fractional dosing, including 5 related reports or trial protocols. Twelve of the studies were randomized controlled trials (RCT), and were assessed as being of good quality, according to the criteria defined by Harris et al. One trial was considered as having a high risk of bias due to significant issues with the randomization process and concerns
with missing outcome data and selection of the reported outcomes This trial was later excluded from the PHAC analysis because it did not have any peer-reviewed published results.
# Intradermal fractional dosing
The DSEN MAGIC team rapid review on fractional ID influenza vaccination identified 29 studies. Most of the 29 RCTs were rated as having some
concerns with bias (n=17), based on the Cochrane Risk of Bias tool for RCTs , and two studies (Chuaychoo, 2010 and Han 2013) had a high risk of bias. Issues were most often noted for the randomization process, deviations from the intended intervention, and bias in the selection of reported results.
Evidence from the DSEN MAGIC team reviews and additional analyses by PHAC technical staff are presented in Tables 9, 10, and 11.
# III.1 Vaccine Efficacy and Effectiveness
## III.1.1 Fractional intramuscular dosing
There were no studies included in the rapid review that assessed the efficacy of fractional IM administration of influenza vaccine. Two studies were identified that assessed the effectiveness of fractional IM administration of influenza vaccine. Both studies were RCTs that assessed the efficacy of a 7.5 mcg of HA per strain dose of a quadrivalent influenza vaccine versus a 15 mcg of HA per strain dose in adults.
The first study was conducted by Kramer et al. (2006), in a population of adult healthcare workers 18 years of age and older. The study reported on clinical diagnoses of influenza-like illness (ILI) and laboratory-confirmed influenza (type of test not specified). Laboratory testing was only completed for individuals who had a clinical diagnosis of influenza. This RCT study found that 6.8% (n=15 of 222) of individuals who received the half-dose received a clinical diagnosis of ILI compared to 3.6% (n=8 of 222) of those that received the standard 15 mcg of HA per strain dose; however, only one participant in the study (an individual that received the 15 mcg of HA per strain dose) had laboratory-confirmed influenza infection and this difference for the laboratory-confirmed outcome was not statistically significant (relative risk . The second study by Engler et al. (2008) assessed the efficacy of a half dose compared to a full dose of influenza vaccine against medical visits for ILI involving the upper and lower respiratory tract, but with no laboratory confirmation, in adults 18 to 49 (n=558) and 50 to 64 years of age (n=556), and there was no statistically significant difference in the relative risk between vaccine groups, before and after adjusting for confounders (18-49 year olds: adjusted RR: 1.01, 95% CI: 0.70-1.46; 50-64 year olds: adjusted RR: 1.07, 95% CI: 0.53-2.18).
## III.1.2 Fractional intradermal dosing
Two studies assessed the efficacy of fractional ID administration of influenza vaccine against laboratory-confirmed influenza infection or ILI in adults using trivalent influenza vaccine. A meta-analysis of these two studies indicated no significant difference in the risk of influenza infection/ILI from the ID administration of a 9 mcg of HA per strain dose of influenza vaccine compared to 15 mcg of HA per strain IM dose (Figure 1). Note that the figure below also describes the comparison of 15 mcg of HA per strain ID and IM. These data were not used to inform this Statement, as it was not considered a fractional dose.
Text description
The following information is depicted in this figure:
Effect estimates from the single studies:
Pooled results:
# III.2 Immunogenicity
The serological assessments of antibody responses to vaccination are based on the geometric mean titres (GMT) assessed using a hemagglutinin inhibition assay (HI). The assessments used by regulators are: GMT ratio, seroprotection rate, and seroconversion rate. The United States (US) Food and Drug Administration (FDA) has published definitions for these serological assessments and define criteria for the immunogenicity data required for influenza vaccine licensure in the US (Table 5). Correlates of protection that are not based on HI antibody titres have not been well established.
## III.2.1 Fractional intramuscular dosing
Ten published studies were identified that assessed immunogenicity outcomes
for fractional doses of influenza vaccines administered intramuscularly. The 10 studies were all RCTs and were considered to be of good quality according to Harris et al. criteria. Of the 10 studies, two were conducted in adults within the range of ages of 18 and 64 and one was conducted in adults 65 years of age and older. The other seven studies
were all conducted in children within the range of 6 to 35 months of age . Only one study in adults and four studies in children assessed the difference in immunogenicity between fractional and standard dose IM administration of influenza vaccine statistically.
One study statistically compared the immune response following the IM administration of a fractional dose (7.5 mcg of HA per strain) of influenza vaccine to the standard dose in adults. Engler et al. (2008) reported that the study groups that received a fractional dose of 7.5 mcg of HA per strain had statistically lower proportions of seroconversion and seroprotection post-vaccination when compared to the groups that had received the full dose for all strains. The exception to this was seroprotection against influenza B in the 18 to 49 years of age subgroup and seroconversion for influenza A(H1N1) in the 50 to 64 years of age subgroup, which showed no significant difference between 7.5 mcg of HA per strain and 15 mcg of HA per strain.
Four studies statistically assessed the difference in immunogenicity between a full dose and a half dose of influenza vaccine in children 6 to 35 months of age. Results from these studies were mixed. Langley et al. (2012) reported no significant difference based on GMT ratios (GMT of full dose/GMT of fractional dose) post-vaccination between the two study groups, and Halasa et al. (2015) found no significant difference in the absolute difference in GMTs. Robertson et al. (2019) reported better GMTs in groups that received the full dose compared to the half dose of influenza vaccine based on GMT ratios (lower limit of 95% CI was greater than 1 for all strains); however, they reported non-significant differences in seroconversion rates between the two study groups for all strains except for influenza A(H1N1) (difference in seroconversion for A(H1N1): 5.1, 95% CI: 0.189 to 10.0). Pavia-Ruz et al. (2013) reported contradictory results, with the group receiving a half dose experiencing higher GMTs and seroconversion rates compared to the group that received the full dose of vaccine, with the exception of influenza B (Yam) with regard to seroconversion rates, for which there was no statistically significant difference between the two groups. In a non-statistical
comparison, the group that received 7.5 mcg of HA per strain of Fluarix ® appeared to have similar immunogenicity to those that received 15 mcg of HA per strain Fluarix® (i.e., 95% CI were widely overlapping).
Additional studies (one in adults and two in children) that assessed varying fractional doses of influenza vaccine (3 mcg, 6 mcg, 7.5 mcg, and 9 mcg of HA per strain) reported on GMT rise, seroprotection rates, and seroconversion rates for the different study groups, but did not compare them statistically. In general, as the dose of influenza vaccine decreased, the immunogenic response also decreased; however, most lower doses continued to meet criteria set for non-inferiority, despite the reduced response compared to full dose (according to current US FDA or previous European Medicines Agency criteria).
## III.2.2 Fractional intradermal dosing
Of the thirty studies identified in the rapid review, 16 studies assessed immunogenicity outcomes for fractional doses of influenza
vaccine administered intradermally, all of which were RCTs.
A meta-analysis demonstrated no significant difference in the seroconversion rate for the study groups that had received fractionated doses (3 mcg, 6 mcg, 7.5 mcg or 9 mcg of HA per strain) by ID administration compared to 15 mcg of HA per strain dose given intramuscularly for influenza A(H1N1), A(H3N2), or B (Table 1).
A meta-analysis was also performed for seroprotection rates compared to a full 15 mcg of HA per strain per IM dose, and found no significant difference in seroprotection rates against influenza A(H1N1), A(H3N2), or B for groups that had received ID administration of influenza vaccine at doses of 3 mcg of HA per strain, 7.5 mcg of HA per strain, or 9 mcg of HA per strain (Table 1). However, rates of seroprotection were significantly lower for those that had received a dose of 6 mcg of HA per strain for influenza A(H1N1) (risk ratio : 0.93, 95% confidence interval : 0.88-0.99) and influenza B (RR: 0.92, 95% CI: 0.86-0.98) compared to the full IM dose.
A further sub-analysis was performed by the DSEN MAGIC team to assess immunogenicity in adults 60 years of age and older. The only fractional ID dose assessed by the studies that had sufficient data for inclusion in the sub-analysis was 9 mcg of HA per strain dose. Similar to the overall results, there was no significant difference in seroconversion or seroprotection rates between older adults that had received the fractional 9 mcg of HA per strain ID dose compared to those that received the full, 15 mcg of HA per strain IM dose (Table 2).
Outcome significantly higher with ID administration
No significant difference in outcome between ID and IM administration
Outcome significantly lower with ID administration
No significant difference in outcome between ID and IM administration
# III.3 Safety
## III.3.1 Adverse Events with IM administration
Children
The rapid review found 9 studies that assessed safety outcomes (local, systemic, and severe AEs) of fractional IM influenza vaccine (IIV3: 5 studies, IIV4: 3 studies, IIV3 and IIV4: 1 study) in infants or toddlers in the range of 6 to 36 months of age. Children that received one or two half doses (7.5 mcg of HA per strain) of influenza vaccine (dependent on whether they had ever received an influenza vaccine previously) generally reported similar levels of reactogenicity and AEs when compared to those that received one or two standard doses. In some instances, AEs appeared to be slightly more common with the full dose of influenza vaccine compared to the half dose, however there was no consistent trend.
Adults
Three studies were identified in the rapid review that assessed safety of fractional IM influenza vaccination in adults: 2 of the studies involved
adults between the ages of 18 to 64 (18 to 49 and 18 to 65) and one study included older adults >65 years of age. Belshe et al. (2008) reported no differences in the occurrence of AEs between any of the study groups (doses assessed: 3 mcg, 6 mcg, 9 mcg, and 15 mcg of HA per strain). The other study, by Engler et al. (2008), that assessed safety in adults less than 65 years of age also found no statistically significant difference in the occurrence of AEs after adjusting to only include clinically significant pain levels (≥ 3 out of 5 using a visual analog scale). The study conducted in older adults found no significant difference in the proportion of individuals that experienced AEs or in the severity of the AEs between the group that received the fractional dose (9 mcg of HA per strain) and the group that received the full standard dose.
## III.3.2 Adverse events associated with ID administration
Twenty-four studies were identified that assessed the safety of ID administration of influenza vaccine and were able to be included in a meta-analysis performed by the DSEN MAGIC team . The studies identified included various fractional doses (3 mcg, 6 mcg, 9 mcg of HA per strain), as well as a full non-fractional dose (i.e. 15 mcg of HA per strain) of ID administered influenza vaccine. Because ID administration of influenza vaccine is not authorized in Canada, there is a lack of data not only for ID administration of fractional doses, but of the full, non-fractional dose as well. Since the safety of ID administration of a full dose of influenza vaccine is likely comparable to that of fractional doses, evidence regarding safety for the full non-fractional dose was also considered to enhance the evidence base for this outcome.
Overall, the risk of ecchymosis, erythema, pruritus, and swelling occurring post-vaccination at the injection site was significantly higher with ID administration of influenza vaccine compared to IM administration. However, the risk of pain at the injection site was not significantly different for ID administration of 6 mcg, 9 mcg and 15 mcg of HA per strain compared to administration of 15 mcg per strain IM; whereas the risk of pain after the ID administration of a 3 mcg of HA per strain dose was significantly lower (Table 3). Unlike with local AEs, there was in general no significant difference in the risk of systemic events with ID influenza vaccine administration compared to IM administration, with the exception of chills and fever which were higher for ID administration but only at the 9 mcg per strain dose level and not at the lower or higher dose levels (Table 4).
AE significantly lower with ID administration
No significant difference between ID and IM
AE significantly higher with ID administration
No significant difference between ID and IM
AE significantly higher with ID administration
IV. Feasibility
An assessment of EEFA of influenza vaccine fractional dosing strategies was conducted according to established NACI methods. The assessment of feasibility in particular identified several significant issues that warrant further discussion within the Statement.
# Logistics for fractional dosing strategies
Both fractional dosing strategies (IM and ID) assessed in this Statement would require using influenza vaccine that has been packaged in the format and of an antigen concentration authorized for use in Canada. Therefore, administering a fractional dose would require administering a lower volume of vaccine to achieve the desired lower dose, which is only possible when influenza immunizations have been packaged as multi-dose vials (MDV), and not as pre-filled syringes. A significant proportion of the influenza vaccine supply purchased for public programs is in MDV format; however, the distribution of MDV of influenza vaccine may not be equal across jurisdictions, and varies between provinces, based on provincial vaccine orders. When vaccine has already been ordered in a given season, there is not typically the opportunity to change the supply to MDV mid-season.
Using standard doses, MDVs contain 5 mL of vaccine solution, sufficient to vaccinate 10 individuals. The volume of vaccine for some fractional doses (e.g., 9 mcg of HA per strain is 0.3 mL), would not split evenly from 5 mL vials. Therefore, using fractional doses that do not divide evenly into 5 mL could result in unnecessary vaccine wastage, which would not allow for the full advantage of implementing fractional dosing as a dose sparing strategy. A half dose of influenza vaccine (7.5 mcg of HA per strain) is likely the most feasible fractional dose for influenza vaccine programs, regardless of route of administration, as this dose could allow the full use of the vial without wastage.
ID administration of vaccine requires a different needle gauge than IM administration. Most immunization venues providing influenza vaccines are unlikely to be equipped with a sufficient number of needles necessary for ID administration for the seasonal influenza vaccine program. Depending on the syringe used, different volumes may be more clearly marked (e.g., 0.5 mL, 0.25 mL). Therefore, fractional doses that require a vaccine volume that is not as clearly marked on the syringe may be more difficult to measure accurately in a vaccination setting, leading to variation in the amount of vaccine administered.
# Intradermal administration of influenza vaccine
In addition to the logistical considerations above, the ID administration of fractional doses has further implementation issues.
ID administration requires skill to administer the vaccine correctly. Influenza vaccines in Canada are only authorized for IM administration or nasal spray in the case of LAIV. As such, many influenza vaccinators may be unfamiliar with the requisite technique for ID administration. Inexperience could lead to vaccine administration errors or wasted vaccine product. ID administration also requires creation of an ID wheal or "bleb" and it can be more difficult to perform in older adults, which may slow down the immunization process. As shown in Section III.4.2, ID administration is also associated with a significant increase in local adverse reactions across almost all fractionated dose levels, which could reduce uptake of the vaccine. ID administration by needle and syringe may also require 2 or more injections to administer the full dose, further exacerbating the issues with ID. A needle-free jet injector has been authorized for use in Canada for ID injections. NACI is actively reviewing the evidence on the use of this device to determine if it could potentially be used as an alternative method for administering ID vaccine. Novel technologies for ID injection, such as the needle-free jet injector, may be an option in the future that would facilitate delivery of ID dosing but are not yet widely available in Canadian settings.
Since fractional influenza vaccines doses are considered off-label for all ages, discussion with the patient and additional information in the vaccination consent form would be required. Finally, given that ID is not an authorized route of administration for influenza vaccine, many immunization registries/surveillance systems do not currently have the capacity to input ID as the route of administration, and would therefore require system-level changes before being able to effectively implement ID administration of influenza vaccine. This option would need to be added to these systems in advance of implementing ID administration to ensure the ability to evaluate the safety and effectiveness of ID administration of influenza vaccine.
V. Recommendation
The following section outlines recommendations made by NACI regarding potential fractional influenza vaccine dosing strategies. Additional information on the strength of NACI recommendations and the grading of evidence is available in Table 6.
The following recommendations are meant to be considered in situations of influenza vaccine shortage when it is not possible to procure additional vaccine doses. Policies regarding fractional dosing strategies should be implemented at a jurisdictional level, and vaccination should be consistent with the policy and not subject to individual preference. All recommendations should be considered in the context of a given shortage situation. The extent of the shortage and its potential impact will need to be assessed prior to deciding on the best course of action.
# V.1 Public Health Program Decision-Making
1. NACI recommends that, in the event of a significant population-level shortage of influenza vaccine, a full dose influenza vaccine should continue to be used, and existing vaccine supply should be prioritized for those considered to be at high risk or capable of transmitting to those at high risk of influenza-related complications or hospitalizations (Strong NACI Recommendation).
- NACI concludes that there is fair evidence to recommend the use of a full dose influenza vaccine (15 mcg or 60 mcg HA per strain, dependent on vaccine product) compared to a fractional dose for individuals at high risk or those capable of transmitting to those at high risk of influenza-related complications or hospitalizations (Grade B Evidence).
Summary of evidence and rationale
- Influenza vaccine has previously been shown to be effective in the prevention of morbidity and mortality in individuals who are at high risk of influenza-related complications and hospitalizations.
- Since many of those at high risk of influenza (e.g., older adults, immunocompromised individuals) may have a lower response to influenza vaccination already (due to immunosenescence in older adults or other conditions that alter immune function), it is important to ensure this group continues to receive the full dose of influenza vaccine.
- Although there is some limited evidence on the use of fractional ID doses in adults ≥65 years of age, including those with chronic health conditions, there is no evidence of fractional dosing in other adult high risk-groups.
- There are some efficacy, effectiveness, and immunogenicity data regarding fractional dosing of current influenza vaccine products, but overall insufficient evidence that fractional doses of influenza vaccine provided via IM or ID are effective in healthy individuals. The majority of the evidence identified on fractional dosing is from studies conducted in healthy individuals, particularly in infants and young children, with no underlying chronic conditions.
2. NACI recommends against the use of fractional doses of influenza vaccine in any population (Discretionary NACI Recommendation)
- NACI concludes that there is insufficient overall evidence at this time to recommend the use of fractional IM influenza vaccine doses (Grade I Evidence)
- NACI concludes that there is fair evidence that fractional ID influenza vaccine doses provide a sufficient immune response, but this route of administration is not feasible at this time (Grade B Evidence)
Summary of Evidence and Rationale
- There are some efficacy, effectiveness, and immunogenicity data regarding fractional dosing of current influenza vaccine products, but overall, there is insufficient evidence that fractional doses of influenza vaccine provided via the IM route is effective in healthy individuals. The majority of the evidence identified on fractional dosing is from studies conducted in healthy individuals, mainly young children and infants, with no underlying chronic conditions.
- ID administration of influenza vaccine may be more effective at lower doses than IM and would be reasonable to recommend based on efficacy, effectiveness, immunogenicity, and safety data; however, significant system-level changes are needed to address the feasibility issues associated with this route of administration before it can be considered at a large scale.
- With regard to the safety of fractional doses of influenza vaccines, there is fair evidence that fractional doses of influenza vaccine administered via IM or ID routes do not result in significant differences compared to full dose with regard to severe AEs post-influenza vaccination; however, ID administration of influenza vaccine will likely result in a higher proportion of individuals who experience local AEs.
- Pre-filled syringes cannot be used for IM or ID fractional dosing.
- ID administration of vaccine by syringe and needle requires a different gauge needle than IM administration. Therefore, immunization venues providing influenza vaccines may not be equipped with a sufficient number of needles necessary for ID administration for a seasonal influenza vaccine program unless prepared in advance.
- Significant training would be required to ensure vaccinators are equipped to provide ID influenza vaccinations and feel comfortable doing so. Without training, it is possible that a greater number of vaccine administration errors could occur with ID administration.
- Not all vaccinators are authorized to provide ID administration. The number of vaccinators who are able to provide ID vaccination will vary by jurisdiction.
Specified by the United States Food and Drug Administration
“should/should not be offered”- Known/Anticipated advantages outweigh known/anticipated disadvantages (“should”),
OR Known/Anticipated disadvantages outweigh known/anticipated advantages (“should not”) - Implication: A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present
- B – fair evidence to recommend
- C – conflicting evidence, however other factors may influence decision-making
- D – fair evidence to recommend against
- E – good evidence to recommend against
- I – insufficient evidence (in quality or quantity), however other factors may influence decision-making
“may be considered”- Known/Anticipated advantages closely balanced with known/anticipated disadvantages, OR uncertainty in the evidence of advantages and disadvantages exists
- Implication: A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable
- B – fair evidence to recommend
- C – conflicting evidence, however other factors may influence decision-making
- D – fair evidence to recommend against
- E – good evidence to recommend against
- I – insufficient evidence (in quality or quantity), however other factors may influence decision-making
General design specific criteria are outlined in Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, Atkins D. Current methods of the US Preventive Services Task Force: A review of the process. Am J Prev Med. 2001;20(3):21-35.10
Doses:
7.5 mcg
US
single site
2004–2005 influenza season
7.5 group:
n=222
15 group:
(Fluzone)
Doses:
7.5 mcg
US
multi-center
2004-2005 influenza season
18–49 year old subgroup:
Mean age: 42.3
44.3% female
7.5 mcg group: n=284
15 mcg group: n= 274
50–64 year old subgroup:
Mean age: 55.6
42.6% female
7.5 mcg group: n=276
Relative risk (95% CI) by age group:* 18-49 years:1.01 (0.70-1.46)
- 50-64 years:1.07 (0.53-2.18)
Random effects model
Included: RCTs, non-RCTs, observational studies
Number of participants (observational): 164,021
Age range: all ages
Meta-analysis included a total of 2 RCTs (no observational studies) on the effectiveness of a 9 mcg of HA per strain fractional dose of ID influenza vaccine.
CI:
confidence interval
IIV3:
trivalent inactivated influenza vaccine
RCT:
randomized controlled trial
Doses:- 3 mcg
- 6 mcg
- 9 mcg
- 15 mcg
US
single site
2006-2007 influenza season
mean age: 30
68% female- 3mcg group:
n=29
- 6mcg group:
n=30
- 9mcg:
n=32
- 15mcg:
n=31
3 mcg:* A(H1N1): 62.1 (42.3-79.3)
- A(H3N2): 58.6 (38.9-76.5)
- Influenza B: 51.7 (32.5-70.6)
6 mcg:* A(H1N1): 60.0 (40.6-77.3)
- A(H3N2): 60.0 (40.6-77.3)
- Influenza B: 70.0 (50.6-85.3)
9 mcg:* A(H1N1): 66.7 (47.2-82.7)
- A(H3N2): 90.0 (73.5-97.9)
- Influenza B: 66.7 (47.2-82.7)
15 mcg:* A(H1N1): 67.7 (48.6-83.3)
- A(H3N2): 93.5 (78.6-99.2)
- Influenza B: 67.7 (48.6-83.3)
Proportion that achieved seroprotection (95% CI) 28 days post-vaccination:
3 mcg:* A(H1N1): 72.4 (52.8-87.3)
- A(H3N2): 79.3 (60.3-92.0)
- Influenza B: 89.7 (72.6-97.8)
6 mcg:* A(H1N1): 80 (61.4-92.3)
- A(H3N2): 80 (61.4-92.3)
- Influenza B: 86.7 (69.3-96.2)
9 mcg:* A(H1N1): 83.3 (65.3-94.4)
- A(H3N2): 93.3 (77.9-99.2)
- Influenza B: 93.3 (77.9-99.2)
15 mcg:* A(H1N1): 77.4 (58.9-90.4)
- A(H3N2): 100 (88.8-100)
- Influenza B: 90.3 (74.2-98.0)
(Fluzone)
Doses:- 7.5 mcg
- 15 mcg
US
multi-center
2004-2005 influenza season
18–49 year old subgroup:
Mean age: 42.3
44.3% female- 7.5 mcg group: n=284
- 15 mcg group: n= 274
50–64 year old subgroup:
Mean age: 55.6
42.6% female- 7.5 mcg group: n=276
- 15 mcg group: n= 280
- A(H3N2): 8.4 (0.5-16.2); p=0.04
- Influenza B: 1.27 (1.08-1.50); p=0.002
Difference in proportions that achieved seroconversion (95% CI) 21 days post-vaccination in 50-64 year old age group:* A(H1N1): 4.8 (-0.8-10.5); p=0.09
- A(H3N2): 12.9 (5.2-20.5); p=0.001
- Influenza B: 14.6 (6.8-22.5); p<0.001
Difference in proportions that achieved seroprotection (95% CI) 21 days post-vaccination in 18-49 year old age group:* A(H1N1): 11.8 (3.5-20.0); p=0.005
- A(H3N2): 8.3 (0.8-15.8); p=0.03
- Influenza B: 5.0 (-1.6-11.7); p=0.19
Difference in proportions that achieved seroprotection (95% CI) 21 days post-vaccination in 50-64 year old age group:* A(H1N1): 15.7 (8.1-23.4); p<0.001
- A(H3N2): 9.5 (1.7-17.2); p=0.02
- Influenza B: 8.8 (0.9-16.6); p=0.03
Doses:- 9 mcg
- 15 mcg
US
2007-2008 influenza season
n=64
17.2% female
Mean age: 75.2
- 15 mcg group:
n=65
16.9% female
Mean age: 75.6
Number that achieved seroprotection (%):
9 mcg:* A(H1N1): 37 (57.8%)
- A(H3N2): 48 (75%)
- Influenza B: 11 (17.2%)
15 mcg:* A(H1N1): 42 (65.5%)
- A(H3N2): 49 (76.6%)
- Influenza B: 17 (26.6%)
(Vaxigrip)
Doses:- 7.5 mcg
- 15 mcg
Canada multi-center
2008-2009 influenza season
n=124
50.8% female
Mean age: 12.8 months
- 15 mcg group:
n=128
55.5% female
Mean age: 13.2 months
7.5 mcg:* A(H1N1): 70.5 (61.6-78.4)
- A(H3N2): 67.2 (58.1-75.4)
- Influenza B: 66.4 (57.3-74.7)
15 mcg:* A(H1N1): 81.2 (72.9-87.8)
- A(H3N2): 83.8 (75.8-89.8)
- Influenza B: 80.3 (72-87.1)
Proportion that achieved seroconversion (95% CI) 27-45 days after the 2nd dose of influenza vaccine:
7.5 mcg:* A(H1N1): 70.5 (61.6-78.4)
- A(H3N2): 67.2 (58.1-75.4)
- Influenza B (Yam): 65.6 (56.4-73.9)
15 mcg:* A(H1N1): 80.3 (72-87.1)
- A(H3N2): 81.2 (72.9-87.8)
- Influenza B (Yam): 80.3 (72-87.1)
GMT rise (95% CI) after the 2nd dose of influenza vaccine:
7.5 mcg:* A(H1N1): 10.2 (8.2-12.7)
- A(H3N2): 9.1 (7.5-11.0)
- Influenza B: 8.4 (6.7-10.6)
15 mcg:* A(H1N1): 12.2 (9.8-15.2)
- A(H3N2): 13.0 (10.9-15.7)
- Influenza B: 13.6 (10.8-17.1)
(Flulaval or Vaxigrip)
Doses:- 7.5 mcg
- 15 mcg
Canada multi-center
2008-2009 influenza season
Funded by GlaxoSmith
n=164
42.7% female
Mean age: 18.2 months
- Flulaval 15 mcg group:
n=167
49.3% female
Mean age: 17.5 months
- Vaxigrip 7.5 mcg group:
n=43
60.5% female
Mean age: 17.0 months
7.5 mcg (Vaxigrip):* A(H1N1): 80.6 (64.0-91.8)
- A(H3N2): 77.8 (60.8-89.9)
- Influenza B (Yam): 86.1 (70.5-95.3)
7.5 mcg (Flulaval):* A(H1N1): 51.1 (42.3-60)
- A(H3N2): 61.8 (52.9-70.2)
- Influenza B (Yam): 80.9 (73.1-87.3)
15 mcg (Flulaval):* A(H1N1): 62.1 (53.3-70.4)
- A(H3N2): 74.2 (65.9-81.5)
- Influenza B (Yam): 86.4 (79.3-91.7)
Proportion that achieved seroconversion (95% CI) 28 days post-vaccination:
7.5 mcg (Vaxigrip):* A (H1N1): 83.3 (67.2-93.6)
- A(H3N2): 83.3 (67.2-93.6)
- Influenza B (Yam): 91.7 (77.5-98.2)
7.5 mcg (Flulaval):* A(H1N1): 53.4 (44.5-62.2)
- A(H3N2): 62.6 (53.7-70.9)
- Influenza B (Yam): 84.7 (77.4-90.4)
15 mcg (Flulaval):* A(H1N1): 63.6 (54.8-71.8)
- A(H3N2): 75.0 (66.7-82.1)
- Influenza B (Yam): 92.4 (86.5-96.3)
GMT ratios (95% CI) 28 days post-vaccination (adjusted for prior influenza vaccination, baseline titre – pooled variance):* A(H1N1): 1.25 (0.9-1.75)
- A(H3N2): 1.11 (0.83-1.49)
- Influenza B (Yam): 1.27 (0.93-1.74)
(Fluarix or Fluzone)
Doses:- 7.5 mcg
- 15 mcg
US, Hong Kong, Mexico, Thailand, and Taiwan
Multi-centre
2008-2009 influenza season
Funded by GlaxoSmith
n=1017
50.7% female
Mean age: 21.2 months
- Fluarix 15 mcg group:
n=1013
53.3% female
Mean age: 21.2 months
- Fluzone 7.5 mcg group:
n=1031
49.1% female
Mean age: 21.1 months
7.5 mcg (Fluzone):* A(H1N1): 95.6 (94.2-96.8)
- A(H3N2): 98.2 (97.1-98.9)
- Influenza B (Yam): 90.7 (88.7-92.4)
- Influenza B (Yam): 92.3 (90.5-93.9)
7.5 mcg (Fluarix):* A(H1N1): 68.7 (65.7-71.5)
- A(H3N2): 77.4 (74.7-79.9)
- Influenza B (Yam): 85.7 (83.4-87.8)
- Influenza B (Yam): 88 (85.9-89.9)
15 mcg (Fluarix):* A(H1N1): 74.2 (71.4-76.9)
- A(H3N2): 83.3 (80.8-85.5)
- Influenza B (Yam): 88.8 (86.7-90.7)
- Influenza B (Yam): 90.6 (88.6-92.3)
Proportion that achieved seroconversion (95% CI) 28 days (or 56 for unprimed children) post-vaccination:
7.5 mcg (Fluzone):* A(H1N1): 90.2 (88.2-91.9)
- A(H3N2): 95.9 (94.5-97)
- Influenza B (Yam): 87.8 (85.6-89.7)
- Influenza B (Yam): 89.3 (87.3-91.1)
7.5 mcg (Fluarix):* A(H1N1): 62.5 (59.5-65.5)
- A(H3N2): 73.5 (70.6-76.1)
- Influenza B (Yam): 79.8 (77.2-82.3)
- Influenza B (Yam): 82.6 (80.1-84.9)
15 mcg (Fluarix):* A(H1N1): 69 (66.1-71.8)
- A(H3N2): 79.8 (77.2-82.2)
- Influenza B (Yam): 85.3 (83-87.4)
- Influenza B (Yam): 87.1 (84.8-89.1)
GMT rise (95% CI) post-vaccination:
7.5 mcg (Fluzone):* A(H1N1): 21.4 (19.9-23.1)
- A(H3N2): 24.1 (22.6-25.7)
- Influenza B (Yam): 21.4 (19.7-23.1)
- Influenza B (Yam): 23.1 (21.4-24.9)
7.5 mcg (Fluarix):* A(H1N1): 10.2 (9.2-11.4)
- A(H3N2): 10.4 (9.6-11.3)
- Influenza B (Yam): 13.4 (12.4-14.5)
- Influenza B (Yam): 14.9 (13.7-16.1)
15 mcg (Fluarix):* A(H1N1): 12.4 (11.2-13.7)
- A(H3N2): 14.2 (13.1-15.4)
- Influenza B (Yam): 18.4 (17-20)
- Influenza B (Yam): 19.7 (18.2-21.4)
Difference in immune response of 15 mcg Fluarix compared to 7.5 mcg Fluzone 28 days (or 56 for unprimed children) post-vaccination:
GMT ratio (95% CI):* A(H1N1) : 1.74 (1.54-1.98)
- A(H3N2): 1.72 (1.57-1.89)
- Influenza B (Yam): 1.13 (1.01-1.25)
- Influenza B (Yam): 1.13 (1.02-1.25)
Difference in seroconversion rate (95% CI) :* A(H1N1): 21.19 (17.82-24.58)
- A(H3N2): 16.16 (13.46-18.98)
Influenza B (Yam): 2.48 (-0.49-5.45)
- Influenza B (Yam): 2.25 (-0.55-5.07)
(Fluzone)
Doses:- 7.5 mcg
- 15 mcg
US
Multi-center
October 5, 2010 and March 2, 2012; The studies were conducted before the 2010–2011 and 2011–2012 influenza seasons.
N=204
52% female
Mean age: 14.2 months
Primed subgroup:- 7.5 mcg group:
n=9
66.7% female
Mean age: 23.4 months
- 15 mcg group:
n=21
45.4% female
Mean age: 25.3 months
Influenza vaccine naïve subgroup:- 7.5 mcg group:
n=55
50.7% female
- 15 mcg group:
n=119
52.9% female
7.5 mcg:* A(H1N1): 89 (0.52-1.00)
- A(H3N2): 89 (0.52-1.00)
- Influenza B (Yam): 33 (0.07-0.70)
15 mcg:* A(H1N1): 100 (0.84-1.00)
- A(H3N2): 90 (0.7-0.99)
- Influenza B (Yam): 14 (0.03-0.36)
Proportion of naïve individuals that achieved seroprotection (95% CI) 28 days after the 2nd dose of influenza vaccine:
7.5 mcg:* A(H1N1): 85 (73-94)
- A(H3N2): 15 (6-27)
- Influenza B (Yam): 44 (30-58)
15 mcg:* A(H1N1): 89 (82-94)
- A(H3N2): 15 (9-23)
- Influenza B (Yam): 50 (40-59)
Proportion of primed individuals that achieved seroconversion (95% CI) 28 days post-vaccination:
7.5 mcg:* A(H1N1): 89 (52-100)
- A(H3N2): 78 (40-97)
- Influenza B (Yam): 22 (3-60)
15 mcg:* A(H1N1): 90 (70-99)
- A(H3N2): 86 (64-97)
- Influenza B (Yam): 10 (1-30)
Proportion of naïve individuals that achieved seroconversion (95% CI) 28 days after the 2nd dose of influenza vaccine:
7.5 mcg: - A(H1N1): 78 (65-88)
- A(H3N2): 7 (2-18)
- Influenza B (Yam): 31 (19-45)
15 mcg:* A(H1N1): 85 (77-91)
- A(H3N2): 11 (6-18)
- Influenza B (Yam): 42 (33-51)
Difference in GMT (95% CI) 28 days after last vaccination:
Primed:* A(H1N1): -267.5 (-527.9 to -3.9)
- A(H3N2): -11.0 (-105.1 to 122.2)
- Influenza B (Yam): 3.0 (-7.5 to 14.8)
Naïve:* A(H1N1): -5.7 (-94.9 to 90.2)
- A(H3N2): -1.9 (-2.0 to 5.2)
- Influenza B (Yam): -3.7 (-5.1 to 12.0)
(Fluzone quadrivalent)
Doses:- 7.5 mcg
- 15 mcg
US and Mexico
Multi-centre
2014-2015 influenza season
Funded by GlaxoSmith
n=1028
48.2% female
Mean age: 19.9 months
- 15 mcg group:
n=1013
45.6% female
Mean age: 19.7 months
7.5 mcg:* A(H1N1): 75.4 (72.6-78)
- A(H3N2): 77.8 (75.2-80.3)
- Influenza B (Yam): 88.6 (86.5-90.5)
- Influenza B (Vic): 49.8 (46.7-52.9)
15 mcg:* A(H1N1): 80.4 (77.8-82.8)
- A(H3N2): 82.2 (79.7-84.5)
Influenza B (Yam): 97 (95.8-98)
- Influenza B (Vic): 66 (63-69)
Proportion that achieved seroconversion (95% CI) 28 days (or 56 days for unprimed individuals) post-vaccination:
7.5 mcg:* A(H1N1): 67.3 (64.3-70.3)
- A(H3N2): 69.4 (66.4-72.3)
Influenza B (Yam): 73.8 (70.9-76.5)
- Influenza B (Vic): 48.5 (45.3-51.6)
15 mcg:* A(H1N1): 73.7 (70.8-76.4)
- A(H3N2): 76.1 (73.3-78.8)
Influenza B (Yam): 85.5 (83.2-87.7)
- Influenza B (Vic): 64.9 (61.8-67.9)
GMT rise (95% CI) 28 days (or 56 days for unprimed individuals) post-vaccination:
7.5 mcg:* A(H1N1): 7.7 (7.1-8.3)
- A(H3N2): 8.9 (8.2-9.7)
Influenza B (Yam): 8.1 (7.5-8.8)
- Influenza B (Vic): 5.4 (5.0-5.8)
15 mcg:* A(H1N1): 9 (8.4-9.7)
- A(H3N2): 10.7 (10-11.6)
- Influenza B (Yam): 12.7 (11.7-13.7)
- Influenza B (Vic): 8.7 (8.1-9.4)
Doses:- 7.5 mcg
- 15 mcg
US
Multi-center
2016-2017 influenza season
n=682
49.4% female
Mean age: 20.4 months
- 15 mcg group:
n=682
49.9% female
Mean age: 20.5 months
- A(H3N2): 4.3 (-0.283 to 8.99)
Influenza B (Yam): 3.4 (-2.78 to 5.56)
- Influenza B (Vic): 1.4 (-0.465 to 7.36)
GMT ratios (95% CI) post-vaccination:* A(H1N1): 1.45 (1.19 to 1.77)
- A(H3N2): 1.50 (1.23 to 1.83)
Influenza B (Yam): 1.44 (1.20 to 1.73)
- Influenza b (Vic): 1.33 (1.10 to 1.62)
Doses:- 7.5 mcg
- 15 mcg
Finland and Belgium
Multi-center
2008-2009 influenza season
(Note: only a subset of study groups relevant for this review are presented here. Authors combined the IIV3 and IIV4 groups for analysis in the publication)- IIV3 7.5 mcg group:
n=25
66% female
Mean age: 20 months
- IIV3 15 mcg group:
n=22
27% female
Mean age: 15 months
- IIV4 7.5 mcg group:
n=25
36% female
Mean age: 18 months
- IIV4 15 mcg group:
n=28
46% female
Mean age: 15.2 months
- IIV3 15 mcg group (Vaxigrip):
n=26
50% female
Mean age: 16.1 months
- 7.5 mcg: 65% A(H1N1), 70% A(H3N2), 19% Influenza B (Yam) and 17% Influenza B (Vic).
- 15 mcg: 79% A(H1N1), 71% A(H3N2), 12% influenza B (Yam) and 14% influenza B (Vic).
Proportion (%) that achieved seroconversion on day 50:* 7.5 mcg (Vaxigrip): 96% A(H1N1), 92% A(H3N2) and 42% Influenza B (Yam). Data not reported for influenza B (Vic).
- 7.5 mcg: 62% A(H1N1), 62% A(H3N2), 19% influenza B (Yam) and 17% influenza B (Vic).
- 15 mcg: 79% A(H1N1), 71% A(H3N2), 21% influenza B (Yam) and 14% influenza B (Vic).
GMT rise (post-vaccination GMT / pre-vaccination GMT) on day 50:
7.5 mcg (Vaxigrip): - A(H1N1): 25
- A(H3N2): 27
- Influenza B (Yam): 4.06
7.5 mcg:* A(H1N1): 8.15
- A(H3N2): 8.7
- Influenza B (Yam): 2.39
- Influenza B (Vic): 2.16
15 mcg:* A(H1N1): 10
- A(H3N2): 9.91
- Influenza B (Yam): 2.07
- Influenza B (Vic): 1.94
Random effects model
Included: RCTs, non-RCTs, observational studies
Number of participants (observational): 164,021
Age range: all ages
Meta-analysis included a total of 16 RCTs (no observational studies) on the immunogenicity of fractional doses of IM influenza vaccine (includes 3 mcg, 6 mcg, 7.5 mcg, and 9 mcg).
CI:
confidence interval
GMT:
geometric mean titre
IIV3:
trivalent inactivated influenza vaccine
IIV4:
quadrivalent inactivated influenza vaccine
mcg:
microgram
RCT:
randomized controlled trial
US:
United States
B/Florida/4/2006, which is a B/Florida/4/2006-like strain, as recommended by WHO for influenza season of this study
B/Brisbane/3/2007, which is a B/Florida/4/2006-like strain, as recommended by WHO for influenza season of this study
Calculated as post-vaccination GMT in 7.5 mcg Fluzone / 15 mcg Fluarix, adjusted for baseline titre – pooled variance)
Calculated as seroconversion rate in 7.5 mcg Fluzone – 15 mcg Fluarix
Included: RCTs, non-RCTs, observational studies
13 RCTs were included in the scoping review, including 10 RCTs that had safety data relevant for this Statement (3 in adults, 9 in children).
All studies in children assessed the safety of 7.5 mcg of HA per strain fractional dose compared to standard dose (15 mcg of HA per strain). None of the studies identified in this review reported statistical differences in local or systemic AEs between study groups.
One study compared 3 fractional doses of Fluzone (3 mcg, 6 mcg, 9 mcg of HA per strain) to standard dose, and did not report any differences between the IM vaccination groups. A second in adults less than 65 years of age found no significant differences after adjusting for clinically significant pain levels (determined as ≥3 out of 5 on a visual analogue scale) between groups that had received a 7.5 mcg of HA per strain dose compared to standard dose.
Random effects model
Included: RCTs, non-RCTs, observational studies
Number of participants (observational): 164,021
Age range: all ages
Meta-analysis included a total of 24 RCTs (no observational studies) on the safety of fractional doses of IM influenza vaccine (includes 3 mcg, 6 mcg, 7.5 mcg, and 9 mcg).
AE:
Adverse Event
DSEN:
Drug Safety Effectiveness Network
HA:
hemagglutinin
mcg:
microgram
N/A:
not applicable
RCT:
randomized controlled trial |
Recommendations on fractional influenza vaccine dosing
=======================================================
[Download in PDF format](/content/dam/phac-aspc/documents/services/immunization/national-advisory-committee-on-immunization-naci/recommendations-fractional-influenza-vaccine-dosing/naci-flu-dose-sparing-2020-eng.pdf)
(1.9 MB, 45 pages)
**Organization:** [Public Health Agency of Canada](/en/public-health.html)
**Published:** 2021-01-28
**An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)**
Preamble
--------
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
On this page
------------
* [Summary of the Information Contained in this NACI Supplemental Statement](#sum)
* [I. Introduction](#a1)
* [II. Methods](#a2)
* [III. Fractional Influenza Vaccine doses](#a3)
+ [III.1 Vaccine Efficacy and Effectiveness](#a3.1)
+ [III.2 Immunogenicity](#a3.2)
+ [III.3 Safety](#a3.3)
* [IV. Feasibility](#a4)
* [V. Recommendation](#a5)
+ [V.1 Public Health Program Decision-Making](#a5.1)
* [Tables](#tables)
* [List of Abbreviations](#abbr)
* [Acknowledgements](#ack)
* [References](#ref)
Summary of the Information Contained in this NACI Supplemental Statement
------------------------------------------------------------------------
The following highlights key information for immunization providers. Please refer to the remainder of this supplemental statement for details.
### 1. What
Influenza vaccination in Canada is provided annually through provincial and territorial seasonal influenza vaccine programs. Due to the rapid timelines required for vaccine production each year, any significant impact to the manufacturing process may cause delays in influenza vaccine delivery or decrease the overall number of doses produced, potentially resulting in vaccine shortages for a season. A significant and unexpected increase in demand for the influenza vaccine may also lead to insufficient supply, as the number of doses available is based on orders made primarily in the spring months. A strategy for the administration of fractional influenza vaccine doses (i.e., less than a full dose) might be considered in these situations, as the use of fractional doses would provide vaccine programs the ability to vaccinate a larger number of people with the amount of vaccine that is available.
### 2. Who
This supplemental statement provides an evidence summary and recommendations on the topic of fractional influenza vaccine doses for consideration by public health programs during a significant influenza vaccine shortage.
### 3. How
In the event of a significant population-level shortage of the currently available influenza vaccine products, NACI recommends that full dose influenza vaccine should continue to be used and existing vaccine supply should be prioritized for those considered to be at high risk or capable of transmitting to those at high risk of influenza-related complications or hospitalizations. NACI recommends against the use of fractional doses of influenza vaccines in any population.
### 4. Why
There is some, but still insufficient, evidence that fractional doses of influenza vaccine provided via the intramuscular (IM) route are effective and immunogenic in healthy individuals. Although there is some evidence on the use of fractional intradermal (ID) doses in adults ≥65 years of age, including those with chronic health conditions, that demonstrates that lower doses may be immunogenic in this population, there is no evidence regarding the use of fractional dosing in other adult high-risk groups. Moreover, administering influenza vaccines through the ID route, while using regular syringes, has been determined to not be feasible.
Since many of those at high risk of influenza (e.g., adults 65 years of age and older, individuals with specific underlying chronic health conditions) may have a lower immune response to influenza vaccination already (due to immunosenescence in older adults or a condition that alters immune function), it is important to ensure that those at high risk continue to receive the full dose of influenza vaccine.
There is fair evidence that fractional doses of influenza vaccine administered via the IM and ID routes do not result in a significant difference with regard to severe systemic adverse events (AEs) post-influenza vaccination; however, ID administration of influenza vaccine will likely result in a higher proportion of individuals who experience local AEs.
There are feasibility issues when considering fractional dosing of current influenza immunizations or administration of ID doses of influenza vaccines. Pre-filled syringes cannot be used for fractional dosing. ID administration of vaccine requires a different gauge needle than IM administration, and training and skill in ID administration that not all vaccinators will have. The volume of vaccine to be administered is high, requiring two ID injections if regular needles and syringes are used. The majority of studies of administration of influenza vaccine by the ID route used micro-needle injectors for administration. The use of fractional doses is not covered within influenza vaccine product monographs and would therefore require a novel communication and consent plan for any off-label dosing if it were adopted. Moreover, implementation of such an ID immunization program would require monitoring for any potential modification to a seasonal influenza vaccine program running low on vaccine supply and thus would be a challenge without significant advanced planning.
I. Introduction
---------------
Influenza is a viral infection that is estimated to cause approximately 12,200 hospitalizations[Reference 1](#ref1) and 3,500 deaths[Reference 2](#ref2) in Canada annually. All provinces and territories in Canada have implemented seasonal influenza vaccination programs, with the aim of reducing morbidity and mortality caused by influenza-associated illness[Reference 3](#ref3). Although influenza programs vary across the country, all programs cover individuals who are at high risk of severe outcomes due to influenza and individuals that are capable of transmitting influenza to those at high risk (e.g., household members, healthcare workers).
Influenza vaccine for use in publicly funded programs in Canada is coordinated by the federal government's Public Services and Procurement Canada, and vaccine orders are completed in the spring in advance of the next influenza season[Reference 4](#ref4). The schedule for finalizing influenza vaccine orders is generally consistent for all countries in the Northern Hemisphere, as vaccine manufacturers must follow strict timelines to produce influenza vaccine with the recommended strain composition for the next season. The strain composition for the upcoming Northern Hemisphere
season is announced by the World Health Organization annually in February [Reference 5](#ref5). Significant changes to the amount of influenza vaccine ordered are, therefore, difficult once the influenza season has begun. In addition, unforeseen influenza vaccine production issues or an unexpected increase in demand for influenza vaccine could result in a delay or decrease in vaccine available for Canadians. In the event that a significant shortage of influenza vaccine were to occur in Canada, guidance on appropriate strategies for fractional dosing, or dose sparing, would be needed. However, significant global influenza vaccine shortages are extremely rare, given the variety of influenza vaccine products available on the market, with any issues that do arise typically being isolated to only one vaccine product or manufacturer.
In Canada, influenza vaccines are currently authorized for IM administration only, apart from the live-attenuated influenza vaccine (LAIV), which is administered intranasally[Reference 6](#ref6). The stated dose of an influenza vaccine is based on the hemagglutinin (HA) content within the vaccine. Standard dose influenza vaccines contain 15 mcg of HA per strain and are delivered in 0.5 mL volume. Therefore, the total amount of HA in standard dose trivalent vaccines is 45 mcg, and the total amount of HA in standard dose quadrivalent vaccines is 60 mcg. Fractional dosing strategies are those where less than the standard amount of HA antigen and thus less volume of vaccine is administered during influenza vaccination, increasing the overall number of doses available. For the purposes of these recommendations, NACI considered two different strategies:
1. Fractional intramuscular (IM) administration of influenza vaccine
2. Fractional intradermal (ID) administration of influenza vaccine
### Guidance Objective
The objective of this advisory committee supplemental statement is to review the available evidence for efficacy, effectiveness, immunogenicity, and safety of fractional influenza vaccine dosing, and to provide guidance on potential fractional dosing strategies in the event of a significant influenza vaccine shortage in Canada.
II. Methods
-----------
In brief, the broad stages in the preparation of a NACI Advisory Committee Statement are:
1. Knowledge synthesis - individual studies were retrieved and key data abstracted, and the level (i.e., study design) and quality of the evidence assessed. This information is summarized in Summary of Evidence Tables.
2. Synthesis of the body of evidence of benefits and harms, considering the quality of the evidence and magnitude of effects observed.
3. Translation of evidence into recommendations.
Further information on NACI's evidence-based methods is available in: [Evidence-Based Recommendations for Immunization: Methods of the NACI, January 2009, CCDR](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2009-35/methods-national-advisory-committee-immunization.html).
In preparation for this Statement, two reviews were conducted to gather evidence to inform NACI's recommendations regarding the use of fractional dosing strategies. The review methodologies were developed in collaboration with the Methods and Applications Group for Indirect Comparisons (MAGIC) through the Drug Safety and Effectiveness Network (DSEN). The methods were specified *a priori* in a written protocol that included the research questions, search strategy, inclusion and exclusion criteria, and quality assessment. The reviews were completed by MAGIC, with additional data extraction (notably immunogenicity outcomes as indirect evidence for effectiveness for IM administration of fractional doses) completed by PHAC.
### Research question #1
What is the safety and effectiveness[Footnote a](#fna) of using fractional dosing strategies to deliver IM seasonal influenza vaccines?
### Research question #2
What is the safety and effectiveness[Footnote a](#fna) of using fractional dosing strategies to deliver seasonal influenza vaccine by ID administration?
The search strategies were developed based on the research questions and pre-defined PICOST[Reference 7](#ref7)[Reference 8](#ref8), in conjunction with an experienced librarian. For both reviews, EMBASE and MEDLINE electronic databases were searched for research articles, with the review of IM studies looking at publications in the last 20 years and the review of ID studies looking at publications in the last 10 years. The Cochrane library, the Cochrane Central Register of Controlled Trials, and international clinical trial registries were also searched for additional studies. Searches were restricted to articles published in English. Additionally, hand-searching of the reference lists of included articles and relevant systematic reviews were performed.
Screening of citations and full-text articles were completed using a standard form based on study eligibility criteria. The forms were pilot-tested between two reviewers until 70% or greater agreement was reached, after which screening was completed by one reviewer.
One reviewer extracted data from the studies included for review into an evidence table using a piloted data abstraction template designed to capture information on study design, vaccine characteristics, population and outcomes of interest. A second reviewer independently validated the abstracted data.
For the review of ID administration of fractional influenza vaccine, the DSEN MAGIC team conducted all data extraction and performed a meta-analysis for effectiveness, immunogenicity, and safety outcomes[Reference 8](#ref8). The risk of bias for the studies included as part of the ID review was assessed using the Cochrane Tool for Risk of Bias in Randomized Controlled Studies.
For the IM fractional dose review, the DSEN MAGIC team extracted and narratively summarized the data for effectiveness and safety, and provided PHAC with a list of studies that assessed immunogenicity outcomes. PHAC then extracted the immunogenicity data from the studies provided, and summarized the evidence narratively. The level of evidence (i.e., study design) and methodological quality of studies included in the IM review were assessed independently by two reviewers with PHAC using the design-specific criteria outlined by Harris et al.(2001)[Reference 9](#ref9), which has been adopted by NACI for rating the internal validity of individual studies.
### Development of Recommendations
Following critical appraisal of individual studies, summary tables (Tables 9, 10, and 11) were prepared with ratings of the quality of the evidence using NACI's methodological hierarchy, and proposed recommendations for vaccine use were developed. The evidence and proposed recommendations were discussed by the NACI Influenza Working Group (IWG) and considered the
Ethics, Equity, Feasibility, and Acceptability (EEFA) framework [Reference 10](#ref10). Following a thorough review of the evidence, NACI approved the recommendation contained in this statement on November 2, 2020. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the following sections.
III. Fractional Influenza Vaccine doses
---------------------------------------
### Intramuscular fractional dosing
Thirteen studies were identified through the DSEN MAGIC team review on IM fractional dosing[Reference 7](#ref7), including 5 related reports or trial protocols. Twelve of the studies were randomized controlled trials (RCT), and were assessed as being of good quality, according to the criteria defined by Harris et al. One trial was considered as having a high risk of bias due to significant issues with the randomization process and concerns
with missing outcome data and selection of the reported outcomes [Reference 11](#ref11) This trial was later excluded from the PHAC analysis because it did not have any peer-reviewed published results.
### Intradermal fractional dosing
The DSEN MAGIC team rapid review on fractional ID influenza vaccination identified 29 studies. Most of the 29 RCTs were rated as having some
concerns with bias (n=17), based on the Cochrane Risk of Bias tool for RCTs [Reference 12](#ref12), and two studies (Chuaychoo, 2010 and Han 2013) had a high risk of bias. Issues were most often noted for the randomization process, deviations from the intended intervention, and bias in the selection of reported results[Reference 7](#ref7).
Evidence from the DSEN MAGIC team reviews and additional analyses by PHAC technical staff are presented in Tables 9, 10, and 11.
### III.1 Vaccine Efficacy and Effectiveness
#### III.1.1 Fractional intramuscular dosing
There were no studies included in the rapid review that assessed the efficacy of fractional IM administration of influenza vaccine. Two studies were identified that assessed the effectiveness of fractional IM administration of influenza vaccine[Reference 13](#ref13)[Reference 14](#ref14). Both studies were RCTs that assessed the efficacy of a 7.5 mcg of HA per strain dose of a quadrivalent influenza vaccine versus a 15 mcg of HA per strain dose in adults.
The first study was conducted by Kramer et al. (2006), in a population of adult healthcare workers 18 years of age and older. The study reported on clinical diagnoses of influenza-like illness (ILI) and laboratory-confirmed influenza (type of test not specified). Laboratory testing was only completed for individuals who had a clinical diagnosis of influenza. This RCT study found that 6.8% (n=15 of 222) of individuals who received the half-dose received a clinical diagnosis of ILI compared to 3.6% (n=8 of 222) of those that received the standard 15 mcg of HA per strain dose; however, only one participant in the study (an individual that received the 15 mcg of HA per strain dose) had laboratory-confirmed influenza infection and this difference for the laboratory-confirmed outcome was not statistically significant (relative risk [RR]: 0.53, 95% confidence interval [CI]: 0.23-1.23)[Reference 13](#ref13). The second study by Engler et al. (2008) assessed the efficacy of a half dose compared to a full dose of influenza vaccine against medical visits for ILI involving the upper and lower respiratory tract, but with no laboratory confirmation, in adults 18 to 49 (n=558) and 50 to 64 years of age (n=556), and there was no statistically significant difference in the relative risk between vaccine groups, before and after adjusting for confounders (18-49 year olds: adjusted RR: 1.01, 95% CI: 0.70-1.46; 50-64 year olds: adjusted RR: 1.07, 95% CI: 0.53-2.18).
#### III.1.2 Fractional intradermal dosing
Two studies assessed the efficacy of fractional ID administration of influenza vaccine against laboratory-confirmed influenza infection or ILI in adults using trivalent influenza vaccine[Reference 15](#ref15)[Reference 16](#ref16). A meta-analysis of these two studies[Reference 8](#ref8) indicated no significant difference in the risk of influenza infection/ILI from the ID administration of a 9 mcg of HA per strain dose of influenza vaccine compared to 15 mcg of HA per strain IM dose (Figure 1). Note that the figure below also describes the comparison of 15 mcg of HA per strain ID and IM. These data were not used to inform this Statement, as it was not considered a fractional dose.
**Figure 1. Risk ratio of influenza infection and/or ILI of ID administration compared to 15 mcg of HA per strain dose IM**[Figure 1 Footnote a](#f1fna)
Figure 1 Footnote a
Figure reproduced from MAGIC report.
[Figure 1 Return to footnote a referrer](#f1fna-rf)
Text description
Figure 1 depicts a forest plot showing the results of a random-effects meta-analysis reporting risk of influenza and/or ILI of ID influenza vaccine administration compared to 15 mcg of HA per strain dose IM. The leftmost column shows the identities of the four included studies, which are represented by the name of the first author and the year of publication. Next, to the right, data regarding the number of patients having the outcome of interest (Events) and the sample size of the intervention (ID administration) and comparison group (IM administration) are presented. The next column visually displays the results. The x-axis representing RR estimates and 95% CI ranges from 0.1 to 10. The vertical line of "no effect" appears at the value of 1 and separates outcomes that favor ID (on the left) and IM administration (on the right). Studies are stratified by HA per strain ID dose of influenza vaccine. Each horizontal line on the forest plot represents an individual study with the result plotted as a box and the 95% CI of the result displayed as the line. The size of the box surrounding each estimate represents the relative weight of that study in producing the pooled result. The blue diamonds show the pooled results when the individual studies are combined together and averaged. The horizontal points of the diamonds are the limits of the 95% CI of each combined point estimate. The rightmost column presents the same information that is contained in the diagram in numerical format.
The following information is depicted in this figure:
Effect estimates from the single studies:
| Author | ID Dose vs. 15 mcg IM | ID Events | ID Sample Size | IM Events | IM Sample Size | RR [95% CI] | Weight |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Chuaychoo 2016 | 9 mcg | 4 | 75 | 6 | 74 | 0.66 [0.19;2.24] | 3.3% |
| Nougarede 2014 | 9 mcg | 0 | 38 | 1 | 42 | 0.37 [0.02;8.77] | 0.5% |
| Hung 2014 | 15 mcg | 11 | 31 | 11 | 30 | 0.97 [0.50;1.89] | 11.2% |
| PuigBarbera 2014 | 15 mcg | 127 | 101963 | 133 | 62058 | 0.58 [0.46;0.74] | 84.9% |
Pooled results:
| Statistical model | ID Dose vs. 15 mcg IM | ID Events | ID Sample Size | IM Events | IM Sample Size | Pooled RR [95% CI] | Weight | Heterogeneity (I2),
p value |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Random effect model | 9 mcg | - | 113 | - | 116 | 0.61 [0.19;1.91] | 3.8% | 0%, p=0.74 |
| Random effect model | 15 mcg | - | 101994 | - | 62088 | 0.68 [0.43;1.08] | 96.2% | 49%, p=0.16 |
| Random effect model | All studies | - | 102107 | - | 62204 | 0.62 [0.49;0.77] | 100.0% | 4% [0%,90%] p=0.74 |
### III.2 Immunogenicity
The serological assessments of antibody responses to vaccination are based on the geometric mean titres (GMT) assessed using a hemagglutinin inhibition assay (HI). The assessments used by regulators are: GMT ratio, seroprotection rate, and seroconversion rate. The United States (US) Food and Drug Administration (FDA) has published definitions for these serological assessments and define criteria for the immunogenicity data required for influenza vaccine licensure in the US[Reference 17](#ref17) (Table 5). Correlates of protection that are not based on HI antibody titres have not been well established.
#### III.2.1 Fractional intramuscular dosing
Ten published studies were identified that assessed immunogenicity outcomes
for fractional doses of influenza vaccines administered intramuscularly[Reference 14](#ref14)[Reference 18](#ref18)[Reference 19](#ref19)[Reference 20](#ref20)[Reference 21](#ref21)[Reference 22](#ref22)[Reference 23](#ref23)[Reference 24](#ref24)[Reference 25](#ref25)[Reference 26](#ref26). The 10 studies were all RCTs and were considered to be of good quality according to Harris et al. criteria. Of the 10 studies, two were conducted in adults within the range of ages of 18 and 64[Reference 14](#ref14)[Reference 18](#ref18) and one was conducted in adults 65 years of age and older[Reference 19](#ref19). The other seven studies
were all conducted in children within the range of 6 to 35 months of age[Reference 20](#ref20)[Reference 21](#ref21)[Reference 22](#ref22)[Reference 23](#ref23)[Reference 24](#ref24)[Reference 25](#ref25)[Reference 26](#ref26) . Only one study in adults and four studies in children assessed the difference in immunogenicity between fractional and standard dose IM administration of influenza vaccine statistically.
One study statistically compared the immune response following the IM administration of a fractional dose (7.5 mcg of HA per strain) of influenza vaccine to the standard dose in adults[Reference 14](#ref14). Engler et al. (2008) reported that the study groups that received a fractional dose of 7.5 mcg of HA per strain had statistically lower proportions of seroconversion and seroprotection post-vaccination when compared to the groups that had received the full dose for all strains. The exception to this was seroprotection against influenza B in the 18 to 49 years of age subgroup and seroconversion for influenza A(H1N1) in the 50 to 64 years of age subgroup, which showed no significant difference between 7.5 mcg of HA per strain and 15 mcg of HA per strain.
Four studies statistically assessed the difference in immunogenicity between a full dose and a half dose of influenza vaccine in children 6 to 35 months of age[Reference 21](#ref21)[Reference 22](#ref22)[Reference 23](#ref23)[Reference 25](#ref25). Results from these studies were mixed. Langley et al. (2012) reported no significant difference based on GMT ratios (GMT of full dose/GMT of fractional dose) post-vaccination between the two study groups, and Halasa et al. (2015) found no significant difference in the absolute difference in GMTs. Robertson et al. (2019) reported better GMTs in groups that received the full dose compared to the half dose of influenza vaccine based on GMT ratios (lower limit of 95% CI was greater than 1 for all strains); however, they reported non-significant differences in seroconversion rates between the two study groups for all strains except for influenza A(H1N1) (difference in seroconversion for A(H1N1): 5.1, 95% CI: 0.189 to 10.0). Pavia-Ruz et al. (2013) reported contradictory results, with the group receiving a half dose experiencing higher GMTs and seroconversion rates compared to the group that received the full dose of vaccine, with the exception of influenza B (Yam) with regard to seroconversion rates, for which there was no statistically significant difference between the two groups. In a non-statistical
comparison, the group that received 7.5 mcg of HA per strain of Fluarix ® appeared to have similar immunogenicity to those that received 15 mcg of HA per strain Fluarix® (i.e., 95% CI were widely overlapping).
Additional studies (one in adults and two in children) that assessed varying fractional doses of influenza vaccine (3 mcg, 6 mcg, 7.5 mcg, and 9 mcg of HA per strain) reported on GMT rise, seroprotection rates, and seroconversion rates for the different study groups, but did not compare them statistically. In general, as the dose of influenza vaccine decreased, the immunogenic response also decreased[Reference 20](#ref20)[Reference 24](#ref24)[Reference 26](#ref26); however, most lower doses continued to meet criteria set for non-inferiority, despite the reduced response compared to full dose (according to current US FDA or previous European Medicines Agency criteria).
#### III.2.2 Fractional intradermal dosing
Of the thirty studies identified in the rapid review, 16 studies assessed immunogenicity outcomes for fractional doses of influenza
vaccine administered intradermally[Reference 15](#ref15)[Reference 16](#ref16)[Reference 19](#ref19)[Reference 27](#ref27)[Reference 28](#ref28)[Reference 29](#ref29)[Reference 30](#ref30)[Reference 31](#ref31)[Reference 32](#ref32)[Reference 33](#ref33)[Reference 34](#ref34)[Reference 35](#ref35)[Reference 36](#ref36)[Reference 37](#ref37)[Reference 38](#ref38)[Reference 39](#ref39), all of which were RCTs.
A meta-analysis[Reference 8](#ref8) demonstrated no significant difference in the seroconversion rate for the study groups that had received fractionated doses (3 mcg, 6 mcg, 7.5 mcg or 9 mcg of HA per strain) by ID administration compared to 15 mcg of HA per strain dose given intramuscularly for influenza A(H1N1), A(H3N2), or B (Table 1).
A meta-analysis was also performed for seroprotection rates compared to a full 15 mcg of HA per strain per IM dose, and found no significant difference in seroprotection rates against influenza A(H1N1), A(H3N2), or B for groups that had received ID administration of influenza vaccine at doses of 3 mcg of HA per strain, 7.5 mcg of HA per strain, or 9 mcg of HA per strain (Table 1). However, rates of seroprotection were significantly lower for those that had received a dose of 6 mcg of HA per strain for influenza A(H1N1) (risk ratio [RR]: 0.93, 95% confidence interval [CI]: 0.88-0.99) and influenza B (RR: 0.92, 95% CI: 0.86-0.98) compared to the full IM dose.
A further sub-analysis was performed by the DSEN MAGIC team to assess immunogenicity in adults 60 years of age and older. The only fractional ID dose assessed by the studies that had sufficient data for inclusion in the sub-analysis was 9 mcg of HA per strain dose[Reference 19](#ref19)[Reference 29](#ref29)[Reference 30](#ref30). Similar to the overall results, there was no significant difference in seroconversion or seroprotection rates between older adults that had received the fractional 9 mcg of HA per strain ID dose compared to those that received the full, 15 mcg of HA per strain IM dose (Table 2).
Table 1. Risk ratios of seroconversion and seroprotection rates for ID compared to standard dose of IM administration[Table 1 Footnote a](#t1fna)
| | ID Dose vs. 15mcg IM | Number of Studies | Risk Ratio [95% CI] | I2 |
| Seroconversion H1N1 | 3 mcg | 2 | 1.77 [0.43-7.28][Table 1 Footnote c](#t1fnc) | 82.6 |
| 6 mcg | 3 | 1.00 [0.78-1.28][Table 1 Footnote c](#t1fnc) | 87.7 |
| 7.5 mcg | 3 | 1.01 [0.80-1.28][Table 1 Footnote c](#t1fnc) | 0 |
| 9 mcg | 10 | 1.02 [0.93-1.12][Table 1 Footnote c](#t1fnc) | 59 |
| Seroconversion H3N2 | 3 mcg | 2 | 1.14 [0.56-2.31][Table 1 Footnote c](#t1fnc) | 81.3 |
| 6 mcg | 3 | 0.98 [0.97-1.00][Table 1 Footnote c](#t1fnc) | 0 |
| 7.5 mcg | 3 | 0.92 [0.63-1.33][Table 1 Footnote c](#t1fnc) | 63.8 |
| 9 mcg | 11 | 1.01 [0.95-1.06][Table 1 Footnote c](#t1fnc) | 38 |
| Seroconversion B Strain | 3 mcg | 2 | 1.46 [0.67-1.99][Table 1 Footnote c](#t1fnc) | 53.5 |
| 6 mcg | 3 | 0.95 [0.68-1.32][Table 1 Footnote c](#t1fnc) | 88.3 |
| 7.5 mcg | 3 | 1.21 [0.79-1.85][Table 1 Footnote c](#t1fnc) | 43.9 |
| 9 mcg | 11 | 0.95 [0.84-1.08][Table 1 Footnote c](#t1fnc) | 57.1 |
| Seroprotection H1N1 | 3 mcg | 3 | 1.00 [0.78-1.28][Table 1 Footnote c](#t1fnc) | 87.7 |
| 6 mcg | 3 | 0.93 [0.88-0.99][Table 1 Footnote d](#t1fnd) | 37.5 |
| 7.5 mcg | 3 | 1.07 [1.01-1.12][Table 1 Footnote b](#t1fnb) | 0 |
| 9 mcg | 12 | 1.00 [0.98-1.03][Table 1 Footnote c](#t1fnc) | 33 |
| Seroprotection H3N2 | 3 mcg | 3 | 0.98 [0.97-1.00][Table 1 Footnote c](#t1fnc) | 0 |
| 6 mcg | 3 | 1.00 [0.99-1.01][Table 1 Footnote c](#t1fnc) | 0 |
| 7.5 mcg | 3 | 1.01 [0.96-1.06][Table 1 Footnote c](#t1fnc) | 36.6 |
| 9 mcg | 12 | 1.00 [0.99-1.00][Table 1 Footnote c](#t1fnc) | 0 |
| Seroprotection B Strain | 3 mcg | 3 | 0.95 [0.68-1.32][Table 1 Footnote c](#t1fnc) | 88.3 |
| 6 mcg | 3 | 0.92 [0.86-0.98][Table 1 Footnote d](#t1fnd) | 0 |
| 7.5 mcg | 3 | 1.13 [0.78-1.66][Table 1 Footnote c](#t1fnc) | 58.2 |
| 9 mcg | 12 | 0.99 [0.95-1.03][Table 1 Footnote c](#t1fnc) | 50 |
|
Table 1 Footnote a
Table reproduced from MAGIC report with modifications.
[Table 1 Return to footnote a referrer](#t1fna-rf)
Table 1 Footnote b
Outcome significantly higher with ID administration
[Table 1 Return to footnote b referrer](#t1fnb-rf)
Table 1 Footnote c
No significant difference in outcome between ID and IM administration
[Table 1 Return to footnote c referrer](#t1fnc-rf)
Table 1 Footnote d
Outcome significantly lower with ID administration
[Table 1 Return to footnote d referrer](#t1fnd-rf)
|
Table 2. Risk ratios of seroconversion and seroprotection rates for ID compared to standard dose of IM administration in adults 60 years of age and older[Table 2 Footnote a](#t2fna)
| | ID Dose vs. 15 mcg IM | Number of Studies Pooled | Risk Ratio [95% CI] | I2 |
| Seroconversion H1N1 | 9 mcg | 2 | 1.01 [0.58-1.77][Table 2 Footnote b](#t2fnb) | 87 |
| Seroconversion H3N2 | 9 mcg | 2 | 1.02 [0.83-1.25][Table 2 Footnote b](#t2fnb) | 0 |
| Seroconversion B | 9 mcg | 2 | 1.00 [0.60-1.67][Table 2 Footnote b](#t2fnb) | 0 |
| Seroprotection H1N1 | 9 mcg | 4 | 0.98 [0.88-1.09][Table 2 Footnote b](#t2fnb) | 24.1 |
| Seroprotection H3N2 | 9 mcg | 4 | 1.03 [0.94-1.12][Table 2 Footnote b](#t2fnb) | 0 |
| Seroprotection B | 9 mcg | 4 | 0.95 [0.71-1.27][Table 2 Footnote b](#t2fnb) | 0 |
|
Table 2 Footnote a
Table reproduced from MAGIC report with modifications.
[Table 2 Return to footnote a referrer](#t2fna-rf)
Table 2 Footnote b
No significant difference in outcome between ID and IM administration
[Table 2 Return to footnote b referrer](#t2fnb-rf)
|
### III.3 Safety
#### III.3.1 Adverse Events with IM administration
**Children**
The rapid review found 9 studies that assessed safety outcomes (local, systemic, and severe AEs) of fractional IM influenza vaccine (IIV3: 5 studies, IIV4: 3 studies, IIV3 and IIV4: 1 study) in infants or toddlers in the range of 6 to 36 months of age[Reference 20](#ref20)[Reference 21](#ref21)[Reference 22](#ref22)[Reference 23](#ref23)[Reference 24](#ref24)[Reference 25](#ref25)[Reference 26](#ref26). Children that received one or two half doses (7.5 mcg of HA per strain) of influenza vaccine (dependent on whether they had ever received an influenza vaccine previously) generally reported similar levels of reactogenicity and AEs when compared to those that received one or two standard doses. In some instances, AEs appeared to be slightly more common with the full dose of influenza vaccine compared to the half dose, however there was no consistent trend.
**Adults**
Three studies were identified in the rapid review that assessed safety of fractional IM influenza vaccination in adults: 2 of the studies involved
adults between the ages of 18 to 64 (18 to 49 and 18 to 65)[Reference 14](#ref14)[Reference 18](#ref18) and one study included older adults >65 years of age[Reference 19](#ref19). Belshe et al. (2008) reported no differences in the occurrence of AEs between any of the study groups (doses assessed: 3 mcg, 6 mcg, 9 mcg, and 15 mcg of HA per strain)[Reference 18](#ref18). The other study, by Engler et al. (2008), that assessed safety in adults less than 65 years of age also found no statistically significant difference in the occurrence of AEs after adjusting to only include clinically significant pain levels (≥ 3 out of 5 using a visual analog scale)[Reference 14](#ref14). The study conducted in older adults found no significant difference in the proportion of individuals that experienced AEs or in the severity of the AEs between the group that received the fractional dose (9 mcg of HA per strain) and the group that received the full standard dose[Reference 19](#ref19).
#### III.3.2 Adverse events associated with ID administration
Twenty-four studies were identified that assessed the safety of ID administration of influenza vaccine and were able to be included in a meta-analysis performed by the DSEN MAGIC team [Reference 15](#ref15)[Reference 16](#ref16)[Reference 19](#ref19)[Reference 27](#ref27)[Reference 28](#ref28)[Reference 29](#ref29)[Reference 30](#ref30)[Reference 31](#ref31)[Reference 33](#ref33)[Reference 34](#ref34)[Reference 35](#ref35)[Reference 36](#ref36)[Reference 37](#ref37)[Reference 39](#ref39)[Reference 40](#ref40)[Reference 41](#ref41)[Reference 42](#ref42)[Reference 43](#ref43)[Reference 44](#ref44)[Reference 45](#ref45)[Reference 46](#ref46)[Reference 47](#ref47)[Reference 48](#ref48)[Reference 49](#ref49). The studies identified included various fractional doses (3 mcg, 6 mcg, 9 mcg of HA per strain), as well as a full non-fractional dose (i.e. 15 mcg of HA per strain) of ID administered influenza vaccine. Because ID administration of influenza vaccine is not authorized in Canada, there is a lack of data not only for ID administration of fractional doses, but of the full, non-fractional dose as well. Since the safety of ID administration of a full dose of influenza vaccine is likely comparable to that of fractional doses, evidence regarding safety for the full non-fractional dose was also considered to enhance the evidence base for this outcome.
Overall, the risk of ecchymosis, erythema, pruritus, and swelling occurring post-vaccination at the injection site was significantly higher with ID administration of influenza vaccine compared to IM administration. However, the risk of pain at the injection site was not significantly different for ID administration of 6 mcg, 9 mcg and 15 mcg of HA per strain compared to administration of 15 mcg per strain IM; whereas the risk of pain after the ID administration of a 3 mcg of HA per strain dose was significantly lower (Table 3). Unlike with local AEs, there was in general no significant difference in the risk of systemic events with ID influenza vaccine administration compared to IM administration, with the exception of chills and fever which were higher for ID administration but only at the 9 mcg per strain dose level and not at the lower or higher dose levels (Table 4).
Table 3. Risk of Local Adverse Events with ID compared to IM administration[Table 3 Footnote a](#t3fna)
| | ID Dose vs 15 mcg IM | Number of Studies Pooled | Risk Ratio [95% CI] | I2 |
| Ecchymosis | 9 mcg | 7 | 1.67 [1.12-2.48][Table 3 Footnote d](#t3fnd) | 55 |
| 15 mcg | 9 | 1.06 [0.73-1.57][Table 3 Footnote c](#t3fnc) | 0 |
| Erythema | 3 mcg | 3 | 9.62 [1.07-86.56][Table 3 Footnote d](#t3fnd) | 97.2 |
| 6 mcg | 2 | 23.79 [14.42-39.23][Table 3 Footnote d](#t3fnd) | 0 |
| 9 mcg | 14 | 4.56 [3.05-6.82][Table 3 Footnote d](#t3fnd) | 93.9 |
| 15 mcg | 16 | 3.68 [3.19-4.25][Table 3 Footnote d](#t3fnd) | 8.8 |
| Induration | 9 mcg | 5 | 3.27 [1.65-6.46][Table 3 Footnote d](#t3fnd) | 95.4 |
| 15 mcg | 9 | 2.98 [2.32-3.84][Table 3 Footnote d](#t3fnd) | 42.6 |
| Pain | 3 mcg | 4 | 0.34 [0.20-0.56][Table 3 Footnote b](#t3fnb) | 21.9 |
| 6 mcg | 2 | 0.98 [0.38-2.49][Table 3 Footnote c](#t3fnc) | 68.3 |
| 9 mcg | 12 | 0.95 [0.86-1.05][Table 3 Footnote c](#t3fnc) | 34.4 |
| 15 mcg | 16 | 0.94 [0.72-1.21][Table 3 Footnote c](#t3fnc) | 61.3 |
| Pruritus | 6 mcg | 2 | 15.22 [4.77-48.54][Table 3 Footnote d](#t3fnd) | 0 |
| 9 mcg | 9 | 4.24 [3.16-5.70][Table 3 Footnote d](#t3fnd) | 56.2 |
| 15 mcg | 6 | 4.01 [3.13-5.15][Table 3 Footnote d](#t3fnd) | 0 |
| Swelling | 3 mcg | 2 | 20.16 [4.68-86.82][Table 3 Footnote d](#t3fnd) | 51.3 |
| 9 mcg | 13 | 5.23 [3.58-7.62][Table 3 Footnote d](#t3fnd) | 84.4 |
| 15 mcg | 12 | 3.47 [2.21-5.45][Table 3 Footnote d](#t3fnd) | 71.9 |
|
Table 3 Footnote a
Table reproduced from MAGIC report with modifications.
[Table 3 Return to footnote a referrer](#t3fna-rf)
Table 3 Footnote b
AE significantly lower with ID administration
[Table 3 Return to footnote b referrer](#t3fnb-rf)
Table 3 Footnote c
No significant difference between ID and IM
[Table 3 Return to footnote c referrer](#t3fnc-rf)
Table 3 Footnote d
AE significantly higher with ID administration
[Table 3 Return to footnote d referrer](#t3fnd-rf)
|
Table 4. Risks of Systemic Adverse Events with ID compared to IM administration[Table 4 Footnote a](#t4fna)
| | ID Dose vs 15 mcg IM | Number of Studies Pooled | Risk Ratio [95% CI] | I2 |
| Arthralgia | 15 mcg | 3 | 1.17 [0.39-3.53][Table 4 Footnote b](#t4fnb) | 22.7 |
| Chills and shivering | 9 mcg | 7 | 1.24 [1.03-1.50][Table 4 Footnote c](#t4fnc) | 0 |
| 15 mcg | 10 | 1.08 [0.78-1.51][Table 4 Footnote b](#t4fnb) | 0 |
| Fever | 6 mcg | 2 | 0.54 [0.17-1.71][Table 4 Footnote b](#t4fnb) | 34.5 |
| 9 mcg | 11 | 1.36 [1.03-1.80][Table 4 Footnote c](#t4fnc) | 0 |
| 15 mcg | 13 | 0.89 [0.59-1.34][Table 4 Footnote b](#t4fnb) | 0 |
| Headache | 3 mcg | 2 | 1.09 [0.86-1.37][Table 4 Footnote b](#t4fnb) | 0 |
| 6 mcg | 2 | 0.83 [0.39-1.78][Table 4 Footnote b](#t4fnb) | 68 |
| 9 mcg | 13 | 1.03 [0.96-1.11][Table 4 Footnote b](#t4fnb) | 0 |
| 15 mcg | 9 | 1.16 [0.94-1.45][Table 4 Footnote b](#t4fnb) | 0 |
| Malaise | 9 mcg | 7 | 1.05 [0.94-1.20][Table 4 Footnote b](#t4fnb) | 7.1 |
| 15 mcg | 14 | 0.97 [0.78-1.22][Table 4 Footnote b](#t4fnb) | 0 |
| Myalgia | 9 mcg | 12 | 1.24 [0.93-1.65][Table 4 Footnote b](#t4fnb) | 74.8 |
| 15 mcg | 9 | 0.84 [0.63-1.12][Table 4 Footnote b](#t4fnb) | 29.4 |
| Nausea | 9 mcg | 3 | 0.93 [0.37-2.31][Table 4 Footnote b](#t4fnb) | 0 |
| 15 mcg | 2 | 1.05 [0.33-3.33][Table 4 Footnote b](#t4fnb) | 0 |
|
Table 4 Footnote a
Table reproduced from MAGIC report with modifications.
[Table 4 Return to footnote a referrer](#t4fna-rf)
Table 4 Footnote b
No significant difference between ID and IM
[Table 4 Return to footnote b referrer](#t4fnb-rf)
Table 4 Footnote c
AE significantly higher with ID administration
[Table 4 Return to footnote c referrer](#t4fnc-rf)
|
IV. Feasibility
---------------
An assessment of EEFA of influenza vaccine fractional dosing strategies was conducted according to established NACI methods[Reference 10](#ref10). The assessment of feasibility in particular identified several significant issues that warrant further discussion within the Statement.
### Logistics for fractional dosing strategies
Both fractional dosing strategies (IM and ID) assessed in this Statement would require using influenza vaccine that has been packaged in the format and of an antigen concentration authorized for use in Canada. Therefore, administering a fractional dose would require administering a lower volume of vaccine to achieve the desired lower dose, which is only possible when influenza immunizations have been packaged as multi-dose vials (MDV), and not as pre-filled syringes. A significant proportion of the influenza vaccine supply purchased for public programs is in MDV format; however, the distribution of MDV of influenza vaccine may not be equal across jurisdictions, and varies between provinces, based on provincial vaccine orders. When vaccine has already been ordered in a given season, there is not typically the opportunity to change the supply to MDV mid-season.
Using standard doses, MDVs contain 5 mL of vaccine solution, sufficient to vaccinate 10 individuals. The volume of vaccine for some fractional doses (e.g., 9 mcg of HA per strain is 0.3 mL), would not split evenly from 5 mL vials. Therefore, using fractional doses that do not divide evenly into 5 mL could result in unnecessary vaccine wastage, which would not allow for the full advantage of implementing fractional dosing as a dose sparing strategy. A half dose of influenza vaccine (7.5 mcg of HA per strain) is likely the most feasible fractional dose for influenza vaccine programs, regardless of route of administration, as this dose could allow the full use of the vial without wastage.
ID administration of vaccine requires a different needle gauge than IM administration. Most immunization venues providing influenza vaccines are unlikely to be equipped with a sufficient number of needles necessary for ID administration for the seasonal influenza vaccine program. Depending on the syringe used, different volumes may be more clearly marked (e.g., 0.5 mL, 0.25 mL). Therefore, fractional doses that require a vaccine volume that is not as clearly marked on the syringe may be more difficult to measure accurately in a vaccination setting, leading to variation in the amount of vaccine administered.
### Intradermal administration of influenza vaccine
In addition to the logistical considerations above, the ID administration of fractional doses has further implementation issues.
ID administration requires skill to administer the vaccine correctly. Influenza vaccines in Canada are only authorized for IM administration or nasal spray in the case of LAIV. As such, many influenza vaccinators may be unfamiliar with the requisite technique for ID administration. Inexperience could lead to vaccine administration errors or wasted vaccine product. ID administration also requires creation of an ID wheal or "bleb" and it can be more difficult to perform in older adults, which may slow down the immunization process. As shown in Section III.4.2, ID administration is also associated with a significant increase in local adverse reactions across almost all fractionated dose levels, which could reduce uptake of the vaccine. ID administration by needle and syringe may also require 2 or more injections to administer the full dose, further exacerbating the issues with ID. A needle-free jet injector has been authorized for use in Canada for ID injections[Reference 50](#ref50). NACI is actively reviewing the evidence on the use of this device to determine if it could potentially be used as an alternative method for administering ID vaccine. Novel technologies for ID injection, such as the needle-free jet injector, may be an option in the future that would facilitate delivery of ID dosing but are not yet widely available in Canadian settings.
Since fractional influenza vaccines doses are considered off-label for all ages, discussion with the patient and additional information in the vaccination consent form would be required. Finally, given that ID is not an authorized route of administration for influenza vaccine, many immunization registries/surveillance systems do not currently have the capacity to input ID as the route of administration, and would therefore require system-level changes before being able to effectively implement ID administration of influenza vaccine. This option would need to be added to these systems in advance of implementing ID administration to ensure the ability to evaluate the safety and effectiveness of ID administration of influenza vaccine.
V. Recommendation
-----------------
The following section outlines recommendations made by NACI regarding potential fractional influenza vaccine dosing strategies. Additional information on the strength of NACI recommendations and the grading of evidence is available in Table 6.
The following recommendations are meant to be considered in situations of influenza vaccine shortage when it is not possible to procure additional vaccine doses. Policies regarding fractional dosing strategies should be implemented at a jurisdictional level, and vaccination should be consistent with the policy and not subject to individual preference. All recommendations should be considered in the context of a given shortage situation. The extent of the shortage and its potential impact will need to be assessed prior to deciding on the best course of action.
### V.1 Public Health Program Decision-Making
**1. NACI recommends that, in the event of a significant population-level shortage of influenza vaccine, a full dose influenza vaccine should continue to be used, and existing vaccine supply should be prioritized for those considered to be at high risk or capable of transmitting to those at high risk[Footnote b](#fnb) of influenza-related complications or hospitalizations (Strong NACI Recommendation).**
* NACI concludes that there is fair evidence to recommend the use of a full dose influenza vaccine (15 mcg or 60 mcg HA per strain, dependent on vaccine product) compared to a fractional dose for individuals at high risk or those capable of transmitting to those at high risk of influenza-related complications or hospitalizations (Grade B Evidence).
**Summary of evidence and rationale**
* Influenza vaccine has previously been shown to be effective in the prevention of morbidity and mortality in individuals who are at high risk of influenza-related complications and hospitalizations.
* Since many of those at high risk of influenza (e.g., older adults, immunocompromised individuals) may have a lower response to influenza vaccination already (due to immunosenescence in older adults or other conditions that alter immune function), it is important to ensure this group continues to receive the full dose of influenza vaccine.
* Although there is some limited evidence on the use of fractional ID doses in adults ≥65 years of age, including those with chronic health conditions, there is no evidence of fractional dosing in other adult high risk-groups.
* There are some efficacy, effectiveness, and immunogenicity data regarding fractional dosing of current influenza vaccine products, but overall insufficient evidence that fractional doses of influenza vaccine provided via IM or ID are effective in healthy individuals. The majority of the evidence identified on fractional dosing is from studies conducted in healthy individuals, particularly in infants and young children, with no underlying chronic conditions.
**2. NACI recommends against the use of fractional doses of influenza vaccine in any population (Discretionary NACI Recommendation)**
* NACI concludes that there is insufficient overall evidence at this time to recommend the use of fractional IM influenza vaccine doses (Grade I Evidence)
* NACI concludes that there is fair evidence that fractional ID influenza vaccine doses provide a sufficient immune response, but this route of administration is not feasible at this time (Grade B Evidence)
**Summary of Evidence and Rationale**
* There are some efficacy, effectiveness, and immunogenicity data regarding fractional dosing of current influenza vaccine products, but overall, there is insufficient evidence that fractional doses of influenza vaccine provided via the IM route is effective in healthy individuals. The majority of the evidence identified on fractional dosing is from studies conducted in healthy individuals, mainly young children and infants, with no underlying chronic conditions.
* ID administration of influenza vaccine may be more effective at lower doses than IM and would be reasonable to recommend based on efficacy, effectiveness, immunogenicity, and safety data; however, significant system-level changes are needed to address the feasibility issues associated with this route of administration before it can be considered at a large scale.
* With regard to the safety of fractional doses of influenza vaccines, there is fair evidence that fractional doses of influenza vaccine administered via IM or ID routes do not result in significant differences compared to full dose with regard to severe AEs post-influenza vaccination; however, ID administration of influenza vaccine will likely result in a higher proportion of individuals who experience local AEs.
* Pre-filled syringes cannot be used for IM or ID fractional dosing.
* ID administration of vaccine by syringe and needle requires a different gauge needle than IM administration. Therefore, immunization venues providing influenza vaccines may not be equipped with a sufficient number of needles necessary for ID administration for a seasonal influenza vaccine program unless prepared in advance.
* Significant training would be required to ensure vaccinators are equipped to provide ID influenza vaccinations and feel comfortable doing so. Without training, it is possible that a greater number of vaccine administration errors could occur with ID administration.
* Not all vaccinators are authorized to provide ID administration. The number of vaccinators who are able to provide ID vaccination will vary by jurisdiction.
Tables
-------
Table 5. Serological Assay Definitions and Thresholds for Protection
Specified by the United States Food and Drug Administration[Reference 19](#ref19)
| Serological assay | Definition | Threshold |
| --- | --- | --- |
| ***GMT ratio*** | Ratio of GMT post-vaccination of licensed vaccine to GMT post-vaccination of new vaccine | Non-inferiority: The upper bound of the two-sided 95% CI on
the ratio of the GMTs should not exceed 1.5. |
| ***Seroprotection*** | Proportion of subjects achieving an HI titre of ≥1:40 post-vaccination | Placebo-controlled: Lower limit of the two-sided 95% CI for the percent of subjects achieving seroprotection should meet or exceed 70% (for adults <65 and children) or 60% (for adults ≥65) |
| ***Seroconversion*** | Proportion of subjects achieving an increase from ≤1:10 HI titre pre-vaccination to ≥1:40 post-vaccination or achieving at least four-fold rise in HI titres | Non-inferiority: Upper limit of the two-sided 95% CI on the difference between the seroconversion rates (rate of licensed vaccine – rate of new vaccine) should not exceed 10 percentage points.
Placebo-controlled: Lower limit of the two-sided 95% CI for the percent of subjects achieving seroprotection should meet or exceed 40% (for adults <65 and children) or 30% (for adults ≥65) |
| **Abbreviations:** CI: confidence interval, GMT: geometric mean titre, HI: hemagglutination inhibition. |
**Table 6. NACI Recommendations: Strength of Recommendation and Grade of Evidence**
| Strength of NACI Recommendation
Based on factors not isolated to strength of evidence (e.g., public health need) | Grade of Evidence
Based on assessment of the body of evidence |
| --- | --- |
| **Strong**
“**should/should not be** offered”* Known/Anticipated advantages outweigh known/anticipated disadvantages (“should”),
OR Known/Anticipated disadvantages outweigh known/anticipated advantages (“should not”) * Implication: A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present
| * A - good evidence to recommend
* B – fair evidence to recommend
* C – conflicting evidence, however other factors may influence decision-making
* D – fair evidence to recommend against
* E – good evidence to recommend against
* I – insufficient evidence (in quality or quantity), however other factors may influence decision-making
|
| **Discretionary**
“may be considered”* Known/Anticipated advantages closely balanced with known/anticipated disadvantages, OR uncertainty in the evidence of advantages and disadvantages exists
* Implication: A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable
| * A - good evidence to recommend
* B – fair evidence to recommend
* C – conflicting evidence, however other factors may influence decision-making
* D – fair evidence to recommend against
* E – good evidence to recommend against
* I – insufficient evidence (in quality or quantity), however other factors may influence decision-making
|
Table 7. Ranking Individual Studies: Levels of Evidence Based on Research Design
| Level | Description |
| --- | --- |
| I | Evidence from randomized controlled trial(s). |
| II-1 | Evidence from controlled trial(s) without randomization. |
| II-2 | Evidence from cohort or case-control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy. |
| II-3 | Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence. |
| III | Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees. |
Table 8. Ranking Individual Studies: Quality (internal validity) Rating of Evidence
| Quality Rating | Description |
| --- | --- |
| Good | A study (including meta-analyses or systematic reviews) that meets all design- specific criteria[Table 8 Footnote a](#t8fna) well. |
| Fair | A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion[Table 8 Footnote a](#t8fna) but has no known "fatal flaw". |
| Poor | A study (including meta-analyses or systematic reviews) that has at least one design-specific[Table 8 Footnote a](#t8fna) "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations. |
|
Table 8 Footnote a
General design specific criteria are outlined in Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, Atkins D. Current methods of the US Preventive Services Task Force: A review of the process. Am J Prev Med. 2001;20(3):21-35.10
[Table 8 Return to footnote a referrer](#t8fna-rf)
|
Table 9. Summary of Evidence Related to the Comparative Efficacy and Effectiveness of Fractional vs Full-dose Influenza Vaccine for IM and ID
| Study Details | Summary |
| --- | --- |
| Study | Vaccine | Study Design | Participants | Summary of Key Findings | Level of Evidence | Quality |
| Intramuscular |
| --- |
| **Kramer JS, Durham C, Schroeder T, Garrelts JC**. *Effectiveness of half-dose versus full-dose influenza vaccine in health care workers*. American journal of health-system pharmacy. 2006 Nov 1;63(21):2111-5. | IIV3 (Fluzone)
Doses:
7.5 mcg
15 mcg | RCT
US
single site
2004–2005 influenza season
No funding declared | Healthy adults ≥18 years of age
7.5 group:
n=222
15 group:
n=222 | Study participants self-reported their physician's diagnosis of influenza to the study investigators, who then attempted to obtain laboratory confirmation of the physician's diagnosis.
There was no difference between the full-dose (15 mcg) and half-dose (7.5 mcg) groups in clinical diagnosis of influenza (4% versus 7%; p = 0.198; relative risk = 0.53 [95% CI 0.23–1.23]). Of those that had a clinical diagnosis of influenza, none of the participants who received 7.5 mcg dose had laboratory-confirmed influenza, and one of the participants who received 15 mcg dose had laboratory-confirmed influenza (13%). | I | Good |
| **Engler RJ, Nelson MR, Klote MM, VanRaden MJ, Huang CY, Cox NJ, Klimov A, Keitel WA, Nichol KL, Carr WW, Treanor JJ.** *Half-vs full-dose trivalent inactivated influenza vaccine (2004-2005): age, dose, and sex effects on immune responses.* Archives of internal medicine. 2008 Dec 8;168(22):2405-14. | IIV3
(Fluzone)
Doses:
7.5 mcg
15 mcg | RCT
US
multi-center
2004-2005 influenza season
This study was supported by the Office of the Army Surgeon General in collaboration with Walter Reed Army Medical Center and Healthcare System; the North Atlantic Regional Medical Command; the US Army Medical Research and Materiel Command; the NIAID, the NIH, and the US CDC | Healthy adults 18–64 years of age
18–49 year old subgroup:
Mean age: 42.3
44.3% female
7.5 mcg group: n=284
15 mcg group: n= 274
50–64 year old subgroup:
Mean age: 55.6
42.6% female
7.5 mcg group: n=276
15 mcg group: n= 280 | Relative risk of 1 or more medical visits for ILI involving the upper or lower respiratory tract:
**Relative risk (95% CI) by age group:*** 18-49 years:1.01 (0.70-1.46)
* 50-64 years:1.07 (0.53-2.18)
| I | Good |
| Intradermal |
| **Oluwaseun Egunsola, John Taplin, Liza Mastikhina, Joyce Li, Diane Lorenzetti, Laura E. Dowsett, Tom Noseworthy, Fiona Clement.** *Intradermal versus intramuscular administration of influenza vaccination.* University of Calgary, Health Technology Assessment Unit. Produced for DSEN MAGIC Team. July 21, 2020. | Seasonal inactivated influenza vaccine | Rapid review and meta-analysis
Random effects model
Included: RCTs, non-RCTs, observational studies
Funding: Canadian Institute for Health Research (DSEN) | Number of participants (RCTs): 13,759
Number of participants (observational): 164,021
Age range: all ages
Sub-analysis: 60 years of age and older | Primary findings:
Meta-analysis included a total of 2 RCTs (no observational studies) on the effectiveness of a 9 mcg of HA per strain fractional dose of ID influenza vaccine.
Refer to the ID Dose = 9 portion of figure 1 within this statement for results on the effectiveness of 9 mcg of HA per strain ID dosing in adults against influenza infection and ILI. Effectiveness estimates for influenza infection and ILI were combined in this analysis. | Meta-analysis | N/A |
| **Abbreviations:**
CI:
confidence interval
IIV3:
trivalent inactivated influenza vaccine
RCT:
randomized controlled trial
|
Table 10. Summary of Evidence Related to the Comparative Immunogenicity of Fractional vs Full-dose Influenza Vaccine for IM and ID
| Study Details | Summary |
| --- | --- |
| Study | Vaccine | Study Design | Participants | Summary of Key Findings | Level of Evidence | Quality |
| Intramuscular |
| --- |
| **Belshe RB, Newman FK, Wilkins K, Graham IL, Babusis E, Ewell M, Frey SE.** *Comparative immunogenicity of trivalent influenza vaccine administered by intradermal or intramuscular route in healthy adults.* Vaccine. 2007 Sep 17;25(37-38):6755-63. | IIV3 (Fluzone)
Doses:* 3 mcg
* 6 mcg
* 9 mcg
* 15 mcg
| RCT
US
single site
2006-2007 influenza season
Funding provided by N01-AI-25464. | Healthy adults 18–49 years of age
mean age: 30
68% female* 3mcg group:
n=29
* 6mcg group:
n=30
* 9mcg:
n=32
* 15mcg:
n=31
| **Proportion that achieved seroconversion (95% CI) 28 days post-vaccination:**
**3 mcg:*** A(H1N1): 62.1 (42.3-79.3)
* A(H3N2): 58.6 (38.9-76.5)
* Influenza B: 51.7 (32.5-70.6)
**6 mcg:*** A(H1N1): 60.0 (40.6-77.3)
* A(H3N2): 60.0 (40.6-77.3)
* Influenza B: 70.0 (50.6-85.3)
**9 mcg:*** A(H1N1): 66.7 (47.2-82.7)
* A(H3N2): 90.0 (73.5-97.9)
* Influenza B: 66.7 (47.2-82.7)
**15 mcg:*** A(H1N1): 67.7 (48.6-83.3)
* A(H3N2): 93.5 (78.6-99.2)
* Influenza B: 67.7 (48.6-83.3)
**Proportion that achieved seroprotection (95% CI) 28 days post-vaccination:**
**3 mcg:*** A(H1N1): 72.4 (52.8-87.3)
* A(H3N2): 79.3 (60.3-92.0)
* Influenza B: 89.7 (72.6-97.8)
**6 mcg:*** A(H1N1): 80 (61.4-92.3)
* A(H3N2): 80 (61.4-92.3)
* Influenza B: 86.7 (69.3-96.2)
**9 mcg:*** A(H1N1): 83.3 (65.3-94.4)
* A(H3N2): 93.3 (77.9-99.2)
* Influenza B: 93.3 (77.9-99.2)
**15 mcg:*** A(H1N1): 77.4 (58.9-90.4)
* A(H3N2): 100 (88.8-100)
* Influenza B: 90.3 (74.2-98.0)
| I | Good |
| **Engler RJ, Nelson MR, Klote MM, VanRaden MJ, Huang CY, Cox NJ, Klimov A, Keitel WA, Nichol KL, Carr WW, Treanor JJ.** *Half-vs full-dose trivalent inactivated influenza vaccine (2004-2005): age, dose, and sex effects on immune responses.* Archives of internal medicine. 2008 Dec 8;168(22):2405-14. | IIV3
(Fluzone)
Doses:* 7.5 mcg
* 15 mcg
| RCT
US
multi-center
2004-2005 influenza season
This study was supported by the Office of the Army Surgeon General in collaboration with Walter Reed Army Medical Center and Healthcare System; the North Atlantic Regional Medical Command; the US Army Medical Research and Materiel Command; the NIAID, the NIH, and the US CDC | Healthy adults 18–64 years of age
18–49 year old subgroup:
Mean age: 42.3
44.3% female* 7.5 mcg group: n=284
* 15 mcg group: n= 274
50–64 year old subgroup:
Mean age: 55.6
42.6% female* 7.5 mcg group: n=276
* 15 mcg group: n= 280
| **Difference in proportions (% in 15 mcg group - % in 7.5 mcg group) that achieved seroconversion (95% CI) 21 days post-vaccination in 18-49 year old age group:*** A(H1N1): 6.6 (1.0-12.2); p=0.02
* A(H3N2): 8.4 (0.5-16.2); p=0.04
* Influenza B: 1.27 (1.08-1.50); p=0.002
**Difference in proportions that achieved seroconversion (95% CI) 21 days post-vaccination in 50-64 year old age group:*** A(H1N1): 4.8 (-0.8-10.5); p=0.09
* A(H3N2): 12.9 (5.2-20.5); p=0.001
* Influenza B: 14.6 (6.8-22.5); p<0.001
**Difference in proportions that achieved seroprotection (95% CI) 21 days post-vaccination in 18-49 year old age group:*** A(H1N1): 11.8 (3.5-20.0); p=0.005
* A(H3N2): 8.3 (0.8-15.8); p=0.03
* Influenza B: 5.0 (-1.6-11.7); p=0.19
**Difference in proportions that achieved seroprotection (95% CI) 21 days post-vaccination in 50-64 year old age group:*** A(H1N1): 15.7 (8.1-23.4); p<0.001
* A(H3N2): 9.5 (1.7-17.2); p=0.02
* Influenza B: 8.8 (0.9-16.6); p=0.03
| I | Good |
| **Chi RC, Rock MT, Neuzil KM.** *Immunogenicity and safety of intradermal influenza vaccination in healthy older adults*. Clinical infectious diseases. 2010 May 15;50(10):1331-8. | IIV3 (Fluzone)
Doses:* 9 mcg
* 15 mcg
| RCT
US
2007-2008 influenza season
Funded by PATH | Adults ≥65 year of age, excluding those with serious or unstable conditions* 9 mcg group:
n=64
17.2% female
Mean age: 75.2
* 15 mcg group:
n=65
16.9% female
Mean age: 75.6
| **Proportion that achieved seroprotection 4 weeks post-vaccination:**
**Number that achieved seroprotection (%):**
**9 mcg:*** A(H1N1): 37 (57.8%)
* A(H3N2): 48 (75%)
* Influenza B: 11 (17.2%)
**15 mcg:*** A(H1N1): 42 (65.5%)
* A(H3N2): 49 (76.6%)
* Influenza B: 17 (26.6%)
| - | - |
| **Skowronski DM, Hottes TS, Chong M, De Serres G, Scheifele DW, Ward BJ, Halperin SA, Janjua NZ, Chan T, Sabaiduc S, Petric M**. *Randomized controlled trial of dose response to influenza vaccine in children aged 6 to 23 months*. Pediatrics. 2011 Amcg 1;128(2):e276-89. | IIV3
(Vaxigrip)
Doses:* 7.5 mcg
* 15 mcg
| RCT
Canada multi-center
2008-2009 influenza season
Funding for this study was provided by PHAC and the Ministère de la Santé et des Services Sociaux du Québec. | Healthy children 6-23 months of age* 7.5 mcg group:
n=124
50.8% female
Mean age: 12.8 months
* 15 mcg group:
n=128
55.5% female
Mean age: 13.2 months
| **Proportion that achieved seroprotection (95% CI) 27-45 days after the 2nd dose of influenza vaccine:**
**7.5 mcg:*** A(H1N1): 70.5 (61.6-78.4)
* A(H3N2): 67.2 (58.1-75.4)
* Influenza B: 66.4 (57.3-74.7)
**15 mcg:*** A(H1N1): 81.2 (72.9-87.8)
* A(H3N2): 83.8 (75.8-89.8)
* Influenza B: 80.3 (72-87.1)
**Proportion that achieved seroconversion (95% CI) 27-45 days after the 2nd dose of influenza vaccine:**
**7.5 mcg:*** A(H1N1): 70.5 (61.6-78.4)
* A(H3N2): 67.2 (58.1-75.4)
* Influenza B (Yam): 65.6 (56.4-73.9)
**15 mcg:*** A(H1N1): 80.3 (72-87.1)
* A(H3N2): 81.2 (72.9-87.8)
* Influenza B (Yam): 80.3 (72-87.1)
**GMT rise (95% CI) [post-vaccination GMT / pre-vaccination GMT] after the 2nd dose of influenza vaccine:**
**7.5 mcg:*** A(H1N1): 10.2 (8.2-12.7)
* A(H3N2): 9.1 (7.5-11.0)
* Influenza B: 8.4 (6.7-10.6)
**15 mcg:*** A(H1N1): 12.2 (9.8-15.2)
* A(H3N2): 13.0 (10.9-15.7)
* Influenza B: 13.6 (10.8-17.1)
| I | Good |
| **Langley JM, Vanderkooi OG, Garfield HA, Hebert J, Chandrasekaran V, Jain VK, Fries L**. *Immunogenicity and safety of 2 dose levels of a thimerosal-free trivalent seasonal influenza vaccine in children aged 6–35 months: a randomized, controlled trial.* Journal of the Pediatric Infectious Diseases Society. 2012 Mar 1;1(1):55-63. | IIV3
(Flulaval or Vaxigrip)
Doses:* 7.5 mcg
* 15 mcg
| RCT
Canada multi-center
2008-2009 influenza season
Funded by GlaxoSmith
Kline Biologicals | Healthy children 6-35 months of age* Flulaval 7.5 mcg group:
n=164
42.7% female
Mean age: 18.2 months
* Flulaval 15 mcg group:
n=167
49.3% female
Mean age: 17.5 months
* Vaxigrip 7.5 mcg group:
n=43
60.5% female
Mean age: 17.0 months
| **Proportion that achieved seroprotection (95% CI) 28 days post-vaccination:**
**7.5 mcg (Vaxigrip):*** A(H1N1): 80.6 (64.0-91.8)
* A(H3N2): 77.8 (60.8-89.9)
* Influenza B (Yam): 86.1 (70.5-95.3)
**7.5 mcg (Flulaval):*** A(H1N1): 51.1 (42.3-60)
* A(H3N2): 61.8 (52.9-70.2)
* Influenza B (Yam): 80.9 (73.1-87.3)
**15 mcg (Flulaval):*** A(H1N1): 62.1 (53.3-70.4)
* A(H3N2): 74.2 (65.9-81.5)
* Influenza B (Yam): 86.4 (79.3-91.7)
**Proportion that achieved seroconversion (95% CI) 28 days post-vaccination:**
**7.5 mcg (Vaxigrip):*** A (H1N1): 83.3 (67.2-93.6)
* A(H3N2): 83.3 (67.2-93.6)
* Influenza B (Yam): 91.7 (77.5-98.2)
**7.5 mcg (Flulaval):*** A(H1N1): 53.4 (44.5-62.2)
* A(H3N2): 62.6 (53.7-70.9)
* Influenza B (Yam): 84.7 (77.4-90.4)
**15 mcg (Flulaval):*** A(H1N1): 63.6 (54.8-71.8)
* A(H3N2): 75.0 (66.7-82.1)
* Influenza B (Yam): 92.4 (86.5-96.3)
**GMT ratios (95% CI) [Flulaval 15 mcg / Flulaval 7.5 mcg] 28 days post-vaccination (adjusted for prior influenza vaccination, baseline titre – pooled variance):*** A(H1N1): 1.25 (0.9-1.75)
* A(H3N2): 1.11 (0.83-1.49)
* Influenza B (Yam): 1.27 (0.93-1.74)
Children received 1 or 2 doses, depending on previous influenza vaccination. | I | Good |
| **Pavia-Ruz N, Angel Rodriguez Weber M, Lau YL, Nelson EA, Kerdpanich A, Huang LM, Silas P, Qaqundah P, Blatter M, Jeanfreau R, Lei P.** *A randomized controlled study to evaluate the immunogenicity of a trivalent inactivated seasonal influenza vaccine at two dosages in children 6 to 35 months of age.* Human vaccines & immunotherapeutics. 2013 Sep 19;9(9):1978-88. | IIV3
(Fluarix or Fluzone)
Doses:* 7.5 mcg
* 15 mcg
| RCT
US, Hong Kong, Mexico, Thailand, and Taiwan
Multi-centre
2008-2009 influenza season
Funded by GlaxoSmith
Kline Biologicals | Healthy children 6-35 months of age* Fluarix 7.5 mcg group:
n=1017
50.7% female
Mean age: 21.2 months
* Fluarix 15 mcg group:
n=1013
53.3% female
Mean age: 21.2 months
* Fluzone 7.5 mcg group:
n=1031
49.1% female
Mean age: 21.1 months
| **Proportion that achieved seroprotection (95% CI) 28 days (or 56 for unprimed children) post-vaccination:**
**7.5 mcg (Fluzone):*** A(H1N1): 95.6 (94.2-96.8)
* A(H3N2): 98.2 (97.1-98.9)
* Influenza B (Yam)[Table 10 Footnote a](#t10fna): 90.7 (88.7-92.4)
* Influenza B (Yam)[Table 10 Footnote b](#t10fnb): 92.3 (90.5-93.9)
**7.5 mcg (Fluarix):*** A(H1N1): 68.7 (65.7-71.5)
* A(H3N2): 77.4 (74.7-79.9)
* Influenza B (Yam)[Table 10 Footnote a](#t10fna): 85.7 (83.4-87.8)
* Influenza B (Yam)[Table 10 Footnote b](#t10fnb): 88 (85.9-89.9)
**15 mcg (Fluarix):*** A(H1N1): 74.2 (71.4-76.9)
* A(H3N2): 83.3 (80.8-85.5)
* Influenza B (Yam)[Table 10 Footnote a](#t10fna): 88.8 (86.7-90.7)
* Influenza B (Yam)[Table 10 Footnote b](#t10fnb): 90.6 (88.6-92.3)
**Proportion that achieved seroconversion (95% CI) 28 days (or 56 for unprimed children) post-vaccination:**
**7.5 mcg (Fluzone):*** A(H1N1): 90.2 (88.2-91.9)
* A(H3N2): 95.9 (94.5-97)
* Influenza B (Yam)[Table 10 Footnote a](#t10fna): 87.8 (85.6-89.7)
* Influenza B (Yam)[Table 10 Footnote b](#t10fnb): 89.3 (87.3-91.1)
**7.5 mcg (Fluarix):*** A(H1N1): 62.5 (59.5-65.5)
* A(H3N2): 73.5 (70.6-76.1)
* Influenza B (Yam)[Table 10 Footnote a](#t10fna): 79.8 (77.2-82.3)
* Influenza B (Yam)[Table 10 Footnote b](#t10fnb): 82.6 (80.1-84.9)
**15 mcg (Fluarix):*** A(H1N1): 69 (66.1-71.8)
* A(H3N2): 79.8 (77.2-82.2)
* Influenza B (Yam)[Table 10 Footnote a](#t10fna): 85.3 (83-87.4)
* Influenza B (Yam)[Table 10 Footnote b](#t10fnb): 87.1 (84.8-89.1)
**GMT rise (95% CI) [post-vaccination GMT / pre-vaccination GMT] post-vaccination:**
**7.5 mcg (Fluzone):*** A(H1N1): 21.4 (19.9-23.1)
* A(H3N2): 24.1 (22.6-25.7)
* Influenza B (Yam)[Table 10 Footnote a](#t10fna): 21.4 (19.7-23.1)
* Influenza B (Yam)[Table 10 Footnote b](#t10fnb): 23.1 (21.4-24.9)
**7.5 mcg (Fluarix):*** A(H1N1): 10.2 (9.2-11.4)
* A(H3N2): 10.4 (9.6-11.3)
* Influenza B (Yam)[Table 10 Footnote a](#t10fna): 13.4 (12.4-14.5)
* Influenza B (Yam)[Table 10 Footnote b](#t10fnb): 14.9 (13.7-16.1)
**15 mcg (Fluarix):*** A(H1N1): 12.4 (11.2-13.7)
* A(H3N2): 14.2 (13.1-15.4)
* Influenza B (Yam)[Table 10 Footnote a](#t10fna): 18.4 (17-20)
* Influenza B (Yam)[Table 10 Footnote b](#t10fnb): 19.7 (18.2-21.4)
**Difference in immune response of 15 mcg Fluarix compared to 7.5 mcg Fluzone 28 days (or 56 for unprimed children) post-vaccination:**
**GMT ratio[Table 10 Footnote c](#t10fnc) (95% CI):*** A(H1N1) : 1.74 (1.54-1.98)
* A(H3N2): 1.72 (1.57-1.89)
* Influenza B (Yam)[Table 10 Footnote a](#t10fna): 1.13 (1.01-1.25)
* Influenza B (Yam)[Table 10 Footnote b](#t10fnb): 1.13 (1.02-1.25)
**Difference in seroconversion rate[Table 10 Footnote d](#t10fnd) (95% CI) :*** A(H1N1): 21.19 (17.82-24.58)
* A(H3N2): 16.16 (13.46-18.98)
Influenza B (Yam)[Table 10 Footnote a](#t10fna): 2.48 (-0.49-5.45)
* Influenza B (Yam)[Table 10 Footnote b](#t10fnb): 2.25 (-0.55-5.07)
Children received 1 or 2 doses, depending on previous influenza vaccination. | I | Good |
| **Halasa NB, Gerber MA, Berry AA, Anderson EL, Winokur P, Keyserling H, Eckard AR, Hill H, Wolff MC, McNeal MM, Edwards KM.** *Safety and immunogenicity of full-dose trivalent inactivated influenza vaccine (TIV) compared with half-dose TIV administered to children 6 through 35 months of age.* Journal of the Pediatric Infectious Diseases Society. 2015 Sep 1;4(3):214-24. | IIV3
(Fluzone)
Doses:* 7.5 mcg
* 15 mcg
| RCT
US
Multi-center
October 5, 2010 and March 2, 2012; The studies were conducted before the 2010–2011 and 2011–2012 influenza seasons.
Funded by the National Institutes of Health Clinical and Translational Science Awards Program, the National Center for Advancing Translational Sciences, and the National Institute of Allergy and Infectious Diseases | Healthy children 6-35 months of age
N=204
52% female
Mean age: 14.2 months
Primed subgroup:* 7.5 mcg group:
n=9
66.7% female
Mean age: 23.4 months
* 15 mcg group:
n=21
45.4% female
Mean age: 25.3 months
Influenza vaccine naïve subgroup:* 7.5 mcg group:
n=55
50.7% female
* 15 mcg group:
n=119
52.9% female
| **Proportion of primed individuals that achieved seroprotection (95% CI) 28 days post-vaccination:**
**7.5 mcg:*** A(H1N1): 89 (0.52-1.00)
* A(H3N2): 89 (0.52-1.00)
* Influenza B (Yam): 33 (0.07-0.70)
**15 mcg:*** A(H1N1): 100 (0.84-1.00)
* A(H3N2): 90 (0.7-0.99)
* Influenza B (Yam): 14 (0.03-0.36)
**Proportion of naïve individuals that achieved seroprotection (95% CI) 28 days after the 2nd dose of influenza vaccine:**
**7.5 mcg:*** A(H1N1): 85 (73-94)
* A(H3N2): 15 (6-27)
* Influenza B (Yam): 44 (30-58)
**15 mcg:*** A(H1N1): 89 (82-94)
* A(H3N2): 15 (9-23)
* Influenza B (Yam): 50 (40-59)
**Proportion of primed individuals that achieved seroconversion (95% CI) 28 days post-vaccination:**
**7.5 mcg:*** A(H1N1): 89 (52-100)
* A(H3N2): 78 (40-97)
* Influenza B (Yam): 22 (3-60)
**15 mcg:*** A(H1N1): 90 (70-99)
* A(H3N2): 86 (64-97)
* Influenza B (Yam): 10 (1-30)
**Proportion of naïve individuals that achieved seroconversion (95% CI) 28 days after the 2nd dose of influenza vaccine:**
**7.5 mcg:** * A(H1N1): 78 (65-88)
* A(H3N2): 7 (2-18)
* Influenza B (Yam): 31 (19-45)
**15 mcg:*** A(H1N1): 85 (77-91)
* A(H3N2): 11 (6-18)
* Influenza B (Yam): 42 (33-51)
**Difference in GMT (95% CI) [15 mcg - 7.5 mcg] 28 days after last vaccination:**
**Primed:*** A(H1N1): -267.5 (-527.9 to -3.9)
* A(H3N2): -11.0 (-105.1 to 122.2)
* Influenza B (Yam): 3.0 (-7.5 to 14.8)
**Naïve:*** A(H1N1): -5.7 (-94.9 to 90.2)
* A(H3N2): -1.9 (-2.0 to 5.2)
* Influenza B (Yam): -3.7 (-5.1 to 12.0)
| I | Good |
| **Jain VK, Domachowske JB, Wang L, Ofori-Anyinam O, Rodríguez-Weber MA, Leonardi ML, Klein NP, Schlichter G, Jeanfreau R, Haney BL, Chu L.** *Time to change dosing of inactivated quadrivalent influenza vaccine in young children: evidence from a phase III, randomized, controlled trial.* Journal of the Pediatric Infectious Diseases Society. 2017 Mar 1;6(1):9-19. | IIV4
(Fluzone quadrivalent)
Doses:* 7.5 mcg
* 15 mcg
| RCT
US and Mexico
Multi-centre
2014-2015 influenza season
Funded by GlaxoSmith
Kline Biologicals | Healthy children 6-35 months of age* 7.5 mcg group:
n=1028
48.2% female
Mean age: 19.9 months
* 15 mcg group:
n=1013
45.6% female
Mean age: 19.7 months
| **Proportion that achieved seroprotection (95% CI) 28 days (or 56 days for unprimed individuals) post-vaccination:**
**7.5 mcg:*** A(H1N1): 75.4 (72.6-78)
* A(H3N2): 77.8 (75.2-80.3)
* Influenza B (Yam): 88.6 (86.5-90.5)
* Influenza B (Vic): 49.8 (46.7-52.9)
**15 mcg:*** A(H1N1): 80.4 (77.8-82.8)
* A(H3N2): 82.2 (79.7-84.5)
Influenza B (Yam): 97 (95.8-98)
* Influenza B (Vic): 66 (63-69)
**Proportion that achieved seroconversion (95% CI) 28 days (or 56 days for unprimed individuals) post-vaccination:**
**7.5 mcg:*** A(H1N1): 67.3 (64.3-70.3)
* A(H3N2): 69.4 (66.4-72.3)
Influenza B (Yam): 73.8 (70.9-76.5)
* Influenza B (Vic): 48.5 (45.3-51.6)
**15 mcg:*** A(H1N1): 73.7 (70.8-76.4)
* A(H3N2): 76.1 (73.3-78.8)
Influenza B (Yam): 85.5 (83.2-87.7)
* Influenza B (Vic): 64.9 (61.8-67.9)
**GMT rise (95% CI) 28 days (or 56 days for unprimed individuals) post-vaccination:**
**7.5 mcg:*** A(H1N1): 7.7 (7.1-8.3)
* A(H3N2): 8.9 (8.2-9.7)
Influenza B (Yam): 8.1 (7.5-8.8)
* Influenza B (Vic): 5.4 (5.0-5.8)
**15 mcg:*** A(H1N1): 9 (8.4-9.7)
* A(H3N2): 10.7 (10-11.6)
* Influenza B (Yam): 12.7 (11.7-13.7)
* Influenza B (Vic): 8.7 (8.1-9.4)
| I | Good |
| **Robertson CA, Mercer M, Selmani A, Klein NP, Jeanfreau R, Greenberg DP.** *Safety and immunogenicity of a full-dose, split-virion, inactivated, quadrivalent influenza vaccine in healthy children 6-35 months of age: a randomized controlled clinical trial.* The Pediatric infectious disease journal. 2019 Mar;38(3):323.) | IIV4
Doses:* 7.5 mcg
* 15 mcg
| RCT
US
Multi-center
2016-2017 influenza season
Funded by Sanofi Pasteur | Healthy children 6-35 months of age* 7.5 mcg group:
n=682
49.4% female
Mean age: 20.4 months
* 15 mcg group:
n=682
49.9% female
Mean age: 20.5 months
| **Difference in seroconversion rate (95% CI) [% in 15 mcg group – % 7.5 mcg group] post-vaccination:*** A(H1N1): 5.1 (0.189 to 10.0)
* A(H3N2): 4.3 (-0.283 to 8.99)
Influenza B (Yam): 3.4 (-2.78 to 5.56)
* Influenza B (Vic): 1.4 (-0.465 to 7.36)
**GMT ratios (95% CI) [15 mcg group / 7.5 mcg group] post-vaccination:*** A(H1N1): 1.45 (1.19 to 1.77)
* A(H3N2): 1.50 (1.23 to 1.83)
Influenza B (Yam): 1.44 (1.20 to 1.73)
* Influenza b (Vic): 1.33 (1.10 to 1.62)
| I | Good |
| **Della Cioppa G, Vesikari T, Sokal E, Lindert K, Nicolay U.** *Trivalent and quadrivalent MF59®-adjuvanted influenza vaccine in young children: a dose-and schedule-finding study.* Vaccine. 2011 Nov 3;29(47):8696-704. | IIV3 or IIV4
Doses:* 7.5 mcg
* 15 mcg
| RCT
Finland and Belgium
Multi-center
2008-2009 influenza season
Funded by Novartis | Healthy children 6-35 months of age
(Note: only a subset of study groups relevant for this review are presented here. Authors combined the IIV3 and IIV4 groups for analysis in the publication)* IIV3 7.5 mcg group:
n=25
66% female
Mean age: 20 months
* IIV3 15 mcg group:
n=22
27% female
Mean age: 15 months
* IIV4 7.5 mcg group:
n=25
36% female
Mean age: 18 months
* IIV4 15 mcg group:
n=28
46% female
Mean age: 15.2 months
* IIV3 15 mcg group (Vaxigrip):
n=26
50% female
Mean age: 16.1 months
| **Proportion (%) that had achieved seroprotection on day 50:*** **7.5 mcg (Vaxigrip):** 96% A(H1N1), 92% A(H3N2) and 42% Influenza B (Yam). Data not reported for Influenza B (Vic).
* **7.5 mcg:** 65% A(H1N1), 70% A(H3N2), 19% Influenza B (Yam) and 17% Influenza B (Vic).
* **15 mcg:** 79% A(H1N1), 71% A(H3N2), 12% influenza B (Yam) and 14% influenza B (Vic).
**Proportion (%) that achieved seroconversion on day 50:*** **7.5 mcg (Vaxigrip):** 96% A(H1N1), 92% A(H3N2) and 42% Influenza B (Yam). Data not reported for influenza B (Vic).
* **7.5 mcg:** 62% A(H1N1), 62% A(H3N2), 19% influenza B (Yam) and 17% influenza B (Vic).
* **15 mcg:** 79% A(H1N1), 71% A(H3N2), 21% influenza B (Yam) and 14% influenza B (Vic).
**GMT rise (post-vaccination GMT / pre-vaccination GMT) on day 50:**
**7.5 mcg (Vaxigrip):** * A(H1N1): 25
* A(H3N2): 27
* Influenza B (Yam): 4.06
**7.5 mcg:*** A(H1N1): 8.15
* A(H3N2): 8.7
* Influenza B (Yam): 2.39
* Influenza B (Vic): 2.16
**15 mcg:*** A(H1N1): 10
* A(H3N2): 9.91
* Influenza B (Yam): 2.07
* Influenza B (Vic): 1.94
| I | Good |
| Intradermal |
| **Oluwaseun Egunsola, John Taplin, Liza Mastikhina, Joyce Li, Diane Lorenzetti, Laura E. Dowsett, Tom Noseworthy, Fiona Clement.** *Intradermal versus intramuscular administration of influenza vaccination.* University of Calgary, Health Technology Assessment Unit. Produced for DSEN MAGIC Team. July 21, 2020. | Seasonal inactivated influenza vaccine | Rapid review and meta-analysis
Random effects model
Included: RCTs, non-RCTs, observational studies
Funding: Canadian Institute for Health Research (DSEN) | Number of participants (RCTs): 13,759
Number of participants (observational): 164,021
Age range: all ages
Sub-analysis: 60 years of age and older | Primary findings:
Meta-analysis included a total of 16 RCTs (no observational studies) on the immunogenicity of fractional doses of IM influenza vaccine (includes 3 mcg, 6 mcg, 7.5 mcg, and 9 mcg).
Refer to tables 1 and 2 within this statement for results on seroconversion and seroprotection in all ages and in adults 60 years of age and older respectively. | Meta-analysis | N/A |
| **Abbreviations:**
CI:
confidence interval
GMT:
geometric mean titre
IIV3:
trivalent inactivated influenza vaccine
IIV4:
quadrivalent inactivated influenza vaccine
mcg:
microgram
RCT:
randomized controlled trial
US:
United States
|
|
Table 10 Footnote a
B/Florida/4/2006, which is a B/Florida/4/2006-like strain, as recommended by WHO for influenza season of this study
[Table 10 Return to footnote a referrer](#t10fna-rf)
Table 10 Footnote b
B/Brisbane/3/2007, which is a B/Florida/4/2006-like strain, as recommended by WHO for influenza season of this study
[Table 10 Return to footnote b referrer](#t10fnb-rf)
Table 10 Footnote c
Calculated as post-vaccination GMT in 7.5 mcg Fluzone / 15 mcg Fluarix, adjusted for baseline titre – pooled variance)
[Table 10 Return to footnote c referrer](#t10fnc-rf)
Table 10 Footnote d
Calculated as seroconversion rate in 7.5 mcg Fluzone – 15 mcg Fluarix
[Table 10 Return to footnote d referrer](#t10fnd-rf)
|
Table 11. Summary of Evidence Related to the Safety of Fractional Influenza Vaccine for IM and ID
| Study Details | Summary |
| --- | --- |
| Study | Vaccine | Study Design | Participants | Summary of Key Findings | Level of Evidence | Quality |
| Intramuscular |
| --- |
| **Antony J, Rios P, Williams C, Ramkissoon N, Straus SE, Tricco AC.** *Safety and effectiveness of dose-sparing strategies for seasonal influenza vaccine: a rapid scoping review of fractional dosing of the intramuscular influenza vaccine.* medRxiv. 2020 Jan 1. | Standard dose inactivated seasonal influenza vaccines | Scoping review
Included: RCTs, non-RCTs, observational studies
Funding: Canadian Institute for Health Research (DSEN) | Age range: all ages | Primary findings:
13 RCTs were included in the scoping review, including 10 RCTs that had safety data relevant for this Statement (3 in adults, 9 in children).
All studies in children assessed the safety of 7.5 mcg of HA per strain fractional dose compared to standard dose (15 mcg of HA per strain). None of the studies identified in this review reported statistical differences in local or systemic AEs between study groups.
One study compared 3 fractional doses of Fluzone (3 mcg, 6 mcg, 9 mcg of HA per strain) to standard dose, and did not report any differences between the IM vaccination groups. A second in adults less than 65 years of age found no significant differences after adjusting for clinically significant pain levels (determined as ≥3 out of 5 on a visual analogue scale) between groups that had received a 7.5 mcg of HA per strain dose compared to standard dose.
A single study in older adults was identified, and found no difference in the occurrence or severity of AEs between groups that received a fractional dose of 9 mcg of HA per strain versus standard dose. No serious AEs that were considered related to the vaccine were found. | Review | N/A |
| Intradermal |
| **Oluwaseun Egunsola, John Taplin, Liza Mastikhina, Joyce Li, Diane Lorenzetti, Laura E. Dowsett, Tom Noseworthy, Fiona Clement.** *Intradermal versus intramuscular administration of influenza vaccination.* University of Calgary, Health Technology Assessment Unit. Produced for DSEN MAGIC Team. July 21, 2020. | Seasonal inactivated influenza vaccine | Rapid review and meta-analysis
Random effects model
Included: RCTs, non-RCTs, observational studies
Funding: Canadian Institute for Health Research (DSEN) | Number of participants (RCTs): 13,759
Number of participants (observational): 164,021
Age range: all ages
Sub-analysis: 60 years of age and older | Primary findings:
Meta-analysis included a total of 24 RCTs (no observational studies) on the safety of fractional doses of IM influenza vaccine (includes 3 mcg, 6 mcg, 7.5 mcg, and 9 mcg).
Refer to tables 3 and 4 within this statement for results on local and systemic AEs respectively. No sub-analysis by age is available for this outcome. | Meta-analysis | N/A |
| **Abbreviations:**
AE:
Adverse Event
DSEN:
Drug Safety Effectiveness Network
HA:
hemagglutinin
mcg:
microgram
N/A:
not applicable
RCT:
randomized controlled trial
|
List of Abbreviations
---------------------
AE
Adverse event
CI
Confidence interval
DSEN
Drug Safety Effectiveness Network
EEFA
Ethics, equity, feasibility, and acceptability
FDA
Food and Drug Administration
GMT
Geometric mean titre
HA
Hemagglutinin
HI
Hemagglutination inhibition
ID
Intradermal
IIV3
Trivalent inactivated influenza vaccine
IIV4
Quadrivalent inactivated influenza vaccine
ILI
Influenza-like illness
IM
Intramuscular
IWG
Influenza Working Group
MAGIC
Methods and Applications Group for Indirect Comparisons
mcg
Micrograms
MDV
Multi-dose vial
mL
Milliliter
N/A
Not applicable
NACI
National Advisory Committee on Immunization
PHAC
Public Health Agency of Canada
RCT
Randomized controlled trial
RR
Relative risk (also known as risk ratio)
US
United States
Acknowledgements
----------------
**This statement was prepared by:** K Young, P Doyon-Plourde, E Poirier, R Stirling, A Sinilaite, and R Harrison, on behalf of the NACI Influenza Working Group and was approved by NACI
**NACI gratefully acknowledges the contribution of:** A House, M Laplante, M Tunis, L Zhao, and the DSEN MAGIC team
### NACI Influenza Working Group
**Members:** R Harrison (Chair), N Dayneka, I Gemmill, K Klein, D Kumar, J Langley, J McElhaney, A McGeer, D Moore, S Smith, and B Warshawsky
**Liaison representatives:** L Grohskopf (Centers for Disease Control and Prevention [CDC], US)
**Ex-officio representatives:** L Whitmore (Centre for Immunization and Respiratory Infectious Diseases [CIRID], PHAC), A Gartley (First Nations and Inuit Health Branch [FNIHB], Indigenous Services Canada [ISC]), and J Xiong (Biologic and Radiopharmaceutical Drugs Directorate [BRDD], Health Canada [HC]).
### NACI
**Members:** C Quach (Chair), S Deeks (Vice-Chair), J Bettinger, N Dayneka, P De Wals, E Dubé, V Dubey, S Gantt, R Harrison, K Hildebrand, K Klein, J Papenburg, C Rotstein, B Sander, S Smith and S Wilson.
**Liaison representatives:** LM Bucci (Canadian Public Health Association), E Castillo (Society of Obstetricians and Gynaecologists of Canada), A Cohn (CDC, US), L Dupuis (Canadian Nurses Association), J Emili (College of Family Physicians of Canada), D Fell (Canadian Association for Immunization Research Evaluation), M Lavoie (Council of Chief Medical Officers of Health), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), and A Pham-Huy (Association of Medical Microbiology and Infectious Disease Canada).
**Ex-officio representatives:** D Danoff (Marketed Health Products Directorate, HC), E Henry (CIRID, PHAC), M Lacroix (Public Health Ethics Consultative Group, PHAC), J Pennock (CIRID, PHAC), R Pless (BRDD, HC), G Poliquin (National Microbiology Laboratory, PHAC), V Beswick-Escanlar (National Defense and the Canadian Armed Forces), and T Wong (FNIHB, ISC).
References
----------
Reference 1
Schanzer DL, McGeer A, Morris K. Statistical estimates of respiratory admissions attributable to seasonal and pandemic influenza for Canada. Influenza Other Respir Viruses. 2013;7(5):799-808.
[Return to reference 1](#ref1-rf)
Reference 2
Schanzer DL, Sevenhuysen C, Winchester B, Mersereau T. Estimating influenza deaths in Canada, 1992-2009. PLoS One. 2013;8(11):e80481.
[Return to reference 2](#ref2-rf)
Reference 3
Public Health Agency of Canada. Provincial and Territorial Immunization Information [Internet]. Ottawa, ON. Updated Date modified: 08 July 2020. Cited 17 Sept 2020. Available from: https://www.canada.ca/en/public-health/services/provincial-territorial-immunization-information.html
[Return to reference 3](#ref3-rf)
Reference 4
Public Health Agency of Canada. Supply and Distribution of Influenza Vaccine in Canada [Internet]. Ottawa, ON. Updated Date modified: 28 Apr 2017. Cited 17 Sept 2020. Available from: https://www.canada.ca/en/public-health/services/immunization/supply-distribution-influenza-vaccine-canada.html
[Return to reference 4](#ref4-rf)
Reference 5
World Health Organization. Influenza vaccine viruses and reagents [Internet]. Geneva, Switzerland. Cited 17 Sept 2020. Available from: https://www.who.int/influenza/vaccines/virus/en/
[Return to reference 5](#ref5-rf)
Reference 6
National Advisory Committee on Immunization Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2020–2021, Appendix A [Internet]. Ottawa: Public Health Agency of Canada; 2020. Available from: https://www.canada.ca/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2020-2021.html#appA
[Return to reference 6](#ref6-rf)
Reference 7
Antony J, Rios P, Williams C, Ramkissoon N, Straus SE, Tricco AC. Safety and effectiveness of dose-sparing strategies for seasonal influenza vaccine: a rapid scoping review of fractional dosing of the intramuscular influenza vaccine. medRxiv. 2020 Jan 1.
[Return to reference 7](#ref7-rf)
Reference 8
Oluwaseun Egunsola, John Taplin, Liza Mastikhina, Joyce Li, Diane Lorenzetti, Laura E. Dowsett, Tom Noseworthy, Fiona Clement. Intradermal versus intramuscular administration of influenza vaccination. University of Calgary, Health Technology Assessment Unit. Produced for DSEN MAGIC Team. July 21, 2020.
[Return to reference 8](#ref8-rf)
Reference 9
Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med 2001;20:21-35.
[Return to reference 9](#ref9-rf)
Reference 10
Ismail SJ, Hardy K, Tunis MC, Young K, Sicard N, Quach C. A framework for the systematic consideration of ethics, equity, feasibility, and acceptability in vaccine program recommendations. Vaccine. 2020 Jun 10.
[Return to reference 10](#ref10-rf)
Reference 11
Clinical Trial Results: A Phase IIIB, observer-blind, randomized, parallel groups, extension study to evaluate the immunogenicity and safety following a single intramuscular dose of FLUAD or Agrippal S1 influenza vaccines in healthy children previously vaccinated in the V70P5 study. [Internet]. 2016 [cited July 6, 2020]. Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-021644-18/results.
[Return to reference 11](#ref11-rf)
Reference 12
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savović J, Schulz KF, Weeks L, Sterne JA. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. Bmj. 2011 Oct 18;343:d5928.
[Return to reference 12](#ref12-rf)
Reference 13
Kramer JS, Durham C, Schroeder T, Garrelts JC. Effectiveness of half-dose versus full-dose influenza vaccine in health care workers. Am J Health Syst Pharm. 2006;63(21):2111-5.
[Return to reference 13](#ref13-rf)
Reference 14
Engler RJ, Nelson MR, Klote MM, VanRaden MJ, Huang CY, Cox NJ, et al. Half- vs full-dose trivalent inactivated influenza vaccine (2004-2005): age, dose, and sex effects on immune responses. Arch Intern Med. 2008;168(22):2405-14.
[Return to reference 14](#ref14-rf)
Reference 15
Chuaychoo B, Kositanont U, Rittayamai N, et al. The immunogenicity of the intradermal injection of seasonal trivalent influenza vaccine containing influenza A(H1N1)pdm09 in COPD patients soon after a pandemic. Hum Vaccin Immunother 2016;12(7):1728-37. doi: https://dx.doi.org/10.1080/21645515.2016.1149276
[Return to reference 15](#ref15-rf)
Reference 16
Nomcgarede N, Bisceglia H, Rozieres A, et al. Nine mmcg intradermal influenza vaccine and 15 mmcg intramuscular influenza vaccine induce similar cellular and humoral immune responses in adults. Hum Vaccin Immunother 2014;10(9):2713-20. doi: https://dx.doi.org/10.4161/hv.29695
[Return to reference 16](#ref16-rf)
Reference 17
US Food and Drug Administration. Guidance for industry: Clinical data needed to support the licensure of seasonal inactivated influenza vaccines. [Internet]. 2007. [cited 2019 July 15]. Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm091990.pdf
[Return to reference 17](#ref17-rf)
Reference 18
Belshe RB, Newman FK, Wilkins K, Graham IL, Babusis E, Ewell M, Frey SE. Comparative immunogenicity of trivalent influenza vaccine administered by intradermal or intramuscular route in healthy adults. Vaccine. 2007 Sep 17;25(37-38):6755-63.
[Return to reference 18](#ref18-rf)
Reference 19
Chi RC, Rock MT, Neuzil KM. Immunogenicity and safety of intradermal influenza vaccination in healthy older adults. Clinical infectious diseases. 2010 May 15;50(10):1331-8.
[Return to reference 19](#ref19-rf)
Reference 20
Skowronski DM, Hottes TS, Chong M, De Serres G, Scheifele DW, Ward BJ, Halperin SA, Janjua NZ, Chan T, Sabaiduc S, Petric M. Randomized controlled trial of dose response to influenza vaccine in children aged 6 to 23 months. Pediatrics. 2011 Amcg 1;128(2):e276-89.
[Return to reference 20](#ref20-rf)
Reference 21
Langley JM, Vanderkooi OG, Garfield HA, Hebert J, Chandrasekaran V, Jain VK, Fries L. Immunogenicity and safety of 2 dose levels of a thimerosal-free trivalent seasonal influenza vaccine in children aged 6–35 months: a randomized, controlled trial. Journal of the Pediatric Infectious Diseases Society. 2012 Mar 1;1(1):55-63.
[Return to reference 21](#ref21-rf)
Reference 22
Pavia-Ruz N, Angel Rodriguez Weber M, Lau YL, Nelson EA, Kerdpanich A, Huang LM, Silas P, Qaqundah P, Blatter M, Jeanfreau R, Lei P. A randomized controlled study to evaluate the immunogenicity of a trivalent inactivated seasonal influenza vaccine at two dosages in children 6 to 35 months of age. Human vaccines & immunotherapeutics. 2013 Sep 19;9(9):1978-88.
[Return to reference 22](#ref22-rf)
Reference 23
Halasa NB, Gerber MA, Berry AA, Anderson EL, Winokur P, Keyserling H, Eckard AR, Hill H, Wolff MC, McNeal MM, Edwards KM. Safety and immunogenicity of full-dose trivalent inactivated influenza vaccine (TIV) compared with half-dose TIV administered to children 6 through 35 months of age. Journal of the Pediatric Infectious Diseases Society. 2015 Sep 1;4(3):214-24.
[Return to reference 23](#ref23-rf)
Reference 24
Jain VK, Domachowske JB, Wang L, Ofori-Anyinam O, Rodríguez-Weber MA, Leonardi ML, Klein NP, Schlichter G, Jeanfreau R, Haney BL, Chu L. Time to change dosing of inactivated quadrivalent influenza vaccine in young children: evidence from a phase III, randomized, controlled trial. Journal of the Pediatric Infectious Diseases Society. 2017 Mar 1;6(1):9-19.
[Return to reference 24](#ref24-rf)
Reference 25
Robertson CA, Mercer M, Selmani A, Klein NP, Jeanfreau R, Greenberg DP. Safety and immunogenicity of a full-dose, split-virion, inactivated, quadrivalent influenza vaccine in healthy children 6-35 months of age: a randomized controlled clinical trial. The Pediatric infectious disease journal. 2019 Mar;38(3):323.
[Return to reference 25](#ref25-rf)
Reference 26
Della Cioppa G, Vesikari T, Sokal E, Lindert K, Nicolay U. Trivalent and quadrivalent MF59®-adjuvanted influenza vaccine in young children: a dose-and schedule-finding study. Vaccine. 2011 Nov 3;29(47):8696-704.
[Return to reference 26](#ref26-rf)
Reference 27
Arnou R, Eavis P, De Juanes Pardo JR, et al. Immunogenicity, large scale safety and lot consistency of an intradermal influenza vaccine in adults aged 18-60 years: Randomized, controlled, phase III trial. Hum 2010;6(4):346-54. doi: http://dx.doi.org/10.4161/hv.6.4.10961
[Return to reference 27](#ref27-rf)
Reference 28
Carter C, Houser KV, Yamshchikov GV, et al. Safety and immunogenicity of investigational seasonal influenza hemagglutinin DNA vaccine followed by trivalent inactivated vaccine administered intradermally or intramuscularly in healthy adults: An open-label randomized phase 1 clinical trial. PLoS ONE 2019;14(9) doi: http://dx.doi.org/10.1371/journal.pone.0222178
[Return to reference 28](#ref28-rf)
Reference 29
Chuaychoo B, Kositanont U, Niyomthong P, et al. Comparison of immunogenicity between intradermal and intramuscular injections of repeated annual identical influenza virus strains post-pandemic (2011-2012) in COPD patients. Hum Vaccin Immunother 2019:1-9. doi: https://dx.doi.org/10.1080/21645515.2019.1692559
[Return to reference 29](#ref29-rf)
Reference 30
Chuaychoo B, Kositanont U, Rittayamai N, et al. The immunogenicity of the intradermal injection of seasonal trivalent influenza vaccine containing influenza A(H1N1)pdm09 in COPD patients soon after a pandemic. Hum Vaccin Immunother 2016;12(7):1728-37. doi: https://dx.doi.org/10.1080/21645515.2016.1149276
[Return to reference 30](#ref30-rf)
Reference 31
Chuaychoo B, Wongsurakiat P, Nana A, et al. The immunogenicity of intradermal influenza vaccination in COPD patients. Vaccine 2010;28(24):4045-51. doi: https://dx.doi.org/10.1016/j.vaccine.2010.04.006
[Return to reference 31](#ref31-rf)
Reference 32
Della Cioppa G, Nicolay U, Lindert K, et al. A dose-ranging study in older adults to compare the safety and immunogenicity profiles of MF59 R-adjuvanted and non-adjuvanted seasonal influenza vaccines following intradermal and intramuscular administration. Hum Vaccin Immunother 2014;10(6):1701-10. doi: https://dx.doi.org/10.4161/hv.28618
[Return to reference 32](#ref32-rf)
Reference 33
Esposito S, Daleno C, Picciolli I, et al. Immunogenicity and safety of intradermal influenza vaccine in children. Vaccine 2011;29(44):7606-10. doi: https://dx.doi.org/10.1016/j.vaccine.2011.08.021
[Return to reference 33](#ref33-rf)
Reference 34
Frenck RW, Jr., Belshe R, Brady RC, et al. Comparison of the immunogenicity and safety of a split-virion, inactivated, trivalent influenza vaccine (Fluzone R) administered by intradermal and intramuscular route in healthy adults. Vaccine 2011;29(34):5666-74. doi: https://dx.doi.org/10.1016/j.vaccine.2011.06.010
[Return to reference 34](#ref34-rf)
Reference 35
Gorse GJ, Falsey AR, Johnson CM, et al. Safety and immunogenicity of revaccination with reduced dose intradermal and standard dose intramuscular influenza vaccines in adults 18-64 years of age. Vaccine 2013;31(50):6034-40. doi: https://dx.doi.org/10.1016/j.vaccine.2013.09.012
[Return to reference 35](#ref35-rf)
Reference 36
Han SH, Woo JH, Weber F, et al. Immunogenicity and safety of Intanza/IDflu intradermal influenza vaccine in South Korean adults : A multicenter, randomized trial. Human Vaccines and Immunotherapeutics 2013;9(9):1971-77. doi: http://dx.doi.org/10.4161/hv.25295
[Return to reference 36](#ref36-rf)
Reference 37
Hung IF, Levin Y, To KK, et al. Dose sparing intradermal trivalent influenza (2010/2011) vaccination overcomes reduced immunogenicity of the 2009 H1N1 strain. Vaccine 2012;30(45):6427-35. doi: https://dx.doi.org/10.1016/j.vaccine.2012.08.014
[Return to reference 37](#ref37-rf)
Reference 38
Song JY, Cheong HJ, Noh JY, et al. Long-term immunogenicity of the influenza vaccine at reduced intradermal and full intramuscular doses among healthy young adults. Clin 2013;2(2):115-9. doi: https://dx.doi.org/10.7774/cevr.2013.2.2.115
[Return to reference 38](#ref38-rf)
Reference 39
Levin Y, Kochba E, Kenney R. Clinical evaluation of a novel microneedle device for intradermal delivery of an influenza vaccine: are all delivery methods the same? Vaccine 2014;32(34):4249-52. doi: https://dx.doi.org/10.1016/j.vaccine.2014.03.024
[Return to reference 39](#ref39-rf)
Reference 40
Ansaldi F, Orsi A, de Florentiis D, et al. Head-to-head comparison of an intradermal and a virosome influenza vaccine in patients over the age of 60: evaluation of immunogenicity, cross-protection, safety and tolerability. Hum Vaccin Immunother 2013;9(3):591-8.
[Return to reference 40](#ref40-rf)
Reference 41
Boonnak K, Dhitavat J, Thantamnu N, et al. Immune responses to intradermal and intramuscular inactivated influenza vaccine among older age group. Vaccine 2017;35(52):7339-46. doi: https://dx.doi.org/10.1016/j.vaccine.2017.10.106
[Return to reference 41](#ref41-rf)
Reference 42
Chan TC, Hung IF, Chan KH, et al. Immunogenicity and safety of intradermal trivalent influenza vaccination in nursing home older adults: a randomized controlled trial. J Am Med Dir Assoc 2014;15(8):607.e5-12. doi: https://dx.doi.org/10.1016/j.jamda.2014.05.002
[Return to reference 42](#ref42-rf)
Reference 43
Garg S, Thongcharoen P, Praphasiri P, et al. Randomized Controlled Trial to Compare Immunogenicity of Standard-Dose Intramuscular Versus Intradermal Trivalent Inactivated Influenza Vaccine in HIV-Infected Men Who Have Sex With Men in Bangkok, Thailand. Clin Infect Dis 2016;62(3):383-91. doi: https://dx.doi.org/10.1093/cid/civ884
[Return to reference 43](#ref43-rf)
Reference 44
Hung IFN, Zhang AJ, To KKW, et al. Topical imiquimod before intradermal trivalent influenza vaccine for protection against heterologous non-vaccine and antigenically drifted viruses: A single-centre, double-blind, randomised, controlled phase 2b/3 trial. Lancet Infect Dis 2016;16(2):209-18. doi: http://dx.doi.org/10.1016/S1473-3099%2815%2900354-0
[Return to reference 44](#ref44-rf)
Reference 45
Hung IF, Zhang AJ, To KK, et al. Immunogenicity of intradermal trivalent influenza vaccine with topical imiquimod: a double blind randomized controlled trial. Clin Infect Dis 2014;59(9):1246-55. doi: https://dx.doi.org/10.1093/cid/ciu582
[Return to reference 45](#ref45-rf)
Reference 46
Patel SM, Atmar RL, El Sahly HM, et al. A phase I evaluation of inactivated influenza A/H5N1 vaccine administered by the intradermal or the intramuscular route. Vaccine 2010;28(17):3025-9. doi: https://dx.doi.org/10.1016/j.vaccine.2009.10.152
[Return to reference 46](#ref46-rf)
Reference 47
Seo YB, Choi WS, Lee J, et al. Comparison of the immunogenicity and safety of the conventional subunit, MF59-adjuvanted, and intradermal influenza vaccines in the elderly. Clin Vaccine Immunol 2014;21(7):989-96. doi: https://dx.doi.org/10.1128/CVI.00615-13
[Return to reference 47](#ref47-rf)
Reference 48
Tsang P, Gorse GJ, Strout CB, et al. Immunogenicity and safety of Fluzone( R) intradermal and high-dose influenza vaccines in older adults ≥65 years of age: a randomized, controlled, phase II trial. Vaccine 2014;32(21):2507-17. doi: https://dx.doi.org/10.1016/j.vaccine.2013.09.074
[Return to reference 48](#ref48-rf)
Reference 49
Van Damme P, Arnou R, Kafeja F, et al. Evaluation of non-inferiority of intradermal versus adjuvanted seasonal influenza vaccine using two serological techniques: a randomised comparative study. BMC Infect Dis 2010;10:134. doi: https://dx.doi.org/10.1186/1471-2334-10-134
[Return to reference 49](#ref49-rf)
Reference 50
Health Canada. MEDICAL INTERNATIONAL TECHNOLOGIES (MIT CANADA) INC. MED-JET NEEDLE FREE DRUG DELIVERY DEVICE. License number 70009. Available from: https://health-products.canada.ca/mdall-limh/information.do?companyId\_idCompanie=115973&lang=eng
[Return to reference 50](#ref50-rf)
Footnotes
---------
Footnote a
Although not explicitly stated in the research questions, immunogenicity evidence was also included in both reviews to supplement efficacy and effectiveness data.
[Return to footnote a referrer](#fna-rf)
Footnote b
A full list of people considered to be at high risk or capable of transmitting to those at high risk of influenza-related complications or hospitalizations is available in the Annual NACI Statement on Seasonal Influenza Vaccine (Refer to List 1 therein).
[Return to footnote b referrer](#fnb-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Share this page
---------------
* [Blogger](https://www.blogger.com/blog_this.pyra?t=&u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Frecommendations-fractional-influenza-vaccine-dosing.html%3Fhq_e%3Del%26hq_m%3D2176760%26hq_l%3D1%26hq_v%3D5d6bc46451&n=Recommendations%20on%20fractional%20influenza%20vaccine%20dosing%20-%20Canada.ca)
* [Diigo](https://www.diigo.com/post?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Frecommendations-fractional-influenza-vaccine-dosing.html%3Fhq_e%3Del%26hq_m%3D2176760%26hq_l%3D1%26hq_v%3D5d6bc46451&title=Recommendations%20on%20fractional%20influenza%20vaccine%20dosing%20-%20Canada.ca)
* [Email](mailto:?subject=Recommendations%20on%20fractional%20influenza%20vaccine%20dosing%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Frecommendations-fractional-influenza-vaccine-dosing.html%3Fhq_e%3Del%26hq_m%3D2176760%26hq_l%3D1%26hq_v%3D5d6bc46451%0A)
* [Facebook](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Frecommendations-fractional-influenza-vaccine-dosing.html%3Fhq_e%3Del%26hq_m%3D2176760%26hq_l%3D1%26hq_v%3D5d6bc46451&t=Recommendations%20on%20fractional%20influenza%20vaccine%20dosing%20-%20Canada.ca)
* [Gmail](https://mail.google.com/mail/?view=cm&fs=1&tf=1&to=&su=Recommendations%20on%20fractional%20influenza%20vaccine%20dosing%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Frecommendations-fractional-influenza-vaccine-dosing.html%3Fhq_e%3Del%26hq_m%3D2176760%26hq_l%3D1%26hq_v%3D5d6bc46451%0A)
* [LinkedIn®](https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Frecommendations-fractional-influenza-vaccine-dosing.html%3Fhq_e%3Del%26hq_m%3D2176760%26hq_l%3D1%26hq_v%3D5d6bc46451&title=Recommendations%20on%20fractional%20influenza%20vaccine%20dosing%20-%20Canada.ca&ro=false&summary=&source=)
* [MySpace](https://www.myspace.com/Modules/PostTo/Pages/?u=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Frecommendations-fractional-influenza-vaccine-dosing.html%3Fhq_e%3Del%26hq_m%3D2176760%26hq_l%3D1%26hq_v%3D5d6bc46451&t=Recommendations%20on%20fractional%20influenza%20vaccine%20dosing%20-%20Canada.ca)
* [Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Frecommendations-fractional-influenza-vaccine-dosing.html%3Fhq_e%3Del%26hq_m%3D2176760%26hq_l%3D1%26hq_v%3D5d6bc46451&media=&description=Recommendations%20on%20fractional%20influenza%20vaccine%20dosing%20-%20Canada.ca)
* [reddit](https://reddit.com/submit?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Frecommendations-fractional-influenza-vaccine-dosing.html%3Fhq_e%3Del%26hq_m%3D2176760%26hq_l%3D1%26hq_v%3D5d6bc46451&title=Recommendations%20on%20fractional%20influenza%20vaccine%20dosing%20-%20Canada.ca)
* [TinyURL](https://tinyurl.com/create.php?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Frecommendations-fractional-influenza-vaccine-dosing.html%3Fhq_e%3Del%26hq_m%3D2176760%26hq_l%3D1%26hq_v%3D5d6bc46451)
* [tumblr](https://www.tumblr.com/share/link?url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Frecommendations-fractional-influenza-vaccine-dosing.html%3Fhq_e%3Del%26hq_m%3D2176760%26hq_l%3D1%26hq_v%3D5d6bc46451&name=Recommendations%20on%20fractional%20influenza%20vaccine%20dosing%20-%20Canada.ca&description=)
* [Twitter](https://twitter.com/intent/tweet?text=Recommendations%20on%20fractional%20influenza%20vaccine%20dosing%20-%20Canada.ca&url=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Frecommendations-fractional-influenza-vaccine-dosing.html%3Fhq_e%3Del%26hq_m%3D2176760%26hq_l%3D1%26hq_v%3D5d6bc46451)
* [Whatsapp](https://api.whatsapp.com/send?text=Recommendations%20on%20fractional%20influenza%20vaccine%20dosing%20-%20Canada.ca%0A%0Ahttps%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Frecommendations-fractional-influenza-vaccine-dosing.html%3Fhq_e%3Del%26hq_m%3D2176760%26hq_l%3D1%26hq_v%3D5d6bc46451)
* [Yahoo! Mail](https://compose.mail.yahoo.com/?to=&subject=Recommendations%20on%20fractional%20influenza%20vaccine%20dosing%20-%20Canada.ca&body=https%3A%2F%2Fwww.canada.ca%2Fen%2Fpublic-health%2Fservices%2Fimmunization%2Fnational-advisory-committee-on-immunization-naci%2Frecommendations-fractional-influenza-vaccine-dosing.html%3Fhq_e%3Del%26hq_m%3D2176760%26hq_l%3D1%26hq_v%3D5d6bc46451%0A)
No endorsement of any products or services is expressed or implied.
[Share this page](#shr-pg0)
Date modified:
2021-01-28
| None | None |
88386f98aaf0d6d4ec62d749e0fb7df56015eea8 | cma | Mumps vaccine: Canadian Immunization Guide | Mumps vaccine: Canadian Immunization Guide
Key information (refer to text and tables for details)
# What
- Outbreaks of mumps continue to occur in Canada; the majority of outbreak-related mumps cases in Canada in recent years have occurred in young adults aged 15-39 years and the proportion of cases aged 20 years and older has increased.
- Complications such as orchitis and oophoritis are relatively frequent; permanent sequelae like deafness are rare.
- Mumps vaccine is available as measles-mumps-rubella (MMR) or measles-mumps-rubella-varicella (MMRV) vaccine.
- Mumps vaccine effectiveness has been estimated at 62% to 91% for 1 dose and 76% to 95% for 2 doses.
- Reactions to MMR vaccine are generally mild and transient and include pain and redness at the injection site, fever less than 39°C, and rash. Reactions to MMRV vaccine include: pain and redness at the injection site and fever less than 39°C in 10% or more of vaccine recipients; measles-like, rubella-like or varicella-like rash, swelling at the injection site and fever greater than 39°C in less than 10% of vaccine recipients.
- When the first dose is administered to children 12 to 23 months of age as MMRV vaccine, there is a higher risk of fever and febrile seizures in the 7 to 10 days after vaccination when compared to separate administration of MMR and univalent varicella vaccine at the same visit.
# Who
- Mumps-containing vaccine is recommended for routine immunization of children and for immunization of children and adolescents who missed mumps immunization on the routine schedule.
- Mumps-containing vaccine is recommended for susceptible adults born in or after 1970.
- Adults born before 1970 are generally presumed to have acquired natural immunity to mumps; however, susceptible health care workers, travellers to destinations outside of Canada, and military personnel should receive MMR vaccine, regardless of year of birth.
# How
- Routine childhood immunization: 2 doses of any mumps-containing (MMR or MMRV) vaccine. The first dose of mumps-containing vaccine should be administered at 12 to 15 months of age and the second dose at 18 months of age or any time thereafter, but no later than around school entry.
- Children and adolescents who are previously unimmunized: 2 doses of mumps-containing vaccine. MMRV vaccine may be used in healthy children aged 12 months to less than 13 years.
- Susceptible adults born in or after 1970: 1 dose of MMR vaccine. Those who are at the greatest risk of mumps exposure (travellers to destinations outside of Canada, health care workers, students in post-secondary educational settings, and military personnel) should receive 2 doses of MMR vaccine.
- Susceptible health care workers and military personnel born before 1970: 2 doses of MMR vaccine.
- Susceptible travellers to destinations outside of Canada born before 1970: 1 dose of MMR vaccine.
- Susceptible students in post-secondary educational settings born before 1970: 1 dose of MMR vaccine should be considered.
# Why
- Mumps occurs worldwide and outbreaks continue to occur.
- Complications of mumps disease are relatively frequent, although permanent sequelae are rare.
Epidemiology
# Disease description
## Infectious agent
Mumps virus is a member of the Paramyxoviridae family.
## Reservoir
Humans
## Transmission
Mumps virus is transmitted primarily by large droplet spread, as well as by direct contact with infected respiratory droplets or saliva. The incubation period is between 12 and 25 days (average 16 to 18 days). Mumps virus has been isolated from saliva 7 days before to 9 days after the onset of symptoms, with maximum infectiousness between 2 days before to 5 days after onset of symptoms. Infected individuals who are asymptomatic can still transmit mumps to others.
## Risk factors
In general, people who have not had mumps or who have not been vaccinated are at risk of being infected. In Canada, most adults born before 1970 are presumed to have acquired natural immunity to mumps; however, some individuals may not have had mumps disease and may be susceptible. A second dose of mumps vaccine was routinely given in combination with measles and rubella vaccine (MMR) for measles control, beginning in 1996 to 1997. People born between 1970 and 1990 represent a group vulnerable to mumps infection, as these individuals are less likely to have received two doses of mumps-containing vaccine or been alive when the wild virus circulated widely.
## Seasonal and temporal patterns
Historically, the incidence of mumps disease peaked in the spring and winter months in temperate zones. It is now restricted to sporadic cases and outbreaks.
## Spectrum of clinical illness
About 40% of people infected with mumps develop acute parotitis, which is unilateral in about 25% of cases. Non-specific or primarily respiratory symptoms occur in about one-half of infected individuals. Subclinical infection is common. Although complications are relatively frequent, permanent sequelae are rare. Before the widespread use of vaccine, mumps was a major cause of viral meningitis. Mumps meningoencephalitis can, rarely, result in permanent neurologic sequelae, including paralysis, seizures, cranial nerve palsies and hydrocephalus. Permanent deafness may occur, at an estimated rate of 0.5 to 5.0 per 100,000 mumps cases. Orchitis occurs in 20% to 30% of post-pubertal male cases and oophoritis in 5% of post-pubertal female cases. Involvement of the reproductive organs is commonly unilateral; therefore, sterility is rare. Mumps infection in pregnancy has not been associated with congenital malformations, but mumps infection during the first trimester of pregnancy may increase spontaneous abortion.
# Disease distribution
## Global
Mumps occurs worldwide, with cases reported throughout the year and epidemics occurring every 2 to 5 years. Mumps remains endemic in many countries.
## National
Since the authorization of mumps vaccine in Canada in 1969 and the subsequent introduction of a routine two-dose MMR vaccination schedule in 1996/97, the number of reported mumps cases nationally has decreased by more than 99%. The age distribution of mumps in Canada has also changed. The majority of cases during 2014 to 2018 have been observed in the 20 to less than 40 year old age group. During this time period, the highest incidence rates were reported in adults 20 to 24 years (3.8 cases per 100,000 population). Mumps continues to be a cyclical disease in Canada, with outbreaks occurring every few years and otherwise low incidence rates.
Preparations authorized for use in Canada
# Mumps-containing vaccines
- M-M-R®II (live attenuated combined measles, mumps and rubella vaccine), Merck Canada Inc. (MMR)
- PRIORIX® (live attenuated combined measles, mumps and rubella vaccine), GlaxoSmithKline Inc. (MMR)
- PRIORIX-TETRA® (live attenuated combined measles, mumps, rubella and varicella vaccine), GlaxoSmithKline Inc. (MMRV)
- ProQuad™ (live attenuated combined measles, mumps, rubella and varicella vaccine), Merck Canada Inc. (MMRV)
In Canada, mumps vaccine is available only in combination with measles and rubella vaccine (MMR) or measles, rubella and varicella vaccine (MMRV). All vaccines licensed for the prevention of mumps (MMR and MMRV) in Canada contain the Jeryl Lynn attenuated mumps virus strain that belongs to genotype A. In some other countries, measles vaccine alone is given and mumps vaccination is not offered.
For complete prescribing information, consult the product leaflet or information contained within the product monograph available through Health Canada's .
Immunogenicity, efficacy and effectiveness
# Immunogenicity
In clinical studies, a single injection of MMR vaccine induced measles antibodies in 95%, mumps antibodies in 96%, and rubella antibodies in 99% of previously seronegative children.
In 12 month old children, a single dose of MMRV vaccine results in similar seroconversion rates as those achieved after concomitant administration of MMR vaccine and univalent varicella vaccine. A study of children receiving 2 doses of MMRV vaccine during the second year of life noted seropositivity for measles, mumps, rubella and varicella of 99%, 97.4%, 100% and 99.4% respectively by the third year post-vaccination.
# Efficacy and effectiveness
Mumps vaccine effectiveness has been estimated at 62% to 91% for 1 dose and 76% to 95% for 2 doses. Somewhat lower vaccine effectiveness has been observed in outbreak settings, especially when exposures occurred in close-contact settings. Mumps outbreaks have been reported in populations with greater than 95% coverage with single dose mumps-containing vaccine, suggesting that 1 dose of mumps-containing vaccine is not sufficient to prevent mumps outbreaks. In some instances, outbreaks have arisen in settings with high 2 dose coverage. Waning immunity appears to contribute to the risk of mumps in vaccinated individuals.
There are no data regarding the long-term effectiveness of MMRV vaccine.
Recommendations for use
# Children
### Routine schedule
Healthy children (12 months to less than 13 years of age)
For routine immunization of children aged 12 months to less than 13 years, 2 doses of mumps-containing vaccine, using either MMR or MMRV vaccine, should be administered. The first dose of mumps-containing vaccine should be administered at 12 to 15 months of age and the second dose at 18 months of age or any time thereafter, but no later than around school entry.
### Catch-up and accelerated schedules
Children (12 months to less than 13 years of age)
Two doses of mumps-containing vaccine, using either MMR or MMRV vaccine, should be administered to children less than 13 years of age who were not immunized on the routine schedule. For preschool aged children, 2 doses of mumps-containing vaccine should be administered before school entry (4 to 6 years of age). Children who previously received a single dose of MMR vaccine should receive a second dose at least 4 weeks after the first dose. The minimum interval between doses of mumps-containing vaccine is 4 weeks.
Adolescents (13 to less than 18 years of age)
Mumps-susceptible adolescents (refer to for criteria for immunity) should receive 2 doses of MMR vaccine, given at least 4 weeks apart.
# Adults
## Healthy adults (18 years of age and older)
Mumps-susceptible adults (refer to for criteria for immunity) should receive 1 or 2 doses of MMR vaccine as appropriate for age and risk factors. If 2 doses are needed, MMR vaccine should be administered with a minimum interval of 4 weeks between doses.
## Routine schedule
Adults born before 1970 are generally presumed to have acquired natural immunity to mumps; however, some of these individuals may be susceptible.
Adults without contraindications, born in or after 1970 who do not meet the definition of mumps immunity (refer to for criteria for immunity) should be immunized with 1 dose of MMR vaccine.
# High risk individuals
## Health care workers
## Students in post-secondary educational settings
Students born in or after 1970, who do not meet the definition of mumps immunity (refer to for criteria for immunity) should receive 2 doses of MMR vaccine. In students born before 1970, administration of 1 dose of MMR vaccine should be considered.
## Military personnel
Military personnel, regardless of their year of birth, who do not meet the definition of mumps immunity (refer to for criteria for immunity) should receive 2 doses of MMR vaccine.
## Travellers
# Susceptibility and immunity
+ Children 12 months to less than 18 years of age: 2 doses
+ Adults born in or after 1970: 1 dose,OR
- History of laboratory confirmed infectionOR
- Laboratory evidence of immunityOR
- Born before 1970
- History of laboratory confirmed infectionOR
- Laboratory evidence of immunity
+ If born in or after 1970: 2 doses
+ If born before 1970: 1 doseOR
- History of laboratory confirmed infectionOR
- Laboratory evidence of immunity
+ If born in or after 1970: 2 doses
+ If born before 1970: consider 1 dose if no documentation of receipt of mumps-containing vaccineOR
- History of laboratory confirmed infectionOR
- Laboratory evidence of immunity
- History of laboratory confirmed infectionOR
- Laboratory evidence of immunity
Mumps-containing vaccine
Immunization against mumps and measles is provided in a combination vaccine (MMR or MMRV). For guidance on measles immunization for travellers refer to Measles Vaccine in Part 4 for additional information.
# Booster doses and re-immunization
Re-immunization with mumps-containing vaccine after age and risk appropriate vaccination is not necessary.
# Post-exposure immunization
Post-exposure vaccination with MMR vaccine should be given to susceptible individuals because exposure may not result in infection, and the MMR vaccine will induce protection against subsequent exposures. There is no evidence of increased risk of adverse reactions from immunization with MMR vaccine if an individual is already immune to one or more components of the vaccine or infected by mumps virus. There are no data on the use of MMRV vaccine in post-exposure situations.
## Outbreak control
The size, scope and duration of mumps outbreaks can be variable and their progression and peak is difficult to predict given delays in reporting, health seeking behaviours, and the relatively long incubation period for the mumps virus. Furthermore, circulation of mumps virus in highly immunized populations may be undetected and determining immunization status of cases and contacts may be challenging in many jurisdictions in Canada due to variability in the availability of comprehensive immunization registries.
The public health response to mumps includes management of cases and contacts and identifying social networks to define the at-risk population when contact follow-up is not feasible; and maintaining/enhancing surveillance for further cases and disease outcomes (e.g., hospitalizations, complications). Generally, a mumps outbreak is controlled by:
- Defining the at-risk population(s) and transmission setting(s)
- Preventing further transmission through isolation of cases and contact education/ awareness
- Vaccination of under-immunized groups
- Good risk communication
In an outbreak setting, implementation of an outbreak dose of MMR vaccine may be considered as a part of the broader outbreak management strategy. In addition, MMR vaccine (up to a third dose) may be considered for close contacts following exposure to a case of mumps in an outbreak setting. However, due to the potential logistical challenges that are associated with program implementation (such as those related to vaccine supply and acquisition costs, vaccine uptake and virus susceptibility determination and the absence of immunization records or information on the exposures), it is important to promptly assess the outbreak characteristics and define the populations that have or may be exposed to the disease.
Implementation of immunization programs early during a mumps outbreak (during the time of rapidly increasing case counts) is important, as early vaccination is likely to be the most effective intervention to control the outbreak. While immunization in later stages of the outbreak (e.g. following the peak of the outbreak) may benefit individuals, its effect at the population-level is uncertain.
Various options for the implementation of an outbreak dose of MMR vaccine are available, including immunization according to time since last dose, setting and level of exposure, and age and risk of complications. Understanding the nature of the outbreak (person-place-time) as well as access to the immunization history of the target group will be critically important for informing the choice and delivery of the outbreak dose strategy, including whether an outbreak dose should be the 1st, 2nd or 3rd dose of mumps-containing vaccine.
For a list of considerations for Mumps Outbreak Management options please see .
The vaccine recommendations and other information provided in the Canadian Immunization Guide are intended to complement and, where applicable, update the published in 2010, which provide more detailed and comprehensive information on the principles of mumps outbreak management beyond immunization. For further information regarding mumps outbreak control, refer to the Public Health Agency of Canada's (PHAC) .
Vaccination of specific populations
# Persons with inadequate immunization records
Children and adults who are susceptible to mumps, including those lacking adequate documentation of immunization, should be started on an immunization schedule appropriate for their age and risk factors. Mumps-containing vaccine may be given regardless of possible previous receipt of the vaccine because additional adverse events associated with repeated immunization have not been demonstrated. Refer to in Part 3 for additional information.
# Pregnancy and breastfeeding
Immunity to measles, mumps and rubella should be reviewed in women of reproductive age, and vaccination should be recommended to susceptible non-pregnant women. Women should delay pregnancy by at least 4 weeks following vaccination with MMR vaccine.
MMR and MMRV vaccines are contraindicated in pregnancy because of the theoretical risk to the fetus. However, there is no evidence demonstrating a teratogenic risk from the vaccines and termination of pregnancy should not be recommended following inadvertent immunization with either of these vaccines on the basis of fetal risks following maternal immunization. There was no evidence of Congenital Rubella Syndrome in any of the offspring of 226 women inadvertently vaccinated during pregnancy. In some situations, potential benefits of vaccination with MMR vaccine may outweigh risks, such as during measles or rubella outbreaks, in which case vaccination may be considered based on recommendations from public health officials. Pregnant women who are susceptible to mumps should have vaccination offered post-partum.
Susceptible women who are breastfeeding should be vaccinated with MMR vaccine.
# Patients in health care institutions
Susceptible residents of long-term care facilities should receive measles, mumps and rubella-containing vaccine as appropriate for their age and risk factors. Refer to in Part 3 for additional information.
# Persons with chronic diseases
## Neurologic disorders
People with conditions such as autism spectrum disorders or demyelinating disorders, including multiple sclerosis, should receive all routinely recommended immunizations, including mumps-containing vaccine.
# Immunocompromised persons
Individuals who are immunocompromised, either due to underlying conditions or immunosuppressive agents, are more susceptible to infections including mumps. They may be more likely to experience more severe disease and complications. The safety and effectiveness of the mumps vaccine is determined by the type of immunodeficiency and degree of immunosuppression.
In general, immunocompromised people should not receive live vaccines because of the risk of disease caused by the vaccine strains. When considering immunization of an immunocompromised person with a live vaccine, approval from the individual's attending physician should be obtained before vaccination. For complex cases, referral to a physician with expertise in immunization or immunodeficiency is advised.
# Household contacts
Susceptible household contacts of immunocompromised people should be considered a priority to receive a mumps-containing vaccine as appropriate for age and risk factors.
# Travellers
Protection against mumps is especially important for people planning travel to destinations outside of Canada. Travellers to destinations outside Canada, born in or after 1970, who do not meet the definition of mumps immunity (refer to for criteria for immunity) should receive 2 doses of mumps-containing vaccine.
Travellers to destinations outside of Canada, born before 1970, who do not meet the definition of mumps immunity (refer to for criteria for immunity) should receive 1 dose of MMR vaccine.
Mumps is endemic in many countries. Refer to for additional information.
# Persons new to Canada
Health care providers who see persons newly arrived in Canada should review the immunization status and update immunization for these individuals as necessary. In many countries outside of Canada, mumps and rubella vaccines are in limited use and measles vaccine alone is given. A Canadian study showed that more than one-third of new immigrants and refugees, particularly women, were susceptible to measles, mumps, or rubella. Refer to in Part 3 for additional information.
# Workers
It is recommended that all health care workers be immune to mumps. Health care workers, regardless of their year of birth, who do not meet the definition of mumps immunity (refer to for criteria for immunity) should be vaccinated accordingly so that they have received 2 doses of MMR vaccine. Refer to in Part 3 for additional information.
Serologic testing
Serologic testing is not recommended before or after receiving mumps-containing vaccine. For further information regarding mumps serology refer to the PHAC .
Administration practices
# Dose and route of administration
Dose
Each dose of mumps-containing vaccine is 0.5 mL.
Route of administration
MMR vaccine should be administered subcutaneously (SC). MMRV vaccine should be administered according to the product monograph.
## Interchangeability of vaccines
On the basis of expert opinion, the MMR vaccines authorized for use in Canada may be used interchangeably. Refer to for information about interchangeability of MMRV vaccines. Refer to in Part 1 for additional information.
## Concurrent administration with other vaccines
MMR vaccine may be administered concurrently with, or at any time before or after, non-live vaccines, live oral vaccines, or live intranasal influenza vaccine (LAIV).
MMR vaccine may be administered together with other routinely provided live parenteral vaccines. If not given concomitantly, a minimum interval of 4 weeks is recommended between administration of MMR and other live parenteral vaccines. This recommendation is to address the risk of interference from the vaccine given first on the vaccine given later.
Different injection sites and separate needles and syringes must be used for concomitant parenteral injections. Refer to in Part 1 for additional information about concomitant administration of mumps-containing vaccine with other vaccines.
Storage and handling requirements
Safety and adverse events
# Common and local adverse events
## Measles-Mumps-Rubella vaccine
Adverse events following immunization with MMR vaccine occur less frequently and are less severe than those associated with natural disease. Adverse reactions are less frequent after the second dose of vaccine and tend to occur only in individuals not protected by the first dose. Six to 23 days after immunization with MMR vaccine, approximately 5% of immunized children experience malaise and fever (with or without rash) lasting up to 3 days. Parotitis, rash, lymphadenophy, and joint symptoms also occur occasionally after immunization with MMR vaccine. There are no known serious vaccine safety concerns following the administration of a third dose of MMR vaccine.
## Measles-Mumps-Rubella-Varicella vaccine
Pain and redness at the injection site or fever less than 39°C occur in 10% or more of vaccine recipients. Rash, including measles-like, rubella-like and varicella-like rash, as well as swelling at the injection site and fever greater than 39°C occur in 1% to less than 10% of vaccine recipients. As varicella-like rashes that occur within the 2 weeks after immunization may be caused by wild-type virus (varicella virus circulating in the community), health care providers should obtain specimens from the vaccine recipient to determine whether the rash is due to natural varicella infection or to the vaccine-derived strain.
## Rubella-containing vaccines
Acute transient arthritis or arthralgia may occur 1 to 3 weeks after immunization with rubella-containing vaccine. It lasts for about 1 to 3 weeks, and rarely recurs. It is more common in post-pubertal females, among whom arthralgia develops in 25% and arthritis in 10% after immunization with rubella-containing vaccine. There is no evidence of increased risk of new onset chronic arthropathies.
# Less common and serious or severe adverse events
Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association. Anaphylaxis following vaccination with MMR or MMRV vaccine may occur but is very rare.
## Immune Thrombocytopenic Purpura
Rarely, Immune Thrombocytopenic Purpura (ITP) occurs within 6 weeks after immunization with MMR or MMRV vaccine. In most children, post-immunization thrombocytopenia resolves within 3 months without serious complications. In individuals who experienced ITP with the first dose of MMR or MMRV vaccine, serologic status may be evaluated to determine whether an additional dose of vaccine is needed for protection. The potential risk to benefit ratio should be carefully evaluated before considering vaccination in such cases.
## Encephalitis
Encephalitis has been reported in association with administration of measles vaccine in approximately 1 per million doses distributed in North America, which is much lower than the incidence observed with natural measles disease (1 per 1,000 cases).
## Febrile seizures
Between the ages of 12 to 23 months, when the first dose of vaccine for measles and varicella is administered as MMRV vaccine, there is a higher risk of fever and febrile seizures in the 7 to 10 days after vaccination when compared to separate administration of MMR and varicella vaccine at the same visit. For additional information about febrile seizures following the administration of MMRV vaccine, refer to in Part 4.
# Other safety issues
In the mid to late 1990s, researchers from the United Kingdom reported an association between MMR vaccine and inflammatory bowel disease, and MMR vaccine and autism. Rigorous scientific studies and reviews of the evidence have been done worldwide, and there is now considerable evidence to refute those claims. In 2010, the original study suggesting a link between the MMR vaccine and autism was found to be fraudulent and was retracted.
# Guidance on reporting Adverse Events Following Immunization (AEFI)
To ensure the ongoing safety of vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in some jurisdictions, reporting is mandatory under the law.
Vaccine providers are asked to report AEFIs through local public health officials and to check for specific AEFI reporting requirements in their province or territory. In general, any serious or unexpected adverse event felt to be temporally related to vaccination should be reported. The following AEFIs in particular, should be reported:
- Febrile seizures within 30 days after vaccination with MMR or MMRV vaccine.
- Varicella that is moderate (50 to 500 lesions) or severe (more than 500 vesicular lesions or associated complications or hospital admission) and occurs 7 to 21 days after vaccination with MMRV vaccine.
- Any serious or unexpected adverse event temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.
# Contraindications and precautions
MMR and MMRV vaccines are contraindicated in persons with a history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine, with the exception of egg allergy. Refer to in Part 1 for a list of vaccines authorized for use in Canada and their contents.
In situations of suspected hypersensitivity or non-anaphylactic allergy to vaccine components, investigation is indicated which may involve immunization in a controlled setting. Consultation with an allergist is advised.
Although the measles and mumps components of MMR and MMRV vaccines are produced in chick embryo cell culture and may contain traces of residual egg and chicken protein, the trace amount of egg or chicken protein in the vaccine appears to be insufficient to cause an allergic reaction in egg-allergic individuals. Skin testing is not recommended prior to vaccination as it does not predict reaction to the vaccine. MMR or MMRV vaccine can be administered in the routine manner to people who have a history of anaphylactic hypersensitivity to hens' eggs. Prior egg ingestion is not a prerequisite for immunization with egg protein-containing vaccine. For all vaccines, immunization should always be performed by personnel with the capability and facilities to manage adverse events post-vaccination. Refer to in Part 2 for additional information.
Children with a known or suspected family history of congenital or hereditary immunodeficiency that is a contraindication to vaccination with live vaccine should not receive live vaccines unless their immune competence has been established. Refer to in Part 3 for additional information.
MMR and MMRV vaccines are contraindicated during pregnancy because of the theoretical risk to the fetus. Refer to in Part 3 for additional information.
Measles-containing vaccines are contraindicated in individuals with active, untreated tuberculosis (TB) as a precautionary measure. Although TB may be exacerbated by natural measles infection, there is no evidence that measles-containing vaccines have such an effect. Nonetheless, anti-tuberculous therapy for active TB disease is advisable before administering measles-containing vaccines and it may be prudent to avoid live viral vaccines in those with active TB disease until treatment is underway. Consultation with an expert in infectious diseases is recommended.
A history of febrile seizures or a family history of seizures is not a contraindication for the use of MMRV vaccine.
Administration of MMR or MMRV vaccine should be postponed in persons with a severe acute illness. Persons with a minor acute illness, with or without fever, may be vaccinated.
It is recommended to avoid the use of salicylates (medications derived from salicylic acid, such as acetylsalicylic acid ) for 6 weeks after immunization with MMRV vaccine because of an association between wild-type varicella, salicylate therapy and Reye's syndrome.
Other considerations
# Drug interactions
## Systemic antiviral therapy
Systemic antiviral therapy (such as acyclovir, valacyclovir, famciclovir) should be avoided in the peri-immunization period, as it may affect the reproduction of the vaccine virus and consequently may reduce the efficacy of varicella-containing vaccine such as MMRV. On the basis of expert opinion, it is recommended that people taking long-term antiviral therapy should discontinue these drugs, if possible, from at least 24 hours before administration of MMRV vaccine and should not restart antiviral therapy until 14 days after vaccine administration.
## Tuberculin skin testing or Interferon Gamma Release Assay
The measles component in measles-containing vaccines can temporarily suppress tuberculin reactivity, resulting in false-negative results. If tuberculin skin testing or an interferon gamma relase assay (IGRA) test is required, it should be done on the same day as immunization or delayed for at least 4 weeks after measles vaccination. Vaccination with measles-containing vaccine may take place at any time after tuberculin skin testing has been performed and read.
## Human immunoglobulin or other blood products
Passive immunization with human Ig or receipt of most other blood products can interfere with the immune response to MMR and MMRV vaccines. Refer to in Part 1 for recommended intervals between the administration of Ig preparations or other blood products and MMR and MMRV vaccines.
Chapter revision process
This chapter has been updated in accordance with the National Advisory Committee on Immunization Statement (NACI): . The recommendations on mumps outbreak management provided in this chapter and the statement are based on the best current available scientific knowledge and are intended to complement and, where applicable, update the published in 2010. |
Mumps vaccine: Canadian Immunization Guide
===========================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-13-meningococcal-vaccine.html "Meningococcal vaccine: Canadian immunization guide")
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-15-pertussis-vaccine.html "Pertussis vaccine: Canadian immunization guide")
**Last partial content update** (see [Table of updates](/en/public-health/services/canadian-immunization-guide/updates.html)): August 2021
**August 2021:** This chapter has been updated to align with the National Advisory Committee on Immunization Statement (NACI): [Use of Measles-Mumps-Rubella (MMR) Vaccine for the Management of Mumps Outbreaks in Canada](/en/public-health/services/publications/vaccines-immunization/use-measles-mumps-rubella-vaccine-management-outbreaks-canada.html).
Updates include:
* The section on "Epidemiology" provides additional information on transmission, risk factors, and national incidence rates of mumps cases.
* The section on "Outbreak control" was revised to provide additional information on mumps outbreak management. In an outbreak setting, implementation of an outbreak dose of MMR vaccine may be considered as a part of the broader outbreak management strategy.
* The section on "Guidance on reporting Adverse Events Following Immunization (AEFI)" was updated to expand on AEFI reporting requirements.
* New section for the chapter revision process added.
**Last complete chapter revision:** April 2015
On this page
------------
* [Key information](#p4c13a1)
* [Epidemiology](#p4c13a2)
* [Preparations authorized for use in Canada](#p4c13a3)
* [Immunogenicity, efficacy and effectiveness](#p4c13a4)
* [Recommendations for use](#p4c13a5)
+ [Table 1: Criteria for mumps immunity](#p4c13t1)
* [Vaccination of specific populations](#p4c13a6)
* [Serologic testing](#p4c13a7)
* [Administration practices](#p4c13a8)
* [Storage and handling requirements](#p4c13a9)
* [Safety and adverse events](#p4c13a10)
* [Other considerations](#p4c13a11)
+ [Drug interactions](#p4c13a11.1)
* [Chapter revision process](#p4c13a12)
* [Selected references](#p4c13a13)
Key information (refer to text and tables for details)
------------------------------------------------------
### What
* Outbreaks of mumps continue to occur in Canada; the majority of outbreak-related mumps cases in Canada in recent years have occurred in young adults aged 15-39 years and the proportion of cases aged 20 years and older has increased.
* Complications such as orchitis and oophoritis are relatively frequent; permanent sequelae like deafness are rare.
* Mumps vaccine is available as measles-mumps-rubella (MMR) or measles-mumps-rubella-varicella (MMRV) vaccine.
* Mumps vaccine effectiveness has been estimated at 62% to 91% for 1 dose and 76% to 95% for 2 doses.
* Reactions to MMR vaccine are generally mild and transient and include pain and redness at the injection site, fever less than 39°C, and rash. Reactions to MMRV vaccine include: pain and redness at the injection site and fever less than 39°C in 10% or more of vaccine recipients; measles-like, rubella-like or varicella-like rash, swelling at the injection site and fever greater than 39°C in less than 10% of vaccine recipients.
* When the first dose is administered to children 12 to 23 months of age as MMRV vaccine, there is a higher risk of fever and febrile seizures in the 7 to 10 days after vaccination when compared to separate administration of MMR and univalent varicella vaccine at the same visit.
### Who
* Mumps-containing vaccine is recommended for routine immunization of children and for immunization of children and adolescents who missed mumps immunization on the routine schedule.
* Mumps-containing vaccine is recommended for susceptible adults born in or after 1970.
* Adults born before 1970 are generally presumed to have acquired natural immunity to mumps; however, susceptible health care workers, travellers to destinations outside of Canada, and military personnel should receive MMR vaccine, regardless of year of birth.
### How
* **Routine childhood immunization:** 2 doses of any mumps-containing (MMR or MMRV) vaccine. The first dose of mumps-containing vaccine should be administered at 12 to 15 months of age and the second dose at 18 months of age or any time thereafter, but no later than around school entry.
* **Children and adolescents who are previously unimmunized:** 2 doses of mumps-containing vaccine. MMRV vaccine may be used in healthy children aged 12 months to less than 13 years.
* **Susceptible adults born in or after 1970**: 1 dose of MMR vaccine. Those who are at the greatest risk of mumps exposure (travellers to destinations outside of Canada, health care workers, students in post-secondary educational settings, and military personnel) should receive 2 doses of MMR vaccine.
* **Susceptible health care workers and military personnel born before 1970**: 2 doses of MMR vaccine.
* **Susceptible travellers to destinations outside of Canada born before 1970**: 1 dose of MMR vaccine.
* **Susceptible students in post-secondary educational settings born before 1970:** 1 dose of MMR vaccine should be considered.
### Why
* Mumps occurs worldwide and outbreaks continue to occur.
* Complications of mumps disease are relatively frequent, although permanent sequelae are rare.
Epidemiology
------------
### Disease description
#### Infectious agent
Mumps virus is a member of the Paramyxoviridae family.
#### Reservoir
Humans
#### Transmission
Mumps virus is transmitted primarily by large droplet spread, as well as by direct contact with infected respiratory droplets or saliva. The incubation period is between 12 and 25 days (average 16 to 18 days). Mumps virus has been isolated from saliva 7 days before to 9 days after the onset of symptoms, with maximum infectiousness between 2 days before to 5 days after onset of symptoms. Infected individuals who are asymptomatic can still transmit mumps to others.
#### Risk factors
In general, people who have not had mumps or who have not been vaccinated are at risk of being infected. In Canada, most adults born before 1970 are presumed to have acquired natural immunity to mumps; however, some individuals may not have had mumps disease and may be susceptible. A second dose of mumps vaccine was routinely given in combination with measles and rubella vaccine (MMR) for measles control, beginning in 1996 to 1997. People born between 1970 and 1990 represent a group vulnerable to mumps infection, as these individuals are less likely to have received two doses of mumps-containing vaccine or been alive when the wild virus circulated widely.
#### Seasonal and temporal patterns
Historically, the incidence of mumps disease peaked in the spring and winter months in temperate zones. It is now restricted to sporadic cases and outbreaks.
#### Spectrum of clinical illness
About 40% of people infected with mumps develop acute parotitis, which is unilateral in about 25% of cases. Non-specific or primarily respiratory symptoms occur in about one-half of infected individuals. Subclinical infection is common. Although complications are relatively frequent, permanent sequelae are rare. Before the widespread use of vaccine, mumps was a major cause of viral meningitis. Mumps meningoencephalitis can, rarely, result in permanent neurologic sequelae, including paralysis, seizures, cranial nerve palsies and hydrocephalus. Permanent deafness may occur, at an estimated rate of 0.5 to 5.0 per 100,000 mumps cases. Orchitis occurs in 20% to 30% of post-pubertal male cases and oophoritis in 5% of post-pubertal female cases. Involvement of the reproductive organs is commonly unilateral; therefore, sterility is rare. Mumps infection in pregnancy has not been associated with congenital malformations, but mumps infection during the first trimester of pregnancy may increase spontaneous abortion.
### Disease distribution
#### Global
Mumps occurs worldwide, with cases reported throughout the year and epidemics occurring every 2 to 5 years. Mumps remains endemic in many countries.
#### National
Since the authorization of mumps vaccine in Canada in 1969 and the subsequent introduction of a routine two-dose MMR vaccination schedule in 1996/97, the number of reported mumps cases nationally has decreased by more than 99%. The age distribution of mumps in Canada has also changed. The majority of cases during 2014 to 2018 have been observed in the 20 to less than 40 year old age group. During this time period, the highest incidence rates were reported in adults 20 to 24 years (3.8 cases per 100,000 population). Mumps continues to be a cyclical disease in Canada, with outbreaks occurring every few years and otherwise low incidence rates.
Preparations authorized for use in Canada
-----------------------------------------
### Mumps-containing vaccines
* **M-M-R®II** (live attenuated combined measles, mumps and rubella vaccine), Merck Canada Inc. (MMR)
* **PRIORIX®** (live attenuated combined measles, mumps and rubella vaccine), GlaxoSmithKline Inc. (MMR)
* **PRIORIX-TETRA®** (live attenuated combined measles, mumps, rubella and varicella vaccine), GlaxoSmithKline Inc. (MMRV)
* **ProQuad**™ (live attenuated combined measles, mumps, rubella and varicella vaccine), Merck Canada Inc. (MMRV)
In Canada, mumps vaccine is available only in combination with measles and rubella vaccine (MMR) or measles, rubella and varicella vaccine (MMRV). All vaccines licensed for the prevention of mumps (MMR and MMRV) in Canada contain the Jeryl Lynn attenuated mumps virus strain that belongs to genotype A. In some other countries, measles vaccine alone is given and mumps vaccination is not offered.
For complete prescribing information, consult the product leaflet or information contained within the product monograph available through Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
Refer to [Contents of Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for a list of vaccines available for use in Canada and their contents.
Immunogenicity, efficacy and effectiveness
------------------------------------------
### Immunogenicity
In clinical studies, a single injection of MMR vaccine induced measles antibodies in 95%, mumps antibodies in 96%, and rubella antibodies in 99% of previously seronegative children.
In 12 month old children, a single dose of MMRV vaccine results in similar seroconversion rates as those achieved after concomitant administration of MMR vaccine and univalent varicella vaccine. A study of children receiving 2 doses of MMRV vaccine during the second year of life noted seropositivity for measles, mumps, rubella and varicella of 99%, 97.4%, 100% and 99.4% respectively by the third year post-vaccination.
### Efficacy and effectiveness
Mumps vaccine effectiveness has been estimated at 62% to 91% for 1 dose and 76% to 95% for 2 doses. Somewhat lower vaccine effectiveness has been observed in outbreak settings, especially when exposures occurred in close-contact settings. Mumps outbreaks have been reported in populations with greater than 95% coverage with single dose mumps-containing vaccine, suggesting that 1 dose of mumps-containing vaccine is not sufficient to prevent mumps outbreaks. In some instances, outbreaks have arisen in settings with high 2 dose coverage. Waning immunity appears to contribute to the risk of mumps in vaccinated individuals.
There are no data regarding the long-term effectiveness of MMRV vaccine.
Recommendations for use
-----------------------
### Children
##### Routine schedule
Healthy children (12 months to less than 13 years of age)
For routine immunization of children aged 12 months to less than 13 years, 2 doses of mumps-containing vaccine, using either MMR or MMRV vaccine, should be administered. The first dose of mumps-containing vaccine should be administered at 12 to 15 months of age and the second dose at 18 months of age or any time thereafter, but no later than around school entry.
##### Catch-up and accelerated schedules
Children (12 months to less than 13 years of age)
Two doses of mumps-containing vaccine, using either MMR or MMRV vaccine, should be administered to children less than 13 years of age who were not immunized on the routine schedule. For preschool aged children, 2 doses of mumps-containing vaccine should be administered before school entry (4 to 6 years of age). Children who previously received a single dose of MMR vaccine should receive a second dose at least 4 weeks after the first dose. The minimum interval between doses of mumps-containing vaccine is 4 weeks.
Adolescents (13 to less than 18 years of age)
Mumps-susceptible adolescents (refer to [Table 1](#p4c13t1) for criteria for immunity) should receive 2 doses of MMR vaccine, given at least 4 weeks apart.
Refer to [Timing of Vaccine Administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) in Part 1 for additional information about [delayed immunization schedules](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html#p1c9a2) and [accelerated immunization schedules](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html#p1c9a3).
### Adults
#### Healthy adults (18 years of age and older)
Mumps-susceptible adults (refer to [Table 1](#p4c13t1) for criteria for immunity) should receive 1 or 2 doses of MMR vaccine as appropriate for age and risk factors. If 2 doses are needed, MMR vaccine should be administered with a minimum interval of 4 weeks between doses.
#### Routine schedule
Adults **born before 1970** are generally presumed to have acquired natural immunity to mumps; however, some of these individuals may be susceptible.
Adults without contraindications, **born in or after 1970** who do not meet the definition of mumps immunity (refer to [Table 1](#p4c13t1) for criteria for immunity) should be immunized with 1 dose of MMR vaccine.
### High risk individuals
#### Health care workers
Refer to [Workers](#p4c13a6h) section.
#### Students in post-secondary educational settings
Students **born in or after 1970**, who do not meet the definition of mumps immunity (refer to [Table 1](#p4c13t1) for criteria for immunity) should receive 2 doses of MMR vaccine. In students **born before 1970**, administration of 1 dose of MMR vaccine should be considered.
#### Military personnel
Military personnel, regardless of their year of birth, who do not meet the definition of mumps immunity (refer to [Table 1](#p4c13t1) for criteria for immunity) should receive 2 doses of MMR vaccine.
#### Travellers
Refer to [Travellers](#p4c13a6f) section.
Refer to [Immunization of Adults](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-2-immunization-of-adults.html) in Part 3 for additional information about routinely recommended immunization for adults as well as vaccines recommended for adults in specific risk situations.
### Susceptibility and immunity
[Table 1](#p4c13t1) provides a summary of criteria for mumps immunity.
Table 1: Criteria for mumps immunity
| Routine immunization | Health care workers | Travellers to destinations outside Canada[Table 1 note 3](#p4c13t1fn3) | Students in post-secondary educational settings | Military personnel |
| --- | --- | --- | --- | --- |
| * Documentation of vaccination:
+ Children 12 months to less than 18 years of age: 2 doses[Table 1 note 1](#p4c13t1fn1)
+ Adults born in or after 1970: 1 dose[Table 1 note 1](#p4c13t1fn1),[Table 1 note 2](#p4c13t1fn2)**OR**
* History of laboratory confirmed infection**OR**
* Laboratory evidence of immunity**OR**
* Born before 1970
| * Documentation of vaccination with 2 doses[Table 1 note 1](#p4c13t1fn1) (regardless of year of birth)**OR**
* History of laboratory confirmed infection**OR**
* Laboratory evidence of immunity
| * Documentation of vaccination:
+ If born in or after 1970: 2 doses[Table 1 note 1](#p4c13t1fn1)
+ If born before 1970: 1 dose[Table 1 note 1](#p4c13t1fn1)**OR**
* History of laboratory confirmed infection**OR**
* Laboratory evidence of immunity
| * Documentation of vaccination:
+ If born in or after 1970: 2 doses[Table 1 note 1](#p4c13t1fn1)
+ If born before 1970: consider 1 dose[Table 1 note 1](#p4c13t1fn1) if no documentation of receipt of mumps-containing vaccine**OR**
* History of laboratory confirmed infection**OR**
* Laboratory evidence of immunity
| * Documentation of vaccination with 2 doses[Table 1 note 1](#p4c13t1fn1)(regardless of year of birth)**OR**
* History of laboratory confirmed infection**OR**
* Laboratory evidence of immunity
|
|
Table 1 notes
Table 1 note 1
Mumps-containing vaccine
[Return to table 1 note 1 referrer](#p4c13t1fn1-rf)
Table 1 note 2
Refer to additional recommendations for [health care workers](#p4c13a6h), [travellers to destinations outside of Canada](#p4c13a6f), [students in post-secondary educational settings](#p4c13a5b1) and [military personnel](#p4c13a5b2).
[Return to table 1 note 2 referrer](#p4c13t1fn2-rf)
Table 1 note 3
Immunization against mumps and measles is provided in a combination vaccine (MMR or MMRV). For guidance on measles immunization for travellers refer to Measles Vaccine in Part 4 for additional information.
[Return to table 1 note 3 referrer](#p4c13t1fn3-rf)
|
### Booster doses and re-immunization
Re-immunization with mumps-containing vaccine after age and risk appropriate vaccination is not necessary.
### Post-exposure immunization
Post-exposure vaccination with MMR vaccine should be given to susceptible individuals because exposure may not result in infection, and the MMR vaccine will induce protection against subsequent exposures. There is no evidence of increased risk of adverse reactions from immunization with MMR vaccine if an individual is already immune to one or more components of the vaccine or infected by mumps virus. There are no data on the use of MMRV vaccine in post-exposure situations.
#### Outbreak control
The size, scope and duration of mumps outbreaks can be variable and their progression and peak is difficult to predict given delays in reporting, health seeking behaviours, and the relatively long incubation period for the mumps virus. Furthermore, circulation of mumps virus in highly immunized populations may be undetected and determining immunization status of cases and contacts may be challenging in many jurisdictions in Canada due to variability in the availability of comprehensive immunization registries.
The public health response to mumps includes management of cases and contacts and identifying social networks to define the at-risk population when contact follow-up is not feasible; and maintaining/enhancing surveillance for further cases and disease outcomes (e.g., hospitalizations, complications). Generally, a mumps outbreak is controlled by:
* Defining the at-risk population(s) and transmission setting(s)
* Preventing further transmission through isolation of cases and contact education/ awareness
* Vaccination of under-immunized groups
* Good risk communication
In an outbreak setting, implementation of an outbreak dose of MMR vaccine may be considered as a part of the broader outbreak management strategy. In addition, MMR vaccine (up to a third dose) may be considered for close contacts following exposure to a case of mumps in an outbreak setting. However, due to the potential logistical challenges that are associated with program implementation (such as those related to vaccine supply and acquisition costs, vaccine uptake and virus susceptibility determination and the absence of immunization records or information on the exposures), it is important to promptly assess the outbreak characteristics and define the populations that have or may be exposed to the disease.
Implementation of immunization programs early during a mumps outbreak (during the time of rapidly increasing case counts) is important, as early vaccination is likely to be the most effective intervention to control the outbreak. While immunization in later stages of the outbreak (e.g. following the peak of the outbreak) may benefit individuals, its effect at the population-level is uncertain.
Various options for the implementation of an outbreak dose of MMR vaccine are available, including immunization according to time since last dose, setting and level of exposure, and age and risk of complications. Understanding the nature of the outbreak (person-place-time) as well as access to the immunization history of the target group will be critically important for informing the choice and delivery of the outbreak dose strategy, including whether an outbreak dose should be the 1st, 2nd or 3rd dose of mumps-containing vaccine.
For a list of considerations for Mumps Outbreak Management options please see [NACI statement on the Use of Measles-Mumps-Rubella (MMR) Vaccine for the Management of Mumps Outbreaks in Canada](/en/public-health/services/publications/vaccines-immunization/use-measles-mumps-rubella-vaccine-management-outbreaks-canada.html).
The vaccine recommendations and other information provided in the Canadian Immunization Guide are intended to complement and, where applicable, update the [Guidelines for the Prevention and Control of Mumps Outbreaks in Canada](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2010-36/guidelines-prevention-control-mumps-outbreaks-canada.html) published in 2010, which provide more detailed and comprehensive information on the principles of mumps outbreak management beyond immunization. For further information regarding mumps outbreak control, refer to the Public Health Agency of Canada's (PHAC) [Supplement: Guidelines for the Prevention and Control of Mumps Outbreaks in Canada](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2010-36/guidelines-prevention-control-mumps-outbreaks-canada.html).
Vaccination of specific populations
-----------------------------------
### Persons with inadequate immunization records
Children and adults who are susceptible to mumps, including those lacking adequate documentation of immunization, should be started on an immunization schedule appropriate for their age and risk factors. Mumps-containing vaccine may be given regardless of possible previous receipt of the vaccine because additional adverse events associated with repeated immunization have not been demonstrated. Refer to [Immunization of Persons with Inadequate Immunization Records](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-3-immunization-persons-inadequate-immunization-records.html) in Part 3 for additional information.
### Pregnancy and breastfeeding
Immunity to measles, mumps and rubella should be reviewed in women of reproductive age, and vaccination should be recommended to susceptible non-pregnant women. Women should delay pregnancy by at least 4 weeks following vaccination with MMR vaccine.
MMR and MMRV vaccines are contraindicated in pregnancy because of the theoretical risk to the fetus. However, there is no evidence demonstrating a teratogenic risk from the vaccines and termination of pregnancy should not be recommended following inadvertent immunization with either of these vaccines on the basis of fetal risks following maternal immunization. There was no evidence of Congenital Rubella Syndrome in any of the offspring of 226 women inadvertently vaccinated during pregnancy. In some situations, potential benefits of vaccination with MMR vaccine may outweigh risks, such as during measles or rubella outbreaks, in which case vaccination may be considered based on recommendations from public health officials. Pregnant women who are susceptible to mumps should have vaccination offered post-partum.
Susceptible women who are breastfeeding should be vaccinated with MMR vaccine.
Refer to [Blood Products, Human Immunoglobulin and Timing of Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) in Part 1 for information about mumps vaccination of post-partum women who have received Rh immune globulin (RhIg). Refer to [Immunization in Pregnancy and Breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3 for additional information.
### Patients in health care institutions
Susceptible residents of long-term care facilities should receive measles, mumps and rubella-containing vaccine as appropriate for their age and risk factors. Refer to [Immunization of Patients in Health Care Institutions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-6-immunization-patients-health-care-institutions.html) in Part 3 for additional information.
### Persons with chronic diseases
Refer to [Measles Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html) for additional information. Refer to [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional general information about vaccination of people with chronic diseases.
#### Neurologic disorders
People with conditions such as autism spectrum disorders or demyelinating disorders, including multiple sclerosis, should receive all routinely recommended immunizations, including mumps-containing vaccine.
### Immunocompromised persons
Individuals who are immunocompromised, either due to underlying conditions or immunosuppressive agents, are more susceptible to infections including mumps. They may be more likely to experience more severe disease and complications. The safety and effectiveness of the mumps vaccine is determined by the type of immunodeficiency and degree of immunosuppression.
In general, immunocompromised people should not receive live vaccines because of the risk of disease caused by the vaccine strains. When considering immunization of an immunocompromised person with a live vaccine, **approval from the individual's attending physician should be obtained before vaccination**. For complex cases, referral to a physician with expertise in immunization or immunodeficiency is advised.
Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional information.
### Household contacts
Susceptible household contacts of immunocompromised people should be considered a priority to receive a mumps-containing vaccine as appropriate for age and risk factors.
Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 and [Contraindications and precautions](#p4c13a10e) for additional information.
### Travellers
Protection against mumps is especially important for people planning travel to destinations outside of Canada. Travellers to destinations outside Canada, **born in or after 1970**, who do not meet the definition of mumps immunity (refer to [Table 1](#p4c13t1) for criteria for immunity) should receive 2 doses of mumps-containing vaccine.
Travellers to destinations outside of Canada, **born before 1970**, who do not meet the definition of mumps immunity (refer to [Table 1](#p4c13t1) for criteria for immunity) should receive 1 dose of MMR vaccine.
Mumps is endemic in many countries. Refer to [Mumps reported cases by country](https://apps.who.int/gho/data/view.main.1540_53) for additional information.
Refer to [Immunization of Travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) in Part 3 for additional information.
### Persons new to Canada
Health care providers who see persons newly arrived in Canada should review the immunization status and update immunization for these individuals as necessary. In many countries outside of Canada, mumps and rubella vaccines are in limited use and measles vaccine alone is given. A Canadian study showed that more than one-third of new immigrants and refugees, particularly women, were susceptible to measles, mumps, or rubella. Refer to [Immunization of Persons New to Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-10-immunization-persons-new-canada.html) in Part 3 for additional information.
### Workers
It is recommended that all health care workers be immune to mumps. Health care workers, regardless of their year of birth, who do not meet the definition of mumps immunity (refer to [Table 1](#p4c13t1) for criteria for immunity) should be vaccinated accordingly so that they have received 2 doses of MMR vaccine. Refer to [Immunization of Workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html) in Part 3 for additional information.
Serologic testing
-----------------
Serologic testing is not recommended before or after receiving mumps-containing vaccine. For further information regarding mumps serology refer to the PHAC [Supplement: Guidelines for the prevention and control of mumps outbreaks in Canada](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2010-36/guidelines-prevention-control-mumps-outbreaks-canada.html).
Administration practices
------------------------
### Dose and route of administration
Dose
Each dose of mumps-containing vaccine is 0.5 mL.
Route of administration
MMR vaccine should be administered subcutaneously (SC). MMRV vaccine should be administered according to the product monograph.
Refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for additional information about pre-vaccination and post-vaccination counseling, vaccine preparation and administration technique, and infection prevention and control.
#### Interchangeability of vaccines
On the basis of expert opinion, the MMR vaccines authorized for use in Canada may be used interchangeably. Refer to [Varicella (chickenpox) Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-24-varicella-chickenpox-vaccine.html) for information about interchangeability of MMRV vaccines. Refer to [Principles of Vaccine Interchangeability](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-7-principles-vaccine-interchangeability.html) in Part 1 for additional information.
#### Concurrent administration with other vaccines
MMR vaccine may be administered concurrently with, or at any time before or after, non-live vaccines, live oral vaccines, or live intranasal influenza vaccine (LAIV).
MMR vaccine may be administered together with other routinely provided live parenteral vaccines. If not given concomitantly, a minimum interval of 4 weeks is recommended between administration of MMR and other live parenteral vaccines. This recommendation is to address the risk of interference from the vaccine given first on the vaccine given later.
Different injection sites and separate needles and syringes must be used for concomitant parenteral injections. Refer to [Timing of Vaccine Administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) in Part 1 for additional information about concomitant administration of mumps-containing vaccine with other vaccines.
Storage and handling requirements
---------------------------------
Refer to [Storage and Handling of Immunizing Agents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-9-storage-handling-immunizing-agents.html) in Part 1 for storage and handling recommendations for mumps-containing vaccines.
Safety and adverse events
-------------------------
### Common and local adverse events
#### Measles-Mumps-Rubella vaccine
Adverse events following immunization with MMR vaccine occur less frequently and are less severe than those associated with natural disease. Adverse reactions are less frequent after the second dose of vaccine and tend to occur only in individuals not protected by the first dose. Six to 23 days after immunization with MMR vaccine, approximately 5% of immunized children experience malaise and fever (with or without rash) lasting up to 3 days. Parotitis, rash, lymphadenophy, and joint symptoms also occur occasionally after immunization with MMR vaccine. There are no known serious vaccine safety concerns following the administration of a third dose of MMR vaccine.
#### Measles-Mumps-Rubella-Varicella vaccine
Pain and redness at the injection site or fever less than 39°C occur in 10% or more of vaccine recipients. Rash, including measles-like, rubella-like and varicella-like rash, as well as swelling at the injection site and fever greater than 39°C occur in 1% to less than 10% of vaccine recipients. As varicella-like rashes that occur within the 2 weeks after immunization may be caused by wild-type virus (varicella virus circulating in the community), health care providers should obtain specimens from the vaccine recipient to determine whether the rash is due to natural varicella infection or to the vaccine-derived strain.
#### Rubella-containing vaccines
Acute transient arthritis or arthralgia may occur 1 to 3 weeks after immunization with rubella-containing vaccine. It lasts for about 1 to 3 weeks, and rarely recurs. It is more common in post-pubertal females, among whom arthralgia develops in 25% and arthritis in 10% after immunization with rubella-containing vaccine. There is no evidence of increased risk of new onset chronic arthropathies.
### Less common and serious or severe adverse events
Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association. Anaphylaxis following vaccination with MMR or MMRV vaccine may occur but is very rare.
#### Immune Thrombocytopenic Purpura
Rarely, Immune Thrombocytopenic Purpura (ITP) occurs within 6 weeks after immunization with MMR or MMRV vaccine. In most children, post-immunization thrombocytopenia resolves within 3 months without serious complications. In individuals who experienced ITP with the first dose of MMR or MMRV vaccine, serologic status may be evaluated to determine whether an additional dose of vaccine is needed for protection. The potential risk to benefit ratio should be carefully evaluated before considering vaccination in such cases.
#### Encephalitis
Encephalitis has been reported in association with administration of measles vaccine in approximately 1 per million doses distributed in North America, which is much lower than the incidence observed with natural measles disease (1 per 1,000 cases).
#### Febrile seizures
Between the ages of 12 to 23 months, when the first dose of vaccine for measles and varicella is administered as MMRV vaccine, there is a higher risk of fever and febrile seizures in the 7 to 10 days after vaccination when compared to separate administration of MMR and varicella vaccine at the same visit. For additional information about febrile seizures following the administration of MMRV vaccine, refer to [Measles Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html) in Part 4.
### Other safety issues
In the mid to late 1990s, researchers from the United Kingdom reported an association between MMR vaccine and inflammatory bowel disease, and MMR vaccine and autism. Rigorous scientific studies and reviews of the evidence have been done worldwide, and there is now considerable evidence to refute those claims. In 2010, the original study suggesting a link between the MMR vaccine and autism was found to be fraudulent and was retracted.
### Guidance on reporting Adverse Events Following Immunization (AEFI)
To ensure the ongoing safety of vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in some jurisdictions, reporting is mandatory under the law.
Vaccine providers are asked to report AEFIs through local public health officials and to check for specific AEFI reporting requirements in their province or territory. In general, any serious or unexpected adverse event felt to be temporally related to vaccination should be reported. The following AEFIs in particular, should be reported:
* Febrile seizures within 30 days after vaccination with MMR or MMRV vaccine.
* Varicella that is moderate (50 to 500 lesions) or severe (more than 500 vesicular lesions or associated complications or hospital admission) and occurs 7 to 21 days after vaccination with MMRV vaccine.
* Any serious or unexpected adverse event temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.
Refer to [Reporting Adverse Events Following Immunization (AEFI) in Canada](/en/public-health/services/immunization/reporting-adverse-events-following-immunization/user-guide-completion-submission-aefi-reports.html) and [Adverse Events Following Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) in Part 2 for additional information about AEFI reporting.
### Contraindications and precautions
MMR and MMRV vaccines are contraindicated in persons with a history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine, with the exception of egg allergy. Refer to [Contents of Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for a list of vaccines authorized for use in Canada and their contents.
In situations of suspected hypersensitivity or non-anaphylactic allergy to vaccine components, investigation is indicated which may involve immunization in a controlled setting. Consultation with an allergist is advised.
Although the measles and mumps components of MMR and MMRV vaccines are produced in chick embryo cell culture and may contain traces of residual egg and chicken protein, the trace amount of egg or chicken protein in the vaccine appears to be insufficient to cause an allergic reaction in egg-allergic individuals. Skin testing is not recommended prior to vaccination as it does not predict reaction to the vaccine. MMR or MMRV vaccine can be administered in the routine manner to people who have a history of anaphylactic hypersensitivity to hens' eggs. Prior egg ingestion is not a prerequisite for immunization with egg protein-containing vaccine. For all vaccines, immunization should always be performed by personnel with the capability and facilities to manage adverse events post-vaccination. Refer to [Contraindications and Precautions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html) in Part 2 for additional information.
Children with a known or suspected family history of congenital or hereditary immunodeficiency that is a contraindication to vaccination with live vaccine should not receive live vaccines unless their immune competence has been established. Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional information.
MMR and MMRV vaccines are contraindicated during pregnancy because of the theoretical risk to the fetus. Refer to [Immunization in Pregnancy and Breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3 for additional information.
Measles-containing vaccines are contraindicated in individuals with active, untreated tuberculosis (TB) as a precautionary measure. Although TB may be exacerbated by natural measles infection, there is no evidence that measles-containing vaccines have such an effect. Nonetheless, anti-tuberculous therapy for active TB disease is advisable before administering measles-containing vaccines and it may be prudent to avoid live viral vaccines in those with active TB disease until treatment is underway. Consultation with an expert in infectious diseases is recommended.
A history of febrile seizures or a family history of seizures is not a contraindication for the use of MMRV vaccine.
Administration of MMR or MMRV vaccine should be postponed in persons with a severe acute illness. Persons with a minor acute illness, with or without fever, may be vaccinated.
It is recommended to avoid the use of salicylates (medications derived from salicylic acid, such as acetylsalicylic acid [ASA]) for 6 weeks after immunization with MMRV vaccine because of an association between wild-type varicella, salicylate therapy and Reye's syndrome.
Refer to [Contraindications and Precautions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html) in Part 2 for additional general information.
Other considerations
--------------------
### Drug interactions
#### Systemic antiviral therapy
Systemic antiviral therapy (such as acyclovir, valacyclovir, famciclovir) should be avoided in the peri-immunization period, as it may affect the reproduction of the vaccine virus and consequently may reduce the efficacy of varicella-containing vaccine such as MMRV. On the basis of expert opinion, it is recommended that people taking long-term antiviral therapy should discontinue these drugs, if possible, from at least 24 hours before administration of MMRV vaccine and should not restart antiviral therapy until 14 days after vaccine administration.
#### Tuberculin skin testing or Interferon Gamma Release Assay
The measles component in measles-containing vaccines can temporarily suppress tuberculin reactivity, resulting in false-negative results. If tuberculin skin testing or an interferon gamma relase assay (IGRA) test is required, it should be done on the same day as immunization or delayed for at least 4 weeks after measles vaccination. Vaccination with measles-containing vaccine may take place at any time after tuberculin skin testing has been performed and read.
#### Human immunoglobulin or other blood products
Passive immunization with human Ig or receipt of most other blood products can interfere with the immune response to MMR and MMRV vaccines. Refer to [Blood Products, Human Ommunoglobulin and Timing of Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) in Part 1 for recommended intervals between the administration of Ig preparations or other blood products and MMR and MMRV vaccines.
Chapter revision process
------------------------
This chapter has been updated in accordance with the National Advisory Committee on Immunization Statement (NACI): [Use of Measles-Mumps-Rubella (MMR) Vaccine for the Management of Mumps Outbreaks in Canada](/en/public-health/services/publications/vaccines-immunization/use-measles-mumps-rubella-vaccine-management-outbreaks-canada.html). The recommendations on mumps outbreak management provided in this chapter and the statement are based on the best current available scientific knowledge and are intended to complement and, where applicable, update the [Guidelines for the Prevention and Control of Mumps Outbreaks in Canada](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2010-36/guidelines-prevention-control-mumps-outbreaks-canada.html) published in 2010.
Selected references
-------------------
* American Academy of Pediatrics. In: Pickering LK, Baker CJ, Kimberlin DW, et al. (editors). Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.
* Boulianne N, De Serres G, Ratnam S et al. Measles, mumps and rubella antibodies in children 5-6 years after immunization: effect of vaccine type and age at vaccination. Vaccine 1995;13(16):1611-6.
* Caplan CE. Mumps in the era of vaccines. CMAJ 1999;160(6):865-6.
* Centers for Disease Control and Prevention. The Pink Book: Epidemiology and Prevention of Vaccine Preventable Diseases. Updated 13th ed.; 2015. Accessed June 2015 at: http://www.cdc.gov/vaccines/pubs/pinkbook/index.html
* Centers for Disease Control and Prevention. Use of Combination Measles, Mumps, Rubella and Varicella Vaccine. Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 2010;59(03):1-12.
* Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices Provisional Recommendations for Measles-Mumps-Rubella (MMR) 'Evidence of Immunity' Requirements for Healthcare Personnel. 2009.
* Centers for Disease Control and Prevention. Measles, Mumps, and Rubella - Vaccine Use and Strategies for Elimination of Measles, Rubella, and Congenital Rubella Syndrome and Control of Mumps: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1998; 47(RR-8):1-57.
* Cooney MK, Fox JP, Hall CE. The Seattle Virus Watch, VI. Observations of infections with and illness due to parainfluenza, mumps, and respiratory syncytial viruses and Mycoplasma pneumoniae. Am J Epidemiol 1975;101(6):532-51.
* Davidkin I, Valle M, Julkunen I. Persistence of anti-mumps virus antibodies after a two-dose MMR vaccination at nine-year follow-up. Vaccine 1995;13(16):1617-22.
* Duclos P, Ward BJ. Measles vaccines: a review of adverse events. Drug Saf 1998;19(6):435-54.
* Falk WA, Buchan K, Dow M et al. The epidemiology of mumps in Southern Alberta, 1980-1982. Am J Epidemiol 1989;130(4):736-49.
* GlaxoSmithKline Inc. Product Monograph - PRIORIX-TETRA™. May 2010.
* GlaxoSmithKline Inc. Product Monograph - PRIORIX®. November 2008.
* Griffin MR, Ray WA, Mortimer EA et al. Risk of seizures after measles-mumps-rubella immunization. Pediatrics 1991;88(5):881-5.
* Jadavji T, Scheifele D, Halperin S. Thrombocytopenia after immunization of Canadian children, 1992 to 2001. Pediatr Infect Dis J 2003;22(2):119-22.
* James JM, Burks AW, Roberson PK et al. Safe administration of the measles vaccine to children allergic to eggs. N Engl J Med 1995;332(19):1262-6.
* Merck Frosst Canada Ltd. Product Monograph - M-M-R®II. February 2009.
* Miller E, Goldacre M, Pugh S et al. Risk of aseptic meningitis after measles, mumps and rubella vaccine in U.K. children. Lancet 1993;341(8851):979-82.
* National Advisory Committee on Immunization. Statement on measles-mumps-rubella-varicella vaccine. Can Commun Dis Rep 2010;36(ACS-9):1-22.
* National Advisory Committee on Immunization. An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI). Use of Measles-Mumps-Rubella (MMR) Vaccine for the Management of Mumps Outbreaks in Canada, July 2021. Retrieved from: https://www.canada.ca/en/public-health/services/publications/vaccines-immunization/use-measles-mumps-rubella-vaccine-management-outbreaks-canada.html.
* National Advisory Committee on Immunization. Statement on mumps vaccine. Can Commun Dis Rep 2007;33(ACS-8):1-10.
* Peltola H, Heinonen OP, Valle M et al. The elimination of indigenous measles, mumps and rubella from Finland by a 12 year two-dose vaccination program. N Engl J Med 1994;331(21):1397-1402.
* Public Health Agency of Canada. Supplement: Guidelines for the prevention and control of mumps outbreaks in Canada. Can Commun Dis Rep 2010;36(S1):1-46.
* West R, Roberts PM. Measles, mumps and rubella vaccine: current safety issues. BioDrugs 1999;12(6):423-9.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-13-meningococcal-vaccine.html "Meningococcal vaccine: Canadian immunization guide")
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-15-pertussis-vaccine.html "Pertussis vaccine: Canadian immunization guide")
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-06-21
| None | None |
c6d613c72252f4e4165e7e99adeb46cec7a5ce3b | cma | **Immunization of immunocompromised persons: Canadian Immunization Guide** | Immunization of immunocompromised persons: Canadian Immunization Guide
Introduction and general principles
Individuals may be immunocompromised as a result of a congenital condition, an illness or medications that suppress immune function. In general, immunocompromised persons are more susceptible to vaccine-preventable infections and may have severe infections. The safety and effectiveness of vaccines in immunocompromised persons are determined by the type of immunodeficiency and degree of immunosuppression. Each immunocompromised person is different and presents unique considerations regarding immunization. The relative degree of immunodeficiency is variable depending on the underlying condition, the progression of disease and use of immunosuppressive agents. Immunodeficiency can also vary over time in many people and the decision to recommend for or against a particular vaccine will depend upon a case-by-case analysis of the risks and benefits. There is potential for serious illness and death if immunocompromised people are under-immunized and every effort should be made to ensure adequate protection through immunization; however, inappropriate use of live vaccines can cause serious adverse events in some immunocompromised people as a result of uncontrolled replication of the vaccine virus or bacterium.
Primary care providers and specialists caring for immunocompromised patients share responsibility for ensuring appropriate vaccination of immunocompromised patients and their households. When in doubt, primary care providers should consult a specialist with experience in managing patients with the specific immunocompromising condition of concern.
The following recommendations reflect general best practices and are subject to individual considerations and new evidence as it arises.
# Inactivated vaccines
Inactivated vaccines may generally be administered to immunocompromised people if indicated because the antigens in the vaccine cannot replicate and there is no increase in the risk of vaccine-associated adverse events; however, the magnitude and duration of vaccine-induced immunity are often reduced. For complex cases, referral to a physician with expertise in immunization and/or immunodeficiency is advised.
# Live attenuated vaccines
In general, people who are severely immunocompromised or in whom immune status is uncertain should not receive live vaccines because of the risk of disease caused by the vaccine strains. In less severely immunocompromised people, the benefits of vaccination with routinely recommended live vaccines may outweigh risks. Before giving an immunocompromised person a live vaccine, a physician with expertise in immunodeficiency should be consulted.
# Immunoglobulins
For temporary passive protection against some infections, immunoglobulin therapy (nonspecific or pathogen specific) may be indicated for pre or post exposure. The monoclonal antibody preparation, Palivizumab (SynagisTM) is an antibody directed specifically against respiratory syncytial virus (RSV) that may be considered to reduce complications of RSV infection in children less than 24 months of age who are severely immunocompromised.
# Serologic testing and re-immunization
Immune response to vaccines may be inadequate in immunocompromised people and vaccinees may remain susceptible despite vaccination. If serologic testing is available and there is a clear antibody correlate of protection, measurement of post-immunization antibody titres to determine immune response and guide re-vaccination and post-exposure management should be considered. For infants less than 18 months of age, a positive serologic test may detect maternal antibody and not reflect an active immune response in the infant. Seroconversion or an increase in titre, or a repeat test after 18 months of age showing persistent antibody, indicate an active response. Results of serologic testing may also be confounded by passive antibody in those receiving immunoglobulin therapy.
Please note that the information in the text and tables is complementary and both should be used. Refer to in Part 4 for additional information, especially concerning vaccine doses, schedules and boosters.
# General principles
Several general principles apply to the immunization of immunocompromised individuals:
- Maximize benefit while minimizing harm.
- Susceptibility to infection and ability to respond to a vaccine vary according to degree of immune suppression.
- Immunize at the time when maximum immune response can be anticipated.
+ Immunize prior to any planned immunosuppression, if possible.
+ Delay immunization if the immunodeficiency is transient (if this can be done safely because exposure is unlikely).
+ Stop or reduce immunosuppression to permit better vaccine response, if appropriate.
- Consider the immunization environment broadly.
+ Vaccinate family members and other close contacts when appropriate.
+ Strongly encourage up-to-date vaccinations, including annual influenza vaccination, for all healthcare workers providing care to immunocompromised people.
- Avoid live vaccines unless:
+ immunosuppression is mild and data are available to support their use.
+ the risk of natural infection is greater than the risk of immunization.
- Monitor serologic response, if appropriate test and correlate of protection is available, and boost if antibody level is inadequate.
+ The magnitude and duration of vaccine-induced immunity are often reduced in immunocompromised individuals.
# Family or medical history
Primary or secondary immunodeficiencies may be undiagnosed in young children presenting for routine immunizations, which include live vaccines. This is particularly important to consider in infants receiving live vaccines before 12 months of age.
A significant primary immunodeficiency in which live vaccines would be contraindicated usually declares itself in the first few months of life. The only live vaccine routinely given to children less than 12 months of age is rotavirus, which can be given as early as 6 weeks of age. Chronic rotavirus infection from the vaccine strain has occurred in infants with unrecognized severe combined immunodeficiency. BCG vaccine is given at birth in some populations and measles vaccine may be given at 6-12 months of age in an outbreak or after exposure.
Clues pointing to the presence of significant immunodeficiency may be found in the medical or family history. Infants with a history of failure to thrive, recurrent or prolonged oral candidiasis despite treatment, or recurrent serious infections such as pneumonia or sepsis may have an immunodeficiency. A family history of primary immunodeficiency may be known or may be suspected on the basis of a family history of early infant deaths. However, the family history can be negative. Routine newborn screening for severe combined immunodeficiency is now performed in some regions of Canada. Maternal human immunodeficiency virus (HIV) infection puts the infant at risk of immunodeficiency in the first year of life if HIV has been transmitted to the infant. Routine prenatal blood work in Canada includes HIV testing. If an infant shows clinical clues suggesting immunodeficiency, the mother's prenatal HIV screening result should be obtained. If a mother was not screened in pregnancy, the possibility of perinatal HIV infection from undiagnosed maternal infection should be considered.
Primary immunodeficiency
There are currently more than 300 distinct genetic defects of immunity. These are grouped under general headings below.
# Predominantly antibody (B cell) deficiencies
B cell defects (defects of humoral immunity) include X-linked agammaglobulinemia (XLA), common variable immunodeficiency (CVID), selective immunoglobulin A (IgA) deficiency, specific polysaccharide antibody deficiency (SPAD), and immunoglobulin G (IgG) subclass deficiency.
Individuals with defects in antibody production are highly susceptible to encapsulated bacteria such as *Streptococcus pneumoniae, Haemophilus influenzae- and *Neisseria meningitidis.*
- Most patients with severe defects of antibody production, such as XLA or CVID are not able to mount a significant humoral response. While administration of inactivated vaccines is not harmful, it may be futile. As a general rule, people with severe antibody defects can be protected from many of the vaccine preventable infections with the use of replacement immunoglobulin (Ig) therapy or pathogen-specific Ig preparations; however, the level of antibody to specific pathogens in these products may be variable.
- For those with less severe antibody deficiency and expected ability to mount some antibody response, especially selective IgA deficiency or IgG subclass deficiency, vaccination is recommended to increase the level of protection. Receipt of replacement Ig is not a contraindication for use of inactivated vaccines; however, Ig can interfere with the immune response to some live attenuated viral vaccines such as measles and varicella vaccine.
- Repeat doses of Ig should not be given to individuals with known selective IgA deficiency unless the benefit outweighs the risk, because of the very rare risk of an anaphylactic reaction to traces of IgA in the product. If indicated, an Ig product with the least amount of IgA should be used and given with caution under close observation.
## Inactivated vaccines
In general, inactivated vaccines should be administered according to routine immunization schedules to people with less severe primary B cell defects who have some capacity for B or T cell responses. Hepatitis B vaccine should be given at double the routine dose and using a 3- or 4-dose schedule. Human papillomavirus (HPV) vaccine should be given following routine age indications but using a 3-dose schedule regardless of age.
In addition to routine vaccines, individuals with primary B cell defects should receive pneumococcal conjugate vaccine regardless of age, pneumococcal polysaccharide vaccine if 2 years of age or older, and one dose of *Haemophilus influenzae- type b (Hib) vaccine after age 5 years regardless of prior Hib vaccination history. Quadrivalent conjugate meningococcal vaccine is recommended and meningococcal B vaccine should be considered if 2 months of age or older. For infants 6 months of age or older, inactivated influenza vaccine should be given annually, even if receiving Ig, as Ig may not have antibody to the current influenza strains. However, humoral response may be reduced.
## Live attenuated vaccines
Patients with severe B cell defects (XLA, CVID), and others receiving regular immunoglobulin replacement therapy, should not receive measles-mumps-rubella (MMR), measles-mumps-rubella-varicella (MMRV) or varicella vaccines as Ig will interfere with the efficacy of these vaccines.
Individuals with partial B cell defects and known intact T cell immunity and some ability to produce antibody who are not receiving Ig should receive MMR and univalent varicella vaccines as appropriate for age. MMRV has not been evaluated in immunodeficiency. All other live vaccines such as rotavirus, live attenuated influenza, live herpes zoster vaccine, Bacille Calmette-Guérin (BCG), oral polio, smallpox, oral typhoid and yellow fever vaccines are contraindicated. If travel to an area where yellow fever is being transmitted cannot be avoided, consideration of vaccination in consultation with a specialist is advised.
People with selective IgA deficiency who have no concomitant defects in T cell function can receive most live vaccines. Live mucosal vaccines (rotavirus, live attenuated influenza vaccine (LAIV), oral typhoid) are likely safe and may be used although there may be lack of mucosal response. Some experts prefer to use inactivated vaccines if available (e.g., inactivated influenza vaccine, parenteral inactivated typhoid vaccine). However, given that there are limited data on the use of live mucosal vaccines, consultation with an immunologist is advised and immunization with these vaccines should be individually assessed.
The diagnosis of IgG subclass deficiency should be based on documented failure to produce adequate amounts of specific antibody and not on quantitative Ig levels. Individuals with documented IgG subclass deficiency with intact T cell function who are not receiving regular Ig replacement therapy can receive routine live vaccines although response may be suboptimal. All live vaccines may be given to individuals with isolated SPAD.
# Combined T and B cell immunodeficiencies (with or without associated /syndromic features) and Immune dysregulation
Individuals with T cell or combined deficiency are particularly susceptible to infections with virtually all viruses and many bacteria. T cell defects may be severe (e.g., severe combined immunodeficiency, complete DiGeorge syndrome) or partial (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome, ataxia telangiectasia, hyper IgM syndrome, hyper IgE syndrome, X-linked lymphoproliferative disease, familial predisposition to hemophagocytic lymphohistiocytosis). Those with severe defects will not respond to any vaccines. Those with partial defects may have some response.
## Inactivated vaccines
For those with severe combined immunodeficiency, administration of inactivated vaccines is not harmful, but will not provide protection.
Inactivated vaccines should be given to those with partial immunodeficiency although response may be suboptimal. Hepatitis B vaccine should be given at double the routine dose and using a routine 3- or 4-dose schedule. HPV vaccine should be given following routine age indications but using a 3-dose schedule regardless of age.
In addition to routine vaccines, individuals with partial T cell or combined defects should receive pneumococcal conjugate vaccine regardless of age, pneumococcal polysaccharide vaccine if 2 years of age or older, and one dose of Hib vaccine after age 5 years regardless of prior Hib vaccination history. Quadrivalent conjugate meningococcal vaccine is recommended and meningococcal B vaccine should be considered if 2 months of age or older. Inactivated influenza vaccine should be given annually, as Ig may not protect. However, humoral response may be reduced.
## Live attenuated vaccines
All live attenuated vaccines are contraindicated for individuals with severe T cell defects. Exposure to natural infection or inadvertent live attenuated vaccine administration can usually be managed with rapid administration of Ig or pathogen-specific Ig with or without appropriate antiviral treatment. Live vaccines are also generally contraindicated for those with Wiskott-Aldrich syndrome, ataxia telangiectasia, X-linked lymphoproliferative disease, or familial predisposition to hemophagocytic lymphohistiocytosis.
Live attenuated vaccines may be considered for those with partial T cell defects after assessment of immune competence. Those with partial DiGeorge syndrome, or other combined defects, and a total CD4 lymphocyte count of > 500 x 106/L and normal mitogen response should receive MMR and univalent varicella vaccines as MMRV has not been evaluated in this population. MMRV and other live vaccines are contraindicated.
# Phagocytic and neutrophil disorders
People with phagocytic and neutrophil disorders (e.g., congenital neutropenia, cyclic neutropenia, leukocyte adhesion and migration defects, chronic granulomatous disease (CGD), myeloperoxidase deficiency and Chediak-Higashi syndrome) are at increased risk for bacterial infections.
## Inactivated vaccines
All routine inactivated vaccines and others required because of travel or exposure should be given. Pneumococcal conjugate vaccine (regardless of age) and pneumococcal polysaccharide vaccine if 2 years of age or older are indicated for all conditions other than CGD. CGD does not increase the risk of invasive pneumococcal disease, so conjugate vaccine should be used according to routine schedules and polysaccharide vaccine is not indicated. Inactivated influenza vaccine should be given annually. Influenza vaccine is especially important in patients with CGD due to increased morbidity and mortality with staphylococcal lung infections that are associated with influenza.
## Live attenuated vaccines
Live bacterial vaccines (BCG, oral typhoid) are contraindicated in all phagocytic or neutrophil defects. Live attenuated viral vaccines (rotavirus, MMR, varicella, MMRV, herpes zoster) should be given according to routine schedules to persons with neutropenia or CGD, and live attenuated influenza vaccine (LAIV) or yellow fever vaccine may be given if indicated. All live attenuated viral vaccines are contraindicated with leukocyte adhesion defect (LAD), Chediak-Higashi syndrome and other defects in cytotoxic granule release, and in any other undefined phagocytic cell defect.
# Complement deficiency
Individuals with complement, properdin, factor D or B or mannan-binding lectin deficiency are particularly susceptible to infections with *N. meningitidis- but also susceptible to other encapsulated bacteria such as *S. pneumoniae- and *Haemophilus influenzae*. In general, response to vaccines is expected to be normal and there are no contraindications.
## Inactivated vaccines
Inactivated vaccines should be administered according to routine immunization schedules.
In addition to routine vaccines, quadrivalent conjugate meningococcal vaccine is recommended and meningococcal B vaccine should be considered if 2 months of age or older. Pneumococcal conjugate vaccine should be given regardless of age, pneumococcal polysaccharide vaccine if 2 years of age or older, and one dose of Hib vaccine after age 5 years regardless of prior Hib vaccination history. Influenza vaccine (inactivated or live attenuated, as appropriate for age) should be given annually.
## Live attenuated vaccines
Individuals with complement deficiency should receive all routine live attenuated vaccines and any other live vaccines that are indicated (e.g., for travel or after exposure).
# Defects of innate immunity
Innate immune defects of cytokine generation or cellular activation, such as defects of the interferon-gamma/interleukin-12 axis, increase susceptibility to mycobacterial disease. Toll-like receptor signaling pathway deficiencies (i.e. IRAK4 and MyD88 deficiency) increase susceptibility to pneumococcal and other pyogenic bacterial infections. Some innate defects may result in increased susceptibility to viral infections.
## Inactivated vaccines
All routine inactivated vaccines should be given. Persons with IRAK4 and MyD88 deficiency or other defects causing increased risk for pyogenic bacterial infections should receive conjugate pneumococcal vaccine regardless of age and polysaccharide pneumococcal vaccine at age ≥ 2 years. Other inactivated vaccines should be used as indicated for travel or exposure.
## Live attenuated vaccines
A specialist should be consulted before giving live vaccines to persons with innate immune defects of cytokine generation or response or cellular activation defects. Persons with interferon gamma/interleukin-12 axis defects have a greater susceptibility to intracellular bacteria (i.e. salmonella or mycobacteria). For those patients, live bacterial vaccines (BCG, oral typhoid) are contraindicated. Live viral vaccines are contraindicated in patients with defects in alpha/beta or gamma interferon production. All live vaccines are contraindicated in nuclear factor kappa B pathway defects.
- Use 5 dose schedule for post exposure prophylaxis
- Post-immunization serology recommended
Abbreviations:
anti-HBs = antibody to hepatitis B surface antigen
Ig = immunoglobulin
Most patients with severe B cell deficiency (e.g., X-linked agammaglobulinemia, common variable immunodeficiency) and patients with severe T cell defects (e.g., severe combined immunodeficiency, complete DiGeorge syndrome) are unable to respond to any vaccine. Inactivated vaccines are safe but not effective. They should be given only if some antibody production is expected. Those with less severe defects should receive inactivated vaccines as indicated here.
Given as combined vaccine (diphtheria, tetanus, pertussis; ± polio, Hib depending on age and previous vaccine history).
Routine use: Follow routine immunization schedules with age-appropriate booster doses.
May be given as combined vaccine.
Regardless of prior history of Hib vaccination and at least 1 year after any previous dose
Initially annual monitoring of antibody levels may be considered. Optimal timing and frequency should be based on the severity of the immunocompromised state and the ongoing risk of acquisition of HB infection.
Recombinant inactivated zoster vaccine may be considered in immunocompromised adults ≥ 50 years of age on a case by case basis. Data on the use in immunocompromised individuals is limited, but based on the burden of zoster illness in this population and the general safety of inactivated vaccines, the benefits of vaccination are expected to outweigh the risks.
For CGD, give pneumococcal conjugate vaccine according to the routine schedule; pneumococcal polysaccharide vaccine is not indicated.
Persons with IRAK4 and MyD88 deficiency or other innate defects causing increased risk for pyogenic bacterial infections should receive polysaccharide pneumococcal vaccine at age ≥ 2 years.
Abbreviation: Ig = immunoglobulin
Major B cell deficiency: X-linked agammaglobulinemia, common variable immunodeficiency and other major antibody defects: all live vaccines contraindicated. Those with partial B cell defects and known intact T cell function who are not receiving regular Ig therapy may receive MMR and varicella vaccines. Other live vaccines are contraindicated.
Severe combined immunodeficiency, complete DiGeorge syndrome and others with severe T cell deficiency: all live vaccines contraindicated. Those with partial defects (see text) may receive MMR and varicella vaccine.
All live vaccines contraindicated with leukocyte adhesion defect, Chediak-Higashi syndrome and other defects in cytotoxic granule release, and any other undefined phagocyte defect
A specialist should be consulted before giving live vaccines to persons with defects of cytokine generation / response or cellular activation defects. Live bacterial vaccines are contraindicated in defects of interferon gamma/interleukin-12 pathways. Live viral vaccines are contraindicated in patients with defects of alpha or gamma interferon production. All live vaccines are contraindicated in nuclear factor kappa B pathway defects.
Consult with immunologist in cases of IgA deficiency; some experts may prefer inactivated vaccine for persons with IgA deficiency
Routine use: follow routine immunization schedules with age-appropriate booster doses
Regular immunoglobulin replacement therapy will affect the efficacy of the vaccine. Refer to for the recommended intervals between Ig and subsequent immunization.
If travel to an area where yellow fever is being transmitted cannot be avoided, consider use of the vaccine in consultation with a specialist.
Acquired (secondary) immunodeficiency
Acquired immunodeficiency states result from medical conditions that directly or indirectly cause immunosuppression (e.g., malignant hematologic disorders or solid tumours, hematopoietic stem cell transplantation, HIV-infection). Acquired immunodeficiency may also occur due to immunosuppressive therapies (e.g., long-term steroid treatment, cancer chemotherapy, other cytotoxic therapy, biological response modifiers, calcineurin inhibitors, radiation therapy) used to treat these conditions as well as to treat solid organ transplant recipients and a range of chronic inflammatory conditions (e.g., inflammatory bowel disease, arthritis, psoriasis, systemic lupus erythematosus).
# Acquired complement deficiency
People who are receiving the terminal complement inhibitor eculizumab (Soliris™, Alexion Pharmaceuticals Inc.) for paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome or other conditions are at high risk of invasive meningococcal infections. In addition to all age-appropriate routine vaccines, quadrivalent conjugate meningococcal vaccine is recommended and meningococcal B vaccine should be considered. They must be vaccinated at least 2 weeks prior to receiving the first dose of eculizumab, if possible, and every 3-5 years thereafter if they continue to use the drug.
Hemolysis can be precipitated by the combination of meningococcal B vaccines and eculizumab if the underlying hemolytic condition is not yet under control. For patients already receiving eculizumab, meningococcal B vaccine should be given after the underlying hemolytic condition is under control and less than one week after a dose of eculizumab. For more information, refer to the .
# Malignant hematologic disorders
(e.g., leukemia, lymphomas, blood dyscrasias or other malignant neoplasms affecting the bone marrow or lymphatic systems)
## Inactivated vaccines
In general, inactivated vaccines should be administered to people with malignant hematologic disorders according to routine immunization schedules, although response may be sub-optimal. Immunization should be given at least 2 weeks prior to the start of immunosuppressive therapy or when immunosuppressive therapy is at the lowest level unless the risk of imminent exposure to the pathogen is high. Hepatitis B vaccine should be given at double the routine dose and using a 3 or 4 dose schedule. HPV vaccine should be given following routine age indications but using a 3 dose schedule regardless of age. Doses of any vaccine received while on immunosuppressive therapy should be repeated once no longer immune suppressed, unless an adequate antibody response can be demonstrated.
Individuals with malignant hematologic neoplasms should also receive conjugate pneumococcal vaccine (regardless of age), pneumococcal polysaccharide vaccine if age 2 years or more, and one dose of Hib vaccine after age 5 years regardless of prior Hib vaccination history, because of increased susceptibility to these infections. For infants 6 months of age or older, annual immunization with inactivated influenza vaccine is also recommended.
## Live attenuated vaccines
Live attenuated vaccines are contraindicated in individuals with severe immunodeficiency due to blood dyscrasias, lymphomas, leukemias of any type, or other malignant neoplasms affecting the bone marrow or lymphatic systems and in people undergoing immunosuppressive chemotherapy or radiotherapy treatment for these conditions.
In general, if the cancer is in remission and chemotherapy and/or radiotherapy have been completed for at least 3 months, and T cell function is normal, the person is no longer considered immunocompromised and live vaccines may be given. Live vaccines should be deferred for at least 6 months after therapy with anti B-cell antibody.
# Non-hematologic malignant solid tumours
## Inactivated vaccines
Inactivated vaccines should be administered to people with malignant solid tumours according to routine immunization schedules. Immunization should be given at least 2 weeks prior to the start of immunosuppressive therapy or when immunosuppressive therapy is at the lowest level unless the risk of imminent exposure to the pathogen is high. Hepatitis B vaccine should be given at double the routine dose and using a 3- or 4-dose schedule. HPV vaccine should be given following routine age indications but using a 3-dose schedule regardless of age. Doses of any vaccine received while on immunosuppressive therapy should be repeated once no longer immune suppressed unless an adequate antibody response can be demonstrated.
In addition, pneumococcal conjugate vaccine (regardless of age) and polysaccharide vaccine (if age 2 years or more) should be given because of increased susceptibility to invasive pneumococcal disease. For infants 6 months of age or older, annual immunization with inactivated influenza vaccine is also recommended.
## Live attenuated vaccines
Live vaccines are contraindicated in people undergoing immunosuppressive treatment for any malignant solid tumour.
In general, if chemotherapy has been completed for at least 3 months and the cancer is in remission, the person is no longer considered immunocompromised.
# Hematopoietic stem cell transplantation (HSCT): autologous or allogeneic
HSCT is the transplantation of hematopoietic stem cells following bone marrow ablation or non-ablative conditioning (chemotherapy and/or radiotherapy to deplete the hematopoietic system prior to transplant). HSCT recipients receive either their own cells (autologous HSCT) or cells from a donor (allogeneic HSCT). Stem cells are sourced from bone marrow, peripheral blood, or umbilical cord blood.
Virtually all HSCT recipients experience a prolonged period of immune suppression following transplantation. Antibody titres to vaccine-preventable diseases decrease after allogeneic or autologous HSCT. Duration of immune suppression varies, depending on type of transplant (allogeneic or autologous), stem cell source, stem cell manipulation and post-transplant complications. Allogeneic HSCT recipients experience profound immune suppression in the post-transplant period, with recovery of the immune system approximately 1-2 years after HSCT. However, this recovery is delayed in the presence of immunosuppressive medication and chronic graft-versus-host disease (cGVHD). Recovery usually occurs earlier after autologous HSCT but still requires several months.
In general, T cells capable of responding to new antigens are generated at 6 to 12 months after transplant, earlier in young children and later in adults. Although reconstitution occurs earlier after autologous HSCT than after allogeneic HSCT, the approaches to vaccination are the same. Efficacy data for vaccines in HSCT recipients are limited.
Vaccination in accordance with transplant centre-specific immunization guidelines is generally part of routine post-transplant care provided by the transplant centres.
# Pre-HSCT immunization
If time permits, careful consideration must be given to the pre-transplant immunization status of the HSCT candidate. All routine inactivated vaccines should be given as appropriate for age. In addition, conjugate pneumococcal vaccine (regardless of age) and polysaccharide pneumococcal vaccine (if age 2 years or more) should be given if not previously received. If the transplant is planned during the influenza season, inactivated influenza vaccine should be given. Inactivated vaccines should be given at least 2 weeks prior to onset of the pre-transplant conditioning regimen. Live vaccines should not be given within 4 weeks of the start of conditioning. BCG should not be given at any time to those with a condition that will likely eventually require HSCT. BCG may persist in the body for at least a few years, and perhaps indefinitely, so there is a theoretical risk of reactivation post-transplant.
Donor vaccination may improve responses of the HSCT recipient to some vaccines; however, due to logistical and ethical issues it is often not feasible. When the HSCT donor is related to the recipient, consideration should be given to immunizing the donor before stem cell collection. As a minimum, the donor should have received all routine age-appropriate vaccines including routine boosters, COVID-19 vaccines, and influenza vaccine if stem cell collection is to occur during the influenza season. Inactivated vaccines should be given at least 2 weeks prior to stem cell collection. Live parenteral vaccines are contraindicated within 4 weeks of stem cell collection. For autologous HSCT, inactivated vaccines should be given at least 2 weeks before and live parenteral vaccines at least 4 weeks before stem cell collection.
If indicated for age and by immune status, and if feasible, a primary series of a non-live COVID-19 vaccine should be completed at least 2 weeks prior to onset of the pre-transplant conditioning regimen for allogeneic HSCT and at least 2 weeks prior to stem cell collection for autologous HSCT.
Doses of COVID-19 vaccine may be given at an interval shorter than the recommended interval of 8 weeks, respecting the minimum authorized interval.
If the recipient or donor is eligible for a booster dose, consideration should be given to administering the booster at least 2 weeks prior to stem cell collection, if feasible.
At this time, it is not known if giving an extra dose of COVID-19 vaccine prior to conditioning or stem cell collection would improve response to COVID-19 vaccine post-HSCT.
If transplantation is urgent, it should not be delayed to facilitate donor or recipient vaccination.
# Post-HSCT immunization
HSCT recipients should be viewed as "never immunized" and require re-immunization after transplant because the ablation of hematopoietic cells in the bone marrow pre-transplant eliminates most or all immune memory. In addition, certain vaccine preventable diseases pose increased risk for HSCT recipients of all ages (e.g., pneumococcus, Hib, measles, varicella, and influenza). HSCT recipients respond poorly to polysaccharide vaccines, such as pneumococcal polysaccharide 23-valent vaccine. If serologic testing is available and there is a clear antibody correlate of protection, measurement of post-immunization antibody titres to determine immune response and guide re-vaccination and post-exposure management should be considered.
## Inactivated vaccines
All routine inactivated vaccines should be given (or repeated) for HSCT recipients generally beginning 6 to 12 months post-transplant (pneumococcal conjugate vaccine may be given beginning at 3 to 6 months post-transplant, inactivated influenza vaccine may be given beginning at 4 to 6 months post-transplant). Pneumococcal conjugate vaccine and Hib vaccine should be given regardless of age. Those 2 years of age or older should receive pneumococcal polysaccharide vaccine at 12 to 18 months post-transplant (6 to 12 months after the last dose of pneumococcal conjugate vaccine) if no GVHD. Hepatitis B vaccine should be given at double the dose used in the routine 3-dose schedule. HPV vaccine should be given using a 3-dose schedule, regardless of age. For those with risk factors for invasive meningococcal disease (e.g., functional hyposplenia), quadrivalent conjugate meningococcal is recommended and meningococcal B vaccine should be considered.
The primary series (initial or repeat) of COVID-19 vaccine should be initiated 3 to 6 months after HSCT. In general, it is recommended that the immunization of immunocompromised persons occur at a time when the immune response can be maximized. However, delaying COVID-19 vaccination to maximize the immune response needs to be weighed against the risk of infection while waiting, taking into consideration risk of exposure and local transmission of SARS-CoV-2. Time of initiation should also take into account the immune status of the HSCT recipient, including B-lymphocyte counts, receipt of immunosuppressive therapy currently or within the past 3 months, rituximab therapy or other anti-B cell monoclonal antibody within the last 12 months, and active GVHD or moderate to severe cGVHD.
Individuals with recent or current immunosuppressive therapy or active cGVHD are expected to have lower seroconversion rates, but nevertheless, rates of 56%, 63% and 73% have been reported in HSCT recipients on immunosuppression. New cGVHD and worsening of cGVHD have occasionally been reported after receipt of a COVID-19 vaccine, but whether or not vaccination was causal is not known. Patients at risk for GVHD should be advised that a cGVHD flare may occur but relationship to the vaccine is unknown. Careful monitoring of patients with a history of cGVHD is warranted. If new onset or exacerbation of GVHD occurs after COVID-19 vaccination, the decision to give a further dose should be made on an individual basis, taking into consideration risk of exposure to SARS-CoV-2 and the severity of the GVHD.
## Live attenuated vaccines
MMR and univalent varicella vaccines may be considered 24 months or more post-transplant provided there is no evidence of chronic GVHD, immunosuppression has been discontinued for at least 3 months, the underlying disease for which the transplant was done (if immunosuppressive), is not active, and the person is considered immunocompetent by a transplant specialist. Yellow fever vaccine may be given if the above criteria are met and travel to an area with risk of yellow fever acquisition cannot be avoided. Other live vaccines are contraindicated. Note that some HSCT recipients may be receiving regular doses of immunoglobulin which will interfere with the response to live vaccines, in which case these vaccines (excluding yellow fever), should be deferred until 8-11 months after the last dose of immunoglobulin. Live herpes zoster vaccine is not recommended post HSCT.
- Pre-exposure prophylaxis for travel: consider Ig with hepatitis A vaccine unless receiving routine IG replacement therapy.
- Post-exposure prophylaxis: Ig recommended along with hepatitis A vaccine unless receiving routine IG replacement therapy.
- Double the routine dose; 3 or 4 dose schedule recommended
- Post-immunization monitoring of anti-HBs titres recommended with booster dose if titre less than 10 IU/L
- 3 doses of Pneu-C-13 vaccine at least 4 weeks apart
- If GVHD, give 4th dose of Pneu-C-13 and delay polysaccharide until GVHD resolved
- Consider re-immunization after 1 year
- Give as needed for post-exposure management
- Use 5 dose schedule for post-exposure prophylaxis
- Beginning 6 to 12 months post-HSCT for pre-exposure prophylaxis
- Post-immunization serology recommended
- Serology recommended after 2nd dose
- Serology recommended after 2nd dose
Abbreviations:
anti-HBs = antibody to hepatitis B surface antigen
Ig = immunoglobulin
For preferred type of COVID-19 vaccine, intervals between doses, and booster dose recommendations, refer to the chapter.
Given as combined vaccine (diphtheria, tetanus, pertussis; ± polio, Hib depending on age and previous vaccine history).
May be given as a combined vaccine.
Initially annual monitoring of antibody levels may be considered. Optimal timing and frequency should be based on the severity of the immunocompromised state and the ongoing risk of acquisition of HB infection.
Recombinant inactivated zoster vaccine may be considered in immunocompromised adults ≥ 50 years of age on a case by case basis. Data on the use in immunocompromised individuals is limited, but based on the burden of zoster illness in this population and the general safety of inactivated vaccines, the benefits of vaccination are expected to outweigh the risks.
Give when immunosuppression has been discontinued for at least 3 months, no chronic GVHD, no Ig in the past 8 to 11 months (except for yellow fever vaccine) and considered immunocompetent by a transplant specialist.
# Solid organ transplantation
Solid organ transplant recipients are at increased risk of severe illness with many vaccine preventable diseases, including invasive pneumococcal or Hib disease, influenza, varicella, and HPV-related diseases.
# Pre-solid organ transplantation
Pre-transplant immunization is routine at most transplant centres. Ideally, all non-immune solid organ transplantation candidates should be immunized prior to transplantation and as early in the course of disease as possible because vaccine response may be reduced in people with organ failure pre-transplant. In addition, vaccines are more immunogenic if given before transplantation because the immunosuppressive medications given after transplant to prevent and treat rejection of the transplanted organ may diminish the vaccine response. It is especially important that live vaccines are given pre-transplant if possible, as these will be contraindicated post-transplant. MMR and varicella vaccine may be given to infants 6-11 months of age if transplantation is expected to occur before age 12 months. If transplantation is delayed, repeat doses should be given starting at one year of age.
Inactivated vaccines should be given according to routine immunization schedules, with the exceptions that hepatitis B vaccine should be given at double the usual dose using a 3- or 4-dose schedule if on dialysis or immunocompromised. If immunocompromised, HPV vaccine should be given using a 3-dose schedule regardless of age. In general, routine age indications should be followed, however HPV vaccination may be considered prior to an imminent transplantation in a 7- or 8-year-old child, recognizing that there is no immunogenicity data for this age group. The risk of HPV-associated warts is high post-transplant; HPV 9- or 4-valent vaccine will provide additional protection over that of the 2-valent vaccine. In addition, transplant candidates should receive pneumococcal conjugate vaccine regardless of age, pneumococcal polysaccharide vaccine if 2 years of age or older, and one dose of Hib vaccine after age 5 years regardless of prior Hib vaccination history.
Inactivated influenza vaccine should be given annually. Hepatitis A vaccine is indicated for liver transplant candidates and others with risk factors for hepatitis A. Quadrivalent conjugate meningococcal vaccine is recommended and meningococcal B vaccine should be considered if there are risk factors for meningococcal infection (e.g., hyposplenia, complement deficiency, or increased risk of exposure from travel or occupation).
Inactivated vaccines should be given at least 2 weeks before transplantation and live attenuated vaccines (MMR, MMRV, varicella, zoster, rotavirus, LAIV) should be given at least 4 weeks prior to transplantation. Live zoster vaccine should be used only if the inactivated zoster vaccine is contraindicated or unavailable. BCG may persist in the body for at least a few years, and perhaps indefinitely. It should not be given to any patient who is anticipated to likely need an organ transplant in the future, unless potential benefit outweighs the risk of reactivation post-transplant.
Antibody response should be determined by serology for those vaccines with an antibody correlate of immunity available. For infants less than 18 months of age, presence of passive maternal antibody must be considered.
Living donors should have received all age-appropriate vaccines. Live vaccines should not be given in the 4 weeks before organ procurement.
# Post-solid organ transplantation
Solid organ recipients generally receive lifelong immunosuppression, which varies substantially depending on the organ transplanted. Usually the degree of immune suppression is greatest in the first 3 to 6 months post-transplant, although this timeline varies if treatment for acute organ rejection is required. In the absence of this later scenario, immune suppression typically progresses to the maintenance phase between 6 months -1 year, but a significant degree of immune suppression persists indefinitely. A minority of transplant recipients who experience chronic rejection, persistent organ dysfunction, or chronic infections, remain profoundly immune suppressed.
## Inactivated vaccines
In general, vaccination with inactivated vaccines should not be re-initiated until maintenance immunosuppression is attained. Recommended inactivated vaccines that were not given pre-transplant and recommended booster doses should be given. Hepatitis B vaccine should be given at double the usual dose and using a 3-dose or 4-dose schedule. HPV vaccine should be given following routine age indications but using a 3-dose schedule, regardless of age.
If serologic testing is available and there is a clear antibody correlate of protection, measurement of post-immunization antibody titres to determine immune response and guide re-vaccination and post-exposure management should be considered.
## Live attenuated vaccines
Live vaccines are generally contraindicated after transplant. However, univalent varicella vaccine has been given to selected pediatric renal and liver transplant recipients without recent graft rejection and receiving minimal or no immune suppression; consultation with an expert is advised regarding varicella vaccination of non-immune organ transplant recipients.
Most newly transplanted solid organ recipients receive vaccination in accordance with transplant centre-specific immunization guidelines as part of routine post-transplant care.
- Individuals 5 years of age and older: 1 dose recommended
- Individuals 5 years of age and older: 1 dose recommended
- Pre-exposure prophylaxis for travel: consider Ig with hepatitis A vaccine
- Post-exposure prophylaxis: Ig recommended along with hepatitis A vaccine
- Post-immunization monitoring of anti-HBs titres recommended with booster dose if titre less than 10 IU/L
- May be considered for pre-transplant administration prior to routinely recommended age, if reasonably close to minimum recommended age for vaccination
- Use 5 dose schedule for post-exposure prophylaxis
- Post-immunization serology recommended
- Post-immunization serology recommended
- Post-immunization serology recommended
- Consider post-immunization serology
Abbreviations:
anti-HBs = antibody to hepatitis B surface antigen
Ig = immunoglobulin
Whenever possible, vaccine series should be completed pre-transplantation. Vaccines given post-transplant may not be sufficiently immunogenic.
Inactivated vaccines should be given at least 2 weeks before transplantation and, in general, should not be given post-transplant until baseline immunosuppression levels are attained
Given as combined vaccine (diphtheria, tetanus, pertussis; ± polio, Hib depending on age and previous vaccine history).
Routine use: follow routine immunization schedules with age-appropriate booster doses
May be given as combined vaccine.
Regardless of prior history of Hib vaccination and at least 1 year after any previous dose
Initially annual monitoring of antibody levels may be considered. Optimal timing and frequency should be based on the severity of the immunocompromised state and the ongoing risk of acquisition of HB infection.
Recombinant inactivated zoster vaccine may be considered in immunocompromised adults ≥ 50 years of age on a case by case basis. Data on the use in immunocompromised individuals is limited, but based on the burden of zoster illness in this population and the general safety of inactivated vaccines, the benefits of vaccination are expected to outweigh the risks
Pneu-C-13 vaccine followed by Pneu-P-23 vaccine is recommended. Antibody titres decline after 3 years; however, experience with re-immunization with Pneu-C-13 after solid organ transplant is limited.
Live attenuated vaccines should be given at least 4 weeks prior to transplantation
BCG may remain in the body for at least a few years, and perhaps indefinitely. Use only if benefit outweighs potential risk of reactivation post-transplant
MMR and univalent varicella vaccine may be given to infants as early as 6 months of age if transplantation is anticipated before 12 months of age. If transplantation is delayed, repeat doses should be given starting at one year of age. MMRV not recommended for age < 12 months at this time.
# Immunosuppressive therapy
Long-term immunosuppressive therapy is used for various disease conditions including cancer, organ transplantation, GVHD following HSCT, and chronic inflammatory conditions (e.g., inflammatory bowel disease, inflammatory arthritis, psoriasis, systemic lupus erythematosus). Therapies include cancer chemotherapy, radiation therapy, long term high-dose steroid treatment (prednisone equivalent of ≥ 2 mg/kg/day or 20 mg/day if weight > 10 kg, for ≥ 14 days), cytotoxic drugs, calcineurin inhibitors, chimeric antigen receptor (CAR) T cell therapy targeting lymphocytes, biological response modifiers and antibodies that target lymphocytes.
Most of these therapies have their greatest impact on cell-mediated immunity, although T cell-dependent antibody production can also be adversely affected. Monoclonal antibodies that deplete B cells profoundly affect antibody production; this effect can last for several months or years following completion of therapy. The nature of the person's underlying disease should also be considered.
CAR T cell cancer immunotherapy involves reprogramming a patient’s own T cells to identify and eliminate malignant cells. The patient’s T cells are obtained, modified in a laboratory, then infused back into the individual. Commercial CAR T cells from allogeneic donors are also available. CAR T cell therapy is used most frequently to treat hematologic malignancies, especially of B cell origin (e.g., CD19). This therapy eliminates malignant as well as normal cells expressing the target antigen, resulting in profound and prolonged loss of B lymphocytes and thus antibody production.
In general, if a patient is 3 months post-chemotherapy and the cancer is in remission, or if immunosuppression has been discontinued for at least 3 months (6 months or more for anti-B cell antibodies or CAR T cells targeting lymphocytes), the person is no longer considered immunocompromised.
# Prior to immunosuppressive therapy
Vaccination status should be reviewed for immunocompetent persons who might be anticipating initiation of immunosuppressive treatments or who have diseases that might lead to immunodeficiency. Ideally, all appropriate routine vaccines or boosters should be administered before the initiation of immunosuppressive therapy so that optimal immunogenicity is achieved. Although inactivated vaccines can be safely administered at any time before, during or after immunosuppression, inactivated vaccines should be administered at least 14 days before initiation of immunosuppressive therapy to optimize immunogenicity. Live vaccines should be administered at least 4 weeks before immunosuppressive therapy is started to reduce the risk of disease caused by the vaccine strain.
People undergoing immunosuppressive therapy are at higher risk of invasive pneumococcal disease and influenza-related complications; therefore, in addition to routine vaccines they should receive conjugate pneumococcal vaccine regardless of age and polysaccharide pneumococcal vaccine if aged 2 years or more, as well as annual immunization with inactivated influenza vaccine. Hib vaccine may be recommended in some circumstances, such as following organ transplants.
# During or after immunosuppressive therapy
If immunization cannot be completed prior to initiation of immunosuppressive therapy, generally a period of at least 3 months should elapse between therapy cessation and the administration of inactivated vaccines (if possible, to ensure maximum immunogenicity) or live vaccines (to reduce the risk of disease caused by the vaccine strain). However, this interval may vary with the type and intensity of treatment, underlying disease, or urgency of vaccination if vaccines are needed for post-exposure or outbreak management. For example, whereas immunization can occur as early as 4 weeks following discontinuation of long term high-dose systemic steroid therapy, a longer interval of 6 to 12 months or more may be required in case of therapy with rituximab (or other monoclonal anti-B cell antibody) and some other biological response modifiers. B cell enumeration is generally performed during rituximab therapy and should be reviewed prior to immunization.
Recipients of CAR T cell therapy directed against lymphocytes should be regarded as “never immunized” and managed as HSCT recipients are. The primary series (initial or repeat) of inactivated vaccines, including COVID-19 vaccines which should be initiated 3 to 6 months after CAR T cell therapy. Antibody response is unlikely while B cell aplasia persists, but cellular responses may occur.
Live vaccines may be given immediately on discontinuation of high dose steroid therapy if duration was less than 14 days. Corticosteroid therapy is not a contraindication to immunization with live vaccines when steroid therapy is short-term (i.e., less than 14 days); or low-to-moderate dose (prednisone equivalent of less than 2 mg/kg/day or less than 20 mg/day if weight > 10 kg); or physiologic replacement therapy; or administered topically, inhaled, or locally injected (e.g., joint injection). An exception is LAIV, which is contraindicated in individuals with severe asthma who are currently receiving high dose inhaled steroids.
For recipients of therapy with long term effects on the immune system, such as CAR T directed against lymphocytes, anti-B cell antibody, and some other biological response modifiers, live vaccines should not be given until adequate immune reconstitution has been confirmed by an expert.
The following principles apply if immunosuppressive therapy cannot be stopped.
## Inactivated vaccines
Inactivated vaccines (as indicated under “Prior to immunosuppressive therapy”, above) may be administered if needed during immunosuppression. If risk of exposure is low, inactivated vaccines may be temporarily delayed until the person is the least immunosuppressed. Doses may need to be repeated when the person is no longer immunosuppressed unless antibody response can be demonstrated. Hepatitis B vaccine should be given at double the usual dose and using a 3- or 4-dose schedule. HPV vaccine should be given following routine age indications but using a 3-dose schedule, regardless of age. Inactivated influenza vaccine should be given during influenza season except for those on induction chemotherapy for leukemia or receiving anti-B cell antibodies, who are unlikely to respond. If zoster vaccine is indicated, inactivated zoster vaccine should be considered.
## Live attenuated vaccines
Live vaccines are generally contraindicated. Because immunosuppressive drugs have been reported to cause reactivation of latent tuberculosis infection and predisposition to other opportunistic infections, avoidance of live vaccines during high level immunosuppressive therapy is prudent.
The safety and efficacy of live vaccines during low dose intermittent or maintenance therapy with non-corticosteroid immunosuppressive drugs are generally unknown, with the exception of varicella and live herpes zoster (HZ) vaccines, which can be considered for those receiving low dose methotrexate (≤ 0.4 mg/kg/week); azathioprine (≤ 3 mg/kg/day), or 6-mercaptopurine (≤ 1.5 mg/kg/day). Inactivated herpes zoster vaccine should be used unless it is contraindicated or unavailable. If combination low dose immunosuppression is being used, an expert should be consulted. A careful risk benefit assessment should be done if other live attenuated vaccines are to be considered in patients on low dose immunosuppression.
# Infants exposed to immunosuppressive therapy in the womb
Special consideration should be given to immunizing infants who have been exposed to monoclonal antibodies in the womb. Some monoclonal antibodies taken during pregnancy can, similar to maternal antibodies, pass through the placental barrier, potentially resulting in various forms of temporary immunosuppression in infants. For example, rituximab taken during pregnancy is associated with B-cell depletion in both mother and fetus, while infliximab can be detected in infants up to 6 months after birth.
- Due to the potential risk of disseminated disease, administration of BCG and oral polio vaccines is contraindicated in such infants who are less than 6 months of age. A longer interval of 6-12 months should be observed following rituximab therapy. Oral polio vaccine is no longer used in Canada but continues to be used in some other countries.
- There are no data at this time regarding the potential risk associated with rotavirus (RV) vaccine in these infants. Prior to RV immunization, laboratory tests may be useful in assessing humoral and cellular immune status. When considering immunization in the absence of laboratory test results, the decision to immunize should be based on an individual risk-benefit assessment. For example, in jurisdictions with ongoing RV immunization programs, indirect protection through herd immunity is likely to be high and withholding immunization may be considered until more information about the effects of monoclonal antibodies in the womb becomes available. Alternatively, in jurisdictions that do not have RV immunization programs and where exposure to wild-type rotavirus may be high, immunization with RV vaccine may be prudent to reduce the risk of potential complications from RV infection.
- Immune responses to live vaccines that are administered at or after one year of age (e.g., MMR or MMRV vaccine) are not considered to be affected by exposure to monoclonal antibodies in the womb.
- Infants exposed to monoclonal antibodies in the womb should receive all inactivated vaccines according to routine schedule, keeping in mind that immune response during the first few months may be suboptimal, depending on the monoclonal used and the gestational period during which it was administered.
Monoclonal antibodies administered to the mother during breastfeeding are thought to have very little or no impact on the infant. Transfer of monoclonal antibodies through breast milk is limited, and the minimal quantities that are ingested are likely to be broken down in the infant’s gastrointestinal tract. Infants of breastfeeding women receiving monoclonal antibody treatment post-partum should therefore be immunized with both live and inactivated vaccines according to routine schedules, unless the infant was also exposed to monoclonal antibody in the womb.
# HIV infection
The degree of immune suppression varies widely among HIV-infected individuals, reflecting disease stage and response to antiretroviral therapy. Immune suppression is approximately predicted by a recent CD4 count and CD4 percentage.
Children who are immune suppressed at HIV diagnosis and have already received routine vaccines should have antibody titres measured where possible and, if indicated, should be revaccinated after immune recovery.
## Inactivated vaccines
When possible, vaccines should be given early in the course of HIV infection although there is no contraindication to the use of inactivated vaccines at any time. If immune suppression is severe in an untreated or newly treated patient and likelihood of exposure to the vaccine-preventable disease is low, vaccination may be deferred pending immune recovery after effective antiretroviral therapy.
Inactivated vaccines should be administered to HIV-infected people according to routine immunization schedules, with the exceptions that hepatitis B vaccine should be given at double the routine dose and using a 3 or 4 dose schedule. HPV vaccine should be given following routine age indications but using a 3 dose schedule regardless of age. There is a high risk of HPV-associated warts with HIV infection; HPV 9 or 4 valent vaccine will provide additional protection over that of the 2 valent vaccine. For those 6 months of age or older, annual immunization with inactivated influenza vaccine is recommended. HIV-infected people should also receive pneumococcal conjugate vaccine regardless of age, pneumococcal polysaccharide vaccine if 2 years of age or older, and one dose of Hib vaccine after age 5 years regardless of prior Hib vaccination. Quadrivalent conjugate meningococcal vaccine is recommended and meningococcal B vaccine should be considered. Hepatitis A vaccine is recommended for those with risk factors for hepatitis A acquisition. If herpes zoster vaccine is indicated by age, inactivated zoster vaccine should be considered.
## Live attenuated vaccines
The risks and benefits of a live vaccine need to be carefully considered in consultation with an infectious disease specialist/immunologist.
In general, infants should receive rotavirus vaccine according to routine schedule, as risk from infection with wild strain outweighs theoretical risk from the vaccine. If the infant is known to have severe immunodeficiency, consultation with a specialist is recommended.
MMR, varicella, live herpes zoster vaccines may be considered early in the course of HIV-infection if immune function is normal. Although LAIV is generally contraindicated, studies have shown it to be safe and immunogenic and many experts would consider using it for HIV-infected children on antiretroviral therapy and with normal immune function (see below). MMRV and other live vaccines are contraindicated at this time because of lack of data on safety. If immune suppression is already advanced at diagnosis, live vaccines should be deferred pending potential immune recovery with treatment. Consensus thresholds based on immunologic categories have been determined for the use of MMR, univalent varicella, live zoster vaccines and LAIV as follows:
- Asymptomatic HIV-infected children 12 months of age and older without severe immunosuppression (i.e., CD4 ≥ 15% and CD4 cell count ≥ 500 × 106/L for at least 6 months in children 1 through 5 years old and ≥ 15% and CD4 cell count ≥ 200 × 106/L for at least 6 months in those 6 through 13 years of age) may receive MMR and univalent varicella vaccines.
- Immunization with MMR may be considered for susceptible HIV-infected adolescents and adults with CD4 cell count ≥ 200 × 106/L. There are no published data on the use of varicella vaccine in susceptible HIV-infected adults. HIV-infected adults should be asked for a history of varicella disease or vaccination, and if negative for both, serology should be requested to determine susceptibility. Based on expert opinion, varicella immunization may be considered for susceptible HIV-infected adults with CD4 cell count ≥200 × 106/L.
- Inactivated zoster vaccine is preferred. Live zoster vaccine may be considered if not severely immunosuppressed and inactivated vaccine is contraindicated or unavailable. Live zoster vaccine is contraindicated in persons with CD4 cell count < 200 × 106/L.
- If MMR or varicella vaccines were given to individuals with perinatal HIV infection before antiretroviral therapy was begun and serological response is not demonstrated, doses should be repeated once on effective therapy for at least 6 months.
- Live attenuated influenza vaccine may be considered in otherwise healthy HIV-infected patients aged 5–17 years on combination antiretroviral therapy regimen for ≥16 weeks with CD4 T-lymphocyte percentage ≥15 and HIV plasma RNA <60 000 copies.
- Individuals 5 years of age and older: 1 dose recommended
- Pre-exposure prophylaxis for travel: consider Ig with hepatitis A vaccine
- Post-exposure prophylaxis: Ig recommended along with hepatitis A vaccine unless immune function is normal
- Post-immunization monitoring of anti-HBs titres recommended with booster dose if titre less than 10 IU/L
- Use 5 dose schedule for post-exposure prophylaxis
- Post-immunization serology recommended
Contraindicated if CD4 < 200 x 106 cells/L
- Adolescents and adults: consider 2 doses 3-6 months apart if susceptible and not significantly immunocompromised
- Contraindicated in advanced HIV/AIDS
- If given to an individual with perinatal HIV infection before antiretroviral therapy was begun and serological response is not demonstrated, doses should be repeated once on effective therapy for at least 6 months
- Consider post-immunization serology
If the infant is known to have severe immunodeficiency, consult a specialist in pediatric HIV or immunology
- Adolescents and adults: consider 2 doses 3-6 months apart if susceptible and not significantly immunocompromised
- Contraindicated in advanced HIV/AIDS
- If given to child with perinatal HIV infection before antiretroviral therapy was begun and serological response is not demonstrated, doses should be repeated once on effective therapy for at least 6 months
- Consider post-immunization serology
- Vaccinate well in advance of travel to monitor potential adverse events
- Consider post-immunization serology
Abbreviations:
HBV = Hepatitis B virus
HCV = Hepatitis C virus
anti-HBs = antibody to hepatitis B surface antigen
LAIV = Live attenuated influenza vaccine
Given as combined vaccine (diphtheria, tetanus, pertussis; ± polio, Hib depending on age and previous vaccine history).
Routine use: follow routine immunization schedules with age-appropriate booster doses
May be given as combined vaccine.
Regardless of prior history of Hib vaccination and at least 1 year after any previous dose
Initially annual monitoring of antibody levels may be considered. Optimal timing and frequency should be based on the severity of the immunocompromised state and the ongoing risk of acquisition of HB infection
Recombinant inactivated zoster vaccine may be considered in immunocompromised adults ≥ 50 years of age on a case by case basis. Data on the use in immunocompromised individuals is limited, but based on the burden of zoster illness in this population and the general safety of inactivated vaccines, the benefits of vaccination are expected to outweigh the risks
2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014; 58(3):e44-100.
Close contacts
Annual influenza vaccine and up-to-date routine immunizations are recommended for household members and other close contacts of people with chronic diseases, as well as for their health care workers. Non-immunized close contacts of immunocompromised people should be immunized against pertussis, Hib, rotavirus, pneumococcus, measles, mumps, rubella, varicella, zoster and influenza as appropriate for age. Non-immune household or close contacts of immunocompromised people should be given hepatitis B vaccine. In addition, non-immune close contacts of HSCT recipients and close contacts of solid organ transplant candidates and recipients should receive hepatitis A vaccine if other risks for hepatitis A infection are present.
Vaccine viruses in MMR vaccine are not transmitted to contacts. Transmission of varicella vaccine virus from people with post-varicella vaccine rash occurs but is rare. Susceptible close contacts of immunocompromised people should receive MMR, MMRV, varicella or herpes zoster vaccine as appropriate for age. If the varicella vaccine recipient develops a varicella-like rash, the rash should be covered and the vaccinee should avoid direct contact with the immunocompromised person for the duration of the rash.
Infants living in households with persons who have or are suspected to have immunosuppressive conditions or who are receiving immunosuppressive medications can receive rotavirus vaccine. Following administration of rotavirus vaccine, viral antigen shedding in the stool may be detected in some vaccinees and may persist for up to 4 weeks. Transmission to household contacts occurs but is uncommon and many experts believe that the benefit of protecting immunocompromised household contacts from naturally occurring rotavirus by immunizing infants outweighs the theoretical risk of transmitting vaccine virus. To minimize the risk of transmission of vaccine virus during the 4 weeks after immunization, careful hand washing should be performed after contact with the vaccinated infant, especially after handling feces (e.g., after changing a diaper), and before food preparation or direct contact with the immunocompromised person.
Annual influenza immunization with influenza vaccine is recommended for close contacts of immunocompromised persons. Because of the theoretical risk for transmission, recipients of live attenuated influenza vaccine should avoid close association with persons with severe immunocompromising conditions (e.g., hematopoietic stem cell transplant recipients requiring isolation in hospital) for at least 2 weeks following vaccination.
Oral polio vaccine should not be administered to household contacts of an immunocompromised person. If there are household contacts who have received live, oral polio vaccine in another country within the last 6 weeks, they should not have contact with immunocompromised persons. Oral polio vaccine is not available in Canada.
Smallpox vaccine is available in Canada only for selected personnel working with vaccinia virus in research laboratories, or if an exposure to smallpox were to occur. Generally, smallpox vaccine should not be administered to household or close contacts of an immunocompromised person in a non-emergency situation. If vaccination is required in an outbreak situation, precautions should be taken to prevent spread to the immunocompromised person and other household and close contacts.
Immunocompromised travellers
A growing number of Canadians with reduced immune competence are travelling to tropical and low-income countries. Although the degree and range of infectious disease risks can increase significantly when an immunocompromised individual travels to other countries, the principles outlined above apply.
Travellers may require additional vaccines, depending on their destinations. Some travel vaccines may be contraindicated in immunocompromised individuals.
For additional information about immunization of immunocompromised travellers, refer to the Committee to Advise on Tropical Medicine and Travel statement on in Part 4 and in Part 3. |
**Immunization of immunocompromised persons: Canadian Immunization Guide**
==========================================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html)
Notice
------
This chapter has not yet been updated with the following statement from the National Advisory Committee on Immunization (NACI):
* February 24, 2023: [Public health level recommendations on the use of pneumococcal vaccines in adults, including the use of 15-valent and 20-valent conjugate vaccines.](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/public-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html)
This CIG chapter has not been completely updated to contain all pertinent information regarding COVID-19 vaccines. For this information, refer to the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html).
Last partial content update (see [Table of updates](/en/public-health/services/canadian-immunization-guide/updates.html)): March 2023
March 2023: This chapter was updated to incorporate guidance from the National Advisory Committee on Immunization (NACI) statement: [Recommended use of palivizumab to reduce complications of respiratory syncytial virus infection in infants](/en/public-health/services/publications/vaccines-immunization/palivizumab-respiratory-syncitial-virus-infection-infants.html).
Last complete chapter revision: May 2018
On this page
------------
* [Introduction and general principles](#a1)
+ [Serologic testing and re-immunization](#a2)
+ [General principles](#a3)
+ [Family or medical history](#a4)
* [Primary immunodeficiency](#a5)
+ [Predominantly antibody (B cell) deficiencies](#a6)
+ [Combined T and B cell immunodeficiencies (with or without associated /syndromic features) and Immune dysregulation](#a7)
+ [Phagocytic and neutrophil disorders](#a8)
+ [Complement deficiency](#a9)
+ [Defects of innate immunity](#a10)
- [Table 1: Vaccination of persons with primary immunodeficiencies - inactivated vaccines](#t1)
- [Table 2: Vaccination of persons with primary immunodeficiencies - live attenuated vaccines](#t2)
* [Acquired (secondary) immunodeficiency](#a13)
+ [Acquired complement deficiency](#a14)
+ [Malignant hematologic disorders](#a15)
+ [Non-hematologic malignant solid tumours](#a16)
+ [Hematopoietic stem cell transplantation (HSCT) - autologous or allogeneic](#a17)
- [Pre-HSCT immunization](#a18)
- [Post-HSCT immunization](#a19)
* [Table 3: Post-transplantation vaccination of hematopoietic stem cell transplantation (HSCT) recipients](#t3)
+ [Solid organ transplantation](#a21)
- [Pre-solid organ transplantation](#a22)
- [Post-solid organ transplantation](#a23)
* [Table 4: Vaccination of solid organ transplant candidates and recipients](#t4)
+ [Immunosuppressive therapy](#a25)
- [Prior to immunosuppressive therapy](#a26)
- [During or after immunosuppressive therapy](#a27)
- [Infants exposed to immunosuppressive therapy in the womb](#a28)
+ [HIV infection](#a29)
- [Table 5: Vaccination of HIV-infected persons](#t5)
* [Close contacts](#a31)
* [Immunocompromised travellers](#a32)
* [Selected references](#a33)
Introduction and general principles
-----------------------------------
Individuals may be immunocompromised as a result of a congenital condition, an illness or medications that suppress immune function. In general, immunocompromised persons are more susceptible to vaccine-preventable infections and may have severe infections. The safety and effectiveness of vaccines in immunocompromised persons are determined by the type of immunodeficiency and degree of immunosuppression. Each immunocompromised person is different and presents unique considerations regarding immunization. The relative degree of immunodeficiency is variable depending on the underlying condition, the progression of disease and use of immunosuppressive agents. Immunodeficiency can also vary over time in many people and the decision to recommend for or against a particular vaccine will depend upon a case-by-case analysis of the risks and benefits. There is potential for serious illness and death if immunocompromised people are under-immunized and every effort should be made to ensure adequate protection through immunization; however, inappropriate use of live vaccines can cause serious adverse events in some immunocompromised people as a result of uncontrolled replication of the vaccine virus or bacterium.
Primary care providers and specialists caring for immunocompromised patients share responsibility for ensuring appropriate vaccination of immunocompromised patients and their households. When in doubt, primary care providers should consult a specialist with experience in managing patients with the specific immunocompromising condition of concern.
The following recommendations reflect general best practices and are subject to individual considerations and new evidence as it arises.
### Inactivated vaccines
Inactivated vaccines may generally be administered to immunocompromised people if indicated because the antigens in the vaccine cannot replicate and there is no increase in the risk of vaccine-associated adverse events; however, the magnitude and duration of vaccine-induced immunity are often reduced. For complex cases, referral to a physician with expertise in immunization and/or immunodeficiency is advised.
### Live attenuated vaccines
In general, people who are **severely immunocompromised or in whom immune status is uncertain should not receive live vaccines because of the risk of disease caused by the vaccine strains**. In less severely immunocompromised people, the benefits of vaccination with routinely recommended live vaccines may outweigh risks. Before giving an immunocompromised person a live vaccine, a physician with expertise in immunodeficiency should be consulted.
### Immunoglobulins
For temporary passive protection against some infections, immunoglobulin therapy (nonspecific or pathogen specific) may be indicated for pre or post exposure. The monoclonal antibody preparation, Palivizumab (SynagisTM) is an antibody directed specifically against respiratory syncytial virus (RSV) that may be considered to reduce complications of RSV infection in children less than 24 months of age who are severely immunocompromised.
### Serologic testing and re-immunization
Immune response to vaccines may be inadequate in immunocompromised people and vaccinees may remain susceptible despite vaccination. If serologic testing is available and there is a clear antibody correlate of protection, measurement of post-immunization antibody titres to determine immune response and guide re-vaccination and post-exposure management should be considered. For infants less than 18 months of age, a positive serologic test may detect maternal antibody and not reflect an active immune response in the infant. Seroconversion or an increase in titre, or a repeat test after 18 months of age showing persistent antibody, indicate an active response. Results of serologic testing may also be confounded by passive antibody in those receiving immunoglobulin therapy.
Please note that the information in the text and tables is complementary and both should be used. Refer to [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information, especially concerning vaccine doses, schedules and boosters.
### General principles
Several general principles apply to the immunization of immunocompromised individuals:
* Maximize benefit while minimizing harm.
* Susceptibility to infection and ability to respond to a vaccine vary according to degree of immune suppression.
* Immunize at the time when maximum immune response can be anticipated.
+ Immunize prior to any planned immunosuppression, if possible.
+ Delay immunization if the immunodeficiency is transient (if this can be done safely because exposure is unlikely).
+ Stop or reduce immunosuppression to permit better vaccine response, if appropriate.
* Consider the immunization environment broadly.
+ Vaccinate family members and other close contacts when appropriate.
+ Strongly encourage up-to-date vaccinations, including annual influenza vaccination, for all healthcare workers providing care to immunocompromised people.
* Avoid live vaccines unless:
+ immunosuppression is mild and data are available to support their use.
+ the risk of natural infection is greater than the risk of immunization.
* Monitor serologic response, if appropriate test and correlate of protection is available, and boost if antibody level is inadequate.
+ The magnitude and duration of vaccine-induced immunity are often reduced in immunocompromised individuals.
### Family or medical history
Primary or secondary immunodeficiencies may be undiagnosed in young children presenting for routine immunizations, which include live vaccines. This is particularly important to consider in infants receiving live vaccines **before 12 months of age**.
A significant primary immunodeficiency in which live vaccines would be contraindicated usually declares itself in the first few months of life. The only live vaccine routinely given to children less than 12 months of age is rotavirus, which can be given as early as 6 weeks of age. Chronic rotavirus infection from the vaccine strain has occurred in infants with unrecognized severe combined immunodeficiency. BCG vaccine is given at birth in some populations and measles vaccine may be given at 6-12 months of age in an outbreak or after exposure.
Clues pointing to the presence of significant immunodeficiency may be found in the medical or family history. Infants with a history of failure to thrive, recurrent or prolonged oral candidiasis despite treatment, or recurrent serious infections such as pneumonia or sepsis may have an immunodeficiency. A family history of primary immunodeficiency may be known or may be suspected on the basis of a family history of early infant deaths. However, the family history can be negative. Routine newborn screening for severe combined immunodeficiency is now performed in some regions of Canada. Maternal human immunodeficiency virus (HIV) infection puts the infant at risk of immunodeficiency in the first year of life if HIV has been transmitted to the infant. Routine prenatal blood work in Canada includes HIV testing. If an infant shows clinical clues suggesting immunodeficiency, the mother's prenatal HIV screening result should be obtained. If a mother was not screened in pregnancy, the possibility of perinatal HIV infection from undiagnosed maternal infection should be considered.
Primary immunodeficiency
------------------------
There are currently more than 300 distinct genetic defects of immunity. These are grouped under general headings below.
Refer to [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for information regarding immunization of asplenic or hyposplenic people.
### Predominantly antibody (B cell) deficiencies
B cell defects (defects of humoral immunity) include X-linked agammaglobulinemia (XLA), common variable immunodeficiency (CVID), selective immunoglobulin A (IgA) deficiency, specific polysaccharide antibody deficiency (SPAD), and immunoglobulin G (IgG) subclass deficiency.
Individuals with defects in antibody production are highly susceptible to encapsulated bacteria such as *Streptococcus pneumoniae, Haemophilus influenzae* and *Neisseria meningitidis.*
* Most patients with severe defects of antibody production, such as XLA or CVID are not able to mount a significant humoral response. While administration of inactivated vaccines is not harmful, it may be futile. As a general rule, people with severe antibody defects can be protected from many of the vaccine preventable infections with the use of replacement immunoglobulin (Ig) therapy or pathogen-specific Ig preparations; however, the level of antibody to specific pathogens in these products may be variable.
* For those with less severe antibody deficiency and expected ability to mount some antibody response, especially selective IgA deficiency or IgG subclass deficiency, vaccination is recommended to increase the level of protection. Receipt of replacement Ig is not a contraindication for use of inactivated vaccines; however, Ig can interfere with the immune response to some live attenuated viral vaccines such as measles and varicella vaccine.
* Repeat doses of Ig should not be given to individuals with known selective IgA deficiency unless the benefit outweighs the risk, because of the very rare risk of an anaphylactic reaction to traces of IgA in the product. If indicated, an Ig product with the least amount of IgA should be used and given with caution under close observation.
#### Inactivated vaccines
In general, inactivated vaccines should be administered according to routine immunization schedules to people with less severe primary B cell defects who have some capacity for B or T cell responses. Hepatitis B vaccine should be given at double the routine dose and using a 3- or 4-dose schedule. Human papillomavirus (HPV) vaccine should be given following routine age indications but using a 3-dose schedule regardless of age.
In addition to routine vaccines, individuals with primary B cell defects should receive pneumococcal conjugate vaccine regardless of age, pneumococcal polysaccharide vaccine if 2 years of age or older, and one dose of *Haemophilus influenzae* type b (Hib) vaccine after age 5 years regardless of prior Hib vaccination history. Quadrivalent conjugate meningococcal vaccine is recommended and meningococcal B vaccine should be considered if 2 months of age or older. For infants 6 months of age or older, inactivated influenza vaccine should be given annually, even if receiving Ig, as Ig may not have antibody to the current influenza strains. However, humoral response may be reduced.
#### Live attenuated vaccines
Patients with severe B cell defects (XLA, CVID), and others receiving regular immunoglobulin replacement therapy, should not receive measles-mumps-rubella (MMR), measles-mumps-rubella-varicella (MMRV) or varicella vaccines as Ig will interfere with the efficacy of these vaccines.
Individuals with **partial B cell defects and** **known intact T cell immunity** and some ability to produce antibody who are not receiving Ig should receive MMR and univalent varicella vaccines as appropriate for age. MMRV has not been evaluated in immunodeficiency. All other live vaccines such as rotavirus, live attenuated influenza, live herpes zoster vaccine, Bacille Calmette-Guérin (BCG), oral polio, smallpox, oral typhoid and yellow fever vaccines are contraindicated. If travel to an area where yellow fever is being transmitted cannot be avoided, consideration of vaccination in consultation with a specialist is advised.
People with **selective IgA deficiency who have no concomitant defects in T cell function** can receive most live vaccines. Live mucosal vaccines (rotavirus, live attenuated influenza vaccine (LAIV), oral typhoid) are likely safe and may be used although there may be lack of mucosal response. Some experts prefer to use inactivated vaccines if available (e.g., inactivated influenza vaccine, parenteral inactivated typhoid vaccine). However, given that there are limited data on the use of live mucosal vaccines, consultation with an immunologist is advised and immunization with these vaccines should be individually assessed.
The diagnosis of **IgG subclass deficiency** should be based on documented failure to produce adequate amounts of specific antibody and not on quantitative Ig levels. Individuals with documented IgG subclass deficiency with intact T cell function who are not receiving regular Ig replacement therapy can receive routine live vaccines although response may be suboptimal. All live vaccines may be given to individuals with isolated **SPAD**.
Refer to [Blood Products, Human Immunoglobulin and Timing of Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) in Part 1 for the recommended intervals between Ig and subsequent immunization.
Refer to [Table 1](#t1) and [Table 2](#t2) and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
### Combined T and B cell immunodeficiencies (with or without associated /syndromic features) and Immune dysregulation
Individuals with T cell or combined deficiency are particularly susceptible to infections with virtually all viruses and many bacteria. T cell defects may be **severe** (e.g., severe combined immunodeficiency, complete DiGeorge syndrome) or **partial** (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome, ataxia telangiectasia, hyper IgM syndrome, hyper IgE syndrome, X-linked lymphoproliferative disease, familial predisposition to hemophagocytic lymphohistiocytosis). Those with severe defects will not respond to any vaccines. Those with partial defects may have some response.
#### Inactivated vaccines
For those with severe combined immunodeficiency, administration of inactivated vaccines is not harmful, but will not provide protection.
Inactivated vaccines should be given to those with partial immunodeficiency although response may be suboptimal. Hepatitis B vaccine should be given at double the routine dose and using a routine 3- or 4-dose schedule. HPV vaccine should be given following routine age indications but using a 3-dose schedule regardless of age.
In addition to routine vaccines, individuals with partial T cell or combined defects should receive pneumococcal conjugate vaccine regardless of age, pneumococcal polysaccharide vaccine if 2 years of age or older, and one dose of Hib vaccine after age 5 years regardless of prior Hib vaccination history. Quadrivalent conjugate meningococcal vaccine is recommended and meningococcal B vaccine should be considered if 2 months of age or older. Inactivated influenza vaccine should be given annually, as Ig may not protect. However, humoral response may be reduced.
#### Live attenuated vaccines
All live attenuated vaccines are contraindicated for individuals with severe T cell defects. Exposure to natural infection or inadvertent live attenuated vaccine administration can usually be managed with rapid administration of Ig or pathogen-specific Ig with or without appropriate antiviral treatment. Live vaccines are also generally contraindicated for those with Wiskott-Aldrich syndrome, ataxia telangiectasia, X-linked lymphoproliferative disease, or familial predisposition to hemophagocytic lymphohistiocytosis.
Live attenuated vaccines may be considered for those with partial T cell defects after assessment of immune competence. Those with partial DiGeorge syndrome, or other combined defects, and a total CD4 lymphocyte count of > 500 x 106/L and normal mitogen response should receive MMR and univalent varicella vaccines as MMRV has not been evaluated in this population. MMRV and other live vaccines are contraindicated.
Refer to [Blood Products, Human Immunoglobulin and Timing of Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) in Part 1 for the recommended intervals between Ig and subsequent immunization.
Refer to [Table 1](#t1), [Table 2](#t2) and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
### Phagocytic and neutrophil disorders
People with **phagocytic and neutrophil disorders** (e.g., congenital neutropenia, cyclic neutropenia, leukocyte adhesion and migration defects, chronic granulomatous disease (CGD), myeloperoxidase deficiency and Chediak-Higashi syndrome) are at increased risk for bacterial infections.
#### Inactivated vaccines
All routine inactivated vaccines and others required because of travel or exposure should be given. Pneumococcal conjugate vaccine (regardless of age) and pneumococcal polysaccharide vaccine if 2 years of age or older are indicated for all conditions other than CGD. CGD does not increase the risk of invasive pneumococcal disease, so conjugate vaccine should be used according to routine schedules and polysaccharide vaccine is not indicated. Inactivated influenza vaccine should be given annually. Influenza vaccine is especially important in patients with CGD due to increased morbidity and mortality with staphylococcal lung infections that are associated with influenza.
#### Live attenuated vaccines
Live bacterial vaccines (BCG, oral typhoid) are contraindicated in all phagocytic or neutrophil defects. Live attenuated viral vaccines (rotavirus, MMR, varicella, MMRV, herpes zoster) should be given according to routine schedules to persons with neutropenia or CGD, and live attenuated influenza vaccine (LAIV) or yellow fever vaccine may be given if indicated. All live attenuated viral vaccines are contraindicated with leukocyte adhesion defect (LAD), Chediak-Higashi syndrome and other defects in cytotoxic granule release, and in any other undefined phagocytic cell defect.
Refer to [Table 1](#t1), [Table 2](#t2) and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
### Complement deficiency
Individuals with complement, properdin, factor D or B or mannan-binding lectin deficiency are particularly susceptible to infections with *N. meningitidis* but also susceptible to other encapsulated bacteria such as *S. pneumoniae* and *Haemophilus influenzae*. In general, response to vaccines is expected to be normal and there are no contraindications.
#### Inactivated vaccines
Inactivated vaccines should be administered according to routine immunization schedules.
In addition to routine vaccines, quadrivalent conjugate meningococcal vaccine is recommended and meningococcal B vaccine should be considered if 2 months of age or older. Pneumococcal conjugate vaccine should be given regardless of age, pneumococcal polysaccharide vaccine if 2 years of age or older, and one dose of Hib vaccine after age 5 years regardless of prior Hib vaccination history. Influenza vaccine (inactivated or live attenuated, as appropriate for age) should be given annually.
#### Live attenuated vaccines
Individuals with complement deficiency should receive all routine live attenuated vaccines and any other live vaccines that are indicated (e.g., for travel or after exposure).
Refer to [Table 1](#t1), [Table 2](#t2) and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
### Defects of innate immunity
Innate immune defects of cytokine generation or cellular activation, such as defects of the interferon-gamma/interleukin-12 axis, increase susceptibility to mycobacterial disease. Toll-like receptor signaling pathway deficiencies (i.e. IRAK4 and MyD88 deficiency) increase susceptibility to pneumococcal and other pyogenic bacterial infections. Some innate defects may result in increased susceptibility to viral infections.
#### Inactivated vaccines
All routine inactivated vaccines should be given. Persons with IRAK4 and MyD88 deficiency or other defects causing increased risk for pyogenic bacterial infections should receive conjugate pneumococcal vaccine regardless of age and polysaccharide pneumococcal vaccine at age ≥ 2 years. Other inactivated vaccines should be used as indicated for travel or exposure.
#### Live attenuated vaccines
A specialist should be consulted before giving live vaccines to persons with innate immune defects of cytokine generation or response or cellular activation defects. Persons with interferon gamma/interleukin-12 axis defects have a greater susceptibility to intracellular bacteria (i.e. salmonella or mycobacteria). For those patients, live bacterial vaccines (BCG, oral typhoid) are contraindicated. Live viral vaccines are contraindicated in patients with defects in alpha/beta or gamma interferon production. All live vaccines are contraindicated in nuclear factor kappa B pathway defects.
Refer to [Table 1](#t1) and [Table 2](#t2) for recommendations for vaccination of persons with primary immunodeficiencies and to [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
Table 1: Vaccination of persons with primary immunodeficiencies - Inactivated vaccines
(Refer to text and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) for additional information)
| Inactivated vaccines | Primary Immunodeficiency | Comments |
| --- | --- | --- |
| B cell deficiency[Footnote 1](#fnt11) | Combined T, B cell deficiency[Footnote 1](#fnt11) | Phagocytic & neutrophil disorders | Complement deficiency | Innate immune defects |
| Cholera and travellers' diarrhea (inactivated) | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | |
| Diphtheria[Footnote 2](#fnt12) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | |
| *Haemophilus influenzae* type b (Hib)[Footnote 4](#fnt14) | Children less than 5 years of age: routine use | Children less than 5 years of age: routine use | Children less than 5 years of age: routine use | Children less than 5 years of age: routine use | Children less than 5 years of age: routine use | |
| Individuals 5 years of age and older: 1 dose recommended[Footnote 5](#fnt15) | Individuals 5 years of age and older: 1 dose recommended[Footnote 5](#fnt15) | | Individuals 5 years of age and older: 1 dose recommended[Footnote 5](#fnt15) | |
| Hepatitis A | Use if indicated\* | Use if indicated\* | Use if indicated | Use if indicated | Use if indicated\* | \* Pre-exposure prophylaxis for travel: consider Ig with hepatitis A vaccine unless receiving routine IG replacement therapy
\* Post-exposure prophylaxis: Ig recommended in addition to vaccine unless receiving routine IG replacement therapy. |
| Hepatitis B | Recommended\*\* | Recommended\*\* | Routine Use | Routine Use | Routine Use | \*\* Double the routine dose and use 3 or 4 dose schedule
\*\* Post-immunization monitoring of anti-HBs titres recommended with booster dose if titre less than 10 IU/L[Footnote 6](#fnt16) |
| Herpes zoster (recombinant inactivated) | Consider if indicated by age[Footnote 7](#fnt17) | Consider if indicated by age[Footnote 7](#fnt17) | Consider if indicated by age[Footnote 7](#fnt17) | Consider if indicated by age[Footnote 7](#fnt17) | Consider if indicated by age[Footnote 7](#fnt17) | |
| HPV | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | 3-dose schedule recommended |
| Influenza (inactivated) | Recommended annually | Recommended annually | Recommended annually | Recommended annually | Recommended annually | |
| Japanese encephalitis | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | |
| Meningococcal quadrivalent conjugate | Recommended | Recommended | Routine use | Recommended | Routine use | If recommended, start at age 2 months or at diagnosis if later. Booster doses required every 3-5 years. |
| Meningococcal B | Should be considered | Should be considered | Use if indicated | Should be considered | Use if indicated | If indicated, start at age 2 months, or at diagnosis if later. Booster doses required every 3-5 years. |
| Pertussis[Footnote 2](#fnt12) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | |
| Pneumococcal conjugate 13-valent (Pneu-C-13) | Recommended regardless of age | Recommended regardless of age | Recommended regardless of age[Footnote 8](#fnt18) | Recommended regardless of age | Recommended regardless of age | Should be followed, at age at least 2 years and at least 2 months after last dose with pneumococcal polysaccharide vaccine |
| Pneumococcal polysaccharide (Pneu-P-23) | Recommended if 2 years of age or older | Recommended if 2 years of age or older | Recommended if 2 years of age or older[Footnote 8](#fnt18) | Recommended if 2 years of age or older | Use if indicated[Footnote 9](#fnt19) | One re-immunization recommended 5 years after first dose |
| Polio[Footnote 2](#fnt12) (inactivated) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | |
| Rabies | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | * Do not use intradermally
* Use 5 dose schedule for post exposure prophylaxis
* Post-immunization serology recommended
|
| Tetanus[Footnote 2](#fnt12) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | Routine use[Footnote 3](#fnt13) | |
| Typhoid (inactivated) | Use if indicated | Use if indicated | Use if indicated | Use if indicated | Use if indicated | |
|
Abbreviations:
anti-HBs = antibody to hepatitis B surface antigen
Ig = immunoglobulin
Footnote 1
Most patients with severe B cell deficiency (e.g., X-linked agammaglobulinemia, common variable immunodeficiency) and patients with severe T cell defects (e.g., severe combined immunodeficiency, complete DiGeorge syndrome) are unable to respond to any vaccine. Inactivated vaccines are safe but not effective. They should be given only if some antibody production is expected. Those with less severe defects should receive inactivated vaccines as indicated here.
[Return to footnote 1 referrer](#fnt11-1-rf)
Footnote 2
Given as combined vaccine (diphtheria, tetanus, pertussis; ± polio, Hib depending on age and previous vaccine history).
[Return to footnote 2 referrer](#fnt12-1-rf)
Footnote 3
Routine use: Follow routine immunization schedules with age-appropriate booster doses.
[Return to footnote 3 referrer](#fnt13-1-rf)
Footnote 4
May be given as combined vaccine.
[Return to footnote 4 referrer](#fnt14-1-rf)
Footnote 5
Regardless of prior history of Hib vaccination and at least 1 year after any previous dose
[Return to footnote 5 referrer](#fnt15-1-rf)
Footnote 6
Initially annual monitoring of antibody levels may be considered. Optimal timing and frequency should be based on the severity of the immunocompromised state and the ongoing risk of acquisition of HB infection.
[Return to footnote 6 referrer](#fnt16-1-rf)
Footnote 7
Recombinant inactivated zoster vaccine may be considered in immunocompromised adults ≥ 50 years of age on a case by case basis. Data on the use in immunocompromised individuals is limited, but based on the burden of zoster illness in this population and the general safety of inactivated vaccines, the benefits of vaccination are expected to outweigh the risks.
[Return to first footnote 7 referrer](#fnt17-1-rf)
Footnote 8
For CGD, give pneumococcal conjugate vaccine according to the routine schedule; pneumococcal polysaccharide vaccine is not indicated.
[Return to first footnote 8 referrer](#fnt18-1-rf)
Footnote 9
Persons with IRAK4 and MyD88 deficiency or other innate defects causing increased risk for pyogenic bacterial infections should receive polysaccharide pneumococcal vaccine at age ≥ 2 years.
[Return to footnote 9 referrer](#fnt19-1-rf)
|
Table 2: Vaccination of persons with primary immunodeficiencies - Live attenuated vaccines
(Refer to text and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) for additional information)
| Live attenuated vaccines | Primary Immunodeficiency | Comments |
| --- | --- | --- |
| Minor B cell deficiency[Footnote 1](#fnt21)
(Partial B cell defects, IgA deficiency, IgG subclass deficiency, SPAD) | Partial T cell, combined T, B deficiency[Footnote 2](#fnt22) | Phagocytic & neutrophil disorders (see exceptions)[Footnote 3](#fnt23) | Complement deficiency | Innate immune defects[Footnote 4](#fnt24) |
| BCG | Contraindicated for minor B cell deficiencies except for isolated IgA deficiency, IgG subclass deficiency, SPAD: use if indicated | Contraindicated | Contraindicated | Use if indicated | Contraindicated | |
| Herpes zoster (live) | Contraindicated | Contraindicated | Use if indicated by age and inactivated vaccine is contraindicated or unavailable | Use if indicated by age and inactivated vaccine is contraindicated or unavailable | Contraindicated | |
| Influenza (live) | Contraindicated for minor B cell deficiencies except for isolated IgA deficiency, IgG subclass deficiency, SPAD: Consider use[Footnote 5](#fnt25) | Contraindicated - use inactivated | Use if indicated | Use if indicated | Consult specialist | |
| MMR | Routine use\*[Footnote 6](#fnt26)[Footnote 7](#fnt27) | Use if T cell function meets criteria (see text)\* | Routine use | Routine use | Consult specialist | \*B or T cell or combined deficiency: Consider post-immunization serology and re-immunize if protective titres not achieved |
| MMRV | Contraindicated for minor B cell deficiencies except for isolated IgA deficiency, IgG subclass deficiency, SPAD: Consider use | Contraindicated | Routine use | Routine use | Consult specialist | |
| Rotavirus | Contraindicated for minor B cell deficiencies except for isolated IgA deficiency, IgG subclass deficiency, SPAD: Consider use | Contraindicated | Routine use | Routine use | Consult specialist | |
| Smallpox | Contraindicated for minor B cell deficiencies except for isolated IgA deficiency, IgG subclass deficiency, SPAD: Use if indicated | Contraindicated | Use if indicated | Use if indicated | Consult specialist | |
| Typhoid (live) | Contraindicated for minor B cell deficiencies except for isolated IgA deficiency, IgG subclass deficiency, SPAD: Consider use[Footnote 5](#fnt25) | Contraindicated; if indicated, use inactivated | Contraindicated; if indicated, use inactivated | Use if indicated | Contraindicated; if indicated use inactivated | |
| Varicella (univalent) | Routine use\*[Footnote 6](#fnt26)[Footnote 7](#fnt27) | Use if T cell function meets criteria (see text)\* | Routine use | Routine use | Consult specialist | \*B or T cell or combined deficiency: Consider post-immunization serology and re-immunize if protective titres not achieved |
| Yellow fever | Contraindicated for minor B cell deficiencies except for isolated IgA deficiency, IgG subclass deficiency, SPAD: Use if indicated[Footnote 8](#fnt28) | Contraindicated | Use if indicated | Use if indicated | Consult specialist | |
|
Abbreviation: Ig = immunoglobulin
Footnote 1
Major B cell deficiency: X-linked agammaglobulinemia, common variable immunodeficiency and other major antibody defects: all live vaccines contraindicated. Those with partial B cell defects and known intact T cell function who are not receiving regular Ig therapy may receive MMR and varicella vaccines. Other live vaccines are contraindicated.
[Return to footnote 1 referrer](#fnt21-1-rf)
Footnote 2
Severe combined immunodeficiency, complete DiGeorge syndrome and others with severe T cell deficiency: all live vaccines contraindicated. Those with partial defects (see text) may receive MMR and varicella vaccine.
[Return to footnote 2 referrer](#fnt22-1-rf)
Footnote 3
All live vaccines contraindicated with leukocyte adhesion defect, Chediak-Higashi syndrome and other defects in cytotoxic granule release, and any other undefined phagocyte defect
[Return to footnote 3 referrer](#fnt23-1-rf)
Footnote 4
A specialist should be consulted before giving live vaccines to persons with defects of cytokine generation / response or cellular activation defects. Live bacterial vaccines are contraindicated in defects of interferon gamma/interleukin-12 pathways. Live viral vaccines are contraindicated in patients with defects of alpha or gamma interferon production. All live vaccines are contraindicated in nuclear factor kappa B pathway defects.
[Return to footnote 4 referrer](#fnt24-1-rf)
Footnote 5
Consult with immunologist in cases of IgA deficiency; some experts may prefer inactivated vaccine for persons with IgA deficiency
[Return to footnote 5 referrer](#fnt25-1-rf)
Footnote 6
Routine use: follow routine immunization schedules with age-appropriate booster doses
[Return to footnote 6 referrer](#fnt26-1-rf)
Footnote 7
Regular immunoglobulin replacement therapy will affect the efficacy of the vaccine. Refer to [Blood products, human immunoglobulin and timing of immunization in Part 1](https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-11-blood-products-human-immune-globulin-timing-immunization.html) for the recommended intervals between Ig and subsequent immunization.
[Return to footnote 7 referrer](#fnt27-1-rf)
Footnote 8
If travel to an area where yellow fever is being transmitted cannot be avoided, consider use of the vaccine in consultation with a specialist.
[Return to footnote 8 referrer](#fnt28-1-rf)
|
Acquired (secondary) immunodeficiency
-------------------------------------
Acquired immunodeficiency states result from medical conditions that directly or indirectly cause immunosuppression (e.g., malignant hematologic disorders or solid tumours, hematopoietic stem cell transplantation, HIV-infection). Acquired immunodeficiency may also occur due to immunosuppressive therapies (e.g., long-term steroid treatment, cancer chemotherapy, other cytotoxic therapy, biological response modifiers, calcineurin inhibitors, radiation therapy) used to treat these conditions as well as to treat solid organ transplant recipients and a range of chronic inflammatory conditions (e.g., inflammatory bowel disease, arthritis, psoriasis, systemic lupus erythematosus).
Refer to [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for information regarding immunization of asplenic or hyposplenic people, as well as other chronic diseases.
### Acquired complement deficiency
People who are receiving the terminal complement inhibitor eculizumab (Soliris™, Alexion Pharmaceuticals Inc.) for paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome or other conditions are at high risk of invasive meningococcal infections. In addition to all age-appropriate routine vaccines, quadrivalent conjugate meningococcal vaccine is recommended and meningococcal B vaccine should be considered. They must be vaccinated at least 2 weeks prior to receiving the first dose of eculizumab, if possible, and every 3-5 years thereafter if they continue to use the drug.
Hemolysis can be precipitated by the combination of meningococcal B vaccines and eculizumab if the underlying hemolytic condition is not yet under control. For patients already receiving eculizumab, meningococcal B vaccine should be given after the underlying hemolytic condition is under control and less than one week after a dose of eculizumab. For more information, refer to the [Recalls and safety alerts](http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2016/60752a-eng.php).
### Malignant hematologic disorders
(e.g., leukemia, lymphomas, blood dyscrasias or other malignant neoplasms affecting the bone marrow or lymphatic systems)
#### Inactivated vaccines
In general, inactivated vaccines should be administered to people with malignant hematologic disorders according to routine immunization schedules, although response may be sub-optimal. Immunization should be given at least 2 weeks prior to the start of immunosuppressive therapy or when immunosuppressive therapy is at the lowest level unless the risk of imminent exposure to the pathogen is high. Hepatitis B vaccine should be given at double the routine dose and using a 3 or 4 dose schedule. HPV vaccine should be given following routine age indications but using a 3 dose schedule regardless of age. Doses of any vaccine received while on immunosuppressive therapy should be repeated once no longer immune suppressed, unless an adequate antibody response can be demonstrated.
Individuals with malignant hematologic neoplasms should also receive conjugate pneumococcal vaccine (regardless of age), pneumococcal polysaccharide vaccine if age 2 years or more, and one dose of Hib vaccine after age 5 years regardless of prior Hib vaccination history, because of increased susceptibility to these infections. For infants 6 months of age or older, annual immunization with inactivated influenza vaccine is also recommended.
#### Live attenuated vaccines
Live attenuated vaccines are contraindicated in individuals with severe immunodeficiency due to blood dyscrasias, lymphomas, leukemias of any type, or other malignant neoplasms affecting the bone marrow or lymphatic systems and in people undergoing immunosuppressive chemotherapy or radiotherapy treatment for these conditions.
In general, if the cancer is in remission and chemotherapy and/or radiotherapy have been completed for at least 3 months, and T cell function is normal, the person is no longer considered immunocompromised and live vaccines may be given. Live vaccines should be deferred for at least 6 months after therapy with anti B-cell antibody.
### Non-hematologic malignant solid tumours
#### Inactivated vaccines
Inactivated vaccines should be administered to people with malignant solid tumours according to routine immunization schedules. Immunization should be given at least 2 weeks prior to the start of immunosuppressive therapy or when immunosuppressive therapy is at the lowest level unless the risk of imminent exposure to the pathogen is high. Hepatitis B vaccine should be given at double the routine dose and using a 3- or 4-dose schedule. HPV vaccine should be given following routine age indications but using a 3-dose schedule regardless of age. Doses of any vaccine received while on immunosuppressive therapy should be repeated once no longer immune suppressed unless an adequate antibody response can be demonstrated.
In addition, pneumococcal conjugate vaccine (regardless of age) and polysaccharide vaccine (if age 2 years or more) should be given because of increased susceptibility to invasive pneumococcal disease. For infants 6 months of age or older, annual immunization with inactivated influenza vaccine is also recommended.
#### Live attenuated vaccines
Live vaccines are contraindicated in people undergoing immunosuppressive treatment for any malignant solid tumour.
In general, if chemotherapy has been completed for at least 3 months and the cancer is in remission, the person is no longer considered immunocompromised.
### Hematopoietic stem cell transplantation (HSCT): autologous or allogeneic
HSCT is the transplantation of hematopoietic stem cells following bone marrow ablation or non-ablative conditioning (chemotherapy and/or radiotherapy to deplete the hematopoietic system prior to transplant). HSCT recipients receive either their own cells (autologous HSCT) or cells from a donor (allogeneic HSCT). Stem cells are sourced from bone marrow, peripheral blood, or umbilical cord blood.
Virtually all HSCT recipients experience a prolonged period of immune suppression following transplantation. Antibody titres to vaccine-preventable diseases decrease after allogeneic or autologous HSCT. Duration of immune suppression varies, depending on type of transplant (allogeneic or autologous), stem cell source, stem cell manipulation and post-transplant complications. Allogeneic HSCT recipients experience profound immune suppression in the post-transplant period, with recovery of the immune system approximately 1-2 years after HSCT. However, this recovery is delayed in the presence of immunosuppressive medication and chronic graft-versus-host disease (cGVHD). Recovery usually occurs earlier after autologous HSCT but still requires several months.
In general, T cells capable of responding to new antigens are generated at 6 to 12 months after transplant, earlier in young children and later in adults. Although reconstitution occurs earlier after autologous HSCT than after allogeneic HSCT, the approaches to vaccination are the same. Efficacy data for vaccines in HSCT recipients are limited.
Vaccination in accordance with transplant centre-specific immunization guidelines is generally part of routine post-transplant care provided by the transplant centres.
### Pre-HSCT immunization
If time permits, careful consideration must be given to the pre-transplant immunization status of the HSCT candidate. All routine inactivated vaccines should be given as appropriate for age. In addition, conjugate pneumococcal vaccine (regardless of age) and polysaccharide pneumococcal vaccine (if age 2 years or more) should be given if not previously received. If the transplant is planned during the influenza season, inactivated influenza vaccine should be given. Inactivated vaccines should be given at least 2 weeks prior to onset of the pre-transplant conditioning regimen. Live vaccines should not be given within 4 weeks of the start of conditioning. BCG should not be given at any time to those with a condition that will likely eventually require HSCT. BCG may persist in the body for at least a few years, and perhaps indefinitely, so there is a theoretical risk of reactivation post-transplant.
Donor vaccination may improve responses of the HSCT recipient to some vaccines; however, due to logistical and ethical issues it is often not feasible. When the HSCT donor is related to the recipient, consideration should be given to immunizing the donor before stem cell collection. As a minimum, the donor should have received all routine age-appropriate vaccines including routine boosters, COVID-19 vaccines, and influenza vaccine if stem cell collection is to occur during the influenza season. Inactivated vaccines should be given at least 2 weeks prior to stem cell collection. Live parenteral vaccines are contraindicated within 4 weeks of stem cell collection. For autologous HSCT, inactivated vaccines should be given at least 2 weeks before and live parenteral vaccines at least 4 weeks before stem cell collection.
If indicated for age and by immune status, and if feasible, a primary series of a non-live COVID-19 vaccine should be completed at least 2 weeks prior to onset of the pre-transplant conditioning regimen for allogeneic HSCT and at least 2 weeks prior to stem cell collection for autologous HSCT.
Doses of COVID-19 vaccine may be given at an interval shorter than the recommended interval of 8 weeks, respecting the minimum authorized interval.
If the recipient or donor is eligible for a booster dose, consideration should be given to administering the booster at least 2 weeks prior to stem cell collection, if feasible.
At this time, it is not known if giving an extra dose of COVID-19 vaccine prior to conditioning or stem cell collection would improve response to COVID-19 vaccine post-HSCT.
If transplantation is urgent, it should not be delayed to facilitate donor or recipient vaccination.
### Post-HSCT immunization
HSCT recipients should be viewed as "never immunized" and require re-immunization after transplant because the ablation of hematopoietic cells in the bone marrow pre-transplant eliminates most or all immune memory. In addition, certain vaccine preventable diseases pose increased risk for HSCT recipients of all ages (e.g., pneumococcus, Hib, measles, varicella, and influenza). HSCT recipients respond poorly to polysaccharide vaccines, such as pneumococcal polysaccharide 23-valent vaccine. If serologic testing is available and there is a clear antibody correlate of protection, measurement of post-immunization antibody titres to determine immune response and guide re-vaccination and post-exposure management should be considered.
#### Inactivated vaccines
All routine inactivated vaccines should be given (or repeated) for HSCT recipients generally beginning 6 to 12 months post-transplant (pneumococcal conjugate vaccine may be given beginning at 3 to 6 months post-transplant, inactivated influenza vaccine may be given beginning at 4 to 6 months post-transplant). Pneumococcal conjugate vaccine and Hib vaccine should be given regardless of age. Those 2 years of age or older should receive pneumococcal polysaccharide vaccine at 12 to 18 months post-transplant (6 to 12 months after the last dose of pneumococcal conjugate vaccine) if no GVHD. Hepatitis B vaccine should be given at double the dose used in the routine 3-dose schedule. HPV vaccine should be given using a 3-dose schedule, regardless of age. For those with risk factors for invasive meningococcal disease (e.g., functional hyposplenia), quadrivalent conjugate meningococcal is recommended and meningococcal B vaccine should be considered.
The primary series (initial or repeat) of COVID-19 vaccine should be initiated 3 to 6 months after HSCT. In general, it is recommended that the immunization of immunocompromised persons occur at a time when the immune response can be maximized. However, delaying COVID-19 vaccination to maximize the immune response needs to be weighed against the risk of infection while waiting, taking into consideration risk of exposure and local transmission of SARS-CoV-2. Time of initiation should also take into account the immune status of the HSCT recipient, including B-lymphocyte counts, receipt of immunosuppressive therapy currently or within the past 3 months, rituximab therapy or other anti-B cell monoclonal antibody within the last 12 months, and active GVHD or moderate to severe cGVHD.
Individuals with recent or current immunosuppressive therapy or active cGVHD are expected to have lower seroconversion rates, but nevertheless, rates of 56%, 63% and 73% have been reported in HSCT recipients on immunosuppression. New cGVHD and worsening of cGVHD have occasionally been reported after receipt of a COVID-19 vaccine, but whether or not vaccination was causal is not known. Patients at risk for GVHD should be advised that a cGVHD flare may occur but relationship to the vaccine is unknown. Careful monitoring of patients with a history of cGVHD is warranted. If new onset or exacerbation of GVHD occurs after COVID-19 vaccination, the decision to give a further dose should be made on an individual basis, taking into consideration risk of exposure to SARS-CoV-2 and the severity of the GVHD.
#### Live attenuated vaccines
MMR and univalent varicella vaccines may be considered 24 months or more post-transplant provided there is no evidence of chronic GVHD, immunosuppression has been discontinued for at least 3 months, the underlying disease for which the transplant was done (if immunosuppressive), is not active, and the person is considered immunocompetent by a transplant specialist. Yellow fever vaccine may be given if the above criteria are met and travel to an area with risk of yellow fever acquisition cannot be avoided. Other live vaccines are contraindicated. Note that some HSCT recipients may be receiving regular doses of immunoglobulin which will interfere with the response to live vaccines, in which case these vaccines (excluding yellow fever), should be deferred until 8-11 months after the last dose of immunoglobulin. Live herpes zoster vaccine is not recommended post HSCT.
Refer to [Table 3](#t3) and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for recommendations for HSCT recipients.
Table 3: Post-transplantation vaccination of hematopoietic stem cell transplantation (HSCT) recipients
(Refer to text and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) for additional information)| Vaccine | Post-transplantation | Comments |
| --- | --- | --- |
| Inactivated vaccines |
| --- |
| Cholera and travellers' diarrhea (inactivated) | Use if indicated | Beginning 6 months post-HSCT |
| COVID-19[Footnote 1](#fnt31) | Recommended: 3 doses and booster(s) | Beginning 3 to 6 months post-HSCT |
| Diphtheria[Footnote 2](#fnt31) | Recommended: 3 doses | Beginning 6 to 12 months post-HSCT |
| Haemophilus influenzae type b (Hib)[Footnote 3](#fnt33) | Recommended: 3 doses | Beginning 6 to 12 months post-HSCT |
| Hepatitis A | Use if indicated | * Beginning 6 months post-HSCT
* Pre-exposure prophylaxis for travel: consider Ig with hepatitis A vaccine unless receiving routine IG replacement therapy.
* Post-exposure prophylaxis: Ig recommended along with hepatitis A vaccine unless receiving routine IG replacement therapy.
|
| Hepatitis B | Recommended: 3 or 4 doses. Use double the routine dose if already immunocompromised | * Beginning 6 to 12 months post-HSCT
* Double the routine dose; 3 or 4 dose schedule recommended
* Post-immunization monitoring of anti-HBs titres recommended with booster dose if titre less than 10 IU/L[Footnote 4](#fnt34)
|
| Herpes zoster (recombinant inactivated) | Consider if indicated by age[Footnote 5](#fnt35) | |
| HPV | Recommended if indicated by age: 3 doses | Beginning 6 to 12 months post-HSCT; 3 dose schedule |
| Influenza (inactivated) | Recommended annually
2 doses the first year post transplant if less than 9 years old | Beginning 4 to 6 months post-HSCT |
| Japanese encephalitis | Use if indicated | Beginning 6 months post-HSCT |
| Meningococcal conjugate | Routine use. Use quadrivalent conjugate meningococcal vaccine if indicated by risk factors for invasive meningococcal disease (e.g., functional hyposplenia) | Beginning 6 months post-HSCT |
| Meningococcal B | Should be considered if indicated by risk factors for invasive meningococcal disease (e.g., functional hyposplenia) | Beginning 6 months post-HSCT |
| Pertussis[Footnote 2](#fnt32) | Recommended: 3 doses for children and adolescents up to age 18
1 dose for adults 18 years of age and older | Beginning 6 to 12 months post-HSCT |
| Pneumococcal conjugate 13-valent (Pneu-C-13) | Recommended: 3 doses, regardless of age | * Beginning 3 to 6 months post-HSCT
* 3 doses of Pneu-C-13 vaccine at least 4 weeks apart
|
| Pneumococcal polysaccharide
(Pneu-P-23) | Recommended: 1 dose | * Give 12 to 18 months post-HSCT if no GVHD (6 to 12 months after the last dose of Pneu-C-13)
* If GVHD, give 4th dose of Pneu-C-13 and delay polysaccharide until GVHD resolved
* Consider re-immunization after 1 year
|
| Polio (inactivated)[Footnote 2](#fnt32) | Recommended: 3 doses | Beginning 6 to 12 months post-HSCT |
| Rabies | Use if indicated | * Do not use intradermally
* Give as needed for post-exposure management
* Use 5 dose schedule for post-exposure prophylaxis
* Beginning 6 to 12 months post-HSCT for pre-exposure prophylaxis
* Post-immunization serology recommended
|
| Tetanus[Footnote 2](#fnt32) | Recommended: 3 doses | * Beginning 6 to 12 months post-HSCT
|
| Typhoid (inactivated) | Use if indicated | * Beginning 6 months post-HSCT
|
| Live vaccines |
| Bacille Calmette-Guérin (BCG) | Contraindicated | |
| Herpes zoster (live) | Contraindicated. Use inactivated vaccine | |
| Influenza (live) | Not recommended - use inactivated vaccine | |
| Measles-mumps-rubella | Recommended: 2 doses[Footnote 6](#fnt36) | * Beginning 24 months post-HSCT
* Serology recommended after 2nd dose
|
| MMRV | Contraindicated | |
| Rotavirus | Contraindicated | |
| Smallpox | Contraindicated | |
| Typhoid (live) | Contraindicated - if indicated use inactivated | |
| Varicella (univalent) | Recommended: 2 doses[Footnote 6](#fnt36) | * Beginning 24 months post-HSCT
* Serology recommended after 2nd dose
|
| Yellow fever | May be given if indicated[Footnote 6](#fnt36) | * Beginning 24 months post-HSCT
|
|
Abbreviations:
anti-HBs = antibody to hepatitis B surface antigen
Ig = immunoglobulin
Footnote 1
For preferred type of COVID-19 vaccine, intervals between doses, and booster dose recommendations, refer to the [COVID-19 vaccine](https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) chapter.
[Return to footnote 1 referrer](#fnt31-1-rf)
Footnote 2
Given as combined vaccine (diphtheria, tetanus, pertussis; ± polio, Hib depending on age and previous vaccine history).
[Return to footnote 2 referrer](#fnt32-1-rf)
Footnote 3
May be given as a combined vaccine.
[Return to footnote 3 referrer](#fnt33-1-rf)
Footnote 4
Initially annual monitoring of antibody levels may be considered. Optimal timing and frequency should be based on the severity of the immunocompromised state and the ongoing risk of acquisition of HB infection.
[Return to footnote 4 referrer](#fnt34-1-rf)
Footnote 5
Recombinant inactivated zoster vaccine may be considered in immunocompromised adults ≥ 50 years of age on a case by case basis. Data on the use in immunocompromised individuals is limited, but based on the burden of zoster illness in this population and the general safety of inactivated vaccines, the benefits of vaccination are expected to outweigh the risks.
[Return to footnote 5 referrer](#fnt35-1-rf)
Footnote 6
Give when immunosuppression has been discontinued for at least 3 months, no chronic GVHD, no Ig in the past 8 to 11 months (except for yellow fever vaccine) and considered immunocompetent by a transplant specialist.
[Return to footnote 6 referrer](#fnt36-1-rf)
|
### Solid organ transplantation
Solid organ transplant recipients are at increased risk of severe illness with many vaccine preventable diseases, including invasive pneumococcal or Hib disease, influenza, varicella, and HPV-related diseases.
### Pre-solid organ transplantation
Pre-transplant immunization is routine at most transplant centres. Ideally, all non-immune solid organ transplantation candidates should be immunized prior to transplantation and as early in the course of disease as possible because vaccine response may be reduced in people with organ failure pre-transplant. In addition, vaccines are more immunogenic if given before transplantation because the immunosuppressive medications given after transplant to prevent and treat rejection of the transplanted organ may diminish the vaccine response. It is especially important that live vaccines are given pre-transplant if possible, as these will be contraindicated post-transplant. MMR and varicella vaccine may be given to infants 6-11 months of age if transplantation is expected to occur before age 12 months. If transplantation is delayed, repeat doses should be given starting at one year of age.
Inactivated vaccines should be given according to routine immunization schedules, with the exceptions that hepatitis B vaccine should be given at double the usual dose using a 3- or 4-dose schedule if on dialysis or immunocompromised. If immunocompromised, HPV vaccine should be given using a 3-dose schedule regardless of age. In general, routine age indications should be followed, however HPV vaccination may be considered prior to an imminent transplantation in a 7- or 8-year-old child, recognizing that there is no immunogenicity data for this age group. The risk of HPV-associated warts is high post-transplant; HPV 9- or 4-valent vaccine will provide additional protection over that of the 2-valent vaccine. In addition, transplant candidates should receive pneumococcal conjugate vaccine regardless of age, pneumococcal polysaccharide vaccine if 2 years of age or older, and one dose of Hib vaccine after age 5 years regardless of prior Hib vaccination history.
Inactivated influenza vaccine should be given annually. Hepatitis A vaccine is indicated for liver transplant candidates and others with risk factors for hepatitis A. Quadrivalent conjugate meningococcal vaccine is recommended and meningococcal B vaccine should be considered if there are risk factors for meningococcal infection (e.g., hyposplenia, complement deficiency, or increased risk of exposure from travel or occupation).
Inactivated vaccines should be given at least 2 weeks before transplantation and live attenuated vaccines (MMR, MMRV, varicella, zoster, rotavirus, LAIV) should be given at least 4 weeks prior to transplantation. Live zoster vaccine should be used only if the inactivated zoster vaccine is contraindicated or unavailable. BCG may persist in the body for at least a few years, and perhaps indefinitely. It should not be given to any patient who is anticipated to likely need an organ transplant in the future, unless potential benefit outweighs the risk of reactivation post-transplant.
Antibody response should be determined by serology for those vaccines with an antibody correlate of immunity available. For infants less than 18 months of age, presence of passive maternal antibody must be considered.
Refer to [Table 4](#t4) and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for recommendations for vaccination of solid organ transplant candidates.
Living donors should have received all age-appropriate vaccines. Live vaccines should not be given in the 4 weeks before organ procurement.
### Post-solid organ transplantation
Solid organ recipients generally receive lifelong immunosuppression, which varies substantially depending on the organ transplanted. Usually the degree of immune suppression is greatest in the first 3 to 6 months post-transplant, although this timeline varies if treatment for acute organ rejection is required. In the absence of this later scenario, immune suppression typically progresses to the maintenance phase between 6 months -1 year, but a significant degree of immune suppression persists indefinitely. A minority of transplant recipients who experience chronic rejection, persistent organ dysfunction, or chronic infections, remain profoundly immune suppressed.
#### Inactivated vaccines
In general, vaccination with inactivated vaccines should not be re-initiated until maintenance immunosuppression is attained. Recommended inactivated vaccines that were not given pre-transplant and recommended booster doses should be given. Hepatitis B vaccine should be given at double the usual dose and using a 3-dose or 4-dose schedule. HPV vaccine should be given following routine age indications but using a 3-dose schedule, regardless of age.
If serologic testing is available and there is a clear antibody correlate of protection, measurement of post-immunization antibody titres to determine immune response and guide re-vaccination and post-exposure management should be considered.
#### Live attenuated vaccines
Live vaccines are generally contraindicated after transplant. However, univalent varicella vaccine has been given to selected pediatric renal and liver transplant recipients without recent graft rejection and receiving minimal or no immune suppression; consultation with an expert is advised regarding varicella vaccination of non-immune organ transplant recipients.
Most newly transplanted solid organ recipients receive vaccination in accordance with transplant centre-specific immunization guidelines as part of routine post-transplant care.
Refer to [Table 4](#t4) and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for recommendations for vaccination of solid organ transplant recipients.
Table 4: Vaccination of solid organ transplant candidates and recipients
(Refer to text and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) for additional information)| Vaccine | Pre-transplant[Footnote 1](#fnt41)[Footnote 2](#fnt42) | Post-transplant
(if not completed pre-transplant) | Comments |
| --- | --- | --- | --- |
| Inactivated vaccines[Footnote 2](#fnt42) |
| --- |
| Cholera and travellers' diarrhea (inactivated) | Use if indicated | Use if indicated | |
| Diphtheria[Footnote 3](#fnt43) | Routine use[Footnote 4](#fnt44) | Routine use[Footnote 4](#fnt44) | |
| Haemophilus influenzae type b (Hib)[Footnote 5](#fnt45) | * Children less than 5 years of age: routine use
* Individuals 5 years of age and older: 1 dose recommended[Footnote 6](#fnt46)
| * Children less than 5 years of age: routine use
* Individuals 5 years of age and older: 1 dose recommended[Footnote 6](#fnt46)
| |
| Hepatitis A | Recommended for liver transplant candidates and others with chronic liver disease
Otherwise, use if indicated | Recommended for liver transplant recipients and others with chronic liver disease
Otherwise, use if indicated | Post-transplant:
* Pre-exposure prophylaxis for travel: consider Ig with hepatitis A vaccine
* Post-exposure prophylaxis: Ig recommended along with hepatitis A vaccine
|
| Hepatitis B | Recommended | Recommended | * Double the routine dose and 3 or 4-dose schedule recommended post-transplant, and pre-transplant if on hemodialysis or otherwise immunocompromised
* Post-immunization monitoring of anti-HBs titres recommended with booster dose if titre less than 10 IU/L[Footnote 7](#fnt47)
|
| Herpes zoster (recombinant inactivated) | Consider if indicated by age[Footnote 8](#fnt48) | Consider if indicated by age[Footnote 8](#fnt48) | |
| HPV | Routine use | Routine use | * 3 dose schedule recommended
* May be considered for pre-transplant administration prior to routinely recommended age, if reasonably close to minimum recommended age for vaccination
|
| Influenza (inactivated) | Recommended annually | Recommended annually | |
| Japanese encephalitis | Use if indicated | Use if indicated | |
| Meningococcal
Conjugate | Routine use.
Use quadrivalent meningococcal vaccine if indicated by risk factors for invasive meningococcal disease | Routine use
Use quadrivalent meningococcal vaccine if indicated by risk factors for invasive meningococcal disease | |
| Meningococcal B | Should be considered if indicated by risk factors for invasive meningococcal disease | Should be considered if indicated by risk factors for invasive meningococcal disease | |
| Pertussis[Footnote 3](#fnt43) | Routine use | Routine use | |
| Pneumococcal conjugate 13-valent | Recommended regardless of age | Recommended regardless of age | Should be followed, at age at least 2 years and at least 2 months after last dose, with pneumococcal polysaccharide vaccine[Footnote 9](#fnt49) |
| Pneumococcal polysaccharide | Recommended if 2 years of age or older | Recommended if 2 years of age or older | One life-time re-immunization recommended, 5 years after first dose |
| Polio (inactivated)[Footnote 3](#fnt43) | Routine use | Routine use | |
| Rabies | Use if indicated | Use if indicated | * Do not use intradermally
* Use 5 dose schedule for post-exposure prophylaxis
* Post-immunization serology recommended
|
| Tetanus[Footnote 3](#fnt43) | Routine use | Routine use | |
| Typhoid (inactivated) | Use if indicated | Use if indicated | |
| Live attenuated vaccines[Footnote 10](#fnt410) |
| Bacille Calmette-Guérin (BCG) | Contraindicated unless potential benefit outweighs the risk[Footnote 11](#fnt411) | Contraindicated | |
| Herpes zoster (live) | Give if indicated by age. Inactivated vaccine is preferred. Live vaccine should be used only if the inactivated vaccine is contraindicated or unavailable. | Contraindicated. If indicated by age, use inactivated vaccine. | |
| Influenza (live) | Use if indicated | Not recommended; use inactivated vaccine | |
| Measles-mumps-rubella | Recommended[Footnote 12](#fnt412) | Not recommended | * Complete 2-dose series 4 weeks or more pre-transplant
* Post-immunization serology recommended
|
| MMRV | Recommended if age appropriate [Footnote 12](#fnt412) | Not recommended | * Complete 2-dose series 4 weeks or more pre-transplant
* Post-immunization serology recommended
|
| Rotavirus | Routine use | Not recommended | |
| Smallpox | Contraindicated | Contraindicated | |
| Typhoid (live) | Use if indicated | Contraindicated; if indicated, use inactivated vaccine | |
| Varicella | Recommended[Footnote 12](#fnt412) | Not recommended | * Complete 2-dose series 4 weeks or more pre-transplant
* Consider post-immunization serology
|
| Yellow fever | Use if indicated | Contraindicated | |
|
Abbreviations:
anti-HBs = antibody to hepatitis B surface antigen
Ig = immunoglobulin
Footnote 1
Whenever possible, vaccine series should be completed pre-transplantation. Vaccines given post-transplant may not be sufficiently immunogenic.
[Return to footnote 1 referrer](#fnt41-1-rf)
Footnote 2
Inactivated vaccines should be given at least 2 weeks before transplantation and, in general, should not be given post-transplant until baseline immunosuppression levels are attained
[Return to footnote 2 referrer](#fnt42-1-rf)
Footnote 3
Given as combined vaccine (diphtheria, tetanus, pertussis; ± polio, Hib depending on age and previous vaccine history).
[Return to footnote 3 referrer](#fnt43-1-rf)
Footnote 4
Routine use: follow routine immunization schedules with age-appropriate booster doses
[Return to footnote 4 referrer](#fnt44-1-rf)
Footnote 5
May be given as combined vaccine.
[Return to footnote 5 referrer](#fnt45-1-rf)
Footnote 6
Regardless of prior history of Hib vaccination and at least 1 year after any previous dose
[Return to footnote 6 referrer](#fnt46-1-rf)
Footnote 7
Initially annual monitoring of antibody levels may be considered. Optimal timing and frequency should be based on the severity of the immunocompromised state and the ongoing risk of acquisition of HB infection.
[Return to footnote 7 referrer](#fnt47-1-rf)
Footnote 8
Recombinant inactivated zoster vaccine may be considered in immunocompromised adults ≥ 50 years of age on a case by case basis. Data on the use in immunocompromised individuals is limited, but based on the burden of zoster illness in this population and the general safety of inactivated vaccines, the benefits of vaccination are expected to outweigh the risks
[Return to footnote 8 referrer](#fnt48-1-rf)
Footnote 9
Pneu-C-13 vaccine followed by Pneu-P-23 vaccine is recommended. Antibody titres decline after 3 years; however, experience with re-immunization with Pneu-C-13 after solid organ transplant is limited.
[Return to footnote 9 referrer](#fnt49-1-rf)
Footnote 10
Live attenuated vaccines should be given at least 4 weeks prior to transplantation
[Return to footnote 10 referrer](#fnt410-1-rf)
Footnote 11
BCG may remain in the body for at least a few years, and perhaps indefinitely. Use only if benefit outweighs potential risk of reactivation post-transplant
[Return to footnote 11 referrer](#fnt411-1-rf)
Footnote 12
MMR and univalent varicella vaccine may be given to infants as early as 6 months of age if transplantation is anticipated before 12 months of age. If transplantation is delayed, repeat doses should be given starting at one year of age. MMRV not recommended for age < 12 months at this time.
[Return to footnote 12 referrer](#fnt412-1-rf)
|
### Immunosuppressive therapy
Long-term immunosuppressive therapy is used for various disease conditions including cancer, organ transplantation, GVHD following HSCT, and chronic inflammatory conditions (e.g., inflammatory bowel disease, inflammatory arthritis, psoriasis, systemic lupus erythematosus). Therapies include cancer chemotherapy, radiation therapy, long term high-dose steroid treatment (prednisone equivalent of ≥ 2 mg/kg/day or 20 mg/day if weight > 10 kg, for ≥ 14 days), cytotoxic drugs, calcineurin inhibitors, chimeric antigen receptor (CAR) T cell therapy targeting lymphocytes, biological response modifiers and antibodies that target lymphocytes.
Most of these therapies have their greatest impact on cell-mediated immunity, although T cell-dependent antibody production can also be adversely affected. Monoclonal antibodies that deplete B cells profoundly affect antibody production; this effect can last for several months or years following completion of therapy. The nature of the person's underlying disease should also be considered.
CAR T cell cancer immunotherapy involves reprogramming a patient’s own T cells to identify and eliminate malignant cells. The patient’s T cells are obtained, modified in a laboratory, then infused back into the individual. Commercial CAR T cells from allogeneic donors are also available. CAR T cell therapy is used most frequently to treat hematologic malignancies, especially of B cell origin (e.g., CD19). This therapy eliminates malignant as well as normal cells expressing the target antigen, resulting in profound and prolonged loss of B lymphocytes and thus antibody production.
In general, if a patient is 3 months post-chemotherapy and the cancer is in remission, or if immunosuppression has been discontinued for at least 3 months (6 months or more for anti-B cell antibodies or CAR T cells targeting lymphocytes), the person is no longer considered immunocompromised.
### Prior to immunosuppressive therapy
Vaccination status should be reviewed for immunocompetent persons who might be anticipating initiation of immunosuppressive treatments or who have diseases that might lead to immunodeficiency. Ideally, all appropriate routine vaccines or boosters should be administered before the initiation of immunosuppressive therapy so that optimal immunogenicity is achieved. Although inactivated vaccines can be safely administered at any time before, during or after immunosuppression, inactivated vaccines should be administered at least 14 days before initiation of immunosuppressive therapy to optimize immunogenicity. Live vaccines should be administered at least 4 weeks before immunosuppressive therapy is started to reduce the risk of disease caused by the vaccine strain.
People undergoing immunosuppressive therapy are at higher risk of invasive pneumococcal disease and influenza-related complications; therefore, in addition to routine vaccines they should receive conjugate pneumococcal vaccine regardless of age and polysaccharide pneumococcal vaccine if aged 2 years or more, as well as annual immunization with inactivated influenza vaccine. Hib vaccine may be recommended in some circumstances, such as following organ transplants.
Refer to [vaccine-specific chapters](http://dev.healthycanadians.gc.ca/publications/healthy-living-vie-saine/4-canadian-immunization-guide-canadien-immunisation/index-eng.php) in Part 4 for additional information.
### During or after immunosuppressive therapy
If immunization cannot be completed prior to initiation of immunosuppressive therapy, generally a period of at least 3 months should elapse between therapy cessation and the administration of inactivated vaccines (if possible, to ensure maximum immunogenicity) or live vaccines (to reduce the risk of disease caused by the vaccine strain). However, this interval may vary with the type and intensity of treatment, underlying disease, or urgency of vaccination if vaccines are needed for post-exposure or outbreak management. For example, whereas immunization can occur as early as 4 weeks following discontinuation of long term high-dose systemic steroid therapy, a longer interval of 6 to 12 months or more may be required in case of therapy with rituximab (or other monoclonal anti-B cell antibody) and some other biological response modifiers. B cell enumeration is generally performed during rituximab therapy and should be reviewed prior to immunization.
Recipients of CAR T cell therapy directed against lymphocytes should be regarded as “never immunized” and managed as HSCT recipients are. The primary series (initial or repeat) of inactivated vaccines, including COVID-19 vaccines which should be initiated 3 to 6 months after CAR T cell therapy. Antibody response is unlikely while B cell aplasia persists, but cellular responses may occur.
Live vaccines may be given immediately on discontinuation of high dose steroid therapy if duration was less than 14 days. Corticosteroid therapy is not a contraindication to immunization with live vaccines when steroid therapy is short-term (i.e., less than 14 days); or low-to-moderate dose (prednisone equivalent of less than 2 mg/kg/day or less than 20 mg/day if weight > 10 kg); or physiologic replacement therapy; or administered topically, inhaled, or locally injected (e.g., joint injection). An exception is LAIV, which is contraindicated in individuals with severe asthma who are currently receiving high dose inhaled steroids.
For recipients of therapy with long term effects on the immune system, such as CAR T directed against lymphocytes, anti-B cell antibody, and some other biological response modifiers, live vaccines should not be given until adequate immune reconstitution has been confirmed by an expert.
The following principles apply **if immunosuppressive therapy cannot be stopped**.
#### Inactivated vaccines
Inactivated vaccines (as indicated under “Prior to immunosuppressive therapy”, above) may be administered if needed during immunosuppression. If risk of exposure is low, inactivated vaccines may be temporarily delayed until the person is the least immunosuppressed. Doses may need to be repeated when the person is no longer immunosuppressed unless antibody response can be demonstrated. Hepatitis B vaccine should be given at double the usual dose and using a 3- or 4-dose schedule. HPV vaccine should be given following routine age indications but using a 3-dose schedule, regardless of age. Inactivated influenza vaccine should be given during influenza season except for those on induction chemotherapy for leukemia or receiving anti-B cell antibodies, who are unlikely to respond. If zoster vaccine is indicated, inactivated zoster vaccine should be considered.
#### Live attenuated vaccines
Live vaccines are generally contraindicated. Because immunosuppressive drugs have been reported to cause reactivation of latent tuberculosis infection and predisposition to other opportunistic infections, avoidance of live vaccines during high level immunosuppressive therapy is prudent.
The safety and efficacy of live vaccines during low dose intermittent or maintenance therapy with non-corticosteroid immunosuppressive drugs are generally unknown, with the exception of varicella and live herpes zoster (HZ) vaccines, which can be considered for those receiving low dose methotrexate (≤ 0.4 mg/kg/week); azathioprine (≤ 3 mg/kg/day), or 6-mercaptopurine (≤ 1.5 mg/kg/day). Inactivated herpes zoster vaccine should be used unless it is contraindicated or unavailable. If combination low dose immunosuppression is being used, an expert should be consulted. A careful risk benefit assessment should be done if other live attenuated vaccines are to be considered in patients on low dose immunosuppression.
### Infants exposed to immunosuppressive therapy in the womb
Special consideration should be given to immunizing infants who have been exposed to monoclonal antibodies in the womb. Some monoclonal antibodies taken during pregnancy can, similar to maternal antibodies, pass through the placental barrier, potentially resulting in various forms of temporary immunosuppression in infants. For example, rituximab taken during pregnancy is associated with B-cell depletion in both mother and fetus, while infliximab can be detected in infants up to 6 months after birth.
* Due to the potential risk of disseminated disease, administration of BCG and oral polio vaccines is contraindicated in such infants who are less than 6 months of age. A longer interval of 6-12 months should be observed following rituximab therapy. Oral polio vaccine is no longer used in Canada but continues to be used in some other countries.
* There are no data at this time regarding the potential risk associated with rotavirus (RV) vaccine in these infants. Prior to RV immunization, laboratory tests may be useful in assessing humoral and cellular immune status. When considering immunization in the absence of laboratory test results, the decision to immunize should be based on an individual risk-benefit assessment. For example, in jurisdictions with ongoing RV immunization programs, indirect protection through herd immunity is likely to be high and withholding immunization may be considered until more information about the effects of monoclonal antibodies in the womb becomes available. Alternatively, in jurisdictions that do not have RV immunization programs and where exposure to wild-type rotavirus may be high, immunization with RV vaccine may be prudent to reduce the risk of potential complications from RV infection.
* Immune responses to live vaccines that are administered at or after one year of age (e.g., MMR or MMRV vaccine) are not considered to be affected by exposure to monoclonal antibodies in the womb.
* Infants exposed to monoclonal antibodies in the womb should receive all inactivated vaccines according to routine schedule, keeping in mind that immune response during the first few months may be suboptimal, depending on the monoclonal used and the gestational period during which it was administered.
Monoclonal antibodies administered to the mother during breastfeeding are thought to have very little or no impact on the infant. Transfer of monoclonal antibodies through breast milk is limited, and the minimal quantities that are ingested are likely to be broken down in the infant’s gastrointestinal tract. Infants of breastfeeding women receiving monoclonal antibody treatment post-partum should therefore be immunized with both live and inactivated vaccines according to routine schedules, unless the infant was also exposed to monoclonal antibody in the womb.
Refer to [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
### HIV infection
The degree of immune suppression varies widely among HIV-infected individuals, reflecting disease stage and response to antiretroviral therapy. Immune suppression is approximately predicted by a recent CD4 count and CD4 percentage.
Children who are immune suppressed at HIV diagnosis and have already received routine vaccines should have antibody titres measured where possible and, if indicated, should be revaccinated after immune recovery.
#### Inactivated vaccines
When possible, vaccines should be given early in the course of HIV infection although there is no contraindication to the use of inactivated vaccines at any time. If immune suppression is severe in an untreated or newly treated patient and likelihood of exposure to the vaccine-preventable disease is low, vaccination may be deferred pending immune recovery after effective antiretroviral therapy.
Inactivated vaccines should be administered to HIV-infected people according to routine immunization schedules, with the exceptions that hepatitis B vaccine should be given at double the routine dose and using a 3 or 4 dose schedule. HPV vaccine should be given following routine age indications but using a 3 dose schedule regardless of age. There is a high risk of HPV-associated warts with HIV infection; HPV 9 or 4 valent vaccine will provide additional protection over that of the 2 valent vaccine. For those 6 months of age or older, annual immunization with inactivated influenza vaccine is recommended. HIV-infected people should also receive pneumococcal conjugate vaccine regardless of age, pneumococcal polysaccharide vaccine if 2 years of age or older, and one dose of Hib vaccine after age 5 years regardless of prior Hib vaccination. Quadrivalent conjugate meningococcal vaccine is recommended and meningococcal B vaccine should be considered. Hepatitis A vaccine is recommended for those with risk factors for hepatitis A acquisition. If herpes zoster vaccine is indicated by age, inactivated zoster vaccine should be considered.
#### Live attenuated vaccines
The risks and benefits of a live vaccine need to be carefully considered in consultation with an infectious disease specialist/immunologist.
In general, infants should receive rotavirus vaccine according to routine schedule, as risk from infection with wild strain outweighs theoretical risk from the vaccine. If the infant is known to have severe immunodeficiency, consultation with a specialist is recommended.
MMR, varicella, live herpes zoster vaccines may be considered early in the course of HIV-infection if immune function is normal. Although LAIV is generally contraindicated, studies have shown it to be safe and immunogenic and many experts would consider using it for HIV-infected children on antiretroviral therapy and with normal immune function (see below). MMRV and other live vaccines are contraindicated at this time because of lack of data on safety. If immune suppression is already advanced at diagnosis, live vaccines should be deferred pending potential immune recovery with treatment. Consensus thresholds based on immunologic categories have been determined for the use of MMR, univalent varicella, live zoster vaccines and LAIV as follows:
* Asymptomatic HIV-infected children 12 months of age and older without severe immunosuppression (i.e., CD4 ≥ 15% and CD4 cell count ≥ 500 × 106/L for at least 6 months in children 1 through 5 years old and ≥ 15% and CD4 cell count ≥ 200 × 106/L for at least 6 months in those 6 through 13 years of age) may receive MMR and univalent varicella vaccines.
* Immunization with MMR may be considered for susceptible HIV-infected adolescents and adults with CD4 cell count ≥ 200 × 106/L. There are no published data on the use of varicella vaccine in susceptible HIV-infected adults. HIV-infected adults should be asked for a history of varicella disease or vaccination, and if negative for both, serology should be requested to determine susceptibility. Based on expert opinion, varicella immunization may be considered for susceptible HIV-infected adults with CD4 cell count ≥200 × 106/L.
* Inactivated zoster vaccine is preferred. Live zoster vaccine may be considered if not severely immunosuppressed and inactivated vaccine is contraindicated or unavailable. Live zoster vaccine is contraindicated in persons with CD4 cell count < 200 × 106/L.
* If MMR or varicella vaccines were given to individuals with perinatal HIV infection before antiretroviral therapy was begun and serological response is not demonstrated, doses should be repeated once on effective therapy for at least 6 months.
* Live attenuated influenza vaccine may be considered in otherwise healthy HIV-infected patients aged 5–17 years on combination antiretroviral therapy regimen for ≥16 weeks with CD4 T-lymphocyte percentage ≥15 and HIV plasma RNA <60 000 copies.
Refer to [Table 5](#t5) for recommendations for vaccination of HIV-infected persons and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
Table 5: Vaccination of HIV-infected persons
(Refer to text and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) for additional information)| Vaccine | Recommendation | Comments |
| --- | --- | --- |
| Inactivated vaccines |
| --- |
| Cholera and travellers' diarrhea (inactivated) | Use if indicated | |
| Diphtheria[Footnote 1](#fnt51) | Routine use[Footnote 2](#fnt52) | |
| *Haemophilus influenzae* type b (Hib)[Footnote 3](#fnt53) | * Children less than 5 years of age: routine use
* Individuals 5 years of age and older: 1 dose recommended [Footnote 4](#fnt54)
| |
| Hepatitis A | Use if indicated | * Recommended for HIV-infected individuals with risk factors such as chronic liver disease including HBV or HCV infection, living in a community where hepatitis A is endemic, men who have sex with men or illicit drug use
* Pre-exposure prophylaxis for travel: consider Ig with hepatitis A vaccine
* Post-exposure prophylaxis: Ig recommended along with hepatitis A vaccine unless immune function is normal
|
| Hepatitis B | Recommended | * Double the usual dose is recommended
* Post-immunization monitoring of anti-HBs titres recommended with booster dose if titre less than 10 IU/L[Footnote 5](#fnt55)
|
| Herpes zoster (recombinant inactivated) | Consider if indicated by age[Footnote 6](#fnt56) | |
| HPV | Routine use | 3-dose schedule recommended |
| Influenza (inactivated) | Recommended annually | |
| Japanese encephalitis | Use if indicated | |
| Meningococcal conjugate | Quadrivalent conjugate meningococcal vaccine recommended | Starting at 2 months of age or at diagnosis if diagnosed later. Booster doses required every 3-5 years. |
| Meningococcal B | Should be considered | |
| Pertussis[Footnote 1](#fnt51) | Routine use | |
| Pneumococcal conjugate 13-valent | Recommended regardless of age | Should be followed, at least 2 years of age and at least 2 months after last dose, with pneumococcal polysaccharide vaccine |
| Pneumococcal polysaccharide | Recommended if age 2 years or more | One re-immunization recommended, 5 years after first dose |
| Polio (inactivated)[Footnote 1](#fnt51) | Routine use | |
| Rabies | Use if indicated | Do not use intradermally
* Use 5 dose schedule for post-exposure prophylaxis
* Post-immunization serology recommended
|
| Tetanus[Footnote 1](#fnt51) | Routine use | |
| Typhoid (inactivated) | Use if indicated | |
| Live attenuated vaccines |
| Bacille Calmette-Guérin (BCG) | Contraindicated | |
| Herpes zoster (live) | If indicated by age and not severely immunosuppressed and inactivated vaccine is contraindicated or unavailable. |
Contraindicated if CD4 < 200 x 106 cells/L
|
| Influenza (live) | Not recommended, use inactivated vaccine | Some experts advise that LAIV may be considered in otherwise healthy HIV-infected children on combination antiretroviral therapy regimen for ≥16 weeks with CD4 T-lymphocyte percentage ≥15 and HIV plasma RNA <60 000 copies [Footnote 7](#fnt57) |
| Measles-mumps-rubella | * Children ≥ 12 months of age: Recommended 2 doses 3-6 months apart, if not significantly immunocompromised
* Adolescents and adults: consider 2 doses 3-6 months apart if susceptible and not significantly immunocompromised
* Contraindicated in advanced HIV/AIDS
| * Give if CD4 ≥ 15% and ≥ 500 x 106 cells /L for at least 6 months if age less than 6 years; if CD4 ≥ 15% and ≥ 200 x 106 cells /L for at least 6 months if age 6-13 years; if CD4 cell count ≥ 200 x 106 cells /L if age ≥ 14 years.
* If given to an individual with perinatal HIV infection before antiretroviral therapy was begun and serological response is not demonstrated, doses should be repeated once on effective therapy for at least 6 months
* Consider post-immunization serology
|
| MMRV | Contraindicated | |
| Rotavirus | Routine use unless severely immunocompromised |
If the infant is known to have severe immunodeficiency, consult a specialist in pediatric HIV or immunology
|
| Smallpox | Contraindicated | |
| Typhoid (live) | Contraindicated; if indicated, use inactivated vaccine | |
| Varicella (univalent) | * Children ≥ 12 months of age: Recommended 2 doses 3-6 months apart if not significantly immunocompromised
* Adolescents and adults: consider 2 doses 3-6 months apart if susceptible and not significantly immunocompromised
* Contraindicated in advanced HIV/AIDS
| * Give if CD4 cell count ≥ 15% and ≥ 500 x 106 cells /L for at least 6 months if age less than 6 years and if CD4 cell count ≥ 15% and ≥ 200 x 106 cells /L for at least 6 months if older
* If given to child with perinatal HIV infection before antiretroviral therapy was begun and serological response is not demonstrated, doses should be repeated once on effective therapy for at least 6 months
* Consider post-immunization serology
|
| Yellow fever | May be considered if asymptomatic and not significantly immune compromised | * May be considered if CD4 count greater than 200 x 106/L (or if age 9 months - 5 years and asymptomatic with CD4 ≥ 15 %). Consult specialist in HIV infection / immunology.
* Vaccinate well in advance of travel to monitor potential adverse events
* Consider post-immunization serology
|
|
Abbreviations:
HBV = Hepatitis B virus
HCV = Hepatitis C virus
anti-HBs = antibody to hepatitis B surface antigen
LAIV = Live attenuated influenza vaccine
Footnote 1
Given as combined vaccine (diphtheria, tetanus, pertussis; ± polio, Hib depending on age and previous vaccine history).
[Return to footnote 1 referrer](#fnt51-1-rf)
Footnote 2
Routine use: follow routine immunization schedules with age-appropriate booster doses
[Return to footnote 2 referrer](#fnt52-1-rf)
Footnote 3
May be given as combined vaccine.
[Return to footnote 3 referrer](#fnt53-1-rf)
Footnote 4
Regardless of prior history of Hib vaccination and at least 1 year after any previous dose
[Return to footnote 4 referrer](#fnt54-1-rf)
Footnote 5
Initially annual monitoring of antibody levels may be considered. Optimal timing and frequency should be based on the severity of the immunocompromised state and the ongoing risk of acquisition of HB infection
[Return to footnote 5 referrer](#fnt55-1-rf)
Footnote 6
Recombinant inactivated zoster vaccine may be considered in immunocompromised adults ≥ 50 years of age on a case by case basis. Data on the use in immunocompromised individuals is limited, but based on the burden of zoster illness in this population and the general safety of inactivated vaccines, the benefits of vaccination are expected to outweigh the risks
[Return to footnote 6 referrer](#fnt56-1-rf)
Footnote 7
2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014; 58(3):e44-100.
[Return to footnote 7 referrer](#fnt57-1-rf)
|
Close contacts
--------------
Annual influenza vaccine and up-to-date routine immunizations are recommended for household members and other close contacts of people with chronic diseases, as well as for their health care workers. Non-immunized close contacts of immunocompromised people should be immunized against pertussis, Hib, rotavirus, pneumococcus, measles, mumps, rubella, varicella, zoster and influenza as appropriate for age. Non-immune household or close contacts of immunocompromised people should be given hepatitis B vaccine. In addition, non-immune close contacts of HSCT recipients and close contacts of solid organ transplant candidates and recipients should receive hepatitis A vaccine if other risks for hepatitis A infection are present.
Vaccine viruses in MMR vaccine are not transmitted to contacts. Transmission of varicella vaccine virus from people with post-varicella vaccine rash occurs but is rare. Susceptible close contacts of immunocompromised people should receive MMR, MMRV, varicella or herpes zoster vaccine as appropriate for age. If the varicella vaccine recipient develops a varicella-like rash, the rash should be covered and the vaccinee should avoid direct contact with the immunocompromised person for the duration of the rash.
Infants living in households with persons who have or are suspected to have immunosuppressive conditions or who are receiving immunosuppressive medications can receive rotavirus vaccine. Following administration of rotavirus vaccine, viral antigen shedding in the stool may be detected in some vaccinees and may persist for up to 4 weeks. Transmission to household contacts occurs but is uncommon and many experts believe that the benefit of protecting immunocompromised household contacts from naturally occurring rotavirus by immunizing infants outweighs the theoretical risk of transmitting vaccine virus. To minimize the risk of transmission of vaccine virus during the 4 weeks after immunization, careful hand washing should be performed after contact with the vaccinated infant, especially after handling feces (e.g., after changing a diaper), and before food preparation or direct contact with the immunocompromised person.
Annual influenza immunization with influenza vaccine is recommended for close contacts of immunocompromised persons. Because of the theoretical risk for transmission, recipients of live attenuated influenza vaccine should avoid close association with persons with severe immunocompromising conditions (e.g., hematopoietic stem cell transplant recipients requiring isolation in hospital) for at least 2 weeks following vaccination.
Oral polio vaccine should not be administered to household contacts of an immunocompromised person. If there are household contacts who have received live, oral polio vaccine in another country within the last 6 weeks, they should not have contact with immunocompromised persons. Oral polio vaccine is not available in Canada.
Smallpox vaccine is available in Canada only for selected personnel working with vaccinia virus in research laboratories, or if an exposure to smallpox were to occur. Generally, smallpox vaccine should not be administered to household or close contacts of an immunocompromised person in a non-emergency situation. If vaccination is required in an outbreak situation, precautions should be taken to prevent spread to the immunocompromised person and other household and close contacts.
Immunocompromised travellers
----------------------------
A growing number of Canadians with reduced immune competence are travelling to tropical and low-income countries. Although the degree and range of infectious disease risks can increase significantly when an immunocompromised individual travels to other countries, the principles outlined above apply.
Travellers may require additional vaccines, depending on their destinations. Some travel vaccines may be contraindicated in immunocompromised individuals.
For additional information about immunization of immunocompromised travellers, refer to the Committee to Advise on Tropical Medicine and Travel statement on [The immunocompromised traveller,](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2007-33/immunocompromised-traveller.html) [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 and [Immunization of travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) in Part 3.
Selected references
-------------------
* Abid, MA, Abid MB. SARS-CoV-2 vaccine response in CAR T-cell therapy recipients: A systematic review and preliminary observations. Hematological Oncology 10.1002/hon.2957. 15 Dec. 2021, doi:10.1002/hon.2957. https://onlinelibrary.wiley.com/doi/10.1002/hon.2957
* Alashkar F., Vance C., Herich-Terhurne D., Preising N., Duhrsen U., Roth A. Serologic response to meningococcal vaccination in patients with paroxysmal nocturnal hemoglobinuria (PNH) chronically treated with the terminal complement inhibitor eculizumab. Ann Hematol. 2017 01 Apr 2017;96(4):589-96.
* Bombardier C, Hazlewood GS, Akhavan P, Schieir O, Dooley A, Haraoui B, et al. Canadian rheumatology association recommendations for the pharmacological management of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs: Part II safety. J Rheumatol. 2012;39(8):1583-602.
* Danzinger-Isakov L, Kumar D, AST Infectious Diseases Community of Practice, the AST Infectious Diseases Community of Practice. Guidelines for Vaccination of Solid Organ Transplant Candidates and Recipients. American Journal of Transplantation. 2009;9(s4):S258-62.
* Eibl M.M., Wolf HM. Vaccination in patients with primary immune deficiency, secondary immune deficiency and autoimmunity with immune regulatory abnormalities. Immunotherapy. 2015 December 2015;7(12):1273-92.
* Glück T, Müller-Ladner U. Vaccination in Patients with Chronic Rheumatic or Autoimmune Diseases. Clinical Infectious Diseases. 2008;46(9):1459-65.
* Health Canada. Alert: Soliris (eculizumab) - Increased risk of hemolysis or low hemoglobin with serogroup B meningococcal vaccination. [Internet]. Ottawa: Health Canada; 2016-10-25 [updated 2016-10-25; cited 2016-10-25]. Available from: http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2016/60752a-eng.php.
* Janssen M, Bruns A, Kuball J et al. Vaccine responses in adult hematopoietic stem cell transplant recipients: A comprehensive review. Cancers 2021, 13, 6140. https://doi.org/10.3390/cancers13236140
* Kimberlin, MD, FAAP, David W., Long, MD, FAAP, Sarah S., Brady MT, Jackson MA. Red Book 2015: 2015 Report of the Committee on Infectious Diseases. 30th ed. Chicago; Elk Grove Village: American Academy of Pediatrics; 2015.
* Leiding JW, MD, Holland SM, MD. Warts and all: Human papillomavirus in primary immunodeficiencies. Journal of Allergy and Clinical Immunology, The. 2012;130(5):1030-48.
* Levin MJ, Song L, Fenton T, Nachman S, Patterson J, Walker R, et al. Shedding of live vaccine virus, comparative safety, and influenza-specific antibody responses after administration of live attenuated and inactivated trivalent influenza vaccines to HIV-infected children. Vaccine. 2008;26(33):4210-7.
* L'Huillier A.G., Kumar D. Immunizations in solid organ and hematopoeitic stem cell transplant patients: A comprehensive review. Human Vaccines and Immunotherapeutics. 2015 01 Jan 2015;11(12):2852-63.
* Ling J, Koren G. Challenges in vaccinating infants born to mothers taking immunoglobulin biologicals during pregnancy. Expert review of vaccines. 2016; 15(2):239-56.
* Ljungman P, Cordonnier C, Einsele H et al. Vaccination of hematopoietic cell transplant recipients. Bone Marrow Transplant 2009;44:521-6.
* Löbermann M, Boršo D, Hilgendorf I, Fritzsche C, Zettl UK, Reisinger EC. Immunization in the adult immunocompromised host. Autoimmunity Reviews. 2011; 2012; 11(3):212-8.
* MacNeil J.R., Rubin L.G., Patton M., Ortega-Sanchez I.R., Martin SW. Recommendations for Use of Meningococcal Conjugate Vaccines in HIV-Infected Persons - Advisory Committee on Immunization Practices, 2016. MMWR. Morbidity and mortality weekly report. 2016 04 Nov 2016; 65(43):1189-94.
* Lopez A., Mariette X., Bachelez H., Belot A., Bonnotte B., Hachulla E., et al. Vaccination recommendations for the adult immunosuppressed patient: A systematic review and comprehensive field synopsis. J Autoimmun. 2017 June 2017;80:10-27.
* Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. [Internet]. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult\_oi.pdf. Accessed June 26, 2019
* Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected Children. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/oi\_guidelines\_pediatrics.pdf. Accessed June 26, 2019
* Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for primary immunodeficiency 2015. J Clin Immunol. 2015 Nov;35(8):696-726.
* Pinto M.V., Bihari S., Snape MD. Immunisation of the immunocompromised child. J Infect. 2016 05 Jul 2016; 72:S13-22.
* Public Health Agency of Canada. National Advisory Committee on Immunization (NACI) Statement: Recommended use of palivizumab to reduce complications of respiratory syncytial virus infection in infants June 01, 2022. Accessed February 17, 2023 at https://www.canada.ca/en/public-health/services/publications/vaccines-immunization/palivizumab-respiratory-syncitial-virus-infection-infants.html
* Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M, et al. 2013; IDSA clinical practice guideline for vaccination of the immunocompromised host. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2014;58(3):309-18.
* Shearer W.T., Fleisher T.A., Buckley R.H., Ballas Z., Ballow M., Blaese R.M., et al. Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts. J Allergy Clin Immunol. 2014 April 2014;133(4):961-6.
* Sobh A, MD, Bonilla, Francisco A.,MD, PhD. Vaccination in Primary Immunodeficiency Disorders. Journal of Allergy and Clinical Immunology: In Practice. 2016;4(6):1066-75.
* Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplantation Recipients: A Global Perspective. Biology of Blood and Marrow Transplantation. 2009;15(10):1143-238.
* Yazdani R, Azizi G, Abolhassani H, Aghamohammadi A. Selective IgA Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management. Scand J Immunol. 2017;85(1):3-12.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-03-28
| None | None |
29533c04cdf86cfe03896c7530f9d143cc1e27bc | cma | **Vaccine safety and pharmacovigilance: Canadian Immunization Guide** | Vaccine safety and pharmacovigilance: Canadian Immunization Guide
Introduction
Since vaccines are usually given to healthy people, especially children, tolerance for adverse events following immunization (AEFI) is low. Perceived vaccine safety risks receive as much media attention as real safety risks and can be difficult to dispel despite credible scientific evidence. Loss of confidence in the safety of vaccines threatens the continued success of immunization programs.
Health care providers can develop competency in vaccine safety by:
- integrating knowledge about the main steps in vaccine development and evaluation into their practice.
- providing evidence-based information on the benefits and risks of vaccines.
- anticipating, identifying, reporting and managing AEFI as appropriate to their practice setting.
Vaccine safety applies not only to vaccine development but also to immunization practices for as long as a product is used. The term vaccine pharmacovigilance defines the science and activities related to the detection, assessment, understanding and communication of adverse events following immunization (AEFI) and other vaccine-related or immunization-related issues, and to the prevention of untoward effects of the vaccine or immunization. Health care providers have important roles to play in vaccine pharmacovigilance, including gaining and maintaining public confidence in the safety of vaccines.
This chapter and the Adverse Events Following Immunization chapter are intended to support health professionals learning the three immunization competencies listed above. To find out more about vaccine safety, you may refer to:
- The Canadian Immunization Guide's in Part 4. These contain key condensed pre-authorization and post-marketing evidence-based safety data
- Health Canada's which includes Canadian vaccine product monographs
Vaccine pharmacovigilance: overview
# Definitions of key vaccine pharmacovigilance terms
Pharmacovigilance in general, and as related to vaccines in particular, has many key concepts and terms that are important to understanding vaccine safety. The terms are used throughout this chapter and for ease of reference are defined below in alphabetical order.
Adverse events following immunization (AEFI): any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the usage of a vaccine. The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, symptom or disease.
This general definition is meant to guide timely AEFI reporting even before any certainty regarding causality can be established.
## Adverse reaction frequency terms
- Very common: occurring in 10% or more of subjects
- Common: occurring in 1% to less than 10% of subjects
- Uncommon: occurring in 0.1% to less than 1% of subjects
- Rare: occurring in 0.01% to less than 0.1% of subjects
- Very Rare: occurring in less than 0.01% of subjects
Good Clinical Practice (GCP): a standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.
Good Laboratory Practice (GLP): the organizational process and the conditions under which laboratory studies are planned, performed, monitored, recorded, archived and reported. It is intended to promote the quality and validity of test data and improve the international acceptance of data generated in adherence to its principles.
Good Manufacturing Practices (GMP): the part of quality assurance that ensures that drugs are consistently produced and controlled in such a way to meet the quality standards appropriate to their intended use, as required by the marketing authorization.
Market Authorization Holders (MAH): the manufacturers or importers that have the legal authority to market their drug in Canada.
Notice of Compliance (NOC): A Notice of Compliance is issued pursuant to paragraph C.08.004(1)(a) of the Food and Drug Regulations when Health Canada has determined that the information submitted by the manufacturer has met Health Canada's standards for quality, efficacy and safety and complied with sections C.08.002 or C.08.003 of the Food and Drug Regulations.
Risk Management Plan (RMP): a document thatsummarizes known important safety information about a health product; identifies gaps in knowledge; outlines how known and potential safety concerns will be monitored by the market authorization holder; and provides a proposal to minimize any identified or potential risk.
Vaccine Attributable Risk: the difference between the frequency of an event in the vaccinated compared to unvaccinated population.
Vaccine Safety Signal: any information that arises from one or multiple sources and suggests a new potentially causal association, or a new aspect of a known adverse reaction (increased severity and/or increased frequency), between immunization and an event or set of related events, and is judged to be of sufficient concern to justify verification and remedial action if appropriate.
# Vaccine product life cycle
Before the 1960s, it was erroneously thought that everything that could be known about a product could be learned prior to its authorization. The modern era of pharmacovigilance started with the understanding that while sufficient evidence of safety, efficacy and quality is an absolute requirement for regulators to grant authorization for marketing a product, sufficient evidence does not mean knowing everything that can be known about a product. It is impossible to learn everything about a product before its authorization and efforts to do so may delay proven product benefit from being realized in the population.
The concept of a life cycle for vaccines and other marketed products underscores the fact that knowledge regarding product safety and efficacy must be sought after as well as before marketing authorization.
- Good Laboratory Practice
1. Phase I
2. Phase II
3. Phase III
- Good Clinical Practice
1. very common
2. common
3. uncommon1 +/- rare
- Good Manufacturing Practice
- Other international quality guidance documents (ICH, WHO, other regulators)
- production processes and quality control
- production facilities
- Good Manufacturing Practice
- Other international quality guidance documents (ICH, WHO, other regulators)
Consistency testing
Sample analysis
- Good Manufacturing Practice
- Good Manufacturing Practice
- Public health legislation in some provinces and territories makes AEFI reporting mandatory
Randomized controlled trials
Vaccine attributable risk
Abbreviations:
AEFI: Adverse Events Following Immunization
Vaccine pharmacovigilance activities in Canada
As summarized in and , vaccine safety assessment and monitoring is a continuum that spans all phases of the vaccine product 'life cycle' from discovery through market authorization and beyond. In Canada, many stakeholders and activities are involved. More detail on the specific processes and stakeholder activities in Canada that contribute to vaccine safety are provided below.
# Regulatory quality oversight and pharmacovigilance activities
The Health Products and Food Branch (HPFB) at Health Canada has the mandate to manage the health-related risks and benefits of health products and food by:
- minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food;
- providing information to Canadians so they can make healthy, informed decisions about their health
## Authorization for marketing a vaccine in Canada
Health Canada's Biologics and Genetic Therapies Directorate (BGTD) , including vaccines. Before manufacturers or sponsors are eligible to market a product in Canada, they must submit a "New Drug Submission". This submission contains extensive information and data about the vaccine's safety, efficacy and quality, including the results of the non-clinical and clinical studies, details regarding the production of the vaccine, packaging and labeling details, and information regarding therapeutic claims and side effects. The quality evaluation of the submission includes an onsite evaluation of the production facilities as well as laboratory testing of samples from three to five consecutive lots (or batches of vaccine production) to verify manufacturing consistency.
After BGTD determines that the vaccine is compliant with the , Health Canada will issue a and a for market authorization.
Compliance with Good Manufacturing Practices (GMP) is an additional Health Canada requirement for selling vaccines in Canada. The Health Canada Regulatory Operations and Enforcement Branch ensures this compliance through issuance of Establishment Licenses for manufacturing sites in Canada via its own GMP inspections or through Mutual Recognition Agreements with international regulatory bodies, such as the European Medicines Agency, for manufacturing sites outside of Canada.
## Quality monitoring activities
These strategies allow Health Canada to assess how well the manufacturing process is controlled and that the quality control tests remain suitable.
### Lot Release Program
Each vaccine lot is subject to the lot release program before sale in Canada. The results of key quality control tests performed throughout the manufacturing process of each individual vaccine lot must be submitted to Health Canada for review before a release letter is issued to allow the sale of the lot on the Canadian market. The purpose of the is to ensure to the extent possible that each newly manufactured batch of vaccine matches the lots used to generate the safety and efficacy data for market authorization. As part of its lot release program, Health Canada performs testing of most vaccine lots as per its Lot Release Guidelines.
Vaccine manufacturers may be requested to submit a Yearly Biological Product Report. This report contains production information on both drug substance and drug product lots, including test methods and results, reasons for any recalls and corrective action taken, as well as other pertinent post-market information.
In addition, regular Good Manufacturing Practice inspections are conducted to ensure continued compliance and renewal of establishment licenses for vaccine manufacturing facilities.
## Safety monitoring activities
### Canada Vigilance Program
Market authorization holders (i.e., the sponsors or manufacturers that have the legal authority to market their drug in Canada) are required to report serious adverse reactions to the , as mandated by the Food and Drugs Act and Regulations. The Canada Vigilance Program also accepts reports from health professionals and consumers. This information is one of the tools that enable Health Canada to monitor the safety profile of vaccines to determine if their benefits continue to outweigh their risks.
### Safety reports
The Food and Drugs Act and Regulations require market authorization holders to analyze adverse drug reaction data for safety concerns and prepare an annual summary report which represents a comprehensive assessment of the worldwide safety data of the vaccine. Market authorization holders must also notify Health Canada if they become aware of a significant change in the product benefit-risk profile.
Safety reports are assessed by Health Canada and, if specific safety issues are identified, additional safety information may be requested.
### Risk management plans
Health Canada reviews the when the market authorization holder is seeking authorization to market a new vaccine in Canada but can also request for one to be submitted at other times.
### Product risk/benefit assessments
Health Canada can ask the market authorization holder to submit a benefit-risk assessment of a therapeutic health product when the benefit-risk profile of a product has changed. Health Canada evaluators reviewing benefit-risk assessments use science-based procedures to determine whether the benefits outweigh the risks or whether the product needs regulatory intervention.
### Canadian Adverse Events Following Immunization Surveillance System (CAEFISS)
The is a collaborative post-marketing federal/provincial/territorial (F/P/T) passive surveillance system with the following objectives:
- to continuously monitor the safety of marketed vaccines in Canada;
- to identify increases in the frequency or severity of previously identified vaccine-related reactions;
- to identify previously unknown AEFI that could possibly be related to a vaccine (unexpected AEFI);
- to identify areas that require further investigation and/or research; and
- to provide timely information on AEFI reporting profiles for vaccines marketed in Canada that can help inform immunization-related decisions.
CAEFISS includes spontaneous, enhanced and active AEFI reporting processes. Each province and territory has their own reporting system that includes activities at the local/regional as well as the provincial/territorial levels. All provincial and territorial systems are part of CAEFISS.
Spontaneous AEFI reports may come from health care professionals and the public. F/P/T immunization program authorities encourage vaccine providers and others to report AEFI of particular public health importance and sometimes conduct enhanced AEFI surveillance as part of new publicly-funded immunization programs or as a response to possible emerging vaccine safety signals. In most jurisdictions (Ontario, Quebec, Nova Scotia, Manitoba, New Brunswick, Saskatchewan, Prince Edward Island and Northwest Territories, British Columbia, Alberta and Nunavut) AEFI reporting is a legislated requirement.
### Immunization Monitoring Program ACTive (IMPACT)
There is also an active syndromic surveillance component to CAEFISS. This is provided by Canada's . IMPACT is a pediatric hospital-based network funded by the Public Health Agency of Canada (PHAC) and administered by the Canadian Paediatric Society (CPS). IMPACT conducts national surveillance for selected AEFIs, vaccine failures and vaccine preventable diseases in children. The 12 IMPACT hospitals encompass approximately 90% of tertiary care pediatric beds in Canada. Nurse monitors actively search for children admitted to IMPACT hospitals with neurologic and other AEFIs of public health importance. The nurse monitors determine whether these events meet a standard case definition and have occurred within a specific interval following immunization that could implicate the vaccine as a possible cause. All such AEFI are reported to PHAC as well as to local public health officials and are included in CAEFISS.
### AEFI report flow and associated activities
Local public health officials are usually the first to receive an AEFI report. A public health professional reviews the report to determine the safety of administering further doses of the implicated vaccine(s). Efforts may also be made to gather additional information, validate a report diagnosis, and follow up investigation results and/or final outcome of the AEFI. Vaccine safety signals such as unexpected events or increases in severity or frequency of expected AEFI, especially vaccination site reactions or allergic events, may first be recognized at the local level. Such concerns are communicated to appropriate regional and/or provincial/territorial personnel for further assessment and investigation, if needed. Refer to for a diagram illustrating the AEFI report flow.
Provincial/territorial immunization programs receive and review all AEFI reports to carry out jurisdictional level analysis including estimation of rates of occurrence of specific AEFI and, in some cases, preparation of periodic jurisdictional summaries. With a larger volume of reports than is seen at local levels, this is another opportunity to identify possible vaccine safety signals and take action as appropriate. Actions may include: undertaking additional epidemiological investigation; consulting with experts, advising federal public health or regulatory authorities; or creating an AEFI alert to notify and seek input from all F/P/T vaccine safety leads. In addition to being the lead on jurisdictional pharmacovigilance activities, P/T vaccine safety coordinators remove personal identifiers in AEFI reports and send the reports to PHAC.
Vaccine Safety Section at PHAC receives AEFI reports from multiple sources (provinces, federal jurisdictions and IMPACT), identifies duplicates and collates them into a national database. The key activities at the national level include coding of AEFI using the international Medical Dictionary for Regulatory Activities (MedDRA) and medical case review to detect vaccine safety signals, including any unexpected or unusual AEFI. Analyses are done regularly to search for vaccine safety signals, and information is shared with Health Canada. Reports are produced for F/P/T review as well as review by the National Advisory Committee on Immunization (NACI).
### Vaccine Vigilance Working Group
The includes members representing all federal (First Nations and Inuit Health Branch, National Defence and the Canadian Armed Forces, Royal Canadian Mounted Police, Correctional Services of Canada) and P/T immunization programs as well as Health Canada regulators and IMPACT. The working group reports to the Canadian Immunization Committee and its activities include:
- preparation of national guidelines and procedures for monitoring AEFIs in Canada;
- providing a national forum to identify, share and promote best practices regarding vaccine pharmacovigilance; and
- providing a national vaccine safety surveillance network that can rapidly share and disseminate information to appropriate stakeholders regarding vaccine safety signals or other relevant issues.
Key Stakeholder Roles and Responsibilities
Timely, comprehensive and multidirectional communication between key stakeholders is essential to the effectiveness of the pharmacovigilance process. For example:
- Scientists and regulators give information to health care providers and public health authorities;
- Health care providers need to give information to public health authorities;
- Public Health authorities collate and analyze information for regulators, healthcare providers, scientists and consumers.
- Vaccine lot release program
- Reviews/approves post-marketing product changes that could impact quality, safety or efficacy
- Reviews safety data submitted by market authorization holders (adverse reaction reports, safety reports, issue-specific safety reports, risk management plans, etc.)
- Conducts risk-benefit assessments
- Issues risk communications
- During inspections, monitors and enforces vaccine industry compliance with the Food and Drugs Act and Regulations, including Good Manufacturing Practice
- Comply with the Food and Drugs Act and Regulations, including Good Laboratory Practice, Good Clinical Practice, and Good Manufacturing Practice
- Prepare Annual Summary Reports
- NACI Secretariat coordinates and supports the activities of NACI such as evidence reviews and publications, including the Canadian Immunization Guide and position statements.
- Provinces and territories
- First Nations & Inuit Health Branch
- Department of National Defense
- Royal Canadian Mounted Police
- Correctional Services of Canada
- Collates, codes, reviews, analyzes and communicates jurisdictional level AEFI report data from multiple sources
- Jurisdictional vaccine safety signal detection/investigation
- Share de-identified jurisdictional AEFI report data with PHAC
- Conduct individual public health action after an AEFI (e.g., AEFI validation and/or investigation; decisions on future re-immunization)
- Provide evidence-based information on the benefits and risks of vaccines
- Anticipate, identify, report and manage AEFI as part of their clinical and/or public health professional practice
- Notify their healthcare provider about AEFIs to enable prompt assessment, appropriate management, and timely reporting.
Global pharmacovigilance partners
Vaccine pharmacovigilance is a global effort with many participants conducting similar activities to those outlined in , and and sharing vaccine safety information. In addition to individual country pharmacovigilance systems, Canada's other global partners in vaccine pharmacovigilance are briefly described below with a link to more detailed information.
# World Health Organization (WHO)
The WHO has a mandate from member states to develop, establish and promote international standards with respect to a wide variety of products including biologics such as vaccines. Since 1965, the WHO has had a global program for International Drug Monitoring based at the in Sweden. The Centre receives a subset of AEFI report data gathered by member states which enable the main objective of the program: safety signal detection at a global level.
In 1999, the WHO established the (GACVS) to provide independent evidence-based responses to safety issues of global concern. The expert committee meets twice yearly (usually June and December) and publishes their conclusions and recommendations shortly thereafter in the WHO Weekly Epidemiological Record. The GACVS also maintains a subject-specific topic index at their website. As part of their work, GACVS established the which identifies and promotes websites on vaccine safety that adhere to good information practices.
# Council for International Organizations of Medical Sciences (CIOMS)
The Council for International Organizations of Medical Sciences is an international, non-governmental, non-profit organization established jointly by the WHO and the United Nations Educational, Scientific and Cultural Organization (UNESCO) in 1949 to facilitate and promote international activities in the field of biomedical sciences, including making recommendations on the assessment and monitoring of adverse reactions. The WHO and CIOMS jointly formed a Working Group to develop definitions relevant to vaccine pharmacovigilance which were published in 2012.
# Brighton Collaboration
The , so named because it was initiated in 1999 at a Vaccine conference in Brighton, England, is a global expert network which seeks to create methodological standards for vaccine pharmacovigilance, including standardized case definitions of AEFI. These case definitions have been adopted by the Vaccine Vigilance Working Group (VVWG) and are captured to some extent in the National .
# Health and Medicine Division of the National Academies of Sciences, Engineering and Medicine
The United States National Academy of Sciences formed the Institute of Medicine in 1970 to function as an independent, expert professional body that examines issues of relevance to the health of the public. In March 2016, the Institute of Medicine was renamed the Health and Medicine Division (HMD). Since 1991 several vaccine safety issues have been rigorously assessed by Immunization Safety Review Committees. These committees contain a broad range of expertise in clinical medicine (pediatrics, internal medicine, infectious disease, nursing), public health (epidemiology, biostatistics, health communication), medical research (immunology, genetics, neurology) as well as risk perception, decision analysis and ethics. Since 2001, an absolute criterion for committee membership has been lack of any association with vaccine manufacturers or their parent organizations and no prior function as a legal expert witness.
For each issue studied, the HMD's Immunization Safety Committee reviews all pertinent theoretical, experimental, clinical and epidemiologic evidence and hears presentations from the public and health professionals. There is no prior assumption regarding a positive or negative connection between the vaccine and the issue at hand. The scientific evidence is then reviewed, and biologic mechanisms for a possible causal association carefully considered. Prior to publication, each report is reviewed by a separate expert panel, chosen by the National Academies of Sciences but anonymous to the Committee. Reviewer's comments are given due consideration, but ultimately the final published report represents the consensus of the safety Committee alone. All can be viewed online. |
**Vaccine safety and pharmacovigilance: Canadian Immunization Guide**
=====================================================================
**For healthcare professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html)
**Last complete chapter revision** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): December 2019
**December 2019:** This chapter was completely reviewed with several revisions which expand on the previous contents related to vaccine pharmacovigilance definitions, regulations, processes and stakeholders related to Canadian and international vaccine safety and pharmacovigilance.
Learn how vaccine safety is assured and monitored from pre-licensure to post-immunization and who is responsible for what in Canada.
On this page
------------
* [Introduction](#s1)
* [Vaccine Pharmacovigilance: Overview](#s2)
+ [Definitions of key vaccine pharmacovigilance terms](#s2-1)
+ [Vaccine product life cycle](#s2-2)
- [Table 1: Pre-marketing evaluation of safety and quality.](#t1)
- [Table 2: Post-marketing regulatory oversight and pharmacovigilance activities](#t2)
* [Vaccine pharmacovigilance activities in Canada](#s3)
* [Key Stakeholder Roles and Responsibilities](#s4)
+ [Table 3: Key stakeholder roles and responsibilities for pharmacovigilance in Canada](#t3)
* [Global Pharmacovigilance Partners](#s5)
* [Selected References](#s6)
Introduction
------------
Since vaccines are usually given to healthy people, especially children, tolerance for adverse events following immunization (AEFI) is low. Perceived vaccine safety risks receive as much media attention as real safety risks and can be difficult to dispel despite credible scientific evidence. Loss of confidence in the safety of vaccines threatens the continued success of immunization programs.
Health care providers can develop competency in vaccine safety by:
* integrating knowledge about the main steps in vaccine development and evaluation into their practice.
* providing evidence-based information on the benefits and risks of vaccines.
* anticipating, identifying, reporting and managing AEFI as appropriate to their practice setting.
Vaccine safety applies not only to vaccine development but also to immunization practices for as long as a product is used. The term **vaccine pharmacovigilance** defines the science and activities related to the detection, assessment, understanding and communication of adverse events following immunization (AEFI) and other vaccine-related or immunization-related issues, and to the prevention of untoward effects of the vaccine or immunization. Health care providers have important roles to play in vaccine pharmacovigilance, including gaining and maintaining public confidence in the safety of vaccines.
This chapter and the Adverse Events Following Immunization chapter are intended to support health professionals learning the three immunization competencies listed above. To find out more about vaccine safety, you may refer to:
* The Canadian Immunization Guide's [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4. These contain key condensed pre-authorization and post-marketing evidence-based safety data
* [National Advisory Committee on Immunization (NACI) statements](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci.html) which present detailed vaccine safety data
* [Immunization Competencies for Health Professionals](/en/public-health/services/publications/healthy-living/immunization-competencies-health-professionals.html). This guide presents the essential topics that should be learned and taught for effective and safe immunization
* Health Canada's [Drug Product Database](https://health-products.canada.ca/dpd-bdpp/index-eng.jsp) which includes Canadian vaccine product monographs
Vaccine pharmacovigilance: overview
-----------------------------------
### Definitions of key vaccine pharmacovigilance terms
Pharmacovigilance in general, and as related to vaccines in particular, has many key concepts and terms that are important to understanding vaccine safety. The terms are used throughout this chapter and for ease of reference are defined below in alphabetical order.
**Adverse events following immunization (AEFI):** any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the usage of a vaccine. The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, symptom or disease.
This general definition is meant to guide timely AEFI reporting even before any certainty regarding causality can be established.
#### Adverse reaction frequency terms
* **Very common:** occurring in 10% or more of subjects
* **Common:** occurring in 1% to less than 10% of subjects
* **Uncommon:** occurring in 0.1% to less than 1% of subjects
* **Rare:** occurring in 0.01% to less than 0.1% of subjects
* **Very Rare:** occurring in less than 0.01% of subjects
**Good Clinical Practice (GCP):** a standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.
**Good Laboratory Practice (GLP):** the organizational process and the conditions under which laboratory studies are planned, performed, monitored, recorded, archived and reported. It is intended to promote the quality and validity of test data and improve the international acceptance of data generated in adherence to its principles.
**Good Manufacturing Practices (GMP):** the part of quality assurance that ensures that drugs are consistently produced and controlled in such a way to meet the quality standards appropriate to their intended use, as required by the marketing authorization.
**Market Authorization Holders (MAH):** the manufacturers or importers that have the legal authority to market their drug in Canada.
**Notice of Compliance (NOC):** A Notice of Compliance is issued pursuant to paragraph C.08.004(1)(a) of the Food and Drug Regulations when Health Canada has determined that the information submitted by the manufacturer has met Health Canada's standards for quality, efficacy and safety and complied with sections C.08.002 or C.08.003 of the Food and Drug Regulations.
**Risk Management Plan (RMP):** a document thatsummarizes known important safety information about a health product; identifies gaps in knowledge; outlines how known and potential safety concerns will be monitored by the market authorization holder; and provides a proposal to minimize any identified or potential risk.
**Vaccine Attributable Risk**: the difference between the frequency of an event in the vaccinated compared to unvaccinated population.
**Vaccine Safety Signal:** any information that arises from one or multiple sources and suggests a new potentially causal association, or a new aspect of a known adverse reaction (increased severity and/or increased frequency), between immunization and an event or set of related events, and is judged to be of sufficient concern to justify verification and remedial action if appropriate.
### Vaccine product life cycle
Before the 1960s, it was erroneously thought that everything that could be known about a product could be learned prior to its authorization. The modern era of pharmacovigilance started with the understanding that while sufficient evidence of safety, efficacy and quality is an absolute requirement for regulators to grant authorization for marketing a product, sufficient evidence does not mean knowing everything that can be known about a product. It is impossible to learn everything about a product before its authorization and efforts to do so may delay proven product benefit from being realized in the population.
The concept of a life cycle for vaccines and other marketed products underscores the fact that knowledge regarding product safety and efficacy must be sought after as well as before marketing authorization.
[Table 1](#t1) and [Table 2](#t2) describe the phases of the vaccine life cycle along with associated studies and regulatory requirements as appropriate, and what each contributes to knowledge about and/or assurance of vaccine product safety. The pharmacovigilance activities shown in the tables are global in scope and information is shared so that new evidence can be applied to ensure the ongoing safe use of vaccines.
Table 1: Pre-marketing evaluation of safety and quality[Table 1 footnote 1](#t1fn1)
| Vaccine life cycle phase | Type of study | Regulatory requirement /guidance | What it provides regarding vaccine safety |
| --- | --- | --- | --- |
| Non-clinical testing | Laboratory and animal testing | * Food and Drugs Act and Regulations
* Good Laboratory Practice
| Information on possible safety concerns |
| Clinical trials
1. Phase I
2. Phase II
3. Phase III
| Human subjects:
1. 1-10
2. 100-1,000
3. 1,000-30,000
| * Food and Drugs Act and Regulations
* Good Clinical Practice
| Type of vaccine adverse reactions that are:
1. very common[Table 1 footnote 1](#t1fn1)
2. common[Table 1 footnote 1](#t1fn1)
3. uncommon1 +/- rare[Table 1 footnote 1](#t1fn1)
|
| Validation of manufacturing process | Validation of each step in the manufacturing process, from seed lot or cell bank production to delivery and related quality control tests | * Food and Drugs Act and Regulations
* Good Manufacturing Practice
* Other international quality guidance documents (ICH, WHO, other regulators)
| Documentation needed for regulatory review of:
* production processes and quality control
* production facilities
|
| On-site evaluation of manufacturing process | Site visit by Health Canada product specialists to evaluate production processes and facilities | * Food and Drugs Act and Regulations
* Good Manufacturing Practice
* Other international quality guidance documents (ICH, WHO, other regulators)
| Ensures that the manufacturing process is capable of consistently delivering quality product |
| Lot release program:
Consistency testing
| Health Canada laboratories test samples from 3 or more consecutive lots | * Food and Drugs Act and Regulations
| Quality of vaccine |
| Drug Establishment licensing | Site visit by Health Canada specialists to evaluate the drug establishment
Sample analysis
Review of new and annual license applications | * Food and Drugs Act and Regulations
* Good Manufacturing Practice
| Ensures facilities in which the product is manufactured are appropriate to the specifications that apply to that product
Quality of vaccines |
|
Table 1 footnote 1
Refer to [Definitions of key vaccine pharmacovigilance terms](#s2-1)
[Return to first Table 1 footnote 1 referrer](#t1fn1-1-rf)
|
Table 2: Post-marketing regulatory oversight and pharmacovigilance activities[Table 2 footnote 1](#t2fn1)
| Vaccine life cycle phase | Type of study | Regulatory requirement /guidance | What it provides regarding vaccine safety |
| --- | --- | --- | --- |
| Lot release program | Health Canada bases the level of regulatory oversight (testing and/or protocol review) on the degree of risk linked to the product | * Food and Drugs Act and Regulations
| Lot release risk-based approach to testing and oversight allows for enhanced post-market surveillance of vaccines |
| Establishment inspections | Regulator inspections of production facilities, usually every 2-3 years
| * Food and Drugs Act and Regulations
* Good Manufacturing Practice
| Ensures ongoing quality of vaccine production |
| Expanded vaccine safety data collection in target and special populations | Scientific and/or epidemiological studies of human populations involving hundreds to many thousands | * Food and Drugs Act and Regulations
| Safety profile in special populations not studied as part of pre-marketing clinical trials (e.g., diabetics)
Possible interactions with other vaccines |
| Adverse events following immunization (AEFI) surveillance systems | Spontaneous, enhanced and/or active AEFI reporting systems | * Food and Drug Act and Regulations: for Market Authorization Holders
* Public health legislation in some provinces and territories makes AEFI reporting mandatory
| Detection of vaccine safety signals which are then investigated to determine root cause |
| Post-marketing studies | Population-based epidemiological studies
Randomized controlled trials
Individual case clinical investigation | May be requested by regulators in response to new vaccine safety signals. | Rare and very rare vaccine product-related reactions
Vaccine attributable risk
Evidence that certain AEFI are actually coincidental events |
|
Abbreviations:
AEFI: Adverse Events Following Immunization
Table 2 footnote 1
Refer to [Definitions of key vaccine pharmacovigilance terms](#s2-1)
[Return to Table 2 footnote 1 referrer](#t2fn1-rf)
|
Vaccine pharmacovigilance activities in Canada
----------------------------------------------
As summarized in [Table 1](#t1) and [Table 2](#t2), vaccine safety assessment and monitoring is a continuum that spans all phases of the vaccine product 'life cycle' from discovery through market authorization and beyond. In Canada, many stakeholders and activities are involved. More detail on the specific processes and stakeholder activities in Canada that contribute to vaccine safety are provided below.
### Regulatory quality oversight and pharmacovigilance activities
The Health Products and Food Branch (HPFB) at Health Canada has the mandate to manage the health-related risks and benefits of health products and food by:
* minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food;
* providing information to Canadians so they can make healthy, informed decisions about their health
#### Authorization for marketing a vaccine in Canada
Health Canada's Biologics and Genetic Therapies Directorate (BGTD) [regulates biologic drugs (Schedule D) for human use in Canada](/en/health-canada/services/drugs-health-products/biologics-radiopharmaceuticals-genetic-therapies/regulatory-roadmap-for-biologic-drugs.html), including vaccines. Before manufacturers or sponsors are eligible to market a product in Canada, they must submit a "New Drug Submission". This submission contains extensive information and data about the vaccine's safety, efficacy and quality, including the results of the non-clinical and clinical studies, details regarding the production of the vaccine, packaging and labeling details, and information regarding therapeutic claims and side effects. The quality evaluation of the submission includes an onsite evaluation of the production facilities as well as laboratory testing of samples from three to five consecutive lots (or batches of vaccine production) to verify manufacturing consistency.
After BGTD determines that the vaccine is compliant with the [Canada's Food and Drugs Act and Regulations](https://laws-lois.justice.gc.ca/eng/regulations/C.R.C.%2C_c._870/index.html), Health Canada will issue a [Notice of Compliance](/en/health-canada/services/drugs-health-products/drug-products/notice-compliance.html) and a [Drug Identification Number (DIN)](/en/health-canada/services/drugs-health-products/drug-products/fact-sheets/drug-identification-number.html) for market authorization.
Compliance with Good Manufacturing Practices (GMP) is an additional Health Canada requirement for selling vaccines in Canada. The Health Canada Regulatory Operations and Enforcement Branch ensures this compliance through issuance of Establishment Licenses for manufacturing sites in Canada via its own GMP inspections or through Mutual Recognition Agreements with international regulatory bodies, such as the European Medicines Agency, for manufacturing sites outside of Canada.
#### Quality monitoring activities
These strategies allow Health Canada to assess how well the manufacturing process is controlled and that the quality control tests remain suitable.
##### Lot Release Program
Each vaccine lot is subject to the lot release program before sale in Canada. The results of key quality control tests performed throughout the manufacturing process of each individual vaccine lot must be submitted to Health Canada for review before a release letter is issued to allow the sale of the lot on the Canadian market. The purpose of the [Lot Release Program](/en/health-canada/services/drugs-health-products/biologics-radiopharmaceuticals-genetic-therapies/applications-submissions/guidance-documents/release/guidance-sponsors-program-schedule-biologic-drugs.html) is to ensure to the extent possible that each newly manufactured batch of vaccine matches the lots used to generate the safety and efficacy data for market authorization. As part of its lot release program, Health Canada performs testing of most vaccine lots as per its Lot Release Guidelines.
Vaccine manufacturers may be requested to submit a Yearly Biological Product Report. This report contains production information on both drug substance and drug product lots, including test methods and results, reasons for any recalls and corrective action taken, as well as other pertinent post-market information.
In addition, regular Good Manufacturing Practice inspections are conducted to ensure continued compliance and renewal of establishment licenses for vaccine manufacturing facilities.
#### Safety monitoring activities
##### Canada Vigilance Program
Market authorization holders (i.e., the sponsors or manufacturers that have the legal authority to market their drug in Canada) are required to report serious adverse reactions to the [Canada Vigilance Program](/en/health-canada/services/drugs-health-products/medeffect-canada/canada-vigilance-program.html), as mandated by the Food and Drugs Act and Regulations. The Canada Vigilance Program also accepts reports from health professionals and consumers. This information is one of the tools that enable Health Canada to monitor the safety profile of vaccines to determine if their benefits continue to outweigh their risks.
##### Safety reports
The Food and Drugs Act and Regulations require market authorization holders to analyze adverse drug reaction data for safety concerns and prepare an annual summary report which represents a comprehensive assessment of the worldwide safety data of the vaccine. Market authorization holders must also notify Health Canada if they become aware of a significant change in the product benefit-risk profile.
Safety reports are assessed by Health Canada and, if specific safety issues are identified, additional safety information may be requested.
##### Risk management plans
Health Canada reviews the [Risk Management Plan](/en/health-canada/services/drugs-health-products/reports-publications/medeffect-canada/profile-guidance-document-submission-risk-management-plans-follow-commitments.html) when the market authorization holder is seeking authorization to market a new vaccine in Canada but can also request for one to be submitted at other times.
##### Product risk/benefit assessments
Health Canada can ask the market authorization holder to submit a benefit-risk assessment of a therapeutic health product when the benefit-risk profile of a product has changed. Health Canada evaluators reviewing benefit-risk assessments use science-based procedures to determine whether the benefits outweigh the risks or whether the product needs regulatory intervention.
##### Canadian Adverse Events Following Immunization Surveillance System (CAEFISS)
The [Canadian Adverse Events Following Immunization Surveillance System (CAEFISS)](/en/public-health/services/immunization/canadian-adverse-events-following-immunization-surveillance-system-caefiss.html) is a collaborative post-marketing federal/provincial/territorial (F/P/T) passive surveillance system with the following objectives:
* to continuously monitor the safety of marketed vaccines in Canada;
* to identify increases in the frequency or severity of previously identified vaccine-related reactions;
* to identify previously unknown AEFI that could possibly be related to a vaccine (unexpected AEFI);
* to identify areas that require further investigation and/or research; and
* to provide timely information on AEFI reporting profiles for vaccines marketed in Canada that can help inform immunization-related decisions.
CAEFISS includes spontaneous, enhanced and active AEFI reporting processes. Each province and territory has their own reporting system that includes activities at the local/regional as well as the provincial/territorial levels. All provincial and territorial systems are part of CAEFISS.
Spontaneous AEFI reports may come from health care professionals and the public. F/P/T immunization program authorities encourage vaccine providers and others to report AEFI of particular public health importance and sometimes conduct enhanced AEFI surveillance as part of new publicly-funded immunization programs or as a response to possible emerging vaccine safety signals. In most jurisdictions (Ontario, Quebec, Nova Scotia, Manitoba, New Brunswick, Saskatchewan, Prince Edward Island and Northwest Territories, British Columbia, Alberta and Nunavut) AEFI reporting is a legislated requirement.
Refer to [Adverse Events Following Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) in Part 2 for information on AEFI definitions, as well as reporting and managing AEFIs.
##### Immunization Monitoring Program ACTive (IMPACT)
There is also an active syndromic surveillance component to CAEFISS. This is provided by Canada's [Immunization Monitoring Program ACTive (IMPACT)](https://www.cps.ca/en/impact). IMPACT is a pediatric hospital-based network funded by the Public Health Agency of Canada (PHAC) and administered by the Canadian Paediatric Society (CPS). IMPACT conducts national surveillance for selected AEFIs, vaccine failures and vaccine preventable diseases in children. The 12 IMPACT hospitals encompass approximately 90% of tertiary care pediatric beds in Canada. Nurse monitors actively search for children admitted to IMPACT hospitals with neurologic and other AEFIs of public health importance. The nurse monitors determine whether these events meet a standard case definition and have occurred within a specific interval following immunization that could implicate the vaccine as a possible cause. All such AEFI are reported to PHAC as well as to local public health officials and are included in CAEFISS.
##### AEFI report flow and associated activities
**Local public health officials** are usually the first to receive an AEFI report. A public health professional reviews the report to determine the safety of administering further doses of the implicated vaccine(s). Efforts may also be made to gather additional information, validate a report diagnosis, and follow up investigation results and/or final outcome of the AEFI. Vaccine safety signals such as unexpected events or increases in severity or frequency of expected AEFI, especially vaccination site reactions or allergic events, may first be recognized at the local level. Such concerns are communicated to appropriate regional and/or provincial/territorial personnel for further assessment and investigation, if needed. Refer to [Figure 1: Public Health Reporting Pathway for Adverse Events Following Immunization (AEFIs) to CAEFISS](/en/public-health/services/immunization/canadian-adverse-events-following-immunization-surveillance-system-caefiss.html#f1) for a diagram illustrating the AEFI report flow.
**Provincial/territorial immunization programs** receive and review all AEFI reports to carry out jurisdictional level analysis including estimation of rates of occurrence of specific AEFI and, in some cases, preparation of periodic jurisdictional summaries. With a larger volume of reports than is seen at local levels, this is another opportunity to identify possible vaccine safety signals and take action as appropriate. Actions may include: undertaking additional epidemiological investigation; consulting with experts, advising federal public health or regulatory authorities; or creating an AEFI alert to notify and seek input from all F/P/T vaccine safety leads. In addition to being the lead on jurisdictional pharmacovigilance activities, P/T vaccine safety coordinators remove personal identifiers in AEFI reports and send the reports to PHAC.
**Vaccine Safety Section at PHAC** receives AEFI reports from multiple sources (provinces, federal jurisdictions and IMPACT), identifies duplicates and collates them into a national database. The key activities at the national level include coding of AEFI using the international Medical Dictionary for Regulatory Activities (MedDRA) and medical case review to detect vaccine safety signals, including any unexpected or unusual AEFI. Analyses are done regularly to search for vaccine safety signals, and information is shared with Health Canada. Reports are produced for F/P/T review as well as review by the National Advisory Committee on Immunization (NACI).
##### Vaccine Vigilance Working Group
The [Vaccine Vigilance Working Group (VVWG)](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2014-40/ccdr-volume-40-s-3-december-4-2014/ccdr-volume-40-s-3-december-4-2014-2.html) includes members representing all federal (First Nations and Inuit Health Branch, National Defence and the Canadian Armed Forces, Royal Canadian Mounted Police, Correctional Services of Canada) and P/T immunization programs as well as Health Canada regulators and IMPACT. The working group reports to the Canadian Immunization Committee and its activities include:
* preparation of national guidelines and procedures for monitoring AEFIs in Canada;
* providing a national forum to identify, share and promote best practices regarding vaccine pharmacovigilance; and
* providing a national vaccine safety surveillance network that can rapidly share and disseminate information to appropriate stakeholders regarding vaccine safety signals or other relevant issues.
Key Stakeholder Roles and Responsibilities
------------------------------------------
[Table 3](#t3) summarizes the key stakeholder roles and responsibilities for pharmacovigilance in Canada. Some stakeholders such as vaccine manufacturers and regulatory authorities have roles and responsibilities throughout the product life cycle (refer to [Table 1](#t1) and [Table 2](#t2)), whereas others such as public health authorities and vaccine providers are involved later in the process, from about the time the product is authorized for marketing in Canada.
Timely, comprehensive and multidirectional communication between key stakeholders is essential to the effectiveness of the pharmacovigilance process. For example:
* Scientists and regulators give information to health care providers and public health authorities;
* Health care providers need to give information to public health authorities;
* Public Health authorities collate and analyze information for regulators, healthcare providers, scientists and consumers.
Table 3: Key stakeholder roles and responsibilities for pharmacovigilance in Canada[Table 3 footnote 1](#t3fn1)
| Stakeholder | Specific group | Role/responsibility |
| --- | --- | --- |
| Health Canada regulators | Health Products and Food Branch (HPFB): Biologics and Genetic Therapies Directorate (BGTD) | * Requires sufficient evidence of safety, efficacy and quality to authorize vaccine for sale in Canada
* Vaccine lot release program
* Reviews/approves post-marketing product changes that could impact quality, safety or efficacy
|
| Health Products and Food Branch (HPFB): Marketed Health Products Directorate (MHPD) | * Collects suspected adverse reaction reports from market authorization holders
* Reviews safety data submitted by market authorization holders (adverse reaction reports, safety reports, issue-specific safety reports, risk management plans, etc.)
* Conducts risk-benefit assessments
* Issues risk communications
|
| Regulatory Operations and Enforcement Branch: Health Product Compliance Directorate | * Provides establishment licensing and inspections
* During inspections, monitors and enforces vaccine industry compliance with the Food and Drugs Act and Regulations, including Good Manufacturing Practice
|
| Vaccine industry | Vaccine market authorization holders | * Monitor the safety of their vaccines
* Comply with the Food and Drugs Act and Regulations, including Good Laboratory Practice, Good Clinical Practice, and Good Manufacturing Practice
* Prepare Annual Summary Reports
|
| Federal, provincial, territorial (F/P/T) public health authorities | Public Health Agency of Canada | * Collates, codes, reviews, analyzes and communicates national level AEFI report data from multiple sources
* NACI Secretariat coordinates and supports the activities of NACI such as evidence reviews and publications, including the Canadian Immunization Guide and position statements.
|
| Canadian health jurisdictions immunization programs for:
* Provinces and territories
* First Nations & Inuit Health Branch
* Department of National Defense
* Royal Canadian Mounted Police
* Correctional Services of Canada
| * AEFI surveillance at the jurisdictional level
* Collates, codes, reviews, analyzes and communicates jurisdictional level AEFI report data from multiple sources
* Jurisdictional vaccine safety signal detection/investigation
* Share de-identified jurisdictional AEFI report data with PHAC
|
| Local public health officials | * Report AEFIs to jurisdictional public health officials
* Conduct individual public health action after an AEFI (e.g., AEFI validation and/or investigation; decisions on future re-immunization)
|
| Health professionals | Scientists, expert clinicians and networks | * Conduct research and contribute to surveillance of vaccine and immunization safety
|
| Members of the National Advisory Committee on Immunization (NACI) | * Review evidence on vaccine risk and benefit to provide expert recommendations for vaccine use
|
| Vaccine providers and other health care providers, as appropriate to their clinical and/or public health professional practice | * Administer vaccine
* Provide evidence-based information on the benefits and risks of vaccines
* Anticipate, identify, report and manage AEFI as part of their clinical and/or public health professional practice
|
| Consumers | Vaccinees or their parent/guardian(s) | * Seek information needed to make decisions about vaccination
* Notify their healthcare provider about AEFIs to enable prompt assessment, appropriate management, and timely reporting.
|
|
Table 3 footnote 1
Refer to [Definitions of key vaccine pharmacovigilance terms](#s2-1)
[Return to Table 3 footnote 1 referrer](#t3fn1-rf)
|
Global pharmacovigilance partners
---------------------------------
Vaccine pharmacovigilance is a global effort with many participants conducting similar activities to those outlined in [Table 1](#t1), [Table 2](#t2) and [Table 3](#t3) and sharing vaccine safety information. In addition to individual country pharmacovigilance systems, Canada's other global partners in vaccine pharmacovigilance are briefly described below with a link to more detailed information.
### World Health Organization (WHO)
The WHO has a mandate from member states to develop, establish and promote international standards with respect to a wide variety of products including biologics such as vaccines. Since 1965, the WHO has had a global program for International Drug Monitoring based at the [Uppsala Monitoring Centre](https://www.who-umc.org/) in Sweden. The Centre receives a subset of AEFI report data gathered by member states which enable the main objective of the program: safety signal detection at a global level.
In 1999, the WHO established the [Global Advisory Committee on Vaccine Safety](https://www.who.int/vaccine_safety/committee/en/) (GACVS) to provide independent evidence-based responses to safety issues of global concern. The expert committee meets twice yearly (usually June and December) and publishes their conclusions and recommendations shortly thereafter in the WHO Weekly Epidemiological Record. The GACVS also maintains a subject-specific topic index at their website. As part of their work, GACVS established the [Vaccine Safety Net](https://www.vaccinesafetynet.org/) which identifies and promotes websites on vaccine safety that adhere to good information practices.
### Council for International Organizations of Medical Sciences (CIOMS)
The Council for International Organizations of Medical Sciences is an international, non-governmental, non-profit organization established jointly by the WHO and the United Nations Educational, Scientific and Cultural Organization (UNESCO) in 1949 to facilitate and promote international activities in the field of biomedical sciences, including making recommendations on the assessment and monitoring of adverse reactions. The WHO and CIOMS jointly formed a Working Group to develop definitions relevant to vaccine pharmacovigilance which were published in 2012.
### Brighton Collaboration
The [Brighton Collaboration](https://www.brightoncollaboration.org/), so named because it was initiated in 1999 at a Vaccine conference in Brighton, England, is a global expert network which seeks to create methodological standards for vaccine pharmacovigilance, including standardized case definitions of AEFI. These case definitions have been adopted by the Vaccine Vigilance Working Group (VVWG) and are captured to some extent in the National [Adverse Events Following Immunization Report Form](/en/public-health/services/immunization/reporting-adverse-events-following-immunization/form.html).
### Health and Medicine Division of the National Academies of Sciences, Engineering and Medicine
The United States National Academy of Sciences formed the Institute of Medicine in 1970 to function as an independent, expert professional body that examines issues of relevance to the health of the public. In March 2016, the Institute of Medicine was renamed the Health and Medicine Division (HMD). Since 1991 several vaccine safety issues have been rigorously assessed by Immunization Safety Review Committees. These committees contain a broad range of expertise in clinical medicine (pediatrics, internal medicine, infectious disease, nursing), public health (epidemiology, biostatistics, health communication), medical research (immunology, genetics, neurology) as well as risk perception, decision analysis and ethics. Since 2001, an absolute criterion for committee membership has been lack of any association with vaccine manufacturers or their parent organizations and no prior function as a legal expert witness.
For each issue studied, the HMD's Immunization Safety Committee reviews all pertinent theoretical, experimental, clinical and epidemiologic evidence and hears presentations from the public and health professionals. There is no prior assumption regarding a positive or negative connection between the vaccine and the issue at hand. The scientific evidence is then reviewed, and biologic mechanisms for a possible causal association carefully considered. Prior to publication, each report is reviewed by a separate expert panel, chosen by the National Academies of Sciences but anonymous to the Committee. Reviewer's comments are given due consideration, but ultimately the final published report represents the consensus of the safety Committee alone. All [HMD vaccine safety reports](http://www.nationalacademies.org/hmd/Global/Topics/Vaccines.aspx) can be viewed online.
Selected references
-------------------
* Asturias EJ, Wharton M, Pless R et al. *Contributions and challenges for worldwide vaccine safety: The Global Advisory Committee on Vaccine Safety at 15 years.* Vaccine 2016; 34(29): 3342-3349.
* Council for International Organizations of Medical Sciences (CIOMS). *[*Report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance: Definition and Application of Terms for Vaccine Pharmacovigilance* (PDF document)](http://www.who.int/vaccine_safety/initiative/tools/CIOMS_report_WG_vaccine.pdf)*. 2012. Accessed December 2012 at: http://www.who.int/vaccine\_safety/initiative/tools/CIOMS\_report\_WG\_vaccine.pdf
* Dellepiane N, Griffiths E, Milstien JB. *New challenges in assuring vaccine quality*. Bulletin WHO 2000; 78(2): 155-62.
* Institute of Medicine 2013. [The childhood immunization schedule and safety: Stakeholder concerns, scientific evidence, and future studies](http://nationalacademies.org/HMD/Reports/2013/The-Childhood-Immunization-Schedule-and-Safety.aspx). Washington, DC: The National Academies Press.
* Offit PA. *The Cutter Incident - How America's First Polio Vaccine Led to the Growing Vaccine Crisis*. 2005. Yale University Press, New Haven and London.
* World Health Organization. *Guidelines for preparing core clinical safety information on drugs - report of the Council for International Organizations of Medical Sciences (CIOMS) Working Group III. (Chapter 5, Good Safety Information Practice).*Geneva: WHO, 1994.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2019-12-23
| None | None |
985f0a45509b9c9261e73c787328df087355e304 | cma | Planning guidance for administration of COVID-19 vaccine | Planning guidance for administration of COVID-19 vaccine
Introduction
Immunizing all Canadians with COVID-19 vaccine in a timely way will be a major challenge. In support of this massive undertaking, the Public Health Agency of Canada (PHAC) has developed planning guidance for the administration of COVID-19 vaccine. The primary audiences for this guidance are the federal/provincial/territorial (FPT) governments, Indigenous leadership and public health authorities, although the guidance should also be of use to regional and local health authorities, health professional associations, and others involved in COVID-19 vaccine deployment and program implementation.
The goal of Canada's COVID-19 immunization response is to enable as many Canadians as possible to be immunized against COVID-19 as quickly as possible, while ensuring that high-risk populations are prioritized.
Provinces and territories (PTs) are responsible for administering COVID-19 vaccine to their residents; however, there are also some federal departments (e.g., Department of National Defence, Global Affairs Canada, Correctional Services Canada and Indigenous Services Canada) that provide health services, including immunizations, directly to specific populations. All jurisdictions will work together with partners from many sectors, experts, Indigenous leaders and other Canadians:
- To provide safe and effective vaccines as quickly as possible to all who want them;
- To allocate, distribute and administer vaccines as efficiently, equitably and effectively as possible; and
- To monitor the safety, coverage and effectiveness of COVID-19 vaccine.
The term “Canadians” is intended to be interpreted broadly. It refers to everyone in Canada, whether or not they are citizens, as well as Canada-based staff and their dependents and locally engaged staff at Canadian missions abroad, and Canadian active duty personnel (Canadian Forces) abroad.
General considerations
There will be many challenges in planning for the administration of COVID-19 vaccine. These include uncertainties around product availability in terms of timelines and quantities, and the need to deal with multiple products with differing presentations, number of doses needed, storage requirements and potentially even different indications for use. The extreme storage and handling requirements of the two vaccine candidates that are expected to be available first will be particularly challenging. All jurisdictions and vaccine providers will need to keep their plans flexible to deal with these uncertainties and changing circumstances as the immunization response rolls out.
Existing immunization programs and prior experience with mass campaigns including the 2009 pandemic provide a strong basis for meeting the challenges involved with administering COVID-19 vaccine. The use of established practices and systems whenever possible to distribute and administer COVID-19 vaccine and monitor adverse reactions and vaccine effectiveness will support the success of the COVID-19 immunization response.
It is recommended that each jurisdiction build on its seasonal influenza immunization strategies, using tailored approaches to deal with the unique needs of key populations, diverse settings and vulnerable populations. Language, age, ability, sex, gender, culture, race and ethnicity, and religious beliefs are aspects of Canada's diversity that may affect the delivery and uptake of vaccine in each jurisdiction.
Specific planning considerations are recommended to identify and address the unique needs of each jurisdiction's populations and communities, to ensure access to COVID-19 vaccine. PTs should collaborate with Indigenous leadership in planning and carrying out the distribution of vaccine to Indigenous populations, including remote and isolated communities.
Vaccine distribution, storage and handling
The manufacturers and Health Canada will provide early estimates of when COVID-19 vaccine will be available and in what quantities. These estimates may be subject to considerable change during the manufacturing and regulatory processes.
A National Operations Centre has been established to manage the logistics of vaccine distribution and tracking across Canada. Distribution of COVID-19 vaccine to the FPT jurisdictions will begin as soon as vaccine is authorized for use and is available from the manufacturer. Amounts to be allocated to PTs and federal departments will follow principles for equitable allocation. Vaccine for second doses will be allocated at the same time as the first dose quantities to ensure that there is sufficient quantity available for the second dose at the appropriate interval after the first dose.
# Vaccine storage and handling
Strict attention must be paid to maintaining cold chain requirements when vaccine is being transported, distributed and stored. Two of the potential vaccine candidates require specialized frozen transport and storage, which will represent some significant logistical challenges in Canada. In this case, stability data will be used to determine how long these vaccines are refrigerator stable after thawing and if they can be transported in the thawed state. These constraints could impact how PTs manage and distribute the vaccine (e.g., need for more frequent, smaller shipments from depots capable of storing and transporting frozen product).
Detailed advice and training materials on storage and handling of the COVID-19 vaccines anticipated for use in Canada will be provided by the manufacturers, and guidelines for safe transport, storage and handling will be updated by PHAC. Jurisdictions should ensure that appropriate cold chain procedures, equipment and capacity are in place by confirming adequate vaccine storage space in purpose-built vaccine refrigerators (and/or freezers as required), management of dry ice in accordance with safe handling practices for hazardous materials, performing routine temperature monitoring and equipment maintenance, and reviewing procedures for transporting vaccine to off-site clinics. If vaccine is to be supplied to community practitioners and health care facilities, their storage and handling procedures should comply with public health requirements. Arrangements for the physical security of vaccine should be made for all stages of vaccine delivery and storage.
Packaging specifications for products are under development. All vaccines will be in multidose vials for the initial rollout. Vials per secondary carton may vary, in addition to packaging details for products with adjuvant (e.g., supplied in separate vials as was the case for H1N1 vaccine). Information on whether products can be repackaged into smaller units for distribution to vaccine providers who cannot manage larger package sizes will be provided when available.
Inventory management at all levels is essential to maximize available vaccine supplies and anticipate future needs. Accurate real-time knowledge of vaccine supply and inventory can allow for adjustments to vaccine shipments or clinic schedules as needed. The inventory system should be able to track vaccine lots so that if needed, specified lots can be put on hold or recalled. Vaccine bar coding could assist in this tracking process.
Recommendations for vaccine use
The National Advisory Committee on Immunization (NACI) will provide expert advice and guidance on the use of COVID-19 vaccines, including identifying key populations for early immunization which will inform vaccine allocation to PTs.
# Vaccine recommendations
The NACI COVID-19 vaccine statement will be prepared as a living document and be updated as new vaccines or indications for use become available. Key sections in the recommendations will include populations for whom vaccine is particularly recommended, vaccine safety, products available for use, choice of vaccine products and vaccine administration, e.g., dosages and schedules based on clinical trials of the new products.
If passive immunizing agents emerge for prophylaxis, such as monoclonal antibodies or convalescent plasma, NACI will also consider guidance for these products.
# Recommendations on key populations for early immunization
It is anticipated that vaccine will become available in stages and initial quantities will be quite limited. To help planning for the equitable allocation and use of COVID-19 vaccine(s) when limited supplies necessitate recommendations for some groups to be immunized before others, NACI developed . This interim guidance has been subsequently updated – for details on the updated NACI recommendations and sequencing, see .
Sub-prioritization within these populations will be required in the context of vaccine supply limitations and will be carried out in collaboration with the Canadian Immunization Committee. As provinces and territories are responsible for COVID-19 vaccine delivery in their jurisdiction, they will make final decisions that best meet the needs of their respective populations.
Vaccine administration
In a pandemic, it is important to be able to administer vaccine as quickly as it becomes available. There were many challenges with this process during the 2009 H1N1 immunization campaign, especially in the initial management of priority populations when supplies were limited.
The Canadian Immunization Committee (CIC) and its subcommittees will provide advice on the implementation of the COVID-19 immunization response including vaccine administration, and a forum for FPT information sharing and troubleshooting.
# Planning considerations
The efficient administration of COVID-19 vaccine can be based in large part on established practices such as seasonal influenza programs; however, modifications are needed in the context of COVID-19. These modifications include:
- Adaptions to usual immunization procedures in the presence of COVID-19 activity (e.g., screening; physical distancing; appropriate infection, prevention and control practices; and paperless processes);
- Taking measures to reduce crowding at immunization clinics (e.g., immunization by appointment) and considering other options in appropriate circumstances (e.g., outreach programs, drive-in or drive-through clinics in good weather);
- Using appropriate strategies to reach identified key populations, such as persons in long term care homes and other congregate living settings for seniors, health care workers (HCWs), persons at increased risk of severe illness and death from COVID-19, and Indigenous communities; and
- Maintaining flexibility to deal with unexpected changes in vaccine supply, delivery dates or recommendations.
It is anticipated that PTs will provide direction to regional and local health departments about the range of strategies to be used to provide COVID-19 vaccine to the public. Considerations include the capacity to store the vaccine properly and the need to minimize wastage, given that vaccine will be supplied in multidose vials without preservative.
Vaccines have traditionally been administered by public health nurses and/or by doctors and nurses in primary care; however, most provinces have now expanded pharmacists' scope of practice to include administration of vaccine. Other potential vaccine providers, such as paramedics, may also be needed to provide surge capacity or outreach for the administration of COVID-19 vaccine. PTs may wish to further expand the range of providers who can administer vaccine or to expand the scope of immunization practice of existing providers like pharmacists to additional routes of administration, age groups or settings.
Some additional planning considerations for the administration of COVID-19 vaccine include the following:
- It is anticipated that vaccine will become available in stages, and that there may be ongoing interruptions and changes to scheduled deliveries that will affect supply.
- Historical data from the 2009 influenza pandemic and seasonal influenza immunization campaigns may help jurisdictions estimate vaccine uptake, but uptake can be affected by many factors, especially public perceptions of pandemic impact and vaccine safety. Planning for an average upper limit of 75% vaccine uptake (as recommended in the ) should be adequate in most areas, but uptake may be higher in some jurisdictions and settings.
- Jurisdictions should plan to implement a two-dose program as required for most candidate vaccines. The second dose must be given within a certain time frame and with the same product. Vaccine recipients should be provided with information about how and when to get the second dose and consideration given to use of recall/reminder systems to promote their return.
- As more than one type of COVID-19 vaccine will be used in Canada, for purposes of monitoring safety and vaccine effectiveness, it is essential to record the specific products and vaccine lots supplied to jurisdictions and administered to individuals.
- Information systems are needed to track individual immunizations, including lot numbers, and provide second dose reminders to clients.
- PHAC will be developing fact sheets, informed consent materials and model medical directives for PT use to ensure consistency.
- Jurisdictions should recommend a standard approach to vaccine preparation (e.g., timing/mixing of adjuvant) and infection prevention and control measures with use of multidose vials.
- Jurisdictions should determine human resource requirements and be prepared to activate established mutual aid agreements for HCW surge capacity, if required.
- Staff that might be called upon to administer COVID-19 vaccine should be trained in advance and given opportunities to practise their skills.
- Planners should consider unique approaches for vaccine hesitant individuals in immunization communication strategies.
Detailed advice for planning immunization clinics can be found in the . This document also touches on alternate delivery methods that may be useful in special circumstances.
# Vulnerable and hard to reach populations
Immunization providers will have to reach vulnerable people who may have physical or mental disabilities or low literacy, as well as people who may experience a lack of mobility, homelessness or cultural or social isolation.
Useful strategies include:
- translating immunization materials into appropriate languages;
- having translators available at clinics;
- organizing rides to clinics or providing taxi chits or bus tickets;
- enlisting younger or multilingual family members to assist in communication;
- offering home visits if resources permit;
- holding immunization clinics at food banks or food lines, shelters or other places where vulnerable persons might gather (e.g., drop-in services, consumption treatment centres, pharmacies or clinics providing specific services); and
- working with outreach/mental health/social support case workers.
# Remote and isolated and Indigenous communities
Indigenous Services Canada (ISC) is working to ensure that remote and isolated and other Indigenous communities will have equitable access to COVID-19 vaccine once it is available. This is being done in collaboration with Indigenous partners, regional offices, provinces and territories, and PHAC.
ISC is also working on guidance for immunization delivery and messaging and education for when vaccine is available. Resources such as *Planning Guidance for Vaccine Clinics during COVID-19 in Indigenous Communities- have been shared across their networks.
# Ancillary immunization supplies
In preparation for the administration of COVID-19 vaccine, the Government of Canada is securing more than 75 million syringes, needles, alcohol swabs and other supplies (including gauze and sharps containers), enough to provide two doses of COVID-19 vaccine to every Canadian when vaccine is ready.
Monitoring vaccine safety, uptake and effectiveness
The scale of the COVID-19 immunization response warrants careful attention to vaccine safety to minimize risk and maximize the benefits of COVID-19 vaccine. Despite all the knowledge gained about a product pre-market, it is not possible to detect all adverse events following immunization (AEFIs) at that stage, especially if they are very rare. Rapid and continuous post-market vaccine safety surveillance is critical to capture all reports of serious and unexpected AEFIs for all vaccines authorized in Canada and to act on safety signals in a timely way.
# Mechanisms to support post-market vaccine safety surveillance
The approach to COVID-19 vaccine safety will leverage and build upon the infrastructure and systems already in place for monitoring seasonal influenza and other vaccines. Post-marketing surveillance for adverse events is undertaken by PHAC and HC in collaboration with PT partners and other key stakeholders, through the following mechanisms:
- The is managed by PHAC and is an FPT post-market vaccine safety monitoring system that includes spontaneous, enhanced and active AEFI reporting processes. During the pandemic, this surveillance system will be used to receive AEFI reports from PTs for signal detection, analysis and reporting. Expedited AEFI surveillance will be carried out during and following the administration of COVID-19 vaccine to report aggregate counts of AEFIs on a weekly basis. This will allow PHAC to detect potential safety signals for further investigation sooner than with a standard passive surveillance system.
- The is a paediatric, hospital-based network administered by the Canadian Paediatric Society. IMPACT conducts active, targeted syndromic surveillance for AEFI considered to be of special importance. All such AEFIs are reported to PHAC and local public health officials and are included in CAEFISS. During a large cale immunization campaign, additional selected diseases or surveillance targets may be added if a connection to vaccine is suspected. IMPACT also conducts national surveillance for vaccine failures and selected vaccine-preventable diseases in children.
AEFI reports must be quickly passed on to PHAC for collation into CAEFISS, with serious events given priority. A vaccine safety signal from AEFI reports could include a new and potentially causal association, or a new aspect of a known association. Safety signals are investigated so that the cause can be assessed and action taken if appropriate. Such actions may include updates to the product monograph, recall of a vaccine lot or revisions to vaccine recommendations or administration practices.
# External networks
Several external networks will also be engaged to monitor COVID-19 AEFIs and conduct special studies on COVID-19 vaccine safety and effectiveness. The is a collaboration of leading vaccine researchers and institutions in Canada. CIRN networks that will be involved in COVID-19 vaccine safety initiatives include:
- The – CANVAS provides enhanced surveillance by assessing vaccine safety in various age groups immediately following the yearly launch of influenza vaccine campaigns. CANVAS processes can be applied to COVID-19 vaccines.
- The – This is a national network of expert clinicians across the country established to investigate and manage patients with AEFIs or underlying conditions that may be contraindications to immunization.
# Federal Provincial Territorial Vaccine Vigilance Working Group
The Vaccine Vigilance Working Group (VVWG) is a national safety committee that reports to the CIC. It has participants from all PTs and federal immunization programs together with IMPACT, Health Canada regulators and other representatives. The VVWG will play an important vaccine safety role during the COVID-19 immunization response by facilitating the development of guidelines, standards, protocols and best practices to improve FPT post market safety surveillance in Canada. It will share and rapidly disseminate information within the network and to appropriate stakeholders regarding vaccine safety issues or signals.
Measuring vaccine uptake as COVID-19 vaccine is being administered to Canadians allows public health authorities to determine if it is in line with expectations. If uptake is lower than expected, additional strategies or promotional efforts may be needed for specific key populations or in general. The results may also lead to adjustment of recommendations or of vaccine allocations to FPT jurisdictions.
At present, each PT maintains its own system for tracking immunization data using electronic databases or paper-based systems or a combination of both. To support the monitoring of real-time vaccine uptake, key data elements such as age, sex and risk groups should be determined and the relevant information collected from all vaccine recipients, including those immunized by non-public health providers. This information should be rapidly collated and analyzed. Immunization registry development should be actively pursued in jurisdictions without existing registries in order to support the data needs of the COVID-19 immunization response. In September 2020, PHAC offered funding to PTs for registry enhancement of their registries.
The FPT Canadian Immunization Registry and Coverage Network (CIRC), a CIC subcommittee, developed functional standards for immunization registries in 2019, which were endorsed by CIC. CIRC is therefore best positioned to develop data standards and facilitate the collection and sharing of available vaccine uptake reports from jurisdictions during the administration of COVID-19 vaccine. CIRC members have agreed to make weekly reports on the number of vaccine doses administered in their jurisdiction, broken down by recipients' age and gender, as well as the number of doses administered to the populations targeted for early immunization (e.g., long-term care residents, health care workers, Indigenous populations).
Planning is also underway for repeated monthly national coverage surveys through Statistics Canada to estimate PT coverage levels. The COVID-19 Vaccination Coverage Survey will supplement data from PT registries to gain information on knowledge, attitudes and beliefs about COVID-19 immunization among immunized and unimmunized persons, reasons for being immunized or not immunized and sociodemographic information such as ethnicity and Indigenous identity.
Vaccine effectiveness measures how well a vaccine works when it is in general use in real-life circumstances (unlike the ideal circumstances of a clinical trial where vaccine efficacy is measured). Vaccine effectiveness is usually monitored by studies using a test-negative design; such studies have been used for years to measure the effectiveness of influenza vaccines in Canada. The and the of CIRN are well placed to provide similar information on the effectiveness of the COVID-19 vaccine. Special studies may also be conducted in selected populations.
Public and professional communication and engagement
Careful planning to ensure readiness of the general public and the health community for a COVID-19 vaccine should begin well in advance of vaccine availability. In dealing with the uncertainties surrounding a new vaccine, especially products that use a novel technology, early and effective communication is necessary to build trust, correct misinformation and overcome vaccine hesitancy. Maintaining confidence in the COVID-19 immunization program is a major challenge, and concerns and misinformation about COVID-19 vaccines are already beginning to circulate.
Public and professional communications proved to be one of the more challenging aspects of the 2009 influenza pandemic response. Improving communication strategies by applying lessons learned from this experience should result in increased public confidence that translates to higher immunization coverage. These relate to both content and use of effective communication strategies. Immunization information should be communicated in meaningful, culturally relevant and personal terms, and crowd out misinformation.
While all government levels are involved in immunization communications, messaging needs to be coordinated and consistent. Established FPT networks, including the Public Health Network Communications Group, are being used to coordinate the COVID-19 communications response, including immunization issues. The federal government is addressing the overall response and regulatory and safety issues. PTs will focus on the immunization response in their own jurisdiction and regional and local health departments will provide local details.
The communication strategy is being informed through ongoing behavioural research to better understand the knowledge, attitudes and beliefs and decision-making behaviours of Canadians regarding COVID-19 vaccine.
# Public communication and engagement
The groundwork for public acceptance of COVID-19 vaccine needs to be laid well in advance of actual vaccine availability. All communication strategies should take into consideration the diverse communication needs of population groups based on ethnicity/culture, ability status, language, education/literacy, age and other factors. Both the risk of COVID-19 infection and the risks and benefits associated with immunization, including the contribution of individual immunization to herd immunity, should be communicated effectively. The process and rationale for immunizing people in stages as vaccine becomes available should be carefully explained so that persons eligible for early immunization do not feel like test subjects, and others understand that their turn will come.
Public interest in and concerns over vaccine safety will likely be significant. Provision of detailed information about vaccine regulation and safety monitoring is important and vaccine misinformation should be addressed quickly and aggressively. It is also important to plan for communications in the event of a vaccine safety signal that arises either outside or within Canada.
Multiple strategies, including traditional media, local and ethnic media and social media, should be used to provide immunization program information to engage a diverse audience. Tailored approaches will be needed for vulnerable populations, such as provision of information in multiple formats. Community leaders can be asked to convey accurate information and champion the immunization program. Involvement of stakeholders (e.g., Indigenous health and immigrant/refugee organizations) can help make communications materials and strategies more appropriate for the target audiences.
As vaccine becomes available, messaging about eligibility may be challenging as information is complex and subject to change. Communication should be clear that although the goal is to make vaccine available to all Canadians, it will become available in stages, requiring targeted distribution in a fair and equitable manner.
# Health care sector communication and engagement
Health care providers play a central role in encouraging COVID-19 immunization, especially if they have been immunized themselves or intend to do so. It is important to keep them well informed about the safety and effectiveness of the COVID-19 vaccines being used, so they can present a unified message of strong support from the health care community.
Outreach to health care providers should use trusted sources and networks, and timely updates should be provided, for example through webinars that are being developed on COVID-19 vaccines. Challenges include conveying the need for flexibility because vaccine recommendations may change over time as more information becomes available. Rationale should be provided for recommendations on key populations for early COVID-19 immunization and for differences from other countries (especially the USA). Any PT adaptation of national prioritization recommendations should be clearly explained to practitioners in that jurisdiction.
Engaging the health care sector requires collaboration between jurisdictions:
- FPT and professional association website information should include links to Government of Canada information on the COVID-19 vaccine, such as the regulatory process, vaccine safety, the current product information leaflet and national vaccine recommendations.
- PTs should provide information to vaccine providers within their jurisdiction about the plans for administration of COVID-19 vaccine, including any jurisdictional modifications to the response.
- Regional and local public health authorities can help to ensure that information and guidelines are disseminated to local HCWs and that these workers are provided with details of the local immunization response. |
Planning guidance for administration of COVID-19 vaccine
=========================================================
On this page
------------
* [Introduction](#a1)
* [General considerations](#a2)
* [Vaccine distribution, storage and handling](#a3)
+ [Vaccine storage and handling](#a31)
* [Recommendations for vaccine use](#a4)
+ [Vaccine recommendations](#a41)
+ [Recommendations on key populations for early immunization](#a42)
* [Vaccine administration](#a5)
+ [Planning considerations](#a51)
+ [Vulnerable and hard to reach populations](#a52)
+ [Remote and isolated and Indigenous communities](#a53)
+ [Ancillary immunization supplies](#a54)
* [Monitoring vaccine safety, uptake and effectiveness](#a6)
+ [Mechanisms to support post-market vaccine safety surveillance](#a61)
+ [External networks](#a62)
+ [Federal, Provincial and Territorial Vaccine Vigilance Working Group](#a63)
* [Public and professional communication and engagement](#a7)
+ [Public communication and engagement](#a71)
+ [Health care sector communication and engagement](#a72)
* [References](#a8)
Introduction
------------
Immunizing all Canadians with COVID-19 vaccine in a timely way will be a major challenge. In support of this massive undertaking, the Public Health Agency of Canada (PHAC) has developed planning guidance for the administration of COVID-19 vaccine. The primary audiences for this guidance are the federal/provincial/territorial (FPT) governments, Indigenous leadership and public health authorities, although the guidance should also be of use to regional and local health authorities, health professional associations, and others involved in COVID-19 vaccine deployment and program implementation.
The goal of Canada's COVID-19 immunization response is to enable as many Canadians as possible to be immunized against COVID-19 as quickly as possible, while ensuring that high-risk populations are prioritized.
Provinces and territories (PTs) are responsible for administering COVID-19 vaccine to their residents; however, there are also some federal departments (e.g., Department of National Defence, Global Affairs Canada, Correctional Services Canada and Indigenous Services Canada) that provide health services, including immunizations, directly to specific populations. All jurisdictions will work together with partners from many sectors, experts, Indigenous leaders and other Canadians:
* To provide safe and effective vaccines as quickly as possible to all who want them;
* To allocate, distribute and administer vaccines as efficiently, equitably and effectively as possible; and
* To monitor the safety, coverage and effectiveness of COVID-19 vaccine.
The term “Canadians” is intended to be interpreted broadly. It refers to everyone in Canada, whether or not they are citizens, as well as Canada-based staff and their dependents and locally engaged staff at Canadian missions abroad, and Canadian active duty personnel (Canadian Forces) abroad.
General considerations
----------------------
There will be many challenges in planning for the administration of COVID-19 vaccine. These include uncertainties around product availability in terms of timelines and quantities, and the need to deal with multiple products with differing presentations, number of doses needed, storage requirements and potentially even different indications for use. The extreme storage and handling requirements of the two vaccine candidates that are expected to be available first will be particularly challenging. All jurisdictions and vaccine providers will need to keep their plans flexible to deal with these uncertainties and changing circumstances as the immunization response rolls out.
Existing immunization programs and prior experience with mass campaigns including the 2009 pandemic provide a strong basis for meeting the challenges involved with administering COVID-19 vaccine. The use of established practices and systems whenever possible to distribute and administer COVID-19 vaccine and monitor adverse reactions and vaccine effectiveness will support the success of the COVID-19 immunization response.
It is recommended that each jurisdiction build on its seasonal influenza immunization strategies, using tailored approaches to deal with the unique needs of key populations, diverse settings and vulnerable populations. Language, age, ability, sex, gender, culture, race and ethnicity, and religious beliefs are aspects of Canada's diversity that may affect the delivery and uptake of vaccine in each jurisdiction.
Specific planning considerations are recommended to identify and address the unique needs of each jurisdiction's populations and communities, to ensure access to COVID-19 vaccine. PTs should collaborate with Indigenous leadership in planning and carrying out the distribution of vaccine to Indigenous populations, including remote and isolated communities.
Vaccine distribution, storage and handling
------------------------------------------
The manufacturers and Health Canada will provide early estimates of when COVID-19 vaccine will be available and in what quantities. These estimates may be subject to considerable change during the manufacturing and regulatory processes.
A National Operations Centre has been established to manage the logistics of vaccine distribution and tracking across Canada. Distribution of COVID-19 vaccine to the FPT jurisdictions will begin as soon as vaccine is authorized for use and is available from the manufacturer. Amounts to be allocated to PTs and federal departments will follow principles for equitable allocation. Vaccine for second doses will be allocated at the same time as the first dose quantities to ensure that there is sufficient quantity available for the second dose at the appropriate interval after the first dose.
### Vaccine storage and handling
Strict attention must be paid to maintaining cold chain requirements when vaccine is being transported, distributed and stored. Two of the potential vaccine candidates require specialized frozen transport and storage, which will represent some significant logistical challenges in Canada. In this case, stability data will be used to determine how long these vaccines are refrigerator stable after thawing and if they can be transported in the thawed state. These constraints could impact how PTs manage and distribute the vaccine (e.g., need for more frequent, smaller shipments from depots capable of storing and transporting frozen product).
Detailed advice and training materials on storage and handling of the COVID-19 vaccines anticipated for use in Canada will be provided by the manufacturers, and guidelines for safe transport, storage and handling will be updated by PHAC. Jurisdictions should ensure that appropriate cold chain procedures, equipment and capacity are in place by confirming adequate vaccine storage space in purpose-built vaccine refrigerators (and/or freezers as required), management of dry ice in accordance with safe handling practices for hazardous materials, performing routine temperature monitoring and equipment maintenance, and reviewing procedures for transporting vaccine to off-site clinics. If vaccine is to be supplied to community practitioners and health care facilities, their storage and handling procedures should comply with public health requirements. Arrangements for the physical security of vaccine should be made for all stages of vaccine delivery and storage.
Packaging specifications for products are under development. All vaccines will be in multidose vials for the initial rollout. Vials per secondary carton may vary, in addition to packaging details for products with adjuvant (e.g., supplied in separate vials as was the case for H1N1 vaccine). Information on whether products can be repackaged into smaller units for distribution to vaccine providers who cannot manage larger package sizes will be provided when available.
Inventory management at all levels is essential to maximize available vaccine supplies and anticipate future needs. Accurate real-time knowledge of vaccine supply and inventory can allow for adjustments to vaccine shipments or clinic schedules as needed. The inventory system should be able to track vaccine lots so that if needed, specified lots can be put on hold or recalled. Vaccine bar coding could assist in this tracking process.
Recommendations for vaccine use
-------------------------------
The National Advisory Committee on Immunization (NACI) will provide expert advice and guidance on the use of COVID-19 vaccines, including identifying key populations for early immunization which will inform vaccine allocation to PTs.
### Vaccine recommendations
The NACI COVID-19 vaccine statement will be prepared as a living document and be updated as new vaccines or indications for use become available. Key sections in the recommendations will include populations for whom vaccine is particularly recommended, vaccine safety, products available for use, choice of vaccine products and vaccine administration, e.g., dosages and schedules based on clinical trials of the new products.
If passive immunizing agents emerge for prophylaxis, such as monoclonal antibodies or convalescent plasma, NACI will also consider guidance for these products.
### Recommendations on key populations for early immunization
It is anticipated that vaccine will become available in stages and initial quantities will be quite limited. To help planning for the equitable allocation and use of COVID-19 vaccine(s) when limited supplies necessitate recommendations for some groups to be immunized before others, NACI developed [*Preliminary guidance on key populations for early COVID-19 immunization*](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-key-populations-early-covid-19-immunization.html). This interim guidance has been subsequently updated – for details on the updated NACI recommendations and sequencing, see *[Guidance on the Prioritization of Initial Doses of COVID-19 Vaccine(s)](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-prioritization-initial-doses-covid-19-vaccines.html)*.
Sub-prioritization within these populations will be required in the context of vaccine supply limitations and will be carried out in collaboration with the Canadian Immunization Committee. As provinces and territories are responsible for COVID-19 vaccine delivery in their jurisdiction, they will make final decisions that best meet the needs of their respective populations.
Vaccine administration
----------------------
In a pandemic, it is important to be able to administer vaccine as quickly as it becomes available. There were many challenges with this process during the 2009 H1N1 immunization campaign, especially in the initial management of priority populations when supplies were limited.
The Canadian Immunization Committee (CIC) and its subcommittees will provide advice on the implementation of the COVID-19 immunization response including vaccine administration, and a forum for FPT information sharing and troubleshooting.
### Planning considerations
The efficient administration of COVID-19 vaccine can be based in large part on established practices such as seasonal influenza programs; however, modifications are needed in the context of COVID-19. These modifications include:
* Adaptions to usual immunization procedures in the presence of COVID-19 activity (e.g., screening; physical distancing; appropriate infection, prevention and control practices; and paperless processes);
* Taking measures to reduce crowding at immunization clinics (e.g., immunization by appointment) and considering other options in appropriate circumstances (e.g., outreach programs, drive-in or drive-through clinics in good weather);
* Using appropriate strategies to reach identified key populations, such as persons in long term care homes and other congregate living settings for seniors, health care workers (HCWs), persons at increased risk of severe illness and death from COVID-19, and Indigenous communities; and
* Maintaining flexibility to deal with unexpected changes in vaccine supply, delivery dates or recommendations.
It is anticipated that PTs will provide direction to regional and local health departments about the range of strategies to be used to provide COVID-19 vaccine to the public. Considerations include the capacity to store the vaccine properly and the need to minimize wastage, given that vaccine will be supplied in multidose vials without preservative.
Vaccines have traditionally been administered by public health nurses and/or by doctors and nurses in primary care; however, most provinces have now expanded pharmacists' scope of practice to include administration of vaccine. Other potential vaccine providers, such as paramedics, may also be needed to provide surge capacity or outreach for the administration of COVID-19 vaccine. PTs may wish to further expand the range of providers who can administer vaccine or to expand the scope of immunization practice of existing providers like pharmacists to additional routes of administration, age groups or settings.
Some additional planning considerations for the administration of COVID-19 vaccine include the following:
* It is anticipated that vaccine will become available in stages, and that there may be ongoing interruptions and changes to scheduled deliveries that will affect supply.
* Historical data from the 2009 influenza pandemic and seasonal influenza immunization campaigns may help jurisdictions estimate vaccine uptake, but uptake can be affected by many factors, especially public perceptions of pandemic impact and vaccine safety. Planning for an average upper limit of 75% vaccine uptake (as recommended in the [vaccine annex for the Canadian Pandemic Influenza Preparedness guidance](/en/public-health/services/flu-influenza/canadian-pandemic-influenza-preparedness-planning-guidance-health-sector/vaccine-annex.html)) should be adequate in most areas, but uptake may be higher in some jurisdictions and settings.
* Jurisdictions should plan to implement a two-dose program as required for most candidate vaccines. The second dose must be given within a certain time frame and with the same product. Vaccine recipients should be provided with information about how and when to get the second dose and consideration given to use of recall/reminder systems to promote their return.
* As more than one type of COVID-19 vaccine will be used in Canada, for purposes of monitoring safety and vaccine effectiveness, it is essential to record the specific products and vaccine lots supplied to jurisdictions and administered to individuals.
* Information systems are needed to track individual immunizations, including lot numbers, and provide second dose reminders to clients.
* PHAC will be developing fact sheets, informed consent materials and model medical directives for PT use to ensure consistency.
* Jurisdictions should recommend a standard approach to vaccine preparation (e.g., timing/mixing of adjuvant) and infection prevention and control measures with use of multidose vials.
* Jurisdictions should determine human resource requirements and be prepared to activate established mutual aid agreements for HCW surge capacity, if required.
* Staff that might be called upon to administer COVID-19 vaccine should be trained in advance and given opportunities to practise their skills.
* Planners should consider unique approaches for vaccine hesitant individuals in immunization communication strategies.
Detailed advice for planning immunization clinics can be found in the [Planning Guidance for Immunization Clinics for COVID-19 Vaccines](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/planning-immunization-clinics-covid-19-vaccines.html). This document also touches on alternate delivery methods that may be useful in special circumstances.
### Vulnerable and hard to reach populations
Immunization providers will have to reach vulnerable people who may have physical or mental disabilities or low literacy, as well as people who may experience a lack of mobility, homelessness or cultural or social isolation.
Useful strategies include:
* translating immunization materials into appropriate languages;
* having translators available at clinics;
* organizing rides to clinics or providing taxi chits or bus tickets;
* enlisting younger or multilingual family members to assist in communication;
* offering home visits if resources permit;
* holding immunization clinics at food banks or food lines, shelters or other places where vulnerable persons might gather (e.g., drop-in services, consumption treatment centres, pharmacies or clinics providing specific services); and
* working with outreach/mental health/social support case workers.
### Remote and isolated and Indigenous communities
Indigenous Services Canada (ISC) is working to ensure that remote and isolated and other Indigenous communities will have equitable access to COVID-19 vaccine once it is available. This is being done in collaboration with Indigenous partners, regional offices, provinces and territories, and PHAC.
ISC is also working on guidance for immunization delivery and messaging and education for when vaccine is available. Resources such as *Planning Guidance for Vaccine Clinics during COVID-19 in Indigenous Communities* have been shared across their networks.
### Ancillary immunization supplies
In preparation for the administration of COVID-19 vaccine, the Government of Canada is securing more than 75 million syringes, needles, alcohol swabs and other supplies (including gauze and sharps containers), enough to provide two doses of COVID-19 vaccine to every Canadian when vaccine is ready.
Monitoring vaccine safety, uptake and effectiveness
---------------------------------------------------
The scale of the COVID-19 immunization response warrants careful attention to vaccine safety to minimize risk and maximize the benefits of COVID-19 vaccine. Despite all the knowledge gained about a product pre-market, it is not possible to detect all adverse events following immunization (AEFIs) at that stage, especially if they are very rare. Rapid and continuous post-market vaccine safety surveillance is critical to capture all reports of serious and unexpected AEFIs for all vaccines authorized in Canada and to act on safety signals in a timely way.
### Mechanisms to support post-market vaccine safety surveillance
The approach to COVID-19 vaccine safety will leverage and build upon the infrastructure and systems already in place for monitoring seasonal influenza and other vaccines. Post-marketing surveillance for adverse events is undertaken by PHAC and HC in collaboration with PT partners and other key stakeholders, through the following mechanisms:
* [Health Canada's Canada Vigilance Program](/en/health-canada/services/drugs-health-products/medeffect-canada/canada-vigilance-program.html) collects and assesses reports of suspected adverse reactions to marketed health products in Canada, including vaccines. Manufacturers are required to report serious adverse reaction reports from Canada and serious, unexpected international reports. This system also receives reports directly from health care providers, patients and their families. All reports, whatever the source, are evaluated by HC for causality and signal detection, using established processes for timely review and reporting. Systems for data sharing with PHAC are also in place.
* The [Canadian Adverse Events Following Immunization Surveillance System (CAEFISS)](/en/public-health/services/immunization/canadian-adverse-events-following-immunization-surveillance-system-caefiss.html) is managed by PHAC and is an FPT post-market vaccine safety monitoring system that includes spontaneous, enhanced and active AEFI reporting processes. During the pandemic, this surveillance system will be used to receive AEFI reports from PTs for signal detection, analysis and reporting. Expedited AEFI surveillance will be carried out during and following the administration of COVID-19 vaccine to report aggregate counts of AEFIs on a weekly basis. This will allow PHAC to detect potential safety signals for further investigation sooner than with a standard passive surveillance system.
* The [Immunization Monitoring Program ACTive (IMPACT) network](https://www.cps.ca/en/impact) is a paediatric, hospital-based network administered by the Canadian Paediatric Society. IMPACT conducts active, targeted syndromic surveillance for AEFI considered to be of special importance. All such AEFIs are reported to PHAC and local public health officials and are included in CAEFISS. During a large cale immunization campaign, additional selected diseases or surveillance targets may be added if a connection to vaccine is suspected. IMPACT also conducts national surveillance for vaccine failures and selected vaccine-preventable diseases in children.
AEFI reports must be quickly passed on to PHAC for collation into CAEFISS, with serious events given priority. A vaccine safety signal from AEFI reports could include a new and potentially causal association, or a new aspect of a known association. Safety signals are investigated so that the cause can be assessed and action taken if appropriate. Such actions may include updates to the product monograph, recall of a vaccine lot or revisions to vaccine recommendations or administration practices.
### External networks
Several external networks will also be engaged to monitor COVID-19 AEFIs and conduct special studies on COVID-19 vaccine safety and effectiveness. The [Canadian Immunization Research Network (CIRN)](http://cirnetwork.ca/) is a collaboration of leading vaccine researchers and institutions in Canada. CIRN networks that will be involved in COVID-19 vaccine safety initiatives include:
* The [Canadian Vaccine Safety (CANVAS) Network](http://cirnetwork.ca/%20network/national-ambulatory-network) – CANVAS provides enhanced surveillance by assessing vaccine safety in various age groups immediately following the yearly launch of influenza vaccine campaigns. CANVAS processes can be applied to COVID-19 vaccines.
* The [Special Immunization Clinics Network](http://cirnetwork.ca/%20network/special-immunization) – This is a national network of expert clinicians across the country established to investigate and manage patients with AEFIs or underlying conditions that may be contraindications to immunization.
### Federal Provincial Territorial Vaccine Vigilance Working Group
The Vaccine Vigilance Working Group (VVWG) is a national safety committee that reports to the CIC. It has participants from all PTs and federal immunization programs together with IMPACT, Health Canada regulators and other representatives. The VVWG will play an important vaccine safety role during the COVID-19 immunization response by facilitating the development of guidelines, standards, protocols and best practices to improve FPT post market safety surveillance in Canada. It will share and rapidly disseminate information within the network and to appropriate stakeholders regarding vaccine safety issues or signals.
**Measuring vaccine uptake** as COVID-19 vaccine is being administered to Canadians allows public health authorities to determine if it is in line with expectations. If uptake is lower than expected, additional strategies or promotional efforts may be needed for specific key populations or in general. The results may also lead to adjustment of recommendations or of vaccine allocations to FPT jurisdictions.
At present, each PT maintains its own system for tracking immunization data using electronic databases or paper-based systems or a combination of both. To support the monitoring of real-time vaccine uptake, key data elements such as age, sex and risk groups should be determined and the relevant information collected from all vaccine recipients, including those immunized by non-public health providers. This information should be rapidly collated and analyzed. Immunization registry development should be actively pursued in jurisdictions without existing registries in order to support the data needs of the COVID-19 immunization response. In September 2020, PHAC offered funding to PTs for registry enhancement of their registries.
The **FPT Canadian Immunization Registry and Coverage Network (CIRC)**, a CIC subcommittee, developed functional standards for immunization registries in 2019, which were endorsed by CIC. CIRC is therefore best positioned to develop data standards and facilitate the collection and sharing of available vaccine uptake reports from jurisdictions during the administration of COVID-19 vaccine. CIRC members have agreed to make weekly reports on the number of vaccine doses administered in their jurisdiction, broken down by recipients' age and gender, as well as the number of doses administered to the populations targeted for early immunization (e.g., long-term care residents, health care workers, Indigenous populations).
Planning is also underway for repeated monthly national coverage surveys through Statistics Canada to estimate PT coverage levels. The COVID-19 Vaccination Coverage Survey will supplement data from PT registries to gain information on knowledge, attitudes and beliefs about COVID-19 immunization among immunized and unimmunized persons, reasons for being immunized or not immunized and sociodemographic information such as ethnicity and Indigenous identity.
**Vaccine effectiveness** measures how well a vaccine works when it is in general use in real-life circumstances (unlike the ideal circumstances of a clinical trial where vaccine efficacy is measured). Vaccine effectiveness is usually monitored by studies using a test-negative design; such studies have been used for years to measure the effectiveness of influenza vaccines in Canada. The [Canadian Influenza Sentinel Practitioner Surveillance Network (SPSN)](http://www.bccdc.ca/health-info/diseases-conditions/influenza/sentinel-network-spsn) and the [Serious Outcomes Surveillance (SOS) Network](http://cirnetwork.ca/network/serious-outcomes/) of CIRN are well placed to provide similar information on the effectiveness of the COVID-19 vaccine. Special studies may also be conducted in selected populations.
Public and professional communication and engagement
----------------------------------------------------
Careful planning to ensure readiness of the general public and the health community for a COVID-19 vaccine should begin well in advance of vaccine availability. In dealing with the uncertainties surrounding a new vaccine, especially products that use a novel technology, early and effective communication is necessary to build trust, correct misinformation and overcome vaccine hesitancy.[Footnote 1](#fn1) Maintaining confidence in the COVID-19 immunization program is a major challenge, and concerns and misinformation about COVID-19 vaccines are already beginning to circulate.
Public and professional communications proved to be one of the more challenging aspects of the 2009 influenza pandemic response. Improving communication strategies by applying lessons learned from this experience[Footnote 2](#fn2) should result in increased public confidence that translates to higher immunization coverage. These relate to both content and use of effective communication strategies. Immunization information should be communicated in meaningful, culturally relevant and personal terms, and crowd out misinformation.
While all government levels are involved in immunization communications, messaging needs to be coordinated and consistent. Established FPT networks, including the Public Health Network Communications Group, are being used to coordinate the COVID-19 communications response, including immunization issues. The federal government is addressing the overall response and regulatory and safety issues. PTs will focus on the immunization response in their own jurisdiction and regional and local health departments will provide local details.
The communication strategy is being informed through ongoing behavioural research to better understand the knowledge, attitudes and beliefs and decision-making behaviours of Canadians regarding COVID-19 vaccine.
### Public communication and engagement
The groundwork for public acceptance of COVID-19 vaccine needs to be laid well in advance of actual vaccine availability. All communication strategies should take into consideration the diverse communication needs of population groups based on ethnicity/culture, ability status, language, education/literacy, age and other factors. Both the risk of COVID-19 infection and the risks and benefits associated with immunization, including the contribution of individual immunization to herd immunity, should be communicated effectively. The process and rationale for immunizing people in stages as vaccine becomes available should be carefully explained so that persons eligible for early immunization do not feel like test subjects, and others understand that their turn will come.
Public interest in and concerns over vaccine safety will likely be significant. Provision of detailed information about vaccine regulation and safety monitoring is important and vaccine misinformation should be addressed quickly and aggressively. It is also important to plan for communications in the event of a vaccine safety signal that arises either outside or within Canada.
Multiple strategies, including traditional media, local and ethnic media and social media, should be used to provide immunization program information to engage a diverse audience. Tailored approaches will be needed for vulnerable populations, such as provision of information in multiple formats. Community leaders can be asked to convey accurate information and champion the immunization program. Involvement of stakeholders (e.g., Indigenous health and immigrant/refugee organizations) can help make communications materials and strategies more appropriate for the target audiences.
As vaccine becomes available, messaging about eligibility may be challenging as information is complex and subject to change. Communication should be clear that although the goal is to make vaccine available to all Canadians, it will become available in stages, requiring targeted distribution in a fair and equitable manner.
### Health care sector communication and engagement
Health care providers play a central role in encouraging COVID-19 immunization, especially if they have been immunized themselves or intend to do so. It is important to keep them well informed about the safety and effectiveness of the COVID-19 vaccines being used, so they can present a unified message of strong support from the health care community.
Outreach to health care providers should use trusted sources and networks, and timely updates should be provided, for example through webinars that are being developed on COVID-19 vaccines. Challenges include conveying the need for flexibility because vaccine recommendations may change over time as more information becomes available. Rationale should be provided for recommendations on key populations for early COVID-19 immunization and for differences from other countries (especially the USA). Any PT adaptation of national prioritization recommendations should be clearly explained to practitioners in that jurisdiction.
Engaging the health care sector requires collaboration between jurisdictions:
* FPT and professional association website information should include links to Government of Canada information on the COVID-19 vaccine, such as the regulatory process, vaccine safety, the current product information leaflet and national vaccine recommendations.
* PTs should provide information to vaccine providers within their jurisdiction about the plans for administration of COVID-19 vaccine, including any jurisdictional modifications to the response.
* Regional and local public health authorities can help to ensure that information and guidelines are disseminated to local HCWs and that these workers are provided with details of the local immunization response.
References
----------
Footnote 1
Deroo SS, Pudalov NJ, Fu LY. Planning for a COVID-19 Vaccination Program. JAMA 2020 May 18. doi: 10.1001/jama.2020.8711. Online ahead of print.
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
Public Health Agency of Canada. Lessons learned review: Public Health Agency of Canada and Health Canada response to the 2009 H1N1 pandemic. November 2010. Available from: https://www.canada.ca/content/dam/phac-aspc/migration/phac-aspc/about\_apropos/evaluation/reports-rapports/2010-2011/h1n1/pdf/h1n1-eng.pdf
[Return to first footnote 2 referrer](#fn2-1-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2020-12-21
| None | None |
c351ee918c9a20429a12ce199c8ed20c2b63bec4 | cma | Immunization of adults: Canadian Immunization Guide | Immunization of adults: Canadian Immunization Guide
Introduction
Prevention of infection by immunization is not just for children; adults require immunization to restore waning immunity against some vaccine preventable diseases and to establish immunity against other diseases that are more common in adults. In addition, immunization of adults prevents infection and, therefore, subsequent exposure of young children and others at increased risk of vaccine preventable diseases. For example, adults who are in contact with infants should be prioritized to receive pertussis and influenza vaccination to reduce the risk of transmission of these infections to infants who are too young to be fully protected. Some vaccines are needed by all adults and other vaccines may be required due to individual risk resulting from occupation, travel, underlying illness, lifestyle or age.
In recent years, new vaccines such as herpes zoster and human papillomavirus have become available for adults. Despite these advances, the vaccination rates of adults in Canada are low, with the result that many adults remain vulnerable to vaccine preventable diseases.
Common reasons for incomplete immunization in adulthood include:
- lack of recognition of the importance of adult immunization
- lack of recommendations from health care providers
- lack of health care provider's knowledge about adult immunization and recommended vaccines
- misrepresentation and misunderstanding of the risks of vaccine and benefits of disease prevention in adults
- lack of understanding of vaccine safety and efficacy
- missed opportunities for vaccination in health care providers' offices, hospitals and nursing homes
- lack of publicly funded vaccine and reimbursement to vaccine providers
- lack of coordinated immunization programs for adults
- lack of regulatory or legal requirements
- fear of injections
- lack of availability of up-to-date records and recording systems
Adult immunization is an emerging issue that has seen an increasing emphasis in clinical care and health professional training programs.
Health care provider responsibilities
Health care providers have a responsibility to ensure that adults under their care have continuing and updated protection against vaccine preventable diseases through appropriate immunization. When considering immunization, the person's medical history will help to determine whether other immunizations are needed in addition to routinely recommended vaccines. Refer to and in Part 3 for further information on how health conditions may modify vaccine recommendations.
Health care providers should provide adults under their care with factual information about immunization, including:
- information about vaccines
- expert recommendations regarding the use of vaccines
- benefits and risks of vaccination
- cost of the vaccine if it is not publicly funded
- possible consequences of declining a vaccine
- where vaccine can be obtained if the health care provider is unable to provide the vaccine
When more than one dose of a vaccine is required for optimal protection, the health care provider should arrange follow-up to encourage completion of the vaccine series.
Strategies to improve vaccine uptake in adults
All adults should be counselled concerning their immunization status. Opportunities for general immunization counselling of adults include:
- new patient encounters
- periodic health examinations
- pregnancy and the immediate post-partum period
- visits for chronic disease management
- assessment of new immigrants
- parents attending their child's vaccination visits
- hospitalization, especially when diagnosed with a chronic disease
- management protocols on admission to nursing homes, long-term care institutions, and acute care institutions
- management protocols on admission to health professional training programs
- new employee assessments in day care, health care and health care-related facilities
- persons requesting specific vaccination(s)
- persons with evidence of risk taking behaviour, such as illicit drug use or a sexually transmitted infection
- individuals requesting advice concerning travel
Health care providers should regularly review individuals under their care to ensure that the person's immunization status is up to date and that they have been made aware of new vaccines that are or may be indicated for them. Practitioners should routinely audit immunization records during clinical encounters; scheduling record audits on a set birthday, for example, to coincide with a mid-decade birthday (i.e., 25, 35 years of age, etc.), is one effective reminder strategy. Health care institutions should have policies addressing immunization issues for patients and personnel.
Additional effective strategies for increasing the uptake of immunization by adults include patient and health care provider education about indicated prevention practices, and increasing accessibility to immunization through immunization clinics and greater engagement of non-physician staff in the execution of immunization programs. A sample adult immunization record and information resources for adult immunization are available on the website.
Recommended immunization for adults
All adults in Canada without contraindications should be routinely immunized against vaccine preventable diseases. Routinely recommended adult immunizations are summarized in . Recommended immunization schedules for adults who have no record or an uncertain immunization history are available in in Part 1.
In addition to routinely recommended immunization, certain vaccines are recommended for adults in specific risk situations. These recommendations are summarized in . International travellers and workers in specific risk situations require assessment of immunization status, completion of routinely recommended vaccine series, and booster doses as necessary. Refer to , , and in Part 3; and in Part 4 for additional information.
# Diphtheria toxoid-, tetanus toxoid-, containing vaccine
All adults in Canada should be immunized against diphtheria and tetanus. Booster doses of diphtheria and tetanus toxoid-containing vaccine are recommended every 10 years. Refer to and in Part 4 for additional information.
# Herpes zoster (shingles) vaccine
A two dose series of Recombinant Zoster Vaccine, (RZV) is recommended for adults 50 years of age or older without contraindications, including those who have previously been immunized with Live Zoster Vaccine (LZV), or who have had a previous episode of herpes zoster (HZ). Re-immunization with RZV may be considered at least one year after LZV or at least one year after an episode of HZ. In immunocompetent adults in whom RZV is contraindicated or when the vaccine is unavailable or inaccessible, LZV may be considered. Adults aged 50 years and older who are known to be *varicella zoster virus- seronegative should receive univalent varicella (chickenpox) vaccine, rather than herpes zoster (shingles) vaccine. Routine testing of adults aged 50 years and older for *varicella zoster virus- antibody prior to immunization is not recommended. Refer to -vaccine.html) in Part 4 for additional information.
# Human papillomavirus vaccine
Bivalent or quadrivalent or nonavalent human papillomavirus (HPV) vaccine is recommended for women up to and including 26 years of age and may be administered to those 27 years of age and older who are at ongoing risk of exposure. Quadrivalent or nonavalent HPV vaccine is recommended for men up to and including 26 years of age and may be administered to men 27 years of age and older who are at ongoing risk of exposure. Refer to in Part 4 for additional information.
# Influenza vaccine
Seasonal influenza vaccine is recommended annually for all adults without contraindications, with particular focus on individuals who are at high risk of influenza-related complications or hospitalization, who are capable of transmitting influenza to those at high risk, who provide essential community services and who are in direct contact during culling operations with poultry infected with avian influenza. Refer to in Part 4 for additional information.
# Measles-mumps- rubella vaccine
Combined measles-mumps-rubella (MMR) vaccine is recommended for vaccination of adults born in or after 1970 susceptible to one or more of these viruses. Although adults born before 1970 are assumed to have acquired natural immunity, those at the greatest risk of measles or mumps exposure, such as travellers, health care workers, students in post-secondary educational settings, and military personnel, may require immunization. If MMR vaccine is indicated for a pregnant woman, it should be provided after delivery, preferably prior to discharge from hospital. Refer to , and in Part 4 for additional information including criteria for determining susceptibility/immunity to measles, mumps and rubella.
# Meningococcal vaccine
Healthy adults up to and including 24 years of age should receive meningococcal vaccine if it was not received in adolescence. Either a meningococcal conjugate monovalent or a meningococcal conjugate quadrivalent vaccine, depending on local epidemiology and programmatic considerations, is recommended for young adults, even if they have previously been vaccinated as an infant or toddler. In addition, multicomponent meningococcal vaccine may be considered on an individual basis to protect against invasive meningococcal disease caused by relevant serogroup B strains. Adults with specific risk conditions (refer to ) are recommended to receive meningococcal conjugate quadrivalent vaccine, multicomponent meningococcal vaccine or both vaccines, depending on the risk situation. Refer to in Part 4 for additional information.
# Pertussis-containing vaccine
All adults (18 years of age and older) should receive one dose of acellular pertussis-containing vaccine (tetanus, diphtheria in Part 4 for additional information.
# Pneumococcal vaccine
Pneumococcal polysaccharide 23-valent (Pneu-P-23) vaccine is recommended for all adults 65 years of age and older. For additional information about the immunization of adults at highest risk of invasive pneumococcal disease refer to , in Part 4, and and in Part 3.
# Poliomyelitis vaccine
All adults in Canada should be immune to polio. For previously unimmunized adults, a primary series of inactivated poliomyelitis vaccine (IPV) should be provided at the time of immunization with a tetanus and diphtheria toxoid-containing vaccine. For adults that have previously received a primary series of tetanus and diphtheria toxoid-containing vaccine, IPV-containing vaccine can be provided at the time of routine tetanus and diphtheria toxoid-containing vaccine booster immunization. Unimmunized or incompletely immunized adults at increased risk of exposure should complete a primary series of IPV-containing vaccine; previously immunized adults at increased risk of exposure should receive a single lifetime booster dose of IPV-containing vaccine. Refer to and in Part 4 for additional information.
# Varicella (chickenpox) vaccine
Univalent varicella vaccine is recommended for susceptible adults 18 to 49 years of age. Refer to in Part 4 for additional information. For adults 50 years of age and older refer to -vaccine.html) in Part 4.
- Booster dose every 10 years
- 50 years of age and older previously received LZV - 2 doses RZV, at least 1 year after immunization with LZV
- 50 years of age and older previous episode of HZ - 2 doses RZV, at least 1 year after episode of HZ
- immunocompetent individuals 50 years of age and older where RZV is contraindicated, unavailable or inaccessible - 1 dose LZV
- Men up to and including 26 years of age - HPV4 or HPV9 vaccine
- Born before 1970 - consider immune
- Adults who will be in close contact with young infants should be immunized as early as possible
- One dose of Tdap vaccine should be administered in every pregnancy, ideally between 27 and 32 weeks of gestation.
- If vaccine is indicated, pregnant women should be immunized after delivery
- Known seronegative adults 50 years of age and older - 2 doses - routine testing is not advised
HPV
human papillomavirus
HPV2
human papillomavirus bivalent vaccine
HPV4
human papillomavirus quadrivalent vaccine
HPV9
human papillomavirus nonavalent vaccine
LZV
live zoster vaccine
RZV
recombinant zoster vaccine
- who are long-term travellers to high prevalence countries (in exceptional circumstances as noted above)
- Consider use for prevention of travellers' diarrhea in adults:
+ with chronic diseases at risk for complications
+ at increased risk of acquiring travellers' diarrhea
+ who are immunosuppressed
+ with a history of repeated severe travellers' diarrhea
- malignant hematologic disorders
- HIV
- anatomic or functional asplenia or hyposplenism
- solid organ transplant recipients
- cochlear implant recipients
- who are immigrants from HA endemic areas
- who are household or close contacts of children adopted from HA endemic countries
- in communities or populations at risk of outbreaks or in which HA is highly endemic
- who are household or close contacts of proven or suspected cases of HA
- with occupational or lifestyle risk for exposure
- with chronic liver disease from any cause, including those infected with hepatitis B and C
- receiving plasma-derived replacement clotting factors
- who are household or sexual contacts of acute HB cases and HB carriers, including close contacts of children adopted from HB endemic countries if the adopted child is HBsAg positive
- with occupational or lifestyle risk for exposure
- travelling to HB endemic areas
- in communities or populations in which HB is highly endemic
- who are residents of institutions for the developmentally challenged or inmates of correctional facilities
- with chronic liver disease, including those infected with hepatitis C
- with chronic renal disease, including patients on chronic dialysis
- hemophiliacs and other people who receive repeated infusions of blood or blood products
- who have undergone hematopoietic stem cell transplantation or are awaiting solid organ transplant
- who have congenital immunodeficiencies
- who are HIV-infected
- Bivalent HPV vaccine may be considered for women 27 years of age and older at ongoing risk of exposure
- capable of transmitting influenza to individuals at high risk
- who provide essential community services
- in direct contact during culling operations with poultry infected with avian influenza
- travelling to endemic area(s) during transmission season with specified exposure risks
+ If susceptible and at increased risk of exposure (travellers to destinations outside of Canada, health care workers, students in post-secondary educational settings, and military personnel) - 2 doses, at least 4 weeks apart.
- Recommended for adults born before 1970 if:
+ non-immune military personnel or health care workers - 2 doses, at least 4 weeks apart
+ non-immune travellers - 1 dose
+ non-immune students - consider 1 dose
- who are travellers:
+ for whom meningococcal vaccine is recommended or required, including travellers to sub-Saharan African and pilgrims to the Hajj in Mecca, Saudi Arabia
+ to an area with a hyperendemic strain or an outbreak that is known to be caused by a serogroup that can be prevented by the vaccine
- at high risk of meningococcal disease due to medical conditions:
+ anatomic or functional asplenia or hyposplenism (including sickle cell disease)
+ congenital complement, properdin, factor D or primary antibody deficiencies
+ acquired complement deficiency due to receipt of the terminal complement inhibitor eculizumab
+ should be considered for adults who are HIV-infected
- who are close contacts of a case of invasive meningococcal disease caused by a vaccine preventable serogroup
- who are at increased risk of IPD due to lifestyle factors:
+ persons with alcoholism
+ smokers
+ persons who are homeless
+ should be considered for individuals who use illicit drugs
- who are at high risk of IPD due to an underlying medical condition:
+ asthma requiring regular medical care
+ chronic cerebral spinal fluid leak
+ chronic neurologic condition that may impair clearance of oral secretions
+ cochlear implants (including adults who are to receive implants)
+ chronic cardiac or pulmonary disease
+ diabetes mellitus
+ chronic kidney disease
+ chronic liver disease (including hepatic cirrhosis due to any cause)
- sickle cell disease or other hemoglobinopathies
- congenital immunodeficiencies involving any part of the immune system, including B-lymphocyte (humoral) immunity, T-lymphocyte (cell) mediated immunity, complement system (properdin or factor D deficiencies), or phagocytic functions
- HIV infection
- immunosuppressive therapy including use of long-term corticosteroids, chemotherapy, radiation therapy, post-organ transplant therapy, and biologic and non-biologic immunosuppressive therapies for rheumatologic and other inflammatory diseases
- malignant neoplasms including leukemia and lymphoma
- solid organ or islet cell transplant (candidate or recipient)
- nephrotic syndrome
- following HSCT
- health care workers who have close contact with individuals who might be excreting wild type or vaccine type poliovirus
- members of communities or specific population groups with disease caused by polio
- people who come in close contact with those who may be excreting poliovirus such as people working with refugees, military personnel and people on humanitarian missions in endemic countries
- laboratory workers handling specimens that may contain poliovirus
- family or close contacts of internationally adopted infants who may have been or will be vaccinated with oral polio vaccine (OPV)
For previously unimmunized adults - primary series of IPV-containing vaccine
- with lifestyle risk of exposure
- travelling to high-risk areas with specified exposure risks
- who have ongoing household or intimate exposure to a *S. typhi- carrier
- with occupational risk of exposure
- with occupational risk of exposure
Consider immunization of healthy adults aged 60 years and over if travel to areas with risk of yellow fever transmission cannot be avoided and a high level of protection against mosquito exposure is not feasible.
Based on a case-by-case assessment of benefit versus risk, the use of a one-time booster dose is recommended for certain individuals.
Re-immunization every 10 years is recommended for:- laboratory personnel working with YF virus unless measured neutralizing antibody titre to yellow fever virus confirms ongoing protection
- HIV-positive individuals who are travelling to countries with risk of YF transmission
Choice of meningococcal vaccine(s) varies with risk situation. Refer to in Part 4 for additional information.
BCG
Bacille Calmette-Guérin
HBsAg
hepatitis B surface antigen
HA
Hepatitis A
HB
Hepatitis B
Hib
*Haemophilus influenzae- type b
HIV
human immunodeficiency virus
HSCT
hematopoietic stem cell transplantation
IPD
invasive pneumococcal disease
IPV
inactivated poliomyelitis vaccine
LZV
live zoster vaccine
OPV
-ral live poliomyelitis vaccine
RZV
recombinant zoster vaccine
TB
tuberculosis
Tdap
tetanus toxoid, diphtheria toxoid (reduced), acellular pertussis (reduced) - containing vaccine |
Immunization of adults: Canadian Immunization Guide
====================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-3-immunization-persons-inadequate-immunization-records.html)
Notice
------
* This CIG chapter has not been updated to contain any information regarding COVID-19 vaccines, refer to the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) .
**Last partial content update** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): March 2023
**March 2023** - [Table 2](#a4.2): Adult immunization - recommendations for specific risk situations was updated to align with changes made to the [Yellow fever vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-25-yellow-fever-vaccine.html) chapter in Part 4 regarding booster doses of Yellow Fever vaccine.
**Last complete chapter revision:** July 2015
On this page
------------
* [Introduction](#a1)
* [Health care provider responsibilities](#a2)
* [Strategies to improve vaccine uptake in adults](#a3)
* [Recommended immunization for adults](#a4)
+ [Table 1: Adult immunization - recommendations for routine immunization in healthy adults at low risk](#a4.1)
+ [Table 2: Adult immunization - recommendations for specific risk situations](#a4.2)
* [Selected references](#a5)
Introduction
------------
Prevention of infection by immunization is not just for children; adults require immunization to restore waning immunity against some vaccine preventable diseases and to establish immunity against other diseases that are more common in adults. In addition, immunization of adults prevents infection and, therefore, subsequent exposure of young children and others at increased risk of vaccine preventable diseases. For example, adults who are in contact with infants should be prioritized to receive pertussis and influenza vaccination to reduce the risk of transmission of these infections to infants who are too young to be fully protected. Some vaccines are needed by all adults and other vaccines may be required due to individual risk resulting from occupation, travel, underlying illness, lifestyle or age.
In recent years, new vaccines such as herpes zoster and human papillomavirus have become available for adults. Despite these advances, the vaccination rates of adults in Canada are low, with the result that many adults remain vulnerable to vaccine preventable diseases.
Common reasons for incomplete immunization in adulthood include:
* lack of recognition of the importance of adult immunization
* lack of recommendations from health care providers
* lack of health care provider's knowledge about adult immunization and recommended vaccines
* misrepresentation and misunderstanding of the risks of vaccine and benefits of disease prevention in adults
* lack of understanding of vaccine safety and efficacy
* missed opportunities for vaccination in health care providers' offices, hospitals and nursing homes
* lack of publicly funded vaccine and reimbursement to vaccine providers
* lack of coordinated immunization programs for adults
* lack of regulatory or legal requirements
* fear of injections
* lack of availability of up-to-date records and recording systems
Adult immunization is an emerging issue that has seen an increasing emphasis in clinical care and health professional training programs.
Health care provider responsibilities
-------------------------------------
Health care providers have a responsibility to ensure that adults under their care have continuing and updated protection against vaccine preventable diseases through appropriate immunization. When considering immunization, the person's medical history will help to determine whether other immunizations are needed in addition to routinely recommended vaccines. Refer to [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) and [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for further information on how health conditions may modify vaccine recommendations.
Health care providers should provide adults under their care with factual information about immunization, including:
* information about vaccines
* expert recommendations regarding the use of vaccines
* benefits and risks of vaccination
* cost of the vaccine if it is not publicly funded
* possible consequences of declining a vaccine
* where vaccine can be obtained if the health care provider is unable to provide the vaccine
When more than one dose of a vaccine is required for optimal protection, the health care provider should arrange follow-up to encourage completion of the vaccine series.
Strategies to improve vaccine uptake in adults
----------------------------------------------
All adults should be counselled concerning their immunization status. Opportunities for general immunization counselling of adults include:
* new patient encounters
* periodic health examinations
* pregnancy and the immediate post-partum period
* visits for chronic disease management
* assessment of new immigrants
* parents attending their child's vaccination visits
* hospitalization, especially when diagnosed with a chronic disease
* management protocols on admission to nursing homes, long-term care institutions, and acute care institutions
* management protocols on admission to health professional training programs
* new employee assessments in day care, health care and health care-related facilities
* persons requesting specific vaccination(s)
* persons with evidence of risk taking behaviour, such as illicit drug use or a sexually transmitted infection
* individuals requesting advice concerning travel
Health care providers should regularly review individuals under their care to ensure that the person's immunization status is up to date and that they have been made aware of new vaccines that are or may be indicated for them. Practitioners should routinely audit immunization records during clinical encounters; scheduling record audits on a set birthday, for example, to coincide with a mid-decade birthday (i.e., 25, 35 years of age, etc.), is one effective reminder strategy. Health care institutions should have policies addressing immunization issues for patients and personnel.
Additional effective strategies for increasing the uptake of immunization by adults include patient and health care provider education about indicated prevention practices, and increasing accessibility to immunization through immunization clinics and greater engagement of non-physician staff in the execution of immunization programs. A sample adult immunization record and information resources for adult immunization are available on the [Immunize Canada](http://www.immunize.ca/en/specific-groups/adults.aspx) website.
Recommended immunization for adults
-----------------------------------
All adults in Canada without contraindications should be routinely immunized against vaccine preventable diseases. Routinely recommended adult immunizations are summarized in [Table 1](#4.1). Recommended immunization schedules for adults who have no record or an uncertain immunization history are available in [Recommended immunization schedules](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-13-recommended-immunization-schedules.html) in Part 1.
In addition to routinely recommended immunization, certain vaccines are recommended for adults in specific risk situations. These recommendations are summarized in [Table 2](#4.2). International travellers and workers in specific risk situations require assessment of immunization status, completion of routinely recommended vaccine series, and booster doses as necessary. Refer to [Immunization of travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html), [Immunization of workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html), [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) and [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3; and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
### Diphtheria toxoid-, tetanus toxoid-, containing vaccine
All adults in Canada should be immunized against diphtheria and tetanus. Booster doses of diphtheria and tetanus toxoid-containing vaccine are recommended every 10 years. Refer to [Diphtheria toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-4-diphtheria-toxoid.html) and [Tetanus toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html) in Part 4 for additional information.
### Herpes zoster (shingles) vaccine
A two dose series of Recombinant Zoster Vaccine, (RZV) is recommended for adults 50 years of age or older without contraindications, including those who have previously been immunized with Live Zoster Vaccine (LZV), or who have had a previous episode of herpes zoster (HZ). Re-immunization with RZV may be considered at least one year after LZV or at least one year after an episode of HZ. In immunocompetent adults in whom RZV is contraindicated or when the vaccine is unavailable or inaccessible, LZV may be considered. Adults aged 50 years and older who are known to be *varicella zoster virus* seronegative should receive univalent varicella (chickenpox) vaccine, rather than herpes zoster (shingles) vaccine. Routine testing of adults aged 50 years and older for *varicella zoster virus* antibody prior to immunization is not recommended. Refer to [Herpes Zoster (Shingles) Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-8-herpes-zoster-(shingles)-vaccine.html) in Part 4 for additional information.
### Human papillomavirus vaccine
Bivalent or quadrivalent or nonavalent human papillomavirus (HPV) vaccine is recommended for women up to and including 26 years of age and may be administered to those 27 years of age and older who are at ongoing risk of exposure. Quadrivalent or nonavalent HPV vaccine is recommended for men up to and including 26 years of age and may be administered to men 27 years of age and older who are at ongoing risk of exposure. Refer to [Human Papillomavirus vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-9-human-papillomavirus-vaccine.html) in Part 4 for additional information.
### Influenza vaccine
Seasonal influenza vaccine is recommended annually for all adults without contraindications, with particular focus on individuals who are at high risk of influenza-related complications or hospitalization, who are capable of transmitting influenza to those at high risk, who provide essential community services and who are in direct contact during culling operations with poultry infected with avian influenza. Refer to [Influenza vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html) in Part 4 for additional information.
### Measles-mumps- rubella vaccine
Combined measles-mumps-rubella (MMR) vaccine is recommended for vaccination of adults born in or after 1970 susceptible to one or more of these viruses. Although adults born before 1970 are assumed to have acquired natural immunity, those at the greatest risk of measles or mumps exposure, such as travellers, health care workers, students in post-secondary educational settings, and military personnel, may require immunization. If MMR vaccine is indicated for a pregnant woman, it should be provided after delivery, preferably prior to discharge from hospital. Refer to [Measles vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html), [Mumps vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-14-mumps-vaccine.html) and [Rubella vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-20-rubella-vaccine.html) in Part 4 for additional information including criteria for determining susceptibility/immunity to measles, mumps and rubella.
### Meningococcal vaccine
Healthy adults up to and including 24 years of age should receive meningococcal vaccine if it was not received in adolescence. Either a meningococcal conjugate monovalent or a meningococcal conjugate quadrivalent vaccine, depending on local epidemiology and programmatic considerations, is recommended for young adults, even if they have previously been vaccinated as an infant or toddler. In addition, multicomponent meningococcal vaccine may be considered on an individual basis to protect against invasive meningococcal disease caused by relevant serogroup B strains. Adults with specific risk conditions (refer to [Table 2](#p3c1t2) ) are recommended to receive meningococcal conjugate quadrivalent vaccine, multicomponent meningococcal vaccine or both vaccines, depending on the risk situation. Refer to [Meningococcal Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-13-meningococcal-vaccine.html) in Part 4 for additional information.
### Pertussis-containing vaccine
All adults (18 years of age and older) should receive one dose of acellular pertussis-containing vaccine (tetanus, diphtheria [reduced], acellular pertussis [reduced] [Tdap]) if it was not previously received during adulthood. This vaccine can be administered regardless of the interval since the last dose of tetanus and diphtheria toxoid-containing vaccine. In particular, adults who have not previously received Tdap vaccine in adulthood, and who anticipate having regular contact with an infant, should receive Tdap vaccine, ideally administered at least 2 weeks before contact with the infant. All pregnant women should receive one dose of Tdap vaccine in every pregnancy, ideally between 27 and 32 weeks of gestation. Refer to [Pertussis vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-15-pertussis-vaccine.html) in Part 4 for additional information.
### Pneumococcal vaccine
Pneumococcal polysaccharide 23-valent (Pneu-P-23) vaccine is recommended for all adults 65 years of age and older. For additional information about the immunization of adults at highest risk of invasive pneumococcal disease refer to [Table 2](#a4.2), [Pneumococcal vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html) in Part 4, and [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) and [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3.
### Poliomyelitis vaccine
All adults in Canada should be immune to polio. For previously unimmunized adults, a primary series of inactivated poliomyelitis vaccine (IPV) should be provided at the time of immunization with a tetanus and diphtheria toxoid-containing vaccine. For adults that have previously received a primary series of tetanus and diphtheria toxoid-containing vaccine, IPV-containing vaccine can be provided at the time of routine tetanus and diphtheria toxoid-containing vaccine booster immunization. Unimmunized or incompletely immunized adults at increased risk of exposure should complete a primary series of IPV-containing vaccine; previously immunized adults at increased risk of exposure should receive a single lifetime booster dose of IPV-containing vaccine. Refer to [Table 2](#a4.2) and [Poliomyelitis vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-17-poliomyelitis-vaccine.html) in Part 4 for additional information.
### Varicella (chickenpox) vaccine
Univalent varicella vaccine is recommended for susceptible adults 18 to 49 years of age. Refer to [Varicella (chickenpox) vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-24-varicella-chickenpox-vaccine.html) in Part 4 for additional information. For adults 50 years of age and older refer to [Herpes Zoster (Shingles) Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-8-herpes-zoster-(shingles)-vaccine.html) in Part 4.
Table 1: Adult immunization - recommendations for routine immunization in healthy adults at low risk| Vaccine | Recommendations for routine immunization |
| --- | --- |
| Diphtheria, Tetanus | * Primary series for previously unimmunized adults
* Booster dose every 10 years
|
| Herpes zoster (shingles) | * 50 years of age and older - 2 doses RZV
* 50 years of age and older previously received LZV - 2 doses RZV, at least 1 year after immunization with LZV
* 50 years of age and older previous episode of HZ - 2 doses RZV, at least 1 year after episode of HZ
* immunocompetent individuals 50 years of age and older where RZV is contraindicated, unavailable or inaccessible - 1 dose LZV
|
| Human papillomavirus (HPV) | * Women up to and including 26 years of age - bivalent (HPV2) or quadrivalent (HPV4) or nonavalent (HPV9) vaccine
* Men up to and including 26 years of age - HPV4 or HPV9 vaccine
|
| Influenza | Annually |
| Measles, mumps | * Susceptible adults born in or after 1970 - 1 dose
* Born before 1970 - consider immune
|
| Meningococcal conjugate | Adults up to and including 24 years of age not immunized in adolescence - 1 dose |
| Pertussis | * One dose of acellular pertussis-containing vaccine in adulthood
* Adults who will be in close contact with young infants should be immunized as early as possible
* One dose of Tdap vaccine should be administered in every pregnancy, ideally between 27 and 32 weeks of gestation.
|
| Pneumococcal polysaccharide 23-valent | 65 years of age and older - 1 dose |
| Polio | * Primary series for previously unimmunized adults when a primary series of tetanus toxoid- and diphtheria toxoid- containing vaccine is being given or with routine tetanus toxoid- and diphtheria toxoid- containing vaccine booster doses
|
| Rubella | * Susceptible adults - 1 dose
* If vaccine is indicated, pregnant women should be immunized after delivery
|
| Varicella (chickenpox) | * Susceptible adults up to and including 49 years of age - 2 doses; if only one dose was previously received, a second dose should be provided
* Known seronegative adults 50 years of age and older - 2 doses - routine testing is not advised
|
| Refer to [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information. Refer to Immunization in [Pregnancy and Breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3 for recommendations for women who are pregnant or lactating. Refer to [Table 2](#a4.2) for recommendations for adults with risk factors.
Table 1 - Abbreviations
HPV
human papillomavirus
HPV2
human papillomavirus bivalent vaccine
HPV4
human papillomavirus quadrivalent vaccine
HPV9
human papillomavirus nonavalent vaccine
LZV
live zoster vaccine
RZV
recombinant zoster vaccine
|
Table 2: Adult immunization - recommendations for specific risk situations| Vaccine | Recommendations for risk situations[Footnote 1](#fnt2f1) |
| --- | --- |
| Bacille Calmette-Guérin (BCG) | Consider use for adults:* who may be repeatedly exposed to persons with untreated, inadequately treated or drug-resistant active tuberculosis (TB) in conditions in which protective measures against infection are not feasible and when early identification and treatment of latent TB infection are not available
* who are long-term travellers to high prevalence countries (in exceptional circumstances as noted above)
|
| Cholera and travellers' diarrhea | * Consider use for **cholera prevention** in adult travellers to cholera-endemic area(s) at high risk of exposure, including those with occupational risk for exposure (e.g., health care or humanitarian workers in endemic countries)
* Consider use for **prevention of travellers' diarrhea** in adults:
+ with chronic diseases at risk for complications
+ at increased risk of acquiring travellers' diarrhea
+ who are immunosuppressed
+ with a history of repeated severe travellers' diarrhea
|
| *Haemophilus influenzae* type b (Hib) | Recommended following hematopoietic stem cell transplantation (HSCT) and for adults with increased risk of invasive Hib disease:* congenital (primary) immunodeficiencies
* malignant hematologic disorders
* HIV
* anatomic or functional asplenia or hyposplenism
* solid organ transplant recipients
* cochlear implant recipients
|
| Hepatitis A (HA) | Recommended for adults:* travelling to HA endemic areas
* who are immigrants from HA endemic areas
* who are household or close contacts of children adopted from HA endemic countries
* in communities or populations at risk of outbreaks or in which HA is highly endemic
* who are household or close contacts of proven or suspected cases of HA
* with occupational or lifestyle risk for exposure
* with chronic liver disease from any cause, including those infected with hepatitis B and C
* receiving plasma-derived replacement clotting factors
|
| Hepatitis B (HB) | Recommended for adults:* who have immigrated to Canada from areas where there is a high prevalence of HB and are known to be susceptible to HB
* who are household or sexual contacts of acute HB cases and HB carriers, including close contacts of children adopted from HB endemic countries if the adopted child is HBsAg positive
* with occupational or lifestyle risk for exposure
* travelling to HB endemic areas
* in communities or populations in which HB is highly endemic
* who are residents of institutions for the developmentally challenged or inmates of correctional facilities
* with chronic liver disease, including those infected with hepatitis C
* with chronic renal disease, including patients on chronic dialysis
* hemophiliacs and other people who receive repeated infusions of blood or blood products
* who have undergone hematopoietic stem cell transplantation or are awaiting solid organ transplant
* who have congenital immunodeficiencies
* who are HIV-infected
|
| Herpes zoster (shingles) | * RZV (not LZV) may be considered for immunocompromised adults 50 years of age and older based on a case-by-case assessment of the benefits vs risks.
|
| Human papillomavirus (HPV) | * Quadrivalent or nonavalent HPV vaccine may be considered for men and women 27 years of age and older at ongoing risk of exposure
* Bivalent HPV vaccine may be considered for women 27 years of age and older at ongoing risk of exposure
|
| Influenza | Recommended annually for all adults, with focus on adults:* at high risk of influenza-related complications
* capable of transmitting influenza to individuals at high risk
* who provide essential community services
* in direct contact during culling operations with poultry infected with avian influenza
|
| Japanese encephalitis | Recommended for adults:* with occupational risk for exposure
* travelling to endemic area(s) during transmission season with specified exposure risks
Booster dose 12 months after primary immunization for persons at continuous risk |
| Measles, mumps | * Recommended for adults born in or after 1970:
+ If susceptible and at increased risk of exposure (travellers to destinations outside of Canada, health care workers, students in post-secondary educational settings, and military personnel) - 2 doses, at least 4 weeks apart.
* Recommended for adults born before 1970 if:
+ non-immune military personnel or health care workers - 2 doses, at least 4 weeks apart
+ non-immune travellers - 1 dose
+ non-immune students - consider 1 dose
|
| Meningococcal conjugate quadrivalent[Footnote 2](#fnt2f2), Multicomponent meningococcal[Footnote 2](#fnt2f2) | Recommended for adults[Footnote 2](#fnt2f2):* with occupational risk for exposure (i.e., laboratory workers; military personnel during recruit training and on deployments during which the risk of infection is elevated)
* who are travellers:
+ for whom meningococcal vaccine is recommended or required, including travellers to sub-Saharan African and pilgrims to the Hajj in Mecca, Saudi Arabia
+ to an area with a hyperendemic strain or an outbreak that is known to be caused by a serogroup that can be prevented by the vaccine
* at high risk of meningococcal disease due to medical conditions:
+ anatomic or functional asplenia or hyposplenism (including sickle cell disease)
+ congenital complement, properdin, factor D or primary antibody deficiencies
+ acquired complement deficiency due to receipt of the terminal complement inhibitor eculizumab
+ should be considered for adults who are HIV-infected
* who are close contacts of a case of invasive meningococcal disease caused by a vaccine preventable serogroup
|
| Pneumococcal polysaccharide 23-valent | Recommended for adults without immunosuppression:* who are residents of long-term care facilities
* who are at increased risk of IPD due to lifestyle factors:
+ persons with alcoholism
+ smokers
+ persons who are homeless
+ should be considered for individuals who use illicit drugs
* who are at high risk of IPD due to an underlying medical condition:
+ asthma requiring regular medical care
+ chronic cerebral spinal fluid leak
+ chronic neurologic condition that may impair clearance of oral secretions
+ cochlear implants (including adults who are to receive implants)
+ chronic cardiac or pulmonary disease
+ diabetes mellitus
+ chronic kidney disease
+ chronic liver disease (including hepatic cirrhosis due to any cause)
Recommended for adults with immunosuppression following immunization with pneumococcal conjugate 13-valent vaccine |
| Pneumococcal conjugate 13-valent | Recommended for adults with immunosuppression:* asplenia (functional or anatomic)
* sickle cell disease or other hemoglobinopathies
* congenital immunodeficiencies involving any part of the immune system, including B-lymphocyte (humoral) immunity, T-lymphocyte (cell) mediated immunity, complement system (properdin or factor D deficiencies), or phagocytic functions
* HIV infection
* immunosuppressive therapy including use of long-term corticosteroids, chemotherapy, radiation therapy, post-organ transplant therapy, and biologic and non-biologic immunosuppressive therapies for rheumatologic and other inflammatory diseases
* malignant neoplasms including leukemia and lymphoma
* solid organ or islet cell transplant (candidate or recipient)
* nephrotic syndrome
* following HSCT
|
| Polio | Recommended for:* adults travelling to, or receiving travellers from, areas where poliovirus is known or suspected to be circulating
* health care workers who have close contact with individuals who might be excreting wild type or vaccine type poliovirus
* members of communities or specific population groups with disease caused by polio
* people who come in close contact with those who may be excreting poliovirus such as people working with refugees, military personnel and people on humanitarian missions in endemic countries
* laboratory workers handling specimens that may contain poliovirus
* family or close contacts of internationally adopted infants who may have been or will be vaccinated with oral polio vaccine (OPV)
For previously unimmunized adults - primary series of IPV-containing vaccine
For previously immunized adults - one lifetime booster dose of IPV-containing vaccine |
| Rabies | Recommended for pre-exposure prophylaxis for adults:* with occupational risk of exposure
* with lifestyle risk of exposure
* travelling to high-risk areas with specified exposure risks
|
| Smallpox | Recommended only for adults with a specific occupational risk of exposure to the smallpox virus |
| Typhoid | Recommended for adults:* travelling to endemic area(s) with specified exposure risks
* who have ongoing household or intimate exposure to a *S. typhi* carrier
* with occupational risk of exposure
Booster doses if at ongoing risk |
| Yellow fever | Recommended for healthy adults:* less than 60 years of age travelling to areas where there is evidence of yellow fever (YF) transmission or if the vaccine is required for foreign travel
* with occupational risk of exposure
Consider immunization of healthy adults aged 60 years and over if travel to areas with risk of yellow fever transmission cannot be avoided and a high level of protection against mosquito exposure is not feasible.
Based on a case-by-case assessment of benefit versus risk, the use of a **one-time** booster dose is recommended for certain individuals.
Re-immunization every 10 years is recommended for:* laboratory personnel working with YF virus unless measured neutralizing antibody titre to yellow fever virus confirms ongoing protection
* HIV-positive individuals who are travelling to countries with risk of YF transmission
|
| Refer to [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 and the [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) and [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional information.
Table 2 footnote 1
Refer to vaccine-specific chapters in Part 4 for recommendations on post-exposure prophylaxis and outbreak management.
[Return to footnote 1 referrer](#fnt2f1-rf)
Table 2 footnote 2
Choice of meningococcal vaccine(s) varies with risk situation. Refer to [Meningococcal vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-13-meningococcal-vaccine.html) in Part 4 for additional information.
[Return to footnote 2 referrer](#fnt2f2-rf)
Table 2 - Abbreviations
BCG
Bacille Calmette-Guérin
HBsAg
hepatitis B surface antigen
HA
Hepatitis A
HB
Hepatitis B
Hib
*Haemophilus influenzae* type b
HIV
human immunodeficiency virus
HSCT
hematopoietic stem cell transplantation
IPD
invasive pneumococcal disease
IPV
inactivated poliomyelitis vaccine
LZV
live zoster vaccine
OPV
oral live poliomyelitis vaccine
RZV
recombinant zoster vaccine
TB
tuberculosis
Tdap
tetanus toxoid, diphtheria toxoid (reduced), acellular pertussis (reduced) - containing vaccine
|
Selected references
-------------------
* Canadian Coalition for Immunization Awareness and Promotion. *Adult Immunization. Are you up to date pamphlet from Immunize Canada.* May 2012. Accessed February 2015.
* Canadian Medical Protective Association. *New Vaccines - What are your obligations? An article for physicians by physicians*. Originally published September 2008, revised January 2009. Accessed February 2015.
* Committee to Advise on Tropical Medicine and Travel (CATMAT). *Statement on new oral cholera and travellers' diarrhea vaccination.* Can Comm Dis Rep 2005;31(ACS7):1-12.
* Committee to Advise on Tropical Medicine and Travel (CATMAT). *Poliomyelitis vaccination for international travellers.* Can Comm Dis Rep 2003;29(ACS-10):1-7.
* Coulibaly N, De Serres G. *Coverage of anti-tetanus vaccinations in adults in Canada-year 2002.* Can J Public Health 2004;95(6):456-9.
* Health Canada. *Smallpox vaccination of laboratory workers.* Can Commun Dis Rep 2004;30(19):167-9.
* Johansen H, Nguyen K, Mao L et al. *Influenza vaccination.* Health Rep 2004;15(2):33-43.
* Johnston BL, Conly JM. *Routine adult immunization in Canada: recommendations and performance.* Can J Infect Dis 2002;13(4):226-231.
* Lau DT, Hewlett AT. *Screening for hepatitis A and B antibodies in patients with chronic liver disease.* Am J Med 2005;118 Suppl 10A:28S-33S.
* Shefer A, Briss P, Rodewald L, et al. *Improving immunization coverage rates: an evidence-based review of the literature.* Epidemiol Rev 1999;21(1):96-142.
* Spira AM. *Preparing the traveller.* Lancet 2003;361(9366):1368-81.
* Stone EG, Morton SC, Hulscher ME et al. *Interventions that increase use of adult immunization and cancer screening services: a meta-analysis.* Ann Intern Med 2002;136(9):641-51.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-3-immunization-persons-inadequate-immunization-records.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-03-01
| None | None |
db62aa0b01b21e915ddb689ee347d3890e2f7c53 | cma | Guidance on the use of influenza vaccine in the presence of COVID-19 | Guidance on the use of influenza vaccine in the presence of COVID-19
February 6, 2023
On this page
In light of the COVID-19 pandemic, the Public Health Agency of Canada (PHAC), in consultation with the National Advisory Committee on Immunization (NACI) and the Canadian Immunization Committee (CIC), has developed additional guidance on influenza vaccination. Every year, individuals with influenza and influenza-related complications increase the demand on the healthcare system in the fall and winter months. During the COVID-19 pandemic, it will be important to minimize the morbidity and mortality related to potential influenza and COVID-19 co-circulation and to reduce the burden on the Canadian health care system to enhance the capacity to respond to ongoing COVID-19 activity.
This webpage is designed to support provincial and territorial vaccine programs and primary care providers in offering influenza vaccine during the COVID-19 pandemic. The guidance on this page is based on currently available scientific evidence and expert opinion and will be updated and added to as necessary throughout the influenza season as new evidence emerges. This webpage should be considered in concert with influenza vaccine recommendations provided in the .
Who should receive the influenza vaccine during the COVID-19 pandemic?
The influenza vaccine should continue to be offered to anyone 6 months of age and older who does not have contraindications to the vaccine. NACI provides a .
To reduce the risk of severe illness that could potentially arise from co-infection with SARS-CoV-2 and influenza, individuals who fall into the following groups are also particularly recommended to receive the influenza vaccine:
- People with
- People capable of transmitting influenza to those at high risk of severe illness related to COVID-19
Information on what is presently known about the clinical features of COVID-19, including presentation, comorbidities and the spectrum of disease severity, is available in the developed by PHAC.
Considerations for influenza vaccination during the COVID-19 pandemic
Every appropriate opportunity to vaccinate against influenza should be taken. Vaccination against influenza remains the most effective way to prevent influenza illness and influenza-related complications, and is an important component of managing health care system capacity during the influenza season in the context of any ongoing COVID-19 activity.
# Individuals with symptomatic COVID-19 or asymptomatic SARS-CoV-2 infection
Individuals with COVID-19 or asymptomatic SARS-CoV-2 infection should not leave isolation solely to be vaccinated against influenza. In the outpatient setting vaccination should be deferred until the end of the isolation period as these individuals may transmit COVID-19 to others, including healthcare providers. In the inpatient or congregate living setting, individuals with COVID-19 or asymptomatic SARS-CoV-2 infection can be vaccinated against influenza, with appropriate infection prevention and control measures in place. In all scenarios, given the optimal timing of influenza vaccination for individuals with COVID-19 is still unknown, consideration can be given to deferring vaccination until the resolution of acute illness.
# Individuals with symptoms of an acute respiratory infection
Individuals with symptoms of acute respiratory infection can be vaccinated against influenza. However, in the outpatient setting, vaccination should be deferred until the resolution of symptoms, given the possibility of unknowingly transmitting COVID-19 or other respiratory infections to others, including healthcare providers. A symptomatic patient who presents to an outpatient setting may be vaccinated at the discretion of the clinic. Individuals in inpatient or congregate living settings with acute respiratory infection symptoms can be vaccinated against influenza, with appropriate infection prevention and control measures in place. More information on vaccinating individuals during acute illness can be found in the Canadian Immunization Guide’s section on .
# Individuals currently in quarantine (self-isolation) for SARS-CoV-2 infection (COVID-19)
Individuals in quarantine for COVID-19 or asymptomatic SARS-CoV-2 infection can be vaccinated against influenza but should not leave quarantine solely to do so. In the outpatient setting, vaccination should be deferred until the end of the quarantine period given the possibility of unknowingly transmitting COVID-19 to others, including healthcare providers. An individual in quarantine who presents to an outpatient setting may be vaccinated at the discretion of the clinic. In the inpatient or congregate living setting, individuals in quarantine can be vaccinated against influenza.
Concurrent administration with other vaccines
For people 6 months of age and older, all seasonal influenza vaccines, including live-attenuated influenza vaccine (LAIV), may be given at the same time as, or at any time before or after, administration of other vaccines, including COVID-19 vaccines.
NACI will continue to monitor the evidence base, including ongoing and anticipated trials investigating influenza vaccines administered at the same time as, or any time before or after, COVID-19 vaccines and update its recommendations as needed. Readers should consult the for updated NACI guidance and for further information on across all eligible age groups.
Seasonal influenza vaccine: Benefits, safety and adverse events
# Potential association between influenza vaccine and SARS-CoV-2 infection
The hypothesis that influenza vaccine increases risk of SARS-CoV-2 infection or severe outcomes related to COVID-19 is not supported by the current evidence base.
Concerns regarding this issue, which have not been substantiated, emerged following the publication of a study conducted in the United States (U.S.) to explore the phenomenon of influenza vaccine interference. This study was based on U.S. Department of Defense (DoD) data from the 2017-2018 influenza season and found that the odds of seasonal coronavirus infection (SARS-CoV-2 was not assessed) were higher in individuals vaccinated with influenza vaccine compared to those who were not. However, an analysis conducted in response, using 7 years of data from the Canadian Sentinel Practitioner Surveillance Network (SPSN) did not find any evidence to suggest that influenza vaccine increases the risk of infections from seasonal coronaviruses (SARS-CoV-2 was not assessed). A number of studies have since been published that show that rather than increase the risk of SARS-CoV-2 infection, influenza vaccine may instead reduce the risk of SARS-CoV-2 infection . Further research is needed to better understand the specific relationship between influenza vaccination and the likelihood of SARS-CoV-2 infection, and whether influenza vaccine also reduces the severity of and/or risk of serious outcomes due to COVID-19.
The influenza vaccine has a longstanding safety record and is a critical tool to protect against influenza-related disease and reduce the influenza-associated burden on the Canadian health care system, which is even more important for this influenza season, in the context of COVID-19.
Therefore, influenza vaccine should continue to be offered to everyone 6 months of age and older who does not have contraindications to the vaccine.
PHAC will continue to monitor the evidence for this phenomenon and will issue new guidance as needed. |
Guidance on the use of influenza vaccine in the presence of COVID-19
=====================================================================
**February 6, 2023**
On this page
------------
* [Who should receive the influenza vaccine during the COVID-19 pandemic?](#a2)
* [Considerations for influenza vaccination during the COVID-19 pandemic](#a6)
+ [Individuals with symptomatic COVID-19 or asymptomatic SARS-CoV-2 infection](#a20)
+ [Individuals with symptoms of an acute respiratory infection](#a21)
+ [Individuals currently in quarantine (self-isolation) for SARS-CoV-2 infection (COVID-19)](#a22)
+ [Concurrent administration with other vaccines](#a23)
* [Seasonal influenza vaccine: Benefits, safety and adverse events](#a3)
+ [Potential association between influenza vaccine and SARS-CoV-2 infection](#a31)
* [References](#a5)
In light of the COVID-19 pandemic, the Public Health Agency of Canada (PHAC), in consultation with the National Advisory Committee on Immunization (NACI) and the Canadian Immunization Committee (CIC), has developed additional guidance on influenza vaccination. Every year, individuals with influenza and influenza-related complications increase the demand on the healthcare system in the fall and winter months. During the COVID-19 pandemic, it will be important to minimize the morbidity and mortality related to potential influenza and COVID-19 co-circulation and to reduce the burden on the Canadian health care system to enhance the capacity to respond to ongoing COVID-19 activity.
This webpage is designed to support provincial and territorial vaccine programs and primary care providers in offering influenza vaccine during the COVID-19 pandemic. The guidance on this page is based on currently available scientific evidence and expert opinion and will be updated and added to as necessary throughout the influenza season as new evidence emerges. This webpage should be considered in concert with influenza vaccine recommendations provided in the [*NACI Statement on Seasonal Influenza Vaccine for 2022-2023*](https://www.canada.ca/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html).
Who should receive the influenza vaccine during the COVID-19 pandemic?
----------------------------------------------------------------------
The influenza vaccine should continue to be offered to anyone 6 months of age and older who does not have contraindications to the vaccine. NACI provides a [list of groups for whom influenza vaccination is particularly recommended](https://www.canada.ca/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023.html#List1).
To reduce the risk of severe illness that could potentially arise from co-infection with SARS-CoV-2 and influenza, individuals who fall into the following groups are also particularly recommended to receive the influenza vaccine:
* People with [underlying medical conditions associated with more severe COVID-19 disease](https://www.canada.ca/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/signs-symptoms-severity.html#a3)
* People capable of transmitting influenza to those at high risk of severe illness related to COVID-19
Information on what is presently known about the clinical features of COVID-19, including presentation, comorbidities and the spectrum of disease severity, is available in the [*COVID-19 signs, symptoms and severity of disease: A clinician guide*](https://www.canada.ca/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/signs-symptoms-severity.html) developed by PHAC.
Considerations for influenza vaccination during the COVID-19 pandemic
---------------------------------------------------------------------
Every appropriate opportunity to vaccinate against influenza should be taken. Vaccination against influenza remains the most effective way to prevent influenza illness and influenza-related complications, and is an important component of managing health care system capacity during the influenza season in the context of any ongoing COVID-19 activity.
### Individuals with symptomatic COVID-19 or asymptomatic SARS-CoV-2 infection
Individuals with COVID-19 or asymptomatic SARS-CoV-2 infection should not leave isolation solely to be vaccinated against influenza. In the outpatient setting vaccination should be deferred until the end of the isolation period as these individuals may transmit COVID-19 to others, including healthcare providers. In the inpatient or congregate living setting, individuals with COVID-19 or asymptomatic SARS-CoV-2 infection can be vaccinated against influenza, with appropriate infection prevention and control measures in place. In all scenarios, given the optimal timing of influenza vaccination for individuals with COVID-19 is still unknown, consideration can be given to deferring vaccination until the resolution of acute illness.
### Individuals with symptoms of an acute respiratory infection
Individuals with symptoms of acute respiratory infection can be vaccinated against influenza. However, in the outpatient setting, vaccination should be deferred until the resolution of symptoms, given the possibility of unknowingly transmitting COVID-19 or other respiratory infections to others, including healthcare providers. A symptomatic patient who presents to an outpatient setting may be vaccinated at the discretion of the clinic. Individuals in inpatient or congregate living settings with acute respiratory infection symptoms can be vaccinated against influenza, with appropriate infection prevention and control measures in place. More information on vaccinating individuals during acute illness can be found in the Canadian Immunization Guide’s section on [*Contraindications and precautions associated with specific conditions: Acute Illness*](https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html#a4).
### Individuals currently in quarantine (self-isolation) for SARS-CoV-2 infection (COVID-19)
Individuals in quarantine for COVID-19 or asymptomatic SARS-CoV-2 infection can be vaccinated against influenza but should not leave quarantine solely to do so. In the outpatient setting, vaccination should be deferred until the end of the quarantine period given the possibility of unknowingly transmitting COVID-19 to others, including healthcare providers. An individual in quarantine who presents to an outpatient setting may be vaccinated at the discretion of the clinic. In the inpatient or congregate living setting, individuals in quarantine can be vaccinated against influenza.
Concurrent administration with other vaccines
---------------------------------------------
For people 6 months of age and older, all seasonal influenza vaccines, including live-attenuated influenza vaccine (LAIV), may be given at the same time as, or at any time before or after, administration of other vaccines, including COVID-19 vaccines.
NACI will continue to monitor the evidence base, including ongoing and anticipated trials investigating influenza vaccines administered at the same time as, or any time before or after, COVID-19 vaccines and update its recommendations as needed. Readers should consult the [current Canadian Immunization Guide chapter on COVID-19 vaccine](https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) for updated NACI guidance and for further information on [concurrent administration of COVID-19 vaccines with other vaccines](https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html#a8.3) across all eligible age groups.
Seasonal influenza vaccine: Benefits, safety and adverse events
---------------------------------------------------------------
### Potential association between influenza vaccine and SARS-CoV-2 infection
The hypothesis that influenza vaccine increases risk of SARS-CoV-2 infection or severe outcomes related to COVID-19 is not supported by the current evidence base.
Concerns regarding this issue, which have not been substantiated, emerged following the publication of a study[Footnote 1](#fn1) conducted in the United States (U.S.) to explore the phenomenon of influenza vaccine interference. This study was based on U.S. Department of Defense (DoD) data from the 2017-2018 influenza season and found that the odds of seasonal coronavirus infection (SARS-CoV-2 was not assessed) were higher in individuals vaccinated with influenza vaccine compared to those who were not[Footnote 1](#fn1). However, an analysis conducted in response, using 7 years of data from the Canadian Sentinel Practitioner Surveillance Network (SPSN) did not find any evidence to suggest that influenza vaccine increases the risk of infections from seasonal coronaviruses (SARS-CoV-2 was not assessed)[Footnote 2](#fn2). A number of studies have since been published that show that rather than increase the risk of SARS-CoV-2 infection, influenza vaccine may instead reduce the risk of SARS-CoV-2 infection [Footnote 3](#fn3)[Footnote 4](#fn4)[Footnote 5](#fn5)[Footnote 6](#fn6)[Footnote 7](#fn7)[Footnote 8](#fn8)[Footnote 9](#fn9)[Footnote 10](#fn10)[Footnote 11](#fn11)[Footnote 12](#fn12)[Footnote 13](#fn13)[Footnote 14](#fn14)[Footnote 15](#fn15)[Footnote 16](#fn16)[Footnote 17](#fn17). Further research is needed to better understand the specific relationship between influenza vaccination and the likelihood of SARS-CoV-2 infection, and whether influenza vaccine also reduces the severity of and/or risk of serious outcomes due to COVID-19.
The influenza vaccine has a longstanding safety record and is a critical tool to protect against influenza-related disease and reduce the influenza-associated burden on the Canadian health care system, which is even more important for this influenza season, in the context of COVID-19.
Therefore, influenza vaccine should continue to be offered to everyone 6 months of age and older who does not have contraindications to the vaccine.
PHAC will continue to monitor the evidence for this phenomenon and will issue new guidance as needed.
References
----------
### Footnotes
Footnote 1
Wolff GG. (2020). Influenza vaccination and respiratory virus interference among Department of Defense personnel during the 2017-2018 influenza season. Vaccine. 38: 350-354. doi: 10.1016/j.vaccine.2019.10.005. Epub 2019 Oct 10.
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
Skowronski DM, Zou M, Clarke Q, Chambers C, Dickinson JA, Sabaiduc S, Olsha R, Gubbay JB, Drews SJ, Charest H, Winter AL, Jassem A, Murti M, Krajden M, De Serres G. Influenza Vaccine Does Not Increase the Risk of Coronavirus or Other Noninfluenza Respiratory Viruses: Retrospective Analysis From Canada, 2010-2011 to 2016-2017. Clin Infect Dis. 2020 Nov 19;71(16):2285-2288. doi: 10.1093/cid/ciaa626.
[Return to footnote 2 referrer](#fn2-rf)
Footnote 3
Yang MJ, Rooks BJ, Le TTT, Santiago IO, Diamond J, Dorsey NL, et al. Influenza Vaccination and Hospitalizations Among COVID-19 Infected Adults. J Am Board Fam Med. 2021 Feb;34(Supplement):S179–82.
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
Wilcox CR, Islam N, Dambha-Miller H. Association between influenza vaccination and hospitalisation or all-cause mortality in people with COVID-19: a retrospective cohort study. BMJ Open Resp Res. 2021 Mar;8(1):e000857.
[Return to footnote 4 referrer](#fn4-rf)
Footnote 5
Umasabor-Bubu OQ, Bubu OM, Mbah AK, Nakeshbandi M, Taylor TN. Association between Influenza Vaccination and severe COVID-19 outcomes at a designated COVID-only hospital in Brooklyn. American Journal of Infection Control. 2021 Apr;S0196655321002017.
[Return to footnote 5 referrer](#fn5-rf)
Footnote 6
Taghioff SM, Slavin BR, Holton T, Singh D. Examining the potential benefits of the influenza vaccine against SARS-CoV-2: A retrospective cohort analysis of 74,754 patients. PLoS ONE. 2021 Aug 3;16(8):e0255541.
[Return to footnote 6 referrer](#fn6-rf)
Footnote 7
Su W, Wang H, Sun C, Li N, Guo X, Song Q, et al. The Association Between Previous Influenza Vaccination and Coronavirus Disease 2019 Infection Risk and Severity: A Systematic Review and Meta-Analysis. American Journal of Preventive Medicine. 2022 Mar;S0749379722001313.
[Return to footnote 7 referrer](#fn7-rf)
Footnote 8
Sánchez-García C, Salinas-Aguirre JE, Rodríguez-Muñoz L, Rodríguez-Sánchez R, Díaz-Castaño A, Bernal-Gómez R. History of influenza immunization in COVID-19 patients: impact on mortality. GMM. 2021 Jun 14;157(1):6504.
[Return to footnote 8 referrer](#fn8-rf)
Footnote 9
Paganoti C de F, Rodrigues AS, Francisco RPV, Costa RA da. The Influenza Vaccine May Protect Pregnant and Postpartum Women against Severe COVID-19. Vaccines. 2022 Jan 28;10(2):206.
[Return to footnote 9 referrer](#fn9-rf)
Footnote 10
Kowalska M, Niewiadomska E, Barański K, Kaleta-Pilarska A, Brożek G, Zejda JE. Association between Influenza Vaccination and Positive SARS-CoV-2 IgG and IgM Tests in the General Population of Katowice Region, Poland. Vaccines. 2021 Apr 21;9(5):415.
[Return to footnote 10 referrer](#fn10-rf)
Footnote 11
Huang K, Lin SW, Sheng WH, Wang CC. Influenza vaccination and the risk of COVID-19 infection and severe illness in older adults in the United States. Sci Rep. 2021 Dec;11(1):11025.
[Return to footnote 11 referrer](#fn11-rf)
Footnote 12
Green I, Ashkenazi S, Merzon E, Vinker S, Golan-Cohen A. The association of previous influenza vaccination and coronavirus disease-2019. Human Vaccines & Immunotherapeutics. 2021 Jul 3;17(7):2169–75.
[Return to footnote 12 referrer](#fn12-rf)
Footnote 13
Erismis B, Karabela SN, Eksi F, Karandere F, Dogan B, Okay F, et al. Annual influenza vaccination effect on the susceptibility to COVID-19 infection. Cent Eur J Public Health. 2021 Mar 31;29(1):14–7.
[Return to footnote 13 referrer](#fn13-rf)
Footnote 14
Conlon A, Ashur C, Washer L, Eagle KA, Hofmann Bowman MA. Impact of the influenza vaccine on COVID-19 infection rates and severity. American Journal of Infection Control. 2021 Jun;49(6):694–700.
[Return to footnote 14 referrer](#fn14-rf)
Footnote 15
Chen AT, Stacey HD, Marzok A, Singh P, Ang J, Miller MS, et al. Effect of Inactivated Influenza Vaccination on Human Coronavirus Infection: Secondary Analysis of a Randomized Trial in Hutterite Colonies. Vaccine. 2021 Oct;S0264410X21013414.
[Return to footnote 15 referrer](#fn15-rf)
Footnote 16
Bozek A, Kozłowska R, Galuszka B, Grzanka A. Impact of influenza vaccination on the risk of SARS-CoV-2 infection in a middle-aged group of people. Human Vaccines & Immunotherapeutics. 2021 Apr 29;1–5.
[Return to footnote 16 referrer](#fn16-rf)
Footnote 17
Wang R, Liu M, Liu J. The Association between Influenza Vaccination and COVID-19 and Its Outcomes: A Systematic Review and Meta-Analysis of Observational Studies. Vaccines (Basel) 2021 May 20;9(5):10.3390/vaccines9050529.
[Return to footnote 17 referrer](#fn17-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-02-06
| None | None |
ceba575816bd4b10db977b3a8656269c7728b338 | cma | Typhoid vaccine: Canadian Immunization Guide | Typhoid vaccine: Canadian Immunization Guide
Key Information
What
- Typhoid fever is caused by *Salmonella enterica- subspecies enterica serovar Typhi (S. typhi).
- S. typhi is generally transmitted through ingestion of food and water contaminated with the feces of people with the disease or who are chronic S. typhi carriers.
- Clinical course ranges from mild illness with low grade fever to severe systemic disease with abdominal perforation and extra-intestinal infection that, if untreated, may be fatal.
- There are 2 authorized typhoid vaccines: parenteral (Typh-I) and oral (Typh-O). These vaccines provide approximately 50% protection against clinical disease.
- Protection following Typh-I vaccine lasts for 3 years; protection following Typh-O vaccine lasts for about 7 years.
- The most commonly reported adverse events following immunization with Typh-I vaccine are injection site reactions (pain, swelling); the most commonly reported adverse events following receipt of Typh-O vaccine are abdominal pain, nausea, diarrhea, vomiting, fever, headache and rash.
Who
- Typhoid immunization is recommended for most persons, 2 years of age and older, travelling to South Asia including Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka.
- Typhoid immunization is not routinely recommended for travel outside of South Asia; however, it might be considered for travellers to other areas, such as Africa, based on individual-specific risk factors and personal preference.
- Typhoid immunization is recommended for laboratory personnel at risk of exposure to S. typhi and for people in close contact with S. typhi carriers.
How
- A single 0.5 mL dose of Typh-I vaccine should be administered for people 2 years of age and older when indicated.
- One capsule of Typh-O should be taken on alternate days to a total of 4 capsules of vaccine for people 5 years of age and older. Typh-O vaccine should be taken approximately 1 hour before, or 2 hours after a meal.
- Typh-O vaccine is contraindicated in individuals with an acute gastrointestinal condition and in immunocompromised persons, including those with known HIV infection.
- Administration of oral cholera vaccine and Typh-O vaccine should be separated by at least 8 hours.
- Typh-O vaccine may be given concomitantly with or at any time before or after any parenteral vaccine.
- Typh-I vaccine and other travel vaccines may be given concomitantly.
Why
- The World Health Organization (WHO) has estimated that there are 21 million cases of typhoid per year. About 2% to 5% of untreated typhoid cases become chronic carriers.
- The case fatality rate is approximately 10% for untreated cases in low income settings and less than 1% for patients receiving care in high income countries.
This chapter update was conducted in collaboration with the Recommendations are based on CATMAT’s .
Epidemiology
# Disease description
Infectious agent
Typhoid fever is caused by a bacterium, *Salmonella enterica- subspecies enterica serovar Typhi (S. typhi). It is a subset of the clinical syndrome known as “enteric fever”, caused by several *Salmonella- species. The clinical presentation is similar for all of these species; however the vaccine is only active against S.typhi. For additional information about , refer to the Pathogen Safety Datasheet.
Reservoir
Humans
Transmission
S. typhi is generally transmitted through ingestion of food and water contaminated with the feces of people with the disease or those who are chronic S. typhi carriers. The incubation period is usually 8 to 14 days (range, 3 days to more than 60 days). Individuals infected with S. typhi are infectious as long as they are excreting the bacilli, usually from the first week of infection until symptoms have resolved. However, 10% of untreated individuals excrete the bacilli for 3 months or more after initially contracting the disease and 2% to 5% of untreated individuals become asymptomatic chronic carriers.
Risk factors
The overall risk of developing typhoid during travel to typhoid endemic countries is very low (less than 1 case per 100,000 travellers). The strongest and most consistent predictor of typhoid risk in travellers is destination of travel. The estimated risk of developing travel-associated typhoid is about: 1 in 3,000 travellers for travel to South Asia (high risk), 1 in 50,000 to 100,000 travellers for travel to Sub-Saharan Africa, North Africa, the Middle East and South America (intermediate risk), and less than 1 in 300,000 travellers for travel to the Caribbean, Central America and Eastern Mediterranean (low risk).
It is known that people with anatomic or functional asplenia (that is, from sickle cell disease) are at increased risk of severe disease from encapsulated bacteria. Several studies have identified travelling children, longer duration of travel, the presence of achlorhydria or use of acid suppression therapy, and travellers visiting friends or relatives, as factors that increase the risk of travel-associated typhoid. The incremental magnitude of risk that these factors contribute in addition to travel destination is unclear.
Although immunocompromised conditions, such as HIV infection, are recognized to predispose to more severe and complicated infections, in general they do not appear to be associated with an increased risk of S. typhi infection.
In Canada, chronic S. typhi carriers pose the greatest public health risk, particularly when they are working in the food industry.
Spectrum of clinical illness
Typhoid fever is a systemic illness of varying severity. The clinical course ranges from mild illness with low grade fever to severe systemic disease with abdominal perforation and extra-intestinal infection that, if untreated, may be fatal. Symptoms may include fever, headache, abdominal pain, nausea, vomiting, malaise, anorexia, bradycardia, splenomegaly, cough, rose spots on the trunk, and constipation. The case fatality rate is approximately 10% for untreated cases in low income settings and less than 1% for patients receiving care in high income countries. Between 2% and 5% of typhoid cases become chronic carriers, sometimes shedding bacteria in stool for years.
# Disease distribution
## Incidence and prevalence
Global
S. typhi infection continues to be a chief cause of enteric disease and remains a significant public health issue in low and middle income countries, principally among children. The WHO estimates the global incidence of typhoid fever to be 21 million cases per year, with 222,000 associated deaths annually. Globally, it is estimated that more than 90% of typhoid cases and deaths occur in Asian countries, predominantly in South Asia.
The incidence of typhoid fever in high income countries is low at <15 cases per 100,000 persons per year. The majority of cases of typhoid fever in these countries occur among travellers returning from endemic areas in low and middle income countries.
National
In Canada, where most cases of typhoid occur in travellers, there was a mean of 144 cases of typhoid reported annually (2004 to 2013), with a mean incidence rate of 0.43 per 100,000 population. In a recent study in Quebec, more than 90%of typhoid cases reported by international travellers were people who were travelling for the purpose of visiting family members or friends living abroad.
Preparations Authorized for Use in Canada
Typhoid-containing vaccines
- TYPHIM Vi® (*Salmonella- typhi Vi capsular polysaccharide vaccine for injection), Sanofi Pasteur SA (manufacturer), Sanofi Pasteur Ltd. (distributor) (Typh-I)
- Vivotif® (live, oral, attenuated TY21A typhoid vaccine),PaxVax Berna GmbH. (manufacturer), Crucell Vaccines Inc. (distributor) (Typh-O)
There are no authorized vaccines to protect against S. paratyphi infection (paratyphoid).
For complete prescribing information, consult the product leaflet or information contained within the product monograph available through Health Canada’s .
Immunogenicity, Efficacy and Effectiveness
# Immunogenicity
Typh-I vaccine
Immunity following Typh-I vaccine is thought to last for 3 years.
Typh-O vaccine
Protective antibodies are detectable for about 7 years following receipt of Typh-O vaccine.
# Efficacy and effectiveness
Efficacy of typhoid vaccine, both oral and intramuscular formulations, in preventing typhoid is approximately 50%. Evidence suggests that oral typhoid vaccine provides some protection against paratyphoid; however, the evidence is insufficient to recommend the off-label use of typhoid vaccine for this indication.
Recommendations for Use
# Travellers
## Children (2 to 17 years of age) and adults (18 years of age and older)
Typh-I vaccine is indicated for persons 2 years of age and older and Typh-O vaccine may be used in people 5 years of age and older who are travelling to endemic areas.
Most Canadian travellers visiting South Asia (including Afghanistan, Bangladesh, Butan, India, Maldives, Maldives, Nepal, Pakistan and Sri Lanka) should be offered typhoid vaccine. The risk of typhoid is highest for persons travelling to India, Pakistan, and Bangladesh. Data suggest that most cases of typhoid occur when travellers stay more than 2 weeks.
The decision of whether to immunize a traveller for destinations other than South Asia (for example, Africa) should be carefully balanced against the presence of other factors that may increase the risk of travel-associated typhoid: travelling children; travellers visiting friends and relatives; longer duration of travel and prolonged exposure to potentially contaminated food and water; anatomic or functional asplenia (including sickle cell anemia), the presence of achlorhydria or the use of acid suppression therapy; and personal preference.
Immunization is only modestly effective against typhoid and provides no protection against other fecal-oral diseases; therefore, all travellers should be advised to adhere to basic sanitation and food and water precautions irrespective of whether they are immunized against typhoid.
Contacts of chronic carriers
Typhoid immunization is recommended for individuals with ongoing or intimate exposure (for example, family member) to a chronic carrier of S. typhi.
# Schedule
Typh-I vaccine
Persons 2 years of age and older for whom the vaccine is indicated should receive a single 0.5 mL dose intramuscularly at least 14 days prior to potential exposure.
Typh-O vaccine
Persons 5 years of age and older for whom the vaccine is indicated should take 1 capsule on alternate days to a total of 4 capsules. All 4 capsules must be taken for optimal protection. Minor variations in dosing schedule are not expected to affect efficacy. However, if it is necessary to repeat the series because of a longer interval between doses (more than 1 week), the administration of an additional full course of vaccine is not harmful. The capsules should be administered in accordance with the instructions in the manufacturer’s product leaflet. Immunization (i.e. ingestion of all 4 capsules) should be completed at least 7 days prior to potential exposure.
- Individuals with an acute gastrointestinal condition and in immunocompromised persons.
Based on the Committee to Advise on Tropical Medicine and Travel (CATMAT) Statement on International Travellers and Typhoid. Can Commun Dis Rep 2014;40(4).
Re-immunization should be carried out if a person remains at risk in conditions of repeated or continuous exposure. There is no data on continued protection in travellers.
This recommendation is consistent with the Health Canada's vaccine authorization for re-immunization every 7 years.
# Booster doses and re-immunization
Periodic booster doses in persons at continued risk of typhoid may be expected to increase antibody titres and to maintain protection. Booster doses should be offered when a person remains at risk in conditions of repeated or continuous exposure. For Typh-I vaccine, a booster dose should be administered every 3 years. For Typh-O vaccine, a booster of 4 doses should be administered every 7 years.
## Outbreak control
Typhoid immunization is not routinely recommended for the control or containment of typhoid outbreaks in Canada.
Vaccination of Specific Populations
# Pregnancy and breastfeeding
No information is available on the safety of Typh-I vaccine in pregnancy; however, there is no theoretical reason to suspect an increased risk from inactivated vaccines, such as Typh-I vaccine. Typhoid vaccine should be considered in pregnant women, when indicated for travel to endemic areas, the presence of risk factors, and personal preference. Breastfeeding women may be given inactivated Typh-I vaccine.
Before immunization of pregnant women with Typh-O vaccine, the benefits of administration must be carefully weighed against potential adverse events. Typh-O vaccine should only be used in pregnancy when there is a high risk of infection and Typh-I vaccine is not available. It is not known if the live bacteria or any other component of Typh-O vaccine can pass into breast milk.
# Immunocompromised persons
Typh-I vaccine may be administered to immunocompromised persons if indicated; however, an adequate response may not be achieved. When considering immunization of an immunocompromised person with Typh-I vaccine, consultation with the individual's health care provider may be of assistance. For complex cases, referral to a health care provider with expertise in immunization or immunodeficiency is advised. Typh-O vaccine should not be given to immunocompromised persons, including those with known HIV infection.
## Household contacts
Household contacts of immunocompromised persons may receive Typh-O vaccine; healthy persons vaccinated with Typh-O vaccine do not shed vaccine-strain organisms in their stool and secondary transmission to contacts does not occur.
# Workers
Typhoid vaccine is recommended for laboratory personnel regularly working with S. typhi. Technicians working in routine microbiology laboratories do not need to be vaccinated with typhoid vaccine.
Vaccine Administration Practices
# Dose
Each dose of Typh-I vaccines is 0.5 mL.
Each dose of Typh-O vaccine is 1 capsule.
# Route of administration
Typh-I vaccine
should be administered intramuscularly. Typh-O vaccine should be administered orally; it can be self-administered.
# Interchangeability of vaccines
Although there are no data regarding the interchangeability of typhoid vaccines, it is presumed that boosting can be performed with any of the available formulations, regardless of the vaccine used initially. The boosting interval should correspond to the interval established for the preceding vaccine.
# Concurrent administration with other vaccines
The administration of oral cholera and travellers’ diarrhea vaccine and Typh-O vaccine capsules should be separated by at least 8 hours; Typh-O vaccine can be given concomitantly with or at any time before or after any parenteral vaccine. There is no known interaction between Typh-I vaccine and other travel vaccines, such as hepatitis A vaccine, yellow fever vaccine and hepatitis B vaccine.
# Serologic testing
Serologic testing is not recommended before or after receiving typhoid vaccine.
Storage and Handling Requirements
Typhoid vaccines should be stored at +2°C to +8°C and should not be frozen. Typh-O vaccine should be protected from light, moisture and high humidity.
Safety and Adverse Events
# Common and local adverse events
Typh-I vaccine
Common adverse events (1% to 10% of vaccine recipients) include: injection site tenderness, induration, redness or pain, fever, headache, general malaise or myalgia.
Typh-O vaccine
Common adverse events include: abdominal pain, nausea, diarrhea, vomiting, fever, headache and rash.
## Less common and serious or severe adverse events
Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association. Anaphylaxis following vaccination with typhoid vaccine is very rare.
## Guidance on reporting Adverse Events Following Immunization (AEFI)
Vaccine providers are asked to report, through local public health officials, any serious or unexpected adverse event temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.
# Contraindications and precautions
Typhoid vaccine is contraindicated in people with a history of anaphylaxis after previous administration of the vaccine and in people with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container.
Typh-O vaccine is contraindicated in individuals with an acute gastrointestinal condition and in immunocompromised persons.
Administration of typhoid vaccine should be postponed in persons with severe acute illness. Persons with minor acute illness (with or without fever) may be vaccinated.
## Drug-drug and drug-food interactions
The Typh-O vaccine series should be finished at least 3 days before commencing, or initiated at least 3 days after completing, treatment with sulphonamides or other antibiotics active against S. typhi, or antimalarials. Exceptions include chloroquine, mefloquine and atovaquone/proguanil (MALARONE®), as these antimalarials do not affect the immune response to Typh-O vaccine and can be administered at the same time as, or at any interval before or after Typh-O vaccine.
Typh-O vaccine should be taken approximately 1 hour before, or 2 hours after a meal. Alcoholic beverages should not be consumed 1 hour before or 2 hours after taking Typh-O vaccine.
Typh-I or Typh-O vaccines can be given before, concurrently with, or after immunoglobulin or other blood products. |
Typhoid vaccine: Canadian Immunization Guide
=============================================
**For health professionals**
**Last partial content update** (see [Table of updates](/en/public-health/services/canadian-immunization-guide/updates.html)): November 2021
A change has been made in the “Drug-drug and drug-food interactions” sub-section regarding the interval between the oral typhoid vaccine and certain antibiotics and antimalarials.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-24-varicella-chickenpox-vaccine.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](page-24-varicella-chickenpox-vaccine.html)
Last complete chapter revision (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): April 2017
On this page
------------
* [Key Information](#a1)
* [Epidemiology](#a2)
* [Preparations Authorized for Use in Canada](#a3)
* [Immunogenicity, Efficacy and Effectiveness](#a4)
* [Recommendations for Use](#a5)
+ [Travellers](#a51)
+ [Table 1: Summary of typhoid vaccines authorized for use in Canada](#a52)
+ [Booster doses and re-immunization](#a53)
* [Vaccination of Specific Populations](#a6)
+ [Pregnancy and breastfeeding](#a61)
+ [Immunocompromised persons](#a62)
+ [Workers](#a63)
* [Vaccine Administration Practices](#a7)
* [Storage and Handling Requirements](#a8)
* [Safety and Adverse Events](#a9)
+ [Common and local adverse events](#a91)
+ [Contraindications and precautions](#a92)
* [Selected References](#a10)
Key Information
---------------
**What**
* Typhoid fever is caused by *Salmonella enterica* subspecies enterica serovar Typhi (S. typhi).
* S. typhi is generally transmitted through ingestion of food and water contaminated with the feces of people with the disease or who are chronic S. typhi carriers.
* Clinical course ranges from mild illness with low grade fever to severe systemic disease with abdominal perforation and extra-intestinal infection that, if untreated, may be fatal.
* There are 2 authorized typhoid vaccines: parenteral (Typh-I) and oral (Typh-O). These vaccines provide approximately 50% protection against clinical disease.
* Protection following Typh-I vaccine lasts for 3 years; protection following Typh-O vaccine lasts for about 7 years.
* The most commonly reported adverse events following immunization with Typh-I vaccine are injection site reactions (pain, swelling); the most commonly reported adverse events following receipt of Typh-O vaccine are abdominal pain, nausea, diarrhea, vomiting, fever, headache and rash.
**Who**
* Typhoid immunization is recommended for most persons, 2 years of age and older, travelling to South Asia including Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka.
* Typhoid immunization is not routinely recommended for travel outside of South Asia; however, it might be considered for travellers to other areas, such as Africa, based on individual-specific risk factors and personal preference.
* Typhoid immunization is recommended for laboratory personnel at risk of exposure to S. typhi and for people in close contact with S. typhi carriers.
**How**
* A single 0.5 mL dose of Typh-I vaccine should be administered for people 2 years of age and older when indicated.
* One capsule of Typh-O should be taken on alternate days to a total of 4 capsules of vaccine for people 5 years of age and older. Typh-O vaccine should be taken approximately 1 hour before, or 2 hours after a meal.
* Typh-O vaccine is contraindicated in individuals with an acute gastrointestinal condition and in immunocompromised persons, including those with known HIV infection.
* Administration of oral cholera vaccine and Typh-O vaccine should be separated by at least 8 hours.
* Typh-O vaccine may be given concomitantly with or at any time before or after any parenteral vaccine.
* Typh-I vaccine and other travel vaccines may be given concomitantly.
**Why**
* The World Health Organization (WHO) has estimated that there are 21 million cases of typhoid per year. About 2% to 5% of untreated typhoid cases become chronic carriers.
* The case fatality rate is approximately 10% for untreated cases in low income settings and less than 1% for patients receiving care in high income countries.
This chapter update was conducted in collaboration with the [Committee to Advise on Tropical Medicine and Travel (CATMAT).](/en/public-health/services/catmat.html) Recommendations are based on CATMAT’s [Statement on International Travellers and Typhoid](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2014-40/ccdr-volume-40-4-february-20-2014/ccdr-volume-40-4-february-20-2014-1.html).
Epidemiology
------------
### Disease description
**Infectious agent**
Typhoid fever is caused by a bacterium, *Salmonella enterica* subspecies enterica serovar Typhi (S. typhi). It is a subset of the clinical syndrome known as “enteric fever”, caused by several *Salmonella* species. The clinical presentation is similar for all of these species; however the vaccine is only active against S.typhi. For additional information about *[Salmonella enterica](/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/salmonella-enterica.html)*, refer to the Pathogen Safety Datasheet.
**Reservoir**
Humans
**Transmission**
S. typhi is generally transmitted through ingestion of food and water contaminated with the feces of people with the disease or those who are chronic S. typhi carriers. The incubation period is usually 8 to 14 days (range, 3 days to more than 60 days). Individuals infected with S. typhi are infectious as long as they are excreting the bacilli, usually from the first week of infection until symptoms have resolved. However, 10% of untreated individuals excrete the bacilli for 3 months or more after initially contracting the disease and 2% to 5% of untreated individuals become asymptomatic chronic carriers.
**Risk factors**
The overall risk of developing typhoid during travel to typhoid endemic countries is very low (less than 1 case per 100,000 travellers). The strongest and most consistent predictor of typhoid risk in travellers is destination of travel. The estimated risk of developing travel-associated typhoid is about: 1 in 3,000 travellers for travel to South Asia (high risk), 1 in 50,000 to 100,000 travellers for travel to Sub-Saharan Africa, North Africa, the Middle East and South America (intermediate risk), and less than 1 in 300,000 travellers for travel to the Caribbean, Central America and Eastern Mediterranean (low risk).
It is known that people with anatomic or functional asplenia (that is, from sickle cell disease) are at increased risk of severe disease from encapsulated bacteria. Several studies have identified travelling children, longer duration of travel, the presence of achlorhydria or use of acid suppression therapy, and travellers visiting friends or relatives, as factors that increase the risk of travel-associated typhoid. The incremental magnitude of risk that these factors contribute in addition to travel destination is unclear.
Although immunocompromised conditions, such as HIV infection, are recognized to predispose to more severe and complicated infections, in general they do not appear to be associated with an increased risk of S. typhi infection.
In Canada, chronic S. typhi carriers pose the greatest public health risk, particularly when they are working in the food industry.
**Spectrum of clinical illness**
Typhoid fever is a systemic illness of varying severity. The clinical course ranges from mild illness with low grade fever to severe systemic disease with abdominal perforation and extra-intestinal infection that, if untreated, may be fatal. Symptoms may include fever, headache, abdominal pain, nausea, vomiting, malaise, anorexia, bradycardia, splenomegaly, cough, rose spots on the trunk, and constipation. The case fatality rate is approximately 10% for untreated cases in low income settings and less than 1% for patients receiving care in high income countries. Between 2% and 5% of typhoid cases become chronic carriers, sometimes shedding bacteria in stool for years.
### Disease distribution
#### Incidence and prevalence
**Global**
S. typhi infection continues to be a chief cause of enteric disease and remains a significant public health issue in low and middle income countries, principally among children. The WHO estimates the global incidence of typhoid fever to be 21 million cases per year, with 222,000 associated deaths annually. Globally, it is estimated that more than 90% of typhoid cases and deaths occur in Asian countries, predominantly in South Asia.
The incidence of typhoid fever in high income countries is low at <15 cases per 100,000 persons per year. The majority of cases of typhoid fever in these countries occur among travellers returning from endemic areas in low and middle income countries.
**National**
In Canada, where most cases of typhoid occur in travellers, there was a mean of 144 cases of typhoid reported annually (2004 to 2013), with a mean incidence rate of 0.43 per 100,000 population. In a recent study in Quebec, more than 90%of typhoid cases reported by international travellers were people who were travelling for the purpose of visiting family members or friends living abroad.
Preparations Authorized for Use in Canada
-----------------------------------------
**Typhoid-containing vaccines**
* **TYPHIM Vi®** (*Salmonella* typhi Vi capsular polysaccharide vaccine for injection), Sanofi Pasteur SA (manufacturer), Sanofi Pasteur Ltd. (distributor) (Typh-I)
* **Vivotif®** (live, oral, attenuated TY21A typhoid vaccine),PaxVax Berna GmbH. (manufacturer), Crucell Vaccines Inc. (distributor) (Typh-O)
There are no authorized vaccines to protect against S. paratyphi infection (paratyphoid).
For complete prescribing information, consult the product leaflet or information contained within the product monograph available through Health Canada’s [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
Refer to [Contents of Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for a list of vaccines authorized for use in Canada and their contents.
Immunogenicity, Efficacy and Effectiveness
------------------------------------------
### Immunogenicity
**Typh-I vaccine**
Immunity following Typh-I vaccine is thought to last for 3 years.
**Typh-O vaccine**
Protective antibodies are detectable for about 7 years following receipt of Typh-O vaccine.
### Efficacy and effectiveness
Efficacy of typhoid vaccine, both oral and intramuscular formulations, in preventing typhoid is approximately 50%. Evidence suggests that oral typhoid vaccine provides some protection against paratyphoid; however, the evidence is insufficient to recommend the off-label use of typhoid vaccine for this indication.
Recommendations for Use
-----------------------
### Travellers
#### Children (2 to 17 years of age) and adults (18 years of age and older)
Typh-I vaccine is indicated for persons 2 years of age and older and Typh-O vaccine may be used in people 5 years of age and older who are travelling to endemic areas.
Most Canadian travellers visiting South Asia (including Afghanistan, Bangladesh, Butan, India, Maldives, Maldives, Nepal, Pakistan and Sri Lanka) should be offered typhoid vaccine. The risk of typhoid is highest for persons travelling to India, Pakistan, and Bangladesh. Data suggest that most cases of typhoid occur when travellers stay more than 2 weeks.
The decision of whether to immunize a traveller for destinations other than South Asia (for example, Africa) should be carefully balanced against the presence of other factors that may increase the risk of travel-associated typhoid: travelling children; travellers visiting friends and relatives; longer duration of travel and prolonged exposure to potentially contaminated food and water; anatomic or functional asplenia (including sickle cell anemia), the presence of achlorhydria or the use of acid suppression therapy; and personal preference.
Immunization is only modestly effective against typhoid and provides no protection against other fecal-oral diseases; therefore, all travellers should be advised to adhere to basic sanitation and food and water precautions irrespective of whether they are immunized against typhoid.
Refer to [Immunization of Travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) in Part 3 for additional information about typhoid vaccination of travellers.
**Contacts of chronic carriers**
Typhoid immunization is recommended for individuals with ongoing or intimate exposure (for example, family member) to a chronic carrier of S. typhi.
### Schedule
[Table 1](#a52) provides a summary of typhoid vaccines available for use in Canada.
**Typh-I vaccine**
Persons 2 years of age and older for whom the vaccine is indicated should receive a single 0.5 mL dose intramuscularly at least 14 days prior to potential exposure.
**Typh-O vaccine**
Persons 5 years of age and older for whom the vaccine is indicated should take 1 capsule on alternate days to a total of 4 capsules. All 4 capsules must be taken for optimal protection. Minor variations in dosing schedule are not expected to affect efficacy. However, if it is necessary to repeat the series because of a longer interval between doses (more than 1 week), the administration of an additional full course of vaccine is not harmful. The capsules should be administered in accordance with the instructions in the manufacturer’s product leaflet. Immunization (i.e. ingestion of all 4 capsules) should be completed at least 7 days prior to potential exposure.
Table 1: Summary of Typhoid Vaccines Authorized for Use in Canada[Table 1 footnote 1](#tfn1-1)
| Vaccines | Parenteral inactivated vaccines
(Typh-I) | Oral, live attenuated vaccine
(Typh-O) |
| --- | --- | --- |
| **Authorized for use in persons** | 2 years of age and older | 5 years of age and older |
| **Protection begins** | 14 days following vaccination | 7 days following vaccination |
| **Dose and schedule** | 1 dose: 0.5 mL | 1 capsule taken on alternate days, total of 4 capsules |
| **Route of administration** | Intramuscular injection | Oral |
| **Contraindications** | Individuals with hypersensitivity or anaphylaxis to any component of the vaccine or its container. | * Individuals with hypersensitivity to any component of the vaccine or the enteric-coated capsule.
* Individuals with an acute gastrointestinal condition and in immunocompromised persons.
|
| **Re-immunization**[Table 1 footnote 2](#tfn2-2) | Every 3 years | Every 7 years[Table 1 footnote 3](#tfn3-3) |
|
Table 1 - Footnote 1
Based on the Committee to Advise on Tropical Medicine and Travel (CATMAT) Statement on International Travellers and Typhoid. Can Commun Dis Rep 2014;40(4).
[Return to Table 2 footnote 1 referrer](#tfn1)
Table 1 - Footnote 2
Re-immunization should be carried out if a person remains at risk in conditions of repeated or continuous exposure. There is no data on continued protection in travellers.
[Return to Table 2 footnote 2 referrer](#tfn2)
Table 1 - Footnote 3
This recommendation is consistent with the Health Canada's vaccine authorization for re-immunization every 7 years.
[Return to Table 2 footnote 3 referrer](#tfn3)
|
Refer to additional information contained within the product monographs available through Health Canada's [Drug product database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
### Booster doses and re-immunization
Periodic booster doses in persons at continued risk of typhoid may be expected to increase antibody titres and to maintain protection. Booster doses should be offered when a person remains at risk in conditions of repeated or continuous exposure. For Typh-I vaccine, a booster dose should be administered every 3 years. For Typh-O vaccine, a booster of 4 doses should be administered every 7 years.
#### Outbreak control
Typhoid immunization is not routinely recommended for the control or containment of typhoid outbreaks in Canada.
Vaccination of Specific Populations
-----------------------------------
### Pregnancy and breastfeeding
No information is available on the safety of Typh-I vaccine in pregnancy; however, there is no theoretical reason to suspect an increased risk from inactivated vaccines, such as Typh-I vaccine. Typhoid vaccine should be considered in pregnant women, when indicated for travel to endemic areas, the presence of risk factors, and personal preference. Breastfeeding women may be given inactivated Typh-I vaccine.
Before immunization of pregnant women with Typh-O vaccine, the benefits of administration must be carefully weighed against potential adverse events. Typh-O vaccine should only be used in pregnancy when there is a high risk of infection and Typh-I vaccine is not available. It is not known if the live bacteria or any other component of Typh-O vaccine can pass into breast milk.
Refer to [Immunization in Pregnancy and Breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3 for additional information about vaccination of women who are pregnant or breastfeeding.
### Immunocompromised persons
Typh-I vaccine may be administered to immunocompromised persons if indicated; however, an adequate response may not be achieved. When considering immunization of an immunocompromised person with Typh-I vaccine, consultation with the individual's health care provider may be of assistance. For complex cases, referral to a health care provider with expertise in immunization or immunodeficiency is advised. Typh-O vaccine should not be given to immunocompromised persons, including those with known HIV infection.
#### Household contacts
Household contacts of immunocompromised persons may receive Typh-O vaccine; healthy persons vaccinated with Typh-O vaccine do not shed vaccine-strain organisms in their stool and secondary transmission to contacts does not occur.
Refer to [Contraindications and precautions](#a92). Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional information.
### Workers
Typhoid vaccine is recommended for laboratory personnel regularly working with S. typhi. Technicians working in routine microbiology laboratories do not need to be vaccinated with typhoid vaccine.
Refer to [Immunization of Workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html) in Part 3 for additional information about vaccination of workers.
Vaccine Administration Practices
--------------------------------
### Dose
Each dose of Typh-I vaccines is 0.5 mL.
Each dose of Typh-O vaccine is 1 capsule.
### Route of administration
Typh-I vaccine
should be administered intramuscularly. Typh-O vaccine should be administered orally; it can be self-administered.
Refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for additional information about pre-vaccination and post-vaccination counselling, vaccine preparation and administration technique, and infection prevention and control.
### Interchangeability of vaccines
Although there are no data regarding the interchangeability of typhoid vaccines, it is presumed that boosting can be performed with any of the available formulations, regardless of the vaccine used initially. The boosting interval should correspond to the interval established for the preceding vaccine.
Refer to [Principles of Vaccine Interchangeability](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-7-principles-vaccine-interchangeability.html) in Part 1 for additional information about vaccine interchangeability.
### Concurrent administration with other vaccines
The administration of oral cholera and travellers’ diarrhea vaccine and Typh-O vaccine capsules should be separated by at least 8 hours; Typh-O vaccine can be given concomitantly with or at any time before or after any parenteral vaccine. There is no known interaction between Typh-I vaccine and other travel vaccines, such as hepatitis A vaccine, yellow fever vaccine and hepatitis B vaccine.
Refer to [Timing of Vaccine Administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) in Part 1 for additional information about concurrent administration of vaccines.
### Serologic testing
Serologic testing is not recommended before or after receiving typhoid vaccine.
Storage and Handling Requirements
---------------------------------
Typhoid vaccines should be stored at +2°C to +8°C and should not be frozen. Typh-O vaccine should be protected from light, moisture and high humidity.
Refer to [Storage and Handling of Immunizing Agents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-9-storage-handling-immunizing-agents.html) in Part 1 for additional information and recommendations.
Safety and Adverse Events
-------------------------
### Common and local adverse events
**Typh-I vaccine**
Common adverse events (1% to 10% of vaccine recipients) include: injection site tenderness, induration, redness or pain, fever, headache, general malaise or myalgia.
**Typh-O vaccine**
Common adverse events include: abdominal pain, nausea, diarrhea, vomiting, fever, headache and rash.
#### Less common and serious or severe adverse events
Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association. Anaphylaxis following vaccination with typhoid vaccine is very rare.
#### Guidance on reporting Adverse Events Following Immunization (AEFI)
Vaccine providers are asked to report, through local public health officials, any serious or unexpected adverse event temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.
Refer to [Reporting Adverse Events Following Immunization (AEFI) in Canada](/en/public-health/services/immunization/reporting-adverse-events-following-immunization/user-guide-completion-submission-aefi-reports.html) and [Adverse Events Following Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) in Part 2 for additional information about AEFI reporting.
### Contraindications and precautions
Typhoid vaccine is contraindicated in people with a history of anaphylaxis after previous administration of the vaccine and in people with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container.
Refer to [Contents of Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for a list of vaccines authorized for use in Canada and their contents.
Typh-O vaccine is contraindicated in individuals with an acute gastrointestinal condition and in immunocompromised persons.
Administration of typhoid vaccine should be postponed in persons with severe acute illness. Persons with minor acute illness (with or without fever) may be vaccinated.
Refer to [Contraindications and Precautions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html) in Part 2 for additional information. Refer to [Pregnancy and Breastfeeding](#a61) for additional information about vaccination of women who are pregnant or breastfeeding.
#### Drug-drug and drug-food interactions
The Typh-O vaccine series should be finished at least 3 days before commencing, or initiated at least 3 days after completing, treatment with sulphonamides or other antibiotics active against S. typhi, or antimalarials. Exceptions include chloroquine, mefloquine and atovaquone/proguanil (MALARONE®), as these antimalarials do not affect the immune response to Typh-O vaccine and can be administered at the same time as, or at any interval before or after Typh-O vaccine.
Typh-O vaccine should be taken approximately 1 hour before, or 2 hours after a meal. Alcoholic beverages should not be consumed 1 hour before or 2 hours after taking Typh-O vaccine.
Typh-I or Typh-O vaccines can be given before, concurrently with, or after immunoglobulin or other blood products.
Selected References
-------------------
* American Public Health Association. Control of Communicable Diseases Manual. 19th ed. Washington; 2008.
* Basnyat B, Maskey AP, Zimmerman MD et al. Enteric (typhoid) fever in travelers. Clin Infect Dis 2005 Nov 15;41(10):1467-72.
* Beeching NJ, Clarke PD, Kitchin NR et al. Comparison of two combined vaccines against typhoid fever and hepatitis A in healthy adults. Vaccine 2004;23(1):29-35.
* Begier EM, Burwen DR, Haber P, Ball R, the Vaccine Adverse Event Reporting System Working Group. Postmarketing safety surveillance for typhoid fever vaccines from the Vaccine Adverse Event Reporting System, July 1990 through June 2002. Clin Infect Dis 2004;38(6):771-79.
* Bhutta ZA. Typhoid fever: current concepts. Infect Dis Clin Pract 2006 Sep;14(5):266-72.
* Bui YG, Trepanier S, Milord F et al. Cases of malaria, hepatitis A, and typhoid fever among VFRs, Quebec (Canada). J Travel Med 2011;18(6):373-8.
* Campbell JD, Levine MM. Typhoid and cholera vaccines. In: Jong EC, Zuckerman JN, eds. Travelers’ vaccines. Hamilton, Ontario: Decker Inc, 2004:162-84.
* Centers for Disease Control and Prevention. Health Information for International Travel 2016. The Yellow Book. Accessed January 2017. Available from: https://wwwnc.cdc.gov/travel/page/yellowbook-home-2014
* Chen LH, Wilson ME, Davis X et al. Illness in long-term travelers visiting GeoSentinel clinics. Emerg Infect Dis 2009 Nov;15(11):1773-82.
* Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on international travellers and typhoid. Can Commun Dis Rep 2014;40(4). Accessed April 2016 at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/14vol40/dr-rm40-04/dr-rm40-04-tropmed-eng.php
* Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull World Health Organ 2004 May;82(5):346-53.
* Ekdahl K, de Jong B, Andersson Y. Risk of travel-associated typhoid and paratyphoid fevers in various regions. J Travel Med 2005;12(4):197-204.
* Emergent Travel Health Inc. Product Monograph - Vivotif®. November 2020.
* Fraser A, Goldberg E, Acosta CJ et al. Vaccines for preventing typhoid fever (Review). Cochrane Database Syst Rev 2007;3 CD001261.
* Keystone JS, Kozarsky PE, Freedman DO et al. Travel medicine. Elsevier, 2004.
* Lin FY, Ho VA, Khiem HB et al.The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five year old children. N Engl J Med 2001;344(17):1263-69.
* Loebermann M, Kollaritsch H, Ziegler T. A randomized, open-label study of the immunogenicity and reactogenicity of three lots of a combined typhoid fever/hepatitis A vaccine in healthy adults. Clin Ther 2004;26(7):1084-91.
* Lynch MF, Blanton EM, Bulens S et al. Typhoid fever in the United States, 1999-2006. JAMA 2009 Aug 26;302(8):859-65.
* Parry CM, Hien TT, Dougan G et al. Typhoid fever. N Engl J Med 2002;347(22):1770-82.
* Public Health Agency of Canada. Notifiable Diseases On-Line. Accessed April 2016 at: http://dsol-smed.phac-aspc.gc.ca/dsol-smed/ndis/charts.php?c=yl
* Sanofi Pasteur Ltd. Product Monograph - TYPHIM Vi®. November 2013.
* Steinberg EB, Bishop R, Haber P et al. Typhoid fever in travelers: Who should be targeted for prevention? Clin Infect Dis 2004;39(2):186-91.
* World Health Organization. Immunization, Vaccines and Biologicals: Typhoid. Accessed April 2016. Available from: http://www.who.int/immunization/diseases/typhoid/en/
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-24-varicella-chickenpox-vaccine.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* [Next Page](page-24-varicella-chickenpox-vaccine.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-05-10
| None | None |
465bccb7a6328f2b0e66d3daf39fc387eab1f53e | cma | COVID-19 signs, symptoms and severity of disease: A clinician guide | COVID-19 signs, symptoms and severity of disease: A clinician guide
Last updated: June 1, 2022
The information below is based on currently available scientific evidence and informed by expert clinician opinion, and is subject to change as new information becomes available. This document is intended to provide clinicians with interim information on currently known clinical features of COVID-19, including signs and symptoms, incubation period, disease severity and risk factors for severe disease and SARS-CoV-2 variants of concern.
On this page
Signs and symptoms
COVID-19 includes clinical features that present in varying ways with respect to frequency and severity and vary by age, vaccination status and variants of concern. Published reports often over-represent individuals who have more severe symptoms, and these may differ across care settings and between different age groups and vaccine statuses. Symptoms that are absent at the onset of illness may develop over time with disease progression. To date, there remains no comprehensive list of symptoms that has been validated to have high specificity or sensitivity for COVID-19. The ZOE COVID Study from the United Kingdom is a comprehensive system that tracks COVID-19 symptoms. This study found that symptom frequency and severity has varied by circulating variant and by vaccination status. During the Omicron wave that began in November 2021, those who have had at least 2 vaccinations reported milder symptoms; typical symptoms reported during the Omicron wave included runny nose, headache, sneezing, and sore throat. This response is different than the predominant symptoms earlier in the pandemic, which included fever, cough, chills and muscle pain. When fever occurred in Omicron cases, it was more frequently reported in unvaccinated than in vaccinated cases.
As new variants emerge and more of the population becomes vaccinated, there will be ongoing changes in the patterns of symptoms that individuals experience. With Omicron, clinical presumptive diagnosis should be considered with symptoms compatible with COVID-19 and a history of contact with known case(s). Testing may either not be available, or accurate, early in the course of illness. The patient however, should be advised to take a Point of Care antigen or NAAT test for SARS-CoV-2, when and where available, and follow local/regional public health authority recommendations for cases and contacts. Patients should always be encouraged to seek medical consultation if experiencing worsening symptoms of concern. Table 1 below outlines the common, less frequent, and rare symptoms reported by those with COVID-19 during the Omicron wave.
- Sneezing
- Sore throat
- Headache
- Joint pain
- Chills
- Fever
- Dizziness
- Muscle pain
- Gastrointestinal symptoms (nausea, diarrhea, abdominal pain)
- Hoarse voice
- New loss of or altered sense of smell
- Chest pain
- Irregular heartbeat
- Shortness of breath
- Skin changes
- Delirium
- Confusion/brain fog
With the Omicron variant, loss or altered sense of smell is less prevalent than with the Delta variant, and sore throat and hoarse voice were significantly more prevalent. Those infected during the Omicron wave are less likely to experience at least one out of the three classic COVID-19 symptoms (fever, loss of smell, and persistent cough) compared with individuals infected during the Delta wave. Duration of acute symptoms for those with the Delta variant was longer than those with the Omicron variant (mean duration 9 days vs. 7 days). Regardless of the variant, the duration of symptoms is shorter for those who received three doses of vaccines (Delta mean duration 8 vs. Omicron duration 4 days). Some people can present symptoms for weeks of months after their initial recovery. See for details on symptoms, mental health, prevention, diagnosis and treatment.
Clinicians should remain aware of signs and symptoms that warrant more urgent or emergency medical attention. Patients with mild disease should be informed to seek medical attention should they experience any of the following:
- trouble breathing or severe shortness of breath
- persistent pressure or pain in the chest
- new onset of confusion or altered level of consciousness
- inability to wake up or stay awake
- pale, gray, or blue-colored skin, lips, or nail beds
# Multisystem inflammatory syndrome – children (MIS-C)
In early 2020, MIS-C was newly confirmed to be associated with to SARS-CoV-2 infection. It is characterized by hyperinflammation and multi-organ involvement, and presents with clinical features similar to Kawasaki disease and toxic shock syndrome. Symptoms typically occur around 2-6 weeks after the initial infection. In Canada, MIS-C is rare, with 269 cases reported to the Public Health Agency of Canada between March 11, 2020 and October 2, 2021. in infants as young as one week to youth as old as 18 years, with a median age of six years. Cases were more likely to occur in males than females (58% vs 42%). Almost all MIS-C cases (99%) required hospitalization and 36% required intensive care unit admission. No deaths from MIS-C have been reported in Canada as of May 31, 2022.
# Multisystem inflammatory syndrome – adults (MIS-A)
Multisystem inflammatory syndrome is a rare but severe complication of SARS-CoV-2 that may also occur in adults. Symptoms typically occur around 2-12 weeks after the initial infection. CDC has developed a .
In September 2021, a systematic review of all MIS-A publications reported a total of 221 cases, with a median age of 21 years and 70% of the cases being male. Most patients with MIS-A presented with fever (96%), hypotension (60%), cardiac dysfunction (54%), shortness of breath (52%), and/or diarrhea (52%). The median number of organ systems involved was 5. The median hospital stay was 8 days; and of those hospitalized, 57% were admitted to the intensive care unit (ICU). Of those admitted to the ICU, 47% required respiratory support and 7% died. Most patients had elevated markers of coagulopathy and/or inflammation (90%) and a positive SARS-CoV-2 serologic finding (72%).
Although rare, it is important to recognize the symptoms of MIS-A, as it is a serious hyperinflammatory condition associated with COVID-19 and can lead to multiorgan failure.
# COVID-19 symptoms in children
In earlier waves of the pandemic, typical symptoms of COVID-19 in children were fever (46-64%) and cough (32-56%). However, many children were asymptomatic or only had a few symptoms. More recently, with the Omicron variant, symptoms have been shown to more likely be upper respiratory, as noted in Table 1 above. Young children are especially vulnerable to upper respiratory acute infection due to their small and relatively collapsible airways. This has resulted in some children experiencing laryngotracheobronchitis, or croup. Croup is classically characterized by a sudden onset "barking cough," inspiratory stridor, and respiratory distress. Some small case series of croup have been reported during the Omicron wave and have been associated with SARS-CoV-2 infection. It is still unknown if cases of croup are due to SARS-CoV-2 or a co-infection with another virus. Other than croup, children's symptoms mimic those of adults for Omicron, which are predominantly upper respiratory symptoms, including runny nose, sneezing and sore throat. Hospitalized children are more likely to have fever, abdominal symptoms like vomiting, and shortness of breath, along with cough and the other upper respiratory symptoms. Symptoms of COVID-19 may overlap with that of other viral infections, including influenza and other respiratory and enteric viral infections. The true incidence of asymptomatic COVID-19 infection is unknown. However, asymptomatic COVID-19 infection has been reported in up to 45% of children who had surveillance testing done at the time of hospitalization for a non-COVID indication.
A MMWR report on hospitalized children aged 5-11 years with SARS-CoV-2 infections in 14 U.S. states found that during the Omicron wave, unvaccinated children had double the rate of hospitalization compared to vaccinated children. Thirty percent (30%) of hospitalized children had no underlying medical conditions, and children with diabetes and obesity were more likely to develop severe COVID-19. Intensive care unit admission occurred in 19% of hospitalized cases. Increasing COVID-19 vaccination coverage among children aged 5–11 years, especially those at higher risk of severe disease, may help prevent hospitalizations and severe outcomes associated with COVID-19.
When assessing children, it is important to consider that the signs and symptoms of COVID-19 are similar to those of other infectious and non-infectious conditions, including influenza, other viral upper respiratory infections, streptococcal pharyngitis, asthma and allergies. The lack of specificity of signs or symptoms and the significant proportion of asymptomatic infections makes symptom-based screening for identification of SARS-CoV-2 in children difficult.
# COVID-19 symptoms in older adults
Older adults may present with atypical symptoms due to age-related weakening of the immune system. Weakened immunity can also lead to increased risk of infection. Clinical presentation may differ in older adults, and COVID-19 symptoms may need to be evaluated using a slightly different approach in this patient population.
Symptoms that may present differently in older individuals include: fever (may present with lower temperatures), cough and shortness of breath (differentiate from chronic lung conditions), loss of taste or smell (differentiate if due to medications or neurodegenerative processes causing sensory impairment), and fatigue and body ache (common in older individuals). Sore throat, new-onset congestion, nausea, vomiting, or diarrhea may be more valuable as diagnostic criteria for SARS-CoV-2 infection in older individuals.
In a multicenter study of seven emergency departments in the US, delirium was one of the presenting symptoms in 226 (28%) of 817 patients with COVID-19 and exclusively the primary presenting complaint in 16% of patients with a mean age of 78 years. Estimates of falls and frailty, as a presenting symptom of COVID-19, ranged between 23.5% and 32%. In addition, dehydration in older adults should be considered as an important presentation of COVID-19. Therefore, it is important to ensure older adults receive their recommended vaccination series and boosters as they become available via regional/provincial/territorial public health authorities.
To review the most up-to-date information on Age groups by hospitalizations, ICU admissions and deaths see .
Asymptomatic infection
A person who is asymptomatic is someone who has tested positive for SARS-CoV-2 test and has never developed any symptoms. During the Omicron wave, a large study in South Africa estimated that 31% of cases were asymptomatic (approximately 1 in 3 cases). This study also reported high viral loads in asymptomatic cases. The asymptomatic carriage rate was similar in SARS-CoV-2 seropositive and seronegative cases.
Incubation period
The pre-Omicron incubation period for COVID-19 had been estimated to range from 2 to 14 days, with a median of 4-7 days from exposure to symptom onset. Omicron has been found to have an incubation period of a median of 2-4 days, and its associated viral loads have been reported to peak in saliva 1-2 days before positive results can be seen in PCR or rapid antigen tests. Omicron has also been found to be more transmissible, have a higher attack rate and a higher basic reproduction number (R0) than other variants.
The world's first "human challenge" trial where volunteers were intentionally exposed to a challenge virus from the B1-lineage of SARS-CoV-2, which included the Alpha, Beta and Delta variants, found that the presence of symptoms did not change with viral load. The viral load in the airways in these infected patients was not related to whether the individual developed symptoms or the severity of illness. In infected individuals, the peak viral load occurred on day 5, with the virus first detected in the throat and then rising to significantly higher levels in the nose. The challenge study found that viral loads were detectable in the nose and throat within 24 hours of inoculation, although symptoms became apparent a little later, i.e., within 2-4 days.
It is now known that SARS-CoV-2 RNA can be detected in the upper or lower respiratory tract for weeks after illness onset. However, detection of viral RNA does not necessarily mean that a patient can transmit the virus. Evidence has shown that an individual may be infectious for up to 3 days prior to any presentation of symptoms. The levels of viral RNA from saliva, sputum, nasopharyngeal or other upper respiratory specimens, and stool samples appear to be highest soon after symptom onset.
Disease severity and risk factors for severe disease
There is a spectrum of COVID-19 disease severity, ranging from asymptomatic, mild, moderate, to severe and critical disease. Severe disease occurs more often in older age and in those with underlying medical conditions, and the risk increases with the number of underlying medical conditions.
The conditions identified below are those for which conclusive evidence is available.
# Underlying medical conditions associated with more severe COVID-19 disease
- Cancer
- Cerebrovascular disease
- Chronic kidney disease
- Chronic liver diseases (limited to: cirrhosis, non-alcoholic fatty liver disease, alcoholic liver disease, and autoimmune hepatitis)
- Chronic lung diseases (limited to: bronchiectasis, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary hypertension, pulmonary embolism)
- Cystic fibrosis
- Diabetes mellitus, type 1 and type 2
- Disabilities (e.g. Down syndrome, learning, intellectual, or developmental disabilities; ADHD; cerebral palsy; congenital disabilities; spinal cord injuries)
- Heart conditions (e.g., cardiomyopathies, coronary artery disease, heart failure, etc.)
- HIV infection
- Mental health disorders (limited to: mood disorders, including depression; schizophrenia spectrum disorders)
- Obesity
- Pregnancy and recent pregnancy
- Primary immunodeficiency diseases
- Smoking, current or former
- Solid organ or blood stem cell transplant
- Tuberculosis
- Use of corticosteroids or other immunosuppressive medication
Certain medical and/or social vulnerabilities, may make it more difficult for patients to recognize, clearly communicate, or act on symptoms' progression. Affected individuals may include: people experiencing intellectual, developmental, or cognitive disabilities; people who use substances regularly; people who live with mental health conditions; and persons experiencing homelessness or who are unhoused. These patients need closer attention and monitoring.
SARS-CoV-2 variants of concern (VOC)
The SARS-CoV-2 virus has naturally mutated or changed over time. Mutations may increase or decrease transmissibility or virulence, or lead to immune escape or reduced responses to therapeutics compared to non-variant viruses. Compared to the original strain of SARS-CoV-2, we have seen an increased transmissibility with Omicron. Over time, new variants will emerge, and the transmissibility and virulence will be expected to change. |
COVID-19 signs, symptoms and severity of disease: A clinician guide
====================================================================
Last updated: June 1, 2022
The information below is based on currently available scientific evidence and informed by expert clinician opinion, and is subject to change as new information becomes available. This document is intended to provide clinicians with interim information on currently known clinical features of COVID-19, including signs and symptoms, incubation period, disease severity and risk factors for severe disease and SARS-CoV-2 variants of concern.
On this page
------------
* [Signs and symptoms](#a1)
* [Asymptomatic infection](#a5)
* [Incubation period](#a2)
* [Disease severity and risk factors for severe disease](#a3)
* [SARS-CoV-2 variants of concern (VOC)](#a4)
* [Acknowledgments](#a6)
* [Bibliography](#a7)
Signs and symptoms
------------------
COVID-19 includes clinical features that present in varying ways with respect to frequency and severity and vary by age, vaccination status and variants of concern. Published reports often over-represent individuals who have more severe symptoms, and these may differ across care settings and between different age groups and vaccine statuses. Symptoms that are absent at the onset of illness may develop over time with disease progression. To date, there remains no comprehensive list of symptoms that has been validated to have high specificity or sensitivity for COVID-19. The ZOE COVID Study from the United Kingdom is a comprehensive system that tracks COVID-19 symptoms. This study found that symptom frequency and severity has varied by circulating variant and by vaccination status. During the Omicron wave that began in November 2021, those who have had at least 2 vaccinations reported milder symptoms; typical symptoms reported during the Omicron wave included runny nose, headache, sneezing, and sore throat. This response is different than the predominant symptoms earlier in the pandemic, which included fever, cough, chills and muscle pain. When fever occurred in Omicron cases, it was more frequently reported in unvaccinated than in vaccinated cases.
As new variants emerge and more of the population becomes vaccinated, there will be ongoing changes in the patterns of symptoms that individuals experience. With Omicron, clinical presumptive diagnosis should be considered with symptoms compatible with COVID-19 and a history of contact with known case(s). Testing may either not be available, or accurate, early in the course of illness. The patient however, should be advised to take a Point of Care antigen or NAAT test for SARS-CoV-2, when and where available, and follow local/regional public health authority recommendations for cases and contacts. Patients should always be encouraged to seek medical consultation if experiencing worsening symptoms of concern. **Table 1** below outlines the common, less frequent, and rare symptoms reported by those with COVID-19 during the Omicron wave.
Table 1: Common, less frequent and rare symptoms for individuals with COVID-19 during the Omicron wave
| Common symptoms
(>50%) | Less frequent symptoms
(≤ 50%) | Rare symptoms
(<10%) |
| --- | --- | --- |
| * Runny nose
* Sneezing
* Sore throat
* Headache
| * Persistent cough
* Joint pain
* Chills
* Fever
* Dizziness
* Muscle pain
* Gastrointestinal symptoms (nausea, diarrhea, abdominal pain)
* Hoarse voice
* New loss of or altered sense of smell
| * Swollen glands
* Chest pain
* Irregular heartbeat
* Shortness of breath
* Skin changes
* Delirium
* Confusion/brain fog
|
| Note: It is important to evaluate whether the patient's symptoms are new, worsening, or different from their baseline. |
With the Omicron variant, loss or altered sense of smell is less prevalent than with the Delta variant, and sore throat and hoarse voice were significantly more prevalent. Those infected during the Omicron wave are less likely to experience at least one out of the three classic COVID-19 symptoms (fever, loss of smell, and persistent cough) compared with individuals infected during the Delta wave. Duration of acute symptoms for those with the Delta variant was longer than those with the Omicron variant (mean duration 9 days vs. 7 days). Regardless of the variant, the duration of symptoms is shorter for those who received three doses of vaccines (Delta mean duration 8 vs. Omicron duration 4 days). Some people can present symptoms for weeks of months after their initial recovery. See [long COVID](/en/public-health/services/diseases/2019-novel-coronavirus-infection/symptoms/post-covid-19-condition.html) for details on symptoms, mental health, prevention, diagnosis and treatment.
Clinicians should remain aware of signs and symptoms that warrant more urgent or emergency medical attention. Patients with mild disease should be informed to seek medical attention should they experience any of the following:
* trouble breathing or severe shortness of breath
* persistent pressure or pain in the chest
* new onset of confusion or altered level of consciousness
* inability to wake up or stay awake
* pale, gray, or blue-colored skin, lips, or nail beds
### Multisystem inflammatory syndrome – children (MIS-C)
In early 2020, MIS-C was newly confirmed to be associated with to SARS-CoV-2 infection. It is characterized by hyperinflammation and multi-organ involvement, and presents with clinical features similar to Kawasaki disease and toxic shock syndrome. Symptoms typically occur around 2-6 weeks after the initial infection. In Canada, MIS-C is rare, with 269 cases reported to the Public Health Agency of Canada between March 11, 2020 and October 2, 2021. [Cases have been reported](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2021-47/issue-11-november-2021/multisystem-inflammatory-syndrome-children-canada.html) in infants as young as one week to youth as old as 18 years, with a median age of six years. Cases were more likely to occur in males than females (58% vs 42%). Almost all MIS-C cases (99%) required hospitalization and 36% required intensive care unit admission. No deaths from MIS-C have been reported in Canada as of May 31, 2022.
### Multisystem inflammatory syndrome – adults (MIS-A)
Multisystem inflammatory syndrome is a rare but severe complication of SARS-CoV-2 that may also occur in adults. Symptoms typically occur around 2-12 weeks after the initial infection. CDC has developed a [working case definition for MIS-A](https://www.cdc.gov/mis/mis-a/hcp.html).
In September 2021, a systematic review of all MIS-A publications reported a total of 221 cases, with a median age of 21 years and 70% of the cases being male. Most patients with MIS-A presented with fever (96%), hypotension (60%), cardiac dysfunction (54%), shortness of breath (52%), and/or diarrhea (52%). The median number of organ systems involved was 5. The median hospital stay was 8 days; and of those hospitalized, 57% were admitted to the intensive care unit (ICU). Of those admitted to the ICU, 47% required respiratory support and 7% died. Most patients had elevated markers of coagulopathy and/or inflammation (90%) and a positive SARS-CoV-2 serologic finding (72%).
Although rare, it is important to recognize the symptoms of MIS-A, as it is a serious hyperinflammatory condition associated with COVID-19 and can lead to multiorgan failure.
### COVID-19 symptoms in children
In earlier waves of the pandemic, typical symptoms of COVID-19 in children were fever (46-64%) and cough (32-56%). However, many children were asymptomatic or only had a few symptoms. More recently, with the Omicron variant, symptoms have been shown to more likely be upper respiratory, as noted in Table 1 above. Young children are especially vulnerable to upper respiratory acute infection due to their small and relatively collapsible airways. This has resulted in some children experiencing laryngotracheobronchitis, or croup. Croup is classically characterized by a sudden onset "barking cough," inspiratory stridor, and respiratory distress. Some small case series of croup have been reported during the Omicron wave and have been associated with SARS-CoV-2 infection. It is still unknown if cases of croup are due to SARS-CoV-2 or a co-infection with another virus. Other than croup, children's symptoms mimic those of adults for Omicron, which are predominantly upper respiratory symptoms, including runny nose, sneezing and sore throat. Hospitalized children are more likely to have fever, abdominal symptoms like vomiting, and shortness of breath, along with cough and the other upper respiratory symptoms. Symptoms of COVID-19 may overlap with that of other viral infections, including influenza and other respiratory and enteric viral infections. The true incidence of asymptomatic COVID-19 infection is unknown. However, asymptomatic COVID-19 infection has been reported in up to 45% of children who had surveillance testing done at the time of hospitalization for a non-COVID indication.
A MMWR report on hospitalized children aged 5-11 years with SARS-CoV-2 infections in 14 U.S. states found that during the Omicron wave, unvaccinated children had double the rate of hospitalization compared to vaccinated children. Thirty percent (30%) of hospitalized children had no underlying medical conditions, and children with diabetes and obesity were more likely to develop severe COVID-19. Intensive care unit admission occurred in 19% of hospitalized cases. Increasing COVID-19 vaccination coverage among children aged 5–11 years, especially those at higher risk of severe disease, may help prevent hospitalizations and severe outcomes associated with COVID-19.
When assessing children, it is important to consider that the signs and symptoms of COVID-19 are similar to those of other infectious and non-infectious conditions, including influenza, other viral upper respiratory infections, streptococcal pharyngitis, asthma and allergies. The lack of specificity of signs or symptoms and the significant proportion of asymptomatic infections makes symptom-based screening for identification of SARS-CoV-2 in children difficult.
### COVID-19 symptoms in older adults
Older adults may present with atypical symptoms due to age-related weakening of the immune system. Weakened immunity can also lead to increased risk of infection. Clinical presentation may differ in older adults, and COVID-19 symptoms may need to be evaluated using a slightly different approach in this patient population.
Symptoms that may present differently in older individuals include: fever (may present with lower temperatures), cough and shortness of breath (differentiate from chronic lung conditions), loss of taste or smell (differentiate if due to medications or neurodegenerative processes causing sensory impairment), and fatigue and body ache (common in older individuals). Sore throat, new-onset congestion, nausea, vomiting, or diarrhea may be more valuable as diagnostic criteria for SARS-CoV-2 infection in older individuals.
In a multicenter study of seven emergency departments in the US, delirium was one of the presenting symptoms in 226 (28%) of 817 patients with COVID-19 and exclusively the primary presenting complaint in 16% of patients with a mean age of 78 years. Estimates of falls and frailty, as a presenting symptom of COVID-19, ranged between 23.5% and 32%. In addition, dehydration in older adults should be considered as an important presentation of COVID-19. Therefore, it is important to ensure older adults receive their recommended vaccination series and boosters as they become available via regional/provincial/territorial public health authorities.
To review the most up-to-date information on Age groups by hospitalizations, ICU admissions and deaths see [COVID-19 epidemiological summary](https://health-infobase.canada.ca/covid-19/epidemiological-summary-covid-19-cases.html#a6).
Asymptomatic infection
----------------------
A person who is **asymptomatic** is someone who has tested positive for SARS-CoV-2 test and has never developed any symptoms. During the Omicron wave, a large study in South Africa estimated that 31% of cases were asymptomatic (approximately 1 in 3 cases). This study also reported high viral loads in asymptomatic cases. The asymptomatic carriage rate was similar in SARS-CoV-2 seropositive and seronegative cases.
Incubation period
-----------------
The pre-Omicron incubation period for COVID-19 had been estimated to range from 2 to 14 days, with a median of 4-7 days from exposure to symptom onset. Omicron has been found to have an incubation period of a median of 2-4 days, and its associated viral loads have been reported to peak in saliva 1-2 days before positive results can be seen in PCR or rapid antigen tests. Omicron has also been found to be more transmissible, have a higher attack rate and a higher basic reproduction number (R0) than other variants.
The world's first "human challenge" trial where volunteers were intentionally exposed to a challenge virus from the B1-lineage of SARS-CoV-2, which included the Alpha, Beta and Delta variants, found that the presence of symptoms did not change with viral load. The viral load in the airways in these infected patients was not related to whether the individual developed symptoms or the severity of illness. In infected individuals, the peak viral load occurred on day 5, with the virus first detected in the throat and then rising to significantly higher levels in the nose. The challenge study found that viral loads were detectable in the nose and throat within 24 hours of inoculation, although symptoms became apparent a little later, i.e., within 2-4 days.
It is now known that SARS-CoV-2 RNA can be detected in the upper or lower respiratory tract for weeks after illness onset. However, detection of viral RNA does not necessarily mean that a patient can transmit the virus. Evidence has shown that an individual may be infectious for up to 3 days prior to any presentation of symptoms. The levels of viral RNA from saliva, sputum, nasopharyngeal or other upper respiratory specimens, and stool samples appear to be highest soon after symptom onset.
Disease severity and risk factors for severe disease
----------------------------------------------------
There is a spectrum of COVID-19 disease severity, ranging from asymptomatic, mild, moderate, to severe and critical disease. Severe disease occurs more often in older age and in those with underlying medical conditions, and the risk increases with the number of underlying medical conditions.
The conditions identified below are those for which conclusive evidence is available.
### Underlying medical conditions associated with more severe COVID-19 disease
* Cancer
* Cerebrovascular disease
* Chronic kidney disease
* Chronic liver diseases (limited to: cirrhosis, non-alcoholic fatty liver disease, alcoholic liver disease, and autoimmune hepatitis)
* Chronic lung diseases (limited to: bronchiectasis, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary hypertension, pulmonary embolism)
* Cystic fibrosis
* Diabetes mellitus, type 1 and type 2
* Disabilities (e.g. Down syndrome, learning, intellectual, or developmental disabilities; ADHD; cerebral palsy; congenital disabilities; spinal cord injuries)
* Heart conditions (e.g., cardiomyopathies, coronary artery disease, heart failure, etc.)
* HIV infection
* Mental health disorders (limited to: mood disorders, including depression; schizophrenia spectrum disorders)
* Obesity
* Pregnancy and recent pregnancy
* Primary immunodeficiency diseases
* Smoking, current or former
* Solid organ or blood stem cell transplant
* Tuberculosis
* Use of corticosteroids or other immunosuppressive medication
Certain medical and/or social vulnerabilities, may make it more difficult for patients to recognize, clearly communicate, or act on symptoms' progression. Affected individuals may include: people experiencing intellectual, developmental, or cognitive disabilities; people who use substances regularly; people who live with mental health conditions; and persons experiencing homelessness or who are unhoused. These patients need closer attention and monitoring.
SARS-CoV-2 variants of concern (VOC)
------------------------------------
The SARS-CoV-2 virus has naturally mutated or changed over time. Mutations may increase or decrease transmissibility or virulence, or lead to immune escape or reduced responses to therapeutics compared to non-variant viruses. Compared to the original strain of SARS-CoV-2, we have seen an increased transmissibility with Omicron. Over time, new variants will emerge, and the transmissibility and virulence will be expected to change.
Acknowledgements
----------------
Dr. Marianna Ofner, Dr. Marina Salvadori, Yung-En Chung, Dr. Michael Green, Aidan Pucchio, Denise Gravel-Tropper, Dr. Mireille Plamondon and Dr. Ewa Rajda.
Bibliography
------------
Adamson B, Sikka R, Wyllie AL, Premsriut P. Discordant SARS-CoV-2 PCR and rapid antigen test results when infectious: a December 2021 occupational case series. (2022). medRxiv 22268770 [Preprint]. 2022 Jan 5.
Ahmada F., Ahmeda., A, Rajendraprasada S.S., Lorangera F., Guptaa S., Velagapudia M…Moore D. (2021). Multisystem inflammatory syndrome in adults: A rare sequela of SARS-CoV-2 infection. International Journal of Infectious Diseases, 2021-07-01, Volume 108, Pages 209-211.
Alene, M., Yismaw, L., Assemie, M.A., Ketema, D.B., Mengist, B., Kassie, B., & Birhan, T.Y. (2021). PLOS ONE Magnitude of asymptomatic COVID-19 cases throughout the course of infection: A systematic review and meta-analysis. https://doi.org/10.1371/journal.pone.0249090.
Argenziano M,G., Bruce S,L., Slater C.L., Tiao, J.R., Baldwin, M.R., Barr, R.G., Barr 4., …, Ruijun Chen. (2020). Characterization and Clinical Course of 1000 Patients with COVID-19 in New York: retrospective case series. BMJ 29(369),m1996. doi: 10.1136/bmj.m1996.
Auwaerter P.G. Coronavirus COVID-19 (SARS-CoV-2): Johns Hopkins ABX Guide. Coronavirus COVID-19 (SARS-CoV-2) | Johns Hopkins ABX Guide. https://www.hopkinsguides.com/hopkins/view/Johns\_Hopkins\_ABX\_Guide/540747/all/Coronavirus\_COVID\_19\_\_SARS\_CoV\_2\_.
Bai, Y., Yao, L., Wei, T., Tian, F., Jin, D., Chen, L., & Wang, M. (2020). Presumed Asymptomatic Carrier Transmission of COVID-19. Jama 323(14):1406-1407. doi: 10.1001/jama.2020.2565.
Bullard, J., Dust, K., Funk, D., Strong, J.E., Alexander, D., Garnett, L., …Poliquin G. (2020). Predicting infectious SARS-CoV-2 from diagnostic samples. Clin Infect Dis 71(10):2663-2666. doi: 10.1093/cid/ciaa638.
Burke, R.M., Killerby, M.E., Newton, S., Ashworth; C.D., Berns, A.L., Brennan, S.,... Case Investigation Form Working Group. (2020). Symptom Profiles of a Convenience Sample of Patients with COVID-19 - United States, January-April 2020. MMWR Morb Mortal Wkly Rep, 69(28):904-908.doi: http://dx.doi.org/10.15585/mmwr.mm6928a2.
Cai, J., Xu, J., Lin, D., Zhi, Y., Lei, X., Zhenghai, Q., … Mei. Z. (2020). A Case Series of children with 2019 novel coronavirus infection: clinical and epidemiological features. Clin Infect Dis. 71(6):1547--1551. doi:10.1093/cid/ciaa198.
Casey, M., Griffin, J., McAloon, C.G., Byrne, A.W., Madden, J.M., McEvoy, D.,... More, S.J. (2020). Estimating pre-symptomatic transmission of COVID-19: a secondary analysis using published data. https://www.medrxiv.org/content/10.1101/2020.05.08.20094870v1.full.pdf
Centers for Disease Control and Prevention. (2021). Multisystem Inflammatory Syndrome in Children (MIS-C): Information for Healthcare Providers About Talking with Families and Caregivers. Updated Dec. 14. https://www.cdc.gov/mis/mis-c/hcp/provider-families.html.
Centers for Disease Control and Prevention. (2022). CDC Science Brief: Evidence used to update the list of underlying medical conditions that increase a person's risk of severe illness from COVID-19. Updated Feb. 15. https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/underlying-evidence-table.html.
Chan, J.F., Yuan, S., Kok, K.H., To, K.K., Chu, H., Yang, J., …Hui, C.K. (2020). A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet, 395(10223):514-523. doi:https://doi.org/10.1016/S0140-6736(20)30154-9.
Chau, V.Q., Giustino, G., Mahmood, K.,Oliveros, E., Neibart, E., Oloomi, M., & Mancini, D.M. (2020). Cardiogenic shock and hyperinflammatory syndrome in young males with COVID-19. Circ Heart Fail, 13(10):e007485. doi: 10.1161/CIRCHEARTFAILURE.120.007485.
Centres for Effective Practice. COVID-19: Clinical Guidance for Primary Care Providers. https://tools.cep.health/tool/covid-19/#screening-covid19.
Cevik, M., Tate, M., Lloyd, O., Maraolo, A.E., Schafers, J., & Ho, A. (2021). SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis. The Lancet Microbe, 2(1), E13-E22. doi.org/10.1016/S2666-5247(20)30172-5.
Chen, N., Zhou, M., Dong, X., Qu. J., Gong, F., Han, Y., …Zhang, L. (2020). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet, 395(10223):507-513.
Chen, L., Deng, C., Chen, X., Zhang, X., Chen, B., Yu, H., …Sun X. (2020). Ocular manifestations and clinical characteristics of 534 cases of COVID-19 in China: A cross-sectional study. Acta Ophthalmologica 98(8): 951-959.
Clerkin, K.J., Fried, J.A., Raikhelkar, J., Sayer, G., Griffin, J.M., Masoumi, A., …Uriel, N. (2020). Coronavirus Disease 2019 (COVID-19) and cardiovascular disease. Circulation,141(20):1648-1655. doi: 10.1161/CIRCULATIONAHA.120.046941.
Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020. (2020). MMWR Morb Mortal Wkly Rep, 69:422-426. doi: http://dx.doi.org/10.15585/mmwr.mm6914e4.
Dadamo, H., Yoshikawa, T., & Ouslander, J.G. (2020). Coronavirus Disease 2019 in geriatrics and long-term care: The ABCDs of COVID-19. J Am Geriatr Soc, 68(5); 912-917. doi.org/10.1111/jgs.16445.
De Giorgi, F., Fabbian, F., Greco, S., Di Simone, E., De Giorgio, R., Passaro, A., …COMorbidity Evaluation of INTernal MEDicine COVID19 (OUTCOME-INTMED-COV19) Study Collaborators. (2020). Prediction of in-hospital mortality of patients with SARS-CoV-2 infection by comorbidity indexes: an Italian internal medicine single center study Eur Rev Med Pharmacol Sci., 24(19), 10258-10266.
Dominguez-Ramirez, L., Rodriguez-Perez, F., Sosa-Jurado, F., Santos-Lopez, G. & Cortes-Hernandez, P. (2020). The role of metabolic comorbidity in COVID-19 mortality of middle-aged adults. The case of Mexico. medRxiv 2020.12.15.20244160; doi: 10.1101/2020.12.15.20244160.
Dong, Y., Mo, X., Hu, Y., Qi, X., Jiang, F., Jiang, Z. & Tong, S. (2020). Epidemiology of COVID-19 Among Children in China. Pediatrics 145(6): e20200702.
Eliezer, M., Hautefort, C., Hamel, A., Verillaud, B., Herman, P., Houdart, E. & Eliot C. (2020). Sudden and complete olfactory loss function as a possible symptom of COVID-19. JAMA Otolaryngol Head Neck Surg, 146(7):674-675.
Ehrlich J.R., Ramke J., Macleod D., et al. (2021). Association between vision impairment and mortality: a systematic review and meta-analysis. Lancet Glob Health; 9(4):e418–e430.
Feldstein, L.R., Tenforde, M.W., Friedman, K.G., Newhams, M., Rose, E.B., Dapul, H., … for the Overcoming COVID-19 Investigators. (2021). Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19. JAMA, 325(11):1074-1087. doi:10.1001/jama.2021.2091.
Flodgren, G.M. (2020). Immunity after SARS-CoV-2 infection, 1st update - a rapid review. Oslo: Norwegian Institute of Public Health, 2020. https://www.fhi.no/en/publ/2020/Immunity-after-SARS-CoV-2-infection-1st-update/.
Freedman, S.B., and Kellner, J.D. (2021). Protecting Canada's children from the consequences of the fourth wave of the COVID-19 pandemic. CMAJ September 27, 2021 193 (38) E1500-E1502; DOI: https://doi.org/10.1503/cmaj.211513.
Funk, A.L., Florin, T.A., Dalziel, S.R., et al. (2021). Prospective cohort study of children with suspected SARS-CoV-2 infection presenting to paediatric emergency departments: a Paediatric Emergency Research Networks (PERN) Study Protocol. BMJ Open;11:e042121. doi:10.1136/ bmjopen-2020-042121.
Fu, L., Bingyi, W., Yuan, T., Chen, X., Ao, Y. Fitzpatric, T.,... Zou, H. (2020). Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review and meta-analysis. J Infect, 80(6):656-665.
Gates, M., Pillay, J., Wingert, A., Guitard, S., Rahman, S., Zakher, B.,... Hartling, L. (2021). Risk factors associated with severe outcomes of COVID-19: An updated rapid review to inform national guidance on vaccine prioritization in Canada. medRxiv. https://doi.org/10.1101/2021.04.23.21256014.
Garrett, N., Tapley, A., Andriessen, J., Seocharan, I., Fisher, L.H….Corey, L. (2022). High Rate of Asymptomatic Carriage Associated with Variant Strain Omicron. – medRxiv, Jan 14;2021.12.20.21268130. doi: 10.1101/2021.12.20.21268130. Preprint.
Gawronska, K., Lorkowski, J. (2021). Falls as one of the atypical presentations of COVID-19 in older population. Geriatr Orthop Surg Rehabil; 12:2151459321996619.
Gold, J.A.W., Wong, K.K., Szablewskiet, C.M., Patel, P.R., Rossaw, J., da Silva, J., …Jackson, B.R. (2020). Characteristics and Clinical Outcomes of Adult Patients Hospitalized with COVID-19 - Georgia, March 2020. MMWR Morb Mortal Wkly Rep. 2020. 69(18);545-550.
Götzinger, F., Santiago-García, B., Noguera-Julián, A., Lanaspa, M., Lancella, L., Carducci, F.I.C.,... ptbnet COVID-19 Study Group. (2020). COVID-19 in Children and Adolescents in Europe: A Multinational, Multicentre Cohort Study. Lancet Child Adolesc Health, 4(9):653-661. doi:10.1016/S2352-4642(20)30177-2.
Goyal, P., Choi, J.J., Pinheiro, L.C., Schenck, E.J., Chen, R., Jabri, A., …Safford, M.M. (2020). Clinical characteristics of Covid-19 in New York City. N Engl J Med, 382:2372-2374. doi: 10.1056/NEJMc2010419NEJMc2010419.
Grant, M.C., Geoghegan, L., Arbyn, M., Mohammed, A., McGuinness, L., Clarke, E.L., & Wade, R.G. (2020). PLOS ONE The prevalence of symptoms in 24,410 adults infected by the novel coronavirus (SARS-CoV-2; COVID-19): A systematic review and meta-analysis of 148 studies from 9 countries. Published: June 23, 2020. https://doi.org/10.1371/journal.pone.0234765.
Grifoni, A., Weiskopf, D., Ramirez, S.I., Mateus, J., Dan, J.M., Rydyznski-Moderbacher, C., …Sette, A. (2020). Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell, 181(7):1489-1501.e15. doi: 10.1016/j.cell.2020.05.015.
Guan, W.J., Ni, Z.Y., Hu, Y., Liang, W., Ou, C., He, J., …China Medical Treatment Expert Group for Covid-19. (2020). Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med, 382:1708-1720. doi: 10.1056/NEJMoa2002032.
Havers, F.P., Reed, C., Lim, T., Montgomery, J.M., Klena, J.D., Hall, A.J., … Krapiunaya, I. (2020). Seroprevalence of antibodies to SARS-CoV-2 in 10 sites in the United States, March 23-May 12, 2020. JAMA Intern Med, 180(12):1576-1586. doi:10.1001/jamainternmed.2020.4130.
Jansen, L., Tegomoh, B., Lange, K., et al. (2021). Investigation of a SARS-CoV-2 B.1.1.529 (Omicron) Variant Cluster – Nebraska, November-December 2021. MMWR Morb Mortal Wkly Rep; 70: 1782-1784.
He, X., Lau E.H.Y., Wu, P., Deng, X., Wang, J., Yiu, X.H., …Leung, G.M. (2020). Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med 26, 672-675. https://doi.org/10.1038/s41591-020-0869-5.
Hoehl, S., Rabenau, H., Berger, A., Kortenbusch, M., Cinatl, J., Bojkova, D., …Ciesek, S. (2020). Evidence of SARS-CoV-2 Infection in Returning Travelers from Wuhan, China. N Engl J Med, 382(13):1278-1280. doi: 10.1056/NEJMc2001899.
Hu, Z., Song, C., Xu, C., Jin, G,. Chen, Y., Xu, X., …, Shen, H. (2020). Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. Sci China Life Sci, 63(5):706-711. doi: 10.1007/s11427-020-1661-4.
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., …Cao, B. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5.
Irfan, O., Muttalib, F., Tang, K., Jiang, L., Lassi, Z.S., Bhutta, Z.,... Lassi, Z.S. (2021). Clinical characteristics, treatment and outcomes of paediatric COVID-19: a systematic review and meta-analysis. Arch Dis Child, 106(5):440-448. doi: 10.1136/archdischild-2020-321385.
Jarrett, P.G., Rockwood, K., Carver, D., Stolee, P., & Cosway, S. (2020). Illness presentation in elderly patients. Arch Intern Med,1995;155(10):1060-4.
Jones, T.C., Mühlemann, B., Veith, T., Biele, G., Zuchowski, M., Hofmann, J., … Drosten, C. (2021). An analysis of SARS-CoV-2 viral load by patient age. Science eabi5273. DOI: 10.1126/science.abi5273doi:10.1101/2020.06.08.20125484.
Jung, Y.J., Yoon, J.L., Kim, H.S., Lee, A.Y., Kim, M.Y., & Cho, J.J. (2017). Atypical clinical presentation of geriatric syndrome in elderly patients with pneumonia or coronary artery disease. Ann of Geri Med and Res, 21(4):158-63. 2.
Kam, K.Q., Yung, C.F., Cui, L., Lin, R.T.P., Mak, T.M., Maiwald, M., …Thoon, K.C. (20220). A Well Infant with Coronavirus Disease 2019 (COVID-19) with High Viral Load. Clin Infect Dis, 71(15):847-849. doi: 10.1093/cid/ciaa201.
Kennedy, M., Helfand, B.K.I., Gou, R.Y., et al. (2020) Delirium in older patients with COVID-19 presenting to the emergency department. JAMA Netw Open 2020; 3(11):e2029540.
Kumar, A., Arora, A., Sharma, P., Anikhindi, S. A., Bansal, N., Singla, V.,... Srivastava, A. (2020). Clinical features of covid-19 and factors associated with severe clinical course: A systematic review and meta-analysis. SSRN Electronic Journal. doi:10.2139/ssrn.3566166.
Lauer, S. A., Grantz, K. H., Bi, Q., Jones, F. K., Zheng, Q., Meredith, H. R.,... Lessler, J. (2020). The incubation period of Coronavirus DISEASE 2019 (COVID-19) from publicly REPORTED Confirmed Cases: Estimation and application. Annals of Internal Medicine, 172(9), 577-582. doi:10.7326/m20-0504.
Laverty, M., Salvadori, M.I., Squires, S.G., Ahmed, M.A., Eisenbeis, L., Lee, S.J., … Li, Y.A. (2021). Multisystem inflammatory syndrome in children in Canada. Can Commun Dis Rep 2021; 47 (11):461–5. https://doi.org/10.14745/ccdr.
Lechien, J.R., Chiesa-Estomba, C.M., Place, S., Laethem, Y.V., Cabaraux, P., Mat, Q.,... COVID-19 Task Force of YO-IFOS. (2020). Clinical and epidemiological characteristics of 1,420 European patients with mild-to-moderate coronavirus disease 2019. J Intern Med, 288(3):335-344. doi: 10.1111/joim.13089.
Li, L.Q., Huang, T., Wang, Y.Q., Wang, Z.P., Liang, Y., Huang, T.B.,... Wang, Y. (2020). COVID-19 novel coronavirus patients' clinical characteristics, discharge rate and fatality rate of meta-analysis. J Med Virol, 92(6):577-583.doi:10.1002/jmv.25757.
Li, Q., Guan, X., Wu, P., Wang, X., Zhou, L., Tong, Y.,... Feng, Z. (20220). Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med 2020; 382:1199-207.
Li, R., Pei, S., Chen, B., Song, Y., Zhang, T., Yang, W., & Shaman, J. (2020). Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2). Science, 368(6490), 489-493. doi.org/10.1126/science.abb3221.
Lippi, G., & Plebani, M. (2020). Laboratory abnormalities in patients with COVID-2019 infection. Clin Chem Lab Med, 58(7):1131-1134. doi: 10.1515/cclm-2020-0198.
Liguoro, I., Pilotto, C., Bonanni. M., Ferrari, M.E., Pusiol, A., Nocerino, A., … Cogo, P. E., (2020). SARS-CoV-2 Infection in Children and Newborns: A Systematic Review. Eur J Pediatr, 1-18. doi: 10.1007/s00431-020-03684-7 2020. doi:10.21203/rs.3.rs-24629/v1.
Lovato, A.m & de Filippis, C. (2020). Clinical Presentation of COVID-19: A Systematic Review Focusing on Upper Airway Symptoms. Ear Nose Throat J, 99(9):569-576. doi: 10.1177/0145561320920762.
Lu, X., Zhang, L., Du, H., Zhang, J., Li, Y.Y., Qu, J.,... the Chinese Pediatric Novel Coronavirus Study Team. (20220.) SARS-CoV-2 Infection in Children. N Engl J Med, 23;382:1663-1665. doi:10.1056/NEJMc2005073.
Magro, C., Mulvey, J.J., Berlin, D., Nuovo, G., Salvatore, S., Harp.,... Laurence, J. (2020). Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res, 220:1-13. doi: 10.1016/j.trsl.2020.04.007.
Malone, M.L., Hogan, T.M., Perry, A., Biese, K., Bonner, A., Pagel, P., & Unroe, K.T. (2020). COVID-19 in older adults - Key points for emergency department providers. J of Geri Emerg Med, 1(4):1-11.
Mannheim, J., Gretsch, S., Layden, J.E., & Fricchione, M.J. (2020). Characteristics of Hospitalized Pediatric Coronavirus Disease 2019 Cases in Chicago, Illinois, March-April 2020. J Pediatric Infect Dis Soc, 9(5):519-522. doi:10.1093/jpids/piaa070.
McMichael, T.M., Clark, S., Pogosjans, S., Kay, M., Lewis, J., Baer, A.,... and CDC COVID-19 Investigation Team. (2020). COVID-19 in a Long-Term Care Facility - King County, Washington, February 27-March 9, 2020. MMWR Morbidity and mortality weekly report, 69(12):339-342.
Mizumoto, K., Kagaya, K., Zarebski, A., & Chowell, G. (2020). Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro surveillance: bulletin Europeen sur les maladies transmissibles - European communicable disease bulletin, 25(10).
Morris, S.B., Schwartz, N.G., Patel, P., Abbo, L., Beauchamps, L., Balan, S., & Godfred-Cato, S. (2020). Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection - United Kingdom and United States, March-August 2020. MMWR Weekly, 69(40);1450-1456. doi: dx.doi.org/10.15585/mmwr.mm6940e1.
National COVID-19 Clinical Evidence Taskforce. Caring for people with COVID-19. Supporting Australia's healthcare professionals with continually updated, evidence-based clinical guidelines. 10/06/21: Weekly Communique from the National Steering Committee. https://covid19evidence.net.au/.
Norman, D.C. (2000). Fever in the elderly. Clin Infect Dis 31(1):148–151.
O'Hanlon S.K.I,S. (2020). Delirium: a missing piece in the COVID-19 pandemic puzzle. Age Ageing 2020: 49(4):497–498.
Oran, D.P, & Topol, E.J. (2020). Prevalence of Asymptomatic SARS-CoV-2 Infection. Ann Intern Med, 173:362-367. doi:10.7326/M20-3012.
Oxley, T.J., Mocco, J., Majidi, S., Kellner, C.P., Shoirah, H., Singh, I.P.,... Fifi, J.T. (2020). Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med, 382:e60. doi: 10.1056/NEJMc2009787.
Pan, L., Mu, M., Yang, P., Sun, Y., Wang, R., Yan, J.,... Tu, L. (2020). Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. Am J Gastroenterol, 115(5): 766-773. doi: 10.14309/ajg.0000000000000620.
Pan, X., Chen, D., Xia, Y., Wu, X, Li, T., Ou, X.,... Liu, J. (2020). Asymptomatic cases in a family cluster with SARS-CoV-2 infection. Lancet Infect Dis, 20(4):410-411. doi:10.1016/S1473-3099(20)30114-6.
Patel, P., DeCuir, J., Abrams, J., Campbell, A., Godfred-Cata, S., Belay, E.D. (2021). Clinical Characteristics of Multisystem Inflammatory Syndrome in Adults A Systematic Review. JAMA Network Open. 2021;4(9):e2126456.doi:10.1001/jamanetworkopen.2021.26456.
Poline, J., Gaschignard, J., Leblanc, C., Madhi, F., Foucaud, E., Nattes, E.,... Ouldali, N. (2020). Systematic Severe Acute Respiratory Syndrome Coronavirus 2 Screening at Hospital Admission in Children: A French Prospective Multicenter Study. Clin Infect Dis, ciaa1044. doi: 10.1093/cid/ciaa1044.
Public Health Agency of Canada. (2022). COVID-19 daily epidemiology update. https://health-infobase.canada.ca/covid-19/epidemiological-summary-covid-19-cases.html#a9. Accessed May 10, 2022.
Qian G, Yang N, Ma AHY, Wang, L., Li, G., Chen, X., & Chen, X. (2020). A COVID-19 Transmission within a family cluster by presymptomatic infectors in China. Clin Infect Dis, 71(15):861-862. doi: 10.1093/cid/ciaa316.
Radia, T., Williams, N., Agrawal, P., Harman, K., Weale, J., Cook, J., Gupta, A. Multi-system inflammatory syndrome in children & adolescents (MIS-C): A systematic review of clinical features and presentation. (2021). Paediatr Respir Rev. Jun; 38:51-57. doi: 10.1016/j.prrv.2020.08.001. Epub 2020 Aug 11.
Riphagen, S., Gomez, X., Gonzalex-Martinez, C., Wilkinson, N., & Theocharis, P. (2020). Hyperinflammatory shock in children during COVID-19 pandemic Lancet, Volume 395, Issue 10237, P1607-1608, May 23, 2020. doi: https://doi.org/10.1016/S0140-6736(20)31094-1.
Rodriguez-Morales, A.J., Cardona-Ospina, J.A., Gutiérrez-Ocampo E, Villamizar-Peña, R., Holguin-Rivera, Y., Escalera-Antezana, J.P.,... Latin American Network of Coronavirus Disease 2019-COVID-19 Research (LANCOVID-19). (2020). Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis. Travel Med Inf Dis, 34:101623. doi: 10.1016/j.tmaid.2020.101623.
Rosenberg, E.S., Tesoriero, J.M., Rosenthal, E.M., Chung, R., Barranco, M.A., Styer, L.M.,... Zucker, H.A. (2020). (2020). Cumulative incidence and diagnosis of SARS-CoV-2 infection in New York. Ann Epidemiol., 48:23-29. doi:10.1016/j.annepidem.2020.06.004.
Rosenthal, N., Cao, Z., Gundrum, J., Sianis, J., & Safo, S. (2020). Risk Factors Associated with In-Hospital Mortality in a US National Sample of Patients With COVID-19. JAMA Netw Open, 3(12):e2029058. doi:10.1001/jamanetworkopen.2020.29058.
Rothe, C., Schunk, M., Sothmann, P., Bretzel, G., Froeschl, G., Wallrauch, C.,... Hoelscher, M. (2020). Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. N Engl J Med, 382:970-971. doi: 10.1056/NEJMc2001468.
Roxby, A.C., Greninger, A.L., Hatfield, K.M., Lynch, J.B., Dellit, T.H., James, A.,... Neme, S. (2020). Detection of SARS-CoV-2 Among Residents and Staff Members of an Independent and Assisted Living Community for Older Adults -- Seattle, Washington, 2020. MMWR, 69(14):416-418. doi:10.15585/mmwr.mm6914e2.
Santos, M.O., Goncalves, L.C., Silva, P.A.G., Moreira, A.L.E., Ito, R.M, Peixoto, F.A.O…Avelino, M.A.G. (2021). Multisystem inflammatory syndrome (MIS-C): a systematic review and meta-analysis of clinical characteristics, treatment, and outcomes. J Pediatr (Rio J). 2021 Dec 3; S0021-7557(21)00148-0. doi: 10.1016/j.jped.2021.08.006.
Shekerdemian, L.S., Mahmood, N.R., Wolfe, K.K., Riggs, B.J., Ross, C.E., McKiernan, C.A.,... the International COVID-19 PICU Collaborative. (2020). Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units. JAMA Pediatr, 174(9):868-873. doi:10.1001/jamapediatrics.2020.1948.
Shi, H., Han, X., Jiang, N., Cao, Y., Alwalid, O., Gu, J., Fan, Y., & Zheng, C. (2020). Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis, 20(4):425-434.
Shi, D.S., Whitaker, M., Marks, K.J., et al. (2022). Hospitalizations of Children Aged 5-11 Years with Laboratory-Confirmed COVID-19 – COVID-NET, 14 States, March 2020-February 2022. MMWR Morb Mortal Wkly Rep. ePub: 19 April 2022.
Soresina, A., Moratto, D., Chiarini, M., Paolillo, C., Baresi, G., Focà, E.,... Badolato, R. (2020). Two X‐linked agammaglobulinemia patients develop pneumonia as COVID‐19 manifestation but recover. Pediatr Allergy Immunol, 31(5):565-569. doi: 10.1111/pai.13263.
Spinato, G., Fabbris, C., Polesel, J., Cazzador, D., Borsetto, D., Hopkins, C., & Boscolo-Rizzo, P. (2020). Alterations in Smell or Taste in Mildly Symptomatic Outpatients With SARS-CoV-2 Infection. JAMA, 323(20):2089-2090. doi:10.1001/jama.2020.6771.
Sun, L., Shen, L., Fan, J., Gu, F., Hu, M., An, Y.,... Bi, J. (2020). Clinical Features of Patients with Coronavirus Disease 2019 (COVID‐19) from a Designated Hospital in Beijing, China. J Med Virol, 92(10):2055-2066. doi: 10.1002/jmv.25966.
Teherani, M.F., Kao, C.M., Camacho-Gonzalez, A., Banskota, S., Shane, A.L., Linam, W.M., & Jaggi, P. (2020). Burden of Illness in Households With Severe Acute Respiratory Syndrome Coronavirus 2-Infected Children. J Pediatric Infect Dis Soc, 9(5):613-616. doi:10.1093/jpids/piaa097.
Tillett, R.L., Sevinsky, J.R., Hartley P.D., Kerwin, H., Crawford, N., Gorzalski, A.,... Pandori, M. (2021). Genomic Evidence for a Case of Reinfection with SARS-CoV-2 Lancet Infect Dis, 21: 52-55. doi.org/10.1016/S1473-3099(20)30764-7.
To, K. K., Hung, I. F., Ip, J. D., Chu, A. W., Chan, W., Tam, A. R.,... Yuen, K. (2020). Coronavirus Disease 2019 (COVID-19) Re-infection by a Phylogenetically Distinct Severe Acute Respiratory Syndrome Coronavirus 2 Strain Confirmed by Whole Genome Sequencing. Clinical Infectious Diseases. doi:10.1093/cid/ciaa1275.
To, K.K., Tsang, O.T., Leung, W.S., Tam, A.R., Wu, T., Lung, D.C.,... Yuen, K. (2020). Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis., 20(5):565-574. doi:10.1016/S1473-3099(20)30196-1.
Tong, Z.D., Tang, A., Li, K.F., Li, P., Wang, H., Yi, J.,... Yan, J. (2020). Potential Presymptomatic Transmission of SARS-CoV-2, Zhejiang Province, China, 2020. Emerg Infect Dis, 26(5):1052-1054. doi:10.3201/eid2605.200198.
Verdoni, L., Mazza, A., Gervasoni, A., Martelli, L., Ruggeri, M., Ciuffreda, M.,... D'Antiga, L; (2020.) An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet, 395(10239), 1771-1778. doi: https://doi.org/10.1016/S0140-6736(20)31103-X.
Viner, R.M., Ward, J.L., Hudson, L.D., Ashe, M., Patel, S.V., Hargreaves, D., & Whittaker, E. (2020). Systematic review of reviews of symptoms and signs of COVID-19 in children and adolescents. Arch Dis Child. archdischild-2020-320972. doi: 10.1136/archdischild-2020-320972.
Wang, D., Hu, B., Hu, C., Zhu, F., Liu, X., Zhang, J.,... Peng, Z. (2020). Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA, 323(11): 1061-1069. doi:10.1001/jama.2020.1585.
Wang, X., Zhou, Q., He, Y., Liu, L., Ma., X, Wei, X.,... Gao, Z. (2020). Nosocomial Outbreak of 2019 Novel Coronavirus Pneumonia in Wuhan, China. Eur Respir J, 55(6):2000544. doi: 10.1183/13993003.00544-2020.
Wang, Y., Liu, Y., Liu, L., Wang, X., Luo, N., & Ling, L. (2020). Clinical outcome of 55 asymptomatic cases at the time of hospital admission infected with SARS-Coronavirus-2 in Shenzhen, China. J Infect Dis, 221(11):1770-1774. doi: 10.1093/infdis/jiaa119.
Wei, M., Yuan, J., Liu, Y., Fu, T., Yu, X., & Zhang, Z.J. (2020). Novel Coronavirus Infection in Hospitalized Infants Under 1 Year of Age in China. JAMA, 323(13):1313-1314. doi:10.1001/jama.2020.2131.
Wei, W.E., Li, Z., Chiew, C.J., Yong, S.E., Toh, M.P., & Lee, V.J. (2020). Presymptomatic Transmission of SARS-CoV-2 - Singapore, January 23--March 16, 2020. MMWR, 69:411-5. doi:10.15585/mmwr.mm6914e1.
Williamson, E.J., Walker, A.J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C.E.,... Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821):430-436. doi: 10.1038/s41586-020-2521-4.
Wölfel, R., Corman, V.M., Guggemos, W., Seilmaier, M., Zange, S., Müller, M.A.,... Wendtner, C. (2020). Virological assessment of hospitalized patients with COVID-2019. Nature, 581(7809):465-469. doi:10.1038/s41586-020-2196-x.
Wu, C., Chen, X., Cai, Y., Xia, J., Zhou, X., Xu, S.,... Song, Y. (2020). Risk Factors Associated with Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med., 2020 Mar 13; e200994.
Wu, Z., McGoogan, J.M. Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases from the Chinese Center for Disease Control and Prevention. JAMA Intern Med, 180(7):934-943. doi:10.1001/jamainternmed.2020.0994.
Wu. L., Wang, N., Chang, Y., Tian, X., Na, D., Zhang.,... Liang, G. (2007). Duration of antibody responses after severe acute respiratory syndrome. Emerg Infect Dis. 2007;13(10):1562-1564. doi:10.3201/eid1310.070576.
Xu, X., Wu, X., Jiang, X., Xu, J., Ying, L., Ma, C.,... Li, L. (2020). Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ, 368:m606. doi: https://doi.org/10.1136/bmj.m606.
Yahav, D., Yelin, D., Eckerle, I., Eberjardt, C.S., Wang, J., Cao, B., & Kaiser, L. (2021). Definitions for coronavirus disease 2019 reinfection, relapse and PCR re-positivity. Clin Microbiol Infect, 27(3): 315-318. doi: 10.1016/j.cmi.2020.11.028.
Yang, J., Zheng, Y., Gou, X., Pu, K., Chen, Z., Guo, Q.,... Zhou, Y. (2020). Prevalence of Comorbidities and Its Effects in Patients Infected With SARS-CoV-2: A Systematic Review and Meta-Analysis. Int J Infect Dis, 94:91-95. doi: 10.1016/j.ijid.2020.03.017.
Yang, X., Yum Y., Xu, J., Shu, H., Xia, J., Liu, H.,... Shang, Y. (2020). Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory Medicine, 8(5):475-481. doi:https://doi.org/10.1016/S2213-2600(20)30079-5.
Yasuhara, J., Watanabe, K., Takagi, H., Sumitomo, & N., Kuno, T. (2020). COVID-19 and multisystem inflammatory syndrome in children: A systematic review and meta-analysis. Pediatr Pulmonol, 55(10):2565-2575. doi: 10.1002/ppul.24991.
Young, B.E., Ong, S.W.X., Kalimuddin, S., Low, J.G., Tan, S.Y., Loh, J.,... the Singapore 2019 Novel Coronavirus Outbreak Research Team. (2020). Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA, 323(15):1488-1494. doi:10.1001/jama.2020.3204.
Zhao, J., Yuan, Q., Wang, H., Liu, W., Liao, X., Su, Y.,... Zhang, Z. (2020). Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis, 71(16):2027-2034. doi: 10.1093/cid/ciaa344.
Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z.,... Cao, B. (2020). Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet 395(10229):1054-1062. doi:10.1016/s0140-6736(20)30566-3.
Zhu, J., Pan., J., Pang, J., Zhong, Z., Li, H., He, C.,... Zhao, C. (2020). Clinical characteristics of 3,062 COVID-19 patients: a meta-analysis. J Med Virol, 92(10):1902-1914. doi: 10.1002/jmv.25884.
Zimmermann, P., & Curtis, N. (2020). COVID-19 in Children, Pregnancy and Neonates. The Pediatric Infectious Disease Journal, 39(6):469-477. doi:10.1097/inf.0000000000002700.
Zou, L., Ruan, F., Huang, M., Liang, L., Huang, H., Hong, Z.,... Wu, J. (2020). SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N Engl J Med, 382:1177-1179. doi: 10.1056/NEJMc2001737.
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2022-06-22
| None | None |
3f4624e2f740827dbe756341394910bb41b3ed6f | cma | Immunization of travellers: Canadian Immunization Guide | Immunization of travellers: Canadian Immunization Guide
For health professionals
Notice
- This CIG chapter has not been updated to contain any information regarding COVID-19 vaccines, refer to the .
- This chapter has not yet been updated with the following statements from the :
Last partial content update (see ): February 2023
February 2023 - This chapter was updated to align with changes made to the chapter in Part 4 regarding individuals previously immunized with bivalent oral poliomyelitis vaccine (bOPV).
Last complete chapter revision: (see ): April 2017
April 2017 - This chapter has been reviewed and revised to align with the updated chapters on and .
On this page
Travel health information
Immunization to protect travellers can be life-saving and is a cornerstone of travel health protection. Other protective measures, such as sanitation and hygiene, food precautions, insect or animal bite prevention, and injury prevention, are also essential for health protection while travelling and are complementary to immunization. An understanding of the personal protective measures recommended for travellers is an integral part of travel preparation; refer to the (CATMAT) website for additional information.
Travellers can be exposed to different health risks abroad than they are at home. Information about immunization requirements and recommendations related to travel is available from travel health clinics or public health agencies. Extensive information regarding travel-related diseases and immunization of travellers is available from the Government of Canada's webpage. Additional information is available from the (CDC) in the United States and the (WHO).
This chapter update was conducted in collaboration with the Committee to Advise on Tropical Medicine and Travel (CATMAT). Recommendations relating to travel vaccines are based .
Immunization of travellers
Travellers, in particular those travelling to countries with health risks that are greater than in Canada, should seek medical advice pre-departure. Pre-travel consultation affords an opportunity for health care providers to review the traveller's itinerary and to develop appropriate health protection recommendations. It also allows for the review of preventive measures for travel-related illnesses and is an opportunity to assess the overall immunization status of travellers. Unimmunized or incompletely immunized travellers should be offered vaccination as recommended in the routine immunization schedules (refer to in Part 1). A health care provider or travel health clinic should be consulted as early as possible, ideally at least 4 to 6 weeks in advance of travel, to provide sufficient time for completion of optimal immunization schedules. Even if a traveller is departing at short notice, a pre-travel consultation is recommended. In cases where there is insufficient time for the optimal immunization schedule, refer to the in Part 4 for the suggested rapid or accelerated schedule.
The immunizations recommended for travellers vary according to the: traveller's age, immunization history, and existing medical conditions; destination(s); planned activities; duration and nature of travel (for example, staying in urban hotels vs. visiting remote rural areas); legal requirements for entry into countries being visited; travellers' own concerns and preferences and the amount of time available before departure. Immunizations related to travel can be categorized as those that are considered routine (part of the recommended primary series of immunizations or routine booster doses); those required by international law; and those recommended for maintenance of health while travelling.
Routine immunizations
Unimmunized or incompletely immunized travellers should receive routine immunizations as appropriate for age and individual risk factors. Travellers may require additional doses or booster doses of routine immunizations, or a change in the routine immunization schedule. Refer to in Part 1 for a summary of the recommended immunization schedules for infants, children and adults. Recommendations for modification of the routine immunization schedule in relation to travel follow.
# Accelerated primary vaccination schedule - infants
For infants who will be travelling, the primary vaccination series with diphtheria, tetanus, acellular pertussis, inactivated polio, Haemophilus influenzae type b, with or without hepatitis B (DTaP-IPV-Hib or DTaP-HB-IPV-Hib) vaccine and pneumococcal conjugate vaccine may be started at 6 weeks of age. Rotavirus vaccine may be given at 6 weeks of age concomitantly with these vaccines. The first dose of measles-mumps-rubella (MMR) vaccine should be given at an earlier age than usual for children travelling outside of Canada where the disease is of concern or travelling to locations experiencing outbreaks (refer to in Part 4). Refer to in Part 4 and in Part 1 for additional information including the minimum interval between vaccine doses to achieve maximum vaccination protection prior to travel. Refer to the for additional information on accelerated pediatric vaccine schedules.
# Hepatitis B vaccine
Travel is a good opportunity to offer hepatitis B (HB) immunization to children and adults who have not been previously vaccinated. HB vaccine should be particularly recommended to travellers who will be residing in areas with high levels of HB endemicity or working in health care facilities, and those likely to have contact with blood or to have sexual contact with residents of such areas. HB immunization is recommended for children who will live in an area where HB is endemic. HB is endemic in the Far East, the Middle East, Africa, South America, Eastern Europe and Central Asia. Refer to a WHO map of for additional information. Refer to in Part 4 and to the CATMAT for additional information.
Concomitant immunization with hepatitis A (HA) and HB vaccines is recommended as HA vaccination is also indicated for travellers to endemic countries. For those who are susceptible to both HA and HB virus, a combined HAHB vaccine can be used. For travellers presenting less than 21 days before departure, monovalent HA and HB vaccines should be administered separately, with the completion of both vaccine series as recommended. Refer to in Part 4 for additional information.
# Measles, mumps and rubella vaccine
Measles, mumps and rubella are endemic in many countries and therefore protection against these diseases is especially important for travellers.
Travellers born in or after 1970, who do not have documented evidence of receiving 2 doses of MMR vaccine on or after their first birthday, or laboratory evidence of immunity, or a history of laboratory confirmed measles disease, should be vaccinated accordingly so that they have received 2 doses of MMR vaccine. MMR vaccine may be given as early as 6 months of age for children travelling outside of Canada where the disease is of concern or travelling to locations experiencing outbreaks. However, 2 additional doses of measles-containing vaccine must be administered after the child is 12 months old to ensure long lasting immunity to measles.
Travellers born before 1970, who do not have documented evidence of receiving MMR vaccine on or after their first birthday, or laboratory evidence of immunity, or a history of laboratory confirmed measles or mumps disease, should receive 1 dose of MMR vaccine.
# Varicella vaccine
It is important that people travelling or living abroad be immune to varicella. In tropical climates, varicella tends to occur at older ages and at any time of the year. Adolescent and adult immigrants born in tropical countries, therefore, are more likely to be susceptible to varicella as compared to the Canadian population.
Two doses of univalent varicella (chickenpox) vaccine or measles-mumps-rubella-varicella (MMRV) vaccine are recommended for immunization of healthy children aged 12 months to 12 years of age. Two doses of univalent varicella vaccine are recommended for susceptible adolescents (13 to 17 years of age) and susceptible adults (18 to 49 years of age). In the rare circumstance that an adult aged 50 years or older is known to be serologically susceptible to varicella, based on previous testing for another reason, and is without contraindications, the individual should be vaccinated with two doses of univalent varicella vaccine. For the prevention of shingles (reactivated varicella infection) the herpes zoster (shingles) vaccine is recommended for adults without contraindications if they are 50 years of age and older. Refer to and -vaccine.html) in Part 4 for additional information.
# Pertussis vaccine - adults
For pertussis prevention, acellular pertussis-containing vaccine (tetanus, reduced diphtheria, reduced acellular pertussis in Part 4 for additional information.
# Poliomyelitis vaccine - adults
Unimmunized or incompletely immunized travellers should receive an IPV-containing vaccine if they are travelling to areas where poliovirus is known or suspected to be circulating.
Previous poliovirus vaccination is only considered valid if individuals have documented proof of age-appropriate complete immunization against the three types of poliovirus (e.g., receipt of inactivated poliomyelitis vaccine (IPV), fractional IPV, trivalent oral poliomyelitis vaccine, or combination of bivalent oral poliomyelitis vaccine (bOPV) and monovalent oral poliomyelitis vaccine type 2). For adults previously immunized against polio, a single lifetime booster dose of IPV-containing vaccine is recommended for those at increased risk of exposure to polio (e.g., military personnel, workers in refugee camps in endemic areas, travellers to areas where poliovirus is known or suspected to be circulating). Previously unvaccinated adults should receive 3 doses of IPV-containing vaccine. Refer to in Part 4 for additional information.
Polio remains endemic in Afghanistan and Pakistan. Additional countries may be affected by outbreaks of imported wild poliovirus or circulating vaccine-derived poliovirus.
# Tetanus and diphtheria vaccine - adults
Travel is a good opportunity to provide tetanus and diphtheria immunization to adults who have not been previously vaccinated. A 3 dose primary series should be given to unimmunized adults; the first dose should contain acellular pertussis vaccine. For immunization of adults that have not been immunized against polio, all doses should contain polio vaccine. Previously immunized adult travellers should receive a booster dose of tetanus and diphtheria toxoid-containing vaccine every 10 years. Refer to and in Part 4 for additional information.
Tetanus occurs worldwide and diphtheria is endemic throughout many regions of the world.
Required immunizations
The following immunizations may be a requirement of international law or proof of immunization may be considered a visa requirement:
# Meningococcal vaccine
As a condition of entry, Saudi Arabia requires proof of meningococcal immunization for travellers arriving for the purpose of Umrah or pilgrimage (Hajj) and for seasonal workers. Adults and children aged over 2 years must receive 1 dose of the quadrivalent (ACYW-135) meningococcal vaccine and show proof of vaccination on a valid International Certificate of Vaccination or Prophylaxis. Vaccination is to be administered no less than 10 days before arrival in Saudi Arabia.
Visit the Saudi Arabia Ministry of Health website for vaccination requirements.
# Yellow fever vaccine
Yellow fever (YF) vaccine is unique amongst travel vaccines in that its use is governed by the International Health Regulations. Yellow fever immunization, documented by an International Certificate of Vaccination or Prophylaxis, is required to enter certain countries. The WHO publishes a list of yellow fever certificate requirements and recommendations. This country list is updated annually and can be found on the WHO website.
YF vaccine is recommended for travellers to yellow fever risk areas in Africa and Central and South America. The decision to immunize a traveller against YF should take into account the traveller's itinerary and the associated risk for exposure to YF virus, the requirements of the country to be visited (including stopovers and airport transit), and individual risk factors for serious adverse events following vaccination.
The International Certificate of Vaccination or Prophylaxis is valid beginning 10 days after primary immunization. An important amendment was made in May 2014 to Annex 7 of the International Health Regulations (2005) which extended the validity of the International Certificate of Vaccination or Prophylaxis against yellow fever from 10 years to lifetime. This requirement came into force on 11 July 2016. The status of YF vaccination requirements is published in the WHO country list as stated above.
Travellers requiring the certificate but in whom the YF vaccine is medically contraindicated can be provided with an International Certificate of Medical Contraindication to Vaccination by a Yellow Fever Vaccination Centre following an individual risk assessment. Travellers without a valid International Certificate of Vaccination or Prophylaxis or an International Certificate of Medical Contraindication to Vaccination may be denied entry into a country requiring such documentation, may be quarantined, or may be offered immunization at the point of entry (for example, at the airport), potentially putting the health of the traveller at risk. Although usually accepted, the International Health Regulations do not compel any country to accept an International Certificate of Medical Contraindication to Vaccination.
In Canada, Yellow Fever Vaccination Centre clinics are designated by the Public Health Agency of Canada (or in the case of the Canadian Forces, by the Directorate of Force Health Protection) to provide the International Certificate of Vaccination or Prophylaxis, or the International Certificate of Medical Contraindication to Vaccination. Refer to the list of designated .
Recommended immunizations
Based on a risk assessment of the travel itinerary, the nature of travel, and the traveller's underlying health, the following vaccines should be considered (also refer to ):
# Hepatitis A vaccine
Protection against HA is recommended for all travellers to endemic countries, especially if they are travelling to rural areas or places with inadequate sanitary facilities. Hepatitis A is one of the most common vaccine preventable diseases in travellers. Hepatitis A containing vaccine is the preferred agent for pre-exposure prophylaxis of travellers 6 months of age and older. For pre-exposure prophylaxis of infants less than 6 months of age, immunocompromised persons, and people for whom HA vaccine is contraindicated, human immune globulin (Ig) may be indicated. Refer to in Part 4 for additional information. Refer to the CATMAT for additional information on rapid dosing schedules.
# Influenza vaccine
All travellers are encouraged to receive influenza vaccine. Influenza occurs year-round in the tropics, while in temperate northern and southern countries, influenza activity peaks generally during the winter season (November to March in the Northern Hemisphere and April to October in the Southern Hemisphere). Vaccines prepared specifically for use in the Southern Hemisphere are not available in Canada, and the extent to which the recommended vaccine components for the Southern Hemisphere may overlap with those in available Canadian formulations will vary. Refer to in Part 4 for additional information.
# Japanese encephalitis vaccine
Japanese encephalitis (JE) vaccine is recommended for adult travellers with a high exposure risk going to JE endemic or epidemic areas during the transmission season. The risk for acquiring JE is low for most travellers, particularly for short-term visitors to major urban areas, because the mosquito vector for JE and its animal reservoir(s) are primarily found in rural agricultural areas. Japanese encephalitis occurs in many areas of Asia, especially in the south east and in parts of the western Pacific, and is the leading cause of viral encephalitis in Asia. Refer to in Part 4 for additional information.
# Meningococcal vaccine
Travellers to destinations where risk of meningococcal transmission is high should be vaccinated with a meningococcal conjugate quadrivalent vaccine (Men-C-ACYW), multicomponent meningococcal vaccine (4CMenB), or both vaccines, depending on the risk of meningococcal disease in the area of travel.
Invasive meningococcal disease occurs sporadically worldwide and in focal epidemics. The traditional endemic areas of the world include the savannah areas of sub-Saharan Africa, extending from Gambia and Senegal in the west to Ethiopia and Western Eritrea in the east. Meningococcal disease is also associated with the Hajj, an Islamic pilgrimage to Mecca, Saudi Arabia. Refer to the CATMAT for additional information. Refer to the WHO website for updates.
# Rabies vaccine
Travellers to rabies endemic areas where there is poor or unknown access to adequate and safe post-exposure management, as well as frequent and long-term travellers to high-risk areas should be considered for pre-exposure rabies immunization. Children, especially those who are too young to understand either the need to avoid animals or to report a traumatic animal contact, should receive pre-exposure immunization when travelling to endemic areas.
Pre-exposure rabies vaccination obviates the requirement for rabies immune globulin if rabies exposure occurs, which may be unsafe or unavailable in many countries with high rabies risk. Refer to in Part 4 for additional information including post-exposure prophylaxis.
Public health officials should be consulted regarding travellers who have had an exposure to a potentially rabid animal in a low resource country, even if the traveller has received a complete course of post-exposure prophylaxis in that country. The prevalence of rabies in low resource countries is often much higher than in Canada and there may be concerns about the efficacy of available vaccines in these countries.
To identify high-risk areas, refer to the WHO .
# Typhoid vaccine
Travellers to South Asia (including Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka) 2 years of age and older should be offered typhoid vaccine.
Typhoid immunization is not routinely recommended for travel outside of South Asia, although, it might be considered for travellers to other areas, such as Africa. The decision of whether a traveller should be immunized when travelling to destinations other than South Asia should be carefully balanced against the presence of other factors that may increase the risk of travel-associated typhoid, such as visiting residents of the country in their homes, or longer duration of travel which may prolong exposure to potentially contaminated food and water. Immunization is not routinely recommended for short-term holidays in resort hotels.
# Bacille Calmette-Guérin (BCG) vaccine
In exceptional circumstances, immunization with BCG vaccine may be considered for travellers planning extended stays in areas or countries of high tuberculosis prevalence. Consultation with an infectious disease or travel medicine specialist is recommended. Refer to in Part 4, the CATMAT Statement on and the for additional information.
# Cholera and travellers' diarrhea vaccine
Travellers to cholera-endemic countries who may be at significantly increased risk of exposure, for example, humanitarian workers or health care providers working in endemic countries, may benefit from cholera vaccination. Most travellers following the usual tourist itineraries in countries affected by cholera are at extremely low risk of acquiring cholera infection. For protection against travellers' diarrhea, vaccination with cholera and travellers' diarrhea vaccine is of limited benefit and is not routinely recommended, except for high-risk travellers who are 2 years of age and older.
Immunocompromised travellers
For information about immunization of travellers who are immunocompromised refer to in Part 3, in Part 4, and the CATMAT .
Pregnant and breastfeeding travellers
For information about immunization of pregnant or breastfeeding travellers refer to in Part 3, in Part 4, and the CATMAT .
Older travellers
In older adults, both vaccine efficacy and the risk of adverse reactions may be affected by age. Declining cell-mediated and humoral immunity influence the response to immunization, potentially resulting in diminished, delayed, and less durable immune responses and greater susceptibility to adverse effects of some vaccines, especially yellow fever. Older adults may also be more vulnerable to disease and complications for some vaccine preventable illnesses, such as hepatitis A, typhoid fever, and yellow fever. For additional information refer to the CATMAT .
Pediatric travellers
Travel immunization recommendations for children will vary with the individual risk of exposure and the severity of potential infection. Some travel-related infections, such as hepatitis A, typhoid, and rabies, are more likely to occur in pediatric travellers than in adult travellers. Children are at higher risk for meningococcal infections. For additional information regarding immunization of pediatric travelers, refer to the CATMAT .
Travellers who visit friends and relatives
Those who travel with the intention of visiting friends and relatives or other residents of the country in their homes are at increased risk of travel-related infections. Adults, and particularly children, are at greater risk due to both demographic and travel-related characteristics such as travelling for longer periods, travelling to rural areas, travelling to destinations with higher risk for tropical diseases, and are less likely to seek pre-travel health advice. Refer to the CATMAT for additional information. |
Immunization of travellers: Canadian Immunization Guide
========================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-10-immunization-persons-new-canada.html)
Notice
------
* This CIG chapter has not been updated to contain any information regarding COVID-19 vaccines, refer to the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html).
* This chapter has not yet been updated with the following statements from the [Committee to Advise on Tropical Medicine and Travel (CATMAT)](/en/public-health/services/catmat.html):
+ [Statement on Prevention of Japanese Encephalitis](/en/public-health/services/catmat/statement-prevention-japanese-encephalitis.html)
+ [Statement on the Use of Booster Doses of Yellow Fever Vaccine](/en/public-health/services/publications/diseases-conditions/use-booster-doses-yellow-fever-vaccine.html)
**Last partial content update** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): February 2023
**February 2023** - This chapter was updated to align with changes made to the [Poliomyelitis vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-17-poliomyelitis-vaccine.html) chapter in Part 4 regarding individuals previously immunized with bivalent oral poliomyelitis vaccine (bOPV).
**Last complete chapter revision:** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): April 2017
**April 2017** - This chapter has been reviewed and revised to align with the updated chapters on [Typhoid Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-23-typhoid-vaccine.html) and [Cholera and Enterotoxigenic Escherichia coli (ETEC) Traveller's Diarrhea Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-3-cholera-enterotoxigenic-escherichia-coli-travellers-diarrhea-vaccine.html).
On this page
------------
* [Travel health information](#a1)
* [Immunization of travellers](#a2)
* [Routine immunizations](#a3)
* [Required immunizations](#a4)
* [Recommended immunizations](#a5)
* [Immunocompromised travellers](#a6)
* [Pregnant and breastfeeding travellers](#a7)
* [Older travellers](#a8)
* [Pediatric travellers](#a9)
* [Travellers who visit friends and relatives](#a10)
* [Selected references](#a11)
Travel health information
-------------------------
Immunization to protect travellers can be life-saving and is a cornerstone of travel health protection. Other protective measures, such as sanitation and hygiene, food precautions, insect or animal bite prevention, and injury prevention, are also essential for health protection while travelling and are complementary to immunization. An understanding of the personal protective measures recommended for travellers is an integral part of travel preparation; refer to the [Committee to Advise on Tropical Medicine and Travel](/en/public-health/services/catmat.html) (CATMAT) website for additional information.
Travellers can be exposed to different health risks abroad than they are at home. Information about immunization requirements and recommendations related to travel is available from travel health clinics or public health agencies. Extensive information regarding travel-related diseases and immunization of travellers is available from the Government of Canada's [Travelling abroad](https://travel.gc.ca/travelling) webpage. Additional information is available from the [Centers for Disease Control and Prevention](http://wwwnc.cdc.gov/travel/) (CDC) in the United States and the [World Health Organization](http://www.who.int/ith/en/) (WHO).
This chapter update was conducted in collaboration with the Committee to Advise on Tropical Medicine and Travel (CATMAT). Recommendations relating to travel vaccines are based [CATMAT Statements and Recommendations](/en/public-health/services/catmat.html).
Immunization of travellers
--------------------------
Travellers, in particular those travelling to countries with health risks that are greater than in Canada, should seek medical advice pre-departure. Pre-travel consultation affords an opportunity for health care providers to review the traveller's itinerary and to develop appropriate health protection recommendations. It also allows for the review of preventive measures for travel-related illnesses and is an opportunity to assess the overall immunization status of travellers. Unimmunized or incompletely immunized travellers should be offered vaccination as recommended in the routine immunization schedules (refer to [Recommended immunization schedules](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-13-recommended-immunization-schedules.html) in Part 1). A health care provider or travel health clinic should be consulted as early as possible, ideally at least 4 to 6 weeks in advance of travel, to provide sufficient time for completion of optimal immunization schedules. Even if a traveller is departing at short notice, a pre-travel consultation is recommended. In cases where there is insufficient time for the optimal immunization schedule, refer to the [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for the suggested rapid or accelerated schedule.
The immunizations recommended for travellers vary according to the: traveller's age, immunization history, and existing medical conditions; destination(s); planned activities; duration and nature of travel (for example, staying in urban hotels vs. visiting remote rural areas); legal requirements for entry into countries being visited; travellers' own concerns and preferences and the amount of time available before departure. Immunizations related to travel can be categorized as those that are considered **routine** (part of the recommended primary series of immunizations or routine booster doses); those **required** by international law; and those **recommended** for maintenance of health while travelling.
Refer to [Immunization of workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html) in Part 3 for additional information about immunization of travellers planning to work abroad in occupations with increased risk of exposure to vaccine preventable diseases (for example, humanitarian relief or refugee workers, health care workers). Refer to [Immunization of persons new to Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-10-immunization-persons-new-canada.html) for additional information about immunization of family members travelling outside of Canada to adopt a child.
Routine immunizations
---------------------
Unimmunized or incompletely immunized travellers should receive routine immunizations as appropriate for age and individual risk factors. Travellers may require additional doses or booster doses of routine immunizations, or a change in the routine immunization schedule. Refer to [Recommended immunization schedules](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-13-recommended-immunization-schedules.html) in Part 1 for a summary of the recommended immunization schedules for infants, children and adults. Recommendations for modification of the routine immunization schedule in relation to travel follow.
### Accelerated primary vaccination schedule - infants
For infants who will be travelling, the primary vaccination series with diphtheria, tetanus, acellular pertussis, inactivated polio, Haemophilus influenzae type b, with or without hepatitis B (DTaP-IPV-Hib or DTaP-HB-IPV-Hib) vaccine and pneumococcal conjugate vaccine may be started at 6 weeks of age. Rotavirus vaccine may be given at 6 weeks of age concomitantly with these vaccines. The first dose of measles-mumps-rubella (MMR) vaccine should be given at an earlier age than usual for children travelling outside of Canada where the disease is of concern or travelling to locations experiencing outbreaks (refer to [Measles Vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html) in Part 4). Refer to [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 and [Timing of Vaccine Administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) in Part 1 for additional information including the minimum interval between vaccine doses to achieve maximum vaccination protection prior to travel. Refer to the [CATMAT Statement on International Travellers Who Intend to Visit Friends and Relatives](/en/public-health/services/catmat/statement-international-travellers-visit.html) for additional information on accelerated pediatric vaccine schedules.
### Hepatitis B vaccine
Travel is a good opportunity to offer hepatitis B (HB) immunization to children and adults who have not been previously vaccinated. HB vaccine should be particularly recommended to travellers who will be residing in areas with high levels of HB endemicity or working in health care facilities, and those likely to have contact with blood or to have sexual contact with residents of such areas. HB immunization is recommended for children who will live in an area where HB is endemic. HB is endemic in the Far East, the Middle East, Africa, South America, Eastern Europe and Central Asia. Refer to a WHO map of [Hepatitis B, countries and areas of risk](http://gamapserver.who.int/mapLibrary/Files/Maps/Global_HepB_ITHRiskMap.png) for additional information. Refer to [Hepatitis B vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-7-hepatitis-b-vaccine.html) in Part 4 and to the CATMAT [Summary of recommendations for the prevention of viral hepatitis during travel](http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/14vol40/dr-rm40-13/dr-rm40-13-clin-2-eng.php) for additional information.
Concomitant immunization with hepatitis A (HA) and HB vaccines is recommended as HA vaccination is also indicated for travellers to endemic countries. For those who are susceptible to both HA and HB virus, a combined HAHB vaccine can be used. For travellers presenting less than 21 days before departure, monovalent HA and HB vaccines should be administered separately, with the completion of both vaccine series as recommended. Refer to [Hepatitis A vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html) in Part 4 for additional information.
### Measles, mumps and rubella vaccine
Measles, mumps and rubella are endemic in many countries and therefore protection against these diseases is especially important for travellers.
Travellers born in or after 1970, who do not have documented evidence of receiving 2 doses of MMR vaccine on or after their first birthday, or laboratory evidence of immunity, or a history of laboratory confirmed measles disease, should be vaccinated accordingly so that they have received 2 doses of MMR vaccine. MMR vaccine may be given as early as 6 months of age for children travelling outside of Canada where the disease is of concern or travelling to locations experiencing outbreaks. However, 2 additional doses of measles-containing vaccine must be administered after the child is 12 months old to ensure long lasting immunity to measles.
Travellers born before 1970, who do not have documented evidence of receiving MMR vaccine on or after their first birthday, or laboratory evidence of immunity, or a history of laboratory confirmed measles or mumps disease, should receive 1 dose of MMR vaccine.
Refer to [Measles vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html), [Mumps vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-14-mumps-vaccine.html) and [Rubella vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-20-rubella-vaccine.html) in Part 4 for additional information.
### Varicella vaccine
It is important that people travelling or living abroad be immune to varicella. In tropical climates, varicella tends to occur at older ages and at any time of the year. Adolescent and adult immigrants born in tropical countries, therefore, are more likely to be susceptible to varicella as compared to the Canadian population.
Two doses of univalent varicella (chickenpox) vaccine or measles-mumps-rubella-varicella (MMRV) vaccine are recommended for immunization of healthy children aged 12 months to 12 years of age. Two doses of univalent varicella vaccine are recommended for susceptible adolescents (13 to 17 years of age) and susceptible adults (18 to 49 years of age). In the rare circumstance that an adult aged 50 years or older is known to be serologically susceptible to varicella, based on previous testing for another reason, and is without contraindications, the individual should be vaccinated with two doses of univalent varicella vaccine. For the prevention of shingles (reactivated varicella infection) the herpes zoster (shingles) vaccine is recommended for adults without contraindications if they are 50 years of age and older. Refer to [Varicella (chickenpox) vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-24-varicella-chickenpox-vaccine.html) and [Herpes Zoster (Shingles) vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-8-herpes-zoster-(shingles)-vaccine.html) in Part 4 for additional information.
### Pertussis vaccine - adults
For pertussis prevention, acellular pertussis-containing vaccine (tetanus, reduced diphtheria, reduced acellular pertussis [Tdap]) is recommended for adults who have not previously received a dose in adulthood, regardless of the interval from the last dose of tetanus and diphtheria toxoid-containing vaccine. The pre-travel consultation is an opportunity to give the adult booster to those who may not otherwise seek immunization from a vaccine provider. Refer to [Pertussis vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-15-pertussis-vaccine.html) in Part 4 for additional information.
### Poliomyelitis vaccine - adults
Unimmunized or incompletely immunized travellers should receive an IPV-containing vaccine if they are travelling to areas where poliovirus is known or suspected to be circulating.
Previous poliovirus vaccination is only considered valid if individuals have documented proof of age-appropriate complete immunization against the three types of poliovirus (e.g., receipt of inactivated poliomyelitis vaccine (IPV), fractional IPV, trivalent oral poliomyelitis vaccine, or combination of bivalent oral poliomyelitis vaccine (bOPV) and monovalent oral poliomyelitis vaccine type 2). For adults previously immunized against polio, a single lifetime booster dose of IPV-containing vaccine is recommended for those at increased risk of exposure to polio (e.g., military personnel, workers in refugee camps in endemic areas, travellers to areas where poliovirus is known or suspected to be circulating). Previously unvaccinated adults should receive 3 doses of IPV-containing vaccine. Refer to [Poliomyelitis vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-17-poliomyelitis-vaccine.html) in Part 4 for additional information.
Polio remains endemic in Afghanistan and Pakistan. Additional countries may be affected by outbreaks of imported wild poliovirus or circulating vaccine-derived poliovirus.
Refer to the [WHO Global Polio Eradication Initiative](http://polioeradication.org/) for up-to-date information about the current status of polio around the world, including any [temporary recommendations](http://www.polioeradication.org/Keycountries/PolioEmergency.aspx) which may require proof of polio vaccination for travellers entering affected countries.
Refer to [Poliomyelitis vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-17-poliomyelitis-vaccine.html) in Part 4 for additional information.
### Tetanus and diphtheria vaccine - adults
Travel is a good opportunity to provide tetanus and diphtheria immunization to adults who have not been previously vaccinated. A 3 dose primary series should be given to unimmunized adults; the first dose should contain acellular pertussis vaccine. For immunization of adults that have not been immunized against polio, all doses should contain polio vaccine. Previously immunized adult travellers should receive a booster dose of tetanus and diphtheria toxoid-containing vaccine every 10 years. Refer to [Tetanus Toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-22-tetanus-toxoid.html) and [Diphtheria toxoid](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-4-diphtheria-toxoid.html) in Part 4 for additional information.
Tetanus occurs worldwide and diphtheria is endemic throughout many regions of the world.
Required immunizations
----------------------
The following immunizations may be a requirement of international law or proof of immunization may be considered a visa requirement:
### Meningococcal vaccine
As a condition of entry, Saudi Arabia requires proof of meningococcal immunization for travellers arriving for the purpose of Umrah or pilgrimage (Hajj) and for seasonal workers. Adults and children aged over 2 years must receive 1 dose of the quadrivalent (ACYW-135) meningococcal vaccine and show proof of vaccination on a valid International Certificate of Vaccination or Prophylaxis. Vaccination is to be administered no less than 10 days before arrival in Saudi Arabia.
Visit the Saudi Arabia Ministry of Health website for vaccination requirements.
### Yellow fever vaccine
Yellow fever (YF) vaccine is unique amongst travel vaccines in that its use is governed by the International Health Regulations. Yellow fever immunization, documented by an International Certificate of Vaccination or Prophylaxis, is required to enter certain countries. The WHO publishes a list of yellow fever certificate requirements and recommendations. This country list is updated annually and can be found on the WHO [International Travel and Health](http://www.who.int/ith/en/) website.
YF vaccine is recommended for travellers to yellow fever risk areas in Africa and Central and South America. The decision to immunize a traveller against YF should take into account the traveller's itinerary and the associated risk for exposure to YF virus, the requirements of the country to be visited (including stopovers and airport transit), and individual risk factors for serious adverse events following vaccination.
The International Certificate of Vaccination or Prophylaxis is valid beginning 10 days after primary immunization. An important amendment was made in May 2014 to Annex 7 of the International Health Regulations (2005) which extended the validity of the International Certificate of Vaccination or Prophylaxis against yellow fever from 10 years to lifetime. This requirement came into force on 11 July 2016. The status of YF vaccination requirements is published in the WHO country list as stated above.
Travellers requiring the certificate but in whom the YF vaccine is medically contraindicated can be provided with an International Certificate of Medical Contraindication to Vaccination by a Yellow Fever Vaccination Centre following an individual risk assessment. Travellers without a valid International Certificate of Vaccination or Prophylaxis or an International Certificate of Medical Contraindication to Vaccination may be denied entry into a country requiring such documentation, may be quarantined, or may be offered immunization at the point of entry (for example, at the airport), potentially putting the health of the traveller at risk. Although usually accepted, the International Health Regulations do not compel any country to accept an International Certificate of Medical Contraindication to Vaccination.
In Canada, Yellow Fever Vaccination Centre clinics are designated by the Public Health Agency of Canada (or in the case of the Canadian Forces, by the Directorate of Force Health Protection) to provide the International Certificate of Vaccination or Prophylaxis, or the International Certificate of Medical Contraindication to Vaccination. Refer to the list of designated [Yellow fever vaccination centres in Canada](/en/public-health/services/travel-health/yellow-fever.html).
Refer to [Yellow Fever vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-25-yellow-fever-vaccine.html) in Part 4 and the CATMAT [Statement for travellers and yellow fever](http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/13vol39/acs-dcc-2/index-eng.php) for additional information.
Recommended immunizations
-------------------------
Based on a risk assessment of the travel itinerary, the nature of travel, and the traveller's underlying health, the following vaccines should be considered (also refer to [Yellow Fever vaccine](#a4.2)):
### Hepatitis A vaccine
Protection against HA is recommended for all travellers to endemic countries, especially if they are travelling to rural areas or places with inadequate sanitary facilities. Hepatitis A is one of the most common vaccine preventable diseases in travellers. Hepatitis A containing vaccine is the preferred agent for pre-exposure prophylaxis of travellers 6 months of age and older. For pre-exposure prophylaxis of infants less than 6 months of age, immunocompromised persons, and people for whom HA vaccine is contraindicated, human immune globulin (Ig) may be indicated. Refer to [Hepatitis A vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-6-hepatitis-a-vaccine.html) in Part 4 for additional information. Refer to the CATMAT [Summary of recommendations for the prevention of viral hepatitis during travel](http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/14vol40/dr-rm40-13/dr-rm40-13-clin-2-eng.php) for additional information on rapid dosing schedules.
Refer to a WHO [map of countries or areas at risk for hepatitis A](http://gamapserver.who.int/mapLibrary/Files/Maps/Global_HepA_ITHRiskMap.png).
### Influenza vaccine
All travellers are encouraged to receive influenza vaccine. Influenza occurs year-round in the tropics, while in temperate northern and southern countries, influenza activity peaks generally during the winter season (November to March in the Northern Hemisphere and April to October in the Southern Hemisphere). Vaccines prepared specifically for use in the Southern Hemisphere are not available in Canada, and the extent to which the recommended vaccine components for the Southern Hemisphere may overlap with those in available Canadian formulations will vary. Refer to [Influenza vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-10-influenza-vaccine.html) in Part 4 for additional information.
### Japanese encephalitis vaccine
Japanese encephalitis (JE) vaccine is recommended for adult travellers with a high exposure risk going to JE endemic or epidemic areas during the transmission season. The risk for acquiring JE is low for most travellers, particularly for short-term visitors to major urban areas, because the mosquito vector for JE and its animal reservoir(s) are primarily found in rural agricultural areas. Japanese encephalitis occurs in many areas of Asia, especially in the south east and in parts of the western Pacific, and is the leading cause of viral encephalitis in Asia. Refer to [Japanese Encephalitis vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-11-japanese-encephalitis-vaccine.html) in Part 4 for additional information.
Refer to the WHO [map of the countries or areas at risk for JE](http://gamapserver.who.int/mapLibrary/Files/Maps/Global_JE_ITHRiskMap.png).
### Meningococcal vaccine
Travellers to destinations where risk of meningococcal transmission is high should be vaccinated with a meningococcal conjugate quadrivalent vaccine (Men-C-ACYW), multicomponent meningococcal vaccine (4CMenB), or both vaccines, depending on the risk of meningococcal disease in the area of travel.
Refer to [Meningococcal](#a4.1) above for information about the requirement for meningococcal vaccination as a condition to entry for certain travellers to Saudi Arabia. Refer to [Meningococcal vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-13-meningococcal-vaccine.html) in Part 4 for additional information.
Invasive meningococcal disease occurs sporadically worldwide and in focal epidemics. The traditional endemic areas of the world include the savannah areas of sub-Saharan Africa, extending from Gambia and Senegal in the west to Ethiopia and Western Eritrea in the east. Meningococcal disease is also associated with the Hajj, an Islamic pilgrimage to Mecca, Saudi Arabia. Refer to the CATMAT [Statement on meningococcal disease and the international traveller](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2015-41/ccdr-volume-41-05-may-7-2015/ccdr-volume-41-05-may-7-2015-1.html) for additional information. Refer to the WHO [meningococcal disease outbreak](http://www.who.int/csr/don/archive/disease/meningococcal_disease/en/) website for updates.
### Rabies vaccine
Travellers to rabies endemic areas where there is poor or unknown access to adequate and safe post-exposure management, as well as frequent and long-term travellers to high-risk areas should be considered for pre-exposure rabies immunization. Children, especially those who are too young to understand either the need to avoid animals or to report a traumatic animal contact, should receive pre-exposure immunization when travelling to endemic areas.
Pre-exposure rabies vaccination obviates the requirement for rabies immune globulin if rabies exposure occurs, which may be unsafe or unavailable in many countries with high rabies risk. Refer to [Rabies vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-18-rabies-vaccine.html) in Part 4 for additional information including post-exposure prophylaxis.
Public health officials should be consulted regarding travellers who have had an exposure to a potentially rabid animal in a low resource country, even if the traveller has received a complete course of post-exposure prophylaxis in that country. The prevalence of rabies in low resource countries is often much higher than in Canada and there may be concerns about the efficacy of available vaccines in these countries.
To identify high-risk areas, refer to the WHO [map of areas at risk for rabies transmission](http://www.who.int/rabies/Global_distribution_risk_humans_contracting_rabies_2013.png?ua=1).
### Typhoid vaccine
Travellers to South Asia (including Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka) 2 years of age and older should be offered typhoid vaccine.
Typhoid immunization is not routinely recommended for travel outside of South Asia, although, it might be considered for travellers to other areas, such as Africa. The decision of whether a traveller should be immunized when travelling to destinations other than South Asia should be carefully balanced against the presence of other factors that may increase the risk of travel-associated typhoid, such as visiting residents of the country in their homes, or longer duration of travel which may prolong exposure to potentially contaminated food and water. Immunization is not routinely recommended for short-term holidays in resort hotels.
Refer to CATMAT [Statement on international travellers and typhoid](http://publications.gc.ca/site/eng/460371/publication.html) and [Typhoid vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-23-typhoid-vaccine.html) in Part 4 for additional information.
### Bacille Calmette-Guérin (BCG) vaccine
In exceptional circumstances, immunization with BCG vaccine may be considered for travellers planning extended stays in areas or countries of high tuberculosis prevalence. Consultation with an infectious disease or travel medicine specialist is recommended. Refer to [Bacille Calmette-Guérin vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-2-bacille-calmette-guerin-vaccine.html) in Part 4, the CATMAT Statement on [Risk assessment and prevention of tuberculosis among travellers](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2009-35/risk-assessment-prevention-tuberculosis-travellers.html) and the [Canadian TB Standards (chapter 16)](/en/public-health/services/infectious-diseases/canadian-tuberculosis-standards-7th-edition/edition-12.html) for additional information.
### Cholera and travellers' diarrhea vaccine
Travellers to cholera-endemic countries who may be at significantly increased risk of exposure, for example, humanitarian workers or health care providers working in endemic countries, may benefit from cholera vaccination. Most travellers following the usual tourist itineraries in countries affected by cholera are at extremely low risk of acquiring cholera infection. For protection against travellers' diarrhea, vaccination with cholera and travellers' diarrhea vaccine is of limited benefit and is not routinely recommended, except for high-risk travellers who are 2 years of age and older.
Refer to [Cholera and Enterotoxigenic Escherichia coli (ETEC) diarrhea vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-3-cholera-enterotoxigenic-escherichia-coli-travellers-diarrhea-vaccine.html) in Part 4 and the CATMAT [Statement on traveller's diarrhea](/en/public-health/services/catmat/statement-travellers-diarrhea.html) for additional information. Refer to the WHO [map of the areas reporting cholera outbreaks](http://gamapserver.who.int/mapLibrary/Files/Maps/Global_ChoeraCases_ITHRiskMap.png).
Immunocompromised travellers
----------------------------
For information about immunization of travellers who are immunocompromised refer to [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3, [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4, and the CATMAT [Statement on the immunocompromised traveller](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2007-33/immunocompromised-traveller.html).
Pregnant and breastfeeding travellers
-------------------------------------
For information about immunization of pregnant or breastfeeding travellers refer to [Immunization in pregnancy and breastfeeding](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-4-immunization-pregnancy-breastfeeding.html) in Part 3, [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4, and the CATMAT [Statement on pregnancy and travel](https://www.canada.ca/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2010-36/canada-communicable-disease-report-7.html).
Older travellers
----------------
In older adults, both vaccine efficacy and the risk of adverse reactions may be affected by age. Declining cell-mediated and humoral immunity influence the response to immunization, potentially resulting in diminished, delayed, and less durable immune responses and greater susceptibility to adverse effects of some vaccines, especially yellow fever. Older adults may also be more vulnerable to disease and complications for some vaccine preventable illnesses, such as hepatitis A, typhoid fever, and yellow fever. For additional information refer to the CATMAT [Statement on older travellers](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/statement-on-older-travellers.html).
Pediatric travellers
--------------------
Travel immunization recommendations for children will vary with the individual risk of exposure and the severity of potential infection. Some travel-related infections, such as hepatitis A, typhoid, and rabies, are more likely to occur in pediatric travellers than in adult travellers. Children are at higher risk for meningococcal infections. For additional information regarding immunization of pediatric travelers, refer to the CATMAT [Statement on pediatric travellers](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2010-36/canada-communicable-disease-report/canada-communicable-disease-report.html).
Travellers who visit friends and relatives
------------------------------------------
Those who travel with the intention of visiting friends and relatives or other residents of the country in their homes are at increased risk of travel-related infections. Adults, and particularly children, are at greater risk due to both demographic and travel-related characteristics such as travelling for longer periods, travelling to rural areas, travelling to destinations with higher risk for tropical diseases, and are less likely to seek pre-travel health advice. Refer to the CATMAT [Statement on international travellers who intend to visit friends and relatives](/en/public-health/services/catmat/statement-international-travellers-visit.html) for additional information.
Selected references
-------------------
* Centers for Disease Control and Prevention. Health Information for International Travel 2016. The Yellow Book. Accessed January 2017 at: https://wwwnc.cdc.gov/travel/page/yellowbook-home-2014
* Committee to Advise on Tropical Medicine and Travel. Statement for Travellers and Yellow Fever. Can Comm Dis Rep 2013;39(ACS-2):1-20. Accessed January 2017 at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/13vol39/acs-dcc-2/index-eng.php
* Committee to Advise on Tropical Medicine and Travel. Statement on Personal Protective Measures to Prevent Arthropod Bites - Update. Can Commun Dis Rep 2012;28(ACS-2):1-18. Accessed January 2017 at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/12vol38/acs-dcc-3/index-eng.php
* Committee to Advise on Tropical Medicine and Travel. Statement on Older Travellers. Can Commun Dis Rep 2011;37(ACS-2):1-24. Accessed January 2017 at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/11vol37/acs-2/index-eng.php
* Committee to Advise on Tropical Medicine and Travel. Statement on Protection against Japanese Encephalitis. Can Commun Dis Rep 2011;37(ACS-1):1-13. Accessed January 2017 at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/11vol37/acs-1/index-eng.php
* Committee to Advise on Tropical Medicine and Travel. Statement on Pediatric Travellers. Can Commun Dis Rep 2010;36(ACS-3):1-31. Accessed January 2017 at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/10vol36/acs-3/june-juin-2010-eng.php
* Committee to Advise on Tropical Medicine and Travel. Statement on Poliovirus and the International Traveller. Can Commun Dis Rep 2014;40-13. Accessed January 2017 at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/14vol40/dr-rm40-13/dr-rm40-13-com-eng.php
* Committee to Advise on Tropical Medicine and Travel. Statement on Pregnancy and Travel. Can Commun Dis Rep 2010;36(ACS-2):1-43. Accessed January 2017 at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/10vol36/acs-2/index-eng.php
* Committee to Advise on Tropical Medicine and Travel. Risk Assessment and Prevention of Tuberculosis among Travellers. Can Comm Dis Rep 2009;37(ACS-5):1-20. Accessed January 2017 at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/09vol35/acs-dcc-5/index-eng.php
* Committee to Advise on Tropical Medicine and Travel. Statement on Meningococcal Vaccination for Travellers. Can Commun Dis Rep 2009;35(ACS-4):1-22. Accessed January 2017 at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/09vol35/acs-dcc-4/index-eng.php
* Committee to Advise on Tropical Medicine and Travel. Statement on Hepatitis Vaccines for Travellers. Can Comm Dis Rep. 2008;34(ACS-2):1-24. Accessed January 2017 at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/08vol34/acs-2/index-eng.php
* Committee to Advise on Tropical Medicine and Travel. The Immunocompromised Traveller. Can Commun Dis Rep 2007;33(ACS-4):1-24. Accessed January 2017 at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/07vol33/acs-04/index-eng.php
* Committee to Advise on Tropical Medicine and Travel. Summary of Recommendations for the Prevention of Viral Hepatitis during Travel. Can Commun Dis Rep 2014;40-13. Accessed January 2017 at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/14vol40/dr-rm40-13/dr-rm40-13-clin-2-eng.php
* Committee to Advise on Tropical Medicine and Travel. Summary of the Statement on International Travellers and Typhoid. Can Commun Dis Rep 2014:40-4. Accessed January 2017 at: http://publications.gc.ca/collections/collection\_2014/aspc-phac/HP40-98-2014-eng.pdf
* Committee to Advise on Tropical Medicine and Travel. Statement on International Travellers Who Intend to Visit Friends and Relatives. Public Health Agency of Canada, 2015. Accessed: January 2017 at: http://www.phac-aspc.gc.ca/tmp-pmv/catmat-ccmtmv/friends-amis-eng.php
* World Health Organization (WHO). International travel and health. Geneva: WHO, 2012. Accessed January 2017 at: http://www.who.int/ith/en/
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-10-immunization-persons-new-canada.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-07-27
| None | None |
e8d12556d7f6b3a8933ddaeb840268f8e888657c | cma | Recommended immunization schedules: Canadian Immunization Guide | Recommended immunization schedules: Canadian Immunization Guide
For health professionals
Notice
This chapter has not yet been updated with the following statement from the National Advisory Committee on Immunization (NACI):
- February 24, 2023:
This CIG chapter has not been updated to contain any information regarding COVID-19 vaccines, refer to the .
Last partial content update (see ): July 2023
Clarifications were made to Table 5 to better align with information provided in Part 4 chapters.
Last complete chapter revision: December 2013
On this page
General recommendations
Administration of vaccines in accordance with the immunization schedules summarized in the following tables will provide optimal protection from vaccine preventable diseases for most individuals. However, modifications of the recommended schedule may be necessary due to missed appointments or illness. In general, interruption of an immunization series does not require restarting the vaccine series, regardless of the interval between doses. Individuals with interrupted immunization schedules should be vaccinated to complete the appropriate schedule for their current age. Refer to in Part 1 and in Part 4 for additional information.
Similar, but not identical, vaccines may be available from different manufacturers; therefore, it is useful to review the relevant in the Canadian Immunization Guide as well as the manufacturer's product leaflet or product monograph before administering a vaccine. Refer to in Part 1 for information about the interchangeability of similar vaccines from different manufacturers. Product monographs are periodically updated; it is a best practice to consult the information contained within the product monographs available through .
- For children at-risk due to underlying medical conditions, refer to for additional recommendations for immunization.
or
or
or
or 4th dose
2 or 3 doses
1 or 2 doses
1 dose
For abbreviations and brand names of vaccines refer to in Part 1.
(HPV): Girls, 9-14 years of age: HPV bivalent (HPV2) or HPV quadrivalent (HPV4) vaccine or HPV nonavalent (HPV9) vaccine - months 0 and 6-12 (first dose = month 0). Alternatively, a 3 dose schedule may be used for HPV2 vaccine - months 0, 1 and 6 (first dose = month 0), for HPV4 vaccine - months 0, 2 and 6 (first dose = month 0), and HPV nonavalent (HPV9) vaccine - months 0, 2 and 6 (first dose = month 0). Boys, 9-14 years of age: HPV4 or HPV9 vaccine - months 0 and 6-12 (first dose = month 0). Alternatively, a 3 dose schedule may be used for HPV4 vaccine - months 0, 2 and 6 (first dose = month 0), and HPV9 vaccine - months 0, 2 and 6 (first dose = month 0). For a 2 or 3 dose schedule, the minimum interval between first and last doses is 6 months.
Influenza: recommended annually for anyone 6 months of age and older without contraindications. Children 6 months-less than 9 years of age, receiving influenza vaccine for the first time - 2 doses, at least 4 weeks apart. Children 6 months-8 years of age, previously immunized with influenza vaccine and children 9 years of age and older - 1 dose.
- For children at-risk due to underlying medical conditions, refer to for additional recommendations for immunization.
For abbreviations and brand names of vaccines refer to in Part 1.
Diphtheria toxoid- tetanus toxoid- acellular pertussis- inactivated polio- *Haemophilus influenzae- type b (DTaP-IPV-Hib) or diphtheria toxoid- tetanus toxoid- acellular pertussis- inactivated polio (DTaP-IPV): 4 doses of DTaP-IPV-containing vaccine. The number of doses of Hib-containing vaccine required varies by age at first dose. If first visit at 12-14 months of age: 1 dose of Hib-containing vaccine at first visit and booster dose at least 2 months after the previous dose. If first visit at 15 months-less than 60 months of age: 1 dose of Hib-containing vaccine. If first visit at 60 months of age or older, Hib-containing vaccine is not required.
Diphtheria toxoid- tetanus toxoid- acellular pertussis- inactivated polio (DTaP-IPV) or tetanus toxoid- reduced diphtheria toxoid- reduced acellular pertussis- inactivated polio (Tdap-IPV): if the fourth dose of DTaP-IPV vaccine was given before the fourth birthday, a booster dose of DTaP-IPV or Tdap-IPV vaccine should be provided at 4-6 years of age.
Pneumococcal conjugate 13-valent: 12-23 months of age - 2 doses, at least 8 weeks apart. 24-59 months of age - 1 dose.
Meningococcal conjugate monovalent: 12-59 months of age - 1 dose; 5-11 years of age - consider 1 dose.
Measles-mumps-rubella: 2 doses, at least 4 weeks apart; second dose after 18 months of age, but should be given no later than around school entry.
Varicella: 2 doses, at least 3 months apart; second dose after 18 months of age, but should be given no later than around school entry. A minimum interval of 4 weeks between doses may be used if rapid, complete protection is required.
Measles-mumps-rubella-varicella: 2 doses, at least 3 months apart; second dose after 18 months of age, but should be given no later than around school entry. A minimum interval of 4 weeks between doses may be used if rapid, complete protection is required.
Hepatitis B: 3 doses - months 0, 1 and 6 (first dose = month 0) with at least 4 weeks between the first and second dose, 2 months between the second and third dose, and 4 months between the first and third dose.
Influenza: 2 doses, at least 4 weeks apart.
- For children at-risk due to underlying medical conditions, refer to for additional recommendations for immunization.
9-14 years of age
15-17 years of age
For abbreviations and brand names of vaccines refer to in Part 1.
Tetanus toxoid- reduced diphtheria toxoid- reduced acellular pertussis- inactivated polio (Tdap-IPV): 2 doses, 8 weeks apart; third dose 6-12 months after second dose.
Tetanus toxoid- reduced diphtheria toxoid- reduced acellular pertussis: 10 years after last dose of Tdap-IPV.
Meningococcal conjugate monovalent: 7-11 years of age - consider 1 dose.
Meningococcal conjugate monovalent or quadrivalent: 12-17 years of age - 1 dose, even if meningococcal conjugate vaccine received at a younger age. Vaccine chosen depends on local epidemiology and programmatic considerations.
Measles-mumps-rubella: 2 doses, at least 4 weeks apart.
Varicella (chickenpox): 7-12 years of age - 2 doses, at least 3 months apart. 13 years of age and older - 2 doses, at least 6 weeks apart. A minimum interval of 4 weeks between doses may be used if rapid, complete protection is required.
Measles-mumps-rubella-varicella: 7-12 years of age - 2 doses, at least 3 months apart. A minimum interval of 4 weeks between doses may be used if rapid, complete protection is required.
Hepatitis B: 7-17 years of age - 3 doses, months 0, 1 and 6 (first dose = month 0) with at least 4 weeks between the first and second dose, 2 months between the second and third dose, and 4 months between the first and third dose. 11-15 years of age - two doses; schedule depends on the product used.
Human papillomavirus (HPV): Girls, 9-14 years of age - HPV bivalent (HPV2) or HPV quadrivalent (HPV4) vaccine or HPV nonavalent (HPV9) - months 0 and 6-12 (first dose = month 0). Alternatively, a 3 dose schedule may be used for HPV2 vaccine - months 0, 1 and 6 (first dose = month 0), for HPV4 vaccine - months 0, 2 and 6 (first dose = month 0), and for HPV nonavalent (HPV9) vaccine - months 0, 2 and 6 (first dose = month 0). Boys, 9-14 years of age HPV4 vaccine or HPV9 - months 0 and 6-12 (first dose = month 0). Alternatively, a 3 dose schedule may be used for HPV4 or HPV9 vaccine - months 0, 2 and 6 (first dose = month 0). For a 2 or 3 dose schedule, the minimum interval between first and last doses is 6 months.
Human papillomavirus: Girls, 15-17 years of age: HPV2 vaccine - months 0, 1 and 6 (first dose = month 0), HPV4 vaccine - months 0, 2 and 6 (first dose = month 0) or HPV9 vaccine - months 0, 2 and 6 (first dose = month 0). Boys, 15-17 years of age: HPV4 vaccine - months 0, 2 and 6 (first dose = month 0) or HPV9 vaccine - months 0, 2 and 6 (first dose = month 0). In individuals who received the first dose of HPV2 or HPV4 or HPV9 vaccine between 9-14 years of age, a 2 dose schedule can be used with the second dose administered at least 6 months after the first dose.
Influenza: children less than 9 years of age - 2 doses, at least 4 weeks apart. Children 9 years of age and older - 1 dose.
1 or 2 doses
1 dose
For abbreviations and brand names of vaccines refer to in Part 1.
*Haemophilus influenzae- type b (Hib): 5 years of age and older with increased risk of invasive Hib disease - 1 dose regardless of prior history of Hib vaccination and at least 1 year after any previous dose.
Pneumococcal polysaccharide 23-valent: children 2 years of age or older at high risk of invasive pneumococcal disease (IPD) - 1 dose. Children at highest risk of IPD including those with functional or anatomic asplenia or sickle cell disease; hepatic cirrhosis; chronic renal failure; nephrotic syndrome; HIV infection; and immunosuppression related to disease or therapy - 1 booster dose after 5 years. If pneumococcal conjugate 13-valent (Pneu-C-13) vaccine is also required, it should be provided first, followed by Pneu-P-23 vaccine, at least 8 weeks later.
Pneumococcal conjugate 13-valent: infants at high risk of IPD - in addition to the doses at 2, 4, and 12 months of age, give an extra dose at 6 months to make a 4 dose primary series. Children aged 3 years and older at high risk of IPD who have not previously received Pneu-C-13 vaccine - 1 dose
Meningococcal conjugate quadrivalent (Men-C-ACYW): infants and children at high risk of invasive meningococcal disease (IMD): 2-11 months of age - 2 or 3 doses of Men-C-ACYW-CRM vaccine, 8 weeks apart with another dose between 12-23 months of age and at least 8 weeks after the previous dose; 12-23 months of age - 2 doses of Men-C-ACYW-CRM vaccine,8 weeks apart; 24 months of age and older - 2 doses of any Men-C-ACYW vaccine, 8 weeks apart. Give additional booster doses every 3 to 5 years if last vaccinated at 6 years of age and younger and every 5 years if last vaccinated at 7 years of age and older.
Multicomponent meningococcal (4CMenB): infants and children at high risk of IMD should be considered for immunization: 2-11 months of age - 2 or 3 doses of 4CMenB vaccine, 8 weeks apart with another dose between 12-23 months of age and at least 8 weeks after the previous dose; 1-10 years of age- 2 doses of 4CMenB vaccine, 8 weeks apart; 11 years of age and older - 2 doses of 4CMenB vaccine, at least 4 weeks apart. The need for and timing of 4CMenB vaccine booster doses have not yet been determined.
Hepatitis A: 6 months of age and older in high-risk groups: 2 doses, given 6-36 months apart (depending on product used).
Hepatitis B: 3 or 4 doses of higher dose of monovalent hepatitis B vaccine recommended for those with certain immunocompromising conditions, chronic renal failure and dialysis. Premature infants weighing less than 2,000 grams at birth born to HB infected mothers: 4 doses.
Influenza: recommended annually for all individuals 6 months of age and older without contraindications, with focus on children at risk of influenza-related complications. Children 6 months-less than 9 years of age receiving influenza vaccine for the first time: 2 doses, at least 4 weeks apart. Children 6 months-8 years of age, previously immunized with influenza vaccine and children 9 years of age and older: 1 dose.
- For adults considered at-risk, refer to for additional recommendations for immunization.
Tdap
Td
For abbreviations and brand names of vaccines refer to in Part 1.
Three doses of either tetanus toxoid- reduced diphtheria (Td, if not previously immunized with tetanus or diphtheria), or polio-containing vaccine if at increased risk of polio (Tdap-IPV, if not previously immunized with tetanus, diphtheria and polio, or IPV, if not previously immunized with polio) provided with an interval of 8 weeks between the first two doses followed by a third dose administered 6 to 12 months after the second dose. One dose of reduced acellular pertussis-containing vaccine should be provided to those who never previously received a pertussis-containing vaccine in adulthood.
Adults who are unimmunized against polio but are not at increased risk and have had a primary series of tetanus and diphtheria containing vaccine, should receive IPV-containing vaccine as a part of their next tetanus and diphtheria booster.
Tetanus toxoid- reduced diphtheria toxoid (Td): 10 years after last dose of Td-containing vaccine.
Measles-mumps-rubella (MMR): adults born in or after 1970 - 1 dose, except - travellers, health care workers, students in post-secondary educational settings, and military personnel - 2 doses, at least 4 weeks apart. Adults born before 1970 can be presumed to have acquired natural immunity to measles and mumps and do not need MMR vaccination except - non-immune military personnel or health care workers (2 doses, at least 4 weeks apart), non-immune travellers (1 dose), non-immune students in post-secondary educational settings (consider 1 dose). Rubella-susceptible adults, regardless of age - 1 dose.
Varicella (chickenpox): adults 18-49 years of age - 2 doses, at least 6 weeks apart; adults 50 years of age and older are generally presumed to be immune.
Recombinant Zoster Vaccine (RZV): adults 50 years of age and older - 2 doses, 2 to 6 months apart; may be considered for immunocompromised adults 50 years of age and older based on a case-by-case assessment of benefits vs risks.
Pneumococcal polysaccharide 23-valent: adults 65 years of age and older - 1 dose; immunocompetent residents of long-term care facilities 18-64 years of age - 1 dose.
Meningococcal conjugate monovalent or quadrivalent: adults less than 25 years of age - 1 dose (vaccine chosen depends on local epidemiology).
Human papillomavirus (HPV): recommended for women up to and including 26 years of age, may be given to women 27 years of age and older at ongoing risk of exposure: HPV bivalent (HPV2) vaccine - months 0, 1 and 6 (first dose = month 0), HPV quadrivalent (HPV4) vaccine - months 0, 2 and 6 (first dose = month 0) or nonavalent (HPV9) vaccine- months 0, 2 and 6 (first dose = month 0). Recommended for men up to and including 26 years of age, may be given to men 27 years of age and older at ongoing risk of exposure: HPV4 or HPV9 vaccine - months 0, 2 and 6 (first dose = month 0).
Influenza: 1 dose recommended for adults without contraindications, with focus on: adults at high risk of influenza-related complications (including pregnant women, adults 65 years of age and older); adults capable of transmitting influenza to individuals at high risk; adults who provide essential community services; and people in direct contact during culling operations with poultry infected with avian influenza.
- For adults considered at-risk, refer to for additional recommendations for immunization.
For abbreviations and brand names of vaccines refer to in Part 1.
Tetanus toxoid- reduced diphtheria toxoid: 1 booster dose every 10 years.
Tetanus toxoid- reduced diphtheria toxoid- reduced acellular pertussis (Tdap): 1 dose in adulthood for pertussis protection regardless of interval since last dose of tetanus toxoid- and diphtheria toxoid-containing vaccine; 1 dose in every pregnancy, ideally between 27 and 32 weeks of gestation, for pertussis protection of infants. Refer to in Part 4 for additional information.
Pneumococcal polysaccharide 23-valent: adults 65 years of age and older - 1 dose.
Recombinant Zoster Vaccine (RZV): adults 50 years of age and older - 2 doses, 2 to 6 months apart and at least one year after LZV.
Influenza: recommended for all adults without contraindications, with focus on: adults at high risk of influenza-related complications (including pregnant women, adults 65 years of age and older); adults capable of transmitting influenza to individuals at high risk; adults who provide essential community services; and people in direct contact during culling operations with poultry infected with avian influenza. One dose annually.
List is not exhaustive of travel vaccines. For abbreviations and brand names of vaccines refer to in Part 1.
*Haemophilus influenzae- type b (Hib): adults with increased risk of invasive Hib disease - 1 dose regardless of prior history of Hib vaccination and at least 1 year after any previous dose.
Inactivated polio: 1 booster dose for adults at increased risk of exposure to polio.
Measles-mumps-rubella (MMR): adults born in or after 1970 - 1 dose, except - travellers, health care workers, students in post-secondary educational settings, and military personnel - 2 doses, at least 4 weeks apart. Adults born before 1970 can be assumed to have acquired natural immunity to measles and mumps and do not need MMR vaccination except - non-immune military personnel or health care workers (2 doses, at least 4 weeks apart), non-immune travellers (1 dose), non-immune students in post-secondary educational settings (consider 1 dose). Rubella-susceptible adults, regardless of age - 1 dose.
Pneumococcal conjugate 13-valent (Pneu-C-13): adults with HIV or immunocompromising conditions (except hematopoietic stem cell transplant recipients ) - 1 dose of Pneu-C-13 vaccine followed 8 weeks later by 1 dose of pneumococcal polysaccharide 23-valent (Pneu-P-23) vaccine. Administer Pneu-C-13 vaccine dose at least 1 year after any previous dose of Pneu-P-23 vaccine.
Pneumococcal polysaccharide 23-valent: adults at high risk of invasive pneumococcal disease (IPD), including adults with alcoholism, smokers, and persons who are homeless - 1 dose. One dose should be considered for adults who use illicit drugs. Adults at highest risk of IPD, including those with functional or anatomic asplenia or sickle cell disease; hepatic cirrhosis; chronic renal failure; nephrotic syndrome; HIV infection; and immunosuppression related to disease or therapy - 1 booster dose at least 5 years from first vaccination with Pneu-P-23 vaccine.
Meningococcal conjugate quadrivalent: in previously unimmunized adults at high risk of invasive meningococcal disease (IMD) - 2 doses, 8 weeks apart. In previously immunized adults -booster dose every 3 to 5 years if last vaccinated at 6 years of age and younger and every 5 years for those last vaccinated at 7 years of age and older.
Multicomponent meningococcal (4CMenB): adults at high risk of IMD should be considered for immunization - 2 doses of 4CMenB vaccine, at least 4 weeks apart.
Hepatitis A: adults in high risk groups - 2 doses, 6-36 months apart (depending on product used).
Hepatitis B (HB): adults in high risk groups - 3 or 4 dose schedule (depending on product used). Higher dose of monovalent HB vaccine recommended for those with certain immunocompromising conditions, chronic renal failure and dialysis.
Hepatitis A-hepatitis B: adults without chronic renal failure and immunocompromising conditions: combined vaccine preferred if both hepatitis A and standard dosage hepatitis B vaccines are recommended - 3 or 4 dose schedule.
Influenza: recommended for all adults, with focus on adults at high risk of influenza-related complications - 1 dose annually.
Typhoid: adults with ongoing or intimate exposure to a chronic carrier of *Salmonella typhi* - 1 dose injectable typhoid vaccine or 4 doses oral typhoid vaccine; re-immunization recommended if at continuing risk.
Rabies: adults at high risk of close contact with rabid animals - 3 doses for pre-exposure immunization. Periodic serologic testing and booster doses (if required) for those at continuing high risk.
Varicella: adults 18 to less than 50 years of age without history of VZV infection (self-reported or diagnosed by a health care provider), documented evidence of immunization with 2 doses of a varicella-containing vaccine or laboratory evidence of immunity - 2 doses. Self-reported history or health care provider diagnosis is not considered a reliable correlate of immunity for pregnant women with significant exposure to varicella zoster virus, immunocompromised individuals and health care workers who are newly hired into the Canadian health care system. |
Recommended immunization schedules: Canadian Immunization Guide
================================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-12-immunization-records.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-14-basic-immunology-vaccinology.html)
Notice
------
This chapter has not yet been updated with the following statement from the National Advisory Committee on Immunization (NACI):
* February 24, 2023: [Public health level recommendations on the use of pneumococcal vaccines in adults, including the use of 15-valent and 20-valent conjugate vaccines.](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/public-health-level-recommendations-use-pneumococcal-vaccines-adults-including-use-15-valent-20-valent-conjugate-vaccines.html)
This CIG chapter has not been updated to contain any information regarding COVID-19 vaccines, refer to the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html).
**Last partial content update** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): July 2023
Clarifications were made to Table 5 to better align with information provided in Part 4 chapters.
**Last complete chapter revision**: December 2013
On this page
------------
* [General recommendations](#p1c12a1)
* [Table 1: Routine childhood immunization schedule, infants and children (birth to 17 years of age)](#p1c12a2)
* [Table 2: Recommended immunization schedule, children (less than 7 years of age), NOT Previously Immunized as Infants](#p1c12a3)
* [Table 3: Recommended immunization schedule, children (7 to 17 years of age), NOT Previously Immunized](#p1c12a4)
* [Table 4: Additional recommended immunizations, children (birth to 17 years of age), Considered AT RISK due to Underlying Medical Conditions](#p1c12a5)
* [Table 5: Recommended immunization schedule, adults (18 years of age and older), NOT Previously Immunized](#p1c12a6)
* [Table 6: Recommended immunizations, adults (18 years of age and older), Previously Immunized](#p1c12a7)
* [Table 7: Additional recommended immunizations, adults (18 years of age and older), Considered **at risk**](#p1c12a8)
General recommendations
-----------------------
Administration of vaccines in accordance with the immunization schedules summarized in the following tables will provide optimal protection from vaccine preventable diseases for most individuals. However, modifications of the recommended schedule may be necessary due to missed appointments or illness. In general, interruption of an immunization series does not require restarting the vaccine series, regardless of the interval between doses. Individuals with interrupted immunization schedules should be vaccinated to complete the appropriate schedule for their current age. Refer to [Timing of vaccine administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) in Part 1 and [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
Similar, but not identical, vaccines may be available from different manufacturers; therefore, it is useful to review the relevant [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in the Canadian Immunization Guide as well as the manufacturer's product leaflet or product monograph before administering a vaccine. Refer to [Principles of vaccine interchangeability](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-7-principles-vaccine-interchangeability.html) in Part 1 for information about the interchangeability of similar vaccines from different manufacturers. Product monographs are periodically updated; it is a best practice to consult the information contained within the product monographs available through [Health Canada's Drug Product Database](http://www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php).
Table 1: Routine childhood immunization schedule, infants and children (birth to 17 years of age)
-------------------------------------------------------------------------------------------------
* **For children at-risk due to underlying medical conditions**, refer to [Table 4](#p1c12t4) for additional recommendations for immunization.
* [ ] = dose(s) may not be required depending upon age of child or vaccine used or both (refer to the relevant [vaccine-specific chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 and [provincial/territorial schedule](http://www.healthycanadians.gc.ca/healthy-living-vie-saine/immunization-immunisation/children-enfants/schedule-calendrier-eng.php)). mos = months. yrs = years. P/T = provincial and territorial.
* Refer to [Timing of vaccine administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) and [Vaccine administration practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 regarding administration of multiple injections.
* Refer to [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
Table 1: Routine childhood immunization schedule, infants and children (birth to 17 years of age)
| Vaccine[Footnote \*](#p1c12t1fn*) | Age |
| --- | --- |
| Birth | 2 mos | 4 mos | 6 mos | 12 mos | 15 mos | 18 mos | 23 mos | 2 years | 4 years | 5 years | 6 years | 9 years | 12 years | 14 years | 15 years | 16 years | 17 years |
| **DTaP-IPV-Hib**
or**DTaP-HB-IPV-Hib** | - | [Table 1 - Footnote A](#p1c12t1fta)
or [Table 1 - Footnote B](#p1c12t1ftb)
1st dose | [Table 1 - Footnote A](#p1c12t1fta)
or [Table 1 - Footnote B](#p1c12t1ftb)
2nd dose | [Table 1 - Footnote A](#p1c12t1fta)
or [Table 1 - Footnote B](#p1c12t1ftb)
3rd dose | [Table 1 - Footnote A](#p1c12t1fta)
or 4th dose
Generally at 18 months of age | - | - | - | - | - | - | - | - | - | - |
| **DTaP-IPV**
or**Tdap-IPV** | - | - | - | - | - | - | - | - | - | [Table 1 - Footnote C](#p1c12t1ftc) | - | - | - | - | - | - |
| **Tdap** | - | - | - | - | - | - | - | - | - | - | - | - | - | - | [Table 1 - Footnote D](#p1c12t1ftd) | - |
| **Rot** | - | [Table 1 - Footnote E](#p1c12t1fte)
2 or 3 doses
Complete series before 8 months | - | - | - | - | - | - | - | - | - | - | - | - | - | - |
| **Pneu-C-13** | - | [Table 1 - Footnote F](#p1c12t1ftf) | [Table 1 - Footnote F](#p1c12t1ftf) | - | - | - | - | - | - | - | - | - | - | - | - |
| **Men-C-C** | - | [Table 1 - Footnote [G]](#p1c12t1ftg)
According to P/T schedule | [Table 1 - Footnote G](#p1c12t1ftg)
Generally at 12 months | - | - | - | - | - | - | - | - |
| **Men-C-C**
or**Men-C-ACYW** | - | - | - | - | - | - | - | - | - | - | - | - | - | [Table 1 - Footnote H](#p1c12t1fth) | - | - | - | - |
| **MMR** and **Var** | - | - | - | - | [Table 1 - Footnote I](#p1c12t1fti) + [Table 1 - Footnote J](#p1c12t1ftj) | [Table 1 - Footnote I](#p1c12t1fti) + [Table 1 - Footnote J](#p1c12t1ftj) | - | - | - | - | - | - |
| **OR** |
| **MMRV** | - | - | - | - | [Table 1 - Footnote K](#p1c12t1ftk) | [Table 1 - Footnote K](#p1c12t1ftk)
Generally at 4-6 years | - | - | - | - | - | - |
| **HB** | [Table 1 - Footnote L](#p1c12t1ftl)
3 doses | - | - | - | - | - | - | - | - | - | - | - | - | - |
| **OR** |
| **HB** | - | - | - | - | - | - | - | - | - | - | - | - | [Table 1 - Footnote M](#p1c12t1ftm)
2 or 3 doses |
| **HPV** | - | - | - | - | - | - | - | - | - | - | - | - | [Table 1 - Footnote N](#p1c12t1ftn)
2 or 3 doses | - | - | - |
| **OR** |
| **HPV** | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | [Table 1 - Footnote O](#p1c12t1fto)
3 doses |
| **Inf** | - | - | - | [Table 1 - Footnote P](#p1c12t1ftp)
1 or 2 doses
Recommended annually | [Table 1 - Footnote P](#p1c12t1ftp)
1 dose
Recommended annually |
|
Table 1 - Footnote \*
For abbreviations and brand names of vaccines refer to [Contents of immunizing agents authorized for use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1.
[Return to Table 1 first footnote \* referrer](#p1c12t1fn*-rf)
Table 1 - Footnote A
[**Diphtheria toxoid- tetanus toxoid- acellular pertussis- inactivated polio- *Haemophilus influenzae* type b**](#p4c21a6a1) (DTaP-IPV-Hib). For infants and children beginning primary immunization at 7 months of age and older, the number of doses of Hib vaccine required varies by age.
[Return to first Table 1 footnote A referrer](#p1c12t1fta-rf)
Table 1 - Footnote B
[**Diphtheria toxoid- tetanus toxoid- acellular pertussis- hepatitis B- inactivated polio- *Haemophilus influenzae* type b**](#p4c21a6a1) (DTaP-HB-IPV-Hib). Alternative schedules may be used : DTaP-HB-IPV-Hib at 2, 4 and 12-23 months of age with DTaP-IPV-Hib vaccine at 6 months of age; or DTaP-HB-IPV -Hib at 2, 4 and 6 months of age with DTaP-IPV-Hib vaccine at 12-23 months of age.
[Return to first Table 1 footnote B referrer](#p1c12t1ftb-rf)
Table 1 - Footnote C
[**Diphtheria toxoid- tetanus toxoid- acellular pertussis- inactivated polio**](#p4c21a6b) or [**tetanus toxoid- reduced diphtheria toxoid- reduced acellular pertussis- inactivated polio**](#p4c21a6b).
[Return to Table 1 footnote C referrer](#p1c12t1ftc-rf)
Table 1 - Footnote D
[**Tetanus toxoid- reduced diphtheria toxoid- reduced acellular pertussis**](#p4c21a6b) (Tdap): 10 years after last dose of DTaP- or Tdap-containing vaccine.
[Return to Table 1 footnote D referrer](#p1c12t1ftd-rf)
Table 1 - Footnote E
[**Rotavirus**](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-19-rotavirus-vaccine.html): Rotavirus pentavalent vaccine - 3 doses, 4 to 10 weeks apart; Rotavirus monovalent vaccine - 2 doses, at least 4 weeks apart. Give the first dose starting at 6 weeks and before 15 weeks of age. Administer all doses before 8 months of age.
[Return to Table 1 footnote E referrer](#p1c12t1fte-rf)
Table 1 - Footnote F
[**Pneumococcal conjugate 13-valent**](#schedule) (Pneu-C-13): healthy infants beginning primary immunization at 2-6 months of age: 3 or 4 dose schedule. For a 3 dose schedule : 2, 4 months of age, followed by a booster dose at 12 months of age. For a 4 dose schedule: minimum of 8 weeks interval between doses beginning at 2 months of age, followed by a booster dose at 12-15 months of age. Healthy infants beginning primary immunization at 7-11 months of age : 2 doses, at least 8 weeks apart followed by a booster dose at 12-15 months of age, at least 8 weeks after the second dose. Children who have received age-appropriate pneumococcal vaccination with a pneumococcal conjugate vaccine but not Pneu-C-13 vaccine: 12-35 months of age - 1 dose; 36-59 months of age and of aboriginal origin or attend group child care - 1 dose; other healthy children 36-59 months of age - consider 1 dose.
[Return to first Table 1 footnote F referrer](#p1c12t1ftf-rf)
Table 1 - Footnote G
[**Meningococcal conjugate monovalent**](#p4c12a6a1): children 12-48 months of age: 1 dose routinely provided at 12 months of age, regardless of any doses given during the first year of life. Immunization may be considered for unimmunized children 5-11 years of age.
[Return to first Table 1 footnote G referrer](#p1c12t1ftg-rf)
Table 1 - Footnote H
[**Meningococcal conjugate monovalent**](#p4c12a6a1) or [**meningococcal conjugate quadrivalent**](#p4c12a6a1): early adolescence (around 12 years of age) - 1 dose, even if meningococcal conjugate vaccine received at a younger age. Vaccine chosen depends on local epidemiology and programmatic considerations.
[Return to Table 1 footnote H referrer](#p1c12t1fth-rf)
Table 1 - Footnote I
[**Measles-mumps-rubella**](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html): first dose at 12-15 months of age; second dose at 18 months of age or anytime thereafter, but should be given no later than around school entry.
[Return to first Table 1 footnote I referrer](#p1c12t1fti-rf)
Table 1 - Footnote J
[**Varicella (chickenpox)**](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-24-varicella-chickenpox-vaccine.html): first dose at 12-15 months of age; second dose at 18 months of age or anytime thereafter, but should be given no later than around school entry.
[Return to first Table 1 footnote J referrer](#p1c12t1ftj-rf)
Table 1 - Footnote K
[**Measles-mumps-rubella-varicella**](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html): first dose at 12-15 months of age; second dose at 18 months of age or anytime thereafter, but should be given no later than around school entry.
[Return to first Table 1 footnote K referrer](#p1c12t1ftk-rf)
Table 1 - Footnote L
[**Hepatitis B**](#p4c6a6a1) : months 0, 1 and 6 (first dose = month 0) with at least 4 weeks between the first and second dose, at least 2 months between the second and third dose, and at least 4 months between the first and third dose. Alternatively, can be administered as DTaP-HB-IPV-Hib vaccine, with first dose at 2 months of age.
[Return to Table 1 footnote L referrer](#p1c12t1ftl-rf)
Table 1 - Footnote M
[**Hepatitis B**](#p4c6a6a1): 9-17 years of age - months 0, 1 and 6 (first dose = month 0) with at least 4 weeks between the first and second dose, at least 2 months between the second and third dose, and at least 4 months between the first and third dose. 11-15 years of age - 2 doses; schedule depends on the product used.
[Return to Table 1 footnote M referrer](#p1c12t1ftm-rf)
Table 1 - Footnote N
**[Human papillomavirus](#p4c8a6a4)** (HPV): Girls, 9-14 years of age: HPV bivalent (HPV2) or HPV quadrivalent (HPV4) vaccine or HPV nonavalent (HPV9) vaccine - months 0 and 6-12 (first dose = month 0). Alternatively, a 3 dose schedule may be used for HPV2 vaccine - months 0, 1 and 6 (first dose = month 0), for HPV4 vaccine - months 0, 2 and 6 (first dose = month 0), and HPV nonavalent (HPV9) vaccine - months 0, 2 and 6 (first dose = month 0). Boys, 9-14 years of age: HPV4 or HPV9 vaccine - months 0 and 6-12 (first dose = month 0). Alternatively, a 3 dose schedule may be used for HPV4 vaccine - months 0, 2 and 6 (first dose = month 0), and HPV9 vaccine - months 0, 2 and 6 (first dose = month 0). For a 2 or 3 dose schedule, the minimum interval between first and last doses is 6 months.
[Return to Table 1 footnote N referrer](#p1c12t1ftn-rf)
Table 1 - Footnote O
[**Human papillomavirus**](#p4c8a6a4): Girls, 15-17 years of age: HPV2 vaccine - months 0, 1 and 6 (first dose = month 0), HPV4 vaccine - months 0, 2 and 6 (first dose = month 0) or HPV9 vaccine - months 0, 2 and 6 (first dose = month 0). Boys, 15-17 years of age: HPV4 vaccine - months 0, 2 and 6 (first dose = month 0) or HPV9 vaccine - months 0, 2 and 6 (first dose = month 0). In individuals who received the first dose of HPV2 or HPV4 or HPV9 vaccine between 9-14 years of age, a 2 dose schedule can be used with the second dose administered at least 6 months after the first dose.
[Return to Table 1 footnote O referrer](#p1c12t1fto-rf)
Table 1 - Footnote P
**Influenza**: recommended annually for anyone 6 months of age and older without contraindications. Children 6 months-less than 9 years of age, receiving influenza vaccine for the first time - 2 doses, at least 4 weeks apart. Children 6 months-8 years of age, previously immunized with influenza vaccine and children 9 years of age and older - 1 dose.
[Return to first Table 1 footnote P referrer](#p1c12t1ftp-rf)
|
Table 2: Recommended Immunization Schedule, Children (less than 7 years of age), NOT Previously Immunized as Infants
--------------------------------------------------------------------------------------------------------------------
* **For children at-risk due to underlying medical conditions**, refer to [Table 4](#p1c12t4) for additional recommendations for immunization.
* [ ] = dose(s) may not be required depending upon age of child or vaccine used or both (refer to the relevant [vaccine-specific chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 and [provincial/territorial schedule](http://www.healthycanadians.gc.ca/healthy-living-vie-saine/immunization-immunisation/children-enfants/schedule-calendrier-eng.php)). mos = months.
* Refer to [Timing of vaccine administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) and [Vaccine administration practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 regarding administration of multiple injections.
* Refer to [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
Table 2: Recommended immunization schedule, children (less than 7 years of age), not previously immunized as Infants
| Vaccine[Footnote \*](#p1c12t2fn*) | First visit | Time after first visit | 6-12 mos
after last dose |
| --- | --- | --- | --- |
| 4 weeks | 8 weeks | 3 mos | 4 mos | 6 mos |
| **DTaP-IPV-Hib**
or**DTaP-IPV** | [Footnote A](#p1c12t2fna) | - | [Footnote A](#p1c12t2fna) | - | [Footnote A](#p1c12t2fna) | - | [Footnote A](#p1c12t2fna) [Footnote [B]](#p1c12t2fnb) |
| **Pneu-C-13** | [Footnote [C]](#p1c12t2fnc) | - | [Footnote [C]](#p1c12t2fnc) | - | - | - | - |
| **Men-C-C** | [Footnote D](#p1c12t2fnd) | - | - | - | - | - | - |
| **MMR** | [Footnote E](#p1c12t2fne) | [Footnote E](#p1c12t2fne) | - | - | - | - | - |
| **Var** | [Footnote F](#p1c12t2fnf) | - | - | [Footnote F](#p1c12t2fnf) | - | - | - |
| **OR** |
| **MMRV** | [Footnote G](#p1c12t2fng) | - | - | [Footnote G](#p1c12t2fng) | - | - | - |
| **HB** | [Footnote [H]](#p1c12t2fnh) | [Footnote [H]](#p1c12t2fnh) | - | - | - | [Footnote [H]](#p1c12t2fnh) | - |
| **Inf** | [Footnote I](#p1c12t2fni) | [Footnote I](#p1c12t2fni) | - | - | - | - | - |
|
Table 2 - Footnote \*
For abbreviations and brand names of vaccines refer to [Contents of Immunizing agents authorized for use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1.
[Return to Table 2 footnote \* referrer](#p1c12t2fn*-rf)
Table 2 - Footnote A
**Diphtheria toxoid- tetanus toxoid- acellular pertussis- inactivated polio- *Haemophilus influenzae* type b** (DTaP-IPV-Hib) or **diphtheria toxoid- tetanus toxoid- acellular pertussis- inactivated polio** (DTaP-IPV): 4 doses of DTaP-IPV-containing vaccine. The number of doses of Hib-containing vaccine required varies by age at first dose. If first visit at 12-14 months of age: 1 dose of Hib-containing vaccine at first visit and booster dose at least 2 months after the previous dose. If first visit at 15 months-less than 60 months of age: 1 dose of Hib-containing vaccine. If first visit at 60 months of age or older, Hib-containing vaccine is not required.
[Return to first Table 2 footnote A referrer](#p1c12t2fna-rf)
Table 2 - Footnote B
**Diphtheria toxoid- tetanus toxoid- acellular pertussis- inactivated polio** (DTaP-IPV) or **tetanus toxoid- reduced diphtheria toxoid- reduced acellular pertussis- inactivated polio** (Tdap-IPV): if the fourth dose of DTaP-IPV vaccine was given before the fourth birthday, a booster dose of DTaP-IPV or Tdap-IPV vaccine should be provided at 4-6 years of age.
[Return to Table 2 footnote B referrer](#p1c12t2fnb-rf)
Table 2 - Footnote C
**Pneumococcal conjugate 13-valent**: 12-23 months of age - 2 doses, at least 8 weeks apart. 24-59 months of age - 1 dose.
[Return to first Table 2 footnote C referrer](#p1c12t2fnc-rf)
Table 2 - Footnote D
**Meningococcal conjugate monovalent**: 12-59 months of age - 1 dose; 5-11 years of age - consider 1 dose.
[Return to Table 2 footnote D referrer](#p1c12t2fnd-rf)
Table 2 - Footnote E
**Measles-mumps-rubella**: 2 doses, at least 4 weeks apart; second dose after 18 months of age, but should be given no later than around school entry.
[Return to first Table 2 footnote E referrer](#p1c12t2fne-rf)
Table 2 - Footnote F
**Varicella**: 2 doses, at least 3 months apart; second dose after 18 months of age, but should be given no later than around school entry. A minimum interval of 4 weeks between doses may be used if rapid, complete protection is required.
[Return to first Table 2 footnote F referrer](#p1c12t2fnf-rf)
Table 2 - Footnote G
**Measles-mumps-rubella-varicella**: 2 doses, at least 3 months apart; second dose after 18 months of age, but should be given no later than around school entry. A minimum interval of 4 weeks between doses may be used if rapid, complete protection is required.
[Return to first Table 2 footnote G referrer](#p1c12t2fng-rf)
Table 2 - Footnote H
**Hepatitis B**: 3 doses - months 0, 1 and 6 (first dose = month 0) with at least 4 weeks between the first and second dose, 2 months between the second and third dose, and 4 months between the first and third dose.
[Return to first Table 2 footnote H referrer](#p1c12t2fnh-rf)
Table 2 - Footnote I
**Influenza**: 2 doses, at least 4 weeks apart.
[Return to first Table 2 footnote I referrer](#p1c12t2fni-rf)
|
Table 3: Recommended immunization schedule, children (7 to 17 years of age), not previously immunized
-----------------------------------------------------------------------------------------------------
* **For children at-risk due to underlying medical conditions,** refer to [Table 4](#p1c12t4) for additional recommendations for immunization.
* [ ] = dose(s) may not be required depending upon age of child or vaccine used or both (refer to the relevant [vaccine-specific chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 and [provincial/territorial schedule](http://www.healthycanadians.gc.ca/healthy-living-vie-saine/immunization-immunisation/children-enfants/schedule-calendrier-eng.php)). mos = months. yrs = years.
* Refer to [Timing of vaccine administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) and [Vaccine administration practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 regarding administration of multiple injections.
* Refer to the [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
Table 3: Recommended immunization schedule, children (7 to 17 years of age), not previously immunized
| Vaccine[Table 3 Footnote \*](#p1c12t3fn*) | First visit | Time after first visit | 6-12 mos after last dose | 10 yrs after last dose |
| --- | --- | --- | --- | --- |
| 4 weeks | 8 weeks | 3 mos | 6 mos |
| **Tdap-IPV
Tdap** | [Table 3 Footnote A](#p1c12t3fna) | - | [Table 3 Footnote A](#p1c12t3fna) | | - | [Table 3 Footnote A](#p1c12t3fna) | [Table 3 Footnote B](#p1c12t3fnb) |
| **Men-C-C** | [Table 3 Footnote [C]](#p1c12t3fnc)
7-11 years of age | - | - | - | - | - | - |
| OR |
| **Men-C-C**
or**Men-C-ACYW** | [Table 3 Footnote D](#p1c12t3fnd)
12-17 years of age | - | - | - | - | - | - |
| **MMR** | [Table 3 Footnote E](#p1c12t3fne) | [Table 3 Footnote E](#p1c12t3fne) | - | - | - | - | - |
| **Var** | [Table 3 Footnote F](#p1c12t3fnf) | - | - | [Table 3 Footnote F](#p1c12t3fnf) | - | - | - |
| OR |
| **MMRV** | [Table 3 Footnote G](#p1c12t3fng)
7-12 years of age | - | - | [Table 3 Footnote G](#p1c12t3fng) | - | - | - |
| **HB** | [Table 3 Footnote H](#p1c12t3fnh) | [Table 3 Footnote [H]](#p1c12t3fnh) | - | - | [Table 3 Footnote H](#p1c12t3fnh) | - | - |
| **HPV** | [Table 3 Footnote I](#p1c12t3fni)
9-14 years of age | - | - | - | [Table 3 Footnote I](#p1c12t3fni) | - | - |
| OR |
| **HPV** | [Table 3 Footnote I](#p1c12t3fni)
9-14 years of age
3 doses | - | - |
| OR |
| **HPV** | [Table 3 Footnote J](#p1c12t3fnj)
15-17 years of age
3 doses | - | - |
| **Inf** | [Table 3 Footnote K](#p1c12t3fnk)
7-8 years of age | [Table 3 Footnote K](#p1c12t3fnk) | - | - | - | - | - |
| OR |
| **Inf** | [Table 3 Footnote K](#p1c12t3fnk)
9-17 years of age | - | - | - | - | - | - |
|
Table 3 - Footnote \*
For abbreviations and brand names of vaccines refer to [Contents of immunizing agents authorized for use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1.
[Return to Table 3 footnote \* referrer](#p1c12t3fn*-rf)
Table 3 - Footnote A
**Tetanus toxoid- reduced diphtheria toxoid- reduced acellular pertussis- inactivated polio** (Tdap-IPV): 2 doses, 8 weeks apart; third dose 6-12 months after second dose.
[Return to first Table 3 footnote A referrer](#p1c12t3fna-rf)
Table 3 - Footnote B
**Tetanus toxoid- reduced diphtheria toxoid- reduced acellular pertussis**: 10 years after last dose of Tdap-IPV.
[Return to Table 3 footnote B referrer](#p1c12t3fnb-rf)
Table 3 - Footnote C
**Meningococcal conjugate monovalent**: 7-11 years of age - consider 1 dose.
[Return to Table 3 footnote C referrer](#p1c12t3fnc-rf)
Table 3 - Footnote D
**Meningococcal conjugate monovalent or quadrivalent**: 12-17 years of age - 1 dose, even if meningococcal conjugate vaccine received at a younger age. Vaccine chosen depends on local epidemiology and programmatic considerations.
[Return to Table 3 footnote D referrer](#p1c12t3fnd-rf)
Table 3 - Footnote E
**Measles-mumps-rubella**: 2 doses, at least 4 weeks apart.
[Return to first Table 3 footnote E referrer](#p1c12t3fne-rf)
Table 3 - Footnote F
**Varicella (chickenpox)**: 7-12 years of age - 2 doses, at least 3 months apart. 13 years of age and older - 2 doses, at least 6 weeks apart. A minimum interval of 4 weeks between doses may be used if rapid, complete protection is required.
[Return to first Table 3 footnote F referrer](#p1c12t3fnf-rf)
Table 3 - Footnote G
**Measles-mumps-rubella-varicella**: 7-12 years of age - 2 doses, at least 3 months apart. A minimum interval of 4 weeks between doses may be used if rapid, complete protection is required.
[Return to first Table 3 footnote G referrer](#p1c12t3fng-rf)
Table 3 - Footnote H
**Hepatitis B**: 7-17 years of age - 3 doses, months 0, 1 and 6 (first dose = month 0) with at least 4 weeks between the first and second dose, 2 months between the second and third dose, and 4 months between the first and third dose. 11-15 years of age - two doses; schedule depends on the product used.
[Return to first Table 3 footnote H referrer](#p1c12t3fnh-rf)
Table 3 - Footnote I
**Human papillomavirus** (HPV): Girls, 9-14 years of age - HPV bivalent (HPV2) or HPV quadrivalent (HPV4) vaccine or HPV nonavalent (HPV9) - months 0 and 6-12 (first dose = month 0). Alternatively, a 3 dose schedule may be used for HPV2 vaccine - months 0, 1 and 6 (first dose = month 0), for HPV4 vaccine - months 0, 2 and 6 (first dose = month 0), and for HPV nonavalent (HPV9) vaccine - months 0, 2 and 6 (first dose = month 0). Boys, 9-14 years of age HPV4 vaccine or HPV9 - months 0 and 6-12 (first dose = month 0). Alternatively, a 3 dose schedule may be used for HPV4 or HPV9 vaccine - months 0, 2 and 6 (first dose = month 0). For a 2 or 3 dose schedule, the minimum interval between first and last doses is 6 months.
[Return to first Table 3 footnote I referrer](#p1c12t3fni-rf)
Table 3 - Footnote J
**Human papillomavirus**: Girls, 15-17 years of age: HPV2 vaccine - months 0, 1 and 6 (first dose = month 0), HPV4 vaccine - months 0, 2 and 6 (first dose = month 0) or HPV9 vaccine - months 0, 2 and 6 (first dose = month 0). Boys, 15-17 years of age: HPV4 vaccine - months 0, 2 and 6 (first dose = month 0) or HPV9 vaccine - months 0, 2 and 6 (first dose = month 0). In individuals who received the first dose of HPV2 or HPV4 or HPV9 vaccine between 9-14 years of age, a 2 dose schedule can be used with the second dose administered at least 6 months after the first dose.
[Return to first Table 3 footnote J referrer](#p1c12t3fnj-rf)
Table 3 - Footnote K
**Influenza**: children less than 9 years of age - 2 doses, at least 4 weeks apart. Children 9 years of age and older - 1 dose.
[Return to Table 3 footnote K referrer](#p1c12t3fnk-rf)
|
Table 4: Additional recommended immunizations, children (birth to 17 years of age), considered at risk due to underlying medical conditions
-------------------------------------------------------------------------------------------------------------------------------------------
* [ ] = dose(s) may not be required depending upon age of child or vaccine used or both (refer to [vaccine-specific chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 and [provincial/territorial schedule](http://www.healthycanadians.gc.ca/healthy-living-vie-saine/immunization-immunisation/children-enfants/schedule-calendrier-eng.php)). mos = months. yrs = years.
* Refer to [Immunization of travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) and [Immunization of workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html) in Part 3 for additional information about vaccines recommended for travellers and workers.
* Refer to [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) and [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional condition-specific recommendations.
* Refer to [Timing of vaccine administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) and [Vaccine administration practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 regarding administration of multiple injections.
* Refer to the [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information
Table 4: Additional recommended immunizations, children (birth to 17 years of age), considered at risk due to underlying medical condition
| Vaccine[Footnote \*](#p1c12t4fn*) | Age |
| --- | --- |
| Birth | 2 mos | 6 mos | 12 mos | 15 mos | 18 mos | 23 mos | 2 years | 3 years | 5-8 yrs | 9-17 yrs |
| **Hib** | - | - | - | - | - | - | - | - | - | [Footnote A](#p1c12t4fna)
1 dose |
| **Pneu-P-23** | - | - | - | - | - | - | - | [Footnote B](#p1c12t4fnb)
1 dose + 1 booster dose if at highest risk |
| **Pneu-C-13** | - | - | [Footnote C](#p1c12t4fnc) | - | - | - | - | - | [Footnote [C]](#p1c12t4fnc)
If not previously received |
| **Men-C-ACYW** | - | [Footnote D](#p1c12t4fnd)
2, 3 or 4 doses + additional booster doses | - |
| **4CMenB** | - | [Footnote E](#p1c12t4fne)
2, 3 or 4 doses + additional booster doses |
| **HA** | - | - | - | [Footnote F](#p1c12t4fnf)
2 doses |
| **HB** | [Footnote G](#p1c12t4fng)
3 or 4 doses |
| **Inf** | - | - | [Footnote H](#p1c12t4fnh)
1 or 2 doses
Recommended annually | [Footnote H](#p1c12t4fnh)
1 dose
Recommended annually |
|
Footnote \*
For abbreviations and brand names of vaccines refer to [Contents of immunizing agents authorized for use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1.
[Return to Table 4 footnote \* referrer](#p1c12t4fn*-rf)
Table 4 - Footnote A
***Haemophilus influenzae* type b** (Hib): 5 years of age and older with increased risk of invasive Hib disease - 1 dose regardless of prior history of Hib vaccination and at least 1 year after any previous dose.
[Return to Table 4 footnote A referrer](#p1c12t4fna-rf)
Table 4 - Footnote B
**Pneumococcal polysaccharide 23-valent**: children 2 years of age or older at high risk of invasive pneumococcal disease (IPD) - 1 dose. Children at highest risk of IPD including those with functional or anatomic asplenia or sickle cell disease; hepatic cirrhosis; chronic renal failure; nephrotic syndrome; HIV infection; and immunosuppression related to disease or therapy - 1 booster dose after 5 years. If pneumococcal conjugate 13-valent (Pneu-C-13) vaccine is also required, it should be provided first, followed by Pneu-P-23 vaccine, at least 8 weeks later.
[Return to Table 4 footnote B referrer](#p1c12t4fnb-rf)
Table 4 - Footnote C
**Pneumococcal conjugate 13-valent**: infants at high risk of IPD - in addition to the doses at 2, 4, and 12 months of age, give an extra dose at 6 months to make a 4 dose primary series. Children aged 3 years and older at high risk of IPD who have not previously received Pneu-C-13 vaccine - 1 dose
[Return to first Table 4 footnote C referrer](#p1c12t4fnc-rf)
Table 4 - Footnote D
**Meningococcal conjugate quadrivalent** (Men-C-ACYW): infants and children at high risk of invasive meningococcal disease (IMD): 2-11 months of age - 2 or 3 doses of Men-C-ACYW-CRM vaccine, 8 weeks apart with another dose between 12-23 months of age and at least 8 weeks after the previous dose; 12-23 months of age - 2 doses of Men-C-ACYW-CRM vaccine,8 weeks apart; 24 months of age and older - 2 doses of any Men-C-ACYW vaccine, 8 weeks apart. Give additional booster doses every 3 to 5 years if last vaccinated at 6 years of age and younger and every 5 years if last vaccinated at 7 years of age and older.
[Return to Table 4 footnote D referrer](#p1c12t4fnd-rf)
Table 4 - Footnote E
**Multicomponent meningococcal** (4CMenB): infants and children at high risk of IMD should be considered for immunization: 2-11 months of age - 2 or 3 doses of 4CMenB vaccine, 8 weeks apart with another dose between 12-23 months of age and at least 8 weeks after the previous dose; 1-10 years of age- 2 doses of 4CMenB vaccine, 8 weeks apart; 11 years of age and older - 2 doses of 4CMenB vaccine, at least 4 weeks apart. The need for and timing of 4CMenB vaccine booster doses have not yet been determined.
[Return to Table 4 footnote E referrer](#p1c12t4fne-rf)
Table 4 - Footnote F
**Hepatitis A**: 6 months of age and older in high-risk groups: 2 doses, given 6-36 months apart (depending on product used).
[Return to Table 4 footnote F referrer](#p1c12t4fnf-rf)
Table 4 - Footnote G
**Hepatitis B**: 3 or 4 doses of higher dose of monovalent hepatitis B vaccine recommended for those with certain immunocompromising conditions, chronic renal failure and dialysis. Premature infants weighing less than 2,000 grams at birth born to HB infected mothers: 4 doses.
[Return to Table 4 footnote G referrer](#p1c12t4fng-rf)
Table 4 - Footnote H
**Influenza**: recommended annually for all individuals 6 months of age and older without contraindications, with focus on children at risk of influenza-related complications. Children 6 months-less than 9 years of age receiving influenza vaccine for the first time: 2 doses, at least 4 weeks apart. Children 6 months-8 years of age, previously immunized with influenza vaccine and children 9 years of age and older: 1 dose.
[Return to first Table 4 footnote H referrer](#p1c12t4fnh-rf)
|
Table 5: Recommended immunization schedule, adults (18 years of age and older), not previously immunized
--------------------------------------------------------------------------------------------------------
* For adults considered at-risk, refer to [Table 7](#p1c12t7) for additional recommendations for immunization.
* [ ] = dose(s) may not be required depending upon age of vaccinee or vaccine used or both (refer to [vaccine-specific chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 and [provincial/territorial schedule](http://www.healthycanadians.gc.ca/healthy-living-vie-saine/immunization-immunisation/children-enfants/schedule-calendrier-eng.php)). mos = months.
* Refer to [Immunization of travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) and [Immunization of workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html) in Part 3 for additional information about vaccines recommended for travellers and workers.
* Refer to [Timing of vaccine vdministration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) and [Vaccine vdministration practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 regarding administration of multiple injections.
* Refer to [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for further information.
Table 5: Recommended immunization schedule, adults (18 years of age and older), not previously immunized
| Vaccine[Footnote \*](#p1c12t5fn*) | First visit | Time after First visit | 6-12 mos after last dose | 10 years after last dose |
| --- | --- | --- | --- | --- |
| 4 weeks | 6 weeks | 8 weeks | 6 mos |
| **Tdap-IPV
Tdap
Td
IPV** | [Footnote A](#p1c12t5fna) | - | - | [Footnote A](#p1c12t5fna) | - | [Footnote A](#p1c12t5fna) | [Footnote B](#p1c12t5fnb) |
| **MMR** | [Footnote C](#p1c12t5fnc) | - | - | - | - | - | - |
| **Var** | [Footnote D](#p1c12t5fnd)
18-49 years of age | - | [Footnote D](#p1c12t5fnd) | - | - | - | - |
| **OR** |
| **RZV** | [Footnote E](#p1c12t5fne)
50 years of age and over | - | - | [Footnote E](#p1c12t5fne) | - | - | - |
| **Pneu-P-23** | [Footnote F](#p1c12t5fnf) | - | - | - | - | - | - |
| **Men-C-C**
or**Men-C-ACYW** | [Footnote G](#p1c12t5fng)
18-24 years of age | - | - | - | - | - | - |
| **HPV** | [Footnote H](#p1c12t5fnh)
3 doses | - | - |
| **Inf** | [Footnote I](#p1c12t5fni)
Annually |
|
Footnote \*
For abbreviations and brand names of vaccines refer to [Contents of immunizing agents authorized for use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1.
[Return to Table 5 footnote \* referrer](#p1c12t5fn*-rf)
Table 5 - Footnote A
Three doses of either tetanus toxoid- reduced diphtheria (Td, if not previously immunized with tetanus or diphtheria), or polio-containing vaccine if at increased risk of polio (Tdap-IPV, if not previously immunized with tetanus, diphtheria and polio, or IPV, if not previously immunized with polio) provided with an interval of 8 weeks between the first two doses followed by a third dose administered 6 to 12 months after the second dose. One dose of reduced acellular pertussis-containing vaccine should be provided to those who never previously received a pertussis-containing vaccine in adulthood.
Adults who are unimmunized against polio but are not at increased risk and have had a primary series of tetanus and diphtheria containing vaccine, should receive IPV-containing vaccine as a part of their next tetanus and diphtheria booster.
[Return to Table 5 footnote A referrer](#p1c12t5fna-rf)
Table 5 - Footnote B
**Tetanus toxoid- reduced diphtheria toxoid** (Td): 10 years after last dose of Td-containing vaccine.
[Return to Table 5 footnote B referrer](#p1c12t5fnb-rf)
Table 5 - Footnote C
**Measles-mumps-rubella** (MMR): adults born **in or after 1970** - 1 dose, except - travellers, health care workers, students in post-secondary educational settings, and military personnel - 2 doses, at least 4 weeks apart. Adults born **before 1970** can be presumed to have acquired natural immunity to measles and mumps and do not need MMR vaccination except - non-immune military personnel or health care workers (2 doses, at least 4 weeks apart), non-immune travellers (1 dose), non-immune students in post-secondary educational settings (consider 1 dose). Rubella-susceptible adults, regardless of age - 1 dose.
[Return to Table 5 footnote C referrer](#p1c12t5fnc-rf)
Table 5 - Footnote D
**Varicella (chickenpox)**: adults 18-49 years of age - 2 doses, at least 6 weeks apart; adults 50 years of age and older are generally presumed to be immune.
[Return to first Table 5 footnote D referrer](#p1c12t5fnd-rf)
Table 5 - Footnote E
**Recombinant Zoster Vaccine (RZV):** adults 50 years of age and older - 2 doses, 2 to 6 months apart; may be considered for immunocompromised adults 50 years of age and older based on a case-by-case assessment of benefits vs risks.[Return to Table 5 footnote E referrer](#p1c12t5fne-rf)
Table 5 - Footnote F
**Pneumococcal polysaccharide 23-valent**: adults 65 years of age and older - 1 dose; immunocompetent residents of long-term care facilities 18-64 years of age - 1 dose.
[Return to Table 5 footnote F referrer](#p1c12t5fnf-rf)
Table 5 - Footnote G
**Meningococcal conjugate monovalent or quadrivalent**: adults less than 25 years of age - 1 dose (vaccine chosen depends on local epidemiology).
[Return to Table 5 footnote G referrer](#p1c12t5fng-rf)
Table 5 - Footnote H
**Human papillomavirus** (HPV): recommended for women up to and including 26 years of age, may be given to women 27 years of age and older at ongoing risk of exposure: HPV bivalent (HPV2) vaccine - months 0, 1 and 6 (first dose = month 0), HPV quadrivalent (HPV4) vaccine - months 0, 2 and 6 (first dose = month 0) or nonavalent (HPV9) vaccine- months 0, 2 and 6 (first dose = month 0). Recommended for men up to and including 26 years of age, may be given to men 27 years of age and older at ongoing risk of exposure: HPV4 or HPV9 vaccine - months 0, 2 and 6 (first dose = month 0).
[Return to Table 5 footnote H referrer](#p1c12t5fnh-rf)
Table 5 - Footnote I
**Influenza**: 1 dose recommended for adults without contraindications, with focus on: adults at high risk of influenza-related complications (including pregnant women, adults 65 years of age and older); adults capable of transmitting influenza to individuals at high risk; adults who provide essential community services; and people in direct contact during culling operations with poultry infected with avian influenza.
[Return to Table 5 footnote I referrer](#p1c12t5fni-rf)
|
Table 6: Recommended immunizations, adults (18 years of age and older), previously immunized
--------------------------------------------------------------------------------------------
* **For adults considered at-risk**, refer to [Table 7](#p1c12t7) for additional recommendations for immunization.
* [] = dose may not be required.
* Refer to [Immunization of travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) and [Immunization of workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html) in Part 3 for additional information about vaccines recommended for travellers and workers.
* Refer to [Timing of vaccine administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) and [Vaccine administration practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 regarding administration of multiple injections.
* Refer to [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
Table 6: Recommended immunizations, adults (18 years of age and older), previously immunized
| Vaccine[Footnote \*](#p1c12t6fn*) | Age |
| --- | --- |
| 18-26 years | 27-49 years | 50-59 years | 60 years | 65 years and older |
| **Td** | [Footnote A](#p1c12t6fna)
1 dose every 10 years |
| **Tdap** | [Footnote B](#p1c12t6fnb)
1 dose |
| **Pneu-P-23** | - | - | - | - | [Footnote C](#p1c12t6fnc)
1 dose |
| **RZV** | - | - | [Footnote D](#p1c12t6fnd)
2 doses |
| **Inf** | [Footnote E](#p1c12t6fne)
Annually |
|
Footnote \*
For abbreviations and brand names of vaccines refer to [Contents of immunizing agents authorized for use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1.
[Return to Table 6 footnote \* referrer](#p1c12t6fn*-rf)
Table 6 - Footnote A
**Tetanus toxoid- reduced diphtheria toxoid:** 1 booster dose every 10 years.
[Return to Table 6 footnote A referrer](#p1c12t6fna-rf)
Table 6 - Footnote B
**Tetanus toxoid- reduced diphtheria toxoid- reduced acellular pertussis (Tdap):** 1 dose in adulthood for pertussis protection regardless of interval since last dose of tetanus toxoid- and diphtheria toxoid-containing vaccine; 1 dose in every pregnancy, ideally between 27 and 32 weeks of gestation, for pertussis protection of infants. Refer to [Pertussis vaccine](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-15-pertussis-vaccine.html) in Part 4 for additional information.
[Return to Table 6 footnote B referrer](#p1c12t6fnb-rf)
Table 6 - Footnote C
**Pneumococcal polysaccharide 23-valent:** adults 65 years of age and older - 1 dose.
[Return to Table 6 footnote C referrer](#p1c12t6fnc-rf)
Table 6 - Footnote D
**Recombinant Zoster Vaccine (RZV):** adults 50 years of age and older - 2 doses, 2 to 6 months apart and at least one year after LZV.
[Return to Table 6 footnote D referrer](#p1c12t6fnd-rf)
Table 6 - Footnote E
**Influenza:** recommended for all adults without contraindications, with focus on: adults at high risk of influenza-related complications (including pregnant women, adults 65 years of age and older); adults capable of transmitting influenza to individuals at high risk; adults who provide essential community services; and people in direct contact during culling operations with poultry infected with avian influenza. One dose annually.
[Return to Table 6 footnote E referrer](#p1c12t6fne-rf)
|
Table 7: Additional recommended immunizations, adults (18 years of age and older), considered at risk
-----------------------------------------------------------------------------------------------------
* Refer to [Immunization of travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) and [Immunization of workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html) in Part 3 for information about vaccines recommended for travellers and workers.
* Refer to [Immunization of immunocompromised persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) and [Immunization of persons with chronic diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for additional condition-specific immunization recommendations.
* Refer to [Timing of vaccine administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) and [Vaccine administration practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 regarding administration of multiple injections.
* Refer to [vaccine-specific chapters](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html) in Part 4 for additional information.
Table 7: Additional recommended immunizations, adults (18 years of age and older), considered at risk
| Vaccine[Footnote \*](#p1c12t7fn*) | Age |
| --- | --- |
| 18 years of age and older |
| **Hib** | [Footnote A](#p1c12t7fna)
1 dose |
| **IPV** | [Footnote B](#p1c12t7fnb)
1 booster dose |
| **MMR** | [Footnote C](#p1c12t7fnc)
Second dose |
| **Pneu-C-13** | [Footnote D](#p1c12t7fnd)
1 dose |
| **Pneu-P-23** | [Footnote E](#p1c12t7fne)
1 dose + 1 booster dose if at highest risk |
| **Men-C-ACYW** | [Footnote F](#p1c12t7fnf)
2 doses + booster doses |
| **4CMenB** | [Footnote G](#p1c12t7fng)
2 doses |
| **HA** | [Footnote H](#p1c12t7fnh)
2 doses |
| **HB** | [Footnote I](#p1c12t7fni)
3 or 4 doses |
| **OR** |
| **HAHB** | [Footnote J](#p1c12t7fnj)
3 or 4 doses |
| **Inf** | [Footnote K](#p1c12t7fnk)
Annually |
| **Typh-I** | [Footnote L](#p1c12t7fnl)
1 dose + booster doses if at ongoing risk |
| **OR** |
| **Typh-O** | [Footnote L](#p1c12t7fnl)
4 doses + booster doses if at ongoing risk |
| **Rab** | [Footnote M](#p1c12t7fnm)
3 doses + booster doses if required |
| **Var** | [Footnote N](#p1c12t7fnn)
2 doses |
|
Footnote \*
List is not exhaustive of travel vaccines. For abbreviations and brand names of vaccines refer to [Contents of immunizing agents authorized for use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1.
[Return to Table 7 footnote \* referrer](#p1c12t7fn*-rf)
Table 7 - Footnote A
***Haemophilus influenzae* type b** (Hib): adults with increased risk of invasive Hib disease - 1 dose regardless of prior history of Hib vaccination and at least 1 year after any previous dose.
[Return to Table 7 footnote A referrer](#p1c12t7fna-rf)
Table 7 - Footnote B
**Inactivated polio:** 1 booster dose for adults at increased risk of exposure to polio.
[Return to Table 7 footnote B referrer](#p1c12t7fnb-rf)
Table 7 - Footnote C
**Measles-mumps-rubella** (MMR): adults born **in or after 1970** - 1 dose, except - travellers, health care workers, students in post-secondary educational settings, and military personnel - 2 doses, at least 4 weeks apart. Adults born **before 1970** can be assumed to have acquired natural immunity to measles and mumps and do not need MMR vaccination except - non-immune military personnel or health care workers (2 doses, at least 4 weeks apart), non-immune travellers (1 dose), non-immune students in post-secondary educational settings (consider 1 dose). Rubella-susceptible adults, regardless of age - 1 dose.
[Return to Table 7 footnote C referrer](#p1c12t7fnc-rf)
Table 7 - Footnote D
**Pneumococcal conjugate 13-valent** (Pneu-C-13): adults with HIV or immunocompromising conditions (except hematopoietic stem cell transplant recipients [HSCT]) - 1 dose of Pneu-C-13 vaccine followed 8 weeks later by 1 dose of pneumococcal polysaccharide 23-valent (Pneu-P-23) vaccine. Administer Pneu-C-13 vaccine dose at least 1 year after any previous dose of Pneu-P-23 vaccine.
[Return to Table 7 footnote D referrer](#p1c12t7fnd-rf)
Table 7 - Footnote E
**Pneumococcal polysaccharide 23-valent**: adults at high risk of invasive pneumococcal disease (IPD), including adults with alcoholism, smokers, and persons who are homeless - 1 dose. One dose should be considered for adults who use illicit drugs. Adults at highest risk of IPD, including those with functional or anatomic asplenia or sickle cell disease; hepatic cirrhosis; chronic renal failure; nephrotic syndrome; HIV infection; and immunosuppression related to disease or therapy - 1 booster dose at least 5 years from first vaccination with Pneu-P-23 vaccine.
[Return to Table 7 footnote E referrer](#p1c12t7fne-rf)
Table 7 - Footnote F
**Meningococcal conjugate quadrivalent**: in previously unimmunized adults at high risk of invasive meningococcal disease (IMD) - 2 doses, 8 weeks apart. In previously immunized adults -booster dose every 3 to 5 years if last vaccinated at 6 years of age and younger and every 5 years for those last vaccinated at 7 years of age and older.
[Return to Table 7 footnote F referrer](#p1c12t7fnf-rf)
Table 7 - Footnote G
**Multicomponent meningococcal** (4CMenB): adults at high risk of IMD should be considered for immunization - 2 doses of 4CMenB vaccine, at least 4 weeks apart.
[Return to Table 7 footnote G referrer](#p1c12t7fng-rf)
Table 7 - Footnote H
**Hepatitis A**: adults in high risk groups - 2 doses, 6-36 months apart (depending on product used).
[Return to Table 7 footnote H referrer](#p1c12t7fnh-rf)
Table 7 - Footnote I
**Hepatitis B** (HB): adults in high risk groups - 3 or 4 dose schedule (depending on product used). Higher dose of monovalent HB vaccine recommended for those with certain immunocompromising conditions, chronic renal failure and dialysis.
[Return to Table 7 footnote I referrer](#p1c12t7fni-rf)
Table 7 - Footnote J
**Hepatitis A-hepatitis B**: adults without chronic renal failure and immunocompromising conditions: combined vaccine preferred if both hepatitis A and standard dosage hepatitis B vaccines are recommended - 3 or 4 dose schedule.
[Return to Table 7 footnote J referrer](#p1c12t7fnj-rf)
Table 7 - Footnote K
**Influenza**: recommended for all adults, with focus on adults at high risk of influenza-related complications - 1 dose annually.
[Return to Table 7 footnote K referrer](#p1c12t7fnk-rf)
Table 7 - Footnote L
**Typhoid**: adults with ongoing or intimate exposure to a chronic carrier of *Salmonella typhi* - 1 dose injectable typhoid vaccine or 4 doses oral typhoid vaccine; re-immunization recommended if at continuing risk.
[Return to first Table 7 footnote L referrer](#p1c12t7fnl-rf)
Table 7 - Footnote M
**Rabies**: adults at high risk of close contact with rabid animals - 3 doses for pre-exposure immunization. Periodic serologic testing and booster doses (if required) for those at continuing high risk.
[Return to Table 7 footnote M referrer](#p1c12t7fnm-rf)
Table 7 - Footnote N
**Varicella**: adults 18 to less than 50 years of age without history of VZV infection (self-reported or diagnosed by a health care provider), documented evidence of immunization with 2 doses of a varicella-containing vaccine or laboratory evidence of immunity - 2 doses. Self-reported history or health care provider diagnosis is not considered a reliable correlate of immunity for pregnant women with significant exposure to varicella zoster virus, immunocompromised individuals and health care workers who are newly hired into the Canadian health care system.
[Return to Table 7 footnote N referrer](#p1c12t7fnn-rf)
|
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-12-immunization-records.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information.html)
* [Next Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-14-basic-immunology-vaccinology.html)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-07-28
| None | None |
0e69bc1c06e13c818c5a9c2d6846f7bf6106cdd5 | cma | Interim guidance on the use of pneumococcal 15-valent conjugate vaccine (PNEU-C-15) in pediatric populations | Interim guidance on the use of pneumococcal 15-valent conjugate vaccine (PNEU-C-15) in pediatric populations
Preamble
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing, and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Background
On November 16, 2021, Health Canada authorized the use of a pneumococcal conjugate 15-valent vaccine, PNEU-C-15 (Vaxneuvance®) , for adults 18 years of age and older. An age extension for the use of PNEU-C-15 in the pediatric population was authorized on July 8, 2022, under a priority review. This vaccine provides additional protection against two serotypes (22F and 33F) compared to the currently authorized pneumococcal conjugate 13-valent vaccine, PNEU-C-13 (Prevnar 13®). PNEU-C-15 is currently indicated for active immunization of infants, children and adolescents from 6 weeks through 17 years of age (prior to the 18th birthday) and adults 18 years of age and older for the prevention of invasive pneumococcal disease (IPD), including sepsis, meningitis, complicated pneumonia with or without empyema and bacteremia) caused by *Streptococcus pneumoniae- serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F).
In Canada, current routine immunization programs for healthy infants include the use of pneumococcal conjugate (PNEU-C) vaccines provided either using a 3-dose schedule (at 2 months, 4 months, and 12 months of age) or a 4-dose schedule (at 2 months, 4 months and 6 months followed by a booster dose at 12 to 15 months of age). The routine immunization schedule for healthy low-risk children in the province of Quebec is a mixed schedule that includes the use of PNEU-C-10 at 2 and 4 months of age and the use of PNEU-C-13 at 12 months of age . For children at high risk, there is an additional dose of PNEU-C-10 at 6 months of age.
Among infants at high risk of IPD due to an underlying medical condition, the current routine immunization programs in all provinces and territories include receipt of PNEU-C vaccine in a 4 dose schedule (at 2 months, 4 months and 6 months followed by a booster dose at 12 to 15 months of age) as well as one dose of PNEU-P-23 vaccine at 24 months of age, at least 8 weeks after the last PNEU-C-13 vaccine dose . Children and adolescents at highest risk of IPD should also receive 1 booster dose of PNEU-P-23 vaccine .
In 2019, based on the childhood National Immunization Coverage Survey (cNICS), it was estimated that 84.4% of 2-year-old children in Canada had 3 or 4 doses of the pneumococcal vaccine . The current national vaccination coverage goal by 2025 is to have 95% of 2-year-old children immunized with 3 or 4 doses of the recommended pneumococcal vaccine(s) . Some but not all jurisdictions have already achieved the target.
Statement objective
The primary objective of this Interim Guidance is to review evidence on the safety and immunogenicity of PNEU-C-15 in the pediatric age group and to develop interim recommendations on its interchangeability with PNEU-C-13 for use in routine pediatric schedules as well as for children at high risk of IPD.
Methods
NACI reviewed key questions raised in consultation with the Canadian Immunization Committee and the Pneumococcal Working Group (PWG). These included the need for evidence pertaining to the burden of disease to be prevented in the target population(s), the safety, immunogenicity, efficacy, and effectiveness of the vaccine(s), vaccine schedules, and other aspects of the overall pediatric pneumococcal vaccine immunization strategy. A rapid evidence synthesis of clinical trials was performed by the NACI Secretariat and reviewed by the PWG on September 28, 2022.
NACI reviewed this evidence on October 3rd, 2022. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are further described in the text. NACI voted on the interim recommendations on the use of PNEU-C-15 in pediatric populations on October 4, 2022, and recommendations were approved on December 12, 2022.
For additional information and NACI's current recommendations on the use of pneumococcal vaccines in children, please refer to the in the .
Further information on NACI's process and procedures is available elsewhere .
Vaccine
In Canada, four preparations, PNEU-C-10 (SynflorixTM) , PNEU-C-13 (PREVNAR®13) , PNEU-C-15 (Vaxneuvance®) , and PNEU-P-23 (Pneumovax®23) of pneumococcal vaccine are currently authorized for use in persons less than 18 years of age (). All vaccines are indicated for the prevention of IPD caused by *S. pneumoniae- vaccine-contained serotypes.
Non-Typeable Haemophilus influenza (NTHi) protein D, diphtheria, and tetanus toxoid carrier protein.
34 mcg total concentration of non-toxic variant of diphtheria toxin CRM197 carrier protein (individually conjugated).
125 mcg aluminum as aluminum phosphate adjuvant
30 mcg total concentration of non-toxic variant diphtheria toxin CRM197 carrier protein.
125 mcg of
aluminum (as aluminum phosphate adjuvant).
1.55 mg L-histidine, 1 mg of polysorbate 20,
4.5 mg sodium chloride and water for
No adjuvant
Evidence summary
# Burden of disease
IPD became nationally notifiable in 2000; before this time, only cases of pneumococcal meningitis were notifiable nationally. With the implementation of routine childhood pneumococcal immunization with PNEU-C-7 vaccine between 2002 and 2006, and PNEU-C-13 vaccine between 2010 and 2012, IPD incidence among children less than two years of age has decreased substantially from a peak of 73.0 cases per 100,000 population in 2003 to an average of 16.2 cases per 100,000 population between 2015 and 2019 .
Based on the data reported to Canadian Notifiable Disease Surveillance System (CNDSS), IPD due to PNEU-C-13 serotypes decreased in all pediatric age groups between 2011 and 2020 . During this period, the decrease ranged from approximately 42% in the 2- to 4-year-old age group to approximately 20% in other age groups. IPD due to serotype 3 deceased from 6.8% in 2011 to 4.9% on 2020 among children less than 2 years old, while it increased from 11.1% in 2011 to 15.8% in 2020 among children 2 to 4 years old. At the same time, IPD cases due to the two additional serotypes 22F and 33F included in the newly authorized PNEU-C-15 vaccine increased from 7.9% to 15.9% in the less than 2 year old age group, and from 11.8% to 18.4% in the 2- to 4-year-old age group .
The proportion of serotypes 22F and 33F in children 0 to 4 years of age increased from 9.6% in 2011 to 16.7% in 2020. In the 5- to 17-year-old age group, the proportion of these serotypes increased from 5.4% in 2011 to 20.2% in 2019, before decreasing back to 5.0% in 2020. The proportion of serotype 3 in children 0 to 4 years old stayed relatively stable (8.7% in 2011, 8.3% in 2020) and for those 5 to 17 years old, it increased from 6.7% in 2011 to 20.0% in 2020. Data for 2020 may not be reflective of the actual trend as the COVID-19 pandemic may have impacted disease incidence in all age groups.
Serotype 22F was more commonly (11.7%) reported in 2020 among IPD cases in children less than 5 years of age than serotype 33F (5.0%). In 2020, serotypes 3, 22F, 10A, 19A and 15B/C were the most common causes of pediatric IPD, representing approximately half of the cases. Serotype 3 alone caused 11.3% of all pediatric IPD cases in 2020, it was least prevalent (4.9%) in the less than 2 year old age group.
# Evidence on safety, immunogenicity, and efficacy of PNEU-C-15 in pediatric populations
NACI reviewed the evidence on safety, and immunogenicity of PNEU-C-15 vaccine from eight Phase 2/3 clinical trials which included a range of pediatric populations and which used different vaccine schedules (). An additional trial, V114-022 , provided immunogenicity and safety data following the immunization of hematopoietic stem cell transplant (HSCT) recipients.
Since there are currently no efficacy or effectiveness data available for PNEU-C-15 vaccine for any pediatric indication, the basis for regulatory authorization was the demonstration of comparable safety and immunogenicity (non-inferiority for serotypes common to PNEU-C-13 and superiority for two additional serotypes) in relation to PNEU-C-13 vaccine.
PNEU-C-15, Lot 2 (N=350),
PNEU-C-13 (N=860)
IgG GMC at 30 days PD3
12 to 23 months of age (day 1 and week 8),
P/P/P/V (N=180),
P/P/V/V (N=180),
P/V/V/V (N=180),
PNEU-C-13 (N=593)
## Immunogenicity summary
NACI reviewed the available evidence on immunogenicity of PNEU-C-15 in mixed PNEU-C-15 and PNEU-C-13 regimens (pertaining to routine immunization programs for infants and children without IPD risk factors) as well as evidence on immunogenicity of PNEU-C-15 in high-risk pediatric populations. Additional details on immunogenicity findings that were reported in PNEU-C-15 clinical trials in pediatric populations are provided in .
### Immunogenicity of PNEU-C-15 in mixed PNEU-C-15 and PNEU-C-13 regimens
To address the policy question of PNEU-C-15 interchangeability with PNEU-C-13, NACI reviewed the evidence on immunogenicity in the mixed PNEU-C-15 and PNEU-C-13 regimen (interchangeability trial, V114-027 ). Overall, available evidence suggests that the vaccines had comparable immune responses for the 13 shared serotypes. The immune response to the two additional serotypes (22F, 33F) and for serotypes 3 was higher after PNEU-C-15 compared to PNEU-C-13. In one study, V114-029 immune responses to serotypes 22F, 33F and 3 were superior following PNEU-C-15 compared to PNEU-C-13 ().
In the V114-027 trial, 900 healthy participants 40 to 90 days of age were randomized to one of five groups (n=180 per group) to receive a complete four dose series with PNEU-C-13, PNEU-C-15 or mixed regimen initiated with one, two or three doses of PNEU-C-13 and continued with PNEU-C-15.
When assessed by serotype-specific IgG GMCs and IgG GMC ratios, a mixed regimen of PNEU-C-15 and PNEU-C-13 30 days after dose 4 (administered at approximately 12 to 15 months of age) elicited generally comparable immune responses to a complete 4-dose regimen of PNEU-C-13 for the 13 shared serotypes.
At 30 days following the receipt of the third dose, serotype-specific immune responses for the 13 shared serotypes were generally comparable across intervention groups as assessed by the proportions of participants meeting the pre-specified IgG seroresponse threshold value of ≥0.35 µg/mL and IgG GMCs. In contrast, serotype-specific immune responses for unique serotypes 22F and 33F were higher in PNEU-C-15 vaccine recipients. Immune responses for serotype 33F increased incrementally with additional PNEU-C-15 doses received in the infant series (as assessed by response rates and IgG GMCs) while they remained unchanged for serotype 22F.
### Immunogenicity of PNEU-C-15 in pediatric populations at high-risk of IPD
To address the policy question of PNEU-C-15 interchangeability with the currently recommended PNEU-C-13 for children at increased risk of IPD, NACI reviewed the evidence of immunogenicity data from two studies. Overall, in high-risk populations, PNEU-C-15 had comparable immunogenicity to PNEU-C-13 for shared serotypes.
In the V114-23 and V114-030 trials children 5-17 years old living with sickle cell disease and children 6-17 years old living with HIV, respectively, were randomized to receive either PNEU-C-15 or PNEU-C-13 and PNEU-C-15+PNEU-P-23 or PNEU-C-13+PNEU-P-23. When assessed by serotype-specific IgG GMC and OPA GMT at 30 days post vaccination, immune responses were generally similar between the intervention and comparator groups for the shared serotypes and higher for the PNEU-C-15 unique serotypes, 22F and 33F. At 30 days following the administration of PNEU-P-23 in V114-030, IgG GMC and OPA GMTs were numerically similar for all 13 shared and the two unique serotypes.
## Safety summary
In all studies, the evidence on safety showed that PNEU-C-15 is safe in healthy children and in select special populations. Safety following immunization with PNEU-C-15 vaccine was measured in all Phase 2/3 clinical trials that included healthy children (six studies), children with sickle cell disease (one study) and HIV infection (one study). The measured safety endpoints included the proportion of participants with solicited local and systemic adverse events (AEs) 1 to 14 days post vaccination, maximum body temperature measurements (1–7 days post vaccination) and serious adverse events (SAEs), up to 6 months following vaccination.
In the pivotal study , in which PNEU-C-15 was administered as a 3-dose series (V114-025), the safety profile was found to be generally comparable to PNEU-C-13 (). An integrated safety analysis was conducted for healthy infants (studies 025 , 027 , 029 , and 031 ) in the final safety database including 3,592 participants receiving at least one dose of PNEU-C-15 and 2,062 receiving at least one dose of PNEU-C-13.
The proportions of participants with local and systemic AEs (solicited and unsolicited) after each dose in the primary series, after the toddler booster dose, and after any dose were generally comparable in both intervention groups. In infants, the most frequently reported AEs following each dose were irritability (45.7%), somnolence (21.8%), injection-site pain (21%), decreased appetite (19.4%) and other injection-site reactions (erythema, swelling, induration; all less than 22%) (). The majority of participants who received PNEU-C-15 reported maximum body temperature measurements of less than 38.0 °C, with a temperature distribution that was comparable between intervention groups. Of the participants with a maximum body temperature higher than 38.0 °C, the majority had a maximum body temperature below 39.0 °C.
SAEs were reported for up to 5.5% of participants following each dose of PNEU-C-15 and up to 4.7% of participants following each dose of PNEU-C-13. While the majority of SAEs were deemed to be not vaccine-related, there were three vaccine-related SAEs reported in 2 participants in the PNEU-C-15 group and 1 participant in the PNEU-C-13 group (all were pyrexia requiring hospitalization). There were 4 deaths reported among study participants, of which none were considered to be related to the study interventions. The safety profile of mixed dosing regimens with PNEU-C-15 was comparable to complete PNEU-C-13 and PNEU-C-15.
In children with sickle cell disease or living with HIV infection , the safety profile was generally consistent with the safety profile in healthy children.
# Evidence on concurrent administration of PNEU-C-15 with other routinely administered pediatric vaccines
Concurrent administration of PNEU-C-15 with other routinely administered pediatric vaccines was assessed in three clinical trials (protocols 025 , 027 and 029 ) involving over 1,700 infants and toddlers , In addition to PNEU-C-15, study participants also received diphtheria, tetanus, pertussis, poliomyelitis (serotypes 1, 2 and 3), hepatitis A, hepatitis B, *Haemophilus influenzae- type b, measles, mumps, rubella, varicella, and rotavirus vaccine, either as monovalent or combination vaccines within the primary infant series or with the toddler booster dose.
Immune responses to all antigens provided concomitantly with PNEU-C-15 met non-inferiority criteria as assessed by the individual antigen-specific response rates (for the combination and monovalent vaccines) or GMT (rotavirus vaccine) at 30 days following vaccine administration. Overall, all studies reviewed by NACI showed that PNEU-C-15 can be administered concurrently with other routine pediatric vaccines.
Recommendation
Following the review of key evidence summarized above, NACI makes the following interim recommendation for public health program level decision-making.
Please see for a more detailed explanation of strength of NACI recommendations and grade of the body of evidence.
NACI recommends that PNEU-C-15 vaccine may be used interchangeably with PNEU-C-13 vaccine in children less than 18 years of age. A pneumococcal vaccine series may be started or completed with either vaccine. (Discretionary NACI recommendation)
Summary of evidence, rationale, and additional considerations:
- There are currently no data on efficacy or effectiveness that would allow a comparative assessment of clinical outcomes of vaccination with PNEU-C-15 versus PNEU-C-13.
- In immunogenicity studies, PNEU-C-15 has shown to have comparable immune responses to PNEU-C-13 for shared serotypes and higher immune responses for unique serotypes as measured by seroresponse rates, total antibody levels, and functional antibody levels.
- PNEU-C-15 has been shown to have comparable safety profile to PNEU-C-13 when given as a single vaccine type series, when used in mixed PNEU-C-15/PNEU-C-13 schedules and when concurrently administered with other routine pediatric vaccines.
- PNEU-C-15 has the potential to prevent up to about 20% more cases of IPD in children 4 years of age and younger based on CNDSS epidemiology data.
- Introduction of PNEU-C-15 programs into routine schedules may provide additional benefit through direct effects on non-invasive pneumococcal infections (e.g., acute otitis media , community acquired pneumonia ). In addition, further indirect benefits of broadened protection could be expected in adults over time, as suggested by the reduction of IPD burden in older adults following the introduction of routine PNEU-C pediatric programs.
- Although NACI has not conducted any cost-effectiveness analysis, if product costs were equivalent, then PNEU-C-15 could potentially provide greater health gains and lead to reduced healthcare utilization compared to PNEU-C-13 due to the protection anticipated from two additional serotypes.
- NACI's recommendations for the use of PNEU-P-23 in combination with PNEU-C-13 or PNEU-C-15 for high-risk children remain unchanged.
Strength of NACI recommendation
based on factors not isolated to strength of evidence
Programmatic considerations table
Additional information on PNEU-C-15 is contained within the product monograph available through Health Canada's .
- Higher immune response for non-shared STs and for serotype 3
- Non-inferiority of PNEU-C-15 when concurrently administered with other routine childhood vaccines and in a mixed schedules with PNEU-C-13
- Comparable safety profile for PNEU-C-15 vs. PNEU-C-13
- No data on the clinical significance of higher/lower serotype-specific immune responses including for serotype 3 and unique PNEU-C-15 non PNEU-C- 13 serotypes.
- No data on vaccine effectiveness or immunogenicity for PNEU-C-15 in immunocompromised children or other special populations not included in the trials
- Impact on the epidemiology of overall pneumococcal disease burden in children and adults and effect on serotype switching
- Cost-effectiveness of the use of PNEU-C-15 vs. PNEU-C-13 was not evaluated for this statement/recommendation.
In general, vaccines with increased number of antigens will likely broaden protection not only in terms of IPD, but also non-invasive pneumococcal disease which may include AOM, CAP and other pneumococcal infections. For example, in one European study , among children aged 6–36 months with clinically diagnosed AOM, 8% of infections were caused by PNEU-C-15 unique serotypes.
Given the significant number of AOM and CAP infections, even small percent reductions in cases have the potential to significantly reduce the overall pneumococcal disease burden. In addition, further indirect benefits of broadened protection could be expected over time in adults, as suggested by the reduction of IPD burden in older adults following the introduction of previous routine PNEU-C pediatric programs.
Research priorities
- Determining the direct (children) and indirect (adults) impact of PNEU-C-15 programs on the burden of disease (AOM, pneumonia, IPD) in individuals with and without risk factors for invasive disease in the context of different vaccines and vaccine schedules used in Canada.
- Determining the vaccine effectiveness of PNEU-C-15 in healthy and in immunocompromised pediatric population.
- Determining the duration of immunity for PNEU-C-15 only and in mixed schedule programs.
- Assessing the cost effectiveness of PNEU-C-15 in pediatric population. |
Interim guidance on the use of pneumococcal 15-valent conjugate vaccine (PNEU-C-15) in pediatric populations
=============================================================================================================
**Published:** March 21, 2023
[Download in PDF format](/content/dam/hc-sc/documents/services/publications/vaccines-immunization/national-advisory-committee-immunization-interim-guidance-pneumococcal-15-valent-conjugate-vaccine-pneu-c-15-pediatric-populations/national-advisory-committee-immunization-interim-guidance-pneumococcal-15-valent-conjugate-vaccine-pneu-c-15-pediatric-populations.pdf)
(681 KB, 28 pages)
**Organization:** [Public Health Agency of Canada](/en/public-health.html)
**Date published:** March 21, 2023
**Cat.:** HP40-336/1-2023E-PDF
**ISBN:** 978-0-660-47847-0
**Pub.:** 220797
On this page
------------
* [Preamble](#a1)
* [Background](#a2)
* [Statement objective](#a3)
* [Methods](#a4)
* [Vaccine](#a5)
* [Evidence summary](#a6)
+ [Burden of disease](#a7)
+ [Evidence on safety, immunogenicity, and efficacy of PNEU-C-15 in pediatric populations](#a8)
+ [Evidence on concurrent administration of PNEU-C-15 with other routinely administered pediatric vaccines](#a9)
* [Recommendation](#a10)
* [Programmatic considerations table](#a11)
* [Research priorities](#a12)
* [List of abbreviations](#a13)
* [Acknowledgements](#a14)
* [Appendix A: Immunogenicity of PNEU-C-15 in pediatric populations](#a15)
* [References](#a16)
Preamble
--------
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing, and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Background
----------
On November 16, 2021, Health Canada authorized the use of a pneumococcal conjugate 15-valent vaccine, PNEU-C-15 (Vaxneuvance®) [Footnote 1](#fn1), for adults 18 years of age and older. An age extension for the use of PNEU-C-15 in the pediatric population was authorized on July 8, 2022, under a priority review. This vaccine provides additional protection against two serotypes (22F and 33F) compared to the currently authorized pneumococcal conjugate 13-valent vaccine, PNEU-C-13 (Prevnar 13®). PNEU-C-15 is currently indicated for active immunization of infants, children and adolescents from 6 weeks through 17 years of age (prior to the 18th birthday) and adults 18 years of age and older for the prevention of invasive pneumococcal disease (IPD), including sepsis, meningitis, complicated pneumonia with or without empyema and bacteremia) caused by *Streptococcus pneumoniae* serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F).
In Canada, current routine immunization programs for healthy infants include the use of pneumococcal conjugate (PNEU-C) vaccines provided either using a 3-dose schedule (at 2 months, 4 months, and 12 months of age) or a 4-dose schedule (at 2 months, 4 months and 6 months followed by a booster dose at 12 to 15 months of age). The routine immunization schedule for healthy low-risk children in the province of Quebec is a mixed schedule that includes the use of PNEU-C-10 at 2 and 4 months of age and the use of PNEU-C-13 at 12 months of age [Footnote 2](#fn2). For children at high risk, there is an additional dose of PNEU-C-10 at 6 months of age.
Among infants at high risk of IPD due to an underlying medical condition, the current routine immunization programs in all provinces and territories include receipt of PNEU-C vaccine in a 4 dose schedule (at 2 months, 4 months and 6 months followed by a booster dose at 12 to 15 months of age) as well as one dose of PNEU-P-23 vaccine at 24 months of age, at least 8 weeks after the last PNEU-C-13 vaccine dose [Footnote 3](#fn3). Children and adolescents at highest risk of IPD should also receive 1 booster dose of PNEU-P-23 vaccine [Footnote 3](#fn3).
In 2019, based on the childhood National Immunization Coverage Survey (cNICS), it was estimated that 84.4% of 2-year-old children in Canada had 3 or 4 doses of the pneumococcal vaccine [Footnote 4](#fn4). The current national vaccination coverage goal by 2025 is to have 95% of 2-year-old children immunized with 3 or 4 doses of the recommended pneumococcal vaccine(s) [Footnote 5](#fn5). Some but not all jurisdictions have already achieved the target.
Statement objective
-------------------
The primary objective of this Interim Guidance is to review evidence on the safety and immunogenicity of PNEU-C-15 in the pediatric age group and to develop interim recommendations on its interchangeability with PNEU-C-13 for use in routine pediatric schedules as well as for children at high risk of IPD.
Methods
-------
NACI reviewed key questions raised in consultation with the Canadian Immunization Committee and the Pneumococcal Working Group (PWG). These included the need for evidence pertaining to the burden of disease to be prevented in the target population(s), the safety, immunogenicity, efficacy, and effectiveness of the vaccine(s), vaccine schedules, and other aspects of the overall pediatric pneumococcal vaccine immunization strategy. A rapid evidence synthesis of clinical trials was performed by the NACI Secretariat and reviewed by the PWG on September 28, 2022.
NACI reviewed this evidence on October 3rd, 2022. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are further described in the text. NACI voted on the interim recommendations on the use of PNEU-C-15 in pediatric populations on October 4, 2022, and recommendations were approved on December 12, 2022.
For additional information and NACI's current recommendations on the use of pneumococcal vaccines in children, please refer to the [pneumococcal vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html) in the [Canadian Immunization Guide (CIG)](/en/public-health/services/canadian-immunization-guide.html).
Further information on NACI's process and procedures is available elsewhere [Footnote 6](#fn6) [Footnote 7](#fn7).
Vaccine
-------
In Canada, four preparations, PNEU-C-10 (SynflorixTM) [Footnote 8](#fn8), PNEU-C-13 (PREVNAR®13) [Footnote 9](#fn9), PNEU-C-15 (Vaxneuvance®) [Footnote 1](#fn1), and PNEU-P-23 (Pneumovax®23) [Footnote 10](#fn10) of pneumococcal vaccine are currently authorized for use in persons less than 18 years of age ([Table 1](#t1)). All vaccines are indicated for the prevention of IPD caused by *S. pneumoniae* vaccine-contained serotypes.
Table 1: Comparison of vaccines authorized for use in persons less than 18 years of age in Canada
|
Details | SYNFLORIXTM
(PNEU-C-10) [Footnote 8](#fn8) | PREVNAR®13
(PNEU-C-13) [Footnote 9](#fn9) | VAXNEUVANCE®
(PNEU-C-15) [Footnote 1](#fn1) | PNEUMOVAX®23
(PNEU-P-23) [Footnote 10](#fn10 ) |
| --- | --- | --- | --- | --- |
| Manufacturer | GSK | Pfizer | Merck | Merck |
| Date of initial authorization in Canada | December 11, 2008 | December 21, 2009 | November 16, 2021 (adults)
July 8, 2022 (pediatric) | December 23, 1983 |
| Indication | Indicated for the protection against diseases caused by *S. pneumoniae* vaccine-contained serotypes in infants and children from 6 weeks up to 5 years of age. | Indicated for the protection against IPD (all age groups) and AOM (6 weeks to 5 years of age) caused by *S. pneumoniae* vaccine-contained serotypes in infants and children from 6 weeks to less than 18 years of age. | Indicated for the protection against IPD caused by *S. pneumoniae* vaccine-contained serotypes in infants and children from 6 weeks to less than 18 years of age. | Indicated for the protection against IPD caused by *S. pneumoniae* vaccine-contained serotypes in children from 2 to less than 18 years of age at high risk of IPD. |
| Type of vaccine | Conjugate | Conjugate | Conjugate | Polysaccharide |
| Composition / carrier protein / adjuvant | 1 mcg of each saccharide for *S. pneumoniae* serotypes 1, 5, 6B, 7F, 9V, 14 and 23F, and 3 mcg of saccharide for serotype 4, 18C and 19F.
Non-Typeable Haemophilus influenza (NTHi) protein D, diphtheria, and tetanus toxoid carrier protein.
Aluminium (as aluminium phosphate), sodium chloride and water for injections. | 2.2 mcg of each saccharide for *S. pneumoniae* serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F and 23F, 4.4 mcg of saccharide for serotype 6B.
34 mcg total concentration of non-toxic variant of diphtheria toxin CRM197 carrier protein (individually conjugated).
125 mcg aluminum as aluminum phosphate adjuvant
4.25 mg sodium chloride, 100 mcg polysorbate 80, 295 mcg succinic acid and water for injection. | 2.0 mcg each of polysaccharide serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F and 4.0 mcg of polysaccharide serotype 6B.
30 mcg total concentration of non-toxic variant diphtheria toxin CRM197 carrier protein.
125 mcg of
aluminum (as aluminum phosphate adjuvant).
1.55 mg L-histidine, 1 mg of polysorbate 20,
4.5 mg sodium chloride and water for
injection. | 25 mcg each capsular polysaccharide serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23Fand 33F.
No adjuvant
Sodium chloride 0.9 % w/w, phenol 0.25% w/w, (preservative) and water for injection to volume. |
| Route of administration | Intramuscular injection | Intramuscular injection | Intramuscular injection | Intramuscular or subcutaneous injection |
| Contraindications | Known hypersensitivity to any component of the vaccine. | Known hypersensitivity to any component of the vaccine, including diphtheria toxoid. | History of a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine or any diphtheria toxoid-containing vaccine. | Known hypersensitivity (e.g., anaphylaxis) to any component of the vaccine. |
| Storage requirements | Single-dose prefilled syringe. Refrigerate at 2°C to 8°C. Do not freeze. Store in original package. | Single-dose prefilled syringe. Refrigerate at 2°C to 8°C. Do not freeze. Store in original package. | Single-dose prefilled syringe. Refrigerate at 2°C to 8°C. Do not freeze. Protect from light. Administer as soon as possible after being removed from the refrigerator. | Multi-dose vial.
Refrigerate at 2°C to 8°C. Discard opened vial after 48 hours. |
Evidence summary
----------------
### Burden of disease
IPD became nationally notifiable in 2000; before this time, only cases of pneumococcal meningitis were notifiable nationally. With the implementation of routine childhood pneumococcal immunization with PNEU-C-7 vaccine between 2002 and 2006, and PNEU-C-13 vaccine between 2010 and 2012, IPD incidence among children less than two years of age has decreased substantially from a peak of 73.0 cases per 100,000 population in 2003 to an average of 16.2 cases per 100,000 population between 2015 and 2019 [Footnote 11](#fn11).
Based on the data reported to Canadian Notifiable Disease Surveillance System (CNDSS), IPD due to PNEU-C-13 serotypes decreased in all pediatric age groups between 2011 and 2020 [Footnote 12](#fn12). During this period, the decrease ranged from approximately 42% in the 2- to 4-year-old age group to approximately 20% in other age groups. IPD due to serotype 3 deceased from 6.8% in 2011 to 4.9% on 2020 among children less than 2 years old, while it increased from 11.1% in 2011 to 15.8% in 2020 among children 2 to 4 years old. At the same time, IPD cases due to the two additional serotypes 22F and 33F included in the newly authorized PNEU-C-15 vaccine increased from 7.9% to 15.9% in the less than 2 year old age group, and from 11.8% to 18.4% in the 2- to 4-year-old age group [Footnote 12](#fn12).
The proportion of serotypes 22F and 33F in children 0 to 4 years of age increased from 9.6% in 2011 to 16.7% in 2020. In the 5- to 17-year-old age group, the proportion of these serotypes increased from 5.4% in 2011 to 20.2% in 2019, before decreasing back to 5.0% in 2020. The proportion of serotype 3 in children 0 to 4 years old stayed relatively stable (8.7% in 2011, 8.3% in 2020) and for those 5 to 17 years old, it increased from 6.7% in 2011 to 20.0% in 2020. Data for 2020 may not be reflective of the actual trend as the COVID-19 pandemic may have impacted disease incidence in all age groups.
Serotype 22F was more commonly (11.7%) reported in 2020 among IPD cases in children less than 5 years of age than serotype 33F (5.0%). In 2020, serotypes 3, 22F, 10A, 19A and 15B/C were the most common causes of pediatric IPD, representing approximately half of the cases. Serotype 3 alone caused 11.3% of all pediatric IPD cases in 2020, it was least prevalent (4.9%) in the less than 2 year old age group.
### Evidence on safety, immunogenicity, and efficacy of PNEU-C-15 in pediatric populations
NACI reviewed the evidence on safety, and immunogenicity of PNEU-C-15 vaccine from eight Phase 2/3 clinical trials [Footnote 13](#fn13) [Footnote 14](#fn14) [Footnote 15](#fn15) [Footnote 16](#fn16) [Footnote 17](#fn17) [Footnote 18](#fn18) [Footnote 19](#fn19) [Footnote 20](#fn20) which included a range of pediatric populations and which used different vaccine schedules ([Table 2](#t2)). An additional trial, V114-022 [Footnote 21](#fn21), provided immunogenicity and safety data following the immunization of hematopoietic stem cell transplant (HSCT) recipients.
Since there are currently no efficacy or effectiveness data available for PNEU-C-15 vaccine for any pediatric indication, the basis for regulatory authorization was the demonstration of comparable safety and immunogenicity (non-inferiority for serotypes common to PNEU-C-13 and superiority for two additional serotypes) in relation to PNEU-C-13 vaccine.
Table 2. Summary of PNEU-C-15 clinical trials
|
Study | Population | Treatments (planned number of participants per group) | Dosing schedule | Primary immunogenicity evaluation |
| --- | --- | --- | --- | --- |
| V114-008 [Footnote 13](#fn13)
lot consistency (Phase 2) | Healthy infants
(42 to 90 days of age) | PNEU-C-15, Lot 1 (N=350),
PNEU-C-15, Lot 2 (N=350),
PNEU-C-13 (N=350) | 3 + 1
(2, 4, 6 and 12 to 15 months of age) | Proportion with IgG ≥0.35 µg/mL for 13 shared serotypes at 30 days PD3
IgG GMC at 30 days PD3 |
| V114-029 [Footnote 18](#fn18)
pivotal | Healthy term and preterm infants
(42 to 90 days of age) | PNEU-C-15 (N=860),
PNEU-C-13 (N=860)
\*concomitant administration with routinely administered pediatric vaccines | 3 + 1
(2, 4, 6 and 12 to 15 months of age) | IgG response rates at 30 days PD3
IgG GMC at 30 days PD3
IgG GMC at 30 days PD4 |
| V114-031 [Footnote 20](#fn20)
safety | Healthy term and preterm infants
(42 to 90 days of age) | PNEU-C-15 (N=2000),
PNEU-C-13 (N=400) | 3 + 1
(2, 4, 6 and 12 to 15 months of age) | None |
| V114-024 [Footnote 15](#fn15)
catch-up | Healthy infants, children, and adolescents
(7 months to 17 years of age) | PNEU-C-15 (N=300),
PNEU-C-13 (N=300) | 7 to 11 months of age (day 1, week 4 and week 12),
12 to 23 months of age (day 1 and week 8),
2 to 17 years of age (day 1) | IgG GMC at 30 days following the last dose |
| V114-027 [Footnote 17](#fn17)
interchangeability | Healthy term and preterm infants
(42 to 90 days of age) | P/P/P/P (N=180),
P/P/P/V (N=180),
P/P/V/V (N=180),
P/V/V/V (N=180),
V/V/V/V (N=180) | 3 + 1
(2, 4, 6 and 12 to 15 months of age) | IgG GMC for the 13 shared serotypes at 30 days PD4 (group 2, group 3, group 4 vs. group 1) |
| V114-023 [Footnote 14](#fn14)
sickle cell | Children with sickle cell disease
(5 to 17 years of age) | PNEU-C-15 (N=69),
PNEU-C-13 (N=33) | Single dose
(day 1) | IgG GMC at Day 30 |
| V114-030 [Footnote 19](#fn19)
HIV | Children with HIV
(6 to 17 years of age) | PNEU-C-15 (N=203),
PNEU-C-13 (N=204) | Single dose (day 1) followed by a single dose of PNEU-P-23 (week 8) | IgG GMC at Day 30 |
| V114-025 [Footnote 16](#fn16)
EU 2+1 regimen pivotal trial | Healthy term and preterm infants
(2 to 15 months) | PNEU-C-15 (N=591),
PNEU-C-13 (N=593)
with Infanrix4 + Rotarix | 2 or 3 + 1 (preterm infants)
(2 or 2&3, 4, and 11 to 15 months) | IgG response rates at 30 days post toddler dose
IgG GMC at 30 days post toddler dose |
| V114-022 [Footnote 21](#fn21)
stem cell transplant recipients | Adults and children (3 to <18 years of age) who are HSCT recipients | PNEU-C-15 (N=139),
PNEU-C-13 (N=138) | 3 + 1
(day 1, 30 and 60, and 12 months after HSCT) | IgG GMC at 30 days following dose 3 |
| **Abbreviations:** V=PNEU-C-15; P=PNEU-C-13; HSCT= hematopoietic stem cell transplant; GMC= geometric mean antibody concentration; IgG=immunoglobulin G; PD3/4=post dose 3 or 4. |
#### Immunogenicity summary
NACI reviewed the available evidence on immunogenicity of PNEU-C-15 in mixed PNEU-C-15 and PNEU-C-13 regimens (pertaining to routine immunization programs for infants and children without IPD risk factors) as well as evidence on immunogenicity of PNEU-C-15 in high-risk pediatric populations. Additional details on immunogenicity findings that were reported in PNEU-C-15 clinical trials in pediatric populations are provided in [Appendix A](#a15).
##### Immunogenicity of PNEU-C-15 in mixed PNEU-C-15 and PNEU-C-13 regimens
To address the policy question of PNEU-C-15 interchangeability with PNEU-C-13, NACI reviewed the evidence on immunogenicity in the mixed PNEU-C-15 and PNEU-C-13 regimen (interchangeability trial, V114-027 [Footnote 17](#fn17)). Overall, available evidence suggests that the vaccines had comparable immune responses for the 13 shared serotypes. The immune response to the two additional serotypes (22F, 33F) and for serotypes 3 was higher after PNEU-C-15 compared to PNEU-C-13. In one study, V114-029 immune responses to serotypes 22F, 33F and 3 were superior following PNEU-C-15 compared to PNEU-C-13 ([Appendix A](#a15)).
In the V114-027 trial, 900 healthy participants 40 to 90 days of age were randomized to one of five groups (n=180 per group) to receive a complete four dose series with PNEU-C-13, PNEU-C-15 or mixed regimen initiated with one, two or three doses of PNEU-C-13 and continued with PNEU-C-15.
When assessed by serotype-specific IgG GMCs and IgG GMC ratios, a mixed regimen of PNEU-C-15 and PNEU-C-13 30 days after dose 4 (administered at approximately 12 to 15 months of age) elicited generally comparable immune responses to a complete 4-dose regimen of PNEU-C-13 for the 13 shared serotypes.
At 30 days following the receipt of the third dose, serotype-specific immune responses for the 13 shared serotypes were generally comparable across intervention groups as assessed by the proportions of participants meeting the pre-specified IgG seroresponse threshold value of ≥0.35 µg/mL and IgG GMCs. In contrast, serotype-specific immune responses for unique serotypes 22F and 33F were higher in PNEU-C-15 vaccine recipients. Immune responses for serotype 33F increased incrementally with additional PNEU-C-15 doses received in the infant series (as assessed by response rates and IgG GMCs) while they remained unchanged for serotype 22F.
##### Immunogenicity of PNEU-C-15 in pediatric populations at high-risk of IPD
To address the policy question of PNEU-C-15 interchangeability with the currently recommended PNEU-C-13 for children at increased risk of IPD, NACI reviewed the evidence of immunogenicity data from two studies. Overall, in high-risk populations, PNEU-C-15 had comparable immunogenicity to PNEU-C-13 for shared serotypes.
In the V114-23 [Footnote 14](#fn14) and V114-030 [Footnote 19](#fn19) trials children 5-17 years old living with sickle cell disease and children 6-17 years old living with HIV, respectively, were randomized to receive either PNEU-C-15 or PNEU-C-13 and PNEU-C-15+PNEU-P-23 or PNEU-C-13+PNEU-P-23. When assessed by serotype-specific IgG GMC and OPA GMT at 30 days post vaccination, immune responses were generally similar between the intervention and comparator groups for the shared serotypes and higher for the PNEU-C-15 unique serotypes, 22F and 33F. At 30 days following the administration of PNEU-P-23 in V114-030, IgG GMC and OPA GMTs were numerically similar for all 13 shared and the two unique serotypes.
#### Safety summary
In all studies, the evidence on safety showed that PNEU-C-15 is safe in healthy children and in select special populations. Safety following immunization with PNEU-C-15 vaccine was measured in all Phase 2/3 clinical trials that included healthy children [Footnote 13](#fn13) [Footnote 15](#fn15) [Footnote 16](#fn16) [Footnote 17](#fn17) [Footnote 18](#fn18) [Footnote 20](#fn20) (six studies), children with sickle cell disease [Footnote 14](#fn14) (one study) and HIV infection[Footnote 19](#fn19) (one study). The measured safety endpoints included the proportion of participants with solicited local and systemic adverse events (AEs) 1 to 14 days post vaccination, maximum body temperature measurements (1–7 days post vaccination) and serious adverse events (SAEs), up to 6 months following vaccination.
In the pivotal study [Footnote 16](#fn16), in which PNEU-C-15 was administered as a 3-dose series (V114-025), the safety profile was found to be generally comparable to PNEU-C-13 [Footnote 16](#fn16) ([Table 9, Appendix A](#t9)). An integrated safety analysis [Footnote 1](#fn1) was conducted for healthy infants (studies 025 [Footnote 16](#fn16), 027 [Footnote 17](#fn17), 029 [Footnote 18](#fn18), and 031 [Footnote 20](#fn20)) in the final safety database including 3,592 participants receiving at least one dose of PNEU-C-15 and 2,062 receiving at least one dose of PNEU-C-13.
The proportions of participants with local and systemic AEs (solicited and unsolicited) after each dose in the primary series, after the toddler booster dose, and after any dose were generally comparable in both intervention groups. In infants, the most frequently reported AEs following each dose were irritability (45.7%), somnolence (21.8%), injection-site pain (21%), decreased appetite (19.4%) and other injection-site reactions (erythema, swelling, induration; all less than 22%) ([Table 10, Appendix A](#t10)). The majority of participants who received PNEU-C-15 reported maximum body temperature measurements of less than 38.0 °C, with a temperature distribution that was comparable between intervention groups. Of the participants with a maximum body temperature higher than 38.0 °C, the majority had a maximum body temperature below 39.0 °C.
SAEs were reported for up to 5.5% of participants following each dose of PNEU-C-15 and up to 4.7% of participants following each dose of PNEU-C-13. While the majority of SAEs were deemed to be not vaccine-related, there were three vaccine-related SAEs reported in 2 participants in the PNEU-C-15 group and 1 participant in the PNEU-C-13 group (all were pyrexia requiring hospitalization). There were 4 deaths reported among study participants, of which none were considered to be related to the study interventions. The safety profile of mixed dosing regimens with PNEU-C-15 was comparable to complete PNEU-C-13 and PNEU-C-15.
In children with sickle cell disease or living with HIV infection [Footnote 14](#fn14) [Footnote 19](#fn19), the safety profile was generally consistent with the safety profile in healthy children.
### Evidence on concurrent administration of PNEU-C-15 with other routinely administered pediatric vaccines
Concurrent administration of PNEU-C-15 with other routinely administered pediatric vaccines was assessed in three clinical trials (protocols 025 [Footnote 16](#fn16), 027 [Footnote 17](#fn17) and 029 [Footnote 18](#fn18)) involving over 1,700 infants and toddlers [Footnote 16](#fn16) [Footnote 17](#fn17) [Footnote 18](#fn18), In addition to PNEU-C-15, study participants also received diphtheria, tetanus, pertussis, poliomyelitis (serotypes 1, 2 and 3), hepatitis A, hepatitis B, *Haemophilus influenzae* type b, measles, mumps, rubella, varicella, and rotavirus vaccine, either as monovalent or combination vaccines within the primary infant series or with the toddler booster dose.
Immune responses to all antigens provided concomitantly with PNEU-C-15 met non-inferiority criteria as assessed by the individual antigen-specific response rates (for the combination and monovalent vaccines) or GMT (rotavirus vaccine) at 30 days following vaccine administration. Overall, all studies reviewed by NACI showed that PNEU-C-15 can be administered concurrently with other routine pediatric vaccines.
Recommendation
--------------
Following the review of key evidence summarized above, NACI makes the following interim recommendation for public health program level decision-making.
Please see [Table 3](#t3) for a more detailed explanation of strength of NACI recommendations and grade of the body of evidence.
**NACI recommends that PNEU-C-15 vaccine may be used interchangeably with PNEU-C-13 vaccine in children less than 18 years of age. A pneumococcal vaccine series may be started or completed with either vaccine.** (Discretionary NACI recommendation)
Summary of evidence, rationale, and additional considerations:
* There are currently no data on efficacy or effectiveness that would allow a comparative assessment of clinical outcomes of vaccination with PNEU-C-15 versus PNEU-C-13.
* In immunogenicity studies, PNEU-C-15 has shown to have comparable immune responses to PNEU-C-13 for shared serotypes and higher immune responses for unique serotypes as measured by seroresponse rates, total antibody levels, and functional antibody levels.
* PNEU-C-15 has been shown to have comparable safety profile to PNEU-C-13 when given as a single vaccine type series, when used in mixed PNEU-C-15/PNEU-C-13 schedules and when concurrently administered with other routine pediatric vaccines.
* PNEU-C-15 has the potential to prevent up to about 20% more cases of IPD in children 4 years of age and younger based on CNDSS epidemiology data.
* Introduction of PNEU-C-15 programs into routine schedules may provide additional benefit through direct effects on non-invasive pneumococcal infections (e.g., acute otitis media [AOM], community acquired pneumonia [CAP]). In addition, further indirect benefits of broadened protection could be expected in adults over time, as suggested by the reduction of IPD burden in older adults following the introduction of routine PNEU-C pediatric programs.
* Although NACI has not conducted any cost-effectiveness analysis, if product costs were equivalent, then PNEU-C-15 could potentially provide greater health gains and lead to reduced healthcare utilization compared to PNEU-C-13 due to the protection anticipated from two additional serotypes.
* NACI's recommendations for the use of PNEU-P-23 in combination with PNEU-C-13 or PNEU-C-15 for high-risk children remain unchanged.
Table 3. Strength of NACI recommendations
|
Strength of NACI recommendation
based on factors not isolated to strength of evidence
(e.g., public health need) | Strong | Discretionary |
| --- | --- | --- |
| **Wording** | "should/should not be offered" | "may/may not be offered" |
| **Rationale** | Known/anticipated advantages outweigh known/anticipated disadvantages ("should"),**or** Known/Anticipated disadvantages outweigh known/anticipated advantages ("should not") | Known/anticipated advantages are closely balanced with known/anticipated disadvantages,**or** uncertainty in the evidence of advantages and disadvantages exists |
| **Implication** | A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present. | A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable. |
Programmatic considerations table
---------------------------------
Additional information on PNEU-C-15 is contained within the product monograph available through Health Canada's [Drug Product Database (DPD)](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
Table 4. Summary of PNEU-C-15 knowns and unknowns for use in pediatric population
|
Risk-benefit analysis | Knowns | Unknowns |
| --- | --- | --- |
| **Benefits** | * Immune responses for PNEU-C-15 were comparable /non-inferior to PNEU-C-13 for all shared STs
* Higher immune response for non-shared STs and for serotype 3
* Non-inferiority of PNEU-C-15 when concurrently administered with other routine childhood vaccines and in a mixed schedules with PNEU-C-13
* Comparable safety profile for PNEU-C-15 vs. PNEU-C-13
| * No efficacy/effectiveness data on PNEU-C-15 to assess clinical outcomes.
* No data on the clinical significance of higher/lower serotype-specific immune responses including for serotype 3 and unique PNEU-C-15 non PNEU-C- 13 serotypes.
* No data on vaccine effectiveness or immunogenicity for PNEU-C-15 in immunocompromised children or other special populations not included in the trials
* Impact on the epidemiology of overall pneumococcal disease burden in children and adults and effect on serotype switching
* Cost-effectiveness of the use of PNEU-C-15 vs. PNEU-C-13 was not evaluated for this statement/recommendation.
|
| **Risks** | * Serotype-specific variability with observed lower GMCs for some serotypes in PNEU-C-15 vs. PNEU-C-13
| * Potential rare and very rare adverse events specific to PNEU-C-15
|
In general, vaccines with increased number of antigens will likely broaden protection not only in terms of IPD, but also non-invasive pneumococcal disease which may include AOM, CAP and other pneumococcal infections. For example, in one European study [Footnote 22](#fn22), among children aged 6–36 months with clinically diagnosed AOM, 8% of infections were caused by PNEU-C-15 unique serotypes.
Given the significant number of AOM and CAP infections, even small percent reductions in cases have the potential to significantly reduce the overall pneumococcal disease burden. In addition, further indirect benefits of broadened protection could be expected over time in adults, as suggested by the reduction of IPD burden in older adults following the introduction of previous routine PNEU-C pediatric programs.
Research priorities
-------------------
* Determining the direct (children) and indirect (adults) impact of PNEU-C-15 programs on the burden of disease (AOM, pneumonia, IPD) in individuals with and without risk factors for invasive disease in the context of different vaccines and vaccine schedules used in Canada.
* Determining the vaccine effectiveness of PNEU-C-15 in healthy and in immunocompromised pediatric population.
* Determining the duration of immunity for PNEU-C-15 only and in mixed schedule programs.
* Assessing the cost effectiveness of PNEU-C-15 in pediatric population.
List of abbreviations
---------------------
AEFI
Adverse event following immunization
AOM
Acute otitis media
CAP
Community acquired pneumonia
CI
Confidence interval
CIC
Canadian Immunization Committee
GMC
Geometric mean concentration
HIV
Human Immunodeficiency Virus
IgG
Immunoglobulin G
IPD
Invasive pneumococcal disease
NACI
National Advisory Committee on Immunization
NOC
Notice of Compliance
PHAC
Public Health Agency of Canada
PNEU-C-13
13-valent conjugate pneumococcal vaccine
PNEU-C-15
15-valent conjugate pneumococcal vaccine
PWG
Pneumococcal working group
ST
Serotype
Acknowledgements
----------------
**This statement was prepared by:** K Hildebrand, O Baclic, R Pless, A Wierzbowski and E Wong on behalf of the NACI Pneumococcal Working Group and was approved by NACI.
**NACI gratefully acknowledges the contribution of**: A Li, A Golden, W Demczuk, A Griffith, I Martin, M Salvadori, C Tremblay, M Tunis, and J Zafack.
### NACI Pneumococcal Working Group
**NACI Pneumococcal Working Group Members**: K Hildebrand (Chair), J Papenburg, P De Wals, N Brousseau, J Bettinger, D Fisman, J Kellner, S Rechner, G Tyrrell, A McGeer, S Nasreen, and M Kobayashi (Centers for Disease Control and Prevention, US).
**Ex-officio representatives:** M Knight (First Nations and Inuit Health Branch, ISC), G Coleman (Biologic and Radiopharmaceutical Drugs Directorate, HC), A Y Li (VPD Surveillance), I Martin (National Microbiology Laboratory) and G Metz (Vaccine Safety).
**PHAC participants**: E Wong, A Wierzbowski, R Pless, O Baclic, M Tunis, A Stevens, N Islam, A Tuite, MW Yeung, A Killikelly, Robert MacTavish, Fiann Crane, F Khan, M Hersi, A Simmons, and C Tremblay.
### NACI
**NACI members**: S Deeks (Chair), R Harrison (Vice-Chair), M Andrew, J Bettinger, N Brousseau, H Decaluwe, P De Wals, E Dubé, V Dubey, K Hildebrand, K Klein, M O'Driscoll, J Papenburg, A Pham-Huy, B Sander, and S Wilson.
**Liaison representatives**: L Bill/ M Nowgesic (Canadian Indigenous Nurses Association), LM Bucci (Canadian Public Health Association), E Castillo (Society of Obstetricians and Gynaecologists of Canada), J Comeau (Association of Medical Microbiology and Infectious Disease Control), M Osmack (Indigenous Physicians Association of Canada), J Potter (College of Family Physicians of Canada), M Lavoie (Council of Chief Medical Officers of Health), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), and A Ung (Canadian Pharmacists Association).
**Former liaison representatives**: L Dupuis (Canadian Nurses Association), D Fell (Canadian Association for Immunization Research and Evaluation), J Hu (College of Family Physicians of Canada)
**Ex-officio representatives**: V Beswick-Escanlar (National Defence and the Canadian Armed Forces), E Henry (Centre for Immunization and Respiratory Infectious Diseases (CIRID), PHAC), M Lacroix (Public Health Ethics Consultative Group, PHAC), C Pham (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada), S Ogunnaike-Cooke (CIRID, PHAC), P Fandja (Marketed Health Products Directorate, HC), M Routledge (National Microbiology Laboratory, PHAC), and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada).
**Former ex-officio representatives**: C Lourenco (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada), K Robinson (Marketed Health Products Directorate, HC)
Appendix A: Immunogenicity of PNEU-C-15 in pediatric populations
----------------------------------------------------------------
Immunogenicity following immunization with PNEU-C-15 was reported in seven Phase 2/3 clinical trials that included healthy children (five studies [Footnote 13](#fn13) [Footnote 15](#fn15) [Footnote 16](#fn16) [Footnote 17](#fn17) [Footnote 18](#fn18)), children with sickle cell disease (one study [Footnote 14](#fn14)) and HIV infection (one study [Footnote 19](#fn19)). The measured outcomes included serotype-specific immunoglobulin G (IgG) responses (reported as the proportion of study participants meeting the IgG threshold value of ≥0.35 μg/mL), geometric mean concentrations (GMC) and opsonophagocytic activity (OPA) geometric mean titres (GMT) at 30 days after dose administration.
In the pivotal double-blind clinical trial V114-025 [Footnote 16](#fn16), immunogenicity was measured in healthy infants aged 2 to 15 months who were vaccinated with PNEU-C-13 (n=591) or PNEU-C-15 (n=588) at 2, 4 and 11–15 months of age. One month following dose 3, non-inferior seroresponse (based on the lower bound of the 95% CI for the percentage point difference being greater than -10 points) was observed for all 13 shared serotypes, and higher immune responses were observed for the two PNEU-C-15 unique serotypes ([Table 5, Appendix A](#t5)).
Similarly, at one month post dose 3, IgG GMC values were found to be non-inferior (based on the lower bound of the 2-sided 95% CI for the GMC ratio being >0.5) for all 13 shared serotypes and superior for the PNEU-C-15 unique serotypes ([Table 6, Appendix A](#t6)). Of note, although numerically similar, all observed GMC values were generally lower for PNEU-C-15 compared to PNEU-C-13, except for ST3. When assessed by OPA GMT, functional antibodies were found to be generally comparable for all shared serotypes.
In another pivotal double-blind clinical trial (V114-029 [Footnote 18](#fn18)) immunogenicity was assessed in over 1,700 healthy infants 6 to 12 weeks of age using a four dose schedule (vaccine provided at 2, 4, 6 and 12-15 months of age). One month following dose 4, seroresponse rates after PNEU-C-15 administration were found to be non-inferior for all 13 shared serotypes and superior for the two unique types compared to PNEU-C-13 ([Table 7, Appendix A](#t7)).
In the V114-029 trial, measurement of serotype-specific IgG GMC at 30 days following the 3 dose primary series also demonstrated non-inferiority to PNEU-C-13 for the majority of serotypes, with a response to only one serotype (6A) not meeting the non-inferiority criteria by a small margin (the lower bound of the 2-sided 95% CI for the GMC ratio being 0.48) ([Table 8, Appendix A](#t8)). In addition, 30 days following both dose 3 and dose 4, superiority was demonstrated for the two PNEU-C-15 unique serotypes as well as ST3. Serotype-specific OPA GMT at 30 days following the 3 dose primary series and toddler booster dose were reported to be numerically similar to PNEU-C-13 for the shared serotypes and higher for the unique serotypes.
### Clinical trial data on PNEU-C-15 in children
Table 5. Comparison of PNEU-C-13 vs PNEU-C-15 seroresponse rates at 30 days following dose 3 according to serotype (V114-025)
|
Serotype | Observed response, % | % Difference (95% CI\*) |
| --- | --- | --- |
| PNEU-C-15 (N=588) | PNEU-C-13 (N=591) | (PNEU-C-15 vs. PNEU-C-13) |
| 1 | 97 | 99 | -2.8 (-4.7 to -1.3) |
| 3 | 92 | 84 | 8.2 (4.4 to 12.2) |
| 4 | 96 | 98 | -2.2 (-4.5 to -0.1) |
| 5 | 99 | 100 | -0.9 (-2.2 to -0.2) |
| 6A | 99 | 99 | -0.4 (-1.9 to 1.1) |
| 6B | 97 | 99 | -1.7 (-3.5 to -0.1) |
| 7F | 100 | 100 | 0.0 (-0.0 to 0.9) |
| 9V | 99 | 100 | -1.1 (-2.4 to -0.4) |
| 14 | 100 | 100 | -0.2 (-1.0 to 0.5) |
| 18C | 99 | 99 | -0.4 (-1.8 to 0.9) |
| 19A | 99 | 100 | -0.9 (-2.2 to -0.2) |
| 19F | 100 | 100 | -0.4 (-1.3 to 0.3) |
| 23F | 97 | 97 | -0.5 (-2.7 to 1.5) |
| 22F | 100 | 6 | 93.8 (91.5 to 95.6) |
| 33F | 99 | 4 | 94.9 (92.7 to 96.5) |
| \*p-value for all GMC ratios <0.001.
**Abbreviations:** CI=confidence interval; N=Number of participants randomized and vaccinated |
Table 6. Comparison of serotype-specific IgG GMCs at 30 days following dose 3 (V114-025)
|
Serotype | IgG GMC | GMC ratio (95% CI)\* |
| --- | --- | --- |
| PNEU-C-15 (N=588) | PNEU-C-13 (N=591) | (PNEU-C-15 vs. PNEU-C-13) |
| 1 | 1.3 | 2.1 | 0.62 (0.57 to 0.68) |
| 3 | 0.8 | 0.7 | 1.28 (1.17 to 1.39) |
| 4 | 1.3 | 1.7 | 0.75 (0.68 to 0.82) |
| 5 | 2.0 | 3.1 | 0.64 (0.59 to 0.70) |
| 6A | 3.1 | 4.6 | 0.68 (0.61 to 0.76) |
| 6B | 4.2 | 4.4 | 0.95 (0.85 to 0.76) |
| 7F | 3.1 | 3.9 | 0.79 (0.72 to 0.85) |
| 9V | 2.1 | 3.0 | 0.72 (0.66 to 0.78) |
| 14 | 5.3 | 7.0 | 0.75 (0.67 to 0.83) |
| 18C | 1.9 | 2.2 | 0.88 (0.80 to 0.95) |
| 19A | 4.7 | 5.7 | 0.83 (0.75 to 0.91) |
| 19F | 4.1 | 4.6 | 0.88 (0.80 to 0.97) |
| 23F | 1.5 | 1.8 | 0.87 (0.79 to 0.97) |
| 22F | 6 | 0.08 | 71.19 (65.16 to 79.10) |
| 33F | 3.4 | 0.07 | 46.58 (42.19 to 51.42) |
| \*p-value for all GMC ratios <0.001.
**Abbreviations:** CI=confidence interval; GMC=geometric mean concentration (mcg/mL); IgG=immunoglobulin G; N=Number of participants randomized and vaccinated. |
Table 7. Comparison of PNEU-C-13 vs PNEU-C-15 seroresponse rates at 30 days following dose 3 according to serotype (V114-029)
|
Serotype | Observed response, % | % Difference (95% CI) |
| --- | --- | --- |
| PNEU-C-15 (N=858) | PNEU-C-13 (N=856) | (PNEU-C-15 vs. PNEU-C-13) |
| 1 | 95.7 | 99.1 | -3.4 (-5.2 to -1.8) |
| 3 | 94.7 | 79.2 | 15.6 (12.1 to 19.2) |
| 4 | 96.4 | 98.6 | -2.2 (-4.0 to –0.6) |
| 5 | 95.3 | 97.4 | -2.1 (-4.2 to -0.2) |
| 6A | 93.7 | 98.6 | -4.9 (-7.1 to –3.0) |
| 6B | 88.6 | 92.0 | -3.4 (-6.6 to –0.3) |
| 7F | 99.0 | 99.8 | -0.8 (-1.9 to –0.1) |
| 9V | 97.1 | 98.2 | -1.0 (-2.8 to 0.6) |
| 14 | 97.9 | 97.9 | -0.0 (-1.6 to 1.6) |
| 18C | 97.4 | 98.3 | -0.9 (-2.6 to 0.7) |
| 19A | 97.9 | 99.7 | -1.8 (-3.2 to -0.8) |
| 19F | 99.0 | 100.0 | -1.0 (-2.1 to –0.4) |
| 23F | 91.5 | 91.8 | -0.3 (-3.2 to 2.7) |
| 22F | 98.6 | 91.8 | 6.7 (4.6 to 9.2) |
| 33F | 87.3 | 91.8 | -4.5 (-7.8 to –1.3) |
| **Abbreviations:** CI= confidence interval; N= Number of participants randomized and vaccinated. |
Table 8. Comparison of serotype-specific IgG GMCs at 30 days following dose 4 (V114-029)
|
Serotype | PNEU-C-15 (N=858) | PNEU-C-13 (N=856) | GMC ratio[Footnote a](#fna)
(PNEU-C-15 / PNEU-C-13)
(95% CI) |
| --- | --- | --- | --- |
| n | GMC | n | GMC |
| 13 shared[Footnote b](#fnb) |
| --- |
| 1 | 715 | 1.35 | 685 | 2.03 | 0.66 (0.62 to 0.72) |
| 3 | 712 | 0.96 | 686 | 0.71 | 1.35 (1.25 to 1.46) |
| 4 | 713 | 1.23 | 682 | 1.60 | 0.77 (0.71 to 0.84) |
| 5 | 713 | 2.49 | 682 | 3.95 | 0.63 (0.58 to 0.69) |
| 6A | 713 | 3.70 | 682 | 6.21 | 0.60 (0.54 to 0.65) |
| 6B | 712 | 4.76 | 682 | 6.43 | 0.74 (0.67 to 0.81) |
| 7F | 714 | 3.42 | 686 | 4.85 | 0.70 (0.65 to 0.77) |
| 9V | 716 | 2.40 | 686 | 3.29 | 0.73 (0.67 to 0.80) |
| 14 | 716 | 5.61 | 685 | 6.95 | 0.81 (0.73 to 0.89) |
| 18C | 713 | 2.62 | 684 | 3.08 | 0.85 (0.78 to 0.93) |
| 19A | 715 | 4.10 | 685 | 5.53 | 0.74 (0.68 to 0.80) |
| 19F | 715 | 3.55 | 685 | 4.47 | 0.79 (0.74 to 0.86) |
| 23F | 713 | 2.04 | 683 | 3.32 | 0.61 (0.56 to 0.68) |
| 2 unique to PNEU-C-15 |
| 22F | 714 | 7.52 | ‡ | ‡ | 4.69 (4.30 to 5.11) |
| 33F | 714 | 4.15 | ‡ | ‡ | 2.59 (2.36 to 2.83) |
|
Footnote a
GMC ratio and CI are calculated using the t-distribution with the variance estimate from a ST-specific linear model utilizing the natural log-transformed antibody concentrations as the response and a single term for vaccination group.
[Return to footnote a referrer](#fna-rf)
Footnote b
A conclusion of non-inferiority is based on the lower bound of the 2-sided 95% CI for the GMC ratio (PNEU-C-15 / PNEU-C-13) being >0.5.
[Return to footnote b referrer](#fnb-rf)
‡ A conclusion of non-inferiority of PNEU-C-15 to PNEU-C-13 is based on the comparison of the GMC for the 2 additional STs to the lowest responding PNEU-C-13 ST (ST4), excluding ST3.**Abbreviations:** CI=confidence interval; GMC=geometric mean concentration (mcg/mL); IgG=immunoglobulin G; N=Number of participants randomized and vaccinated; n=number of participants contributing to the analysis; ST=serotype. |
Table 9. Comparison of seroresponse rates following the use of different schedules using PNEU-C-13 and/or PNEU-C-15 at 30 days after dose 3 (V114-027)
|
Arm/Group title | Group 1: PNEU-C-13-PNEU-C-13-PNEU-C-13-PNEU-C-13 | Group 2: PNEU-C-13-PNEU-C-13-PNEU-C-13-PNEU-C-15 | Group 3: PNEU-C-13-PNEU-C-13-PNEU-C-15-PNEU-C-15 | Group 4: PNEU-C-13-PNEU-C-15-PNEU-C-15-PNEU-C-15 | Group 5: PNEU-C-15-PNEU-C-15-PNEU-C-15-PNEU-C-15 |
| --- | --- | --- | --- | --- | --- |
| Overall number of participants analyzed | 179 | 181 | 178 | 179 | 179 |
| ST1 | Number analyzed | 142 participants | 142 participants | 129 participants | 138 participants | 148 participants |
| % of participants (95% CI) | 97.9 | 100 | 99.2 | 97.8 | 96.6 |
| (94.0 to 99.6) | (97.4 to 100.0) | (95.8 to 100.0) | (93.8 to 99.5) | (92.3 to 98.9) |
| ST3 | Number analyzed | 142 participants | 142 participants | 129 participants | 138 participants | 147 participants |
| % of participants (95% CI) | 73.2 | 73.9 | 79.1 | 81.9 | 93.9 |
| (65.2 to 80.3) | (65.9 to 80.9) | (71.0 to 85.7) | (74.4 to 87.9) | (88.7 to 97.2) |
| ST4 | Number analyzed | 141 participants | 139 participants | 128 participants | 137 participants | 147 participants |
| % of participants (95% CI) | 97.9 | 98.6 | 93 | 94.2 | 96.6 |
| (93.9 to 99.6) | (94.9 to 99.8) | (87.1 to 96.7) | (88.8 to 97.4) | (92.2 to 98.9) |
| ST5 | Number analyzed | 141 participants | 141 participants | 128 participants | 138 participants | 148 participants |
| % of participants (95% CI) | 97.9 | 99.3 | 97.7 | 97.1 | 98 |
| (93.9 to 99.6) | (96.1 to 100.0) | (93.3 to 99.5) | (92.7 to 99.2) | (94.2 to 99.6) |
| ST6A | Number analyzed | 140 participants | 140 participants | 128 participants | 138 participants | 148 participants |
| % of participants (95% CI) | 99.3 | 99.3 | 99.2 | 97.1 | 98.6 |
| (96.1 to 100.0) | (96.1 to 100.0) | (95.7 to 100.0) | (92.7 to 99.2) | (95.2 to 99.8) |
| ST6B | Number analyzed | 138 participants | 140 participants | 127 participants | 138 participants | 147 participants |
| % of participants (95% CI) | 91.3 | 94.3 | 96.1 | 95.7 | 95.2 |
| (85.3 to 95.4) | (89.1 to 97.5) | (91.1 to 98.7) | (90.8 to 98.4) | (90.4 to 98.1) |
| ST7F | Number analyzed | 142 participants | 142 participants | 129 participants | 138 participants | 148 participants |
| % of participants (95% CI) | 100 | 100 | 100 | 100 | 100 |
| (97.4 to 100.0) | (97.4 to 100) | (97.2 to 100.0) | (97.4 to 100.0) | (97.5 to 100.0) |
| ST9V | Number analyzed | 143 participants | 142 participants | 128 participants | 138 participants | 148 participants |
| % of participants (95% CI) | 96.5 | 96.5 | 96.1 | 95.7 | 98.6 |
| (92.0 to 98.9) | (92.0 to 98.8) | (91.1 to 98.7) | (90.8 to 98.4) | (95.2 to 99.8) |
| ST14 | Number analyzed | 142 participants | 142 participants | 128 participants | 138 participants | 148 participants |
| % of participants (95% CI) | 98.6 | 98.6 | 96.9 | 100 | 98.6 |
| (95.0 to 99.8) | (95.0 to 99.8) | (92.2 to 99.1) | (97.4 to 100.0) | (95.2 to 99.8) |
| ST18C | Number analyzed | 142 participants | 142 participants | 129 participants | 138 participants | 148 participants |
| % of participants (95% CI) | 95.8 | 100 | 99.2 | 97.8 | 98 |
| (91.0 to 98.4) | (97.4 to 100.0) | (95.8 to 100.0) | (93.8 to 99.5) | (94.2 to 99.6) |
| ST19A | Number analyzed | 143 participants | 142 participants | 129 participants | 138 participants | 148 participants |
| % of participants (95% CI) | 99.3 | 100 | 98.4 | 97.1 | 97.3 |
| (96.2 to 100.0) | (97.4 to 100.0) | (94.5 to 99.8) | (92.7 to 99.2) | (93.2 to 99.3) |
| ST19F | Number analyzed | 143 participants | 142 participants | 128 participants | 138 participants | 148 participants |
| % of participants (95% CI) | 99.3 | 99.3 | 99.2 | 100 | 100 |
| (96.2 to 100.0) | (96.1 to 100.0) | (95.7 to 100.0) | (97.4 to 100.0) | (97.5 to 100.0) |
| ST23F | Number analyzed | 140 participants | 140 participants | 128 participants | 135 participants | 147 participants |
| % of participants (95% CI) | 91.4 | 97.9 | 90.6 | 92.6 | 94.6 |
| (85.5 to 95.5) | (93.9 to 99.6) | (84.2 to 95.1) | (86.8 to 96.4) | (89.6 to 97.6) |
| ST22F | Number analyzed | 138 participants | 140 participants | 128 participants | 137 participants | 148 participants |
| % of participants (95% CI) | 2.9 | 1.4 | 93.8 | 99.3 | 98.6 |
| (0.8 to 7.3) | (0.2 to 5.1) | (88.1 to 97.3) | (96.0 to 100.0) | (95.2 to 99.8) |
| ST33F | Number analyzed | 141 participants | 139 participants | 127 participants | 137 participants | 148 participants |
| % of participants (95% CI) | 2.1 | 2.2 | 39.4 | 75.9 | 93.2 |
| (0.4 to 6.1) | (0.4 to 6.2) | (30.8 to 48.4) | (67.9 to 82.8) | (87.9 to 96.7) |
| All randomized participants who were compliant with the protocol, got scheduled dosing of PNEU-C-15 or PNEU-C-13, had IgG concentration ≥0.35µg/mL data available for serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, 22F or 33F in Groups 1, 2, 3, 4 or 5 at 30 Days post Vaccination 3.
**Abbreviations:** CI=confidence interval; ST=serotype. |
Table 10. Comparison of IgG GMC following the use of different schedules using PNEU-C-13 and/or PNEU-C-15 at 30 days after dose 4 (V114-027)
|
Arm/Group title | Group 1: Prevnar 13™-Prevnar 13™-Prevnar 13™-Prevnar 13™ | Group 2: Prevnar 13™-Prevnar 13™-Prevnar 13™-V114 | Group 3: Prevnar 13™-Prevnar 13™-V114-V114 | Group 4: Prevnar 13™-V114-V114-V114 |
| --- | --- | --- | --- | --- |
| Overall number of participants analyzed | 179 | 181 | 178 | 179 |
| ST1 | Number analyzed | 147 participants | 151 participants | 128 participants | 139 participants |
| µg/mL (95% CI) | 2.02 | 1.69 | 1.89 | 1.68 |
| (1.78 to 2.30) | (1.48 to 1.93) | (1.63 to 2.18) | (1.48 to 1.91) |
| ST3 | Number analyzed | 148 participants | 151 participants | 128 participants | 139 participants |
| µg/mL (95% CI) | 0.72 | 0.77 | 0.68 | 0.73 |
| (0.64 to 0.82) | (0.68 to 0.87) | (0.61 to 0.77) | (0.66 to 0.82) |
| ST4 | Number analyzed | 146 participants | 151 participants | 128 participants | 139 participants |
| µg/mL (95% CI) | 1.51 | 1.33 | 1.27 | 1.23 |
| (1.30 to 1.76) | (1.14 to 1.56) | (1.10 to 1.46) | (1.08 to 1.41) |
| ST5 | Number analyzed | 147 participants | 151 participants | 128 participants | 138 participants |
| µg/mL (95% CI) | 3.66 | 3.39 | 3.82 | 2.9 |
| (3.18 to 4.20) | (2.91 to 3.94) | (3.23 to 4.51) | (2.50 to 3.38) |
| ST6A | Number analyzed | 146 participants | 151 participants | 128 participants | 139 participants |
| µg/mL (95% CI) | 6.42 | 7.16 | 7.16 | 5.17 |
| (5.56 to 7.42) | (6.30 to 8.15) | (6.17 to 8.30) | (4.43 to 6.03) |
| ST6B | Number analyzed | 146 participants | 151 participants | 128 participants | 139 participants |
| µg/mL (95% CI) | 6.15 | 7.58 | 6.64 | 6.62 |
| (5.36 to 7.07) | (6.61 to 8.68) | (5.73 to 7.69) | (5.75 to 7.62) |
| ST7F | Number analyzed | 146 participants | 151 participants | 128 participants | 139 participants |
| µg/mL (95% CI) | 5.1 | 5.69 | 5.06 | 3.98 |
| (4.43 to 5.88) | (4.93 to 6.56) | (4.33 to 5.92) | (3.47 to 4.57) |
| ST9V | Number analyzed | 147 participants | 151 participants | 128 participants | 139 participants |
| µg/mL (95% CI) | 2.93 | 2.76 | 2.57 | 2.46 |
| (2.56 to 3.34) | (2.41 to 3.16) | (2.22 to 2.97) | (2.19 to 2.78) |
| ST14 | Number analyzed | 146 participants | 151 participants | 128 participants | 139 participants |
| µg/mL (95% CI) | 7.62 | 10.59 | 10.91 | 7.87 |
| (6.55 to 8.86) | (9.01 to 12.44) | (9.29 to 12.81) | (6.77 to 9.16) |
| ST18C | Number analyzed | 147 participants | 151 participants | 128 participants | 139 participants |
| µg/mL (95% CI) | 2.57 | 3.88 | 3.7 | 2.76 |
| (2.21 to 2.99) | (3.38 to 4.45) | (3.20 to 4.29) | (2.42 to 3.15) |
| ST19A | Number analyzed | 148 participants | 151 participants | 128 participants | 139 participants |
| µg/mL (95% CI) | 5.92 | 5.52 | 5.2 | 4.95 |
| (5.15 to 6.80) | (4.88 to 6.25) | (4.42 to 6.12) | (4.27 to 5.73) |
| ST19F | Number analyzed | 148 participants | 151 participants | 128 participants | 139 participants |
| µg/mL (95% CI) | 4.78 | 4.88 | 5.02 | 4.6 |
| (4.22 to 5.42) | (4.33 to 5.51) | (4.40 to 5.73) | (4.00 to 5.28) |
| ST23F | Number analyzed | 146 participants | 150 participants | 127 participants | 138 participants |
| µg/mL (95% CI) | 2.89 | 2.72 | 2.29 | 2.22 |
| (2.42 to 3.44) | (2.33 to 3.18) | (1.93 to 2.70) | (1.92 to 2.56) |
| All randomized participants who were compliant with the protocol, got scheduled dosing of V114 or Prevnar 13™ and had IgG GMC data for serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F or 23F in Groups 1, 2, 3, 4 or 5 at 30 Days post Vaccination 4. 13 IgG serotypes in Groups 2, 3, 4 were compared to Group 1 as a protocol-specified primary outcome analysis; 13 IgG serotypes in Group 5 were compared to Group 1 as a separate protocol-specified secondary outcome analysis and reported later.
**Abbreviations:** CI=confidence interval; ST=serotype. |
Table 11. Comparison of AEs reported in infants (V114-025)
|
Adverse event information | **Adverse events (AEs), n(%)** |
| --- | --- |
| **PNEU-C-15 (N=587)** | **PNEU-C-13 (N=591)** |
| One or more AE | 555 (94.5) | 550 (93.1) |
| Injection-site | 427 (72.7) | 398 (67.3) |
| Systemic | 536 (91.3) | 526 (89.0) |
| Vaccine-related AEs | 535 (91.1) | 525 (88.8) |
| Injection-site | 427 (72.7) | 398 (67.3) |
| Systemic | 483 (82.3) | 461 (78.0) |
| Serious AEs | 57 (9.7) | 70 (11.8) |
| Serious vaccine-related | 0 (0.0) | 1 (0.2) |
| Deaths | 0 (0.0) | 0 (0.0) |
| Vaccine discontinuation due to an AE | 0 (0.0) | 0 (0.0) |
| Injection site pain | 238 (40.5) | 173 (29.3) |
| Decreased appetite | 199 (33.9) | 198 (33.5) |
| Irritability | 421 (71.7) | 392 (66.3) |
| Somnolence | 271 (46.2) | 247 (41.8) |
| Urticaria | 22 (3.7) | 23 (3.9) |
| **Abbreviations:** AE=adverse event; N=Number of participants randomized and vaccinated; n=number of participants contributing to the analysis. |
Table 12. Percentage of participants with solicited local and systemic adverse reactions within 14 days post vaccination in infants receiving a primary series (protocols 025, 027, 029 and 031)
|
Dose | Dose 1 | Dose 2 | Dose 3 |
| --- | --- | --- | --- |
| | PNEU-C-15 (%) N=3,589 | PNEU-C-13 (%) N=2,058 | PNEU-C-15 (%) N=3,589 | PNEU-C-13 (%) N=2,058 | PNEU-C-15 (%) N=3,589 | PNEU-C-13 (%) N=2,058 |
| Local reactions[Footnote a](#fnt12a) |
| --- |
| Pain | 27.1 | 24.1 | 19.8 | 18.0 | 19.1 | 18.8 |
| Erythema | 17.1 | 14.1 | 20.0 | 20.8 | 17.0 | 19.1 |
| Swelling | 13.7 | 11.6 | 11.6 | 10.7 | 9.9 | 9.3 |
| Induration | 12.6 | 13.5 | 12.6 | 15.9 | 11.4 | 13.1 |
| Systemic reactions[Footnote b](#fnt12b) |
| Decreased appetite | 17.0 | 15.9 | 15.4 | 14.0 | 13.9 | 14.3 |
| Irritability | 55.1 | 53.2 | 50.7 | 47.3 | 47.0 | 43.7 |
| Somnolence | 40.7 | 41.3 | 27.5 | 27.8 | 22.8 | 24.1 |
| Urticaria | 1.1 | 1.5 | 1.4 | 1.6 | 1.6 | 1.8 |
| Elevated body temperature[Footnote c](#fnt12c)[Footnote d](#fnt12d) |
| ≥38.0 C and <39.0 C | 43.4 | 42.0 | 39.3 | 39.6 | 35.7 | 37.4 |
| ≥39.0 C and <40.0 C | 2.2 | 2.6 | 3.4 | 4.6 | 3.5 | 3.1 |
| ≥40.0 C | 0.2 | 0.0 | 0.3 | 0.4 | 0.5 | 0.2 |
|
Footnote a
Full term infants in Protocol 025 received Dose 1 and Dose 2 as part of a 2-dose primary series. Preterm infants in Protocol 025 received Dose 1, Dose 2, and Dose 3 as part of a 3-dose primary series.
[Return to footnote a referrer](#fnt12a-rf)
Footnote b
Solicited on Day 1 through Day 14 postvaccination following each dose.
[Return to footnote b referrer](#fnt12b-rf)
Footnote c
Solicited on Day 1 through Day 7 postvaccination following each dose.
[Return to footnote c referrer](#fnt12c-rf)
Footnote d
Percentages reflect the number of participants with temperature data based on a rectal equivalent temperature.
[Return to footnote d referrer](#fnt12d-rf)
**Abbreviations:** N=Number of participants vaccinated. |
References
----------
Footnote 1
Product Monograph: Vaxneuvance® Pneumococcal 15-valent Conjugate Vaccine [CRM197 Protein], adsorbed [Internet]. Kirkland (QC): Merck Canada Inc.; 2022 Jul 08 [cited 2022 Oct 24]. Available from: https://pdf.hres.ca/dpd\_pm/00066824.PDF.
[Return to footnote 1 referrer](#fn1-rf)
Footnote 2
Pneumococcal vaccination program [Internet]. Québec (CA): Gouvernement du Québec; 2023 Feb 03 [cited 2023 Feb 23]. Available from: https://www.quebec.ca/en/health/advice-and-prevention/vaccination/pneumococcal-vaccination-program.
[Return to footnote 2 referrer](#fn2-rf)
Footnote 3
Public Health Agency of Canada. Canadian Immunization Guide: Part 4 - Active Vaccines: Pneumococcal Vaccine [Internet]. Ottawa (ON): Public Health Agency of Canada; 2022 Sep 13 [cited 2022 Oct 24]. Available from: https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html.
[Return to footnote 3 referrer](#fn3-rf)
Footnote 4
Highlights from the 2019 childhood National Immunization Coverage Survey (cNICS) [Internet]. Ottawa (ON): Public Health Agency of Canada; 2022 Dec 22 [cited 2023 Feb 23]. Available from: https://www.canada.ca/en/public-health/services/publications/vaccines-immunization/2019-highlights-childhood-national-immunization-coverage-survey.html.
[Return to footnote 4 referrer](#fn4-rf)
Footnote 5
Vaccination Coverage Goals and Vaccine Preventable Disease Reduction Targets by 2025 [Internet]. Ottawa (ON): Public Health Agency of Canada; 2022 Aug 16 [cited 2022 Oct 24]. Available from: https://www.canada.ca/en/public-health/services/immunization-vaccine-priorities/national-immunization-strategy/vaccination-coverage-goals-vaccine-preventable-diseases-reduction-targets-2025.html.
[Return to footnote 5 referrer](#fn5-rf)
Footnote 6
Ismail SJ, Langley JM, Harris TM, Warshawsky BF, Desai S, FarhangMehr M. Canada's National Advisory Committee on Immunization (NACI): Evidence-based decision-making on vaccines and immunization. Vaccine. 2010;28:A58,63. doi: 10.1016/j.vaccine.2010.02.035.
[Return to footnote 6 referrer](#fn6-rf)
Footnote 7
Ismail SJ, Hardy K, Tunis MC, Young K, Sicard N, Quach C. A framework for the systematic consideration of ethics, equity, feasibility, and acceptability in vaccine program recommendations. Vaccine. 2020 Aug 10;38(36):5861,5876. doi: 10.1016/j.vaccine.2020.05.051.
[Return to footnote 7 referrer](#fn7-rf)
Footnote 8
Product Monograph: SynflorixTM Pneumococcal conjugate vaccine (Non-Typeable Haemophilus influenzae (NTHi) protein D, diphtheria or tetanus toxoid conjugates) adsorbed [Internet]. Mississauga (ON): GlaxoSmithKline Inc.; 2019 Nov 13 [cited 2022 Oct 24]. Available from: https://pdf.hres.ca/dpd\_pm/00053908.PDF.
[Return to footnote 8 referrer](#fn8-rf)
Footnote 9
PRODUCT MONOGRAPH: Prevnar\* 13 **-** Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein) Suspension for Intramuscular Injection Active Immunizing Agent [Internet]. Kirkland (QC): Pfizer Canada ULC; 2019 Aug 8 [cited 2022 Oct 24]. Available from: https://pdf.hres.ca/dpd\_pm/00052583.PDF.
[Return to footnote 9 referrer](#fn9-rf)
Footnote 10
PRODUCT MONOGRAPH: PNEUMOVAX\* 23 (pneumococcal vaccine, polyvalent, MSD Std.) Solution for injection Active Immunizing Agent Against Infections Caused by Pneumococci [Internet]. Kirkland (QC): Merck Canada Inc.; 2016 Jul 27 [cited 2022 Oct 24]. Available from: https://pdf.hres.ca/dpd\_pm/00035855.PDF.
[Return to footnote 10 referrer](#fn10-rf)
Footnote 11
Vaccine Preventable Disease: Surveillance Report to December 31, 2019 [Internet]. Ottawa (ON): Public Health Agency of Canada; 2022 Dec 15 [cited 2023 Feb 23]. Available from: https://www.canada.ca/en/public-health/services/publications/healthy-living/vaccine-preventable-disease-surveillance-report-2019.html.
[Return to footnote 11 referrer](#fn11-rf)
Footnote 12
Golden A, Griffith A, Demczuk W, Lefebvre B, McGeer A, Tyrrell G, *et al*. Invasive Pneumococcal Disease Surveillance in Canada, 2020. Can Commun Dis Rep. 2022;48(9):396,406. https://doi.org/10.14745/ccdr.v48i09a04.
[Return to footnote 12 referrer](#fn12-rf)
Footnote 13
Platt HL, Greenberg D, Tapiero B, *et al*., V114-008 SG. A Phase II Trial of Safety, Tolerability and Immunogenicity of V114, a 15-Valent Pneumococcal Conjugate Vaccine, Compared with 13-Valent Pneumococcal Conjugate Vaccine in Healthy Infants. Pediatr Infect Dis J. 2020 Aug;39(8):763,770. doi: 10.1097/INF.0000000000002765.
[Return to footnote 13 referrer](#fn13-rf)
Footnote 14
Merck Sharp, Dohme LLC. A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in Children with Sickle Cell Disease (V114–023/PNEU-SICKLE) [Internet]. Bethesda (MD): U.S. National Library of Medicine; 2021 Jun 16 [cited 2022 Oct 24]. Available from: https://clinicaltrials.gov/ct2/show/results/NCT03731182.
[Return to footnote 14 referrer](#fn14-rf)
Footnote 15
Merck Sharp, Dohme LLC. Safety and Immunogenicity of Catch-Up Vaccination Regimens of V114 (V114–024) [Internet]. Bethesda (MD): U.S. National Library of Medicine; 2023 Jan 13 [cited 2023 Feb 23]. Available from: https://clinicaltrials.gov/ct2/show/NCT03885934.
[Return to footnote 15 referrer](#fn15-rf)
Footnote 16
Merck Sharp, Dohme LLC. Safety, Tolerability, and Immunogenicity of V114 in Healthy Infants (V114-025) (PNEU-PED-EU-1) [Internet]. Bethesda (MD): U.S. National Library of Medicine; 2021 Dec 16 [cited 2022 Oct 24]. Available from: https://clinicaltrials.gov/ct2/show/NCT04031846.
[Return to footnote 16 referrer](#fn16-rf)
Footnote 17
Merck Sharp, Dohme LLC. A study to evaluate the Interchangeability of V114 and Prevnar 13 in Healthy Infants (V114–027/PNEU-DIRECTION) [Internet]. Bethesda (MD): U.S. National Library of Medicine; 2023 Jan 17 [cited 2023 Feb 23]. Available from: https://clinicaltrials.gov/ct2/show/NCT03620162.
[Return to footnote 17 referrer](#fn17-rf)
Footnote 18
Merck Sharp, Dohme LLC. Safety, Tolerability, and Immunogenicity of V114 in Healthy Infants (V114–029) [Internet]. Bethesda (MD): U.S. National Library of Medicine; 2022 Mar 25 [cited 2022 Oct 24]. Available from: https://clinicaltrials.gov/ct2/show/NCT03893448.
[Return to footnote 18 referrer](#fn18-rf)
Footnote 19
Merck Sharp, Dohme LLC. Safety, Tolerability, and Immunogenicity of V114 Followed by Administration of PNEUMOVAX™23 Eight Weeks Later in Children Infected with Human Immunodeficiency Virus (HIV) (V114–030/PNEU-WAY PED) [Internet]. Bethesda (MD): U.S. National Library of Medicine; 2021 Dec 09 [cited 2022 Oct 24]. Available from: https://clinicaltrials.gov/ct2/show/NCT03921424.
[Return to footnote 19 referrer](#fn19-rf)
Footnote 20
Merck Sharp, Dohme LLC. A Study to Evaluate the Safety and Tolerability of V114 in Healthy Infants (V114–031/PNEU-LINK) [Internet]. Bethesda (MD): U.S. National Library of Medicine; 2022 Oct 03 [cited 2022 Oct 24]. Available from: https://clinicaltrials.gov/ct2/show/NCT03692871.
[Return to footnote 20 referrer](#fn20-rf)
Footnote 21
Merck Sharp, Dohme LLC. A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in Allogeneic Hematopoietic Stem Cell Transplant Recipients (V114-022/PNEU-STEM) [Internet]. Bethesda (MD): U.S. National Library of Medicine; 2022 Oct 20 [cited 2022 Oct 24]. Available from: https://clinicaltrials.gov/ct2/show/NCT03565900.
[Return to footnote 21 referrer](#fn21-rf)
Footnote 22
Kaur R, Fuji N, Pichichero ME. Dynamic Changes in Otopathogens Colonizing the Nasopharynx and Causing Acute Otitis Media in Children After 13-Valent (PCV13) Pneumococcal Conjugate Vaccination During 2015-2019. Eur J Clin Microbiol Infect Dis. 2022 Jan;41(1):37,44. doi: 10.1007/s10096-021-04324-0.
[Return to footnote 22 referrer](#fn22-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-03-21
| None | None |
dc3dacd57f7f029e5e09850cfdc53d5510558af1 | cma | Sexually transmitted and blood-borne infections: Guides for health professionals | Sexually transmitted and blood-borne infections: Guides for health professionals
The Public Health Agency of Canada (PHAC) provides public health guidance for the prevention and management of sexually transmitted and blood-borne infections (STBBI). PHAC's STBBI guides for healthcare providers and public health professionals outline national recommendations for:
- the screening and diagnosis of STBBI
- the treatment of sexually transmitted infections (STI) of national public health importance
These guides replace the Canadian Guidelines on Sexually Transmitted Infections. PHAC's STBBI guides do not supersede:
- provincial/territorial legislative, regulatory, policy and practice requirements
- any professional guidelines that govern the practise of health professionals in their respective jurisdictions, whose recommendations may differ due to local epidemiology or context
Treatment recommendations include indications for the .
Sexually transmitted and blood-borne infection guides
Find key information and public health guidance for the screening, diagnosis and treatment (if available) of:
Information on best practices for the prevention and management of STBBI:
# Updates to the Guide
National Advisory Committee on Sexually Transmitted and Blood-Borne Infections (NAC-STBBI)
PHAC's STBBI guidelines are developed in collaboration with an expert advisory committee with from across Canada. .
# NAC-STBBI statements |
Sexually transmitted and blood-borne infections: Guides for health professionals
=================================================================================
The Public Health Agency of Canada (PHAC) provides public health guidance for the prevention and management of sexually transmitted and blood-borne infections (STBBI). PHAC's STBBI guides for healthcare providers and public health professionals outline national recommendations for:
* the screening and diagnosis of STBBI
* the treatment of sexually transmitted infections (STI) of national public health importance
These guides replace the Canadian Guidelines on Sexually Transmitted Infections. PHAC's STBBI guides do not supersede:
* provincial/territorial legislative, regulatory, policy and practice requirements
* any professional guidelines that govern the practise of health professionals in their respective jurisdictions, whose recommendations may differ due to local epidemiology or context
Treatment recommendations include indications for the [level and quality of evidence](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/levels-quality-evidence.html).
Sexually transmitted and blood-borne infection guides
-----------------------------------------------------
Find key information and public health guidance for the screening, diagnosis and treatment (if available) of:
* [Chlamydia (including lymphogranuloma venereum)](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/chlamydia-lgv.html)
* [Genital herpes](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/herpes-simplex-virus.html)
* [Gonorrhea](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/gonorrhea.html)
* [Hepatitis B](https://www.canada.ca/en/public-health/services/reports-publications/primary-care-management-hepatitis-b-quick-reference.html)
* [Human immunodeficiency virus (HIV)](https://www.canada.ca/en/public-health/services/hiv-aids/hiv-screening-testing-guide.html)
* [Human papillomavirus (HPV)](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/sexually-transmitted-infections/canadian-guidelines-sexually-transmitted-infections-33.html)
* [*Mycoplasma genitalium*](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/mycoplasma-genitalium.html)
* [Syphilis](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/syphilis.html)
Information on best practices for the prevention and management of STBBI:
* [Sexually transmitted blood borne infections (STBBI) prevention guide](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/stbbi-prevention-guide.html)
* [STI-associated syndromes guide: Syndromic management](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/sti-associated-syndromes.html)This guide provides an overview of the management of the following sexually transmitted infection (STI)-associated syndromes: anogenital ulcers, cervicitis, epididymitis, pelvic inflammatory disease (PID), proctitis, urethritis and vaginitis.
### Updates to the Guide
| Guide | Changes/Updates | Date |
| --- | --- | --- |
| [Chlamydia](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/chlamydia-lgv/screening-diagnostic-testing.html) and [gonorrhea](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/gonorrhea/screening-diagnostic-testing.html) | Update to the screening recommendation for chlamydia and gonorrhea in pregnancy to reflect the recently published recommendation. | April 2023 |
| [Chlamydia](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/chlamydia-lgv.html), [gonorrhea](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/gonorrhea.html) and [syphilis](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/syphilis.html) | Update to the epidemiology data contained within the guides to reflect recently published reports. | June 2022 |
| [Chlamydia](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/chlamydia-lgv.html), [gonorrhea](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/gonorrhea.html), [genital herpes](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/herpes-simplex-virus.html), [mycoplasma genitalium](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/mycoplasma-genitalium.html) and [syphilis](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/syphilis.html) | Changes to the language around sex/gender in order to be more inclusive. | June 2022 |
National Advisory Committee on Sexually Transmitted and Blood-Borne Infections (NAC-STBBI)
------------------------------------------------------------------------------------------
PHAC's STBBI guidelines are developed in collaboration with an expert advisory committee with [members](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/national-advisory-committee-stbbi/membership.html) from across Canada. [Learn about the advisory committee](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2020-46/issue-11-12-november-5-2020/sexually-transmitted-blood-borne-infections-guideline.html).
### NAC-STBBI statements
* [NAC-STBBI recommendations on screening for Chlamydia trachomatis and Neisseria gonorrhoeae in pregnancy (October 2022)](/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/national-advisory-committee-stbbi/statements/recommendations-screening-chlamydia-trachomatis-neisseria-gonorrhoeae-pregnancy.html)
Additional resources
--------------------
PHAC also produces awareness resources based on the guidelines. These resources for health professionals include factsheets, infographics and Canada Communicable Disease Report (CCDR) articles.
### Awareness resources
* [Hepatitis C for health professionals](/en/public-health/services/diseases/hepatitis-c/health-professionals-hepatitis-c.html#a2)
* [HIV for health professionals](/en/public-health/services/diseases/hiv-aids/health-professionals.html)
* [Summary: HIV antiretroviral medication coverage in Canada](/en/public-health/services/publications/diseases-conditions/summary-hiv-antiretroviral-medication-coverage.html)
### Factsheets/infographic
* [Approach to HIV Screening: Types of HIV Screening Tests](/en/public-health/services/publications/diseases-conditions/hiv-factsheet-types-screening-tests.html)
* [HIV factsheet: Biomedical prevention of HIV – PrEP and PEP](/en/public-health/services/publications/diseases-conditions/hiv-factsheet-biomedical-prevention-prep-pep.html)
* [HIV factsheet: Screening and testing](/en/public-health/services/publications/diseases-conditions/hiv-factsheet-screening-testing.html)
* [HIV factsheet: U=U for health professionals](/en/public-health/services/publications/diseases-conditions/hiv-factsheet-undetectable-untransmittable-health-professionals.html)
**Previous**
* [Summary of Recommendations for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Syphilis](/en/services/health/publications/diseases-conditions/guidelines-sti-recommendations-chlamydia-trachomatis-neisseria-gonorrhoeae-syphilis-2019.html)
* [Canadians are still reluctant to get tested for sexually transmitted and blood-borne infections (STBBI)](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2019-45/issue-2-february-7-2019/article-5-addressing-reluctance-stbbi-screening.html)
* [Hepatitis C virus (HCV): Screening and testing for health professionals](/en/public-health/services/publications/diseases-conditions/hepatitis-c-screening-testing-health-professionals.html)
### CCDR articles
* [Translating evidence into practice with the National Advisory Committee on Sexually Transmitted and Blood-Borne Infections](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2020-46/issue-11-12-november-5-2020/sexually-transmitted-blood-borne-infections-guideline.html)
* [Addressing the rising rates of gonorrhea and drug-resistant gonorrhea: There is no time like the present](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2019-45/issue-2-february-7-2019/article-2-preventing-spread-drug-resistant-gonorrhea.html)
### CDN STBBI Guidelines mobile application
Get the most up-to-date recommendations for the management of sexually transmitted and blood-borne infections on your mobile device.
[Download on the App Store
](https://itunes.apple.com/ca/app/canadian-guidelines-on-sexually/id958263397?mt=8)
[Get it on Google play
](https://play.google.com/store/apps/details?id=ca.gc.hcsc.sti)
### STBBI: Barriers to Screening
Free and accredited online course for health professionals on barriers to STBBI screening.
[Register for the course](https://ubccpd.ca/learn/learning-activities/course?eventtemplate=330)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-05-08
| None | None |
69d000cb885f2dfe9a5270cab1e42ef446c46441 | cma | Yellow fever vaccine: Canadian Immunization Guide | Yellow fever vaccine: Canadian Immunization Guide
Key information
# What
- Yellow Fever (YF) virus is transmitted to humans through the bite of an infected mosquito.
- YF is endemic and intermittently epidemic in sub-Saharan Africa and tropical South America. Risk for acquiring YF is low for travellers, particularly those staying in highly developed major urban areas.
- YF is unique among diseases in that there are International Health Regulations (IHR) which outline the requirements for proof of vaccination when travelling to specific countries. In Canada, YF vaccine is only available at Yellow Fever vaccination centres designated by the Public Health Agency of Canada (PHAC).
- YF vaccine has a seroconversion rate of 95% to 99%; immunity is presumed to be lifelong in healthy individuals.
- The most common adverse events (AE) following YF vaccination are pain, inflammation and swelling at the injection site; weakness, headache, and myalgia.
# Who
- YF vaccine is recommended for healthy persons 9 months of age and older.
- YF vaccine may be considered in infants 6 to 8 months of age travelling to countries with risk of YF transmission.
- Persons 60 years of age and older should be considered for primary YF vaccination if travelling to countries with risk of YF transmission. Serious adverse events (SAEs) following vaccination occur more frequently in adults over 60 years of age.
- YF vaccine is recommended for laboratory personnel who work with YF virus.
# How
- Primary immunization is achieved with one dose of YF vaccine.
- The International Certificate of Vaccination or Prophylaxis becomes valid 10 days after primary vaccination.
- While re-vaccination with YF vaccine is not indicated for the majority of immunocompetent travellers, in certain situations booster doses may be required.
- In general, immunocompromised persons, pregnant or lactating persons, and persons with a history of thymus disease should not receive YF vaccine.
- Counselling on routine insect protection and precautions should be provided to all travellers regardless of YF vaccine vaccination status.
# Why
- YF immunization (documented by an International certificate of vaccination or prophylaxis) is required to enter certain countries in Africa and South America regardless of the traveller's country of origin. Other countries may require YF vaccination of travellers if the traveller has passed through endemic countries.
- Between 1970 and 2015, 10 cases of YF were reported in unvaccinated travellers from the United States and Europe who visited YF endemic areas of Africa and South America, 8 of whom died. In 1987, there was 1 documented case of yellow fever in a vaccinated traveler; that traveller survived.
- Outbreaks of YF continue to be reported in countries where YF has been identified as a risk.
Epidemiology
# Disease description
## Infectious agent
Yellow fever (YF) is caused by a ribonucleic acid (RNA) virus from the family flaviviridae.
For more information, refer to the .
## Reservoir
Humans and non-human primates
## Transmission
YF virus is transmitted to humans through the bite of an infected mosquito, primarily *Aedes- or *Haemogogus- species. The incubation period is 3 to 6 days. Humans infected with YF virus experience the highest levels of viremia and are infectious to mosquitoes shortly before the onset of fever and for 3 to 5 days afterwards. Because of the high level of viremia in humans, blood borne transmission of YF virus can theoretically occur through transfusion of blood products, intravenous drug use and needle stick injuries. Probable transmission of vaccine strain YF virus from a mother to her infant through breastfeeding has been reported. Vaccine-associated viremia occurs 4 to 10 days after primary YF vaccination and lasts for up to 5 days. Sustained transmission is not possible in Canada because the recognized mosquito vectors are not present.
## Risk factors
A traveller's risk for acquiring YF is determined by multiple factors including: immunization status, use of personal protection measures against mosquito bites, location and time of travel, duration of exposure, activities while travelling, and local rate of virus transmission. In endemic areas, the risk for acquiring YF is low for most travellers, particularly those staying in highly developed major urban areas. Greater risk exists for travellers who:
- are unvaccinated
- visit rural, forest or jungle areas
- stay for longer periods of time
- participate in outdoor activities such as recreation or fieldwork
## Seasonal/temporal patterns
Yellow fever is endemic and intermittently epidemic in sub-Saharan Africa and tropical South America. In West Africa and South America, YF virus transmission is usually associated with the mid-to-late rainy season when the number of mosquitoes generally increases. However, YF virus can be transmitted during the dry season.
## Spectrum of clinical illness
Clinical presentation of YF varies in severity from asymptomatic to fatal. When symptomatic, YF is typically characterized by an acute onset of symptoms including fever, chills, headache, backache, prostration (state of weakness), muscle pain, joint pain, nausea, vomiting, photophobia, mild jaundice, and epigastric pain. For others, after a brief remission lasting anywhere between hours to a day, symptoms worsen and the disease advances, eventually leading to renal failure, hemorrhagic symptoms, and thrombocytopenia. Treatment is symptomatic and supportive. The case fatality rate for persons with severe disease is 30%-60%.
# Disease distribution
## Incidence/prevalence
### Global
The World Health Organization (WHO) estimates that approximately 200,000 YF cases occur annually, with up to 30,000 deaths. YF is endemic and intermittently epidemic in sub-Saharan Africa and tropical South America. In South America, transmission of YF virus occurs mainly in forest areas rather than in urban areas. In Africa, the majority of outbreaks have been reported from West Africa where YF transmission occurs in both rural and densely populated urban areas. The mosquito vectors are present in Asia; however, there have been no documented cases of transmission.
Between 1970 and 2015, 10 cases of YF were reported in unvaccinated travellers from the United States and Europe who visited YF endemic areas of Africa and South America, 8 of whom died. In 1987, there was 1 documented case of yellow fever in a vaccinated traveller.
YF is unique among diseases in that there are International Health Regulations which outline the requirements for proof of vaccination when travelling to specific countries.
Information about countries with risk of yellow fever transmission and countries requiring yellow fever vaccination is available through the ). Yellow fever risk maps are also available through the .
### National
YF is a nationally and internationally notifiable disease.
## Recent outbreaks
Yellow fever outbreaks are reported in the .
Preparations authorized for use in Canada
In Canada, YF vaccine is only available at yellow fever vaccination centres designated by PHAC. For more information, refer to the list of or call 613-957-8739 or send an email to
# Yellow fever vaccine
- YF-VAX®: live, attenuated, yellow fever vaccine, Sanofi Pasteur Limited. (YF)
For complete prescribing information, consult the product leaflet or information contained within Health Canada's authorized product monographs available through the .
Immunogenicity, efficacy and effectiveness
# Immunogenicity
More than 80% of persons immunized with YF vaccine develop neutralizing antibodies 10 days after vaccination and more than 99% by 28 days after vaccination. In immunocompetent individuals, a single dose of yellow fever vaccine likely confers life-long immunity.
# Efficacy and effectiveness
Efficacy studies of YF vaccine have not been performed.
YF vaccine appears to provide long-term protection against yellow fever disease. After the administration of more than 540 million doses of YF vaccine, only 23 cases of vaccine failure were reported. Sixteen cases occurred in individuals who received a dose of YF vaccine within the last 10 years, one occurred at 20 years and one at 27 years post-vaccination.
Recommendations for use
# Infants up to 8 months of age
Infants less than 6 months of age are at greater risk for YF vaccine-associated neurotropic disease (YEL-AND) following YF vaccination and should not receive YF vaccine.
In general, infants under the age of 9 months should not be vaccinated against YF. However, the Advisory Committee on Immunization Practices (ACIP) in the United States recommends that for infants 6 to 8 months of age travelling to an endemic or transitional area, when travel is unavoidable, the decision to vaccinate needs to balance the risks of YF virus exposure with the risk for AE following immunization (AEFIs). YF vaccination requirements may also differ for infants in certain countries. Although the risk of serious adverse neurologic events is less than that of infants less than six months of age, it is still higher than that of infants 9 months and older.
# Healthy individuals (9 months of age and older)
One dose of YF vaccine is recommended for immunocompetent individuals who are 9 months of age and older and who travel to countries with risk of YF transmission.
At 9 months of age, the risk of SAEs becomes much lower and antibody response increases, thus improving the safety and efficacy profiles of the YF vaccine.
Given the more frequent occurrence of SAEs in older adults, immunocompetent individuals 60 years of age and older should be considered for primary YF vaccination only if travel to countries with risk of YF transmission cannot be avoided and a high level of protection against mosquito exposure is not feasible. YF vaccine is also recommended for laboratory personnel who work with YF virus.
For more information, refer to .
# Booster doses and re-immunization
Booster doses of YF vaccine are not recommended for most immunocompetent travellers. The Committee to Advise on Tropical Medicine and Travel (CATMAT) recommends that, based on a case-by-case assessment of benefit versus risk, the use of a one-time booster dose is recommended for:
- Individuals in whom response to prior vaccination may have been diminished (e.g., who were pregnant or taking immunosuppressive medication, or had an immunocompromising illness at the time of vaccination, and those who underwent a hematopoietic stem cell transplant since their last YF vaccine dose).
- Individuals who received a previous dose which may have been inadequate for long term protection (e.g., fractional dose, undocumented or improperly documented dose or a dose administered by a non-accredited provider).
- Individuals at particularly high risk of exposure (e.g., travelling to an area experiencing an epidemic or major outbreak, or travelling frequently or for prolonged periods to countries with risk of YF transmission): the booster should be considered if at least 10 years have elapsed since primary vaccination and no previous booster doses were administered.
Re-immunization every 10 years is recommended for:
- laboratory personnel working with YF virus unless measured neutralizing antibody titre to yellow fever virus confirms ongoing protection
- HIV-positive individuals who are travelling to countries with risk of YF transmission
There is very little information on longer-term immune response in those vaccinated in early childhood; research is ongoing to determine the duration of immunity in infants and young children after a single dose of vaccine. At this point, CATMAT does not make specific recommendations for a booster dose of the YF vaccine in young children. Individual assessment of risks and benefits should be done if considering re-immunization of children who received a single dose of vaccine prior to 1 year of age. Serology may be considered in this case where the immune response to prior YF vaccination may be diminished, if travelling to an area with risk of transmission.
In 2014, the WHO stated that a single dose of yellow fever vaccine confers life-long immunity and revised the International Health Regulations. As of July 2016, revaccination or a booster dose of yellow fever vaccine is not required of international travellers as a condition of entry into a country.
Vaccination of specific populations
# Pregnancy and breastfeeding
In general, YF vaccine, like other live viral vaccines, should be avoided in pregnancy. Pregnant or breastfeeding individuals should be considered for YF immunization only if they are travelling to countries with risk of YF transmission, travel cannot be postponed, and a high level of protection against mosquito exposure is not feasible.
While the effects of YF vaccine in pregnancy are not well documented, many pregnant individuals have received the vaccine without significant AE There have been numerous studies of individuals who were exposed to YF vaccine during pregnancy, using both active and passive surveillance methods for the ascertainment of AE involving the fetus; in these, no worrisome safety signals were detected. One study documented an increased rate of minor skin malformations (such as small nevi) in offspring of vaccinated mothers as compared to the reference population, thought to be due to evaluation bias. Inadvertent immunization of pregnant individuals is not an indication for termination of pregnancy.
Seroconversion rates are lower in pregnant individuals who are immunized, especially in the third trimester. Antibody titres may be considered post-immunization to ensure appropriate immune response in individuals who remain at risk for YF. Refer to for additional information. If serology is not available and an individual is travelling to a country with risk of YF transmission after completion of a pregnancy, revaccination prior to travel should be considered.
If pregnant individuals must travel to a country that requires documentation, but where there is no risk of YF transmission, a waiver or Certificate of Medical Contraindication to Vaccination should be provided.
In general, breastfeeding individuals should not be vaccinated, particularly when infants are under 9 months of age. There have been 3 reported cases of probable transmission of vaccine strain of YF virus from a mother to her infant through breastfeeding, resulting in encephalitis in the infants. If, for entry to a country, a yellow fever vaccination certificate is required and there is no risk of acquiring yellow fever in the region to be visited, a waiver of vaccination should be sought. If travel to a highly endemic area cannot be postponed, the mother should be given information on the rare risk of vaccination causing disease in the infant, which should be weighed against the risk of yellow fever infection in the mother and infant.
For additional information, refer to in Part 3 and .
# Immunocompromised persons
In general, immunocompromised persons should not receive YF vaccine because of the risk of disease caused by the vaccine strain. When considering immunization of an immunocompromised person, approval from the individual's attending physician should be obtained before vaccination. For complex cases, referral to a physician with expertise in immunization and/or immunodeficiency is advised.
For the immunocompromised traveller, the potential risks associated with administering the YF vaccine should be weighed against the potential benefits. Where there is a country-specific vaccine requirement but the risks associated with vaccine administration outweigh the medical benefits, a Certificate of Medical Contraindication to Vaccination should be provided. Travellers thought to have a mild degree of immune suppression who will be at significant risk for acquiring YF (e.g., travel to an area of endemic or transitional transmission risk), should be offered YF vaccine and advised of the theoretical risks. Profoundly immune suppressed travellers, who in spite of being informed of the risks, plan a trip to an area of active YF risk, should obtain advice from a travel medicine expert and should rigorously adhere to mosquito protection measures.
# Persons with chronic diseases
# Travellers
The decision to immunize a traveller against YF should take into account the traveller's itinerary and the associated risk for exposure to YF virus, the requirements of the country to be visited (including stopovers and airport transit), individual risk factors (e.g., age, immune status), and the potential for SAEs following vaccination.
There are countries where yellow fever transmission occurs that do not have requirements for vaccination for entry and therefore unvaccinated travellers may be at greater risk, especially if visiting a yellow fever risk area.
YF vaccine is recommended for immunocompetent travellers (9 months and older) passing through, visiting or living in countries with risk of YF transmission or when YF immunization is required to enter the country. Refer to the list of countries with risk of YF transmission and countries requiring YF vaccination available through WHO. Some countries may also require YF immunization if transiting through a country/region at risk of YF transmission
YF vaccine is recommended for those travelling to countries in which there is increased risk of exposure to mosquitoes because of prolonged stay, heavy exposure to mosquitoes, or inability to avoid mosquito bites.
YF vaccination is generally not recommended for travellers visiting countries with low potential for YF virus exposure, including those whose itineraries are restricted to areas with no risk. For additional information, refer to .
## International certificates of vaccination or prophylaxis (ICVP)
Under the WHO's International Health Regulations, YF immunization (documented by ICVP) is required to enter certain countries in Africa and South America regardless of the traveller's country of origin.
Other countries require YF vaccination of travellers if the traveller has passed through endemic countries.
In some Asian and tropical countries where YF disease does not exist but the transmitting mosquito is present, immunization is required for travellers arriving from an endemic country to prevent importation of the disease.
Some countries do not require YF vaccination of infants younger than a certain age (e.g., less than 1 year).For immunized individuals, the ICVP is valid for the person's lifetime, beginning 10 days after primary immunization and immediately after re-immunization. Travellers requiring the certificate but in whom the YF vaccine is medically contraindicated (refer to ) can be provided with an International Certificate of Medical Contraindication to Vaccination by the yellow fever vaccination centre following an individual risk assessment. Travellers without a valid ICVP or a Certificate of Medical Contraindication to Vaccination may be denied entry into a country requiring such documentation, quarantined, or offered immunization at the point of entry (e.g., at the airport), potentially putting the health of the traveller at risk.
The ICVP is issued only to individuals who receive a full dose of the YF vaccine. For more information, refer to CATMAT's .
### Travellers planning for stopovers and airport transit
Transit times of 12 hours or less in an international airport poses very low risk for YF virus transmission irrespective of the YF risk classification of the country in which the airport is located. Such a transit typically does not warrant vaccination, since immunization is not medically indicated.
However, defining specific entry requirements is under the control of each individual country. Some countries will not allow entry without proper documentation of vaccination or certificate of medical contraindication. Travellers without proper documentation may be denied entry or subjected to vaccination at the airport.
This should be considered during review of itineraries and pre-travel counselling. In cases when vaccination is not medically indicated but there is concern that lack of documentation may jeopardize travel, providing a medical certificate of contraindication may be considered. Unfortunately, some countries may deny entry despite proper documentation of medical contraindication to vaccination.
Vaccine providers should check the Government of Canada, or ) for an updated list of countries considered endemic or transitional for YF and/or requiring YF vaccination for entry.
Destination-specific recommendations for immunization against YF are available on the Government of Canada website.
# Workers
Laboratory personnel who work with YF virus and those working in endemic YF areas should receive YF vaccine. For additional information, refer to , and in Part 3.
Serologic testing
Serologic testing is generally not recommended for immunocompetent individuals. However, serologic testing may still be useful in cases where there is concern about the ability of an individual to generate a sustained immune response to the YF vaccine. An antibody titre (plaque reduction neutralization test) of greater than 1:20 indicates serological response.
Due to the low level of evidence on the long-term protection of the YF vaccine, an antibody titre (plaque reduction neutralisation test) may be considered if more than 10 years have lapsed since the most recent vaccination for immunocompetent individuals with a particularly high risk of exposure including:
- laboratory personnel working with YF virus
- travellers and workers with regular and ongoing risk of exposure to YF endemic areas
An antibody titre may also be considered post-vaccination for individuals whose response to prior YF vaccination may have been diminished, at time of immunization, including those who were:
- pregnant
- taking immunosuppressive medication
- affected by an immunocompromising illness
Alternatively, as there may often be challenges or delays in acquiring serology, and given that severe AE from re-immunization are very rare, a booster dose may be administered to these specific groups to ensure protection before subsequent travel to areas with risk of YF transmission. For additional information, refer to .
Given the uncertainty in longer-term immune response in those vaccinated in early childhood, serology may also be considered for travellers who received a single dose of YF vaccine prior to 1 year of age.
Administration practices
# Dose, route of administration, and schedule
## Dose
Each dose is 0.5 mL.
## Route of administration
YF vaccine should be administered subcutaneously.
### Schedule
One dose of YF vaccine should be administered. Persons who receive YF vaccines in countries other than the United States and Canada and who have proof of vaccination should be considered protected against YF.
In the event of a shortage, some travellers going to yellow fever endemic or epidemic regions may not have access to a full dose of yellow fever vaccine, and as such, these travellers face the choice of not receiving a vaccine or receiving a fractional dose of vaccine. However, according to the WHO, a fractional dose of the yellow fever vaccine would not qualify for the ICVP under the International Health Regulations.
The ICVP is issued only to individuals who receive a full dose of the YF vaccine. For more information, refer to CATMAT's .
# Concurrent administration with other vaccines
YF vaccine may be administered concomitantly with the following vaccines: measles, mumps, rubella, polio, diphtheria, tetanus, pertussis, hepatitis B, hepatitis A, oral cholera, and oral or parenteral typhoid.
Different injection sites and separate needles and syringes must be used for concomitant parenteral injections.
If not given concurrently, a minimal interval of 4 weeks is recommended between administration of YF vaccine and other live parenteral vaccines.
Oral typhoid or oral cholera vaccine can be administered at any interval before or after YF vaccine.
There are no data available regarding possible interference between YF vaccine and rabies, human papillomavirus, Japanese encephalitis, live attenuated influenza, or varicella vaccines.
Storage requirements
Store YF vaccine in a refrigerator at +2°C to +8°C. Do not freeze. Refrigerate the reconstituted vaccine and use within 1 hour following reconstitution. Refer to in Part 1 for additional general information.
Safety and adverse events
In the last few years, a number of rare, but serious reactions to YF vaccination have
been documented, mostly following the first dose. However, YF vaccines are generally well tolerated. Based on years of observational data, severe adverse reactions to booster doses of YF vaccine are very rare.
Reactions to the vaccine are usually mild and transient in nature. Mild AE such as headaches, myalgia, and low-grade fever may last for 5 to 10 days after vaccination. Less than 0.2% of recipients had to limit daily activities due to an adverse event following vaccination.
Reporting rates of SAEs increase with increasing age.
# Common and very common adverse events
Common AE occur in 1% to less than 10% of vaccinees. Very common AE occur in 10% or more of vaccinees.
In clinical trials, the most common AE were injection site reactions such as localized edema and a mass or pain at the injection site. Other very common AE following immunization included headache and myalgia.
Common AE included nausea and rash.
# Uncommon, rare and very rare adverse events
Uncommon AE occur in 0.1% to less than 1% of vaccinees. Rare and very rare AE occur, respectively, in 0.01% to less than 0.1% of vaccinees.
Anaphylaxis was reported in 1.3 per 100,000 vaccine doses distributed based on reporting rates to the United States Vaccine Adverse Event Reporting System (VAERS) from 2007-2013. This rate includes reports where another vaccine was co-administered with YF vaccine. For anaphylactic reactions where the dose number was known, all occurred after primary vaccination.
## YF vaccine-associated neurotropic disease (YEL-AND)
YEL-AND is a group of clinical syndromes that includes meningoencephalitis (neurotropic disease), acute disseminated encephalomyelitis, Guillain Barré syndrome, and acute bulbar palsy.
Neurotropic disease occurs as a result of YF vaccine virus invasion of the central nervous system (CNS). The other syndromes are autoimmune manifestations in which antibodies and/or T-cells produced in response to the vaccine cross-react with neuronal epitopes leading to CNS or peripheral nerve damage. The clinical course is typically brief with generally complete recovery. Fatality is rare.
YEL-AND can present in any age group, within 30 days following immunization and is seen almost exclusively in primary vaccine recipients. Children less than nine months of age and older persons are at greater risk for YEL-AND.
YEL-AND was reported in 0.8 per 100,000 vaccine doses distributed, largely following primary vaccination, based on reporting rates to the United States VAERS from 2007-2013. The reporting rate was triple for those 60 to 69 years of age (2.5 per 100,000 doses) and double for those over 70 years of age (1.6 per 100,000 doses). These rates include reports where another vaccine was co-administered with YF vaccine. When infants and elderly are not given the vaccine, recent surveillance data suggest population-based incidence rates drop close to zero.
## YF vaccine-associated viscerotropic disease (YEL-AVD)
YEL-AVD is characterized by severe illness and multi-organ failure. It resembles wild-type YF infection with onset is within 10 days of vaccination.
YEL-AVD was reported in 0.3 per 100,000 vaccine doses distributed, largely following primary vaccination, based on reporting rates to the United States VAERS from 2007-2013. This rate includes reports where another vaccine was co-administered with YF vaccine.
The risk of YEL-AVD increases with age. Incidence is estimated to be 1.0-1.1 per 100,000 for those 60-69 years of age; 2.3-3.2 per 100,000 for those over 70 years of age. The case fatality rate is 65% overall and is higher in women than men (90% versus 50%).
YEL-AVD is seen almost exclusively in primary vaccine recipients. Extensive investigations of cases suggest that YEL-AVD is linked to various host factors including older age, and thymus disease (thymoma, myasthenia gravis, thymectomy), and is not associated with a change in virulence of the vaccine virus.
# Other safety issues
Based on 3 case reports, YF virus may be transmitted from a lactating mother to her infant. Further research is required to establish the risk of infant exposure through breastfeeding as the frequency is unknown.
For more information, refer to .
# Guidance on reporting Adverse Events Following Immunization (AEFI)
To ensure the ongoing safety of vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in some jurisdictions, reporting is mandatory under the law.
Vaccine providers are asked to report AEFIs through local public health officials and to check for specific AEFI reporting requirements in their province or territory. In general, any serious or unexpected adverse event felt to be temporally related to vaccination should be reported.
Vaccine providers are asked to report the following AEFIs in particular:
- YF vaccine-associated neurotropic disease (YEL-AND)
- YF vaccine-associated viscerotropic disease (YEL-AVD)
- Any serious or unexpected adverse event felt to be temporally related to vaccination
For additional information about AEFI reporting, please refer to For general vaccine safety information, refer to in Part 2.
# Contraindications and precautions
There is an association between YF vaccine-associated viscerotropic disease (YEL-AVD) and a history of thymus disease. Therefore, YF vaccine is contraindicated for persons with a history of thymus disease with abnormal immune function (e.g., thymoma, thymectomy, myasthenia gravis).
YF vaccine is contraindicated in persons with history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Individuals requiring YF immunization who have suspected hypersensitivity or non-anaphylactic allergy to vaccine components, including chicken or egg proteins and gelatin, should be referred to an allergist for evaluation.
Infants less than 6 months of age should not receive YF vaccine because of the risk of YEL-AND.
Administration of YF vaccine should be postponed in persons with moderate or severe acute illness. Persons with minor acute illness (with or without fever) may be vaccinated.
For use of YF vaccine in immunocompromised persons, refer to the in Part 3.
For more information, refer to in Part 2.
Other considerations
# Drug interactions
The effect of YF vaccine on tuberculin reactivity is unknown. Until data are available, if tuberculin skin testing or an Interferon Gamma Release Assay (IGRA) is required, it should be done on the same day as immunization or delayed for at least 4 weeks after YF vaccination.
Vaccination with YF vaccine may take place at any time after tuberculin skin testing has been performed and/or read.
Chapter revision process
This chapter update was conducted in collaboration with the . Recommendations are based on CATMAT's . |
Yellow fever vaccine: Canadian Immunization Guide
==================================================
**For health professionals**
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-24-varicella-chickenpox-vaccine.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* Next Page
**Last complete chapter revision** (see [Table of Updates](/en/public-health/services/canadian-immunization-guide/updates.html)): March 2023
**March 2023**: This chapter has been reviewed and revised to align with the [Statement on the Use of Booster Doses of Yellow Fever Vaccine](/en/public-health/services/publications/diseases-conditions/use-booster-doses-yellow-fever-vaccine.html) from the [Committee to Advise on Tropical Medicine and Travel (CATMAT)](/en/public-health/services/catmat.html).
Revisions to this chapter include:
* The section on epidemiology was updated to expand on affected areas and number of cases.
* International regulations no longer require proof of **re-vaccination** or a booster dose of yellow fever (YF) vaccine: a single dose confers lifelong immunity for most travellers. A booster dose is recommended for certain individuals. Refer to [Booster doses and re-immunization](#a5.3) for details.
* The proof of YF vaccination entered on the International certificate of vaccination or prophylaxis should notate the duration of validity as "For the lifetime of the person vaccinated" as suggested by the World Health Organization (WHO).
* YF vaccine is contraindicated in individuals with a past history of thymus disease with abnormal immune function (e.g., thymoma, thymectomy, myasthenia gravis). Previous guidance stated that YF vaccine was "generally not recommended".
On This Page
------------
* [Key information](#a1)
* [Epidemiology](#a2)
* [Preparations authorized for use in Canada](#a3)
* [Immunogenicity, efficacy and effectiveness](#a4)
* [Recommendations for use](#a5)
+ [Infants up to 8 months](#a5.1)
+ [Healthy individuals (9 months of age and older)](#a5.2)
+ [Booster doses and re-immunization](#a5.3)
* [Vaccination of specific populations](#a6)
* [Serologic testing](#a7)
* [Administration practices](#a8)
* [Storage requirements](#a9)
* [Safety and adverse events](#a10)
* [Other considerations](#a11)
* [Chapter revision process](#a12)
* [Acknowledgements](#a13)
* [Selected references](#a14)
Key information
---------------
### What
* Yellow Fever (YF) virus is transmitted to humans through the bite of an infected mosquito.
* YF is endemic and intermittently epidemic in sub-Saharan Africa and tropical South America. Risk for acquiring YF is low for travellers, particularly those staying in highly developed major urban areas.
* YF is unique among diseases in that there are International Health Regulations (IHR) which outline the requirements for proof of vaccination when travelling to specific countries. In Canada, YF vaccine is only available at Yellow Fever vaccination centres designated by the Public Health Agency of Canada (PHAC).
* YF vaccine has a seroconversion rate of 95% to 99%; immunity is presumed to be lifelong in healthy individuals.
* The most common adverse events (AE) following YF vaccination are pain, inflammation and swelling at the injection site; weakness, headache, and myalgia.
### Who
* YF vaccine is recommended for healthy persons 9 months of age and older.
* YF vaccine may be considered in infants 6 to 8 months of age travelling to countries with risk of YF transmission.
* Persons 60 years of age and older should be considered for primary YF vaccination if travelling to countries with risk of YF transmission. Serious adverse events (SAEs) following vaccination occur more frequently in adults over 60 years of age.
* YF vaccine is recommended for laboratory personnel who work with YF virus.
### How
* Primary immunization is achieved with one dose of YF vaccine.
* The International Certificate of Vaccination or Prophylaxis becomes valid 10 days after primary vaccination.
* While re-vaccination with YF vaccine is not indicated for the majority of immunocompetent travellers, in certain situations booster doses may be required.
* In general, immunocompromised persons, pregnant or lactating persons, and persons with a history of thymus disease should not receive YF vaccine.
* Counselling on routine insect protection and precautions should be provided to all travellers regardless of YF vaccine vaccination status.
### Why
* YF immunization (documented by an International certificate of vaccination or prophylaxis) is required to enter certain countries in Africa and South America regardless of the traveller's country of origin. Other countries may require YF vaccination of travellers if the traveller has passed through endemic countries.
* Between 1970 and 2015, 10 cases of YF were reported in unvaccinated travellers from the United States and Europe who visited YF endemic areas of Africa and South America, 8 of whom died. In 1987, there was 1 documented case of yellow fever in a vaccinated traveler; that traveller survived.
* Outbreaks of YF continue to be reported in countries where YF has been identified as a risk.
Epidemiology
------------
### Disease description
#### Infectious agent
Yellow fever (YF) is caused by a ribonucleic acid (RNA) virus from the family flaviviridae.
For more information, refer to the [Pathogen Safety Data Sheet](/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/yellow-fever-virus.html).
#### Reservoir
Humans and non-human primates
#### Transmission
YF virus is transmitted to humans through the bite of an infected mosquito, primarily *Aedes* or *Haemogogus* species. The incubation period is 3 to 6 days. Humans infected with YF virus experience the highest levels of viremia and are infectious to mosquitoes shortly before the onset of fever and for 3 to 5 days afterwards. Because of the high level of viremia in humans, blood borne transmission of YF virus can theoretically occur through transfusion of blood products, intravenous drug use and needle stick injuries. Probable transmission of vaccine strain YF virus from a mother to her infant through breastfeeding has been reported. Vaccine-associated viremia occurs 4 to 10 days after primary YF vaccination and lasts for up to 5 days. Sustained transmission is not possible in Canada because the recognized mosquito vectors are not present.
#### Risk factors
A traveller's risk for acquiring YF is determined by multiple factors including: immunization status, use of personal protection measures against mosquito bites, location and time of travel, duration of exposure, activities while travelling, and local rate of virus transmission. In endemic areas, the risk for acquiring YF is low for most travellers, particularly those staying in highly developed major urban areas. Greater risk exists for travellers who:
* are unvaccinated
* visit rural, forest or jungle areas
* stay for longer periods of time
* participate in outdoor activities such as recreation or fieldwork
#### Seasonal/temporal patterns
Yellow fever is endemic and intermittently epidemic in sub-Saharan Africa and tropical South America. In West Africa and South America, YF virus transmission is usually associated with the mid-to-late rainy season when the number of mosquitoes generally increases. However, YF virus can be transmitted during the dry season.
#### Spectrum of clinical illness
Clinical presentation of YF varies in severity from asymptomatic to fatal. When symptomatic, YF is typically characterized by an acute onset of symptoms including fever, chills, headache, backache, prostration (state of weakness), muscle pain, joint pain, nausea, vomiting, photophobia, mild jaundice, and epigastric pain. For others, after a brief remission lasting anywhere between hours to a day, symptoms worsen and the disease advances, eventually leading to renal failure, hemorrhagic symptoms, and thrombocytopenia. Treatment is symptomatic and supportive. The case fatality rate for persons with severe disease is 30%-60%.
### Disease distribution
#### Incidence/prevalence
##### Global
The World Health Organization (WHO) estimates that approximately 200,000 YF cases occur annually, with up to 30,000 deaths. YF is endemic and intermittently epidemic in sub-Saharan Africa and tropical South America. In South America, transmission of YF virus occurs mainly in forest areas rather than in urban areas. In Africa, the majority of outbreaks have been reported from West Africa where YF transmission occurs in both rural and densely populated urban areas. The mosquito vectors are present in Asia; however, there have been no documented cases of transmission.
Between 1970 and 2015, 10 cases of YF were reported in unvaccinated travellers from the United States and Europe who visited YF endemic areas of Africa and South America, 8 of whom died. In 1987, there was 1 documented case of yellow fever in a vaccinated traveller.
YF is unique among diseases in that there are International Health Regulations which outline the requirements for proof of vaccination when travelling to specific countries.
Information about countries with risk of yellow fever transmission and countries requiring yellow fever vaccination is available through the [World Health Organization](https://www.who.int/publications/m/item/countries-with-risk-of-yellow-fever-transmission-and-countries-requiring-yellow-fever-vaccination-(may-2021)). Yellow fever risk maps are also available through the [Centers for Disease Control and Prevention](https://www.cdc.gov/yellowfever/maps/index.html).
##### National
YF is a nationally and internationally notifiable disease.
#### Recent outbreaks
Yellow fever outbreaks are reported in the [WHO Disease Outbreak News](https://www.who.int/emergencies/disease-outbreak-news).
Preparations authorized for use in Canada
-----------------------------------------
In Canada, YF vaccine is only available at yellow fever vaccination centres designated by PHAC. For more information, refer to the list of [Yellow Fever Vaccination Centres in Canada](/en/public-health/services/travel-health/yellow-fever.html) or call 613-957-8739 or send an email to [[email protected]](mailto:[email protected])
### Yellow fever vaccine
* **YF-VAX®:** live, attenuated, yellow fever vaccine, Sanofi Pasteur Limited. (YF)
For complete prescribing information, consult the product leaflet or information contained within Health Canada's authorized product monographs available through the [Drug Product Database](https://health-products.canada.ca/dpd-bdpp/index-eng.jsp).
Refer to Table 1 in [Contents of Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 for a list of all vaccines authorized for use in Canada and their contents.
Immunogenicity, efficacy and effectiveness
------------------------------------------
### Immunogenicity
More than 80% of persons immunized with YF vaccine develop neutralizing antibodies 10 days after vaccination and more than 99% by 28 days after vaccination. In immunocompetent individuals, a single dose of yellow fever vaccine likely confers life-long immunity.
### Efficacy and effectiveness
Efficacy studies of YF vaccine have not been performed.
YF vaccine appears to provide long-term protection against yellow fever disease. After the administration of more than 540 million doses of YF vaccine, only 23 cases of vaccine failure were reported. Sixteen cases occurred in individuals who received a dose of YF vaccine within the last 10 years, one occurred at 20 years and one at 27 years post-vaccination.
Recommendations for use
-----------------------
### Infants up to 8 months of age
Infants less than 6 months of age are at greater risk for YF vaccine-associated neurotropic disease (YEL-AND) following YF vaccination and **should not** receive YF vaccine.
In general, infants under the age of 9 months **should not** be vaccinated against YF. However, the Advisory Committee on Immunization Practices (ACIP) in the United States recommends that for infants 6 to 8 months of age travelling to an endemic or transitional area, when travel is unavoidable, the decision to vaccinate needs to balance the risks of YF virus exposure with the risk for AE following immunization (AEFIs). YF vaccination requirements may also differ for infants in certain countries. Although the risk of serious adverse neurologic events is less than that of infants less than six months of age, it is still higher than that of infants 9 months and older.
### Healthy individuals (9 months of age and older)
One dose of YF vaccine is recommended for immunocompetent individuals who are 9 months of age and older and who travel to countries with risk of YF transmission.
At 9 months of age, the risk of SAEs becomes much lower and antibody response increases, thus improving the safety and efficacy profiles of the YF vaccine.
Given the more frequent occurrence of SAEs in older adults, immunocompetent individuals 60 years of age and older should be considered for primary YF vaccination only if travel to countries with risk of YF transmission cannot be avoided and a high level of protection against mosquito exposure is not feasible. YF vaccine is also recommended for laboratory personnel who work with YF virus.
For more information, refer to [Travellers](#travellers).
### Booster doses and re-immunization
Booster doses of YF vaccine are not recommended for most immunocompetent travellers. The Committee to Advise on Tropical Medicine and Travel (CATMAT) recommends that, based on a case-by-case assessment of benefit versus risk, the use of a **one-time** booster dose is recommended for:
* Individuals in whom response to prior vaccination may have been diminished (e.g., who were pregnant or taking immunosuppressive medication, or had an immunocompromising illness at the time of vaccination, and those who underwent a hematopoietic stem cell transplant since their last YF vaccine dose).
* Individuals who received a previous dose which may have been inadequate for long term protection (e.g., fractional dose, undocumented or improperly documented dose or a dose administered by a non-accredited provider).
* Individuals at particularly high risk of exposure (e.g., travelling to an area experiencing an epidemic or major outbreak, or travelling frequently or for prolonged periods to countries with risk of YF transmission): the booster should be considered if at least 10 years have elapsed since primary vaccination and no previous booster doses were administered.
Re-immunization every 10 years is recommended for:
* laboratory personnel working with YF virus unless measured neutralizing antibody titre to yellow fever virus confirms ongoing protection
* HIV-positive individuals who are travelling to countries with risk of YF transmission
There is very little information on longer-term immune response in those vaccinated in early childhood; research is ongoing to determine the duration of immunity in infants and young children after a single dose of vaccine. At this point, CATMAT does not make specific recommendations for a booster dose of the YF vaccine in young children. Individual assessment of risks and benefits should be done if considering re-immunization of children who received a single dose of vaccine prior to 1 year of age. Serology may be considered in this case where the immune response to prior YF vaccination may be diminished, if travelling to an area with risk of transmission.
In 2014, the WHO stated that a single dose of yellow fever vaccine confers life-long immunity and revised the International Health Regulations. As of July 2016, revaccination or a booster dose of yellow fever vaccine is not required of international travellers as a condition of entry into a country.
Vaccination of specific populations
-----------------------------------
### Pregnancy and breastfeeding
In general, YF vaccine, like other live viral vaccines, should be avoided in pregnancy. Pregnant or breastfeeding individuals should be considered for YF immunization only if they are travelling to countries with risk of YF transmission, travel cannot be postponed, and a high level of protection against mosquito exposure is not feasible.
While the effects of YF vaccine in pregnancy are not well documented, many pregnant individuals have received the vaccine without significant AE There have been numerous studies of individuals who were exposed to YF vaccine during pregnancy, using both active and passive surveillance methods for the ascertainment of AE involving the fetus; in these, no worrisome safety signals were detected. One study documented an increased rate of minor skin malformations (such as small nevi) in offspring of vaccinated mothers as compared to the reference population, thought to be due to evaluation bias. Inadvertent immunization of pregnant individuals is not an indication for termination of pregnancy.
Seroconversion rates are lower in pregnant individuals who are immunized, especially in the third trimester. Antibody titres may be considered post-immunization to ensure appropriate immune response in individuals who remain at risk for YF. Refer to [Serologic testing](#a7) for additional information. If serology is not available and an individual is travelling to a country with risk of YF transmission after completion of a pregnancy, revaccination prior to travel should be considered.
If pregnant individuals must travel to a country that requires documentation, but where there is no risk of YF transmission, a waiver or Certificate of Medical Contraindication to Vaccination should be provided.
In general, breastfeeding individuals should not be vaccinated, particularly when infants are under 9 months of age. There have been 3 reported cases of probable transmission of vaccine strain of YF virus from a mother to her infant through breastfeeding, resulting in encephalitis in the infants. If, for entry to a country, a yellow fever vaccination certificate is required and there is no risk of acquiring yellow fever in the region to be visited, a waiver of vaccination should be sought. If travel to a highly endemic area cannot be postponed, the mother should be given information on the rare risk of vaccination causing disease in the infant, which should be weighed against the risk of yellow fever infection in the mother and infant.
For additional information, refer to [Immunization of Travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) in Part 3 and [Travellers](#travellers).
### Immunocompromised persons
In general, immunocompromised persons should not receive YF vaccine because of the risk of disease caused by the vaccine strain. When considering immunization of an immunocompromised person, approval from the individual's attending physician should be obtained before vaccination. For complex cases, referral to a physician with expertise in immunization and/or immunodeficiency is advised.
For the immunocompromised traveller, the potential risks associated with administering the YF vaccine should be weighed against the potential benefits. Where there is a country-specific vaccine requirement but the risks associated with vaccine administration outweigh the medical benefits, a Certificate of Medical Contraindication to Vaccination should be provided. Travellers thought to have a mild degree of immune suppression who will be at significant risk for acquiring YF (e.g., travel to an area of endemic or transitional transmission risk), should be offered YF vaccine and advised of the theoretical risks. Profoundly immune suppressed travellers, who in spite of being informed of the risks, plan a trip to an area of active YF risk, should obtain advice from a travel medicine expert and should rigorously adhere to mosquito protection measures.
Refer to [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 for additional information. Refer to [Booster doses and re-immunization](#a5.3), [Serologic testing](#a7), and [Contraindications and precautions](#contraindications-and-precautions) for additional information.
### Persons with chronic diseases
Refer to [Contraindications and precautions](#contraindications-and-precautions) and [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) in Part 3 for information regarding specific chronic diseases.
### Travellers
The decision to immunize a traveller against YF should take into account the traveller's itinerary and the associated risk for exposure to YF virus, the requirements of the country to be visited (including stopovers and airport transit), individual risk factors (e.g., age, immune status), and the potential for SAEs following vaccination.
There are countries where yellow fever transmission occurs that do not have requirements for vaccination for entry and therefore unvaccinated travellers may be at greater risk, especially if visiting a yellow fever risk area.
YF vaccine is recommended for immunocompetent travellers (9 months and older) passing through, visiting or living in countries with risk of YF transmission or when YF immunization is required to enter the country. Refer to the list of countries with risk of YF transmission and countries requiring YF vaccination available through WHO. Some countries may also require YF immunization if transiting through a country/region at risk of YF transmission
YF vaccine is recommended for those travelling to countries in which there is increased risk of exposure to mosquitoes because of prolonged stay, heavy exposure to mosquitoes, or inability to avoid mosquito bites.
YF vaccination is generally not recommended for travellers visiting countries with low potential for YF virus exposure, including those whose itineraries are restricted to areas with no risk. For additional information, refer to [Travellers planning for stopovers and airport transit](#travellers-stopovers-airport-transit).
#### International certificates of vaccination or prophylaxis (ICVP)
Under the WHO's International Health Regulations, YF immunization (documented by ICVP) is required to enter certain countries in Africa and South America regardless of the traveller's country of origin.
Other countries require YF vaccination of travellers if the traveller has passed through endemic countries.
In some Asian and tropical countries where YF disease does not exist but the transmitting mosquito is present, immunization is required for travellers arriving from an endemic country to prevent importation of the disease.
Some countries do not require YF vaccination of infants younger than a certain age (e.g., less than 1 year).For immunized individuals, the ICVP is valid for the person's lifetime, beginning 10 days after primary immunization and immediately after re-immunization. Travellers requiring the certificate but in whom the YF vaccine is medically contraindicated (refer to [Contraindications and precautions](#contraindications-and-precautions)) can be provided with an International Certificate of Medical Contraindication to Vaccination by the yellow fever vaccination centre following an individual risk assessment. Travellers without a valid ICVP or a Certificate of Medical Contraindication to Vaccination may be denied entry into a country requiring such documentation, quarantined, or offered immunization at the point of entry (e.g., at the airport), potentially putting the health of the traveller at risk.
The ICVP is issued only to individuals who receive a full dose of the YF vaccine. For more information, refer to CATMAT's [Interim Canadian recommendations for the use of fractional dose of yellow fever vaccine during a vaccine shortage](/en/public-health/services/publications/diseases-conditions/interim-recommendations-fractional-dose-yellow-fever-vaccine-shortage.html).
##### Travellers planning for stopovers and airport transit
Transit times of 12 hours or less in an international airport poses very low risk for YF virus transmission irrespective of the YF risk classification of the country in which the airport is located. Such a transit typically does not warrant vaccination, since immunization is not medically indicated.
However, defining specific entry requirements is under the control of each individual country. Some countries will not allow entry without proper documentation of vaccination or certificate of medical contraindication. Travellers without proper documentation may be denied entry or subjected to vaccination at the airport.
This should be considered during review of itineraries and pre-travel counselling. In cases when vaccination is not medically indicated but there is concern that lack of documentation may jeopardize travel, providing a medical certificate of contraindication may be considered. Unfortunately, some countries may deny entry despite proper documentation of medical contraindication to vaccination.
Vaccine providers should check the Government of Canada, [CDC](https://www.cdc.gov/yellowfever/index.html) or [WHO website](https://www.who.int/publications/m/item/countries-with-risk-of-yellow-fever-transmission-and-countries-requiring-yellow-fever-vaccination-(may-2021)) for an updated list of countries considered endemic or transitional for YF and/or requiring YF vaccination for entry.
Destination-specific recommendations for immunization against YF are available on the Government of Canada [Travel Health and Safety](https://travel.gc.ca/travelling/health-safety/vaccines) website.
### Workers
Laboratory personnel who work with YF virus and those working in endemic YF areas should receive YF vaccine. For additional information, refer to [Booster doses and re-immunization](#a5.3), [Serologic testing](#a7) and [Immunization of Workers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-11-immunization-workers.html) in Part 3.
Serologic testing
-----------------
Serologic testing is generally not recommended for immunocompetent individuals. However, serologic testing may still be useful in cases where there is concern about the ability of an individual to generate a sustained immune response to the YF vaccine. An antibody titre (plaque reduction neutralization test) of greater than 1:20 indicates serological response.
Due to the low level of evidence on the long-term protection of the YF vaccine, an antibody titre (plaque reduction neutralisation test) may be considered if more than 10 years have lapsed since the most recent vaccination for immunocompetent individuals with a **particularly high risk** of exposure including:
* laboratory personnel working with YF virus
* travellers and workers with regular and ongoing risk of exposure to YF endemic areas
An antibody titre may also be considered post-vaccination for individuals whose response to prior YF vaccination may have been diminished, at time of immunization, including those who were:
* pregnant
* taking immunosuppressive medication
* affected by an immunocompromising illness
Alternatively, as there may often be challenges or delays in acquiring serology, and given that severe AE from re-immunization are very rare, a booster dose may be administered to these specific groups to ensure protection before subsequent travel to areas with risk of YF transmission. For additional information, refer to [Booster doses and re-immunization](#a5.3).
Given the uncertainty in longer-term immune response in those vaccinated in early childhood, serology may also be considered for travellers who received a single dose of YF vaccine prior to 1 year of age.
Administration practices
------------------------
### Dose, route of administration, and schedule
#### Dose
Each dose is 0.5 mL.
#### Route of administration
YF vaccine should be administered subcutaneously.
Refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 for additional information.
##### Schedule
One dose of YF vaccine should be administered. Persons who receive YF vaccines in countries other than the United States and Canada and who have proof of vaccination should be considered protected against YF.
In the event of a shortage, some travellers going to yellow fever endemic or epidemic regions may not have access to a full dose of yellow fever vaccine, and as such, these travellers face the choice of not receiving a vaccine or receiving a fractional dose of vaccine. However, according to the WHO, a fractional dose of the yellow fever vaccine would not qualify for the ICVP under the International Health Regulations.
The ICVP is issued only to individuals who receive a full dose of the YF vaccine. For more information, refer to CATMAT's [Interim Canadian recommendations for the use of fractional dose of yellow fever vaccine during a vaccine shortage](/en/public-health/services/publications/diseases-conditions/interim-recommendations-fractional-dose-yellow-fever-vaccine-shortage.html).
### Concurrent administration with other vaccines
YF vaccine may be administered concomitantly with the following vaccines: measles, mumps, rubella, polio, diphtheria, tetanus, pertussis, hepatitis B, hepatitis A, oral cholera, and oral or parenteral typhoid.
Different injection sites and separate needles and syringes must be used for concomitant parenteral injections.
If not given concurrently, a minimal interval of 4 weeks is recommended between administration of YF vaccine and other live parenteral vaccines.
Oral typhoid or oral cholera vaccine can be administered at any interval before or after YF vaccine.
There are no data available regarding possible interference between YF vaccine and rabies, human papillomavirus, Japanese encephalitis, live attenuated influenza, or varicella vaccines.
Refer to [Timing of Vaccine Administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) in Part 1 for additional general information.
Storage requirements
--------------------
Store YF vaccine in a refrigerator at +2°C to +8°C. Do not freeze. Refrigerate the reconstituted vaccine and use within 1 hour following reconstitution. Refer to [Storage and Handling of Immunizing Agents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-9-storage-handling-immunizing-agents.html) in Part 1 for additional general information.
Safety and adverse events
-------------------------
Refer to [Adverse Events Following Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) in Part 2 for additional general information on vaccine safety.
In the last few years, a number of rare, but serious reactions to YF vaccination have
been documented, mostly following the first dose. However, YF vaccines are generally well tolerated. Based on years of observational data, severe adverse reactions to booster doses of YF vaccine are very rare.
Reactions to the vaccine are usually mild and transient in nature. Mild AE such as headaches, myalgia, and low-grade fever may last for 5 to 10 days after vaccination. Less than 0.2% of recipients had to limit daily activities due to an adverse event following vaccination.
Reporting rates of SAEs increase with increasing age.
### Common and very common adverse events
Common AE occur in 1% to less than 10% of vaccinees. Very common AE occur in 10% or more of vaccinees.
In clinical trials, the most common AE were injection site reactions such as localized edema and a mass or pain at the injection site. Other very common AE following immunization included headache and myalgia.
Common AE included nausea and rash.
### Uncommon, rare and very rare adverse events
Uncommon AE occur in 0.1% to less than 1% of vaccinees. Rare and very rare AE occur, respectively, in 0.01% to less than 0.1% of vaccinees.
Anaphylaxis was reported in 1.3 per 100,000 vaccine doses distributed based on reporting rates to the United States Vaccine Adverse Event Reporting System (VAERS) from 2007-2013. This rate includes reports where another vaccine was co-administered with YF vaccine. For anaphylactic reactions where the dose number was known, all occurred after primary vaccination.
#### YF vaccine-associated neurotropic disease (YEL-AND)
YEL-AND is a group of clinical syndromes that includes meningoencephalitis (neurotropic disease), acute disseminated encephalomyelitis, Guillain Barré syndrome, and acute bulbar palsy.
Neurotropic disease occurs as a result of YF vaccine virus invasion of the central nervous system (CNS). The other syndromes are autoimmune manifestations in which antibodies and/or T-cells produced in response to the vaccine cross-react with neuronal epitopes leading to CNS or peripheral nerve damage. The clinical course is typically brief with generally complete recovery. Fatality is rare.
YEL-AND can present in any age group, within 30 days following immunization and is seen almost exclusively in primary vaccine recipients. Children less than nine months of age and older persons are at greater risk for YEL-AND.
YEL-AND was reported in 0.8 per 100,000 vaccine doses distributed, largely following primary vaccination, based on reporting rates to the United States VAERS from 2007-2013. The reporting rate was triple for those 60 to 69 years of age (2.5 per 100,000 doses) and double for those over 70 years of age (1.6 per 100,000 doses). These rates include reports where another vaccine was co-administered with YF vaccine. When infants and elderly are not given the vaccine, recent surveillance data suggest population-based incidence rates drop close to zero.
#### YF vaccine-associated viscerotropic disease (YEL-AVD)
YEL-AVD is characterized by severe illness and multi-organ failure. It resembles wild-type YF infection with onset is within 10 days of vaccination.
YEL-AVD was reported in 0.3 per 100,000 vaccine doses distributed, largely following primary vaccination, based on reporting rates to the United States VAERS from 2007-2013. This rate includes reports where another vaccine was co-administered with YF vaccine.
The risk of YEL-AVD increases with age. Incidence is estimated to be 1.0-1.1 per 100,000 for those 60-69 years of age; 2.3-3.2 per 100,000 for those over 70 years of age. The case fatality rate is 65% overall and is higher in women than men (90% versus 50%).
YEL-AVD is seen almost exclusively in primary vaccine recipients. Extensive investigations of cases suggest that YEL-AVD is linked to various host factors including older age, and thymus disease (thymoma, myasthenia gravis, thymectomy), and is not associated with a change in virulence of the vaccine virus.
### Other safety issues
Based on 3 case reports, YF virus may be transmitted from a lactating mother to her infant. Further research is required to establish the risk of infant exposure through breastfeeding as the frequency is unknown.
For more information, refer to [Pregnancy and breastfeeding](#pregnancy-breastfeeding).
### Guidance on reporting Adverse Events Following Immunization (AEFI)
To ensure the ongoing safety of vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in some jurisdictions, reporting is mandatory under the law.
Vaccine providers are asked to report AEFIs through local public health officials and to check for specific AEFI reporting requirements in their province or territory. In general, any serious or unexpected adverse event felt to be temporally related to vaccination should be reported.
Vaccine providers are asked to report the following AEFIs in particular:
* YF vaccine-associated neurotropic disease (YEL-AND)
* YF vaccine-associated viscerotropic disease (YEL-AVD)
* Any serious or unexpected adverse event felt to be temporally related to vaccination
For additional information about AEFI reporting, please refer to [Reporting Adverse Events Following Immunization (AEFI) in Canada.](/en/public-health/services/immunization/reporting-adverse-events-following-immunization/form.html) For general vaccine safety information, refer to [Adverse Events Following Immunization](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/adverse-events-following.html) in Part 2.
### Contraindications and precautions
There is an association between YF vaccine-associated viscerotropic disease (YEL-AVD) and a history of thymus disease. Therefore, YF vaccine is contraindicated for persons with a history of thymus disease with abnormal immune function (e.g., thymoma, thymectomy, myasthenia gravis).
YF vaccine is contraindicated in persons with history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Individuals requiring YF immunization who have suspected hypersensitivity or non-anaphylactic allergy to vaccine components, including chicken or egg proteins and gelatin, should be referred to an allergist for evaluation.
Refer to Table 1 in [Contents of Immunizing Agents Authorized for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html#p1c14t1) in Part 1 for a list of vaccines authorized for use in Canada and their contents.
Infants less than 6 months of age should not receive YF vaccine because of the risk of YEL-AND.
Administration of YF vaccine should be postponed in persons with moderate or severe acute illness. Persons with minor acute illness (with or without fever) may be vaccinated.
For use of YF vaccine in immunocompromised persons, refer to the [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3.
For more information, refer to [Contraindications and Precautions](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html) in Part 2.
Other considerations
--------------------
### Drug interactions
The effect of YF vaccine on tuberculin reactivity is unknown. Until data are available, if tuberculin skin testing or an Interferon Gamma Release Assay (IGRA) is required, it should be done on the same day as immunization or delayed for at least 4 weeks after YF vaccination.
Vaccination with YF vaccine may take place at any time after tuberculin skin testing has been performed and/or read.
Chapter revision process
------------------------
This chapter update was conducted in collaboration with the [Committee to Advise on Tropical Medicine and Travel (CATMAT)](/en/public-health/services/catmat.html). Recommendations are based on CATMAT's [Statement on the Use of Booster Doses of Yellow Fever Vaccine](/en/public-health/services/publications/diseases-conditions/use-booster-doses-yellow-fever-vaccine.html).
Acknowledgements
----------------
PHAC would like to acknowledge the contributions of the CATMAT Yellow Fever Working Group, and PHAC participants C Jensen, N Mohamed, O Baclic, and E Abrams.
Selected references
-------------------
* Committee to Advise on Tropical Medicine and Travel. Statement on the Use of Booster Doses of Yellow Fever Vaccine. Ottawa: Public Health Agency of Canada; 2018. Retrieved from: https://www.canada.ca/en/public-health/services/publications/diseases-conditions/use-booster-doses-yellow-fever-vaccine.html
* Committee to Advise on Tropical Medicine and Travel. Statement for travellers and yellow fever. Can Comm Dis Rep. 2013;39(2):1.
* Disease News Outbreak - Yellow fever - Brazil [Internet]. Geneva: World Health Organization; 2018 [updated 2018-03-09; cited 2018-03-09]. Available from: http://www.who.int/csr/don/09-march-2018-yellow-fever-brazil/en/
* International and travel health [Internet]. Geneva: World Health Organization; 2017 [updated 31-01-2017; cited 2018-03-02]. Available from: http://www.who.int/ith/en/
* Kimberlin DW, Long SS, Brady MT. Red Book 2015: Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, Chicago: American Academy of Pediatrics; 2015.
* Lindsey NP, Rabe IB, Miller ER, Fischer M, Staples JE. Adverse event reports following yellow fever vaccination, 2007-13. J Travel Med. 2016;23(5). https://doi.org/10.1093/jtm/taw045
* MMWR - Yellow fever vaccine recommendations of ACIP, 2010 https://www.cdc.gov/mmwr/pdf/rr/rr5907.pdf
* MMWR - Yellow fever vaccine recommendations of ACIP, 2015 https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6423a5.htm
* New yellow fever vaccination requirements for travellers [Internet]. Geneva: World Health Organization; 2016 [updated 2016-07-27; cited 2018-03-02]. Available from: http://www.who.int/ith/updates/20160727/en
* Plotkin SA, Orenstein WA, Offit PA. Vaccines. Seventh ed. Philadelphia, PA: Elsevier; 2018.
* Procedures for Yellow Fever Vaccination Centres in Canada. [Internet]. Ottawa: Public Health Agency of Canada; 2015 [cited 2017-02-03]. Available from: https://www.canada.ca/en/public-health/services/travel-health/yellow-fever/procedures/procedures-yellow-fever-centres.html
* Sanofi Pasteur Limited. Product Monograph - YF-VAX®. April 2019.
* Trollfors B. Red Book: 2009 Report of the Committee on Infectious Disease. Acta Pædiatrica. 2010;99(3):479-.
* Yellow fever among travellers returning from South America. [Internet]. Stockholm: European Centre for Disease Prevention and Control.; 2017 [cited 2018-03-03]. Available from: https://ecdc.europa.eu/en/publications-data/yellow-fever-among-travellers-returning-south-america-march-2017
* Yellow fever vaccination booster [Internet]. Geneva: World Health Organization; 2014 [updated 2014-10-24; cited 2018-03-02]. Available from: http://www.who.int/ith/updates/20140605/en
* Yellow Fever Working Group on behalf of the Committee to Advise on Tropical Medicine and Travel (CATMAT). Interim Canadian recommendations for the use of a fractional dose of yellow fever vaccine during a vaccine shortage. Can Comm Dis Rep 2016;42:158-60.
* [Previous Page](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-24-varicella-chickenpox-vaccine.html)
* [Table of Contents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines.html)
* Next Page
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-03-01
| None | None |
66ad1ac3d0e6fc37c01bbaf1931bc8bb6b5a58a0 | cma | Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2022–2023 | Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2022–2023 |
Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2022–2023
===========================================================================================================
[Download in PDF format](/content/dam/phac-aspc/documents/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2022-2023/naci-2022-2023-statement.pdf)
(777 KB, 78 pages)
**Organization:** [Public Health Agency of Canada](/en/public-health.html)
**Published:** 2022-06-08
An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)
**Important notice:** Update to age indication for InfluvacⓇ Tetra (BGP Pharma ULC, operating as Mylan, d.b.a. Viatris Canada):
InfluvacⓇ Tetra egg-based, subunit, quadrivalent inactivated influenza vaccine is now authorized by Health Canada for use in 6 months and older. Refer to the [product monograph](https://www.mylan.ca/-/media/mylanca/documents/english/product-pdf/influvac-tetra-pm-en.pdf?la=en-ca) for further details.
This updated authorized age for use supersedes the information for InfluvacⓇ Tetra found in Table 2, Table 3 and various other sections within the National Advisory Committee on Immunization (NACI) Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2022–2023
**Important notice:** Update to age indication for FlucelvaxⓇ Quad (Seqirus):
FlucelvaxⓇ Quad (Seqirus) standard dose mammalian cell culture-based quadrivalent inactivated influenza vaccine is now authorized by Health Canada for use in persons 6 months and older. Refer to the [product monograph](https://pdf.hres.ca/dpd_pm/00062010.PDF) for further details.
This updated authorized age for use supersedes the information for FlucelvaxⓇ Quad found in Table 2, Table 3 and various other sections within the National Advisory Committee on Immunization (NACI) Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2022–2023
Table of Contents
-----------------
1. [Introduction](#a1)
* [I.1 New or Updated Information for 2022–2023](#a1.1)
* [I.2 Abbreviations for Influenza Vaccines](#a1.2)
* [I.3 Background](#a1.3)
2. [Canadian Immunization Guide chapter on influenza: clinical information for vaccine providers](#a2)
* [II.1 Key Information](#a2.1)
* [II.2 Epidemiology](#a2.2)
* [II.3 Vaccine Products Authorized for Use in Canada](#a2.3)
* [II.4 Efficacy, Effectiveness, and Immunogenicity](#a2.4)
* [II.5 Choice of Seasonal Influenza Vaccine](#a2.5)
* [II.6 Vaccine Administration](#a2.6)
* [II.7 Vaccine Safety and Adverse Events](#a2.7)
* [II.8 Travellers](#a2.8)
3. [Particularly recommended vaccine recipients: additional information](#a3)
* [III.1 People at High Risk of Influenza-Related Complications or Hospitalization](#a3.1)
* [III.2 People Capable of Transmitting Influenza to Those at High Risk of Influenza-Related Complications or Hospitalization](#a3.2)
* [III.3 Others](#a3.3)
4. [Vaccine preparations authorized for use in Canada: additional information](#a4)
* [IV.1 Inactivated Influenza Vaccine (IIV)](#a4.1)
* [IV.2 Recombinant quadrivalent influenza vaccine (RIV4)](#a4.2)
* [IV.3 Live Attenuated Influenza Vaccine (LAIV)](#a4.3)
* [IV.4 Schedule](#a4.4)
* [IV.5 Concurrent Administration with Other Vaccines](#a4.5)
* [IV.6 Additional Vaccine Safety Considerations](#a4.6)
5. [Choice of seasonal influenza vaccine: additional information](#a5)
* [V.1 Children](#a5.1)
* [V.2 Adults](#a5.2)
6. [List of abbreviations](#a6)
7. [Acknowledgments](#a7)
8. [Appendix A: characteristics of influenza vaccines available for use in Canada, 2022–2023](#a8)
9. [References](#a9)
Preamble
--------
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (hereafter referred to as PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflicts of interest.
I. Introduction
---------------
This document, the “Advisory Committee Statement: Canadian Immunization Guide Chapter on Influenza and National Advisory Committee on Immunization (NACI) Statement on Seasonal Influenza Vaccine for 2022–2023”, updates NACI's recommendations regarding the use of seasonal influenza vaccines.
### I.1 New or Updated Information for 2022–2023
#### Use of seasonal influenza vaccine in the context of coronavirus disease 2019 (COVID-19)
**Guidance on the use of seasonal influenza vaccine in the presence COVID-19**
Seasonal influenza presents an ongoing disease burden in Canada during the fall and winter months, however the epidemiology of influenza has changed during the course of the pandemic. Influenza vaccine is the most effective way to prevent influenza illness and influenza-related complications, and is an important component of managing health care system capacity during the influenza season in the context of any ongoing COVID-19 activity.
PHAC, in consultation with NACI and the Canadian Immunization Committee, has developed guidance on the administration of seasonal influenza vaccine to support provincial and territorial vaccine programs and primary care providers during the COVID-19 pandemic:
* [Guidance on the use of seasonal influenza vaccine in the presence of COVID-19](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-use-influenza-vaccine-covid-19.html)
The guidance on this page is based on currently available scientific evidence and expert opinion and will be updated and added to as necessary throughout the influenza season as new evidence emerges. This web page should be considered in concert with recommendations regarding the use of seasonal influenza vaccines provided in this NACI Statement*.*
#### Guidance on concurrent administration of influenza and COVID-19 vaccines
NACI guidance outlines that administration of COVID-19 vaccines may occur at the same time as, or at any time before or after influenza immunization (including all seasonal influenza vaccines or LAIV) for those aged 5 years and older. [NACI currently recommends](https://www.canada.ca/content/dam/phac-aspc/documents/services/immunization/national-advisory-committee-on-immunization-naci/naci-summary-july-14-2022.pdf) that, as a precautionary measure, children 6 months to 5 years of age wait at least 14 days between COVID-19 vaccines and non-COVID-19 vaccines, including the influenza vaccine.
Readers should consult the [Canadian Immunization Guide (CIG) COVID-19 chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) for updated NACI guidance and further information on concurrent administration of COVID-19 vaccines with influenza vaccines across all eligible age groups.
#### Inclusion of recombinant quadrivalent seasonal influenza vaccine
Supemtek™ (RIV4) is a recombinant quadrivalent seasonal influenza vaccine produced by Sanofi Pasteur that was authorized for use in Canada on January 14, 2021, in adults 18 years of age and older. Supemtek is the first and, to date, the only recombinant influenza vaccine licensed in Canada. Based on a review of available pre-licensure and post-market clinical trial and surveillance data, NACI has concluded that Supemtek may be considered for use among the quadrivalent influenza vaccines offered to adults 18 years of age and older *(Discretionary NACI Recommendation)*. Refer to the [NACI Supplemental Statement: Recombinant Influenza Vaccines](/en/public-health/services/publications/vaccines-immunization/recombinant-influenza-vaccines-supplemental-statement-canadian-immunization-guide-seasonal-influenza-vaccine-2022-2023.html), for additional information supporting this recommendation.
#### Updated recommendations on mammalian cell culture-based quadrivalent influenza vaccine
FlucelvaxⓇ Quad (IIV4-cc) is the first and, to date, the only mammalian cell culture-based inactivated seasonal influenza vaccine available for use in Canada. It was first authorized for use in Canada in adults and children 9 years of age and older on November 22, 2019. Recommendations and supporting evidence on the use of Flucelvax Quad in adults and children 9 years of age and older can be found in the [NACI Supplemental Statement – Mammalian Cell Culture-Based Influenza Vaccines](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/mammalian-cell-culture-based-influenza-vaccines.html) and were also incorporated into the Statement on Seasonal Influenza Vaccine for 2021–2022.
On March 8, 2021, Health Canada approved an expanded age indication for the use of Flucelvax Quad in children down to 2 years of age and older. Based on a review of Health Canada assessments of clinical trial evidence submitted by the manufacturer in support of the age indication extension, NACI has concluded that Flucelvax Quad may be considered among the quadrivalent influenza vaccines offered to adults and children 2 years of age and older. Refer to [section IV.1 Inactivated Influenza Vaccine (IIV)](#a4.1) later in the statement for additional information supporting this recommendation.
### I.2 Abbreviations for Influenza Vaccines
The abbreviations used in this document for the different influenza vaccines are as follows:
Table 1. NACI influenza vaccine abbreviations
| Influenza vaccine category | Formulation | Type | Current NACI abbreviation[Table 1 Footnote a](#t1fna) |
| --- | --- | --- | --- |
| Inactivated influenza vaccine (IIV) | Trivalent (IIV3) | Standard dose[Table 1 Footnote b](#t1fnb), unadjuvanted,
IM administered, egg-based | IIV3-SD |
| Adjuvanted[Table 1 Footnote c](#t1fnc),
IM administered, egg-based | IIV3-Adj |
| High dose[Table 1 Footnote d](#t1fnd),
unadjuvanted,
IM administered, egg-based | IIV3-HD |
| Quadrivalent (IIV4) | Standard dose[Table 1 Footnote b](#t1fnb),
unadjuvanted,
IM administered, egg-based | IIV4-SD |
| Standard dose[Table 1 Footnote b](#t1fnb), unadjuvanted, IM administered, cell culture-based | IIV4-cc |
| High dose[Table 1 Footnote d](#t1fnd),
unadjuvanted,
IM administered, egg-based | IIV4-HD |
| Recombinant influenza vaccine (RIV) | Quadrivalent (RIV4) | Recombinante[Table 1 Footnote e](#t1fne), unadjuvanted, IM administered | RIV4 |
| Live attenuated influenza vaccine (LAIV) | Trivalent (LAIV3) | Unadjuvanted,
nasal spray, egg-based | LAIV3 |
| Quadrivalent (LAIV4) | Unadjuvanted,
nasal spray, egg-based | LAIV4 |
| **Abbreviations:** IIV: inactivated influenza vaccine; IIV3: trivalent inactivated influenza vaccine; IIV3-Adj: adjuvanted egg-based trivalent inactivated influenza vaccine; IIV3-HD: high-dose egg-based trivalent inactivated influenza vaccine; IIV3-SD: standard-dose egg-based trivalent inactivated influenza vaccine; IIV4: quadrivalent inactivated influenza vaccine; IIV4-cc: standard-dose cell culture-based quadrivalent inactivated influenza vaccine; IIV4-HD: high-dose egg-based quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose egg-based quadrivalent inactivated influenza vaccine; IM: intramuscular; LAIV: live attenuated influenza vaccine; LAIV3: egg-based trivalent live attenuated influenza vaccine; LAIV4: egg-based quadrivalent live attenuated influenza vaccine. |
|
Table 1 Footnote a
The numeric suffix denotes the number of antigens contained in the vaccine (“3” refers to the trivalent formulation and “4” refers to the quadrivalent formulation). The hyphenated suffix “-SD” (where “SD” is used to denote “standard dose” for an IIV) is used when referring to IIV products that do not have an adjuvant, contain 15 µg hemagglutinin (HA) per strain and are administered as a 0.5 mL dose by intramuscular injection; “-cc” (where “cc” denotes “cell culture”) refers to an IIV product that is made from influenza virus grown in cell cultures instead of chicken eggs (FlucelvaxⓇ Quad); “-Adj” (where “Adj” is used to abbreviate “adjuvanted”) refers to an IIV with an adjuvant (IIV3-Adj for FluadⓇ or Fluad PediatricⓇ); and “-HD” refers to an IIV that contains higher antigen content than 15 µg HA per strain standard IIV dose (IIV3-HD for FluzoneⓇ High-Dose or IIV4-HD for FluzoneⓇ High-Dose Quadrivalent).
[Table 1 Return to footnote a referrer](#t1fna-rf)
Table 1 Footnote b
15 µg HA per strain.
[Table 1 Return to footnote b referrer](#t1fnb-rf)
Table 1 Footnote c
7.5 µg (in 0.25 mL) or 15 µg (in 0.5 mL) HA per strain.
[Table 1 Return to footnote c referrer](#t1fnc-rf)
Table 1 Footnote d
60 µg HA per strain.
[Table 1 Return to footnote d referrer](#t1fnd-rf)
Table 1 Footnote e
45 µg HA per strain.
[Table 1 Return to footnote e referrer](#t1fne-rf)
|
### I.3 Background
The [World Health Organization’s (WHO) recommendations on the composition of influenza virus vaccines](https://www.who.int/teams/global-influenza-programme/vaccines/who-recommendations) are typically available in February of each year for the upcoming season in the Northern Hemisphere. The WHO recommends that three influenza strains be included in the trivalent seasonal influenza vaccine: one influenza A(H1N1), one influenza A(H3N2), and one influenza B. Quadrivalent seasonal influenza vaccines should contain the three strains recommended for the trivalent vaccine, as well as an influenza B virus from the lineage that is not included in the trivalent vaccine.
Annual recommendations on the use of influenza vaccine in Canada are developed by the NACI Influenza Working Group (IWG) for consideration by NACI. Recommendations are developed based on a review of a variety of issues, which can include: the burden of influenza illness and the target populations for vaccination; efficacy, effectiveness, immunogenicity, and safety of influenza vaccines; vaccine schedules; and other aspects of influenza immunization. In addition, PHAC has expanded the mandate of NACI to include the consideration of programmatic factors in developing their recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels. These programmatic factors include economics, ethics, equity, feasibility, and acceptability. Details regarding NACI's evidence-based process for developing a statement are outlined in [Evidence-based Recommendations for Immunization − Methods of the National Advisory Committee on Immunization](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2009-35/methods-national-advisory-committee-immunization.html).
Health care providers in Canada should offer the seasonal influenza vaccine as soon as feasible after it becomes available in the fall, since seasonal influenza activity may start as early as October in the Northern Hemisphere. Decisions regarding the precise timing of vaccination in a given setting or geographic area should be made according to local epidemiologic factors (influenza activity, timing, and intensity), opportune moments for vaccination, as well as programmatic considerations. Further advice regarding the timing of influenza vaccination programs may be obtained through consultation with local public health agencies.
Although vaccination before the onset of the influenza season is strongly preferred, influenza vaccine may still be administered up until the end of the season. Delayed administration may result in lost opportunities to prevent infection from exposures that occur prior to vaccination, and individuals seeking vaccination should be informed that vaccine administered during an influenza outbreak may not provide optimal protection. Vaccine providers should use every opportunity to administer influenza vaccine to individuals at risk who have not already been vaccinated during the current season, even after influenza activity has been documented in the community.
Every year, individuals with influenza and influenza-related complications increase the demand on the healthcare system in the fall and winter months. During the COVID-19 pandemic, influenza vaccination remains a critical tool to minimize the morbidity and mortality related to potential influenza and COVID-19 co-circulation and to reduce the burden on the Canadian health care system to enhance the capacity to respond to ongoing COVID-19 activity.
II. Canadian Immunization Guide Chapter on Influenza: Clinical Information for Vaccine Providers
------------------------------------------------------------------------------------------------
The [Canadian Immunization Guide](/en/public-health/services/canadian-immunization-guide.html) (CIG) is written primarily for health care providers (frontline clinicians and public health practitioners) but it is also used by policy makers, program planners, and the general public. The CIG has been a trusted, reader-friendly summary of the vaccine statements provided by NACI since 1979.
The information in this section replaces the influenza chapter of the CIG. With a new NACI Statement on Seasonal Influenza Vaccine required each year, readers will have quick access to the information that they require within one document, whether it is the relevant influenza vaccine information written primarily for frontline vaccine providers as is found in this section, or the more detailed technical information that is found in the rest of this statement, commencing in [Section III](#a3).
### II.1 Key Information
The following highlights key information for vaccine providers. Please refer to the remainder of this statement for additional details.
#### What
* Influenza in humans is a respiratory infection caused primarily by influenza A and B viruses. Seasonal influenza epidemics occur annually in Canada, generally in the late fall and winter months. Prior to the COVID-19 pandemic, influenza occurred globally with an annual attack rate estimated at 5–10% in adults and 20–30% in children[Footnote 1](#fn1).
* Symptoms of influenza typically include the sudden onset of fever, cough, and muscle aches. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week to 10 days, but some people are at greater risk of severe complications, such as pneumonia or death. Influenza infection can also worsen certain chronic conditions, such as heart disease[Footnote 2](#fn2).
* Inactivated influenza vaccines (IIV) (which include standard dose, high dose, cell culture-based or adjuvanted vaccines), recombinant influenza vaccine (RIV), and live attenuated influenza vaccine (LAIV) are all authorized for use in Canada; some protect against 3 strains of influenza (i.e., trivalent formulations, IIV3) and some protect against 4 strains of influenza (i.e., quadrivalent formulations: IIV4, RIV4, or LAIV4).
* The influenza vaccines are safe and well-tolerated. The IIV cannot cause influenza illness because IIV do not contain live virus. Similarly, the RIV does not contain live influenza virus but instead contains non-infectious viral proteins. The live attenuated influenza vaccines contain weakened viruses.
#### Who
NACI makes the following recommendations for individual-level and public health program-level decision making. Individual-level recommendations are intended for people wishing to protect themselves from influenza or for vaccine providers wishing to advise individual patients about preventing influenza. Program-level recommendations are intended for provinces and territories responsible for making decisions on publicly funded immunization programs. Individual-level and program-level recommendations may differ, as the important factors to consider when recommending a vaccine for a population (e.g., population demographics, economic considerations) may be different than for an individual.
##### Recommendation for individual-level decision making
* NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have contraindications to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended (see [List 1](#List1)). These groups include:
+ people at high risk of severe disease, influenza-related complications or hospitalization;
+ people capable of transmitting influenza to those at high risk;
+ people who provide essential community services; and
+ people in direct contact with poultry infected with avian influenza during culling operations.
In infants less than 6 months of age influenza vaccine is less immunogenic than in older children and adults and does not confer sufficient protection to make the vaccine useful in this age group[Footnote 3](#fn3). Currently, authorized influenza vaccines are not indicated for use in infants less than 6 months of age. For these reasons, NACI recommends that influenza vaccine should not be offered to infants less than 6 months of age. However, as infants less than 6 months of age are at high risk of influenza-related illness, the influenza vaccine should be offered to individuals who are pregnant, and any household contacts and care providers of infants (see [List 1](#List1)).
##### Recommendation for public health program-level decision-making
The national goal of the annual influenza immunization programs in Canada is to prevent serious illness caused by influenza and its complications, including death. Programmatic decisions to provide influenza vaccination to target populations as part of publicly funded provincial and territorial programs depend on many factors, such as cost-effectiveness evaluation and other programmatic and operational factors.
* NACI recommends that influenza vaccine should be offered as a priority to the groups for whom influenza vaccination is particularly recommended (see [List 1](#List1) in the section below).
#### List 1: Groups for whom influenza vaccination is particularly recommended
**People at high risk of influenza-related complications or hospitalization**
* All children 6–59 months of age
* Adults and children with the following chronic health conditions[List 1 Footnote a](#l1fna):
+ cardiac or pulmonary disorders (includes bronchopulmonary dysplasia, cystic fibrosis, and asthma);
+ diabetes mellitus and other metabolic diseases;
+ cancer, immune compromising conditions (due to underlying disease, therapy, or both, such as solid organ transplant or hematopoietic stem cell transplant recipients);
+ renal disease;
+ anemia or hemoglobinopathy;
+ neurologic or neurodevelopment conditions (includes neuromuscular, neurovascular, neurodegenerative, neurodevelopmental conditions, and seizure disorders [and, for children, includes febrile seizures and isolated developmental delay], but excludes migraines and psychiatric conditions without neurological conditions);
+ morbid obesity (BMI of 40 and over); and
+ children 6 months to 18 years of age undergoing treatment for long periods with acetylsalicylic acid, because of the potential increase of Reye’s syndrome associated with influenza.
* All pregnant individuals;
* People of any age who are residents of nursing homes and other chronic care facilities;
* Adults 65 years of age and older; and
* Indigenous peoples.
**People capable of transmitting influenza to those at high risk**
* Health care and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk;
* Household contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated:
+ household contacts of individuals at high risk;
+ household contacts of infants less than 6 months of age, as these infants are at high risk but cannot receive influenza vaccine;
+ members of a household expecting a newborn during the influenza season;
* Those providing regular child care to children 0–59 months of age, whether in or out of the home; and
* Those who provide services within closed or relatively closed settings to people at high risk (e.g., crew on a ship).
**Others**
* People who provide essential community services; and
* People who are in direct contact with poultry infected with avian influenza during culling operations.
List 1 Footnote a
Refer to [Immunization of Persons with Chronic Diseases](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-7-immunization-persons-with-chronic-diseases.html) and [Immunization of Immunocompromised Persons](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html) in Part 3 of the CIG for additional information about vaccination of people with chronic diseases.
[List 1 Return to footnote a referrer](#fn1-rf)
#### How
The benefits and risks of influenza vaccination should be discussed prior to vaccination, including the risks of not being immunized.
##### Choice of influenza vaccine
A variety of influenza vaccines are authorized for use in Canada, some of which are authorized for use only in specific age groups. Therefore, the choice of influenza vaccine has become more complex. Refer to [Section II.5](#a2.5) for recommendations on the choice of influenza vaccine by age group.
##### Dose and route of administration
The dose and route of administration vary by influenza vaccine product (see [Section II.6](#a2.6) for details). For recommendations on which vaccines are recommended in different age groups, refer to Table 2.
* With the exception of IIV4-HD, most unadjuvanted IIVs are administered as a 0.5 mL intramuscular (IM) injection for everyone 6 months of age and older, The following IIVs are administered as a 0.5 mL IM injection but are only authorized in older age groups: AfluriaⓇ Tetra (5 years and older), InfluvacⓇ Tetra (3 years and older), and FlucelvaxⓇ Quad (2 years and older);
* IIV4-HD (FluzoneⓇ High-Dose Quadrivalent) is administered as a 0.7 mL IM injection for adults 65 years of age and older;
* MF59-adjuvanted IIV3 (FluadⓇ) is administered as a 0.5 mL IM injection for adults 65 years of age and older. A pediatric formulation is also available (Fluad PediatricⓇ), and is administered as a 0.25 mL IM injection for children 6–23 months of age;
* RIV4 (Supemtek™) is administered as a 0.5 mL IM injections for adults 18 years of age and older;
* LAIV (FluMistⓇ Quadrivalent) is administered as 0.2 mL given intranasally (0.1 mL in each nostril) for individuals 2–59 years of age.
##### Schedule
NACI recommends that:
* Adults and children 9 years of age and older should receive 1 dose of influenza vaccine each year; and
* Children 6 months to less than 9 years of age who have never received the seasonal influenza vaccine in a previous influenza season should be given 2 doses of influenza vaccine in the current season, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been properly vaccinated with one or more doses of seasonal influenza vaccine in any previous season should receive 1 dose of influenza vaccine per season thereafter.
##### Contraindications
For all influenza vaccines (IIV, RIV4 and LAIV), NACI recommends that influenza vaccination should not be given to:
* People who have had an anaphylactic reaction to a specific influenza immunization, or to any of the components of a specific influenza vaccine, with the exception of egg (refer to [Section II.7](#a2.7) for more information);
+ If an individual is found to have an anaphylactic reaction to a component in one influenza vaccine, consideration may be given to offering another influenza vaccine that does not contain the implicated component, in consultation with an allergy expert. Individuals who have an allergy to substances that are not components of the influenza vaccine are not at increased risk of allergy to influenza vaccine.
+ Egg allergy is **not** a contraindication for influenza vaccination, as there is a low risk of adverse events (AEs) associated with the trace amounts of ovalbumin allowed in some influenza vaccines manufactured using eggs. Egg-allergic individuals may be vaccinated against influenza using any age-appropriate product, including LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg, and in any setting where vaccines are routinely administered. The IIV4-cc and RIV4 are completely egg-free (ovalbumin-free).
+ As with any vaccine product, vaccine providers should be prepared for managing possible allergic reactions including anaphylaxis, and have the necessary equipment to respond to a vaccine emergency at all times.
* People who have developed Guillain-Barré Syndrome (GBS) within 6 weeks of a previous influenza vaccination (refer to [Section II.7](#a2.7) for more information), unless another cause was found for the GBS.
+ For those people, the potential risk for a recurrent episode of GBS associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.
For LAIV, in addition to the above-mentioned contraindications, NACI also recommends that LAIV should not be given to:
* People with immune compromising conditions, with the exception of children with stable HIV infection on anti-retroviral therapy (ART) "[also sometimes referred to as highly active anti-retroviral therapy (HAART)]" and with adequate immune function (see [Section IV.2](#a4.2) for more information);
+ Immune compromising conditions may be due to underlying disease, therapy, or both.
* People with severe asthma (defined as currently on oral or high-dose inhaled glucocorticosteroids or active wheezing) or medically attended wheezing in the 7 days prior to the proposed date of vaccination, due to increased risk of wheezing following administration of LAIV;
+ LAIV is not contraindicated for people with a history of stable asthma or recurrent wheeze, which is not active.
* Children less than 24 months of age, due to increased risk of wheezing following administration of LAIV;
* Children 2–17 years of age currently receiving aspirin or aspirin-containing therapy, because of the association of Reye’s syndrome with aspirin and wild-type influenza infection;
* Pregnant individuals; because it is a live attenuated vaccine and there is a lack of safety data at this time:
+ LAIV is not contraindicated in breastfeeding (lactating) individuals; however, there is limited data for the use of LAIV in this population
* LAIV should not be administered until 48 hours after antiviral agents active against influenza (e.g., oseltamivir, zanamivir) are stopped, and those antiviral agents, unless medically indicated, should not be administered until 2 weeks after receipt of LAIV so that the antiviral agents do not inactivate the replicating vaccine virus.
+ If these anti-viral agents are administered within this time frame (i.e., from 48 hours pre-vaccination with LAIV to 2 weeks post-vaccination), re-vaccination should take place at least 48 hours after the antivirals are stopped, or IIV could be given at any time.
Refer to [Contents of Immunizing Agents Available for Use in Canada](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-15-contents-immunizing-agents-available-use-canada.html) in Part 1 of the CIG for a list of all vaccines authorized for use in Canada and their contents and to [Vaccine Safety](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) in Part 2 of the CIG for information regarding the management of adverse events (AEs), including anaphylaxis.
##### Precautions
NACI recommends that:
* Influenza vaccination should usually be postponed in people with serious acute illnesses until their symptoms have abated;
+ In a regular influenza season, vaccination should not be delayed because of minor or moderate acute illness, with or without fever. During the COVID-19 pandemic, immunizers should refer to [Guidance on the use of influenza vaccine in the presence of COVID-19](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-use-influenza-vaccine-covid-19.html) for additional advice on this issue from the Public Health Agency of Canada.
* If significant nasal congestion is present that might impede delivery of LAIV to the nasopharyngeal mucosa, IIV can be administered or LAIV can be deferred until resolution of the congestion;
* LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection; and
* LAIV recipients who are less than 18 years of age should avoid the use of aspirin-containing products for at least 4 weeks after receipt of LAIV.
Refer to [Section II.7](#a2.7) for additional information on influenza vaccine-related precautions
##### Concurrent administration with other vaccines
NACI recommends that:
* Administration of COVID-19 vaccines may occur at the same time as, or at any time before or after influenza immunization (including all seasonal influenza vaccines or LAIV) for those aged 5 years and older. Readers should consult the [Canadian Immunization Guide (CIG) COVID-19 chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) for updated NACI guidance on the concurrent administration of influenza and COVID-19 vaccines as the number of authorized COVID-19 vaccines and the age groups eligible to receive them expand.
+ It should be noted that no studies have been conducted on the co-administration of recombinant zoster vaccine (RZV) with adjuvanted or high-dose influenza vaccine. No immune response interference or safety concerns have been demonstrated when RZV is administered concurrently with standard dose, unadjuvanted vaccine[Footnote 4](#fn4).
* Different injection sites and separate needles and syringes should be used for concurrent parenteral injections.
#### Why
* Vaccination is the most effective way to prevent influenza and its complications.
* Vaccinated individuals who are protected from influenza will not pass infection to others.
* Although most people will recover fully from influenza infection in 7–10 days, influenza can lead to severe disease, and/or complications, including hospitalization and death.
* Annual vaccination is required because the specific strains in the vaccine are reviewed each year by WHO and are often changed to provide a better match against the viruses expected to circulate in that given year, and because the body's immune response to influenza vaccination is transient and may not persist beyond a year.
### II.2 Epidemiology
#### Disease description
Influenza is a respiratory illness caused by the influenza A and B viruses in humans and can cause mild to severe illness, which can result in hospitalization or death. Certain populations, such as young children, older adults, and those with chronic health conditions, may be at higher risk for serious influenza complications such as viral pneumonia, secondary bacterial pneumonia, and worsening of underlying medical conditions.
#### Infectious agent
There are two main types of influenza virus that cause seasonal epidemics in humans: A and B. Influenza A viruses are classified into subtypes based on two surface proteins: hemagglutinin (HA) and neuraminidase (NA). Three subtypes of HA (H1, H2, and H3) and two subtypes of NA (N1 and N2) are recognized among influenza A viruses as having caused widespread human disease over the decades. Immunity to the HA and NA proteins reduces the likelihood of infection and together with immunity to the internal viral proteins, lessens the severity of disease if infection occurs.
Influenza B viruses have evolved into two antigenically distinct lineages since the mid-1980s, represented by B/Yamagata/16/88-like and B/Victoria/2/87-like viruses. Viruses from both the B/Yamagata and B/Victoria lineages contribute variably to influenza illness each year. Globally, influenza circulation has been at a historical low since the onset of the COVID-19 pandemic, and with the implementation of non-pharmaceutical public health measures against COVID-19 in Canada. There has been a virtual absence of any B/Yamagata detections globally[Footnote 5](#fn5).
Over time, antigenic variation (antigenic drift) of strains occurs within an influenza A subtype or a B lineage. The ever-present possibility of antigenic drift, which may occur in one or more influenza virus strains, requires seasonal influenza vaccines to be reformulated annually, with one or more vaccine strains changing in most seasons.
#### Transmission
Influenza is primarily transmitted by aerosols and droplets spread through coughing or sneezing, and through direct or indirect contact with respiratory secretions.
The incubation period of seasonal influenza is usually about 2 days but can range from 1–4 days[Footnote 6](#fn6). Adults may be able to spread influenza to others from 1 day before symptom onset to approximately 5 days after symptoms start. Children and people with weakened immune systems may be infectious longer.
#### Risk factors
The people at greatest risk of influenza-related complications are adults and children with chronic health conditions (see [List 1](#List1)), residents of nursing homes and other chronic care facilities, adults 65 years of age and older, children 0–59 months of age, pregnant individuals, and Indigenous peoples.
#### Seasonal and temporal patterns
Influenza activity in Canada is usually low in the late spring and summer, begins to increase over the fall, and peaks in the winter months. Depending on the year, one or more peaks may occur as early as the fall and into the spring. Influenza season in Canada can last for many months, and more than one influenza strain typically circulates each season.
#### Spectrum of clinical illness
Symptoms typically include the sudden onset of fever, cough, and muscle aches. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week or 10 days. More rarely, central nervous system involvement, acute myositis, myocarditis or pericarditis have been described. In addition, complications including pneumonia, respiratory failure, cardiovascular complications, or worsening of underlying chronic medical conditions may occur.
#### Disease incidence
Global
Worldwide, annual epidemics result in approximately one billion cases of influenza, three to five million cases of severe illness, and 290,000 to 650,000 deaths. Prior to the COVID-19 pandemic, the global annual attack rate was estimated to be 5–10% in adults and 20–30% in children[Footnote 1](#fn1). For current international influenza activity information, refer to WHO's [Global Influenza Program website](https://www.who.int/teams/global-influenza-programme/surveillance-and-monitoring/influenza-updates/current-influenza-update).
National
Together, influenza and pneumonia are ranked among the top 10 leading causes of death in Canada[Footnote 7](#fn7). The FluWatch program is Canada's national surveillance system, which monitors the spread of influenza and influenza-like illnesses (ILI) continually throughout the year. In the five seasons prior to the COVID-19 pandemic (2014–2015 to 2018-2019 season), an average of 40,000 laboratory-confirmed cases of influenza were reported to FluWatch each year. Although the burden of influenza can vary from year to year, it is estimated that there are an average of 12,200 hospitalizations related to influenza and approximately 3,500 deaths attributable to influenza annually[Footnote 8](#fn8)[Footnote 9](#fn9). Current influenza activity information can be found on the [FluWatch website](/en/public-health/services/diseases/flu-influenza/influenza-surveillance.html).
It should be noted that the incidence of influenza is often underreported since the illness may be confused with other viral illnesses and many people with ILI do not seek medical care or have viral diagnostic testing done.
### II.3 Vaccine Products Authorized for Use in Canada
This section describes the influenza vaccine products that are authorized for use in Canada for the 2022–2023 season. All influenza vaccines available in Canada have been authorized by Health Canada. However, not all products authorized for use are necessarily available in the marketplace. The vaccine manufacturers determine whether they will make any or all of their products available in a given market. Provincial and territorial health authorities then determine which of the products available for purchase will be used in their respective publicly funded influenza immunization programs and for which population groups.
The antigenic characteristics of circulating influenza virus strains provide the basis for selecting the strains included in each year's vaccine. Vaccine selection by the WHO generally occurs more than 6 months prior to the start of the influenza season to allow time for the vaccine manufacturers to produce the required quantity of vaccine. All manufacturers that distribute influenza vaccine products in Canada confirm to Health Canada that the vaccines to be marketed in Canada for the upcoming influenza season contain the WHO's recommended antigenic strains for the Northern Hemisphere. Vaccine producers may use antigenically equivalent strains because of their growth properties. The strains recommended for egg-based products may differ somewhat from the strains chosen for cell-culture based products to account for differences in the production platforms.
There are three categories of influenza vaccine authorized for use in Canada: IIV, RIV, and LAIV. Trivalent (3-strain) vaccines contain one A(H1N1) strain, one A(H3N2) strain, and one influenza B strain from one of the two lineages. Quadrivalent (4-strain) vaccines contain the strains in the trivalent vaccine plus an influenza B strain from the other lineage. Most influenza vaccines currently authorized for use in Canada are made from influenza viruses grown in chicken eggs. However, there are two exceptions. The influenza viruses used to produce Flucelvax Quad are propagated in a mammalian cell line (Madin-Darby Canine Kidney cells), while the Supemtek vaccine technology uses recombinant HA produced in a proprietary insect cell line using a baculovirus vector for protein expression.
A summary of the characteristics of influenza vaccines available in Canada during the 2022–2023 influenza season can be found in [Appendix A](#a8). For complete prescribing information, readers should consult the product monographs available through Health Canada's [Drug Product Database](/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).
#### Inactivated influenza vaccine (IIV)
IIVs currently authorized for use in Canada are a mix of split virus and subunit vaccines. In split virus vaccines, the virus has been disrupted by a detergent. In subunit vaccines, HA and NA have been further purified by removal of other viral components. All IIVs currently available in Canada are produced in eggs, with the exception of FlucelvaxⓇ Quad (IIV4-cc), which is a mammalian cell culture-based quadrivalent inactivated, subunit influenza vaccine that is prepared from viruses propagated in mammalian cell lines [proprietary 33016-PF Madin-Darby Canine Kidney (MDCK) cell lines] adapted to grow freely in suspension in culture medium. The production of IIV4-cc does not depend on egg supply as it does not require egg-grown candidate vaccine viruses.
The IIVs available in Canada are in a standard dose formulation or in a formulation designed to enhance the immune response in specific age groups, through the use of a higher dose of HA antigen or the inclusion of an adjuvant. Refer to [Basic Immunology and Vaccinology](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-14-basic-immunology-vaccinology.html) in Part 1 of the CIG for more information about inactivated vaccines.
Standard-dose IIVs are available in Canada as quadrivalent formulations (IIV4-SD: AfluriaⓇ Tetra, FlulavalⓇ Tetra, FluzoneⓇ Quadrivalent, and InfluvacⓇ Tetra; IIV4-cc: FlucelvaxⓇ Quad). These vaccines are unadjuvanted, contain a standard dose of antigen (15 µg HA per strain), and are administered as a 0.5 mL dose by IM injection. Influvac Tetra may be administered by IM or deep subcutaneous injection.
The adjuvanted IIVs (IIV-Adj) currently authorized for use in Canada are trivalent subunit IIVs that contain the adjuvant MF59, which is an oil-in-water emulsion composed of squalene as the oil phase that is stabilized with the surfactants polysorbate 80 and sorbitan triolate in citrate buffer. IIV-Adj contains 7.5 µg HA per strain administered as a 0.25 mL dose by IM injection for children 6–23 months of age (Fluad PediatricⓇ) or 15 µg HA per strain administered as a 0.5 mL dose by IM injection for adults 65 years of age and older (FluadⓇ). Other IIVs do not contain an adjuvant.
There is one high-dose IIV (IIV-HD) currently authorized for use in Canada; a quadrivalent unadjuvanted, split virus IIV that contains 60 µg HA per strain and is administered as a 0.7 mL dose by IM injection (FluzoneⓇ High-Dose Quadrivalent).
#### Recombinant influenza vaccine (RIV)
There is currently only one RIV authorized for use in Canada: Supemtek™ (RIV4), a quadrivalent unadjuvanted, baculovirus-expressed seasonal influenza vaccine that contains 45 µg HA per strain and is administered as a 0.5 mL dose by IM injection for adults 18 years of age and older. RIV contains recombinant HAs produced in an insect cell line using genetic sequences from cell-derived influenza viruses. The production of RIV does not depend on egg supply as it does not require egg-grown candidate vaccine viruses.
#### Live attenuated influenza vaccine (LAIV)
LAIV is given as an intranasal spray. The influenza viruses contained in LAIV are attenuated so that they do not cause influenza and are cold-adapted and temperature sensitive, so that they replicate in the nasal mucosa rather than the lower respiratory tract. LAIV contains standardized quantities of fluorescent focus units (FFU) of live attenuated reassortants and is given as a 0.2 mL dose (0.1 mL in each nostril).
A quadrivalent product (LAIV4; FluMistⓇ Quadrivalent) is authorized for use in Canada for children 2–17 years of age and adults 18–59 years of age. The trivalent formulation (LAIV3) is no longer available in Canada.
### II.4 Efficacy, Effectiveness, and Immunogenicity
#### Efficacy and effectiveness
Influenza vaccine has been shown in randomized controlled clinical trials to be efficacious in providing protection against influenza infection and illness. However, the effectiveness of the vaccine—that is, how it performs in settings that are more reflective of usual health care practice—can vary from season to season and by influenza vaccine strain type and subtype. Influenza vaccine effectiveness (VE) depends on how well the vaccine strains match with circulating influenza viruses, the type and subtype of the circulating virus, as well as the health and age of the individual receiving the vaccine. Even when there is a less-than-ideal match or lower VE against one strain, the possibility of lower VE should not preclude vaccination, particularly for people at high risk of influenza-related complications and hospitalization, since vaccinated individuals are still more likely to be protected compared to those who are unvaccinated.
#### Immunogenicity
Antibody response after vaccination depends on several factors, including the age of the recipient, prior and subsequent exposure to antigens, and the presence of immune compromising conditions. Protective levels of humoral antibodies, which correlate with protection against influenza infection, are generally achieved by 2 weeks after vaccination; however, there may be some protection afforded before that time.
### II.5 Choice of Seasonal Influenza Vaccine
The decision to include specific influenza vaccines as part of publicly funded provincial and territorial programs depends on several factors, including cost-effectiveness evaluation and other programmatic and operational factors, such as implementation strategies. Not all products will be made available in all jurisdictions and availability of some products may be limited; therefore, officials in individual provinces and territories should be consulted regarding the products available in individual jurisdictions.
With the availability of influenza vaccines that are designed to enhance immunogenicity in specific age groups, the choice of product has become more complex.
#### Choice of influenza vaccine by age group
##### Recommendations for individual-level decision making
* NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have a contraindication to the vaccine. [Table 2](#t2) provides age group-specific recommendations for the age-appropriate influenza vaccine types authorized for use in Canada.
##### Recommendations for public health program-level decision making
* NACI recommends that any of the age-appropriate influenza vaccine types available for use may be considered for people without contraindications to the vaccine. [Table 2](#t2) provides age group-specific recommendations for the age-appropriate influenza vaccine types authorized in Canada.
Table 2: Recommendations on choice of influenza vaccine type for individual- and public health program-level decision making by age group
| Recipient by age group | Vaccine types authorized for use | Recommendations on choice of influenza vaccine |
| --- | --- | --- |
| 6–23 months | * IIV3-SD[Table 2 Footnote a](#t2fna)
* IIV3-Adj
* IIV4-SD
| * A quadrivalent influenza vaccine authorized for this age group should be used in infants and young children without contraindications, given the burden of influenza B disease in this age group and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine.
* If a quadrivalent vaccine is not available, any of the available trivalent vaccines licensed for this age group should be used
|
| 2–17 years[Table 2 Footnote b](#t2fnb) | * IIV3-SD[Table 2 Footnote a](#t2fna)
* IIV4-SD
* IIV4-cc
* LAIV4
| * An age appropriate quadrivalent influenza vaccine (IIV4-SD, LAIV4, or IIV4-cc) should be used in children without contraindications or precautions (see text below applicable to LAIV), including those with chronic health conditions, given the burden of influenza B disease in this age group and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine.
* LAIV4 may be given to children with:
+ stable, non-severe asthma;
+ cystic fibrosis who are not being treated with immunosuppressive drugs (e.g., prolonged systemic corticosteroids); and
+ stable HIV infection, if the child is currently being treated with ART (i.e., HAART) and has adequate immune function.
* LAIV should not be used in children or adolescents for whom it is contraindicated or for whom there are warning and precautions such as those with:
+ severe asthma (defined as currently on oral or high-dose inhaled glucocorticosteroids or active wheezing);
+ medically attended wheezing in the 7 days prior to vaccination;
+ current receipt of aspirin or aspirin-containing therapy;
+ immune compromising conditions, with the exception of stable HIV infection, i.e., if the child is treated with HAART (for at least 4 months) and has adequate immune function.
+ pregnancy
- In pregnancy, IIV4-SD or IIV4-cc should be used instead.
* If IIV4-SD, IIV4-cc, and LAIV4 are not available, IIV3-SD should be used.
|
| 18–59 years | * IIV3-SD[Table 2 Footnote a](#t2fna)
* IIV4-SD
* IIV4-cc
* RIV4
* LAIV4
| * Any of the available influenza vaccines authorized for this age group should be used in adults 18-59 years without contraindications or precautions, noting the following consideration and exceptions:
+ There is some evidence that IIV may provide better efficacy than LAIV in healthy adults; and
* LAIV is not recommended for:
+ pregnant individuals;
+ adults with any of the chronic health conditions identified in [List 1](#List1), including immune compromising conditions; and
+ health care workers
|
| 60–64 years | * IIV3-SD[Table 2 Footnote a](#t2fna)
* IIV4-SD
* IIV4-cc
* RIV4
| * Any of the available influenza vaccines authorized for this age group should be used in adults 60-64 years without contraindications.
|
| 65 years and older[Table 2 Footnote c](#t2fnc) | * IIV3-SD[Table 2 Footnote a](#t2fna)
* IIV3-Adj
* IIV4-SD
* IIV4-HD[Table 2 Footnote d](#t2fnd)
* IIV4-cc
* RIV4
| **Individual-level decision-making*** IIV-HD should be used over IIV-SD, given the burden of influenza A(H3N2) disease and the good evidence of IIV3-HD providing better protection compared to IIV3-SD in adults 65 years of age and older.
+ Other than a recommendation for using IIV-HD over IIV-SD formulations, NACI has not made comparative individual-level recommendations on the use of the other available vaccines in this age group. In the absence of a specific product, any of the available age appropriate influenza vaccines should be used.
| **Public health program-level decision-making*** Any of the available influenza vaccines authorized in this age group should be used.
+ There is insufficient evidence on the incremental value of different influenza vaccines (i.e. cost-effectiveness assessments have not been performed by NACI) to make comparative public health program-level recommendations on the use of the available vaccines.
|
| **Abbreviations:** ART: antiretroviral therapy; HAART: highly active antiretroviral therapy; IIV: inactivated influenza vaccine; IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-cc: quadrivalent mammalian cell –culture-based inactivated influenza vaccine; IIV4-HD: high-dose quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; RIV4: quadrivalent recombinant influenza vaccine; LAIV: live attenuated influenza vaccine; LAIV4: quadrivalent live attenuated influenza vaccine. |
|
Table 2 Footnote a
IIV3-SD formulations will not be available for use in Canada during the 2022-2023 influenza season
[Table 2 Return to footnote a referrer](#t2fna-rf)
Table 2 Footnote b
Refer to [Table 4](#t4) for a summary of vaccine characteristics of LAIV compared with IIV in children 2–17 years of age.
[Table 2 Return to footnote b referrer](#t2fnb-rf)
Table 2 Footnote c
Refer to [Table 5](#t5) for a comparison of the vaccine characteristics of influenza vaccine types available for use in adults 65 years of age and older.
[Table 2 Return to footnote c referrer](#t2fnc-rf)
Table 2 Footnote d
IIV3-HD formulations will not be authorized or available for use in Canada during the 2022-2023 influenza season.
[Table 2 Return to footnote d referrer](#t2fnd-rf)
|
### II.6 Vaccine Administration
#### Dose, route of administration, and schedule
With the variety of influenza vaccines available for use in Canada, it is important for vaccine providers to note the specific differences in age indication, route of administration, dosage, and schedule for the products that they will be using (see [Table 3](#t3)). Key relevant details and differences between vaccine products are also highlighted in [Appendix A](#a8).
For influenza vaccines given by the IM route, the anterolateral thigh muscle is the recommended site in infants 6–12 months of age. The anterolateral thigh or the deltoid muscle can be used for toddlers and older children. The deltoid muscle of the arm is the preferred injection site in adolescents and adults. For more information on vaccine administration, please refer to [Vaccine Administration Practices](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-8-vaccine-administration-practices.html) in Part 1 of the CIG.
Table 3: Recommended dose and route of administration, by age, for influenza vaccine types authorized for the 2022–2023 influenza season
| Age group | Influenza vaccine type (route of administration) | Number of doses required |
| --- | --- | --- |
| IIV3-SD[Table 3 Footnote a](#t3fna) or IIV4-SD[Table 3 Footnote b](#t3fnb)
(IM) | IIV4-cc[Table 3 Footnote c](#t3fnc)
(IM) | IIV3-Adj[Table 3 Footnote d](#t3fnd)
(IM) | IIV4-HD[Table 3 Footnote e](#t3fne)
(IM) | **RIV4**[Table 3 Footnote f](#t3fnf)
(IM) | LAIV4[Table 3 Footnote g](#t3fng)
(intranasal) |
| 6–23 months | 0.5 mL[Table 3 Footnote h](#t3fnh) | - | 0.25 mL | - | - | - | 1 or 2[Table 3 Footnote i](#t3fni) |
| 2–8 years | 0.5 mL | - | - | - | - | 0.2 mL
(0.1 mL per nostril) | 1 or 2[Table 3 Footnote i](#t3fni) |
| 9–17 years | 0.5 mL | 0.5 mL | - | - | - | 0.2 mL
(0.1 mL per nostril) | 1 |
| 18–59 years | 0.5 mL | 0.5 mL | - | - | 0.5 mL | 0.2 mL
(0.1 mL per nostril) | 1 |
| 60–64 years | 0.5 mL | 0.5 mL | - | - | 0.5 mL | - | 1 |
| 65 years and older | 0.5 mL | 0.5 mL | 0.5 mL | 0.7 mL | 0.5 mL | - | 1 |
| **Abbreviations:** IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV4-cc: quadrivalent mammalian cell-culture based inactivated influenza vaccine; IIV4-HD: high-dose quadrivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; RIV4: quadrivalent recombinant influenza vaccine; IM: intramuscular; LAIV4: quadrivalent live attenuated influenza vaccine. |
|
Table 3 Footnote a
IIV3-SD formulations (AgrifluⓇ [6 months and older] and InfluvacⓇ [3 years and older]) are authorized but will not be available for use in Canada during the 2022-2023 influenza season.
[Table 3 Return to footnote a referrer](#t3fna-rf)
Table 3 Footnote b
AfluriaⓇ Tetra (5 years and older), FlulavalⓇ Tetra (6 months and older), FluzoneⓇ Quadrivalent (6 months and older), InfluvacⓇ Tetra (3 years and older).
[Table 3 Return to footnote b referrer](#t3fnb-rf)
Table 3 Footnote c
FlucelvaxⓇ Quad (2 years and older)
[Table 3 Return to footnote c referrer](#t3fnc-rf)
Table 3 Footnote d
Fluad PediatricⓇ (6–23 months) or FluadⓇ (65 years and older)
[Table 3 Return to footnote d referrer](#t3fnd-rf)
Table 3 Footnote e
FluzoneⓇ High-Dose Quadrivalent (65 years and older)
[Table 3 Return to footnote e referrer](#t3fne-rf)
Table 3 Footnote f
Supemtek™ (18 years and older)
[Table 3 Return to footnote f referrer](#t3fnf-rf)
Table 3 Footnote g
FluMistⓇ Quadrivalent (2–59 years)
[Table 3 Return to footnote g referrer](#t3fng-rf)
Table 3 Footnote h
Evidence suggests moderate improvement in antibody response in infants, without an increase in reactogenicity, with the use of full vaccine doses (0.5 mL) for unadjuvanted inactivated influenza vaccines[Footnote 10](#fn10)[Footnote 11](#fn11). This moderate improvement in antibody response without an increase in reactogenicity is the basis for the full dose recommendation for unadjuvanted inactivated vaccine for all ages. For more information, refer to [Statement on Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-acs-5.html)*.*
[Table 3 Return to footnote h referrer](#t3fnh-rf)
Table 3 Footnote i
Children 6 months to less than 9 years of age receiving seasonal influenza vaccine for the first time in their life should be given 2 doses of influenza vaccine, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been properly vaccinated with one or more doses of seasonal influenza vaccine in the past should receive 1 dose of influenza vaccine per season thereafter.
[Table 3 Return to footnote i referrer](#t3fni-rf)
|
#### Booster doses and revaccination
Booster doses are not required within the same influenza season. However, children 6 months to less than 9 years of age who have not previously received the seasonal influenza vaccine require 2 doses of influenza vaccine, with a minimum of 4 weeks between doses (see [Table 3](#t3)). Only one dose of influenza vaccine per season is recommended for everyone else. Two doses of seasonal influenza vaccine in older adults do not appear to improve the immune response to the vaccine compared to one dose[Footnote 12](#fn12).
#### Serological testing
Serologic testing is not necessary or recommended before or after receiving seasonal influenza vaccine.
#### Storage requirements
Influenza vaccine should be stored at +2°C to +8°C and should not be frozen. Refer to the individual product monographs for further details. Refer to [Storage and Handling of Immunizing Agents](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-9-storage-handling-immunizing-agents.html) in Part 1 of the CIG for additional information.
#### Concurrent administration with other vaccines
All seasonal influenza vaccines, including LAIV, may be given at the same time as, or at any time before or after administration of other vaccines (either live or inactivated), including COVID-19 vaccines for those aged 5 years and older. Refer to the [CIG and latest NACI COVID-19 vaccine guidance](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) for any additional emerging guidance on concurrent administration with COVID-19 vaccines as new products emerge or there are COVID-19 age eligibility expansions.
In theory, the administration of two live vaccines sequentially within less than 4 weeks could reduce the efficacy of the second vaccine. Studies have been done showing no interference when administering LAIV3 concurrently with: measles, mumps, rubella (MMR); measles, mumps, rubella, varicella (MMRV); or live oral polio vaccines[Footnote 13](#fn13)[Footnote 14](#fn14)[Footnote 15](#fn15). No studies have been done to assess the possibility of interference between LAIV and other live vaccines during concurrent administration, or on LAIV effectiveness given before or after other live vaccines. Additional information regarding concurrent administration with other vaccines can be found in [Section IV.5](#a4.5) of this statement.
Given the lack of data for immune interference, and based on expert opinion, NACI recommends that LAIV can be given together with or at any time before or after the administration of any other live attenuated or inactivated vaccine. However, some vaccine providers may continue to choose to give LAIV and other live vaccines separated by at least 4 weeks, based on the theoretical possibility of immune interference, although NACI does not believe that this precaution is necessary for LAIV. The use of an inactivated influenza vaccine would avoid this theoretical concern. Note that the timing rules related to two parenteral live vaccines (e.g., MMR and varicella vaccines) still apply. For more information regarding vaccination administration timing rules, please refer to [Timing of Vaccine Administration](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-1-key-immunization-information/page-10-timing-vaccine-administration.html) in Part 1 of the CIG.
When more than one injection is given at a single clinic visit, it is preferable to administer them in different limbs. If it is not possible to do so, injections given in one limb should be separated by a distance of at least 2.5 cm (1 inch). A separate needle and syringe should be used for each injection.
The target groups for influenza and pneumococcal polysaccharide vaccines overlap considerably. Vaccine providers should take the opportunity to vaccinate eligible people against pneumococcal disease when influenza vaccine is given.
#### Concurrent administration with other adjuvanted vaccines
Data are limited regarding concurrent administration of adjuvanted vaccines with other adjuvanted or nonadjuvanted vaccines.
RZV is an example of a recombinant adjuvanted subunit herpes zoster vaccine (ShingrixⓇ, GlaxoSmithKline) that is authorized for use in Canada in adults 50 years of age and older; therefore, the target age group for herpes zoster vaccine and influenza vaccine overlap. RZV has been shown to be safe and effective when given concurrently with unadjuvanted, standard dose influenza vaccines[Footnote 4](#fn4). However, no studies have been conducted that have assessed the co-administration of RZV with adjuvanted or high dose influenza vaccine[Footnote 16](#fn16). It should be noted that RZV and IIV-adj currently authorized for use in Canada contain the adjuvants AS01B and MF59 respectively. How these adjuvants may interact when RZV and IIV-adj are administered concurrently is not known and some providers may prefer to use non-adjuvanted influenza vaccine in this situation.
NACI will continue to review the evidence and update guidance accordingly.
### II.7 Vaccine Safety and Adverse Events
Post-marketing surveillance of influenza vaccines in Canada has shown that seasonal influenza vaccines have a safe and stable profile. In addition to routine surveillance, every year during the seasonal influenza vaccination campaigns, PHAC and the Federal/Provincial/Territorial Vaccine Vigilance Working Group (VVWG) of the Canadian Immunization Committee conduct weekly expedited surveillance of adverse events following immunization (AEFI) for current influenza vaccines in order to identify vaccine safety signals in a timely manner. Refer to the [Canadian Adverse Events Following Immunization Surveillance System](/en/public-health/services/immunization/canadian-adverse-events-following-immunization-surveillance-system-caefiss.html) (CAEFISS) web page for more information on post-marketing surveillance and AEFIs in Canada. In addition, the Canadian National Vaccine Safety (CANVAS) Network, a national network of sites across Canada for active vaccine safety surveillance, collects and analyzes information on AEFIs after influenza vaccination to provide influenza vaccine safety information to public health authorities during the core weeks of the annual influenza vaccination campaign.
All influenza vaccines currently authorized for use in Canada are considered safe for use in people with latex allergies. The multi-dose vial formulations of inactivated influenza vaccine that are authorized for use in Canada contain minute quantities of thimerosal, which is used as a preservative [Footnote 17](#fn17)[Footnote 18](#fn18) to keep the product sterile. Large cohort studies of administrative health databases have found no association between childhood vaccination with thimerosal-containing vaccines and neurodevelopmental outcomes, including autistic-spectrum disorders[Footnote 19](#fn19). All single dose formulations of IIV and LAIV are thimerosal-free. Refer to [Vaccine Safety](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) in Part 2 of the CIG for additional information.
#### Common adverse events
With IM administered influenza vaccines, injection site reactions are common but are generally classified as mild and transient. IIV3-Adj tends to produce more extensive injection site reactions than unadjuvanted IIV3, but these reactions are also generally mild and resolve spontaneously within a few days. IIV-HD tends to induce higher rates of systemic reactions compared to IIV-SD, but most of these reactions are mild and short-lived. Recombinant vaccines appear to have a similar safety profile to IIVs. The most common AEs experienced by recipients of LAIV3 are nasal congestion and runny nose, which are also reported for LAIV4. Refer to the relevant subsections of [Section IV](#a4) for additional information.
#### Less common and serious or severe adverse events
Serious adverse events (SAEs) are rare following influenza vaccination, and in most cases, data are insufficient to determine a causal association. Allergic responses to influenza vaccine are a rare consequence of hypersensitivity to some components of the vaccine or its container. Refer to [Section IV.5](#a4.5) below for additional information.
#### Other reported adverse events and conditions
##### Guillain-Barré syndrome
Studies suggest that the absolute risk of Guillain-Barré syndrome (GBS) in the period following seasonal and A(H1N1)pdm09 influenza vaccination is about one excess case per million vaccinations[Footnote 20](#fn20)[Footnote 21](#fn21), and that the risk of GBS associated with influenza illness (about 17 cases per million influenza-coded health care encounters, which are a proxy for influenza illness) is higher than that associated with influenza vaccination[Footnote 21](#fn21).
Although the evidence considering influenza vaccination and GBS is inadequate to accept or reject a causal relation between GBS in adults and seasonal influenza vaccination, avoiding subsequent influenza vaccination of individuals known to have had GBS without other known etiology within 6 weeks of a previous influenza vaccination appears prudent at this time. However, the potential risk of GBS recurrence associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.
##### Oculorespiratory syndrome
Oculorespiratory syndrome (ORS), the presence of bilateral red eyes and one or more associated respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, or sore throat) that starts within 24 hours of vaccination, with or without facial oedema, was identified during the 2000–2001 influenza season[Footnote 22](#fn22). Since then, there have been far fewer cases per year reported to CAEFISS[Footnote 23](#fn23). ORS is not considered to be an allergic response. People who have an occurrence or recurrence of ORS upon vaccination do not necessarily experience further episodes with future vaccinations.
Individuals who have experienced ORS without lower respiratory tract symptoms may be safely revaccinated with influenza vaccine. Individuals who experienced ORS with lower respiratory tract symptoms should have an expert review. Health care providers who are unsure whether an individual previously experienced ORS versus an immunoglobulin E (IgE) mediated hypersensitivity immune response should seek advice. Data on clinically significant AEs do not support the preference of one vaccine product over another when revaccinating those who have previously experienced ORS.
#### Allergic reactions to previous vaccine doses
Expert review of the benefits and risks of vaccination should be sought for those who have previously experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of influenza vaccination, an apparent significant allergic reaction to the vaccine, or any other symptoms that could indicate a significant allergic reaction (e.g., throat constriction, difficulty swallowing) that raise concern regarding the safety of revaccination. This advice may be obtained from experts in infectious disease, allergy, and immunology, or public health that can be found in various health settings, including the [Special Immunization Clinic (SIC) network](https://cirnetwork.ca/network/special-immunization/).
In view of the considerable morbidity and mortality associated with influenza and rarity of true vaccine allergy, a diagnosis of allergy to an influenza vaccine should not be made without confirmation, which may involve consultation with an allergy or immunology expert.
#### Drug interactions
Although influenza vaccine can inhibit the clearance of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine. Statins have effects on the immune system in addition to their therapeutic cholesterol-lowering actions. Two published studies have found that adults who are regular statin users (at least 65 years of age[Footnote 24](#fn24) in one study and 45 years and older in the other[Footnote 25](#fn25) ) had an apparent decreased response to influenza vaccination as measured by reduced geometric mean titres (GMT)[Footnote 24](#fn24) or reduced VE against medically attended acute respiratory illness[Footnote 25](#fn25). Statins are widely used in the same adult populations who are also at-risk for influenza-related complications and hospitalizations. Therefore, if these preliminary findings are confirmed in future studies, concurrent statin use in adult populations could have implications for influenza VE and how this use is assessed in the measurement of VE. NACI will continue to monitor the literature related to this issue.
#### Guidance on reporting adverse events following immunization
To ensure the ongoing safety of influenza vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in most jurisdictions, reporting is mandatory under the law.
An AEFI is any untoward medical occurrence that follows vaccination and that does not necessarily have a causal relationship with the usage of a vaccine. The AEFI may be any unfavourable or unintended sign, abnormal laboratory finding, symptom, or disease. In general, any AEFI felt to be temporally related to vaccination and for which there is no other clear cause at the time of reporting should be reported. Of particular interest are those AEFIs which are considered serious or unexpected. A serious AEFI is an adverse event that is life threatening or results in death, requires hospitalization or prolongation of an existing hospitalization, results in residual disability or causes congenital malformation[Footnote 26](#fn26). An unexpected AEFI is an event that is not listed in the approved product monograph but may be due to the vaccination, or one whose nature, severity, specificity, or outcome is not consistent with the term or description used in the product monograph[Footnote 26](#fn26). Vaccine providers are asked to [report AEFIs through local public health officials](/en/public-health/services/immunization/federal-provincial-territorial-contact-information-aefi-related-questions.html) and to check for specific AEFI reporting requirements in their province or territory. If there is any doubt as to whether or not an event should be reported, a conservative approach should be taken and the event should be reported.
For influenza vaccines, the following AEFIs are of particular interest:
* ORS; and
* GBS within 6 weeks following vaccination.
Refer to [Reporting Adverse Events Following Immunization (AEFI) in Canada](/en/public-health/services/immunization/reporting-adverse-events-following-immunization/form.html) for additional information about AEFI reporting and to [Vaccine Safety](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) in Part 2 of the CIG for general vaccine safety information.
### II.8 Travellers
Influenza occurs year-round in the tropics. In temperate northern and southern countries, influenza activity generally peaks during the winter season (November to March in the Northern Hemisphere and April to October in the Southern Hemisphere).
* NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older, including travellers, who does not have a contraindication to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended (see [List 1](#List1)).
Vaccines prepared specifically for use in the Southern Hemisphere are not available in Canada, and the extent to which recommended vaccine components for the Southern Hemisphere may overlap with those in available Canadian formulations will vary. A decision for or against revaccination (i.e., boosting) of travellers to the Southern Hemisphere between April and October, if they had already been vaccinated in the preceding fall or winter with the Northern Hemisphere's vaccine, depends on individual risk assessment, the similarity between the Northern and Southern Hemisphere vaccines, the similarity between the Northern Hemisphere vaccine strains and currently circulating strains in the Southern Hemisphere, and the availability of a reliable and safe vaccine at the traveller's destination. Refer to [Immunization of Travellers](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-9-immunization-travellers.html) in Part 3 of the CIG for additional general information.
*This concludes the summary of relevant influenza vaccine information typically found in the Canadian Immunization Guide. Additional technical information related to seasonal influenza vaccine can be found in the remainder of this statement.*
III. Particularly Recommended Vaccine Recipients: Additional Information
------------------------------------------------------------------------
The groups for whom influenza vaccination is particularly recommended are presented in [List 1](#List1) of Section II. Additional information regarding these particularly recommended recipients is provided below.
### III.1 People at High Risk of Influenza-Related Complications or Hospitalization
#### All children 6–59 months of age
On the basis of existing data, NACI recommends the inclusion of all children 6–59 months of age among those for whom influenza vaccine is particularly recommended.
Refer to the [Statement on Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-acs-5.html) for additional details on children 6–23 months of age and to the [Statement on Seasonal Influenza Vaccine for 2012–2013](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2012-38/statement-on-seasonal-influenza-vaccine-2012-2013.html) for children 24–59 months of age.
#### Adults and children with chronic health conditions
A number of chronic health conditions, as noted in [List 1](#List1), are associated with increased risk of influenza-related complications, and influenza can lead to exacerbation of the chronic disease. Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected people. Vaccine effectiveness may be lower in people with immune compromising conditions than in healthy adults.
##### Neurologic or neurodevelopment conditions
Neurologic or neurodevelopment conditions (NNCs) that pose increased risk for severe disease or complications from influenza include neuromuscular, neurovascular, neurodegenerative, neurodevelopment conditions, and seizure disorders (and, for children, include febrile seizures and isolated developmental delay), but exclude migraines and psychiatric conditions without neurological conditions. Based on reviews of evidence and expert opinion, NACI includes adults and children with NNCs among the groups for whom influenza vaccination is particularly recommended. Refer to the NACI [Statement on Seasonal Influenza Vaccine for 2018–2019](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2018-2019.html) for a summary of the rationale supporting this decision and the [Literature Review on Individuals with Neurologic or Neurodevelopment Conditions and Risk of Serious Influenza-Related Complications](/en/public-health/services/publications/healthy-living/executive-summary-literature-review-individuals-neurologic-neurodevelopment-conditions-risk-serious-influenza-related-complications.html) for additional details of the evidence reviews.
#### All pregnant individuals
NACI recommends the inclusion of all pregnant individuals, at any stage of pregnancy, among those who are particularly recommended to receive IIV. This is due to the risk of influenza-associated morbidity amongst those who are pregnant,[Footnote 27](#fn27)[Footnote 28](#fn28)[Footnote 29](#fn29)[Footnote 30](#fn30)[Footnote 31](#fn31) evidence of adverse neonatal outcomes associated with respiratory hospitalization during pregnancy or influenza during pregnancy[Footnote 32](#fn32)[Footnote 33](#fn33)[Footnote 34](#fn34)[Footnote 35](#fn35), evidence that vaccination of pregnant individuals protects their newborns from influenza and influenza-related hospitalization[Footnote 36](#fn36)[Footnote 37](#fn37)[Footnote 38](#fn38)[Footnote 39](#fn39) and evidence that infants born during influenza season to vaccinated individuals are less likely to be premature, small for gestational age, and of low birth weight than if born to individuals that had not received an influenza vaccine[Footnote 40](#fn40)[Footnote 41](#fn41)[Footnote 42](#fn42)[Footnote 43](#fn43). The risk of influenza-related hospitalization increases with length of gestation (i.e., it is higher in the third trimester than in the second).
The safety of IIV during pregnancy has been reviewed[Footnote 42](#fn42). Active studies of influenza vaccination during pregnancy have not shown evidence of harm to the pregnant individual or fetus associated with influenza vaccination[Footnote 44](#fn44). Although the cumulative sample size of active studies of influenza vaccination in pregnant individuals is relatively small, particularly in the first trimester, passive surveillance has not raised any safety concerns despite widespread use of IIV during pregnancy over several decades[Footnote 29](#fn29)[Footnote 30](#fn30)[Footnote 45](#fn45)[Footnote 46](#fn46). Surveillance following the use of both adjuvanted and unadjuvanted 2009 pandemic influenza A(H1N1) vaccines in more than 100,000 pregnant persons in Canada and more than 488,000 pregnant persons in Europe[Footnote 47](#fn47) has not revealed any safety concerns.
Very limited peer-reviewed, published data pertaining to safety of vaccination with RIV4 during pregnancy is currently available to inform vaccine-associated risks. Refer to the [Supplemental Statement on Recombinant Influenza Vaccines](/en/public-health/services/publications/vaccines-immunization/recombinant-influenza-vaccines-supplemental-statement-canadian-immunization-guide-seasonal-influenza-vaccine-2022-2023.html), for more information.
Refer to the [Statement on Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-acs-5.html) and the [Statement on Seasonal Influenza Vaccine for 2012–2013](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2012-38/statement-on-seasonal-influenza-vaccine-2012-2013.html) for further details on influenza vaccination during pregnancy.
#### People of any age who are residents of nursing homes and other chronic care facilities
Residents of nursing homes and other chronic care facilities often have one or more chronic health conditions and live in institutional environments that may facilitate the spread of influenza.
#### Adults 65 years of age and older
Hospitalization attributable to influenza in this age group is estimated at 125–228 per 100,000 healthy people[Footnote 48](#fn48), and influenza-attributed mortality rates increase with increased age[Footnote 49](#fn49).
#### Indigenous peoples
Based on a body of evidence indicating a higher rate of influenza-associated hospitalization and death among Indigenous peoples, NACI recommends the inclusion of this population among those for whom the influenza vaccine is particularly recommended.
it has been proposed that the increased risk of severe influenza outcomes in the Indigenous populations is a consequence of many factors, including high prevalence of chronic health conditions (e.g., diabetes, chronic lung disease, end-stage kidney disease, cardiovascular disease, obesity)[Footnote 50](#fn50), delayed access to health care, and increased susceptibility to disease because of poor housing and overcrowding[Footnote 51](#fn51)[Footnote 52](#fn52)[Footnote 53](#fn53). Refer to the [Statement on Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-acs-5.html) for further details.
### III.2 People Capable of Transmitting Influenza to Those at High Risk of Influenza-Related Complications or Hospitalization
People who are potentially capable of transmitting influenza to those at high risk should receive annual vaccination, regardless of whether the high-risk individual has been vaccinated. Vaccination of Health Care Workers (HCW) decreases their own risk of illness[Footnote 54](#fn54)[Footnote 55](#fn55), as well as the risk of death and other serious outcomes among the individuals for whom they provide care[Footnote 56](#fn56)[Footnote 57](#fn57)[Footnote 58](#fn58)[Footnote 59](#fn59). Vaccination of HCWs and residents of nursing homes is associated with decreased risk of ILI outbreaks[Footnote 60](#fn60).
People who are more likely to transmit influenza to those at high risk of influenza-related complications or hospitalization include:
* HCWs and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk; and
* Contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated.
#### Health care workers and other care providers in facilities and community settings
##### Vaccination of health care workers and other care providers
For the purposes of this statement, HCWs and other care providers in facilities and community settings refers to HCWs, regular visitors, emergency response workers, those who work in continuing care or long-term care facilities or residences, those who provide home care for people at high risk, and students of related health care services. HCWs include any person, paid or unpaid, who provides services, works, volunteers, or trains in a hospital, clinic, or other health care facility.
Transmission of influenza to patients at high risk of influenza-associated complications results in significant morbidity and mortality. Four cluster randomized controlled trials (RCTs) conducted in geriatric long-term care settings have demonstrated that vaccination of HCWs is associated with substantial decreases in influenza-like illness[Footnote 57](#fn57)[Footnote 58](#fn58)[Footnote 59](#fn59) and all-cause mortality[Footnote 56](#fn56)[Footnote 57](#fn57)[Footnote 58](#fn58)[Footnote 59](#fn59) in the residents. In addition, due to their occupation and close contact with people who may be infected with influenza, HCWs are themselves at increased risk of infection[Footnote 61](#fn61).
As previously stated, children 0–59 months of age, adults and children with chronic health conditions, pregnant individuals, people of any age who are residents of nursing homes and other chronic care facilities, and adults 65 years of age and older are at greater risk of more severe complications from influenza or worsening of their underlying condition. Given the potential for HCWs and other care providers to transmit influenza to individuals at high risk and knowing that vaccination is the most effective way to prevent influenza, NACI recommends that, in the absence of contraindications, HCWs and other care providers in facilities and community settings should be vaccinated against influenza annually. NACI considers the receipt of influenza vaccination to be an essential component of the standard of care for all HCWs and other care providers for their own protection and that of their patients. This group should consider annual influenza vaccination as part of their responsibilities to provide the highest standard of care.
Although current influenza vaccine coverage for HCWs is higher than in the general public[Footnote 62](#fn62)[Footnote 63](#fn63), it remains below the national goal of 80% coverage for HCWs in Canada[Footnote 64](#fn64). Comprehensive vaccination programs should be adopted that address HCWs' acceptance of the vaccine and facilitate the process of vaccinating HCWs to improve uptake of the influenza vaccine beyond the current level. HCW influenza vaccination programs that have successfully increased vaccine coverage of HCWs have included a combination of education, increased awareness, accessible on-site vaccination delivery options for all HCWs, visible support from senior staff and other leaders, and regular review and improvement of vaccination strategies[Footnote 65](#fn65)[Footnote 66](#fn66)[Footnote 67](#fn67)[Footnote 68](#fn68)[Footnote 69](#fn69)[Footnote 70](#fn70).
##### Outbreak management in health care facilities
As noted in PHAC's [Guidance: Infection Prevention and Control Measures for Healthcare Workers in Acute Care and Long-term Care Settings for seasonal influenza](/en/public-health/services/infectious-diseases/nosocomial-occupational-infections/guidance-infection-prevention-control-measures-healthcare-workers-acute-care-long-term-care-settings.html)*,* all health care organizations should have a written plan for managing an influenza outbreak in their facilities. Inherent in such plans should be policies and programs to optimize HCW's influenza vaccination[Footnote 71](#fn71). As part of outbreak management, the above-mentioned PHAC guidance suggests consideration of chemoprophylaxis for all unvaccinated HCWs, unless contraindications exist. Refer to the [Association of Medical Microbiology and Infectious Disease Canada](https://www.ammi.ca/guidelines/) (AMMI Canada) website for guidelines regarding the use of antiviral medications for prophylaxis.
#### Contacts of individuals at high risk of influenza complications
Vaccination is recommended for contacts, both adults and children, of individuals at high risk of influenza-related complications or hospitalization (see [List 1](#List1)), whether or not the individual at high risk has been vaccinated. These contacts include: household contacts and care providers of individuals at high risk, household contacts and care providers of infants less than 6 months of age (as these infants are at high risk of complications from influenza but cannot receive influenza vaccine), members of a household expecting a newborn during the influenza season, household contacts and care providers (whether in or out of the home) of children 0–59 months of age, and providers of services within closed or relatively closed settings with people at high risk of influenza-related complications (e.g., crew on a ship).
### III.3 Others
#### People who provide essential community services
Vaccination for these individuals should be encouraged to minimize the disruption of services and routine activities during annual influenza epidemics. People who provide essential community services, including healthy working adults, should consider annual influenza vaccination, as this intervention has been shown to decrease work absenteeism due to respiratory and related illnesses[Footnote 54](#fn54)[Footnote 55](#fn55)[Footnote 72](#fn72)[Footnote 73](#fn73)[Footnote 74](#fn74).
#### People in direct contact with poultry infected with avian influenza during culling operations
##### Poultry workers
Although seasonal influenza vaccination will not prevent avian influenza infection, some countries[Footnote 75](#fn75)and provinces have recommended influenza vaccination on a yearly basis for poultry workers, based on the rationale that preventing infection with human influenza strains may reduce the theoretical potential for human-avian reassortment of genes, should such workers become co-infected with human and avian influenza viruses[Footnote 76](#fn76).
NACI recommends seasonal influenza vaccination for people who may be in direct contact with poultry infected with avian influenza during culling operations, as these individuals may be at increased risk of avian influenza infection because of exposure during the culling operation[Footnote 77](#fn77)[Footnote 78](#fn78)[Footnote 79](#fn79)[Footnote 80](#fn80). Refer to the [Statement on Seasonal Influenza Vaccine for 2013–2014](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2013-39/statement-on-seasonal-influenza-vaccine-2013-2014.html) for further information supporting this recommendation.
Direct contact may be defined as sufficient contact with infected poultry to allow transmission of an avian virus to the exposed person. The relevant individuals include those performing the cull, as well as others who may be directly exposed to the avian virus, such as supervising veterinarians and inspectors. It is recommended that biosecurity measures such as personal protective equipment and antivirals be used. Refer to [Human Health Issues Related to Avian Influenza in Canada](/en/public-health/services/reports-publications/human-health-issues-related-avian-influenza.html) for PHAC recommendations on the management of domestic avian influenza outbreaks.
##### Swine workers
NACI has concluded that there is insufficient evidence at this time to recommend routine influenza vaccination specifically for swine workers; however, NACI recommends that influenza vaccination should be offered to anyone 6 months of age and older who does not have contraindications to the vaccine.
Refer to the [Statement on Seasonal Influenza Vaccine for 2013–2014](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2013-39/statement-on-seasonal-influenza-vaccine-2013-2014.html) for further information supporting this recommendation.
IV. Vaccine Preparations Authorized for Use in Canada: Additional Information
-----------------------------------------------------------------------------
The following sections describe information on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccines that are authorized for use in Canada by type: IIV, RIV and LAIV. Refer to [Appendix A](#a8) for a summary of the characteristics of specific influenza vaccine products available in Canada for the 2022–2023 season.
NACI acknowledges that evidence related to influenza vaccine performance, particularly with respect to vaccine efficacy and effectiveness, is constantly evolving with advances in research methodology and accumulation of data over many influenza seasons. Therefore, the evidence summarized in this section may not include the latest studies. However, in accordance with usual practice, NACI continues to closely monitor the emerging evidence on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccines to update and to make recommendations when warranted.
### IV.1 Inactivated Influenza Vaccine (IIV)
IIVs contain standardized amounts of the HA protein from representative seed strains of the two human influenza A subtypes (H3N2 and H1N1) and either one (for trivalent vaccines) or both (for quadrivalent vaccines) of the two influenza B lineages (Yamagata or Victoria). IIVs currently authorized for use in Canada are a mix of split virus and subunit vaccines, both consisting of disrupted virus particles. Split virus vaccines contain whole inactivated viruses split with detergent, ether, or both, while subunit vaccines are made of purified HA and NA. The amount of NA in the vaccines is not standardized. HA-based serum antibody produced to one influenza A subtype is anticipated to provide little or no protection against strains belonging to the other subtype. The potential for trivalent vaccine to stimulate antibody protection across B lineages requires further evaluation and may be dependent upon factors such as age and prior antigenic experience with the two B lineages[Footnote 81](#fn81)[Footnote 82](#fn82)[Footnote 83](#fn83)[Footnote 84](#fn84)[Footnote 85](#fn85)[Footnote 86](#fn86).
Because of potential changes in the circulating influenza virus from year to year and waning immunity in vaccine recipients, annual influenza vaccination is recommended. Although NACI is aware of some recent studies that suggest that vaccine induced protection may be greater in individuals who have no recent vaccine history, optimal protection against influenza, season after season, is best achieved through annual influenza vaccination[Footnote 87](#fn87)[Footnote 88](#fn88). NACI will continue to monitor this issue.
#### Immunological considerations related to children
Young children have a high burden of illness and their vaccine-induced immune response is not as robust as older children. However, some studies suggest moderate improvement in antibody response in young children, without an increase in reactogenicity, with the use of a full vaccine dose (0.5 mL) for IIV-SDs[Footnote 10](#fn10)[Footnote 11](#fn11)[Footnote 89](#fn89). On the basis of this moderate improvement in antibody response without an increase in reactogenicity, NACI recommends the use of a 0.5 mL dose for all recipients of IIV-SDs, including young children.
**Immunological considerations related to older adults and those with immune compromising conditions**
Although the initial antibody response in older adults may be lower to some influenza vaccine components when compared to those in other age groups, a literature review identified no evidence for a subsequent antibody decline that was any more rapid in older adults than in younger age groups[Footnote 90](#fn90).
Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected patients[Footnote 91](#fn91)[Footnote 92](#fn92)[Footnote 93](#fn93)[Footnote 94](#fn94).
Most studies have shown that administration of a second dose of influenza vaccine in the same season to older adults or other individuals who may have an altered immune response does not result in a clinically significant antibody boost[Footnote 13](#fn13)[Footnote 95](#fn95)[Footnote 96](#fn96)[Footnote 97](#fn97).
#### Standard-dose, egg-based, trivalent inactivated influenza vaccine (IIV3-SD)
Vaccines currently authorized for use:
* \*AgrifluⓇ (Seqirus)
* \*InfluvacⓇ (BGP Pharma ULC, operating as Mylan, doing business as (d.b.a.) Viatris Canada)
\*Vaccine is not currently available in Canada.
##### Efficacy and effectiveness
The NACI [Literature Review on Influenza Vaccination in Healthy 5–18 Year Olds](http://publications.gc.ca/site/eng/469070/publication.html) found that vaccine efficacy or vaccine effectiveness (VE) of IIV3-SD against laboratory-confirmed influenza was variable but was most frequently between 65–85%[Footnote 98](#fn98)[Footnote 99](#fn99)[Footnote 100](#fn100)[Footnote 101](#fn101)[Footnote 102](#fn102)[Footnote 103](#fn103)[Footnote 104](#fn104)[Footnote 105](#fn105)[Footnote 106](#fn106)[Footnote 107](#fn107)[Footnote 108](#fn108)[Footnote 109](#fn109)[Footnote 110](#fn110)[Footnote 111](#fn111)[Footnote 112](#fn112)[Footnote 113](#fn113)[Footnote 114](#fn114)[Footnote 115](#fn115)[Footnote 116](#fn116). In the NACI literature review on [Influenza Vaccine Effectiveness, Immunogenicity, and Safety in Healthy Adults 19–64 Years Old](http://publications.gc.ca/site/eng/469067/publication.html), efficacy against laboratory-confirmed influenza for IIV3-SD in healthy adults 18–64 years of age ranged widely from as low as 15% to as high as 75%, with the majority of studies estimating efficacy at 50–60%. Refer to the [Statement on Seasonal Influenza Vaccine for 2018–2019](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2018-2019.html) for a more detailed summary of efficacy and effectiveness evidence for IIV3-SD in healthy children 5–18 years of age and healthy adults 19–64 years of age.
In older adults, VE of IIV3-SD is about half of that in healthy adults and varies depending on the outcomes measured and the study population[Footnote 117](#fn117)[Footnote 118](#fn118). Systematic reviews have demonstrated that influenza vaccine decreases the incidence of pneumonia, hospital admissions, and deaths in older adults[Footnote 117](#fn117) and reduces exacerbations in people with chronic obstructive pulmonary disease[Footnote 119](#fn119). The NACI [Literature Review on the Comparative Effectiveness and Immunogenicity of Subunit and Split Virus Inactivated Influenza Vaccines in Adults 65 Years of Age and Older](/en/public-health/services/publications/healthy-living/literature-review-comparative-effectiveness-immunogenicity-subunit-split-virus-inactivated-influenza-vaccines-adults-65-years-older.html) found no statistically significant differences in VE of subunit IIV3-SD compared with split virus IIV3-SD in adults 65 years of age and older against infection with any influenza virus strain, or against infection with influenza A(H1N1), A(H3N2), or B virus specifically.
In observational studies, influenza vaccination has been shown to reduce the number of physician visits, hospitalizations, and deaths in adults 18–64 years of age with high-risk medical conditions[Footnote 120](#fn120), hospitalizations for cardiac disease and stroke in adults 65 years of age and older[Footnote 121](#fn121), and hospitalization and deaths in adults 18 years of age and older with diabetes mellitus[Footnote 122](#fn122) during influenza epidemics. Observational studies that use non-specific clinical outcomes or that do not take into account differences in functional status or health-related behaviours should be interpreted with caution[Footnote 123](#fn123)[Footnote 124](#fn124)[Footnote 125](#fn125)[Footnote 126](#fn126)[Footnote 127](#fn127).
##### Immunogenicity
Both humoral and cell-mediated immune responses are thought to play a role in immunity to influenza. While humoral immunity is thought to play a primary role in protection against infection, cell-mediated immunity, notably cytotoxic T lymphocyte responses to internal viral components, is increasingly invoked as important in protecting against severe outcomes of influenza, particularly those associated with subtype HA variations (shift and drift)[Footnote 128](#fn128). The IM administration of IIV3-SD results in the production of circulating immunoglobulin G (IgG) antibodies to the viral HA and NA proteins, as well as a more limited cytotoxic T lymphocyte response.
##### Safety
Studies evaluating the safety of IIV3-SDs in healthy children have found a good safety profile with no SAE of note[Footnote 129](#fn129). The most common solicited local reactions are pain and redness at the injection site, while the most common solicited systemic reactions are irritability, malaise, and headache. Mild injection site reactions, primarily soreness at the vaccination site, have been found to occur in 7% or less of healthy children who are less than 3 years of age[Footnote 130](#fn130)[Footnote 131](#fn131)[Footnote 132](#fn132). Post-vaccination fever may be observed in 12% or less of vaccinated children 1–5 years of age[Footnote 103](#fn103)[Footnote 132](#fn132).
For adults, IIV3-SDs have been demonstrated to have a good safety profile with acceptable reactogenicity[Footnote 129](#fn129). Common local reactions at injection site include redness, swelling, pain, and induration. These reactions last 2–3 days and rarely interfere with normal activities. Common systemic reactions include headache, malaise, myalgia, fatigue, arthralgia, and fever.
##### Standard-dose, egg-based, quadrivalent inactivated influenza vaccine (IIV4-SD)
Vaccines currently authorized for use:
* AfluriaⓇ Tetra (Seqirus)
* FlulavalⓇ Tetra (GlaxoSmithKline)
* FluzoneⓇ Quadrivalent (Sanofi Pasteur)
* InfluvacⓇ Tetra (BGP Pharma ULC, operating as Mylan, d.b.a. Viatris Canada)
##### Efficacy and effectiveness
In the NACI [Literature Review on Quadrivalent Influenza Vaccines](http://publications.gc.ca/site/eng/469075/publication.html), only one study was identified that measured IIV4-SD efficacy. In that study, efficacy was estimated at 59% in children 3–8 years of age, in comparison to children who received hepatitis A vaccine[Footnote 133](#fn133). No literature was found in this review on efficacy or effectiveness directly comparing trivalent and quadrivalent formulations.
##### Immunogenicity
In the same review of the literature noted above, NACI reviewed the immunogenicity data for IIV4-SD produced by manufacturers who supplied influenza vaccine in Canada at the time of the literature review: AstraZeneca, GlaxoSmithKline, and Sanofi Pasteur. The results of phase II and III trials that compared trivalent formulations to quadrivalent formulations generally showed non-inferiority of the quadrivalent products for the A(H3N2), A(H1N1), and B strain contained in the trivalent formulations. As expected, these studies showed that the immune response to the B strain that was not in the trivalent formulation was better in subjects who received the quadrivalent vaccine, which contained the additional B strain. These findings were consistent across age groups. Refer to the [Literature Review on Quadrivalent Influenza Vaccines](http://publications.gc.ca/site/eng/469075/publication.html) for additional details.
In the phase III trials, recipients of the trivalent formulations showed, to a lesser degree, some immune response to the B strain not contained in the trivalent formulation. In one study of adults, both the trivalent and quadrivalent vaccines met all the European Medicines Agency Committee for Medicinal Products for Human Use and the United States Food and Drug Administration criteria for evaluation of influenza vaccine immunogenicity, including for the B strain not in the trivalent vaccine.
In all other studies, the trivalent vaccine failed at least one of the criteria for seroprotection or seroconversion for the missing B strain. It has been hypothesized that there is some level of cross-reactivity between B strains. The degree of cross protection against infection with one lineage provided by immunization against the other lineage is uncertain[Footnote 134](#fn134).
##### Safety
Pre-licensure clinical trials (refer to [Literature Review on Quadrivalent Influenza Vaccines](http://publications.gc.ca/site/eng/469075/publication.html)) and post-marketing surveillance showed that IIV4-SD had a similar safety profile to IIV3-SD[Footnote 135](#fn135).
#### Standard dose mammalian cell culture-based quadrivalent inactivated influenza vaccine (IIV-cc)
Vaccine currently authorized for use:
* FlucelvaxⓇ Quad (Seqirus)
**Methods**
NACI reviewed the Health Canada assessment of a Phase 3/4 randomized clinical trial of Flucelvax Quad efficacy, immunogenicity and safety in children 2 years to less than18 years of age submitted by the manufacturer in support of an age extension for the use of the vaccine to adults and children 2 years of age and older. The clinical trial was conducted in 8 countries in Europe and South East Asia over three influenza seasons (Southern Hemisphere 2017 influenza season and the 2017–2018 and 2018–2019 Northern Hemisphere influenza seasons). Overall, the quality of the evidence was considered good.
In support of the original recommendation for use of the Flucelvax Quad in adults and children 9 years of age and older, NACI conducted a systematic review of the literature to examine vaccine efficacy, effectiveness, immunogenicity, and safety data for this age group.
##### Efficacy and effectiveness
Four observational studies, two peer-reviewed and two not peer-reviewed (conference abstracts and posters) were identified through the systematic review, which assessed the VE of IIV4-cc compared to egg-based IIV against laboratory-confirmed influenza infection during the 2017–2018 influenza season in the United States[Footnote 136](#fn136)[Footnote 137](#fn137)[Footnote 138](#fn138)[Footnote 139](#fn139).Of these four studies, two were of good quality[Footnote 137](#fn137)[138](#fn138), while the quality of the other two studies[Footnote 136](#fn136)[Footnote 139](#fn139) could not be assessed because they were published as conference abstracts or posters. IIV4-cc may be more effective than egg-based IIV3 and IIV4 influenza vaccines against non-laboratory confirmed influenza-related outcomes, including influenza-related health care interactions and ILI. Although some data suggests that IIV4-cc may be more effective against laboratory-confirmed influenza A(H3N2) virus infection than egg-based IIV, there was no consistent and statistically significant difference in effectiveness identified for adults or children vaccinated with IIV4-cc compared to egg-based IIV. Evidence for the efficacy of IIV4-cc is based on the efficacy studies for the trivalent formulation, IIV3-cc.
Refer to the [NACI Supplemental Statement on Mammalian Cell Culture-Based Influenza Vaccines](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/mammalian-cell-culture-based-influenza-vaccines.html) for further details.
The Phase 3/4 RCT of Flucelvax Quad for children 2 years to 18 years met the pre-defined success criterion for efficacy against PCR- or culture-confirmed influenza due to any strain starting 14 days after the last dose in these children. The overall estimate of vaccine efficacy did not differ significantly when analyzed by subgroup (e.g., age, sex, race, influenza vaccination history, influenza season). When analyzed by influenza subtype/lineage in children 2 years to less than 18 years of age, the vaccine was found to be more efficacious against influenza A/H1N1 than against either A/H3N2 or influenza B during the three influenza seasons. Estimates of efficacy by influenza subtype/lineage in children 2 years to less than 4 years of age and children 2 years to less than 9 years of age were comparable to the estimates in children 2 years to less than 18 years of age, although with wider confidence intervals around the point estimates (which included zero for estimates of efficacy against influenza A/H3N2).
##### Immunogenicity
The immunogenicity for IIV4-cc is supported by evidence from the clinical development program for the IIV3-cc (authorization never sought in Canada), which has been licensed in the US and Europe and is produced using the same Madin-Darby Canine Kidney (MDCK) manufacturing platform[Footnote 140](#fn140)[Footnote 141](#fn141)[Footnote 142](#fn142)[Footnote 143](#fn143). IIV3-cc has demonstrated non-inferiority to standard egg-based IIV3 comparators, for hemagglutinin inhibition antibody responses to A(H3N2), A(H1N1) and B strains in adults 18 years of age and older, and for A(H1N1) and B strains specifically, but not A(H3N2), in children, based on post-vaccination GMT ratios and seroconversion rates[Footnote 144](#fn144)[Footnote 145](#fn145)[Footnote 146](#fn146)[Footnote 147](#fn147). There is fair evidence that IIV4-cc has non-inferior immunogenicity to other inactivated influenza vaccines, based on direct and indirect evidence in adults and children 9 years of age and older.
Two studies[Footnote 148](#fn148)[Footnote 149](#fn149) that assessed the immunogenicity of IIV4-cc compared to different IIV3-cc formulations (produced by Seqirus using the same MDCK cell culture-based manufacturing process) were identified in this review; one study was conducted with adult participants18 years of age and older, while the other study focused on pediatric participants. In both studies, Flucelvax Quad demonstrated non-inferiority, based on geometric mean titre rise and seroconversion rates, and met the threshold for seroprotection for all influenza strains contained in the IIV3-cc vaccines, including superior immunogenicity for the B strain not contained in IIV3-cc.
In support of the use of the vaccine in adults and children 2 years of age and older, immunogenicity was assessed in a subset of the phase 3/4 RCT study participants 2 years to less than 9 years of age during the Northern Hemisphere influenza seasons (2017–2018 and 2018–2019), based on blood samples collected on the day of vaccination and 21 days after receipt of the last dose of vaccine. Participants experienced a substantial increase in antibody titres in response to vaccination, based on GMT ratios, seroconversion rates and seroprotection rates. The responses were generally highest against influenza A/H1N1 than for the other influenza subtypes/lineages. However, the immunogenicity results for influenza A/H3N2 were affected by differing hemagglutination abilities of the circulating strains and differences in the hemagglutination inhibition assays used in the two influenza seasons.
##### Safety
There is fair evidence that IIV4-cc is a safe and well-tolerated alternative to conventional egg-based influenza vaccines for children and adults. Two peer-reviewed randomized controlled trials assessed the safety of IIV4-cc; with one focused on healthy adults[Footnote 148](#fn148) and the other on healthy children[Footnote 149](#fn149). Most systemic reactions were mild and resolved within 3 days. SAEs were rare and similar in frequency between cell culture-based and conventional egg-based influenza vaccines. Studies that assessed the safety of Flucelvax were considered to supplement the evidence base for safety. Overall, local and systemic solicited reactions as well as unsolicited AEs and SAE are comparable to those typically observed with other injectable egg-derived IIV3s. The evidence on safety was consistent across studies and showed that there was no significant difference in adults and children compared to comparator vaccines. Flucelvax, also has an established record of safety in other jurisdictions, and no new safety signals have been identified through routine pharmacovigilance in the US or Europe where the vaccine is licensed[Footnote 144](#fn144)[Footnote 145](#fn145)[Footnote 150](#fn150). The vaccine is safe to use during pregnancy, as no safety signals have been detected in this population. IIV4-cc is made using MDCK cells, which are developed from a canine source. An allergy to dogs is not considered a contraindication to the vaccine, based on a review of two in vitro allergenicity studies[Footnote 151](#fn151)[Footnote 152](#fn152).
The analysis of vaccine safety in a clinical trial in children 2 years to less than 18 years of age were consistent with the findings of the previous NACI systematic literature review summarized above. The majority of solicited (local and systemic) and unsolicited adverse events were mild to moderate in severity and resolved spontaneously within 1 to 3 days post-vaccination, with no significant differences in rates between the Flucelvax Quad and comparator vaccine recipients. There were low (less than or equal to 1.3%) and comparable proportions of serious adverse events identified in Flucelvax Quad and comparator vaccine recipients, with no serious adverse events determined to be related to receipt of the assigned vaccine.
#### Adjuvanted inactivated influenza vaccine (IIV-Adj)
Vaccines currently authorized for use:
* FluadⓇ (Seqirus)
* Fluad PediatricⓇ (Seqirus)
#### Fluad (adults 65 years of age and older)
##### Efficacy and effectiveness
There is fair evidence that the MF59-adjuvanted Fluad (IIV3-Adj) may be effective at reducing the risk of hospitalization for influenza and influenza complications in older adults compared to unvaccinated individuals. However, there is insufficient evidence that IIV3-Adj is more effective at reducing the risk of hospitalization for influenza and influenza complications in older adults compared to those who received unadjuvanted subunit IIV3-SD. Refer to the NACI [Literature Review Update on the Efficacy and Effectiveness of High-Dose and MF59-Adjuvanted Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older](/en/public-health/services/publications/healthy-living/executive-summary-literature-review-update-efficacy-effectiveness-fluzone-high-dose-fluad-trivalent-inactivated-influenza-vaccines-adults-65-older.html) for more information on the efficacy and effectiveness of IIV3-Adj in adults 65 years of age and older.
##### Immunogenicity
The mechanism of action of MF59 is not fully determined and has primarily been studied using in vitro and mouse models. From these studies, it appears that MF59 may act differently from aluminum-based adjuvants. These studies show that MF59 acts in the muscle fibres to create a local immune-stimulatory environment at the injection site[Footnote 153](#fn153). MF59 allows for an increased influx of phagocytes (e.g., macrophages, monocytes) to the site of injection. The recruited phagocytes are further stimulated by MF59, thereby increasing the production of chemokines to attract more innate immune cells and inducing differentiation of monocytes into dendritic cells[Footnote 154](#fn154)[Footnote 155](#fn155). MF59 further facilitates the internalization of antigen by these dendritic cells[Footnote 154](#fn154)[Footnote 156](#fn156). The overall higher number of cells available locally increases the likelihood of interaction between an antigen presenting cell and the antigen, leading to more efficient transport of antigen to the lymph nodes, with resulting improved T cell priming[Footnote 154](#fn154).
There is evidence from RCTs that IIV3-Adj elicits non-inferior immune responses compared to the unadjuvanted subunit and split virus IIV3-SDs; however, superiority of IIV3-Adj to these vaccines by pre-defined criteria has not been consistently demonstrated. Refer to the [Statement on Seasonal Influenza Vaccine for 2018–2019](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2018-2019.html) for more information on the immunogenicity of IIV3-Adj in adults 65 years of age and older.
##### Safety
IIV3-Adj produces injection site reactions (pain, erythema, and induration) significantly more frequently than IIV3-SD, but they are classified as mild and transient. Systemic reactions (myalgia, headache, fatigue, and malaise) are comparable or more frequent with IIV3-Adj compared to IIV3-SD and are rated as mild to moderate and transient. SAEs were uncommon and were comparable to IIV3-SD. Refer to the [Recommendations on the use of MF59-Adjuvanted Trivalent Influenza Vaccine (FluadⓇ): Supplemental Statement of Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-4.html) for additional information on the safety of IIV3-Adj in adults 65 years of age and older.
#### Fluad Pediatric (children 6–23 months of age)
##### Efficacy and effectiveness
A pre-licensure efficacy trial in children 6–71 months of age found a higher relative efficacy for IIV-Adj than the unadjuvanted IIV3-SD[Footnote 157](#fn157). However, the findings of this study should be interpreted with caution. The comparator unadjuvanted IIV3 used in this trial was shown, in an unrelated study, to induce a lower immune response compared to another unadjuvanted IIV3-SD. There were concerns raised by a European Medicines Agency inspection about the quality of diagnostic laboratory testing and validity of ascertainment of influenza cases. The study administered 0.25 mL doses of the comparator unadjuvanted IIV3-SD for children less than 36 months of age, which is lower than the dose of 0.5 mL of unadjuvanted IIV3-SD or IIV4-SD that is recommended for this age group in Canada. Refer to the NACI [Literature Review on Pediatric FluadⓇ Influenza Vaccine Use in Children 6–72 Months of Age](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/literature-review-on-pediatric-fluad-influenza-vaccine-use-children-6-72-months.html) for more information on the efficacy and effectiveness of IIV3-Adj in children.
##### Immunogenicity
In children, there is limited but consistent evidence that IIV3-Adj is more immunogenic than IIV3-SD against both influenza A and B[Footnote 157](#fn157)[Footnote 158](#fn158)[Footnote 159](#fn159)[Footnote 160](#fn160)[Footnote 161](#fn161)[Footnote 162](#fn162). In particular, a single dose of IIV3-Adj is more immunogenic than a single dose of IIV3-SD, and has been shown in one study to produce greater GMTs than 2 doses of IIV3-SD against influenza A[Footnote 162](#fn162). However, similar to IIV3-SD, IIV3-Adj generally induced a weaker hemagglutination-inhibition antibody response against B strains compared to A strains and therefore 2 doses of IIV3-Adj are still necessary for first-time recipients to achieve a satisfactory immune response against influenza B.
Almost all of the pre-licensure pediatric studies used vaccine formulations of 0.25 mL in children 6–35 months of age, both for IIV3-Adj and the comparator unadjuvanted influenza vaccine (NACI recommends 0.5 mL dosage of IIV3-SD or IIV4-SD for all age groups). There is limited immunogenicity evidence comparing IIV3-Adj at 0.25 mL dose to IIV3-SD or IIV4-SD at 0.5 mL dose in the 6–23 month age group. Refer to the NACI [Literature Review on Pediatric FluadⓇ Influenza Vaccine Use in Children 6–72 Months of Age](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/literature-review-on-pediatric-fluad-influenza-vaccine-use-children-6-72-months.html#s4) for more information on the immunogenicity of IIV3-Adj in children.
##### **Safety**
The safety data in children are consistent with what is known about IIV3-Adj’s safety profile in adults. In pediatric trials, IIV3-Adj was more reactogenic than IIV3-SD, with recipients experiencing 10–15% more solicited local and systemic reactions. However, most reactions were mild and resolved quickly. A dose-ranging study of MF59-adjuvanted and unadjuvanted IIV3 and IIV4 did not find an increased risk of AEs associated with increased MF59 dose, antigen dose, or the addition of a second B strain; however, the reactogenicity of 15 µg formulations were slightly higher for both adjuvanted and unadjuvanted vaccines compared to the corresponding 7.5 µg formulations[Footnote 160](#fn160).
There are currently no data on the effects of long-term or repeated administration of adjuvanted influenza vaccines in children. The most significant experience with an adjuvanted influenza vaccine in children was the AS03-adjuvanted A(H1N1) pandemic vaccine that has been associated with an increased risk of narcolepsy. A study comparing two AS03-adjuvanted A(H1N1) vaccine products (Pandemrix and Arepanrix) has suggested that the underlying immune mediated mechanism associated with the increased narcolepsy risk may not be initiated by the adjuvant, but by the A(H1N1) nucleoprotein viral antigen, given that the study found significant antigenic differences between the two A(H1N1) pandemic vaccines[Footnote 163](#fn163). However, the pandemic vaccine was a single strain adjuvanted vaccine administered only during one season, and it is unknown what effects a multi-strain adjuvanted vaccine or an adjuvanted vaccine administered for more than one season may have in young children.
Refer to the NACI [Literature Review on Pediatric FluadⓇ Influenza Vaccine Use in Children 6-72 Months of Age](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/literature-review-on-pediatric-fluad-influenza-vaccine-use-children-6-72-months.html#s4d) for additional information on the safety of IIV3-Adj in children.
#### High-dose inactivated influenza vaccine (IIV-HD)
Vaccines currently authorized for use:
* FluzoneⓇ High-Dose Quadrivalent (Sanofi Pasteur)
##### Efficacy and effectiveness
There is good evidence that Fluzone High-Dose (IIV3-HD) provides better protection compared with IIV3-SD in adults 65 years of age and older. Two studies found that IIV3-HD may provide greater benefit in adults 75 years of age and older compared to adults 65–74 years of age[Footnote 164](#fn164)[Footnote 165](#fn165). The efficacy results for IIV3-HD are inferred to IIV4-HD based on the non-inferior immunogenicity, described in the next section.
Refer to the NACI [Literature Review Update on the Efficacy and Effectiveness of High-Dose and MF59-Adjuvanted Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older](/en/public-health/services/publications/healthy-living/executive-summary-literature-review-update-efficacy-effectiveness-fluzone-high-dose-fluad-trivalent-inactivated-influenza-vaccines-adults-65-older.html) for more information on the efficacy and effectiveness of IIV3-HD in adults 65 years of age and older.
##### Immunogenicity
Five studies compared the rates of seroconversion for study participants receiving IIV3-HD and IIV3-SD among those 65 years of age and older[Footnote 166](#fn166)[Footnote 167](#fn167)[Footnote 168](#fn168)[Footnote 169](#fn169)[Footnote 170](#fn170)[Footnote 171](#fn171). Rates of seroconversion were found to be about 19% higher (ranging from 8–39% higher) for those receiving the higher dose vaccine across all three vaccine strains. Similarly, rates of seroconversion were higher for those receiving the high- compared to standard-dose vaccines for participants 75 years of age and older and for a cohort of participants with underlying cardiopulmonary disease.
Eight studies reported higher rates of seroprotection for older adults receiving IIV3-HD compared to those vaccinated with IIV3-SD[Footnote 166](#fn166)[Footnote 167](#fn167)[Footnote 168](#fn168)[Footnote 169](#fn169)[Footnote 170](#fn170)[Footnote 171](#fn171)[Footnote 172](#fn172)[Footnote 173](#fn173). Seroprotection was significantly higher for all 3 strains in the vaccine in three of five studies assessing significance. There were different results in the remaining studies. In the study by Couch et al., seroprotection was higher only against A(H1N1), possibly attributed to the fact that 78% of participants were vaccinated against the same influenza strains within 6 months prior to the study[Footnote 167](#fn167). In Nace et al., seroprotection was higher against A(H3N2) and B but not A(H1N1); the lack of higher seroprotection against A(H1N1) may be attributed to strain circulation during the study that made it difficult to assess seroprotection against this subtype[Footnote 152](#fn152).
GMT ratios (GMTR) of participants’ responses to high- versus standard-dose influenza vaccines were reported in several studies and were calculated for those that provided group-specific, post-vaccination titres for each of the vaccines[Footnote 166](#fn166)[Footnote 167](#fn167)[Footnote 168](#fn168)[Footnote 169](#fn169)[Footnote 170](#fn170)[Footnote 172](#fn172)[Footnote 173](#fn173). Seroresponse to the B strains in the vaccines was about 1.5 times greater (1.3–1.7) in the IIV3-HD recipients than the IIV3-SD recipients. The GMTR of the A strains was about 1.8 times higher for those receiving IIV3-HD compared to IIV3-SD, ranging from 1.6–2.3.
There is good evidence that the immunogenicity for Fluzone High Dose Quadrivalent (IIV4-HD) is non-inferior to IIV3-HD[Footnote 174](#fn174)[Footnote 175](#fn175). In a pivotal RCT, IIV4-HD met all non-inferiority criteria set by the US Food and Drug Administration, based on GMTR and seroconversion rates when compared to IIV3-HD[Footnote 175](#fn175). Immunogenicity for IIV4-HD was superior for the influenza B strain not contained within the trivalent high dose vaccine[Footnote 175](#fn175).
##### Safety
IIV3-HD has been observed to produce a higher rate of some systemic and local reactions than IIV3-SD. Studies have reported higher rates of malaise, myalgia, and moderate to severe fever. Most systemic reactions were mild and resolved within 3 days. SAEs were rare and similar in frequency between standard-dose and high-dose vaccines. When comparing the two high dose vaccine products, IIV4-HD has been shown to produce a comparable rate of systemic and local reactions compared to IIV3-HD. A comparable proportion of study participants also experienced unsolicited and serious AEs[Footnote 175](#fn175).
Refer to NACI’s [A Review of the Literature of High Dose Seasonal Influenza Vaccine for Adults 65 Years and Older](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/a-review-literature-high-dose-seasonal-influenza-vaccine-adults-65-years-older.html) for details on IIV3-HD.
### IV.2 Recombinant quadrivalent influenza vaccine (RIV4)
Vaccines currently authorized for use:
* Supemtek™ (Sanofi Pasteur)
#### Methods
For the review of evidence relating to RIV, NACI used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework to organize the information and develop recommendations for RIV. Further information on this framework can be found in the [GRADE handbook](https://training.cochrane.org/resource/grade-handbook).
#### Efficacy and effectiveness
One RCT was identified that assessed the relative vaccine efficacy (rVE) of RIV4 compared to egg-based IIV4 against laboratory confirmed influenza infection in adults 50 years of age and older during the 2014-2015 influenza season in the United States[Footnote 176](#fn176). The certainty of evidence for this outcome was rated as low and suggested that RIV4 may be more effective than egg-based IIV4 influenza vaccines against laboratory-confirmed influenza A virus infection, but not laboratory-confirmed influenza B virus infection in older adults.
Overall, there is fair evidence (of low certainty) that the efficacy of RIV4 is non-inferior to traditional egg-based comparators, based on data in adults aged 50 years and older.
Refer to the [NACI Supplemental Statement on Recombinant Influenza Vaccines](/en/public-health/services/publications/vaccines-immunization/recombinant-influenza-vaccines-supplemental-statement-canadian-immunization-guide-seasonal-influenza-vaccine-2022-2023.html), for further details.
#### Immunogenicity
Eight RCTs[Footnote 176](#fn176)[Footnote 177](#fn177)[Footnote 178](#fn178)[Footnote 179](#fn179)[Footnote 180](#fn180)[Footnote 181](#fn181)[Footnote 182](#fn182)[Footnote 183](#fn183) were identified that assessed the immunogenicity of RIV4. Of these studies, two were conducted during the 2014-2015 influenza season[Footnote 176](#fn176)[Footnote 179](#fn179), three were conducted over the 2017-2018 influenza season[Footnote 177](#fn177)[Footnote 181](#fn181)[Footnote 182](#fn182), and three were conducted over the 2018-2019 influenza season[Footnote 178](#fn178)[Footnote 180](#fn180)[Footnote 183](#fn183). The RCTs were of good quality overall. Non-inferiority was assessed using the criteria specified by the US FDA[Footnote 139](#fn139).
The eight RCTs compared rates of seroconversion for RIV4 recipients with IIV3-HD, IIV3-Adj, IIV4-SD, and IIV4-cc recipients aged 18 years of age or older. In four[Footnote 177](#fn177)[Footnote 178](#fn178)[Footnote 181](#fn181)[Footnote 183](#fn183) of the eight studies, rates of seroconversion were similar in those receiving RIV4 compared to those receiving IIV3-HD, IIV3-Adj, IIV4-SD, and IIV4-cc against influenza A/H1N1, A/H3N2, B/Yamagata lineage and B/Victoria lineage. There were different results in the remaining studies. The two studies by Dunkle et al.[Footnote 176](#fn176)[Footnote 179](#fn179) demonstrated that, compared to IIV4-SD, RIV4 did not meet the non-inferiority threshold in HI antibody responses against B/Victoria lineage in adults 18 to 64 years of age. Additionally, rates of seroconversion following RIV4 did not meet the non-inferiority threshold compared to IIV4-SD against influenza A/H1N1 in adults 64 and older[Footnote 176](#fn176). Non-inferiority could not be assessed for the remaining two RCTs[Footnote 180](#fn180)[Footnote 182](#fn182) as these studies did not state confidence intervals for seroconversion estimates. Pooled seroconversion data from three[Footnote 176](#fn176)[Footnote 178](#fn178)[Footnote 181](#fn181) of the eight RCTs identified in adult participants 50 years of age and older using a random-effects model revealed that RIV4 induced similar antibody responses compared to IIV4-SD, IIV3-HD, and IIV3-Adj.
Four RCTs reported comparable or greater rates of seroprotection for study participants receiving RIV4 compared to those receiving IIV3-HD, IIV3-Adj, IIV4-SD, and IIV4-cc among adults 18 years of age and older[Footnote 176](#fn176)[Footnote 177](#fn177)[Footnote 178](#fn178)[Footnote 183](#fn183). The four studies had varying findings. In two of the four studies, RIV4 met the non-inferiority criteria specified by the US FDA for all tested influenza strains including A/H1N1, A/H3N2, B/Yamagata lineage, and B/Victoria lineage[Footnote 178](#fn178)[Footnote 183](#fn183). Across the four RCTs, RIV4 met non-inferiority criteria against five of seven tested strains of A/H3N2. In the study by Belongia et al.[Footnote 177](#fn177), RIV4 demonstrated lower rates of seroprotection for older adults 65 to 74 years of age against two of four tested strains of A/H3N2. However, one limitation was the small sample size of the study. In the study by Dunkle et al. (2017a)[Footnote 176](#fn176), RIV4 met the non-inferiority threshold for seroprotection against influenza A/H1N1, A/H3N2, and B/Yamagata lineage, but not against influenza B/Victoria lineage in adults aged 50 and older.
GMTR of participants’ responses to RIV4 versus IIV4-SD were reported in three RCTs[Footnote 176](#fn176)[Footnote 179](#fn179)[Footnote 183](#fn183)[Footnote 184](#fn184). In one study, RIV4 met the non-inferiority criteria specified by the US FDA for all tested A/H1N1, A/H3N2, B/Yamagata lineage, and B/Victoria lineage influenza strains[Footnote 183](#fn183). In two of the three studies, seroresponses to A/H1N1, A/H3N2, and B/Yamagata lineage in RIV4 recipients were comparable to seroresponses in IIV4-SD recipients based on the GMTR[Footnote 176](#fn176)[Footnote 179](#fn179)[Footnote 184](#fn184). However, the GMTR against B/Victoria lineage for IIV4-SD recipients compared to RIV4 recipients did not meet the non-inferiority criteria set by the US FDA[Footnote 139](#fn139).
Overall, there is fair evidence (of moderate certainty) that the immunogenicity for RIV4 is non-inferior to traditional egg-based comparators, based on data in adults aged 18 years and older.
#### Safety
Six studies[Footnote 176](#fn176)[Footnote 178](#fn178)[Footnote 179](#fn179)[Footnote 181](#fn181)[Footnote 185](#fn185)[Footnote 186](#fn186) were identified that assessed the safety of RIV4 in adults, including five RCTs and one review of post-marketing surveillance data from the United States. Of these studies, two were conducted during the 2014-2015 influenza season[Footnote 176](#fn176)[Footnote 179](#fn179), two were conducted during the 2017-2018 influenza season[Footnote 181](#fn181)[Footnote 186](#fn186), one was conducted during the 2018-2019 influenza season[Footnote 178](#fn178), and one study reported data from the Vaccine Adverse Event Reporting System (VAERS) from July 1, 2017 through June 30, 2020[Footnote 185](#fn185). Most systemic reactions reported by the clinical trials were mild to moderate in severity and were transient in nature. Adverse events were similar in frequency between recombinant and conventional egg-based influenza vaccines. Although serious AEs were reported across clinical trials, none were considered by the authors to be related to the trial vaccines. RIV4 also has an established record of safety in other jurisdictions, and no safety signals have been identified through routine pharmacovigilance in the US, where the vaccine is licensed[Footnote 185](#fn185). Most AE reported to VAERS following RIV4 administration were non-serious. When data from two RCTs[Footnote 176](#fn176)[Footnote 178](#fn178) conducted among adult participants 50 years of age and older were combined and weighted using a random-effects model, there was no difference in the odds of experiencing a SAE following administration of RIV4 and traditional egg-based IIV3-HD and IIV4-SD vaccine comparators. No published clinical data pertaining to safety of vaccination with RIV4 during pregnancy is currently available to inform vaccine-associated risks.
Overall, there is evidence of moderate certainty that RIV4 is a safe and well-tolerated alternative to conventional egg-based influenza vaccines for adults.
### IV.3 Live Attenuated Influenza Vaccine (LAIV)
LAIV contains standardized quantities of FFU of live attenuated influenza virus reassortants. The virus strains in LAIV are cold-adapted and temperature sensitive, so they replicate in the nasal mucosa rather than the lower respiratory tract, and they are attenuated, so they do not produce ILI. There have been no reported or documented cases, and no theoretical or scientific basis to suggest transmission of vaccine virus would occur to the individual administering LAIV. As a live replicating whole virus formulation administered intranasally, it elicits mucosal immunity, which may more closely mimic natural infection.
Vaccine currently authorized for use:
* FluMistⓇ Quadrivalent (AstraZeneca)
#### Efficacy and effectiveness
After careful review of the available Canadian and international LAIV VE data over many influenza seasons, NACI concluded that the current evidence is consistent with LAIV providing comparable protection against influenza to that afforded by IIV and does not support a recommendation for the preferential use of LAIV in children 2–17 years of age.
Observational studies from the United States found low effectiveness of LAIV against circulating post-2009 pandemic A(H1N1) (A(H1N1)pdm09), in 2013–2014 and 2015–2016; however, reduced LAIV effectiveness was not observed in Canada or any other countries that have investigated the issue. Manufacturer investigation identified potential reduced replicative fitness of the A(H1N1)pdm09-like LAIV viruses in the nasal mucosa from the two affected A(H1N1)-dominant seasons compared to pre-2009 pandemic influenza A(H1N1) LAIV viruses as contributing to the poor LAIV effectiveness against circulating A(H1N1),[Footnote 187](#fn187). This finding led to the manufacturer replacing the A(H1N1)pdm09 component of LAIV with new strains, with the A/Slovenia/2903/2015 being the strain that has been used since the 2017–2018 season. In adults, studies have found IIV-SD to be similarly or more efficacious or effective compared with LAIV.
Refer to the [Statement on Seasonal Influenza Vaccine for 2018–2019](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2018-2019.html) for detailed information supporting this recommendation.
#### Immunogenicity
LAIV, which is administered by the intranasal route, is thought to result in an immune response that mimics that induced by natural infection with wild-type viruses, with the development of both mucosal and systemic immunity. Local mucosal antibodies protect the upper respiratory tract and may be more important for protection than serum antibody.
Studies have demonstrated that the presence of a hemagglutination-inhibition antibody response after the administration of LAIV3 is predictive of protection. However, efficacy studies have shown protection in the absence of a significant antibody response as well[Footnote 188](#fn188). In these studies, LAIV3 has generally been shown to be equally, if not more, immunogenic compared to IIV3-SD for all 3 strains in children, whereas IIV3-SD was typically more immunogenic in adults than LAIV3. Greater rates of seroconversion to LAIV3 occurred in baseline seronegative individuals compared to baseline seropositive individuals in both pediatric and adult populations, because pre-existing immunity may interfere with response to a live vaccine. Refer to the NACI [Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMistⓇ): Supplemental Statement on Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-2.html) for further details regarding the immunogenicity of LAIV3.
LAIV4 has shown non-inferiority based on immunogenicity compared to LAIV3 in both children and adults. The immune response to the B strain found only in the quadrivalent formulation was better in children who received the quadrivalent vaccine[Footnote 189](#fn189)[Footnote 190](#fn190)[Footnote 191](#fn191).
**Safety**
The most common AEs experienced by recipients of LAIV3 are nasal congestion and runny nose, which are also reported for LAIV4. In a large efficacy trial, rates of wheezing were statistically higher among children 6–23 months of age for LAIV3 compared to IIV3-SD (188). This finding is expected to be the same for recipients of LAIV4; however, pre-licensure clinical studies for LAIV4 were conducted only in adults and children 2 years of age and older. LAIV4 is not authorized in children less than 2 years of age.
Studies on LAIV3 have shown that vaccine virus can be recovered by nasal swab in children and adults following vaccination (i.e., “shedding”). The frequency of shedding decreases with increasing age and time since vaccination. Shedding is generally below the levels needed to transmit infection, although in rare instances, shed vaccine viruses can be transmitted from vaccine recipients to unvaccinated people. Refer to the NACI [Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMistⓇ): Supplemental Statement on Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-2.html) for more information on LAIV and viral shedding.
#### Considerations related to individuals with HIV infection
Following a review of the literature regarding the use of LAIV in HIV-infected individuals, NACI concluded that LAIV is immunogenic in children with stable HIV infection on HAART and with adequate immune function. In addition, NACI concluded that LAIV appears to have a similar safety profile as IIV in children on HAART and with stable HIV infection with regard to frequency and severity of AEs[Footnote 192](#fn192). As expected, injection site reactions were seen only with IIV and nasal symptoms were more common with LAIV. However, the evidence base is too small to effectively detect uncommon, rare, and very rare AEs related to the use of LAIV in in this population. Nasal spray may be preferable to IM injection for some individuals who are averse to receiving the vaccine by injection. Therefore, NACI recommends that LAIV may be considered as an option for children 2–17 years of age with stable HIV infection on HAART and with adequate immune function. LAIV should be considered only in children with HIV who meet the following criteria:
* Receiving ART for 4 months or longer;
* CD4 count equal to or greater than 500/µL if 2–5 years of age, or ≥200/µL if 6–17 years of age (measured within 100 days before administration of LAIV); and
* HIV plasma RNA less than 10,000 copies/mL (measured within 100 days before administration of LAIV).
IM influenza vaccination is still considered the standard for children living with HIV by NACI and the Canadian Pediatric and Perinatal HIV/AIDS Research Group, particularly for those without HIV viral load suppression (i.e., plasma HIV RNA >40 copies/mL). However, if IM vaccination is not accepted by the individual or substitute decision maker, LAIV would be a reasonable option for children meeting the criteria listed above.
Refer to the [NACI Statement on the Use of LAIV in HIV-Infected Individuals](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/live-attenuated-influenza-vaccine-hiv-infected-individuals.html) for more information on the use of LAIV in this population.
### IV.4 Schedule
The first time that children 6 months to less than 9 years of age receive seasonal influenza vaccination, a two-dose schedule is required to achieve protection[Footnote 193](#fn193)[Footnote 194](#fn194)[Footnote 195](#fn195). Several studies have looked at whether these two initial doses need to be given in the same season[Footnote 83](#fn83)[Footnote 84](#fn84)[Footnote 196](#fn196). Englund et al. reported similar immunogenicity in children 6–23 months of age whether 2 doses were given in the same or separate seasons when there was no change, or only minor vaccine strain change, in vaccine formulation between seasons[Footnote 83](#fn83)[Footnote 84](#fn84). However, seroprotection rates to the B component were considerably reduced in the group that received only one dose in the subsequent season when there was a major B lineage change, suggesting that the major change in B virus lineage reduced the priming benefit of previous vaccination[Footnote 82](#fn82)[Footnote 84](#fn84). Issues related to effective prime-boost when there is a major change in influenza B lineage across sequential seasons require further evaluation [Footnote 197](#fn197). Because children 6–23 months of age are less likely to have had prior priming exposure to an influenza virus, special effort is warranted to ensure that a two-dose schedule is followed for previously unvaccinated children in this age group.
### IV.5 Concurrent Administration with Other Vaccines
All seasonal influenza vaccines, including LAIV, may be given at the same time as, or at any time before or after administration of other vaccines, including COVID-19 vaccines for those aged 5 years and older.
NACI will continue to monitor the evidence base, including ongoing and anticipated trials investigating influenza vaccines administered at the same time as, or any time before or after, COVID-19 vaccines and update its recommendations as needed.
Refer to the [NACI Statement on the Use of COVID-19 Vaccines](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/recommendations-use-covid-19-vaccines.html#a7.7) and the CIG COVID-19 chapter for current recommendations concerning the use of COVID-19 vaccines and further information on concurrent administration of COVID-19 vaccines with other vaccines.
In general, NACI recommends that two live parenteral vaccines be administered either on the same day or at least 4 weeks apart[Footnote 198](#fn198). This recommendation is based largely on a single study from 1965 that demonstrated immune interference between smallpox vaccine and measles vaccine administered 9–15 days apart. Subsequent studies have revealed conflicting results on immune interference between live vaccines[Footnote 199](#fn199)[Footnote 200](#fn200)[Footnote 201](#fn201)[Footnote 202](#fn202). No studies were found on potential immune interference between LAIV and other live attenuated vaccines (oral or parenteral) administered within 4 weeks. A few studies on concurrent administration of LAIV3 with MMR, varicella, and oral polio vaccines did not find evidence of clinically significant immune interference[Footnote 12](#fn12)[Footnote 14](#fn14)[Footnote 15](#fn15). One study reported a statistically significant but not clinically meaningful decrease in seroresponse rates to rubella antigen when administered concurrently with LAIV.
In theory, the administration of two live vaccines sequentially within less than 4 weeks could reduce the efficacy of the second vaccine. Possible immune mechanisms include: the inhibitory and immunomodulatory effects of systemic and locally produced cytokines on B- and T-cell response and viral replication; immunosuppression induced by certain viruses (such as measles); and direct viral interference as a result of competition for a common niche. Mucosal vaccines may have less impact on a parenteral vaccine and vice versa. The immune response with a mucosal vaccine may be compartmentalized to the mucosa while that to a parenteral vaccine is systemic. It is likely that there is some interaction between the systemic and mucosal compartments; however, the extent to which this interaction occurs is not known.
Given the lack of data for immune interference, and based on expert opinion, NACI recommends that LAIV can be given together with or at any time before or after the administration of any other live attenuated or inactivated vaccine. However, some vaccine providers may continue to choose to give LAIV and other live vaccines separated by at least 4 weeks, based on the theoretical possibility of immune interference, although NACI does not believe that this precaution is necessary for LAIV. The use of an inactivated influenza vaccine would avoid this theoretical concern.
### IV.6 Additional Vaccine Safety Considerations
Influenza vaccine is safe and well tolerated. Contraindications, precautions, and common AEs are described in [Section II](#a2). Additional information regarding egg-allergic individuals and GBS is provided below.
#### Egg-allergic individuals
After careful review of clinical and post-licensure safety data, NACI has concluded that egg-allergic individuals may be vaccinated against influenza using any influenza vaccine, including egg-based vaccines and LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg and without any particular consideration, including vaccination setting. The amount of trace ovalbumin allowed in influenza vaccines that are authorized for use in Canada is associated with a low risk of AE, and in addition, two of the authorized products do not contain any ovalbumin. The observation period post-vaccination is as recommended in [Vaccine Safety](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-2-vaccine-safety.html) in Part 2 of the CIG. As with all vaccine administration, vaccine providers should be prepared with the necessary equipment, knowledge, and skills to respond to a vaccine emergency at all times.
Refer to the [Statement on Seasonal Influenza Vaccine for 2018–2019](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2018-2019.html) for safety data supporting this recommendation for IIV and LAIV.
#### Guillain-Barré syndrome
In a review of studies conducted between 1976 and 2005, the United States Institute of Medicine concluded that the 1976 “swine flu” vaccine was associated with an elevated risk of GBS. However, evidence was inadequate to accept or to reject a causal relation between GBS in adults and seasonal influenza vaccination[Footnote 203](#fn203). The attributable risk of GBS in the period following seasonal and monovalent 2009 pandemic influenza vaccination is about one excess case per million vaccinations[Footnote 20](#fn20)[Footnote 21](#fn21). In a self-controlled study that explored the risk of GBS after seasonal influenza vaccination and after influenza health care encounters (a proxy for influenza illness), the attributable risks were 1.03 GBS admissions per million vaccinations compared with 17.2 GBS admissions per million influenza-coded health care encounters[Footnote 21](#fn21). This finding shows that both influenza vaccination and influenza illness are associated with small attributable risks of GBS, but the risk of GBS associated with influenza illness is notably higher than with influenza vaccination. The self-controlled study also found that the risk of GBS after vaccination was highest during weeks 2–4, whereas for influenza illness, the risk was greatest within the first week after a health care encounter and decreased thereafter, but remained significantly elevated for up to 4 weeks. The risk of GBS associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and all the other benefits of influenza vaccination[Footnote 204](#fn204)[Footnote 205](#fn205)[Footnote 206](#fn206)[Footnote 207](#fn207).
V. Choice of Seasonal Influenza Vaccine: Additional Information
---------------------------------------------------------------
With the recent availability of a number of new influenza vaccines, some of which are designed to enhance immunogenicity in specific age groups, the choice of product is now more complex. [Section II.5](#a2.5) summarizes NACI’s recommendations on the choice of currently authorized influenza vaccines. This section provides more details for these recommendations.
### V.1 Children
#### Burden of disease in children
Canadian surveillance data from 2001–2002 to 2012–2013 has shown that influenza B strains accounted for 17% of laboratory-confirmed tests for influenza in children, which is a higher proportion of disease burden due to influenza B infection compared to other age groups.
Although children less than 24 months of age comprise approximately 2% of the Canadian population[Footnote 208](#fn208), children 0–23 months of age averaged 10.8% of reported influenza B cases (range: 8.3–13.7%), using case-based laboratory data from 2001–2012 (excluding 2009). With respect to severe outcomes (e.g., hospitalization, intensive care unit admission, and death), influenza B was confirmed in 15.5–58.3% (median: 38.4%) of pediatric influenza-associated hospitalizations (children 16 years of age and younger) reported by the Canadian Immunization Monitoring Program Active (IMPACT) surveillance network between 2004–2005 and 2012–2013 (excluding the 2009–2010 pandemic season)[Footnote 209](#fn209).
The IMPACT study also found that the proportion of deaths attributable to influenza (any strain) was significantly greater for children admitted to hospital with influenza B (1.1%) than for those admitted with influenza A (0.4%). The proportion of hospitalizations due to influenza B relative to all influenza hospitalizations has been generally similar to the proportion of influenza B detections relative to all influenza infections in the general population during the same time period. Additional information can be found in the [Statement on Seasonal Influenza Vaccine for 2014–2015.](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/statement-on-seasonal-influenza-vaccine-2014-2015.html)
In the NACI [Literature Review on Quadrivalent Influenza Vaccines](http://publications.gc.ca/site/eng/469075/publication.html), a review of B lineage antigens included in the Canadian influenza vaccines and the circulating strains each season indicates a match in five of the 12 seasons from 2001–2002 through to 2012–2013, a moderate match (about 50% from each lineage) in 1 season, and a mismatch in remaining 6 influenza seasons (i.e., 70% or more of the characterized B strains were of the opposite lineage to the antigen in that season’s vaccine).
#### Children 6–23 months of age
Three types of influenza vaccine are authorized for use in children 6–23 months of age: IIV3-SD, IIV3-Adj, and IIV4-SD.
Given the burden of influenza B disease in children and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine, NACI recommends that a quadrivalent influenza vaccine should be used. If a quadrivalent vaccine is not available, any of the available age-appropriate trivalent vaccines should be used.
There is insufficient evidence to make comparative recommendations on the use of IIV3-Adj over IIV3-SD.
#### Children 2–17 years of age
Four types of influenza vaccine have been authorized for use in children 2–17 years of age (IIV3-SD, IIV4-SD, IIV4-cc, and LAIV4.
Given the burden of influenza B disease in children and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine, NACI recommends that an age appropriate quadrivalent vaccine should be used. If a quadrivalent vaccine is not available, an age-appropriate trivalent vaccine should be used.
The current evidence does not support a recommendation for the preferential use of LAIV in children and adolescents 2–17 years of age. Refer to the NACI [Statement on Seasonal Influenza Vaccine for 2018–2019](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2018-2019.html) for information supporting this recommendation.
##### Children 2–17 years of age with chronic health conditions
NACI recommends that any age-appropriate influenza vaccine (IIV or LAIV) may be considered for children 2–17 years of age with chronic health conditions; however, LAIV should not be used for children with severe asthma (as defined as currently on oral or high-dose inhaled glucocorticosteroids or with active wheezing), those with medically attended wheezing in the 7 days prior to vaccination, those currently receiving aspirin or aspirin-containing therapy, and those with immune compromising conditions, excluding those with stable HIV infection on HAART and with adequate immune function. LAIV is also contraindicated in pregnant adolescents. Children and adolescents for whom LAIV is contraindicated should receive IIV. If IIV is used, NACI recommends that a quadrivalent vaccine should be used. If a quadrivalent vaccine is not available, an age-appropriate trivalent vaccine should be used.
NACI recommends that LAIV may be given to children with stable, non-severe asthma, children with cystic fibrosis who are not treated with immunosuppressive drugs, such as prolonged systemic corticosteroids, and children with stable HIV infection on HAART and with adequate immune function.
Refer to the NACI [Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMistⓇ): Supplemental Statement on Seasonal Influenza Vaccine for 2011–2012](/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2011-37/canada-communicable-disease-report-2.html) for additional information supporting these recommendations.
##### Summary of vaccine characteristics for decision making
IIV3-SD, IIV4-SD, IIV4-cc, and LAIV4 are authorized for use in Canada for children 2–17 years of age. The comparison of the vaccine characteristics of IIV and LAIV, in [Table 4](#Table4) below, may be considered in making a decision on the preferred vaccine option(s) for use by an individual or a public health program. Note that although data comparing LAIV to IIV4-cc are not available, IIV-cc is comparable to egg-based IIV.
Table 4: Vaccine characteristics of live attenuated influenza vaccine (LAIV) compared with inactivated influenza vaccine (IIV) in children 2–17 years of age
| Considerations[Table 4 Footnote a](#t4fna) | LAIV[Table 4 Footnote b](#t4fnb) compared with IIV[Table 4 Footnote c](#t4fnc) |
| --- | --- |
| Efficacy and effectiveness | There was early evidence of superior efficacy of LAIV3 compared with IIV3-SD in children less than 6 years of age from randomized controlled trials, with weaker evidence of superior efficacy in older children. However, later post-marketing and surveillance studies across multiple influenza seasons found comparable protection against influenza for LAIV and IIV, with findings of reduced effectiveness for LAIV against A(H1N1) in some studies. |
| Like IIV4-SD, LAIV4 is expected to provide additional protection against the influenza B strain not contained in IIV3-SD. |
| Immunogenicity | LAIV3 has been shown to be as immunogenic as IIV3-SD, depending on age, with LAIV4 being non-inferior to LAIV3. |
| Safety | Rhinitis (runny nose) and nasal congestion are more common with LAIV. Clinical studies and post-marketing studies showed a similar safety profile to IIV. |
| Contraindications | There are vaccine contraindications specific to LAIV. LAIV is contraindicated for children with severe asthma, medically attended wheezing in the 7 days prior to vaccination, and immune compromising conditions (with the exception of children with stable HIV infection on HAART and with adequate immune function), as well as those currently receiving aspirin or aspirin-containing therapy. LAIV is also contraindicated for pregnant adolescents. |
| Acceptability | Delivery of LAIV as a nasal spray may be preferable for children who are averse to receiving the vaccine by needle injection. |
| **Abbreviations:** HAART: highly active antiretroviral therapy; IIV: inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; LAIV: live attenuated influenza vaccine; LAIV3: trivalent live attenuated influenza vaccine; LAIV4: quadrivalent live attenuated influenza vaccine. |
|
Table 4 Footnote a
NACI has not assessed the comparative cost-effectiveness of authorized influenza vaccine types for children 2–17 years of age.
[Table 4 Return to footnote a referrer](#t4fna-rf)
Table 4 Footnote b
The trivalent formulation of LAIV (LAIV3) received a Notice of Compliance from Health Canada in June 2010 and was first used in publicly funded immunization programs in Canada for the 2012–2013 influenza season. The quadrivalent formulation (LAIV4) was approved for use in Canada for the 2014–2015 season and has been in use since that time. LAIV3 is no longer available in Canada.
[Table 4 Return to footnote b referrer](#t4fnb-rf)
Table 4 Footnote c
Both trivalent and quadrivalent IIV-SD (IIV3-SD and IIV4-SD) are authorized for use in Canada for the 2021–2022 influenza season. Data comparing LAIV to IIV4-cc are not available, however IIV-cc is comparable to egg-based IIV.
[Table 4 Return to footnote c referrer](#t4fnc-rf)
|
### V.2 Adults
#### Burden of disease in adults
A study focusing on estimates of deaths associated with influenza in the United States has established that the average annual rate of influenza-associated deaths for adults aged 65 years of age and older was 17.0 deaths per 100,000 (range: 2.4–36.7)[Footnote 210](#fn210). The study also states that of deaths coded as being influenza- or pneumonia-related, persons 65 years of age and older accounted for 87.9% of the overall estimated annual average number of deaths. When influenza-related deaths among adults 65 years of age and older were estimated using codes for underlying respiratory and circulatory causes of death, these estimates increased to 66.1 deaths per 100,000 (range: 8.0–121.1) and 89.4%, respectively. This study described a wide variation in the estimated number of deaths from season to season, which was closely related to the particular influenza virus types and subtypes in circulation. Estimates presented in the study of yearly influenza-associated deaths with underlying pneumonia and influenza causes (1976–2007) reveal a large difference between influenza type A and B with a calculated median of greater than 6,000 deaths associated with influenza type A and half of that number for influenza type B (approximately 3,360) for persons 65 years of age and older. During the 22 seasons in which influenza A(H3N2) was the prominent strain, the average influenza-associated mortality rates were 2.7 times higher than for the nine seasons that it was not (all age groups combined), and on average, there were about 37% more annual influenza-associated deaths, regardless of the primary medical cause of death. A higher risk of hospitalization and death was also reported by Cromer et al. in adults 65 years of age and older, compared to younger adults in their assessment of the burden of influenza in England by age and clinical risk group[Footnote 211](#fn211).
Canadian surveillance data show that hospitalization rates among adults 65 years of age and older were higher during the A(H3N2)-predominant 2014–2015 season compared to the previous five influenza seasons and also compared to the 2012–2013 season when A(H3N2) also predominated; 2014–2015 was a season in which there was a vaccine mismatch with the circulating A(H3N2) strain. Similar to the hospitalization rates, death rates among older adults were highest in the 2014–2015 season compared to the previous five seasons and compared to the previous A(H3N2) season in 2012–2013. Mortality rates among other age groups were similar to or lower than the previous five influenza seasons. Laboratory detections over this same time period showed that influenza seasons in which influenza subtype A(H3N2) predominated, disproportionally affected adults 65 years of age and older, while seasons with greater A(H1N1) detections resulted in a higher proportion of positive cases in younger age groups.
#### Adults 18–59 years of age
Five types of influenza vaccine are authorized for use in adults 18–59 years of age: IIV3-SD, IIV4-SD, IIV4-cc, RIV4, and LAIV4.
NACI recommends that any of the available influenza vaccines should be used in adults without contraindications. IIV or RIV should be used for adults with chronic health conditions identified in [List 1](#List1), HCWs or pregnant persons (noting that no published clinical data pertaining to safety of vaccination with RIV4 during pregnancy is currently available to inform vaccine-associated risks for this population).
#### Adults 60–64 years of age
Four types of influenza vaccine are authorized for use in adults 60–64 years of age: IIV3-SD, IIV4-SD, IIV4-cc, and RIV4.
NACI recommends that any of the available age-appropriate influenza vaccines should be used.
#### Adults 65 years of age and older
Six types of influenza vaccine are authorized for use in adults 65 years of age and older: IIV3-SD, IIV3-Adj, IIV4-SD, IIV4-cc, IIV4-HD, and RIV4.
##### Recommendation for individual-level decision making
When available, IIV-HD should be used over IIV-SD, given the burden of influenza A(H3N2) disease and the good evidence of better protection of IIV3-HD compared to IIV3-SD in adults 65 years of age and older. Based on a review of pre-authorization trials, IIV4-HD is non-inferior to IIV3-HD and is therefore expected to provide the same enhanced protection against A(H3N2) compared to standard dose IIV, including IIV4-SD. Although IIV-HD is expected to provide better protection against influenza A(H3N2) for adults 65 years of age or older, the benefit of providing this vaccine to all adults 65+ as opposed to any other influenza vaccine is not clear (refer to the next section). NACI is currently conducting an updated review of influenza vaccines in this population.
Any of the available influenza vaccines would be preferable to remaining unvaccinated or requesting individuals to return for vaccine. Therefore, in the absence of a specific product, NACI recommends that any of the available influenza vaccines authorized for this age group should be used.
##### Recommendation for public health program-level decision making
IIV3-HD is expected to provide better protection compared to IIV3-SD. Similarly, IIV4-HD is expected to provide better protection compared to IIV4-SD. The previous assessment completed by NACI demonstrated insufficient evidence to make a comparative recommendation on the use of IIV3-HD over IIV3-SD at the programmatic level and a complete assessment that includes economic considerations has not yet been conducted for IIV4-HD. Therefore, NACI currently recommends that any of the available influenza vaccines should be used for public health programs. NACI is in the process of completing an updated assessment on influenza vaccines for adults 65 years of age and older.
Refer to the NACI [Literature Review Update on the Efficacy and Effectiveness of High-Dose (FluzoneⓇ High-Dose) and MF59-Adjuvanted (FluadⓇ) Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older](/en/public-health/services/publications/healthy-living/executive-summary-literature-review-update-efficacy-effectiveness-fluzone-high-dose-fluad-trivalent-inactivated-influenza-vaccines-adults-65-older.html) for additional information supporting these recommendations.
##### Summary of vaccine characteristics for decision making
There are six types of inactivated influenza vaccines (IIV3-SD, IIV3-Adj, IIV4-SD, IIV4-cc, and IIV4-HD) and one type of recombinant influenza vaccine (RIV4) authorized for use in Canada for adults 65 years of age and older. The comparison of vaccine characteristics across vaccine types, in Table 5 below, may be considered in making a decision on the preferred vaccine option(s) for use by an individual or a public health program. Due to the limited available data directly comparing the performance of IIV3-Adj, IIV-HD, IIV4-SD, IIV4-cc, or RIV4, considerations for these vaccines in [Table 5](#Table5) are compared to IIV3-SD for which comparative data on efficacy, effectiveness, and/or immunogenicity with each of IIV3-Adj and IIV4-SD are available. Data directly comparing IIV4-cc and IIV4-HD to IIV3-SD are not available. Comparative data on efficacy, effectiveness, and/or immunogenicity of IIV3-cc and IIV3-SD are available.
Table 5: Comparison of the vaccine characteristics of influenza vaccine types available for use in adults 65 years of age and older
| Considerations[Table 5 Footnote a](#t5fna) | Influenza vaccine type |
| --- | --- |
| IIV3-Adj | IIV4-HD[Table 5 Footnote b](#t5fnb) | IIV4-SD | IIV4-cc[Table 5 Footnote c](#t5fnc) | **RIV4** |
| Burden of disease | Although influenza-associated morbidity and mortality varies each season, in general there is an increased burden of severe disease in adults 65 years of age and older during influenza seasons when influenza A(H3N2) predominates[Footnote 210](#fn210) |
| Efficacy and effectiveness | Overall, insufficient comparative evidence with IIV3-SD to draw conclusion. | Expected[Table 5 Footnote b](#t5fnb) better protection compared with IIV3-SD, particularly against influenza A(H3N2).
Better protection against the influenza B strain not contained in IIV3-HD. | Better protection against the influenza B strain not contained in IIV3-SD. | Expected[Table 5 Footnote c](#t5fnc) better protection against the influenza B strain not contained in IIV3-SD. | Expected[Table 5 Footnote c](#t5fnc) better protection against the influenza B strain not contained in IIV3-SD.Potentially[Table 5 Footnote d](#t5fnd) better protection compared with IIV4 SD. |
| Immunogenicity | Non-inferior immune response compared to IIV3-SD. Superiority to IIV3-SD has not been consistently demonstrated. | Expected[Table 5 Footnote b](#t5fnb) superior immune response to influenza A strains compared to IIV3-SD. Superior immune response to the additional B strain compared to IIV3-HD. | Non-inferior immune response to the strains contained in IIV3-SD with superior immune response to the additional B strain. | Non-inferior immune response to the strains contained in IIV3-cc. Superior immune response against the influenza B strain not contained in IIV3-SD. Non-inferior response expected[Table 5 Footnote c](#t5fnc) compared to IIV3-SD. | Expected[Table 5 Footnote e](#t5fne) non-inferior immune response compared to IIV4-HD, IIV4-cc, IIV3-HD, IIV3-Adj. |
| Contraindications | Same contraindications as IIV3-SD. |
| Safety | Higher rate of injection site reactions than IIV3-SD. Higher or comparable systemic reactions compared to IIV3-SD; systemic reactions were mild to moderate and transient. SAEs were comparable to IIV3-SD and were uncommon. | Higher rate of some systemic reactions than IIV4-SD and the same is expected[Table 5 Footnote b](#t5fnb) compared to IIV3-SD; most systemic reactions were mild and transient. SAEs were rare and similar in frequency to IIV4-SD and the same is expected compared to IIV3-SD[Table 5 Footnote b](#t5fnb). | Pre-licensure clinical trials and post-marketing surveillance showed a similar safety profile to IIV3-SD. | Pre-licensure clinical trials showed a similar safety profile to IIV3-cc. Similar safety profile to IIV3-SD is expected[Table 5 Footnote c](#t5fnc). | Pre-licensure clinical trials showed a similar safety profile to IIV4-SD, IIV3-HD and IIV-Adj. Similar safety profile to IIV3-SD is expected. |
| **Abbreviations:** IIV3-Adj: adjuvanted egg-based trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-cc: standard-dose cell culture-based quadrivalent inactivated influenza vaccine; IIV4-HD: high-dose quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; RIV4: quadrivalent recombinant influenza vaccine; SAE: serious adverse event. |
|
Table 5 Footnote a
NACI has not assessed the comparative cost-effectiveness of available influenza vaccine types for adults 65 years of age and older.
[Table 5 Return to footnote a referrer](#t5fna-rf)
Table 5 Footnote b
Data directly comparing IIV4-HD to IIV3-SD are not available; however, IIV4-HD has been shown to be non-inferior to IIV3-HD and has a comparable rate of systemic and local reactions. Therefore, information presented here is expected to apply to IIV4-HD as well.
[Table 5 Return to footnote b referrer](#t5fnb-rf)
Table 5 Footnote c
Data directly comparing IIV4-cc to IIV3-SD are not available; however, IIV3-cc (licensure never sought in Canada) has been shown to be non-inferior to IIV3-SD. Therefore, information presented here is expected to apply to IIV4-cc as well.
[Table 5 Return to footnote c referrer](#t5fnc-rf)
Table 5 Footnote d
Data directly comparing RIV4 to IIV3-SD are not available; however, RIV4 has been shown to provide better protection than IIV4-SD based on one study conducted during a single influenza season (2014-2015).
[Table 5 Return to footnote d referrer](#t5fnd-rf)
Table 5 Footnote e
Data directly comparing RIV4 to IIV3-SD are not available; however, RIV4 has been shown to be non-inferior to IIV4-SD, IIV4-cc, IIV3-HD and IIV3-Adj against all tested influenza strains (A/H1N1, A/H3N2, B/Yamagata lineage, and B/Victoria lineage) and has a comparable rate of adverse events based on 3 influenza seasons (2014-2015, 2017-2018, 2018-2019). Therefore, information presented here is expected to apply to IIV3-SD as well.
[Table 5 Return to footnote e referrer](#t5fne-rf)
|
#### Adults with chronic health conditions
NACI recommends that any age-appropriate IIV or RIV, but not LAIV, should be offered to adults with chronic health conditions identified in [List 1](#List1), including those with immune compromising conditions.
#### Pregnant individuals
NACI recommends that any age-appropriate IIV or RIV, but not LAIV, should be offered to pregnant individuals (noting that no published clinical data pertaining to safety of vaccination with RIV4 during pregnancy is currently available to inform vaccine-associated risks).
Due to a lack of safety data at this time, LAIV should not be administered to pregnant individuals due to the theoretical risk to the fetus from administering a live virus vaccine. LAIV can be administered to breastfeeding individuals.
#### Health care workers
NACI recommends that any age-appropriate IIV or RIV, but not LAIV, should be offered to HCWs.
Comparative studies in healthy adults have found IIV to be similarly or more efficacious or effective compared with LAIV[Footnote 187](#fn187). In addition, as a precautionary measure, LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection.
VI. List of Abbreviations
-------------------------
AE
Adverse event
AEFI
Adverse event following immunization
ART
Antiretroviral therapy
CAEFISS
Canadian Adverse Events Following Immunization Surveillance System
CI
Confidence interval
CIG
Canadian Immunization Guide
DIN
Drug Identification Number
FFU
Fluorescent focus units
GBS
Guillain-Barré syndrome
GMT
Geometric mean titre
GMTR
Geometric mean titre ratio
HA
Hemagglutinin
HAART
Highly active antiretroviral therapy
HCW
Health care worker
HIV
Human immunodeficiency virus
Ig
Immunoglobulin
IIV
Inactivated influenza vaccine
IIV3
Trivalent inactivated influenza vaccine
IIV3-Adj
Adjuvanted trivalent inactivated influenza vaccine (egg-based)
IIV3-HD
High-dose trivalent inactivated influenza vaccine (egg-based)
IIV3-SD
Standard-dose trivalent inactivated influenza vaccine (egg-based)
IIV4
Quadrivalent inactivated influenza vaccine
IIV4-cc
Mammalian cell culture-based quadrivalent inactivated influenza vaccine
IIV4-HD
High-dose quadrivalent inactivated influenza vaccine (egg-based)
IIV4-SD
Standard-dose quadrivalent inactivated influenza vaccine (egg-based)
ILI
Influenza-like illness
IM
Intramuscular
IMPACT
Immunization Monitoring Program Active
LAIV
Live attenuated influenza vaccine (egg based)
LAIV3
Trivalent live attenuated influenza vaccine (egg based)
LAIV4
Quadrivalent live attenuated influenza vaccine (egg based)
MDCK
Madin-Darby Canine Kidney
MMR
Measles, mumps and rubella
NA
Neuraminidase
NACI
National Advisory Committee on Immunization
ORS
Oculorespiratory syndrome
PHAC
Public Health Agency of Canada
RCT
Randomized controlled trial
RIV
Recombinant influenza vaccine
RIV4
Recombinant quadrivalent influenza vaccine
RNA
Ribonucleic acid
rVE
Relative vaccine efficacy
RZV
Recombinant zoster vaccine
SAE
Serious adverse event
VE
Vaccine effectiveness
WHO
World Health Organization
VII. Acknowledgments
--------------------
**This statement was prepared by:** A Sinilaite, R Stirling, and R Harrison, on behalf of the NACI Influenza Working Group and was approved by NACI.
**NACI gratefully acknowledges the contribution of:** A Gil, C Tremblay, M Tunis, M Xi, and K Young
### NACI Influenza Working Group
**Members:** J Papenburg (Chair), P De Wals, D Fell, I Gemmill, R Harrison, D Kumar, J Langley, A McGeer, and D Moore
**Former members:** N Dayneka, K Klein, J McElhaney, and S Smith
**Liaison representatives:** L Grohskopf (Centers for Disease Control and Prevention [CDC], United States)
**Ex-officio representatives:** C Bancej (Centre for Immunization and Respiratory Infectious Diseases [CIRID], PHAC), J Reiter (First Nations and Inuit Health Branch [FNIHB], Indigenous Services Canada [ISC]), B Warshawsky (Vice President’s Office, Infectious Disease Prevention and Control Branch [IDPCB]), and J Xiong (Biologics and Genetic Therapies Directorate [BGTD], Health Canada [HC]).
### NACI
**Members:** S Deeks (Chair), R Harrison (Vice-Chair), J Bettinger, N Brousseau, P De Wals, E Dubé, V Dubey, K Hildebrand, K Klein, J Papenburg, A Pham-Huy, C Rotstein, B Sander, S Smith, and S Wilson.
**Former member:** C Quach (Chair)
**Liaison** **representatives:** L Bill (Canadian Indigenous Nurses Association), LM Bucci (Canadian Public Health Association), E Castillo (Society of Obstetricians and Gynaecologists of Canada), A Cohn (Centers for Disease Control and Prevention, United States), L Dupuis (Canadian Nurses Association), P Emberley (Canadian Pharmacists Association), J Emili (College of Family Physicians of Canada), D Fell (Canadian Association for Immunization Research and Evaluation), S Funnel (Indigenous Physicians Association of Canada), J Hu (College of Family Physicians of Canada), Noah Ivers (College of Family Physicians of Canada), M Lavoie (Council of Chief Medical Officers of Health), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), A Pham-Huy (Association of Medical Microbiology and Infectious Disease Canada), and A Ung (Canadian Pharmacists Association).
**Ex-officio representatives:** V Beswick-Escanlar (National Defence and the Canadian Armed Forces), E Henry (Centre for Immunization and Respiratory Infectious Diseases [CIRID], PHAC), M Lacroix (Public Health Ethics Consultative Group, PHAC), C Lourenco (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada),D MacDonald (CIRID, PHAC), S Ogunnaike-Cooke (CIRID, PHAC), G Poliquin (National Microbiology Laboratory, PHAC), K Robinson (Marketed Health Products Directorate, HC) and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada).
VIII. Appendix A: Characteristics of Influenza Vaccines Available for Use in Canada, 2022–2023[Appendix A Footnote a](#appafna)
-------------------------------------------------------------------------------------------------------------------------------
| Product name (manufacturer) | Vaccine Characteristic |
| --- | --- |
| Vaccine type | Route of administration | Authorized ages for use | Antigen content for each vaccine strain | Adjuvant | Formats available | Post-puncture shelf life for multi-dose vials | Thimerosal | Antibiotics (traces) | Production medium |
| Quadrivalent |
| --- |
| **FlulavalⓇ Tetra
(GSK)** | IIV4-SD
(split virus) | IM | 6 months and older | 15 µg HA
/0.5 mL dose | None | 5 mL multi-dose vial | 28 days | Yes
(multi-dose vial only) | None | Egg (Avian) |
| **FluzoneⓇ Quadrivalent
(Sanofi Pasteur)** | IIV4-SD
(split virus) | IM | 6 months and older | 15 µg HA
/0.5 mL dose | None | 5 mL multi-dose vial
Single-dose pre-filled syringe without attached needle | Up to expiry date indicated on vial label | Yes
(multi-dose vial only) | None | Egg (Avian) |
| **AfluriaⓇ Tetra
(Seqirus)** | IIV4-SD
(split virus) | IM | 5 years and older | 15 µg HA
/0.5 mL dose | None | 5 mL multi-dose vial
Single dose pre-filled syringe without attached needle | Up to expiry date indicated on vial label | Yes
(multi-dose vial only) | Neomycin and polymyxin B | Egg (Avian) |
| **InfluvacⓇ Tetra
(BGP Pharma ULC, operating as Mylan, d.b.a. Viatris Canada)** | IIV4-SD
(subunit) | IM or deep subcutaneous injection | 6 months and older | 15 µg HA
/0.5 mL dose | None | Single dose pre-filled syringe with or without attached needle | Not applicable | No | Gentamicin or neomycin and polymyxin B[Appendix A Footnote b](#appafnb) | Egg (Avian) |
| **FlucelvaxⓇ Quad (Seqirus)** | IIV4-cc
(subunit) | IM | 6 months and older | 15 µg HA
/0.5 mL dose | None | 5 mL multi-dose vial Single dose pre-filled syringe without attached needle | 28 days | Yes
(multi-dose vial only) | None | Cell culture (Mammalian) |
| **FluzoneⓇ High-Dose Quadrivalent
(Sanofi Pasteur)** | IIV4-HD
(split virus) | IM | 65 years and older | 60 µg HA
/0.7 mL dose | None | Single dose pre-filled syringe without attached needle | Not applicable | No | None | Egg (Avian) |
| **Supemtek™(Sanofi Pasteur)** | RIV4(recombinant protein) | IM | 18 years and older | 45 µg HA/0.5 mL dose | None | Single dose pre-filled syringe without attached needle | Not applicable | No | None | Recombinant (Insect vector-expressed) |
| **FluMistⓇ
Quadrivalent
(AstraZeneca)** | LAIV4
(live attenuated) | Intranasal | 2–59 years | 106.5-7.5 FFU of live attenuated reassortants
/0.2 mL dose
(given as 0.1 mL in each nostril) | None | Single use pre-filled glass sprayer | Not applicable | No | Gentamicin | Egg (Avian) |
| Trivalent |
| **Fluad PediatricⓇ
and FluadⓇ
(Seqirus)** | IIV3-Adj
(subunit) | IM | **Pediatric:**
6–23 months**Adult:**
65 years and older | **Pediatric:**
7.5 µg HA
/0.25 mL dose**Adult:**15 µg HA
/0.5 mL dose | MF59 | Single dose pre-filled syringe without a needle | Not applicable | No | Kanamycin and neomycin | Egg (Avian) |
| **Abbreviations:** FFU: fluorescent focus units; HA: hemagglutinin; IIV3-Adj: adjuvanted egg-based trivalent inactivated influenza vaccine; inactivated influenza vaccine; IIV4-cc: standard-dose cell culture-based quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose egg-based quadrivalent inactivated influenza vaccine; IM: intramuscular; LAIV4: quadrivalent live attenuated influenza vaccine; NA: neuraminidase. |
|
Appendix A Footnote a
Full details of the composition of each vaccine authorized for use in Canada, including other non-medicinal ingredients, and a brief description of its manufacturing process can be found in the product monograph.
[Appendix A Return to footnote a referrer](#appafna-rf)
Appendix A Footnote b
Neomycin and polymyxin B are only used if gentamicin cannot be used. No trace amounts of neomycin or polymyxin B are present if gentamicin was used.
[Appendix A Return to footnote b referrer](#appafnb-rf)
|
IX. References
--------------
Footnote 1
World Health Organization. Influenza (Seasonal): Fact Sheet N°211. 2014. Accessed: 9 October 2018. Available from: http://www.who.int/mediacentre/factsheets/fs211/en/
[Return to footnote 1](#fn1-rf)
Footnote 2
Mamas MA, Fraser D, Neyses L. Cardiovascular Manifestations Associated with Influenza Virus Infection. Int J Cardiol. 2008 Nov ;130(3):304-9.
[Return to footnote 2](#fn2-rf)
Footnote 3
Moriarty LF, Omer SB. Infants and the seasonal influenza vaccine. A global perspective on safety, effectiveness, and alternate forms of protection. Hum Vaccin Immunother. 2014;10(9):2721-8.
[Return to footnote 3](#fn3-rf)
Footnote 4
Schwarz TF, Aggarwal N, Moeckesch B, Et Al. Immunogenicity and Safety of an Adjuvanted Herpes Zoster Subunit Vaccine Coadministered With Seasonal Influenza Vaccine in Adults Aged 50 Years or Older. J Infect Dis. 2017;216(11):1352-61.
[Return to footnote 4](#fn4-rf)
Footnote 5
Koutsakos M, Wheatley AK, Laurie K, Et Al. Influenza Lineage Extinction during the COVID-19 Pandemic? Nature Reviews Microbiology. 2021
[Return to footnote 5](#fn5-rf)
Footnote 6
Spencer JA, Shutt DP, Moser SK, Et Al. Epidemiological Parameter Review and Comparative Dynamics of Influenza, Respiratory Syncytial Virus, Rhinovirus, Human Coronavirus, and Adenovirus. Medrxiv. 2020:2020.02.04.20020404.
[Return to footnote 6](#fn6-rf)
Footnote 7
Statistics Canada. the 10 Leading Causes of Death, 2011. 2014. Accessed: 9 October 2018. Available from: <http://www.statcan.gc.ca/pub/82-625-x/2014001/article/11896-eng.htm>
[Return to footnote 7](#fn7-rf)
Footnote 8
Schanzer DL, Mcgeer A, Morris K. Statistical Estimates of Respiratory Admissions Attributable to Seasonal and Pandemic Influenza for Canada. Influenza Other Respir Viruses. 2013;7(5):799-808.
[Return to footnote 8](#fn8-rf)
Footnote 9
Schanzer DL, Sevenhuysen C, Winchester B, Et Al. Estimating Influenza Deaths in Canada, 1992-2009. Plos One. 2013;8(11):E80481.
[Return to footnote 9](#fn9-rf)
Footnote 10
Langley JM, Vanderkooi OG, Garfield HA, Et Al. Immunogenicity and Safety of 2 Dose Levels of a Thimersol-Free Trivalent Seasonal Influenza Vaccine in Children Aged 6-35 Months. J Ped Infect Dis. 2012;1(1):55-8.
[Return to footnote 10](#fn10-rf)
Footnote 11
Skowronski DM, Hottes TS, Chong M, Et Al. Randomized Controlled Trial of Dose Response to Influenza Vaccine in Children Aged 6 to 23 Months. Pediatrics. 2011;128(2):E276-89.
[Return to footnote 11](#fn11-rf)
Footnote 12
Mcelhaney JE, Hooton JW, Hooton N, Et Al. Comparison of Single versus Booster Dose of Influenza Vaccination on Humoral and Cellular Immune Responses in Older Adults. Vaccine. 2005;23(25):3294-300.
[Return to footnote 12](#fn12-rf)
Footnote 13
Breiman RF, Brooks WA, Goswami D, Et Al. A Multinational, Randomized, Placebo-Controlled Trial to Assess the Immunogenicity, Safety, and Tolerability of Live Attenuated Influenza Vaccine Coadministered with Oral Poliovirus Vaccine in Healthy Young Children. Vaccine. 2009;27(40):5472-9.
[Return to footnote 13](#fn13-rf)
Footnote 14
Lum LC, Borja-Tabora C, Breiman RF, Et Al. Influenza Vaccine Concurrently Administered with a Combination Measles, Mumps, and Rubella Vaccine to Young Children. Vaccine. 2010;28(6):1566-74.
[Return to footnote 14](#fn14-rf)
Footnote 15
Nolan T, Bernstein DI, Block SL, Et Al. Safety and Immunogenicity of Concurrent Administration of Live Attenuated Influenza Vaccine with Measles-Mumps-Rubella and Varicella Vaccines to Infants 12 to 15 Months of Age. Pediatrics. 2008;121(3):508-16.
[Return to footnote 15](#fn15-rf)
Footnote 16
National Advisory Committee on Immunization. Updated Recommendations on the Use of Herpes Zoster Vaccines. Ottawa: Public Health Agency of Canada. 2018; Available At: Https://Www.Canada.Ca/En/Services/Health/Publications/Healthy-Living/Updated-Recommendations-Use-Herpes-Zoster-Vaccines.html.
[Return to footnote 16](#fn16-rf)
Footnote 17
National Advisory Committee Oi. Statement on Thimerosal. Can Commun Dis Rep. 2003;29(-1):1-12.
[Return to footnote 17](#fn17-rf)
Footnote 18
National Advisory Committee on Immunization. Thimerosal: Updated Statement. an Advisory Committee Statement (ACS). Can Commun Dis Rep. 2007;33(ACS-6):1-13.
[Return to footnote 18](#fn18-rf)
Footnote 19
Gerber JS, Offit PA. Vaccines and Autism: A Tale of Shifting Hypotheses. Clin Infect Dis. 2009;48(4):456-61.
[Return to footnote 19](#fn19-rf)
Footnote 20
Centers for Disease Control, and Prevention. Preliminary Results: Surveillance for Guillain-Barré Syndrome after Receipt of Influenza A (H1N1) 2009 Monovalent Vaccine - United States, 2009-2010. MMWR Morb Mortal Wkly Rep. 2010;59(21):657-61.
[Return to footnote 20](#fn20-rf)
Footnote 21
Kwong JC, Vasa PP, Campitelli MA, Et Al. Risk of Guillain-Barré Syndrome after Seasonal Influenza Vaccination and Influenza Health-Care Encounters: A Self-Controlled Study. Lancet Infect Dis. 2013;13(9):769-76.
[Return to footnote 21](#fn21-rf)
Footnote 22
National Advisory Committee on Immunization. Supplementary Statement on Influenza Vaccination: Continued Use of Fluviral® Influenza Vaccine in the 2000-2001 Season. Can Commun Dis Rep. 2001;27(ACS-1):1-3.
[Return to footnote 22](#fn22-rf)
Footnote 23
Ahmadipour N, Watkins K, Fréchette M, Coulby C, Anyoti H, Johnson K. Vaccine Safety Surveillance in Canada: Reports to CAEFISS, 2013–2016. Can Commun Dis Rep. 2018;44((9)):206-14. https://doi.org/10.14745/ccdr.v44i09a04
[Return to footnote 23](#fn23-rf)
Footnote 24
Black S, Nicolay U, Del Giudice G, Et Al. Influence of Statins on Influenza Vaccine Response in Elderly Individuals. J Infect Dis. 2016;213(8):1224-8.
[Return to footnote 24](#fn24-rf)
Footnote 25
Omer SB, Phadke VK, Bednarczyk RA, Et Al. Impact of Statins on Influenza Vaccine Effectiveness against Medically Attended Acute Respiratory Illness. J Infect Dis. 2016;213(8):1216-23.
[Return to footnote 25](#fn25-rf)
Footnote 26
Public Health Agency of Canada. Reporting Adverse Events Following Immunization (AEFI) in Canada: User Guide to Completion and Submission of the AEFI Reports. Ottawa, PHAC. 2004; Available at: Https://Www.Canada.Ca/En/Public-Health/Services/Immunization/Reporting-Adverse-Events-Following-Immunization/User-Guide-Completion-Submission-Aefi-Reports.Html. Accessed 05/23, 2019.
[Return to footnote 26](#fn26-rf)
Footnote 27
Louie JK, Acosta M, Jamieson DJ, Et Al. Severe 2009 H1N1 Influenza in Pregnant and Postpartum Women in California. N Engl J Med. 2010;362(1):27-35.
[Return to footnote 27](#fn27-rf)
Footnote 28
Siston AM, Rasmussen SA, Honein MA, Et Al. Pandemic 2009 Influenza A(H1N1) Virus Illness among Pregnant Women in the United States. JAMA. 2010;303(15):1517-25.
[Return to footnote 28](#fn28-rf)
Footnote 29
Mak TK, Mangtani P, Leese J, Et Al. Influenza Vaccination in Pregnancy: Current Evidence and Selected National Policies. Lancet Infect Dis. 2008;8(1):44-52.
[Return to footnote 29](#fn29-rf)
Footnote 30
Mcneil S, Halperin B, Macdonald N. Influenza in Pregnancy: the Case for Prevention. Adv Exp Med Biol. 2009;634:161-83.
[Return to footnote 30](#fn30-rf)
Footnote 31
Rasmussen SA, Jamieson DJ, Bresee JS. Pandemic Influenza and Pregnant Women. Emerg Infect Dis. 2008;14(1):95-100.
[Return to footnote 31](#fn31-rf)
Footnote 32
Centers for Disease Control, and Prevention. Maternal and Infant Outcomes among Severely Ill Pregnant and Postpartum Women with 2009 Pandemic Influenza A (H1N1)--United States, April 2009-August 2010. MMWR Morb Mortal Wkly Rep. 2011;60(35):1193-6.
[Return to footnote 32](#fn32-rf)
Footnote 33
Pierce M, Kurinczuk J, Spark P, Et Al. Perinatal Outcomes After Maternal 2009/H1N1 Infection: National Cohort Study. BMJ. 2011;342:D3214-.
[Return to footnote 33](#fn33-rf)
Footnote 34
Goldenberg R, Culhane J, Iams J, Et Al. Epidemiology and Causes of Preterm Birth. Lancet. 2008;371(9606):75-84.
[Return to footnote 34](#fn34-rf)
Footnote 35
Mcneil SA, Dodds LA, Fell DB, Et Al. Effect of Respiratory Hospitalization during Pregnancy on Infant Outcomes. Am J Obstet Gynecol. 2011;204(6):S54-7.
[Return to footnote 35](#fn35-rf)
Footnote 36
Zaman K, Roy E, Arifeen SE, Et Al. Effectiveness of Maternal Influenza Immunization in Mothers and Infants. N Engl J Med. 2008;359(15):1555-64.
[Return to footnote 36](#fn36-rf)
Footnote 37
Poehling K, Szilagyi P, Staat M, Et Al. Impact of Maternal Immunization on Influenza Hospitalizations in Infants. Obstet Gynecol. 2011;204(6):S141-8.
[Return to footnote 37](#fn37-rf)
Footnote 38
Eick AA, Uyeki TM, Klimov A, Et Al. Maternal Influenza Vaccination and Effect on Influenza Virus Infection in Young Infants. Arch Pediatr Adolesc Med. 2011;165(2):104-11.
[Return to footnote 38](#fn38-rf)
Footnote 39
France EK, Mcclure D, Hambidge S, Et Al. Impact of Maternal Influenza Vaccination During Pregnancy on the Incidence of Acute Respiratory Illness Visits Among Infants. Arch Pediatr Adolesc Med. 2006;160(12):1277-83.
[Return to footnote 39](#fn39-rf)
Footnote 40
Steinhoff M, Omer S, Roy E, Et Al. Neonatal Outcomes after Influenza Immunization during Pregnancy: A Randomized Controlled Trial. CMAJ. 2012;184(6):645-53.
[Return to footnote 40](#fn40-rf)
Footnote 41
Fell DB, Sprague AE, Liu N, Et Al. H1N1 Influenza Vaccination During Pregnancy and Fetal and Neonatal Outcomes. Am J Public Health. 2012;102(6):E33-40.
[Return to footnote 41](#fn41-rf)
Footnote 42
Omer S, Goodman D, Steinhoff M, Et Al. Maternal Influenza Immunization and Reduced Likelihood of Prematurity and Small For Gestational Age Births: A Retrospective Cohort Study. Plos Med. 2011;8(5):E1000441.
[Return to footnote 42](#fn42-rf)
Footnote 43
Dodds L, Macdonald N, Scott J, Et Al. the Association between Influenza Vaccine in Pregnancy and Adverse Neonatal Outcomes. J Obstetr Gynecol Can. 2012;34(8):714-20.
[Return to footnote 43](#fn43-rf)
Footnote 44
Macdonald NE, Riley LE, Steinhoff MC. Influenza Immunization in Pregnancy. Obstet Gynecol. 2009;114(2):365-8.
[Return to footnote 44](#fn44-rf)
Footnote 45
Tamma PD, Ault KA, Del Rio C, Et Al. Safety of Influenza Vaccination during Pregnancy. Am J Obstet Gynecol. 2009;201(6):547-52.
[Return to footnote 45](#fn45-rf)
Footnote 46
Moro PL, Broder K, Zheteyeva Y, Et Al. Adverse Events in Pregnant Women Following Administration of Trivalent Inactivated Influenza Vaccine and Live Attenuated Influenza Vaccine in the Vaccine Adverse Event Reporting System, 1990-2009. Am J Obstet Gynecol. 2011;204(2):146e1-7.
[Return to footnote 46](#fn46-rf)
Footnote 47
European MA. Fifteenth Pandemic Pharmacovigilance Update. Http://Www.Ema.Europa.Eu/Pdfs/Influenza/21323810en.Pdf Ed. London: European Medicines Agency; 2010. Accessed: 9 October 2018. Available from: https://www.ema.europa.eu/documents/report/fifteenth-pandemic-pharmacovigilance-update\_en.pdf
[Return to footnote 47](#fn47-rf)
Footnote 48
Simonsen L, Fukuda K, Schonberger LB, Et Al. the Impact of Influenza Epidemics on Hospitalizations. J Infect Dis. 2000;181(3):831-7.
[Return to footnote 48](#fn48-rf)
Footnote 49
Schanzer DL, Tam TW, Langley JM, Et Al. Influenza-Attributable Deaths, Canada 1990-1999. Epidemiol Infect. 2007;135(7):1109-16.
[Return to footnote 49](#fn49-rf)
Footnote 50
Centers for Disease Control, and Prevention. Deaths Related to 2009 Pandemic Influenza A (H1N1) Among American Indian/Alaska Natives - 12 States, 2009. MMWR Morb Mortal Wkly Rep. 2009;58(48):1341-4.
[Return to footnote 50](#fn50-rf)
Footnote 51
National Center for ES. Individuals, Families and Children in Poverty. Status and Trends in the Education of American Indians and Alaska Natives. Http://Nces.Ed.Gov/Pubs2008/Nativetrends/Ind\_1\_6.Asp Ed. Washington, DC: US Department of Education; 2008. Accessed: 9 October 2018. Available from: http://nces.ed.gov/pubs2008/nativetrends/ind\_1\_6.asp
[Return to footnote 51](#fn51-rf)
Footnote 52
Indigenous and Northern AC. Highlights from the Report of the Royal Commission on Aboriginal Peoples - People to People, Nation to Nation. 2010; 2016.
[Return to footnote 52](#fn52-rf)
Footnote 53
Clark M, Riben P, Nowgesic E. the Association of Housing Density, Isolation and Tuberculosis in Canadian First Nations Communities. Int J Epidemiol. 2002;31(5):940-5.
[Return to footnote 53](#fn53-rf)
Footnote 54
Saxen H, Virtanen M. Randomized, Placebo-Controlled Double Blind Study on the Efficacy of Influenza Immunization on Absenteeism of Health Care Workers. Pediatr Infect Dis J. 1999;18(9):779-83.
[Return to footnote 54](#fn54-rf)
Footnote 55
Wilde JA, Mcmillan JA, Serwint J, Et Al. Effectiveness of Influenza Vaccine in Health Care Professionals: A Randomized Trial. JAMA. 1999;281(10):908-13.
[Return to footnote 55](#fn55-rf)
Footnote 56
Carman WF, Elder AG, Wallace LA, Et Al. Effects of Influenza Vaccination of Health-Care Workers on Mortality of Elderly People in Long-Term Care: A Randomised Controlled Trial. Lancet. 2000;355(9198):93-7.
[Return to footnote 56](#fn56-rf)
Footnote 57
Hayward AC, Harling R, Wetten S, Et Al. Effectiveness of an Influenza Vaccine Programme For Care Home Staff to Prevent Death, Morbidity, and Health Service Use Among Residents: Cluster Randomised Controlled Trial. BMJ. 2006;333(7581):1241.
[Return to footnote 57](#fn57-rf)
Footnote 58
Potter J, Stott DJ, Roberts MA, Et Al. Influenza Vaccination of Health Care Workers in Long-Term-Care Hospitals Reduces the Mortality of Elderly Patients. J Infect Dis. 1997;175(1):1-6.
[Return to footnote 58](#fn58-rf)
Footnote 59
Lemaitre M, Meret T, Rothan-Tondeur M, Et Al. Effect of Influenza Vaccination of Nursing Home Staff on Mortality of Residents: A Cluster-Randomized Trial. J Am Geriatr Soc. 2009;57(9):1580-6.
[Return to footnote 59](#fn59-rf)
Footnote 60
Shugarman LR, Hales C, Setodji CM, Et Al. the Influence of Staff and Resident Immunization Rates on Influenza-Like Illness Outbreaks in Nursing Homes. J Am Med Dir Assoc. 2006;7(9):562-7.
[Return to footnote 60](#fn60-rf)
Footnote 61
Kuster SP, Shah PS, Coleman BL, Et Al. Incidence of Influenza in Healthy Adults and Healthcare Workers: A Systematic Review and Meta-Analysis. Plos One. 2011;6(10):E26239.
[Return to footnote 61](#fn61-rf)
Footnote 62
Buchan SA, Kwong JC. Influenza Immunization among Canadian Health Care Personnel: A Cross-Sectional Study. CMAJ Open. 2016;4(3):E479-88.
[Return to footnote 62](#fn62-rf)
Footnote 63
Hussain H, Mcgeer A, Mcneil S, Et Al. Factors Associated with Influenza Vaccination Among Healthcare Workers in Acute Care Hospitals in Canada. Influenza Other Respir Viruses. 2018;12(3):319-25.
[Return to footnote 63](#fn63-rf)
Footnote 64
Public Health Agency of Canada. Vaccination Coverage Goals and Vaccine Preventable Disease Reduction Targets by 2025. 2019; Available At: Https://Www.Canada.Ca/En/Public-Health/Services/Immunization-Vaccine-Priorities/National-Immunization-Strategy/Vaccination-Coverage-Goals-Vaccine-Preventable-Diseases-Reduction-Targets-2025.Html#Det22. Accessed 05/13, 2019.
[Return to footnote 64](#fn64-rf)
Footnote 65
Bish A, Yardley L, Nicoll A, Et Al. Factors Associated with Uptake of Vaccination against Pandemic Influenza: A Systematic Review. Vaccine. 2011;29(38):6472-84.
[Return to footnote 65](#fn65-rf)
Footnote 66
Dini G, Toletone A, Sticchi L, Et Al. Influenza Vaccination in Healthcare Workers: A Comprehensive Critical Appraisal of the Literature. Hum Vaccin Immunother. 2018;14(3):772-89.
[Return to footnote 66](#fn66-rf)
Footnote 67
Hakim H, Gaur AH, Mccullers JA. Motivating Factors for High Rates of Influenza Vaccination among Healthcare Workers. Vaccine. 2011;29(35):5963-9.
[Return to footnote 67](#fn67-rf)
Footnote 68
68. Lytras T, Kopsachilis F, Mouratidou E, Et Al. Interventions to Increase Seasonal Influenza Vaccine Coverage in Healthcare Workers: A Systematic Review and Meta-Regression Analysis. Hum Vaccin Immunother. 2016;12(3):671-81.
[Return to footnote 68](#fn68-rf)
Footnote 69
69. Schmid P, Rauber D, Betsch C, Et Al. Barriers of Influenza Vaccination Intention and Behavior - A Systematic Review of Influenza Vaccine Hesitancy, 2005 - 2016. Plos One. 2017;12(1):E0170550.
[Return to footnote 69](#fn69-rf)
Footnote 70
70. Vasilevska M, Ku J, Fisman DN. Factors Associated with Healthcare Worker Acceptance of Vaccination: a Systematic Review and Meta-Analysis. Infect Control Hosp Epidemiol. 2014;35(6):699-708.
[Return to footnote 70](#fn70-rf)
Footnote 71
71. Accreditation Canada. Infection Prevention and Control Standards. 9th Ed. Ottawa: Accreditation Canada; 2013.
[Return to footnote 71](#fn71-rf)
Footnote 72
Grotto I, Mandel Y, Green MS, Et Al. Influenza Vaccine Efficacy in Young, Healthy Adults. Clin Infect Dis. 1998;26(4):913-7.
[Return to footnote 72](#fn72-rf)
Footnote 73
Leighton L, Williams M, Aubery D, Et Al. Sickness Absence Following a Campaign of Vaccination against Influenza in the Workplace. Occup Med (Lond). 1996;46(2):146-50.
[Return to footnote 73](#fn73-rf)
Footnote 74
Nichol KL, Lind A, Margolis KL, Et Al. the Effectiveness of Vaccination against Influenza in Healthy, Working Adults. N Engl J Med. 1995;333(14):889-93.
[Return to footnote 74](#fn74-rf)
Footnote 75
Department of Health (UK). Flu Vaccination for Poultry Workers. London: Department of Health; 2007.
[Return to footnote 75](#fn75-rf)
Footnote 76
Gray GC, Trampel DW, Roth JA. Pandemic Influenza Planning: Shouldn't Swine and Poultry Workers Be Included? Vaccine. 2007;25(22):4376-81.
[Return to footnote 76](#fn76-rf)
Footnote 77
Bridges CB, Lim W, Hu-Primmer J, Et Al. Risk of Influenza A (H5N1) Infection among Poultry Workers, Hong Kong, 1997-1998. J Infect Dis. 2002;185(8):1005-10.
[Return to footnote 77](#fn77-rf)
Footnote 78
Puzelli S, Di Trani L, Fabiani C, Et Al. Serological Analysis of Serum Samples from Humans Exposed to Avian H7 Influenza Viruses in Italy between 1999 and 2003. J Infect Dis. 2005;192(8):1318-22.
[Return to footnote 78](#fn78-rf)
Footnote 79
Tweed SA, Skowronski DM, David ST, Et Al. Human Illness from Avian Influenza H7N3, British Columbia. Emerg Infect Dis. 2004;10(12):2196-9.
[Return to footnote 79](#fn79-rf)
Footnote 80
Skowronski DM, Li Y, Tweed SA, Et Al. Protective Measures and Human Antibody Response during an Avian Influenza H7N3 Outbreak in Poultry in British Columbia, Canada. CMAJ. 2007;176(1):47-53.
[Return to footnote 80](#fn80-rf)
Footnote 81
Heckler R, Baillot A, Engelmann H, Et Al. Cross-Protection against Homologous Drift Variants of Influenza A and B after Vaccination with Split Vaccine. Intervirology. 2007;50(1):58-62.
[Return to footnote 81](#fn81-rf)
Footnote 82
Walter EB, Neuzil KM, Zhu Y, Et Al. Influenza Vaccine Immunogenicity in 6- to 23-Month-Old Children: Are Identical Antigens Necessary for Priming? Pediatrics. 2006;118(3):E570-8.
[Return to footnote 82](#fn82-rf)
Footnote 83
Englund JA, Walter EB, Fairchok MP, Et Al. A Comparison of 2 Influenza Vaccine Schedules in 6- to 23-Month-Old Children. Pediatrics. 2005;115(4):1039-47.
[Return to footnote 83](#fn83-rf)
Footnote 84
Englund JA, Walter EB, Gbadebo A, Et Al. Immunization with Trivalent Inactivated Influenza Vaccine in Partially Immunized Toddlers. Pediatrics. 2006;118(3):E579-85.
[Return to footnote 84](#fn84-rf)
Footnote 85
Levandowski RA, Gross PA, Weksler M, Et Al. Cross-Reactive Antibodies Induced by a Monovalent Influenza B Virus Vaccine. J Clin Microbiol. 1991;29(7):1530-2.
[Return to footnote 85](#fn85-rf)
Footnote 86
Levandowski RA, Regnery HL, Staton E, Et Al. Antibody Responses to Influenza B Viruses in Immunologically Unprimed Children. Pediatrics. 1991;88(5):1031-6.
[Return to footnote 86](#fn86-rf)
Footnote 87
Mclean HQ, Thompson MG, Sundaram ME, and Et Al. Influenza Vaccine Effectiveness in the United States during 2012-2013: Variable Protection by Age and Virus Type. J Infect Dis. 2015;211(10):1529-40.
[Return to footnote 87](#fn87-rf)
Footnote 88
88. Mclean HQ, Thompson MG, Sundaram ME, Et Al. Impact of Repeated Vaccination on Vaccine Effectiveness against Influenza A(H3N2) and B During 8 Seasons. Clin Infect Dis. 2014;59(10):1375-85.
[Return to footnote 88](#fn88-rf)
Footnote 89
Pavia-Ruz N, Angel Rodriguez Weber M, Lau YL, Et Al. A Randomized Controlled Study to Evaluate the Immunogenicity of a Trivalent Inactivated Seasonal Influenza Vaccine at Two Dosages in Children 6 to 35 Months of Age. Hum Vaccin Immunother. 2013;9(9):1978-88.
[Return to footnote 89](#fn89-rf)
Footnote 90
Skowronski DM, Tweed SA, De Serres G. Rapid Decline of Influenza Vaccine-Induced Antibody in the Elderly: Is it Real, or is it Relevant? J Infect Dis. 2008;197(4):490-502.
[Return to footnote 90](#fn90-rf)
Footnote 91
Anema A, Mills E, Montaner J, Et Al. Efficacy of Influenza Vaccination in HIV-Positive Patients: A Systematic Review and Meta-Analysis. HIV Med. 2008;9(1):57-61.
[Return to footnote 91](#fn91-rf)
Footnote 92
Cooper C, Hutton B, Fergusson D, Et Al. A Review of Influenza Vaccine Immunogenicity and Efficacy in HIV-Infected Adults. Can J Infect Dis Med Microbiol. 2008;19(6):419-23.
[Return to footnote 92](#fn92-rf)
Footnote 93
Scharpe J, Evenepoel P, Maes B, Et Al. Influenza Vaccination is Efficacious and Safe in Renal Transplant Recipients. Am J Transplant. 2008;8(2):332-7.
[Return to footnote 93](#fn93-rf)
Footnote 94
Manuel O, Humar A, Chen MH, Et Al. Immunogenicity and Safety of an Intradermal Boosting Strategy for Vaccination against Influenza in Lung Transplant Recipients. Am J Transplant. 2007;7(11):2567-72.
[Return to footnote 94](#fn94-rf)
Footnote 95
Buxton JA, Skowronski DM, Ng H, Et Al. Influenza Revaccination of Elderly Travelers: Antibody Response to Single Influenza Vaccination and Revaccination at 12 Weeks. J Infect Dis. 2001;184(2):188-91.
[Return to footnote 95](#fn95-rf)
Footnote 96
Ljungman P, Nahi H, Linde A. Vaccination of Patients with Haematological Malignancies with One or Two Doses of Influenza Vaccine: A Randomised Study. Br J Haematol. 2005;130(1):96-8.
[Return to footnote 96](#fn96-rf)
Footnote 97
Gross PA, Weksler ME, Quinnan GVJ, Et Al. Immunization of Elderly People with Two Doses of Influenza Vaccine. J Clin Microbiol. 1987;25(9):1763-5.
[Return to footnote 97](#fn97-rf)
Footnote 98
Cowling BJ, Fang VJ, Nishiura H, Et Al. Increased Risk of Noninfluenza Respiratory Virus Infections Associated with Receipt of Inactivated Influenza Vaccine. Clin Infect Dis. 2012;54(12):1778-83.
[Return to footnote 98](#fn98-rf)
Footnote 99
Cowling BJ, Ng S, Ma ES, Et Al. Protective Efficacy against Pandemic Influenza of Seasonal Influenza Vaccination in Children in Hong Kong: A Randomized Controlled Trial. Clin Infect Dis. 2012;55(5):695-702.
[Return to footnote 99](#fn99-rf)
Footnote 100
100. Fujieda M, Maeda A, Kondo K, Et Al. Inactivated Influenza Vaccine Effectiveness in Children Under 6 Years of Age during the 2002-2003 Season. Vaccine. 2006;24(7):957-63.
[Return to footnote 100](#fn100-rf)
Footnote 101
Katayose M, Hosoya M, Haneda T, Et Al. the Effectiveness of Trivalent Inactivated Influenza Vaccine in Children over Six Consecutive Influenza Seasons. Vaccine. 2011;29(9):1844-9.
[Return to footnote 101](#fn101-rf)
Footnote 102
Kawai N, Ikematsu H, Iwaki N, Et Al. A Prospective, Internet-Based Study of the Effectiveness and Safety of Influenza Vaccination in the 2001-2002 Influenza Season. Vaccine. 2003;21(31):4507-13.
[Return to footnote 102](#fn102-rf)
Footnote 103
Kawai S, Nanri S, Ban E, Et Al. Influenza Vaccination of Schoolchildren and Influenza Outbreaks in a School. Clin Infect Dis. 2011;53(2):130-6.
[Return to footnote 103](#fn103-rf)
Footnote 104
Kwong JC, Ge H, Rosella LC, Et Al. School-Based Influenza Vaccine Delivery, Vaccination Rates, and Healthcare Use in the Context of a Universal Influenza Immunization Program: an Ecological Study. Vaccine. 2010;28(15):2722-9.
[Return to footnote 104](#fn104-rf)
Footnote 105
Kwong JC, Maaten S, Upshur RE, Et Al. the Effect of Universal Influenza Immunization on Antibiotic Prescriptions: an Ecological Study. Clin Infect Dis. 2009;49(5):750-6.
[Return to footnote 105](#fn105-rf)
Footnote 106
Loeb M, Russell ML, Moss L, Et Al. Effect of Influenza Vaccination of Children on Infection Rates in Hutterite Communities: A Randomized Trial. JAMA. 2010;303(10):943-50.
[Return to footnote 106](#fn106-rf)
Footnote 107
Maeda T, Shintani Y, Miyamoto H, Et Al. Prophylactic Effect of Inactivated Influenza Vaccine on Young Children. Pediatr Int. 2002;44(1):43-6.
[Return to footnote 107](#fn107-rf)
Footnote 108
Neuzil KM, Dupont WD, Wright PF, Et Al. Efficacy of Inactivated and Cold-Adapted Vaccines against Influenza an Infection, 1985 to 1990: the Pediatric Experience. Pediatr Infect Dis J. 2001;20(8):733-40.
[Return to footnote 108](#fn108-rf)
Footnote 109
Nicholls S, Carroll K, Crofts J, Et Al. Outbreak of Influenza A (H3N2) in a Highly-Vaccinated Religious Community: A Retrospective Cohort Study. Commun Dis Public Health. 2004;7(4):272-7.
[Return to footnote 109](#fn109-rf)
Footnote 110
Ochiai H, Fujieda M, Ohfuji S, Et Al. Inactivated Influenza Vaccine Effectiveness Against Influenza-Like Illness Among Young Children in Japan--with Special Reference to Minimizing Outcome Misclassification. Vaccine. 2009;27(50):7031-5.
[Return to footnote 110](#fn110-rf)
Footnote 111
Pebody RG, Andrews N, Fleming DM, Et Al. Age-Specific Vaccine Effectiveness of Seasonal 2010/2011 and Pandemic Influenza A(H1N1) 2009 Vaccines in Preventing Influenza in the United Kingdom. Epidemiol Infect. 2012:1-11.
[Return to footnote 111](#fn111-rf)
Footnote 112
Reichert TA, Sugaya N, Fedson DS, Et Al. the Japanese Experience with Vaccinating Schoolchildren against Influenza. N Engl J Med. 2001;344(12):889-96.
[Return to footnote 112](#fn112-rf)
Footnote 113
Treanor JJ, Talbot HK, Ohmit SE, Et Al. Effectiveness of Seasonal Influenza Vaccines in the United States during a Season with Circulation of all Three Vaccine Strains. Clin Infect Dis. 2012;55(7):951-9.
[Return to footnote 113](#fn113-rf)
Footnote 114
Yamaguchi S, Ohfuji S, Hirota Y. Influenza Vaccine Effectiveness in Primary School Children in Japan: A Prospective Cohort Study Using Rapid Diagnostic Test Results. J Infect Chemother. 2010;16(6):407-13.
[Return to footnote 114](#fn114-rf)
Footnote 115
Belongia EA, Kieke BA, Donahue JG, Et Al. Influenza Vaccine Effectiveness in Wisconsin during the 2007-08 Season: Comparison of Interim and Final Results. Vaccine. 2011;29(38):6558-63.
[Return to footnote 115](#fn115-rf)
Footnote 116
Charu V, Viboud C, Simonsen L, Et Al. Influenza-Related Mortality Trends in Japanese and American Seniors: Evidence for the Indirect Mortality Benefits of Vaccinating Schoolchildren. Plos One. 2011;6(11):E26282-.
[Return to footnote 116](#fn116-rf)
Footnote 117
Jefferson T, Di Pietrantonj C, Al-Ansary L, Et Al. Vaccines for Preventing Influenza in the Elderly. Cochrane Database Syst Rev. 2010(2):CD004876.
[Return to footnote 117](#fn117-rf)
Footnote 118
Govaert TM, Thijs CT, Masurel N, Et Al. the Efficacy of Influenza Vaccination in Elderly Individuals. A Randomized Double-Blind Placebo-Controlled Trial. JAMA. 1994;272(21):1661-5.
[Return to footnote 118](#fn118-rf)
Footnote 119
Poole PJ, Chacko E, Wood-Baker R, Et Al. Influenza Vaccine for Patients with Chronic Obstructive Pulmonary Disease. Cochrane Database Syst Rev. 2006(1):CD002733.
[Return to footnote 119](#fn119-rf)
Footnote 120
Hak E, Buskens E, Van Essen GA, Et Al. Clinical Effectiveness of Influenza Vaccination in Persons Younger Than 65 Years with High-Risk Medical Conditions: the PRISMA Study. Arch Intern Med. 2005;165(3):274-80.
[Return to footnote 120](#fn120-rf)
Footnote 121
Nichol KL, Nordin J, Mullooly J, Et Al. Influenza Vaccination and Reduction in Hospitalizations for Cardiac Disease and Stroke among the Elderly. N Engl J Med. 2003;348(14):1322-32.
[Return to footnote 121](#fn121-rf)
Footnote 122
Looijmans-Van Den Akker I, Verheij TJ, Buskens E, Et Al. Clinical Effectiveness of First and Repeat Influenza Vaccination in Adult and Elderly Diabetic Patients. Diabetes Care. 2006;29(8):1771-6.
[Return to footnote 122](#fn122-rf)
Footnote 123
Jackson LA, Jackson ML, Nelson JC, Et Al. Evidence of Bias in Estimates of Influenza Vaccine Effectiveness in Seniors. Int J Epidemiol. 2006;35(2):337-44.
[Return to footnote 123](#fn123-rf)
Footnote 124
Jackson LA, Nelson JC, Benson P, Et Al. Functional Status is a Confounder of the Association of Influenza Vaccine and Risk of All Cause Mortality in Seniors. Int J Epidemiol. 2006;35(2):345-52.
[Return to footnote 124](#fn124-rf)
Footnote 125
Simonsen L. Commentary: Observational Studies and the Art of Accurately Measuring Influenza Vaccine Benefits. Int J Epidemiol. 2007;36(3):631-2.
[Return to footnote 125](#fn125-rf)
Footnote 126
Simonsen L, Viboud C, Taylor RJ. Effectiveness of Influenza Vaccination. N Engl J Med. 2007;357(26):2729-30.
[Return to footnote 126](#fn126-rf)
Footnote 127
Orenstein EW, De Serres G, Haber MJ, Et Al. Methodologic Issues Regarding the Use of Three Observational Study Designs to Assess Influenza Vaccine Effectiveness. Int J Epidemiol. 2007;36(3):623-31.
[Return to footnote 127](#fn127-rf)
Footnote 128
Thomas PG, Keating R, Hulse-Post D, Et Al. Cell-Mediated Protection in Influenza Infection. Emerg Infect Dis. 2006;12(1):48-54.
[Return to footnote 128](#fn128-rf)
Footnote 129
Trombetta CM, Gianchecchi E, Montomoli E. Influenza Vaccines: Evaluation of the Safety Profile. Hum Vaccin Immunother. 2018;14((3)):657-70.
[Return to footnote 129](#fn129-rf)
Footnote 130
Edwards KM, Dupont WD, Westrich MK, Et Al. A Randomized Controlled Trial of Cold-Adapted and Inactivated Vaccines for the Prevention of Influenza a Disease. J Infect Dis. 1994;169(1):68-76.
[Return to footnote 130](#fn130-rf)
Footnote 131
Gonzalez M, Pirez MC, Ward E, Et Al. Safety and Immunogenicity of a Paediatric Presentation of an Influenza Vaccine. Arch Dis Child. 2000;83(6):488-91.
[Return to footnote 131](#fn131-rf)
Footnote 132
Piedra PA, Glezen WP, Mbawuike I, Et Al. Studies on Reactogenicity and Immunogenicity of Attenuated Bivalent Cold Recombinant Influenza Type A (CRA) and Inactivated Trivalent Influenza Virus (TI) Vaccines in Infants and Young Children. Vaccine. 1993;11(7):718-24.
[Return to footnote 132](#fn132-rf)
Footnote 133
Jain VK, Rivera L, Zaman K, Et Al. Vaccine for Prevention of Mild and Moderate-to-Severe Influenza in Children. N Engl J Med. 2013;369(26):2481-91.
[Return to footnote 133](#fn133-rf)
Footnote 134
Belshe RB. the Need for Quadrivalent Vaccine against Seasonal Influenza. Vaccine. 2010;28:D45-53.
[Return to footnote 134](#fn134-rf)
Footnote 135
Haber P, Moro PL, Lewis P, Et Al. Post-Licensure Surveillance of Quadrivalent Inactivated Influenza (IIV4) Vaccine in the United States, Vaccine Adverse Event Reporting System (VAERS), July 1, 2013− May 31, 2015. Vaccine. 2016;34(22):2507-12.
[Return to footnote 135](#fn135-rf)
Footnote 136
Izurieta HS, Chillarige Y, Kelman J, Et Al. Relative Effectiveness of Cell-Cultured and Egg-Based Influenza Vaccines among Elderly Persons in the United States, 2017-18. J Infect Dis. 2019;220((8)):1255-1264.
[Return to footnote 136](#fn136-rf)
Footnote 137
Klein NP, Fireman B, Goddard K, Et Al. LB15. Vaccine Effectiveness of Flucelvax Relative to Inactivated Influenza Vaccine during the 2017–18 Influenza Season in Northern California. Open Forum Infect Dis. 2018;5((Suppl 1)):S764.T.
[Return to footnote 137](#fn137-rf)
Footnote 138
US Armed Forces, Armed Forces Health Surveillance Center. Influenza-Like Illness (ILI). 2015; Available At: Https://Www.Health.Mil/Reference-Center/Publications/2015/10/01/Influenza-Like-Illness. Accessed 07/15, 2019.
[Return to footnote 138](#fn138-rf)
Footnote 139
US Food and Drug Administration. Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines. 2007; Available At: Https://Www.Fda.Gov/Downloads/Biologicsbloodvaccines/Guidancecomplianceregulatoryinformation/Guidances/Vaccines/Ucm091990.Pdf. Accessed 06/05, 2021.
[Return to footnote 139](#fn139-rf)
Footnote 140
Skowronski DM, Janjua NZ, De Serres G, Et Al. Low 2012-13 Influenza Vaccine Effectiveness Associated with Mutation in the Egg-Adapted H3N2 Vaccine Strain Not Antigenic Drift in Circulating Viruses. Plos ONE. 2014;9(3):E92153.
[Return to footnote 140](#fn140-rf)
Footnote 141
Zost SJ, Parkhouse K, Gumina ME, Et Al. Contemporary H3N2 Influenza Viruses Have a Glycosylation Site That Alters Binding of Antibodies Elicited By Egg-Adapted Vaccine Strains. Proceedings of the National Academy of Sciences. 2017;114((47)):12578-83.
[Return to footnote 141](#fn141-rf)
Footnote 142
Wu NC, Zost SJ, Thompson AJ, Et Al. A Structural Explanation for the Low Effectiveness of the Seasonal Influenza H3N2 Vaccine. Plos Pathogens. 2017;13((10)):E1006682.
[Return to footnote 142](#fn142-rf)
Footnote 143
the Francis Crick Institute. Worldwide Influenza Centre: Annual and Interim Reports – February 2018 Interim Report. 2018; Available At: Https://Www.Crick.Ac.Uk/Research/Worldwide-Influenza-Centre/Annual-and-Interim-Reports/. Accessed 07/15, 2019.
[Return to footnote 143](#fn143-rf)
Footnote 144
European Union European Medicines Agency. Assessment Report for Paediatric Studies Submitted According to Article 46 of the Regulation (EC) No 1901/2006. 2015; Available At: Https://Www.Ema.Europa.Eu/En/Documents/Variation-Report/Optaflu-H-C-758-P46-0052-Epar-Assessment-Report\_En.Pdf. Accessed 07/15, 2019.
[Return to footnote 144](#fn144-rf)
Footnote 145
European Union European Medicines Agency. Optaflu European Public Assessment Report: Scientific Discussion. 2007; Available At: Https://Www.Ema.Europa.Eu/En/Documents/Scientific-Discussion/Optaflu-Epar-Scientific-Discussion\_En.Pdf. Accessed 07/15, 2019.
[Return to footnote 145](#fn145-rf)
Footnote 146
US Food and Drug Administration. Flucelvax Quadrivalent. 2019; Available At: Https://Www.Fda.Gov/Vaccines-Blood-Biologics/Vaccines/Flucelvax-Quadrivalent. Accessed 07/15, 2019.
[Return to footnote 146](#fn146-rf)
Footnote 147
US Food and Drug Administration. FLUCELVAX - Seqirus, Inc. 1.14.1.3 US Package Insert. 2019; Available At: Https://Www.Fda.Gov/Media/85322/Download. Accessed 07/15, 2019.
[Return to footnote 147](#fn147-rf)
Footnote 148
Bart S, Cannon K, Herrington D, Et Al. Immunogenicity and Safety of a Cell Culture-Based Quadrivalent Influenza Vaccine in Adults: A Phase III, Double-Blind, Multicenter, Randomized, Non-Inferiority Study. . Hum Vaccines Immunother. 2016;12((9)):2278-88.
[Return to footnote 148](#fn148-rf)
Footnote 149
Hartvickson R, Cruz M, Ervin J, Et Al. Non-Inferiority of Mammalian Cell-Derived Quadrivalent Subunit Influenza Virus Vaccines Compared to Trivalent Subunit Influenza Virus Vaccines in Healthy Children: A Phase III Randomized, Multicenter, Double-Blind Clinical Trial. Int J Infect Dis. 2015;41:65-72.
[Return to footnote 149](#fn149-rf)
Footnote 150
Moro PL, Winiecki S, Lewis P, Et Al. Surveillance of Adverse Events After the First Trivalent Inactivated Influenza Vaccine Produced in Mammalian Cell Culture (Flucelvax) Reported to the Vaccine Adverse Event Reporting System (VAERS), United States, 2013-2015. Vaccine. 2015;33((45)):6684-6688.
[Return to footnote 150](#fn150-rf)
Footnote 151
Bencharitiwong R, Leonard S, Tsai T, Et Al. in Vitro Assessment of the Allergenicity of Novel MF59-Adjuvanted Pandemic H1N1 Influenza Vaccine Produced in Dog Kidney Cells. Hum Vaccin Immunother. 2012;8((7)):863-865.
[Return to footnote 151](#fn151-rf)
Footnote 152
Wanich N, Bencharitiwong R, Tsai T, Et Al. in Vitro Assessment of the Allergenicity of a Novel Influenza Vaccine Produced in Dog Kidney Cells in Individuals with Dog Allergy. Ann Allergy Asthma Immunol. 2010;104(5):426-33.
[Return to footnote 152](#fn152-rf)
Footnote 153
Mosca F, Tritto E, Muzzi A, Et Al. Molecular and Cellular Signatures of Human Vaccine Adjuvants. Proc Natl Acad Sci U S A. 2008;105(30):10501-6.
[Return to footnote 153](#fn153-rf)
Footnote 154
Calabro S, Tortoli M, Baudner B, Et Al. Vaccine Adjuvants Alum and MF59 Induce Rapid Recruitment of Neutrophils and Monocytes that Participate in Antigen Transport to Draining Lymph Nodes. Vaccine. 2011;29(9):1812-23.
[Return to footnote 154](#fn154-rf)
Footnote 155
Seubert A, Monaci E, Pizza M, Et Al. the Adjuvants Aluminum Hydroxide and MF59 Induce Monocyte and Granulocyte Chemoattractants and Enhance Monocyte Differentiation toward Dendritic Cells. J Immunol. 2008;180(8):5402-12.
[Return to footnote 155](#fn155-rf)
Footnote 156
O'Hagan DT, Rappuoli R, De Gregorio E, Et Al. MF59 Adjuvant: the Best Insurance against Influenza Strain Diversity. Expert Rev Vaccines. 2011;10(4):447-62.
[Return to footnote 156](#fn156-rf)
Footnote 157
Vesikari T, Knuf M, Wutzler P, Et Al. Oil-in-Water Emulsion Adjuvant with Influenza Vaccine in Young Children. N Engl J Med. 2011;365:1406-16.
[Return to footnote 157](#fn157-rf)
Footnote 158
Vesikari T, Groth N, Karvonen A, Et Al. MF59 (R)-Adjuvanted Influenza Vaccine (FLUAD (R)) in Children: Safety and Immunogenicity Following a Second Year Seasonal Vaccination. Vaccine. 2009;27:6291-5.
[Return to footnote 158](#fn158-rf)
Footnote 159
Vesikari T, Pellegrini M, Karvonen A, Et Al. Enhanced Immunogenicity of Seasonal Influenza Vaccines in Young Children using MF59 Adjuvant. Pediatr Infect Dis J. 2009;28:563-71.
[Return to footnote 159](#fn159-rf)
Footnote 160
Della Cioppa G, Vesikari T, Sokal E, Lindert K, Nicolay U. Trivalent and Quadrivalent MF59 (R)-Adjuvanted Influenza Vaccine in Young Children: A Dose- and Schedule-Finding Study. Vaccine. 2011;29:8696-704.
[Return to footnote 160](#fn160-rf)
Footnote 161
Zedda L, Forleo-Neto E, Vertruyen A, Et Al. Dissecting the Immune Response to MF59-Adjuvanted and Nonadjuvanted Seasonal Influenza Vaccines in Children Less than Three Years of Age. Pediatr Infect Dis J. 2015;34(1):73-8.
[Return to footnote 161](#fn161-rf)
Footnote 162
Nolan T, Bravo L, Ceballos A, Et Al. Enhanced and Persistent Antibody Response against Homologous and Heterologous Strains Elicited By a MF59-Adjuvanted Influenza Vaccine in Infants and Young Children. Vaccine. 2014;32(46):6146-56.
[Return to footnote 162](#fn162-rf)
Footnote 163
Vaarala O, Vuorela A, Partinen M, Et Al. Antigenic Differences between AS03 Adjuvanted Influenza A (H1N1) Pandemic Vaccines: Implications for Pandemrix-Associated Narcolepsy Risk. Plos One. 2014;9(12):E114361.
[Return to footnote 163](#fn163-rf)
Footnote 164
Diaz Granados CA, Dunning AJ, Robertson CA, Et Al. Efficacy and Immunogenicity of High-Dose Influenza Vaccine in Older Adults by Age, Comorbidities, and Frailty. J Am Geriatr Soc. 2014;62:S37-8.
[Return to footnote 164](#fn164-rf)
Footnote 165
Izurieta HS, Thadani N, Shay DK, Et Al. Comparative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines in US Residents Aged 65 Years and Older from 2012 to 2013 Using Medicare Data: A Retrospective Cohort Analysis. Lancet Infect Dis. 2015;15(3):293-300.
[Return to footnote 165](#fn165-rf)
Footnote 166
Falsey AR, Treanor JJ, Tornieporth N, Et Al. Randomized, Double-Blind Controlled Phase 3 Trial Comparing the Immunogenicity of High-Dose and Standard-Dose Influenza Vaccine in Adults 65 Years of Age and Older. J Infect Dis. 2009;200(2):172-80.
[Return to footnote 166](#fn166-rf)
Footnote 167
Couch RB, Winokur P, Brady R, Et Al. Safety and Immunogenicity of a High Dosage Trivalent Influenza Vaccine among Elderly Subjects. Vaccine. 2007;25(44):7656-63.
[Return to footnote 167](#fn167-rf)
Footnote 168
Keitel WA, Atmar RL, Cate TR, Et Al. Safety of High Doses of Influenza Vaccine and Effect on Antibody Responses in Elderly Persons. Arch Intern Med. 2006;166(10):1121-7.
[Return to footnote 168](#fn168-rf)
Footnote 169
Pasteur S. Study of Fluzone® Influenza Virus Vaccine 2011-2012 Formulation (Intramuscular Route) Among Adults. 2013; 2014.
[Return to footnote 169](#fn169-rf)
Footnote 170
Tsang P, Gorse GJ, Strout CB, Et Al. Immunogenicity and Safety of Fluzone Intradermal and High-Dose Influenza Vaccines in Older Adults >65 Years of Age: A Randomized, Controlled, Phase II Trial. Vaccine. 2014;32(21):2507-17.
[Return to footnote 170](#fn170-rf)
Footnote 171
Nace DA, Lin CJ, Ross TM, Et Al. Randomized, Controlled Trial of High-Dose Influenza Vaccine among Frail Residents of Long-Term Care Facilities. J Infect Dis. 2015;211(12):1915-24.
[Return to footnote 171](#fn171-rf)
Footnote 172
Diazgranados CA, Dunning AJ, Jordanov E, Et Al. High-Dose Trivalent Influenza Vaccine Compared to Standard Dose Vaccine in Elderly Adults: Safety, Immunogenicity and Relative Efficacy during the 2009-2010 Season. Vaccine. 2013;31(6):861-6.
[Return to footnote 172](#fn172-rf)
Footnote 173
Diazgranados CA, Dunning AJ, Kimmel M, Et Al. Efficacy of High-Dose versus Standard-Dose Influenza Vaccine in Older Adults. N Engl J Med. 2014;371(7):635-45.
[Return to footnote 173](#fn173-rf)
Footnote 174
Sanofi Pasteur. Product Monograph: FLUZONE® High-Dose Quadrivalent. 2019; Available At: Https://Health-Products.Canada.Ca/Dpd-Bdpp/Info.Do?Lang=En&Code=99020. Accessed 09/15, 2020.
[Return to footnote 174](#fn174-rf)
Footnote 175
Chang LJ, Meng Y, Janosczyk H, Et Al. Safety and Immunogenicity of High-Dose Quadrivalent Influenza Vaccine in Adults ≥65 Years of Age: A Phase 3 Randomized Clinical Trial. Vaccine. 2019;37(39):5825-34.
[Return to footnote 175](#fn175-rf)
Footnote 176
Dunkle LM, Izikson R, Patriarca P, Et Al. Efficacy of Recombinant Influenza Vaccine in Adults 50 Years of Age or Older. N Engl J Med. 2017;376(25):2427-36.
[Return to footnote 176](#fn176-rf)
Footnote 177
Belongia EA, Levine MZ, Olaiya O, Et Al. Clinical Trial to Assess Immunogenicity of High-Dose, Adjuvanted, and Recombinant Influenza Vaccines against Cell-Grown A(H3N2) Viruses in Adults 65 to 74 Years, 2017–2018. Vaccine. 2020;38(15):3121-8.
[Return to footnote 177](#fn177-rf)
Footnote 178
Shinde V, Cai R, Plested J, Et Al. Induction of Cross-Reactive Hemagglutination Inhibiting Antibody and Polyfunctional CD4+ T-Cell Responses by a Recombinant Matrix-M–Adjuvanted Hemagglutinin Nanoparticle Influenza Vaccine. Clinical Infectious Diseases. 2020:Ciaa1673.
[Return to footnote 178](#fn178-rf)
Footnote 179
Dunkle LM, Izikson R, Patriarca PA, Et Al. Randomized Comparison of Immunogenicity and Safety of Quadrivalent Recombinant Versus Inactivated Influenza Vaccine in Healthy Adults 18–49 Years of Age. J Infect Dis. 2017;216(10):1219-26.
[Return to footnote 179](#fn179-rf)
Footnote 180
Wang W, Alvarado-Facundo E, Vassell R, Et Al. Comparison of A(H3N2) Neutralizing Antibody Responses Elicited by 2018–2019 Season Quadrivalent Influenza Vaccines Derived from Eggs, Cells, and Recombinant Hemagglutinin. Clinical Infectious Diseases. 2020:Ciaa1352.
[Return to footnote 180](#fn180-rf)
Footnote 181
Cowling BJ, Perera RAPM, Valkenburg SA, Et Al. Comparative Immunogenicity of Several Enhanced Influenza Vaccine Options for Older Adults: A Randomized, Controlled Trial. Clin Infect Dis. 2020;71(7):1704-14.
[Return to footnote 181](#fn181-rf)
Footnote 182
Gouma S, Zost SJ, Parkhouse K, Et Al. Comparison of Human H3N2 Antibody Responses Elicited by Egg-Based, Cell-Based, and Recombinant Protein-Based Influenza Vaccines during the 2017-2018 Season. Clin Infect Dis. 2020;71(6):1447-53.
[Return to footnote 182](#fn182-rf)
Footnote 183
Dawood FS, Naleway AL, Flannery B, Levine MZ, Murthy K, Sambhara S, Gangappa S, Edwards L, Ball S, Grant L, Belongia E, Et Al. Comparison of the Immunogenicity of Cell Culture-Based and Recombinant Quadrivalent Influenza Vaccines to Conventional Egg-Based Quadrivalent Influenza Vaccines Amongamong Healthcare Personnel Aged 18–64 Years: A Randomized Open-Label Trial. Clinical Infectious Diseases.Clin Infect Dis. 2021 Jul 10.
[Return to footnote 183](#fn183-rf)
Footnote 184
European Medicines Agency (EMA). Assessment Report: Supemtek. 2020; Available at: Https://Www.Ema.Europa.Eu/En/Documents/Assessment-Report/Supemtek-Epar-Public-Assessment-Report\_En.Pdf. Accessed September 28, 2021.
[Return to footnote 184](#fn184-rf)
Footnote 185
Woo EJ, Moro PL. Postmarketing Safety Surveillance of Quadrivalent Recombinant Influenza Vaccine: Reports to the Vaccine Adverse Event Reporting System. Vaccine. 2021;39(13):1812-7.
[Return to footnote 185](#fn185-rf)
Footnote 186
Cowling BJ, Thompson MG, Ng TWY, Et Al. Comparative Reactogenicity of Enhanced Influenza Vaccines in Older Adults. J Infect Dis. 2020;222(8):1383-91.
[Return to footnote 186](#fn186-rf)
Footnote 187
Grohskopf LA, Sokolow LZ, Fry AM, Et Al. Update: ACIP Recommendations for the Use of Quadrivalent Live Attenuated Influenza Vaccine (LAIV4) - United States, 2018-19 Influenza Season. MMWR Morb Mortal Wkly Rep. 2018;67(22):643-5.
[Return to footnote 187](#fn187-rf)
Footnote 188
National Advisory Committee Oi. Recommendations on the Use of Live, Attenuated Influenza Vaccine (Flumist®): Supplemental Statement on Seasonal Influenza Vaccine 2011-2012. Can Commun Dis Rep. 2011;37(-7):1-77.
[Return to footnote 188](#fn188-rf)
Footnote 189
Block SL, Falloon J, Hirschfield JA, Et Al. Immunogenicity and Safety of a Quadrivalent Live Attenuated Influenza Vaccine in Children. Pediatr Infect Dis J. 2012;31(7):745-51.
[Return to footnote 189](#fn189-rf)
Footnote 190
Block SL, Yi T, Sheldon E, Et Al. A Randomized, Double-Blind Noninferiority Study of Quadrivalent Live Attenuated Influenza Vaccine in Adults. Vaccine. 2011;29(50):9391-7.
[Return to footnote 190](#fn190-rf)
Footnote 191
Medimmune. A Randomized, Partially Blind Active Controlled Study to Evaluate the Immunogenicity of MEDI8662 in Adults 18-49 Years of Age. 2011; 2015.
[Return to footnote 191](#fn191-rf)
Footnote 192
Public Health Agency of Canada. NACI Recommendation on the Use of Live Attenuated Influenza Vaccine (LAIV) in HIV-Infected Individuals. 2020; Available At: Https://Www.Canada.Ca/En/Public-Health/Services/Immunization/National-Advisory-Committee-on-Immunization-Naci/Live-Attenuated-Influenza-Vaccine-Hiv-Infected-Individuals.html.
[Return to footnote 192](#fn192-rf)
Footnote 193
Ritzwoller DP, Bridges CB, Shetterly S, Et Al. Effectiveness of the 2003-2004 Influenza Vaccine Among Children 6 Months to 8 Years of Age, with 1 Vs 2 Doses. Pediatrics. 2005;116(1):153-9.
[Return to footnote 193](#fn193-rf)
Footnote 194
Neuzil KM, Jackson LA, Nelson J, Et Al. Immunogenicity and Reactogenicity of 1 versus 2 Doses of Trivalent Inactivated Influenza Vaccine in Vaccine-Naive 5-8-Year-Old Children. J Infect Dis. 2006;194(8):1032-9.
[Return to footnote 194](#fn194-rf)
Footnote 195
Shuler CM, Iwamoto M, Bridges CB, Et Al. Vaccine Effectiveness against Medically Attended, Laboratory-Confirmed Influenza among Children Aged 6 to 59 Months, 2003-2004. Pediatrics. 2007;119(3):E587-95.
[Return to footnote 195](#fn195-rf)
Footnote 196
Allison MA, Daley MF, Crane LA, Et Al. Influenza Vaccine Effectiveness in Healthy 6- o 21-Month-Old Children during the 2003-2004 Season. J Pediatr. 2006;149(6):755-62.
[Return to footnote 196](#fn196-rf)
Footnote 197
Skowronski DM, Hottes TS, De Serres G, Et Al. Influenza B/Victoria Antigen Induces Strong Recall of B/Yamagata but Lower B/Victoria Response in Children Primed with Two Doses of B/Yamagata. Pediatr Infect Dis J. 2011;30(10):833-9.
[Return to footnote 197](#fn197-rf)
Footnote 198
Public Health Agency of Canada. Canadian Immunization Guide: Part 1 - Key Immunization Information: Timing of Vaccine Administration. 2017; Available At: Https://Www.Canada.Ca/En/Public-Health/Services/Publications/Healthy-Living/Canadian-Immunization-Guide-Part-1-Key-Immunization-Information/Page-10-Timing-Vaccine-Administration.Html. Accessed 10/09, 2018.
[Return to footnote 198](#fn198-rf)
Footnote 199
Nascimento Silva JR, Camacho LA, Siqueira MM, Et Al. Mutual Interference on the Immune Response to Yellow Fever Vaccine and a Combined Vaccine against Measles, Mumps and Rubella. Vaccine. 2011;29(37):6327-34.
[Return to footnote 199](#fn199-rf)
Footnote 200
200. Stefano I, Sato HK, Pannuti CS, Et Al. Recent Immunization against Measles does not Interfere with the Sero-Response to Yellow Fever Vaccine. Vaccine. 1999;17(9-10):1042-6.
[Return to footnote 200](#fn200-rf)
Footnote 201
Tauraso NM, Myers MG, Nau EV, Et Al. Effect of Interval between Inoculation of Live Smallpox and Yellow-Fever Vaccines on Antigenicity in Man. J Infect Dis. 1972;126(4):362-71.
[Return to footnote 201](#fn201-rf)
Footnote 202
Verstraeten T, Jumaan AO, Mullooly JP, Et Al. A Retrospective Cohort Study of the Association of Varicella Vaccine Failure with Asthma, Steroid Use, Age at Vaccination, and Measles-Mumps-Rubella Vaccination. Pediatrics. 2003;112(2):E98-103.
[Return to footnote 202](#fn202-rf)
Footnote 203
Institute of Medicine of the National Academies. Immunization Safety Review: Influenza Vaccines and Neurological Complications. Washington, DC: National Academy of Sciences; 2008.
[Return to footnote 203](#fn203-rf)
Footnote 204
Sivadon-Tardy V, Orlikowski D, Porcher R, Et Al. Guillain-Barre Syndrome and Influenza Virus Infection. Clin Infect Dis. 2009;48(1):48-56.
[Return to footnote 204](#fn204-rf)
Footnote 205
Stowe J, Andrews N, Wise L, Et Al. Investigation of the Temporal Association of Guillain-Barre Syndrome with Influenza Vaccine and Influenza Like Illness using the United Kingdom General Practice Research Database. Am J Epidemiol. 2009;169(3):382-8.
[Return to footnote 205](#fn205-rf)
Footnote 206
Tam CC, O'Brien SJ, Petersen I, Et Al. Guillain-Barre Syndrome and Preceding Infection with Campylobacter, Influenza and Epstein-Barr Virus in the General Practice Research Database. Plos One. 2007;2(4):E344.
[Return to footnote 206](#fn206-rf)
Footnote 207
Andrews N, Stowe J, Al-Shahi Salman R, Et Al. Guillain-Barre Syndrome and H1N1 (2009) Pandemic Influenza Vaccination Using an AS03 Adjuvanted Vaccine in the United Kingdom: Self-Controlled Case Series. Vaccine. 2011;29(45):7878-82.
[Return to footnote 207](#fn207-rf)
Footnote 208
Statistics Canada. Table 051-0001 - Estimates of Population, by Age Group and Sex for July 1, Canada, Provinces and Territories, Annual (Persons Unless Otherwise Noted), CANSIM (Database). 2014; 2015.
[Return to footnote 208](#fn208-rf)
Footnote 209
Tran D, Vaudry W, Moore D, Et Al. Hospitalization for Influenza A versus B. Pediatrics. 2016;138(3):10.1542/Peds.2015,4643. Epub 2016 Aug 17.
[Return to footnote 209](#fn209-rf)
Footnote 210
Centers for Disease Control, and Prevention. Estimates of Deaths Associated with Seasonal Influenza --- United States, 1976-2007. MMWR Morb Mortal Wkly Rep. 2010;59(33):1057-62. https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Guidance-for-Industry--Clinical-Data-Needed-to-Support-the-Licensure-of-Seasonal-Inactivated-Influenza-Vaccines.pdf
[Return to footnote 210](#fn210-rf)
Footnote 211
Assessment report: Supemtek [Internet]. Cromer D, Van Hoek AJ, Jit M, Et Al. the Burden of Influenza in England by Age and Clinical Risk Group: A Statistical Analysis to Inform Vaccine Policy. J Infect. 2014;68(4):363-712021. Available from: https://www.ema.europa.eu/en/documents/assessment-report/supemtek-epar-public-assessment-report\_en.pdf
[Return to footnote 211](#fn211-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-02-16
| None | None |
9014d28e7fcc740e77380d5f324d52a50ee88aff | cma | Guidance on the use of COVID-19 vaccines in the fall of 2023 | Guidance on the use of COVID-19 vaccines in the fall of 2023
Preamble
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI’s independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC’s Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Background
On January 20, 2023, the National Advisory Committee on Immunization (NACI) published , followed by on March 3, 2023.
Since then, the World Health Organization (WHO) has determined that COVID-19 is an established and ongoing health issue and no longer constitutes a public health emergency of international concern. Transition to the long-term management of the COVID-19 pandemic is now needed, but there continue to be uncertainties such as the ongoing epidemiology of COVID-19, duration of protection from current COVID-19 booster doses and previous infection, and vaccine effectiveness (VE) of future vaccines.
On May 18, 2023, the WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) released recommendations for updates to COVID-19 vaccine antigen composition. An approach recommended by TAG-CO-VAC is a monovalent XBB.1 descendent lineage, such as XBB.1.5 or alternatively XBB.1.16. The International Coalition of Medicines Regulatory Authorities (ICMRA), European Centre for Disease Prevention (ECDC), the European Medicines Agency (EMA), and the US Food and Drug Administration Vaccines and Related Biological Products Advisory Committee (FDA VRBPAC) have also released decisions supporting XBB as a candidate for the COVID-19 vaccine composition update. Manufacturers have indicated that new COVID-19 vaccine formulations are in development and products are forthcoming.
Although seasonality of SARS-CoV-2 has not been established, other respiratory viruses such as influenza and respiratory syncytial virus (RSV) typically increase in the fall and winter months. To help reduce the impact of COVID-19 on the health system while other respiratory viruses are circulating and with the expected availability of a new COVID-19 vaccine formulation, NACI is providing guidance on the use of COVID-19 vaccines to inform planning for a vaccination program starting in fall 2023.
Methods
Following preliminary discussions on April 28, 2023, the NACI COVID-19 Working Group and full NACI membership reviewed, on May 23, 2023 and June 6, 2023 respectively, the available evidence on epidemiology, vaccine protection, hybrid immunity, safety, and concurrent administration of COVID-19 vaccine with the seasonal influenza vaccine. Preliminary modelling data were also considered, as well as equity, feasibility and acceptability considerations for a fall 2023 COVID-19 vaccination program. NACI approved these recommendations on June 26, 2023.
For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to NACI: and the of the (CIG).
Further information on is available elsewhere.
Overview of evidence
Available scientific literature (published or pre-print) as of May 19, 2023 is summarized below.
# Epidemiology
- The evolutionary trajectory of SARS-CoV-2, including the emergence of novel variants of concern (VOCs), is uncertain and seasonality of SARS-CoV-2 has not been established.
- Recombinant XBB\- sub-lineages continue to circulate in Canada and globally. XBB.1.5\- is the most prevalent lineage in Canada but is declining as of May 19, 2023 with increases in other XBB\- sub-lineages, such as XBB.1.16.
- Seroepidemiologic studies demonstrate high levels of antibodies to spike antigen attributed to past COVID-19 vaccination and/or SARS-CoV-2 infection in the Canadian population.
- Since the fall of 2022, national surveillance data has shown a surge in COVID-19 cases from late September to November 2022, and a smaller surge in December 2022 and January 2023. Weekly rates and number of cases, hospitalizations and deaths have shown gradual decreases since January 2023, and have been relatively stable up to May 17, 2023.
- Rates of hospitalizations and deaths in Canada continue to be highest for adults 65 years of age and older, with risk increasing with age and highest among those ≥80 years and those who are unvaccinated. Among those under 18 years of age, rates of hospitalizations are highest in children under 1 year of age. Rates of infection and severe disease are lowest for those recently vaccinated and those with hybrid immunity, particularly if the previous infection was with a more recent Omicron strain .
- In addition to age, vaccination status and prior history of SARS-CoV-2 infection, studies looking at risk factors continue to show individuals with comorbidities are at higher risk for severe outcomes due to COVID-19 in adults. Evidence on risk factors for severe COVID-19 illness in children is limited given the much lower incidence of severe illness in this population.
# Vaccine protection
## Duration of vaccine protection of Omicron-containing bivalent mRNA vaccines
- Evidence from the US assessing VE of the BA.4/5 bivalent vaccine show emerging trends in waning vaccine protection against Omicron SARS-CoV-2 infection and hospitalization as was observed with the original monovalent vaccine. Waning protection against severe disease conferred by a bivalent booster dose has also been reported in a Finnish study (pre-print) in adults 65 years of age and older.
- Preliminary data from Ontario (preprint) demonstrates that short-term (<90 to 119 days) VE against severe outcomes in community dwelling adults 50 years of age and older was similar between those receiving original and bivalent mRNA vaccine booster doses and between the available vaccine products (Moderna Spikevax original or bivalent BA.1 and Pfizer-BioNTech Comirnaty original or bivalent BA.4/5) during a period when BA.5 was the predominant Omicron sub-lineage and BQ.1 was emerging.
- There are no data available on the duration of vaccine protection of bivalent mRNA vaccines in children and adolescents. The duration of vaccine protection of the original monovalent mRNA vaccines against infection and severe disease in children and adolescents has been very similar to the trends observed in adults.
+ Several studies have reported waning VE against Omicron infection or symptomatic infection of original monovalent Pfizer-BioNTech Comirnaty in children 5 to 11 years of age (from approximately 40-70% to 20-40% within two months post vaccination with the primary series) , and of any original monovalent mRNA primary series in adolescents (from approximately 50-80% to 20-60% within two months post vaccination) . Limited evidence has also shown waning VE against severe disease due to Omicron
+ There is emerging evidence of waning VE against infection following the primary series in children 6 months to under 5 years of age .
+ There is limited evidence that short term VE (1 to 3 months post-booster) against Omicron infection is restored after an original monovalent booster dose in children and adolescents 5 years of age and older , as well as subsequent waning protection after the booster dose .
## VE in individuals with hybrid immunity
- Hybrid immunity results from ≥1 exposure(s) from vaccination and ≥1 exposure(s) from SARS-CoV-2 infection (before or after vaccination). Earlier NACI statements have summarized evidence demonstrating that previous infection and vaccination may provide superior protection against VOCs, including Omicron, compared with vaccination alone, or previous SARS-CoV-2 infection without vaccination .
- Data have emerged estimating the relative VE of an Omicron-containing bivalent mRNA booster compared to those who did not receive a bivalent booster during a period when BA.5 was the predominant subvariant and stratified by prior documented infection status . The studies demonstrate that the bivalent booster provided additional protection relative to the previous original monovalent booster dose in those without previous SARS-CoV-2 infection and in those with more distant previous infection.
+ A study in the Netherlands assessed relative VE of the bivalent BA.1 mRNA COVID-19 vaccine against SARS-CoV-2 Omicron infection among adults 18 to 85 years of age who had previously received primary vaccination and one or two monovalent booster doses. The relative VE of a BA.1 bivalent booster against infection in adults 18-59 years of age was highest in those with an earlier prior (pre-Omicron) infection (44%; 95% confidence interval .
+ A study in Italy assessed relative VE of the bivalent BA.4/5 mRNA COVID-19 vaccine against severe COVID-19 disease in adults 60 years of age and older who had previously received one monovalent booster . The relative VE of a BA.4/5 bivalent booster against severe COVID-19 disease was comparable between those with no prior infection (59%; 95% CI: 55 to 63%) and those with earlier prior pre-Omicron or Omicron infection (i.e., prior infection that occurred 27 to 39 weeks earlier and was predominantly BA.1 had a relative VE of 62%; 95% CI: 43 to 74% and prior infection 40 or more weeks earlier and was predominantly original and Alpha strains had a relative VE of 62%; 95% CI: 38 to 76%). Relative VE in those with prior infection occurring 17 to 26 weeks earlier was lowest but also imprecise (10%; 95% CI: −44 to 44%; predominantly BA.5 or BA.2 infection).
+ In the above studies, hybrid immunity from a previous original monovalent booster in the context of a more recent Omicron infection were not improved by a bivalent booster, possibly because protection from hybrid immunity remained high. Protection from hybrid immunity in vaccinated individuals who had an earlier infection and/or earlier vaccination with the original monovalent COVID-19 vaccine would have had a longer time to wane, thereby contributing to higher relative VE after receiving a bivalent booster.
## Vaccination of individuals who are pregnant
- Studies continue to support vaccination during pregnancy. Vaccination with original mRNA COVID-19 vaccines has been shown to confer protection to the pregnant individual as well as protection against Omicron SARS-CoV-2 infection and hospitalization in infants <6 months of age (who are not yet eligible for vaccination) when compared to infants of individuals who were unvaccinated or did not receive at least one dose (either dose 2 of a primary series or a booster dose) of COVID-19 vaccine during pregnancy . Protection in infants was highest in the first two months of life and decreased by four to six months of age .
- Systematic reviews assessing the safety of COVID-19 vaccines during pregnancy have not identified any adverse effects specific to pregnancy.
- No evidence on VE against infant outcomes is available for vaccination with bivalent mRNA vaccines in persons who are pregnant.
## Post-COVID-19 condition
- Post COVID-19 condition (PCC) is a condition in which symptoms following a SARS-CoV-2 infection persist for more than 8 weeks and are present for 12 or more weeks following the acute phase. Emerging evidence suggests that individuals may be less likely to report experiencing PCC symptoms if infected during the Omicron period compared to those infected with a pre-Omicron variant . Nonetheless it is estimated that approximately 10 to 20% of people who are infected with SARS-CoV-2 develop PCC.
- To the extent that vaccination prevents infection, it also prevents PCC as those who do not become infected do not develop PCC. In addition, there is evidence that those who are vaccinated with at least two doses of the monovalent original COVID-19 vaccine before becoming infected are less likely to develop PCC than those who are not vaccinated before infection. Estimates of PCC protection from pre-infection vaccination vary between studies with a systematic review noting approximately one-third less PCC among two-dose vaccinated people compared to unvaccinated people (OR, 0.64; 95% CI, 0.45–0.92%) . A third dose of COVID-19 vaccine may offer additional protection against PCC compared to receiving one to two doses. Vaccination has not been associated with a higher risk of developing PCC or worsening PCC symptoms.
- Evidence of any positive benefit on PCC from vaccination post-infection is limited .
- There are no studies to date evaluating the effectiveness of bivalent vaccines specifically in reducing the risk of developing PCC.
## Safety of Omicron-containing bivalent mRNA COVID-19 vaccines
- The safety profile of the bivalent mRNA COVID-19 vaccine boosters is comparable to that of original mRNA COVID-19 vaccine boosters among individuals in the authorized age group for mRNA booster doses (i.e., those 5 years and older).
- A statistical signal for ischemic stroke among adults 65 years of age and older was detected in the US Vaccine Safety Datalink (VSD) following administration of Pfizer-BioNTech Comirnaty BA.4/5. This signal has weakened over time since it was first detected in October 2022 and is no longer being detected. It was not noted in the VSD for the Moderna bivalent booster .
- No evidence of a safety signal has been detected for ischemic stroke with either mRNA COVID-19 bivalent boosters in other US safety surveillance systems (as of April 2, 2023) , nor in Canada (as of April 28, 2023), other international regulatory and public health safety monitoring systems, or in global vaccine safety monitoring by Pfizer-BioNTech. A study from England published on June 15, 2023 assessing BA.1 bivalent mRNA vaccines and stroke in adults 50 years of age and older also found no evidence of increased risk of stroke, including among individuals who concurrently received an influenza vaccine.
- Further investigation into the signal in the VSD system revealed that it was seen with concurrent administration of Pfizer-BioNTech bivalent vaccine and high-dose or adjuvanted influenza vaccines, but not with concomitant administration with standard-dose influenza vaccine or when the bivalent Pfizer-BioNTech vaccine was administered alone.
- Recommendations in the US to give concurrent COVID-19 and influenza vaccines have not changed because of the potential signal identified in VSD. Monitoring regarding this safety signal continues.
## Concurrent administration with influenza vaccination
- Except for the ischemic stroke potential safety signal from the VSD noted above, no safety concerns have been identified to date with the concurrent administration of COVID-19 vaccines and influenza vaccines .
- Higher reactogenicity has been observed following concurrent administration of original mRNA COVID-19 vaccines with influenza vaccination compared to influenza vaccination alone, but reactogenicity was comparable to receipt of the COVID-19 vaccine alone .
- Two studies in health care workers have observed a reduced immunologic response to the Pfizer-BioNTech Comirnaty original vaccine when concurrently administered with a quadrivalent influenza vaccine . A reduced immunologic response was also noted in a clinical trial assessing concurrent administration of Novavax Nuvaxovid with influenza vaccines, without an impact on vaccine efficacy for Novavax Nuvaxovid. In another clinical trial, a reduced immune response was not observed in adults aged 65 years and older who received a third dose with Moderna Spikevax original at the same time as a high-dose quadrivalent influenza vaccine.
- NACI continues to monitor the safety of concurrent administration of COVID-19 vaccines and other vaccines, including the seasonal influenza vaccine.
## Ethics, equity, feasibility, and acceptability (EEFA)
- Over the course of the COVID-19 pandemic, many NACI recommendations have been put forward to address the complex vaccine product landscape, reflecting the knowns and unknowns in the available evidence on vaccine protection against SARS-CoV-2-related outcomes, including infection, and symptomatic and severe disease. The transition to a more sustainable approach to the long-term management of COVID-19 includes learning how to manage the COVID-19 vaccine program alongside other public health priorities and longstanding vaccination programs.
- Where possible, simplifying and streamlining the COVID-19 vaccine recommendations for a fall program would facilitate implementation and ease of communication for both provincial and territorial vaccination programs and individual health care providers. However, it continues to be important to highlight specific populations for whom vaccination is particularly important due to biological and/or social risk factors.
- Fewer severe outcomes of COVID-19 have been reported for children (i.e., hospitalizations due to COVID-19, ICU admission, and deaths) compared to older age groups, and COVID-19 vaccine uptake has been low to very low among children under 12 years of age (only 6% of children 6 months to 4 years and 40% of children 5 to 11 years of age have completed a primary series as of June 18, 2023). While most children may have mild or no symptoms, some are at higher risk of severe disease due to COVID-19 or developing PCC. Individual benefit-risk assessments may favour vaccination based on factors including a child’s health status.
- In the fall of 2023, it is anticipated that jurisdictions will likely combine the COVID-19 and influenza vaccination campaigns for operational and logistical reasons. For all currently vaccine-eligible age-groups (i.e., 6 months of age and older for the primary series; 5 years of age and older for booster doses), concurrent administration of any dose of a COVID-19 vaccine with other vaccines (including the seasonal influenza vaccine) has the potential to increase program efficiency and may also increase vaccine coverage. The clinical significance of somewhat lower immunogenicity noted in some studies with concomitant COVID-19 and influenza vaccine administration is uncertain.
- There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions.
## Other considerations
- TAG-CO-VAC has advised that new COVID-19 vaccine formulations should aim to induce antibody responses that neutralize XBB descendent lineages (such as XBB.1.5 or alternatively XBB.1.16), which are the lineages predominantly circulating globally at present. These sublineages have also been demonstrated to be some of the most immune evasive variants to date, based on neutralizing antibody data from individuals vaccinated with current COVID-19 vaccines. TAG-CO-VAC also advised that future formulations of COVID-19 vaccines should move away from inclusion of the original SARS-CoV-2 virus given that the strain is no longer circulating in humans.
- On June 15, 2023, US FDA VRBPAC recommended an update to the COVID-19 vaccine with a monovalent XBB\- targeted formulation after reviewing evidence on epidemiology and pre-clinical and clinical data showing that monovalent XBB-targeted vaccines had similar or slightly higher immune responses against XBB-derivatives compared to bivalent XBB-targeted vaccines.
- Changes to the vaccine formulations are anticipated; however, the vaccine products that will be available in the coming months have yet to be determined.
- Modelling suggests that an additional vaccine dose offered in the fall of 2023 could be expected to prevent thousands of hospitalizations and deaths across the country over the next year. Modelled estimates are dependent on various assumptions, such as durability of protection from vaccination and/or infection and the possibility of a seasonal resurgence in infections.
Recommendations
Please see for an explanation of strong versus discretionary NACI recommendations.
NACI continues to recommend COVID-19 vaccination for those who have not been immunized, as follows:
1. Individuals 5 years of age and older should be immunized with a primary series of an mRNA vaccine. (Strong NACI recommendation)
2. Children 6 months to under 5 years of age may be immunized with a primary series of an mRNA vaccine. (Discretionary NACI recommendation)
Regarding the product offered, when mRNA vaccines are used for the primary series, the bivalent Omicron-containing vaccines can be used for anyone 6 months of age and older. More information is available in the .
For booster doses, previously NACI has recommended that at least one booster dose should be offered to all adults 18 years of age and over, and adolescents 12 to 17 years of age who are at increased risk of severe illness, along with additional specific population recommendations in the and .
Additional details including those pertaining to vaccine schedule (e.g., number of doses, interval between doses) and alternative vaccine products, are available in the of the Canadian Immunization Guide and NACI .
3. Beginning in the fall of 2023 for those previously vaccinated against COVID-19, NACI recommends a dose of the new formulation of COVID-19 vaccine for individuals in the authorized age group if it has been at least 6 months from the previous COVID-19 vaccine dose or known SARS-CoV-2 infection (whichever is later).
Immunization is particularly important for those at increased risk of COVID-19 infection or severe disease, for example:
- Adults 65 years of age or older
- Residents of long-term care homes and other congregate living settings
- Individuals with that place them at higher risk of severe COVID-19
- Individuals who are pregnant
- Individuals in or from First Nations, Métis and Inuit communities\*
- Members of racialized and other equity-deserving communities
- People who provide essential community services
(Strong NACI Recommendation)
\* Autonomous decisions should be made by Indigenous Peoples with the support of healthcare and public health partners in accordance with the .
Rationale and additional considerations:
- A booster dose starting in the fall of 2023 is expected to increase protection against SARS-CoV-2 infection and COVID-19 symptomatic and severe disease that has waned since the last booster vaccination or SARS-CoV-2 infection. Increased protection will help to reduce the impact of COVID-19 on the health system while other respiratory viruses, including influenza and RSV are circulating in the fall and winter of the 2023-2024 respiratory virus season.
- Prior infection along with vaccination (hybrid immunity) offers greater protection against infection and severe disease than vaccination or prior infection alone, particularly when hybrid immunity is in the context of a recent Omicron infection. For this reason, an additional dose of vaccine starting this fall is particularly important for those who have not been previously infected and have protection from vaccination alone. However, even with hybrid immunity, protection against infection will decrease over time and the duration of protection against severe disease varies between studies and is unknown in the context of currently circulating variants. There are no known safety risks with receiving a vaccine after a recent SARS-CoV-2 infection, although evidence shows that the antibody response is higher with longer intervals between infection and vaccination.
- Vaccination of individuals at higher risk for severe COVID-19 will help to reduce their risk of severe disease that could potentially result in hospitalization and death; thus it is particularly important for these individuals to receive a booster dose starting in the fall of 2023.
- Vaccination of individuals at lower risk for severe disease may provide additional benefit to those at higher risk through indirect protection, particularly shortly after vaccination and in the context of hybrid immunity when protection from infection is greatest. There could also be other benefits such as reducing the risk of PCC, but the extent and duration of the benefits are uncertain. Vaccination of health care providers and others who provide essential community services is expected to be important in maintaining health system capacity.
- Booster doses in the fall will be formulations updated to target more recent, immune‑evasive SARS-CoV-2 variants. Individuals vaccinated with the updated formulation are expected to benefit from a better immune response against these variants compared to current vaccines.
- mRNA vaccines remain the preferred COVID-19 vaccine product. A Novavax Nuvaxovid booster should be offered to those 18 years of age and over who are unwilling or unable to receive an mRNA vaccine if it has been at least 6 months from the previous COVID-19 vaccine dose or SARS-CoV-2 infection (whichever is later). Individuals waiting for a new formulation of Novavax Nuvaxovid should assess their individual risk if choosing to delay vaccination.
- COVID-19 vaccines may be given concurrently (i.e., same day), or at any time before or after, non-COVID-19 vaccines (including live and non-live vaccines).
- NACI will continue to monitor the safety and effectiveness of COVID-19 vaccines, including the safety of concurrent administration with other non-COVID-19 vaccines, such as the seasonal influenza vaccine.
NACI will review available information on the new vaccine formulations expected for the fall of 2023 and update recommendations as needed. NACI will continue to monitor the evidence, including SARS-CoV-2 epidemiology and duration of vaccine protection, particularly with regard to severe outcomes, to provide recommendations on the timing of subsequent booster doses if warranted.
Research priorities
1. Continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of COVID-19 vaccines, including with the new formulation, through clinical trials and studies in real-world settings, including the degree and duration of protection conferred by each booster dose against circulating variants. The research should also consider the clinical implications of previous SARS-CoV-2 infection; repeated immunization; and outcomes after infection such as PCC.
2. Further evaluations of the optimal interval between dose administration, as well as further evaluations of the optimal interval between previous SARS-CoV-2 infection and vaccine dose administration.
3. Vigilant monitoring and reporting of adverse events of special interest, including myocarditis and/or pericarditis, to accurately inform potential risks associated with any future booster doses. Global collaboration should be prioritized to enable data sharing so decision makers around the world can weigh benefits and risks of additional booster doses of COVID-19 vaccines.
4. Continuous monitoring of COVID-19 epidemiology in children, including risk factors for severe outcomes and long-term consequences of infection with SARS-CoV-2.
5. Continuous monitoring of COVID-19 epidemiology and VE in special populations at high risk of severe outcomes or long-term consequences of infection with SARS-CoV-2.
6. Further evaluations on the safety, immunogenicity, and effectiveness on the concurrent administration of COVID-19 vaccines with other vaccines across different age groups, including concurrent administration with high dose or adjuvanted influenza vaccine.
7. Further evaluation on the optimal timing and trigger for the initiation of potential future booster dose recommendations, as well as evaluation of potential risks associated with providing booster doses earlier than necessary.
8. Continuous monitoring of vaccine coverage in Canada, for COVID-19 vaccines and other routine vaccines, particularly in the context of COVID-19 vaccine booster doses and including consideration of measures that may reduce the risk of disparities in vaccine confidence and uptake across different sub-populations.
9. Continuous monitoring of epidemiology, SARS-CoV-2 variants, and seasonal trends to inform future programs.
based on factors not isolated to strength of evidence |
Guidance on the use of COVID-19 vaccines in the fall of 2023
=============================================================
[Download in PDF format](/content/dam/phac-aspc/documents/services/publications/vaccines-immunization/national-advisory-committee-immunization-guidance-use-covid-19-vaccines-fall-2023/statement.pdf)
(440 KB, 20 pages)
**Organization:** [Health Canada](/en/services/health.html) or [Public Health Agency of Canada](/en/public-health.html)
**Date published:** July 11, 2023
**Cat.:** HP5-159/1-2023E-PDF
**ISBN:** 978-0-660-49305-3
**Pub.:** 230214
Publication date: July 11, 2023
On this page
------------
* [Preamble](#_Preamble)
* [Background](#_Background)
* [Methods](#_Methods)
* [Overview of evidence](#_Overview_of_Evidence)
+ [Epidemiology](#_Epidemiology)
+ [Vaccine protection](#_Vaccine_protection)
- [Duration of vaccine protection of Omicron-containing bivalent mRNA vaccines](#_Duration_of_vaccine)
- [VE in individuals with hybrid immunity](#_VE_in_individuals)
- [Vaccination of individuals who are pregnant](#_Vaccination_of_individuals)
- [Post-COVID-19 condition](#_Post-COVID-19_Condition)
+ [Safety of Omicron-containing bivalent mRNA COVID-19 vaccines](#_Safety_of_Omicron-containing)
+ [Concurrent administration with influenza vaccination](#_Concurrent_administration_with)
+ [Ethics, equity, feasibility, and acceptability (EEFA)](#_Ethics,_equity,_feasibility,)
+ [Other considerations](#_Other_considerations)
* [Recommendations](#_Recommendations)
* [Research priorities](#_Research_priorities)
* [Table 1. Strength of NACI recommendations](#_Table_1._Strength)
* [Acknowledgments](#_Acknowledgments)
* [References](#_References)
Preamble
--------
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI’s independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC’s Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Background
----------
On January 20, 2023, the National Advisory Committee on Immunization (NACI) published [Guidance on COVID-19 vaccine booster doses: Initial considerations for 2023](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-covid-19-vaccine-booster-doses-initial-considerations-2023.html), followed by [Guidance on an additional COVID-19 booster dose in the spring of 2023 for individuals at high risk of severe illness due to COVID-19](/en/public-health/services/publications/vaccines-immunization/national-advisory-committee-immunization-guidance-additional-covid-19-booster-dose-spring-2023-individuals-high-risk-severe-illness-due-covid-19.html) on March 3, 2023.
Since then, the World Health Organization (WHO) has determined that COVID-19 is an established and ongoing health issue and no longer constitutes a public health emergency of international concern[Footnote 1](#fn1). Transition to the long-term management of the COVID-19 pandemic is now needed, but there continue to be uncertainties such as the ongoing epidemiology of COVID-19, duration of protection from current COVID-19 booster doses and previous infection, and vaccine effectiveness (VE) of future vaccines.
On May 18, 2023, the WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) released recommendations for updates to COVID-19 vaccine antigen composition[Footnote 2](#fn2). An approach recommended by TAG-CO-VAC is a monovalent XBB.1 descendent lineage, such as XBB.1.5 or alternatively XBB.1.16. The International Coalition of Medicines Regulatory Authorities (ICMRA), European Centre for Disease Prevention (ECDC), the European Medicines Agency (EMA), and the US Food and Drug Administration Vaccines and Related Biological Products Advisory Committee (FDA VRBPAC) have also released decisions supporting XBB as a candidate for the COVID-19 vaccine composition update. Manufacturers have indicated that new COVID-19 vaccine formulations are in development and products are forthcoming.
Although seasonality of SARS-CoV-2 has not been established, other respiratory viruses such as influenza and respiratory syncytial virus (RSV) typically increase in the fall and winter months. To help reduce the impact of COVID-19 on the health system while other respiratory viruses are circulating and with the expected availability of a new COVID-19 vaccine formulation, NACI is providing guidance on the use of COVID-19 vaccines to inform planning for a vaccination program starting in fall 2023.
Methods
-------
Following preliminary discussions on April 28, 2023, the NACI COVID-19 Working Group and full NACI membership reviewed, on May 23, 2023 and June 6, 2023 respectively, the available evidence on epidemiology, vaccine protection, hybrid immunity, safety, and concurrent administration of COVID-19 vaccine with the seasonal influenza vaccine. Preliminary modelling data were also considered, as well as equity, feasibility and acceptability considerations for a fall 2023 COVID-19 vaccination program. NACI approved these recommendations on June 26, 2023.
For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to NACI: [Statements and publications](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci.html) and the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) of the [Canadian Immunization Guide](/en/public-health/services/canadian-immunization-guide.html) (CIG).
Further information on [NACI’s process and procedures](file:///C:/Users/Shismail/AppData/Local/Microsoft/Windows/INetCache/Content.Outlook/W1DATXQZ/10.1016/j.vaccine.2010.02.035) is available elsewhere[Footnote 3](#fn3)[Footnote 4](#fn4).
Overview of evidence
--------------------
Available scientific literature (published or pre-print) as of May 19, 2023 is summarized below.
### Epidemiology
* The evolutionary trajectory of SARS-CoV-2, including the emergence of novel variants of concern (VOCs), is uncertain and seasonality of SARS-CoV-2 has not been established.
* Recombinant XBB\* sub-lineages continue to circulate in Canada and globally. XBB.1.5\* is the most prevalent lineage in Canada but is declining as of May 19, 2023 with increases in other XBB\* sub-lineages, such as XBB.1.16[Footnote 5](#fn5).
* Seroepidemiologic studies demonstrate high levels of antibodies to spike antigen attributed to past COVID-19 vaccination and/or SARS-CoV-2 infection in the Canadian population[Footnote 6](#fn6).
* Since the fall of 2022, national surveillance data has shown a surge in COVID-19 cases from late September to November 2022, and a smaller surge in December 2022 and January 2023. Weekly rates and number of cases, hospitalizations and deaths have shown gradual decreases since January 2023, and have been relatively stable up to May 17, 2023[Footnote 7](#fn7).
* Rates of hospitalizations and deaths in Canada continue to be highest for adults 65 years of age and older, with risk increasing with age and highest among those ≥80 years and those who are unvaccinated. Among those under 18 years of age, rates of hospitalizations are highest in children under 1 year of age. Rates of infection and severe disease are lowest for those recently vaccinated[Footnote 8](#fn8) and those with hybrid immunity, particularly if the previous infection was with a more recent Omicron strain[Footnote 9](#fn9) [Footnote 10](#fn10) [Footnote 11](#fn11) [Footnote 12](#fn12) [Footnote 13](#fn13) [Footnote 14](#fn14) [Footnote 15](#fn15) [Footnote 16](#fn16) [Footnote 17](#fn17) [Footnote 18](#fn18) [Footnote 19](#fn19) .
* In addition to age, vaccination status and prior history of SARS-CoV-2 infection, studies looking at risk factors continue to show individuals with comorbidities are at higher risk for severe outcomes due to COVID-19 in adults[Footnote 20](#fn20). Evidence on risk factors for severe COVID-19 illness in children is limited given the much lower incidence of severe illness in this population[Footnote 21](#fn21).
### Vaccine protection
#### Duration of vaccine protection of Omicron-containing bivalent mRNA vaccines
* Evidence from the US assessing VE of the BA.4/5 bivalent vaccine show emerging trends in waning vaccine protection against Omicron SARS-CoV-2 infection and hospitalization as was observed with the original monovalent vaccine[Footnote 22](#fn22)[Footnote 23](#fn23). Waning protection against severe disease conferred by a bivalent booster dose has also been reported in a Finnish study (pre-print) in adults 65 years of age and older[Footnote 24](#fn24).
* Preliminary data from Ontario (preprint) demonstrates that short-term (<90 to 119 days) VE against severe outcomes in community dwelling adults 50 years of age and older was similar between those receiving original and bivalent mRNA vaccine booster doses and between the available vaccine products (Moderna Spikevax original or bivalent BA.1 and Pfizer-BioNTech Comirnaty original or bivalent BA.4/5) during a period when BA.5 was the predominant Omicron sub-lineage and BQ.1 was emerging[Footnote 25](#fn25).
* There are no data available on the duration of vaccine protection of bivalent mRNA vaccines in children and adolescents. The duration of vaccine protection of the original monovalent mRNA vaccines against infection and severe disease in children and adolescents has been very similar to the trends observed in adults.
+ Several studies have reported waning VE against Omicron infection or symptomatic infection of original monovalent Pfizer-BioNTech Comirnaty in children 5 to 11 years of age (from approximately 40-70% to 20-40% within two months post vaccination with the primary series)[Footnote 26](#fn26) [Footnote 27](#fn27)[Footnote 28](#fn28)[Footnote 29](#fn29)[Footnote 30](#fn30) [Footnote 31](#fn31) [Footnote 32](#fn32) [Footnote 33](#fn33) [Footnote 34](#fn34) , and of any original monovalent mRNA primary series in adolescents (from approximately 50-80% to 20-60% within two months post vaccination)[Footnote 30](#fn30) [Footnote 34](#fn34) [Footnote 35](#fn35) [Footnote 36](#fn36)[Footnote 37](#fn37) . Limited evidence has also shown waning VE against severe disease due to Omicron[Footnote 26](#fn26) [Footnote 31](#fn31) [Footnote 32](#fn32) [Footnote 35](#fn35) [Footnote 37](#fn37)
+ There is emerging evidence of waning VE against infection following the primary series in children 6 months to under 5 years of age[Footnote 26](#fn26) [Footnote 38](#fn38).
+ There is limited evidence that short term VE (1 to 3 months post-booster) against Omicron infection is restored after an original monovalent booster dose in children and adolescents 5 years of age and older[Footnote 30](#fn30) [Footnote 33](#fn33) [Footnote 37](#fn37) , as well as subsequent waning protection after the booster dose[Footnote 30](#fn30) [Footnote 39](#fn39).
#### VE in individuals with hybrid immunity
* Hybrid immunity results from ≥1 exposure(s) from vaccination and ≥1 exposure(s) from SARS-CoV-2 infection (before or after vaccination). Earlier NACI statements have summarized evidence demonstrating that previous infection and vaccination may provide superior protection against VOCs, including Omicron, compared with vaccination alone, or previous SARS-CoV-2 infection without vaccination[Footnote 9](#fn9) [Footnote 10](#fn10) [Footnote 11](#fn11) [Footnote 12](#fn12) [Footnote 13](#fn13) [Footnote 14](#fn14) [Footnote 15](#fn15) [Footnote 16](#fn16) [Footnote 17](#fn17) .
* Data have emerged estimating the relative VE of an Omicron-containing bivalent mRNA booster compared to those who did not receive a bivalent booster during a period when BA.5 was the predominant subvariant and stratified by prior documented infection status[Footnote 18](#fn18) [Footnote 19](#fn19) . The studies demonstrate that the bivalent booster provided additional protection relative to the previous original monovalent booster dose in those without previous SARS-CoV-2 infection and in those with more distant previous infection.
+ A study in the Netherlands assessed relative VE of the bivalent BA.1 mRNA COVID-19 vaccine against SARS-CoV-2 Omicron infection among adults 18 to 85 years of age who had previously received primary vaccination and one or two monovalent booster doses. The relative VE of a BA.1 bivalent booster against infection in adults 18-59 years of age was highest in those with an earlier prior (pre-Omicron) infection (44%; 95% confidence interval [CI]: 13 to 64%), followed by those without a prior infection (32%; 95% CI: 14 to 47%), and lowest in those with an Omicron infection (20%; 95% CI: −7 to 40%). This trend was also observed in adults 60 to 85 years of age, with lower relative VE estimates[Footnote 18](#fn18) .
+ A study in Italy assessed relative VE of the bivalent BA.4/5 mRNA COVID-19 vaccine against severe COVID-19 disease in adults 60 years of age and older who had previously received one monovalent booster[Footnote 19](#fn19) . The relative VE of a BA.4/5 bivalent booster against severe COVID-19 disease was comparable between those with no prior infection (59%; 95% CI: 55 to 63%) and those with earlier prior pre-Omicron or Omicron infection (i.e., prior infection that occurred 27 to 39 weeks earlier and was predominantly BA.1 had a relative VE of 62%; 95% CI: 43 to 74% and prior infection 40 or more weeks earlier and was predominantly original and Alpha strains had a relative VE of 62%; 95% CI: 38 to 76%). Relative VE in those with prior infection occurring 17 to 26 weeks earlier was lowest but also imprecise (10%; 95% CI: −44 to 44%; predominantly BA.5 or BA.2 infection).
+ In the above studies, hybrid immunity from a previous original monovalent booster in the context of a more recent Omicron infection were not improved by a bivalent booster, possibly because protection from hybrid immunity remained high. Protection from hybrid immunity in vaccinated individuals who had an earlier infection and/or earlier vaccination with the original monovalent COVID-19 vaccine would have had a longer time to wane, thereby contributing to higher relative VE after receiving a bivalent booster.
#### Vaccination of individuals who are pregnant
* Studies continue to support vaccination during pregnancy. Vaccination with original mRNA COVID-19 vaccines has been shown to confer protection to the pregnant individual as well as protection against Omicron SARS-CoV-2 infection and hospitalization in infants <6 months of age (who are not yet eligible for vaccination) when compared to infants of individuals who were unvaccinated or did not receive at least one dose (either dose 2 of a primary series or a booster dose) of COVID-19 vaccine during pregnancy[Footnote 40](#fn40)[Footnote 41](#fn41) [Footnote 42](#fn42)[Footnote 43](#fn43). Protection in infants was highest in the first two months of life and decreased by four to six months of age[Footnote 41](#fn41) .
* Systematic reviews assessing the safety of COVID-19 vaccines during pregnancy have not identified any adverse effects specific to pregnancy.
* No evidence on VE against infant outcomes is available for vaccination with bivalent mRNA vaccines in persons who are pregnant.
#### Post-COVID-19 condition
* Post COVID-19 condition (PCC) is a condition in which symptoms following a SARS-CoV-2 infection persist for more than 8 weeks and are present for 12 or more weeks following the acute phase. Emerging evidence suggests that individuals may be less likely to report experiencing PCC symptoms if infected during the Omicron period compared to those infected with a pre-Omicron variant[Footnote 44](#fn44) [Footnote 45](#fn45) [Footnote 46](#fn46) . Nonetheless it is estimated that approximately 10 to 20% of people who are infected with SARS-CoV-2 develop PCC[Footnote 47](#fn47)[Footnote 48](#fn48).
* To the extent that vaccination prevents infection, it also prevents PCC as those who do not become infected do not develop PCC. In addition, there is evidence that those who are vaccinated with at least two doses of the monovalent original COVID-19 vaccine before becoming infected are less likely to develop PCC than those who are not vaccinated before infection. Estimates of PCC protection from pre-infection vaccination vary between studies with a systematic review noting approximately one-third less PCC among two-dose vaccinated people compared to unvaccinated people (OR, 0.64; 95% CI, 0.45–0.92%)[Footnote 49](#fn49) . A third dose of COVID-19 vaccine may offer additional protection against PCC compared to receiving one to two doses[Footnote 50](#fn50)[Footnote 51](#fn51). Vaccination has not been associated with a higher risk of developing PCC or worsening PCC symptoms.
* Evidence of any positive benefit on PCC from vaccination post-infection is limited[Footnote 44](#fn44) [Footnote 45](#fn45) [Footnote 46](#fn46) [Footnote 49](#fn49) .
* There are no studies to date evaluating the effectiveness of bivalent vaccines specifically in reducing the risk of developing PCC.
#### Safety of Omicron-containing bivalent mRNA COVID-19 vaccines
* The safety profile of the bivalent mRNA COVID-19 vaccine boosters is comparable to that of original mRNA COVID-19 vaccine boosters among individuals in the authorized age group for mRNA booster doses (i.e., those 5 years and older).
* A statistical signal for ischemic stroke among adults 65 years of age and older was detected in the US Vaccine Safety Datalink (VSD) following administration of Pfizer-BioNTech Comirnaty BA.4/5. This signal has weakened over time since it was first detected in October 2022 and is no longer being detected. It was not noted in the VSD for the Moderna bivalent booster[Footnote 52](#fn52) .
* No evidence of a safety signal has been detected for ischemic stroke with either mRNA COVID-19 bivalent boosters in other US safety surveillance systems (as of April 2, 2023)[Footnote 52](#fn52) , nor in Canada (as of April 28, 2023)[Footnote 53](#fn53), other international regulatory and public health safety monitoring systems, or in global vaccine safety monitoring by Pfizer-BioNTech. A study from England published on June 15, 2023 assessing BA.1 bivalent mRNA vaccines and stroke in adults 50 years of age and older also found no evidence of increased risk of stroke, including among individuals who concurrently received an influenza vaccine[Footnote 54](#fn54).
* Further investigation into the signal in the VSD system revealed that it was seen with concurrent administration of Pfizer-BioNTech bivalent vaccine and high-dose or adjuvanted influenza vaccines, but not with concomitant administration with standard-dose influenza vaccine or when the bivalent Pfizer-BioNTech vaccine was administered alone.
* Recommendations in the US to give concurrent COVID-19 and influenza vaccines have not changed because of the potential signal identified in VSD. Monitoring regarding this safety signal continues.
#### Concurrent administration with influenza vaccination
* Except for the ischemic stroke potential safety signal from the VSD noted above, no safety concerns have been identified to date with the concurrent administration of COVID-19 vaccines and influenza vaccines[Footnote 55](#fn55) [Footnote 56](#fn56) [Footnote 57](#fn57).
* Higher reactogenicity has been observed following concurrent administration of original mRNA COVID-19 vaccines with influenza vaccination compared to influenza vaccination alone, but reactogenicity was comparable to receipt of the COVID-19 vaccine alone[Footnote55](#fn55) .
* Two studies in health care workers have observed a reduced immunologic response to the Pfizer-BioNTech Comirnaty original vaccine when concurrently administered with a quadrivalent influenza vaccine[Footnote 56](#fn56) [Footnote 58](#fn58). A reduced immunologic response was also noted in a clinical trial assessing concurrent administration of Novavax Nuvaxovid with influenza vaccines[Footnote 59](#fn59), without an impact on vaccine efficacy for Novavax Nuvaxovid. In another clinical trial, a reduced immune response was not observed in adults aged 65 years and older who received a third dose with Moderna Spikevax original at the same time as a high-dose quadrivalent influenza vaccine[Footnote 60](#fn60).
* NACI continues to monitor the safety of concurrent administration of COVID-19 vaccines and other vaccines, including the seasonal influenza vaccine.
#### Ethics, equity, feasibility, and acceptability (EEFA)
* Over the course of the COVID-19 pandemic, many NACI recommendations have been put forward to address the complex vaccine product landscape, reflecting the knowns and unknowns in the available evidence on vaccine protection against SARS-CoV-2-related outcomes, including infection, and symptomatic and severe disease. The transition to a more sustainable approach to the long-term management of COVID-19 includes learning how to manage the COVID-19 vaccine program alongside other public health priorities and longstanding vaccination programs.
* Where possible, simplifying and streamlining the COVID-19 vaccine recommendations for a fall program would facilitate implementation and ease of communication for both provincial and territorial vaccination programs and individual health care providers. However, it continues to be important to highlight specific populations for whom vaccination is particularly important due to biological and/or social risk factors.
* Fewer severe outcomes of COVID-19 have been reported for children (i.e., hospitalizations due to COVID-19, ICU admission, and deaths) compared to older age groups, and COVID-19 vaccine uptake has been low to very low among children under 12 years of age (only 6% of children 6 months to 4 years and 40% of children 5 to 11 years of age have completed a primary series as of June 18, 2023)[Footnote 61](#fn61). While most children may have mild or no symptoms, some are at higher risk of severe disease due to COVID-19 or developing PCC. Individual benefit-risk assessments may favour vaccination based on factors including a child’s health status.
* In the fall of 2023, it is anticipated that jurisdictions will likely combine the COVID-19 and influenza vaccination campaigns for operational and logistical reasons. For all currently vaccine-eligible age-groups (i.e., 6 months of age and older for the primary series; 5 years of age and older for booster doses), concurrent administration of any dose of a COVID-19 vaccine with other vaccines (including the seasonal influenza vaccine) has the potential to increase program efficiency and may also increase vaccine coverage. The clinical significance of somewhat lower immunogenicity noted in some studies with concomitant COVID-19 and influenza vaccine administration is uncertain.
* There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions.
#### Other considerations
* TAG-CO-VAC has advised that new COVID-19 vaccine formulations should aim to induce antibody responses that neutralize XBB descendent lineages (such as XBB.1.5 or alternatively XBB.1.16), which are the lineages predominantly circulating globally at present. These sublineages have also been demonstrated to be some of the most immune evasive variants to date, based on neutralizing antibody data from individuals vaccinated with current COVID-19 vaccines. TAG-CO-VAC also advised that future formulations of COVID-19 vaccines should move away from inclusion of the original SARS-CoV-2 virus given that the strain is no longer circulating in humans[Footnote 2](#fn2).
* On June 15, 2023, US FDA VRBPAC recommended an update to the COVID-19 vaccine with a monovalent XBB\* targeted formulation after reviewing evidence on epidemiology and pre-clinical and clinical data showing that monovalent XBB-targeted vaccines had similar or slightly higher immune responses against XBB-derivatives compared to bivalent XBB-targeted vaccines[Footnote 62](#fn62).
* Changes to the vaccine formulations are anticipated; however, the vaccine products that will be available in the coming months have yet to be determined.
* Modelling suggests that an additional vaccine dose offered in the fall of 2023 could be expected to prevent thousands of hospitalizations and deaths across the country over the next year. Modelled estimates are dependent on various assumptions, such as durability of protection from vaccination and/or infection and the possibility of a seasonal resurgence in infections.
Recommendations
---------------
Please see [Table 1](#_Table_1._Strength) for an explanation of strong versus discretionary NACI recommendations.
NACI continues to recommend COVID-19 vaccination for those who have not been immunized, as follows:
1. Individuals 5 years of age and older should be immunized with a primary series of an mRNA vaccine. **(Strong NACI recommendation)**
2. Children 6 months to under 5 years of age may be immunized with a primary series of an mRNA vaccine. **(Discretionary NACI recommendation)**
Regarding the product offered, when mRNA vaccines are used for the primary series, the bivalent Omicron-containing vaccines can be used for anyone 6 months of age and older. More information is available in the [NACI interim guidance on the use of bivalent Omicron-containing COVID-19 vaccines for primary series](/en/public-health/services/publications/vaccines-immunization/national-advisory-committee-immunization-interim-guidance-use-bivalent-omicron-containing-covid-19-vaccines-primary-series.html).
For **booster doses**, previously NACI has recommended that at least one booster dose should be offered to all adults 18 years of age and over, and adolescents 12 to 17 years of age who are at increased risk of severe illness, along with additional specific population recommendations in the [fall of 2022](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-covid-19-vaccine-booster-doses.html) and [spring of 2023](/en/public-health/services/publications/vaccines-immunization/national-advisory-committee-immunization-guidance-additional-covid-19-booster-dose-spring-2023-individuals-high-risk-severe-illness-due-covid-19.html).
Additional details including those pertaining to vaccine schedule (e.g., number of doses, interval between doses) and alternative vaccine products, are available in the [COVID-19 vaccine chapter](/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html) of the Canadian Immunization Guide and NACI [statements and publications](/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci.html).
3. **Beginning in the fall of 2023 for those previously vaccinated against COVID-19, NACI recommends a dose of the new formulation of COVID-19 vaccine for individuals in the authorized age group if it has been at least 6 months from the previous COVID-19 vaccine dose or known SARS-CoV-2 infection (whichever is later).**
**Immunization is particularly important for those at increased risk of COVID-19 infection or severe disease, for example:**
* **Adults 65 years of age or older**
* **Residents of long-term care homes and other congregate living settings**
* **Individuals with** [**underlying medical conditions**](/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/signs-symptoms-severity.html#a3) **that place them at higher risk of severe COVID-19**
* **Individuals who are pregnant**
* **Individuals in or from First Nations, Métis and Inuit communities\***
* **Members of racialized and other equity-deserving communities**
* **People who provide essential community services**
**(Strong NACI Recommendation)**
**\*** Autonomous decisions should be made by Indigenous Peoples with the support of healthcare and public health partners in accordance with the [United Nations Declaration on the Rights of Indigenous Peoples](https://www.justice.gc.ca/eng/declaration/fact-fiche.html).
**Rationale and additional considerations:**
* A booster dose starting in the fall of 2023 is expected to increase protection against SARS-CoV-2 infection and COVID-19 symptomatic and severe disease that has waned since the last booster vaccination or SARS-CoV-2 infection**.** Increased protection will help to reduce the impact of COVID-19 on the health system while other respiratory viruses, including influenza and RSV are circulating in the fall and winter of the 2023-2024 respiratory virus season.
* Prior infection along with vaccination (hybrid immunity) offers greater protection against infection and severe disease than vaccination or prior infection alone, particularly when hybrid immunity is in the context of a recent Omicron infection. For this reason, an additional dose of vaccine starting this fall is particularly important for those who have not been previously infected and have protection from vaccination alone. However, even with hybrid immunity, protection against infection will decrease over time and the duration of protection against severe disease varies between studies and is unknown in the context of currently circulating variants. There are no known safety risks with receiving a vaccine after a recent SARS-CoV-2 infection, although evidence shows that the antibody response is higher with longer intervals between infection and vaccination.
* Vaccination of individuals at higher risk for severe COVID-19 will help to reduce their risk of severe disease that could potentially result in hospitalization and death; thus it is particularly important for these individuals to receive a booster dose starting in the fall of 2023.
* Vaccination of individuals at lower risk for severe disease may provide additional benefit to those at higher risk through indirect protection, particularly shortly after vaccination and in the context of hybrid immunity when protection from infection is greatest. There could also be other benefits such as reducing the risk of PCC, but the extent and duration of the benefits are uncertain. Vaccination of health care providers and others who provide essential community services is expected to be important in maintaining health system capacity.
* Booster doses in the fall will be formulations updated to target more recent, immune‑evasive SARS-CoV-2 variants. Individuals vaccinated with the updated formulation are expected to benefit from a better immune response against these variants compared to current vaccines.
* mRNA vaccines remain the preferred COVID-19 vaccine product. A Novavax Nuvaxovid booster should be offered to those 18 years of age and over who are unwilling or unable to receive an mRNA vaccine if it has been at least 6 months from the previous COVID-19 vaccine dose or SARS-CoV-2 infection (whichever is later). Individuals waiting for a new formulation of Novavax Nuvaxovid should assess their individual risk if choosing to delay vaccination.
* COVID-19 vaccines may be given concurrently (i.e., same day), or at any time before or after, non-COVID-19 vaccines (including live and non-live vaccines).
* NACI will continue to monitor the safety and effectiveness of COVID-19 vaccines, including the safety of concurrent administration with other non-COVID-19 vaccines, such as the seasonal influenza vaccine.
NACI will review available information on the new vaccine formulations expected for the fall of 2023 and update recommendations as needed. NACI will continue to monitor the evidence, including SARS-CoV-2 epidemiology and duration of vaccine protection, particularly with regard to severe outcomes, to provide recommendations on the timing of subsequent booster doses if warranted.
Research priorities
-------------------
1. Continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of COVID-19 vaccines, including with the new formulation, through clinical trials and studies in real-world settings, including the degree and duration of protection conferred by each booster dose against circulating variants. The research should also consider the clinical implications of previous SARS-CoV-2 infection; repeated immunization; and outcomes after infection such as PCC.
2. Further evaluations of the optimal interval between dose administration, as well as further evaluations of the optimal interval between previous SARS-CoV-2 infection and vaccine dose administration.
3. Vigilant monitoring and reporting of adverse events of special interest, including myocarditis and/or pericarditis, to accurately inform potential risks associated with any future booster doses. Global collaboration should be prioritized to enable data sharing so decision makers around the world can weigh benefits and risks of additional booster doses of COVID-19 vaccines.
4. Continuous monitoring of COVID-19 epidemiology in children, including risk factors for severe outcomes and long-term consequences of infection with SARS-CoV-2.
5. Continuous monitoring of COVID-19 epidemiology and VE in special populations at high risk of severe outcomes or long-term consequences of infection with SARS-CoV-2.
6. Further evaluations on the safety, immunogenicity, and effectiveness on the concurrent administration of COVID-19 vaccines with other vaccines across different age groups, including concurrent administration with high dose or adjuvanted influenza vaccine.
7. Further evaluation on the optimal timing and trigger for the initiation of potential future booster dose recommendations, as well as evaluation of potential risks associated with providing booster doses earlier than necessary.
8. Continuous monitoring of vaccine coverage in Canada, for COVID-19 vaccines and other routine vaccines, particularly in the context of COVID-19 vaccine booster doses and including consideration of measures that may reduce the risk of disparities in vaccine confidence and uptake across different sub-populations.
9. Continuous monitoring of epidemiology, SARS-CoV-2 variants, and seasonal trends to inform future programs.
Table 1. Strength of NACI recommendations
-----------------------------------------
| Strength of NACI recommendation
based on factors not isolated to strength of evidence
(e.g., public health need) | Strong | Discretionary |
| --- | --- | --- |
| **Wording** | "**should/should not** be offered" | "**may/may not** be offered" |
| **Rationale** | Known/anticipated advantages outweigh known/anticipated disadvantages ("should"),**or** known/anticipated disadvantages outweigh known/anticipated advantages ("should not"). | Known/anticipated advantages are closely balanced with known/anticipated disadvantages, **or** uncertainty in the evidence of advantages and disadvantages exists. |
| **Implication** | A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present. | A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable. |
Acknowledgments
---------------
**This statement was prepared by**: E Wong, B Warshawsky, MC Tunis, R Harrison, S Wilson, and S Deeks, on behalf of NACI.
**NACI gratefully acknowledges the contribution of**: K Ramotar, C Mauviel, M Salvadori, R Krishnan, J Zafack, SH Lim, K Young, E Tice, and the NACI Secretariat.
**NACI members:**S Deeks (Chair), R Harrison (Vice-Chair), M Andrew, J Bettinger, N Brousseau, H Decaluwe, P De Wals, E Dubé, V Dubey, K Hildebrand, K Klein, M O’Driscoll, J Papenburg, A Pham-Huy, B Sander, and S Wilson.
**Liaison representatives:** L Bill / M Nowgesic (Canadian Indigenous Nurses Association), LM Bucci (Canadian Public Health Association), S Buchan (Canadian Association for Immunization Research and Evaluation), E Castillo (Society of Obstetricians and Gynaecologists of Canada), J Comeau (Association of Medical Microbiology and Infectious Disease Canada), M Lavoie (Council of Chief Medical Officers of Health), J MacNeil (Centers for Disease Control and Prevention, United States), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), M Osmack (Indigenous Physicians Association of Canada), J Potter (College of Family Physicians of Canada), A Ung (Canadian Pharmacists Association).
**Ex-officio representatives:**V Beswick-Escanlar (National Defence and the Canadian Armed Forces), E Henry (Centre for Immunization and Respiratory Infectious Diseases (CIRID), PHAC), M Lacroix (Public Health Ethics Consultative Group, PHAC), P Fandja (Marketed Health Products Directorate, Health Canada), M Su (COVID-19 Epidemiology and Surveillance, PHAC), S Ogunnaike-Cooke (CIRID, PHAC), C Pham (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada), M Routledge (National Microbiology Laboratory, PHAC), and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada).
**NACI COVID-19 Vaccine Working Group**
**Members:** S Wilson (Chair), M Adurogbangba, M Andrew, M Baca-Estrada, Y-G Bui, H Decaluwe, P De Wals, V Dubey, S Hosseini-Moghaddam, M Miller, D Moore, S Oliver, and E Twentyman.
**PHAC Participants:** E Abrams, P Doyon-Plourde, N Forbes, M Hersi, N Islam, SJ Ismail, C Jensen, R Krishnan, SH Lim, R Neves Miranda, J Montroy, R Pless, M Salvadori, E Tice, A Tuite, MC Tunis, B Warshawsky, E Wong, R Ximenes, K Young, and J Zafack.
References
----------
Footnote 1
Statement on the fifteenth meeting of the IHR (2005) Emergency Committee on the COVID-19 pandemic [Internet]. Geneva (CH): World Health Organization; 2023 May 05 [cited 2023 May 25]. Available from: https://www.who.int/news/item/05-05-2023-statement-on-the-fifteenth-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic.
[Return to footnote 1](#fn1-rf)
Footnote 2
Statement on the antigen composition of COVID-19 vaccines [Internet]. Geneva (CH): World Health Organization; 2023 May 18 [cited 2023 May 29]. Available from: https://www.who.int/news/item/18-05-2023-statement-on-the-antigen-composition-of-covid-19-vaccines.
[Return to footnote 2](#fn2-rf)
Footnote 3
Ismail SJ, Langley JM, Harris TM, Warshawsky BF, Desai S, FarhangMehr M. Canada's National Advisory Committee on Immunization (NACI): Evidence-based decision-making on vaccines and immunization. Vaccine. 2010;28:A58,63. doi: 10.1016/j.vaccine.2010.02.035.
[Return to footnote 3](#fn3-rf)
Footnote 4
Ismail SJ, Hardy K, Tunis MC, Young K, Sicard N, Quach C. A framework for the systematic consideration of ethics, equity, feasibility, and acceptability in vaccine program recommendations. Vaccine. 2020 Aug 10;38(36):5861,5876. doi: 10.1016/j.vaccine.2020.05.051.
[Return to footnote 4](#fn4-rf)
Footnote 5
Public Health Agency of Canada. COVID-19 epidemiology update: Testing and variants. Data cut-off 2023 May 19 [Internet]. Ottawa (ON): Government of Canada; 2023 May 19 [cited 2023 May 25]. Available from: https://health-infobase.canada.ca/covid-19/testing-variants.html.
[Return to footnote 5](#fn5-rf)
Footnote 6
Seroprevalence in Canada. Data cut-off 2023 March 31 [Internet]. Montreal (QC): COVID-19 Immunity Task Force (CITF); 2023 Mar 31 [cited 2023 May 22]. Available from: https://www.covid19immunitytaskforce.ca/seroprevalence-in-canada/.
[Return to footnote 6](#fn6-rf)
Footnote 7
COVID-19 epidemiology update: Current situation. Data cut-off May 17, 2023 [Internet]. Ottawa (ON): Government of Canada; 2023 May 17 [cited 2023 May 25]. Available from: https://health-infobase.canada.ca/covid-19/current-situation.html.
[Return to footnote 7](#fn7-rf)
Footnote 8
Public Health Agency of Canada. Surveillance and Epidemiology Division, Centre for Immunization and Respiratory Infectious Diseases, Infectious Disease Prevention and Control Branch. Data cut-off 2023 May 26. Ottawa (ON): PHAC; 2023 May 26.
[Return to footnote 8](#fn8-rf)
Footnote 9
Bobrovitz N, Ware H, Ma X, Li Z, Hosseini R, Cao C, et al. Protective effectiveness of previous SARS-CoV-2 infection and hybrid immunity against the omicron variant and severe disease: a systematic review and meta-regression. Lancet Infect Dis. 2023 May;23(5). https://doi.org/10.1016/S1473-3099(22)00801-5.
[Return to footnote 9](#fn9-rf)
Footnote 10
Carazo S, Skowronski DM, Brisson M, Barkati S, Sauvageau C, Brousseau N, et al. Protection against omicron (B.1.1.529) BA.2 reinfection conferred by primary omicron BA.1 or pre-omicron SARS-CoV-2 infection among health-care workers with and without mRNA vaccination: a test-negative case-control study. Lancet Infect Dis. 2023 Jan;23(1):45-55. https://doi.org/10.1016/S1473-3099(22)00578-3.
[Return to footnote 10](#fn10-rf)
Footnote 11
Carazo S, Skowronski DM, Brisson M, Sauvageau C, Brousseau N, Fafard J, et al. Prior infection- and/or vaccine-induced protection against Omicron BA.1, BA.2 and BA.4/BA.5-related hospitalisations in older adults: a test-negative case-control study in Quebec, Canada. medRxiv. 2022 Dec 27. https://doi.org/10.1101/2022.12.21.22283740.
[Return to footnote 11](#fn11-rf)
Footnote 12
Altarawneh HN, Chemaitelly H, Ayoub HH, Tang P, Hasan MR, Yassine HM, et al. Effects of Previous Infection and Vaccination on Symptomatic Omicron Infections. N Engl J Med. 2022 Jul 7;387(1):21-34. https://doi.org/10.1056/NEJMoa2203965.
[Return to footnote 12](#fn12-rf)
Footnote 13
Cerqueira-Silva T, de Araujo Oliveira V, Paixão ES, Florentino PTV, Penna GO, Pearce N, et al. Vaccination plus previous infection: protection during the omicron wave in Brazil. Lancet Infect Dis. 2022 May 16. https://doi.org/10.1016/S1473-3099(22)00288-2.
[Return to footnote 13](#fn13-rf)
Footnote 14
Chin ET, Leidner D, Lamson L, Lucas K, Studdert DM, Goldhaber-Fiebert JD, et al. Protection against Omicron from Vaccination and Previous Infection in a Prison System. N Engl J Med. 2022 Nov 10;387(19):1770-82. https://doi.org/10.1056/NEJMoa2207082.
[Return to footnote 14](#fn14-rf)
Footnote 15
Vicentini M, Venturelli F, Mancuso P, Bisaccia E, Zerbini A, Massari M, et al. Risk of SARS-CoV-2 Reinfection by Vaccination Status, Predominant Variant, and Time from Previous Infection: A Cohort Study in Italy. SSRN. 2022 Jun 09. https://doi.org/10.2139/ssrn.4132329.
[Return to footnote 15](#fn15-rf)
Footnote 16
Lind ML, Robertson AJ, Silva J, Warner F, Coppi AC, Price N, et al. Effectiveness of Primary and Booster COVID-19 mRNA Vaccination against Omicron Variant SARS-CoV-2 Infection in People with a Prior SARS-CoV-2 Infection. medRxiv. 2022 Apr 25. https://doi.org/10.1101/2022.04.19.22274056.
[Return to footnote 16](#fn16-rf)
Footnote 17
Spreco A, Dahlström Ö, Jöud A, Nordvall D, Fagerström C, Blomqvist E, et al. Effectiveness of the BNT162b2 mRNA Vaccine Compared with Hybrid Immunity in Populations Prioritized and Non-Prioritized for COVID-19 Vaccination in 2021-2022: A Naturalistic Case-Control Study in Sweden. Vaccines (Basel). 2022 Aug 7;10(8):1273. https://doi.org/10.3390/vaccines10081273.
[Return to footnote 17](#fn17-rf)
Footnote 18
Huiberts AJ, Gier Bd, Hoeve CE, Melker HEd, Hahné SJ, Hartog Gd, et al. Effectiveness of bivalent mRNA booster vaccination against SARS-CoV-2 Omicron infection, the Netherlands, September to December 2022. Eurosurveillance. 2023 Feb 16;28(7):2300087. https://doi.org/10.2807/1560-7917.ES.2023.28.7.2300087
[Return to footnote 18](#fn18-rf)
Footnote 19
Fabiani M, Mateo-Urdiales A, Sacco C, Fotakis EA, Rota MC, Petrone D, et al. Protection against severe COVID-19 after second booster dose of adapted bivalent (original/Omicron BA.4-5) mRNA vaccine in persons ≥ 60 years, by time since infection, Italy, 12 September to 11 December 2022. Eurosurveillance. 2023 Feb 23;28(8):2300105. https://doi.org/10.2807/1560-7917.ES.2023.28.8.2300105.
[Return to footnote 19](#fn19-rf)
Footnote 20
RESPIPLUS. Personal Communication. RESPIPLUS Review. 2023 May 02.
[Return to footnote 20](#fn20-rf)
Footnote 21
Kulkarni D, Ismail NF, Zhu F, Wang X, del Carmen Morales G, Allen KE, et al. Epidemiology and Clinical Features of SARS-CoV-2 Infection in Children and Adolescents in the Pre-Omicron Era: A Global Systematic Review and Meta-Analysis. SSRN Prepub. 2023 Mar 26. https://doi.org/10.2139/ssrn.4397814.
[Return to footnote 21](#fn21-rf)
Footnote 22
Link-Gelles R. COVID-19 vaccine effectiveness updates [slides presented at Advisory Committee on Immunization Practices (ACIP) meeting April 19, 2023] [Internet]. Atlanta (GA): Centers for Disease Control and Prevention (CDC); 2023 Apr 19 [cited 2023 May 30]. Available from: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-04-19/05-COVID-Link-Gelles-508.pdf.
[Return to footnote 22](#fn22-rf)
Footnote 23
Lin D, Xu Y, Gu Y, Zeng D, Sunny SK, Moore Z. Durability of Bivalent Boosters against Omicron Subvariants. The New England journal of medicine. 2023 May 11;388(19):1818-20. https://doi.org/10.1056/NEJMc2302462.
[Return to footnote 23](#fn23-rf)
Footnote 24
Poukka E, Nohynek H, Goebeler S, Leino T, Baum U. Bivalent booster effectiveness against severe COVID-19 outcomes in Finland, September 2022 – March 2023. medRxiv. 2023 May 08. https://doi.org/10.1101/2023.03.02.23286561.
[Return to footnote 24](#fn24-rf)
Footnote 25
Grewal, Buchan, Nguyen, Nasreen, Austin, Brown, et al. Effectiveness of mRNA COVID-19 monovalent and bivalent vaccine booster doses against Omicron severe outcomes among adults aged ≥50 years in Ontario, Canada. medRxiv. 2023 Apr 11. https://doi.org/10.1101/2023.04.11.23288403.
[Return to footnote 25](#fn25-rf)
Footnote 26
Lin D, Xu Y, Gu Y, Zeng D, Wheeler B, Young H, et al. Effectiveness of Vaccination and Previous Infection Against Omicron Infection and Severe Outcomes in Children Under 12 Years of Age. medRxiv. 2023 Jan 19. https://doi.org/10.1101/2023.01.18.23284739.
[Return to footnote 26](#fn26-rf)
Footnote 27
Jang EJ, Choe YJ, Kim RK, Park Y. BNT162b2 Vaccine Effectiveness Against the SARS-CoV-2 Omicron Variant in Children Aged 5 to 11 Years. JAMA Pediatrics. 2023 Mar 01;177(3):319-20. https://doi.org/10.1001/jamapediatrics.2022.5221.
[Return to footnote 27](#fn27-rf)
Footnote 28
Sacco C, Del Manso M, Mateo-Urdiales A, Rota MC, Petrone D, Riccardo F, et al. Effectiveness of BNT162b2 vaccine against SARS-CoV-2 infection and severe COVID-19 in children aged 5–11 years in Italy: a retrospective analysis of January–April, 2022. The Lancet (British edition). 2022 Jul 09;400(10346):97-103. https://doi.org/10.1016/S0140-6736(22)01185-0.
[Return to footnote 28](#fn28-rf)
Footnote 29
Tan SHX, Cook AR, Heng D, Ong B, Lye DC, Tan KB. Effectiveness of BNT162b2 Vaccine against Omicron in Children 5 to 11 Years of Age. New England Journal of Medicine. 2022 Aug 11;387(6):525-32. https://doi.org/10.1056/NEJMoa2203209.
[Return to footnote 29](#fn29-rf)
Footnote 30
Cocchio S, Zabeo F, Tremolada G, Facchin G, Venturato G, Marcon T, et al. COVID-19 Vaccine Effectiveness against Omicron Variant among Underage Subjects: The Veneto Region’s Experience. Vaccines (Basel). 2022 Aug 20;10(8):1362. https://doi.org/10.3390/vaccines10081362.
[Return to footnote 30](#fn30-rf)
Footnote 31
Piché-Renaud P, Swayze S, Buchan SA, Wilson SE, Austin PC, Morris SK, et al. COVID-19 Vaccine Effectiveness Against Omicron Infection and Hospitalization. Pediatrics (Evanston). 2023 Mar 03;151(4):e2022059513. https://doi.org/10.1542/peds.2022-059513.
[Return to footnote 31](#fn31-rf)
Footnote 32
Lin D, Gu Y, Xu Y, Zeng D, Wheeler B, Young H, et al. Effects of Vaccination and Previous Infection on Omicron Infections in Children. New England Journal of Medicine. 2022 Sep 22;387(12):1141-3. https://doi.org/10.1056/NEJMc2209371.
[Return to footnote 32](#fn32-rf)
Footnote 33
Khan FL, Nguyen JL, Singh TG, Puzniak LA, Wiemken TL, Schrecker JP, et al. Estimated BNT162b2 Vaccine Effectiveness Against Infection With Delta and Omicron Variants Among US Children 5 to 11 Years of Age. JAMA Network Open. 2022 Dec 14;5(12):e2246915. https://doi.org/10.1001/jamanetworkopen.2022.46915.
[Return to footnote 33](#fn33-rf)
Footnote 34
Fleming-Dutra KE, Britton A, Shang N, Derado G, Link-Gelles R, Accorsi EK, et al. Association of Prior BNT162b2 COVID-19 Vaccination With Symptomatic SARS-CoV-2 Infection in Children and Adolescents During Omicron Predominance. JAMA : the journal of the American Medical Association. 2022 Jun 14;327(22):2210-9. https://doi.org/10.1001/jama.2022.7493.
[Return to footnote 34](#fn34-rf)
Footnote 35
Florentino PTV, Millington T, Cerqueira-Silva T, Robertson C, de Araújo Oliveira V, Júnior JBS, et al. Vaccine effectiveness of two-dose BNT162b2 against symptomatic and severe COVID-19 among adolescents in Brazil and Scotland over time: a test-negative case-control study. Lancet Infect Dis. 2022 -Nov;22(11):1577-86. https://doi.org/10.1016/S1473-3099(22)00451-0.
[Return to footnote 35](#fn35-rf)
Footnote 36
Ionescu IG, Skowronski DM, Sauvageau C, Chuang E, Ouakki M, Kim S, et al. BNT162b2 effectiveness against Delta & Omicron variants in teens by dosing interval and duration. medRxiv. 2022 Jul 13. https://doi.org/10.1101/2022.06.27.22276790.
[Return to footnote 36](#fn36-rf)
Footnote 37
Buchan SA, Nguyen L, Wilson SE, Kitchen SA, Kwong JC. Vaccine Effectiveness of BNT162b2 Against Delta and Omicron Variants in Adolescents. Pediatrics. 2022 Jun 16. https://doi.org/10.1542/peds.2022-057634
[Return to footnote 37](#fn37-rf)
Footnote 38
Fleming-Dutra KE, Ciesla AA, Roper LE, Smith ZR, Miller JD, Accorsi EK, et al. Preliminary Estimates of Effectiveness of Monovalent mRNA Vaccines in Preventing Symptomatic SARS-CoV-2 Infection Among Children Aged 3-5 Years - Increasing Community Access to Testing Program, United States, July 2022-February 2023. MMWR Morb Mortal Wkly Rep. 2023 Feb 17;72(7):177-82. https://doi.org/10.15585/mmwr.mm7207a3.
[Return to footnote 38](#fn38-rf)
Footnote 39
Yan VKC, Cheng FWT, Chui CSL, Lai FTT, Wong CKH, Li X, et al. Effectiveness of BNT162b2 and CoronaVac vaccines in preventing SARS-CoV-2 Omicron infections, hospitalizations, and severe complications in the pediatric population in Hong Kong: a case-control study. Emerging Microbes & Infections. 2023 Mar 15;12(1):2185455. https://doi.org/10.1080/22221751.2023.2185455.
[Return to footnote 39](#fn39-rf)
Footnote 40
Jorgensen SC, Hernandez A, Fell D, Austin PC, D’Souza R, Guttmann A, et al. Effectiveness of Maternal mRNA COVID-19 Vaccination During Pregnancy Against Delta and Omicron SARS-CoV-2 Infection and Hospitalization in Infants: A Test-Negative Design Study. SSRN Electronic Journal. 2022 Nov 08. https://doi.org/10.2139/ssrn.4246651.
[Return to footnote 40](#fn40-rf)
Footnote 41
Zerbo O, Ray GT, Fireman B, Layefsky E, Goddard K, Lewis E, et al. Maternal SARS-CoV-2 vaccination and infant protection against SARS-CoV-2 during the first six months of life. Nat Commun. 2023 Feb 28;14(1):1-8. https://doi.org/10.1038/s41467-023-36547-4.
[Return to footnote 41](#fn41-rf)
Footnote 42
Lipschuetz M, Guedalia J, Cohen SM, Sompolinsky Y, Shefer G, Melul E, et al. Maternal third dose of BNT162b2 mRNA vaccine and risk of infant COVID-19 hospitalization. Nat Med. 2023 Mar 23;29(5):1155-63. https://doi.org/10.1038/s41591-023-02270-2.
[Return to footnote 42](#fn42-rf)
Footnote 43
Jorgensen SCJ, Hernandez A, Fell DB, Austin PC, D’Souza R, Guttmann A, et al. Estimated Effectiveness of Postpartum Maternal Messenger RNA COVID-19 Vaccination Against Delta and Omicron SARS-CoV-2 Infection and Hospitalization in Infants Younger Than 6 Months. JAMA Pediatrics. 2023 Apr 01;177(4):427-30. https://doi.org/10.1001/jamapediatrics.2022.6134.
[Return to footnote 43](#fn43-rf)
Footnote 44
Antonelli M, Pujol JC, Spector TD, Ourselin S, Steves CJ. Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2. The Lancet (British edition). 2022 Jun 18;399(10343):2263-4. https://doi.org/10.1016/S0140-6736(22)00941-2.
[Return to footnote 44](#fn44-rf)
Footnote 45
Spiliopoulos L, Sørensen AIV, Bager P, Nielsen NM, Hansen JV, Koch A, et al. Post-acute symptoms four months after SARS-CoV-2 infection during the Omicron period: a nationwide Danish questionnaire study. medRxiv. 2022 Oct 28. https://doi.org/10.1101/2022.10.12.22280990.
[Return to footnote 45](#fn45-rf)
Footnote 46
Kahlert CR, Strahm C, Güsewell S, Cusini A, Brucher A, Goppel S, et al. Association of viral variant and vaccination status with the occurrence of symptoms compatible with post-acute sequelae after primary SARS-CoV-2 infection. medRxiv. 2022 Oct 22. https://doi.org/10.1101/2022.10.21.22281349.
[Return to footnote 46](#fn46-rf)
Footnote 47
Quinn KL, Katz GM, Bobos P, Sander B, McNaughton CD, Cheung AM, et al. Understanding the Post COVID-19 Condition (Long COVID) in Adults and the Expected Burden for Ontario. Science Briefs of the Ontario COVID-19 Science Advisory Table. 2022 Sep 06;3(65). https://doi.org/10.47326/ocsat.2022.03.65.1.0.
[Return to footnote 47](#fn47-rf)
Footnote 48
Coronavirus disease (COVID-19): Post COVID-19 condition [Internet]. Geneva (CH): World Health Organization; 2023 Mar 28 [cited 2023 Jun 07]. Available from: https://www.who.int/news-room/questions-and-answers/item/coronavirus-disease-(covid-19)-post-covid-19-condition.
[Return to footnote 48](#fn48-rf)
Footnote 49
Watanabe A, Iwagami M, Yasuhara J, Takagi H, Kuno T. Protective effect of COVID-19 vaccination against long COVID syndrome: A systematic review and meta-analysis. Vaccine. 2023 Mar 10;41(11):1783-90. https://doi.org/10.1016/j.vaccine.2023.02.008.
[Return to footnote 49](#fn49-rf)
Footnote 50
Azzolini E, Levi R, Sarti R, Pozzi C, Mollura M, Mantovani A, et al. Association Between BNT162b2 Vaccination and Long COVID After Infections Not Requiring Hospitalization in Health Care Workers. JAMA : the journal of the American Medical Association. 2022 Jul 01;328(7):676-8. https://doi.org/10.1001/jama.2022.11691.
[Return to footnote 50](#fn50-rf)
Footnote 51
Ballouz T, Menges D, Kaufmann M, Amati R, Frei A, Wyl Vv, et al. Post COVID-19 condition after Wildtype, Delta, and Omicron SARS-CoV-2 infection and prior vaccination: Pooled analysis of two population-based cohorts. PLOS ONE. 2022 Feb 22;18(2):e0281429. https://doi.org/10.1371/journal.pone.0281429.
[Return to footnote 51](#fn51-rf)
Footnote 52
Shimabukuro T. mRNA COVID-19 bivalent booster vaccine
safety update [slides presented at Advisory Committee on Immunization Practices (ACIP) meeting April 19, 2023] [Internet]. Atlanta (GA): Centers for Disease Control and Prevention; 2023 Apr 19 [cited 2023 May 25]. Available from: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-04-19/03-COVID-Shimabukuro-508.pdf.
[Return to footnote 52](#fn52-rf)
Footnote 53
Vaccine Safety Surveillance Division. Personal communication. CAEFISS update. 2023 May 18.
[Return to footnote 53](#fn53-rf)
Footnote 54
Andrews N, Stowe J, Miller E, Ramsay M. BA.1 Bivalent COVID-19 Vaccine Use and Stroke in England. JAMA. 2023 Jun 15:e2310123. https://doi.org/10.1001/jama.2023.10123.
[Return to footnote 54](#fn54-rf)
Footnote 55
Janssen C, Mosnier A, Gavazzi G, Combadière B, Crépey P, Gaillat J, et al. Coadministration of seasonal influenza and COVID-19 vaccines: A systematic review of clinical studies. Hum Vaccin Immunother. 2022 Nov 30;18(6):2131166. https://doi.org/10.1080/21645515.2022.2131166.
[Return to footnote 55](#fn55-rf)
Footnote 56
Wagenhäuser I, Reusch J, Gabel A, Höhn A, Lâm T, Almanzar G, et al. Immunogenicity and safety of coadministration of COVID-19 and influenza vaccination. European Respiratory Journal. 2023 Jan 06;61(1):2201390. https://doi.org/10.1183/13993003.01390-2022.
[Return to footnote 56](#fn56-rf)
Footnote 57
Kim A, Kim S, Song J, Hwang S, Nam E, Kwon KT. Adverse Reactions after BNT162b2 Messenger RNA Vaccination for Coronavirus Disease 2019 in Healthcare Workers Compared with Influenza Vaccination. Vaccines (Basel). 2023 Feb 05;11(2):363. https://doi.org/10.3390/vaccines11020363.
[Return to footnote 57](#fn57-rf)
Footnote 58
Radner H, Sieghart D, Jorda A, Fedrizzi C, Hasenöhrl T, Zdravkovic A, et al. Reduced immunogenicity of BNT162b2 booster vaccination in combination with a tetravalent influenza vaccination: results of a prospective cohort study in 838 health workers. Clin Microbiol Infect. 2023 May;29(5):635-41. https://doi.org/10.1016/j.cmi.2022.12.008.
[Return to footnote 58](#fn58-rf)
Footnote 59
Toback S, Galiza E, Cosgrove C, Galloway J, Goodman AL, Swift PA, et al. Safety, immunogenicity, and efficacy of a COVID-19 vaccine (NVX-CoV2373) co-administered with seasonal influenza vaccines: an exploratory substudy of a randomised, observer-blinded, placebo-controlled, phase 3 trial. Lancet Respir Med. 2022 Feb;10(2):167-4. https://doi.org/S2213-2600(21)00409-4.
[Return to footnote 59](#fn59-rf)
Footnote 60
Izikson R, Brune D, Bolduc JS, Bourron P, Fournier M, Moore TM, et al. Safety and immunogenicity of a high-dose quadrivalent influenza vaccine administered concomitantly with a third dose of the mRNA-1273 SARS-CoV-2 vaccine in adults aged ≥65 years: a phase 2, randomised, open-label study. Lancet Respir Med. 2022 Apr 01;10(4):392-9. https://doi.org/10.1016/S2213-2600(21)00557-9.
[Return to footnote 60](#fn60-rf)
Footnote 61
Public Health Agency of Canada. Vaccination coverage by age, sex, and province or territory. Data cut-off April 23, 2023 [Internet]. Ottawa (ON): Government of Canada; 2023 Apr 23 [cited 2023 May 30]. Available from: https://health-infobase.canada.ca/covid-19/vaccination-coverage/#a5.
[Return to footnote 61](#fn61-rf)
Footnote 62
Vaccines and Related Biological Products Advisory Committee June 15, 2023 Meeting Announcement [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2023 Jun 15 [cited 2023 Jun 16]. Available from: https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-june-15-2023-meeting-announcement.
[Return to footnote 62](#fn62-rf)
Report a problem or mistake on this page
Please select all that apply:
A link, button or video is not working
It has a spelling mistake
Information is missing
Information is outdated or wrong
Login error when trying to access an account
I can't find what I'm looking for
Other issue not in this list
Submit
### Thank you for your help!
You will not receive a reply. For enquiries, [contact us](https://www.canada.ca/en/contact/index.html).
Date modified:
2023-07-13
| None | None |
618040ea0912bf302ad48276307ece6b90174ed2 | cma | None | vaccination is recommended during pregnancy in any trimester and while breastfeeding 2. All available COVID-19 vaccines approved in Canada can be used during pregnancy and breastfeeding. Presently, preference is given for the use of mRNA vaccinations during pregnancy as more data on safety and efficacy during pregnancy is available for these vaccines.prioritize for pregnant and breastfeeding individuals. 4. Individuals should not be precluded from vaccination based on pregnancy status or breastfeeding. 5. Given that pregnant people are at increased risk of morbidity from COVID-19 infection, all pregnant persons should be prioritized to receive a COVID-19 vaccination. Vaccinations are an important part of primary and preventative healthcare for pregnant women. The benefit of vaccination during pregnancy for the infant (e.g. pertussis and influenza) is recognized and recommendation of these vaccinations is part of routine prenatal care.Compared to non-pregnant women with COVID-19, pregnant women are at increased risk of admission to hospital, critical care and invasive ventilation compared to age-matched peers. 1,2 Canadian and international data from large studies spanning multiple jurisdictions demonstrate that approximately 7-11% of pregnant women will require hospitalization for COVID-related morbidity and between 1-4% of pregnant women require admission to an intensive care unit (ICU). 1,2,3 Recently, a prospective cohort study of 5183 pregnant women compared to 175 905 non-pregnant women demonstrated that pregnancy conferred an increased risk of death from COVID-19 (OR 1.84,). The risk of severe morbidity from COVID-19 in pregnant women appears to be associated with risk factors including age ≥ 35 years old, asthma, obesity, preexisting diabetes, preexisting hypertension and heart disease. 1,2 In addition, both Canadian and US data 1,2,3 show an increased risk of preterm delivery associated with COVID-19 infection in pregnancy which can result in consequent morbidity to the infant related to prematurity.# COVID-19 vaccines approved for use in Canada mRNA Vaccine Platforms
In Canada, the dominant vaccines in use to prevent infection with SARS-CoV-2 are the mRNA vaccine platforms. This model consists of messenger RNA (mRNA) encapsulated by a lipid nanoparticle (LNP), which allows the mRNA entrance into host (human) cells. The mRNA in the vaccine codes for the SARS-CoV-2 spike protein utilized by the virus to bind to human receptors and promote viral replication. The vaccine provides the host cell instructions to manufacture only this spike protein and express it on its surface. Recognizing the spike protein as a foreign antigen, the host immune system is then activated to produce an immune response. 4 The mRNA does not enter the nucleus or alter human DNA and human cells do not have the machinery to allow it to do so.
The Pfizer-BioNTech and Moderna COVID-19 vaccines were originally evaluated in licensure trials as a series of two intramuscular injections given 21-28 days apart. 5 However, since then, considerable data has been generated on different dosing intervals. 6 The efficacy of the Pfizer-BioNTech COVID-19 vaccine has been demonstrated for adults 16 years and older in Phase II and Phase III trials involving the randomization of approximately 44,000 individuals. 7 These trials demonstrated a vaccine efficacy of 94.6% for preventing symptomatic COVID-19 cases at least 7 days following the second dose. 7 In Phase III trials for the Moderna COVID-19 vaccine involving the randomization of 30,000 individuals, the vaccine was reported to have 94.1% efficacy against symptomatic COVID-19 with no serious safety concerns identified during the initial 2 month follow-up period. 8 Since the initial clinical trials, numerous population-based studies have reported on real-world vaccine efficacy. Among these, Canadian data from Quebec and British Columbia have demonstrated vaccine efficacy greater than 80-90% for infection for at least 4 months after the 2 nd dose and including against infections with Delta variant. 6,9 Vaccine efficacy data specific to pregnant women are emerging and suggest that COVID-19 mRNA vaccine efficacy is comparable to the vaccine efficacy observed in non-pregnant persons. 10,11 In Phase III trials for both Pfizer-BioNTech and Moderna COVID-19 vaccines, there were no clinically meaningful differences in adverse events or severe adverse events in the vaccine group compared to control except for lymphadenopathy which occurred in approximately 0.3% of the vaccine group compared to <0.1% of the placebo group for the Pfizer-BioNTech COVID-19 vaccine. The most reported side effects from the mRNA COVID-19 vaccines were pain at the injection site, fatigue and headache. Fever was reported in 11-16% of patients, particularly following the second dose. 7 Data from the US vsafe pregnancy registry demonstrates that pregnant women are more likely than non-pregnant women to report injection site pain following administration of COVID-19 mRNA vaccines, but are less likely to report headache, myalgia, chills and fever. 12 While pregnant and breastfeeding individuals were excluded from the available Phase II and Phase III studies for the Pfizer-BioNTech and Moderna COVID-19 vaccines a growing body of data demonstrates no difference in rates of spontaneous abortion, stillbirth, preterm birth or other pregnancy complications. The V-Safe registry in the US has reported on over 7,000 pregnant women (including a robust representation of women vaccinated in early pregnancy) who received either the Pfizer-BioNTech vaccine or the Moderna vaccine and identified no differences in the rates of adverse pregnancy and neonatal outcomes in vaccinated women compared to pre-pandemic rates. 11,12 Additional US data from the University of Washington, demonstrated that COVID-19 vaccination in pregnant and lactating individuals can induce an immunogenic response, does not raise significant vaccine-related adverse events or obstetrical and neonatal outcomes, and is effective in preventing COVID-19 disease. 13,14 Most recently, analyses of US and Norwegian population-level data reporting on 105,446 and 18,477 pregnancies, respectively, have demonstrated no evidence of increased risk for early pregnancy loss following Covid-19 vaccination. 15,16 Canadian data on vaccines in pregnancy are now available from Ontario and have been published as 2 online reports. (Better Outcomes Registry & Network (BORN) Ontario. COVID-19 Vaccination During Pregnancy in Ontario: Surveillance Report #2, Reporting Interval December 14, 2020 to June 30, 2021. Ottawa, ON: BORN Ontario; July 30, 2021.) During this entire reporting period, there were 39,985 women who received at least one dose of COVID-19 vaccine during pregnancy. Of note 26,381 had received 1 dose and 13,604 had received 2 doses. Monthly uptake of vaccines increased over this time period from 0.02% to 45.4% by June 2021. There was no evidence of any pregnancy specific increase in any risks associated with vaccine uptake. The second source of Canadian data will be the Canadian COVID-19 Vaccine Registry for Pregnant & Lactating Individuals (COVERED) whose objective is to assess the safety and effectiveness of vaccination against COVID-19 in pregnancy (registration is open and available on the website: /). Data on the safety of COVID-19 vaccines in lactating women or the effects of mRNA vaccines on the breastfed infant or on milk production is limited, however because mRNA vaccines are not live virus vaccines, they are not hypothesized to be a risk to the breastfeeding infant. 17
# Recently approved vaccine platforms
In early 2022, two new vaccines platforms were approved for use in Canada. Novavax Nuvaxovid contains a recombinant SARS-CoV-2 spike protein vaccine and Medicago Covifenz contains a plant-based virus-like particle of the SARS-CoV-2 spike protein. The adjuvants contained in both vaccine platforms are oil-in-water emulsion adjuvants that have been used widely and in diverse populations including pregnant women and children, most notably during the 2009-2010 H1N1 influenza pandemic. 18 Both vaccine platforms use technology that is well established and used for other vaccines that are administered safely to pregnant women (e.g. hepatitis, pertussis and tetanus vaccines). There is no theoretical reason why the Novavax Nuvaxois or the Medicago Covifenz vaccines should not be administered to pregnant or lactating women, although safety and efficacy data specific to pregnancy is not yet available. 19,20 Following informed discussion, these vaccines could be considered as an alternative for pregnant and lactating women who cannot use the mRNA vaccine platform due to side effects or those who are opposed to using an mRNA vaccine platform.
# Considerations for COVID-19 vaccination during pregnancy
Decades of experience with other vaccines administered during pregnancy would suggest that we could expect a similar efficacy for the COVID-19 vaccines in pregnant women compared to non-pregnant women. Vaccines in general are immunogenic, safe, and efficacious when delivered to pregnant persons. Recently COVID-19 vaccination has been shown to be efficacious in preventing infection in pregnant women. 21 While further primary prospective clinical data on safety and efficacy of COVID-19 vaccines in pregnant populations is forthcoming, growing post-marketing surveillance has identified no signals for adverse pregnancy or neonatal outcomes associated with administration of COVID-19 vaccinations.
What is known is that an unvaccinated pregnant woman remains at risk of COVID-19 infection and remains at heightened risk of severe morbidity if infected compared to non-pregnant counterparts. Severe infection with COVID-19 carries risks to maternal, fetal and neonatal health. While pregnancy itself does not appear to increase the risk of becoming infected with SARS-CoV-2, pregnant individuals may be in work-related (e.g. health-care worker, front line workers etc.) or community situations (e.g. caregiver, Indigenous communities, outbreak setting, etc.) where the risk of infection is considerable. Owing to maternal age, underlying comorbidities, or social marginalization, some pregnant individuals are at higher risk of severe COVID-related morbidity.
# We recommend pregnant individuals should be offered vaccination against COVID-19 at any time during pregnancy or while breastfeeding, if no contraindications exist. This recommendation extends to those who have previously been infected with SARS-CoV-2. 22
In Canada, NACI has preferentially advised that "a complete vaccine series with an mRNA COVID-19 vaccine should be offered to individuals in the authorized age group who are pregnant or breastfeeding. Informed consent should include discussion about emerging evidence on the safety of mRNA COVID-19 vaccines in these populations. (Strong NACI Recommendation). Contraindications to vaccination are few and a complete description is available within the National Advisory Committee on Immunization guidance document. 23
# Anticipatory guidance for vaccination during pregnancy
Individuals should be informed of the expected side effects following vaccination. While pain at the injection site, fatigue and headache are the most commonly reported symptoms following vaccination, fever was reported 16% of the time for younger, non-pregnant individuals. 8 Pregnant individuals can be counselled to treat mild post-vaccination fevers with antipyretics (e.g. acetaminophen).
# Timing of vaccination during pregnancy and neonatal protection
The primary indication for administration of COVID-19 vaccination is for maternal protection. Therefore the decision around timing of vaccination should be optimized for maternal benefit. In theory, immunization of a pregnant woman may confer benefit to a newborn infant through a mechanism of maternal vaccination similar to what is seen for pertussis and influenza vaccination during pregnancy. While natural COVID-19 infection does appear to result in placental antibody transfer, vaccination negates the fundamental risk of COVID-19 in pregnancy while conferring the same neonatal benefit. 24 Evidence demonstrates that vaccine-generated antibodies are present in umbilical cord blood following maternal vaccination with a rapid rise in titres occurring by 15d post-vaccination. 14,25 There appears to be efficient antibody transfer via the placenta, similar to pertussis vaccination which does confer neonatal protection. 14,25,26,27 Recent data from a case-control study conducted by the US-CDC demonstrates that receipt of a two-dose series of a mRNA COVID-19 vaccination during pregnancy is associated with a reduction in COVID-associated infant hospitalizations <6 months. 28 In general maternal antibody transfer via the placenta is a more efficient way to confer neonatal protection than breastfeeding. Antibodies are also transferred to breast milk post vaccination, 29,30,31,32,33,34 but there is yet no data on associated neonatal protection.
# Vaccine Spacing
There is no clear evidence to direct whether spacing of other vaccines is required, relative to the COVID-19 vaccine. Recently NACI has changed its recommendation to support simultaneous vaccination of COVID-19 with any other vaccine. This is uniquely applicable to pregnant persons in that there is no required delay of any vaccine (e.g. Tdap or influenza vaccination) or Rh-immunoglobulin for COVID-19 vaccination and vice versa. Of note, pregnant women and infants remain at increased risk of morbidity and mortality from seasonal influenza compared to general population and vaccinating pregnant women against influenza remains part of routine prenatal care during the pandemic.
# Vaccination of the pregnant patient in the context of limited vaccine supply
Given that pregnant women are at higher risk of severe COVID-related morbidity and mortality, they represent a population that should be prioritized for vaccination in situations where vaccine supply is limited. Specifically, the WHO has recommended that pregnant women be prioritized in stage II, representing a situation where the supply is only sufficient to immunize 11-20% of a population. Importantly, the WHO recommendation is upheld in all epidemiologic situations including community transmission, sporadic cases as well as no cases. 35
# Inadvertent pregnancy following vaccination
Individuals who are discovered to be pregnant during their vaccine series or shortly afterward should not be counselled to terminate pregnancy based on having received the vaccine. If conception is presumed to predate the first dose, it is recommended to follow the same procedures for active surveillance (as available) as would be activated if the pregnancy was known at the time of vaccination. A registry to track pregnancy outcomes for individuals receiving any vaccine doses during pregnancy is being planned for Canada. Pregnant individuals can get more information here: /.
Where pregnancy is detected during the vaccine series (i.e. following the first dose, but ahead of the second dose), pregnant individuals should continue to be offered the opportunity to complete their vaccination series. Pregnant individuals should not be precluded or forced to delay the vaccine series in any trimester.
# Individuals contemplating pregnancy
Ideally, an individual would be immunized against COVID-19 ahead of pregnancy to benefit from maximal vaccine efficacy throughout the entire pregnancy. There is no reason to delay pregnancy upon receipt of vaccination.
# Booster doses
Pregnant women mount immune responses comparable to the non-pregnant population and vaccine efficacy of the COVID vaccines among cohorts of pregnant women are comparable to non-pregnant women. There is no data to suggest that pregnant women who meet criteria for a booster dose should be treated differently than the non-pregnant population. While timing and criteria for booster doses may vary by jurisdiction, pregnant women should receive a booster dose when recommended.
# Future research
As the evidence evolves, it is becoming clear that pregnant and postpartum individuals represent a population at increased risk of COVID-related morbidity. Severe COVID-19 infection during pregnancy has important implications for both maternal and fetal health. NACI acknowledges that people of reproductive age constitute a substantial proportion of the Canadian population, yet limited data on the use of COVID-19 vaccine in pregnancy are available. We support NACI's recommendation for the inclusion of pregnant individuals in clinical trials of COVID-19 vaccines. This will help to ensure that this population has equitable access to COVID-19 vaccine options, and that vaccination decisions can be informed by robust safety, immunogenicity, and efficacy data. 36 | vaccination is recommended during pregnancy in any trimester and while breastfeeding 2. All available COVID-19 vaccines approved in Canada can be used during pregnancy and breastfeeding. Presently, preference is given for the use of mRNA vaccinations during pregnancy as more data on safety and efficacy during pregnancy is available for these vaccines.prioritize for pregnant and breastfeeding individuals. 4. Individuals should not be precluded from vaccination based on pregnancy status or breastfeeding. 5. Given that pregnant people are at increased risk of morbidity from COVID-19 infection, all pregnant persons should be prioritized to receive a COVID-19 vaccination. Vaccinations are an important part of primary and preventative healthcare for pregnant women. The benefit of vaccination during pregnancy for the infant (e.g. pertussis and influenza) is recognized and recommendation of these vaccinations is part of routine prenatal care.Compared to non-pregnant women with COVID-19, pregnant women are at increased risk of admission to hospital, critical care and invasive ventilation compared to age-matched peers. 1,2 Canadian and international data from large studies spanning multiple jurisdictions demonstrate that approximately 7-11% of pregnant women will require hospitalization for COVID-related morbidity and between 1-4% of pregnant women require admission to an intensive care unit (ICU). 1,2,3 Recently, a prospective cohort study of 5183 pregnant women compared to 175 905 non-pregnant women demonstrated that pregnancy conferred an increased risk of death from COVID-19 (OR 1.84,). The risk of severe morbidity from COVID-19 in pregnant women appears to be associated with risk factors including age ≥ 35 years old, asthma, obesity, preexisting diabetes, preexisting hypertension and heart disease. 1,2 In addition, both Canadian and US data 1,2,3 show an increased risk of preterm delivery associated with COVID-19 infection in pregnancy which can result in consequent morbidity to the infant related to prematurity.# COVID-19 vaccines approved for use in Canada mRNA Vaccine Platforms
In Canada, the dominant vaccines in use to prevent infection with SARS-CoV-2 are the mRNA vaccine platforms. This model consists of messenger RNA (mRNA) encapsulated by a lipid nanoparticle (LNP), which allows the mRNA entrance into host (human) cells. The mRNA in the vaccine codes for the SARS-CoV-2 spike protein utilized by the virus to bind to human receptors and promote viral replication. The vaccine provides the host cell instructions to manufacture only this spike protein and express it on its surface. Recognizing the spike protein as a foreign antigen, the host immune system is then activated to produce an immune response. 4 The mRNA does not enter the nucleus or alter human DNA and human cells do not have the machinery to allow it to do so.
The Pfizer-BioNTech and Moderna COVID-19 vaccines were originally evaluated in licensure trials as a series of two intramuscular injections given 21-28 days apart. 5 However, since then, considerable data has been generated on different dosing intervals. 6 The efficacy of the Pfizer-BioNTech COVID-19 vaccine has been demonstrated for adults 16 years and older in Phase II and Phase III trials involving the randomization of approximately 44,000 individuals. 7 These trials demonstrated a vaccine efficacy of 94.6% for preventing symptomatic COVID-19 cases at least 7 days following the second dose. 7 In Phase III trials for the Moderna COVID-19 vaccine involving the randomization of 30,000 individuals, the vaccine was reported to have 94.1% efficacy against symptomatic COVID-19 with no serious safety concerns identified during the initial 2 month follow-up period. 8 Since the initial clinical trials, numerous population-based studies have reported on real-world vaccine efficacy. Among these, Canadian data from Quebec and British Columbia have demonstrated vaccine efficacy greater than 80-90% for infection for at least 4 months after the 2 nd dose and including against infections with Delta variant. 6,9 Vaccine efficacy data specific to pregnant women are emerging and suggest that COVID-19 mRNA vaccine efficacy is comparable to the vaccine efficacy observed in non-pregnant persons. 10,11 In Phase III trials for both Pfizer-BioNTech and Moderna COVID-19 vaccines, there were no clinically meaningful differences in adverse events or severe adverse events in the vaccine group compared to control except for lymphadenopathy which occurred in approximately 0.3% of the vaccine group compared to <0.1% of the placebo group for the Pfizer-BioNTech COVID-19 vaccine. The most reported side effects from the mRNA COVID-19 vaccines were pain at the injection site, fatigue and headache. Fever was reported in 11-16% of patients, particularly following the second dose. 7 Data from the US vsafe pregnancy registry demonstrates that pregnant women are more likely than non-pregnant women to report injection site pain following administration of COVID-19 mRNA vaccines, but are less likely to report headache, myalgia, chills and fever. 12 While pregnant and breastfeeding individuals were excluded from the available Phase II and Phase III studies for the Pfizer-BioNTech and Moderna COVID-19 vaccines a growing body of data demonstrates no difference in rates of spontaneous abortion, stillbirth, preterm birth or other pregnancy complications. The V-Safe registry in the US has reported on over 7,000 pregnant women (including a robust representation of women vaccinated in early pregnancy) who received either the Pfizer-BioNTech vaccine or the Moderna vaccine and identified no differences in the rates of adverse pregnancy and neonatal outcomes in vaccinated women compared to pre-pandemic rates. 11,12 Additional US data from the University of Washington, demonstrated that COVID-19 vaccination in pregnant and lactating individuals can induce an immunogenic response, does not raise significant vaccine-related adverse events or obstetrical and neonatal outcomes, and is effective in preventing COVID-19 disease. 13,14 Most recently, analyses of US and Norwegian population-level data reporting on 105,446 and 18,477 pregnancies, respectively, have demonstrated no evidence of increased risk for early pregnancy loss following Covid-19 vaccination. 15,16 Canadian data on vaccines in pregnancy are now available from Ontario and have been published as 2 online reports. (Better Outcomes Registry & Network (BORN) Ontario. COVID-19 Vaccination During Pregnancy in Ontario: Surveillance Report #2, Reporting Interval December 14, 2020 to June 30, 2021. Ottawa, ON: BORN Ontario; July 30, 2021.) During this entire reporting period, there were 39,985 women who received at least one dose of COVID-19 vaccine during pregnancy. Of note 26,381 had received 1 dose and 13,604 had received 2 doses. Monthly uptake of vaccines increased over this time period from 0.02% to 45.4% by June 2021. There was no evidence of any pregnancy specific increase in any risks associated with vaccine uptake. The second source of Canadian data will be the Canadian COVID-19 Vaccine Registry for Pregnant & Lactating Individuals (COVERED) whose objective is to assess the safety and effectiveness of vaccination against COVID-19 in pregnancy (registration is open and available on the website: https://covered.med.ubc.ca/). Data on the safety of COVID-19 vaccines in lactating women or the effects of mRNA vaccines on the breastfed infant or on milk production is limited, however because mRNA vaccines are not live virus vaccines, they are not hypothesized to be a risk to the breastfeeding infant. 17
# Recently approved vaccine platforms
In early 2022, two new vaccines platforms were approved for use in Canada. Novavax Nuvaxovid contains a recombinant SARS-CoV-2 spike protein vaccine and Medicago Covifenz contains a plant-based virus-like particle of the SARS-CoV-2 spike protein. The adjuvants contained in both vaccine platforms are oil-in-water emulsion adjuvants that have been used widely and in diverse populations including pregnant women and children, most notably during the 2009-2010 H1N1 influenza pandemic. 18 Both vaccine platforms use technology that is well established and used for other vaccines that are administered safely to pregnant women (e.g. hepatitis, pertussis and tetanus vaccines). There is no theoretical reason why the Novavax Nuvaxois or the Medicago Covifenz vaccines should not be administered to pregnant or lactating women, although safety and efficacy data specific to pregnancy is not yet available. 19,20 Following informed discussion, these vaccines could be considered as an alternative for pregnant and lactating women who cannot use the mRNA vaccine platform due to side effects or those who are opposed to using an mRNA vaccine platform.
# Considerations for COVID-19 vaccination during pregnancy
Decades of experience with other vaccines administered during pregnancy would suggest that we could expect a similar efficacy for the COVID-19 vaccines in pregnant women compared to non-pregnant women. Vaccines in general are immunogenic, safe, and efficacious when delivered to pregnant persons. Recently COVID-19 vaccination has been shown to be efficacious in preventing infection in pregnant women. 21 While further primary prospective clinical data on safety and efficacy of COVID-19 vaccines in pregnant populations is forthcoming, growing post-marketing surveillance has identified no signals for adverse pregnancy or neonatal outcomes associated with administration of COVID-19 vaccinations.
What is known is that an unvaccinated pregnant woman remains at risk of COVID-19 infection and remains at heightened risk of severe morbidity if infected compared to non-pregnant counterparts. Severe infection with COVID-19 carries risks to maternal, fetal and neonatal health. While pregnancy itself does not appear to increase the risk of becoming infected with SARS-CoV-2, pregnant individuals may be in work-related (e.g. health-care worker, front line workers etc.) or community situations (e.g. caregiver, Indigenous communities, outbreak setting, etc.) where the risk of infection is considerable. Owing to maternal age, underlying comorbidities, or social marginalization, some pregnant individuals are at higher risk of severe COVID-related morbidity.
# We recommend pregnant individuals should be offered vaccination against COVID-19 at any time during pregnancy or while breastfeeding, if no contraindications exist. This recommendation extends to those who have previously been infected with SARS-CoV-2. 22
In Canada, NACI has preferentially advised that "a complete vaccine series with an mRNA COVID-19 vaccine should be offered to individuals in the authorized age group who are pregnant or breastfeeding. Informed consent should include discussion about emerging evidence on the safety of mRNA COVID-19 vaccines in these populations. (Strong NACI Recommendation). Contraindications to vaccination are few and a complete description is available within the National Advisory Committee on Immunization guidance document. 23
# Anticipatory guidance for vaccination during pregnancy
Individuals should be informed of the expected side effects following vaccination. While pain at the injection site, fatigue and headache are the most commonly reported symptoms following vaccination, fever was reported 16% of the time for younger, non-pregnant individuals. 8 Pregnant individuals can be counselled to treat mild post-vaccination fevers with antipyretics (e.g. acetaminophen).
# Timing of vaccination during pregnancy and neonatal protection
The primary indication for administration of COVID-19 vaccination is for maternal protection. Therefore the decision around timing of vaccination should be optimized for maternal benefit. In theory, immunization of a pregnant woman may confer benefit to a newborn infant through a mechanism of maternal vaccination similar to what is seen for pertussis and influenza vaccination during pregnancy. While natural COVID-19 infection does appear to result in placental antibody transfer, vaccination negates the fundamental risk of COVID-19 in pregnancy while conferring the same neonatal benefit. 24 Evidence demonstrates that vaccine-generated antibodies are present in umbilical cord blood following maternal vaccination with a rapid rise in titres occurring by 15d post-vaccination. 14,25 There appears to be efficient antibody transfer via the placenta, similar to pertussis vaccination which does confer neonatal protection. 14,25,26,27 Recent data from a case-control study conducted by the US-CDC demonstrates that receipt of a two-dose series of a mRNA COVID-19 vaccination during pregnancy is associated with a reduction in COVID-associated infant hospitalizations <6 months. 28 In general maternal antibody transfer via the placenta is a more efficient way to confer neonatal protection than breastfeeding. Antibodies are also transferred to breast milk post vaccination, 29,30,31,32,33,34 but there is yet no data on associated neonatal protection.
# Vaccine Spacing
There is no clear evidence to direct whether spacing of other vaccines is required, relative to the COVID-19 vaccine. Recently NACI has changed its recommendation to support simultaneous vaccination of COVID-19 with any other vaccine. This is uniquely applicable to pregnant persons in that there is no required delay of any vaccine (e.g. Tdap or influenza vaccination) or Rh-immunoglobulin for COVID-19 vaccination and vice versa. Of note, pregnant women and infants remain at increased risk of morbidity and mortality from seasonal influenza compared to general population and vaccinating pregnant women against influenza remains part of routine prenatal care during the pandemic.
# Vaccination of the pregnant patient in the context of limited vaccine supply
Given that pregnant women are at higher risk of severe COVID-related morbidity and mortality, they represent a population that should be prioritized for vaccination in situations where vaccine supply is limited. Specifically, the WHO has recommended that pregnant women be prioritized in stage II, representing a situation where the supply is only sufficient to immunize 11-20% of a population. Importantly, the WHO recommendation is upheld in all epidemiologic situations including community transmission, sporadic cases as well as no cases. 35
# Inadvertent pregnancy following vaccination
Individuals who are discovered to be pregnant during their vaccine series or shortly afterward should not be counselled to terminate pregnancy based on having received the vaccine. If conception is presumed to predate the first dose, it is recommended to follow the same procedures for active surveillance (as available) as would be activated if the pregnancy was known at the time of vaccination. A registry to track pregnancy outcomes for individuals receiving any vaccine doses during pregnancy is being planned for Canada. Pregnant individuals can get more information here: http://med-fomridprogram.sites.olt.ubc.ca/vaccine-surveillance/.
Where pregnancy is detected during the vaccine series (i.e. following the first dose, but ahead of the second dose), pregnant individuals should continue to be offered the opportunity to complete their vaccination series. Pregnant individuals should not be precluded or forced to delay the vaccine series in any trimester.
# Individuals contemplating pregnancy
Ideally, an individual would be immunized against COVID-19 ahead of pregnancy to benefit from maximal vaccine efficacy throughout the entire pregnancy. There is no reason to delay pregnancy upon receipt of vaccination.
# Booster doses
Pregnant women mount immune responses comparable to the non-pregnant population and vaccine efficacy of the COVID vaccines among cohorts of pregnant women are comparable to non-pregnant women. There is no data to suggest that pregnant women who meet criteria for a booster dose should be treated differently than the non-pregnant population. While timing and criteria for booster doses may vary by jurisdiction, pregnant women should receive a booster dose when recommended.
# Future research
As the evidence evolves, it is becoming clear that pregnant and postpartum individuals represent a population at increased risk of COVID-related morbidity. Severe COVID-19 infection during pregnancy has important implications for both maternal and fetal health. NACI acknowledges that people of reproductive age constitute a substantial proportion of the Canadian population, yet limited data on the use of COVID-19 vaccine in pregnancy are available. We support NACI's recommendation for the inclusion of pregnant individuals in clinical trials of COVID-19 vaccines. This will help to ensure that this population has equitable access to COVID-19 vaccine options, and that vaccination decisions can be informed by robust safety, immunogenicity, and efficacy data. 36 | None | None |
14a55ff546f190ddb8d9108841077e66398df71a | cma | None | This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY# Terms of Reference 1.Purpose
The Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) aims to develop consensus opinion of oncologists and allied health professionals from across Western Canada, attempting to define best care practices and to improve care and outcomes for patients with gastrointestinal cancers.
# Target Audience
The recommendations presented here are targeted at health care professionals involved in the care of patients with hepato-pancreato-biliary (HPB) cancers.
# Basis of Recommendations
The recommendations are based on the presentation and discussion of the best available evidence. Where applicable, references are cited. Additional evidence has been published since the timing of the 2019 meeting, and the authors have incorporated this, where relevant, into each topic discussion. Barriers to access (e.g., approval but no funding) and limitations in data interpretation continue to make the consensus recommendations relevant, even in light of new data.
# Question 1
What is the current role of stereotactic body radiation (SBRT) in hepatocellular carcinoma (HCC)?
# Recommendations
The role of SBRT in HCC is evolving and clinical trials should always be considered. Cases should be reviewed in multi-disciplinary rounds. SBRT is an option to be considered alongside other ablative therapies. SBRT as a bridge or downstaging to transplant could also be considered in addition to other local regional strategies.
# Summary of Evidence
The role of SBRT continues to be refined, with clinical trial enrollment as the optimal means of advancing its use in HCC. When considered alongside other ablative therapies in a multi-disciplinary discussion, SBRT is best suited for patients with HCC at a higher risk of complications or recurrence following interventional ablative therapies (e.g., tumors >3-5 cm, infiltrative tumors, located near the dome of the liver) . SBRT can also serve as a bridge to or as downsizing for transplant in addition to other local regional strategies. Risks are higher in patients who receive SBRT for central lesions and who go on to have a live donor liver transplant. Thus, multi-disciplinary decision making is crucial for these patients.
Vascular invasion is a poor prognostic factor in HCC patients. Survival is worse in patients with more extensive HCC with vascular involvement (main vessel involvement, occlusive tumor thrombus). For patients with vascular invasion (hepatic vein, portal vein, IVC or branch invasion), SBRT may be used with the goal of debulking or ablating intravascular tumor and increasing the chance of recanalization. A randomized phase II study from Korea demonstrated improved progression free survival (PFS) and overall survival (OS) with radiation therapy combined with TACE compared to sorafenib alone, in patients with macrovascular HCC invasion .
# Question 2
What is the optimal sequence of systemic therapy in patients with advanced HCC? In the first line setting? In the second line setting?
# Recommendations
Sorafenib or lenvatinib are options for first line therapy in patients who are not eligible for local-regional strategies and have a Child-Pugh A score. Sorafenib can also be considered in Child-Pugh B7 in the absence of ascites. The alternate treatment can be considered in cases of intolerance.
In the second line setting, options include regorafenib and cabozantinib.
Clinical trials should be considered. The role of immunotherapy is evolving.
# Summary of Evidence
Sorafenib has been the standard treatment for advanced HCC for over a decade since the SHARP and Asia-Pacific trials showed that sorafenib improved OS compared to placebo . In 2018, the REFLECT trial showed that lenvatinib is non-inferior for OS when compared to sorafenib in the first-line treatment of advanced HCC . Response rates and PFS favored lenvatinib. The patients included in these trials had Child-Pugh A liver function. For patients with Child-Pugh B liver function, sorafenib appears to be safe according to the GIDEON observational study . Many oncologists would treat patients with Child-Pugh B7 liver dysfunction in the absence of ascites if the patient has a good performance status.
In clinical trials, sorafenib has been shown to be associated with toxicities such as palmar-plantar erythrodysesthesia, diarrhea, hypertension, anorexia, weight loss and fatigue . Lenvatinib appears to have lower rates of palmar-plantar erythrodysesthesia, but higher rates of hypertension . Thus, in patients intolerant of sorafenib for such toxicities as palmar-plantar erythrodysesthesia, lenvatinib should be considered. Alternatively, in patients with poorly controlled hypertension, sorafenib would be preferred. Other first-line treatment options, such as the combination of atezolizumab and bevacizumab were not available at the time of this discussion.
In second line setting, post-sorafenib, the RESORCE trial found that regorafenib improves OS compared to placebo (median 10.6 vs. 7.8 months, HR 0.63, 95% CI 0.50-0.79, p < 0.0001). Patients in this study must have tolerated and progressed on sorafenib . In 2018, the CELESTIAL trial found that cabozantinib improves OS compared to placebo (median 10.2 vs. 8.0 months, HR 0.76 95% CI 0.63-0.92, p = 0.005) when given to patients who have been treated with up to two lines of systemic therapy for hepatocellular carcinoma, including previous treatment with sorafenib . The REACH-2 trial evaluated patients after first-line sorafenib with a poorer prognosis with an AFP ≥400 ng/mL, and found that ramucirumab led to a more modest improvement in OS compared to placebo (median 8.5 vs. 7.3 months, HR 0.710, 95% CI 0.531-0.949, p = 0.0199), which though statistically significant may not be as clinically significant .
The prognosis of advanced stage HCC is still very poor despite the recent advances in systemic treatment. Immunotherapy drugs are currently being studied in clinical trials. However, two reported phase III trials of anti-PD1 drug monotherapy (nivolumab, pembrolizumab) have failed to show a statistically significant improvement in overall survival in first-and second-line treatment, respectively, despite previous accelerated FDA conditional approval . Trials of combination treatments including immunotherapy and tyrosine-kinase inhibitors in the first-line setting for advanced HCC are ongoing. The combination of atezolizumab and bevacizumab, compared to sorafenib in the IMbrave150 study, presented at ESMO Asia 2019, after the WCGCCC meeting, suggests that the combination is superior to sorafenib and likely to become a new standard of care in the first line setting . The combination of atezolizumab and bevacizumab is Health Canada approved and received a conditional approval from the national oncology-specific health technology assessment body pan-Canadian Oncology Drug Review (pCODR) assuming the cost-effectiveness of the treatment can be improved upon . Despite support for its use, funding negotiations remain unresolved, limiting its use to a minority of patients who can afford to pay out of pocket or with the assistance of a private drug plan. Patients with a history of autoimmune disease or uncontrolled varices are also ineligible, keeping discussions about lenvatinib and sorafenib in the first-line setting relevant.
Existing second line studies all used sorafenib as a first line treatment, so it is difficult to interpret the efficacy of these novel agents in the context of new data. The RESORCE trial excluded patients who had other systemic treatments beyond sorafenib, while the CELES-TIAL trial included patients with two or more systemic therapies, including 17 patients who had prior immunotherapy, though not specifically in the combination of atezolizumab and bevacizumab . Further expert opinion and limited real-world studies have suggested that the activity of sorafenib and lenvatinib, post-atezolizumab and bevacizumab may have similar activity to the first line setting, suggesting a simple shift in the sequencing discussed at the 2019 WCGCCC meeting .
# Question 3
What are the important dietary interventions in the management of pancreatic cancer? What is the role of pancreatic enzyme replacement therapy?
# Recommendations
All patients with pancreas cancer should be referred to a registered dietitian for specialized nutritional care due to the high risk of malnutrition. Initial care providers should screen patients for pancreatic enzyme deficiency and initiate replacement if needed.
# Summary of the Evidence
Pancreatic cancer is a very aggressive malignancy that is often not diagnosed until an advanced or metastatic stage. More than 80% of patients with PDAC present with malnutrition at diagnosis due to multifactorial causes . It has been estimated that 10-20% of deaths in patients with cancer are related to malnutrition rather than their malignancy . Therefore, it is essential to identify, understand the etiology, and apply appropriate nutritional interventions to curtail the deleterious symptoms of malnutrition and improve clinical outcomes. The three factors which expose pancreatic cancer patients to such a high risk of malnutrition are (1) disease-related malnutrition (anorexia, hypermetabolism), (2) treatment side effects (nausea, vomiting, constipation, diarrhea, mouth sores, taste changes), and (3) exocrine/endocrine dysfunction. A consultation with a specialized registered dietitian can support the patient and team in the identification and management of these issues.
In the setting of cancer, both pancreatic exocrine and endocrine functions can be affected. Endocrine cells make up approximately 5% of the pancreas and function to regulate metabolism in the body through the production and secretion of hormones such as insulin and glucagon. Derangements in this system will present as diabetes mellitus . The majority of pancreatic cells, however, are exocrine cells. The pancreatic exocrine cells produce digestive juices (bicarbonate) and enzymes (protease, amylase, and lipase) which are essential for the neutralization of gastric chyme and the digestion of all macronutrients. Pancreatic enzyme insufficiency (PEI) is defined as the reduced or inappropriate secretion or activity of pancreatic juice and its digestive enzymes, particularly pancreatic lipase. The presence of PEI affects a patients' ability to properly digest and absorb protein (protease), fat (lipase), and complex carbohydrates (amylase).
When assessing this population for PEI, it is important to consider location, size, history of chronic pancreatitis, ductal obstruction and surgical intervention to the pancreas and tumor. The prevalence of PEI post Whipple procedure is 80-90% compared to 20-50% in patients who underwent a distal pancreatectomy. In contrast, 20-60% of patients with unresectable pancreatic adenocarcinoma have PEI .
Signs and symptoms of PEI can be broken down into three main categories; abdominal, nutritional and endocrine. Abdominal symptoms include diarrhea, steatorrhea, fecal urgency, bloating, malodorous gas, GERD, cramping and abdominal pain, and post prandial gurgling. Nutritional symptoms include weight loss, sarcopenia, weakness and fatigue, food avoidance, and fat soluble vitamin deficiency. Endocrine symptoms will present with hypoglycemia or decreased hyperglycemic agent requirements. If a patient has pancreatic adenocarcinoma and any of the above symptoms, the intervention recommended is pancreatic enzyme replacement therapy (PERT) . Patients who have an intact stomach taking enzymes orally require enterically coated versions. The two main brands of these enzymes used in Canada are Creon 10 and 25 and Cotazym ECS 8 and 20. Non-enterically coated enzymes (Viokase, Cotazym) are required for patients with a feeding tube (gastrically or jejunely) or post-gastrectomy. Each capsule of PERT has a combination of protease, lipase and amylase, as broken down in Table 2. The dosing of PERT is primarily based on the cystic fibrosis population and additional enzyme replacement is likely needed for the pancreatic cancer population . PERT is prescribed based on per kilogram body weight of the patient, in a range of 500-2500 units of lipase per kilogram body weight per meal, up to 10 000 units of lipase per kilogram of body weight per day. The risk associated with exceeding this is constipation. PERT should be taken before all meals and snacks that contain macronutrients and will last for up to 1 h after consumption. Larger meals or meals that contain a higher amount of fat will require more PERT for adequate digestion.
The European Society for Clinical Nutrition and Metabolism (ESPEN) and the American Society for Parenteral and Enteral Nutrition (ASPEN) guidelines suggest no macronutrient restriction, with protein requirements elevated to 1.2-2.0g/kilogram body weight/day. Patients on appropriate PERT should feel an improvement in symptom burden and will better absorb the nutrients they are ingesting.
# Question 4
What is the optimal neoadjuvant/adjuvant strategy for pancreas cancer?
# Recommendations
Six months of mFOLFIRINOX is standard adjuvant therapy for patients with resected pancreatic cancer. In patients who are not candidates for mFOLFIRINOX, a combination of gemcitabine/capecitabine or gemcitabine alone or 5FU alone can be considered.
The role of adjuvant radiation is not well defined but may be considered in patients with high risk of local recurrence, in the context of a multidisciplinary discussion.
Cases should be reviewed in a multi-disciplinary fashion to determine the intent and strategy for borderline resectable pancreas cancer. Clinical trials should be considered for these patients. Neoadjuvant chemotherapy using FOLFIRINOX is the preferred strategy. Gemcitabine and Nab-paclitaxel can be considered depending on patient factors and tolerability. Chemoradiotherapy or radiotherapy could be considered in select cases.
In resectable cases, there is no evidence-based role for neoadjuvant chemotherapy to date; clinical trials should be considered.
# Summary of Evidence
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, and only approximately 20% of cases present when disease is localized and amenable to surgical resection . Various trials have assessed the impact of adjuvant therapy after surgical resection of PDAC. The ESPAC-1 study was a two-by-two factorial design, randomizing patients to adjuvant chemoradiation, chemotherapy, both treatments or observation alone, with a goal of assessing the impact of chemoradiation versus no chemoradiation, and chemotherapy versus no chemotherapy on two-year OS . Accrual was poor, therefore patients were accrued in a parallel study known as ESPAC-1 plus, where they were ran-domized to adjuvant chemotherapy with bolus 5-fluorouracil (5FU) and folinic acid versus observation, and clinicians were able to provide chemoradiotherapy if they felt that it was clinically indicated . Overall, the results of ESPAC-1 showed a benefit to adjuvant chemotherapy, with a two-year OS of 40% with chemotherapy compared to 30% with no chemotherapy, and possible harm to the administration of adjuvant chemoradiation, with a two-year OS of 29% with chemoradiation compared to 41% amongst those who received no chemoradiation. ESPAC-1 was not powered to assess the impact of adjuvant chemotherapy to observation, however, the ESPAC-1 plus results showed a similar benefit to adjuvant chemotherapy. The interpretation of these studies is limited by a number of factors, including the complicated study design and radiation techniques used.
However, further trials demonstrated the utility of adjuvant chemotherapy in resectable PDAC. The CONKO-001 trial randomized patients who had undergone a complete macroscopic resection to six cycles of gemcitabine 1000 mg/m 2 on days 1, 8 and 15 of a 28-day cycle or observation . There was a statistically significant improvement in disease free survival (DFS) (median DFS 13.4 months with gemcitabine versus 6.7 months with observation) and OS (5-year OS 20.7% with gemcitabine versus 10.4% with observation), and this benefit persisted in patients with both R0 and R1 resections. A randomized comparison of adjuvant gemcitabine to 5FU showed no difference in OS, however, there was more grade 3 toxicity, including stomatitis, diarrhea and hospitalizations, with 5FU compared to gemcitabine .
The ESPAC-4 study addressed whether six months adjuvant gemcitabine and capecitabine, was superior to gemcitabine alone . Patients with macroscopically complete resection of PDAC, with no evidence of metastatic disease, an Eastern Cooperative Group (ECOG) performance score (PS) of 0-2, who had not received any neoadjuvant chemotherapy, were randomized to combination therapy with gemcitabine 1000 mg/m 2 weekly on days 1, 8 and 15 of a 28 day cycle and capecitabine 1660 mg/m 2 for 21 days followed by a 7 day break, versus gemcitabine alone. Results were stratified by country of enrollment and resection margin status (R0 versus R1). Treatment was to be started within 12 weeks of surgery and enrollment in ESPAC-4 was not restricted by post-operative CA 19-9 levels. The primary endpoint was OS and secondary endpoints included survival at 24 months and 5 years, relapse free survival (RFS), toxicity and quality of life as measured by the EORTC QLQ-C30 questionnaire. The study cohort included patients with a poor prognosis, as 60% of patients had R1 resection margins, 80% had lymph node positive disease, and post-operative CA 19-9 levels ranged from 0.1 to >8000. The median OS with gemcitabine and capecitabine was 28.0 months compared to 25.5 months with gemcitabine alone (hazard ratio 0.82, 95% CI 0.68-0.98, p = 0.032). On multivariable analysis, tumor grade, lymph node status, maximum tumor size, resection margin status and post-operative CA 19-9 levels were independent predictors of OS. Interestingly, there was no difference in RFS between combination therapy and gemcitabine alone (HR 0.86, 95% CI 0.73-1.02, p = 0.082). There was increased grades 3 and 4 toxicity with combination therapy, including increased neutropenia, infections, diarrhea and hand foot syndrome.
APACT is a phase III randomized controlled trial assessing adjuvant nab-paclitaxel plus gemcitabine (NG) compared to gemcitabine alone, with a primary endpoint of independently assessed DFS . Patients with resected PDAC with no evidence of metastatic disease and a post-operative CA 19-9 < 100 were randomized in a 1:1 fashion to the two treatment arms. Results were stratified by geographic region, resection margin status and lymph node status. In total, 24% of patients had R1 margins and 72% had lymph node positive disease. There was no difference in independently assessed DFS between the two treatment groups. The median DFS with NG was 19.4 months, compared to 18.8 months with gemcitabine alone (hazard ratio 0.88, 95% CI 0.73-1.06, p = 0.18). In a pre-planned subgroup analysis, the groups that appeared to benefit from combination therapy included moderate compared to poorly differentiated tumors, lymph node positive disease and normal CA 19-9. There was a statistically significant difference in investigator-assessed DFS, at 16.6 months for NG, compared to 13.7 months for gemcitabine (hazard ratio 0.82, 95% CI 0.694-0.965, p = 0.0168). The difference between independent and investigator assessed DFS may be related to the clinical features that physicians take into consideration, alongside radiologic findings, when assessing disease progression in patients with PDAC. The median OS for those who received NG was 40.5 months, compared to 36.2 months for gemcitabine alone (hazard ratio 0.82, 95% CI 0.68-0.996, p = 0.045), although data are not yet mature.
Investigation of a more intensive adjuvant regimen was investigated in the PA.6 trial . Patients with macroscopic resection of PDAC, with no evidence of metastatic disease were randomized to six months of modified FOLFIRINOX (mFOLFIRINOX), consisting of 46 h infusion of 5FU (2400 mg/m 2 ), leucovorin (400 mg/m 2 ), oxaliplatin (85 mg/m 2 ) and irinotecan (150 mg/m 2 ) given once every two weeks, or gemcitabine 1000 mg/m 2 given on days 1, 8 and 15 on a 28 day schedule. Criteria for enrollment in this study were more stringent, as patients had to be 50 mL/minute, and a post-operative CA 19-9 level 70 years old, representing 20.5% of the study population, the benefit of mFOLFIRINOX over gemcitabine did not reach significance (hazard ratio 0.86, 95% CI, 0.53-1.39). On multivariable analysis, factors independently predictors of worse DFS included tumor grade and portal vein resection. Median OS was also improved with mFOLFIRINOX at 54.5 months compared to 35.0 months with gemcitabine (stratified hazard ratio for death, 0.64; 95% CI, 0.48-0.86; p = 0.003). It should be noted that the median OS seen in the gemcitabine group is longer than what has been seen historically, with many potential reasons, including better surgical technique, patient selection and post-progression therapies. As expected, mFOLFIRINOX was associated with increased toxicity. Grade 3/4 toxicity occurred in 52.9% of patients receiving mFOLFIRINOX, compared to 12.2% of those receiving gemcitabine. Specifically, there was more mucositis, nausea, vomiting, diarrhea, abdominal pain, fatigue, elevated GGT and paresthesias with mFOFLIRINOX. Over 60% of those receiving mFOLFIRINOX received growth factor support, compared to 3.7% of those receiving gemcitabine. There was no difference in grade 3/4 toxicity based on age 70. Due to the superior survival seen with mFOLFIRINOX, it is the adjuvant chemotherapy regimen of choice; however, factors such as age, ECOG PS, comorbidities, post-operative CA 19-9 and chemotherapy toxicity profile should be taken into consideration.
The role of adjuvant radiation is not well defined and results from randomized trials are conflicting. Overall, there is no strong evidence for using radiation therapy for a survival improvement. Adjuvant radiation therapy may be considered in selected patients, following systemic therapy, with the primary goal of reducing the risk of local-regional recurrence and maintaining quality of life. In resectable cases, there is no evidence for the routine use of neoadjuvant radiation therapy . When radiation therapy is used for the treatment of pancreatic cancer, pre-radiation treatment anti-emetics are recommended. For patients with tumors close to the stomach or duodenum (the great majority of pancreatic cancers), proton pump inhibitors are recommended to reduce the risk of gastric toxicity .
When deciding on whether a neoadjuvant approach or an upfront surgical approach should be taken, it is critical to clearly define whether a PDAC is resectable, borderline resectable, borderline unresectable or unresectable. Definitions of resectability have evolved over time and require sufficient radiographic and surgical expertise to determine. The nature and extent of vascular involvement is often a primary determinant of resectability, with abutment indicating ≤180 degree involvement and encasement >180 degree involvement of a particular vessel. To be considered borderline resectable, most guidelines permit superior mesenteric vein/portal vein encasement, as long as reconstruction of the vessel is feasible, while the superior mesenteric artery can typically only have abutment for a case to be considered borderline resectable . Borderline resectable cases typically permit common hepatic artery abutment or short-segment encasement, while most guidelines indicate celiac artery abutment or encasement would render pancreatic cancer unresectable . Notably, there can be exceptions to arterial involvement, as arterial replacement or resections can occasionally be performed by an experienced hepatobiliary surgeon. Given the complexity of the determination, it often falls to the hepatobiliary surgeon with or without a multidisciplinary discussion to elucidate what is safe and feasible. Clear communication is important to set patient and provider expectations, particularly when disease is either unresectable or only borderline resectable so that management plans can be appropriately aligned with realistic goals.
The role of neoadjuvant chemotherapy in patients with resectable disease is unclear. Offering chemotherapy up front in patients with disease that is amenable to surgical resection may offer some benefits. Neoadjuvant treatment may allow for an assessment of tumor biology, including an evaluation of whether disease responds to aggressive chemotherapy. Those with progressive disease despite optimal chemotherapy may be spared from an aggressive and potentially morbid surgery. Giving neoadjuvant chemotherapy has the potential to treat micrometastatic disease and increase R0 resections. Due to the potential for post-operative complications, which may delay or limit the ability to administer adjuvant chemotherapy, giving chemotherapy before surgery may be preferred. Despite these potential benefits, the role of neoadjuvant chemotherapy in patients with resectable PDAC remains unclear, as there is a lack of evidence to support such an approach. A systematic review and meta-analysis attempted to address this question . When including only randomized and prospective phase II and III trials comparing neoadjuvant to adjuvant therapy, only two phase II papers, one of which was randomized, were identified. The inclusion criteria were therefore expanded to include an additional four prospective and three retrospective studies. The analysis favored neoadjuvant therapy for increasing R0 resections and survival at various time points, however, the poor quality and small number of studies limits the ability to make strong conclusions about the role of neoadjuvant therapy in this setting, and ultimately, upfront surgery followed by adjuvant chemotherapy remains the standard of care for patients with resectable PDAC. Ongoing trials, such as the NEOPAC (NCT01521702) and ALLIANCE A021806 studies, will add further information about the role of neoadjuvant therapy for PDAC. One of the challenges of trials in this setting will be to ensure clear definitions of resectable disease and confirming trial participants are indeed eligible , and the endpoints chosen in trials should reflect clinically relevant endpoints including OS and R0 resection rates.
The role of neoadjuvant chemotherapy in borderline resectable PDAC is also unclear. In a phase 2 study of 48 patients with borderline resectable PDAC determined by a multidisciplinary team review, patients received pre-operative FOLFIRINOX followed by neoadjuvant chemoradiation . The primary outcome was R0 resection rate, which was achieved in 65% of patients. The median PFS was 14.7 months and the median OS was 37.7 months. A meta-analysis compared the impact of neoadjuvant therapy (chemotherapy, chemoradiation or both) versus upfront surgery on survival in patients with resectable or borderline resectable PDAC . The median OS with any neoadjuvant therapy was 18.8 months, compared to 14.8 months for those who underwent upfront surgery. A retrospective study of patients with borderline resectable and locally advanced PDAC receiving neoadjuvant FOLFIRINOX versus upfront surgery showed that 92% of patients had an R0 resection who received neoadjuvant FOLFIRINOX . Given the heterogeneity of the populations included in these studies (resectable, borderline resectable and locally advanced disease), as well as the heterogeneity of the neoadjuvant therapies used, one should be cautious when interpreting these results. Ultimately, clear definitions of resectability and well-designed randomized phase 3 trials are required to answer the question of the role of neoadjuvant chemotherapy, and the optimal regimen, in borderline resectable PDAC.
Currently, if patients are to receive neoadjuvant therapy for PDAC, this would best be done on a clinical trial. Cases should be reviewed in a multi-disciplinary fashion to determine the intent and strategy for borderline resectable pancreas cancer as it is important to set realistic expectations for patient outcomes. Neoadjuvant chemotherapy using FOLFIRINOX is the preferred strategy due to its objective response rate (31.6%) in the metastatic setting and efficacy in the adjuvant setting . Notably, an objective response may not translate to conversion from borderline resectable to resectable disease, as there may be specific anatomic considerations required for a response to allow for surgical resectability. NG can be considered depending on patient factors and tolerability, though it does have a lower objective response rate (23%) in the metastatic setting and more questionable benefit in the adjuvant setting . Chemoradiotherapy or radiotherapy alone may be considered in selected cases following systemic therapy. The primary role of radiation therapy is to increase the chance of a R0 resection margin and to reduce the risk of local recurrence. Capecitabine is the preferred radiation sensitizer for patients who have previously received FOLFIRINOX, and it has been shown to be associated with less toxicity than gemcitabine-based chemo-radiation therapy . Gemcitabine-based chemo-radiation therapy is an alternative for patients who have not received FORFIRINOX.
Published after the WCGCCC meeting, the PREOPANC trial randomized patients with resectable and borderline resectable pancreatic cancer to receive chemoradiation with gemcitabine and surgery or surgery alone, followed by adjuvant gemcitabine . This trial demonstrated an improvement in surrogate endpoints such as R0 resection rates (71 vs. 40%), disease-free survival and locoregional failure-free interval with the use of neoadjuvant chemoradiation. No OS benefit was observed initially, though with longer follow-up a potential survival benefit has been suggested . However, this trial utilizes inferior systemic treatment in the control arm with gemcitabine alone and may not be reflective of modern practice. The phase II SWOG S1505 study compared neoadjvuant treatment with mFOLFIRINOX and nab-pacltaxel/gemcitabine and found similar R0 resection rates (73 vs. 70%) but failed to meet pre-specified endpoints to be carried forward . The results from further trials such as PREOPANC II, using FOLFIRINOX are awaited . Despite new data since the WCGCCC meeting, routine use of neoadjuvant treatment remains an area of active research, and there remains a need for better powered studies to determine who best to adopt a neoadjvuant approach for.
# Question 5
What are the current standard surgical options for patients with hepatocellular carcinoma?
# Recommendations
Patients should be referred to a hepatobiliary surgeon to review local regional strategies and for multi-disciplinary review. Multi-disciplinary review should involve representatives from transplant, surgery, radiation oncology, medical oncology and interventional radiology. Surgery remains the gold standard for resectable HCC if able to obtain an adequate future liver remnant (FLR). Transplantation is preferred for non-resectable HCC patients with cirrhosis within transplant criteria.
# Summary of Evidence
Over recent years there have been significant technological and scientific developments related to the treatment of hepatocellular carcinoma. As a result, there are more locoregional treatment options as well as systemic treatment options. Locoregional treatment options include resection, including laparoscopic resection, liver transplantation, thermal ablation (including radiofrequency ablation and microwave ablation), stereotactic body radiotherapy (SBRT), transarterial chemoembolization (TACE), brachytherapy (where available), and transarterial radioembolization (TARE). The nuances of each of these therapeutic modalities, including case-specific feasibility, limitations and precautions, require expert input from specialists from different disciplines. Therefore, an effective multidisciplinary discussion requires the involvement of surgeons, hepatologists, interventional radiologists, radiation oncologists and medical oncologists, as well as diagnostic radiologists.
The diagnosis of HCC is often made based on imaging, without a biopsy. The Liver Imaging Reporting and Data System (LI-RAD) classification of liver lesions enables estimation of the likelihood that a liver lesion is a hepatocellular carcinoma . Expert assessment of liver lesions by a radiologist is therefore integral to clinical management.
Decisions related to the optimal management of hepatocellular carcinoma require a full appreciation of the patient's comorbidities and performance status, as well as an assessment for underlying liver disease and portal hypertension. A full medical evaluation is essential. Liver function is first evaluated by applying Child-Pugh criteria , which requires INR, albumin, total bilirubin, and evaluation for ascites and encephalopathy. If transplantation is being considered, the MELD score can be calculated (based on creatinine, bilirubin, INR and serum sodium) . Good renal function is essential for TACE. If it is unclear whether hepatic fibrosis or cirrhosis is present, ultrasound elastography or MR elastography is helpful . The presence of portal hypertension can be deduced if varices are seen on cross-sectional imaging or esophagogastroscopy, or if there is evidence of hypersplenism such as a large spleen or thrombocytopenia.
Anatomic factors must also be considered. The intent of resection is curative and therefore, it must be feasible to remove the entirety of the tumor while leaving sufficient liver remnant to avoid liver failure. Occasionally, it may be necessary to perform a portal vein embolization on the side that is being removed in order to induce hepatic hypertrophy on the liver remnant. Thermal ablation should be avoided in lesions located centrally, near the bifurcation of the porta hepatis; lesions located near large vessels are susceptible to heat sink , limiting the effectiveness of the procedure; accessing lesions at the liver surface should consider the approach due potential risks of tumor seeding. While transplantation is the best option for healthy patients with poor liver function, it is not indicated in the presence of a large tumor burden. The Milan criteria (a solitary lesion ≤5 cm maximal diameter or up to 3 lesions ≤3 cm) represent conservative criteria, but extended criteria have been more recently introduced with acceptable results .
The Barcelona Clinic Liver Cancer (BCLC) staging system represents one construct that can help to guide treatment options . The BCLC staging system takes into account the Child-Pugh grade of liver function, the size and number of nodules, and performance status (Table 3). In addition, the platelet count should be considered in treatment decisions. The optimal candidate for resection is an individual who is in good medical condition, has good performance status, has good hepatic functional reserve (Child-Pugh A), has a normal platelet count and has no varices. This corresponds to patients in BCLC Stage 0 or A. Having said that, as described above, there are many nuances to decision-making, and alternatives to resection could also be considered. While the BCLC staging system is an excellent construct to help make treatment decisions, it must be appreciated that there are numerous treatment options for each BCLC stage. The best options are a product of local expertise, and they will evolve as the clinical science improves.
# Summary of Evidence
The standard first line therapy options for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) with good performance status include FOLFIRINOX and gemcitabine and nab-paclitaxel . The choice between the two regimens is often dependent on the patient's co-morbidities and physician/patient preference. Although survival outcomes are inferior with gemcitabine alone, it has demonstrated symptomatic clinical benefit, and can be considered when combination therapy is not feasible .
For patients who have progressed from FOLFIRINOX, there is no standard chemotherapy proven with phase III evidence. However, inferring from retrospective studies (ranging from 7 to 69 patients), gemcitabine with nab-paclitaxel has an overall response rate (ORR) of approximately 18% with a median PFS of 3 months and median OS of 5-8 months from the date of starting second line therapy . Given the regimen appears efficacious in the second line, it is the preferred regimen for patients who can tolerate combination chemotherapy. For those that cannot, gemcitabine monotherapy may be considered .
For patients who have progressed on gemcitabine and nab-paclitaxel, liposomal irinotecan and fluorouracil as per NAPOLI-1 trial and OFF regimen as per CONKO-3 trial are reasonable treatment options with phase III evidence . Of note, the PANCREOX study showed conflicting results with the mFOLFOX6 regimen having inferior mOS compared to infusional 5FU (6.1 vs. 9.9 months, HR 1.78 (95%CI 1.08-2.93), p = 0.024) . Therefore, if an oxaliplatin based regimen is utilized then oxaliplatin should be given as per the OFF regimen.
For patients with mPDAC who have known germline BRCA mutations or DNA damage repair (DDR) genes then second line treatment with platinum-based chemotherapy may be considered, especially if they are platinum naïve. This is supported by the Know Your Tumour Type study, where patients with advanced PDAC with DDR (n = 54) was predictive of significant improvement in mOS if treated with platinum-based therapy (2.37 vs. 1.45 years, p < 0.0001) . Similarly, in a smaller study of 71 patients with somatic BRCA mutations where those treated with platinum (n = 22) versus not (n = 21), mOS was improved to 22 vs. 9 months, p = 0.03915 . The DDR genes of interest are pathogenic alterations in BRCA1/2, PALB2, ATM, ATR, ATRX, BAP1, BARD1, BRIP1, CHEK1/2, RAD50/51/51B, or FANCA/C/D2/E/F/G/L if this prospective trial evidence is to be applied. Of note, patients with DDR aberrations may also be more sensitive to 5-FU and irinotecan . For liposomal irinotecan, the benefit seems to be in irinotecan naïve patients where a retrospective study by Glassman DC et al. showed reduced ORR and mOS in prior irinotecan treated patients and naïve patients had similar benefit as per the NAPOLI-1 trial .
Beyond chemotherapy, emerging actionable targets with survival benefits are being identified through next generation sequencing (NGS), particularly in patients with KRAS wildtype mPDAC . However, targeted therapies are not routinely considered outside of a clinical trial. In 0.5-0.8% mPDAC patients with deficiency in mismatch repair protein (dMMR) or microsatellite instability (MSI-H), pembrolizumab has shown to be efficacious . NTRK fusion inhibitors with larorectinib and entrectinib have been recognized as efficacious across multiple tumor types including mPDAC for patients who harbor the fusion . NRG1 is another recurrent fusion found across multiple tumor types with a prevalence of approximately 0.3% in mPDAC . There is emerging evidence that it can be targeted with afatinib with a quick and durable response . The logistical challenge in reliable detection of such a rare mutation across the population poses a barrier to its utility in today's clinical practice.
There is recognition of 5-10% hereditary cancer risk associated with mPDAC diagnosis, which may be higher in certain subpopulations . ASCO and NCCN guidelines recommend that germline testing be considered for all patients with mPDAC in recognition that up to half of the patients may not have a classical family history and germline BRCA mutations may carry treatment implications . However, the implementation of testing across the population remains a significant barrier and is subject to ongoing research . After an initial response to platinum-based chemotherapy, the use of maintenance olaparib compared to placebo demonstrated improved PFS, suggesting activity with the parp inhibitor, but the lack of OS improvement and use of placebo as a control (as opposed to ongoing chemotherapy) casts doubt over its utility despite FDA approval .
# Question 7
What is the preferred adjuvant therapy for patients with early stage biliary tract cancer? What are the preferred first-and second-line systemic therapies in patients with advanced biliary tract cancer? What are potential targeted treatments for biliary tract cancer?
# Recommendations
In the adjuvant setting, capecitabine for 6 months is the preferred option. For positive margin disease, patients should be reviewed in a multi-disciplinary fashion to determine if radiotherapy is reasonable.
In patients with advanced biliary tract cancers, the preferred first line option is gemcitabine and cisplatin. Gemcitabine is an option in patients who cannot tolerate combination therapy.
Fluoropyrimidine-based chemotherapy may be considered in the second line setting.
The role of molecular testing and targeted therapy is evolving. For MSI-high, MMRdeficient advanced biliary cancer, pembrolizumab should be considered for chemotherapy refractory disease.
# Summary of Evidence
The phase III BILCAP trial, randomized 447 patients with resected biliary tract cancers to receive eight cycles of capecitabine (1250 mg/m 2 twice daily on days 1-14 every 21 days) or placebo . In total, 38% had R1 resection. The primary intention-to-treat analysis for OS did not meet statistical significance (51.1 vs. 36.4 months, HR 0.81 95% CI 0.63-1.04, p = 0.097), while per-protocol analysis did (53 vs. 36 months, HR 0.75, 95% CI 0.58-0.97, p = 0.028). Additionally, pre-planned sensitivity analyses adjusting for nodal status, disease grade and sex suggested that capecitabine was beneficial (HR 0.71, 95% CI 0.55-0.92, p = 0.010) and RFS was improved in both intention to treat and per-protocol analysis. Given the magnitude of benefit and supportive analyses, adjuvant capecitabine has been adopted as a new standard of care for patients with resected biliary tract cancer. The benefit of adjuvant radiation or chemoradiation is unclear as there is no prospective, randomized data to support its routine use. However, retrospective data suggests potential benefit, particularly in patients with positive margins, so it is reasonable to have these cases reviewed in a multidisciplinary fashion to determine if radiotherapy should be considered .
Cisplatin and gemcitabine are recommended for first line treatment of metastatic cholangiocarcinoma based on the multicenter ABC-02 trial. In this study, 410 patients were randomly assigned to eight cycles of cisplatin (25 mg/m 2 ) followed by gemcitabine (1000 mg/m 2 ) on days 1 and 8 every 21 days, or gemcitabine alone (1000 mg/m 2 on days 1, 8, and 15 every 28 days) . Median OS was significantly greater with combination therapy (11.7 versus 8.1 months), as was median PFS (8 versus 5 months). For second-line, ABC-06 was the first prospective phase III trial evaluating the benefit of chemotherapy after Cisplatin and Gemcitabine in patients with advanced cholangiocarcinoma. The trial compared infusional fluorouracil plus leucovorin and oxaliplatin (FOLFOX) with active symptom control. FOLFOX improved OS at 6 (61 versus 36%) and 12 months (26 versus 11%) . The incremental benefit of oxaliplatin in addition to fluoropyrimidine alone after cisplatin and gemcitabine is unclear. Whilst there is a lack of prospective evidence, retrospective comparisons indicate oxaliplatin combination achieves a higher objective response rate (8 vs. 1%, p = 0.009), but PFS and OS are not clearly different from a fluoropyrimidine alone .
Molecular targeted therapy has been an emerging area of interest for biliary tract cancers. As with other cancers that are dMMR/MSI-H, immunotherapy has demonstrated activity for this disease subtype . Similarly, TRK inhibitors like larorectinib and entrectinib have been recognized as efficacious for TRK-fusion positive cholangiocarcinomas as well . Several trials are also evaluating the role of FGFR2 transloactions, which are present in approximately 13% of patients with cholangiocarcinoma . Pemigatinib has subsequently received FDA approval due to an objective response rate of 36% and disease control rate of 80% . Infigratinib is another FGFR2 targeted therapy that has received accelerated approval by the FDA . The emerging number of targeted therapies available for intrahepatic cholangiocarcinomas has led to a blanket recommendation by ESMO for routine next generation sequencing for these cancers . However, funding for such testing remains elusive in the publicly funded context of Canada. | This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY# Terms of Reference 1.Purpose
The Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) aims to develop consensus opinion of oncologists and allied health professionals from across Western Canada, attempting to define best care practices and to improve care and outcomes for patients with gastrointestinal cancers.
# Target Audience
The recommendations presented here are targeted at health care professionals involved in the care of patients with hepato-pancreato-biliary (HPB) cancers.
# Basis of Recommendations
The recommendations are based on the presentation and discussion of the best available evidence. Where applicable, references are cited. Additional evidence has been published since the timing of the 2019 meeting, and the authors have incorporated this, where relevant, into each topic discussion. Barriers to access (e.g., approval but no funding) and limitations in data interpretation continue to make the consensus recommendations relevant, even in light of new data.
# Question 1
What is the current role of stereotactic body radiation (SBRT) in hepatocellular carcinoma (HCC)?
# Recommendations
The role of SBRT in HCC is evolving and clinical trials should always be considered. Cases should be reviewed in multi-disciplinary rounds. SBRT is an option to be considered alongside other ablative therapies. SBRT as a bridge or downstaging to transplant could also be considered in addition to other local regional strategies.
# Summary of Evidence
The role of SBRT continues to be refined, with clinical trial enrollment as the optimal means of advancing its use in HCC. When considered alongside other ablative therapies in a multi-disciplinary discussion, SBRT is best suited for patients with HCC at a higher risk of complications or recurrence following interventional ablative therapies (e.g., tumors >3-5 cm, infiltrative tumors, located near the dome of the liver) [1]. SBRT can also serve as a bridge to or as downsizing for transplant in addition to other local regional strategies. Risks are higher in patients who receive SBRT for central lesions and who go on to have a live donor liver transplant. Thus, multi-disciplinary decision making is crucial for these patients.
Vascular invasion is a poor prognostic factor in HCC patients. Survival is worse in patients with more extensive HCC with vascular involvement (main vessel involvement, occlusive tumor thrombus). For patients with vascular invasion (hepatic vein, portal vein, IVC or branch invasion), SBRT may be used with the goal of debulking or ablating intravascular tumor and increasing the chance of recanalization. A randomized phase II study from Korea demonstrated improved progression free survival (PFS) and overall survival (OS) with radiation therapy combined with TACE compared to sorafenib alone, in patients with macrovascular HCC invasion [2].
# Question 2
What is the optimal sequence of systemic therapy in patients with advanced HCC? In the first line setting? In the second line setting?
# Recommendations
# •
Sorafenib or lenvatinib are options for first line therapy in patients who are not eligible for local-regional strategies and have a Child-Pugh A score. Sorafenib can also be considered in Child-Pugh B7 in the absence of ascites. The alternate treatment can be considered in cases of intolerance.
# •
In the second line setting, options include regorafenib and cabozantinib.
# •
Clinical trials should be considered. The role of immunotherapy is evolving.
# Summary of Evidence
Sorafenib has been the standard treatment for advanced HCC for over a decade since the SHARP and Asia-Pacific trials showed that sorafenib improved OS compared to placebo [3,4]. In 2018, the REFLECT trial showed that lenvatinib is non-inferior for OS when compared to sorafenib in the first-line treatment of advanced HCC [5]. Response rates and PFS favored lenvatinib. The patients included in these trials had Child-Pugh A liver function. For patients with Child-Pugh B liver function, sorafenib appears to be safe according to the GIDEON observational study [6]. Many oncologists would treat patients with Child-Pugh B7 liver dysfunction in the absence of ascites if the patient has a good performance status.
In clinical trials, sorafenib has been shown to be associated with toxicities such as palmar-plantar erythrodysesthesia, diarrhea, hypertension, anorexia, weight loss and fatigue [3,4]. Lenvatinib appears to have lower rates of palmar-plantar erythrodysesthesia, but higher rates of hypertension [5]. Thus, in patients intolerant of sorafenib for such toxicities as palmar-plantar erythrodysesthesia, lenvatinib should be considered. Alternatively, in patients with poorly controlled hypertension, sorafenib would be preferred. Other first-line treatment options, such as the combination of atezolizumab and bevacizumab were not available at the time of this discussion.
In second line setting, post-sorafenib, the RESORCE trial found that regorafenib improves OS compared to placebo (median 10.6 vs. 7.8 months, HR 0.63, 95% CI 0.50-0.79, p < 0.0001). Patients in this study must have tolerated and progressed on sorafenib [7]. In 2018, the CELESTIAL trial found that cabozantinib improves OS compared to placebo (median 10.2 vs. 8.0 months, HR 0.76 95% CI 0.63-0.92, p = 0.005) when given to patients who have been treated with up to two lines of systemic therapy for hepatocellular carcinoma, including previous treatment with sorafenib [8]. The REACH-2 trial evaluated patients after first-line sorafenib with a poorer prognosis with an AFP ≥400 ng/mL, and found that ramucirumab led to a more modest improvement in OS compared to placebo (median 8.5 vs. 7.3 months, HR 0.710, 95% CI 0.531-0.949, p = 0.0199), which though statistically significant may not be as clinically significant [9].
The prognosis of advanced stage HCC is still very poor despite the recent advances in systemic treatment. Immunotherapy drugs are currently being studied in clinical trials. However, two reported phase III trials of anti-PD1 drug monotherapy (nivolumab, pembrolizumab) have failed to show a statistically significant improvement in overall survival in first-and second-line treatment, respectively, despite previous accelerated FDA conditional approval [10,11]. Trials of combination treatments including immunotherapy and tyrosine-kinase inhibitors in the first-line setting for advanced HCC are ongoing. The combination of atezolizumab and bevacizumab, compared to sorafenib in the IMbrave150 study, presented at ESMO Asia 2019, after the WCGCCC meeting, suggests that the combination is superior to sorafenib and likely to become a new standard of care in the first line setting [12]. The combination of atezolizumab and bevacizumab is Health Canada approved and received a conditional approval from the national oncology-specific health technology assessment body pan-Canadian Oncology Drug Review (pCODR) assuming the cost-effectiveness of the treatment can be improved upon [13]. Despite support for its use, funding negotiations remain unresolved, limiting its use to a minority of patients who can afford to pay out of pocket or with the assistance of a private drug plan. Patients with a history of autoimmune disease or uncontrolled varices are also ineligible, keeping discussions about lenvatinib and sorafenib in the first-line setting relevant.
Existing second line studies all used sorafenib as a first line treatment, so it is difficult to interpret the efficacy of these novel agents in the context of new data. The RESORCE trial excluded patients who had other systemic treatments beyond sorafenib, while the CELES-TIAL trial included patients with two or more systemic therapies, including 17 patients who had prior immunotherapy, though not specifically in the combination of atezolizumab and bevacizumab [7,8]. Further expert opinion and limited real-world studies have suggested that the activity of sorafenib and lenvatinib, post-atezolizumab and bevacizumab may have similar activity to the first line setting, suggesting a simple shift in the sequencing discussed at the 2019 WCGCCC meeting [14,15].
# Question 3
What are the important dietary interventions in the management of pancreatic cancer? What is the role of pancreatic enzyme replacement therapy?
# Recommendations
All patients with pancreas cancer should be referred to a registered dietitian for specialized nutritional care due to the high risk of malnutrition. Initial care providers should screen patients for pancreatic enzyme deficiency and initiate replacement if needed.
# Summary of the Evidence
Pancreatic cancer is a very aggressive malignancy that is often not diagnosed until an advanced or metastatic stage. More than 80% of patients with PDAC present with malnutrition at diagnosis due to multifactorial causes [16,17]. It has been estimated that 10-20% of deaths in patients with cancer are related to malnutrition rather than their malignancy [18]. Therefore, it is essential to identify, understand the etiology, and apply appropriate nutritional interventions to curtail the deleterious symptoms of malnutrition and improve clinical outcomes. The three factors which expose pancreatic cancer patients to such a high risk of malnutrition are (1) disease-related malnutrition (anorexia, hypermetabolism), (2) treatment side effects (nausea, vomiting, constipation, diarrhea, mouth sores, taste changes), and (3) exocrine/endocrine dysfunction. A consultation with a specialized registered dietitian can support the patient and team in the identification and management of these issues.
In the setting of cancer, both pancreatic exocrine and endocrine functions can be affected. Endocrine cells make up approximately 5% of the pancreas and function to regulate metabolism in the body through the production and secretion of hormones such as insulin and glucagon. Derangements in this system will present as diabetes mellitus [18]. The majority of pancreatic cells, however, are exocrine cells. The pancreatic exocrine cells produce digestive juices (bicarbonate) and enzymes (protease, amylase, and lipase) which are essential for the neutralization of gastric chyme and the digestion of all macronutrients. Pancreatic enzyme insufficiency (PEI) is defined as the reduced or inappropriate secretion or activity of pancreatic juice and its digestive enzymes, particularly pancreatic lipase. The presence of PEI affects a patients' ability to properly digest and absorb protein (protease), fat (lipase), and complex carbohydrates (amylase).
When assessing this population for PEI, it is important to consider location, size, history of chronic pancreatitis, ductal obstruction and surgical intervention to the pancreas and tumor. The prevalence of PEI post Whipple procedure is 80-90% compared to 20-50% in patients who underwent a distal pancreatectomy. In contrast, 20-60% of patients with unresectable pancreatic adenocarcinoma have PEI [19].
Signs and symptoms of PEI can be broken down into three main categories; abdominal, nutritional and endocrine. Abdominal symptoms include diarrhea, steatorrhea, fecal urgency, bloating, malodorous gas, GERD, cramping and abdominal pain, and post prandial gurgling. Nutritional symptoms include weight loss, sarcopenia, weakness and fatigue, food avoidance, and fat soluble vitamin deficiency. Endocrine symptoms will present with hypoglycemia or decreased hyperglycemic agent requirements. If a patient has pancreatic adenocarcinoma and any of the above symptoms, the intervention recommended is pancreatic enzyme replacement therapy (PERT) [19,20]. Patients who have an intact stomach taking enzymes orally require enterically coated versions. The two main brands of these enzymes used in Canada are Creon 10 and 25 and Cotazym ECS 8 and 20. Non-enterically coated enzymes (Viokase, Cotazym) are required for patients with a feeding tube (gastrically or jejunely) or post-gastrectomy. Each capsule of PERT has a combination of protease, lipase and amylase, as broken down in Table 2. The dosing of PERT is primarily based on the cystic fibrosis population and additional enzyme replacement is likely needed for the pancreatic cancer population [16]. PERT is prescribed based on per kilogram body weight of the patient, in a range of 500-2500 units of lipase per kilogram body weight per meal, up to 10 000 units of lipase per kilogram of body weight per day. The risk associated with exceeding this is constipation. PERT should be taken before all meals and snacks that contain macronutrients and will last for up to 1 h after consumption. Larger meals or meals that contain a higher amount of fat will require more PERT for adequate digestion.
The European Society for Clinical Nutrition and Metabolism (ESPEN) and the American Society for Parenteral and Enteral Nutrition (ASPEN) guidelines suggest no macronutrient restriction, with protein requirements elevated to 1.2-2.0g/kilogram body weight/day. Patients on appropriate PERT should feel an improvement in symptom burden and will better absorb the nutrients they are ingesting.
# Question 4
What is the optimal neoadjuvant/adjuvant strategy for pancreas cancer?
# Recommendations
# •
Six months of mFOLFIRINOX is standard adjuvant therapy for patients with resected pancreatic cancer. In patients who are not candidates for mFOLFIRINOX, a combination of gemcitabine/capecitabine or gemcitabine alone or 5FU alone can be considered.
# •
The role of adjuvant radiation is not well defined but may be considered in patients with high risk of local recurrence, in the context of a multidisciplinary discussion.
# •
Cases should be reviewed in a multi-disciplinary fashion to determine the intent and strategy for borderline resectable pancreas cancer. Clinical trials should be considered for these patients. Neoadjuvant chemotherapy using FOLFIRINOX is the preferred strategy. Gemcitabine and Nab-paclitaxel can be considered depending on patient factors and tolerability. Chemoradiotherapy or radiotherapy could be considered in select cases.
# •
In resectable cases, there is no evidence-based role for neoadjuvant chemotherapy to date; clinical trials should be considered.
# Summary of Evidence
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, and only approximately 20% of cases present when disease is localized and amenable to surgical resection [21]. Various trials have assessed the impact of adjuvant therapy after surgical resection of PDAC. The ESPAC-1 study was a two-by-two factorial design, randomizing patients to adjuvant chemoradiation, chemotherapy, both treatments or observation alone, with a goal of assessing the impact of chemoradiation versus no chemoradiation, and chemotherapy versus no chemotherapy on two-year OS [22]. Accrual was poor, therefore patients were accrued in a parallel study known as ESPAC-1 plus, where they were ran-domized to adjuvant chemotherapy with bolus 5-fluorouracil (5FU) and folinic acid versus observation, and clinicians were able to provide chemoradiotherapy if they felt that it was clinically indicated [23]. Overall, the results of ESPAC-1 showed a benefit to adjuvant chemotherapy, with a two-year OS of 40% with chemotherapy compared to 30% with no chemotherapy, and possible harm to the administration of adjuvant chemoradiation, with a two-year OS of 29% with chemoradiation compared to 41% amongst those who received no chemoradiation. ESPAC-1 was not powered to assess the impact of adjuvant chemotherapy to observation, however, the ESPAC-1 plus results showed a similar benefit to adjuvant chemotherapy. The interpretation of these studies is limited by a number of factors, including the complicated study design and radiation techniques used.
However, further trials demonstrated the utility of adjuvant chemotherapy in resectable PDAC. The CONKO-001 trial randomized patients who had undergone a complete macroscopic resection to six cycles of gemcitabine 1000 mg/m 2 on days 1, 8 and 15 of a 28-day cycle or observation [24,25]. There was a statistically significant improvement in disease free survival (DFS) (median DFS 13.4 months with gemcitabine versus 6.7 months with observation) and OS (5-year OS 20.7% with gemcitabine versus 10.4% with observation), and this benefit persisted in patients with both R0 and R1 resections. A randomized comparison of adjuvant gemcitabine to 5FU showed no difference in OS, however, there was more grade 3 toxicity, including stomatitis, diarrhea and hospitalizations, with 5FU compared to gemcitabine [26].
The ESPAC-4 study addressed whether six months adjuvant gemcitabine and capecitabine, was superior to gemcitabine alone [27]. Patients with macroscopically complete resection of PDAC, with no evidence of metastatic disease, an Eastern Cooperative Group (ECOG) performance score (PS) of 0-2, who had not received any neoadjuvant chemotherapy, were randomized to combination therapy with gemcitabine 1000 mg/m 2 weekly on days 1, 8 and 15 of a 28 day cycle and capecitabine 1660 mg/m 2 for 21 days followed by a 7 day break, versus gemcitabine alone. Results were stratified by country of enrollment and resection margin status (R0 versus R1). Treatment was to be started within 12 weeks of surgery and enrollment in ESPAC-4 was not restricted by post-operative CA 19-9 levels. The primary endpoint was OS and secondary endpoints included survival at 24 months and 5 years, relapse free survival (RFS), toxicity and quality of life as measured by the EORTC QLQ-C30 questionnaire. The study cohort included patients with a poor prognosis, as 60% of patients had R1 resection margins, 80% had lymph node positive disease, and post-operative CA 19-9 levels ranged from 0.1 to >8000. The median OS with gemcitabine and capecitabine was 28.0 months compared to 25.5 months with gemcitabine alone (hazard ratio 0.82, 95% CI 0.68-0.98, p = 0.032). On multivariable analysis, tumor grade, lymph node status, maximum tumor size, resection margin status and post-operative CA 19-9 levels were independent predictors of OS. Interestingly, there was no difference in RFS between combination therapy and gemcitabine alone (HR 0.86, 95% CI 0.73-1.02, p = 0.082). There was increased grades 3 and 4 toxicity with combination therapy, including increased neutropenia, infections, diarrhea and hand foot syndrome.
APACT is a phase III randomized controlled trial assessing adjuvant nab-paclitaxel plus gemcitabine (NG) compared to gemcitabine alone, with a primary endpoint of independently assessed DFS [28]. Patients with resected PDAC with no evidence of metastatic disease and a post-operative CA 19-9 < 100 were randomized in a 1:1 fashion to the two treatment arms. Results were stratified by geographic region, resection margin status and lymph node status. In total, 24% of patients had R1 margins and 72% had lymph node positive disease. There was no difference in independently assessed DFS between the two treatment groups. The median DFS with NG was 19.4 months, compared to 18.8 months with gemcitabine alone (hazard ratio 0.88, 95% CI 0.73-1.06, p = 0.18). In a pre-planned subgroup analysis, the groups that appeared to benefit from combination therapy included moderate compared to poorly differentiated tumors, lymph node positive disease and normal CA 19-9. There was a statistically significant difference in investigator-assessed DFS, at 16.6 months for NG, compared to 13.7 months for gemcitabine (hazard ratio 0.82, 95% CI 0.694-0.965, p = 0.0168). The difference between independent and investigator assessed DFS may be related to the clinical features that physicians take into consideration, alongside radiologic findings, when assessing disease progression in patients with PDAC. The median OS for those who received NG was 40.5 months, compared to 36.2 months for gemcitabine alone (hazard ratio 0.82, 95% CI 0.68-0.996, p = 0.045), although data are not yet mature.
Investigation of a more intensive adjuvant regimen was investigated in the PA.6 trial [29]. Patients with macroscopic resection of PDAC, with no evidence of metastatic disease were randomized to six months of modified FOLFIRINOX (mFOLFIRINOX), consisting of 46 h infusion of 5FU (2400 mg/m 2 ), leucovorin (400 mg/m 2 ), oxaliplatin (85 mg/m 2 ) and irinotecan (150 mg/m 2 ) given once every two weeks, or gemcitabine 1000 mg/m 2 given on days 1, 8 and 15 on a 28 day schedule. Criteria for enrollment in this study were more stringent, as patients had to be <79 years old, have an ECOG PS of 0-1, with a bilirubin level < 1.5 times the upper limit of normal, a creatinine clearance of >50 mL/minute, and a post-operative CA 19-9 level <180. The primary endpoint was DFS and other endpoints included OS and safety. Results were stratified by trial center, nodal status, margin status and post-operative CA 19-9 levels. With this stricter inclusion criteria, approximately 40% of patients had R1 resections, 73% had stage IIB disease, and 0.4% had stage III disease. The median DFS with mFOLFIRINOX was 21.6 months, compared to 12.8 months with gemcitabine (stratified hazard ratio 0.58, 95% CI 0.46-0.73, p < 0.001). This benefit with mFOLFIRINOX was seen in all subgroups, including those with T3/4 tumors, N1 disease and R1 resections. In an exploratory subgroup analysis of patients >70 years old, representing 20.5% of the study population, the benefit of mFOLFIRINOX over gemcitabine did not reach significance (hazard ratio 0.86, 95% CI, 0.53-1.39). On multivariable analysis, factors independently predictors of worse DFS included tumor grade and portal vein resection. Median OS was also improved with mFOLFIRINOX at 54.5 months compared to 35.0 months with gemcitabine (stratified hazard ratio for death, 0.64; 95% CI, 0.48-0.86; p = 0.003). It should be noted that the median OS seen in the gemcitabine group is longer than what has been seen historically, with many potential reasons, including better surgical technique, patient selection and post-progression therapies. As expected, mFOLFIRINOX was associated with increased toxicity. Grade 3/4 toxicity occurred in 52.9% of patients receiving mFOLFIRINOX, compared to 12.2% of those receiving gemcitabine. Specifically, there was more mucositis, nausea, vomiting, diarrhea, abdominal pain, fatigue, elevated GGT and paresthesias with mFOFLIRINOX. Over 60% of those receiving mFOLFIRINOX received growth factor support, compared to 3.7% of those receiving gemcitabine. There was no difference in grade 3/4 toxicity based on age <70 or >70. Due to the superior survival seen with mFOLFIRINOX, it is the adjuvant chemotherapy regimen of choice; however, factors such as age, ECOG PS, comorbidities, post-operative CA 19-9 and chemotherapy toxicity profile should be taken into consideration.
The role of adjuvant radiation is not well defined and results from randomized trials are conflicting. Overall, there is no strong evidence for using radiation therapy for a survival improvement. Adjuvant radiation therapy may be considered in selected patients, following systemic therapy, with the primary goal of reducing the risk of local-regional recurrence and maintaining quality of life. In resectable cases, there is no evidence for the routine use of neoadjuvant radiation therapy [30]. When radiation therapy is used for the treatment of pancreatic cancer, pre-radiation treatment anti-emetics are recommended. For patients with tumors close to the stomach or duodenum (the great majority of pancreatic cancers), proton pump inhibitors are recommended to reduce the risk of gastric toxicity [30].
When deciding on whether a neoadjuvant approach or an upfront surgical approach should be taken, it is critical to clearly define whether a PDAC is resectable, borderline resectable, borderline unresectable or unresectable. Definitions of resectability have evolved over time and require sufficient radiographic and surgical expertise to determine. The nature and extent of vascular involvement is often a primary determinant of resectability, with abutment indicating ≤180 degree involvement and encasement >180 degree involvement of a particular vessel. To be considered borderline resectable, most guidelines permit superior mesenteric vein/portal vein encasement, as long as reconstruction of the vessel is feasible, while the superior mesenteric artery can typically only have abutment for a case to be considered borderline resectable [31][32][33][34][35][36]. Borderline resectable cases typically permit common hepatic artery abutment or short-segment encasement, while most guidelines indicate celiac artery abutment or encasement would render pancreatic cancer unresectable [31][32][33][34][35][36]. Notably, there can be exceptions to arterial involvement, as arterial replacement or resections can occasionally be performed by an experienced hepatobiliary surgeon. Given the complexity of the determination, it often falls to the hepatobiliary surgeon with or without a multidisciplinary discussion to elucidate what is safe and feasible. Clear communication is important to set patient and provider expectations, particularly when disease is either unresectable or only borderline resectable so that management plans can be appropriately aligned with realistic goals.
The role of neoadjuvant chemotherapy in patients with resectable disease is unclear. Offering chemotherapy up front in patients with disease that is amenable to surgical resection may offer some benefits. Neoadjuvant treatment may allow for an assessment of tumor biology, including an evaluation of whether disease responds to aggressive chemotherapy. Those with progressive disease despite optimal chemotherapy may be spared from an aggressive and potentially morbid surgery. Giving neoadjuvant chemotherapy has the potential to treat micrometastatic disease and increase R0 resections. Due to the potential for post-operative complications, which may delay or limit the ability to administer adjuvant chemotherapy, giving chemotherapy before surgery may be preferred. Despite these potential benefits, the role of neoadjuvant chemotherapy in patients with resectable PDAC remains unclear, as there is a lack of evidence to support such an approach. A systematic review and meta-analysis attempted to address this question [37]. When including only randomized and prospective phase II and III trials comparing neoadjuvant to adjuvant therapy, only two phase II papers, one of which was randomized, were identified. The inclusion criteria were therefore expanded to include an additional four prospective and three retrospective studies. The analysis favored neoadjuvant therapy for increasing R0 resections and survival at various time points, however, the poor quality and small number of studies limits the ability to make strong conclusions about the role of neoadjuvant therapy in this setting, and ultimately, upfront surgery followed by adjuvant chemotherapy remains the standard of care for patients with resectable PDAC. Ongoing trials, such as the NEOPAC (NCT01521702) and ALLIANCE A021806 studies, will add further information about the role of neoadjuvant therapy for PDAC. One of the challenges of trials in this setting will be to ensure clear definitions of resectable disease and confirming trial participants are indeed eligible [38], and the endpoints chosen in trials should reflect clinically relevant endpoints including OS and R0 resection rates.
The role of neoadjuvant chemotherapy in borderline resectable PDAC is also unclear. In a phase 2 study of 48 patients with borderline resectable PDAC determined by a multidisciplinary team review, patients received pre-operative FOLFIRINOX followed by neoadjuvant chemoradiation [39]. The primary outcome was R0 resection rate, which was achieved in 65% of patients. The median PFS was 14.7 months and the median OS was 37.7 months. A meta-analysis compared the impact of neoadjuvant therapy (chemotherapy, chemoradiation or both) versus upfront surgery on survival in patients with resectable or borderline resectable PDAC [40]. The median OS with any neoadjuvant therapy was 18.8 months, compared to 14.8 months for those who underwent upfront surgery. A retrospective study of patients with borderline resectable and locally advanced PDAC receiving neoadjuvant FOLFIRINOX versus upfront surgery showed that 92% of patients had an R0 resection who received neoadjuvant FOLFIRINOX [41]. Given the heterogeneity of the populations included in these studies (resectable, borderline resectable and locally advanced disease), as well as the heterogeneity of the neoadjuvant therapies used, one should be cautious when interpreting these results. Ultimately, clear definitions of resectability and well-designed randomized phase 3 trials are required to answer the question of the role of neoadjuvant chemotherapy, and the optimal regimen, in borderline resectable PDAC.
Currently, if patients are to receive neoadjuvant therapy for PDAC, this would best be done on a clinical trial. Cases should be reviewed in a multi-disciplinary fashion to determine the intent and strategy for borderline resectable pancreas cancer as it is important to set realistic expectations for patient outcomes. Neoadjuvant chemotherapy using FOLFIRINOX is the preferred strategy due to its objective response rate (31.6%) in the metastatic setting and efficacy in the adjuvant setting [29,42]. Notably, an objective response may not translate to conversion from borderline resectable to resectable disease, as there may be specific anatomic considerations required for a response to allow for surgical resectability. NG can be considered depending on patient factors and tolerability, though it does have a lower objective response rate (23%) in the metastatic setting and more questionable benefit in the adjuvant setting [28,43]. Chemoradiotherapy or radiotherapy alone may be considered in selected cases following systemic therapy. The primary role of radiation therapy is to increase the chance of a R0 resection margin and to reduce the risk of local recurrence. Capecitabine is the preferred radiation sensitizer for patients who have previously received FOLFIRINOX, and it has been shown to be associated with less toxicity than gemcitabine-based chemo-radiation therapy [44]. Gemcitabine-based chemo-radiation therapy is an alternative for patients who have not received FORFIRINOX.
Published after the WCGCCC meeting, the PREOPANC trial randomized patients with resectable and borderline resectable pancreatic cancer to receive chemoradiation with gemcitabine and surgery or surgery alone, followed by adjuvant gemcitabine [45]. This trial demonstrated an improvement in surrogate endpoints such as R0 resection rates (71 vs. 40%), disease-free survival and locoregional failure-free interval with the use of neoadjuvant chemoradiation. No OS benefit was observed initially, though with longer follow-up a potential survival benefit has been suggested [45,46]. However, this trial utilizes inferior systemic treatment in the control arm with gemcitabine alone and may not be reflective of modern practice. The phase II SWOG S1505 study compared neoadjvuant treatment with mFOLFIRINOX and nab-pacltaxel/gemcitabine and found similar R0 resection rates (73 vs. 70%) but failed to meet pre-specified endpoints to be carried forward [47]. The results from further trials such as PREOPANC II, using FOLFIRINOX are awaited [48]. Despite new data since the WCGCCC meeting, routine use of neoadjuvant treatment remains an area of active research, and there remains a need for better powered studies to determine who best to adopt a neoadjvuant approach for.
# Question 5
What are the current standard surgical options for patients with hepatocellular carcinoma?
# Recommendations
# •
Patients should be referred to a hepatobiliary surgeon to review local regional strategies and for multi-disciplinary review. Multi-disciplinary review should involve representatives from transplant, surgery, radiation oncology, medical oncology and interventional radiology. Surgery remains the gold standard for resectable HCC if able to obtain an adequate future liver remnant (FLR). Transplantation is preferred for non-resectable HCC patients with cirrhosis within transplant criteria.
# Summary of Evidence
Over recent years there have been significant technological and scientific developments related to the treatment of hepatocellular carcinoma. As a result, there are more locoregional treatment options as well as systemic treatment options. Locoregional treatment options include resection, including laparoscopic resection, liver transplantation, thermal ablation (including radiofrequency ablation and microwave ablation), stereotactic body radiotherapy (SBRT), transarterial chemoembolization (TACE), brachytherapy (where available), and transarterial radioembolization (TARE). The nuances of each of these therapeutic modalities, including case-specific feasibility, limitations and precautions, require expert input from specialists from different disciplines. Therefore, an effective multidisciplinary discussion requires the involvement of surgeons, hepatologists, interventional radiologists, radiation oncologists and medical oncologists, as well as diagnostic radiologists.
The diagnosis of HCC is often made based on imaging, without a biopsy. The Liver Imaging Reporting and Data System (LI-RAD) classification of liver lesions enables estimation of the likelihood that a liver lesion is a hepatocellular carcinoma [49]. Expert assessment of liver lesions by a radiologist is therefore integral to clinical management.
Decisions related to the optimal management of hepatocellular carcinoma require a full appreciation of the patient's comorbidities and performance status, as well as an assessment for underlying liver disease and portal hypertension. A full medical evaluation is essential. Liver function is first evaluated by applying Child-Pugh criteria [50], which requires INR, albumin, total bilirubin, and evaluation for ascites and encephalopathy. If transplantation is being considered, the MELD score can be calculated (based on creatinine, bilirubin, INR and serum sodium) [51]. Good renal function is essential for TACE. If it is unclear whether hepatic fibrosis or cirrhosis is present, ultrasound elastography or MR elastography is helpful [52]. The presence of portal hypertension can be deduced if varices are seen on cross-sectional imaging or esophagogastroscopy, or if there is evidence of hypersplenism such as a large spleen or thrombocytopenia.
Anatomic factors must also be considered. The intent of resection is curative and therefore, it must be feasible to remove the entirety of the tumor while leaving sufficient liver remnant to avoid liver failure. Occasionally, it may be necessary to perform a portal vein embolization on the side that is being removed in order to induce hepatic hypertrophy on the liver remnant. Thermal ablation should be avoided in lesions located centrally, near the bifurcation of the porta hepatis; lesions located near large vessels are susceptible to heat sink [53], limiting the effectiveness of the procedure; accessing lesions at the liver surface should consider the approach due potential risks of tumor seeding. While transplantation is the best option for healthy patients with poor liver function, it is not indicated in the presence of a large tumor burden. The Milan criteria (a solitary lesion ≤5 cm maximal diameter or up to 3 lesions ≤3 cm) [54] represent conservative criteria, but extended criteria have been more recently introduced with acceptable results [55,56].
The Barcelona Clinic Liver Cancer (BCLC) staging system represents one construct that can help to guide treatment options [57]. The BCLC staging system takes into account the Child-Pugh grade of liver function, the size and number of nodules, and performance status (Table 3). In addition, the platelet count should be considered in treatment decisions. The optimal candidate for resection is an individual who is in good medical condition, has good performance status, has good hepatic functional reserve (Child-Pugh A), has a normal platelet count and has no varices. This corresponds to patients in BCLC Stage 0 or A. Having said that, as described above, there are many nuances to decision-making, and alternatives to resection could also be considered. While the BCLC staging system is an excellent construct to help make treatment decisions, it must be appreciated that there are numerous treatment options for each BCLC stage. The best options are a product of local expertise, and they will evolve as the clinical science improves.
# Summary of Evidence
The standard first line therapy options for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) with good performance status include FOLFIRINOX and gemcitabine and nab-paclitaxel [42,43]. The choice between the two regimens is often dependent on the patient's co-morbidities and physician/patient preference. Although survival outcomes are inferior with gemcitabine alone, it has demonstrated symptomatic clinical benefit, and can be considered when combination therapy is not feasible [58].
For patients who have progressed from FOLFIRINOX, there is no standard chemotherapy proven with phase III evidence. However, inferring from retrospective studies (ranging from 7 to 69 patients), gemcitabine with nab-paclitaxel has an overall response rate (ORR) of approximately 18% with a median PFS of 3 months and median OS of 5-8 months from the date of starting second line therapy [59][60][61][62][63][64][65][66]. Given the regimen appears efficacious in the second line, it is the preferred regimen for patients who can tolerate combination chemotherapy. For those that cannot, gemcitabine monotherapy may be considered [59].
For patients who have progressed on gemcitabine and nab-paclitaxel, liposomal irinotecan and fluorouracil as per NAPOLI-1 trial and OFF regimen as per CONKO-3 trial are reasonable treatment options with phase III evidence [67,68]. Of note, the PANCREOX study showed conflicting results with the mFOLFOX6 regimen having inferior mOS compared to infusional 5FU (6.1 vs. 9.9 months, HR 1.78 (95%CI 1.08-2.93), p = 0.024) [69]. Therefore, if an oxaliplatin based regimen is utilized then oxaliplatin should be given as per the OFF regimen.
For patients with mPDAC who have known germline BRCA mutations or DNA damage repair (DDR) genes then second line treatment with platinum-based chemotherapy may be considered, especially if they are platinum naïve. This is supported by the Know Your Tumour Type study, where patients with advanced PDAC with DDR (n = 54) was predictive of significant improvement in mOS if treated with platinum-based therapy (2.37 vs. 1.45 years, p < 0.0001) [70]. Similarly, in a smaller study of 71 patients with somatic BRCA mutations where those treated with platinum (n = 22) versus not (n = 21), mOS was improved to 22 vs. 9 months, p = 0.03915 [71]. The DDR genes of interest are pathogenic alterations in BRCA1/2, PALB2, ATM, ATR, ATRX, BAP1, BARD1, BRIP1, CHEK1/2, RAD50/51/51B, or FANCA/C/D2/E/F/G/L if this prospective trial evidence is to be applied. Of note, patients with DDR aberrations may also be more sensitive to 5-FU and irinotecan [72]. For liposomal irinotecan, the benefit seems to be in irinotecan naïve patients where a retrospective study by Glassman DC et al. showed reduced ORR and mOS in prior irinotecan treated patients and naïve patients had similar benefit as per the NAPOLI-1 trial [73].
Beyond chemotherapy, emerging actionable targets with survival benefits are being identified through next generation sequencing (NGS), particularly in patients with KRAS wildtype mPDAC [74]. However, targeted therapies are not routinely considered outside of a clinical trial. In 0.5-0.8% mPDAC patients with deficiency in mismatch repair protein (dMMR) or microsatellite instability (MSI-H), pembrolizumab has shown to be efficacious [75][76][77]. NTRK fusion inhibitors with larorectinib and entrectinib have been recognized as efficacious across multiple tumor types including mPDAC for patients who harbor the fusion [78,79]. NRG1 is another recurrent fusion found across multiple tumor types with a prevalence of approximately 0.3% in mPDAC [80]. There is emerging evidence that it can be targeted with afatinib with a quick and durable response [81,82]. The logistical challenge in reliable detection of such a rare mutation across the population poses a barrier to its utility in today's clinical practice.
There is recognition of 5-10% hereditary cancer risk associated with mPDAC diagnosis, which may be higher in certain subpopulations [83][84][85]. ASCO and NCCN guidelines recommend that germline testing be considered for all patients with mPDAC in recognition that up to half of the patients may not have a classical family history and germline BRCA mutations may carry treatment implications [86][87][88][89]. However, the implementation of testing across the population remains a significant barrier and is subject to ongoing research [89]. After an initial response to platinum-based chemotherapy, the use of maintenance olaparib compared to placebo demonstrated improved PFS, suggesting activity with the parp inhibitor, but the lack of OS improvement and use of placebo as a control (as opposed to ongoing chemotherapy) casts doubt over its utility despite FDA approval [85].
# Question 7
What is the preferred adjuvant therapy for patients with early stage biliary tract cancer? What are the preferred first-and second-line systemic therapies in patients with advanced biliary tract cancer? What are potential targeted treatments for biliary tract cancer?
# Recommendations
# •
In the adjuvant setting, capecitabine for 6 months is the preferred option. For positive margin disease, patients should be reviewed in a multi-disciplinary fashion to determine if radiotherapy is reasonable.
# •
In patients with advanced biliary tract cancers, the preferred first line option is gemcitabine and cisplatin. Gemcitabine is an option in patients who cannot tolerate combination therapy.
# •
Fluoropyrimidine-based chemotherapy may be considered in the second line setting.
# •
The role of molecular testing and targeted therapy is evolving. For MSI-high, MMRdeficient advanced biliary cancer, pembrolizumab should be considered for chemotherapy refractory disease.
# Summary of Evidence
The phase III BILCAP trial, randomized 447 patients with resected biliary tract cancers to receive eight cycles of capecitabine (1250 mg/m 2 twice daily on days 1-14 every 21 days) or placebo [90]. In total, 38% had R1 resection. The primary intention-to-treat analysis for OS did not meet statistical significance (51.1 vs. 36.4 months, HR 0.81 95% CI 0.63-1.04, p = 0.097), while per-protocol analysis did (53 vs. 36 months, HR 0.75, 95% CI 0.58-0.97, p = 0.028). Additionally, pre-planned sensitivity analyses adjusting for nodal status, disease grade and sex suggested that capecitabine was beneficial (HR 0.71, 95% CI 0.55-0.92, p = 0.010) and RFS was improved in both intention to treat and per-protocol analysis. Given the magnitude of benefit and supportive analyses, adjuvant capecitabine has been adopted as a new standard of care for patients with resected biliary tract cancer. The benefit of adjuvant radiation or chemoradiation is unclear as there is no prospective, randomized data to support its routine use. However, retrospective data suggests potential benefit, particularly in patients with positive margins, so it is reasonable to have these cases reviewed in a multidisciplinary fashion to determine if radiotherapy should be considered [91].
Cisplatin and gemcitabine are recommended for first line treatment of metastatic cholangiocarcinoma based on the multicenter ABC-02 trial. In this study, 410 patients were randomly assigned to eight cycles of cisplatin (25 mg/m 2 ) followed by gemcitabine (1000 mg/m 2 ) on days 1 and 8 every 21 days, or gemcitabine alone (1000 mg/m 2 on days 1, 8, and 15 every 28 days) [92]. Median OS was significantly greater with combination therapy (11.7 versus 8.1 months), as was median PFS (8 versus 5 months). For second-line, ABC-06 was the first prospective phase III trial evaluating the benefit of chemotherapy after Cisplatin and Gemcitabine in patients with advanced cholangiocarcinoma. The trial compared infusional fluorouracil plus leucovorin and oxaliplatin (FOLFOX) with active symptom control. FOLFOX improved OS at 6 (61 versus 36%) and 12 months (26 versus 11%) [93]. The incremental benefit of oxaliplatin in addition to fluoropyrimidine alone after cisplatin and gemcitabine is unclear. Whilst there is a lack of prospective evidence, retrospective comparisons indicate oxaliplatin combination achieves a higher objective response rate (8 vs. 1%, p = 0.009), but PFS and OS are not clearly different from a fluoropyrimidine alone [94].
Molecular targeted therapy has been an emerging area of interest for biliary tract cancers. As with other cancers that are dMMR/MSI-H, immunotherapy has demonstrated activity for this disease subtype [74,95]. Similarly, TRK inhibitors like larorectinib and entrectinib have been recognized as efficacious for TRK-fusion positive cholangiocarcinomas as well [77,78]. Several trials are also evaluating the role of FGFR2 transloactions, which are present in approximately 13% of patients with cholangiocarcinoma [96]. Pemigatinib has subsequently received FDA approval due to an objective response rate of 36% and disease control rate of 80% [97]. Infigratinib is another FGFR2 targeted therapy that has received accelerated approval by the FDA [98]. The emerging number of targeted therapies available for intrahepatic cholangiocarcinomas has led to a blanket recommendation by ESMO for routine next generation sequencing for these cancers [99]. However, funding for such testing remains elusive in the publicly funded context of Canada.
Funding: The 2019 WCGCCC received unrestricted educational grants from Hoffmann-La Roche, Amgen Canada, IPSEN Biopharmaceutical Canada, Taiho Pharma Canada, BTG International Canada, Eli Lilly Canada Inc., Merck, AstraZeneca, Eisai Inc., Celgene, Servier Canada Inc., and Bayer Canada Inc. During the entire process, the sponsors had no influence whatsoever over the development of the guidelines, and they did not review or read the guidelines before submission. No author was compensated for their work on this article.
Institutional Review Board Statement: Not applicable.
# Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
# Acknowledgments:
The WCGCCC organizing committee thanks all meeting participants for their contributions to the development of this consensus statement. In addition, the committee thanks the meeting sponsors and Buksa Strategic Conference Services for support in organizing the meeting.
Conflicts of Interest: Author R.L.-Y. has had advisory roles for Eisai, Ipsen, AstraZeneca, Roche and Celgene. Author J.D. has clinical trials for BMS, Merck, MedImmune, Astellas Array BioPharma, and is a consultant for AstraZeneca, Eisai, Taiho, and Amgen. Author L.D. is in a licensing agreement with Raysearch. Author C.A.K. received an unrelated research grant from Celgene Inc. Author H.L. received honoraria from Merck, BMS, AstraZeneca, Eisai, Taiho, Roche, Amgen, and Bayer for consultant work. Author K.M. has an advisory role for Pfizer Canada, Eisai Inc., Bayer Canada and has received clinical trials funding from Deciphera Pharmaceuticals, BluePrint Medicines, AstraZeneca. Author V.T. is on the Advisory Board for AstraZeneca, Eisai, Ipsen, and Roche and has also received Clinical Trials/Research Funding through his institution from AstraZeneca, Eisai, Exelixis, Ipsen, Merck, Roche. Author A.Z. has provided consult work for Eisai Inc. The remaining authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. | None | None |
4075b47b6670c0b3a81dc2ef1d15e37e104046af | cma | None | Cannabis use is relatively common in the Canadian population, especially among adolescents and young adults. About one in seven (14.8 per cent) Canadians aged 15+ reported using cannabis in the past year. Although cannabis is sometimes perceived as a relatively safe drug, it has multiple, well-documented risks to both immediate and long-term health. The main risks include cognitive, psychomotor and memory impairments; hallucinations and impaired perception; impaired driving resulting in injuries or fatalities; mental health problems, including psychosis; cannabis use disorder; respiratory problems; and reproductive problems. However, most of these adverse health outcomes are concentrated among those who consume cannabis in high-risk ways. Fatal and nonfatal injuries from motor-vehicle collisions, as well as cannabis use disorder and other mental health problems, are the most common cannabis-related harms negatively impacting public health.# Why Lower-Risk Cannabis Use Guidelines (LRCUG)?
The goals of cannabis legalization and regulation in Canada include the protection of public health and safety. Towards that end, proactive education, prevention and guidance on cannabis use and health are important public health strategies to reduce harms and problems related to cannabis use. While cannabis use comes with the health risks described above, the likelihood or severity of adverse outcomes can be modified through informed choices.
In this context, the main objective of Canada's Lower-Risk Cannabis Use Guidelines (LRCUG) is to provide science-based recommendations to enable people to reduce their health risks associated with cannabis use, similar to the intent of health-oriented guidelines for low-risk drinking, nutrition or sexual behaviour.
# How were the Lower-Risk Cannabis Use Guidelines developed? (LRCUG)
The LRCUG are based on a comprehensive review of scientific studies and data conducted by an international team of addiction and health experts. The scientific version of the Lower-Risk Cannabis Use Guidelines (LRCUG) was published in the American Journal of Public Health in 2017 (see "Reference" on back). All of the data and sources informing the LRCUG can be found in this peer-reviewed publication.
# Who are the LRCUG for?
The LRCUG are a tool for:
- anyone who has made the choice to use or is considering using, as well as their family, friends and peers.
- any professional, organization or government body aiming to improve the health of Canadians who use cannabis through evidence-based information and education.
Individuals who develop problems related to their cannabis use should be encouraged to seek support from a health professional.
# The LRCUG recommendations
The most effective way to avoid the risks of cannabis use is to abstain from use.
# Abstinence
As with any risky behaviour, the safest way to reduce these risks is to avoid the behaviour altogether. The same is true for cannabis use. Those who decide to use cannabis incur a variety of risks related to acute and/or long-term adverse health and social outcomes. The likelihood and severity of these risks will vary, based on characteristics of individual users, their patterns of use, and product qualities.
In addition, the risks may not be the same from person to person, or from one episode of use to another.
Canada has among the highest cannabis use rates in the world.
Fatal and non-fatal injuries from motor-vehicle collisions, as well as cannabis use disorder and other mental health problems, are the most common cannabis-related harms negatively impacting public health.
The LRCUG's 10 recommendations are targeted at people who use cannabis or are considering using cannabis. This evidence summary provides the context for the recommendations, including an overview of research to date. Note that these recommendations are mainly for non-medical cannabis use.
# Age of initial use
Studies show that initiating cannabis at a young ageprimarily before age 16 -increases the risks for a variety of adverse health outcomes. For example, people who start using young are more likely to develop related mental health and education problems, or to experience injuries or other substance use problems. These effects are particularly pronounced in cannabis users who engage in intensive/ frequent use. This may occur, in part, because frequent cannabis use affects the development of the brain, which is not completed until the mid-20s. The younger the age a person initiates cannabis use, the greater the likelihood of more severe health problems.
Delaying cannabis use, at least until after adolescence, will reduce the likelihood or severity of adverse health outcomes.
# Choice of cannabis products
Cannabis consumers should be aware of the nature and composition of the cannabis products that they use. These products vary greatly in cannabis' main psychoactive ingredient, tetrahydrocannabinol (THC). Higher THC potency is strongly related to increased acute and longterm problems, such as mental health problems, cannabis use disorder or injuries. In particular, cannabis extract or concentrate products contain extremely high THC levels. Yet evidence suggests that other cannabinoid components, including cannabidiol (CBD), attenuate some of THC's effects. Using cannabis products with high CBD:THC ratios typically carries less severe health risks.
Synthetic cannabinoids (e.g., K2, Spice) are a relatively new, illegal class of products. Recent reviews on synthetics indicate that they generally have more severe psychoactive impacts and health risks, including cases of death.
Use products with low THC content and high CBD: THC ratios.
Synthetic cannabis products, such as K2 and Spice, should be avoided.
# Cannabis use methods and practices
Many alternative methods for consuming cannabis now exist. Evidence suggests that smoking burnt cannabis, especially combined with tobacco, can result in respiratory problems, possibly including lung cancer. In fact, smoking is likely the most hazardous method of cannabis use. Alternative inhalation methods include vaporizers and e-cigarette devices. While these alternatives reduce key risks to health,
Between 10 and 30 per cent of cannabis users are estimated to develop a cannabis use disorder (including dependence).
# Avoid smoking burnt cannabis and choose safer inhalation methods including vaporizers, e-cigarette devices and edibles.
If cannabis is smoked, avoid harmful practices such as inhaling deeply or breath-holding.
# Frequency and intensity of use
Frequent or intensive cannabis use -defined as daily or near-daily use -are among the strongest and most consistent predictors of severe and/or long-term cannabisrelated health problems, based on the scientific evidence. Such patterns of use increase the likelihood of developing multiple health problems, including changes in brain development or functioning (especially at a younger age), mental health problems, cannabis use disorder, impaired driving, suicidality and poorer educational outcomes.
Avoid frequent or intensive use, and limit consumption to occasional use, such as only one day a week or on weekends, or less.
# Cannabis use and driving
Cannabis impairs cognition, attention, reaction and psychomotor control-all of which are critical skills for driving or operating machinery. Numerous studies have shown that the risk of being involved in a collision and experiencing driving-related injuries, both non-fatal and fatal, is two to three times higher among cannabis-impaired drivers compared with Do not drive or operate other machinery for at least 6 hours after using cannabis. Combining alcohol and cannabis increases impairment and should be avoided.
# Special-risk populations
Some populations have higher or distinct risks for cannabis-related health problems. A substantial proportion of cannabis-related psychosis, and possibly other mental health problems (especially cannabis use disorders), occurs among those with a personal or family history of psychosis or substance use disorders. Furthermore, cannabis use during pregnancy increases the risk of adverse neonatal health outcomes, including low birthweight and growth reduction. This recommendation is based, in part, on precautionary principles.
People with a personal or family history of psychosis or substance use disorders, as well as pregnant women, should not use cannabis at all.
Combining risks or risk behaviours
While data are limited, it is likely that the combination of some of the risk behaviours described in the recommendations will magnify the risk of adverse outcomes from cannabis use. For example, early-onset of cannabis use, combined with frequent use of high-potency cannabis, is likely to disproportionately increase the risks of experiencing both acute and chronic problems.
# Avoid combining any of the risk factors related to cannabis use.
Multiple high-risk behaviours will amplify the likelihood or severity of adverse outcomes.
they are not entirely risk-free. However, rigorous studies on health outcomes are largely lacking. Ingested or "edible" cannabis products bypass inhalation-related risks, but delay the onset of psychoactive effects and may lead to the use of higher doses. If accompanied by adequate cannabis product labeling, packaging and warnings, edibles may offer the safest method of cannabis use.
When smoking cannabis, practices such as "deepinhalation," breath-holding or forceful exhalation (the Valsalva maneuver), are done to increase the absorption of psychoactive ingredients. However, they also disproportionately increase the intake of toxic material into the respiratory system.
non-impaired drivers. There is no evidence for safe levels of cannabis use for driving. After consuming cannabis, individuals should not drive during the period of acute psychoactive effects. These acute impairments set in shortly after use and persist for at least 6 hours, but can vary depending on individual characteristics and constitution, as well as on the potency and type of cannabis used. The risk of a collision is even higher when cannabis and alcohol are used together, since combining these drugs amplify the effects of impairment. | Cannabis use is relatively common in the Canadian population, especially among adolescents and young adults. About one in seven (14.8 per cent) Canadians aged 15+ reported using cannabis in the past year. Although cannabis is sometimes perceived as a relatively safe drug, it has multiple, well-documented risks to both immediate and long-term health. The main risks include cognitive, psychomotor and memory impairments; hallucinations and impaired perception; impaired driving resulting in injuries or fatalities; mental health problems, including psychosis; cannabis use disorder; respiratory problems; and reproductive problems. However, most of these adverse health outcomes are concentrated among those who consume cannabis in high-risk ways. Fatal and nonfatal injuries from motor-vehicle collisions, as well as cannabis use disorder and other mental health problems, are the most common cannabis-related harms negatively impacting public health.# Why Lower-Risk Cannabis Use Guidelines (LRCUG)?
The goals of cannabis legalization and regulation in Canada include the protection of public health and safety. Towards that end, proactive education, prevention and guidance on cannabis use and health are important public health strategies to reduce harms and problems related to cannabis use. While cannabis use comes with the health risks described above, the likelihood or severity of adverse outcomes can be modified through informed choices.
In this context, the main objective of Canada's Lower-Risk Cannabis Use Guidelines (LRCUG) is to provide science-based recommendations to enable people to reduce their health risks associated with cannabis use, similar to the intent of health-oriented guidelines for low-risk drinking, nutrition or sexual behaviour.
# How were the Lower-Risk Cannabis Use Guidelines developed? (LRCUG)
The LRCUG are based on a comprehensive review of scientific studies and data conducted by an international team of addiction and health experts. The scientific version of the Lower-Risk Cannabis Use Guidelines (LRCUG) was published in the American Journal of Public Health in 2017 (see "Reference" on back). All of the data and sources informing the LRCUG can be found in this peer-reviewed publication.
# Who are the LRCUG for?
The LRCUG are a tool for:
• anyone who has made the choice to use or is considering using, as well as their family, friends and peers.
• any professional, organization or government body aiming to improve the health of Canadians who use cannabis through evidence-based information and education.
Individuals who develop problems related to their cannabis use should be encouraged to seek support from a health professional.
# The LRCUG recommendations
The most effective way to avoid the risks of cannabis use is to abstain from use.
1
# Abstinence
As with any risky behaviour, the safest way to reduce these risks is to avoid the behaviour altogether. The same is true for cannabis use. Those who decide to use cannabis incur a variety of risks related to acute and/or long-term adverse health and social outcomes. The likelihood and severity of these risks will vary, based on characteristics of individual users, their patterns of use, and product qualities.
In addition, the risks may not be the same from person to person, or from one episode of use to another.
Canada has among the highest cannabis use rates in the world.
Fatal and non-fatal injuries from motor-vehicle collisions, as well as cannabis use disorder and other mental health problems, are the most common cannabis-related harms negatively impacting public health.
The LRCUG's 10 recommendations are targeted at people who use cannabis or are considering using cannabis. This evidence summary provides the context for the recommendations, including an overview of research to date. Note that these recommendations are mainly for non-medical cannabis use.
# Age of initial use
Studies show that initiating cannabis at a young ageprimarily before age 16 -increases the risks for a variety of adverse health outcomes. For example, people who start using young are more likely to develop related mental health and education problems, or to experience injuries or other substance use problems. These effects are particularly pronounced in cannabis users who engage in intensive/ frequent use. This may occur, in part, because frequent cannabis use affects the development of the brain, which is not completed until the mid-20s. The younger the age a person initiates cannabis use, the greater the likelihood of more severe health problems.
Delaying cannabis use, at least until after adolescence, will reduce the likelihood or severity of adverse health outcomes.
# 2
# Choice of cannabis products
Cannabis consumers should be aware of the nature and composition of the cannabis products that they use. These products vary greatly in cannabis' main psychoactive ingredient, tetrahydrocannabinol (THC). Higher THC potency is strongly related to increased acute and longterm problems, such as mental health problems, cannabis use disorder or injuries. In particular, cannabis extract or concentrate products contain extremely high THC levels. Yet evidence suggests that other cannabinoid components, including cannabidiol (CBD), attenuate some of THC's effects. Using cannabis products with high CBD:THC ratios typically carries less severe health risks.
Synthetic cannabinoids (e.g., K2, Spice) are a relatively new, illegal class of products. Recent reviews on synthetics indicate that they generally have more severe psychoactive impacts and health risks, including cases of death.
Use products with low THC content and high CBD: THC ratios.
# 3
Synthetic cannabis products, such as K2 and Spice, should be avoided.
4
# Cannabis use methods and practices
Many alternative methods for consuming cannabis now exist. Evidence suggests that smoking burnt cannabis, especially combined with tobacco, can result in respiratory problems, possibly including lung cancer. In fact, smoking is likely the most hazardous method of cannabis use. Alternative inhalation methods include vaporizers and e-cigarette devices. While these alternatives reduce key risks to health,
Between 10 and 30 per cent of cannabis users are estimated to develop a cannabis use disorder (including dependence).
# Avoid smoking burnt cannabis and choose safer inhalation methods including vaporizers, e-cigarette devices and edibles.
If cannabis is smoked, avoid harmful practices such as inhaling deeply or breath-holding.
# 6
# Frequency and intensity of use
Frequent or intensive cannabis use -defined as daily or near-daily use -are among the strongest and most consistent predictors of severe and/or long-term cannabisrelated health problems, based on the scientific evidence. Such patterns of use increase the likelihood of developing multiple health problems, including changes in brain development or functioning (especially at a younger age), mental health problems, cannabis use disorder, impaired driving, suicidality and poorer educational outcomes.
Avoid frequent or intensive use, and limit consumption to occasional use, such as only one day a week or on weekends, or less.
# 7
# Cannabis use and driving
Cannabis impairs cognition, attention, reaction and psychomotor control-all of which are critical skills for driving or operating machinery. Numerous studies have shown that the risk of being involved in a collision and experiencing driving-related injuries, both non-fatal and fatal, is two to three times higher among cannabis-impaired drivers compared with Do not drive or operate other machinery for at least 6 hours after using cannabis. Combining alcohol and cannabis increases impairment and should be avoided.
8
# Special-risk populations
Some populations have higher or distinct risks for cannabis-related health problems. A substantial proportion of cannabis-related psychosis, and possibly other mental health problems (especially cannabis use disorders), occurs among those with a personal or family history of psychosis or substance use disorders. Furthermore, cannabis use during pregnancy increases the risk of adverse neonatal health outcomes, including low birthweight and growth reduction. This recommendation is based, in part, on precautionary principles.
People with a personal or family history of psychosis or substance use disorders, as well as pregnant women, should not use cannabis at all.
# 9
Combining risks or risk behaviours
While data are limited, it is likely that the combination of some of the risk behaviours described in the recommendations will magnify the risk of adverse outcomes from cannabis use. For example, early-onset of cannabis use, combined with frequent use of high-potency cannabis, is likely to disproportionately increase the risks of experiencing both acute and chronic problems.
# Avoid combining any of the risk factors related to cannabis use.
Multiple high-risk behaviours will amplify the likelihood or severity of adverse outcomes.
# 10
they are not entirely risk-free. However, rigorous studies on health outcomes are largely lacking. Ingested or "edible" cannabis products bypass inhalation-related risks, but delay the onset of psychoactive effects and may lead to the use of higher doses. If accompanied by adequate cannabis product labeling, packaging and warnings, edibles may offer the safest method of cannabis use.
When smoking cannabis, practices such as "deepinhalation," breath-holding or forceful exhalation (the Valsalva maneuver), are done to increase the absorption of psychoactive ingredients. However, they also disproportionately increase the intake of toxic material into the respiratory system.
non-impaired drivers. There is no evidence for safe levels of cannabis use for driving. After consuming cannabis, individuals should not drive during the period of acute psychoactive effects. These acute impairments set in shortly after use and persist for at least 6 hours, but can vary depending on individual characteristics and constitution, as well as on the potency and type of cannabis used. The risk of a collision is even higher when cannabis and alcohol are used together, since combining these drugs amplify the effects of impairment.
# Acknowledgments
The Lower-Risk Cannabis Use Guidelines (LRCUG) are an evidence-based intervention initiative supported by the Canadian Research Initiative in Substance Misuse (CRISM), funded by the Canadian Institutes of Health Research (CIHR). Other versions version of the LRCUG, such as a pamphlet aimed mainly at cannabis users, are available at camh.ca.
# Disponible en Français
| None | None |
418b6889cf05d9eb2a53a29c560fdbd3fb3a803b | cma | None | # Preamble
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision -making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product mono graphs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest. August 19, 2022, as a booster dose in children 5 to 11 years of age. This is the first COVID-19 vaccine authorized as a booster dose in this age group. A COVID-19 wave driven by the BA.5 and BA.4 Omicron sub-lineages is underway, with increasing rates of hospitalizations and deaths being observed since early summer (1) . As of July 17, 2022, 42% of the population aged 5 to 11 years of age in Canada is vaccinated with a primary series. Hybrid immunity (i.e., protection due to a combination of both infection and appropriate vaccination) has increased as many Canadians, particularly young Canadians, have now been infected with SARS-CoV-2. Although to date Omicron variants have generally been associated with a less severe illness compared to previous strains, Omicron is partially evasive of immunity conferred by ancestral COVID-19 vaccines or a previous infection by pre-Omicron strains. Emerging data on BA.4 or BA.5 also suggests some degree of immune evasion against antibodies triggered by a previous Omicron BA.1 infection (2)(3)(4) . Preliminary evidence in adults suggests infection-and/or vaccine-acquired immunity wanes over time, including protection against severe disease. This supports administration of subsequent vaccine doses (especially in groups at high risk of severe disease and/or waning) to improve protection in case of increases in COVID-19 indicators (e.g., case incidence, test positivity, outbreaks, wastewater signals). Manufacturers are working on new COVID-19 vaccines, including multivalent vaccines and vaccines specifically targeting VOCs, including Omicron variants. A bivalent vaccine, containing the ancestral strain and Omicron BA.1 strain, is anticipated to be available for use in adults in the coming months, and trials in the pediatric population are in progress.
NACI continues to recommend a primary series with an authorized mRNA vaccine in all age groups ≥5 years of age, and a booster dose for those who are eligible. Immunization of those who are eligible for vaccination but have not yet received a primary vaccine series continues to remain a top priority in Canada. For children 6 months to 5 years of age, NACI recommends that a complete series with the Moderna Spikevax (25 mcg) COVID-19 vaccine may be offered at this time.
NACI continues to monitor the rapidly evolving scientific data recognizing that the trajectory of the COVID-19 pandemic remains unclear. Updated recommendations will be made as needed.
NACI's recommendations remain aligned with the goals of the Canadian COVID-19 Pandemic Response that have been updated on February 14, 2022:
- To minimize serious illness and death while minimizing societal disruption as a result of the COVID-19 pandemic. To transition away from the crisis phase towards a more sustainable approach to long term management of COVID-19.
# COVID-19 vaccines authorized for use in children 5 to 11 years of age
The For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to National Advisory Committee on Immunization (NACI): Statements and publications and the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
Further information on NACI's process and procedures is available elsewhere (5,6) .
# Table 1. Factors- for consideration to determine the need for and benefit of a booster dose of COVID-19 vaccine in various populations
# Factors- for consideration Evidence reviewed to determine the need for and benefit of a booster dose of COVID-19 vaccine
Risk
# Recommendations
Please see Table 2 for an explanation of strong versus discretionary NACI recommendations. For further information on these recommendations, please refer to the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
# NACI reiterates previous evidence-informed recommendations for the primary series of
NACI makes the following recommendations on the use of a booster dose in children 5 to 11 years of age.
# For children 5 to 11 years of age with an underlying medical condition that places them at high risk of severe illness due to COVID
# Considerations on when to offer the first booster dose
- NACI recommends that a first booster dose be offered at an interval of at least 6 months since completion of the primary series or SARS-CoV-2 infection, as more time between exposures may result in a better immune response. A longer interval between doses may result in a better response after any subsequent dose, as this allows time for the immune response to mature in breadth and strength. In light of a fall 2022 COVID-19 vaccine booster program, a shorter interval of at least 3 months may be warranted. However, a longer interval between vaccine doses may increase immune memory response which may be an important consideration for longterm immunity in children.
- As protection against infection and severe disease is highest soon after vaccine administration, vaccination at a time of low disease incidence may have limited benefit particularly if there is an extended period of time before the next wave of SARS-CoV-2. A bivalent vaccine containing both the ancestral strain and an Omicron variant of SARS-CoV-2, is anticipated to be available for use in adults in the coming months; however, it is unclear if/when a pediatric bivalent vaccine would become available as trials are still underway. The potential benefits of a new vaccine formulation will need to be weighed against the risk of infection and severe disease while waiting for the vaccine to become available. There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions, with a focus on protecting those at highest risk for serious outcomes from COVID-19 infection.
NACI continues to monitor and assess the evidence as it emerges and will update its recommendations as needed.
# Summary of evidence
Epidemiology, vaccine coverage, and hybrid immunity The risk of severe outcomes, including hospitalization, intensive-care unit (ICU) admissions and deaths, is very low in children 5 to 11 years of age compared to other age groups, and lower in children who have a complete primary series than in children who are unvaccinated. These findings have also been observed during the recent Omicron waves. For the four-week period from March 28 to April 24, 2022, the hospitalization rate in children 5 to 11 years of age who received a complete primary series was 0.5/100,000, compared to 0.9/100,000 in unvaccinated children (7) . Canadian seroprevalence studies from Quebec (January 26, 2022 to February 17, 2022) and British Columbia (March 2022) estimate that 45% to 70% of children 5 to 11 years of age have been previously infected with SARS-CoV-2; most of these infections occurred since Omicron became the dominant variant (8)(9)(10) . Preliminary unpublished data suggests that seroprevalence in individuals less than 17 years of age is higher compared to older age groups (8) . COVID-19 seroprevalence may vary between Canadian jurisdictions. As of July 17, 2022, 42% of children 5 to 11 years of age are vaccinated with a primary series (11) . Booster dose uptake in those ≥12 years of age has declined with decreasing age. The proportion of individuals who are vaccinated with a primary series and have received at least one additional dose falls from 90% in adults aged 80 years and older to 19% in adolescents 12-17 years of age. Hybrid immunity is protection due to a combination of both infection and appropriate vaccination, and has been shown to be more robust than immunity due to infection or vaccination alone. It is expected that children 5 to 11 years of age who have been infe cted with SARS-CoV-2 may optimize their benefit from future vaccine doses by timing them according to the interval since infection, using similar immunological principles to those informing intervals between vaccine doses.
# Vaccine efficacy and vaccine effectiveness and duration of protection following the primary series against Omicron
- The currently available data on vaccine efficacy in the 5 to 11 age group suggest a vaccine efficacy against symptomatic Delta infection of 90.7% shortly after the comple tion of a 2dose primary mRNA vaccination (12) . Protection is lower against Omicron at 51% ~2-3 weeks after vaccination (13,14) . This reflects the reduced protection against Omicron compared to ancestral strain and previous VOCs that has been observed in adolescents and adults. Two additional studies looking at children 5 to 11 years of age fully vaccinated with Pfizer-BioNTech Comirnaty, estimated vaccine effectiveness (VE) of approximately 30% against Omicron infection or SARS-CoV-2 infection during an Omicron-predominant period (14,15) . Similar to data in adolescents and adults, studies looking at children 5 to 11 years of age are also showing that COVID-19 vaccines offer higher protection against hospitalization and severe disease than against infection. VE estimates against severe disease, including hospitalization due to Omicron infection or SARS-CoV-2 infection during an Omicron predominant period, ranged from 41 to 68% in this age group (15)(16)(17) . In adults, VE against severe disease with Omicron infection is approximately 90% shortly after a first booster dose and remains above 75% in most studies up to 20 weeks from the first booster (18)(19)(20)(21) . VE against Omicron infection and/or symptomatic disease from a first booster of mRNA vaccine is approximately 60% shortly after the dose and decreases over time since vaccination in most studies (18-20, 22, 23) . In adolescents 12 to 17 years of age, VE against severe disease with Omicron infection is approximately 66-76% shortly after completion of the primary series and remains between 85-88% in several studies up to at least 25 weeks post-completion of the primary series (24,25) . VE against Omicron infection and/or symptomatic disease after completion of a primary series is approximately 43-75% shortly after the dose and decreases over time since vaccination in most studies (16,17,(24)(25)(26)(27) . No data are available on VE against multisystem inflammatory syndrome in children (MIS-C) due to Omicron infection, however several studies in adolescents 12 to 17 years of age have shown high VE against MIS-C in the pre-Omicron era (28)(29)(30) .
# Clinical trial summary on
# Immunogenicity
- Immunogenicity was evaluated in a subset of 130 participants (31) . Participants received a booster (third) dose at least 175 days after a two-dose primary series and immune responses were measured 1 month following the booster dose (Dose 3 set). As a comparator, 70 participants were randomly selected from the set who received a two-dose primary series (Dose 2 set) in order to compare immune responses 1 month after Dose 2 to immune responses 1 month after dose 3 from the Dose 3 set. After exclusions (prior evidence of SARS-CoV-2 infection, lack of valid immunogenicity results), immunogenicity data for 67 participants in Dose 3 set and 67 participants in the Dose 2 set were analysed. In the Dose 3 set, neutralizing antibody geometric mean titres (GMTs) against the reference strain of SARS-CoV-2 (isolated in January 2020) increased by approximately 10-fold 1 month after a booster dose, compared to GMTs immediately prior to booster administration. The seroresponse rate increased from 77.6 % (95% confidence interval : 65.8 to 86.9%) immediately prior to booster administration to 98.5% (95% CI: 92 to 100%) 1 month after booster administration. The geometric mean ratio (GMR) of GMTs 1 month after a booster dose in the Dose 3 set compared to GMTs 1 month after a primary series (Dose 2 set) was 2.17 (95% CI: 1.76 to 2.68%). Neutralizing antibody titres against Omicron (B1.1.529) after a booster dose were available for 17 participants in the Dose 3 set without evidence of prior infection. O micronspecific titres were approximately 22-fold higher 1 month after a booster dose compared to 1 month after a primary series. In this subset of participants, Omicron -specific titres 1 month after a booster dose were approximately 2.8-fold lower than reference strainspecific titres.
# Safety
- The safety cohort included 401 children 5 to <12 years of age who received a booster (third) dose of Pfizer-BioNTech Comirnaty (10 mcg) COVID-19 vaccine at least 5 months (range 5 to 9 months) after completing a two-dose primary series. The median follow-up time after dose 3 was of 1.3 months (range: 1.0 to 1.8 months). Almost half (47.6 %) of participants were female and the median age at vaccination was 8.0 years. A total of 5.5% of participants were baseline positive for evidence of prior SARS-CoV-2 infection. Safety data are reported for data available up to a cut-off date of March 22, 2022. The booster dose was well tolerated in children 5 to <12 years of age. Most local and systemic adverse events following immunization (AEFI) were mild or moderate in severity. The median onset of solicited adverse events was 1-2 days after dose 3 with a median duration of 1-2 days after onset. After dose 3, AEFIs in decreasing order of frequency were: pain at the injection site, fatigue, headache, muscle pain, swelling, redness, chills, joint pain, fever, diarrhea, and vomiting. No serious adverse events related to the vaccine, no case of MIS-C, myocarditis and/or pericarditis or death were reported. No immediate adverse events were reported within 30 minutes of receiving dose 3 of Pfizer-BioNTech Comirnaty (10 mcg) COVID-19 vaccine. Local reactions were generally reported at similar frequencies after dose 3 compared with after dose 2 except lymphadenopathy which was reported in 2.5% of vaccinees after dose 3 compared to 0.9% after dose 2. The proportion of participants reporting use of antipyretic/pain medication was higher at dose 3 (30.7%) compared to dose 2 (21.8%). Systemic events were reported at similar or slightly higher frequencies after dose 3 compared with after Dose 2. The incidence of systemic events among children 5 to <12 years of age after Dose 3 of Pfizer-BioNTech Comirnaty (10 mcg) COVID-19 vaccine was lower than previously observed in adults ≥18 years of age after dose 3 of Pfizer-BioNTech Comirnaty (30 mcg) COVID-19 vaccine.
Post-market safety surveillance on Pfizer-BioNTech Comirnaty (10 mcg) primary series Real-world post-market safety data show that the Pfizer-BioNTech Comirnaty primary series is well tolerated in children 5 to 11 years of age, where the majority of AEFIs reported are non-serious, and AEs are less frequently reported than in adolescents 12 to 15 years of age (32)(33)(34)(35) . Very rare cases of myocarditis and/or pericarditis have been reported following the Pfizer-BioNTech Comirnaty primary series in children 5 to 11 years of age. However, current data suggests the risk of myocarditis and/or pericarditis following mRNA COVID-19 vaccines is substantially lower in children 5 to 11 years of age compared to adolescents.
In the United States, the risk of myocarditis and/or pericarditis within 7 days following dose 2 of Pfizer-BioNTech Comirnaty COVID-19 vaccine was 2.6 cases per million doses in males aged 5 to 11 years (10 mcg dose) compared to 46.4 and 75.9 cases per million doses among males 12 to 15 and 16 to 17 years of age (30 mcg dose), respectively (35) . Very rare cases of MIS-C have been reported following administration of the Pfizer -BioNTech Comirnaty primary series among individuals aged 5 to 20 years (36)(37)(38) . The rate of MIS-C post vaccination is currently estimated at about 1.1 cases per 1 million doses administered. For some cases, the causal association between the vaccine and MIS-C was unclear as previous history of SARS-CoV-2 infection was also reported (36,37) . While most reports for MIS-C cases were serious and required hospitalization, all described cases had been discharged home and there were no reported deaths.
# Other considerations
# Implication
A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable. | # Preamble
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision -making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product mono graphs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest. August 19, 2022, as a booster dose in children 5 to 11 years of age. This is the first COVID-19 vaccine authorized as a booster dose in this age group. A COVID-19 wave driven by the BA.5 and BA.4 Omicron sub-lineages is underway, with increasing rates of hospitalizations and deaths being observed since early summer (1) . As of July 17, 2022, 42% of the population aged 5 to 11 years of age in Canada is vaccinated with a primary series. Hybrid immunity (i.e., protection due to a combination of both infection and appropriate vaccination) has increased as many Canadians, particularly young Canadians, have now been infected with SARS-CoV-2. Although to date Omicron variants have generally been associated with a less severe illness compared to previous strains, Omicron is partially evasive of immunity conferred by ancestral COVID-19 vaccines or a previous infection by pre-Omicron strains. Emerging data on BA.4 or BA.5 also suggests some degree of immune evasion against antibodies triggered by a previous Omicron BA.1 infection (2)(3)(4) . Preliminary evidence in adults suggests infection-and/or vaccine-acquired immunity wanes over time, including protection against severe disease. This supports administration of subsequent vaccine doses (especially in groups at high risk of severe disease and/or waning) to improve protection in case of increases in COVID-19 indicators (e.g., case incidence, test positivity, outbreaks, wastewater signals). Manufacturers are working on new COVID-19 vaccines, including multivalent vaccines and vaccines specifically targeting VOCs, including Omicron variants. A bivalent vaccine, containing the ancestral strain and Omicron BA.1 strain, is anticipated to be available for use in adults in the coming months, and trials in the pediatric population are in progress.
NACI continues to recommend a primary series with an authorized mRNA vaccine in all age groups ≥5 years of age, and a booster dose for those who are eligible. Immunization of those who are eligible for vaccination but have not yet received a primary vaccine series continues to remain a top priority in Canada. For children 6 months to 5 years of age, NACI recommends that a complete series with the Moderna Spikevax (25 mcg) COVID-19 vaccine may be offered at this time.
NACI continues to monitor the rapidly evolving scientific data recognizing that the trajectory of the COVID-19 pandemic remains unclear. Updated recommendations will be made as needed.
NACI's recommendations remain aligned with the goals of the Canadian COVID-19 Pandemic Response that have been updated on February 14, 2022:
To minimize serious illness and death while minimizing societal disruption as a result of the COVID-19 pandemic. To transition away from the crisis phase towards a more sustainable approach to long term management of COVID-19.
# COVID-19 vaccines authorized for use in children 5 to 11 years of age
The For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to National Advisory Committee on Immunization (NACI): Statements and publications and the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
Further information on NACI's process and procedures is available elsewhere (5,6) .
# Table 1. Factors* for consideration to determine the need for and benefit of a booster dose of COVID-19 vaccine in various populations
# Factors* for consideration Evidence reviewed to determine the need for and benefit of a booster dose of COVID-19 vaccine
Risk
# Recommendations
Please see Table 2 for an explanation of strong versus discretionary NACI recommendations. For further information on these recommendations, please refer to the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
# NACI reiterates previous evidence-informed recommendations for the primary series of
NACI makes the following recommendations on the use of a booster dose in children 5 to 11 years of age.
# For children 5 to 11 years of age with an underlying medical condition that places them at high risk of severe illness due to COVID
# Considerations on when to offer the first booster dose
NACI recommends that a first booster dose be offered at an interval of at least 6 months since completion of the primary series or SARS-CoV-2 infection, as more time between exposures may result in a better immune response. A longer interval between doses may result in a better response after any subsequent dose, as this allows time for the immune response to mature in breadth and strength. In light of a fall 2022 COVID-19 vaccine booster program, a shorter interval of at least 3 months may be warranted. However, a longer interval between vaccine doses may increase immune memory response which may be an important consideration for longterm immunity in children.
As protection against infection and severe disease is highest soon after vaccine administration, vaccination at a time of low disease incidence may have limited benefit particularly if there is an extended period of time before the next wave of SARS-CoV-2. A bivalent vaccine containing both the ancestral strain and an Omicron variant of SARS-CoV-2, is anticipated to be available for use in adults in the coming months; however, it is unclear if/when a pediatric bivalent vaccine would become available as trials are still underway. The potential benefits of a new vaccine formulation will need to be weighed against the risk of infection and severe disease while waiting for the vaccine to become available. There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions, with a focus on protecting those at highest risk for serious outcomes from COVID-19 infection.
NACI continues to monitor and assess the evidence as it emerges and will update its recommendations as needed.
# Summary of evidence
Epidemiology, vaccine coverage, and hybrid immunity The risk of severe outcomes, including hospitalization, intensive-care unit (ICU) admissions and deaths, is very low in children 5 to 11 years of age compared to other age groups, and lower in children who have a complete primary series than in children who are unvaccinated. These findings have also been observed during the recent Omicron waves. For the four-week period from March 28 to April 24, 2022, the hospitalization rate in children 5 to 11 years of age who received a complete primary series was 0.5/100,000, compared to 0.9/100,000 in unvaccinated children (7) . Canadian seroprevalence studies from Quebec (January 26, 2022 to February 17, 2022) and British Columbia (March 2022) estimate that 45% to 70% of children 5 to 11 years of age have been previously infected with SARS-CoV-2; most of these infections occurred since Omicron became the dominant variant (8)(9)(10) . Preliminary unpublished data suggests that seroprevalence in individuals less than 17 years of age is higher compared to older age groups (8) . COVID-19 seroprevalence may vary between Canadian jurisdictions. As of July 17, 2022, 42% of children 5 to 11 years of age are vaccinated with a primary series (11) . Booster dose uptake in those ≥12 years of age has declined with decreasing age. The proportion of individuals who are vaccinated with a primary series and have received at least one additional dose falls from 90% in adults aged 80 years and older to 19% in adolescents 12-17 years of age. Hybrid immunity is protection due to a combination of both infection and appropriate vaccination, and has been shown to be more robust than immunity due to infection or vaccination alone. It is expected that children 5 to 11 years of age who have been infe cted with SARS-CoV-2 may optimize their benefit from future vaccine doses by timing them according to the interval since infection, using similar immunological principles to those informing intervals between vaccine doses.
# Vaccine efficacy and vaccine effectiveness and duration of protection following the primary series against Omicron
The currently available data on vaccine efficacy in the 5 to 11 age group suggest a vaccine efficacy against symptomatic Delta infection of 90.7% shortly after the comple tion of a 2dose primary mRNA vaccination (12) . Protection is lower against Omicron at 51% ~2-3 weeks after vaccination (13,14) . This reflects the reduced protection against Omicron compared to ancestral strain and previous VOCs that has been observed in adolescents and adults. Two additional studies looking at children 5 to 11 years of age fully vaccinated with Pfizer-BioNTech Comirnaty, estimated vaccine effectiveness (VE) of approximately 30% against Omicron infection or SARS-CoV-2 infection during an Omicron-predominant period (14,15) . Similar to data in adolescents and adults, studies looking at children 5 to 11 years of age are also showing that COVID-19 vaccines offer higher protection against hospitalization and severe disease than against infection. VE estimates against severe disease, including hospitalization due to Omicron infection or SARS-CoV-2 infection during an Omicron predominant period, ranged from 41 to 68% in this age group (15)(16)(17) . In adults, VE against severe disease with Omicron infection is approximately 90% shortly after a first booster dose and remains above 75% in most studies up to 20 weeks from the first booster (18)(19)(20)(21) . VE against Omicron infection and/or symptomatic disease from a first booster of mRNA vaccine is approximately 60% shortly after the dose and decreases over time since vaccination in most studies (18-20, 22, 23) . In adolescents 12 to 17 years of age, VE against severe disease with Omicron infection is approximately 66-76% shortly after completion of the primary series and remains between 85-88% in several studies up to at least 25 weeks post-completion of the primary series (24,25) . VE against Omicron infection and/or symptomatic disease after completion of a primary series is approximately 43-75% shortly after the dose and decreases over time since vaccination in most studies (16,17,(24)(25)(26)(27) . No data are available on VE against multisystem inflammatory syndrome in children (MIS-C) due to Omicron infection, however several studies in adolescents 12 to 17 years of age have shown high VE against MIS-C in the pre-Omicron era (28)(29)(30) .
# Clinical trial summary on
# Immunogenicity
Immunogenicity was evaluated in a subset of 130 participants (31) . Participants received a booster (third) dose at least 175 days after a two-dose primary series and immune responses were measured 1 month following the booster dose (Dose 3 set). As a comparator, 70 participants were randomly selected from the set who received a two-dose primary series (Dose 2 set) in order to compare immune responses 1 month after Dose 2 to immune responses 1 month after dose 3 from the Dose 3 set. After exclusions (prior evidence of SARS-CoV-2 infection, lack of valid immunogenicity results), immunogenicity data for 67 participants in Dose 3 set and 67 participants in the Dose 2 set were analysed. In the Dose 3 set, neutralizing antibody geometric mean titres (GMTs) against the reference strain of SARS-CoV-2 (isolated in January 2020) increased by approximately 10-fold 1 month after a booster dose, compared to GMTs immediately prior to booster administration. The seroresponse rate increased from 77.6 % (95% confidence interval [CI]: 65.8 to 86.9%) immediately prior to booster administration to 98.5% (95% CI: 92 to 100%) 1 month after booster administration. The geometric mean ratio (GMR) of GMTs 1 month after a booster dose in the Dose 3 set compared to GMTs 1 month after a primary series (Dose 2 set) was 2.17 (95% CI: 1.76 to 2.68%). Neutralizing antibody titres against Omicron (B1.1.529) after a booster dose were available for 17 participants in the Dose 3 set without evidence of prior infection. O micronspecific titres were approximately 22-fold higher 1 month after a booster dose compared to 1 month after a primary series. In this subset of participants, Omicron -specific titres 1 month after a booster dose were approximately 2.8-fold lower than reference strainspecific titres.
# Safety
The safety cohort included 401 children 5 to <12 years of age who received a booster (third) dose of Pfizer-BioNTech Comirnaty (10 mcg) COVID-19 vaccine at least 5 months (range 5 to 9 months) after completing a two-dose primary series. The median follow-up time after dose 3 was of 1.3 months (range: 1.0 to 1.8 months). Almost half (47.6 %) of participants were female and the median age at vaccination was 8.0 years. A total of 5.5% of participants were baseline positive for evidence of prior SARS-CoV-2 infection. Safety data are reported for data available up to a cut-off date of March 22, 2022. The booster dose was well tolerated in children 5 to <12 years of age. Most local and systemic adverse events following immunization (AEFI) were mild or moderate in severity. The median onset of solicited adverse events was 1-2 days after dose 3 with a median duration of 1-2 days after onset. After dose 3, AEFIs in decreasing order of frequency were: pain at the injection site, fatigue, headache, muscle pain, swelling, redness, chills, joint pain, fever, diarrhea, and vomiting. No serious adverse events related to the vaccine, no case of MIS-C, myocarditis and/or pericarditis or death were reported. No immediate adverse events were reported within 30 minutes of receiving dose 3 of Pfizer-BioNTech Comirnaty (10 mcg) COVID-19 vaccine. Local reactions were generally reported at similar frequencies after dose 3 compared with after dose 2 except lymphadenopathy which was reported in 2.5% of vaccinees after dose 3 compared to 0.9% after dose 2. The proportion of participants reporting use of antipyretic/pain medication was higher at dose 3 (30.7%) compared to dose 2 (21.8%). Systemic events were reported at similar or slightly higher frequencies after dose 3 compared with after Dose 2. The incidence of systemic events among children 5 to <12 years of age after Dose 3 of Pfizer-BioNTech Comirnaty (10 mcg) COVID-19 vaccine was lower than previously observed in adults ≥18 years of age after dose 3 of Pfizer-BioNTech Comirnaty (30 mcg) COVID-19 vaccine.
Post-market safety surveillance on Pfizer-BioNTech Comirnaty (10 mcg) primary series Real-world post-market safety data show that the Pfizer-BioNTech Comirnaty primary series is well tolerated in children 5 to 11 years of age, where the majority of AEFIs reported are non-serious, and AEs are less frequently reported than in adolescents 12 to 15 years of age (32)(33)(34)(35) . Very rare cases of myocarditis and/or pericarditis have been reported following the Pfizer-BioNTech Comirnaty primary series in children 5 to 11 years of age. However, current data suggests the risk of myocarditis and/or pericarditis following mRNA COVID-19 vaccines is substantially lower in children 5 to 11 years of age compared to adolescents.
In the United States, the risk of myocarditis and/or pericarditis within 7 days following dose 2 of Pfizer-BioNTech Comirnaty COVID-19 vaccine was 2.6 cases per million doses in males aged 5 to 11 years (10 mcg dose) compared to 46.4 and 75.9 cases per million doses among males 12 to 15 and 16 to 17 years of age (30 mcg dose), respectively (35) . Very rare cases of MIS-C have been reported following administration of the Pfizer -BioNTech Comirnaty primary series among individuals aged 5 to 20 years (36)(37)(38) . The rate of MIS-C post vaccination is currently estimated at about 1.1 cases per 1 million doses administered. For some cases, the causal association between the vaccine and MIS-C was unclear as previous history of SARS-CoV-2 infection was also reported (36,37) . While most reports for MIS-C cases were serious and required hospitalization, all described cases had been discharged home and there were no reported deaths.
# Other considerations
# Implication
A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable. | None | None |
79c85ae088fd9b1934c8af3f64abc71d49bfcd23 | cma | None | Adherence to consistent post-operative behavioural changes (behaviour modification for nutrition plans, physical activity and vitamin intake) can optimize obesity management and health while minimizing post-operative complications. - Working in partnership, the bariatric surgical centre, the local bariatric medicine specialist, the primary care provider and the patient living with obesity need to establish and commit to a shared care model of chronic disease management for long-term follow-up. - The primary care provider should refer patients with post-bariatric surgery complications back to the bariatric surgical centre, or to a local bariatric medicine specialist.# RECOMMENDATIONS
- Healthcare providers can encourage people who have undergone bariatric surgery to participate and maximize their access to behavioural interventions and allied health services at a bariatric surgical centre (Level 2a, Grade B). 1,2 2. We suggest that bariatric surgical centres communicate a comprehensive care plan to primary care providers on patients who are discharged, including: bariatric procedure, emergency contact numbers, annual blood tests required, long-term vitamin and mineral supplements, medications, behavioural interventions and when to refer back (Level 4, Grade D, consensus).
- We suggest that after a patient has been discharged from the bariatric surgical centre, primary care providers should annually review: nutritional intake, activity, compliance with multivitamin and mineral supplements and weight, as well as assess comorbidities, order laboratory tests to assess for nutritional deficiencies and investigate abnormal results and treat as required (Level 4, Grade D, consensus). 4. We suggest that primary care providers consider referral back to the bariatric surgical centre or to a local specialist for technical or gastrointestinal symptoms, nutritional issues, pregnancy, psychological support, weight regain or other medical issues as described in this chapter related to bariatric surgery (Level 4, Grade D, consensus).
- We suggest that bariatric surgical centres provide follow-up and appropriate laboratory tests at regular intervals post-surgery with access to appropriate healthcare professionals (dietitian, nurse, social worker, surgeon, bariatric physician, psychologist/psychiatrist) until discharge is deemed appropriate for the patient (Level 4, Grade D, consensus).
# Post-bariatric surgery health behaviour changes Post-bariatric surgery diet
Centres that perform bariatric surgery will typically provide patients with a dietary protocol to follow. Initially, over several weeks, patients transition from liquid, to soft and then to a solid diet. Over the long term, patients are encouraged to follow a structured post-bariatric surgical diet involving small portions, three to five balanced and structured meals and healthy snacks (chew foods slowly and avoid sweets). For beverages, patients should not eat and drink at the same time (avoid liquids within 30 minutes of eating solids). Carbonated beverages and caffeinated drinks are to be avoided, as the phosphoric acid and caffeine, respectively, can increase the risk of ulcerations.
After bariatric surgery, patients need to follow a low-fat, moderate carbohydrate and high-protein diet. Post-operative protein recommendations range from 1.2 to 1.5 g/kg/day based on goal body weight (minimum of 60 g protein/day for laparoscopic sleeve gastrectomy/Roux-en-Y gastric bypass, and 80-120 g/day for duodenal switch). Consulting a registered dietitian can support changes in eating behaviours and guide patients on their nutrition needs. 3 There is no advantage to prescribing alternate diets (e.g., low carbohydrate, high protein), probiotics or amino acids. Other behavioural changes to consider Alcohol intake should be minimal or avoided due to changes in pharmacokinetics. For example, in women who are post Rouxen-Y gastric bypass, two alcoholic beverages are equivalent in absorption to four alcoholic beverages. 7 Seven percent of patients report new high-risk alcohol use one year after bariatric surgery, though, on a more positive note, half who reported high-risk alcohol use before surgery discontinued high-risk drinking. 7 Activity: Long term, a standard of 150 to 300 minutes of activity/week is recommended for post-bariatric surgical patients. Post-operative higher-volume exercise can help promote further weight loss but sustaining this level of activity is difficult. 11
Smoking cessation: Abstention from cigarettes is recommended. Cigarette smoking can increase risk of peptic ulcer disease, particularly marginal ulcers.
Marijuana: There is a paucity of studies on the use of marijuana post-bariatric surgery. One concern would be the impact of weight loss and the chronic use of marijuana, which is traditionally known for its "munchies" effect. At this point, moderation, if not abstention, would be a safe recommendation.
# Post-bariatric surgery vitamin supplementation
The evidence for the role of vitamin supplementation (amount, duration) varies depending on which vitamin, mineral or type of bariatric procedure are studied. Generally, some type of vitamin supplementation is needed for all bariatric surgical procedures, with tailoring for those that have a hypoabsorptive component (Roux-en-Y gastric bypass, duodenal switch).
Practically, it makes sense that a standardized minimum prescription of vitamins be set for all bariatric surgeries. It is a natural human tendency to eventually forget to take supplements. Setting a standard means that clinicians can be consistent in their messaging about taking vitamins. Deficiencies of vitamins and some minerals can leave serious and potentially non-reversible side effects. Frequency of laboratory monitoring may vary depending on the individual and type of procedure, but at minimum an annual check should be conducted to ensure that patients are not becoming malnourished. Tables 1 and 2 summarize the recommendations
# KEY MESSAGES FOR PATIENTS LIVING WITH OBESITY WHO HAVE HAD BARIATRIC SURGERY
- If you have had bariatric surgery, it is important for you to take your nutritional supplements lifelong and to continue to follow the post-bariatric surgical nutrition plan, exercise and any other recommendations given by your original specialist team. By doing this, you will increase your chances of staying healthy and reduce complications that can arise from bariatric surgery.
- Attend all scheduled appointments and programming offered by your bariatric surgical site. Once you are discharged from the bariatric surgical site, schedule annual appointments with your primary care provider to check your bloodwork, reassess your medications and address any issues related to changes in your weight.
- After bariatric surgery, it is possible that there can be a negative impact on mood, relationships, body image, development of addictions and reduced ability to cope with stress. If you are struggling, discuss this with your original specialist team or, if you have been discharged, with your primary care provider.
- Remember that your lowest weight post-surgery will occur between 12 to 18 months. After this, there is a natural increase in weight that occurs. If you are gaining excessive amounts of weight, discuss this with your bariatric team or primary care provider.
- If you are 12 to 18 months post-bariatric surgery and are planning a pregnancy, discuss this with your bariatric team, primary care provider and obstetrician.
for vitamin supplementation, associated deficits that can occur with various deficiencies, and frequency of monitoring. Table 3 summarizes clinical features that may point toward a nutrient deficiency. A dietitian can help determine what combination of vitamins makes sense for a patient. In Canada, access to all-in-one bariatric supplements for surgical patients is improving and can help compliance by reducing the number of pills that need to be taken. Gummy vitamins should be avoided as they do not contain essential minerals.
# Post-bariatric surgery complications
Many gastrointestinal (dumping syndrome) and metabolic complications (e.g., bone, kidney stones) can be prevented by following the recommended post-bariatric surgery nutrition plan and vitamin intake.
# Dumping syndrome
Dumping syndrome is divided into early and late phases. Early dumping syndrome occurs within the first hour after a meal. Because of the hyperosmolality of the food, rapid fluid shifts occur from the plasma compartment into the intestinal lumen, resulting in hypotension and a sympathetic nervous system response.
Early dumping is characterized by gastrointestinal symptoms such as abdominal pain, bloating, borborygmi, nausea and diarrhea, and vasomotor symptoms, such as fatigue, desire to lie down after meals (a classic symptom), flushing, palpitations, perspiration, tachycardia, hypotension and, rarely, syncope. In contrast, late dumping usually occurs one to three hours after a meal and is a result of an incretin-driven hyperinsulinemic response after carbohydrate ingestion. Hypoglycemia-related symptoms are related to neuroglycopenia (fatigue, weakness, confusion, hunger and syncope) and autonomic/adrenergic reactivity (perspiration, palpitations, tremor and irritability). 12 Symptoms that persist despite returning to a post-bariatric surgery diet may benefit from a trial of either acarbose, a calcium channel blocker, diazoxide or octreotide. Referral to a bariatric medicine specialist or an endocrinologist for management and to rule out other causes of hypoglycemia (nesidioblastosis, insulinoma, factitious) may be warranted. 13
# Abdominal discomfort
Abdominal discomfort has a long differential from dietary indiscretion (overeating), dumping syndrome, biliary colic, stenosis of the gastrojejunostomy, marginal ulcer or small bowel obstruction. Presentation for small bowel obstruction can come at any time, but can be divided into early ( 1 year; internal hernia, which can be seen after Roux-en-Y gastric bypass or duodenal switch). During the first year, there is a need for a higher level of suspicion for pain secondary to a surgical complication. Tachycardia, unstable vital signs and abdominal pain may be suggestive of a surgical leak, internal hernia or cholecystitis, which warrants immediate surgical referral. With diarrhea, constipation or bloating, referral to a dietitian can help identify healthier food choices and proper fibre content. Probiotics may improve symptomatic gastrointestinal episodes.
There should be a high level of suspicion for an ulceration for patients who use non-steroidal anti-inflammatory drugs (NSAIDS). Referral to the bariatric surgical site should be considered when clinical red flags appear such as unexplained, frequent, moderate-to-severe abdominal pain, daily intolerance to most solid foods, daily nausea and vomiting and/or a significant amount of weight regain (> 25-50% of total weight loss) in a short space of time. Every bariatric patient suffering from persistent vomiting severe enough to interfere with regular nutrition should be promptly started on oral or parenteral thiamine supplementation, even in the absence or before confirmatory laboratory data. 14
# Bone health
Post-bariatric surgery, bone demineralization and fracture risk, 18 particularly after duodenal switch, are increased. A major cause of bone loss is impaired intestinal calcium absorption, which leads to stimulation of parathyroid hormone (secondary hyperparathyroidism) and bone resorption. 17 The evidence for monitoring, prevention and treatment is not well described. At minimum, adequate protein intake in combination with routine physical activity in addition to the routine supplementation of calcium citrate and vitamin D are recommended. 17,19 It is recommended to adjust calcium and vitamin D intake to achieve normal serum calcium, vitamin D and parathyroid hormone levels. Calcium citrate is preferred over calcium carbonate as it is better absorbed in the absence of gastric acid. Elevated parathyroid hormone in the setting of inappropriately high serum calcium and normal vitamin D levels is suggestive of primary hyperparathyroidism and requires further investigation.
The role of bone mineral density testing prior to bariatric surgery is controversial, 20 particularly due to technical difficulties when patients are at a higher body mass index (BMI). We suggest ordering bone mineral density testing on a patient at two years post-surgery, when weight is at its nadir. Subsequent bone mineral density testing can be ordered based on clinical need. 20 If a patient does have osteoporosis, then intravenous bisphosphonates (zolendronate 5 mg once a year, ibandronate 3 mg every three months) are the preferred choice, as there is a risk of anastomotic ulcer with oral bisphosphonates. Prior to starting bisphosphonate therapy, it is important that vitamin D levels be fully replete to prevent the development of hypocalcemia, hypophosphatemia and osteomalacia. 21
# Nephrolithiasis
Patients who have had bariatric surgery are at higher risk of new onset nephrolithiasis, with the mean interval from surgery to diagnosis of nephrolithiasis ranging from 1.5 to 3.6 years. The risk of nephrolithiasis, typically calcium oxalate stones, varies by procedure, being the highest for hypoabsorptive procedures (22% to 28.7%), intermediate for Roux-en-Y gastric bypass (7.65% to 13%) and the lowest for purely restrictive procedures (laparoscopic adjustable gastric banding, laparoscopic sleeve gastrectomy) where it approaches that of non-operative controls. 22 Unabsorbed fat in the intestine binds with calcium, which typically would bind oxalate. Oxalate is reabsorbed from the intestine and is subsequently filtered by the kidney, resulting in hyperoxaluria. With concomitant hypocitraturia (from intestinal alkali loss), there is a higher propensity for calcium oxalate stone formation. Basic therapeutic strategies to manage hyperoxaluria include calcium citrate supplementation, increased hydration, limiting dietary oxalate and adhering to a low-fat diet. 17,23 Commonly, individuals often believe that kidney stones are caused by taking too much calcium, and that calcium supplementation should be discontinued. The exact opposite is true, in that they should remain on their calcium citrate supplementation, which not only helps bind intestinal oxalate but also provides citrate for the urine. There is some evidence to suggest that pyridoxine (B6) deficiency plays a role in kidney stone formation, highlighting the importance of taking vitamin supplementation consistently. 24 Certain probiotics (containing either Lactobacillus alone or in combination with Streptococcus thermophilus and Bifidobacterium) may play a complementary role in reducing gastrointestinal oxalate absorption if basic strategies are insufficient. 25,26
# Psychological complications and treatments post-op
Though bariatric surgery is one of the most effective treatment options for obesity, clinicians should be aware of the potential post-bariatric psychological issues that may arise, including depression, suicide, 27,28 body image disorder, eating disorders, 29 and substance and alcohol abuse. 7 Results from bariatric surgery may not meet a patient's expectations or may not lead toward hoped improvements in quality of life, thus impacting mood. 14 Beyond providing knowledge on diet and exercise, clinicians should address improvement in patient's self-esteem and self-motivation. Patients who have had post-bariatric comprehensive behavioural-motivational nutrition education have decreased risk for depression and improved weight loss outcomes. 1,30,31 Primary care providers may need to refer the post-bariatric surgical patient for more in-depth psychological counselling, such as cognitive or dialectical behaviour therapy. Refer to The Role of Mental Health in Obesity Medicine and Effective Psychological and Behavioural Interventions for People Living with Obesity chapters for more details.
# Weight regain
Nadir weight (lowest weight point) occurs one to two years post-bariatric surgery. Weight loss stops partly because of adaptive changes in the intestine, changed patient habits and metabolic adaptation. 32 After this, it is normal to expect some weight regain. However, there is no consistent absolute number in the literature that defines pathological weight regain post-bariatric surgery. Studies that have been conducted in the bariatric surgery population show that significant weight regain (≥ 15% gain of initial weight loss post-bariatric surgery) occurs in 25-35% of people who undergo surgery two to five years after their initial surgical date. 33 The Swedish Obese Subjects study, the largest non-randomized intervention trial comparing weight loss outcomes in a group of over 4000 surgical and non-surgical individuals, reported that, at 10 years, individuals who underwent Roux-en-Y gastric bypass had a mean weight regain of 12% of total body weight, which translates into regaining 34% of the maximal lost weight achieved at one year. 29,34 The consensus for some Canadian bariatric surgical sites is that weight regain is defined as > 25% regain of total weight lost. The underlying factors that influence weight regain following bariatric surgery are multi-factorial, and include endocrine/metabolic alterations, anatomic surgical failure, nutritional indiscretion, mental health issues and physical inactivity. 29 Even prior to surgery, emphasizing realistic weight trajectories and expectations may theoretically help reduce the anxiety that some patients go through as they mentally try to transition from losing weight to healthy living and maintaining weight loss. Patients who experience weight regain may perceive that the surgery has failed, or they may enter a cycle of helplessness by blaming themselves and feeling shamed. It is important that clinicians mitigate these feelings by explaining that some weight regain following bariatric surgery is normal, and then proceeding in a stepwise approach to address the weight regain. It is neither necessary nor economical to order an esophagogastroduodenoscopy or an upper gastrointestinal contrast study to evaluate the gastrointestinal tract on every patient who is experiencing weight regain following surgery.
The following steps are suggested to address weight regain:
- Ensure that the patient continues to follow the recommended post-bariatric surgery nutrition plan and vitamin intake. Check bloodwork to ensure that vitamin and mineral levels are in the normal range. If a person is malnourished at baseline, then more harm occurs trying to help the person lose further weight.
Referral to a dietitian can be helpful at this stage.
- Psychological intervention may be required to address mood, anxiety, an eating disorder or to help a patient make behaviour changes.
- If on subsequent follow-ups, despite adherence to post-bariatric surgery nutrition plan and vitamin intake, weight does not decrease, then an esophagogastroduodenoscopy or upper gastrointestinal contrast study may rule out an anatomical failure. Detection of an anatomical failure would lead to a referral back the bariatric surgical team.
- Consideration of medications for obesity management post-bariatric surgery may be made for patients who are trying to follow the post-bariatrc surgery nutrition plan and taking their vitamin supplementation. Orlistat should not be used in patients who have had hypoabsorptive procedures. Retrospective reports have demonstrated that liraglutide 35,36 or naltrexone/bupropion 37 may play a role in reducing weight regain.
After all the above steps, if weight regain still remains an issue, then consider referring back to a bariatric surgery centre for eligibility of surgical revision.
# Medications
Following bariatric surgery and the resulting weight loss, many studies demonstrate a reduction of medications for diabetes, dyslipidemia, cardiovascular and anti-hypertensive agents. There are a limited number of publications that focus on the pharmacodynamics of medications post-operatively (Table 4). Ultimately, there remains a large interindividual variation and the therapeutic effects of a medication must be individually dose adjusted.
For the first three to eight weeks post-surgery, medications should be consumed in a crushed or liquid form or by opening capsule contents. It is important that the liquid form does not contain absorbable sugars to avoid dumping syndrome. 38 Some medications, however, should not be crushed. 39 Post Roux-en-Y gastric bypass and duodenal switch, the pharmacokinetic profile of many medicines may be altered due to changed intestinal absorption surface, lipophilicity of drugs, increased pH in the stomach, reduced cytochrome P450 (CYP) enzyme activity and first-pass intestinal metabolism, time after bariatric surgery and changes in volume of distribution. 40 Immediate-release formulations are generally preferred over extended release. Non-steroidal anti-inflammatory drugs should be avoided after Roux-en-Y gastric bypass or duodenal switch due to risk of anastomotic ulceration/perforations. For other bariatric procedures, NSAIDs use should be accompanied with proton pump inhibitors (PPIs) for mucosal protection. 41 Patients who need to remain on low-dose aspirin for secondary prevention may do so but should have additional PPI protection.
Especially for Roux-en-Y gastric bypass and duodenal switch procedures, patients taking long-term warfarin require a post-operative dose reduction of > 20% with closely monitored international normalized ratio (INR). Direct oral anti-coagulants (DOACs) should be avoided due to the potential for decreased drug absorption. If a betablocker after bariatric surgery is needed, a hydrophilic compound like atenolol may be preferred. Bioavailability of oral contraceptives may be reduced post-bariatric surgery, and alternate methods of contraception need to be considered. Anti-diabetic medications with a risk for hypoglycemia (such as sulfonylureas) should be discontinued and insulin doses adjusted. Metformin may be continued but the dose may need to be reduced due to increased absorption. 42 Primary care providers may benefit from working with a patient's community pharmacist for medication adjustments.
# Special considerations for bariatric surgery on fertility
Bariatric surgery should not be considered a treatment for infertility. 43 Many studies related to fertility in women post-bariatric surgery are small, and appropriate control groups have not always been included. Together, the evidence suggests that bariatric surgery improves fertility, whether it is through improvements of sex hormonal profiles or resolution of polycystic ovary syndrome markers, which influence fertility (including anovulation, hirsutism, hormonal changes, insulin resistance, sexual activity and libido). 44 The type of surgery does not appear to be related to changes in fertility, as only the amount of weight lost (a BMI decrease of greater than 5 kg/ m 2 ) and the BMI achieved at time of conception were predictive of becoming pregnant. 45 In men, surgery-induced massive weight loss does not impact sperm quality, but it does increase the quality of sexual function, total testosterone, free testosterone and FSH and reduces prolactin. 46 Overall, in men, the balance between positive (hormonal, psychological and sexual improvements) and negative (nutritional depletion due to selective food maldigestion and malabsorption) impacts will determine the final effect on seminal quality and fertility. 46 Women who became pregnant before one year after bariatric surgery presented with a higher rate of fetal loss in comparison to women whose pregnancy occurred after this period of time (35.5% versus 16.3%). Pregnancy is therefore not recommended in the first 12-18 months following bariatric surgery, 47 by which time weight is more stable and women are able to consume a nutritionally balanced diet. Thus, adequate contraception should be offered to women of reproductive age who undergo bariatric surgery. As estrogen is absorbed in the upper gastrointestinal tract, which is modified during bariatric surgery, oral contraception pills should be avoided for Roux-en-Y gastric bypass and biliopancreatic diversion/duodenal switch. Instead, normal forms of hormonal contraception (etonogestrel implant 48 or a levonorgestrel-releasing intrauterine device 49 may be considered.
There is no definitive contraindication to oral contraception pills for gastric banding and sleeve gastrectomy. 14,50
# Special considerations in women who have had bariatric surgery and pregnancy
Compared with women who have obesity and who have not undergone bariatric surgery, women who became pregnant after bariatric surgery had a lower risk of gestational diabetes, hypertensive disorders and macrosomia. However, risk of small-for-gestational-age newborns increases after bariatric surgery. 51
# Pre-conception care
Women planning conception post-bariatric surgery should have daily oral supplementation with a multivitamin containing 1.0 mg folic acid, beginning at least three months before conception. Women should continue this regime until 12 weeks gestational age. From 12 weeks gestational age, continuing through the pregnancy, and for four to six weeks postpartum or as long as breast feeding continues, continued daily supplementation should consist of a multivitamin with 0.8 mg to 1.0 mg folic acid. 52 B12 levels should be checked and corrected if deficient prior to initiation of additional folic acid. Women are advised to avoid vitamin and mineral preparations which contain vitamin A in the retinol form in the first 12 weeks of pregnancy, as supplements containing retinol may increase the teratogenic risk (especially in the first trimester). It is therefore recommended that pregnant women and those planning pregnancies following bariatric surgery are supplemented with vitamin A in the beta-carotene form.
# Nutritional monitoring during pregnancy
Standard complete multivitamins routinely used post-bariatric surgery should be substituted for prenatal multivitamins to reduce vitamin A intake, which should not exceed 5000 IU/day. Continue all other regular supplementation that the patient typically would be on, and then adjust according to laboratory testing. Laboratory testing at each trimester should include CBC, ferritin, albumin, B12, 25-Hydroxy (OH) vitamin D, calcium, parathyroid hormone and folate. Patients who have had hypoabsorptive surgery should additionally have zinc, copper and vitamin A levels (and possibly vitamin E and K levels with duodenal switch) monitored during pregnancy. 14,44,53,54 If the patient is vitamin A deficient, then supplementation should be in the form of beta-carotene vitamin A. 53 Patients suffering from nausea and intractable vomiting should have immediate B1 supplementation and careful monitoring of B1 levels. Nutrition advice from an experienced registered dietitian should be offered to review deficiencies, vitamin supplementation and ensure a recommended daily protein intake of 60 g. 43 Possible recommended gestational weight gain would be based on pre-pregnancy BMI as per the Institute of Medicine. 55
# Other considerations during pregnancy
In addition to nutritional deficiencies, there is also the potential for severe, life-threatening complications, such as internal hernias, bowel obstructions, volvulus, intussusception and gastric perforations, which generally occur one to three years after bariatric surgery. Because of the upward pressure from the gravid uterus, these late sequelae may present in pregnancy and during the immediate postpartum period. Abdominal pain in a post-bariatric surgical gravid woman would need to include these potential complications in the differential diagnoses. Radiologic evaluation with computed tomography scan should be reviewed by bariatric surgeons or radiologists with specialized expertise in this area. 56 Post-surgical patients may not tolerate the 50 g glucose solution commonly administered at 24-28 weeks of gestation to screen for gestational diabetes. Alternative measures to screen for gestational diabetes should be considered for patients who have undergone hypoabsorptive-type surgery. One proposed alternative is home glucose monitoring (fasting and two-hour post-prandial blood sugar) for approximately one week during the 24-28 weeks of gestation. 43
# Postpartum
Breast feeding should be encouraged. It is important that postpartum bariatric surgical patients continue their recommended vitamin supplementation, as there have been documented cases of nutritional deficiencies in breast-fed infants born to mothers who have had Roux-en-Y gastric bypass. 57 Generally, patients will need two complete OTC MV day to reach the daily recommendations post-bariatric surgery.
The ratio of zinc:copper should remain 8-15 mg:1 mg. It is not uncommon that for duodenal switch, higher supplementation of vitamin D (as high as 50,000 IU 2-3 times/week) may be required. D3 (cholecalciferol) is preferred over D2 (ergocalciferol) for its more potent effect.
Take in divided doses. Calcium citrate (preferred) with or without meals. Calcium carbonate with meals. Titrate to calcium and parathyroid hormone levels. Take before bed. Do not take with calcium as absorption blocked.
Ferrous sulphate is the preferred iron supplement, but others may be considered if this supplement is not tolerated.
Take with vitamin C 250-500 mg for better absorption with non-heme iron supplements.
# Formulations of different non-heme iron supplements (elemental iron mg):
- Ferrous sulphate 300 mg (60 mg),
- Ferrous gluconate 300 mg (35 mg), and - Ferrous fumarate 300 mg (99 mg).
There is no evidence for the role of heme iron supplements (11 mg elemental heme iron/tablet) for prevention of anemia in post-bariatric surgical patients. However, if this is what is tolerated clinically, careful monitoring of CBC and ferritin levels are warranted. Can increase oral non-heme iron intake in divided doses to provide 150-200 mg elemental iron daily (e.g.: ferrous sulfate 300 mg tid). 63 Take separately from calcium supplements, acid-reducing medications -if no response, then consider parenteral iron administration.
# LAB MONITORING
# LAGB or LS RYGB DS Comments
Heme iron for treatment of post-Roux-en-Y gastric bypass iron deficiency is not recommended as first line but may be considered if patient does not tolerate non-heme iron. The dosing would be 4 tablets of heme iron daily.
Source: Shiau, J.
Source: Shiau, J. Source: Shiau, J. | Adherence to consistent post-operative behavioural changes (behaviour modification for nutrition plans, physical activity and vitamin intake) can optimize obesity management and health while minimizing post-operative complications. • Working in partnership, the bariatric surgical centre, the local bariatric medicine specialist, the primary care provider and the patient living with obesity need to establish and commit to a shared care model of chronic disease management for long-term follow-up. • The primary care provider should refer patients with post-bariatric surgery complications back to the bariatric surgical centre, or to a local bariatric medicine specialist.# RECOMMENDATIONS
1. Healthcare providers can encourage people who have undergone bariatric surgery to participate and maximize their access to behavioural interventions and allied health services at a bariatric surgical centre (Level 2a, Grade B). 1,2 2. We suggest that bariatric surgical centres communicate a comprehensive care plan to primary care providers on patients who are discharged, including: bariatric procedure, emergency contact numbers, annual blood tests required, long-term vitamin and mineral supplements, medications, behavioural interventions and when to refer back (Level 4, Grade D, consensus).
3. We suggest that after a patient has been discharged from the bariatric surgical centre, primary care providers should annually review: nutritional intake, activity, compliance with multivitamin and mineral supplements and weight, as well as assess comorbidities, order laboratory tests to assess for nutritional deficiencies and investigate abnormal results and treat as required (Level 4, Grade D, consensus). 4. We suggest that primary care providers consider referral back to the bariatric surgical centre or to a local specialist for technical or gastrointestinal symptoms, nutritional issues, pregnancy, psychological support, weight regain or other medical issues as described in this chapter related to bariatric surgery (Level 4, Grade D, consensus).
5. We suggest that bariatric surgical centres provide follow-up and appropriate laboratory tests at regular intervals post-surgery with access to appropriate healthcare professionals (dietitian, nurse, social worker, surgeon, bariatric physician, psychologist/psychiatrist) until discharge is deemed appropriate for the patient (Level 4, Grade D, consensus).
# Post-bariatric surgery health behaviour changes Post-bariatric surgery diet
Centres that perform bariatric surgery will typically provide patients with a dietary protocol to follow. Initially, over several weeks, patients transition from liquid, to soft and then to a solid diet. Over the long term, patients are encouraged to follow a structured post-bariatric surgical diet involving small portions, three to five balanced and structured meals and healthy snacks (chew foods slowly and avoid sweets). For beverages, patients should not eat and drink at the same time (avoid liquids within 30 minutes of eating solids). Carbonated beverages and caffeinated drinks are to be avoided, as the phosphoric acid and caffeine, respectively, can increase the risk of ulcerations.
After bariatric surgery, patients need to follow a low-fat, moderate carbohydrate and high-protein diet. Post-operative protein recommendations range from 1.2 to 1.5 g/kg/day based on goal body weight (minimum of 60 g protein/day for laparoscopic sleeve gastrectomy/Roux-en-Y gastric bypass, and 80-120 g/day for duodenal switch). Consulting a registered dietitian can support changes in eating behaviours and guide patients on their nutrition needs. 3 There is no advantage to prescribing alternate diets (e.g., low carbohydrate, high protein), probiotics or amino acids. [4][5][6] Other behavioural changes to consider Alcohol intake should be minimal or avoided due to changes in pharmacokinetics. For example, in women who are post Rouxen-Y gastric bypass, two alcoholic beverages are equivalent in absorption to four alcoholic beverages. 7 Seven percent of patients report new high-risk alcohol use one year after bariatric surgery, though, on a more positive note, half who reported high-risk alcohol use before surgery discontinued high-risk drinking. 7 Activity: Long term, a standard of 150 to 300 minutes of activity/week is recommended for post-bariatric surgical patients. Post-operative higher-volume exercise can help promote further weight loss [8][9][10] but sustaining this level of activity is difficult. 11
Smoking cessation: Abstention from cigarettes is recommended. Cigarette smoking can increase risk of peptic ulcer disease, particularly marginal ulcers.
Marijuana: There is a paucity of studies on the use of marijuana post-bariatric surgery. One concern would be the impact of weight loss and the chronic use of marijuana, which is traditionally known for its "munchies" effect. At this point, moderation, if not abstention, would be a safe recommendation.
# Post-bariatric surgery vitamin supplementation
The evidence for the role of vitamin supplementation (amount, duration) varies depending on which vitamin, mineral or type of bariatric procedure are studied. Generally, some type of vitamin supplementation is needed for all bariatric surgical procedures, with tailoring for those that have a hypoabsorptive component (Roux-en-Y gastric bypass, duodenal switch).
Practically, it makes sense that a standardized minimum prescription of vitamins be set for all bariatric surgeries. It is a natural human tendency to eventually forget to take supplements. Setting a standard means that clinicians can be consistent in their messaging about taking vitamins. Deficiencies of vitamins and some minerals can leave serious and potentially non-reversible side effects. Frequency of laboratory monitoring may vary depending on the individual and type of procedure, but at minimum an annual check should be conducted to ensure that patients are not becoming malnourished. Tables 1 and 2 summarize the recommendations
# KEY MESSAGES FOR PATIENTS LIVING WITH OBESITY WHO HAVE HAD BARIATRIC SURGERY
1. If you have had bariatric surgery, it is important for you to take your nutritional supplements lifelong and to continue to follow the post-bariatric surgical nutrition plan, exercise and any other recommendations given by your original specialist team. By doing this, you will increase your chances of staying healthy and reduce complications that can arise from bariatric surgery.
2. Attend all scheduled appointments and programming offered by your bariatric surgical site. Once you are discharged from the bariatric surgical site, schedule annual appointments with your primary care provider to check your bloodwork, reassess your medications and address any issues related to changes in your weight.
3. After bariatric surgery, it is possible that there can be a negative impact on mood, relationships, body image, development of addictions and reduced ability to cope with stress. If you are struggling, discuss this with your original specialist team or, if you have been discharged, with your primary care provider.
4. Remember that your lowest weight post-surgery will occur between 12 to 18 months. After this, there is a natural increase in weight that occurs. If you are gaining excessive amounts of weight, discuss this with your bariatric team or primary care provider.
5. If you are 12 to 18 months post-bariatric surgery and are planning a pregnancy, discuss this with your bariatric team, primary care provider and obstetrician.
for vitamin supplementation, associated deficits that can occur with various deficiencies, and frequency of monitoring. Table 3 summarizes clinical features that may point toward a nutrient deficiency. A dietitian can help determine what combination of vitamins makes sense for a patient. In Canada, access to all-in-one bariatric supplements for surgical patients is improving and can help compliance by reducing the number of pills that need to be taken. Gummy vitamins should be avoided as they do not contain essential minerals.
# Post-bariatric surgery complications
Many gastrointestinal (dumping syndrome) and metabolic complications (e.g., bone, kidney stones) can be prevented by following the recommended post-bariatric surgery nutrition plan and vitamin intake.
# Dumping syndrome
Dumping syndrome is divided into early and late phases. Early dumping syndrome occurs within the first hour after a meal. Because of the hyperosmolality of the food, rapid fluid shifts occur from the plasma compartment into the intestinal lumen, resulting in hypotension and a sympathetic nervous system response.
Early dumping is characterized by gastrointestinal symptoms such as abdominal pain, bloating, borborygmi, nausea and diarrhea, and vasomotor symptoms, such as fatigue, desire to lie down after meals (a classic symptom), flushing, palpitations, perspiration, tachycardia, hypotension and, rarely, syncope. In contrast, late dumping usually occurs one to three hours after a meal and is a result of an incretin-driven hyperinsulinemic response after carbohydrate ingestion. Hypoglycemia-related symptoms are related to neuroglycopenia (fatigue, weakness, confusion, hunger and syncope) and autonomic/adrenergic reactivity (perspiration, palpitations, tremor and irritability). 12 Symptoms that persist despite returning to a post-bariatric surgery diet may benefit from a trial of either acarbose, a calcium channel blocker, diazoxide or octreotide. Referral to a bariatric medicine specialist or an endocrinologist for management and to rule out other causes of hypoglycemia (nesidioblastosis, insulinoma, factitious) may be warranted. 13
# Abdominal discomfort
Abdominal discomfort has a long differential from dietary indiscretion (overeating), dumping syndrome, biliary colic, stenosis of the gastrojejunostomy, marginal ulcer or small bowel obstruction. Presentation for small bowel obstruction can come at any time, but can be divided into early (< 30 days; secondary to adhesions or incarcerated hernias) or late (> 1 year; internal hernia, which can be seen after Roux-en-Y gastric bypass or duodenal switch). During the first year, there is a need for a higher level of suspicion for pain secondary to a surgical complication. Tachycardia, unstable vital signs and abdominal pain may be suggestive of a surgical leak, internal hernia or cholecystitis, which warrants immediate surgical referral. With diarrhea, constipation or bloating, referral to a dietitian can help identify healthier food choices and proper fibre content. Probiotics may improve symptomatic gastrointestinal episodes.
There should be a high level of suspicion for an ulceration for patients who use non-steroidal anti-inflammatory drugs (NSAIDS). Referral to the bariatric surgical site should be considered when clinical red flags appear such as unexplained, frequent, moderate-to-severe abdominal pain, daily intolerance to most solid foods, daily nausea and vomiting and/or a significant amount of weight regain (> 25-50% of total weight loss) in a short space of time. Every bariatric patient suffering from persistent vomiting severe enough to interfere with regular nutrition should be promptly started on oral or parenteral thiamine supplementation, even in the absence or before confirmatory laboratory data. 14
# Bone health
Post-bariatric surgery, bone demineralization [15][16][17] and fracture risk, 18 particularly after duodenal switch, are increased. A major cause of bone loss is impaired intestinal calcium absorption, which leads to stimulation of parathyroid hormone (secondary hyperparathyroidism) and bone resorption. 17 The evidence for monitoring, prevention and treatment is not well described. At minimum, adequate protein intake in combination with routine physical activity in addition to the routine supplementation of calcium citrate and vitamin D are recommended. 17,19 It is recommended to adjust calcium and vitamin D intake to achieve normal serum calcium, vitamin D and parathyroid hormone levels. Calcium citrate is preferred over calcium carbonate as it is better absorbed in the absence of gastric acid. Elevated parathyroid hormone in the setting of inappropriately high serum calcium and normal vitamin D levels is suggestive of primary hyperparathyroidism and requires further investigation.
The role of bone mineral density testing prior to bariatric surgery is controversial, 20 particularly due to technical difficulties when patients are at a higher body mass index (BMI). We suggest ordering bone mineral density testing on a patient at two years post-surgery, when weight is at its nadir. Subsequent bone mineral density testing can be ordered based on clinical need. 20 If a patient does have osteoporosis, then intravenous bisphosphonates (zolendronate 5 mg once a year, ibandronate 3 mg every three months) are the preferred choice, as there is a risk of anastomotic ulcer with oral bisphosphonates. Prior to starting bisphosphonate therapy, it is important that vitamin D levels be fully replete to prevent the development of hypocalcemia, hypophosphatemia and osteomalacia. 21
# Nephrolithiasis
Patients who have had bariatric surgery are at higher risk of new onset nephrolithiasis, with the mean interval from surgery to diagnosis of nephrolithiasis ranging from 1.5 to 3.6 years. The risk of nephrolithiasis, typically calcium oxalate stones, varies by procedure, being the highest for hypoabsorptive procedures (22% to 28.7%), intermediate for Roux-en-Y gastric bypass (7.65% to 13%) and the lowest for purely restrictive procedures (laparoscopic adjustable gastric banding, laparoscopic sleeve gastrectomy) where it approaches that of non-operative controls. 22 Unabsorbed fat in the intestine binds with calcium, which typically would bind oxalate. Oxalate is reabsorbed from the intestine and is subsequently filtered by the kidney, resulting in hyperoxaluria. With concomitant hypocitraturia (from intestinal alkali loss), there is a higher propensity for calcium oxalate stone formation. Basic therapeutic strategies to manage hyperoxaluria include calcium citrate supplementation, increased hydration, limiting dietary oxalate and adhering to a low-fat diet. 17,23 Commonly, individuals often believe that kidney stones are caused by taking too much calcium, and that calcium supplementation should be discontinued. The exact opposite is true, in that they should remain on their calcium citrate supplementation, which not only helps bind intestinal oxalate but also provides citrate for the urine. There is some evidence to suggest that pyridoxine (B6) deficiency plays a role in kidney stone formation, highlighting the importance of taking vitamin supplementation consistently. 24 Certain probiotics (containing either Lactobacillus alone or in combination with Streptococcus thermophilus and Bifidobacterium) may play a complementary role in reducing gastrointestinal oxalate absorption if basic strategies are insufficient. 25,26
# Psychological complications and treatments post-op
Though bariatric surgery is one of the most effective treatment options for obesity, clinicians should be aware of the potential post-bariatric psychological issues that may arise, including depression, suicide, 27,28 body image disorder, eating disorders, 29 and substance and alcohol abuse. 7 Results from bariatric surgery may not meet a patient's expectations or may not lead toward hoped improvements in quality of life, thus impacting mood. 14 Beyond providing knowledge on diet and exercise, clinicians should address improvement in patient's self-esteem and self-motivation. Patients who have had post-bariatric comprehensive behavioural-motivational nutrition education have decreased risk for depression and improved weight loss outcomes. 1,30,31 Primary care providers may need to refer the post-bariatric surgical patient for more in-depth psychological counselling, such as cognitive or dialectical behaviour therapy. Refer to The Role of Mental Health in Obesity Medicine and Effective Psychological and Behavioural Interventions for People Living with Obesity chapters for more details.
# Weight regain
Nadir weight (lowest weight point) occurs one to two years post-bariatric surgery. Weight loss stops partly because of adaptive changes in the intestine, changed patient habits and metabolic adaptation. 32 After this, it is normal to expect some weight regain. However, there is no consistent absolute number in the literature that defines pathological weight regain post-bariatric surgery. Studies that have been conducted in the bariatric surgery population show that significant weight regain (≥ 15% gain of initial weight loss post-bariatric surgery) occurs in 25-35% of people who undergo surgery two to five years after their initial surgical date. 33 The Swedish Obese Subjects study, the largest non-randomized intervention trial comparing weight loss outcomes in a group of over 4000 surgical and non-surgical individuals, reported that, at 10 years, individuals who underwent Roux-en-Y gastric bypass had a mean weight regain of 12% of total body weight, which translates into regaining 34% of the maximal lost weight achieved at one year. 29,34 The consensus for some Canadian bariatric surgical sites is that weight regain is defined as > 25% regain of total weight lost. The underlying factors that influence weight regain following bariatric surgery are multi-factorial, and include endocrine/metabolic alterations, anatomic surgical failure, nutritional indiscretion, mental health issues and physical inactivity. 29 Even prior to surgery, emphasizing realistic weight trajectories and expectations may theoretically help reduce the anxiety that some patients go through as they mentally try to transition from losing weight to healthy living and maintaining weight loss. Patients who experience weight regain may perceive that the surgery has failed, or they may enter a cycle of helplessness by blaming themselves and feeling shamed. It is important that clinicians mitigate these feelings by explaining that some weight regain following bariatric surgery is normal, and then proceeding in a stepwise approach to address the weight regain. It is neither necessary nor economical to order an esophagogastroduodenoscopy or an upper gastrointestinal contrast study to evaluate the gastrointestinal tract on every patient who is experiencing weight regain following surgery.
The following steps are suggested to address weight regain:
• Ensure that the patient continues to follow the recommended post-bariatric surgery nutrition plan and vitamin intake. Check bloodwork to ensure that vitamin and mineral levels are in the normal range. If a person is malnourished at baseline, then more harm occurs trying to help the person lose further weight.
Referral to a dietitian can be helpful at this stage.
• Psychological intervention may be required to address mood, anxiety, an eating disorder or to help a patient make behaviour changes.
• If on subsequent follow-ups, despite adherence to post-bariatric surgery nutrition plan and vitamin intake, weight does not decrease, then an esophagogastroduodenoscopy or upper gastrointestinal contrast study may rule out an anatomical failure. Detection of an anatomical failure would lead to a referral back the bariatric surgical team.
• Consideration of medications for obesity management post-bariatric surgery may be made for patients who are trying to follow the post-bariatrc surgery nutrition plan and taking their vitamin supplementation. Orlistat should not be used in patients who have had hypoabsorptive procedures. Retrospective reports have demonstrated that liraglutide 35,36 or naltrexone/bupropion 37 may play a role in reducing weight regain.
After all the above steps, if weight regain still remains an issue, then consider referring back to a bariatric surgery centre for eligibility of surgical revision.
# Medications
Following bariatric surgery and the resulting weight loss, many studies demonstrate a reduction of medications for diabetes, dyslipidemia, cardiovascular and anti-hypertensive agents. There are a limited number of publications that focus on the pharmacodynamics of medications post-operatively (Table 4). Ultimately, there remains a large interindividual variation and the therapeutic effects of a medication must be individually dose adjusted.
For the first three to eight weeks post-surgery, medications should be consumed in a crushed or liquid form or by opening capsule contents. It is important that the liquid form does not contain absorbable sugars to avoid dumping syndrome. 38 Some medications, however, should not be crushed. 39 Post Roux-en-Y gastric bypass and duodenal switch, the pharmacokinetic profile of many medicines may be altered due to changed intestinal absorption surface, lipophilicity of drugs, increased pH in the stomach, reduced cytochrome P450 (CYP) enzyme activity and first-pass intestinal metabolism, time after bariatric surgery and changes in volume of distribution. 40 Immediate-release formulations are generally preferred over extended release. Non-steroidal anti-inflammatory drugs should be avoided after Roux-en-Y gastric bypass or duodenal switch due to risk of anastomotic ulceration/perforations. For other bariatric procedures, NSAIDs use should be accompanied with proton pump inhibitors (PPIs) for mucosal protection. 41 Patients who need to remain on low-dose aspirin for secondary prevention may do so but should have additional PPI protection.
Especially for Roux-en-Y gastric bypass and duodenal switch procedures, patients taking long-term warfarin require a post-operative dose reduction of > 20% with closely monitored international normalized ratio (INR). Direct oral anti-coagulants (DOACs) should be avoided due to the potential for decreased drug absorption. If a betablocker after bariatric surgery is needed, a hydrophilic compound like atenolol may be preferred. Bioavailability of oral contraceptives may be reduced post-bariatric surgery, and alternate methods of contraception need to be considered. Anti-diabetic medications with a risk for hypoglycemia (such as sulfonylureas) should be discontinued and insulin doses adjusted. Metformin may be continued but the dose may need to be reduced due to increased absorption. 42 Primary care providers may benefit from working with a patient's community pharmacist for medication adjustments.
# Special considerations for bariatric surgery on fertility
Bariatric surgery should not be considered a treatment for infertility. 43 Many studies related to fertility in women post-bariatric surgery are small, and appropriate control groups have not always been included. Together, the evidence suggests that bariatric surgery improves fertility, whether it is through improvements of sex hormonal profiles or resolution of polycystic ovary syndrome markers, which influence fertility (including anovulation, hirsutism, hormonal changes, insulin resistance, sexual activity and libido). 44 The type of surgery does not appear to be related to changes in fertility, as only the amount of weight lost (a BMI decrease of greater than 5 kg/ m 2 ) and the BMI achieved at time of conception were predictive of becoming pregnant. 45 In men, surgery-induced massive weight loss does not impact sperm quality, but it does increase the quality of sexual function, total testosterone, free testosterone and FSH and reduces prolactin. 46 Overall, in men, the balance between positive (hormonal, psychological and sexual improvements) and negative (nutritional depletion due to selective food maldigestion and malabsorption) impacts will determine the final effect on seminal quality and fertility. 46 Women who became pregnant before one year after bariatric surgery presented with a higher rate of fetal loss in comparison to women whose pregnancy occurred after this period of time (35.5% versus 16.3%). Pregnancy is therefore not recommended in the first 12-18 months following bariatric surgery, 47 by which time weight is more stable and women are able to consume a nutritionally balanced diet. Thus, adequate contraception should be offered to women of reproductive age who undergo bariatric surgery. As estrogen is absorbed in the upper gastrointestinal tract, which is modified during bariatric surgery, oral contraception pills should be avoided for Roux-en-Y gastric bypass and biliopancreatic diversion/duodenal switch. Instead, normal forms of hormonal contraception (etonogestrel implant 48 or a levonorgestrel-releasing intrauterine device 49 may be considered.
There is no definitive contraindication to oral contraception pills for gastric banding and sleeve gastrectomy. 14,50
# Special considerations in women who have had bariatric surgery and pregnancy
Compared with women who have obesity and who have not undergone bariatric surgery, women who became pregnant after bariatric surgery had a lower risk of gestational diabetes, hypertensive disorders and macrosomia. However, risk of small-for-gestational-age newborns increases after bariatric surgery. 51
# Pre-conception care
Women planning conception post-bariatric surgery should have daily oral supplementation with a multivitamin containing 1.0 mg folic acid, beginning at least three months before conception. Women should continue this regime until 12 weeks gestational age. From 12 weeks gestational age, continuing through the pregnancy, and for four to six weeks postpartum or as long as breast feeding continues, continued daily supplementation should consist of a multivitamin with 0.8 mg to 1.0 mg folic acid. 52 B12 levels should be checked and corrected if deficient prior to initiation of additional folic acid. Women are advised to avoid vitamin and mineral preparations which contain vitamin A in the retinol form in the first 12 weeks of pregnancy, as supplements containing retinol may increase the teratogenic risk (especially in the first trimester). It is therefore recommended that pregnant women and those planning pregnancies following bariatric surgery are supplemented with vitamin A in the beta-carotene form.
# Nutritional monitoring during pregnancy
Standard complete multivitamins routinely used post-bariatric surgery should be substituted for prenatal multivitamins to reduce vitamin A intake, which should not exceed 5000 IU/day. Continue all other regular supplementation that the patient typically would be on, and then adjust according to laboratory testing. Laboratory testing at each trimester should include CBC, ferritin, albumin, B12, 25-Hydroxy (OH) vitamin D, calcium, parathyroid hormone and folate. Patients who have had hypoabsorptive surgery should additionally have zinc, copper and vitamin A levels (and possibly vitamin E and K levels with duodenal switch) monitored during pregnancy. 14,44,53,54 If the patient is vitamin A deficient, then supplementation should be in the form of beta-carotene vitamin A. 53 Patients suffering from nausea and intractable vomiting should have immediate B1 supplementation and careful monitoring of B1 levels. Nutrition advice from an experienced registered dietitian should be offered to review deficiencies, vitamin supplementation and ensure a recommended daily protein intake of 60 g. 43 Possible recommended gestational weight gain would be based on pre-pregnancy BMI as per the Institute of Medicine. 55
# Other considerations during pregnancy
In addition to nutritional deficiencies, there is also the potential for severe, life-threatening complications, such as internal hernias, bowel obstructions, volvulus, intussusception and gastric perforations, which generally occur one to three years after bariatric surgery. Because of the upward pressure from the gravid uterus, these late sequelae may present in pregnancy and during the immediate postpartum period. Abdominal pain in a post-bariatric surgical gravid woman would need to include these potential complications in the differential diagnoses. Radiologic evaluation with computed tomography scan should be reviewed by bariatric surgeons or radiologists with specialized expertise in this area. 56 Post-surgical patients may not tolerate the 50 g glucose solution commonly administered at 24-28 weeks of gestation to screen for gestational diabetes. Alternative measures to screen for gestational diabetes should be considered for patients who have undergone hypoabsorptive-type surgery. One proposed alternative is home glucose monitoring (fasting and two-hour post-prandial blood sugar) for approximately one week during the 24-28 weeks of gestation. 43
# Postpartum
Breast feeding should be encouraged. It is important that postpartum bariatric surgical patients continue their recommended vitamin supplementation, as there have been documented cases of nutritional deficiencies in breast-fed infants born to mothers who have had Roux-en-Y gastric bypass. 57 Generally, patients will need two complete OTC MV day to reach the daily recommendations post-bariatric surgery.
The ratio of zinc:copper should remain 8-15 mg:1 mg. It is not uncommon that for duodenal switch, higher supplementation of vitamin D (as high as 50,000 IU 2-3 times/week) may be required. D3 (cholecalciferol) is preferred over D2 (ergocalciferol) for its more potent effect.
Take in divided doses. Calcium citrate (preferred) with or without meals. Calcium carbonate with meals. Titrate to calcium and parathyroid hormone levels. Take before bed. Do not take with calcium as absorption blocked.
Ferrous sulphate is the preferred iron supplement, but others may be considered if this supplement is not tolerated.
Take with vitamin C 250-500 mg for better absorption with non-heme iron supplements.
# Formulations of different non-heme iron supplements (elemental iron mg):
• Ferrous sulphate 300 mg (60 mg),
• Ferrous gluconate 300 mg (35 mg), and • Ferrous fumarate 300 mg (99 mg).
There is no evidence for the role of heme iron supplements (11 mg elemental heme iron/tablet) for prevention of anemia in post-bariatric surgical patients. However, if this is what is tolerated clinically, careful monitoring of CBC and ferritin levels are warranted. Can increase oral non-heme iron intake in divided doses to provide 150-200 mg elemental iron daily (e.g.: ferrous sulfate 300 mg tid). 63 Take separately from calcium supplements, acid-reducing medications -if no response, then consider parenteral iron administration.
# LAB MONITORING
# LAGB or LS RYGB DS Comments
Heme iron for treatment of post-Roux-en-Y gastric bypass iron deficiency is not recommended as first line but may be considered if patient does not tolerate non-heme iron. The dosing would be 4 tablets of heme iron daily.
Source: Shiau, J.
Source: Shiau, J. Source: Shiau, J. | None | None |
9987f9601053456435b3b78afaecbe805dcaca26 | cma | None | This document is intended to assist healthcare providers by providing an approach to managing COVID-19 vaccines that are administered in a manner that differs from the BC Immunization Manual guidelines (referred to as vaccine administration errors). This document builds on guidance developed by the Public Health Agency of Canada's Managing COVID-19 vaccine administration errors or deviations and the CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States. There is limited evidence to guide the management of these situations. This document provides guidance only. Health authority protocols may differ from this guidance document and clinical judgement in particular situations may also result in different management decisions than outlined below. Note that this document is to be used only to manage errors that have already occurred. The guidelines within the BC Immunization Manual should be followed when administering COVID-19 vaccines to prevent errors or deviations from occurring. The following will be addressed in this document:Administration error Interim guidance on how to consider the dose and recommended action Site/route Guiding Principle: COVID-19 vaccines should be administered intramuscularly. The vastus lateralis (anterolateral thigh) is recommended for children less than 1 year of age. The vastus lateralis or the deltoid muscle can be used for toddlers and older children. The deltoid is often selected as the injection site in these age groups as temporary muscle pain in the vastus lateralis muscle post-vaccination may affect ambulation. The deltoid muscle of the arm is the preferred injection site in adolescents and adults. When selecting a site, it is important to consider available muscle mass. Clients administered a vaccine in an incorrect site or by an incorrect route should be informed of the potential for local and systemic adverse events. Incorrect site (i.e., site other than the deltoid muscle or vastus lateralis as appropriate for age) Consider the dose valid. Incorrect route (e.g., subcutaneous) Consider the dose valid.Use at a younger age than authorized by Health Canada and/or recommended by NACI Consider the dose valid. Receipt of a WHO EUA qualified COVID-19 vaccine not authorized in Canada (e.g., Sinovac, Sinopharm, Covaxin) at < 18 years of age for one or more doses. Consider the dose valid.Guiding Principle: Doses given longer than the recommended interval: While recommended intervals are optimal, doses delayed beyond the recommended interval are considered valid.#
- Steps to be taken after an error is recognized Steps to be taken after an error is recognized Following the identification of an inadvertent vaccine administration error, healthcare providers should:
- Inform the recipient of the vaccine administration error as soon as possible after it is identified. The recipient should be informed of any implications/recommendations for future doses, and possibility for local or systemic reactions and impact on the effectiveness of the vaccine (if applicable and known). - Report all errors or near miss incidents in accordance with the institutional medication error or professional body's reporting process, including the BC Patient Safety Learning System (PSLS). - If an inadvertent vaccine administration error results in an adverse event following immunization (AEFI), complete the appropriate AEFI Case Report Form found on the Adverse Events Following Immunization page and submit it to the local public health authority. Information on AEFI reporting can be found in the BC Immunization Manual, Part 5 -Adverse events Following Immunization. - Determine how the vaccine administration error occurred and implement strategies to prevent it from happening again. - As with usual practice, when managing errors and deviations, inquire about the client's history of adverse events following vaccination. If they experienced a significant local or systemic reaction, base your decision to offer subsequent doses on a case-by-case basis in consultation with the Medical Health Officer and/or in consultation with an allergist/immunologist. - If the client who had a repeat dose following an invalid dose requires a subsequent dose in the initial series or a booster, give it with a recommended age-appropriate dosage and product. Count the interval from the repeat dose. - Additional resources on vaccine administration practices can be found in the BC Immunization Manual, Appendix B -Administration of Biological Products.
Doses given earlier than the minimum interval: Doses given too close together may result in a suboptimal immune response due to: (1) Less than optimal time to allow for the immune response to mature between doses; and (2) Antibodies produced to the early dose may interfere with the antibody response to the later dose.
For information on recommended and minimum intervals, refer to the respective product pages in the BC Immunization Manual, Part 4-Biological Products, COVID-19 Vaccines.
# Type Administration error
Interim guidance on how to consider the dose and recommended action Subsequent dose of COVID-19 vaccine within the primary series administered prior to the minimum interval.
If the dose was administered at less than the minimum interval, consider the dose invalid and repeat at the recommended interval (counting from the date of the invalid dose). 1 A booster dose of COVID-19 vaccine administered prior to the minimum interval from the last dose of COVID-19 vaccine.
If 8 weeks has passed since the last dose (i.e., primary series or preceding booster) and the current booster dose, consider the current booster dose valid.
If less than 8 weeks has passed since the last dose (i.e., primary series or preceding booster) and the current booster dose, consider the current booster dose invalid and repeat the booster dose 6 months from the invalid dose.
# Higher than authorized dose administered
Guiding Principle: Doses that are higher than authorized are considered valid. The client should be advised of the potential for local and systemic adverse events.
Adult dose provided to a child resulting in a higher than authorized dose. For example a full adult dose of 0.3 mL (30 mcg) Pfizer Bivalent (adult/adolescent formulation) provided to a 5 year old for which a (10 mcg) dose was required.
# Consider this dose valid.
Partial adult dose provided to a child resulting in an equivalent or higher than authorized dose. Examples include:
- 0.2 mL of the Pfizer Bivalent adult/adolescent formulation (i.e., 20 mcg) provided to a 5 year old (rather than the recommended 10 mcg dose).
Consider this dose valid.
# Type Administration error
Interim guidance on how to consider the dose and recommended action - 0.1 mL of the Pfizer Bivalent adult/adolescent formulation (i.e., 10 mcg) provided to a 5 year old (for whom a 10 mcg dose is recommended).
# Less than authorized dose, product or schedule error based on age
(see Diluent section below for specific information regarding Pfizer-BioNTech and the diluent)
# Guiding Principle:
Client should be immunized with the age-appropriate product based on age at presentation. When a client transitions to a different age within the primary series or booster dose, the age-appropriate product based on age at presentation is given.
Lower than the authorized doses may result in a sub-optimal response and may need to be repeated (depending on the product and the age). For complete information on authorized doses per product by age, see the respective product pages, within the BC Immunization Manual, Part 4-Biological Products, COVID-19 Vaccines.
If a repeat dose is indicated, inform the client of the potential for local and systemic adverse events with the repeat dose.
Less than a full dose (dose unknown) was administered (for example, leaked out, equipment failure, client pulled away)
If less than a full dose is administered or the proportion of the dose administered cannot be estimated, consider the dose invalid.
Administer a full repeat dose as soon as the error is recognized. If this is the same clinic day as the invalid dose, use a separate anatomic injection site whenever possible (e.g., different limb).
Children 6 months to 11 years of age Exception to the guiding principle: For Moderna Spikevax, the age appropriate dose for children 6 to 11 years is 50 mcg. For error management, a 25 mcg dose is considered valid for a 6 year old who started the series at 5 years of age. For children starting the series at 6 years of age and for children 7 to 11 years of age, a dose less than 50 mcg is considered invalid. Pfizer-BioNTech Comirnaty 3 mcg dose administered to a child 5 to 11 years (rather than the Consider this dose invalid.
# Type
Administration error Interim guidance on how to consider the dose and recommended action recommended 10 mcg dose) as part of a primary series, or as a booster dose.
Administer a full repeat dose as soon as the error is recognized. If this is the same clinic day as the invalid dose, use a separate anatomic injection site whenever possible (e.g., different limb). 2
Moderna Spikevax 25 mcg dose administered to a 6 year old child who started their primary series at 5 years of age with an age appropriate dose.
Consider this dose valid.
- However, if the error is discovered in time, an additional dose of Moderna Spikevax 25 mcg may be offered on the same clinic day in a separate anatomic injection site whenever possible (e.g., different limb).
- If the additional 25 mcg cannot be given on the same clinic day, do not give an additional dose.
Moderna Spikevax 25 mcg dose administered to a 6 year old child who started their primary series at 6 years of age (rather than the recommended 50 mcg dose).
Consider this dose invalid.
- If the error is discovered in time, an additional dose of Moderna Spikevax 25 mcg may be offered on the same clinic day in a separate anatomic injection site whenever possible (e.g., different limb).
- If the additional 25 mcg cannot be given on the same clinic day, offer a full ageappropriate dose as soon as the error is identified. 2
Moderna Spikevax 25 mcg dose administered to a child 7 to 11 years (rather than the recommended 50 mcg dose).
Consider this dose invalid.
- If the error is discovered in time, an additional dose of Moderna Spikevax 25 mcg may be offered on the same clinic day in a separate anatomic injection site whenever possible (e.g., different limb).
- If the additional 25 mcg cannot be given on the same clinic day, offer a full ageappropriate dose as soon as the error is identified. 2
# Type Administration error Interim guidance on how to consider the dose and recommended action
Adolescents 12 to 17 years of age Exception to the guiding principle: For Moderna Spikevax, the age appropriate dose for adolescents 12 to 17 years of age is 100 mcg within the primary series. However, if a 12-17 year old inadvertently receives a 50 mcg dose of Moderna Spikevax, it is considered valid. Any dose less than 50 mcg is considered invalid.
Pfizer-BioNTech Comirnaty 10 mcg dose administered to individual 12 to 17 years of age (rather than the recommended 30 mcg dose) as part of a primary series, or as a booster dose.
Consider this dose invalid.
Administer a full repeat dose as soon as the error is recognized. If this is the same clinic day as the invalid dose, use a separate anatomic injection site whenever possible (e.g., different limb). 2
- NOTE: If the invalid dose was a booster dose, offer an age-appropriate bivalent COVID-19 mRNA vaccine.
# NOTE:
Any 10 mcg doses that were previously validated prior to October 28, 2022 can remain valid in the Provincial Immunization Registry.
Moderna Spikevax 50 mcg administered to an individual 12 to 17 years of age (rather than the recommended 100 mcg dose) for any or all dose(s) of the primary series.
Consider the dose(s) valid.
- However, if the error is discovered in time, an additional dose of Moderna Spikevax 50 mcg may be offered on the same clinic day in a separate anatomic injection site whenever possible (e.g., different limb).
- If the additional 50 mcg cannot be given on the same clinic day, do not give an additional dose. Moderna Spikevax 25 mcg dose administered to an individual 12 to 17 years of age (rather than the recommended 100 mcg dose) as part of the primary series.
Consider the dose invalid.
Administer a full repeat dose as soon as the error is recognized. If this is the same clinic day as the invalid dose, use a separate anatomic injection site whenever possible (e.g., different limb). 2
# Type
Administration error Interim guidance on how to consider the dose and recommended action - NOTE: Consider offering a full ageappropriate dose of Pfizer-BioNTech Comirnaty (30 mcg) (which is the preferred product for those 12 to 17 years of age).
Moderna Spikevax 25 mcg dose administered to an individual 12 to 17 years of age (rather than the recommended 50 mcg dose) for a booster dose.
Consider the dose invalid.
However, if the error is discovered in time, the repeat dose can be given on the same clinic day:
- If offering Pfizer-BioNTech Comirnaty bivalent vaccine, 30 mcg can be given in a separate anatomic injection site whenever possible in a separate anatomic injection site (e.g., different limb).
- If offering Moderna Spikevax bivalent vaccine, a 25 mcg dose can be given in a separate anatomic injection site whenever possible (e.g., different limb)
If the dose cannot be given on the same clinic day, offer a full age-appropriate bivalent booster dose as soon as the error is identified. 2
# Adults 18 years of age and older
Exception to the guiding principle: For Moderna Spikevax, the age appropriate dose for adults 18 years of age and older is 100 mcg within the primary series. However, if an adult inadvertently receives a 50 mcg dose of Moderna Spikevax, it is considered valid. Any dose less than 50 mcg is considered invalid.
Pfizer-BioNTech Comirnaty 10 mcg dose administered to an individual ≥18 years of age (rather than the recommended 30 mcg dose) for a primary series or booster dose.
Consider the dose invalid.
Administer a full repeat dose as soon as the error is recognized. If this is the same clinic day as the invalid dose, use a separate anatomic injection site whenever possible (e.g., different limb). 2
# Type Administration error
Interim guidance on how to consider the dose and recommended action
- NOTE: If the invalid dose was a booster dose, offer an age-appropriate bivalent COVID-19 mRNA vaccine.
Moderna Spikevax 50 mcg administered to an individual ≥18 years of age (rather than the recommended 100 mcg dose) for any or all dose(s) of the primary series.
Consider the dose valid.
- If the error is discovered in time, offer 50 mcg of the monovalent Moderna Spikevax vaccine on the same clinic day in a separate anatomic injection site whenever possible (e.g., different limb).
- If the additional 50 mcg of Moderna Spikevax dose cannot be given on the same clinic day, do not give an additional dose.
Moderna Spikevax 25 mcg administered to an individual ≥18 years of age (rather than the recommended 50 mcg dose) for the booster dose.
Consider the dose invalid.
- However, if the error is discovered in time, offer a 25 mcg dose of Moderna Spikevax bivalent booster dose on the same clinic day in a separate anatomic injection site whenever possible (e.g., different limb).
- If the dose cannot be given on the same clinic day, offer a full age-appropriate bivalent COVID-19 mRNA vaccine as soon as the error is identified. 2
# Bivalent product error
# Guiding principle:
The primary series is provided with a monovalent formulation, as the bivalent formulations are not approved for doses in the primary series.
An individual receives a bivalent vaccine for one or all doses of the primary series.
Consider this a valid dose.
An adult receives a 0.5 mL (50 mcg) dose of Moderna Spikevax 6 months to 5 year vaccine rather than the recommended Moderna Spikevax bivalent booster dose (50 mcg).
Consider this a valid dose. A 50 mcg dose of a monovalent product is considered a valid booster.
While the monovalent booster dose will boost their immunity and is likely to provide significant protection against hospitalization Type Administration error Interim guidance on how to consider the dose and recommended action and severe disease, an age-appropriate bivalent product may be provided at an interval of at least 8 weeks.
An individual receives an ageappropriate monovalent vaccine instead of a bivalent vaccine for a booster dose.
Consider this a valid dose.
For individuals 5-11 years of age: NACI is currently only recommending one booster dose after the primary series. The client and/or parent/guardian should be reassured that the monovalent booster dose will boost their immunity and is likely to provide significant protection against hospitalization and severe disease, and no recommendation for re-vaccination. However, if the parent/ guardian requests a repeat dose with a bivalent product, an age-appropriate bivalent product may be provided at an interval of at least 8 weeks.
For individuals 12 years of age and older: While the monovalent booster dose will boost their immunity and is likely to provide significant protection against hospitalization and severe disease, an age-appropriate bivalent COVID-19 booster dose may be provided at an interval of at least 8 weeks.
# Storage and handling
Guiding Principle: Storage and handling errors or deviations require individual consideration based on the particular circumstances, in consultation with the BCCDC Pharmacy and based on clinical judgement. If deemed to be invalid, a repeat dose may be given as soon as possible at a different site. Inform the recipient of the potential for local and systemic adverse events For information on Storage and Handling refer to the respective product pages in the BC Immunization Manual, Part 4-Biological Products, COVID-19 Vaccines.
# Reconstitution error (Pfizer-BioNTech only)
Guiding Principle: Reconstitution errors may require individual consideration based on the particular circumstances, in consultation with the BCCDC Pharmacy and based on clinical judgement. If deemed to be invalid a repeat dose may be given as soon as possible at a different site. Inform the recipient of the potential for local and systemic adverse events.
For information on diluent volume per product, refer to the respective product pages in the BC Immunization Manual, Part 4-Biological Products, COVID-19 Vaccines.
Incorrect diluent type (e.g., sterile water instead of 0.9% sodium chloride for Pfizer dilution) Contact BCCDC Pharmacy for guidance. If BCCDC provides information suggesting that the dose be considered invalid and if that seems appropriate based on clinical judgement, a repeat dose may be given as soon as possible in in a separate anatomic injection site whenever possible (e.g., different limb).
ONLY diluent administered (i.e., sterile 0.9% sodium chloride)
Inform the recipient that no vaccine was administered. Administer the authorized (appropriately diluted) dose as soon as
# Type
Administration error Interim guidance on how to consider the dose and recommended action possible in in a separate anatomic injection site whenever possible (e.g., different limb).
Too much diluent administered resulting in a lower than authorized dose.
Consider this an invalid dose. Administer a full repeat dose immediately in a separate anatomic injection site whenever possible (e.g., different limb).
No diluent or less than the recommended diluent, resulting in higher than the authorized dose.
# Consider this dose valid.
Inform the recipient of the potential for local and systemic adverse events.
# More or less than authorized number of doses obtained from vial
Guiding Principle: Depending on the type of supplies used (e.g., low dead volume syringe) the number of doses obtained from vials may vary. As long as the correct volume was drawn up per dose (and the correct amount of diluent was used, if applicable), the doses are valid. | This document is intended to assist healthcare providers by providing an approach to managing COVID-19 vaccines that are administered in a manner that differs from the BC Immunization Manual guidelines (referred to as vaccine administration errors). This document builds on guidance developed by the Public Health Agency of Canada's Managing COVID-19 vaccine administration errors or deviations and the CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States. There is limited evidence to guide the management of these situations. This document provides guidance only. Health authority protocols may differ from this guidance document and clinical judgement in particular situations may also result in different management decisions than outlined below. Note that this document is to be used only to manage errors that have already occurred. The guidelines within the BC Immunization Manual should be followed when administering COVID-19 vaccines to prevent errors or deviations from occurring. The following will be addressed in this document:Administration error Interim guidance on how to consider the dose and recommended action Site/route Guiding Principle: COVID-19 vaccines should be administered intramuscularly. The vastus lateralis (anterolateral thigh) is recommended for children less than 1 year of age. The vastus lateralis or the deltoid muscle can be used for toddlers and older children. The deltoid is often selected as the injection site in these age groups as temporary muscle pain in the vastus lateralis muscle post-vaccination may affect ambulation. The deltoid muscle of the arm is the preferred injection site in adolescents and adults. When selecting a site, it is important to consider available muscle mass. Clients administered a vaccine in an incorrect site or by an incorrect route should be informed of the potential for local and systemic adverse events. Incorrect site (i.e., site other than the deltoid muscle or vastus lateralis as appropriate for age) Consider the dose valid. Incorrect route (e.g., subcutaneous) Consider the dose valid.Use at a younger age than authorized by Health Canada and/or recommended by NACI Consider the dose valid. Receipt of a WHO EUA qualified COVID-19 vaccine not authorized in Canada (e.g., Sinovac, Sinopharm, Covaxin) at < 18 years of age for one or more doses. Consider the dose valid.Guiding Principle: Doses given longer than the recommended interval: While recommended intervals are optimal, doses delayed beyond the recommended interval are considered valid.#
• Steps to be taken after an error is recognized Steps to be taken after an error is recognized Following the identification of an inadvertent vaccine administration error, healthcare providers should:
• Inform the recipient of the vaccine administration error as soon as possible after it is identified. The recipient should be informed of any implications/recommendations for future doses, and possibility for local or systemic reactions and impact on the effectiveness of the vaccine (if applicable and known). • Report all errors or near miss incidents in accordance with the institutional medication error or professional body's reporting process, including the BC Patient Safety Learning System (PSLS). • If an inadvertent vaccine administration error results in an adverse event following immunization (AEFI), complete the appropriate AEFI Case Report Form found on the Adverse Events Following Immunization page and submit it to the local public health authority. Information on AEFI reporting can be found in the BC Immunization Manual, Part 5 -Adverse events Following Immunization. • Determine how the vaccine administration error occurred and implement strategies to prevent it from happening again. • As with usual practice, when managing errors and deviations, inquire about the client's history of adverse events following vaccination. If they experienced a significant local or systemic reaction, base your decision to offer subsequent doses on a case-by-case basis in consultation with the Medical Health Officer and/or in consultation with an allergist/immunologist. • If the client who had a repeat dose following an invalid dose requires a subsequent dose in the initial series or a booster, give it with a recommended age-appropriate dosage and product. Count the interval from the repeat dose. • Additional resources on vaccine administration practices can be found in the BC Immunization Manual, Appendix B -Administration of Biological Products.
Doses given earlier than the minimum interval: Doses given too close together may result in a suboptimal immune response due to: (1) Less than optimal time to allow for the immune response to mature between doses; and (2) Antibodies produced to the early dose may interfere with the antibody response to the later dose.
For information on recommended and minimum intervals, refer to the respective product pages in the BC Immunization Manual, Part 4-Biological Products, COVID-19 Vaccines.
# Type Administration error
Interim guidance on how to consider the dose and recommended action Subsequent dose of COVID-19 vaccine within the primary series administered prior to the minimum interval.
If the dose was administered at less than the minimum interval, consider the dose invalid and repeat at the recommended interval (counting from the date of the invalid dose). 1 A booster dose of COVID-19 vaccine administered prior to the minimum interval from the last dose of COVID-19 vaccine.
If 8 weeks has passed since the last dose (i.e., primary series or preceding booster) and the current booster dose, consider the current booster dose valid.
If less than 8 weeks has passed since the last dose (i.e., primary series or preceding booster) and the current booster dose, consider the current booster dose invalid and repeat the booster dose 6 months from the invalid dose.
# Higher than authorized dose administered
Guiding Principle: Doses that are higher than authorized are considered valid. The client should be advised of the potential for local and systemic adverse events.
Adult dose provided to a child resulting in a higher than authorized dose. For example a full adult dose of 0.3 mL (30 mcg) Pfizer Bivalent (adult/adolescent formulation) provided to a 5 year old for which a (10 mcg) dose was required.
# Consider this dose valid.
Partial adult dose provided to a child resulting in an equivalent or higher than authorized dose. Examples include:
• 0.2 mL of the Pfizer Bivalent adult/adolescent formulation (i.e., 20 mcg) provided to a 5 year old (rather than the recommended 10 mcg dose).
Consider this dose valid.
# Type Administration error
Interim guidance on how to consider the dose and recommended action • 0.1 mL of the Pfizer Bivalent adult/adolescent formulation (i.e., 10 mcg) provided to a 5 year old (for whom a 10 mcg dose is recommended).
# Less than authorized dose, product or schedule error based on age
(see Diluent section below for specific information regarding Pfizer-BioNTech and the diluent)
# Guiding Principle:
Client should be immunized with the age-appropriate product based on age at presentation. When a client transitions to a different age within the primary series or booster dose, the age-appropriate product based on age at presentation is given.
Lower than the authorized doses may result in a sub-optimal response and may need to be repeated (depending on the product and the age). For complete information on authorized doses per product by age, see the respective product pages, within the BC Immunization Manual, Part 4-Biological Products, COVID-19 Vaccines.
If a repeat dose is indicated, inform the client of the potential for local and systemic adverse events with the repeat dose.
Less than a full dose (dose unknown) was administered (for example, leaked out, equipment failure, client pulled away)
If less than a full dose is administered or the proportion of the dose administered cannot be estimated, consider the dose invalid.
Administer a full repeat dose as soon as the error is recognized. If this is the same clinic day as the invalid dose, use a separate anatomic injection site whenever possible (e.g., different limb).
Children 6 months to 11 years of age Exception to the guiding principle: For Moderna Spikevax, the age appropriate dose for children 6 to 11 years is 50 mcg. For error management, a 25 mcg dose is considered valid for a 6 year old who started the series at 5 years of age. For children starting the series at 6 years of age and for children 7 to 11 years of age, a dose less than 50 mcg is considered invalid. Pfizer-BioNTech Comirnaty 3 mcg dose administered to a child 5 to 11 years (rather than the Consider this dose invalid.
# Type
Administration error Interim guidance on how to consider the dose and recommended action recommended 10 mcg dose) as part of a primary series, or as a booster dose.
Administer a full repeat dose as soon as the error is recognized. If this is the same clinic day as the invalid dose, use a separate anatomic injection site whenever possible (e.g., different limb). 2
Moderna Spikevax 25 mcg dose administered to a 6 year old child who started their primary series at 5 years of age with an age appropriate dose.
Consider this dose valid.
• However, if the error is discovered in time, an additional dose of Moderna Spikevax 25 mcg may be offered on the same clinic day in a separate anatomic injection site whenever possible (e.g., different limb).
• If the additional 25 mcg cannot be given on the same clinic day, do not give an additional dose.
Moderna Spikevax 25 mcg dose administered to a 6 year old child who started their primary series at 6 years of age (rather than the recommended 50 mcg dose).
Consider this dose invalid.
• If the error is discovered in time, an additional dose of Moderna Spikevax 25 mcg may be offered on the same clinic day in a separate anatomic injection site whenever possible (e.g., different limb).
• If the additional 25 mcg cannot be given on the same clinic day, offer a full ageappropriate dose as soon as the error is identified. 2
Moderna Spikevax 25 mcg dose administered to a child 7 to 11 years (rather than the recommended 50 mcg dose).
Consider this dose invalid.
• If the error is discovered in time, an additional dose of Moderna Spikevax 25 mcg may be offered on the same clinic day in a separate anatomic injection site whenever possible (e.g., different limb).
• If the additional 25 mcg cannot be given on the same clinic day, offer a full ageappropriate dose as soon as the error is identified. 2
# Type Administration error Interim guidance on how to consider the dose and recommended action
Adolescents 12 to 17 years of age Exception to the guiding principle: For Moderna Spikevax, the age appropriate dose for adolescents 12 to 17 years of age is 100 mcg within the primary series. However, if a 12-17 year old inadvertently receives a 50 mcg dose of Moderna Spikevax, it is considered valid. Any dose less than 50 mcg is considered invalid.
Pfizer-BioNTech Comirnaty 10 mcg dose administered to individual 12 to 17 years of age (rather than the recommended 30 mcg dose) as part of a primary series, or as a booster dose.
Consider this dose invalid.
Administer a full repeat dose as soon as the error is recognized. If this is the same clinic day as the invalid dose, use a separate anatomic injection site whenever possible (e.g., different limb). 2
• NOTE: If the invalid dose was a booster dose, offer an age-appropriate bivalent COVID-19 mRNA vaccine.
# NOTE:
Any 10 mcg doses that were previously validated prior to October 28, 2022 can remain valid in the Provincial Immunization Registry.
Moderna Spikevax 50 mcg administered to an individual 12 to 17 years of age (rather than the recommended 100 mcg dose) for any or all dose(s) of the primary series.
Consider the dose(s) valid.
• However, if the error is discovered in time, an additional dose of Moderna Spikevax 50 mcg may be offered on the same clinic day in a separate anatomic injection site whenever possible (e.g., different limb).
• If the additional 50 mcg cannot be given on the same clinic day, do not give an additional dose. Moderna Spikevax 25 mcg dose administered to an individual 12 to 17 years of age (rather than the recommended 100 mcg dose) as part of the primary series.
Consider the dose invalid.
Administer a full repeat dose as soon as the error is recognized. If this is the same clinic day as the invalid dose, use a separate anatomic injection site whenever possible (e.g., different limb). 2
# Type
Administration error Interim guidance on how to consider the dose and recommended action • NOTE: Consider offering a full ageappropriate dose of Pfizer-BioNTech Comirnaty (30 mcg) (which is the preferred product for those 12 to 17 years of age).
Moderna Spikevax 25 mcg dose administered to an individual 12 to 17 years of age (rather than the recommended 50 mcg dose) for a booster dose.
Consider the dose invalid.
However, if the error is discovered in time, the repeat dose can be given on the same clinic day:
• If offering Pfizer-BioNTech Comirnaty bivalent vaccine, 30 mcg can be given in a separate anatomic injection site whenever possible in a separate anatomic injection site (e.g., different limb).
• If offering Moderna Spikevax bivalent vaccine, a 25 mcg dose can be given in a separate anatomic injection site whenever possible (e.g., different limb)
If the dose cannot be given on the same clinic day, offer a full age-appropriate bivalent booster dose as soon as the error is identified. 2
# Adults 18 years of age and older
Exception to the guiding principle: For Moderna Spikevax, the age appropriate dose for adults 18 years of age and older is 100 mcg within the primary series. However, if an adult inadvertently receives a 50 mcg dose of Moderna Spikevax, it is considered valid. Any dose less than 50 mcg is considered invalid.
Pfizer-BioNTech Comirnaty 10 mcg dose administered to an individual ≥18 years of age (rather than the recommended 30 mcg dose) for a primary series or booster dose.
Consider the dose invalid.
Administer a full repeat dose as soon as the error is recognized. If this is the same clinic day as the invalid dose, use a separate anatomic injection site whenever possible (e.g., different limb). 2
# Type Administration error
Interim guidance on how to consider the dose and recommended action
• NOTE: If the invalid dose was a booster dose, offer an age-appropriate bivalent COVID-19 mRNA vaccine.
Moderna Spikevax 50 mcg administered to an individual ≥18 years of age (rather than the recommended 100 mcg dose) for any or all dose(s) of the primary series.
Consider the dose valid.
• If the error is discovered in time, offer 50 mcg of the monovalent Moderna Spikevax vaccine on the same clinic day in a separate anatomic injection site whenever possible (e.g., different limb).
• If the additional 50 mcg of Moderna Spikevax dose cannot be given on the same clinic day, do not give an additional dose.
Moderna Spikevax 25 mcg administered to an individual ≥18 years of age (rather than the recommended 50 mcg dose) for the booster dose.
Consider the dose invalid.
• However, if the error is discovered in time, offer a 25 mcg dose of Moderna Spikevax bivalent booster dose on the same clinic day in a separate anatomic injection site whenever possible (e.g., different limb).
• If the dose cannot be given on the same clinic day, offer a full age-appropriate bivalent COVID-19 mRNA vaccine as soon as the error is identified. 2
# Bivalent product error
# Guiding principle:
The primary series is provided with a monovalent formulation, as the bivalent formulations are not approved for doses in the primary series.
An individual receives a bivalent vaccine for one or all doses of the primary series.
Consider this a valid dose.
An adult receives a 0.5 mL (50 mcg) dose of Moderna Spikevax 6 months to 5 year vaccine rather than the recommended Moderna Spikevax bivalent booster dose (50 mcg).
Consider this a valid dose. A 50 mcg dose of a monovalent product is considered a valid booster.
While the monovalent booster dose will boost their immunity and is likely to provide significant protection against hospitalization Type Administration error Interim guidance on how to consider the dose and recommended action and severe disease, an age-appropriate bivalent product may be provided at an interval of at least 8 weeks.
An individual receives an ageappropriate monovalent vaccine instead of a bivalent vaccine for a booster dose.
Consider this a valid dose.
For individuals 5-11 years of age: NACI is currently only recommending one booster dose after the primary series. The client and/or parent/guardian should be reassured that the monovalent booster dose will boost their immunity and is likely to provide significant protection against hospitalization and severe disease, and no recommendation for re-vaccination. However, if the parent/ guardian requests a repeat dose with a bivalent product, an age-appropriate bivalent product may be provided at an interval of at least 8 weeks.
For individuals 12 years of age and older: While the monovalent booster dose will boost their immunity and is likely to provide significant protection against hospitalization and severe disease, an age-appropriate bivalent COVID-19 booster dose may be provided at an interval of at least 8 weeks.
# Storage and handling
Guiding Principle: Storage and handling errors or deviations require individual consideration based on the particular circumstances, in consultation with the BCCDC Pharmacy and based on clinical judgement. If deemed to be invalid, a repeat dose may be given as soon as possible at a different site. Inform the recipient of the potential for local and systemic adverse events For information on Storage and Handling refer to the respective product pages in the BC Immunization Manual, Part 4-Biological Products, COVID-19 Vaccines.
# Reconstitution error (Pfizer-BioNTech only)
Guiding Principle: Reconstitution errors may require individual consideration based on the particular circumstances, in consultation with the BCCDC Pharmacy and based on clinical judgement. If deemed to be invalid a repeat dose may be given as soon as possible at a different site. Inform the recipient of the potential for local and systemic adverse events.
For information on diluent volume per product, refer to the respective product pages in the BC Immunization Manual, Part 4-Biological Products, COVID-19 Vaccines.
Incorrect diluent type (e.g., sterile water instead of 0.9% sodium chloride for Pfizer dilution) Contact BCCDC Pharmacy for guidance. If BCCDC provides information suggesting that the dose be considered invalid and if that seems appropriate based on clinical judgement, a repeat dose may be given as soon as possible in in a separate anatomic injection site whenever possible (e.g., different limb).
ONLY diluent administered (i.e., sterile 0.9% sodium chloride)
Inform the recipient that no vaccine was administered. Administer the authorized (appropriately diluted) dose as soon as
# Type
Administration error Interim guidance on how to consider the dose and recommended action possible in in a separate anatomic injection site whenever possible (e.g., different limb).
Too much diluent administered resulting in a lower than authorized dose.
Consider this an invalid dose. Administer a full repeat dose immediately in a separate anatomic injection site whenever possible (e.g., different limb).
No diluent or less than the recommended diluent, resulting in higher than the authorized dose.
# Consider this dose valid.
Inform the recipient of the potential for local and systemic adverse events.
# More or less than authorized number of doses obtained from vial
Guiding Principle: Depending on the type of supplies used (e.g., low dead volume syringe) the number of doses obtained from vials may vary. As long as the correct volume was drawn up per dose (and the correct amount of diluent was used, if applicable), the doses are valid. | None | None |
ed8b373ee1a3ffcd073e994b0c4c0ea43bf6f356 | cma | None | These testing guidelines are meant to provide guidance on recommendations for COVID-19 testing. This testing guidance does not replace the need for clinical judgment, which remains critical in determining whether a COVID-19 test should be offered to a patient. Health-care providers should also apply the principles of equity, cultural safety and humility, and consider contextual factors, such as access to health-care services, personal and community factors, and systemic racism.#
A PCR test may be preferred in specific circumstances such as for variant surveillance. A PCR test is indicated for testing of patients in acute care settings.
Positive rapid antigen test (RAT) results are acceptable for initiating treatment and no confirmatory testing is required for outpatients. If a RAT is negative and clinical suspicion remains high, patients may repeat a RAT or clinicians can order PCR testing.
# Testing recommended by medical health officers in high-risk settings or as part of a public health investigation
Testing is indicated when it changes either individual or community management. Your local medical health officer may issue region-specific recommendations based on epidemiology, vaccination rates or access to health services.
Medical health officers may also recommend testing as part of public health investigations. This may include testing of asymptomatic people who are part of a public health investigation of a case, cluster or an outbreak.
Additional Guidance
# People who have symptoms compatible with COVID-19 who do not meet the above COVID-19 testing recommendations can use a rapid COVID-19 test.
This may be especially important for communities with difficulty accessing testing (and secondary or tertiary care) such as rural, remote, and isolated or Indigenous communities and work-camps, and for Indigenous people living in urban settings. For more information about point-of-care testing for rural, remote, First Nations and Indigenous Communities, please refer to the guidance on the BCCDC website.
# Additional guidance for children
All children who are suspected of having multisystem inflammatory syndrome (MIS-C) should also be tested. Infants less than three months of age who are febrile or who have suspected COVID-19 should be assessed by a health-care provider. For more information on the diagnosis and management of COVID-19, please refer to the BCCDC website.
# Testing for travel purposes
In B.C., testing is not available through the provincial health-care system for screening related to travel. The exception is people requiring testing for medically necessary travel (for example unvaccinated people requiring travel for medical reasons from remote communities).
# Additional guidance for health-care workers
PCR testing is no longer recommended for all health care workers, first responders, staff and residents in congregate settings unless they meet other criteria for testing. People with symptoms compatible of COVID-19 may use a RAT if they wish.
# Specimen Requirements
Please refer to the BCCDC Public Health Laboratory eLab Handbook under COVID-19 virus for specimen requirements | These testing guidelines are meant to provide guidance on recommendations for COVID-19 testing. This testing guidance does not replace the need for clinical judgment, which remains critical in determining whether a COVID-19 test should be offered to a patient. Health-care providers should also apply the principles of equity, cultural safety and humility, and consider contextual factors, such as access to health-care services, personal and community factors, and systemic racism.#
A PCR test may be preferred in specific circumstances such as for variant surveillance. A PCR test is indicated for testing of patients in acute care settings.
Positive rapid antigen test (RAT) results are acceptable for initiating treatment and no confirmatory testing is required for outpatients. If a RAT is negative and clinical suspicion remains high, patients may repeat a RAT or clinicians can order PCR testing.
# Testing recommended by medical health officers in high-risk settings or as part of a public health investigation
Testing is indicated when it changes either individual or community management. Your local medical health officer may issue region-specific recommendations based on epidemiology, vaccination rates or access to health services.
Medical health officers may also recommend testing as part of public health investigations. This may include testing of asymptomatic people who are part of a public health investigation of a case, cluster or an outbreak.
Additional Guidance
# People who have symptoms compatible with COVID-19 who do not meet the above COVID-19 testing recommendations can use a rapid COVID-19 test.
This may be especially important for communities with difficulty accessing testing (and secondary or tertiary care) such as rural, remote, and isolated or Indigenous communities and work-camps, and for Indigenous people living in urban settings. For more information about point-of-care testing for rural, remote, First Nations and Indigenous Communities, please refer to the guidance on the BCCDC website.
# Additional guidance for children
All children who are suspected of having multisystem inflammatory syndrome (MIS-C) should also be tested. Infants less than three months of age who are febrile or who have suspected COVID-19 should be assessed by a health-care provider. For more information on the diagnosis and management of COVID-19, please refer to the BCCDC website.
# Testing for travel purposes
In B.C., testing is not available through the provincial health-care system for screening related to travel. The exception is people requiring testing for medically necessary travel (for example unvaccinated people requiring travel for medical reasons from remote communities).
# Additional guidance for health-care workers
PCR testing is no longer recommended for all health care workers, first responders, staff and residents in congregate settings unless they meet other criteria for testing. People with symptoms compatible of COVID-19 may use a RAT if they wish.
# Specimen Requirements
Please refer to the BCCDC Public Health Laboratory eLab Handbook under COVID-19 virus for specimen requirements | None | None |
daa85a11aed8d7d9d325ef598d1aff5f53857386 | cma | None | # Background
In 2022, an estimated 22,200 Albertans will be diagnosed with cancer and an estimated 7,500 people will die of their disease. 1 Between 2003Between -2007Between and 2028Between -2032, the number of new cancer cases per year in Canada is predicted to increase by 84% in males (from 80,810 to 148,370) and by 74% in females (from 74,164 to 128,830). 2 Active tobacco smoking is the leading preventable risk factor for cancer and is responsible for an estimated 72% of lung cancer cases and 74% of larynx cancer cases in Canada. 3 Tobacco screening and cessation treatment for cancer patients is a key to high-quality oncology care, and the use of clear, direct advice from healthcare providers to stop or reduce smoking continues to be the single most influential way to achieve smoking cessation in most patient populations. Tobacco intervention by health care professionals has been shown to be effective in increasing the abstinence rate in cancer patients. 4 The integration of tobacco screening and cessation treatment into oncology care has been recommended by a number of national and international cancer-focused organizations as a best practice intervention, however, tobacco screening and treatment is not consistently or routinely implemented in cancer care programs across the province.
The "Ask, Advise, Refer" (AAR) brief intervention model has been adopted by Cancer Care Alberta (CCA) as a practice standard for all sites. This guideline presents the key recommendations to support the screening and treatment of tobacco use by cancer patients as a provincial standard of care.
Guideline Questions 1. What is the process for screening and treatment of tobacco use in cancer patients at Cancer Care Alberta? 2. What options are available for cancer patients for nicotine withdrawal and cessation pharmacotherapy? 3. What training and education resources are available for Cancer Care Alberta staff to deliver brief tobacco interventions to cancer patients? 4. How does concurrent tobacco treatment (behavioural and/or pharmacotherapy support) impact cancer treatment (e.g., chemotherapy, radiation, surgery)?
# Search Strategy
The search strategy was selected and reviewed by members of the guideline working group with support from an Alberta Health Services research librarian.
The PubMed, EMBASE, Medline, Cochrane Database of Systematic Reviews, CINAHL, PsycINFO and Pharmacy databases were searched from January 2008 to February 2015 for literature on tobacco cessation interventions in a cancer care setting and associated impacts on tobacco use reduction and/or cessation. A variety of separate and combined search terms were used, including but not limited to: cancer patients, caregiver, staff, tobacco intervention, tobacco cessation treatment, cessation pharmacotherapy, cancer, cancer treatment, risk factors, quality of life, windows of opportunity, recurrence, relapse and quit rates. Results were limited to randomized controlled trials, systematic reviews and observational studies published in English. Grey literature (e.g., Google, Google Scholar, ProQuest) as well as the reference lists of key articles were also searched for additional publications. Excluded from the analysis were pediatric cancer patients, tobacco treatment interventions that occur outside of cancer care (e.g., primary care) and non-oncology patients. A total of 74 studies were identified for inclusion.
Clinical guidelines databases (e.g., National Institute for Health and Care Excellence, the National Guidelines Clearinghouse, SAGE Directory,) and guideline bodies were also searched for guidelines on smoking cessation in cancer care settings. The search returned eight guidelines. A full copy of the evidence tables is available upon request by contacting [email protected].
# Target Population
This guideline applies to all health professionals working with adult cancer patients (aged 18 years and older) at any phase of the cancer care continuum regardless of cancer type, stage (including metastatic) or treatment plan. Components of this guideline are also applicable to the patient's family and/or caregivers, where indicated. This guideline is intended for use in both inpatient and ambulatory (outpatient) settings.
# Scope and Definitions
This guideline outlines recommendations to guide CCA health care professionals who have direct contact with patients and families to deliver brief tobacco intervention as a routine standard of care.
The standards for more intensive intervention are outside of the scope of this guideline.
- Tobacco Use includes the use of cigarettes, cigars, cigarillos, pipe, smokeless tobacco products, waterpipes, and heated tobacco products. Use of the term 'tobacco' in this document does not refer to use of traditional tobacco for ceremonial and/or spiritual purposes, it refers instead to misuse and cessation of commercial tobacco products. - AAR Brief Tobacco Intervention Model is an established model used in a variety of clinical settings. It is designed to be implemented in less than 3 minutes and involves the following three steps: ask about tobacco use, advise to quit, and refer to a local resource for more intensive tobacco treatment counselling or pharmacotherapy. - Health Professional means an individual who is a member of a regulated health discipline, as defined by the Alberta Health Disciplines Act or Health Professions Act, and who provides promotional, preventive, curative, or rehabilitative care as per their defined scope or role. - Digital MySymptom Report -(MSR) is a self-reported questionnaire completed by the patient. The form consists of the electronic revised Edmonton Symptom Assessment System for Cancer, (eESAS-r Cancer), the MyPersonal Needs checklist, and questions designed to satisfy CCA operational and accreditation requirements.
# CCA Inpatient and Outpatient Procedure for Tobacco Treatment
A brief tobacco intervention involves using the "Ask, Advise, Refer" (AAR) model with electronic implementation and documentation in Connect Care. Refer to Appendix A for the Algorithm for the Screening and Treatment of Tobacco Use.
In compliance with the AHS Provincial Tobacco and Smoke Free Environment Policy, patients, family member(s), or those accompanying the patient should be advised that consumption of commercial tobacco and tobacco-like products is not permitted on AHS property, including grounds and facilities. o If the patient is not a tobacco user, stop the intervention.
# Responsibilities of the
# Education and Assessment ("Advise")
- Patients who self-identify as using tobacco should be advised to stop. Advice should be personalized to the patient's cancer type, stage, and treatment plan and broadly address: health effects of continued tobacco in context of cancer treatment. benefits of cessation and/or reduction. benefit of counselling and medication as most effective treatment.
- Advise patients and/or their family members of available local cessation resources including AlbertaQuits, Primary Care Networks, and community pharmacies. Assess patient interest in receiving a referral to such services for counselling and support.
- Document advice given within the patient's chart in Connect Care under "Screenings" "Psychosocial".
- If appropriate, patients should be advised on importance of reducing exposure to secondhand smoke with messaging of cessation to accompanying caregivers/family members who identify as tobacco users.
- A longer tobacco cessation intervention following the 5A's Approach ("Ask, Advise, Assess, Assist, Arrange") can occur when staff knowledge and time enables them to do so. For more information, please reference the resource The 5A's Approach: A Continuum of Brief and Intensive Settings, available from the Alberta Health Services Tobacco, Vaping & Cannabis Program website.
# Referral ("Refer")
- Provide information on AlbertaQuits services and self-help resources for patients and family members interested in quitting.
- Referral Process: CCA staff and prescribers wishing to refer a patient to the AlbertaQuits program can use the following process:
- An order for "Ambulatory Referral to Smoking Cessation Program" is entered in the Connect Care system. - The completed referral form from the Alberta Referral Directory is faxed to AlbertaQuits, using the number at the top of the form. - A tobacco cessation counsellor from AlbertaQuits will then connect with the patient using the contact information provided on the form. See Appendix B for a screen shot of the Connect Care referral process, as well as the AlbertaQuits Helpline Referral Form; this form can also be accessed through the external AHS website.
- For patients not interested in quitting: Advise patients that they can self-refer to AlbertaQuits services at any time by calling the AlbertaQuits Helpline at 1-866-710-7848 or by visiting the AlbertaQuits website. Document refusal in the patient's chart.
# Nicotine Withdrawal and Cessation Pharmacotherapy
# Patients Admitted to Hospital -Inpatients
- Inpatients who self-identify as using tobacco products should be assessed for nicotine withdrawal symptoms and offered the most appropriate Nicotine Replacement Therapy ii.
Tobacco Cessation in Cancer Care -Module 2 "Cessation Pharmacotherapy": describes the types of pharmacotherapies available to support tobacco cessation with a strong focus on the unique considerations when prescribing Nicotine Replacement Therapy and/or pharmacotherapies to patients with cancer.
iii. Tobacco Cessation in Cancer Care -Module 3 "Evidence-Based Programs": provides an overview of current evidence-based best practice for tobacco cessation in cancer care and outlines patient referral processes to cessation programs and services in Alberta.
- AlbertaQuits Learning Series: offers e-learning courses and classroom/virtual trainings to a broad health professional audience.
- Tobacco Comfort Measures and Cessation Support: clinical support primer and tobacco care pathway.
- Tobacco Cessation Toolkit: Includes a variety of tools designed to support healthcare providers in clinical practice.
# Discussion
# Impact of Continued Tobacco Use on Cancer Outcomes
Current evidence strongly supports quitting smoking following a cancer diagnosis. The 2020 Surgeon General's Report on Smoking Cessation concluded that there is sufficient causal evidence between smoking and increased all-cause mortality, increased cancer-specific mortality and increased risk of developing second primary cancers. 5 Smoking was further associated with an increased risk of cancer recurrence, poorer response to treatment and increased treatment-related toxicity. Indeed, estimates suggest that quitting smoking at the time of diagnosis could lower the risk of dying by up to 40% with the benefits of cessation being equal to or exceeding the value of new cancer therapies for some cancer diagnoses. 5 The benefits of cessation go beyond cancers known to be caused by tobacco use, with increased mortality rates associated with continued smoking after diagnosis reported across cancer types and stages of diagnosis. Results of a meta-analysis with early stage non-small cell lung cancer (NSCLC) and limited stage small cell lung cancer (SCLC) showed continued smoking increased the risk of all-cause mortality, recurrence and development of a second primary tumour. 10 In patients with NSCLC, quitting smoking was associated with an estimated five-year survival rate of 70% compared to 33% in those who continued to smoke. Survival rates for patients with SCLC were at 63% and 29% in quitters and those who continued to smoke, respectively. 10 There is consistent evidence that tobacco use, namely smoking, reduces the efficacy of radiation therapy and some chemotherapy agents 5, and increases the risk for treatment-induced complications including surgical site infections, pulmonary function and return to the operating room. 6, Studies further report an association between smoking and increased risk of recurrence following cancer treatments among patients with head and neck cancers, 7,12,17,18 prostate cancer, 19 urothelial cancer, 20 and gastric cancer. 21
# Impact of Tobacco Use on Cancer Treatment: Chemotherapy Considerations
Tobacco smoke can interfere with the pharmacokinetic mechanisms of several chemotherapy drugs potentially causing an altered pharmacologic response. 13,22 Tobacco smoke increases the amount of drug binding protein resulting in induction of cytochrome-450 enzymes (primarily CYP1A2) and UGT isoenzymes which metabolize several chemotherapy drugs. Nicotine replacement therapy does not impact CYP1A2 activity or reduce cancer drug efficacy.
Erlotinib: Commonly used in the treatment of NSCLC and pancreatic cancer, erlotinib is primarily metabolized by CYPs 3A4 and 1A2. Cigarette smoking has been shown to cause induction of several CYP enzymes primarily by CYP3A4 but also by CYP1A2, resulting in more rapid metabolism and decreased systemic exposure to the drug. 23 Data analyzed from seven clinical trials that administered the standard dose of erlotinib (150 mg once daily) found that smoking status was a significant covariate affecting drug clearance. 13 Patients who smoked and who were treated with erlotinib experienced a 23.5% increase in clearance and had lower (nearly half) median steady-state trough plasma concentrations compared to never and former smokers. 13,22 An increased dose of erlotinib may benefit patients with NSCLC who continue to smoke following diagnosis. Dosing consideration should also be given to patients exposed to secondhand smoke. 22 Irinotecan: Smoking is known to alter the pharmacokinetics of irinotecan, a topoisomerase-I inhibitor used to treat a variety of cancers including colon, rectal, lung, and bone cancers. While not definitive, a study of cancer patients treated with irinotecan (n=190) found those who smoked experienced 40% lower systemic exposure to the active metabolite SN-38, 18% faster clearance, and less neutropenia (6% smokers versus 38% nonsmokers) compared to non-smokers. 22 The effects of smoking on irinotecan pharmacokinetics may be attributed to induction and modulation of the CYP3A and UGT1A1 enzymes involved in the drug's metabolism. 13,14 The personalization of irinotecan therapy by increasing dosing in patients who smoke has been proposed. 22
# Quit Behaviours and Efficacy of Tobacco Cessation among Cancer Patients
Long-term abstinence is an important performance measure and clinical outcome for cessation interventions. 24 In the United States, an estimated 62% of patients recently diagnosed with cancer identified as current smokers, recent quitters (quit within the last 12 months), or former smokers. 25 In the short-term, cancer patients experience high cessation rates, relapse is common and higher among those experiencing comorbid mental health and/or addiction issues. A longitudinal study examining smoking behaviours among 154 lung and head/neck cancer patients following surgical treatment found that those who smoked the week before surgery experienced a 60% relapse rate at 12 months following their surgery compared to 13% of patients who were abstinent pre-surgery. 29 Using backward regression analysis, low quitting self-efficacy (p=0.029), higher depression proneness (p=0.037), and fear over cancer recurrence (p=0.028) were cited as reasons for relapse. 29
# Tobacco Screening and Treatment in Healthcare Settings
Clinical practice guidelines from leading national and international health and cancer organizations recommend that all healthcare providers screen for and offer tobacco cessation treatment. Although the 5 A's Approach ("Ask, Advise, Assess, Assist, Arrange") is a recognized gold standard to support tobacco cessation across different health-care settings and populations, 24, several published reports have also highlighted the utility and efficacy of the abbreviated "Ask-Advise-Refer" (AAR) model to promote cessation intervention where time constraints and lack of expertise or resources make it hard for clinicians to deliver a more intensive intervention. 30,34 Integrating the first two steps of the 5A's Approach, the AAR model concludes with a referral to available cessation support services for more intensive tobacco treatment and counselling.
The provision of physician-delivered advice to quit is a critical component of tobacco cessation treatment. The results of a 2012 systematic review and meta-analysis comparing advice to quit to the offer of assistance found that advice to quit on medical grounds increased long-term abstinence by 47%; the authors concluded, however, that offering assistance in the form of behavioural counselling or provision of NRT generated more quit attempts than simply giving advice to quit on medical grounds (behavioural support RR=1.69, 95% CI 1.24-2.31; offering medication RR=1.39, 95% CI 1.25-1.54). 35 While few studies have addressed the optimal intensity of tobacco interventions with cancer patients and their families, evidence conducted within other clinical settings report a dose-response relationship between intervention time and quit success. 30 The 2008 clinical practice guideline from the US Public Health Service reported that abstinence rates increase from 14.4% with brief counselling (<3 minutes) to 18.8% for interventions lasting 4-30 minutes. Optimal total contact time was estimated to be 91-300 minutes, resulting in abstinence rates of roughly 28%. 30 Initiating tobacco screening and intervention at the time of diagnosis and/or during the preoperative period is consistently recommended as best practice regardless of cancer type or level of intervention. 36,37
# Tobacco Treatment Options with Cancer Patients
Similar to the general population, first-line pharmacotherapy for tobacco cessation with cancer patients include all forms of nicotine replacement therapy (NRT), bupropion and varenicline. 36,37 Compared to placebo, varenicline is an effective monotherapy for successful long-term smoking cessation (see Table 1). Combination therapies improve efficacy over monotherapies alone (Table 1). 30 Systematic reviews show that combining bupropion or varenicline with NRT is more efficacious than either varenicline or bupropion alone. 38,39 Compared to NRT monotherapy, bupropion combined with NRT was not found to be more efficacious. 40 Two randomized control trials suggest that varenicline combined with bupropion may be more effective than either monotherapy, however more research is needed. 41,42 Treatment with pharmacotherapy combined with behavioural counseling is more effective than pharmacotherapy or counselling alone in both cancer and non-cancer patients. A 2013 meta-analysis comparing smoking cessation interventions with usual care in cancer patients found that the combined use of pharmacological (NRT and varenicline) and behavioural therapy were most effective at improving quit rates. 24
# Clinical Considerations and Contraindications for Cancer Patients
Nicotine Replace Therapy (NRT): Oral products, including gum, lozenges, spray and inhalers, may be irritating to the oral mucosa and therefore may not be appropriate for use for individuals with oral cancer, or with head and neck cancer who are undergoing radiation and/or receiving chemotherapy with high incidence of stomatitis. 43 Some forms of NRT may be contraindicated in the immediate preand/or post-operative period in patients who undergo tissue reconstruction where revascularization is a concern. These cases should be discussed on an individual basis with the surgeon and health-care team. In such cases, non-nicotine treatments for smoking cessation are alternate options (e.g., varenicline, bupropion).
# Bupropion:
In cancer patients experiencing depression symptoms, bupropion has been shown to increase abstinence rates, decrease withdrawal symptoms and increase quality of life compared to those with no depression symptoms. 44 Bupropion is contraindicated in patients with a history of seizures or those with a predisposition to seizures, such as patients with CNS tumours. 30 The drug should also be avoided breast cancer patients taking tamoxifen as bupropion impacts the metabolism of tamoxifen by inhibiting conversion to its active metabolites. 45 In the general population, bupropion can reduce appetite and prevent weight gain and may warrant monitoring if prescribing in patients who may experience weight loss related to their cancer treatments. 43 Bupropion may be associated with neuropsychiatric symptoms, including suicidal ideation, suicide attempts, depressed mood, hostility, and agitation. Patients taking bupropion should be closely monitored for adverse effects and should stop taking the drug immediately if any of these side effects develop.
Varenicline: To date, there are no reported studies of interactions between varenicline and commonly used lung cancer therapies. 13 A small study testing the effectiveness of varenicline and behavioural support in a cohort of cancer patients reported nausea as the most common side effect, similar to rates reported within general population which has about a 30% incidence. 4 Drug titration and dosing can reduce nausea and should be considered with cancer patients experiencing cancertreatment induced nausea. 43 Varenicline should be used cautiously in patients with a history of seizures or conditions that lower seizure threshold, and close monitoring is required for neuropsychiatric symptoms with consideration of NRT as an alternate treatment option. 46 Due to the psychological and medical vulnerability of cancer patients, varenicline is encouraged to be used along with intensive behavioural counselling to support cessation. 4 While there have been studies of adverse cardiovascular events in patients taking varenicline, overall data suggest that the benefit of varenicline as the most effective cessation drug in clinical trials outweighs the low risk of adverse events associated with its use. 50 Personalization of varenicline and close monitoring are still encouraged if prescribing in patients with cardiovascular disease.
# Vaping
Vaping is the act of inhaling and exhaling an aerosol produced by an electronic smoking product, such as an electronic cigarette. Controversy currently exists as to whether vaping is a safer alternative and a potential harm reduction strategy for adults who currently smoke tobacco products. 51,52 Some research identifies that vaping may be less harmful than smoking because vaping products do not produce smoke, contain tobacco, or involve burning. In addition, except for nicotine, vaping products typically contain a fraction of the 7,000 chemicals found in tobacco smoke and lower levels of several of the harmful chemicals found in smoke. However, other research has identified health risks associated with vaping, including nicotine poisoning and addiction, health risks of other chemicals in vaping, second-hand vapour, and device malfunctions. 52 While evidence is still emerging, these products may reduce health risks and improve success rates for smokers who can't or don't want to quit smoking on their own; however, vaping is not considered a first line smoking cessation therapy. - hand-mouth activity from using the inhaler is preferred by some quitters the inhaler is useful for those with poor oral health or dentures, and for those who cannot chew gum - similar in appearance to a cigarette: designed to be puffed on - not a true inhaler; the nicotine is delivered and absorbed through the lining in the mouth - allows fine tuning of how much and how often the user consumes nicotine
# Nicotine Mouth Spray
Available in a dispenser that contains 150 sprays; each spray delivers 1 mg of nicotine.
- absorbed through the lining in the mouth - do not eat or drink for 15 minutes before using the spray
- hiccups
throat irritation - increased salivation
- if using the spray for the first time, or if the spray has not been used for two days, load the spray pump by pressing on the dispenser several times until a fine spray is released into a tissue - point the spray nozzle towards the open mouth and hold as close as possible to the mouth, avoiding the lips - press down on the dispenser to release a spray into the mouth - do not inhale while spraying and avoid swallowing for a few seconds afterwards - expect a strong mint taste in the mouth
# Development and Revision History
This guideline was developed by a multidisciplinary working group representing members from Cancer Care Alberta, AHS Cancer Prevention and Screening Innovation, the AHS Tobacco, Vaping & Cannabis Program, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial Tumour Teams who were not involved in the guideline's development, including medical oncologists, pharmacists, advanced practice nurses, and respiratory therapists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was first published in October 2015, revised in June 2016 to abbreviate the cessation intervention model to best support adoption across all CCA clinics and settings, and updated in November 2020 and May 2023.
# Maintenance
A formal review of the guideline will be conducted in 2026. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations | # Background
In 2022, an estimated 22,200 Albertans will be diagnosed with cancer and an estimated 7,500 people will die of their disease. 1 Between 2003Between -2007Between and 2028Between -2032, the number of new cancer cases per year in Canada is predicted to increase by 84% in males (from 80,810 to 148,370) and by 74% in females (from 74,164 to 128,830). 2 Active tobacco smoking is the leading preventable risk factor for cancer and is responsible for an estimated 72% of lung cancer cases and 74% of larynx cancer cases in Canada. 3 Tobacco screening and cessation treatment for cancer patients is a key to high-quality oncology care, and the use of clear, direct advice from healthcare providers to stop or reduce smoking continues to be the single most influential way to achieve smoking cessation in most patient populations. Tobacco intervention by health care professionals has been shown to be effective in increasing the abstinence rate in cancer patients. 4 The integration of tobacco screening and cessation treatment into oncology care has been recommended by a number of national and international cancer-focused organizations as a best practice intervention, however, tobacco screening and treatment is not consistently or routinely implemented in cancer care programs across the province.
The "Ask, Advise, Refer" (AAR) brief intervention model has been adopted by Cancer Care Alberta (CCA) as a practice standard for all sites. This guideline presents the key recommendations to support the screening and treatment of tobacco use by cancer patients as a provincial standard of care.
Guideline Questions 1. What is the process for screening and treatment of tobacco use in cancer patients at Cancer Care Alberta? 2. What options are available for cancer patients for nicotine withdrawal and cessation pharmacotherapy? 3. What training and education resources are available for Cancer Care Alberta staff to deliver brief tobacco interventions to cancer patients? 4. How does concurrent tobacco treatment (behavioural and/or pharmacotherapy support) impact cancer treatment (e.g., chemotherapy, radiation, surgery)?
# Search Strategy
The search strategy was selected and reviewed by members of the guideline working group with support from an Alberta Health Services research librarian.
The PubMed, EMBASE, Medline, Cochrane Database of Systematic Reviews, CINAHL, PsycINFO and Pharmacy databases were searched from January 2008 to February 2015 for literature on tobacco cessation interventions in a cancer care setting and associated impacts on tobacco use reduction and/or cessation. A variety of separate and combined search terms were used, including but not limited to: cancer patients, caregiver, staff, tobacco intervention, tobacco cessation treatment, cessation pharmacotherapy, cancer, cancer treatment, risk factors, quality of life, windows of opportunity, recurrence, relapse and quit rates. Results were limited to randomized controlled trials, systematic reviews and observational studies published in English. Grey literature (e.g., Google, Google Scholar, ProQuest) as well as the reference lists of key articles were also searched for additional publications. Excluded from the analysis were pediatric cancer patients, tobacco treatment interventions that occur outside of cancer care (e.g., primary care) and non-oncology patients. A total of 74 studies were identified for inclusion.
Clinical guidelines databases (e.g., National Institute for Health and Care Excellence, the National Guidelines Clearinghouse, SAGE Directory,) and guideline bodies were also searched for guidelines on smoking cessation in cancer care settings. The search returned eight guidelines. A full copy of the evidence tables is available upon request by contacting [email protected].
# Target Population
This guideline applies to all health professionals working with adult cancer patients (aged 18 years and older) at any phase of the cancer care continuum regardless of cancer type, stage (including metastatic) or treatment plan. Components of this guideline are also applicable to the patient's family and/or caregivers, where indicated. This guideline is intended for use in both inpatient and ambulatory (outpatient) settings.
# Scope and Definitions
This guideline outlines recommendations to guide CCA health care professionals who have direct contact with patients and families to deliver brief tobacco intervention as a routine standard of care.
The standards for more intensive intervention are outside of the scope of this guideline.
• Tobacco Use includes the use of cigarettes, cigars, cigarillos, pipe, smokeless tobacco products, waterpipes, and heated tobacco products. Use of the term 'tobacco' in this document does not refer to use of traditional tobacco for ceremonial and/or spiritual purposes, it refers instead to misuse and cessation of commercial tobacco products. • AAR Brief Tobacco Intervention Model is an established model used in a variety of clinical settings. It is designed to be implemented in less than 3 minutes and involves the following three steps: ask about tobacco use, advise to quit, and refer to a local resource for more intensive tobacco treatment counselling or pharmacotherapy. • Health Professional means an individual who is a member of a regulated health discipline, as defined by the Alberta Health Disciplines Act or Health Professions Act, and who provides promotional, preventive, curative, or rehabilitative care as per their defined scope or role. • Digital MySymptom Report -(MSR) is a self-reported questionnaire completed by the patient. The form consists of the electronic revised Edmonton Symptom Assessment System for Cancer, (eESAS-r Cancer), the MyPersonal Needs checklist, and questions designed to satisfy CCA operational and accreditation requirements.
# CCA Inpatient and Outpatient Procedure for Tobacco Treatment
A brief tobacco intervention involves using the "Ask, Advise, Refer" (AAR) model with electronic implementation and documentation in Connect Care. Refer to Appendix A for the Algorithm for the Screening and Treatment of Tobacco Use.
In compliance with the AHS Provincial Tobacco and Smoke Free Environment Policy, patients, family member(s), or those accompanying the patient should be advised that consumption of commercial tobacco and tobacco-like products is not permitted on AHS property, including grounds and facilities. o If the patient is not a tobacco user, stop the intervention.
# Responsibilities of the
# Education and Assessment ("Advise")
o Patients who self-identify as using tobacco should be advised to stop. Advice should be personalized to the patient's cancer type, stage, and treatment plan and broadly address: health effects of continued tobacco in context of cancer treatment. benefits of cessation and/or reduction. benefit of counselling and medication as most effective treatment.
o Advise patients and/or their family members of available local cessation resources including AlbertaQuits, Primary Care Networks, and community pharmacies. Assess patient interest in receiving a referral to such services for counselling and support.
o Document advice given within the patient's chart in Connect Care under "Screenings" "Psychosocial".
o If appropriate, patients should be advised on importance of reducing exposure to secondhand smoke with messaging of cessation to accompanying caregivers/family members who identify as tobacco users.
o A longer tobacco cessation intervention following the 5A's Approach ("Ask, Advise, Assess, Assist, Arrange") can occur when staff knowledge and time enables them to do so. For more information, please reference the resource The 5A's Approach: A Continuum of Brief and Intensive Settings, available from the Alberta Health Services Tobacco, Vaping & Cannabis Program website.
# Referral ("Refer")
o Provide information on AlbertaQuits services and self-help resources for patients and family members interested in quitting.
o Referral Process: CCA staff and prescribers wishing to refer a patient to the AlbertaQuits program can use the following process:
• An order for "Ambulatory Referral to Smoking Cessation Program" is entered in the Connect Care system. • The completed referral form from the Alberta Referral Directory is faxed to AlbertaQuits, using the number at the top of the form. • A tobacco cessation counsellor from AlbertaQuits will then connect with the patient using the contact information provided on the form. See Appendix B for a screen shot of the Connect Care referral process, as well as the AlbertaQuits Helpline Referral Form; this form can also be accessed through the external AHS website.
o For patients not interested in quitting: Advise patients that they can self-refer to AlbertaQuits services at any time by calling the AlbertaQuits Helpline at 1-866-710-7848 or by visiting the AlbertaQuits website. Document refusal in the patient's chart.
# Nicotine Withdrawal and Cessation Pharmacotherapy
# Patients Admitted to Hospital -Inpatients
o Inpatients who self-identify as using tobacco products should be assessed for nicotine withdrawal symptoms and offered the most appropriate Nicotine Replacement Therapy ii.
Tobacco Cessation in Cancer Care -Module 2 "Cessation Pharmacotherapy": describes the types of pharmacotherapies available to support tobacco cessation with a strong focus on the unique considerations when prescribing Nicotine Replacement Therapy and/or pharmacotherapies to patients with cancer.
iii. Tobacco Cessation in Cancer Care -Module 3 "Evidence-Based Programs": provides an overview of current evidence-based best practice for tobacco cessation in cancer care and outlines patient referral processes to cessation programs and services in Alberta.
• AlbertaQuits Learning Series: offers e-learning courses and classroom/virtual trainings to a broad health professional audience.
• Tobacco Comfort Measures and Cessation Support: clinical support primer and tobacco care pathway.
• Tobacco Cessation Toolkit: Includes a variety of tools designed to support healthcare providers in clinical practice.
# Discussion
# Impact of Continued Tobacco Use on Cancer Outcomes
Current evidence strongly supports quitting smoking following a cancer diagnosis. The 2020 Surgeon General's Report on Smoking Cessation concluded that there is sufficient causal evidence between smoking and increased all-cause mortality, increased cancer-specific mortality and increased risk of developing second primary cancers. 5 Smoking was further associated with an increased risk of cancer recurrence, poorer response to treatment and increased treatment-related toxicity. Indeed, estimates suggest that quitting smoking at the time of diagnosis could lower the risk of dying by up to 40% with the benefits of cessation being equal to or exceeding the value of new cancer therapies for some cancer diagnoses. 5 The benefits of cessation go beyond cancers known to be caused by tobacco use, with increased mortality rates associated with continued smoking after diagnosis reported across cancer types and stages of diagnosis. [6][7][8][9] Results of a meta-analysis with early stage non-small cell lung cancer (NSCLC) and limited stage small cell lung cancer (SCLC) showed continued smoking increased the risk of all-cause mortality, recurrence and development of a second primary tumour. 10 In patients with NSCLC, quitting smoking was associated with an estimated five-year survival rate of 70% compared to 33% in those who continued to smoke. Survival rates for patients with SCLC were at 63% and 29% in quitters and those who continued to smoke, respectively. 10 There is consistent evidence that tobacco use, namely smoking, reduces the efficacy of radiation therapy and some chemotherapy agents 5,[11][12][13] and increases the risk for treatment-induced complications including surgical site infections, pulmonary function and return to the operating room. 6,[14][15][16] Studies further report an association between smoking and increased risk of recurrence following cancer treatments among patients with head and neck cancers, 7,12,17,18 prostate cancer, 19 urothelial cancer, 20 and gastric cancer. 21
# Impact of Tobacco Use on Cancer Treatment: Chemotherapy Considerations
Tobacco smoke can interfere with the pharmacokinetic mechanisms of several chemotherapy drugs potentially causing an altered pharmacologic response. 13,22 Tobacco smoke increases the amount of drug binding protein resulting in induction of cytochrome-450 enzymes (primarily CYP1A2) and UGT isoenzymes which metabolize several chemotherapy drugs. Nicotine replacement therapy does not impact CYP1A2 activity or reduce cancer drug efficacy.
Erlotinib: Commonly used in the treatment of NSCLC and pancreatic cancer, erlotinib is primarily metabolized by CYPs 3A4 and 1A2. Cigarette smoking has been shown to cause induction of several CYP enzymes primarily by CYP3A4 but also by CYP1A2, resulting in more rapid metabolism and decreased systemic exposure to the drug. 23 Data analyzed from seven clinical trials that administered the standard dose of erlotinib (150 mg once daily) found that smoking status was a significant covariate affecting drug clearance. 13 Patients who smoked and who were treated with erlotinib experienced a 23.5% increase in clearance and had lower (nearly half) median steady-state trough plasma concentrations compared to never and former smokers. 13,22 An increased dose of erlotinib may benefit patients with NSCLC who continue to smoke following diagnosis. Dosing consideration should also be given to patients exposed to secondhand smoke. 22 Irinotecan: Smoking is known to alter the pharmacokinetics of irinotecan, a topoisomerase-I inhibitor used to treat a variety of cancers including colon, rectal, lung, and bone cancers. While not definitive, a study of cancer patients treated with irinotecan (n=190) found those who smoked experienced 40% lower systemic exposure to the active metabolite SN-38, 18% faster clearance, and less neutropenia (6% smokers versus 38% nonsmokers) compared to non-smokers. 22 The effects of smoking on irinotecan pharmacokinetics may be attributed to induction and modulation of the CYP3A and UGT1A1 enzymes involved in the drug's metabolism. 13,14 The personalization of irinotecan therapy by increasing dosing in patients who smoke has been proposed. 22
# Quit Behaviours and Efficacy of Tobacco Cessation among Cancer Patients
Long-term abstinence is an important performance measure and clinical outcome for cessation interventions. 24 In the United States, an estimated 62% of patients recently diagnosed with cancer identified as current smokers, recent quitters (quit within the last 12 months), or former smokers. 25 In the short-term, cancer patients experience high cessation rates, relapse is common and higher among those experiencing comorbid mental health and/or addiction issues. [26][27][28] A longitudinal study examining smoking behaviours among 154 lung and head/neck cancer patients following surgical treatment found that those who smoked the week before surgery experienced a 60% relapse rate at 12 months following their surgery compared to 13% of patients who were abstinent pre-surgery. 29 Using backward regression analysis, low quitting self-efficacy (p=0.029), higher depression proneness (p=0.037), and fear over cancer recurrence (p=0.028) were cited as reasons for relapse. 29
# Tobacco Screening and Treatment in Healthcare Settings
Clinical practice guidelines from leading national and international health and cancer organizations recommend that all healthcare providers screen for and offer tobacco cessation treatment. Although the 5 A's Approach ("Ask, Advise, Assess, Assist, Arrange") is a recognized gold standard to support tobacco cessation across different health-care settings and populations, 24,[30][31][32][33] several published reports have also highlighted the utility and efficacy of the abbreviated "Ask-Advise-Refer" (AAR) model to promote cessation intervention where time constraints and lack of expertise or resources make it hard for clinicians to deliver a more intensive intervention. 30,34 Integrating the first two steps of the 5A's Approach, the AAR model concludes with a referral to available cessation support services for more intensive tobacco treatment and counselling.
The provision of physician-delivered advice to quit is a critical component of tobacco cessation treatment. The results of a 2012 systematic review and meta-analysis comparing advice to quit to the offer of assistance found that advice to quit on medical grounds increased long-term abstinence by 47%; the authors concluded, however, that offering assistance in the form of behavioural counselling or provision of NRT generated more quit attempts than simply giving advice to quit on medical grounds (behavioural support RR=1.69, 95% CI 1.24-2.31; offering medication RR=1.39, 95% CI 1.25-1.54). 35 While few studies have addressed the optimal intensity of tobacco interventions with cancer patients and their families, evidence conducted within other clinical settings report a dose-response relationship between intervention time and quit success. 30 The 2008 clinical practice guideline from the US Public Health Service reported that abstinence rates increase from 14.4% with brief counselling (<3 minutes) to 18.8% for interventions lasting 4-30 minutes. Optimal total contact time was estimated to be 91-300 minutes, resulting in abstinence rates of roughly 28%. 30 Initiating tobacco screening and intervention at the time of diagnosis and/or during the preoperative period is consistently recommended as best practice regardless of cancer type or level of intervention. 36,37
# Tobacco Treatment Options with Cancer Patients
Similar to the general population, first-line pharmacotherapy for tobacco cessation with cancer patients include all forms of nicotine replacement therapy (NRT), bupropion and varenicline. 36,37 Compared to placebo, varenicline is an effective monotherapy for successful long-term smoking cessation (see Table 1). Combination therapies improve efficacy over monotherapies alone (Table 1). 30 Systematic reviews show that combining bupropion or varenicline with NRT is more efficacious than either varenicline or bupropion alone. 38,39 Compared to NRT monotherapy, bupropion combined with NRT was not found to be more efficacious. 40 Two randomized control trials suggest that varenicline combined with bupropion may be more effective than either monotherapy, however more research is needed. 41,42 Treatment with pharmacotherapy combined with behavioural counseling is more effective than pharmacotherapy or counselling alone in both cancer and non-cancer patients. A 2013 meta-analysis comparing smoking cessation interventions with usual care in cancer patients found that the combined use of pharmacological (NRT and varenicline) and behavioural therapy were most effective at improving quit rates. 24
# Clinical Considerations and Contraindications for Cancer Patients
Nicotine Replace Therapy (NRT): Oral products, including gum, lozenges, spray and inhalers, may be irritating to the oral mucosa and therefore may not be appropriate for use for individuals with oral cancer, or with head and neck cancer who are undergoing radiation and/or receiving chemotherapy with high incidence of stomatitis. 43 Some forms of NRT may be contraindicated in the immediate preand/or post-operative period in patients who undergo tissue reconstruction where revascularization is a concern. These cases should be discussed on an individual basis with the surgeon and health-care team. In such cases, non-nicotine treatments for smoking cessation are alternate options (e.g., varenicline, bupropion).
# Bupropion:
In cancer patients experiencing depression symptoms, bupropion has been shown to increase abstinence rates, decrease withdrawal symptoms and increase quality of life compared to those with no depression symptoms. 44 Bupropion is contraindicated in patients with a history of seizures or those with a predisposition to seizures, such as patients with CNS tumours. 30 The drug should also be avoided breast cancer patients taking tamoxifen as bupropion impacts the metabolism of tamoxifen by inhibiting conversion to its active metabolites. 45 In the general population, bupropion can reduce appetite and prevent weight gain and may warrant monitoring if prescribing in patients who may experience weight loss related to their cancer treatments. 43 Bupropion may be associated with neuropsychiatric symptoms, including suicidal ideation, suicide attempts, depressed mood, hostility, and agitation. Patients taking bupropion should be closely monitored for adverse effects and should stop taking the drug immediately if any of these side effects develop.
Varenicline: To date, there are no reported studies of interactions between varenicline and commonly used lung cancer therapies. 13 A small study testing the effectiveness of varenicline and behavioural support in a cohort of cancer patients reported nausea as the most common side effect, similar to rates reported within general population which has about a 30% incidence. 4 Drug titration and dosing can reduce nausea and should be considered with cancer patients experiencing cancertreatment induced nausea. 43 Varenicline should be used cautiously in patients with a history of seizures or conditions that lower seizure threshold, and close monitoring is required for neuropsychiatric symptoms with consideration of NRT as an alternate treatment option. 46 Due to the psychological and medical vulnerability of cancer patients, varenicline is encouraged to be used along with intensive behavioural counselling to support cessation. 4 While there have been studies of adverse cardiovascular events in patients taking varenicline, [47][48][49] overall data suggest that the benefit of varenicline as the most effective cessation drug in clinical trials outweighs the low risk of adverse events associated with its use. 50 Personalization of varenicline and close monitoring are still encouraged if prescribing in patients with cardiovascular disease.
# Vaping
Vaping is the act of inhaling and exhaling an aerosol produced by an electronic smoking product, such as an electronic cigarette. Controversy currently exists as to whether vaping is a safer alternative and a potential harm reduction strategy for adults who currently smoke tobacco products. 51,52 Some research identifies that vaping may be less harmful than smoking because vaping products do not produce smoke, contain tobacco, or involve burning. In addition, except for nicotine, vaping products typically contain a fraction of the 7,000 chemicals found in tobacco smoke and lower levels of several of the harmful chemicals found in smoke. However, other research has identified health risks associated with vaping, including nicotine poisoning and addiction, health risks of other chemicals in vaping, second-hand vapour, and device malfunctions. 52 While evidence is still emerging, these products may reduce health risks and improve success rates for smokers who can't or don't want to quit smoking on their own; however, vaping is not considered a first line smoking cessation therapy. • hand-mouth activity from using the inhaler is preferred by some quitters the inhaler is useful for those with poor oral health or dentures, and for those who cannot chew gum • similar in appearance to a cigarette: designed to be puffed on • not a true inhaler; the nicotine is delivered and absorbed through the lining in the mouth • allows fine tuning of how much and how often the user consumes nicotine
# Nicotine Mouth Spray
Available in a dispenser that contains 150 sprays; each spray delivers 1 mg of nicotine.
• absorbed through the lining in the mouth • do not eat or drink for 15 minutes before using the spray
• hiccups •
throat irritation • increased salivation
• if using the spray for the first time, or if the spray has not been used for two days, load the spray pump by pressing on the dispenser several times until a fine spray is released into a tissue • point the spray nozzle towards the open mouth and hold as close as possible to the mouth, avoiding the lips • press down on the dispenser to release a spray into the mouth • do not inhale while spraying and avoid swallowing for a few seconds afterwards • expect a strong mint taste in the mouth
# Development and Revision History
This guideline was developed by a multidisciplinary working group representing members from Cancer Care Alberta, AHS Cancer Prevention and Screening Innovation, the AHS Tobacco, Vaping & Cannabis Program, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial Tumour Teams who were not involved in the guideline's development, including medical oncologists, pharmacists, advanced practice nurses, and respiratory therapists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was first published in October 2015, revised in June 2016 to abbreviate the cessation intervention model to best support adoption across all CCA clinics and settings, and updated in November 2020 and May 2023.
# Maintenance
A formal review of the guideline will be conducted in 2026. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
# Disclaimer
The recommendations contained in this guideline are a consensus of the Tobacco Screening and Treatment Guideline Working Group and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2023) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for non-commercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-nc-nd/4.0/.
The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Funding Source
Financial support for the development of Cancer Care Alberta's evidence-based clinical practice guidelines and supporting materials comes from the Cancer Care Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Dr. Charlie Butts has nothing to disclose.
Xanthoula Kostaras has nothing to disclose.
# Citation
| None | None |
a696d9e6dbd0f4aafa0e21d055f4989230931174 | cma | None | Please check the Ministry of Health (MOH) COVID-19 website regularly for updates to this document, mental health resources, and other information. - The latest 'COVID-19 Reference Document for Symptoms' and 'Case Definition' are available and updated on the MOH COVID-19 website. - Please check the Directives, Memorandums and Other Resources page regularly for the most up to date directives. - For detailed clinical care recommendations regarding labour and delivery procedures, please see Maternal Newborn COVID-19 General Guidelines published by the Provincial Council for Maternal and Child Health.# General
Timing and Location 1. Regardless of whether a woman is a suspected or confirmed case of COVID-19, her place of birth should continue to be informed by obstetrical factors and the woman's birth place preferences. Women should deliver in a care environment that can meet both their needs and the needs of the newborn while receiving care for COVID-19.
Movement within and between facilities should be minimized. COVID-19 alone should not be an indication for transfer but may be a consideration.
- Timing of delivery should be determined by obstetrical indications. Suspected or confirmed COVID-19 status alone is not a sufficient indication for induction or caesarean delivery.
Delivery for suspected or confirmed COVID-19 pregnant women may be expedited for fetal reasons, or if it is felt that delivery will help maternal resuscitation. If delivery is required, maternal stabilization should be the priority. for risk of droplet and contact transmission during labour, delivery, and newborn care. Suitable precautions may include: gloves, gown, a surgical/procedure mask, and eye protection (goggles or face shield).
Acute care settings should define the minimum team required to provide a safe caesarean section and aim to eliminate unnecessary HCWs in the operating room (OR).
Only essential OR staff should be in the room for administration of general anesthesia for a caesarian section, such staff should follow Airborne precautions (including appropriately fitted N95 mask). Once intubation is complete, other HCWs may enter the room and use Droplet/Contact precautions.
All staff present in the operating room for caesarean section under regional anesthesia should use Droplet/Contact precautions. In the event that regional anesthesia is not sufficient and the procedure needs to be converted to general
HCWs should screen all pregnant women upon entry and admission to triage area for labour and delivery for symptoms and exposure history, even if they have been screened upon entry to the hospital.
HCWs conducting screening on site should ideally be behind a barrier to protect from Contact/Droplet spread. A plexiglass barrier can protect staff from sneezing/coughing patients. If a plexiglass barrier is not available, staff should maintain a 2-metre distance from the patient. HCWs who do not have a barrier and cannot maintain a 2-metre distance should use Contact/Droplet precautions. This includes the following PPE -gloves, gown, a surgical/procedure mask, and eye protection (goggles or face shield).
Positive Screening: What to do 13. Pregnant patients who screen positive for signs/symptoms of COVID-19 should be treated as suspected for COVID-19, should be given a surgical/procedure mask for all stages of labour (if tolerated) and be advised to perform hand hygiene. As soon as the reception staff is aware that the patient has screened positive, the patient should be placed in a room with the door closed (do not cohort with other patients), where possible, to avoid contact with other patients in common areas of the floor (e.g., waiting rooms).
Mothers with suspected or confirmed COVID-19 should be counseled using a patient-centred approach regarding the risks and benefits of keeping mother and baby together, including strategies to reduce risk of spread if mother and baby remain together (see bullet #22) versus separated (see bullet #23). o The ability to ensure that the support person remains compliant with physical distancing and infection control instructions.
# Institutions may also want to consider that:
- Differing policies may be appropriate for women who are suspected or confirmed COVID-19 than for asymptomatic women.
- If the support person is to accompany a pregnant patient, the same recommendations on PPE precautions must be taken.
- Movement through and between care environments by the support person should be minimized.
- In and Out privileges should be discouraged and supports may be required to remain in the patient room at all times.
- Where in-person support is not possible, virtual and/or alternative options for support should be provided. When distance support is given, practical physical support should be provided.
# Testing of Babies
- Newborns born to mothers with confirmed COVID-19 at the time of birth should be tested for COVID-19 within 24 hours of delivery, regardless of symptoms.
- If maternal testing is pending at the time of mother-baby dyad discharge then follow-up must be ensured such that if maternal testing is positive the baby is tested in a timely manner. If bringing the baby back for testing is impractical, the baby should be tested prior to discharge.
The recommended neonatal sample is a nasopharyngeal swab (NPS) placed in universal transport medium (UTM) for PCR testing. Laboratory investigation of symptomatic newborns may be more extensive, including addition of COVID-19 PCR testing of placental swab or tissue, umbilical cord blood and/or neonatal blood. The decision for expanded testing would be made by the clinical team.
Any symptomatic newborns should also be assessed for other causes of clinical disease according to the clinical findings.
A positive COVID-19 test in a newborn should be discussed with a paediatric infectious disease consultant.
# Care of Babies Born to Suspected or Confirmed
# COVID-19 Mothers
- Given the low risk of vertical transmission and the low risk of aerosol exposure from neonatal resuscitation, Droplet/Contact precautions are suitable for the initial resuscitation of newborns, even those born to suspected or confirmed COVID-19 mothers.
Babies can stay in the mother's postpartum room, though several safety precautions are recommended, where possible, including:
- a private room o mother wearing a mask o hand hygiene before all care of baby o skin hygiene before breastfeeding, and o keeping infant two meters from mother when not providing direct care, including use of a barrier (such as a curtain or incubator) to protect against droplets due to coughing 23. If possible, a separate newborn care area with caregiver should be made available for women who are unable to care for their infants due to symptoms or upon request of the mother/family to prevent COVID-19 transmission to the baby.
Well babies should be discharged early if possible, after proper risk assessment has occurred.
HCWs should provide clear instructions for mothers with confirmed COVID-19 (or who are being assessed for COVID-19) and their infants to continue to follow-up with their primary care provider(s) until 2 weeks postpartum. HCWs should provide advice to the mother on how to self-isolate, and to call ahead to their primary care provider(s) to ensure they can plan for their visit.
# Breastfeeding
Mothers who are confirmed or suspected COVID-19 patients should:
- Wash hands when touching their infant, bottles, breast pump, etc.;
- Be masked while holding or feeding their infant;
- Cough or sneeze away from their infant while holding or feeding;
- Follow breast and skin cleansing hygiene before holding or feeding;
- Ensure pumps and bottles are cleaned according to the institution's Infection Protection and Control policies.
# Care and Testing of Babies in Neonatal Intensive
Care Unit (NICU) and Special Care Nursery (SCN) | Please check the Ministry of Health (MOH) COVID-19 website regularly for updates to this document, mental health resources, and other information. • The latest 'COVID-19 Reference Document for Symptoms' and 'Case Definition' are available and updated on the MOH COVID-19 website. • Please check the Directives, Memorandums and Other Resources page regularly for the most up to date directives. • For detailed clinical care recommendations regarding labour and delivery procedures, please see Maternal Newborn COVID-19 General Guidelines published by the Provincial Council for Maternal and Child Health.# General
Timing and Location 1. Regardless of whether a woman is a suspected or confirmed case of COVID-19, her place of birth should continue to be informed by obstetrical factors and the woman's birth place preferences. Women should deliver in a care environment that can meet both their needs and the needs of the newborn while receiving care for COVID-19.
# 2.
Movement within and between facilities should be minimized. COVID-19 alone should not be an indication for transfer but may be a consideration.
3. Timing of delivery should be determined by obstetrical indications. Suspected or confirmed COVID-19 status alone is not a sufficient indication for induction or caesarean delivery.
# 4.
Delivery for suspected or confirmed COVID-19 pregnant women may be expedited for fetal reasons, or if it is felt that delivery will help maternal resuscitation. If delivery is required, maternal stabilization should be the priority. for risk of droplet and contact transmission during labour, delivery, and newborn care. Suitable precautions may include: gloves, gown, a surgical/procedure mask, and eye protection (goggles or face shield).
# 5.
# 7.
Acute care settings should define the minimum team required to provide a safe caesarean section and aim to eliminate unnecessary HCWs in the operating room (OR).
# 8.
Only essential OR staff should be in the room for administration of general anesthesia for a caesarian section, such staff should follow Airborne precautions (including appropriately fitted N95 mask). Once intubation is complete, other HCWs may enter the room and use Droplet/Contact precautions.
# 9.
All staff present in the operating room for caesarean section under regional anesthesia should use Droplet/Contact precautions. In the event that regional anesthesia is not sufficient and the procedure needs to be converted to general
# 11.
HCWs should screen all pregnant women upon entry and admission to triage area for labour and delivery for symptoms and exposure history, even if they have been screened upon entry to the hospital.
# 12.
HCWs conducting screening on site should ideally be behind a barrier to protect from Contact/Droplet spread. A plexiglass barrier can protect staff from sneezing/coughing patients. If a plexiglass barrier is not available, staff should maintain a 2-metre distance from the patient. HCWs who do not have a barrier and cannot maintain a 2-metre distance should use Contact/Droplet precautions. This includes the following PPE -gloves, gown, a surgical/procedure mask, and eye protection (goggles or face shield).
Positive Screening: What to do 13. Pregnant patients who screen positive for signs/symptoms of COVID-19 should be treated as suspected for COVID-19, should be given a surgical/procedure mask for all stages of labour (if tolerated) and be advised to perform hand hygiene. As soon as the reception staff is aware that the patient has screened positive, the patient should be placed in a room with the door closed (do not cohort with other patients), where possible, to avoid contact with other patients in common areas of the floor (e.g., waiting rooms).
# 14.
Mothers with suspected or confirmed COVID-19 should be counseled using a patient-centred approach regarding the risks and benefits of keeping mother and baby together, including strategies to reduce risk of spread if mother and baby remain together (see bullet #22) versus separated (see bullet #23). o The ability to ensure that the support person remains compliant with physical distancing and infection control instructions.
# Institutions may also want to consider that:
o Differing policies may be appropriate for women who are suspected or confirmed COVID-19 than for asymptomatic women.
o If the support person is to accompany a pregnant patient, the same recommendations on PPE precautions must be taken.
o Movement through and between care environments by the support person should be minimized.
o In and Out privileges should be discouraged and supports may be required to remain in the patient room at all times.
o Where in-person support is not possible, virtual and/or alternative options for support should be provided. When distance support is given, practical physical support should be provided.
# Testing of Babies
17. Newborns born to mothers with confirmed COVID-19 at the time of birth should be tested for COVID-19 within 24 hours of delivery, regardless of symptoms.
18. If maternal testing is pending at the time of mother-baby dyad discharge then follow-up must be ensured such that if maternal testing is positive the baby is tested in a timely manner. If bringing the baby back for testing is impractical, the baby should be tested prior to discharge.
# 19.
The recommended neonatal sample is a nasopharyngeal swab (NPS) placed in universal transport medium (UTM) for PCR testing. Laboratory investigation of symptomatic newborns may be more extensive, including addition of COVID-19 PCR testing of placental swab or tissue, umbilical cord blood and/or neonatal blood. The decision for expanded testing would be made by the clinical team.
Any symptomatic newborns should also be assessed for other causes of clinical disease according to the clinical findings.
# 20.
A positive COVID-19 test in a newborn should be discussed with a paediatric infectious disease consultant.
# Care of Babies Born to Suspected or Confirmed
# COVID-19 Mothers
21. Given the low risk of vertical transmission and the low risk of aerosol exposure from neonatal resuscitation, Droplet/Contact precautions are suitable for the initial resuscitation of newborns, even those born to suspected or confirmed COVID-19 mothers.
# 22.
Babies can stay in the mother's postpartum room, though several safety precautions are recommended, where possible, including:
o a private room o mother wearing a mask o hand hygiene before all care of baby o skin hygiene before breastfeeding, and o keeping infant two meters from mother when not providing direct care, including use of a barrier (such as a curtain or incubator) to protect against droplets due to coughing 23. If possible, a separate newborn care area with caregiver should be made available for women who are unable to care for their infants due to symptoms or upon request of the mother/family to prevent COVID-19 transmission to the baby.
# 24.
Well babies should be discharged early if possible, after proper risk assessment has occurred.
# 25.
HCWs should provide clear instructions for mothers with confirmed COVID-19 (or who are being assessed for COVID-19) and their infants to continue to follow-up with their primary care provider(s) until 2 weeks postpartum. HCWs should provide advice to the mother on how to self-isolate, and to call ahead to their primary care provider(s) to ensure they can plan for their visit.
# Breastfeeding
# 26.
Mothers who are confirmed or suspected COVID-19 patients should:
• Wash hands when touching their infant, bottles, breast pump, etc.;
• Be masked while holding or feeding their infant;
• Cough or sneeze away from their infant while holding or feeding;
• Follow breast and skin cleansing hygiene before holding or feeding;
• Ensure pumps and bottles are cleaned according to the institution's Infection Protection and Control policies.
# Care and Testing of Babies in Neonatal Intensive
Care Unit (NICU) and Special Care Nursery (SCN) | None | None |
75b809bc82916c2337b27a64a6c46273367a029a | cma | None | Treatment complements this guideline. The guideline outlines evidence-based standards and regulatory expectations (i.e., what should be done), and the guide provides further details and clinical anecdotes to help readers operationalize the guidelines (i.e., how to do it).# Introduction
# Introduction
# Opioid use disorder and treatment
Opioid use disorder (OUD) is a chronic, relapsing condition that has significant personal, public health and economic consequences. Many of the fatal and non-fatal overdoses in Canada's epidemic over recent years have occurred in people with OUD. OUD may involve prescription medications (including medications that have been diverted from the medical system), or illicitly manufactured opioids, such as heroin or highly potent street fentanyl and fentanyl analogues.
People can achieve sustained long-term remission from OUD with effective treatment and follow-up. The first-line treatment for moderate to severe OUD is opioid agonist therapy (OAT), ideally combined with behavioural and social supports to optimize the determinants of health and address other psychosocial factors that influence substance use and quality of life. OAT can stabilize the cycle of intoxication and withdrawal, reduce opioid cravings and block the intoxicating effects of other shortacting opioids, including fentanyl. People who are maintained on OAT typically experience significantly improved health and social functioning and a considerable reduction in the risk of overdose and all-cause mortality. Some people do not meet criteria for OUD, yet inject or use illicit drugs that can lead to poisonings, overdose and death. This guideline is not applicable to the management of people in these situations, and recommendations for programs and services to address their needs are beyond the scope of this guideline.
# Introduction
# Background
Each provincial medical regulatory authority (MRA) has its own set of guidelines and standards for OAT. The aim of this unified guideline is to standardize expectations for Canadian prescribers, but not to replace any adopted guidelines; rather, this guideline was developed to complement existing initiatives and to support prescribers with best practices and evidence. It serves as a "guideline of guidelines" by synthesizing key recommendations for treating and managing OUD from existing standards, guidelines, expert opinions and best practices across Canada. The role of the MRAs in regulating the management of OUD varies across the country. Some MRAs write clinical guidelines, provide education and have quality assurance programs that ensure safe OAT prescribing, while in other jurisdictions some of these roles are performed by independent organizations. However, what the MRAs have in common is holding registrants accountable to standards of practice. Prescribers should contact their MRA for specific guidance on this guideline and to clarify regulatory expectations for managing OUD.
# Introduction
# Audience
The primary audience for this document is physicians who prescribe treatment for OUD. However, this guideline may be used by other health care professionals who are authorized to prescribe OAT.
# Scope and process
Establishing new evidence was beyond the scope of this project. Rather, the aim was for representatives from each of the participating MRAs and independent reviewers to reach consensus regarding recommendations from existing guidelines (see the "Key opioid use disorder treatment guidelines" section). Targeted searches of peer-reviewed and grey literature were conducted in the cases of guideline discrepancies or topics with varying degrees of evidence. This document is the outcome of that process: it is a product of synthesized guidelines blended with expert opinions and evidence-based literature.
The guideline was developed using an iterative process that involved three groups: a subject matter expert group, an MRA advisory committee and an external reviewer panel. Each MRA nominated two subject matter experts and one MRA representative. The subject matter experts reviewed existing guidelines and literature and helped to develop the recommendations in this document. The MRA representatives reviewed the recommendations to ensure that they conform to regulatory standards. An external panel of clinical experts who do not have clear ties to an MRA, as well as people with lived experience, then reviewed the recommendations. The subject matter expert group considered their feedback in finalizing the recommendations.
# Introduction | Treatment complements this guideline. The guideline outlines evidence-based standards and regulatory expectations (i.e., what should be done), and the guide provides further details and clinical anecdotes to help readers operationalize the guidelines (i.e., how to do it).# Introduction
# Introduction
# Opioid use disorder and treatment
Opioid use disorder (OUD) is a chronic, relapsing condition that has significant personal, public health and economic consequences. Many of the fatal and non-fatal overdoses in Canada's epidemic over recent years have occurred in people with OUD. OUD may involve prescription medications (including medications that have been diverted from the medical system), or illicitly manufactured opioids, such as heroin or highly potent street fentanyl and fentanyl analogues.
People can achieve sustained long-term remission from OUD with effective treatment and follow-up. The first-line treatment for moderate to severe OUD is opioid agonist therapy (OAT), ideally combined with behavioural and social supports to optimize the determinants of health and address other psychosocial factors that influence substance use and quality of life. OAT can stabilize the cycle of intoxication and withdrawal, reduce opioid cravings and block the intoxicating effects of other shortacting opioids, including fentanyl. People who are maintained on OAT typically experience significantly improved health and social functioning and a considerable reduction in the risk of overdose and all-cause mortality. Some people do not meet criteria for OUD, yet inject or use illicit drugs that can lead to poisonings, overdose and death. This guideline is not applicable to the management of people in these situations, and recommendations for programs and services to address their needs are beyond the scope of this guideline.
# Introduction
# Background
Each provincial medical regulatory authority (MRA) has its own set of guidelines and standards for OAT. The aim of this unified guideline is to standardize expectations for Canadian prescribers, but not to replace any adopted guidelines; rather, this guideline was developed to complement existing initiatives and to support prescribers with best practices and evidence. It serves as a "guideline of guidelines" by synthesizing key recommendations for treating and managing OUD from existing standards, guidelines, expert opinions and best practices across Canada. The role of the MRAs in regulating the management of OUD varies across the country. Some MRAs write clinical guidelines, provide education and have quality assurance programs that ensure safe OAT prescribing, while in other jurisdictions some of these roles are performed by independent organizations. However, what the MRAs have in common is holding registrants accountable to standards of practice. Prescribers should contact their MRA for specific guidance on this guideline and to clarify regulatory expectations for managing OUD.
# Introduction
# Audience
The primary audience for this document is physicians who prescribe treatment for OUD. However, this guideline may be used by other health care professionals who are authorized to prescribe OAT.
# Scope and process
Establishing new evidence was beyond the scope of this project. Rather, the aim was for representatives from each of the participating MRAs and independent reviewers to reach consensus regarding recommendations from existing guidelines (see the "Key opioid use disorder treatment guidelines" section). Targeted searches of peer-reviewed and grey literature were conducted in the cases of guideline discrepancies or topics with varying degrees of evidence. This document is the outcome of that process: it is a product of synthesized guidelines blended with expert opinions and evidence-based literature.
The guideline was developed using an iterative process that involved three groups: a subject matter expert group, an MRA advisory committee and an external reviewer panel. Each MRA nominated two subject matter experts and one MRA representative. The subject matter experts reviewed existing guidelines and literature and helped to develop the recommendations in this document. The MRA representatives reviewed the recommendations to ensure that they conform to regulatory standards. An external panel of clinical experts who do not have clear ties to an MRA, as well as people with lived experience, then reviewed the recommendations. The subject matter expert group considered their feedback in finalizing the recommendations.
# Introduction
# Acknowledgment of other guidelines
Although the process of developing this document involved reviewing and synthesizing recommendations from existing guidelines, two guidelines in particular were important in developing this document: the National Guideline Each perspective uses a chronological approach to presenting information and recommendations (i.e., the order in which the steps would likely occur in practice). Where recommendations are not suited to chronological order, they have been organized alphabetically.
# Introduction
# Key acronyms and terms
# Disclaimer
The developers of this guideline acknowledge that there are provincial and federal legislative and regulatory contexts within which regulated health care providers operate, as well as standards they are expected to meet. The treatment and management of OUD is complex and varies due to many factors (e.g., patient health and social history, prescriber setting, availability of resources), and, as such, prescribers may encounter circumstances where these suggested guidelines are not appropriate or do not apply. This is a dynamic field and prescribers are responsible for staying up to date with emerging evidence. This guideline is not intended to be a comprehensive treatment manual or to replace good clinical judgment.
# Introduction
# Acknowledgments
The inspiration for this document came from Wade Hillier in his role at the College of Physicians and Surgeons of Ontario (CPSO), with which the Centre for Addiction and Mental Health has an established history of collaborating to produce evidence-based publications about mental health and addiction.
In addition to acknowledging the people listed below for their involvement in this project, we also thank the people with lived experience of OUD who reviewed this guideline.
Part A: Preparing to provide opioid agonist therapy
# A1. Reducing harm
# Standards & frameworks for care
Patients with OUD have same-day access to harm reduction services. A comprehensive harm reduction approach includes: outreach services access to naloxone (naloxone kit) sterile drug consumption equipment supervised consumption services education on harm reduction practices infectious disease testing access to primary care vaccinations appropriate referrals to other health and social services.
# Clinical recommendations for prescribers
Routinely offer information and referral to take-home naloxone programs and other harm reduction services.
Provide sterile drug consumption equipment and take-home naloxone kits on-site when possible.
Offer vaccinations as appropriate.
Offer pre-and post-exposure prophylaxis for HIV as indicated.
# Offer contraception and sexually transmitted infection prevention interventions as appropriate.
Offer education and support regarding other relevant public health recommendations.
Consider emerging harm reduction strategies (e.g., "safer supply") on the basis of a thorough assessment of risks related to the patient's health and quality of life, and to public safety.
Safer supply should always be offered in conjunction with safety measures to mitigate risks.
Until stronger evidence is available, emerging approaches should not be viewed as a standard of care.
# A2. Engaging patients in treatment
Standards & frameworks for care Care and care environments are culturally safe and appropriate, and are trauma-informed.
Patients are given the option of engaging in interventions that align with their individual values and beliefs (e.g., based in community, land and culture).
Patients determine their treatment goals. These goals may or may not involve abstinence from substance use, and they may extend beyond substance use outcomes.
Care environments understand and reduce stigma; for example, by avoiding stigmatizing language such as "addict," "clean" and "dirty."
# Clinical recommendations for prescribers
Reduce barriers to accessing care by: offering initial assessment and initiating treatment with minimal to no wait time creating a safe and welcoming environment removing physical access obstructions for patients with mobility impairment avoiding fees for uninsured services.
Communicate evidence in ways that meet the patient's learning needs. Offer to include the patient's support network in discussions and decision making, and facilitate involvement when the patient agrees that it will be beneficial.
Empower the patient with information and support to make choices and partner fully in treatment.
Co-develop treatment approaches and plans that promote achievement of the patient's health and quality-of-life goals, and that ensure: confidentiality cultural safety and appropriateness developmental appropriateness goal-orientation with an understanding of patient priorities freedom from judgment person-centredness trauma-informed care adaptability for changes in the patient's goals and preferences.
Establish indicators for measuring progress toward the patient's goals and jointly establish a plan for revisiting the treatment approach based on the patient's experience and perspective, and on clinical observations.
# A3. Building relationships with patients and other health care and service providers
Standards & frameworks for care
Patients with OUD have comprehensive assessments and care plans that are developed in collaboration with and shared with other care providers (e.g., family physician, nurse practitioner, pharmacist).
Patients receive integrated, concurrent and culturally safe management of their: physical health mental health additional addiction treatment needs needs related to social determinants of health.
Ancillary service providers (e.g., public insurance plans, community housing resources, income support programs) recognize the adverse outcomes of untreated OUD and facilitate stable social environments and access to resources to promote retention in treatment.
# Clinical recommendations for prescribers
Identify patients at risk of OUD and ask about opioid use (prescribed, nonprescribed and illicit) and use of other prescribed and over-the-counter medications; assess further as appropriate.
# A4. Expectations for prescribers of opioid agonist therapy
Standards & frameworks for care
Prescribers stay current on literature, guidelines and best practices to provide a comprehensive range of accessible, evidence-based and trauma-informed treatments and care.
Prescribers seek professional development opportunities that focus on: inclusion, diversity and equity intergenerational trauma individual, family and community healing from trauma.
# Clinical recommendations for prescribers
Engage in continuing professional development to maintain and improve competence in assessing and treating substance use disorders and prescribing OAT.
Establish an ongoing direct relationship with a colleague or collegial group with experience and expertise in treating OUD.
Include multiple disciplines in the patient's team of care providers, depending on the needs identified in the treatment plan; for example: other physician specialists addiction counsellor social worker pharmacist care coordinator peer support worker.
Establish a contingency plan with the patient for continuity of care in the event of your absence or closure of practice that meets the reasonable expectations of the patient and the needs identified in the treatment plan. health hazards that increase the risk of severe adverse events (e.g., using alone, injection use, limited access to safer injecting practices, overdose history, illicit supply, limited access to emergency care) social hazards that increase the risk of severe adverse events (e.g., violent victimization, sex work, involvement in crime, social exclusion, safetysensitive work, risk of child apprehension) access to social supports, including income sources, drug coverage, health care coverage (awareness of coverage is especially important when considering newer buprenorphine products or slow-release oral morphine).
Communicate with the patient before initiating OAT:
Establish that the patient meets criteria for moderate to severe OUD, as outlined in the Diagnostic and Statistical Manual of Mental Disorders.
Ensure that there has been a documented discussion about the benefits, risks and side effects of OAT, and duration of treatment.
Educate the patient about safely storing and disposing of medication to prevent accidental poisoning by children, pets and the public.
Ensure that the patient understands what is expected of the care team, with emphasis on the patient's right to non-judgmental treatment and recourse if they experience stigma and discrimination.
Obtain full informed consent from the patient. Document treatment goals and plans in a signed treatment agreement to be shared with the dispensing pharmacy.
Conduct an abbreviated assessment to expedite initiation of OAT if scheduling a full assessment may delay treatment in a patient at risk of severe adverse outcomes of opioid use. A full assessment with treatment planning should follow within one to two weeks.
In patients who only meet criteria for mild OUD, weigh the risks of potentially long-term OAT against potential short-and long-term benefits. Such decisions should be made jointly with the patient, and documented. Collaborate with the pharmacist and use pharmaceutical information records regularly to monitor patients on medications known to prolong the QTc interval.
# A6. Effective use of ECGs
Review the potential risks and benefits with patients if the QTc interval is higher than 450 msec but less than 500 msec. Monitor more frequently with ECGs and consider dose reductions, with close monitoring for relapse.
Consider the risks and benefits of continued treatment at the current dose of methadone if the QTc interval exceeds 500 msec. Do the following if the QTc is elevated:
Review medication profile to check for other QT-prolonging medication. Discuss alternative agonist therapies (buprenorphine products, slow-release oral morphine).
Check and manage electrolyte abnormalities (including hypokalemia, hypomagnesemia, hypocalcemia).
# Consult a cardiologist.
Collaborate with other prescribers and pharmacists to mitigate arrhythmia risk in patients with concerning QTc intervals.
Recognize that the probability of mortality from non-retention on OAT in a patient who does not wish to change treatment options may exceed the mortality risk presented by an elevated QTc interval.
# A7. Effective use of urine drug testing
Standards & frameworks for care Urine drug testing (UDT) is not used punitively; rather, it is used as one tool in a comprehensive risk assessment to provide information about exposures and risks, promote patient safety, guide care decisions such as adequacy of dose, and monitor progress toward treatment goals. Overuse of UDT may exacerbate stigma and increase service costs.
How UDT can be applied to assessment depends on:
context (e.g., unpredictability of illicit drug market, difficulty in providing a substance use history)
risks (e.g., engagement in safety-sensitive tasks, challenges with multiple CNS depressants) goals (e.g., engagement in positive reinforcement / contingency management programs, goal of abstinence for which UDT results motivate progress).
# Clinical recommendations for prescribers
Conduct UDT when there is a clear plan for how results will benefit the patient and in ways that help to characterize risks and rationalize interventions, at times such as:
when initiating OAT when adjusting doses during stabilization when there is concern about a patient's presentation when the patient requests UDT.
Be mindful that the purpose of UDT is not to "catch a patient lying," but to provide information to help assess and manage risks and guide treatment decisions between clinician and patient.
Assess substance use weekly while stabilizing the patient on OAT; this may involve UDT if clinical assessment, including history, requires supplementary lab investigations.
Conduct UDT every one to three months in a patient with stable OUD on OAT. If unscheduled UDT would impose a net quality-of-life disadvantage (e.g., by interfering with employment or beneficial social engagement), consider scheduled UDT or combining UDT with physician/counselling appointments.
Occasional unscheduled UDT may be helpful to identify medication non-adherence or concomitant use of substances with short elimination half-lives that may not be detected in scheduled testing.
Use clinical judgment and consider the usefulness of history/observation in assessing progress, as well as patient preferences and individual circumstances, when determining the frequency of UDT.
Counsel patients who do not attend UDT within 24 to 48 hours of a request for specimen collection about the value of UDT to the treatment plan, and take measures to facilitate testing if there are barriers.
# Clinical recommendations for prescribers
Avoid taking a punitive approach if a patient provides a tampered specimen.
Seek to understand the patient's concerns about UDT, and explore ways to help them feel comfortable discussing substance use and to make UDT useful to both patient and clinician.
If UDT is used in the context of a contingency management strategy, emphasize positive reinforcement, such as enhancing flexibility in treatment, to help the patient achieve abstinence or quality-of-life goals.
Conduct UDT to help you assess the appropriateness of take-home doses. If test results are consistent with self-report and you determine that the benefits to quality of life and social engagement outweigh the risks of diversion or overdose, consider take-home doses.
Reduce take-home doses if the overall assessment indicates that the risk to the patient or community is greater than any benefit of take-home doses.
Couple this approach with compassionate motivational counselling.
Document UDT results, taking into account the test's relevance and importance to assessment and treatment monitoring, and indicating clinical actions that arise from results in combination with other clinical observations.
Recognize that both laboratory testing and point-of-care immunoassays are useful clinical tools for monitoring OAT safety and effectiveness. The UDT modality used should be justified based on: clinical indication (e.g., urgency of clinical decision making around prescribing safety or immediate safety of take-home dosing) legal indications (monitoring for workplaces or child custody) availability of resources, especially in regions where laboratory access and capacities are limited cost.
Ideally, request that urine specimens are tested using mass spectrometry or chromatography assays by a qualified laboratory because point-of-care testing has limitations due to high risk of error and false negatives. If pointof-care immunoassays are used:
Use only tests approved by Health Canada, and always according to the product monograph.
Understand the sensitivity, specificity, positive and negative predictive values and limitations of the test (e.g., opioid results may be negative when fentanyl has been ingested; cannabinoid results may be negative when synthetic cannabinoids have been used).
Use laboratory testing with mass spectrometry and liquid chromatography to detect the following substances: specific synthetic and semisynthetic opioids (oxycodone, hydromorphone, heroin, fentanyl, newer fentanyl analogues) (some point-of-care tests can now detect fentanyl) types of sedative hypnotics (designer benzodiazepines such as etimazole) synthetic cannabinoids (e.g., Spice).
# Clinical recommendations for prescribers
Consider using laboratory testing with mass spectrometry and liquid chromatography to confirm unexpected test results of immunoassays. For example, some medications and substances can cause false-positive immunoassay results (e.g., quinolones, rifampin, imipramine, dextromethorphan).
Recognize that different screening tests may be required to detect alcohol use. Point-of-care breathylzers can guide safe OAT dose administration in patients who may have been drinking very recently. To detect alcohol use for monitoring purposes, specific tests may be ordered (e.g., ethyl glucuronide, ethyl sulfate, carbohydrate deficient transferrin).
Recognize that UDT results are intended for therapeutic use only and should not be shared with other agencies for non-medical reasons, such as providing evidence for legal purposes (e.g., child-family services, prosecutors).
An appropriate response to an agency could be to write an advocacy letter on behalf of the patient. This letter can describe the patient's clinical stability and make a general statement about the patient's participation in regular UDT for therapeutic purposes.
Patients who request that their UDT results be shared with outside agencies should be advised about the possible unintended consequences of sharing this information.
# A8. Providing prescriptions for opioid agonist therapy
Standards & frameworks for care A secure and accessible modality, in accordance with federal and provincial regulations, is used to ensure the transmission of the correct prescription to the correct pharmacy in a safe and timely manner.
Prescribers avoid financial conflicts of interest when choosing medications, pharmacies and dispensing schedules.
# Clinical recommendations for prescribers
Communicate with the pharmacist before initiating a prescription:
Assess whether the pharmacy is the most appropriate option for the patient, considering various factors and based on availability in the region (e.g., open daily, accepting new patients, geographically accessible, experienced in OUD treatment, able to provide harm reduction resources).
Discuss the patient's current health status and treatment plan. Agree on suitable ways to share information about the patient's progress (including management of lost or missed doses).
Establish processes for urgent communication (e.g., on-call system, afterhours contacts).
Be aware of current or potential medication shortages and work with the pharmacist to mitigate any risks or impact for the patient.
# Clinical recommendations for prescribers
Write prescriptions that are tamper-proof and that indicate the following: date when the prescription was written drug name and dose (mg dose in both words and numbers, as well as total milligram amount in words and numbers, is required by some medical regulatory authorities) start and end date stated as inclusive dosing regimen, including observed and take-home dose days induction dosing schedule with clear instructions special instructions and extraordinary situations.
Before issuing a new prescription (e.g., when changing doses), verify that the patient is able to obtain the new prescription; then cancel any active and outstanding prescriptions to prevent medical/pharmacy error.
Recognize that printed prescriptions have inherent risk and that e-prescribing can reduce lost prescriptions, duplication and diversion. E-prescribing also facilitates communication between prescriber and pharmacist about medication adherence. Understand, however, that e-prescribing can also carry risks (e.g., technology-related issues, including network security issues; reduced patient engagement), and take steps to mitigate them.
Part B: Providing different forms of opioid agonist therapy
# B1. Choosing a pharmacological treatment
Standards & frameworks for care
A prior trial of non-pharmacotherapy or abstinence-based approaches is not a prerequisite for choosing OAT.
Buprenorphine/naloxone (bup/nlx) is rapidly available as the first-line treatment for patients with OUD.
It is recognized that for many patients any OAT carries a substantially lower risk of adverse events than no OAT.
Evidence-based OAT options are exhausted before other options are explored. Alternative pharmacological treatments are approached with caution, and the rationale, including risk-mitigation strategies, is thoroughly documented (e.g., observed dosing, safe storage, overdose prevention).
# Clinical recommendations for prescribers
Avoid withdrawal management as a stand-alone treatment for OUD because this option is not effective or safe.
Ensure before initiating OAT that there has been a documented discussion with the patient about potential issues, side effects, risks, duration of treatment, and difficulty withdrawing and tapering.
Consider treatment intensity when determining the most appropriate OAT option. Adjust the intensity to accommodate the changing circumstances and preferences of the patient.
Initiate OAT with bup/nlx whenever it is assessed to carry a lower risk than other agonist therapies because of its pharmacologic characteristics and the advantages of more flexible take-home dosing.
Consider long-acting preparations of buprenorphine (monthly injections or six-month subdermal implants) when appropriate to facilitate reintegration into society and reduce health care burden.
Initiate OAT with methadone when treatment with bup/nlx is not preferable (e.g., intolerance, patient preference, challenging induction, inadequate response to bup/nlx).
# Part B
# Clinical recommendations for prescribers
Recognize that some patients who show a successful and sustained response to methadone may wish to transition to bup/nlx. This is an option for patients who:
request more treatment flexibility with increased take-home doses are seeing a better side-effect and drug-interaction profile wish to withdraw from OAT but have difficulty tapering off methadone and might better tolerate a taper from bup/nlx.
The decision to transition to bup/nlx must be balanced with potential risks of destabilization, which may increase when transitioning from higher methadone doses. Options to mitigate risk include slowly reducing methadone before making the transition, microdosing bup/nlx or switching to slow-release oral morphine (SROM) for five days after stopping methadone and before initiating bup/nlx.
Consider SROM only when bup/nlx and methadone are ineffective, contraindicated or refused.
If considering SROM in exceptional cases where bup/nlx and methadone have not been tried, conduct a thorough risk assessment and, taking into consideration your experience and the complexity of the case, consult at least one colleague with extensive experience in treating severe OUD.
Conduct a thorough risk assessment if considering SROM in adolescents and older adults because there is little evidence for using SROM in people with a relatively short duration of OUD and because older adults may be susceptible to adverse events due to complicating medical conditions or drug interactions. Also consult a pharmacist when needed.
Ì The assessment should cover exposure and susceptibility factors that may increase risk of severe adverse events, as well as risks to patient health and safety if not retained on agonist therapy.
Recognize that in patients and communities with high rates of illicit fentanyl use, emerging practices include combining methadone and SROM to allow for adequate dosing to meet high levels of tolerance. Some guidance is emerging based on clinical experience, but no clinical trials have been published to date to inform definitive practice guidelines.
# Induction phase
Prescribe 2−4 mg of bup/nlx as an initial supervised dose when the patient is in moderate to severe withdrawal (COWS ≥ 13). Up to 6 mg is acceptable in clinically required situations, but may increase the risk of precipitating withdrawal.
Reassess the patient after one to three hours and prescribe additional observed doses if necessary (e.g., COWS > 8, symptoms of withdrawal).
Be careful not to precipitate withdrawal by giving too high a dose or by medicating in the absence of observable withdrawal.
One or two 2 mg tablets to take home may be provided if repeated observation is not feasible in the clinical setting, with clear instructions on timing the dose to avoid precipitating withdrawal.
Avoid prescribing more than 12 mg total on the first day.
Consider alternative induction approaches such as:
"microdosing," starting with 0.5 mg twice per day, with increasing doses to a total daily dosage of 12 mg over 5-7 days for patients who cannot tolerate the significant period of abstinence needed to start bup/nlx with a conventional induction "rapid microdosing," administering 0.5-1 mg at shorter intervals, up to 12 mg total in a 24-hour period.
# Titration and stabilization phase
Titrate based on withdrawal symptoms and side effects until an optimal dose has been reached, typically on day 3. Doses may be doubled every day, up to a maximum of 24 mg on day 3.
Consider an alternative approach: add up the dose given on day 1 and administer it as the first dose of day 2, followed by additional doses based on the re-emergence of withdrawal symptoms. On day 3, add up the doses administered on day 2 and provide additional doses as necessary. Repeat daily until the patient is stable (no withdrawal, or COWS scores < 8 for 24 hours) or until a maximum of 24 mg per day is achieved.
Use slow titration with older adults, patients taking other CNS depressants and patients with questionable opioid tolerance, balancing the risk of lower treatment retention with the risk of over-sedation:
Increase bup/nlx by 2−6 mg per day until an optimal dose has been reached
(24 hours of no withdrawal symptoms, extinction of cravings to use opioids, absence of toxicity).
# Clinical recommendations for prescribers
Arrange for the patient to be seen by a member of the health care team to assess effectiveness and safety (e.g., excess sedation). Base reassessment frequency on the intensity of induction.
# Maintenance phase
Use clinical judgment to maintain an optimal individualized daily dose, which is up to a maximum of 24 mg per day.
If exceeding 24 mg in exceptional circumstances, inform the patient that this is a departure from approved doses and that there is limited evidence of a benefit with doses higher than 24 mg (and possibly an increased risk of adverse events).
Review the case with an experienced colleague before trialing a dose higher than 24 mg per day and attempt to reduce the dose to approved levels (as tolerated) once the OUD has stabilized.
Recognize alternate-day dosing as an option for patients who are clinically stable at doses less than or equal to 12 mg per day (i.e., 24 mg every other day) and who require less frequent visits to the pharmacy for dosing.
This practice should be balanced with the challenges in managing missed doses, and the patient should be assessed for toxicity/sedation when given this higher dose. Timely communication with the pharmacist is critical.
If the main reason for considering alternate-day dosing is to facilitate fewer pharmacy visits, assess whether take-home doses or switching to an extended-release formulation are a superior approach with your patient.
Discuss the option of switching to buprenorphine extended-release monthly injection or the six-month subdermal buprenorphine implant to enhance medication adherence and convenience for patients who are clinically stable.
Recognize that there is not yet evidence about the long-term safety and effectiveness of depot or implant buprenorphine therapy, and counsel the patient accordingly.
Consider subcutaneous injection if the patient has been stabilized on 8-24 mg sublingual bup/nlx daily for at least seven days. The injection does not require abstinence from other opioids before initiation, but it is preferable.
Consider the subdermal implant if the patient has been stabilized on 8 mg or less of sublingual bup/nlx daily. The implant requires a period of abstinence from opioids before initiation.
Discuss switching to buprenorphine injection or implant if the patient also:
requires less frequent medication administration is comfortable with an invasive procedure or device does not want to administer medications sublingually has drug coverage if the medication is not covered by public health insurance.
Review current evidence for buprenorphine extended-release injection and the six-month buprenorphine implant before discussing them with patients so that you can provide adequate counsel in obtaining informed consent for these newer options.
# Clinical recommendations for prescribers
# UDT and take-home doses
Conduct UDT at least monthly during induction and dose escalation until the patient has reached a stable dose. UDT is useful to characterize risk and give the patient and the prescriber information about other hazard exposures, including interacting substances such as benzodiazepine receptor agonists (BZRAs) and other opioids. It is also useful in the context of take-home dosing.
# Missed doses 1
For missed doses with no relapse to full opioid agonist use: 2 alternate-day doses: suspend bup/nlx until the patient can be reassessed.
≤
Then return the patient to a daily dose schedule, possibly at a lowered dose, to restabilize them before resuming an alternate-day schedule.
For missed doses due to relapse or return to full agonist opioid use: advise the patient to stop using bup/nlx until they are ready to resume OAT. Schedule a new induction date and proceed as described in the "Induction phase" section above.
# B3. Prescribing methadone
# Standards & frameworks for care
Methadone is prescribed in a way that balances the risk of adverse effects to the patient and people in their environment while optimizing the benefits, including retention in treatment and decreased health and quality-of-life harms related to substance use.
# Clinical recommendations for prescribers
# Induction phase (usually first two weeks)
Prescribe an initial dose of 10 mg or less; then increase doses by no more than 5 mg every five days (as necessary) for patients who:
are recently abstinent or use intermittently have unknown tolerance to opioids due to unclear history or lack of collateral information use low-potency opioids (e.g., codeine).
# Part B
# Clinical recommendations for prescribers
Prescribe an initial dose of 5−20 mg; then increase doses by 5−10 mg every three to five days (as necessary) for patients who: Prescribe an initial dose of 5−30 mg; then increase doses by 5−15 mg every three to five days (as necessary) for patients who both:
have high tolerance of high-potency opioids from daily use and have UDT confirmation of recent opioid use do not have risk factors for excessive CNS depression (as listed above).
Consider using a limited duration of SROM for outpatients and immediaterelease oral morphine for inpatients to manage emergent withdrawal while titrating methadone dosing to reach a clinically therapeutic outcome (24 hours without any withdrawal or need for supplemental morphine).
Exercise extreme caution if you are considering rapid and high dose titration (increasing the methadone dose by more than 10 mg at a time in a period under five days).
Consult with a colleague who has experience with rapid and high dose titration.
Conduct a risk-benefit assessment for patients with high tolerance of highpotency opioids for whom slower titration could jeopardize retention in treatment.
Monitor the patient closely, with direct assessment before each dose increase and assurance that the patient has a reliable and involved third party available for frequent contact and check-ins for early detection of methadone toxicity.
Reassess patients frequently during the first two weeks of treatment because they are at the highest risk of fatal overdose during this period. Discuss this risk and strategies to reduce it (e.g., use only small amounts of additional opioids; do not use alone; have a naloxone kit available). Document these discussions and reassess the patient with every subsequent dose increase.
# Titration and stabilization phase
Increase the dose by 5−10 mg every five to seven days to manage withdrawal symptoms and cravings.
# Clinical recommendations for prescribers
# Maintenance phase
Use clinical judgment to determine an appropriate maintenance dose, with treatment objectives generally being to provide 24 hours without opioid withdrawal and to reduce opioid cravings while not causing sedation or toxicity.
Consider tapering down the dose for patients experiencing opioid-induced side effects (e.g., sweating, hypogonadism, severe constipation, adrenal insufficiency) and collaborate with the patient to balance the benefits, disadvantages and risks of methadone treatment.
If rapid metabolism is suspected, confirm with serum methadone levels (with peak/trough ratios > 2:1, wherever possible and available). If not possible, schedule an observation at a time when the emergence of withdrawal can be witnessed after an observed dose.
Adjust treatment accordingly (e.g., split dosing). Split dosing often requires providing evening doses as take-home doses because few patients will be able to attend a pharmacy twice daily for witnessed dosing. Consider clinical stability before offering split dosing, and consult with experienced colleagues on such challenging cases. There is no consensus on the best way to assess the need for split dosing.
Assess for post-dose sedation at peak serum levels for patients on high doses of methadone by arranging a witnessed dose in the pharmacy, with a followup in the clinic two to four hours later.
# UDT and take-home doses
Conduct UDT monthly during induction and dose escalation until the patient has reached a stable dose. Conduct UDT more frequently to confirm abstinence from illicit opioid use and absence of interacting substances such as BZRAs, or in the context of take-home dosing. During stabilization, both scheduled and unscheduled UDT should be used, as appropriate.
# Missed doses
1 or 2 doses: do not reduce the dose unless there are concerns about loss of tolerance or adverse events 3 doses: decrease the dose by 50 per cent 4+ doses: decrease the dose to 30 mg or less.
Re-establish a stable methadone dose in cases of several missed doses, as appropriate. This may not be the same as the previous dose.
Offer one replacement dose of methadone (no more than 50 per cent of the regular dose) if the patient has emesis that was witnessed by a health care provider and that occurred within 15 minutes of an observed dose.
Where emesis can occur due to pregnancy, consider spreading the dosing over 30 minutes. In addition, if emesis is emerging as a recurrent reason for dose replacement, observation for 15 to 20 minutes after dosing may be warranted.
# B4. Prescribing slow-release oral morphine 2
Standards & frameworks for care Slow-release oral morphine (SROM) is available for patients for whom bup/nlx and methadone have been ineffective or are contraindicated or refused.
# Clinical recommendations for prescribers
Consider switching to SROM if the patient:
is an adult with severe OUD has not responded to bup/nlx or methadone, has contraindications to their use or has refused bup/nlx and methadone.
Consult with a specialist if you lack experience in prescribing SROM before initiating treatment. SROM treatment requires diligent measures to avoid overdose and diversion.
Review risks and benefits with the patient, obtain fully informed written consent and ensure rigorous clinical documentation when prescribing SROM.
Understand that evidence supporting the safety and efficacy of SROM in pregnancy is limited. However, this option can be considered at the discretion of the prescriber, weighing the risks and benefits and ensuring discussion of this use with the patient during the consent process.
Prescribe SROM as once-daily witnessed doses (24-hour formulation) to prevent misuse and minimize diversion risk. Exceptions may be considered if the patient shows exceptional and sustained improvements in clinical and social stability.
Review instructions for witnessed ingestion with the dispensing pharmacy because crushing, chewing or dissolving SROM pellets can cause a fatal overdose. Capsules should be opened by the pharmacist and the pellets given to the patient to swallow with water.
# Induction and titration phase
Start with a one-week titration phase aimed at achieving a stable daily dosage.
Separate dosage increases by 48 hours because of the slow-release properties of SROM.
# Part B
# Clinical recommendations for prescribers
For patients using opioids other than methadone (e.g., heroin), prescribe 30-60 mg on the first day and titrate upward according to withdrawal symptoms. Note that in some patients and communities with high rates of illicit fentanyl use, higher doses such as 100-200 mg may be needed to retain the patient in care and mitigate withdrawal.
For patients who are switching from methadone to SROM, prescribe a methadone-to-SROM dose ratio of 1:4 on the first day (e.g., 60 mg methadone = 240 mg SROM) and titrate upward based on withdrawal symptoms and cravings. The ultimate stabilization dose ranges from 1:6 to 1:8.
Use clinical judgment to determine each dose increase. Consider the type of opioid the patient is using, their level of tolerance to opioids and the risk of overdose and diversion versus the risk of lower treatment retention. This clinical judgment is necessary given the current lack of published evidence for optimal SROM dosing.
Some guidelines recommend titrating upward by 30-60 mg every 48 hours;
however, the actual dose should be based on clinical response, type of ongoing opioid use and risk of leaving treatment.
The average total daily SROM dose range is 200-800 mg per day. The full range reported in the literature is 60-1200 mg per day.
# Stabilization phase
Stabilize the once-daily dose at the lowest dose needed to relieve withdrawal symptoms and suppress illicit opioid use. Currently, there is no literature to guide treatment decisions beyond the 36-week duration of clinical trials. In the absence of established guidelines, follow similar stabilization and tapering practices as are used for bup/nlx and methadone.
# UDT and take-home doses
Note that point-of-care UDT may not rule out use of illicit heroin or some prescription drugs (e.g., morphine, codeine) in patients on SROM. Consult with testing laboratories about using mass spectrometry UDT.
Prescribe take-home doses only in exceptional circumstances, where patients show high clinical stability, or when daily witnessed dosing is a barrier to treatment. Consider graduated take-home dosing on a case-by-case basis, using clinical judgment, appropriate monitoring and follow-up to prevent misuse or diversion. Before prescribing, conduct a comprehensive risk assessment and consult a specialist.
Conduct UDT monthly, or more frequently when prescribing take-home dosing.
# Clinical recommendations for prescribers
# Missed doses 3
Work closely with pharmacists to mitigate the risk of over-sedation or overdose caused by rapid loss of tolerance that can result from missed doses of SROM.
Use clinical judgment and consider total daily dose and number of missed doses in determining adjustments after missed doses. Various approaches are available; for example:
Missed
# B5. Prescribing injectable opioid agonist therapy 4
Standards & frameworks for care Supervised injectable OAT (iOAT), using diacetylmorphine or hydromorphone, is available for patients who continue to inject opioids despite adequate trials of methadone and buprenorphine.
Embedded wrap-around care is the preferred model for delivering iOAT. Treatment is integrated with services at community health centres, harm reduction programs and supportive housing programs to reduce barriers to treatment and address a range of health and social needs.
# Medication selection and administration
Provide iOAT as an open-ended treatment, balancing the benefits and risks, with decisions made in collaboration with the patient. If the patient is currently receiving oral OAT, consult with the oral OAT prescriber as part of the assessment process.
Choose between hydromorphone and diacetylmorphine based on availability, patient preference and clinical judgment. Consulting a pharmacist will alert you to prescribing or availability restrictions (security, disposal, preparation, inventory management, documentation requirements).
Supervise self-administered injection, which should involve a pre-injection assessment, direct observation of the injection and disposal of equipment, and a post-injection assessment.
# Induction and titration phase
Start iOAT with three doses per day, in general. Adjust the initial dose over a two-to five-day titration period following this protocol:
For hydromorphone, it is recommended that each dose be increased by 10 mg, to a maximum increase of 30 mg per day.
For diacetylmorphine, it is recommended that each dose be increased by 20 mg, to a maximum increase of 60 mg per day.
# Clinical recommendations for prescribers
Lower the dose or follow a more gradual titration based on the patient's response and safety concerns. Doses can be increased, as long as they are well tolerated, until they reach clinical effect (no use or reduced use of illicit opioids, no cravings) or the patient reaches the following recommended dose maximums:
hydromorphone: 500 mg per day (maximum 200 mg per dose) diacetylmorphine: 1000 mg per day (maximum 400 mg per dose).
Recognize that these titration protocols and doses may not be enough to ease withdrawal symptoms and cravings in patients with very high opioid tolerance due to fentanyl. (See Appendix 7 in the CRISM iOAT clinical guideline for classic and alternative titration protocols.)
# Stabilization and maintenance phase
Consider co-prescription of methadone or SROM to prevent withdrawal and cravings between iOAT doses (i.e., overnight).
Provide comprehensive and continuing care that involves ongoing review and assessment of dosage, side effects, drug interactions, patient goals, physical and mental health and psychosocial functioning.
Recognize that ongoing substance use while on iOAT may be an indication to intensify treatment, which may include increasing the dose of the sustainedrelease OAT, implementing a more intensive model of care or increasing psychosocial and other supports.
# UDT and take-home doses
Recognize that regular and random UDT, which is considered standard care for oral OAT, is not standard care for iOAT because the risk of diversion is low and the patient has frequent contact with care providers. However, UDT can be used as a starting point for discussing harm reduction and safety.
Avoid take-home dosing for iOAT. Supervised administration ensures patient safety before and after treatment is administered and increases public safety by preventing diversion.
# Missed doses
Be vigilant in supervising missed doses due to the short-acting nature of iOAT medications.
If a new, not-yet stabilized patient misses three consecutive doses or one day (whichever is first), restart the titration process, following the titration protocol in Appendix 7 of the CRISM iOAT clinical guideline.
If a stabilized patient misses six consecutive doses or two days (whichever is first), you may be able to provide their usual dose or a reduced dose. See Appendix 8 of the CRISM iOAT clinical guideline for an example of a dose reduction protocol.
If a stabilized patient misses nine consecutive doses or three days (whichever is first), re-titrate entirely, following the titration protocol in Appendix 7 of the CRISM iOAT clinical guideline.
# B6. Prescribing take-home doses
Standards & frameworks for care
Clinical risk assessment and management are used to support patient autonomy and social engagement while respecting patient and public safety.
# Clinical recommendations for prescribers
Support flexibility in treatment with take-home doses unless you estimate that the benefits are exceeded by the risk of:
toxicity from dosing errors harm to susceptible individuals in the patient's environment from exposure to the patient's agonist therapy therapy becoming ineffective due to medication non-adherence victimization of the patient by others in their environment.
These risk estimations should take into account the possibility of: substance interactions (prescribed; non-prescribed; over-the-counter; illicit; licit, including alcohol) un/intentional diversion and possible exposure to susceptible individuals precarious social situations.
Consider that given the inherent safety of bup/nlx over methadone, the schedule for take-home doses can be faster and based on clinical judgment.
Consider prescribing take-home doses of methadone after two consecutive months of clinical stability (usually including reassuring UDT results).
Implement a graduated take-home dosing schedule, rather than providing all doses at once. Prescribe one additional take-home dose every one to four weeks (if necessary), to a maximum of six methadone or 13 bup/nlx takehome doses at a time.
Exceptions to these limits may be considered if a thorough assessment determines that they will promote treatment goals (e.g., productivity, involvement in recovery work) without risking patient and public safety.
Prescribe such that the patient receives a witnessed administration of agonist therapy by pharmacy staff each time they pick up take-home doses.
Transition from frequent to less frequent UDT (e.g., weekly to monthly) as the treatment dose is stabilized, a trusting relationship is established and goals relating to health and quality of life are consolidated. This practice facilitates the patient's engagement in important aspects of their life while providing information about treatment progress, medication adherence and safety.
Facilitate guest dosing (i.e., arranging for the patient to temporarily receive their dose from a different pharmacy) in patients for whom take-home dosing may not support treatment safety and effectiveness, or who are unable to attend their regular pharmacy for an extended time. Collaborate with local pharmacies when necessary (e.g., if the patient is going out of town for a long period).
Reduce or discontinue take-home doses if the patient experiences changes in clinical or social stability that increase the risk of adverse outcomes related to treatment safety and effectiveness.
Part C: Providing opioid agonist therapy in specific settings and populations
# C1. Rural and remote settings
Standards & frameworks for care
All patients with OUD have access to OAT, meeting jurisdictional standards within 48 hours in their communities.
Lack of psychosocial services is not a barrier to initiating and continuing OAT.
# Clinical recommendations for prescribers
Collaborate with available services to prescribe OAT in a safe and accessible way for the patient, regardless of geographical location.
Be prepared to initiate OAT using novel approaches such as telemedicine in partnership with local resources (e.g., nurse practitioners).
Recognize bup/nlx as the best option for improving treatment retention and outcomes in areas where access to care is limited and daily witnessed ingestion of methadone at a pharmacy is not practical.
Consider monthly injections of buprenorphine to reduce barriers to care and increase retention in treatment.
# C2. Virtual care (telemedicine)
Standards & frameworks for care
All patients with OUD have timely access to OAT in their communities and do not face barriers related to health systems infrastructure (e.g., lack of access due to geography, physical disabilities).
# Clinical recommendations for prescribers
Make arrangements when providing access to OAT using remote health care technology to ensure: continuity of agonist therapy without interruption due to pharmaceutical supply, pharmacy closures or public health emergencies ability of local health care providers to assess and manage emergencies (e.g., medication toxicity) availability of ancillary non-pharmacological addiction treatment and recovery services support of a local clinical resource (e.g., nurse practitioner, pharmacist) who can collaborate on providing OAT and ongoing assessment and assistance.
Ensure that a focused physical assessment is completed early in treatment to identify conditions that can complicate substance use or that can affect OAT outcomes.
# C3. Pregnant and postpartum women
Standards & frameworks for care
All pregnant or postpartum women with OUD are offered OAT on an urgent basis.
# Clinical recommendations for prescribers
Understand your child-safety obligations and obligations to maintain confidentiality of patient health information, except in rare cases.
Be familiar with local child-family services and develop working relationships with them if possible to encourage interventions that optimize supports for patients to keep their children, in most cases (for patients who choose to do so).
Consider your familiarity and relationship with local child-family services in deciding whether to encourage patients to disclose their pregnancy. Some services may intervene in ways that are not beneficial to patients or their children, but programs do exist that prepare patients for parenting and help them to navigate prenatal care and benefits.
Recommend against undergoing opioid withdrawal during pregnancy.
Determine which type of OAT to use by considering the patient's circumstances, as well as treatment access and availability.
Offer methadone or bup/nlx as first-line options for OAT during pregnancy.
Recognize that unless it is clinically indicated or requested by the patient:
transitioning between methadone and bup/nlx during pregnancy and postpartum is not recommended for patients who were stable on one of these medications before becoming pregnant transitioning pregnant patients from bup/nlx to buprenorphine monotherapy is not necessary.
Manage opioid withdrawal symptoms by increasing the dose of bup/nlx or methadone and/or administering in divided doses until the postpartum period.
Consider split doses of methadone and buprenorphine, especially in later pregnancy, due to enzyme induction, reduced elimination half-life and increased volume of distribution. Dose increases may be avoided by dividing doses (i.e., two, three or four times daily).
Consider take-home doses of methadone for split dosing even in pregnant patients who may not otherwise be offered them if improved neonatal outcomes and reduced illicit substance during pregnancy justify the potential risks of take-home dosing.
Ensure adequate analgesia (opioid and maximized non-opioid pharmacotherapies) during delivery, in addition to any OAT prescribed for baseline needs.
Monitor patients closely postpartum for the need to reduce the methadone dose.
# Part C
# Clinical recommendations for prescribers
Encourage breastfeeding in general for women on OAT, unless there is a contraindication. Support women in considering all relevant medical and social factors when weighing the benefits and potential harms of breastfeeding. Patients who are breastfeeding and have a lapse to substance use on rare occasions should be advised to discard breast milk for 24 hours and then resume breastfeeding.
Be familiar with the excretion of various substances in breast milk. The amount excreted is insufficient to treat neonatal withdrawal.
Encourage rooming-in as the standard of care for opioid-exposed infants.
Assess and treat neonatal opioid withdrawal symptoms in rooming-in settings, which provide an environment that promotes maternal-neonate attachment.
# C4. Patients who are hospitalized
Standards & frameworks for care
Patients are never subjected to unnecessary withdrawal or forced detoxification. OAT is always maintained during hospital admission to prevent loss of tolerance and unnecessary withdrawal unless there is a contraindication.
Hospital-based prescribers prioritize early identification and intervention in patients with high-risk substance use, including those who meet criteria for OUD. Patients are offered treatment and recovery options across the care continuum, including harm reduction resources and immediate initiation of OAT.
Hospital-based prescribers recognize the need to treat withdrawal if OAT is not immediately available to or accepted by the patient. Symptomatic treatment, which may include bup/nlx, non-opioids and short-acting opioids such as morphine sulphate, is offered to ease withdrawal while assessments and long-term treatment are being determined.
Patients receive care in a non-judgmental environment that supports safety and treatment adherence, and that recognizes that some patients may continue to use substances while hospitalized.
# Clinical recommendations for prescribers
Note: These recommendations are for prescribers working in a hospital setting.
Order an ECG if clinically indicated (e.g., the patient is on more than 120 mg of methadone or has risk factors for prolonged QTc).
Communicate with the patient's community pharmacy to:
verify the patient's current dose and the date it was last observed determine whether the patient is receiving take-home doses and when they were last dispensed discuss the pharmacist's assessment of the patient's stability cancel any outstanding prescriptions for OAT to minimize risk of double dosing during hospitalization or upon discharge.
# Clinical recommendations for prescribers
Notify the patient's regular OAT prescriber on admission and collaborate to: cancel any outstanding prescriptions for OAT ensure that changes in therapy are documented to reduce risk discuss dosage increases and decreases before implementing them, when possible (consult another OAT prescriber if communicating with the regular prescriber is not possible).
Monitor for the emergence of confounding factors during the patient's hospital stay (e.g., drug interactions, drug-disease interactions) and adjust the OAT dose accordingly. Consider split dosing if there is neurological, respiratory or hepatic compromise.
Collaborate with the patient, prescribers, pharmacy team and support network to ensure access to a range of care options that build on the treatment experience and that address key social determinants of health that support ongoing engagement in OAT.
Facilitate seamless and safe transfer of care to the regular prescriber and community pharmacy upon discharge. In some jurisdictions, hospital-based clinicians who do not have OAT prescribing approvals cannot write the discharge prescription, so early coordination with community prescribers or an addiction consultation team is important, especially if discharge is premature or unexpected.
Initiate OAT in hospital whenever possible for patients who are diagnosed with OUD after admission. Collaboration with the care team that will continue the patient's OAT in the community is critical to a successful transfer of care.
# C5. Patients who are incarcerated
Standards & frameworks for care
Patients are never subjected to forced detoxification. OAT is always maintained during incarceration to prevent loss of tolerance and unnecessary withdrawal.
Care standards in correctional settings meet those of treatment standards in the community.
The trusting therapeutic relationship between OAT prescriber and patient remains the focus of treatment, despite challenges associated with providing care in a correctional setting.
Community resources (e.g., OAT programs, experienced colleagues) are readily available for prescribers who work in correctional facilities.
Harm reduction resources and services are provided in correctional settings for patients who use substances, and OAT is offered to patients with OUD who are using those resources if they meet criteria for this treatment.
# Clinical recommendations for prescribers
The patient's regular OAT prescriber should do the following, when requested by the correctional facility: Provide all information necessary for safe and effective OAT.
Collaborate with the prescriber working in the correctional facility and with the community pharmacist, if applicable, to ensure continuity of care before (and at the time of) release.
The prescriber working in a correctional facility should do the following:
Contact the patient's community pharmacy to determine the patient's current dose and date of last dose.
Make every effort to provide continuity of care with the patient's regular OAT prescriber.
Make every attempt to educate the patient about the potential for relapse and the dangers of overdose, particularly in the lead-up to release. The patient should receive a take-home naloxone kit and overdose prevention training prior to release.
Encourage adherence to treatment by supporting the patient's regular dosing schedule and monitoring for potential missed doses (e.g., during events such as court appearances).
Maintain an up-to-date medical chart for the patient (including UDT results).
Avoid discontinuing OAT simply as a consequence of non-reassuring UDT results.
Collaborate with the patient's regular OAT prescriber and pharmacy team before release to provide an update on:
Ì discharge plans that have been made with the patient and support networks (e.g., harm reduction strategies, provision of a naloxone kit, referrals to community organizations that address social determinants of health)
Ì any changes in dosage Ì prescribing of short-term opioid analgesics, psychoactive drugs or medications with the potential to interact with OAT.
Assist the patient in arranging to continue OAT upon release: Ì Communicate with the patient's regular OAT prescriber and give the patient a valid prescription to take to their pharmacy until they are able to see their regular prescriber.
Ì Ensure that a patient who was not on OAT or did not have a regular OAT prescriber prior to incarceration is connected with a prescriber and a pharmacy before release.
Part D: Providing opioid agonist therapy for patients with co-occurring disorders
# D1. General considerations
# Standards & frameworks for care
Prescribers recognize that patients with OUD often have other ongoing health concerns, and support is provided to appropriately manage those concerns.
# Clinical recommendations for prescribers
Encourage patients to attend a primary care provider or team for ongoing preventative care and chronic disease management.
Communicate openly and regularly with the patient's primary care provider.
# D2. Mental health and addiction considerations
Standards & frameworks for care
Patients with OUD who also have a mental health disorder or another substance use disorder are offered concurrent treatment.
# Clinical recommendations for prescribers
Screen and assess OAT patients for mental health disorders (e.g., anxiety, depression, posttraumatic stress disorder [PTSD], personality disorders) and suicidal ideation. If they do not respond to primary care-led treatment or if they require specialized care, refer them to a mental health professional, and reassess them during the course of OUD treatment.
Screen patients for trauma and abuse (past or current) and refer them to counselling if they express interest.
Assess patients periodically for alcohol, nicotine and other substance use, and offer appropriate psychoeducation and treatment. Using cannabis, stimulants or other addictive substances should not be a reason to suspend OAT.
Avoid co-prescribing BZRAs to patients on OAT due to increased risk of respiratory depression, daytime hypersomnolence, cognitive disturbance and overdose death. If clinical assessment, preferably by an addiction psychiatrist, suggests that a trial of BZRAs may be warranted, be aware of the interaction between the BZRA and OAT, adjust the dose and timing accordingly, and dispense only small amounts at a time.
# Clinical recommendations for prescribers
Evaluate the indication for OAT patients who are already on long-term BZRAs. The decision to continue prescribing or to de-prescribe the BZRA needs to be made with attention to other confounding diagnoses, including sedative use disorder and PTSD.
If prescribed for insomnia, BZRAs are indicated only for short-term intermittent use; therefore, a slow and gradual taper can be considered.
If prescribed for anxiety, BZRAs need to be used in a way that reflects guidelines for treating anxiety disorders. Prescribing and monitoring should be done together with clinicians who are familiar with BZRA-OAT interactions, overdose risk and BZRA use disorder. Ì multiple daily doses Ì a high OAT dose Ì other medications or substances with sedating properties.
Collaborate with pharmacists to prevent, monitor and manage drug interactions between OAT and other prescription or non-prescription medications that a patient may be taking. Methadone interactions require particular attention.
Be knowledgeable about local mental health and addiction resources, including wait lists, costs and practitioner expertise and approach in order to provide informed referrals that reflect patient needs and preferences.
# D3. Infectious disease considerations
Standards & frameworks for care
Patient care includes preventative, screening and treatment measures (as needed) for sexually transmitted infections and infectious diseases, such as influenza, hepatitis and HIV, and other public health recommendations.
# Clinical recommendations for prescribers
Screen for the following conditions when beginning OAT, once a year after that and more frequently if the patient has ongoing risk factors: hepatitis A and B, and arrange immunization hepatitis C and HIV, and offer referral and treatment as necessary (ongoing substance use is no longer a contraindication for hepatitis C treatment) sexually transmitted infections as indicated, and treat according to prevailing antimicrobial sensitivities.
# Part D
# Clinical recommendations for prescribers
Offer HIV pre-and post-exposure prophylaxis to patients who meet criteria to receive this preventative measure.
Prioritize patients who face substantial risks of ongoing illicit substance use. When considering priority access to OAT, evaluate risks to the person, society and public health.
Give priority access to untreated HIV-positive patients whenever possible due to the personal and public health consequences of untreated HIV infection.
Dispense antiretroviral and hepatitis C treatment with OAT to improve medication adherence.
Collaborate with pharmacists to prevent, monitor and manage drug interactions between OAT and other prescription or non-prescription medications the patient may be taking. Antimicrobial medications can significantly interact with OAT.
Consult with a knowledgeable physician or pharmacist when providing OAT to patients with HIV/AIDS because some medications that treat HIV/AIDS can affect serum methadone levels.
Counsel patients on ways to prevent reinfection.
# D4. Acute and chronic pain considerations
Standards & frameworks for care
Prescribers are responsible for managing acute and chronic pain in their OAT patients whenever possible.
Patients are supported in finding alternative pain treatments (including non-opioid pharmacotherapy and non-pharmacological therapy) that are financially and geographically accessible and culturally appropriate.
# Clinical recommendations for prescribers
Explore non-pharmacological therapies for treating pain in OAT patients.
Ensure that these therapies align with the patient's goals and values, and that they are culturally appropriate and financially and geographically accessible.
Consider non-opioid analgesic options before opioid options.
Avoid gabapentinoids for the treatment of chronic pain because there is limited evidence for their use in this context (other than for a few specific conditions) and there is a higher risk of mixed CNS depressant overdose in combination with opioid agonists.
Avoid the patient's previously reported opioid of choice if prescribing opioids for acute pain. Dispense the opioid in small amounts (i.e., controlled dispensing, preferably daily) and limit the prescription to the number of days that opioids are typically needed for the specific acute pain condition.
Part E: Discontinuing opioid agonist therapy
# E1. Transferring care
Standards & frameworks for care
Maintaining patient safety is the primary concern when transferring care.
# Clinical recommendations for prescribers
Share treatment progress notes with other providers involved in the patient's care if you have the patient's consent.
Discuss plans for transferring care with the patient and the care team, including the pharmacy, and ensure that everyone involved has a clear understanding of roles, responsibilities and expectations.
Support the patient in finding alternative OAT services if you are closing your practice, and begin well in advance to allow the patient to adjust. Make all reasonable efforts to help find a new prescriber if the patient is moving to another community.
Supply clinical information to permit safe and effective continuation of OAT when fully transferring the patient's care to another prescriber. This information should include:
reason for transfer OAT dosage prescribed medications patient's regular community pharmacy take-home dose flexibility UDT results treatment plan and goals ECG history (for patients on methadone) clinical history.
Ensure that the new prescriber has access to the patient's information at the time of the transfer and at any time after that.
# E2. Tapering and withdrawal management
Standards & frameworks for care
The choice to decrease the dose or discontinue OAT is made by the patient and provider after the patient has been fully informed of the possible consequences.
Withdrawal management (i.e., detoxification without immediate transition to long-term addiction treatment) by itself is not recommended.
# Clinical recommendations for prescribers
Recognize that the longer a patient is retained on OAT, the better the outcomes and the lower the risk of mortality. At least one year of stability on OAT is recommended before initiating a taper.
Discuss the possible risks of discontinuing OAT because research shows high relapse rates and risk of fatal opioid overdose, even after long-term stability.
Consider a slow taper approach (i.e., spread over months or years) for patients with a successful and sustained response to OAT who wish to discontinue OAT.
Increase the frequency of patient contact to ensure adequate support during and after tapering.
Offer relief of symptoms for patients who are in moderate or severe withdrawal from opioids by slowing the taper or increasing the dose of bup/nlx or methadone, or by prescribing non-opioid options (e.g., clonidine, loperamide, dimenhydrinate).
Suggest attempting periodic tapers for patients on high OAT doses (e.g., more than 24 mg of bup/nlx or 120 mg of methadone) if there is low risk of relapse and the patient has been stable for at least one year.
Avoid withdrawal management as a stand-alone treatment because it is associated with loss of tolerance and high risk of overdose death on discharge. This includes rapid inpatient tapers with methadone or bup/nlx. Patients in acute withdrawal should be offered pharmacotherapy to manage symptoms within two hours of presentation (see above for non-opioid options).
Document discussions to ensure that the patient has made an informed decision about the risks and benefits of discontinuing OAT. Ensure that the patient leaves with a naloxone kit, and follow up for psychosocial support.
Maintain an "open door" approach to care so that the patient feels welcomed back in case of relapse or if further support is required.
# C6. Transition-aged youth
Standards & frameworks for care Considerations are made to ensure that patients navigating between adolescent and adult health care services receive adequate and ageappropriate OUD treatment.
# Clinical recommendations for prescribers
Consult an experienced colleague to assist with assessing the role of OAT if you do not have the knowledge, skills or resources to treat adolescents with OUD. Whenever possible, prescribers should have experience working with this population and should collaborate with youth counsellors.
Encourage and facilitate engagement in non-pharmacological treatment (e.g., recovery-oriented services) to complement OAT. You should be familiar with the programs to which you refer adolescents and feel comfortable that they offer evidence-based treatments that support patients on OAT.
Consider bup/nlx as first-line treatment for moderate-to-severe OUD in youth.
# Part C
# Clinical recommendations for prescribers
Consider opioids in addition to bup/nlx or methadone for patients with acute pain that warrants short-term opioid therapy, and/or temporarily split the OAT dose and consider a temporary dose increase to cover the pain.
Consider prescribing methadone in split doses for patients with severe chronic pain who require opioids. Usually this would only be done after the patient reaches a stable, once-daily dose and becomes eligible for take-home doses. If the patient is clinically stable, consider providing the second dose as a take-home dose.
Consider formally or informally consulting with a pain specialist to enhance the patient's treatment plan if chronic pain persists after stabilization and optimization of OAT doses. | None | None |
651092d8b099f71b0bf2de6d8b21f2dc375883ec | cma | None | # Guideline Resource Unit
# Background
Immune checkpoint inhibitors (CPIs) are monoclonal antibodies (mAb) which increase antitumour activity by blocking intrinsic downregulators of immunity. The primary targets of CPIs include the programmed cell death-1 (PD-1) and its ligand PD-L1, as well as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). CPIs are effective in a broad range of cancers and it is anticipated that their indication will continue to expand to a number of additional malignancies. 1 Currently, their use is approved in the setting of melanoma, non-small cell lung carcinoma, renal cell carcinoma, and bladder cancer. 1 Additionally, CPI therapy has shown utility in other malignancies, including head and neck squamous cell, gastric, hepatocellular and ovarian cancers, certain types of breast or colorectal cancer, and Hodgkin lymphoma. 1,2 Drugs in this class include ipilimumab, a selective humanized IgG-4 kappa monoclonal antibody that inhibits CTLA-4 to ultimately activate T cells against malignant tumour cells. 3 Ipilimumab was approved for use in Canada in 2012. The PD-1 targeting monoclonal antibodies nivolumab and pembrolizumab were approved in 2015. 3 Immunotherapies are associated with better tolerance overall compared to traditional chemotherapy agents 2 . By modulating the activity of immune system, immune checkpoint blockade can cause inflammatory side effects, termed immune-related adverse events. Immune-related adverse events (irAEs) are toxicities caused by non-specific activation of the immune system and can affect almost any organ system. Most commonly these irAEs can be organized into the following categories: dermatologic, pulmonary, gastrointestinal, hepatic, and endocrine. 1 Other rarer and potentially lifethreatening toxicities can also occur, involving the central nervous system, cardiovascular, musculoskeletal, and hematologic systems and treatment-related deaths have been reported in up to 2 percent of patients in clinical trials. 1,4,5 irAEs resulting from CPI therapy can have delayed onset and prolonged duration compared to chemotherapy, primarily due to pharmacodynamics differences. 5 For this reason, the clinician needs to remain vigilant. The management approach to irAEs is primarily based on clinical experience, as no prospective trials are available to inform irAE treatment strategies. There is a wide spectrum of potential immune-mediated toxicities which requires collaborative, multidisciplinary management. 4 The underlying pathophysiology of irAEs is thought to be secondary to the role that immune checkpoints play in maintaining immunologic homeostasis. 4 The precise mechanisms that result in irAEs are still being elucidated but potential mechanisms include increasing T cell activity against antigens that are present in tumours and healthy tissue, increasing levels of pre-existing autoantibodies, increase in levels of inflammatory cytokines, and enhanced complement mediated inflammation. 4 PD-1 is thought to inhibit T cells at later stages of the immune response in peripheral tissues, whereas CTLA-4 is believed to act at a more proximal step in immune response, acting in several ways including attenuating T cell response. The irAEs are also different between these two classes of mAb, with more severe toxicities often seen in patients treated with CTLA-4 inhibitors. 6 Guideline Resource Unit PD-L1 mAb Renal cell carcinoma Special access: mesothelioma, non-small cell lung cancer nivolumab (Opdivo) PD-1 mAb Melanoma, renal cell carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma Special access: gastric adenocarcinoma, esophageal or GE junction cancer pembrolizumab (Keytruda) PD-1 mAb Melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, gastric adenocarcinoma, Hodgkin lymphoma, renal cell carcinoma Special access: MMR deficient tumours, bladder cancer, esophageal cancer, triple negative breast cancer, MSI-H endometrial cancer avelumab (Bavencio) PD-L1 mAb Merkel cell carcinoma, urothelial carcinoma durvalumab (Imfinzi) PD-L1 mAb Special access: non-small cell lung cancer, bladder cancer cemiplimab (Libtayo) PD-1 mAb Cutaneous squamous cell carcinoma Special access: basal cell carcinoma, non-small cell lung cancer Guideline Questions
- What are the appropriate protocols for follow-up to monitor for irAEs in adult patients treated with checkpoint inhibitors for cancer? 2. What are the recommended management strategies for irAEs associated with checkpoint inhibitors in adult cancer patients? 3. Is it safe to restart treatment after an irAE?
# Search Strategy
PubMed was searched for articles published before March 2018 with the search terms 'immune checkpoint inhibitor', and 'adverse events', and 'cancer'. Additionally, guidelines from other organizations were included in the literature search. For a detailed description of the literature search and results, please see Appendix A.
# Target Population
The recommendations contained in this guideline are intended for use in adult patients over the age of 18 years who are being considered for or are receiving checkpoint inhibitors as part of their treatment for cancer. Different principles may apply to pediatric and adolescent patients.
# Guideline Resource Unit
# Recommendations
General Approaches to Toxicity Management 1. It is widely acknowledged that cancer patients with pre-existing autoimmune disorders are at an increased risk of developing immune-related adverse events (irAEs). The treating oncologist should weigh the potential benefits of therapy against the risks of adverse events before deciding to proceed with treatment. 2. The current approach to managing irAES incorporates prevention, anticipation, detection, treatment and monitoring. 1 Patients on checkpoint inhibitors (CPI) should be monitored by a health care professional with experience identifying and managing irAEs. 3 Collaborative, multidisciplinary management should be employed by providers across a clinical spectrum.
Patients may play an active role in detecting irAEs, therefore, education in early detection and reporting is paramount in the effective management of irAEs.
No prospective trials have defined the best strategies to manage irAEs. Recommendations for management are based upon expert opinion.
- Immunosuppression is the mainstay of management of immune-mediate toxicity to reduce the state of inflammation. Glucocorticoids are the first-line agent used. If these are not sufficient to manage symptoms, additional immune modulatory drugs may be necessary (e.g. tumour necrosis factor antagonists, mycophenolate mofetil, anti-thymocyte globulin (ATG), calcineurin inhibitors, methotrexate, or intravenous immunoglobulin and plasmapharesis). These agents should be prescribed judiciously to reduce the risk of short-term and long-term toxicities. 5 Retrospective studies suggest that steroid use doesn't change effectiveness of CPI inhibitor therapy but other immunosuppressive medications have not been sufficiently studied. 7,8 Dermatology: Prevention Recommendations 1. At this time, it is not possible to accurately predict which patients are going to be more susceptible to immune-related dermatologic adverse events (irDAEs).
There is no role for pre-treatment with anti-inflammatory dose glucocorticoids to prevent irDAEs with CPI therapies. However, a low threshold for the initiation of irDAE empiric treatment must be maintained. Patients with pre-existing immune-related skin conditions such as psoriasis, bullous pemphigoid, or lupus should be closely monitored both by the treating medical oncologist and dermatologist.
- Avoid skin irritants and excessive sun exposure to limit other aggravating factors to the skin.
# Guideline Resource Unit
Dermatology: Anticipation Recommendations 1. Be aware of the potential immune-related dermatologic toxicities that may occur in patients on CPI therapy, and especially in those who have pre-existing immune-related skin conditions such as psoriasis, bullous pemphigoid, or lupus.
- Patients should be counseled on the potential toxicities that may occur on therapy with these agents as well as the significance of potential symptoms that indicate these irAEs. Skin toxicities are among the most frequent AEs observed in patients treated with CPIs inhibiting either CTLA-4 (~45% with ipilimumab) or PD-1/PD-L1 (~35% with nivolumab and pembrolizumab) for all grade, but equal for grade 3 or higher (1-3%). 9,10 These are typically low grade in severity, and commonly present as maculopapular rash and pruritus. Vitiligo is commonly seen and reported exclusively in the melanoma population and is associated with response to therapy. 11,12 Less commonly, patients can develop lichenoid, eczematous, and bullous dermatitis, and psoriasis. Rare, life-threatening exfoliative conditions have been reported in the literature including Stevens-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN) and drug rash with eosinophilia and systemic symptoms (DRESS). Both patients and clinicians should be aware of the signs and symptoms of these life-threatening immune-mediated dermatologic toxicities.
- Remain vigilant in monitoring for cutaneous toxicities. Skin toxicity typically occurs early on after initiation of therapy but there can be substantial variability in clinical presentation and timing of symptom onset. This mandates careful vigilance for signs of cutaneous toxicity at all points on therapy. Aside from causing potential morbidity and mortality, these are also well recognized factors in treatment patient non-compliance and discontinuation.
# Dermatology: Detection Recommendations
- Complete a thorough physical examination of the skin including the mucosal membranes and an assessment including vital signs and lymph node assessment. 7. Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.
# Pulmonary: Prevention Recommendations
- Careful patient selection is recommended. At this time, it is not possible to accurately predict which patients are going to be more susceptible to immune-related pulmonary adverse events (irPAEs). There is no role for baseline serology, imaging, or other testing. Take caution in patients with underlying lung disease thought to be from an immune-mediated cause.
# Guideline Resource Unit
Pulmonary: Anticipation Recommendations 1. Be aware of the potential immune-related pulmonary toxicities that may occur in patients on CPI therapy. Pulmonary irAEs can be challenging to diagnose as they typically have non-specific presentations (e.g. cough, dyspnea).
- Patients should be counseled on the potential toxicities that may occur on therapy with these agents as well as the significance of potential symptoms that indicate these irAEs. Pneumonitis is the most common lung toxicity observed and accounts for one of the highest rates of CPI-related mortality. 5 The incidence of pneumonitis is higher in patients treated with PD-1/PD-L1 therapy than with CTLA-4 therapy. The combination of PD-1/PD-L1 therapy and anti-CTLA-4 mAbs significantly increases the risk of pneumonitis. 5 Rates of any grade pneumonitis have been documented in 2-5% of patients of patients treated with PD-1 therapy, with 1-2% grade ≥3 events.
In patients treated with combination PD-1/CTLA-4 therapy this increases to 5-10% for any grade toxicity, and up to 4% grade ≥3 events 14,15 .
- Have a low threshold for further investigation in patients being treated with CPIs. Pneumonitis secondary to CPIs can have a wide range of variability both in timing of onset and presentation from a clinical and radiographical perspective 16 .
# Pulmonary: Detection Recommendations
- Pulmonary irAEs can be very challenging to identify due to their non-specific presentation and their occurrence in patients with either primary or metastatic malignancy in the lungs. Any new respiratory symptom should prompt a dedicated evaluation to rule out CPI-induced lung toxicity.
- Complete a comprehensive history and physical exam considering infections processes, other potential drug reactions, radiotherapy, granulomatous diseases, and possible associations with interstitial lung disease.
- Investigate including chest x-ray (repeat weekly if grade 2 or higher) and baseline bloodwork.
Consider screening for viral, opportunistic, or bacterial infections, and consider pulmonary function tests as clinically indicated. A CT scan should be obtained if pneumonitis is suspected. Radiographic features of pneumonitis are not pathognomonic and can have variable appearance including ground glass opacifications, reticular pattern, and focal areas of consolidation. These may reflect patterns consistent with organizing pneumonia or hypersensitivity pneumonitis. 17 4. Typically a lung biopsy is not required for diagnosis. However, if there is clinical or radiographical doubt about the etiology of the presentation then bronchoscopy with bronchoalveolar lavage and biopsy may be helpful. This may rule out acute infection, lepidic or lymphatic spread of disease or other pulmonary inflammatory changes.
Guideline Resource Unit medications should be started immediately in the setting of grade 2 or higher. If there is a suspicion of underlying infection, or in the case of a high-grade pneumonitis, patients may require bronchoscopy to rule out infection before starting immunosuppression. If the infectious status cannot be definitively determined, patients may require oral or IV antibiotics, particularly in the case of high-grade pneumonitis.
- Grade 1 pneumonitis can be followed clinically and repeat radiographic imaging completed in 3-4 weeks. If there is evidence of radiographic improvement or resolution, can consider resuming CPI with close monitoring. If there is no improvement, should be treated as grade 2.
- Grade 2 pneumonitis should be treated with oral corticosteroids at a dose of 1-2 mg/kg/day prednisone (or equivalent). Patients should receive close follow-up to ensure clinical improvement, with repeat chest x-ray in one week. Steroids should be slowly tapered over 4-6 weeks. If there is no clinical improvement after 48-72 hours, treat as grade 3. If there is resolution of symptoms and radiographic improvement to grade 1 or less, can consider re-challenging with CPI.
- If pneumonitis is grade 3 or 4 the patient should be admitted to hospital. Treatment should consist of high-dose IV steroids, methylprednisolone 1-2 mg/mg/d. If there is clinical improvement, start slow taper over 6-8 weeks. If symptoms do not improve after 48-72 hours, additional immunosuppressive strategies should be employed. There is no standard agent in this setting, tumour necrosis alpha (TNFα) inhibitors (e.g. infliximab 5 mg/kg IV), mycophenolate mofetil (MMF) (e.g. 1 g PO/IV bid), tocilizumab, and cyclophosphamide can all be considered. CPI therapy should be permanently discontinued.
Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.
# Gastrointestinal: Prevention Recommendations
- Recommend careful patient selection. Exhibit caution when considering therapy in a patient with underlying diagnosis of inflammatory bowel disease including Crohn's disease or ulcerative colitis, Guideline Resource Unit especially in those with severe underlying disease. These patients may be at higher risk for transient exacerbation of their underlying condition. 4 2. There are currently no known agents to effectively prevent immune-mediate colitis. Studies with budesonide were found to be negative. 18,19 Gastrointestinal: Anticipation Recommendations 1. Be aware of the potential immune-related gastrointestinal (GI) toxicities that may occur in patients on CPI therapy. Have a high degree of clinical suspicion, as some of these toxicities can be nonspecific.
- Patients should be counseled on the potential toxicities that may occur on therapy with these agents as well as the significance of early detection and assessment. The most common presenting symptom is watery diarrhea. Other presenting symptoms include abdominal pain, weight loss, fever, and vomiting. Patients can also present with aphthous ulcers, fissures, and extra-intestinal manifestations of inflammatory bowel disease including skin changes and arthralgias. Upper GI symptoms including dysphagia and epigastric pain have also been reported. 5 3. Have a low threshold for further investigation of GI toxicities in patients being treated with CPIs. Although these can occur with all agents, they are most commonly seen in patients treated with CTLA-4 inhibitors. GI toxicity is one of the most frequent and severe if the irAEs seen with anti-CTLA-4 therapy, with approximately one-third of treated patients developing irAEs related to the GI tract. These include aphthous ulcers, esophagitis, gastritis, diarrhea, and colitis. Diarrhea is the most common of these toxicities, occurring in 27-31% of patients with acute and chronic colitis seen in 8-22%. The rates of diarrhea and colitis are even higher in patients treated with a combination of anti-PD-1/PD-L1 and anti-CTLA4 agents.
- The onset of immune-mediated GI toxicity typically occurs days to weeks after the start of therapy but can occur at any time even after discontinuation of the drug. Studies have shown the time course for colitis to be anywhere from 1-10 doses of ipilimumab with variable pattern. It is seen less commonly with PD-L1 therapy with a median onset of 3 months.
- At this time, it is not possible to predict which patients are going to be more susceptible to colitis from CPI therapy. Ongoing studies are evaluating the role of microbiome composition of a patient's gastrointestinal flora in the development of immune-mediated colitis as well as genetic factors. 23 Gastrointestinal: Detection Recommendations 1. Gastrointestinal irAEs are common and can be potentially severe, therefore both patients and clinicians should recognize the importance of early detection and investigation.
- Complete a comprehensive history and physical exam in patients with diarrhea while on CPI therapy considering infections processes, exposures, and other drugs (including antibiotics).
- Bloodwork should be completed to evaluate for complications including CBC, electrolytes, serum albumin, urea, creatinine. Inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can be helpful.
- Rule out infectious causes of diarrhea including viral (CMV in particular) and bacterial pathogens.
Complete stool tests for enteric pathogens including Clostridium difficile toxin. Be aware that immune mediated colitis and infectious colitis can co-occur.
- Investigate using abdominal x-ray and CT as clinically indicated. These investigations are useful to rule out obstruction, perforation and toxic megacolon.
- Patients who develop persistent or high-grade (≥grade 2) symptoms should be assessed with endoscopy. Immune-mediated colitis typically affects the rectum and sigmoid colon, so sigmoidoscopy is typically sufficient for diagnosis. It may appear as areas of erythema, erosions, exudates, and ulceration. Be aware that normal appearance of endoscopy does not rule out colitis, and biopsies must be obtained. 24 There is evidence that the presence of ulceration may be predictive of a steroid-refractory course, and these patients may require early infliximab. 25,26 7. Screening laboratory investigations such as HIV, hepatitis as well as TB testing should be done in patients who may require infliximab. 24 In the setting of grade 3 diarrhea restarting PD-L1/PD-1 once recovered to grade 1 can still be considered with significant caution, permanently discontinue CTLA-4 agent. In grade 4 toxicity, permanently discontinue CPI.
Note: contraindications to infliximab include severe infection, TB, hypersensitivity to drug, and moderate to severe congestive heart failure. 27 5. Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.
# Hepatic: Prevention Recommendations
- Recommend careful patient selection. An underlying diagnosis of chronic hepatitis is not an absolute contraindication to therapy with PD-1/PD-L1 inhibition. 28
Hepatic: Anticipation Recommendations 1. Complete bloodwork including serum transaminases and bilirubin measurement prior to every cycle of therapy.
- Immune-mediated hepatitis is typically asymptomatic and discovered on routine bloodwork. Hepatic toxicity is seen in ~5-10% of patients treated with anti-PD-1/PD-L1 and anti-CTLA-4 monotherapy and 1-2% of this is ≥ grade 3 in severity. When these drugs are used in combination, the incidence of hepatitis increases to ~25-30%, ~15% of this is ≥ grade 3 in severity. 29,30 Guideline Resource Unit 3. Although most patients are asymptomatic from immune-mediated hepatitis, note any potential symptoms of hepatitis including fever, right upper quadrant pain, and nausea. Counsel patients to inform their health care provider if they develop symptoms of jaundice, drowsiness, dark urine, increase in bruising/bleeding.
# Hepatic: Detection Recommendations
- If serum transaminase elevation is noted, complete a careful assessment of potential causes including drugs (prescription, OTC including Tylenol, herbals), alcohol use, viral causes, and disease progression.
- Liver biopsy is not typically required but may be considered in the case of severe hepatitis of unclear etiology. 1. At this time, there is insufficient evidence to recommend screening with antibodies to predict which patients are going to be more susceptible to CPI-related endocrine complications. There is no role for pre-treatment with anti-inflammatory dose glucocorticoids to prevent the autoimmune endocrinopathies associated with CPI therapy.
Endocrine: Anticipation Recommendations 1,19, 1. Be aware of the potential immune-related endocrine adverse events (irEAE) that can occur with the use of CPIs. It is essential to identify these potential complications early, given the significant morbidity and mortality risk. Endocrine toxicities typically have non-specific symptomatology and endocrinopathies are often long lasting.
- Although the relative frequency of adverse events may vary between agents, in broad groups, hypophysitis (inflammation of the pituitary leading to dysfunction of pituitary hormone secretion and end-organ insufficiency), thyroid disorders (both hypo-& hyperthyroidism), autoimmune diabetes, and adrenalitis (primary adrenal insufficiency) are largely the endocrine complications seen with these drugs.
- Table 6 lists the details on endocrinopathy prevalence with various CPI agents. In addition to the difference in prevalence of endocrinopathy with each CPI agent, it seems that the risk of endocrine side effects vary between tumour groups. The risk of CPI-induced endocrinopathy seems to be increased in the presence of pre-existing organ-specific autoimmune disease and a family history thereof. However, this does not constitute a contraindication to the use of CPIs. It seems that CTLA4 agents and combination CPI therapy (simultaneous or sequential) have the highest rates of associated endocrinopathy. The presented data are approximate based on both clinical trials and clinical experience, they will vary further based upon tumour group, agent and patient comorbidities. 4. Identification of these clinical presentations can be challenging, given that they are often very nonspecific. Consequently, a treating clinician should have a high level of suspicion for irEAEs when evaluating patients on CPIs. Patients need to be counselled on the significance of symptoms that indicate the above endocrine complications. The difficulty lies in that many of the symptoms are non-specific and overlap with symptoms from the underlying tumour, CPI therapy and other nonendocrine side-effects. Due to this, a treating clinician should be aware to have a low threshold to investigate with laboratory investigations and imaging.
- Patients should be advised to monitor for the following symptoms: new onset or persistent headaches, visual changes, palpitations, excess sweating, extreme fatigue or weakness, dizziness or episodes of fainting, change in weight (gain or loss), muscle aches, salt craving, notable behaviour changes, polyuria, polydipsia, nausea, vomiting, or abdominal pain. Details of the more specific symptoms and signs are included in Table 7. 1. Given the prevalence of the side effects, it is reasonable to screen patients on therapy at every clinic visit. It is recommended that baseline levels of thyroid hormone (TSH), blood glucose, electrolytes be done before each treatment cycle. Subsequent thyroid function tests should be Guideline Resource Unit measured during treatment, (e.g. every 4 weeks during the first 6 months then every 3 months for 6-12 months, then every 6 months subsequently). Blood glucose should be monitored with each treatment cycle during induction for 12 weeks, then every 4-6 weeks thereafter. The remainder of imaging and extended laboratory investigation can be completed on a symptom-driven/clinical exam basis. Consider monitoring with baseline early-morning ACTH and cortisol levels at baseline. It is important to assure that the end-organ hormones be ordered in the case of hypophysitis.
# Specific endocrine organ testing as clinically indicated:
- Hypothyroidism (primary): TSH, fT4 1. With the need for ongoing CPI therapy, treatment of endocrine complications should happen with the involvement of an endocrinologist experienced in the management of these complications.
# Endocrine adverse event specific recommendations:
- Hypothyroidism: for thyroid replacement in patients without risk factors full replacement with thyroxine can be estimated at 1.6mcg/kg/d (synthroid or eltroxin are the most common preparations). If the patient is elderly or has significant comorbid cardiac disease, consider 30% replacement dose and a slower titration to normal TSH target.
- If adrenal dysfunction is present, this must always be replaced before thyroid hormone therapy is initiated.
- Hyperthyroidism: For severe hyperthyroidism/concern for thyroid storm: beta blockade, propylthiouracil, steroids (prednisone 1-2mg/kg/d or equivalent), followed by KI solution in an ICU/high observation unit monitored setting is suggested. For less severe forms of hyperthyroidism, methimazole (doses between 5-20 mg daily depending on the biochemistry) may be all that is needed.
- Diabetes: Insulin can be used in any case of hyperglycemia in connection with a diabetes education service for support and titration of doses to glycemic target. A basal bolus insulin regimen should be initiated in the setting of autoimmune diabetes.
- Adrenal Insufficiency: For adrenal replacement, glucocorticoid replacement maintenance with prednisone 5-10 mg daily or hydrocortisone 10 mg twice daily for grade 1. Patients may require mineralocorticoid replacement using fludrocortisone in the setting of primary adrenal insufficiency which is delivered as 0.1mg/day. Titrate based on symptoms. For outpatient management of acute symptoms of grade 2 adrenal insufficiency initiate at two to three times maintenance (if prednisone, 20 mg daily; if hydrocortisone, 20-30 mg twice daily to manage acute symptoms. Taper stress-dose corticosteroids down to maintenance doses over 5-10 days. For grade 3 or 4 adrenal insufficiency urgent hospitalization is required for fluid resuscitation, and IV stress-dose steroids (hydrocortisone 100 mg or dexamethasone 4 mg ). Taper down to maintenance doses over 7-14 days after discharge. o Patient education is crucial. All patients must have education as well as obtaining a medical alert bracelet to trigger stress dosing in the setting on illness, surgery, etc.
- Hypophysitis: Hypophysitis can affect the anterior pituitary, the posterior pituitary or both. Involvement of the posterior pituitary induces diabetes insipidus. Involvement of the anterior pituitary can cause secondary adrenal insufficiency, secondary hypothyroidism, secondary hypogonadism and growth hormone deficiency. These pituitary hormone deficiencies can occur synchronously or metachronously. From an acute management perspective, ADH and cortisol deficiencies are the most critical to diagnose and treat. Corticosteroids should be initiated first when planning hormone replacement therapy for multiple deficiencies. Thyroid replacement follows next in terms of clinical urgency. Initiate corticosteroids several days before thyroid supplementation to prevent adrenal crisis. Detection and replacement of sex steroids and growth hormone are long term considerations. Thus, these do not need to be measured in the acute setting. Given the effect of illness on both gonadal steroid and growth hormones, routine replacement is beyond the scope of these guidelines.
Endocrine: Monitoring Recommendations 1,8,31
- Once identified, the hormone replacement can be achieved and managed throughout the duration of the CPI therapy. It has also been recommended to continue to screen for the symptoms of endocrinopathy after treatment has been completed. This can be accomplished by the routine lab panel being performed q3 months for the first year, q6 months for the second year and symptomguided thereafter. Follow FT4 for thyroid hormone replacement titration (TSH is not accurate).
- Unlike the resolution of many CPI immune-related adverse effects, the endocrine insufficiencies are more likely to be permanent, especially hypothyroidism.
- For many of the non-endocrine immune-mediated toxicities (grade 2-4), anti-inflammatory doses of steroids are recommended to be given. As long as the steroid dose is greater than 10 mg/day of prednisone (or equivalent), the potential for co-existing adrenal insufficiency is moot as adrenal replacement is already being adequately achieved. However, once the dose is below this threshold, there is a potential concern for iatrogenic hypothalamic-pituitary-adrenal (HPA) axis suppression and illness management should be considered until the integrity of the HPA axis has been assessed.
Neurology: Prevention Recommendations 29,30, 1. At this time, it is not possible to accurately predict which patients are going to be more susceptible to immune-related neurologic adverse events (irNAEs). There is no role for baseline serology, imaging, or other neurology testing.
- Patients with pre-existing neurologic conditions, such as myasthenia gravis (MG), multiple sclerosis, or Guillain-Barre syndrome (GBS), should be closely monitored both by the treating medical oncologist and neurologist. There is no role for pre-treatment with anti-inflammatory dose glucocorticoids to prevent irNAEs with CPI therapies. However, a low threshold for the initiation of an irNAE workup and empiric treatment must be maintained.
Neurology: Anticipation Recommendations 1,32
- Be aware of the potential immune-related neurological adverse events (irNAE) that can occur with the use of CPIs. Although irNAEs are rare in patients treated with CPIs, it is essential to identify these potential complications early, given the significant morbidity and mortality risk.
- The relative frequency of adverse events may vary between agents, but irNAE can affect both the central and peripheral nervous systems. Potential neurological adverse events include: immunemediated polyneuropathies (e.g. acute inflammatory demyelinating polyneuropathy (AIDP), GBS, chronic immune demyelinating polyneuropathy (CIDP), other sensory and motor neuropathies), enteric neuropathy, MG, aseptic meningitis, autoimmune encephalitis, transverse myelitis, and ocular inflammatory toxicity. Although these adverse events may occur at any time during treatment, the most common time to onset appears to typically occur between 6 to 13 weeks. 17 3. Identification of these clinical presentations can be challenging, given that they are often very nonspecific. Consequently, a treating clinician should have a high level of suspicion for irNAEs when evaluating patients on CPIs. Although the data on irNAE incidence rates from individual agents is limited (see Table 9), a high level of suspicion for irNAEs must be maintained when evaluating patients on CPIs. Patients should be counselled on the significance of symptoms that can indicate irNAEs. Details of the more specific symptoms and signs are included in Table 10.
- Patients should be advised to monitor for the following symptoms: numbness/tingling in hands/feet, severe muscle weakness/fatigability, headache, fever, confusion, changes in mood/behavior, extreme sensitivity to light, neck stiffness, hallucinations, seizure, blurry/double vision, eye pain/redness. 1. Given the potential for serious irNAE complications, as well as their non-specific clinical presentations, clinicians should monitor patients for signs and symptoms suggestive of acute and subacute polyneuropathies (including AIDP), MG, enteric neuropathy, meningitis, encephalitis, and ocular inflammatory toxicity. No routine screening investigations are indicated, unless there is clinical suspicion. Imaging and extended laboratory investigation should be completed on a clinical basis. Rule out progression of underlying malignancy, seizures, infectious processes, and metabolic derangement as causes of neurological impairment.
- Early involvement of a neurologist is recommended to guide specific testing.
- AIDP can present with symmetrical, progressive weakness and paresthesias. In low grade 1-2, it can manifest with mildly affected mobility/gait limitations. In severe grade > 3 GBS, weakness may affect respiratory muscles and facial oculomotor and oropharyngeal muscles, dysautonomia, and diminished reflexes may be identified. The following should be performed if there is clinical suspicion of GBS:
- Urgent neurological consultation is necessary.
- Prompt exclusion of other potential causes of weakness. This may require MRI to rule out a compressive lesion and evaluate for nerve root enhancement/thickening. - Lumbar puncture may be performed. CSF can show high protein and normal to elevated white blood cell counts in patients with classic GBS. Cytology should be sent on any CSF sample in patients with cancer. - Electromyography (EMG) and nerve conduction studies (NCS).
- Pulmonary function testing with negative inspiratory force and vital capacity.
# Guideline Resource Unit
Note: all grades require work-up and intervention given the potential for progression and risk of respiratory compromise.
- MG may present with fluctuating and fatigable muscle weakness. Weakness often affects the bulbar, ocular, limb, and respiratory muscles. Classically, ptosis, diplopia, dysarthria, and dysphagia may be encountered. If there is clinical suspicion of MG of any grade, the following should be performed:
- Urgent neurological consultation is necessary - Bedside tests have high false-positivity, but the tensilon and ice-pack test, may be performed - EMG and NCS - Autoantibody serum testing for acetylcholine receptor (AChR-Ab). If AChR-Ab are negative, muscle specific tyrosine kinase (MuSK-Ab) may be sent - Creatinine phosphokinase (CPK), ESR, CRP, for concomitant myositis - Pulmonary function assessment with negative inspiratory force and vital capacity Note: all grades require work-up and intervention given the potential for progression and risk of respiratory compromise. 50 5. Autoimmune meningitis (aseptic meningitis) is characterized by fever, nuchal rigidity, and altered mental status. The following should be performed if there is clinical suspicion of meningitis: 1. Treatment of irAEs should occur with the involvement of a neurologist experienced in the management of these complications.
- Grade ≥2 MG, meningitis, encephalitis, or AIDP should result in permanent discontinuation of CPI treatment. The oncologist may consider reinstituting CPI in the setting of grade 1 maximum toxicity after assessing risk/benefits with the patient. The differential must remain broad, necessitating the previously mentioned investigations and initial treatment for severe causes until they are ruled out. In particular, infection must be ruled out. Urgent neurology consultation should be strongly considered to guide management; depending upon the etiology, methylprednisolone (e.g. encephalitis) or IVIG (e.g. AIDP) may be indicated. Other non-corticosteroid immunosuppressive agents may be considered.
- Following the acute use of corticosteroids, a slow taper of corticosteroids must occur over a minimum of 1 month. Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.
In grade 1-2 irNAEs (not including MG, meningitis, encephalitis, or AIDP), re-initiation of CPI therapy may be considered once grade 0-1 is achieved, the steroid dose is <10 mg/day of a prednisone equivalent, and there is no need for a non-corticosteroid immunosuppressant. Close monitoring is necessary for recurrence or worsening of irNAEs.
- Grade > 3 irNAEs must result in the discontinuation of CPI therapy. MG, meningitis, encephalitis, or AIDP of any grade must also result in discontinuation of CPI therapy. A high clinical suspicion must be maintained for recurrence of these irNAEs.
Rheumatology: Prevention Recommendations 31,53,57 1. At this time, it is not possible to accurately predict which patients are going to be more susceptible to immune-related rheumatologic or autoimmune disorder adverse events (irRAEs). There is no role for baseline serology, imaging, or other testing.
- There is no role for pre-treatment with anti-inflammatory dose glucocorticoids to prevent irRAEs with CPI therapies. However, a low threshold for the initiation of an irRAE workup and empiric treatment must be maintained. Patients with pre-existing autoimmune disorders should be closely monitored both by the treating medical oncologist and rheumatologist.
# Guideline Resource Unit
Rheumatology: Anticipation Recommendations 1,32,57
- The first step in anticipation is to be aware of the potential immune-related rheumatologic or autoimmune disorder adverse events (irRAE). It is possible to exacerbate or unmask a rheumatologic condition with CPI therapies. It is important to note that patients with autoimmune disorders were excluded from the clinical trials investigating these CPI agents.
- Patients should to be counselled on the significance of symptoms that indicate the above irRAEs.
Patients with pre-existing autoimmune disorders should be advised that it may be exacerbated by CPI therapy. Unfortunately, the identification of many of these clinical presentations is challenging, given the non-specific and general symptoms. Consequently, a treating clinician should be aware to have a low threshold to investigate with laboratory investigations and imaging. Details of the more specific symptoms and signs are included in Table 12. Patients should be advised to monitor for the following symptoms: painful or swollen joints, rash, weakness, muscle ache or pain, shortness of breath, cough, dry eyes and mouth.
- The relative frequency of adverse events may vary between agents, but potential irRAEs may include: polymyalgia rheumatic (PMR), vasculitis, leukocytoclastic vasculitis, psoriasis, rheumatoid arthritis (RA), tenosynovitis, gout, polymyositis, myositis, ocular myositis, sarcoidosis, systemic lupus erythematosus (SLE), Behcets disease, scleroderma, Sjogren's, and erythema multiforme.
- Data on irRAEs in CPI-treated patients is limited. Mild to moderate arthralgias are seen most commonly at an incidence of up to 40%. 42,54,55 Grade 3 irAEs are less commonly seen but can have a significant impact on quality of life. The most common musculoskeletal and rheumatic irAEs are arthritis, polymyalgia-like syndromes, and myositis 50 . Other irRAEs have also been described, including vasculitis, polymyositis, and temporal arteritis, but at a lower incidence. 56 Although these can occur with both anti-CTLA-4 and PD-1/PD-L1 agents, they occur more frequently with PD-1/PD-L1 inhibitors and with combination therapy.
- Remain vigilant with patients on CPI therapy as irRAEs may occur at any time on treatment and even after treatment discontinuation. 1. Given the potential for serious irRAE complications, as well as their non-specific clinical presentations, clinicians should monitor patients for signs and symptoms suggestive of irRAE conditions including; inflammatory arthritis, polymyositis, myositis, PMR, and be aware for the potential of developing vasculitis, psoriasis, sarcoidosis, SLE, Behcets disease, scleroderma, Sjogren's, and erythema multiforme.
- Inflammatory markers are usually very elevated in patients with irRAE and are useful to differentiate these events from other causes of their symptoms.
# Inflammatory arthritis:
- Clinical presentation can vary, affecting large and/or small joints, can have extra-articular symptoms including rash, tenosynovitis, axial involvement, conjunctivitis and urethritis. - Complete a thorough history and physical exam with examination of all peripheral joints for swelling, pain, and range of motion. - Exclude other causes including septic arthritis, viral polyarthritis, gout.
- Consider imaging of affected joints with plain film x-ray to evaluate for joint damage and rule out bony metastatic disease. - Consider serological testing including ANA, rheumatoid factor (RF), anti-citrullinated protein antibody (anti-CCP), and inflammatory markers erythrocyte sedimentation rate (ESR) and CRP. If symptoms are suggestive of reactive arthritis or affect the spine, consider HLA B27 testing. - Early recognition is critical to avoid erosive joint damage. Referral to a rheumatologist if there is evidence of joint swelling (synovitis) or if symptoms of arthralgia persist >4 weeks.
# Myositis:
- Myositis is a rare but potentially fatal toxicity of CPIs. Patients most commonly present with weakness, primarily in the proximal extremities. In severe cases, can also have myalgia. It can have a fulminant necrotizing course with rhabdomyolysis and involve other skeletal muscle, such as myocardium which can be potentially fatal if treatment is delayed.
- Complete a thorough rheumatologic, neurologic, and dermatologic exam paying specific attention to symptoms of muscle weakness or rash. - Complete blood testing for creatinine kinase (CK), transaminases (AST, ALT) and LDH, inflammatory markers (ESR, CRP). There is no evidence that autoantibodies (anti-Jo, anti-Mi2) have a role in CPI-induced myositis. - Evaluate for other potential causes including drugs, alcohol, infectious, metabolic or electrolyte disorders. - Consider troponin level to evaluate myocardial involvement as well as other cardiac investigations (e.g. echocardiogram) as required. - Consider electromyography (EMG), imaging (MRI), and/or biopsy on an individual basis when diagnosis is uncertain. - Consider paraneoplastic autoantibody testing for myositis and neurologic conditions, such as MG.
- Early referral to a rheumatologist if myositis is grade 2 or higher.
# Polymyalgia rheumatica:
- PMR presents as proximal myalgias and systemic symptoms including fatigue and low grade fever. - Complete a thorough rheumatologic and neurologic examination.
- Assess for symptoms of temporal arteritis including headache, jaw claudication, vision loss, and urgent temporal artery biopsy if this is suspected. - Complete blood testing for inflammatory markers (ESR, CRP) which are elevated in PMR, and investigations required for differential diagnosis; CK, ANA, RF, and anti-CCP (negative in PMR). - Early referral to a rheumatologist if PMR is grade 2 or higher.
# Sjogren's syndrome:
- Can present with sicca symptoms including dry eyes and mouth, enlarged parotid gland, and non-glandular involvement including arthritis and vasculitis. - Complete a thorough rheumatologic and dermatologic examination with assessment of the oropharynx for cracked tongue, lack of saliva pooling. - Complete blood testing including serological markers such as ANA, ENA (anti-Ro/SSA and/or anti-La/SSB antibodies), RF, anti-CCP antibody as sicca symptoms can occur with SLE and RA. - Early referral to a rheumatologist for considering of Schirmer test, minor salivary gland (lower lip) biopsy, sialometry.
# Sarcoid
- Most commonly seen with anti-CTLA4 or anti PD1 use in melanoma
- Presents as cutaneous sarcoidosis, or systemic with lymphadenopathy, lung or neurological and ocular involvement - No specific serum findings - May present with mediastinal or hilar lymphadenopathy on CT, but also parenchymal lung CT changes, such as ground glass opacities 8. Ultimately, early involvement of rheumatology can help to guide testing. 1. With the need for ongoing CPI therapy, treatment of rheumatologic complications should happen with the involvement of a rheumatologist experienced in the management of these complications.
- Corticosteroids can be used as part of initial therapy in inflammatory arthritis as in other irAEs but due to likely prolonged treatment requirements, physicians should consider starting corticosteroid-sparing agents earlier than typically required with other irAEs.
- Following the acute use of corticosteroids, a slow taper of corticosteroids must occur over a minimum of 1 month. Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.
- A number of other rheumatic disorders have been documented as case reports of patients receiving CPIs including vasculitis and lupus-like syndromes. Management and treatment principles are similar to those reported for other CPI-induced rheumatic syndromes.
It is recommended that all patients with inflammatory arthritis be monitored with serial rheumatologic examinations, including inflammatory markers, every 4 to 6 weeks after treatment is instituted.
# Appendix A: Literature Search Details
The literature search performed included a PubMed search that was conducted on 2016 October 8. The following terms for immune checkpoint inhibitors, adverse events and cancer were used in the search.
((immune checkpoint inhibitor*) OR ipilimumab OR pembrolizumab OR lambrolizumab OR nivolumab OR "Anti CTLA-4" OR "Anti CTLA 4" OR "Cytotoxic T-Lymphocyte Associated Protein 4" OR "PD-1" OR "PD-L1" OR "programmed cell death protein 1" OR IDO OR "indoleamine 2,3-dioxygenase" OR tremelimumab OR atezolizumab OR ticilimumab OR indoximod OR 1-methyl-d-tryptophan OR D-1MT OR MDX-010 OR MDX-101 OR BMS-734016 OR MK-3475 OR "SCH 900475") AND ("Drug-Related Side Effects and Adverse Reactions" OR "adverse events" OR toxicity) AND ("Neoplasms" OR oncolog- OR cancer OR malignan*) This search was limited to humans and the English language. No restrictions were applied in regards to study type or publication year. Articles met inclusion criteria if they were peer-reviewed guidelines, reviews or studies that reported on the presentation and prevalence of irAEs, their monitoring, management or follow up. Case reports on the management of toxicities were excluded with the exception of those which were included in overarching reviews. This search yielded 480 articles, of which 9 review articles (6 meta-analyses and 3 pooled analyses) with a focus on investigating checkpoint inhibitor therapy related toxicities in cancer patients were included for data extraction. Eleven studies (7 retrospective reviews, 3 retrospective observational studies, 1 randomized controlled trial and 1 secondary analysis of a phase III trial) were included, as well as 3 guidelines. These articles provided recommendations for the follow-up and management of immune-mediated adverse events.
Another aspect of the search included looking for existing guidelines on this topic that had already been published by prominent cancer associations, including the Canadian Partnership Against Cancer, the National Comprehensive Cancer Network and the American Cancer Society. The mineralocorticoid effect of commonly administered glucocorticoids may be estimated as follows:
- When given at replacement doses, triamcinolone, dexamethasone, and betamethasone have no clinically important mineralocorticoid activity. - 20 mg hydrocortisone and 25 mg of cortisone acetate each provide a mineralocorticoid effect that is approximately equivalent to 0.1 mg fludrocortisone. - Prednisone or prednisolone given at antiinflammatory doses ≥50 mg per day provide a mineralocorticoid effect that is approximately equivalent to 0.1 mg of fludrocortisone.
# Development and Revision History
This guideline was reviewed and endorsed by members of the Alberta Provincial Tumour Teams, including medical oncologists, gynecologic oncologists, hematologists, nurse practitioners, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Tumour Teams, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2020.
# Maintenance
A formal review of the guideline will be conducted in 2021. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations | # Guideline Resource Unit
# Background
Immune checkpoint inhibitors (CPIs) are monoclonal antibodies (mAb) which increase antitumour activity by blocking intrinsic downregulators of immunity. The primary targets of CPIs include the programmed cell death-1 (PD-1) and its ligand PD-L1, as well as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). CPIs are effective in a broad range of cancers and it is anticipated that their indication will continue to expand to a number of additional malignancies. 1 Currently, their use is approved in the setting of melanoma, non-small cell lung carcinoma, renal cell carcinoma, and bladder cancer. 1 Additionally, CPI therapy has shown utility in other malignancies, including head and neck squamous cell, gastric, hepatocellular and ovarian cancers, certain types of breast or colorectal cancer, and Hodgkin lymphoma. 1,2 Drugs in this class include ipilimumab, a selective humanized IgG-4 kappa monoclonal antibody that inhibits CTLA-4 to ultimately activate T cells against malignant tumour cells. 3 Ipilimumab was approved for use in Canada in 2012. The PD-1 targeting monoclonal antibodies nivolumab and pembrolizumab were approved in 2015. 3 Immunotherapies are associated with better tolerance overall compared to traditional chemotherapy agents 2 . By modulating the activity of immune system, immune checkpoint blockade can cause inflammatory side effects, termed immune-related adverse events. Immune-related adverse events (irAEs) are toxicities caused by non-specific activation of the immune system and can affect almost any organ system. Most commonly these irAEs can be organized into the following categories: dermatologic, pulmonary, gastrointestinal, hepatic, and endocrine. 1 Other rarer and potentially lifethreatening toxicities can also occur, involving the central nervous system, cardiovascular, musculoskeletal, and hematologic systems and treatment-related deaths have been reported in up to 2 percent of patients in clinical trials. 1,4,5 irAEs resulting from CPI therapy can have delayed onset and prolonged duration compared to chemotherapy, primarily due to pharmacodynamics differences. 5 For this reason, the clinician needs to remain vigilant. The management approach to irAEs is primarily based on clinical experience, as no prospective trials are available to inform irAE treatment strategies. There is a wide spectrum of potential immune-mediated toxicities which requires collaborative, multidisciplinary management. 4 The underlying pathophysiology of irAEs is thought to be secondary to the role that immune checkpoints play in maintaining immunologic homeostasis. 4 The precise mechanisms that result in irAEs are still being elucidated but potential mechanisms include increasing T cell activity against antigens that are present in tumours and healthy tissue, increasing levels of pre-existing autoantibodies, increase in levels of inflammatory cytokines, and enhanced complement mediated inflammation. 4 PD-1 is thought to inhibit T cells at later stages of the immune response in peripheral tissues, whereas CTLA-4 is believed to act at a more proximal step in immune response, acting in several ways including attenuating T cell response. The irAEs are also different between these two classes of mAb, with more severe toxicities often seen in patients treated with CTLA-4 inhibitors. 6 Guideline Resource Unit PD-L1 mAb Renal cell carcinoma Special access: mesothelioma, non-small cell lung cancer nivolumab (Opdivo) PD-1 mAb Melanoma, renal cell carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma Special access: gastric adenocarcinoma, esophageal or GE junction cancer pembrolizumab (Keytruda) PD-1 mAb Melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, gastric adenocarcinoma, Hodgkin lymphoma, renal cell carcinoma Special access: MMR deficient tumours, bladder cancer, esophageal cancer, triple negative breast cancer, MSI-H endometrial cancer avelumab (Bavencio) PD-L1 mAb Merkel cell carcinoma, urothelial carcinoma durvalumab (Imfinzi) PD-L1 mAb Special access: non-small cell lung cancer, bladder cancer cemiplimab (Libtayo) PD-1 mAb Cutaneous squamous cell carcinoma Special access: basal cell carcinoma, non-small cell lung cancer Guideline Questions
1. What are the appropriate protocols for follow-up to monitor for irAEs in adult patients treated with checkpoint inhibitors for cancer? 2. What are the recommended management strategies for irAEs associated with checkpoint inhibitors in adult cancer patients? 3. Is it safe to restart treatment after an irAE?
# Search Strategy
PubMed was searched for articles published before March 2018 with the search terms 'immune checkpoint inhibitor', and 'adverse events', and 'cancer'. Additionally, guidelines from other organizations were included in the literature search. For a detailed description of the literature search and results, please see Appendix A.
# Target Population
The recommendations contained in this guideline are intended for use in adult patients over the age of 18 years who are being considered for or are receiving checkpoint inhibitors as part of their treatment for cancer. Different principles may apply to pediatric and adolescent patients.
# Guideline Resource Unit
# Recommendations
General Approaches to Toxicity Management 1. It is widely acknowledged that cancer patients with pre-existing autoimmune disorders are at an increased risk of developing immune-related adverse events (irAEs). The treating oncologist should weigh the potential benefits of therapy against the risks of adverse events before deciding to proceed with treatment. 2. The current approach to managing irAES incorporates prevention, anticipation, detection, treatment and monitoring. 1 Patients on checkpoint inhibitors (CPI) should be monitored by a health care professional with experience identifying and managing irAEs. 3 Collaborative, multidisciplinary management should be employed by providers across a clinical spectrum.
Patients may play an active role in detecting irAEs, therefore, education in early detection and reporting is paramount in the effective management of irAEs.
# 3.
No prospective trials have defined the best strategies to manage irAEs. Recommendations for management are based upon expert opinion.
4. Immunosuppression is the mainstay of management of immune-mediate toxicity to reduce the state of inflammation. Glucocorticoids are the first-line agent used. If these are not sufficient to manage symptoms, additional immune modulatory drugs may be necessary (e.g. tumour necrosis factor antagonists, mycophenolate mofetil, anti-thymocyte globulin (ATG), calcineurin inhibitors, methotrexate, or intravenous immunoglobulin and plasmapharesis). These agents should be prescribed judiciously to reduce the risk of short-term and long-term toxicities. 5 Retrospective studies suggest that steroid use doesn't change effectiveness of CPI inhibitor therapy but other immunosuppressive medications have not been sufficiently studied. 7,8 Dermatology: Prevention Recommendations 1. At this time, it is not possible to accurately predict which patients are going to be more susceptible to immune-related dermatologic adverse events (irDAEs).
# 2.
There is no role for pre-treatment with anti-inflammatory dose glucocorticoids to prevent irDAEs with CPI therapies. However, a low threshold for the initiation of irDAE empiric treatment must be maintained. Patients with pre-existing immune-related skin conditions such as psoriasis, bullous pemphigoid, or lupus should be closely monitored both by the treating medical oncologist and dermatologist.
3. Avoid skin irritants and excessive sun exposure to limit other aggravating factors to the skin.
# Guideline Resource Unit
Dermatology: Anticipation Recommendations 1. Be aware of the potential immune-related dermatologic toxicities that may occur in patients on CPI therapy, and especially in those who have pre-existing immune-related skin conditions such as psoriasis, bullous pemphigoid, or lupus.
2. Patients should be counseled on the potential toxicities that may occur on therapy with these agents as well as the significance of potential symptoms that indicate these irAEs. Skin toxicities are among the most frequent AEs observed in patients treated with CPIs inhibiting either CTLA-4 (~45% with ipilimumab) or PD-1/PD-L1 (~35% with nivolumab and pembrolizumab) for all grade, but equal for grade 3 or higher (1-3%). 9,10 These are typically low grade in severity, and commonly present as maculopapular rash and pruritus. Vitiligo is commonly seen and reported exclusively in the melanoma population and is associated with response to therapy. 11,12 Less commonly, patients can develop lichenoid, eczematous, and bullous dermatitis, and psoriasis. Rare, life-threatening exfoliative conditions have been reported in the literature including Stevens-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN) and drug rash with eosinophilia and systemic symptoms (DRESS). Both patients and clinicians should be aware of the signs and symptoms of these life-threatening immune-mediated dermatologic toxicities.
3. Remain vigilant in monitoring for cutaneous toxicities. Skin toxicity typically occurs early on after initiation of therapy but there can be substantial variability in clinical presentation and timing of symptom onset. This mandates careful vigilance for signs of cutaneous toxicity at all points on therapy. Aside from causing potential morbidity and mortality, these are also well recognized factors in treatment patient non-compliance and discontinuation.
# Dermatology: Detection Recommendations
1. Complete a thorough physical examination of the skin including the mucosal membranes and an assessment including vital signs and lymph node assessment. 7. Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.
# Pulmonary: Prevention Recommendations
1. Careful patient selection is recommended. At this time, it is not possible to accurately predict which patients are going to be more susceptible to immune-related pulmonary adverse events (irPAEs). There is no role for baseline serology, imaging, or other testing. Take caution in patients with underlying lung disease thought to be from an immune-mediated cause.
# Guideline Resource Unit
Pulmonary: Anticipation Recommendations 1. Be aware of the potential immune-related pulmonary toxicities that may occur in patients on CPI therapy. Pulmonary irAEs can be challenging to diagnose as they typically have non-specific presentations (e.g. cough, dyspnea).
2. Patients should be counseled on the potential toxicities that may occur on therapy with these agents as well as the significance of potential symptoms that indicate these irAEs. Pneumonitis is the most common lung toxicity observed and accounts for one of the highest rates of CPI-related mortality. 5 The incidence of pneumonitis is higher in patients treated with PD-1/PD-L1 therapy than with CTLA-4 therapy. The combination of PD-1/PD-L1 therapy and anti-CTLA-4 mAbs significantly increases the risk of pneumonitis. 5 Rates of any grade pneumonitis have been documented in 2-5% of patients of patients treated with PD-1 therapy, with 1-2% grade ≥3 events.
In patients treated with combination PD-1/CTLA-4 therapy this increases to 5-10% for any grade toxicity, and up to 4% grade ≥3 events 14,15 .
3. Have a low threshold for further investigation in patients being treated with CPIs. Pneumonitis secondary to CPIs can have a wide range of variability both in timing of onset and presentation from a clinical and radiographical perspective 16 .
# Pulmonary: Detection Recommendations
1. Pulmonary irAEs can be very challenging to identify due to their non-specific presentation and their occurrence in patients with either primary or metastatic malignancy in the lungs. Any new respiratory symptom should prompt a dedicated evaluation to rule out CPI-induced lung toxicity.
2. Complete a comprehensive history and physical exam considering infections processes, other potential drug reactions, radiotherapy, granulomatous diseases, and possible associations with interstitial lung disease.
3. Investigate including chest x-ray (repeat weekly if grade 2 or higher) and baseline bloodwork.
Consider screening for viral, opportunistic, or bacterial infections, and consider pulmonary function tests as clinically indicated. A CT scan should be obtained if pneumonitis is suspected. Radiographic features of pneumonitis are not pathognomonic and can have variable appearance including ground glass opacifications, reticular pattern, and focal areas of consolidation. These may reflect patterns consistent with organizing pneumonia or hypersensitivity pneumonitis. 17 4. Typically a lung biopsy is not required for diagnosis. However, if there is clinical or radiographical doubt about the etiology of the presentation then bronchoscopy with bronchoalveolar lavage and biopsy may be helpful. This may rule out acute infection, lepidic or lymphatic spread of disease or other pulmonary inflammatory changes.
Guideline Resource Unit medications should be started immediately in the setting of grade 2 or higher. If there is a suspicion of underlying infection, or in the case of a high-grade pneumonitis, patients may require bronchoscopy to rule out infection before starting immunosuppression. If the infectious status cannot be definitively determined, patients may require oral or IV antibiotics, particularly in the case of high-grade pneumonitis.
2. Grade 1 pneumonitis can be followed clinically and repeat radiographic imaging completed in 3-4 weeks. If there is evidence of radiographic improvement or resolution, can consider resuming CPI with close monitoring. If there is no improvement, should be treated as grade 2.
3. Grade 2 pneumonitis should be treated with oral corticosteroids at a dose of 1-2 mg/kg/day prednisone (or equivalent). Patients should receive close follow-up to ensure clinical improvement, with repeat chest x-ray in one week. Steroids should be slowly tapered over 4-6 weeks. If there is no clinical improvement after 48-72 hours, treat as grade 3. If there is resolution of symptoms and radiographic improvement to grade 1 or less, can consider re-challenging with CPI.
4. If pneumonitis is grade 3 or 4 the patient should be admitted to hospital. Treatment should consist of high-dose IV steroids, methylprednisolone 1-2 mg/mg/d. If there is clinical improvement, start slow taper over 6-8 weeks. If symptoms do not improve after 48-72 hours, additional immunosuppressive strategies should be employed. There is no standard agent in this setting, tumour necrosis alpha (TNFα) inhibitors (e.g. infliximab 5 mg/kg IV), mycophenolate mofetil (MMF) (e.g. 1 g PO/IV bid), tocilizumab, and cyclophosphamide can all be considered. CPI therapy should be permanently discontinued.
# 5.
Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.
# Gastrointestinal: Prevention Recommendations
1. Recommend careful patient selection. Exhibit caution when considering therapy in a patient with underlying diagnosis of inflammatory bowel disease including Crohn's disease or ulcerative colitis, Guideline Resource Unit especially in those with severe underlying disease. These patients may be at higher risk for transient exacerbation of their underlying condition. 4 2. There are currently no known agents to effectively prevent immune-mediate colitis. Studies with budesonide were found to be negative. 18,19 Gastrointestinal: Anticipation Recommendations 1. Be aware of the potential immune-related gastrointestinal (GI) toxicities that may occur in patients on CPI therapy. Have a high degree of clinical suspicion, as some of these toxicities can be nonspecific.
2. Patients should be counseled on the potential toxicities that may occur on therapy with these agents as well as the significance of early detection and assessment. The most common presenting symptom is watery diarrhea. Other presenting symptoms include abdominal pain, weight loss, fever, and vomiting. Patients can also present with aphthous ulcers, fissures, and extra-intestinal manifestations of inflammatory bowel disease including skin changes and arthralgias. Upper GI symptoms including dysphagia and epigastric pain have also been reported. 5 3. Have a low threshold for further investigation of GI toxicities in patients being treated with CPIs. Although these can occur with all agents, they are most commonly seen in patients treated with CTLA-4 inhibitors. GI toxicity is one of the most frequent and severe if the irAEs seen with anti-CTLA-4 therapy, with approximately one-third of treated patients developing irAEs related to the GI tract. These include aphthous ulcers, esophagitis, gastritis, diarrhea, and colitis. Diarrhea is the most common of these toxicities, occurring in 27-31% of patients with acute and chronic colitis seen in 8-22%. The rates of diarrhea and colitis are even higher in patients treated with a combination of anti-PD-1/PD-L1 and anti-CTLA4 agents.
4. The onset of immune-mediated GI toxicity typically occurs days to weeks after the start of therapy but can occur at any time even after discontinuation of the drug. Studies have shown the time course for colitis to be anywhere from 1-10 doses of ipilimumab with variable pattern. [20][21][22] It is seen less commonly with PD-L1 therapy with a median onset of 3 months.
5. At this time, it is not possible to predict which patients are going to be more susceptible to colitis from CPI therapy. Ongoing studies are evaluating the role of microbiome composition of a patient's gastrointestinal flora in the development of immune-mediated colitis as well as genetic factors. 23 Gastrointestinal: Detection Recommendations 1. Gastrointestinal irAEs are common and can be potentially severe, therefore both patients and clinicians should recognize the importance of early detection and investigation.
2. Complete a comprehensive history and physical exam in patients with diarrhea while on CPI therapy considering infections processes, exposures, and other drugs (including antibiotics).
3. Bloodwork should be completed to evaluate for complications including CBC, electrolytes, serum albumin, urea, creatinine. Inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can be helpful.
4. Rule out infectious causes of diarrhea including viral (CMV in particular) and bacterial pathogens.
Complete stool tests for enteric pathogens including Clostridium difficile toxin. Be aware that immune mediated colitis and infectious colitis can co-occur.
5. Investigate using abdominal x-ray and CT as clinically indicated. These investigations are useful to rule out obstruction, perforation and toxic megacolon.
6. Patients who develop persistent or high-grade (≥grade 2) symptoms should be assessed with endoscopy. Immune-mediated colitis typically affects the rectum and sigmoid colon, so sigmoidoscopy is typically sufficient for diagnosis. It may appear as areas of erythema, erosions, exudates, and ulceration. Be aware that normal appearance of endoscopy does not rule out colitis, and biopsies must be obtained. 24 There is evidence that the presence of ulceration may be predictive of a steroid-refractory course, and these patients may require early infliximab. 25,26 7. Screening laboratory investigations such as HIV, hepatitis as well as TB testing should be done in patients who may require infliximab. 24 In the setting of grade 3 diarrhea restarting PD-L1/PD-1 once recovered to grade 1 can still be considered with significant caution, permanently discontinue CTLA-4 agent. In grade 4 toxicity, permanently discontinue CPI.
Note: contraindications to infliximab include severe infection, TB, hypersensitivity to drug, and moderate to severe congestive heart failure. 27 5. Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.
# Hepatic: Prevention Recommendations
1. Recommend careful patient selection. An underlying diagnosis of chronic hepatitis is not an absolute contraindication to therapy with PD-1/PD-L1 inhibition. 28
Hepatic: Anticipation Recommendations 1. Complete bloodwork including serum transaminases and bilirubin measurement prior to every cycle of therapy.
2. Immune-mediated hepatitis is typically asymptomatic and discovered on routine bloodwork. Hepatic toxicity is seen in ~5-10% of patients treated with anti-PD-1/PD-L1 and anti-CTLA-4 monotherapy and 1-2% of this is ≥ grade 3 in severity. When these drugs are used in combination, the incidence of hepatitis increases to ~25-30%, ~15% of this is ≥ grade 3 in severity. 29,30 Guideline Resource Unit 3. Although most patients are asymptomatic from immune-mediated hepatitis, note any potential symptoms of hepatitis including fever, right upper quadrant pain, and nausea. Counsel patients to inform their health care provider if they develop symptoms of jaundice, drowsiness, dark urine, increase in bruising/bleeding.
# Hepatic: Detection Recommendations
1. If serum transaminase elevation is noted, complete a careful assessment of potential causes including drugs (prescription, OTC including Tylenol, herbals), alcohol use, viral causes, and disease progression.
2. Liver biopsy is not typically required but may be considered in the case of severe hepatitis of unclear etiology. 1. At this time, there is insufficient evidence to recommend screening with antibodies to predict which patients are going to be more susceptible to CPI-related endocrine complications. There is no role for pre-treatment with anti-inflammatory dose glucocorticoids to prevent the autoimmune endocrinopathies associated with CPI therapy.
Endocrine: Anticipation Recommendations 1,19,[31][32][33][34][35][36] 1. Be aware of the potential immune-related endocrine adverse events (irEAE) that can occur with the use of CPIs. It is essential to identify these potential complications early, given the significant morbidity and mortality risk. Endocrine toxicities typically have non-specific symptomatology and endocrinopathies are often long lasting.
2. Although the relative frequency of adverse events may vary between agents, in broad groups, hypophysitis (inflammation of the pituitary leading to dysfunction of pituitary hormone secretion and end-organ insufficiency), thyroid disorders (both hypo-& hyperthyroidism), autoimmune diabetes, and adrenalitis (primary adrenal insufficiency) are largely the endocrine complications seen with these drugs.
3. Table 6 lists the details on endocrinopathy prevalence with various CPI agents. In addition to the difference in prevalence of endocrinopathy with each CPI agent, it seems that the risk of endocrine side effects vary between tumour groups. The risk of CPI-induced endocrinopathy seems to be increased in the presence of pre-existing organ-specific autoimmune disease and a family history thereof. However, this does not constitute a contraindication to the use of CPIs. It seems that CTLA4 agents and combination CPI therapy (simultaneous or sequential) have the highest rates of associated endocrinopathy. The presented data are approximate based on both clinical trials and clinical experience, they will vary further based upon tumour group, agent and patient comorbidities. 4. Identification of these clinical presentations can be challenging, given that they are often very nonspecific. Consequently, a treating clinician should have a high level of suspicion for irEAEs when evaluating patients on CPIs. Patients need to be counselled on the significance of symptoms that indicate the above endocrine complications. The difficulty lies in that many of the symptoms are non-specific and overlap with symptoms from the underlying tumour, CPI therapy and other nonendocrine side-effects. Due to this, a treating clinician should be aware to have a low threshold to investigate with laboratory investigations and imaging.
5. Patients should be advised to monitor for the following symptoms: new onset or persistent headaches, visual changes, palpitations, excess sweating, extreme fatigue or weakness, dizziness or episodes of fainting, change in weight (gain or loss), muscle aches, salt craving, notable behaviour changes, polyuria, polydipsia, nausea, vomiting, or abdominal pain. Details of the more specific symptoms and signs are included in Table 7. 1. Given the prevalence of the side effects, it is reasonable to screen patients on therapy at every clinic visit. It is recommended that baseline levels of thyroid hormone (TSH), blood glucose, electrolytes be done before each treatment cycle. Subsequent thyroid function tests should be Guideline Resource Unit measured during treatment, (e.g. every 4 weeks during the first 6 months then every 3 months for 6-12 months, then every 6 months subsequently). Blood glucose should be monitored with each treatment cycle during induction for 12 weeks, then every 4-6 weeks thereafter. The remainder of imaging and extended laboratory investigation can be completed on a symptom-driven/clinical exam basis. Consider monitoring with baseline early-morning ACTH and cortisol levels at baseline. It is important to assure that the end-organ hormones be ordered in the case of hypophysitis.
# Specific endocrine organ testing as clinically indicated:
• Hypothyroidism (primary): TSH, fT4 1. With the need for ongoing CPI therapy, treatment of endocrine complications should happen with the involvement of an endocrinologist experienced in the management of these complications.
# Endocrine adverse event specific recommendations:
• Hypothyroidism: for thyroid replacement in patients without risk factors full replacement with thyroxine can be estimated at 1.6mcg/kg/d (synthroid or eltroxin are the most common preparations). If the patient is elderly or has significant comorbid cardiac disease, consider 30% replacement dose and a slower titration to normal TSH target.
o If adrenal dysfunction is present, this must always be replaced before thyroid hormone therapy is initiated.
• Hyperthyroidism: For severe hyperthyroidism/concern for thyroid storm: beta blockade, propylthiouracil, steroids (prednisone 1-2mg/kg/d or equivalent), followed by KI solution in an ICU/high observation unit monitored setting is suggested. For less severe forms of hyperthyroidism, methimazole (doses between 5-20 mg daily depending on the biochemistry) may be all that is needed.
• Diabetes: Insulin can be used in any case of hyperglycemia in connection with a diabetes education service for support and titration of doses to glycemic target. A basal bolus insulin regimen should be initiated in the setting of autoimmune diabetes.
• Adrenal Insufficiency: For adrenal replacement, glucocorticoid replacement maintenance with prednisone 5-10 mg daily or hydrocortisone 10 mg twice daily for grade 1. Patients may require mineralocorticoid replacement using fludrocortisone in the setting of primary adrenal insufficiency which is delivered as 0.1mg/day. Titrate based on symptoms. For outpatient management of acute symptoms of grade 2 adrenal insufficiency initiate at two to three times maintenance (if prednisone, 20 mg daily; if hydrocortisone, 20-30 mg twice daily to manage acute symptoms. Taper stress-dose corticosteroids down to maintenance doses over 5-10 days. For grade 3 or 4 adrenal insufficiency urgent hospitalization is required for fluid resuscitation, and IV stress-dose steroids (hydrocortisone 100 mg or dexamethasone 4 mg [if no confirmed diagnosis as this will not affect stimulation testing]). Taper down to maintenance doses over 7-14 days after discharge. o Patient education is crucial. All patients must have education as well as obtaining a medical alert bracelet to trigger stress dosing in the setting on illness, surgery, etc.
• Hypophysitis: Hypophysitis can affect the anterior pituitary, the posterior pituitary or both. Involvement of the posterior pituitary induces diabetes insipidus. Involvement of the anterior pituitary can cause secondary adrenal insufficiency, secondary hypothyroidism, secondary hypogonadism and growth hormone deficiency. These pituitary hormone deficiencies can occur synchronously or metachronously. From an acute management perspective, ADH and cortisol deficiencies are the most critical to diagnose and treat. Corticosteroids should be initiated first when planning hormone replacement therapy for multiple deficiencies. Thyroid replacement follows next in terms of clinical urgency. Initiate corticosteroids several days before thyroid supplementation to prevent adrenal crisis. Detection and replacement of sex steroids and growth hormone are long term considerations. Thus, these do not need to be measured in the acute setting. Given the effect of illness on both gonadal steroid and growth hormones, routine replacement is beyond the scope of these guidelines.
Endocrine: Monitoring Recommendations 1,8,31
1. Once identified, the hormone replacement can be achieved and managed throughout the duration of the CPI therapy. It has also been recommended to continue to screen for the symptoms of endocrinopathy after treatment has been completed. This can be accomplished by the routine lab panel being performed q3 months for the first year, q6 months for the second year and symptomguided thereafter. Follow FT4 for thyroid hormone replacement titration (TSH is not accurate).
2. Unlike the resolution of many CPI immune-related adverse effects, the endocrine insufficiencies are more likely to be permanent, especially hypothyroidism.
3. For many of the non-endocrine immune-mediated toxicities (grade 2-4), anti-inflammatory doses of steroids are recommended to be given. As long as the steroid dose is greater than 10 mg/day of prednisone (or equivalent), the potential for co-existing adrenal insufficiency is moot as adrenal replacement is already being adequately achieved. However, once the dose is below this threshold, there is a potential concern for iatrogenic hypothalamic-pituitary-adrenal (HPA) axis suppression and illness management should be considered until the integrity of the HPA axis has been assessed.
Neurology: Prevention Recommendations 29,30,[38][39][40][41][42][43] 1. At this time, it is not possible to accurately predict which patients are going to be more susceptible to immune-related neurologic adverse events (irNAEs). There is no role for baseline serology, imaging, or other neurology testing.
2. Patients with pre-existing neurologic conditions, such as myasthenia gravis (MG), multiple sclerosis, or Guillain-Barre syndrome (GBS), should be closely monitored both by the treating medical oncologist and neurologist. There is no role for pre-treatment with anti-inflammatory dose glucocorticoids to prevent irNAEs with CPI therapies. However, a low threshold for the initiation of an irNAE workup and empiric treatment must be maintained.
Neurology: Anticipation Recommendations 1,32
1. Be aware of the potential immune-related neurological adverse events (irNAE) that can occur with the use of CPIs. Although irNAEs are rare in patients treated with CPIs, it is essential to identify these potential complications early, given the significant morbidity and mortality risk.
2. The relative frequency of adverse events may vary between agents, but irNAE can affect both the central and peripheral nervous systems. Potential neurological adverse events include: immunemediated polyneuropathies (e.g. acute inflammatory demyelinating polyneuropathy (AIDP), GBS, chronic immune demyelinating polyneuropathy (CIDP), other sensory and motor neuropathies), enteric neuropathy, MG, aseptic meningitis, autoimmune encephalitis, transverse myelitis, and ocular inflammatory toxicity. Although these adverse events may occur at any time during treatment, the most common time to onset appears to typically occur between 6 to 13 weeks. 17 3. Identification of these clinical presentations can be challenging, given that they are often very nonspecific. Consequently, a treating clinician should have a high level of suspicion for irNAEs when evaluating patients on CPIs. Although the data on irNAE incidence rates from individual agents is limited (see Table 9), a high level of suspicion for irNAEs must be maintained when evaluating patients on CPIs. Patients should be counselled on the significance of symptoms that can indicate irNAEs. Details of the more specific symptoms and signs are included in Table 10.
4. Patients should be advised to monitor for the following symptoms: numbness/tingling in hands/feet, severe muscle weakness/fatigability, headache, fever, confusion, changes in mood/behavior, extreme sensitivity to light, neck stiffness, hallucinations, seizure, blurry/double vision, eye pain/redness. 1. Given the potential for serious irNAE complications, as well as their non-specific clinical presentations, clinicians should monitor patients for signs and symptoms suggestive of acute and subacute polyneuropathies (including AIDP), MG, enteric neuropathy, meningitis, encephalitis, and ocular inflammatory toxicity. No routine screening investigations are indicated, unless there is clinical suspicion. Imaging and extended laboratory investigation should be completed on a clinical basis. Rule out progression of underlying malignancy, seizures, infectious processes, and metabolic derangement as causes of neurological impairment.
2. Early involvement of a neurologist is recommended to guide specific testing.
3. AIDP can present with symmetrical, progressive weakness and paresthesias. In low grade 1-2, it can manifest with mildly affected mobility/gait limitations. In severe grade > 3 GBS, weakness may affect respiratory muscles and facial oculomotor and oropharyngeal muscles, dysautonomia, and diminished reflexes may be identified. The following should be performed if there is clinical suspicion of GBS:
• Urgent neurological consultation is necessary.
• Prompt exclusion of other potential causes of weakness. This may require MRI to rule out a compressive lesion and evaluate for nerve root enhancement/thickening. • Lumbar puncture may be performed. CSF can show high protein and normal to elevated white blood cell counts in patients with classic GBS. Cytology should be sent on any CSF sample in patients with cancer. • Electromyography (EMG) and nerve conduction studies (NCS).
• Pulmonary function testing with negative inspiratory force and vital capacity.
# Guideline Resource Unit
Note: all grades require work-up and intervention given the potential for progression and risk of respiratory compromise.
4. MG may present with fluctuating and fatigable muscle weakness. Weakness often affects the bulbar, ocular, limb, and respiratory muscles. Classically, ptosis, diplopia, dysarthria, and dysphagia may be encountered. If there is clinical suspicion of MG of any grade, the following should be performed:
• Urgent neurological consultation is necessary • Bedside tests have high false-positivity, but the tensilon and ice-pack test, may be performed • EMG and NCS • Autoantibody serum testing for acetylcholine receptor (AChR-Ab). If AChR-Ab are negative, muscle specific tyrosine kinase (MuSK-Ab) may be sent • Creatinine phosphokinase (CPK), ESR, CRP, for concomitant myositis • Pulmonary function assessment with negative inspiratory force and vital capacity Note: all grades require work-up and intervention given the potential for progression and risk of respiratory compromise. 50 5. Autoimmune meningitis (aseptic meningitis) is characterized by fever, nuchal rigidity, and altered mental status. The following should be performed if there is clinical suspicion of meningitis: 1. Treatment of irAEs should occur with the involvement of a neurologist experienced in the management of these complications.
•
2. Grade ≥2 MG, meningitis, encephalitis, or AIDP should result in permanent discontinuation of CPI treatment. The oncologist may consider reinstituting CPI in the setting of grade 1 maximum toxicity after assessing risk/benefits with the patient. The differential must remain broad, necessitating the previously mentioned investigations and initial treatment for severe causes until they are ruled out. In particular, infection must be ruled out. Urgent neurology consultation should be strongly considered to guide management; depending upon the etiology, methylprednisolone (e.g. encephalitis) or IVIG (e.g. AIDP) may be indicated. Other non-corticosteroid immunosuppressive agents may be considered.
3. Following the acute use of corticosteroids, a slow taper of corticosteroids must occur over a minimum of 1 month. Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.
# 4.
In grade 1-2 irNAEs (not including MG, meningitis, encephalitis, or AIDP), re-initiation of CPI therapy may be considered once grade 0-1 is achieved, the steroid dose is <10 mg/day of a prednisone equivalent, and there is no need for a non-corticosteroid immunosuppressant. Close monitoring is necessary for recurrence or worsening of irNAEs.
5. Grade > 3 irNAEs must result in the discontinuation of CPI therapy. MG, meningitis, encephalitis, or AIDP of any grade must also result in discontinuation of CPI therapy. A high clinical suspicion must be maintained for recurrence of these irNAEs.
Rheumatology: Prevention Recommendations 31,53,57 1. At this time, it is not possible to accurately predict which patients are going to be more susceptible to immune-related rheumatologic or autoimmune disorder adverse events (irRAEs). There is no role for baseline serology, imaging, or other testing.
2. There is no role for pre-treatment with anti-inflammatory dose glucocorticoids to prevent irRAEs with CPI therapies. However, a low threshold for the initiation of an irRAE workup and empiric treatment must be maintained. Patients with pre-existing autoimmune disorders should be closely monitored both by the treating medical oncologist and rheumatologist.
# Guideline Resource Unit
Rheumatology: Anticipation Recommendations 1,32,57
1. The first step in anticipation is to be aware of the potential immune-related rheumatologic or autoimmune disorder adverse events (irRAE). It is possible to exacerbate or unmask a rheumatologic condition with CPI therapies. It is important to note that patients with autoimmune disorders were excluded from the clinical trials investigating these CPI agents.
2. Patients should to be counselled on the significance of symptoms that indicate the above irRAEs.
Patients with pre-existing autoimmune disorders should be advised that it may be exacerbated by CPI therapy. Unfortunately, the identification of many of these clinical presentations is challenging, given the non-specific and general symptoms. Consequently, a treating clinician should be aware to have a low threshold to investigate with laboratory investigations and imaging. Details of the more specific symptoms and signs are included in Table 12. Patients should be advised to monitor for the following symptoms: painful or swollen joints, rash, weakness, muscle ache or pain, shortness of breath, cough, dry eyes and mouth.
3. The relative frequency of adverse events may vary between agents, but potential irRAEs may include: polymyalgia rheumatic (PMR), vasculitis, leukocytoclastic vasculitis, psoriasis, rheumatoid arthritis (RA), tenosynovitis, gout, polymyositis, myositis, ocular myositis, sarcoidosis, systemic lupus erythematosus (SLE), Behcets disease, scleroderma, Sjogren's, and erythema multiforme.
4. Data on irRAEs in CPI-treated patients is limited. Mild to moderate arthralgias are seen most commonly at an incidence of up to 40%. 42,54,55 Grade 3 irAEs are less commonly seen but can have a significant impact on quality of life. The most common musculoskeletal and rheumatic irAEs are arthritis, polymyalgia-like syndromes, and myositis 50 . Other irRAEs have also been described, including vasculitis, polymyositis, and temporal arteritis, but at a lower incidence. 56 Although these can occur with both anti-CTLA-4 and PD-1/PD-L1 agents, they occur more frequently with PD-1/PD-L1 inhibitors and with combination therapy.
5. Remain vigilant with patients on CPI therapy as irRAEs may occur at any time on treatment and even after treatment discontinuation. 1. Given the potential for serious irRAE complications, as well as their non-specific clinical presentations, clinicians should monitor patients for signs and symptoms suggestive of irRAE conditions including; inflammatory arthritis, polymyositis, myositis, PMR, and be aware for the potential of developing vasculitis, psoriasis, sarcoidosis, SLE, Behcets disease, scleroderma, Sjogren's, and erythema multiforme.
2. Inflammatory markers are usually very elevated in patients with irRAE and are useful to differentiate these events from other causes of their symptoms.
# Inflammatory arthritis:
• Clinical presentation can vary, affecting large and/or small joints, can have extra-articular symptoms including rash, tenosynovitis, axial involvement, conjunctivitis and urethritis. • Complete a thorough history and physical exam with examination of all peripheral joints for swelling, pain, and range of motion. • Exclude other causes including septic arthritis, viral polyarthritis, gout.
• Consider imaging of affected joints with plain film x-ray to evaluate for joint damage and rule out bony metastatic disease. • Consider serological testing including ANA, rheumatoid factor (RF), anti-citrullinated protein antibody (anti-CCP), and inflammatory markers erythrocyte sedimentation rate (ESR) and CRP. If symptoms are suggestive of reactive arthritis or affect the spine, consider HLA B27 testing. • Early recognition is critical to avoid erosive joint damage. Referral to a rheumatologist if there is evidence of joint swelling (synovitis) or if symptoms of arthralgia persist >4 weeks.
# Myositis:
• Myositis is a rare but potentially fatal toxicity of CPIs. Patients most commonly present with weakness, primarily in the proximal extremities. In severe cases, can also have myalgia. It can have a fulminant necrotizing course with rhabdomyolysis and involve other skeletal muscle, such as myocardium which can be potentially fatal if treatment is delayed.
• Complete a thorough rheumatologic, neurologic, and dermatologic exam paying specific attention to symptoms of muscle weakness or rash. • Complete blood testing for creatinine kinase (CK), transaminases (AST, ALT) and LDH, inflammatory markers (ESR, CRP). There is no evidence that autoantibodies (anti-Jo, anti-Mi2) have a role in CPI-induced myositis. • Evaluate for other potential causes including drugs, alcohol, infectious, metabolic or electrolyte disorders. • Consider troponin level to evaluate myocardial involvement as well as other cardiac investigations (e.g. echocardiogram) as required. • Consider electromyography (EMG), imaging (MRI), and/or biopsy on an individual basis when diagnosis is uncertain. • Consider paraneoplastic autoantibody testing for myositis and neurologic conditions, such as MG.
• Early referral to a rheumatologist if myositis is grade 2 or higher.
# Polymyalgia rheumatica:
• PMR presents as proximal myalgias and systemic symptoms including fatigue and low grade fever. • Complete a thorough rheumatologic and neurologic examination.
• Assess for symptoms of temporal arteritis including headache, jaw claudication, vision loss, and urgent temporal artery biopsy if this is suspected. • Complete blood testing for inflammatory markers (ESR, CRP) which are elevated in PMR, and investigations required for differential diagnosis; CK, ANA, RF, and anti-CCP (negative in PMR). • Early referral to a rheumatologist if PMR is grade 2 or higher.
# Sjogren's syndrome:
• Can present with sicca symptoms including dry eyes and mouth, enlarged parotid gland, and non-glandular involvement including arthritis and vasculitis. • Complete a thorough rheumatologic and dermatologic examination with assessment of the oropharynx for cracked tongue, lack of saliva pooling. • Complete blood testing including serological markers such as ANA, ENA (anti-Ro/SSA and/or anti-La/SSB antibodies), RF, anti-CCP antibody as sicca symptoms can occur with SLE and RA. • Early referral to a rheumatologist for considering of Schirmer test, minor salivary gland (lower lip) biopsy, sialometry.
# Sarcoid
• Most commonly seen with anti-CTLA4 or anti PD1 use in melanoma
• Presents as cutaneous sarcoidosis, or systemic with lymphadenopathy, lung or neurological and ocular involvement • No specific serum findings • May present with mediastinal or hilar lymphadenopathy on CT, but also parenchymal lung CT changes, such as ground glass opacities 8. Ultimately, early involvement of rheumatology can help to guide testing. 1. With the need for ongoing CPI therapy, treatment of rheumatologic complications should happen with the involvement of a rheumatologist experienced in the management of these complications.
2. Corticosteroids can be used as part of initial therapy in inflammatory arthritis as in other irAEs but due to likely prolonged treatment requirements, physicians should consider starting corticosteroid-sparing agents earlier than typically required with other irAEs.
3. Following the acute use of corticosteroids, a slow taper of corticosteroids must occur over a minimum of 1 month. Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.
4. A number of other rheumatic disorders have been documented as case reports of patients receiving CPIs including vasculitis and lupus-like syndromes. Management and treatment principles are similar to those reported for other CPI-induced rheumatic syndromes.
# 5.
It is recommended that all patients with inflammatory arthritis be monitored with serial rheumatologic examinations, including inflammatory markers, every 4 to 6 weeks after treatment is instituted.
# Appendix A: Literature Search Details
The literature search performed included a PubMed search that was conducted on 2016 October 8. The following terms for immune checkpoint inhibitors, adverse events and cancer were used in the search.
((immune checkpoint inhibitor*) OR ipilimumab OR pembrolizumab OR lambrolizumab OR nivolumab OR "Anti CTLA-4" OR "Anti CTLA 4" OR "Cytotoxic T-Lymphocyte Associated Protein 4" OR "PD-1" OR "PD-L1" OR "programmed cell death protein 1" OR IDO OR "indoleamine 2,3-dioxygenase" OR tremelimumab OR atezolizumab OR ticilimumab OR indoximod OR 1-methyl-d-tryptophan OR D-1MT OR MDX-010 OR MDX-101 OR BMS-734016 OR MK-3475 OR "SCH 900475") AND ("Drug-Related Side Effects and Adverse Reactions"[Mesh] OR "adverse events" OR toxicity) AND ("Neoplasms"[Mesh] OR oncolog* OR cancer OR malignan*) This search was limited to humans and the English language. No restrictions were applied in regards to study type or publication year. Articles met inclusion criteria if they were peer-reviewed guidelines, reviews or studies that reported on the presentation and prevalence of irAEs, their monitoring, management or follow up. Case reports on the management of toxicities were excluded with the exception of those which were included in overarching reviews. This search yielded 480 articles, of which 9 review articles (6 meta-analyses and 3 pooled analyses) with a focus on investigating checkpoint inhibitor therapy related toxicities in cancer patients were included for data extraction. Eleven studies (7 retrospective reviews, 3 retrospective observational studies, 1 randomized controlled trial and 1 secondary analysis of a phase III trial) were included, as well as 3 guidelines. These articles provided recommendations for the follow-up and management of immune-mediated adverse events.
Another aspect of the search included looking for existing guidelines on this topic that had already been published by prominent cancer associations, including the Canadian Partnership Against Cancer, the National Comprehensive Cancer Network and the American Cancer Society. The mineralocorticoid effect of commonly administered glucocorticoids may be estimated as follows:
• When given at replacement doses, triamcinolone, dexamethasone, and betamethasone have no clinically important mineralocorticoid activity. • 20 mg hydrocortisone and 25 mg of cortisone acetate each provide a mineralocorticoid effect that is approximately equivalent to 0.1 mg fludrocortisone. • Prednisone or prednisolone given at antiinflammatory doses ≥50 mg per day provide a mineralocorticoid effect that is approximately equivalent to 0.1 mg of fludrocortisone.
# Development and Revision History
This guideline was reviewed and endorsed by members of the Alberta Provincial Tumour Teams, including medical oncologists, gynecologic oncologists, hematologists, nurse practitioners, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Tumour Teams, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2020.
# Maintenance
A formal review of the guideline will be conducted in 2021. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
# Funding Source
Financial support for the development of Cancer Care Alberta's evidence-based clinical practice guidelines and supporting materials comes from the Cancer Care Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Dr. Aurore Fife-Mah has nothing to disclose.
Dr. Donald Morris has nothing to disclose.
Dr. Aliyah Pabani has nothing to disclose.
Dr. Vicky Parkins has nothing to disclose.
Dr. Gloria Roldan Urgoiti reports being a principal investigator on two clinical trials sponsored by Roche involving immunotherapy, but no direct compensation. | None | None |
defcb61e89885e9b04d1892bb1b85e982d458b5e | cma | None | Group and full NACI membership respectively reviewed the available evidence on epidemiology and vaccine protection, as well as planning considerations for the next steps of the COVID-19 booster program, including ethics, equity, feasibility and acceptability considerations. NACI also recommended the continued application of the existing decision -making framework for booster doses. NACI approved these recommendations on January 06, 2023. Further information on NACI's process and procedures is available elsewhere (1,2) .# Preamble
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be cond ucted using evidence-informed tools to identify distinct issues that could impact decision -making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the con tents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# Background
The Omicron variant of SARS-CoV-2 virus was first detected in November 2021, with its subvariants continuing to circulate in Canada and globally, more than one year later. The epidemiology of COVID-19 is expected to continue to evolve, and the likelihood, timing, and severity of any potential future resurgence of COVID-19 is uncertain. No strong evidence of seasonality of COVID-19 has emerged to date, and it has yet to be seen whether the incidence of SARS-CoV-2 virus infections will be analogous to other respiratory viruses that increase in the fall and winter seasons, thereby increasing pressure on health systems during this period.
Since September 2021, NACI has been developing and updating guidance on the use of COVID-19 booster doses based on a decision-making framework assessing the need for, and benefit of, additional doses of COVID-19 vaccines in various populations. These decisions were supported by vaccine principles, as well as evidence where available.
The NACI Interim guidance on planning considerations for a fall 2022 COVID-19 vaccine booster program in Canada (June 29, 2022) provided jurisdictions with planning advice for a booster dose program in advance of a possible future surge of COVID-19 in Canada over the fall and winter months and included an updated decision-making framework on booster doses. More specific guidance on vaccination recommendations for the fall of 2022, including booster doses in children 5 to 11 years of age and the use of bivalent Omicron-containing mRNA COVID-19 vaccines, was provided in the following NACI statements: Since then, additional NACI guidance has been requested as provinces and territories begin to consider planning for 2023.
NACI's recommendations remain aligned with the current goals of the Canadian COVID-19 Pandemic Response (as of February 14, 2022):
- To minimize serious illness and death while minimizing societal disruption as a result of the COVID-19 pandemic. - To transition away from the crisis phase towards a more sustainable approach to long term management of COVID-19.
For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to National Advisory Committee on Immunization (NACI): Statements and publications and the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
- Previous waves of SARS-CoV-2 in Canada have occurred over the spring, summer, fall and winter months, with some regional variability. The evolutionary trajectory of SARS-CoV-2, including the emergence of novel variants of concern (VOCs), is uncertain, and the seasonality of SARS-CoV-2 has not been established. - COVID-19 hospitalizations, ICU admissions and deaths continue to occur at a higher baseline frequency since the appearance of Omicron in late 2021 compared to the pre-Omicron period. - Some populations are at increased risk of severe outcomes of COVID-19 due to biological factors (e.g., advanced age, pre-existing medical conditions, pregnancy) and social factors (e.g., socioeconomic status, belonging to a racialized population) that may intersect. However, age continues to be the single greatest risk factor for severe outcomes of COVID-19. Older adults are the most likely to experience severe disease, with hospitalizations, ICU admissions and death rates highest in those 80 years of age and over, and ICU admission rates also high in those 70 to 79 years of age (see the PHAC COVID-19 epidemiology update). - Previously dominant BA.5.2 and BA.5.2.1 Omicron sublineages are decreasing, with more immune-evasive sublineages increasing (e.g., BQ.1, BQ.1.1 and BF.7).
# Duration of protection from booster doses against severe outcomes due to COVID-19
- Thus far, vaccine protection has been shown to wane over time, with protection against severe outcomes persisting longer than protection against symptomatic disease. - For BA.1 and BA.2 sublineages of Omicron, the duration of protection against severe disease such as hospitalization has remained high, with most estimates above 70% out to 26 weeks following receipt of an original (non-bivalent) COVID-19 vaccine booster dose (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) . - Duration of protection against severe disease for more recent variants and new vaccine formulations is not known at this time and continues to be monitored.
- When vaccine programs are implemented, data on duration of protection from the vaccine are often lacking and it is with ongoing monitoring that we determine whether and how often booster doses are required for the population (e.g., booster doses for pertussis in adolescents and adults and no booster doses for either HPV or hepatitis B vaccines).
# Hybrid immunity
- Evidence to date shows that vaccine effectiveness (VE) against BA.1 and BA.2 Omicron sublineages is higher in those who have been both vaccinated and infected with SARS-CoV-2 (i.e., in those who have hybrid immunity to SARS-CoV-2) when compared to those with prior infection alone or vaccination alone (4)(5)(6)(7)(8)(9)(10) . The duration of protection from hybrid immunity has not yet been fully characterized, but is likely to have an impact on the need for and timing of additional booster doses. - In Canada, the hybrid immunity profile differs by age group. A greater proportion of older adults are protected by vaccination only and have not been infected, as compared to younger ages. Adolescents and young adults have the highest proportion of hybrid immunity, and a large proportion of children have been infected but not vaccinated (17) . - Potential vaccination-and/or infection-induced protection against severe outcomes due to infection or reinfection from emerging Omicron sublineages have yet to be determined and the impact of various immunity profiles on protection against future VOCs is unknown. - There are Canadian data suggesting that vaccine protection may reach a plateau for adults with hybrid immunity, and the benefit of additional mRNA COVID-19 vaccine booster doses may be marginal (18) . This study assessed VE of the original mRNA COVID-19 vaccine against BA.2 among healthcare workers, and whether the findings would apply broadly to other COVID-19 vaccines (i.e., Omicron-containing bivalent mRNA vaccines), other VOCs, and populations has yet to be determined.
# Immunogenicity and VE of booster doses of Omicron-containing bivalent mRNA COVID-19 vaccine
- Clinical trials show that a booster dose of Omicron-containing bivalent mRNA COVID-19 vaccine produce higher neutralizing antibody responses against Omicron sublineages than the original vaccines, although preliminary results from small real-world studies have been somewhat variable. The immune response against the ancestral strain is similar after a booster dose of the original or Omicron-containing bivalent mRNA COVID-19 vaccine. - Neutralization of more recent Omicron sublineages such as BQ.1 is reduced compared to neutralization of earlier Omicron sublineages such as BA.1 or BA.5 after booster vaccination with either an original or Omicron-containing bivalent vaccine (19)(20)(21)(22)(23)(24)(25) . - Preliminary data from Ontario demonstrates that short-term (<90 days) VE against severe outcomes in community dwelling adults aged 50 years and older was similar between original and bivalent mRNA COVID-19 vaccine booster doses and between the available vaccine products (Moderna or Pfizer-BioNTech) during a period when BA.5 was the predominant Omicron sublineage and BQ.1 was emerging (26) . - A study from the United States in adults who had received at least 2 doses of an original mRNA COVID-19 vaccine reported improved VE against symptomatic SARS-CoV-2 infection after a subsequent booster dose of BA.4/5 bivalent mRNA vaccine compared to adults who did not receive a bivalent Omicron-containing mRNA COVID-19 vaccine (27) . The relative increase in VE was also larger for individuals with a longer interval since receipt of their previous original dose. A similar trend was observed for protection against COVID-19-associated emergency department/urgent care encounters and hospitalizations (28) .
- Early estimates of VE against hospitalization in immunocompetent adults 65 years of age and older from the United States, reported that a booster dose using a BA.4/5 bivalent Omicron-containing mRNA vaccine provided an additional 73% protection against COVID-19 hospitalization compared with past vaccination with original mRNA COVID-19 vaccines only (≥2 doses given ≥2 months previously) (29) . As original mRNA COVID-19 vaccines are no longer authorized for use in the United States, the effectiveness of bivalent versus original vaccines when used as booster doses in the same time period could not be compared. Of note, the VE studies from the United States were released following NACI deliberations and were not considered as part of decision-making (28,29) .
# Ethics, equity, feasibility and acceptability
- Although age is the greatest risk factor for severe outcomes of COVID-19, intersecting equity factors continue to create disproportionate risk for some key populations. Any future booster program should continue to support reducing the impact on those at highest risk of severe disease. - For all currently vaccine-eligible age-groups (i.e., 6 months of age and older), concurrent administration of any dose of a COVID-19 vaccine with other vaccines (e.g., seasonal inactivated influenza vaccine) has the potential to increase program efficiency and may also increase immunization rates. - There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions, with a focus on protecting those at highest risk for serious outcomes from COVID-19 infection.
# Recommendations
At this time, NACI is reinforcing existing recommendations for COVID-19 vaccines including suggested timing of doses following a previous SARS-CoV-2 infection. The fall 2022 booster program is being used as the reference point to consolidate booster guidan ce that has been published to date. A summary of recommendations for the primary series and booster doses is also provided in Table 1.
It is noted that the start date of the fall 2022 booster program varied across Canadian jurisdictions from August to September 2022.
Please see Table 2 for an explanation of strong versus discretionary NACI recommendations.
# NACI continues to recommend a COVID-19 vaccine primary series as follows:
1) Individuals 5 years of age and older should be immunized with a primary series of an authorized mRNA vaccine. (Strong NACI recommendation)
2) Children 6 months to under 5 years of age may be immunized with a primary series of an authorized mRNA vaccine. (Discretionary NACI recommendation)
Additional details including those pertaining to alternative vaccine products are available in the COVID-19 vaccine chapter in the Canadian Immunization Guide and NACI statements and publications.
# NACI continues to recommend COVID-19 vaccine booster doses as follows:
3 - The first booster dose program for children 5 to 11 years of age coincided with the fall booster dose campaign that targeted individuals 12 years of age and older. To integrate booster dose guidance for both of these age groups, current booster dose recommendations for individuals 5 years of age and older are summarized in Table 1. Children 5 to 11 years of age are recommended to receive only one booster dose at this time. However, at the provider's discretion, an additional booster dose using the bivalent vaccine (as per the recommended interval -see recommendation #7) could be offered to children considered at high risk of severe COVID-19 who have previously received a fall booster dose with the original Pfizer-BioNTech Comirnaty mRNA vaccine. At least one booster dose continues to be recommended for all adults 18 years of age and over.
Regardless of previous booster doses, a booster since the start of fall 2022 should be offered as per the recommended interval b if not already received.
# Adults 18 to 64 years of age
# Should be offered c
Those at increased risk for severe illness from COVID-19:
At least one booster dose continues to be recommended for all adults 18 years of age and over.
Regardless of previous booster doses, a booster since the start of fall 2022 should be offered as per the recommended interval b if not already received.
# Those NOT at increased risk for severe illness from COVID-19:
At least one booster dose continues to be recommended for all adults 18 years of age and over.
A booster since the start of fall 2022 may be offered as per the recommended interval b if not already received.
# Adolescents 12 to 17 years of age Should be offered c
Those at increased risk for severe illness from COVID-19:
At least one booster dose continues to be recommended for adolescents 12 to 17 years of age who are at increased risk of severe illness from COVID-19.
Regardless of previous booster doses, a booster since the start of fall 2022 should be offered as per the recommended interval b if not already received d .
# Those NOT at increased risk for severe illness from COVID-19:
A booster since the start of fall 2022 may be offered as per the recommended interval b if not already received.
Children 5 to 11 years of age Should be offered c
# Those at increased risk for severe illness from COVID-19:
A booster since the start of fall 2022 should be offered as per the recommended interval b if not already received d .
# Those NOT at increased risk for severe illness from COVID-19:
A booster since the start of fall 2022 may be offered as per the recommended interval b if not already received.
# Children 6 months to less than 5 years of age
May be offered c No authorized product; not recommended a. Bivalent Omicron-containing products are preferred for booster doses for the authorized ages. b. The recommended interval between the previous COVID-19 vaccine dose (previous booster or completion of the primary series) and a booster dose is 6 months, and between infection and a booster dose is 6 months (whichever is longer). A shorter interval of at least 3 months may be considered in the context of heightened epidemiologic risk, evolving SARS-COV-2 epidemiology, as well as operational considerations for efficient deployment. c.
Those who are moderately to severely immunocompromised are recommended to receive an additional dose in the primary series. Additional details are available in the COVID-19 vaccine chapter in the Canadian Immunization Guide and NACI statements and publications.
# Considerations regarding potential future booster programs and planning
With the inherent uncertainties around the evolution of the pandemic, it is unclear when the need for additional COVID-19 vaccine booster doses will arise, or to whom booster doses should be offered in the event that they are needed. NACI will continue to monitor the evidence, including SARS-CoV-2 epidemiology and duration of vaccine protection, particularly with regard to severe outcomes, in the coming months to provide recommendations on the timing of subsequent booster doses if warranted. Product options for booster doses could include additional vaccines as they become available.
There are a number of options for the timing of possible future booster doses if additional booster doses are required, and these include the following:
- Offer additional booster doses at a fixed interval from the previous booster dose - Offer additional booster doses at fixed time(s) of year - Offer additional booster doses based on evolving epidemiology - Some combination of the above In addition to monitoring epidemiology, duration of protection from current booster doses and previous infection, safety, immunogenicity, and vaccine effectiveness of bivalent Omicroncontaining vaccines or alternative vaccine products, future booster dose decisions should consider ethics, equity, and acceptability of future booster dose recommendations in addition to feasibility considerations of delivering booster dose campaigns. NACI acknowledges that significant preparations occur every year for the seasonal influenza campaign and will endeavour to provide further advice to inform the potential integration of COVID-19 immunization in advance of the fall of 2023.
# RESEARCH PRIORITIES
- Continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of COVID-19 vaccines, including booster doses, through clinical trials and studies in realworld settings, including the degree and duration of protection conferred by each booster dose against circulating variants. The research should also consider the clinical implications of previous SARS-CoV-2 infection; repeated immunization; and outcomes after any infection such as MIS-C, post-COVID-19 condition/post-acute COVID syndrome (long COVID), or infection-induced myocarditis or pericarditis in adult, adolescent, and pediatric populations. 2. Further evaluations of the optimal interval between dose administration, as well as further evaluations of the optimal interval between previous SARS-CoV-2 infection and vaccine dose administration. 3. Vigilant monitoring and reporting of adverse events of special interest, including myocarditis and/or pericarditis, in order to accurately inform potential risks associated with any future booster doses. Global collaboration should be prioritized to enable dat a sharing so decision makers around the world can weigh benefits and risks of additional booster doses of COVID-19 vaccines. 4. Continuous monitoring of COVID-19 epidemiology and VE in special populations at high risk of severe outcomes or long-term consequences of infection with COVID-19. 5. Further evaluation on the optimal timing and trigger for the initiation of potential future booster dose recommendations, as well as evaluation of potential risks associated with providing booster doses earlier than necessary. 6. Continuous monitoring of vaccine coverage in Canada, for COVID-19 vaccines and other routine vaccines, particularly in the context of COVID-19 vaccine booster doses and including consideration of measures that may reduce the risk of disparities in vaccine confidence and uptake across different sub-populations.
# Implication
A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale f or an alternative approach is present.
A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable. | Group and full NACI membership respectively reviewed the available evidence on epidemiology and vaccine protection, as well as planning considerations for the next steps of the COVID-19 booster program, including ethics, equity, feasibility and acceptability considerations. NACI also recommended the continued application of the existing decision -making framework for booster doses. NACI approved these recommendations on January 06, 2023. Further information on NACI's process and procedures is available elsewhere (1,2) .# Preamble
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be cond ucted using evidence-informed tools to identify distinct issues that could impact decision -making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the con tents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# Background
The Omicron variant of SARS-CoV-2 virus was first detected in November 2021, with its subvariants continuing to circulate in Canada and globally, more than one year later. The epidemiology of COVID-19 is expected to continue to evolve, and the likelihood, timing, and severity of any potential future resurgence of COVID-19 is uncertain. No strong evidence of seasonality of COVID-19 has emerged to date, and it has yet to be seen whether the incidence of SARS-CoV-2 virus infections will be analogous to other respiratory viruses that increase in the fall and winter seasons, thereby increasing pressure on health systems during this period.
Since September 2021, NACI has been developing and updating guidance on the use of COVID-19 booster doses based on a decision-making framework assessing the need for, and benefit of, additional doses of COVID-19 vaccines in various populations. These decisions were supported by vaccine principles, as well as evidence where available.
The NACI Interim guidance on planning considerations for a fall 2022 COVID-19 vaccine booster program in Canada (June 29, 2022) provided jurisdictions with planning advice for a booster dose program in advance of a possible future surge of COVID-19 in Canada over the fall and winter months and included an updated decision-making framework on booster doses. More specific guidance on vaccination recommendations for the fall of 2022, including booster doses in children 5 to 11 years of age and the use of bivalent Omicron-containing mRNA COVID-19 vaccines, was provided in the following NACI statements: Since then, additional NACI guidance has been requested as provinces and territories begin to consider planning for 2023.
NACI's recommendations remain aligned with the current goals of the Canadian COVID-19 Pandemic Response (as of February 14, 2022):
• To minimize serious illness and death while minimizing societal disruption as a result of the COVID-19 pandemic. • To transition away from the crisis phase towards a more sustainable approach to long term management of COVID-19.
For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to National Advisory Committee on Immunization (NACI): Statements and publications and the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
• Previous waves of SARS-CoV-2 in Canada have occurred over the spring, summer, fall and winter months, with some regional variability. The evolutionary trajectory of SARS-CoV-2, including the emergence of novel variants of concern (VOCs), is uncertain, and the seasonality of SARS-CoV-2 has not been established. • COVID-19 hospitalizations, ICU admissions and deaths continue to occur at a higher baseline frequency since the appearance of Omicron in late 2021 compared to the pre-Omicron period. • Some populations are at increased risk of severe outcomes of COVID-19 due to biological factors (e.g., advanced age, pre-existing medical conditions, pregnancy) and social factors (e.g., socioeconomic status, belonging to a racialized population) that may intersect. However, age continues to be the single greatest risk factor for severe outcomes of COVID-19. Older adults are the most likely to experience severe disease, with hospitalizations, ICU admissions and death rates highest in those 80 years of age and over, and ICU admission rates also high in those 70 to 79 years of age (see the PHAC COVID-19 epidemiology update). • Previously dominant BA.5.2 and BA.5.2.1 Omicron sublineages are decreasing, with more immune-evasive sublineages increasing (e.g., BQ.1, BQ.1.1 and BF.7).
# Duration of protection from booster doses against severe outcomes due to COVID-19
• Thus far, vaccine protection has been shown to wane over time, with protection against severe outcomes persisting longer than protection against symptomatic disease. • For BA.1 and BA.2 sublineages of Omicron, the duration of protection against severe disease such as hospitalization has remained high, with most estimates above 70% out to 26 weeks following receipt of an original (non-bivalent) COVID-19 vaccine booster dose (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) . • Duration of protection against severe disease for more recent variants and new vaccine formulations is not known at this time and continues to be monitored.
• When vaccine programs are implemented, data on duration of protection from the vaccine are often lacking and it is with ongoing monitoring that we determine whether and how often booster doses are required for the population (e.g., booster doses for pertussis in adolescents and adults and no booster doses for either HPV or hepatitis B vaccines).
# Hybrid immunity
• Evidence to date shows that vaccine effectiveness (VE) against BA.1 and BA.2 Omicron sublineages is higher in those who have been both vaccinated and infected with SARS-CoV-2 (i.e., in those who have hybrid immunity to SARS-CoV-2) when compared to those with prior infection alone or vaccination alone (4)(5)(6)(7)(8)(9)(10) . The duration of protection from hybrid immunity has not yet been fully characterized, but is likely to have an impact on the need for and timing of additional booster doses. • In Canada, the hybrid immunity profile differs by age group. A greater proportion of older adults are protected by vaccination only and have not been infected, as compared to younger ages. Adolescents and young adults have the highest proportion of hybrid immunity, and a large proportion of children have been infected but not vaccinated (17) . • Potential vaccination-and/or infection-induced protection against severe outcomes due to infection or reinfection from emerging Omicron sublineages have yet to be determined and the impact of various immunity profiles on protection against future VOCs is unknown. • There are Canadian data suggesting that vaccine protection may reach a plateau for adults with hybrid immunity, and the benefit of additional mRNA COVID-19 vaccine booster doses may be marginal (18) . This study assessed VE of the original mRNA COVID-19 vaccine against BA.2 among healthcare workers, and whether the findings would apply broadly to other COVID-19 vaccines (i.e., Omicron-containing bivalent mRNA vaccines), other VOCs, and populations has yet to be determined.
# Immunogenicity and VE of booster doses of Omicron-containing bivalent mRNA COVID-19 vaccine
• Clinical trials show that a booster dose of Omicron-containing bivalent mRNA COVID-19 vaccine produce higher neutralizing antibody responses against Omicron sublineages than the original vaccines, although preliminary results from small real-world studies have been somewhat variable. The immune response against the ancestral strain is similar after a booster dose of the original or Omicron-containing bivalent mRNA COVID-19 vaccine. • Neutralization of more recent Omicron sublineages such as BQ.1 is reduced compared to neutralization of earlier Omicron sublineages such as BA.1 or BA.5 after booster vaccination with either an original or Omicron-containing bivalent vaccine (19)(20)(21)(22)(23)(24)(25) . • Preliminary data from Ontario demonstrates that short-term (<90 days) VE against severe outcomes in community dwelling adults aged 50 years and older was similar between original and bivalent mRNA COVID-19 vaccine booster doses and between the available vaccine products (Moderna or Pfizer-BioNTech) during a period when BA.5 was the predominant Omicron sublineage and BQ.1 was emerging (26) . • A study from the United States in adults who had received at least 2 doses of an original mRNA COVID-19 vaccine reported improved VE against symptomatic SARS-CoV-2 infection after a subsequent booster dose of BA.4/5 bivalent mRNA vaccine compared to adults who did not receive a bivalent Omicron-containing mRNA COVID-19 vaccine (27) . The relative increase in VE was also larger for individuals with a longer interval since receipt of their previous original dose. A similar trend was observed for protection against COVID-19-associated emergency department/urgent care encounters and hospitalizations (28) .
• Early estimates of VE against hospitalization in immunocompetent adults 65 years of age and older from the United States, reported that a booster dose using a BA.4/5 bivalent Omicron-containing mRNA vaccine provided an additional 73% protection against COVID-19 hospitalization compared with past vaccination with original mRNA COVID-19 vaccines only (≥2 doses given ≥2 months previously) (29) . As original mRNA COVID-19 vaccines are no longer authorized for use in the United States, the effectiveness of bivalent versus original vaccines when used as booster doses in the same time period could not be compared. Of note, the VE studies from the United States were released following NACI deliberations and were not considered as part of decision-making (28,29) .
# Ethics, equity, feasibility and acceptability
• Although age is the greatest risk factor for severe outcomes of COVID-19, intersecting equity factors continue to create disproportionate risk for some key populations. Any future booster program should continue to support reducing the impact on those at highest risk of severe disease. • For all currently vaccine-eligible age-groups (i.e., 6 months of age and older), concurrent administration of any dose of a COVID-19 vaccine with other vaccines (e.g., seasonal inactivated influenza vaccine) has the potential to increase program efficiency and may also increase immunization rates. • There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions, with a focus on protecting those at highest risk for serious outcomes from COVID-19 infection.
# Recommendations
At this time, NACI is reinforcing existing recommendations for COVID-19 vaccines including suggested timing of doses following a previous SARS-CoV-2 infection. The fall 2022 booster program is being used as the reference point to consolidate booster guidan ce that has been published to date. A summary of recommendations for the primary series and booster doses is also provided in Table 1.
It is noted that the start date of the fall 2022 booster program varied across Canadian jurisdictions from August to September 2022.
Please see Table 2 for an explanation of strong versus discretionary NACI recommendations.
# NACI continues to recommend a COVID-19 vaccine primary series as follows:
1) Individuals 5 years of age and older should be immunized with a primary series of an authorized mRNA vaccine. (Strong NACI recommendation)
2) Children 6 months to under 5 years of age may be immunized with a primary series of an authorized mRNA vaccine. (Discretionary NACI recommendation)
Additional details including those pertaining to alternative vaccine products are available in the COVID-19 vaccine chapter in the Canadian Immunization Guide and NACI statements and publications.
# NACI continues to recommend COVID-19 vaccine booster doses as follows:
3 • The first booster dose program for children 5 to 11 years of age coincided with the fall booster dose campaign that targeted individuals 12 years of age and older. To integrate booster dose guidance for both of these age groups, current booster dose recommendations for individuals 5 years of age and older are summarized in Table 1. Children 5 to 11 years of age are recommended to receive only one booster dose at this time. However, at the provider's discretion, an additional booster dose using the bivalent vaccine (as per the recommended interval -see recommendation #7) could be offered to children considered at high risk of severe COVID-19 who have previously received a fall booster dose with the original Pfizer-BioNTech Comirnaty mRNA vaccine. At least one booster dose continues to be recommended for all adults 18 years of age and over.
Regardless of previous booster doses, a booster since the start of fall 2022 should be offered as per the recommended interval b if not already received.
# Adults 18 to 64 years of age
# Should be offered c
Those at increased risk for severe illness from COVID-19:
At least one booster dose continues to be recommended for all adults 18 years of age and over.
Regardless of previous booster doses, a booster since the start of fall 2022 should be offered as per the recommended interval b if not already received.
# Those NOT at increased risk for severe illness from COVID-19:
At least one booster dose continues to be recommended for all adults 18 years of age and over.
A booster since the start of fall 2022 may be offered as per the recommended interval b if not already received.
# Adolescents 12 to 17 years of age Should be offered c
Those at increased risk for severe illness from COVID-19:
At least one booster dose continues to be recommended for adolescents 12 to 17 years of age who are at increased risk of severe illness from COVID-19.
Regardless of previous booster doses, a booster since the start of fall 2022 should be offered as per the recommended interval b if not already received d .
# Those NOT at increased risk for severe illness from COVID-19:
A booster since the start of fall 2022 may be offered as per the recommended interval b if not already received.
Children 5 to 11 years of age Should be offered c
# Those at increased risk for severe illness from COVID-19:
A booster since the start of fall 2022 should be offered as per the recommended interval b if not already received d .
# Those NOT at increased risk for severe illness from COVID-19:
A booster since the start of fall 2022 may be offered as per the recommended interval b if not already received.
# Children 6 months to less than 5 years of age
May be offered c No authorized product; not recommended a. Bivalent Omicron-containing products are preferred for booster doses for the authorized ages. b. The recommended interval between the previous COVID-19 vaccine dose (previous booster or completion of the primary series) and a booster dose is 6 months, and between infection and a booster dose is 6 months (whichever is longer). A shorter interval of at least 3 months may be considered in the context of heightened epidemiologic risk, evolving SARS-COV-2 epidemiology, as well as operational considerations for efficient deployment. c.
Those who are moderately to severely immunocompromised are recommended to receive an additional dose in the primary series. Additional details are available in the COVID-19 vaccine chapter in the Canadian Immunization Guide and NACI statements and publications.
# Considerations regarding potential future booster programs and planning
With the inherent uncertainties around the evolution of the pandemic, it is unclear when the need for additional COVID-19 vaccine booster doses will arise, or to whom booster doses should be offered in the event that they are needed. NACI will continue to monitor the evidence, including SARS-CoV-2 epidemiology and duration of vaccine protection, particularly with regard to severe outcomes, in the coming months to provide recommendations on the timing of subsequent booster doses if warranted. Product options for booster doses could include additional vaccines as they become available.
There are a number of options for the timing of possible future booster doses if additional booster doses are required, and these include the following:
• Offer additional booster doses at a fixed interval from the previous booster dose • Offer additional booster doses at fixed time(s) of year • Offer additional booster doses based on evolving epidemiology • Some combination of the above In addition to monitoring epidemiology, duration of protection from current booster doses and previous infection, safety, immunogenicity, and vaccine effectiveness of bivalent Omicroncontaining vaccines or alternative vaccine products, future booster dose decisions should consider ethics, equity, and acceptability of future booster dose recommendations in addition to feasibility considerations of delivering booster dose campaigns. NACI acknowledges that significant preparations occur every year for the seasonal influenza campaign and will endeavour to provide further advice to inform the potential integration of COVID-19 immunization in advance of the fall of 2023.
# RESEARCH PRIORITIES
1. Continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of COVID-19 vaccines, including booster doses, through clinical trials and studies in realworld settings, including the degree and duration of protection conferred by each booster dose against circulating variants. The research should also consider the clinical implications of previous SARS-CoV-2 infection; repeated immunization; and outcomes after any infection such as MIS-C, post-COVID-19 condition/post-acute COVID syndrome (long COVID), or infection-induced myocarditis or pericarditis in adult, adolescent, and pediatric populations. 2. Further evaluations of the optimal interval between dose administration, as well as further evaluations of the optimal interval between previous SARS-CoV-2 infection and vaccine dose administration. 3. Vigilant monitoring and reporting of adverse events of special interest, including myocarditis and/or pericarditis, in order to accurately inform potential risks associated with any future booster doses. Global collaboration should be prioritized to enable dat a sharing so decision makers around the world can weigh benefits and risks of additional booster doses of COVID-19 vaccines. 4. Continuous monitoring of COVID-19 epidemiology and VE in special populations at high risk of severe outcomes or long-term consequences of infection with COVID-19. 5. Further evaluation on the optimal timing and trigger for the initiation of potential future booster dose recommendations, as well as evaluation of potential risks associated with providing booster doses earlier than necessary. 6. Continuous monitoring of vaccine coverage in Canada, for COVID-19 vaccines and other routine vaccines, particularly in the context of COVID-19 vaccine booster doses and including consideration of measures that may reduce the risk of disparities in vaccine confidence and uptake across different sub-populations.
# Implication
A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale f or an alternative approach is present.
A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.
# ACKNOWLEDGMENTS
This statement was prepared by: E Wong, B Warshawsky, SJ Ismail, MC Tunis, R Harrison, S Wilson, and S Deeks, on behalf of NACI.
NACI gratefully acknowledges the contribution of: K Ramotar, C Mauviel, M Salvadori, J Zafack, N Forbes, R Krishnan, J Montroy, A Killikelly, E Tice, and the NACI Secretariat. | None | None |
3e8ecf72998dba97d7b1103fd6da8f8a8d67f3ea | cma | None | # Revision History
July 22, 2021 -Current For this version of the guideline, revisions are highlighted in yellow throughout the document.
October 28, 2020 -Original Release
# A Note on Terminology and Language
In Ontario, there is a diverse range of populations that require pregnancy care as well as a wide range regulated healthcare providers (HCPs) who provide pregnancy care. There are also a variety of settings in which pregnancy care can occur. To support the application of these guidelines to the full spectrum of providers, the wide range of populations and the plethora of settings, the terminology used is meant to be representative. Selected terminology that has been used throughout the guidelines includes:
- pregnant individual/people: woman, transgender individual, non-binary individual, surrogate, gestational carrier - care environment: clinics, offices, community settings, ambulatory care, homes, obstetrical triage, emergency room and birthing centres - healthcare provider: regulated healthcare providers in Ontario, including family physicians, registered midwives, Indigenous midwives, obstetricians, maternalfetal medicine specialists, Registered Nurses and Registered Practical Nurses - support person: spouse, partner, co-decision maker
# Summary of Recommendations
# A. Care of Pregnant Population
# Involvement of Support People in Pregnancy Care
- Visitor and support policies should allow for one support person (at minimum) for significant events in the prenatal period, including pregnancy loss and communication of and consultation for significant complications of pregnancy.
Where in-person support is not possible or permitted, the importance of the support people and partners should be acknowledged, and their involvement facilitated through virtual means.
- The presence of culturally relevant support people is essential to culturally safe care.
# Early Pregnancy Loss and Stillbirth
Presence of Support People at Times of Pregnancy Loss
- Where possible, support person policies should allow pregnant persons who may be losing a pregnancy at any gestational age to have one support person (at minimum) with them.
# Follow-Up of Pregnancy Loss
- Follow-up of early pregnancy loss can often be done virtually, allowing for inperson visits as needed.
- Safe and empathetic care of pregnant individuals at risk of early pregnancy loss must remain a priority during the pandemic.
- Pregnant people experiencing loss should know how to seek emergency care and be reassured that if they need to be seen in person, they will be safe and at low risk of contracting COVID-19
- Surgical management of early pregnancy loss is non-elective and should be maintained as an option for management throughout the pandemic alongside expectant and medication management.
# Stillbirth
- Special care and consideration must be taken in supporting individuals and families experiencing stillbirth during the pandemic. As usual, support systems and grieving venues may be altered or unavailable at such times, the needs of the family must be balanced with public health measures and pandemic protocols.
- The usual stillbirth investigations should continue to take place as well as consideration of COVID-19 testing of the person experiencing stillbirth, the infant and the placenta.
# Termination of Pregnancy First Trimester Medication Termination
- There is good evidence to support first trimester medication termination (up to 70 days GA) with reduced or no ultrasound or visits to hospital, directed by virtual care and handouts with instructions for the termination itself and for posttermination care.
- Care should be taken to ensure safe access to urgent post-abortion care for the small percentage of medication failures; this may involve a pathway with access to places other than busy emergency wards at times of high community transmission.
# Surgical Termination
- Surgical termination is considered an essential service and should remain accessible in the pandemic.
- Surgical termination in a COVID-19 positive person should not be postponed if delay affects the person's safety or access to termination.
# Second and Third Trimester Termination of Pregnancy
- The protection of reproductive rights extends to options to terminate a pregnancy in the second or third trimester; services to persons opting for pregnancy termination, such as safe and supported induction of labour, should remain similar to what is offered in non-pandemic times.
- Mifepristone, administered >12h before the start of induction should be considered to significantly shorten the admission to hospital without increased risk of fetal expulsion prior to hospital admission or other complications.
# Treatment of Tissues, Remains and Stillborn Infants
- Families requesting tissues and remains should be respected as per institutional protocols. Cultural beliefs around burial should be facilitated and Indigenous people should have access to their placenta and remains of fetal tissue at their request for ceremonial purposes.
# Prenatal Screening and Genetic Counseling
Prenatal Screening Ontario (PSO) Adjustments to Screening
- Prenatal screening for Down syndrome and Trisomy 18 should be offered and eFTS continues to be the preferred test in low-risk pregnancies. Where access to NT screening is limited, the following advice from Prenatal Screening Ontario should be followed:
- For singleton pregnancies: if an NT ultrasound cannot be done, order Maternal Serum Screening (MSS, also known as Second Trimester Quad screen)
- For twin pregnancies: NT services should be prioritized. If NT is unavailable or if maternal age is 35 or older at expected date of delivery, publicly funded NIPT will be temporarily available.
- For higher order multiples: NT ultrasound currently is the only screening option available.
# Special Considerations
Preeclampsia Screening
- Pregnant people at risk for preeclampsia benefit from low-dose ASA initiated at or before 16 weeks gestational age. Assessment of risk factors, with or without added serum biomarkers or biophysical markers, can assist in the reduction of the burden of preeclampsia and IUGR on care environments during COVID-19.
# Sexually Transmitted Infections Screening and Treatment During the Pandemic
- Routine screening for STIs in pregnancy, including HIV, syphilis, hepatitis B, chlamydia and gonorrhea, should continue. Resources for screening, testing, contact tracing, education and follow-up should be considered essential services and be preserved during the pandemic.
# Screening for Diabetes in Pregnancy
- Early pregnancy screening for women at risk of pre-existing diabetes should continue unchanged. While it may result in decreased detection of mild disease, screening for gestational diabetes between 24 and 28 weeks may be modified by replacing the OGTT with a random glucose and HbA1c when local lab capacity and/or disease levels necessitate.
# Provision of Ultrasound for Low-Risk Pregnancies
- Access should be preserved to at minimum the following ultrasound scans:
# Management of High-Risk Pregnancy
Frequency and Form of Visits for High-Risk Pregnancies
- The care of high-risk pregnancies will, in essence, remain unchanged but contacts can be reduced by use of virtual visits, clustering of care and avoidance of duplication of assessments.
# Assessment of Fetal Well-being Special Tests
- Assessment of fetal well-being should continue to be performed but steps can be taken to reduce the number of unnecessary assessments through deliberate use of testing and/or special tests.
Perinatal Mood Disorders and Substance Use
- Pregnant and postpartum people, as well as those with pre-existing mental health conditions, are amongst the most vulnerable during the COVID-19 pandemic. Healthcare providers should prioritize the care of this population during the pandemic.
- Providers should increase their awareness of and screening for mood disorders and substance use and adjust the frequency and format of visits to allow for both early detection and intervention.
- Provision of perinatal mental health services should be considered an essential service and while the format may need to be altered, these services should be continued and strengthened throughout the pandemic.
- Existing resources and techniques for supporting pregnant individuals with perinatal mood disorders and substance use can be modified to create formats that are accessible through virtual means or a reduced number of visits.
- Given the likelihood of increased substance use and worsening of pre-existing substance use disorders during the COVID-19 pandemic, all pregnant people should be actively screened for alcohol, cannabis, tobacco, and prescription and recreational drug use at multiple points during the pregnancy.
- Pre-existing pregnancy-specific guidelines on substance use in pregnancy should be supplemented by general COVID-19 substance use guidance.
# Intimate Partner Violence
- Due to the increased rates of IPV during the pandemic, providers should remain vigilant through increased screening for domestic violence as well as maintain a heightened awareness of the signs and symptoms suggestive of IPV.
- Care providers should remain vigilant to the ways in which virtual/remote care may be difficult to safely access for survivors of IPV and in-person care should be used to provide safe alternatives when necessary.
# Birth Planning and Counseling
- Prenatal education can be offered during the pandemic through virtual means. Discussion on specific COVID-19 education should be incorporated into prenatal education and prenatal care.
- All pregnant individuals should explicitly plan for birth keeping in mind the impacts of COVID-19 on their care and care environments.
- Indications and options for IOL, TOLAC and high-risk pregnancies are unchanged by the pandemic. However, it should be acknowledged that the impacts of the pandemic may influence both the care environment and the pregnant person's preferences; shared decision-making should continue with increased attention to these factors.
- Guidance suggests that pregnant people can continue to work during the pandemic taking into consideration work related risk, individual risk and local disease activity. HCPs should continue to recommend appropriate workplace accommodations when risk is considered high.
- Pregnant HCPs may continue to work in clinical roles with proper infection control procedures and consideration of assignment to lower-risk care environments.
Testing for COVID-19 in the Pregnant Population
- Pregnant people should be screened and tested as per guidelines for the general population and should be considered a priority population if access to testing is limited. Testing should be expedited for labouring pregnant individuals and when a prerequisite of transfer to another facility.
- Policies on pre-admission and pre-surgical testing as well as disease clearance should apply to pregnant people in the same way that they do to the general population.
# Surveillance of COVID-19 Positive Pregnancies
- Data collection is urgently needed to provide credible information to facilitate and improve care and to help guide decision making at a provincial level. Hospitals and midwifery practice groups are encouraged to contribute to the data collection for pregnant people with suspected or confirmed COVID-19 through BORN Ontario. Where data is not able to be collected through BORN (e.g., Indigenous Midwifery Programs), interim data collection should be implemented without delay.
# B. Care of the COVID-19 Suspected or Confirmed Pregnant Person
- Routine pregnancy care may be deferred until the pregnant person with COVID-19 is no longer infectious, provided it is safe to do so.
- If possible, provision of pregnancy care, including maternal and fetal assessments as well as ultrasound, can be provided at the same visit to minimize multiple exposures to people and care environments.
- There is evidence showing an increased risk of severe infection with COVID-19 during pregnancy; therefore, increased surveillance for both the pregnant person and the fetus are warranted for the remainder of the pregnancy. - For most pregnancies, a minimum of eight antenatal appointments, with a combination of virtual and in-person care, can be adopted during the pandemic.
- Investigations, including lab and ultrasound, should be clustered where possible to minimize contacts with the health care system.
- Virtual care may replace some in-person in a blended model of care following guidance from professional organizations to ensure safety.
# Technology Access and Equity
- HCPs should assess the pregnant person's needs, means and ability to participate in virtual care and provide accommodations as needed. No pregnant person should be denied appropriate pregnancy care based on their inability to access technology.
Lack of Access to Care, Late to Care
- HCPs must understand systemic barriers to accessing care and the disproportionate health impacts of the pandemic on populations who already carry a higher burden of perinatal morbidity and mortality. Providers must make efforts to create safe spaces and modifications to care for those facing barriers.
# Fear of Accessing Care
- HCPs should be aware of the impact of fear on accessing prenatal care, including COVID-19 testing, and provide reassurance, guidance and resources to minimize this impact.
# Rural and Remote Considerations
- In rural and remote communities, access to essential prenatal testing and diagnostics must be preserved. Where feasible, point of care testing should be made available and test timing should take into account transit times to urban laboratories.
- Virtual care can potentially improve access to prenatal care for rural and remote pregnant individuals, but providers must be aware of issues around access and the quality of technology in rural communities.
- Where possible, care should be provided in a pregnant person's home community. Where travel for care is necessary, visits and testing should be bundled in a way that minimizes travel and post-travel periods of selfisolation/quarantine.
- When pregnant people are required to travel in and out of their home community for prenatal care and birth, isolation and quarantine policies should balance the needs of the community and the impact on the individual and their supports. Anxieties around risk of contracting the virus must be balanced against the necessity of the care being accessed in other communities and safeguards put in place.
- During pregnancy care, providers should enquire directly about access to resources for transmission prevention, including safe housing and clean water.
# Evacuation for Birth
- Increased planning for and education around resources in the planned location of birth will be needed during times of lockdown and phased recovery. Providers should be aware of and explicitly address the emotional and financial costs of evacuation for birth.
- Policies and practices around evacuation for birth must recognize that disproportionate burden carried by Indigenous communities and must be created in a culturally safe manner.
- All rural care providers and environments should be supported in providing care to COVID-19 suspected or positive pregnant people with increased virtual support and education and transfer when appropriate.
# Care in Home and Non-Clinical Settings
- Visits outside of the clinical care environment should be kept to a minimum while recognizing these visits may be necessary in certain situations. Adequate PPE for HCPs, pregnant individuals and their support people, and strict IPAC practices, must be used to make visits in non-clinical environments as safe as possible.
# D. Provider Considerations
Communication During and About the Pandemic
- HCPs and care environments should communicate with pregnant people about changes to care as well as provide information about COVID-19 in pregnancy. They are encouraged to do this through a variety of means, including websites and social media.
- Clear and empathetic communication is a priority. Providers should be aware of the ways in which virtual care and PPE may impact communication.
- Contact information should be collected and confirmed. Pregnant people at all gestational ages should be provided with copies of results to minimize repeat investigations.
# Staffing
- Care environments should prepare for staffing impacts of the pandemic, including by developing emergency staffing plans and by strengthening community partnerships.
- Care environments should communicate clearly with staff about the impacts of COVID-19 on the work environment, including the details of pandemic staffing plans.
# COVID-19 Related Stigma and Violence Directed Against HCPs
- COVID-19-related stigma and violence directed against healthcare workers cannot be tolerated. Care environments and workplaces should actively work to reduce stigma and violence through a multi-faceted approach.
# E. Task Force Health Equity Content
- Providers and care environments should tailor these recommendations to the individuals under their care, consulting those who provide support to specific populations to ensure appropriateness.
# Introduction
In the early months of the COVID-19 pandemic response, PCMCH's Maternal-Neonatal Committee established the first COVID-19 Task Force. This first task force was charged by the Ontario Ministry of Health (MOH) with addressing the immediate maternalneonatal practice concerns relating to interpretations and application of guidelines for intrapartum care. Subsequent to the release of the Maternal-Neonatal Guideline in Spring 2020, the Committee identified the need for additional guidelines in the area of pregnancy care. The Maternal-Neonatal Committee Pregnancy Care Task Force was struck to continue to navigate the multiple practice guidelines from international, national, regional, and local authorities in an attempt to advise the health system and providers on safe practices related to prenatal care.
The task force reviewed English-language clinical guidelines and other guidance documents from government ministries and agencies, professional associations and colleges, international organizations, and other relevant organizations from Canada, the United Kingdom , United States of America , and Australia at the time of publication and with subsequent updates. As guidelines continue to be updated and new evidence emerges, sections of this guideline may no longer be current or applicable to clinical practice.
This Pregnancy Care Task Force was asked to provide the MOH with the recommendations that would standardize practice across the province in an attempt to reduce the variations among providers and across all antenatal care settings in the province of Ontario. The recommendations that follow reflect the current pandemic and integrate best scientific evidence, and are based on the following underlying values and principles.
This guidance provides basic information only. It is not intended to take the place of medical advice, diagnosis or treatment. Please check the PCMCH COVID-19 website and Ontario Ministry of Health (MOH) COVID-19 website regularly for the latest case definition, FAQs and other pertinent information.
# Underlying Values & Principles
In preparation of this guideline, the task force was guided by the following underlying values:
# Beneficence and duty of care
Providing safe and effective care within resource constraints and limitations of evidence
# Access and Equity
Promoting just/fair distribution of benefit and burdens in time of pandemic
# Utility
Balancing evidence and values in order to maximize the greatest possible good for the greatest number of individuals
# Trust:
Foster and maintain the public's trust and health care providers' trust in each other, in leadership, and in their institutions
# Solidarity
Building, preserving, and strengthening inter-professional and inter-institutional collaboration (a responsibility of Health Care Providers (HCPs), institutional leadership, and the MOH)
# Advocacy
Identify emerging health issues in pandemic that require action; promoting public education and engagement; gathering feedback on impact at regional level This guideline aims to:
- conserve quality, consistency and continuity of antenatal care for pregnant people and their supports even in face of changes and restrictions brought on by the pandemic - promote public health aims of reducing COVID-19 transmission and preserving healthcare resources - provide education and opportunity for engagement for HCPs and pregnant people - align with Canadian guidelines, differing only where an Ontario-specific context was needed. The task force made recommendations that represent a general agreement from its members. - support reconciliation through recommendations specific to Indigenous pregnant people and communities (see below) - To bring to the guideline a focus on equity (see below)
# Indigenous Health
It has been said that for Indigenous populations that they "are already walking in a pandemic" .
"Our communities are at the front lines of an inequitable system. The trauma experienced within a health care system that is systematically biased and racist is real for us and for our clients. It's a system that leaves us with limited supplies, inadequate or no clinical space and is painfully slow to respond to our needs. COVID-19 is a new and added layer to this" .
Although Indigenous people comprise approximately four per cent of the population of Ontario, the health inequities that Indigenous people face every day are enormous compared to the rest of the population .
The original people of the land were once healthy and thriving. The colonization of the land they inhabited resulted in the displacement of Indigenous people onto economically unfeasible reserve lands; the devastating and effects of residential schools; the forced sterilization of Indigenous women; the apprehensions of newborns from their families of origin; and the removal of pregnant people from their communities for prenatal and intrapartum care. Such imposed forces created these inequities since settlers landed on the shores of North America.
In recognition of these health inequities, it is contingent upon all HCPs to provide culturally safe trauma--informed care to all Indigenous families. The phrase "Nothing about us without us" reinforces the vision of a shared understanding of the relationship that Indigenous people are asking of their care providers. Another phrase, "ask, don't tell", also brings to light an approach to the provider/patient relationship that allows for the dialogue and respect required to achieve better health outcomes.
Indigenous communities have historically been disadvantaged by a lack of investment in perinatal care in rural, remote and Indigenous communities as well as the practice of evacuation for birth. In addition, historic harms have led to a distrust in the medical system and a reluctance to seek care. During the pandemic, these issues are magnified and negatively impact the ability to enact recommendations designed to maintain quality of care.
While this document focuses on pregnancy care during the COVID-19 pandemic, there is little information and data coming out of Indigenous communities to inform HCPs on current outcomes and changes in the way care is provided . Throughout this document, we have added recommendations in areas where improvements can be made. In responding to the pandemic, as in all areas of healthcare planning, the approach should not deliberately consider the health needs of Indigenous populations but to ask -rather than tell -when making recommendations, incorporating a and process of Indigenous engagement that is led by Indigenous people.
# COVID-19 and Health Equity
While forming the Pregnancy Care Task Force, it was recognized that the impacts of the COVID-19 pandemic and public health measures have had different implications to different populations. As the healthcare system continues to adapt and respond to the needs of Ontarians, the health needs of Indigenous peoples require healthcare providers and organizations to consider a culturally safe and customized response.
For many groups, the pandemic has created particular challenges that then impact and influence their experience of pregnancy within the healthcare system. The task force recognizes that recommendations presented may not be feasible or applicable to meet the needs of these individuals. As providers working and living in a vast and diverse space within Ontario, it must be recognized that many have an experience of being unable to meet the needs of those most vulnerable.
Pregnancy, childbirth and the postnatal period are critical life stages when individuals and their families have a high degree of interaction with multiple providers in the healthcare system. The need for equitable care during these life stages is time sensitive and cannot be delayed during the pandemic response. However, the changes brought about by the pandemic have highlighted and intensified the unintended consequences of current institutional practices and policies, resulting in marginalized and racialized groups being subjected to greater inequities. Efforts to reduce the number of interactions between care providers and pregnant/ postpartum individuals and their families can be adjusted during the pandemic; however, essential elements of care must be maintained.
# A. Care of Pregnant Population
The COVID-19 pandemic has had far-reaching impacts on all care environments. Pregnancy care is an essential service that must continue regardless of disease activity and phase of the pandemic; therefore, providers have been called upon to alter form and frequency of care while still safeguarding the physical and emotional health of pregnant people and their fetuses . Pregnancy is increasingly viewed as a risk factor for more severe outcomes from COVID-19 infection; this factor must also be considered in how pregnancy care is delivered during the pandemic . The following discussion and recommendations will help guide the ways in which care can be modified to balance good outcomes with disease risk mitigation.
# Involvement of Support People in Pregnancy Care
Traditionally, involvement of support people in prenatal care has been high. Pregnancy and the beginnings of a new family are times when pregnant people may desire or need an increased presence of support people, and when non-pregnant family members and supports feel a strong attachment to and involvement in the outcomes. Because of this, the presence of a designated support person during labour and birth continues is commended even during the pandemic .
To reduce transmission and conserve personal protective equipment (PPE) and staff time most healthcare environments have restricted or prohibited support people from attending many appointments, including routine prenatal appointments, scheduled investigations (e.g., ultrasound) and non-scheduled assessment (e.g., triage visits). While these restrictions may be seen as generally reasonable and often necessary for infection control reasons, it is important to consider the value of allowing support people in pregnancy care. This is especially true when pregnancy complications arise, when difficult decisions need to be made or when bad news needs to be communicated (e.g., abnormal test results, significant complications or pregnancy loss). As such, healthcare environments and providers should consider making exceptions to support/visitor restrictions in these circumstances.
At times, it may be appropriate and sufficient for the support person to be present via virtual means (e.g., phone or video), but the need for in-person support at highly emotional times cannot be disregarded. Equally, it must be acknowledged that pregnancy loss and fetal complications have a significant impact on support people over and above their role in supporting the pregnant person. When fetal outcomes are involved, support persons are often also shared-decision makers whose involvement is essential. Consideration should be given to providing consultations virtually where appropriate (e.g., genetic counseling) to facilitate the pregnant person and their supports being together and jointly involved in the consultation.
When support people attend in-person assessments, itis essential that everyone adheres to all infection control procedures, including screening and use of PPE.
The safety of the care team and care environment is paramount and, as such, there will be situations where in-person support cannot be permitted. Depending on the resources available in the care environment, the ability to facilitate in-person support people from one environment to another or during different phases of the pandemic may vary. Care environments should have a mechanism in place for pregnant people to request exceptions and policies should address the additional care needs of various populations (e.g., people living with disabilities, non-English speakers) as well as to encompass the diversity of families we care for (e.g., adoptive and surrogacy families, Indigenous families).
While prohibiting support people from attending routine prenatal care is reasonable to limit possible viral exposures involving them in prenatal care, not only in their supportive role but also to help prepare them for their role in birth and parenting, is important. Achieve this by:
- Encouraging support people to be present for virtual appointments - Facilitating phone or video presence of support people at in-person appointments - Permitting phone or video recordings for women to share (e.g., ultrasound images, fetal heart sounds) - Providing written materials to support conversations on common topics Pregnant people living in Indigenous and fly-in communities must often travel for prenatal care (see Rural and Remote Considerations) and their support people frequently travel with them. Due to public health measures and COVID-19 pandemic restrictions, supports may not be permitted to attend these visits in-person, which adds to the emotional, financial and cultural burden that Indigenous pregnant people must bear. Participation of some community members who represent significant cultural value may be crucial to the provision of care for the pregnant individual. Support person policies should reflect the needs of this population and alternatives to in-person support must be developed in a way that is accessible to them.
Visitor and support policies should allow for one support person (at minimum) for significant events in the prenatal period, including pregnancy loss and communication of and consultation for significant complications of pregnancy. Where in-person support is not possible or permitted, the importance of the support people and partners should be acknowledged, and their involvement facilitated through virtual means.
The presence of culturally relevant support people is essential to culturally safe care.
# Early Pregnancy Loss and Stillbirth
At the time of this guideline, there is no clear evidence that exposure or infection with COVID-19 is a risk factor for early pregnancy loss. There is some emerging populationlevel data to suggest that the incidence of stillbirth has been increasing during the COVID-19 pandemic . It is unclear at this time if this is due to the virus itself, to delayed or different patterns of care, or to socio-economic or other factors. Of note, this section refers to spontaneous pregnancy loss rather than induced terminations and abortions, which are covered in the following section: Termination of Pregnancy .
Losing a pregnancy, whether in the early weeks or the final days, is a highly stressful event that may be worsened in the context of the pandemic. The pregnant person may already be isolated socially, dealing with upheaval in work and childcare with decreased support from family, and is now facing pregnancy loss. They may have had heightened anxiety of being pregnant during the COVID-19 pandemic and may need additional supports and counseling.
It is also very important to recognize that Indigenous people have experienced high levels of intergenerational loss and trauma, including removal of infants from their care in more than one pregnancy. Care providers need to be culturally safe when discussing loss with Indigenous clients .
At-risk marginalized populations, or populations with unique cultural identities, may have customs or different needs when approaching pregnancy loss or stillbirth. Safe environments and spaces must be created that allows their experiences to be respected and valued.
# Presence of Support People at Times of Pregnancy Loss
Due to restrictions on visitors and support people, there is an increased likelihood that a person who has lost their pregnancy will learn of the loss alone in an office, an ultrasound suite or the emergency room. Where possible, a pregnant person experiencing bleeding or lack of fetal movement should be allowed and encouraged to have a support person with them. This is a highly emotional and traumatic experience; it is well-documented that optimal family-centred care has a lasting impact on their mental health and future pregnancy experiences .
With COVID-19 restrictions in place (both medical and in the community), the pregnant person experiencing loss may be feeling very isolated and alone.
# Where possible, support person policies should allow pregnant persons who may be losing a pregnancy at any gestational age to have one support person (at minimum) with them.
HCPs must be highly awareness of this. Their family and friends may be unable to visit or help support them. It is important that care providers recognize this gap in support and, where needed, allocate additional time to ensure effective and safe communication. HCPs should consider making exceptions to visitor restrictions under certain circumstances; for example, respecting cultural practices, accommodating disabilities, mental health support and trauma-informed care, which may necessitate more than one support person's presence.
# Follow-Up of Pregnancy Loss
Follow-up for early pregnancy loss and stillbirth can be done virtually as minimal physical exam is required. However, keep in mind that some pregnant individuals may require more frequent contact than others and an in-person visit may be appropriate. Referral to mental health services remains appropriate as needed and can be done virtually.
When a pregnant individual presents with bleeding during COVID-19, all the usual assessments and care planning must take place. First trimester ultrasound is used to establish the pregnancy location (i.e., intrauterine versus ectopic) as well as to rule out gestational trophoblastic disease (molar pregnancy). Rhesus status should be established, and Rh Immunoglobulin administered if the pregnancy is at or above 49 days at the time of loss.
For early pregnancy loss occurring before 12 weeks with light bleeding, it may be possible for the pregnant person to remain at home, provided they have access to good pain control as well as anti-nausea medication. This can be provided at the time of their assessment to avoid additional travel. For early pregnancy loss occurring after 12 weeks and associated with bleeding, an in-person assessment must be done for assessment, vital signs and standard care in the usual care environments.
All pregnant people must be counselled on how to access telephone advice (based on local protocols) and when to seek emergency attention. Individuals should be counselled that their local in-person emergency and obstetrical care areas are safe places and will not increase their risk of exposure to COVID-19. When attending inperson (including ultrasound exams), if possible, pregnant individuals should have access to a private bathroom to avoid the need for repeated cleaning.
Ideally, at the time of an in-person assessment, any investigations, including ultrasound, quantitative beta HCG, CBC and Rh testing, are all done during the same visit to avoid return visits. Physical examination should be performed by the first provider (e.g., emergency physician) and should not be delayed due to PPE restrictions especially if
# Follow up of early pregnancy loss can often be done virtually, allowing for inperson visits as needed.
an individual is in pain or unstable. Pain and nausea must be well controlled with medication and outpatient prescriptions should be provided. Follow-up and necessary consultations should be arranged and frequently can be provided through virtual means. HCPs should be aware of the role unconscious or hidden biases play in the provision of pain relief for racialized people. Unintended consequences may include inadequate provision of pain relief and lack of acknowledgement for racialized people.
All management options for early pregnancy loss should be available. Expectant management or medication management are preferable to avoid surgical intervention. However, it is also essential for clinicians and hospitals to recognize that a dilatation and curettage procedure is an essential surgery and should continue to be available during the pandemic. The pregnant person should receive counseling regarding different methods for managing early pregnancy loss, and their choice should be included as part of the management planning.
# Stillbirth
Stillbirth presents special challenges given the bereavement experienced by the pregnant individuals and their families. All efforts must be made to select a location where the person experiencing stillbirth can receive care in a sensitive manner, ideally separate from labouring individuals and newborns, following safety and COVID-19 infection control protocols.
In the case of a confirmed stillbirth, a wider circle of supports, including extended family and spiritual support, may be needed. Inclusion of additional support persons and longer hospitalization to facilitate grieving should be considered in the context of local guidelines. Opportunities for others to meet the infant in person may be restricted and families may need to balance the need for culturally appropriate rituals, funeral services and gatherings with the pandemic requirements of isolation and social distancing.
# Safe and empathetic care of pregnant individuals at risk of early pregnancy loss must remain a priority during the pandemic.
Pregnant people experiencing loss should be aware of how to seek emergency care and be reassured that if they need to be seen in person, they will be safe and at low risk of contracting COVID-19.
# Surgical management of early pregnancy loss is non-elective and should be maintained as an option for management throughout the pandemic alongside expectant and medication management.
Medication management of stillbirth during the pandemic should follow intrapartum protocols as covered in the PCMCH Maternal-Neonatal COVID-19 General Guideline. The cause of most stillbirths in Ontario remain unexplained and investigations should continue to follow current guidelines, including sending the placenta for pathology. Although a causal link with COVID-19 infection has not been firmly established, there is evidence suggesting an increase in stillbirth rates during the pandemic . Consideration should be given to testing people who have experienced stillbirth (with NP swab and/or antibody testing) as well as infant and placenta. This will both add to the overall body of knowledge and may give reassurance to the bereaved parent and their supports. Placental pathology may yield important information for future pregnancy planning.
# Termination of Pregnancy
Reproductive rights are considered essential and care should be taken to protect the provision of termination services despite of and especially during the pandemic response. While this provision should never be delayed, policies that minimize the number of required visits should be applied, and procedures should be performed in outpatient settings wherever possible .
# First Trimester Medication Termination
The intake assessment for both medication and surgical termination services can be conducted virtually, and as most women present for termination have already made up their minds, counselling can be reserved for those who are ambivalent or emotionally distressed. In the absence of readily accessible ultrasound, gestational age (GA) can be estimated using last menstrual period (LMP), clinical history and physical examination in women who are certain of the date of their LMP . Ultrasound is needed when uncertainty remains, and access to timely dating ultrasound should be ensured for these pregnancies . In absence of ultrasound, beta-hCG levels can be used to estimate gestational age. For example, the cut-off value of 23,745mlU/mL can be used to detect pregnancies with a gestational age <7 weeks. The risk of ectopic pregnancy potentially missed with a non-ultrasound-based approach of medication terminations is 0.7 per Special care and consideration must be taken in supporting individuals and families experiencing stillbirth during the pandemic. As the usual support systems and grieving venues may be altered or unavailable at such times, the needs of the family must be balanced with public health measures and pandemic protocols.
# The usual stillbirth investigations should continue to take place as well as consideration of COVID-19 testing of the person experiencing stillbirth, the infant and the placenta.
cent and is lower than the 1-2 per cent risk in the general population for whom a delay in first ultrasound assessment to 11-14 weeks gestation is advised .
Up to 70 days (ten weeks) GA, medication termination is preferred over the surgical approach, as long as reasonable access to healthcare is provided for seven to 14 days after administration to manage incomplete abortions and treatment failures . Evidence suggests that many women can safely conduct most of the medication termination processes themselves and in-person contacts and healthcare resources utilization can be reduced. Furthermore, the process can be supervised by a range of care providers, with in person assessment or hospital visits only necessary when complications occur.
Virtual post-termination care is suggested during the COVID-19 pandemic unless the situation allows for a visit to be combined with the administration of longer-term contraception or insertion of an intrauterine device . A variety of options for contacting the individual (e.g., phone, email, contacting a friend) should be offered and emergency contact information should be obtained when possible. The provider should have an accessible system in place in case of emergencies.
Complete abortion is likely when both pregnant person and their clinician believe successful expulsion has taken place, based on history alone. In cases where there is ambiguity, serial beta-hCG measurements can provide definitive evidence of pregnancy termination . A fall of beta-hCG levels of 80 per cent or more from pre-treatment to first follow-up at seven to 14 days is indicative of a completed medication termination. Ultrasound follow-up is equally effective but should be reserved for cases in which incomplete abortion is suspected . A second dose of misoprostol can be considered for completion of a medication termination when there is a retained gestational sac or an ongoing pregnancy. Special risks include need for urgent surgical intervention for heavy bleeding or retained products, and access to surgical resources should be protected. Overall, three to five per cent of women require a subsequent aspiration after failed medication termination.
# There is good evidence to support first trimester medication termination (up to 70 days GA) with reduced or no ultrasound or visits to hospital, directed by virtual care and handouts with instructions for the termination itself and for post termination care.
Care should be taken to ensure safe access to urgent post abortion care for the small percentage of medication failures; this may involve a pathway with access to places other than busy emergency wards at times of high community transmission.
# Surgical Termination
Access to surgical termination through Dilation and Curettage or Evaluation (D&C, D&E) remains essential for the management of the individual who declines medication termination, for medication management failures and incomplete abortions, and the management of the pregnancies that have extended beyond the gestational age for safe out-of-hospital medication management. It should be emphasized that this should not be considered an elective procedure and access to surgical care should be maintained at all times.
Being COVID-19 positive is not an indication for, nor contraindication to, pregnancy termination. Therefore, the time-sensitive procedure should not be delayed if the safety of the pregnant individual is at risk or if delay of the procedure affects the individual's access to termination. Pathways for surgical termination options therefore need to include preparations and precautions for the person who is COVID-19 suspected or positive.
# Second and Third Trimester Termination of Pregnancy
Similar to access to early pregnancy options, access to second and third trimester termination of pregnancy is an essential right and should be protected. Prenatal diagnosis, counselling, support and access to diagnostic procedures such as autopsy and genetic diagnosis should be offered following the same rules and procedures as outside the pandemic.
Although the ability to travel may be impaired, access to third trimester surgical options in the U.S. have remained available to pregnant persons for whom termination in Canada is not considered an option. In circumstances where the person would have considered this option but is inhibited by COVID-19-related travel restrictions, individual providers should do their best to provide alternative options to the pregnant person.
If induction of labour is chosen at early gestational ages or is the only option available, such as in the more advanced pregnancies, the termination of pregnancy is best conducted in hospital. Despite low complication rates, the access to emergency care may be inhibited or associated with delays in treatment for those who present with significant pain or hemorrhage. Counselling, support, options for pain relief and the presence of support people should be made available and should not differ from what is offered to a person experiencing a pregnancy loss.
# Surgical termination is considered an essential service and should remain accessible in the pandemic.
# Surgical termination in a COVID-19 positive person should not be postponed if delay affects the person's safety or access to termination.
The addition of mifepristone prior to the start of induction with misoprostol is associated with a significantly shorter time from the start of misoprostol induction to birth for both live and stillborn fetuses , with >70 per cent of births occurring within 12h after admission to hospital. Mifepristone, taken at least 12h prior to the start of induction, does not increase complication rates or risk of initiation of labour prior to hospital admission and should be considered to reduce the length of stay in hospital during the COVID-19 pandemic.
# Treatment of Tissues, Remains and Stillborn Infants
As of the writing of this guideline, evidence indicates that vertical transmission from a COVID-19 positive person to the fetus is uncommon. Following pregnancy loss or termination, fetal and placental tissues should be managed according to usual institutional protocol, including when the pregnant person is COVID-19 suspected or positive. This can include removal of fetal tissue from hospital at parent request if this is allowed by institutional protocol. Indigenous clients, in particular, may wish to have access to the fetal and the placenta tissues for ceremonial purposes. Cultural practices around timing and nature of burial should be respected and facilitated whenever possible.
Additionally, it is likely that a stillborn infant will be COVID-19 negative (even for COVID-19 positive people) and the risk of transmission from the infant would be low. Memento items including hair locks, hand and footprints, and keepsakes, blankets and outfits can be released to the family in most cases. Care environments are encouraged to allow parents and supports to be able to hold and photograph the infant without wearing PPE. Thorough hand hygiene should nonetheless be recommended.
# The protection of reproductive rights extends to options to terminate a pregnancy in the second or third trimester and services to persons opting for pregnancy termination such as safe and supported induction of labour should remain similar to what is offered in non-pandemic times.
Mifepristone, administered >12h before the start of induction should be considered to significantly shorten the admission to hospital without increased risk of fetal expulsion prior to hospital admission or other complications.
# Families requesting tissues and remains should be respected as per institutional protocols. Cultural beliefs around burial should be facilitated and
Indigenous people should have access to their placenta and remains of fetal tissue at their request for ceremonial purposes.
# Prenatal Screening and Genetic Counseling
Prenatal screening practices during the pandemic are aimed at maintaining an excellent level of prenatal screening, genetic counseling and fetal diagnosis while minimizing exposure of pregnant individuals and providers by limiting the number of screening tests/visits. It should be noted that vulnerable communities and racialized groups that traditionally experience poor access to prenatal care may have more difficulties accessing prenatal screening.
During the COVID-19 pandemic, non-essential in-person healthcare services have been restricted by most care environments. However, as some prenatal screening tests, counseling and fetal diagnosis procedures are time sensitive, alternative care delivery methods for screening and counseling such as virtual care must be considered.
According to national guidelines, all pregnant individuals should be offered enhanced first trimester screening (eFTS), or non-invasive prenatal testing (NIPT),where available and funded as the first choice for prenatal genetic screening. For suspected or confirmed COVID-19 positive pregnant individuals, most fetal screening tests can be delayed for a 14-day isolation period or until infection is resolved to minimize exposure to HCPs. A useful decision making algorithm can be found in the proposed strategy in the Prenatal Screening Update during the COVID-19 Pandemic by the Society of Obstetricians and Gynaecologists of Canada (SOGC).
# Prenatal Screening Ontario (PSO) Adjustments to Screening
Ontario currently uses a two-step prenatal screening system, with eFTS being the first step for most pregnancies, with the exception of those at high risk where NIPT is a first line test. Access to prenatal screening during the COVID-19 pandemic may be impacted by the following :
- Some diagnostic imaging centres are restricted in offering dating and NT ultrasounds.
- Community blood collection services may be consolidated to a smaller number of laboratories.
- Pregnant individuals in self-isolation may miss the NT ultrasound window (11 to 14 weeks). NT ultrasounds are of increased importance for twin pregnancies as serum screening (i.e. MSS) alone is not possible for twin pregnancies. NIPT is available for twin pregnancies and as a result, the MOH will temporarily fund NIPT for twin pregnancies if NT ultrasound is not available. For higher order multiples, NT ultrasound is the only screening option and should therefore be made available to this population throughout the pandemic.
# Special Considerations
Counseling regarding screening options, communication of positive screening results and initiation of follow-up investigations can be conducted virtually. It is ideal if prenatal screening options are discussed at the very first visit to allow the scheduling of the timesensitive dating/NT ultrasound(s).
To reduce visits, a single ultrasound done after 11 weeks can serve as both dating and NT ultrasound where dates are certain. To reduce visits, improve screening, and avoid missing the optimal screening window, accredited diagnostic imaging centers can consider providing a NT measurement when a dating ultrasound is performed within the eFTS gestational age window and directing the patient back to the primary provider for counseling regarding options.
If a diagnostic procedure is indicated in response to genetic screening in a COVID-19 positive person, amniocentesis is preferred over chorionic villus sampling reducing the theoretical risk for vertical transmission from moderate to low.
# Preeclampsia Screening
First trimester screening serum biomarkers (pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PLGF) have been used together with maternal characteristics and biophysical markers to identify pregnancies at risk for preeclampsia, stillbirth and placental abruption . Multiple algorithms exist combining these serum markers with maternal history and factors such as body mass index (BMI), diabetes and biophysical markers such as mean arterial pressure and uterine artery Dopplers .
The goal is to identify pregnant individuals who can benefit from the administration of low-dose aspirin (ASA 150mg daily) starting at 16 weeks or earlier . For instance, the FMF-UK algorithm has been shown to predict approximately 75 to 90 per cent of those who will develop preeclampsia prior to 37 and 34 weeks respectively, at a false positive rate of 10 per cent . The prescription of low-dose aspirin can significantly reduce the incidence of early onset preeclampsia and placental abruption in pregnancies determined to be at increased risk, reducing the burden on healthcare resources in the pandemic .
Although the COVID-19 pandemic restrictions may lead to decreased availability of some aspects of this preeclampsia screening, ASA guidelines such as provided by National Institute for Health and Care Excellence (NICE) and American College of Obstetricians and Gynecologists (ACOG) provide a useful template for preeclampsia prevention in persons at high risk (previous preeclampsia, multiple gestation, chronic hypertension, diabetes or renal disease) or medium risk (nulliparity, family history, age >35y, socioeconomic factors, previous low birthweight infant) . These risk factors can be combined with serum biomarkers if available.
# Sexually Transmitted Infections Screening and Treatment During the Pandemic
Screening for asymptomatic sexually transmitted infections (STIs) that may impact the pregnancy or fetus is routinely performed during pregnancy. Continuing to screen for and treat these illnesses remains vital and should be considered an essential service even at times when the system is under strain . It must be acknowledged that many sexual health clinics, testing, and contact tracing programs are run by public health authorities whose resources have been strained by and/or diverted to COVID-19 related activities. This increases the importance that other maternity care providers ensure that screening is performed, and positive results appropriately acted upon. Where possible, STI screening tests should be bundled with other routine testing and care to minimize contact points with the healthcare system. Timing of testing should bear in mind that increased turnaround times for results may occur.
# Screening for Diabetes in Pregnancy
Routine care in pregnancy includes both screening in the first trimester for pre-existing diabetes in pregnant individual at risk as well as screening for gestational diabetes at 24 to28 weeks with an oral glucose tolerance test. To reduce SARS-coV2 transmission risk during testing, alternative testing strategies have been proposed .
Early pregnancy screening for overt/pre-existing diabetes is recommended for women at increased risk and is achieved through hemoglobin A1C (HbA1c) or fasting glucose test . When included with routine first trimester blood work, this testing increases neither the number of healthcare contacts nor time of contact and therefore should continue as routine.
The use of an oral glucose tolerance test between 24 and 28 weeks has traditionally required the pregnant person to remain in the laboratory environment for one or two hours, which may increase risk of transmission. Additionally, lab capacity and access may be decreased during the pandemic. An alternate strategy of a random glucose measurement, along with an HbA1c, has been proposed . While reducing demand on lab resources and potential exposures for pregnant people, this strategy has a decreased sensitivity and will therefore miss many milder cases of gestational diabetes. Numerous alternatives to the 50g glucose drink provided in laboratory have been investigated but none sufficiently validated to clearly replace the OGTT . Nonetheless, home administration of glucose load 1h prior to the scheduled laboratory appointment for a random glucose could be considered. Decisions of which screening strategy to adopt should be made based on maternal risk factors for diabetes, local lab capacity and local SARS-coV2 activity.
# Provision of Ultrasound for Low-Risk Pregnancies
During pandemic restrictions, access to pregnancy ultrasound may be limited due to reduced capacity in ultrasound clinics and/or the availability of ultrasonographers; however, ultrasound assessment during pregnancy remains important to pregnancy care and management for:
- accurate dating of the pregnancy - assessment of fetal NT between 11 and14 weeks gestation - to diagnose fetal demise and trophoblastic disease - to assess for routine fetal anatomy and detect fetal anomalies between 18 and22 weeks gestation - to facilitate counseling and management of pregnancy termination Early pregnancy screening for women at risk of pre-existing diabetes should continue unchanged. While it may result in decreased detection of mild disease, screening for gestational diabetes between 24-28 may be modified by replacing the OGTT with a random glucose and HbA1c when local lab capacity and/or disease levels necessitate.
- assessment of fetal well-being including fetal growth and assessment of amniotic fluid Additional factors to consider:
- New conditions may arise in low-risk pregnancies that may require additional ultrasound scans and assessment. - If NT is not available, alternative prenatal screening may be offered: Prenatal Screening and Genetic Counseling. - For a person with confirmed or suspected COVID-19, it may be possible to delay ultrasound timing until the person is no longer infectious (i.e., until quarantine period is complete or ten days from onset of symptoms and/or confirmed COVID-19 testing if asymptomatic). For example, the second trimester anatomy could be deferred to 22 weeks if the person is diagnosed with COVID-19 at 19 to20 weeks gestation. - If a pregnancy ultrasound scan must be performed for a person with confirmed or suspected COVID-19, specific clinical protocols must be followed to protect those in contact with the person as well as appropriate cleaning of ultrasound equipment and the clinical environment. - As support people's access to healthcare facilities is limited during the pandemic, ultrasound providers should consider allowing participation during a portion of the ultrasound visit by phone or through a virtual platform, or by providing a photograph or video of the scan for the pregnant person to take home. - Pregnant people should receive education on fetal movement monitoring to reduce the likelihood of third trimester ultrasound scan. - It is recognized that due to reduced access to pregnancy care and missed ultrasound appointments earlier in pregnancy, that access to third trimester ultrasound may become more important for the estimation of fetal weight and assessment of fetal well-being. - For persons with mobility impairments or lack transportation to centres providing pregnancy ultrasound at key moments in early pregnancy, education on fetal movements and provision of additional ultrasound in the third trimester may be appropriate. - It is suggested that standard cleaning protocols be used for all ultrasound equipment according to American Institute of Ultrasound in Medicine (AIUM).
# COVID-19 Vaccination in Pregnancy
Widespread vaccination campaigns are underway and are viewed as a key component to controlling the COVID-19 pandemic. While initial safety studies universally excluded pregnant and lactating individuals, there is increasing real world evidence of both efficacy and safety in these populations . The Better Outcomes Registry & Network (BORN) Ontario is evaluating COVID-19 vaccination in pregnant individuals in Ontario. BORN released an initial report, with data collected from December 14, 2020 to May 31, 2021, with preliminary results that do not suggest any pattern of increased risk for pregnancy (e.g. post-partum hemorrhage) and birth outcomes (e.g. stillbirth, preterm birth, 5-minute Apgar score <7, small for gestational age) among vaccinated pregnant individuals . This, coupled with the increasing evidence of risk for those who contract COVID-19 during pregnancy, has led to recommendations that all pregnant individuals should have access to the vaccine . An informed decision making discussion should include information on risks and benefits of the vaccine, an assessment of whether the vaccine's benefits would outweigh the potential risks to the person and/or fetus and a disclosure that there is limited evidence of the vaccine's effects in pregnant and lactating individuals. A thorough discussion with one's provider can ensure that each person is in a good position to make an informed choice on whether to be vaccinated. Shared decisionmaking tools have been developed to help pregnant individuals and their healthcare providers with this discussion. For example, PCMCH has developed a Patient Information Sheet tool titled, "I am pregnant or breastfeeding. Should I get the COVID-19 Vaccine?" that is available in English and French languages.
The National Advisory Committee on Immunization (NACI) preferentially recommends that a complete vaccine series with an mRNA (Moderna, Pfizer-BioNTech) COVID-19 vaccine should be offered to individuals who are pregnant .
# Management of High-Risk Pregnancy
The definition of a high-risk pregnancy varies considerably. Generally, it is a pregnancy in which the risk of an adverse outcome to the pregnant person, fetus or neonate is increased. The features rendering this pregnancy "high risk" may exist prior to pregnancy, may be related to physiologic characteristics (e.g., age, BMI), may directly link to the pregnancy itself (e.g., multiple gestations) or to factors that develop during the pregnancy (e.g., gestational diabetes, IUGR). There is also the possibility that a pregnancy is considered high risk as a result of the outcome of a previous birth (e.g., preterm birth, preeclampsia, birth by Caesarean birth). As many socio-economic and racial factors increase risk in pregnancy and exacerbate adverse pregnancy outcomes, providers and care environments must make an effort to address racial healthcare disparities and the under-recognition of health risks for racialized groups.
In general, each high-risk condition has a specific management protocol that has been developed, usually in conjunction with professional bodies such as the SOGC, the Association of Ontario Midwives and other professional organizations. While many of
# All pregnant individuals should have access to COVID-19 vaccination at any stage in pregnancy.
these guidelines and recommendations are based on evidence that is of low certainty (GRADE classification), they are used across the province to establish local and regional protocols for the management of these pregnancies.
While it is beyond the scope of this document to provide specific guidance on all conditions that confer risk in pregnancy, several guiding principles should inform the care of high-risk pregnancies during the COVID-19 pandemic.
Frequency and Form of Visits for High-Risk Pregnancies
High-risk pregnancies require greater levels of assessment and surveillance; therefore, it is inappropriate to restrict the frequency of visits in most cases. It is nonetheless recommended that care environments and providers should critically review their protocols and make adjustments based on clinical need as well as current COVID-19specific guidance. For example, where guidelines recommend a range of intervals between visits (e.g., SOGC guidelines on management of twin pregnancies suggest a visit interval of two to four weeks), and where no other risks are identified, the number of visits can be reduced by adhering to the longer end of the time interval.
It may be possible to decrease the number of in-person assessments while still maintaining the same standard of care. Virtual care may be used in situations where direct examination of the pregnant individual is not necessary. As there is generally an increased number of investigations in high-risk pregnancies, clustering of investigations and assessments can reduce the number of contacts. If ultrasound measurements and blood testing can be done locally, virtual interpretation, care and counseling may assist in the care of pregnancies at risk while reducing both in-person contacts and the need for the pregnant person to travel for care.
In many settings, multidisciplinary input is required in the management of high-risk pregnancies. In care environments that specifically serve high-risk pregnancies, pregnant individuals are frequently seen by a variety of care providers at a single visit. While these clinics are efficient by allowing the pregnant individual to have multidisciplinary input in a single visit, they are often high-volume clinics with long wait times, which may create challenges for physical distancing and exposure reduction. A blended model of in-person assessment by one or a few members of the multidisciplinary team and virtual care by others can be effectively used in many settings as the physical examination is generally not necessary by each member of the team.
The care of high-risk pregnancies will, in essence, remain unchanged but contacts can be reduced by use of virtual visits, clustering of care and avoidance of duplication of assessments.
The mainstay of assessing fetal well-being for high-risk pregnancies includes ultrasound estimate of fetal growth, the biophysical profile, doppler flow measurements and the non-stress test. Assessment of fetal well-being should continue to be performed but steps can be taken to reduce the number of unnecessary assessments. Consistent use of standardized fetal growth charts is recommended to reduce investigations and referrals for suspected growth restriction.
The biophysical profile (BPP) classically includes an ultrasound assessment of fetal well-being and a non-stress test. Performing both components increases the duration of the pregnant person's visit but both elements are not always necessary. When the BPP is normal, the NST is often unnecessary. Conversely an isolated determination of amniotic fluid volume (e.g., single deepest pocket) combined with a non-stress test has also been shown to reduce the amount of time taken for a fetal assessment without significantly reducing the ability to measure fetal wellbeing.
# Special Tests
There exist a number of specific laboratory tests that can improve the accuracy of clinical assessment for pregnancy risks and complications. Access to these tests in both low-and high-risk care environments can reduce the number of consultations, transfers and hospital admissions at all times, which is particularly important during the pandemic. Conditions with specific tests that should be available to reduce unnecessary exposure during the pandemic include:
- Preterm rupture of membranes: Diagnostic tests exist with a very high specificity for the presence of amniotic fluid. These more specific tests should be made available for use in place of less reliable tests. - Preterm labour: The fetal fibronectin assay is a test with a very high specificity that can exclude the diagnosis of preterm labour when uterine contractions are suspected or present between 24 and34 weeks gestation . - Preeclampsia: Randomized controlled data has shown that the ratio of soluble FMS-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) (sFlt-1:PIGF) is a sensitive and specific marker for risk of preeclampsia . Wider availability of commercially available tests for measurement of the SFlt-1:PIGF ratio would assist in more appropriate care and reduced referrals.
# Assessment of fetal well-being should continue to be performed but steps can be taken to reduce the number of unnecessary assessments through deliberate use of testing and/or special tests
# Perinatal Mood Disorders and Substance Use
Perinatal mood disorders are common and often under-recognized in pregnancy. The uncertainties created by the pandemic, along with the impacts of social isolation, job loss and societal change, will impact pregnant people significantly . People with preexisting mental health and substance use issues will simultaneously experience possible worsening in their conditions along with decreased access to services and support. For Indigenous communities, rates of prenatal and postpartum mood disorders are higher than the general population .
HCPs should increase their screening and monitoring of pregnant people for perinatal mood disorders and substance use during the pandemic . While it is routine to enquire about mental health and substance use in pregnancy, the impact of the pandemic should prompt providers to be more vigilant than ever. Formal screening using tools such as the EPDS, PHQ-9 or GAD-7 should occur at intake and again in later pregnancy and providers should enquire regularly about coping, mood and substance use (e.g., at every visit). Those experiencing perinatal mood disorders or substance use may require additional prenatal visits. While mental healthcare can lend itself to virtual care, special considerations and additional in-person visits may be warranted for those with psychosocial vulnerabilities. Providers should be conscious of historic harms to Indigenous populations as a result of mental health disorders (e.g., child apprehension) and apply principles of cultural safety when enquiring about, and responding to, perinatal mood disorders and substance use.
When mood disorders and substance use are detected, pregnant people should have prompt access to resources and interventions. Changes in care delivery along with redeployment to pandemic related activities of staff typically working in perinatal mental health (e.g., public health nurses seconded to testing and tracing programs) has meant that many pregnant people have experienced decreased instead of increased access during the early portions of the pandemic. As in other areas of care, innovation and creativity is needed to ensure quality programming can be offered in altered formats such as virtual counselling and education as well as virtual group therapy.
Pregnant and postpartum people, as well as those with pre-existing mental health conditions, are amongst the most vulnerable during the COVID-19 pandemic. Healthcare providers should prioritize the care of this population during the pandemic.
# Providers should increase their awareness of and screening for mood disorders and substance use and adjust the frequency and format of visits to allow for both early detection and intervention.
Where possible, mental health services should be delivered through virtual care, particularly where the condition is mild. Individual consideration should be given to faceto-face care when needed for those with more severe illness or where access to virtual care is limited. Care should be multifaceted and include education about COVID-19 as well as coping, self-care strategies, self-help and the development of social support networks. Existing tools and programs may be updated with COVID-19-specific information and access should be facilitated. Education in the prenatal period should include advice about managing and reducing the impact of maternal mental health disorders both in the immediate postpartum period and for the first year of the child's life. When medications are prescribed, access should be facilitated through such practices as longer prescription periods involving either expanded take-home practices (e.g., for methadone or buprenorphine treatment, sustained release anti-seizure medicines, or neuroleptic depot with informed consent) or periodic delivery of medicines to the home .
Substance use is of particular concern, as evidence to date demonstrates that the stressors brought on by the pandemic has increased substance use in both those with pre-existing use disorders and those without previous problematic use of substances, including tobacco, alcohol, cannabis and illicit drugs . While guidance specific to both pregnancy and the COVID-19 pandemic does not yet exist, existing documents such as the SOGC Clinical Practice Guideline on Substance Use in Pregnancy can be supplemented by COVID-19 specific guidance targeted at the general population such as the COVID-19 Opioid Agonist Treatment Guidance for management of opioid agonist therapy with methadone and buprenorphine and the COVID-19 Alcohol Withdrawal Management Protocol .
Provision of perinatal mental health services should be considered an essential service and while format may need to be altered, these services should be continued and strengthened throughout the pandemic.
# Existing resources and techniques for supporting pregnant individuals with perinatal mood disorders and substance use can be modified to create formats that are accessible through virtual means or a reduced number of visits.
Given the likelihood of increased substance use and worsening of preexisting substance use disorders during the COVID-19 pandemic, all pregnant people should be actively screened for alcohol, cannabis, tobacco, prescription and recreational drug use at multiple points during the pregnancy.
Pre-existing pregnancy specific guidelines on substance use in pregnancy should be supplemented by general COVID-19 substance use guidance.
# Intimate Partner Violence
The UN has noted that "data shows that since the outbreak of COVID-19, reports of violence against women, and particularly domestic violence, have increased in several countries as security, health, and money worries create tensions and strains accentuated by the cramped and confined living conditions of lockdown." . A Government of Canada survey in Spring 2020 revealed that "8% of Canadians reported that they were very or extremely concerned about the possibility of violence in the home. This percentage was higher for women (10%) than men (6%)." . During periods of social distancing, lock-down and quarantine due to COVID-19, more victims are isolated with their abusers, removing times and opportunities to leave and seek help, exacerbating the patterns, frequency and degree of abuse . Providing support for survivors of intimate partner violence (IPV), including shelters, have been deemed essential services in Ontario and these services have been maintained regardless of whether the province is in lockdown or phased recovery.
During prenatal visits, HCPs should follow their usual protocol, best practices or guidelines for the identification of IPV, while being mindful of the increased prevalence of IPV during the COVID-19 pandemic. HCPs should take the opportunity during prenatal visits to ask questions about lived experience at home and be alert to potential indicators (signs and symptoms, behavioural signs and risk factors) of IPV and should ask questions about IPV when present. While COVID-19 specific guidance does not exist, the VEGA Projects Family Violence Handbook: Intimate Partner Violence Section represents an up-to-date resource that can guide response to disclosures of IPV .
Existing hospital based Sexual Assault and Domestic Violence Treatment Centres remain available and are essential services. Indigenous people should have access to culturally relevant support for IPV .
It is important to recognize that virtual care may both diminish pregnant individuals' ability to disclose that they are subject to domestic violence. Virtual care may also increase the violence they suffer as it uses means (e.g., cell phones) that can be tracked, traced and controlled by their abusers, and they may have decreased access to safe conversations as the perpetrator may be simultaneously present in the home. Inperson visits (especially when infection control dictates pregnant individuals attend without their partner) may represent better opportunities to screen for IPV and provide services to those who cannot access services safely, or at all, through virtual/remote means.
Due to the increased rates of IPV during the pandemic, providers should remain vigilant through increased screening for domestic violence as well as maintain a heightened awareness of the signs and symptoms suggestive of IPV.
# Birth Planning and Counseling
# Prenatal Education
Prenatal education has been shown to improve health outcomes and remains an important aspect of pregnancy care even though access to in-person prenatal education has been limited by pandemic restrictions. Most public health units in Ontario offer online courses that can be accessed through the Ontario Prenatal Education Programs Directory. The Directory serves as a resource for prenatal education providers with evidenced-based key messages that can be provided to pregnant people and their supports. Providers should also direct pregnant people towards evidence-based prenatal education resources such as OMama, Pregnancy Info and Best Start . Prenatal education programs will need to address the specific impacts of COVID-19 on pregnancy care and birth. Indigenous people can access information regarding Indigenous prenatal online classes at the Native Youth Sexual Health Network. Pregnant individuals may be seeking culturally specific prenatal care and education or education specific to the needs of a racialized or disabled person.
It is important to recognize that prenatal education includes planning for the postpartum and newborn period as well as preparation for parenting. In-person supports during the postpartum and newborn period have also been limited by the pandemic. As a result, formal prenatal education as well as information provided by care providers should include information about important postpartum and newborn topics like breastfeeding and contraception.
# Planning for Birth
The changes brought about by the pandemic make explicit planning for many aspects of the birth essential. To address health disparities and work towards health equity in pregnancy care, providers should, where possible, connect the pregnant individual with a provider or group that can meet their culturally specific needs.
The location of the birth, including home and birth centre, depends on the preferred choice of the pregnant person and the medical needs for the pregnant person and the infant. Considerations for planning an out-of-hospital birth include appropriate risk screening with the midwife, access to adequate PPE and other infection prevention and control supplies, and timely local access to emergency transport when indicated .
Care providers should remain vigilant to the ways in which virtual/remote care may be difficult to safely access for survivors of IPV and in-person care should be used to provide safe alternatives when necessary.
# Prenatal education can be offered during the pandemic through virtual means. Discussion on specific COVID-19 education should be incorporated into prenatal education and prenatal care.
Pregnant people with symptomatic confirmed or suspected COVID-19 are recommended to labour and give birth in hospital . This recommendation is in light of the challenges associated with ensuring appropriate PPE in the home setting as well as literature reporting increased rates of intrapartum abnormal fetal health surveillance .
HCPs should advise the pregnant individual on how to self-isolate to reduce symptomatic infections at the time of birth, recognizing that this may not be possible for all individuals . For individuals with a scheduled birth (e.g., Caesarean birth, scheduled induction of labour) self-isolation should be considered 14 days prior to the anticipated date of birth. All pregnant people and support people may consider selfisolating at term, although this may be difficult to apply given the unpredictability of birth. Pregnant people may consider having a second support person who is self-isolating and ready to attend the birth in the event that their primary support person becomes ill.
# Induction of Labour
Timing and indications for induction of labour (IOL) can be achieved through shared decision-making with the pregnant person and their provider. IOL may be an important element of the birth plan and COVID-19 hospital protocols may influence its scheduling. More information on this topic can be found in the Maternal-Neonatal COVID-19 General Guideline published by the Provincial Council for Maternal and Child Health (PCMCH).
# Birth After Caesarean Section
There is no evidence to guide clinicians on how to counsel pregnant individuals seeking Trial of Labour After Caesarean Section (TOLAC) during COVID-19. It is recognized that special attention should be taken into consideration by the interprofessional team and the pregnant individual, including the indication for the initial Caesarean section and the history of previous vaginal births . The key concern in management of the TOLAC candidate is avoiding an emergency Caesarean birth requiring a general anesthetic. The factors should be acknowledged and discussed as part of routine shared decision-making. The risks and benefits to both the pregnant individual and the fetus should be discussed. The impact of COVID-19 on our healthcare system may influence the individual's decision about mode and timing of birth.
# Birth Planning for High-Risk Pregnancies
Birth planning for high-risk pregnancies should not change during the COVID-19 pandemic. Each institution should review their policies, protocols and procedures and decide where flexibility could be applied . Planning for high-risk pregnancy and birth may require a transfer of care. Planning for transfer to a different care environment or All pregnant individuals should explicitly plan for birth keeping in mind the impacts of COVID-19 on their care and care environments.
provider should be done in a culturally sensitive manner, taking into account geographical distances.
# Workplace Issues
HCPs are routinely called upon to advise on the safety of work during pregnancy and must be able to address questions and anxieties about working during the pandemic.
While most pregnant people have mild COVID-19, emerging data from Canada and international jurisdictions shows an increased risk of severe illness requiring hospital care and admission to the intensive care unit from COVID-19 in a subset of pregnant people compared to non-pregnant reproductive-aged people or women. There is no evidence that the immune modulations of pregnancy affect the rate or severity of COVID-19 infection. Normal pregnancy alone is not a risk factor for poor prognosis; therefore, SOGC states that pregnant workers can continue to work during the pandemic, taking into consideration work-related risk, individual risk (comorbidities) and local disease activity. Pregnancy-related comorbidities, such as gestational diabetes and gestational hypertension, should be considered risk factors for more severe disease . Within their role as healthcare advisors, an HCP can recommend accommodations or absence from work for pregnant workers in situations where work-related exposure is substantive or individual risk for COVID-19-related morbidity is high. While implementing disease-reducing activities such as screening, physical distancing, hand hygiene and adequate PPE are the responsibility of the workplace, accommodation recommendations may reflect the importance of these measures for all pregnant workers but especially those at increased risk. When making recommendations about workplace absences or accommodations due to COVID-19 risk, HCPs must be cognizant that the financial impacts may extend beyond the absence in pregnancy as it may negatively impact access to parental leave financial support. This may lead pregnant people to choose to remain in a workplace where they do not feel safe.
Pregnant HCPs represent a group that may be at higher risk of occupational exposure. While, the SOGC guidance provides the same advice for all workers, guidance for pregnant HCPs varies across the world.
# Guidance suggests that pregnant people can continue to work during the pandemic taking into consideration work related risk, individual risk, and local disease activity. HCPs should continue to recommend appropriate workplace accommodations when risk is considered high.
Indications and options for IOL, TOLAC and high-risk pregnancies are unchanged by the pandemic. However, it should be acknowledged that the impacts of the pandemic may influence both the care environment and the pregnant person's preferences; shared decision-making should continue with increased attention to these factors.
The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) and the Royal College of Obstetricians & Gynaecologists (RCOG) have suggested that pregnant HCPs be allocated to duties that have a reduced exposure to individuals with or suspected COVID-19. While exclusion from the workplace is not necessary for pregnant HCPs, recommendations may include reassignment to duties with lower exposure risk. All pregnant HCPs who may require an N95 mask should be fit tested in the pregnancy, particularly if weight gain has been significant.
Testing for COVID-19 in the Pregnant Population Just like the general population, most pregnant people with COVID-19 infection will have mild symptoms; however, emerging evidence demonstrates an increased risk of severe illness requiring hospital care and admission to the intensive care unit.
The general approach to COVID-19 symptom screening, exposure screening and testing of pregnant individuals is similar to that for others seen in similar healthcare settings, whether it be in the community or the hospital.
# Testing of Symptomatic Individuals
When entering healthcare settings, all pregnant individuals should be screened for symptoms compatible with COVID-19 prior to every appointment or on arrival to the healthcare setting. Symptomatic pregnant people should be tested for COVID-19, as is recommended for all persons with compatible symptoms.
Whenever pregnant persons are reviewed by non-obstetric HCPs, (e.g., emergency department, assessment centre or community office staff) and determined to have symptoms compatible with COVID-19, it is imperative that appropriate notification is made to the obstetric care team so appropriate follow-up can be arranged. The obstetric care team should also be involved as soon as possible if admission is required due to a COVID-19 compatible illness or if there are any obstetric concerns at the time of the review.
Pregnant individuals who are in labour with symptoms associated with COVID-19 should have laboratory testing expedited to facilitate care with the most information possible available to the healthcare team. To facilitate expedited testing for patients in
# Pregnant HCPs may continue to work in clinical roles with proper infection control procedures and consideration of assignment to lower risk care environments.
Pregnant people should be screened and tested as per guidelines for the general population and should be considered a priority population if access to testing is limited. Testing should be expedited for labouring pregnant individuals and when a prerequisite of transfer to another facility.
labour, the laboratory should be contacted in advance of the specimen being submitted so appropriate prioritization can be organized. The laboratory requisition should also clearly state that the individual is pregnant and in labour. Testing of pregnant or postpartum people requiring inter-facility transfer should be similarly prioritized, particularly where negative testing is a prerequisite of transfer. Pregnant people transferred between facilities should be tested in accordance with provincial recommendations for transfer testing . However, individuals who have previously tested positive for COVID-19. and have since recovered, do not need to be tested prior to or after transfer between facilities unless there has been a new high-risk exposure and/or symptoms . Due to the potential implications for maternal care and the wellbeing of the fetus and newborn, pregnant persons should be a priority group for access to COVID-19 laboratory testing should resources be limited.
# Pre-admission Testing and Testing of Asymptomatic Individuals
Currently routine preadmission testing is not recommended for pregnant individuals as a select group. In accordance with current MOH guidelines, the approach to screening prior to operative procedures should be dictated by the local prevalence of COVID-19 in the community where the hospital is situated. Testing prior to a surgical procedure is not required in areas where community transmission is low. When testing is indicated prior to a surgical procedure during pregnancy, it should be conducted between 24 and 48 hours prior to the procedure date.
# Surveillance of COVID-19 Positive Pregnancies
The Better Outcomes Registry & Network (BORN) is Ontario's prescribed registry for maternal-newborn health and collects and uses data to facilitate and improve care. Existing evidence on impacts and management of COVID-19 in pregnancy and the early newborn period is evolving . BORN is collecting data to support care providers, hospitals, midwifery practice groups, families and policy makers in learning about the impact of COVID-19 in pregnancy.
# Policies on pre-admission and pre-surgical testing as well as disease clearance should apply to pregnant people in the same way that they do to the general population
BORN Ontario has completed the first perinatal surveillance report on COVID-19 and pregnancy in Ontario. To date, many, but not all, of the birthing hospitals in Ontario have agreed to participate in this important data-collection strategy. Ongoing BORN reporting will link with the BORN Information System, which will allow us to learn more about risk factors and outcomes for pregnant people and neonates. Providers, hospitals, and groups are encouraged to participate in ongoing data collection through BORN.
# B. Care of the COVID-19 Suspected or Confirmed Pregnant Person
Pregnant people with suspected or confirmed COVID-19 will continue to require antenatal care, physical assessment and investigations. When symptoms remain mild, it is preferable to defer routine pregnancy care until the person is deemed cleared through resolution of symptoms and a period of self-isolation and/or negative testing. If inperson assessment of COVID-19 positive or suspected people is required, ideally the provider assessment and any necessary investigations can be performed at the same visit to avoid multiple exposures. Emerging data on pregnancy course, complications and outcomes for pregnant people with COVID-19 suggest a probable need for regular maternal and fetal assessment, thus increased surveillance and encounters may be necessary . This may include additional virtual or in-patient visits for pregnant people and increased fetal ultrasound to assess fetal growth and well-being.
Data collection is urgently needed to provide credible information to facilitate and improve care and to help guide decision -making at a provincial level. Hospitals and midwifery practice groups are encouraged to contribute to the data collection for pregnant people with suspected or confirmed COVID-19 through BORN Ontario. Where data is not able to be collected through BORN (e.g. Indigenous Midwifery Programs), interim data collection should be implemented without delay.
Routine pregnancy care may be deferred until the pregnant person with COVID-19 is no longer infectious, provided it is safe to do so.
There is evidence showing an increased risk of severe infection with COVID-19 during pregnancy, therefore, increased surveillance for both the pregnant person and the fetus is warranted for the remainder of the pregnancy.
If possible, provision of pregnancy care including maternal and fetal assessments, as well as ultrasound, can be provided at the same visit to minimize multiple exposures to people and care environments.
# Use of Droplet/Contact PPE
The predominant mode of transmission of COVID-19 is through respiratory droplets and aerosols during close, unprotected contact . Droplet/Contact Precautions are recommended for the routine care of individuals with suspected or confirmed COVID-19. Additional personal protective equipment should be chosen based on point-of-care risk assessment, considering the planned tasks (including surgical procedures and any associated AGMP) and is outlined in the PHO technical brief. Regardless of the vaccination status of the HCP, Droplet/Contact precautions should remain the minimum requirement necessary when providing care to any patient suspected or confirmed to have COVID-19 .
It is recognized that differing policies may apply to those with suspected or confirmed COVID-19 than to asymptomatic persons. Nonetheless, pregnancy care is essential care and COVID-19 suspected and positive people must not be denied access to necessary care based on their COVID-19 status. All care providers and care environments must have access to the necessary PPE to provide this care.
Support People for Pregnant Persons with Suspected or Confirmed COVID-19 Presenting for Pregnancy Care
Guidance on the presence of support people during prenatal care (see Care of Pregnant Population section) is aimed primarily at asymptomatic people. The increased precautions and PPE required for suspected and COVD-19 pregnant people aim to reduce the number of people in care environments, waiting areas and clinical spaces. It is generally recommended that only the pregnant person is present for the visit; decisions on the presence of support people should be based on the needs of the pregnant person, and the risk to HCP and the support person accompanying that individual. These decisions should align with current PH guidance and institutional policies. A support person may join by phone or virtually when appropriate. Under certain circumstances, a support person may be permitted to join a visit in person with advance planning and appropriate precautions taken to protect all involved.
# Care Environment
In populations where there are very few pregnant persons with suspected or confirmed COVID-19, essential pregnancy care may be incorporated into existing care environments with appropriate planning and modification.
Droplet/ Contact precautions are recommended for all HCPs during the routine care of pregnant people with suspected or confirmed COVID-19.
Settings where there are many pregnant individuals with suspected or confirmed COVID-19, it may be necessary to create a dedicated clinic environment and team to provide care. The dedicated clinic environment may be a separate area of the clinic space that accessed through a dedicated entrance and/or elevator, a clinical area that is repurposed for the care of COVID-19 positive individuals or a dedicated area within the health care environment. Ideally, the clinical space will have all the needed equipment for pregnancy care and, if required, investigations such as ultrasound could be performed in the same space. Booking and timing of visits is important to minimize contact and waiting times. If volume of visits is high, it may be necessary for the care team to have additional support such as a patient navigator to ensure safety procedures are followed consistently. Care providers follow PPE protocols and don appropriate PPE and meets pregnant person Pregnant person arrives at meeting location and is escorted to visit room Pregnant person dons mask and performs hand hygiene Care providers ensure there is a designated restroom for pregnant person that has appropriate signage Care provider brings pregnant person to the visit room and places droplet contact sign on door Visit is conducted with electronic charting in the visit room Paper chart to be left outside the room to avoid contamination After visit is completed, pregnant person provided with information regarding next visit before leaving visit room Care provider reminds pregnant person to perform hand hygiene and guides patient to the exit Following visit, care provider places a sign on the door to prevent others from entering visit room Care provider doffs all PPE inside the room except mask in order to escort pregnant person to the exit Care provider alerts sanitation team to perform terminal cleaning twice of the visit room, restroom and equipment When assessing COVID-19 suspected or positive pregnant people, providers should not only provide pregnancy-specific care but also assess the severity of illness. Emergent assessment and possible hospital admission should be considered in the following situations:
- Shortness of breath (unable to walk across room, speak full sentence)
- Cough with blood - Chest pain - Dehydration - Decreased level of consciousness - Oxygen saturation < 94%
- Chest x-ray consistent with pneumonia (e.g., ground glass opacities)
As more information emerges regarding unusual presentations of COVID-19, HCPs should be aware that thromboembolic events may be a presentation of the disease and keep in mind that pregnancy is itself considered a hyper-coagulable state. COVID-19 may influence clinical decision-making on prophylaxis for thromboembolic disease in pregnancy .
# Stress and Stigma with COVID-19
Pregnant people affected by COVID-19 may have many challenges at home, including the need for general social distancing, self-isolation and caring for family members who are also COVID-19 positive. There is also stress associated with the potential impact of the COVID-19 viral infection on the developing fetus and pregnancy course. Due to prolonged home isolation, some pregnant individuals may have faced intimate partner violence (see section Intimate Partner Violence), food insecurity, wage insecurity and difficulty with access to medical services because of ability, lack of transport or other concerns. People with COVID-19 may experience feelings of shame and face discrimination in their community as a result of the infection. Providers should use prenatal encounters to screen for and identify mental health concerns, anxiety and depression, as well exacerbation of pre-existing maternal mental health conditions (see Section Perinatal Mood Disorders and Substance Abuse).
Dedicated care environments for care of COVID-19 positive pregnant people are suggested to minimize exposure of individuals and clinical spaces.
Symptoms of COVID-19 in a pregnant person may require in hospital assessment and possible in-patient admission.
# C. Care Environment Considerations During the Pandemic Infection Control and PPE
Outpatient settings that will be providing care to individuals who may have suspect or confirmed COVID-19 should be equipped with the personal protective equipment required to manage Droplet/Contact Precautions. This includes gowns, gloves, surgical/procedure masks and eye protection (either goggles or face shield). N95 respirators are also required if there are plans to perform aerosol-generating medical procedures. Prior to every interaction, HCPs must conduct a point-of-care risk assessment to determine the level of precautions required. In addition, information on personal protective equipment can be found on the Public Health Ontario (PHO) website under IPAC Recommendations for Use of Personal Protective Equipment for Care of Individuals with Suspect or Confirmed COVID-19.
A summary of required HCP precautions for various outpatient clinic interactions are included in the Occupational Health and Safety section of the MOH Guidance for Primary Care Providers in a Community Setting.
# Screening
According to COVID-19 Patient Screening Guidance Document, active and passive screening strategies should be used in the outpatient setting.
# Active Screening
Pre-screening prior to arrival in outpatient settings is a preferred strategy to identify symptomatic pregnant people or those with recent exposure. Individuals with symptoms compatible with COVID-19 should be referred to an assessment center, clinic or hospital as appropriate for testing. If possible, those with recent exposure or symptoms of COVID-19 should have their outpatient appointment deferred or completed virtually until outside of the incubation period, or symptoms resolve and a test is negative, respectively. For pregnant people who require in-person assessment, the outpatient setting should only complete the assessment if they are able to follow Droplet/Contact precautions. Arrangements should be made so that the individual can be identified, masked and transferred to a single-occupancy room as quickly as possible on arrival.
Pre-screening should not replace on-site screening. All pregnant people (and accompanying individuals, if applicable) should be screened for signs and symptoms compatible with COVID-19 and any exposures to COVID-19 on arrival at the healthcare setting. The staff conducting the screening should be protected by either a physical barrier (e.g., plexiglass), physical distancing (at least a two-metre distance) or PPE (a surgical/procedure mask and eye protection). Individuals identified as having symptoms of COVID-19 or exposure in the preceding 14 days should be provided a medical mask (i.e., surgical/procedure mask), if tolerated, and immediately transferred to a singleoccupancy room.
Screening should be done in accordance with the MOH COVID-19 Reference Document for Symptoms.
# Passive Screening
Signage should be posted at the entry points to the office/clinic and at the reception desk. This signage should direct individuals with symptoms to perform hand hygiene, put on a surgical/procedure mask and identify themselves to reception.
# Access to COVID-19 Assessment Centre/Testing
Testing should be performed when screening reveals a pregnant person with symptoms compatible with COVID-19. Outpatient settings should be aware of the local testing locations and protocols to provide instruction to those who require testing. Testing locations may include assessment centers, clinics and hospitals. Instructions should be provided to ensure safe arrangements are in place for travel to the testing facility and safe procedures are followed on arrival. This includes wearing a surgical/procedure mask, not taking public transit during travel, and performing hand hygiene, wearing a surgical/mask and self-identifying upon arrival at the testing facility.
# Modifications to Usual Visit and Frequency
Routine Pregnancy Assessment Schedule Throughout the pandemic, changes to the form and frequency of visits have been made in all areas of care to reduce exposing care providers and healthy pregnant individuals to the COVID-19 virus. Based on the WHO recommendation of a minimum of eight prenatal visits per pregnancy, alternate visit schedules have been proposed . Some visits can be done virtually to limit the time of in-person exposure, particularly early in the pregnancy, although in-person assessments cannot be completely avoided. Covering all necessary information, as well as adding COVID-19 specific information into a modified schedule, may require additional time, particularly during virtual appointments. There is no evidence on the optimal length of an in-person visit to minimize risk of exposure while providing appropriate client care, but efforts should be made to limit the length of the visit.
The following is proposed as a minimum number of visits during pregnancy. It should be noted that due to the amount of education required, when the number of visits is reduced, they may need to be longer to ensure all essential care is provided. When local disease activity is low and good infection control practices are in place, routine frequency of care remains appropriate, especially when virtual care is included. Highrisk pregnancies should include an individualized plan of care to determine the schedule of visits.
# Recommended Minimum Visit Schedule
In-person and virtual visits can be alternated between first visit (before 12 weeks) up until 34 to 36 week visits. Visits at 38 weeks and onwards should be in person.
# Clustering of Testing/Visits to Minimize Exposure
When possible, testing should be clustered to limit the number of exposures. For instance, a single ultrasound done after 11 weeks can serve as a dating and NT ultrasound. Additionally, trimester specific, laboratory testing can be grouped at the same time (e.g., prenatal blood work with eFTS, gestational diabetes screening with type and screen in preparation for Rh immune globulin). When facilities such as clinic, lab and ultrasound, are co-located, scheduling investigations and assessments at the same time will reduce the number of visits and possibly overall exposure.
# Alternatives to In-person Visits
Virtual care in the form of phone or video visits allow providers to conduct assessments and education without exposure risk. Provincial and national professional organizations have created excellent resources, such as the Virtual Care Playbook and the Virtual visit guide for midwives , for their members on the issues unique to providing virtual care. Providers must consider issues such as security of the platforms they are using, obtaining consent to provider virtual care and appropriate documentation requirements.
As well, ensure that pregnant people are in an appropriate, safe and confidential space for the assessment.
# Technology Access and Equity
While the COVID-19 pandemic has necessitated the rapid adoption of virtual care, not all pregnant individuals have the means to participate equally in virtual care platforms. While the majority of Ontarians have smartphones, not all may have access to sufficient data plans, high-quality Wi-Fi for a video call or enough voice minutes on their phone plan for telephone visits. For some, cultural barriers may exist to accessing virtual care. HCPs may need to adapt the schedule of virtual and in-person visits depending on the pregnant individual's ability to participate in virtual care. Lack of access to virtual care For most pregnancies, a minimum of eight antenatal appointments, with a combination of virtual and in-person care, can be adopted during the pandemic.
Investigations, including lab and ultrasound, should be clustered where possible to minimize contacts with the health care system.
Virtual care may replace some in-person in a blended model of care following guidance from professional organizations to ensure safety.
must not inadvertently intensify health disparities based on social determinants of health such as poverty, homelessness or cultural identity. In some rural and remote locations, inadequate access to broadband internet may impede virtual video visits and necessitate more reliance on telephone-based virtual care. Efforts must be made to minimize inequity in the quality of virtual care based on lack of access to internet services . Efforts must be made to ensure adequate length and quality of calls for those reliant on telephone-based care .
Other groups, such as Deaf/hard of hearing individuals and those who require language interpretation, may be disadvantaged by virtual care unless accommodations are made for their needs. This may require the use of text-based platforms for the Deaf/hard of hearing and the use of platforms that allow for three-way audio or video calls for those who require language interpretation, including ASL.
Lack of Access to Care, Late to Care Pre-existing barriers to accessing prenatal care have been exacerbated by the COVID-19 pandemic. Marginalized groups -including, but not limited to, Black, Indigenous, racialized, newcomer, differently abled, refugee, 2SLGBTQ, homeless, incarcerated, sex workers, people with addictions and people with low socio-economic status -not only are at higher risk of poorer perinatal outcomes generally, but are more vulnerable to the impacts of the pandemic such as precarious employment and social isolation.
They are also at higher risk of contracting COVID-19.
Ontario made universal health care accessible to people without OHIP and removed the three-month waiting period for OHIP as an emergency measure during the pandemic. These were important steps to ensure that those without health insurance have access to care, including prenatal care. Still, many social determinants of health create barriers to timely access to prenatal care. During the pandemic, existing inequities can be amplified , meaning HCPs must be keenly aware of the disproportionate health impacts of the pandemic on populations who already carry a higher burden of perinatal morbidity and mortality. Awareness of these issues (and increased availability and adoption of cultural-safety and antiracism/implicit-bias training) must be a priority for healthcare providers to understand these underlying forces in health inequity. Modifications of the care schedule, method of care (virtual or in-person), length of visits and outreach (follow-up for missed appointments) to pregnant individuals must be made when taking these barriers to care into consideration. Efforts to make the care environment a safe space for those who have experienced healthcare-related trauma will improve access to prenatal care. Indigenous people often come late into care due to fear because of prior experiences of HCPs should assess the pregnant person's needs, means and ability to participate in virtual care and provide accommodations as needed. No pregnant person should be denied appropriate pregnancy care based on their inability to access technology.
racism in the healthcare system. They may be fearful of punitive measures being undertaken because of this, such as healthcare providers calling child protection, often resulting in infant apprehensions. Understanding and having compassion for the underlying layers of trauma is something all healthcare providers need to encompass in their care.
# Fear of Accessing Care
Some pregnant individuals may be reluctant to access in-person scheduled and acute care based on fear of exposure to COVID-19. HCPs, while being sensitive to these fears and providing access to resources for stress and anxiety, should provide reassurance about the safety measures in place in the care environment and the importance of in-person assessments to ensure the well-being of the pregnant individual and the fetus . Assessments such as monitoring blood pressure, ensuring normal fetal growth, and receiving recommended vaccines are essential to the provision of prenatal care that leads to improved perinatal and neonatal outcomes . Additionally, pregnant individuals who are symptomatic for COVID-19 should be reassured about the safety of testing centres and encouraged to access testing when indicated. Fear should not be a deterrent to presenting at a testing centre. Indigenous people often fear accessing care due to prior experiences of racism in the healthcare system. COVID-19 adds an additional layer to that fear.
# Rural and Remote Considerations
The realities of pregnancy and birth in rural and remote communities mean that rural pregnant people have reduced access to care and experience the cultural, financial and emotional burdens of travel for care. These stressors are amplified by the realities of the COVID-19 pandemic and all efforts must be made to ensure that pregnant individuals and their supports living in rural and remote communities have equitable access to quality prenatal care in face of changes in our patterns of care .
As a result of COVID-19-related restrictions, pregnant people in rural and remote communities have had decreased access to routine testing. This is particularly true in fly-in northern communities. Flights and other forms of travel have diminished, resulting
HCPs must understand systemic barriers to accessing care and the disproportionate health impacts of the pandemic on populations who already carry a higher burden of perinatal morbidity and mortality. Providers must make efforts to create safe spaces and modifications to care for those facing barriers.
HCPs should be aware of the impact of fear on accessing prenatal care, including COVID-19 testing, and provide reassurance, guidance and resources to minimize this impact.
in tests cancelled due to delays from collection to arrival at laboratories. As well, some testing (e.g., ultrasound) was provided by visiting providers who are no longer able to visit remote communities due to travel restrictions and isolation practices. In some instances, point-of-care (POC) testing may replace formal laboratory samples. For example, a POC glucose measurement can be done at the same time as the lab draw for gestational diabetes screening.
In rural and remote communities, decreased access to testing and increased turnaround times will result in a longer time between testing and clearance. As a result, pregnant individuals may experience longer periods of isolation even when able to remain in their home community. Increased virtual care and/or provider access to PPE may be required as a result. Rapid and POC testing, as they become more widely available, have the potential to reduce this impact.
Providing prenatal care through virtual means may benefit rural individuals by reducing their need to travel for in-person visits. As well, where pregnant people must leave their home community for birth, the expansion of virtual care may allow them to meet and form a relationship with their care team in the distant community earlier in the pregnancy rather than only at term. Providers must we aware, however, that virtual care is difficult to apply in many rural communities due to poor access to reliable, high-speed internet services and limited access to technology. Healthcare systems should be innovative and flexible in their support of virtual care (e.g., access to nursing station technology for virtual visits with urban providers).
While virtual care can decrease the need for pregnant people to leave their home communities, in-person care will still be required. The limitations on travel and resulting reduction in visiting care providers has highlighted the need to strengthen the prenatal care skill set of local providers. Efforts should be made to support healthcare providers located in rural and remote communities by providing the training, resources and regulatory ability to fill the gaps in care left in human health resources by pandemic restrictions.
In rural and remote communities, access to essential prenatal testing and diagnostics must be preserved. Where feasible, point -of -care testing should be made available and test timing should take into account transit times to urban laboratories.
Virtual care has the potential to improve access to prenatal care for rural and remote pregnant individuals, but providers must be aware of issues of access to and quality of technology in rural communities.
To date, many rural communities in Ontario have experienced low rates of COVID-19 infections. As a result, those who are required to travel for prenatal care, investigations and birth will experience anxiety about contracting the virus during the course of that care. Protections should be in place, and education and reassurance, provided such that essential care is not avoided. Pregnant people traveling from one community to another may experience periods of mandated isolation either when transferred out or upon returning to their home community (or both) as part of efforts to control spread of the virus. This may have significant impacts on not only the person in isolation but also their family and their entire community. Given the frequency of visits and testing during the course of routine prenatal care, a period of 14-day isolation following each visit or test could result in a pregnant person being in isolation for the majority of the pregnancy. This will inevitably lead to the choice to forgo care and/or defy isolation requirements.
Pregnant individuals in remote communities, especially those living in First Nation communities, may not have the options of applying recommendations on reducing disease transmission. For instance, they may not have reliable access to clean water for hand washing or may live in housing that is too crowded to allow for physical distancing. This will be especially true for COVID-19-positive or suspect people required to strictly self-isolate. When providing care to pregnant people in remote communities, providers should enquire directly about access to clean water and physical spaces that allow for isolation. Where they do not have necessary access, HCPs should work with local supports (e.g., hospitals, band councils, municipalities) to secure access to hand sanitizers, masks and other needed resources.
Where possible, care should be provided in a pregnant person's home community. Where travel for care is necessary, visits and testing should be bundled in such a way as to minimize travel and post-travel periods of selfisolation/quarantine.
When pregnant people are required to travel in and out of their home community for prenatal care and birth, isolation and quarantine policies should balance the needs of the community and the impact on the individual and their supports. Anxieties around risk of contracting the virus must be balanced against the necessity of the care being accessed in other communities and safeguards put in place.
During pregnancy care, providers should enquire directly about access to resources for transmission prevention, including safe housing and clean water.
# Evacuation for Birth
Pregnant people who must leave their home community to give birth already carry a significant burden of isolation and displacement around the time of birth. During the pandemic this burden has increased due to restrictions on support people as well as mandated periods of self-isolation. The stress and anxiety caused by this uncertainty should be addressed through increased screening/direct questioning, education and improved access to support, both formal and informal. The financial burden of travel for care has been amplified as a result of pandemic restrictions. While some financial support may be available, it is generally not sufficient to cover costs and not all rural and northern pregnant individuals have access to these financial supports. When prolonged periods of self-isolation are added to the travel time, costs mount considerably. As well, northerners often rely on informal supports such as staying with friends and family in urban communities. When these options become unavailable due to lockdown and phased recovery, options for food and housing such as hotels and restaurants also become less available.
The majority of pregnant people who face evacuation for birth (i.e., who must leave their home community at term and remain in a distant community until birth) are Indigenous people, leading to greater burdens and inequities to this already disadvantaged population. Policies and practices around evacuation for birth must be created in a culturally safe manner supported by existing educational programs around culturally safe care .
Rural hospitals and care providers may feel less equipped to deal with pregnant people who are COVID-19 suspect or positive due to restrictions provided by the physical environment or due to real or perceived lack of knowledge. To reduce spread of COVID-19 and minimize the impact on pregnant individuals, inter-facility transfers should be avoided, where possible. While COVID-19 alone should not be an indication for transfer , rural providers requesting transfer for COVID-19-positive or suspected pregnant individuals should be respected. Where transfer is not deemed necessary, virtual
Increased planning for and education around resources in the planned location of birth will be needed during times of lockdown and phased recovery. Providers should be aware of and explicitly address the emotional and financial costs of evacuation for birth.
Policies and practices around evacuation for birth must recognize that disproportionate burden carried by Indigenous communities and must be created in a culturally safe manner.
All rural care providers and environments should be supported in providing care to COVID-19 suspected or positive pregnant people with increased virtual support and education and transfer when appropriate.
support and education for the rural providers should be provided by expert teams in referral centres. Existing referral systems do not empower midwives and other nonphysician providers to facilitate necessary transfer. Midwives should be made part of the referral system so that seamless care can be provided for the pregnant person without adding additional burden to the provider.
# Care in Home and Non-Clinical Settings
Efforts should be made to minimize non-essential visits, which may include the reduction or elimination of planned antenatal visits in the pregnant person's home or in other non-clinical environments (e.g., shelters, hotels, public spaces). In some cases, these visits may be deemed necessary to provide prenatal care. This may be particularly important for those who would not otherwise access care. In these cases, efforts must be made for all members of the household or other non-clinical environment to be screened in advance of the visit for symptoms of COVID-19 and to limit the number of people present during the visit . All members of the household or non-clinical environment who can wear masks are expected to do so and should be informed of this expectation prior to the visit. The provider must ensure access to adequate PPE and hand hygiene for themselves and appropriate cleaning supplies for surfaces and equipment for the visit. Providers must have sufficient PPE to properly doff and don between environments when traveling between care environments.
# D. Provider Considerations Communication During and About the Pandemic
The COVID-19 pandemic has brought about a significant and constantly evolving change in all pregnancy care environments. For many pregnant people, the uncertainty about what to expect during pregnancy visits and at the time of birth results in increased anxiety. It is important that information about any changes be clearly communicated to pregnant people and they be made aware of sources of up-to-date information.
Providers and care environments are encouraged to use a variety of means to share this information such as in-person communication, conversations during virtual visits, signage, written materials, clinic and hospital websites and social media. Communication with pregnant people should include discussion of ways in which the form and frequency of visits may have changed. It is also important to educate pregnant individuals about issues of security and confidentiality when using virtual platforms. Provincial and national organizations have created resources that can guide these Visits outside of the clinical care environment should be kept to a minimum while recognizing these visits may be necessary in certain situations. Adequate PPE for HCPs, pregnant individuals and their support people, and strict IPAC practices, must be used to make visits in non-clinical environments as safe as possible.
communications as well as provide sample language: Virtual Care Tools by OntarioMD and the Ontario Medical Association.
Pregnant people will have many questions about the potential impact of COVID-19 on their health, the health of their baby, their birth experience, and the safety of things such as workplaces and childcare for other children. HCPs should use a variety of means to provide information on these topics, including sharing websites and resources created for this purpose .
Changes to the care environment may have unintended impacts on communication between providers and pregnant people. Clear and empathetic communication is a priority even when care is provided through virtual means or while wearing PPE. Information should be available in community languages other than English and in visual or easy-to-understand formats as far as possible. Providers should remain cognizant of the ways in which PPE impacts non-verbal communication as well its impact on communities such as the deaf/Deaf/hard of hearing.
Sharing information with pregnant people and their care providers is essential to reduce unnecessary visits and duplication of investigations. All contact numbers should be double-checked to ensure they are correct before the pregnant person leaves care environments such as emergency departments, ultrasound facilities and labs as subsequent health care providers must be able to contact the person directly. It is recommended that pregnant people be given copies of their Ontario Perinatal Record, bloodwork, ultrasounds, etc. (paper or electronic) to carry with them so investigations do not get repeated unnecessarily. Indigenous people may or may not have access to regular means of communication, such as cell phones, in the same way as the rest of the population. Safe and sensitive follow-up should take into consideration how readily the person will be able to participate in the follow-up and no assumptions should be made.
HCPs and care environments should communicate with pregnant people about changes to care as well as provide information about COVID-19 in pregnancy. They are encouraged to do this through a variety of means, including websites and social media.
Clear and empathetic communication is a priority. Providers should be aware of the ways in which virtual care and PPE may impact communication.
Contact information should be collected and confirmed. Pregnant people at all gestational ages should be provided with copies of results to minimize repeat investigations.
# Staffing
Each care environment will be unique in how it provides space and personnel for care during the pandemic. Consideration should be given to a variety of factors when determining how staffing may change, including impact of virtual care, changes in flow of patients, screening requirements and cleaning of clinical spaces. Increased staffing may be necessary and staff may be required to perform duties outside of their typical roles. Illness and isolation requirements may have a significant impact on staff availability. Care environments should prepare emergency staffing plans to respond to possible increased absenteeism and create emergency contact lists. Care environments should establish and strengthen relationships with community partners including public health and municipal governments to coordinate pandemic response, provide consistent communication and share supplies. Healthcare employers should recognize that staff may experience anxiety about the impact of the pandemic on the workplace. Care environments should communicate clearly with their staff about what is known about COVID-19, the impact on the workplace, efforts being made to reduce disease transmission and emergency staffing plans.
# COVID-19 Related Stigma and Violence Directed Against HCPs
HCPs are subject to significant physical and psychological violence, particularly in the face of "work pressure and stress, social instability and the deterioration of personal interrelationships" . Within pregnancy care environments, much of this violence has stemmed from frustration with support person policies and increased IPAC procedures and is exacerbated by the uncertainty and loss of control that pregnant people and their supports are experiencing. Additionally, HCPs have experienced stigma due to perceived increased risk of transmitting the disease, which has resulted in greater social isolation, negative impacts on their relationships with family, and decreased access to community resources and infrastructure. It is unsurprising that there have been increased reports of racialized violence against healthcare workers, particularly those from Asian communities that have been attributed to the impacts of the pandemic .
Care environments should prepare for staffing impacts of the pandemic including by developing emergency staffing plans and by strengthening community partnerships.
Care environments should communicate clearly with staff about the impacts of COVID-19 on the work environment, including the details of pandemic staffing plans.
Workplace violence and stigma have been shown to have significant negative impact on staffing, working environments and organizational efficiency, which makes it imperative that violence and stigma, as well as factors that contribute to them, be addressed . Pre-pandemic guidance such as the WHO Framework Guidelines for Addressing Workplace Violence in the Health Care Sector can be supplemented by specific guidance on reducing violence and stigma due to the pandemic. Care environments should address violence and stigma against healthcare workers through a multifaceted approach including:
- Creating a climate and policies that reject violence against health care workers - Creating a climate and policies that engage and empower HCWs to address violence and stigma - Reducing uncertainty and fear for pregnant people through clear communication within the care environment and with the community at large about changes in care practices - Participating in initiatives that increase community knowledge and address COVID-19 myths - Supporting initiatives that positively portray healthcare workers' contributions (e.g., Health Care Hero campaigns) - Ensuring workers have access to both formal and informal supports that recognize the increased stresses brought on by working during the pandemic
# E. Task Force Health Equity Context
Ontario is home to diverse pregnant and postpartum populations; inclusive of age, gender identity, race, ethnicity or culture, ability and other factors such as geographical location. These factors can greatly influence a person's unique needs and expectations around care management during pregnancy.
When appropriate, HCPs should consult with specialized organizations that support specific populations for assistance in appropriately tailoring these recommendations to the individuals under their care.
Indigenous populations have unique and diverse needs that arise out of being the original people of this land and being colonized and displaced from their home territories. Indigenous people suggest you ask them directly what their needs may be and make appropriate referrals when required.
COVID-19 related stigma and violence directed against healthcare workers cannot be tolerated. Care environments and workplaces should actively work to reduce stigma and violence through a multi-faceted approach.
In writing this guideline, attempts were made to align with emerging policy work on Indigenous cultural safety, vulnerable communities, and principles of diversity equity and inclusion by provincial and national associations, including the SOGC, the Association of Ontario Midwives and the Canadian Association of Perinatal and Women's Health Nurses . The imperative for equity in this pregnancy care guideline comes from national and provincial legislation, regulation, policy and interpretation by PCMCH. The task force took the opportunity to consider vulnerable community pandemic experiences and how we could make representation, research and outcomes improvement processes and priorities more population-based. The task force acknowledges that individual, family and provider experience is essential to understanding population needs and impacts during the pandemic. This guidance reflects expert advice, stakeholder feedback, media scans and anecdotal experience. More sector work is needed to understand the diverse needs and outcomes of expectant and growing families in Ontario. PHO has stated social determinants of health play an important role in the risk of COVID-19 infection, especially when they impact the ability to perform physical distancing . These determinants include:
- gender - socioeconomic position - race/ethnicity - occupation - Indigeneity - homelessness and incarceration
# Understanding and Identifying Vulnerable Populations
Canada's geography and diversity of populations can create challenges in delivering healthcare during a pandemic. Community size and accompanying healthcare resources vary greatly across the country. COVID-19-specific advice for vulnerable populations can be found at: Planning advice for vulnerable populations, which was developed for pandemic influenza but may also be useful for COVID-19 .
According to the Government of Canada website, vulnerable communities include those with:
- Difficulty reading, speaking, understanding or communicating (including French language resources) - Difficulty accessing medical care or health advice Indigenous populations should be asked directly what their needs are and referrals made as required.
Providers and care environments should tailor these recommendations to the individuals under their care, consulting those who provide support to specific populations to ensure appropriateness.
- Difficulty doing preventive activities, like frequent hand washing and covering coughs and sneezes - Ongoing specialized medical care or needs specific medical supplies - Ongoing supervision needs or support for maintaining independence - Difficulty accessing transportation - Economic barriers - Unstable employment or inflexible working conditions - Social or geographic isolation, like in remote and isolated communities, or - Insecure, inadequate or nonexistent housing conditions .
Ontario's Action Plan for Vulnerable People adds additional guidance on those living in high-risk settings, including:
- Homes serving those with developmental disabilities - Shelters for survivors of gender-based violence and human trafficking, and - Children's residential settings, which would include Indigenous residential settings on and off reserve .
Based on client/patient and provider-reported feedback, the Task Force found COVID-19 is having direct and compounding mental and physical impacts on maternal and child health outcomes. The combination of family social isolation, structural barriers to early and regular prenatal care and disproportionate burden of illness in vulnerable populations may have a negative impact on birth outcomes for 2020 and 2021. At a systems level, the maternal and infant population may require the "vulnerable population" designation to ensure adequate planning and resource allocation in pandemic circumstances. Such allocation will need to include culturally safe health data collection, interpretation and public reporting of subpopulation maternal-newborn outcome indicators.
Our Task Force recognized the challenges and limitations of its structure and composition as well as knowledge base. We propose two items for future consideration: 1. Prioritization of staff and committee member health equity and diversity training, including Indigenous Cultural Safety Training for future similar projects; 2. A health equity template, an example of which is provided in the appendix, may help facilitate a more comprehensive embedding of health equity principles during the preparation of healthcare guidelines.
In addition to embedding equity throughout this guideline and recommendations, the task force is using the lessons learned to direct specific system-based recommendations to the MOH as well as to encourage PCMCH to continue to work towards explicitly embedding equity into all of their work.
# Wendy Carew Ontario Health North
# Wendy Katherine
Best Start: Health Nexus
# Contributors
A subcommittee was established to guide and inform the development of this document with a focus on ensuring that the perspectives and lived experiences of Indigenous, Black and people of colour are reflected in these recommendations. We thank these members for their additional time and thoughtful contributions to promote a decolonized, equitable and inclusive process.
The equity subcommittee included: Cynthia Maxwell, Elizabeth Brandeis, Ellen Blais, Katherine (Kate) Miller and Wendy Katherine.
Through the development of this guideline, the Task Force identified a number of additional concerns respecting the delivery of safe and equitable prenatal care for both patients and providers. The PCMCH Recommendations to Address Gaps in Prenatal Care System report, led by the equity subcommittee members, was released in January 2021. This report includes a series of recommendations that signal an opportunity to strengthen the healthcare system for all pregnant people and their families.
In addition to the contributions of the individual task force members, sections of this guideline were developed, reviewed or informed by the following individuals:
# Attiya Khan Family Advisor
# Lynne Giroux Eastern Ontario Health Unit
Naana Jumah Thunder Bay Regional Health Science Centre
# Shelley Dougan Prenatal Screening Ontario-BORN Ontario
Stephanie Black London Health Sciences Centre
# Appendix A: Equity Table
This template was adapted from the Health Equity Impact Assessment (HEIA) workbook, available at www.ontario.ca/healthequity. For the purposes of this task force guidance, the populations listed below correspond to reproductive age Ontarians and children.
Step | # Revision History
July 22, 2021 -Current For this version of the guideline, revisions are highlighted in yellow throughout the document.
October 28, 2020 -Original Release
# A Note on Terminology and Language
In Ontario, there is a diverse range of populations that require pregnancy care as well as a wide range regulated healthcare providers (HCPs) who provide pregnancy care. There are also a variety of settings in which pregnancy care can occur. To support the application of these guidelines to the full spectrum of providers, the wide range of populations and the plethora of settings, the terminology used is meant to be representative. Selected terminology that has been used throughout the guidelines includes:
• pregnant individual/people: woman, transgender individual, non-binary individual, surrogate, gestational carrier • care environment: clinics, offices, community settings, ambulatory care, homes, obstetrical triage, emergency room and birthing centres • healthcare provider: regulated healthcare providers in Ontario, including family physicians, registered midwives, Indigenous midwives, obstetricians, maternalfetal medicine specialists, Registered Nurses and Registered Practical Nurses • support person: spouse, partner, co-decision maker
# Summary of Recommendations
# A. Care of Pregnant Population
# Involvement of Support People in Pregnancy Care
• Visitor and support policies should allow for one support person (at minimum) for significant events in the prenatal period, including pregnancy loss and communication of and consultation for significant complications of pregnancy.
Where in-person support is not possible or permitted, the importance of the support people and partners should be acknowledged, and their involvement facilitated through virtual means.
• The presence of culturally relevant support people is essential to culturally safe care.
# Early Pregnancy Loss and Stillbirth
Presence of Support People at Times of Pregnancy Loss
• Where possible, support person policies should allow pregnant persons who may be losing a pregnancy at any gestational age to have one support person (at minimum) with them.
# Follow-Up of Pregnancy Loss
• Follow-up of early pregnancy loss can often be done virtually, allowing for inperson visits as needed.
• Safe and empathetic care of pregnant individuals at risk of early pregnancy loss must remain a priority during the pandemic.
• Pregnant people experiencing loss should know how to seek emergency care and be reassured that if they need to be seen in person, they will be safe and at low risk of contracting COVID-19
• Surgical management of early pregnancy loss is non-elective and should be maintained as an option for management throughout the pandemic alongside expectant and medication management.
# Stillbirth
• Special care and consideration must be taken in supporting individuals and families experiencing stillbirth during the pandemic. As usual, support systems and grieving venues may be altered or unavailable at such times, the needs of the family must be balanced with public health measures and pandemic protocols.
• The usual stillbirth investigations should continue to take place as well as consideration of COVID-19 testing of the person experiencing stillbirth, the infant and the placenta.
# Termination of Pregnancy First Trimester Medication Termination
• There is good evidence to support first trimester medication termination (up to 70 days GA) with reduced or no ultrasound or visits to hospital, directed by virtual care and handouts with instructions for the termination itself and for posttermination care.
• Care should be taken to ensure safe access to urgent post-abortion care for the small percentage of medication failures; this may involve a pathway with access to places other than busy emergency wards at times of high community transmission.
# Surgical Termination
• Surgical termination is considered an essential service and should remain accessible in the pandemic.
• Surgical termination in a COVID-19 positive person should not be postponed if delay affects the person's safety or access to termination.
# Second and Third Trimester Termination of Pregnancy
• The protection of reproductive rights extends to options to terminate a pregnancy in the second or third trimester; services to persons opting for pregnancy termination, such as safe and supported induction of labour, should remain similar to what is offered in non-pandemic times.
• Mifepristone, administered >12h before the start of induction should be considered to significantly shorten the admission to hospital without increased risk of fetal expulsion prior to hospital admission or other complications.
# Treatment of Tissues, Remains and Stillborn Infants
• Families requesting tissues and remains should be respected as per institutional protocols. Cultural beliefs around burial should be facilitated and Indigenous people should have access to their placenta and remains of fetal tissue at their request for ceremonial purposes.
# Prenatal Screening and Genetic Counseling
Prenatal Screening Ontario (PSO) Adjustments to Screening
• Prenatal screening for Down syndrome and Trisomy 18 should be offered and eFTS continues to be the preferred test in low-risk pregnancies. Where access to NT screening is limited, the following advice from Prenatal Screening Ontario should be followed:
o For singleton pregnancies: if an NT ultrasound cannot be done, order Maternal Serum Screening (MSS, also known as Second Trimester Quad screen)
o For twin pregnancies: NT services should be prioritized. If NT is unavailable or if maternal age is 35 or older at expected date of delivery, publicly funded NIPT will be temporarily available.
o For higher order multiples: NT ultrasound currently is the only screening option available.
# Special Considerations
Preeclampsia Screening
• Pregnant people at risk for preeclampsia benefit from low-dose ASA initiated at or before 16 weeks gestational age. Assessment of risk factors, with or without added serum biomarkers or biophysical markers, can assist in the reduction of the burden of preeclampsia and IUGR on care environments during COVID-19.
# Sexually Transmitted Infections Screening and Treatment During the Pandemic
• Routine screening for STIs in pregnancy, including HIV, syphilis, hepatitis B, chlamydia and gonorrhea, should continue. Resources for screening, testing, contact tracing, education and follow-up should be considered essential services and be preserved during the pandemic.
# Screening for Diabetes in Pregnancy
• Early pregnancy screening for women at risk of pre-existing diabetes should continue unchanged. While it may result in decreased detection of mild disease, screening for gestational diabetes between 24 and 28 weeks may be modified by replacing the OGTT with a random glucose and HbA1c when local lab capacity and/or disease levels necessitate.
# Provision of Ultrasound for Low-Risk Pregnancies
• Access should be preserved to at minimum the following ultrasound scans:
# Management of High-Risk Pregnancy
Frequency and Form of Visits for High-Risk Pregnancies
• The care of high-risk pregnancies will, in essence, remain unchanged but contacts can be reduced by use of virtual visits, clustering of care and avoidance of duplication of assessments.
# Assessment of Fetal Well-being Special Tests
• Assessment of fetal well-being should continue to be performed but steps can be taken to reduce the number of unnecessary assessments through deliberate use of testing and/or special tests.
Perinatal Mood Disorders and Substance Use
• Pregnant and postpartum people, as well as those with pre-existing mental health conditions, are amongst the most vulnerable during the COVID-19 pandemic. Healthcare providers should prioritize the care of this population during the pandemic.
• Providers should increase their awareness of and screening for mood disorders and substance use and adjust the frequency and format of visits to allow for both early detection and intervention.
• Provision of perinatal mental health services should be considered an essential service and while the format may need to be altered, these services should be continued and strengthened throughout the pandemic.
• Existing resources and techniques for supporting pregnant individuals with perinatal mood disorders and substance use can be modified to create formats that are accessible through virtual means or a reduced number of visits.
• Given the likelihood of increased substance use and worsening of pre-existing substance use disorders during the COVID-19 pandemic, all pregnant people should be actively screened for alcohol, cannabis, tobacco, and prescription and recreational drug use at multiple points during the pregnancy.
• Pre-existing pregnancy-specific guidelines on substance use in pregnancy should be supplemented by general COVID-19 substance use guidance.
# Intimate Partner Violence
• Due to the increased rates of IPV during the pandemic, providers should remain vigilant through increased screening for domestic violence as well as maintain a heightened awareness of the signs and symptoms suggestive of IPV.
• Care providers should remain vigilant to the ways in which virtual/remote care may be difficult to safely access for survivors of IPV and in-person care should be used to provide safe alternatives when necessary.
# Birth Planning and Counseling
• Prenatal education can be offered during the pandemic through virtual means. Discussion on specific COVID-19 education should be incorporated into prenatal education and prenatal care.
• All pregnant individuals should explicitly plan for birth keeping in mind the impacts of COVID-19 on their care and care environments.
• Indications and options for IOL, TOLAC and high-risk pregnancies are unchanged by the pandemic. However, it should be acknowledged that the impacts of the pandemic may influence both the care environment and the pregnant person's preferences; shared decision-making should continue with increased attention to these factors.
• Guidance suggests that pregnant people can continue to work during the pandemic taking into consideration work related risk, individual risk and local disease activity. HCPs should continue to recommend appropriate workplace accommodations when risk is considered high.
• Pregnant HCPs may continue to work in clinical roles with proper infection control procedures and consideration of assignment to lower-risk care environments.
Testing for COVID-19 in the Pregnant Population
• Pregnant people should be screened and tested as per guidelines for the general population and should be considered a priority population if access to testing is limited. Testing should be expedited for labouring pregnant individuals and when a prerequisite of transfer to another facility.
• Policies on pre-admission and pre-surgical testing as well as disease clearance should apply to pregnant people in the same way that they do to the general population.
# Surveillance of COVID-19 Positive Pregnancies
• Data collection is urgently needed to provide credible information to facilitate and improve care and to help guide decision making at a provincial level. Hospitals and midwifery practice groups are encouraged to contribute to the data collection for pregnant people with suspected or confirmed COVID-19 through BORN Ontario. Where data is not able to be collected through BORN (e.g., Indigenous Midwifery Programs), interim data collection should be implemented without delay.
# B. Care of the COVID-19 Suspected or Confirmed Pregnant Person
• Routine pregnancy care may be deferred until the pregnant person with COVID-19 is no longer infectious, provided it is safe to do so.
• If possible, provision of pregnancy care, including maternal and fetal assessments as well as ultrasound, can be provided at the same visit to minimize multiple exposures to people and care environments.
• There is evidence showing an increased risk of severe infection with COVID-19 during pregnancy; therefore, increased surveillance for both the pregnant person and the fetus are warranted for the remainder of the pregnancy. • For most pregnancies, a minimum of eight antenatal appointments, with a combination of virtual and in-person care, can be adopted during the pandemic.
• Investigations, including lab and ultrasound, should be clustered where possible to minimize contacts with the health care system.
• Virtual care may replace some in-person in a blended model of care following guidance from professional organizations to ensure safety.
# Technology Access and Equity
• HCPs should assess the pregnant person's needs, means and ability to participate in virtual care and provide accommodations as needed. No pregnant person should be denied appropriate pregnancy care based on their inability to access technology.
Lack of Access to Care, Late to Care
• HCPs must understand systemic barriers to accessing care and the disproportionate health impacts of the pandemic on populations who already carry a higher burden of perinatal morbidity and mortality. Providers must make efforts to create safe spaces and modifications to care for those facing barriers.
# Fear of Accessing Care
• HCPs should be aware of the impact of fear on accessing prenatal care, including COVID-19 testing, and provide reassurance, guidance and resources to minimize this impact.
# Rural and Remote Considerations
• In rural and remote communities, access to essential prenatal testing and diagnostics must be preserved. Where feasible, point of care testing should be made available and test timing should take into account transit times to urban laboratories.
• Virtual care can potentially improve access to prenatal care for rural and remote pregnant individuals, but providers must be aware of issues around access and the quality of technology in rural communities.
• Where possible, care should be provided in a pregnant person's home community. Where travel for care is necessary, visits and testing should be bundled in a way that minimizes travel and post-travel periods of selfisolation/quarantine.
• When pregnant people are required to travel in and out of their home community for prenatal care and birth, isolation and quarantine policies should balance the needs of the community and the impact on the individual and their supports. Anxieties around risk of contracting the virus must be balanced against the necessity of the care being accessed in other communities and safeguards put in place.
• During pregnancy care, providers should enquire directly about access to resources for transmission prevention, including safe housing and clean water.
# Evacuation for Birth
• Increased planning for and education around resources in the planned location of birth will be needed during times of lockdown and phased recovery. Providers should be aware of and explicitly address the emotional and financial costs of evacuation for birth.
• Policies and practices around evacuation for birth must recognize that disproportionate burden carried by Indigenous communities and must be created in a culturally safe manner.
• All rural care providers and environments should be supported in providing care to COVID-19 suspected or positive pregnant people with increased virtual support and education and transfer when appropriate.
# Care in Home and Non-Clinical Settings
• Visits outside of the clinical care environment should be kept to a minimum while recognizing these visits may be necessary in certain situations. Adequate PPE for HCPs, pregnant individuals and their support people, and strict IPAC practices, must be used to make visits in non-clinical environments as safe as possible.
# D. Provider Considerations
Communication During and About the Pandemic
• HCPs and care environments should communicate with pregnant people about changes to care as well as provide information about COVID-19 in pregnancy. They are encouraged to do this through a variety of means, including websites and social media.
• Clear and empathetic communication is a priority. Providers should be aware of the ways in which virtual care and PPE may impact communication.
• Contact information should be collected and confirmed. Pregnant people at all gestational ages should be provided with copies of results to minimize repeat investigations.
# Staffing
• Care environments should prepare for staffing impacts of the pandemic, including by developing emergency staffing plans and by strengthening community partnerships.
• Care environments should communicate clearly with staff about the impacts of COVID-19 on the work environment, including the details of pandemic staffing plans.
# COVID-19 Related Stigma and Violence Directed Against HCPs
• COVID-19-related stigma and violence directed against healthcare workers cannot be tolerated. Care environments and workplaces should actively work to reduce stigma and violence through a multi-faceted approach.
# E. Task Force Health Equity Content
• Providers and care environments should tailor these recommendations to the individuals under their care, consulting those who provide support to specific populations to ensure appropriateness.
# Introduction
In the early months of the COVID-19 pandemic response, PCMCH's Maternal-Neonatal Committee established the first COVID-19 Task Force. This first task force was charged by the Ontario Ministry of Health (MOH) with addressing the immediate maternalneonatal practice concerns relating to interpretations and application of guidelines for intrapartum care. Subsequent to the release of the Maternal-Neonatal Guideline in Spring 2020, the Committee identified the need for additional guidelines in the area of pregnancy care. The Maternal-Neonatal Committee Pregnancy Care Task Force was struck to continue to navigate the multiple practice guidelines from international, national, regional, and local authorities in an attempt to advise the health system and providers on safe practices related to prenatal care.
The task force reviewed English-language clinical guidelines and other guidance documents from government ministries and agencies, professional associations and colleges, international organizations, and other relevant organizations from Canada, the United Kingdom , United States of America , and Australia at the time of publication and with subsequent updates. As guidelines continue to be updated and new evidence emerges, sections of this guideline may no longer be current or applicable to clinical practice.
This Pregnancy Care Task Force was asked to provide the MOH with the recommendations that would standardize practice across the province in an attempt to reduce the variations among providers and across all antenatal care settings in the province of Ontario. The recommendations that follow reflect the current pandemic and integrate best scientific evidence, and are based on the following underlying values and principles.
This guidance provides basic information only. It is not intended to take the place of medical advice, diagnosis or treatment. Please check the PCMCH COVID-19 website and Ontario Ministry of Health (MOH) COVID-19 website regularly for the latest case definition, FAQs and other pertinent information.
# Underlying Values & Principles
In preparation of this guideline, the task force was guided by the following underlying values:
# Beneficence and duty of care
Providing safe and effective care within resource constraints and limitations of evidence
# Access and Equity
Promoting just/fair distribution of benefit and burdens in time of pandemic
# Utility
Balancing evidence and values in order to maximize the greatest possible good for the greatest number of individuals
# Trust:
Foster and maintain the public's trust and health care providers' trust in each other, in leadership, and in their institutions
# Solidarity
Building, preserving, and strengthening inter-professional and inter-institutional collaboration (a responsibility of Health Care Providers (HCPs), institutional leadership, and the MOH)
# Advocacy
Identify emerging health issues in pandemic that require action; promoting public education and engagement; gathering feedback on impact at regional level This guideline aims to:
• conserve quality, consistency and continuity of antenatal care for pregnant people and their supports even in face of changes and restrictions brought on by the pandemic • promote public health aims of reducing COVID-19 transmission and preserving healthcare resources • provide education and opportunity for engagement for HCPs and pregnant people • align with Canadian guidelines, differing only where an Ontario-specific context was needed. The task force made recommendations that represent a general agreement from its members. • support reconciliation through recommendations specific to Indigenous pregnant people and communities (see below) • To bring to the guideline a focus on equity (see below)
# Indigenous Health
It has been said that for Indigenous populations that they "are already walking in a pandemic" [1].
"Our communities are at the front lines of an inequitable system. The trauma experienced within a health care system that is systematically biased and racist is real for us and for our clients. It's a system that leaves us with limited supplies, inadequate or no clinical space and is painfully slow to respond to our needs. COVID-19 is a new and added layer to this" [2].
Although Indigenous people comprise approximately four per cent of the population of Ontario, the health inequities that Indigenous people face every day are enormous compared to the rest of the population [3].
The original people of the land were once healthy and thriving. The colonization of the land they inhabited resulted in the displacement of Indigenous people onto economically unfeasible reserve lands; the devastating and effects of residential schools; the forced sterilization of Indigenous women; the apprehensions of newborns from their families of origin; and the removal of pregnant people from their communities for prenatal and intrapartum care. Such imposed forces created these inequities since settlers landed on the shores of North America.
In recognition of these health inequities, it is contingent upon all HCPs to provide culturally safe trauma--informed care to all Indigenous families. The phrase "Nothing about us without us" reinforces the vision of a shared understanding of the relationship that Indigenous people are asking of their care providers. Another phrase, "ask, don't tell", also brings to light an approach to the provider/patient relationship that allows for the dialogue and respect required to achieve better health outcomes.
Indigenous communities have historically been disadvantaged by a lack of investment in perinatal care in rural, remote and Indigenous communities as well as the practice of evacuation for birth. In addition, historic harms have led to a distrust in the medical system and a reluctance to seek care. During the pandemic, these issues are magnified and negatively impact the ability to enact recommendations designed to maintain quality of care.
While this document focuses on pregnancy care during the COVID-19 pandemic, there is little information and data coming out of Indigenous communities to inform HCPs on current outcomes and changes in the way care is provided [4]. Throughout this document, we have added recommendations in areas where improvements can be made. In responding to the pandemic, as in all areas of healthcare planning, the approach should not deliberately consider the health needs of Indigenous populations but to ask -rather than tell -when making recommendations, incorporating a and process of Indigenous engagement that is led by Indigenous people.
# COVID-19 and Health Equity
While forming the Pregnancy Care Task Force, it was recognized that the impacts of the COVID-19 pandemic and public health measures have had different implications to different populations. As the healthcare system continues to adapt and respond to the needs of Ontarians, the health needs of Indigenous peoples require healthcare providers and organizations to consider a culturally safe and customized response.
For many groups, the pandemic has created particular challenges that then impact and influence their experience of pregnancy within the healthcare system. The task force recognizes that recommendations presented may not be feasible or applicable to meet the needs of these individuals. As providers working and living in a vast and diverse space within Ontario, it must be recognized that many have an experience of being unable to meet the needs of those most vulnerable.
Pregnancy, childbirth and the postnatal period are critical life stages when individuals and their families have a high degree of interaction with multiple providers in the healthcare system. The need for equitable care during these life stages is time sensitive and cannot be delayed during the pandemic response. However, the changes brought about by the pandemic have highlighted and intensified the unintended consequences of current institutional practices and policies, resulting in marginalized and racialized groups being subjected to greater inequities. Efforts to reduce the number of interactions between care providers and pregnant/ postpartum individuals and their families can be adjusted during the pandemic; however, essential elements of care must be maintained.
# A. Care of Pregnant Population
The COVID-19 pandemic has had far-reaching impacts on all care environments. Pregnancy care is an essential service that must continue regardless of disease activity and phase of the pandemic; therefore, providers have been called upon to alter form and frequency of care while still safeguarding the physical and emotional health of pregnant people and their fetuses [5,6,7]. Pregnancy is increasingly viewed as a risk factor for more severe outcomes from COVID-19 infection; this factor must also be considered in how pregnancy care is delivered during the pandemic [8]. The following discussion and recommendations will help guide the ways in which care can be modified to balance good outcomes with disease risk mitigation.
# Involvement of Support People in Pregnancy Care
Traditionally, involvement of support people in prenatal care has been high. Pregnancy and the beginnings of a new family are times when pregnant people may desire or need an increased presence of support people, and when non-pregnant family members and supports feel a strong attachment to and involvement in the outcomes. Because of this, the presence of a designated support person during labour and birth continues is commended even during the pandemic [9].
To reduce transmission and conserve personal protective equipment (PPE) and staff time most healthcare environments have restricted or prohibited support people from attending many appointments, including routine prenatal appointments, scheduled investigations (e.g., ultrasound) and non-scheduled assessment (e.g., triage visits). While these restrictions may be seen as generally reasonable and often necessary for infection control reasons, it is important to consider the value of allowing support people in pregnancy care. This is especially true when pregnancy complications arise, when difficult decisions need to be made or when bad news needs to be communicated (e.g., abnormal test results, significant complications or pregnancy loss). As such, healthcare environments and providers should consider making exceptions to support/visitor restrictions in these circumstances.
At times, it may be appropriate and sufficient for the support person to be present via virtual means (e.g., phone or video), but the need for in-person support at highly emotional times cannot be disregarded. Equally, it must be acknowledged that pregnancy loss and fetal complications have a significant impact on support people over and above their role in supporting the pregnant person. When fetal outcomes are involved, support persons are often also shared-decision makers whose involvement is essential. Consideration should be given to providing consultations virtually where appropriate (e.g., genetic counseling) to facilitate the pregnant person and their supports being together and jointly involved in the consultation.
When support people attend in-person assessments, itis essential that everyone adheres to all infection control procedures, including screening and use of PPE.
The safety of the care team and care environment is paramount and, as such, there will be situations where in-person support cannot be permitted. Depending on the resources available in the care environment, the ability to facilitate in-person support people from one environment to another or during different phases of the pandemic may vary. Care environments should have a mechanism in place for pregnant people to request exceptions and policies should address the additional care needs of various populations (e.g., people living with disabilities, non-English speakers) as well as to encompass the diversity of families we care for (e.g., adoptive and surrogacy families, Indigenous families).
While prohibiting support people from attending routine prenatal care is reasonable to limit possible viral exposures involving them in prenatal care, not only in their supportive role but also to help prepare them for their role in birth and parenting, is important. Achieve this by:
• Encouraging support people to be present for virtual appointments • Facilitating phone or video presence of support people at in-person appointments • Permitting phone or video recordings for women to share (e.g., ultrasound images, fetal heart sounds) • Providing written materials to support conversations on common topics Pregnant people living in Indigenous and fly-in communities must often travel for prenatal care (see Rural and Remote Considerations) and their support people frequently travel with them. Due to public health measures and COVID-19 pandemic restrictions, supports may not be permitted to attend these visits in-person, which adds to the emotional, financial and cultural burden that Indigenous pregnant people must bear. Participation of some community members who represent significant cultural value may be crucial to the provision of care for the pregnant individual. Support person policies should reflect the needs of this population and alternatives to in-person support must be developed in a way that is accessible to them.
Visitor and support policies should allow for one support person (at minimum) for significant events in the prenatal period, including pregnancy loss and communication of and consultation for significant complications of pregnancy. Where in-person support is not possible or permitted, the importance of the support people and partners should be acknowledged, and their involvement facilitated through virtual means.
The presence of culturally relevant support people is essential to culturally safe care.
# Early Pregnancy Loss and Stillbirth
At the time of this guideline, there is no clear evidence that exposure or infection with COVID-19 is a risk factor for early pregnancy loss. There is some emerging populationlevel data to suggest that the incidence of stillbirth has been increasing during the COVID-19 pandemic [8]. It is unclear at this time if this is due to the virus itself, to delayed or different patterns of care, or to socio-economic or other factors. Of note, this section refers to spontaneous pregnancy loss rather than induced terminations and abortions, which are covered in the following section: Termination of Pregnancy .
Losing a pregnancy, whether in the early weeks or the final days, is a highly stressful event that may be worsened in the context of the pandemic. The pregnant person may already be isolated socially, dealing with upheaval in work and childcare with decreased support from family, and is now facing pregnancy loss. They may have had heightened anxiety of being pregnant during the COVID-19 pandemic and may need additional supports and counseling.
It is also very important to recognize that Indigenous people have experienced high levels of intergenerational loss and trauma, including removal of infants from their care in more than one pregnancy. Care providers need to be culturally safe when discussing loss with Indigenous clients [10].
At-risk marginalized populations, or populations with unique cultural identities, may have customs or different needs when approaching pregnancy loss or stillbirth. Safe environments and spaces must be created that allows their experiences to be respected and valued.
# Presence of Support People at Times of Pregnancy Loss
Due to restrictions on visitors and support people, there is an increased likelihood that a person who has lost their pregnancy will learn of the loss alone in an office, an ultrasound suite or the emergency room. Where possible, a pregnant person experiencing bleeding or lack of fetal movement should be allowed and encouraged to have a support person with them. This is a highly emotional and traumatic experience; it is well-documented that optimal family-centred care has a lasting impact on their mental health and future pregnancy experiences [11,10].
With COVID-19 restrictions in place (both medical and in the community), the pregnant person experiencing loss may be feeling very isolated and alone.
# Where possible, support person policies should allow pregnant persons who may be losing a pregnancy at any gestational age to have one support person (at minimum) with them.
HCPs must be highly awareness of this. Their family and friends may be unable to visit or help support them. It is important that care providers recognize this gap in support and, where needed, allocate additional time to ensure effective and safe communication. HCPs should consider making exceptions to visitor restrictions under certain circumstances; for example, respecting cultural practices, accommodating disabilities, mental health support and trauma-informed care, which may necessitate more than one support person's presence.
# Follow-Up of Pregnancy Loss
Follow-up for early pregnancy loss and stillbirth can be done virtually as minimal physical exam is required. However, keep in mind that some pregnant individuals may require more frequent contact than others and an in-person visit may be appropriate. Referral to mental health services remains appropriate as needed and can be done virtually.
When a pregnant individual presents with bleeding during COVID-19, all the usual assessments and care planning must take place. First trimester ultrasound is used to establish the pregnancy location (i.e., intrauterine versus ectopic) as well as to rule out gestational trophoblastic disease (molar pregnancy). Rhesus status should be established, and Rh Immunoglobulin administered if the pregnancy is at or above 49 days at the time of loss.
For early pregnancy loss occurring before 12 weeks with light bleeding, it may be possible for the pregnant person to remain at home, provided they have access to good pain control as well as anti-nausea medication. This can be provided at the time of their assessment to avoid additional travel. For early pregnancy loss occurring after 12 weeks and associated with bleeding, an in-person assessment must be done for assessment, vital signs and standard care in the usual care environments.
All pregnant people must be counselled on how to access telephone advice (based on local protocols) and when to seek emergency attention. Individuals should be counselled that their local in-person emergency and obstetrical care areas are safe places and will not increase their risk of exposure to COVID-19. When attending inperson (including ultrasound exams), if possible, pregnant individuals should have access to a private bathroom to avoid the need for repeated cleaning.
Ideally, at the time of an in-person assessment, any investigations, including ultrasound, quantitative beta HCG, CBC and Rh testing, are all done during the same visit to avoid return visits. Physical examination should be performed by the first provider (e.g., emergency physician) and should not be delayed due to PPE restrictions especially if
# Follow up of early pregnancy loss can often be done virtually, allowing for inperson visits as needed.
an individual is in pain or unstable. Pain and nausea must be well controlled with medication and outpatient prescriptions should be provided. Follow-up and necessary consultations should be arranged and frequently can be provided through virtual means. HCPs should be aware of the role unconscious or hidden biases play in the provision of pain relief for racialized people. Unintended consequences may include inadequate provision of pain relief and lack of acknowledgement for racialized people.
All management options for early pregnancy loss should be available. Expectant management or medication management are preferable to avoid surgical intervention. However, it is also essential for clinicians and hospitals to recognize that a dilatation and curettage procedure is an essential surgery and should continue to be available during the pandemic. The pregnant person should receive counseling regarding different methods for managing early pregnancy loss, and their choice should be included as part of the management planning.
# Stillbirth
Stillbirth presents special challenges given the bereavement experienced by the pregnant individuals and their families. All efforts must be made to select a location where the person experiencing stillbirth can receive care in a sensitive manner, ideally separate from labouring individuals and newborns, following safety and COVID-19 infection control protocols.
In the case of a confirmed stillbirth, a wider circle of supports, including extended family and spiritual support, may be needed. Inclusion of additional support persons and longer hospitalization to facilitate grieving should be considered in the context of local guidelines. Opportunities for others to meet the infant in person may be restricted and families may need to balance the need for culturally appropriate rituals, funeral services and gatherings with the pandemic requirements of isolation and social distancing.
# Safe and empathetic care of pregnant individuals at risk of early pregnancy loss must remain a priority during the pandemic.
Pregnant people experiencing loss should be aware of how to seek emergency care and be reassured that if they need to be seen in person, they will be safe and at low risk of contracting COVID-19.
# Surgical management of early pregnancy loss is non-elective and should be maintained as an option for management throughout the pandemic alongside expectant and medication management.
Medication management of stillbirth during the pandemic should follow intrapartum protocols as covered in the PCMCH Maternal-Neonatal COVID-19 General Guideline. The cause of most stillbirths in Ontario remain unexplained and investigations should continue to follow current guidelines, including sending the placenta for pathology. Although a causal link with COVID-19 infection has not been firmly established, there is evidence suggesting an increase in stillbirth rates during the pandemic [8]. Consideration should be given to testing people who have experienced stillbirth (with NP swab and/or antibody testing) as well as infant and placenta. This will both add to the overall body of knowledge and may give reassurance to the bereaved parent and their supports. Placental pathology may yield important information for future pregnancy planning.
# Termination of Pregnancy
Reproductive rights are considered essential and care should be taken to protect the provision of termination services despite of and especially during the pandemic response. [12] While this provision should never be delayed, policies that minimize the number of required visits should be applied, and procedures should be performed in outpatient settings wherever possible [13] [14].
# First Trimester Medication Termination
The intake assessment for both medication and surgical termination services can be conducted virtually, and as most women present for termination have already made up their minds, counselling can be reserved for those who are ambivalent or emotionally distressed. In the absence of readily accessible ultrasound, gestational age (GA) can be estimated using last menstrual period (LMP), clinical history and physical examination in women who are certain of the date of their LMP [15]. Ultrasound is needed when uncertainty remains, and access to timely dating ultrasound should be ensured for these pregnancies [16]. In absence of ultrasound, beta-hCG levels can be used to estimate gestational age. For example, the cut-off value of 23,745mlU/mL can be used to detect pregnancies with a gestational age <7 weeks. The risk of ectopic pregnancy potentially missed with a non-ultrasound-based approach of medication terminations is 0.7 per Special care and consideration must be taken in supporting individuals and families experiencing stillbirth during the pandemic. As the usual support systems and grieving venues may be altered or unavailable at such times, the needs of the family must be balanced with public health measures and pandemic protocols.
# The usual stillbirth investigations should continue to take place as well as consideration of COVID-19 testing of the person experiencing stillbirth, the infant and the placenta.
cent and is lower than the 1-2 per cent risk in the general population for whom a delay in first ultrasound assessment to 11-14 weeks gestation is advised [17] [18].
Up to 70 days (ten weeks) GA, medication termination is preferred over the surgical approach, as long as reasonable access to healthcare is provided for seven to 14 days after administration to manage incomplete abortions and treatment failures [19]. Evidence suggests that many women can safely conduct most of the medication termination processes themselves and in-person contacts and healthcare resources utilization can be reduced. Furthermore, the process can be supervised by a range of care providers, with in person assessment or hospital visits only necessary when complications occur.
Virtual post-termination care is suggested during the COVID-19 pandemic unless the situation allows for a visit to be combined with the administration of longer-term contraception or insertion of an intrauterine device [20]. A variety of options for contacting the individual (e.g., phone, email, contacting a friend) should be offered and emergency contact information should be obtained when possible. The provider should have an accessible system in place in case of emergencies.
Complete abortion is likely when both pregnant person and their clinician believe successful expulsion has taken place, based on history alone. In cases where there is ambiguity, serial beta-hCG measurements can provide definitive evidence of pregnancy termination [20]. A fall of beta-hCG levels of 80 per cent or more from pre-treatment to first follow-up at seven to 14 days is indicative of a completed medication termination. Ultrasound follow-up is equally effective but should be reserved for cases in which incomplete abortion is suspected [21]. A second dose of misoprostol can be considered for completion of a medication termination when there is a retained gestational sac or an ongoing pregnancy. Special risks include need for urgent surgical intervention for heavy bleeding or retained products, and access to surgical resources should be protected. Overall, three to five per cent of women require a subsequent aspiration after failed medication termination.
# There is good evidence to support first trimester medication termination (up to 70 days GA) with reduced or no ultrasound or visits to hospital, directed by virtual care and handouts with instructions for the termination itself and for post termination care.
Care should be taken to ensure safe access to urgent post abortion care for the small percentage of medication failures; this may involve a pathway with access to places other than busy emergency wards at times of high community transmission.
# Surgical Termination
Access to surgical termination through Dilation and Curettage or Evaluation (D&C, D&E) remains essential for the management of the individual who declines medication termination, for medication management failures and incomplete abortions, and the management of the pregnancies that have extended beyond the gestational age for safe out-of-hospital medication management. It should be emphasized that this should not be considered an elective procedure and access to surgical care should be maintained at all times.
Being COVID-19 positive is not an indication for, nor contraindication to, pregnancy termination. Therefore, the time-sensitive procedure should not be delayed if the safety of the pregnant individual is at risk or if delay of the procedure affects the individual's access to termination. Pathways for surgical termination options therefore need to include preparations and precautions for the person who is COVID-19 suspected or positive.
# Second and Third Trimester Termination of Pregnancy
Similar to access to early pregnancy options, access to second and third trimester termination of pregnancy is an essential right and should be protected. Prenatal diagnosis, counselling, support and access to diagnostic procedures such as autopsy and genetic diagnosis should be offered following the same rules and procedures as outside the pandemic.
Although the ability to travel may be impaired, access to third trimester surgical options in the U.S. have remained available to pregnant persons for whom termination in Canada is not considered an option. In circumstances where the person would have considered this option but is inhibited by COVID-19-related travel restrictions, individual providers should do their best to provide alternative options to the pregnant person.
If induction of labour is chosen at early gestational ages or is the only option available, such as in the more advanced pregnancies, the termination of pregnancy is best conducted in hospital. Despite low complication rates, the access to emergency care may be inhibited or associated with delays in treatment for those who present with significant pain or hemorrhage. Counselling, support, options for pain relief and the presence of support people should be made available and should not differ from what is offered to a person experiencing a pregnancy loss.
# Surgical termination is considered an essential service and should remain accessible in the pandemic.
# Surgical termination in a COVID-19 positive person should not be postponed if delay affects the person's safety or access to termination.
The addition of mifepristone prior to the start of induction with misoprostol is associated with a significantly shorter time from the start of misoprostol induction to birth for both live and stillborn fetuses [22], with >70 per cent of births occurring within 12h after admission to hospital. Mifepristone, taken at least 12h prior to the start of induction, does not increase complication rates or risk of initiation of labour prior to hospital admission [23] and should be considered to reduce the length of stay [24] in hospital during the COVID-19 pandemic.
# Treatment of Tissues, Remains and Stillborn Infants
As of the writing of this guideline, evidence indicates that vertical transmission from a COVID-19 positive person to the fetus is uncommon. Following pregnancy loss or termination, fetal and placental tissues should be managed according to usual institutional protocol, including when the pregnant person is COVID-19 suspected or positive. This can include removal of fetal tissue from hospital at parent request if this is allowed by institutional protocol. Indigenous clients, in particular, may wish to have access to the fetal and the placenta tissues for ceremonial purposes. Cultural practices around timing and nature of burial should be respected and facilitated whenever possible.
Additionally, it is likely that a stillborn infant will be COVID-19 negative (even for COVID-19 positive people) and the risk of transmission from the infant would be low. Memento items including hair locks, hand and footprints, and keepsakes, blankets and outfits can be released to the family in most cases. Care environments are encouraged to allow parents and supports to be able to hold and photograph the infant without wearing PPE. Thorough hand hygiene should nonetheless be recommended.
# The protection of reproductive rights extends to options to terminate a pregnancy in the second or third trimester and services to persons opting for pregnancy termination such as safe and supported induction of labour should remain similar to what is offered in non-pandemic times.
Mifepristone, administered >12h before the start of induction should be considered to significantly shorten the admission to hospital without increased risk of fetal expulsion prior to hospital admission or other complications.
# Families requesting tissues and remains should be respected as per institutional protocols. Cultural beliefs around burial should be facilitated and
Indigenous people should have access to their placenta and remains of fetal tissue at their request for ceremonial purposes.
# Prenatal Screening and Genetic Counseling
Prenatal screening practices during the pandemic are aimed at maintaining an excellent level of prenatal screening, genetic counseling and fetal diagnosis while minimizing exposure of pregnant individuals and providers by limiting the number of screening tests/visits. It should be noted that vulnerable communities and racialized groups that traditionally experience poor access to prenatal care may have more difficulties accessing prenatal screening.
During the COVID-19 pandemic, non-essential in-person healthcare services have been restricted by most care environments. However, as some prenatal screening tests, counseling and fetal diagnosis procedures are time sensitive, alternative care delivery methods for screening and counseling such as virtual care must be considered.
According to national guidelines, all pregnant individuals should be offered enhanced first trimester screening (eFTS), or non-invasive prenatal testing (NIPT),where available and funded as the first choice for prenatal genetic screening. For suspected or confirmed COVID-19 positive pregnant individuals, most fetal screening tests can be delayed for a 14-day isolation period or until infection is resolved to minimize exposure to HCPs. A useful decision making algorithm can be found in the proposed strategy in the Prenatal Screening Update during the COVID-19 Pandemic by the Society of Obstetricians and Gynaecologists of Canada (SOGC).
# Prenatal Screening Ontario (PSO) Adjustments to Screening
Ontario currently uses a two-step prenatal screening system, with eFTS being the first step for most pregnancies, with the exception of those at high risk where NIPT is a first line test. Access to prenatal screening during the COVID-19 pandemic may be impacted by the following [25]:
• Some diagnostic imaging centres are restricted in offering dating and NT ultrasounds.
• Community blood collection services may be consolidated to a smaller number of laboratories.
• Pregnant individuals in self-isolation may miss the NT ultrasound window (11 to 14 weeks). NT ultrasounds are of increased importance for twin pregnancies as serum screening (i.e. MSS) alone is not possible for twin pregnancies. NIPT is available for twin pregnancies and as a result, the MOH will temporarily fund NIPT for twin pregnancies if NT ultrasound is not available. For higher order multiples, NT ultrasound is the only screening option and should therefore be made available to this population throughout the pandemic.
# Special Considerations
Counseling regarding screening options, communication of positive screening results and initiation of follow-up investigations can be conducted virtually. It is ideal if prenatal screening options are discussed at the very first visit to allow the scheduling of the timesensitive dating/NT ultrasound(s).
To reduce visits, a single ultrasound done after 11 weeks can serve as both dating and NT ultrasound where dates are certain. To reduce visits, improve screening, and avoid missing the optimal screening window, accredited diagnostic imaging centers can consider providing a NT measurement when a dating ultrasound is performed within the eFTS gestational age window and directing the patient back to the primary provider for counseling regarding options.
If a diagnostic procedure is indicated in response to genetic screening in a COVID-19 positive person, amniocentesis is preferred over chorionic villus sampling reducing the theoretical risk for vertical transmission from moderate to low.
# Preeclampsia Screening
First trimester screening serum biomarkers (pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PLGF) have been used together with maternal characteristics and biophysical markers to identify pregnancies at risk for preeclampsia, stillbirth and placental abruption [26]. Multiple algorithms exist combining these serum markers with maternal history and factors such as body mass index (BMI), diabetes and biophysical markers such as mean arterial pressure and uterine artery Dopplers [27].
The goal is to identify pregnant individuals who can benefit from the administration of low-dose aspirin (ASA 150mg daily) starting at 16 weeks or earlier [28,29]. For instance, the FMF-UK algorithm has been shown to predict approximately 75 to 90 per cent of those who will develop preeclampsia prior to 37 and 34 weeks respectively, at a false positive rate of 10 per cent [30]. The prescription of low-dose aspirin can significantly reduce the incidence of early onset preeclampsia and placental abruption in pregnancies determined to be at increased risk, reducing the burden on healthcare resources in the pandemic [31].
Although the COVID-19 pandemic restrictions may lead to decreased availability of some aspects of this preeclampsia screening, ASA guidelines such as provided by National Institute for Health and Care Excellence (NICE) and American College of Obstetricians and Gynecologists (ACOG) provide a useful template for preeclampsia prevention in persons at high risk (previous preeclampsia, multiple gestation, chronic hypertension, diabetes or renal disease) or medium risk (nulliparity, family history, age >35y, socioeconomic factors, previous low birthweight infant) [29]. These risk factors can be combined with serum biomarkers if available.
# Sexually Transmitted Infections Screening and Treatment During the Pandemic
Screening for asymptomatic sexually transmitted infections (STIs) that may impact the pregnancy or fetus is routinely performed during pregnancy. Continuing to screen for and treat these illnesses remains vital and should be considered an essential service even at times when the system is under strain [32]. It must be acknowledged that many sexual health clinics, testing, and contact tracing programs are run by public health authorities whose resources have been strained by and/or diverted to COVID-19 related activities. This increases the importance that other maternity care providers ensure that screening is performed, and positive results appropriately acted upon. Where possible, STI screening tests should be bundled with other routine testing and care to minimize contact points with the healthcare system. Timing of testing should bear in mind that increased turnaround times for results may occur.
# Screening for Diabetes in Pregnancy
Routine care in pregnancy includes both screening in the first trimester for pre-existing diabetes in pregnant individual at risk as well as screening for gestational diabetes at 24 to28 weeks with an oral glucose tolerance test. To reduce SARS-coV2 transmission risk during testing, alternative testing strategies have been proposed [33].
Early pregnancy screening for overt/pre-existing diabetes is recommended for women at increased risk and is achieved through hemoglobin A1C (HbA1c) or fasting glucose test [34]. When included with routine first trimester blood work, this testing increases neither the number of healthcare contacts nor time of contact and therefore should continue as routine.
The use of an oral glucose tolerance test between 24 and 28 weeks has traditionally required the pregnant person to remain in the laboratory environment for one or two hours, which may increase risk of transmission. Additionally, lab capacity and access may be decreased during the pandemic. An alternate strategy of a random glucose measurement, along with an HbA1c, has been proposed [33]. While reducing demand on lab resources and potential exposures for pregnant people, this strategy has a decreased sensitivity and will therefore miss many milder cases of gestational diabetes. Numerous alternatives to the 50g glucose drink provided in laboratory have been investigated but none sufficiently validated to clearly replace the OGTT [35]. Nonetheless, home administration of glucose load 1h prior to the scheduled laboratory appointment for a random glucose could be considered. Decisions of which screening strategy to adopt should be made based on maternal risk factors for diabetes, local lab capacity and local SARS-coV2 activity.
# Provision of Ultrasound for Low-Risk Pregnancies
During pandemic restrictions, access to pregnancy ultrasound may be limited due to reduced capacity in ultrasound clinics and/or the availability of ultrasonographers; however, ultrasound assessment during pregnancy remains important to pregnancy care and management for:
• accurate dating of the pregnancy • assessment of fetal NT between 11 and14 weeks gestation • to diagnose fetal demise and trophoblastic disease • to assess for routine fetal anatomy and detect fetal anomalies between 18 and22 weeks gestation • to facilitate counseling and management of pregnancy termination Early pregnancy screening for women at risk of pre-existing diabetes should continue unchanged. While it may result in decreased detection of mild disease, screening for gestational diabetes between 24-28 may be modified by replacing the OGTT with a random glucose and HbA1c when local lab capacity and/or disease levels necessitate.
• assessment of fetal well-being including fetal growth and assessment of amniotic fluid Additional factors to consider:
• New conditions may arise in low-risk pregnancies that may require additional ultrasound scans and assessment. • If NT is not available, alternative prenatal screening may be offered: Prenatal Screening and Genetic Counseling. • For a person with confirmed or suspected COVID-19, it may be possible to delay ultrasound timing until the person is no longer infectious (i.e., until quarantine period is complete or ten days from onset of symptoms and/or confirmed COVID-19 testing if asymptomatic). For example, the second trimester anatomy could be deferred to 22 weeks if the person is diagnosed with COVID-19 at 19 to20 weeks gestation. • If a pregnancy ultrasound scan must be performed for a person with confirmed or suspected COVID-19, specific clinical protocols must be followed to protect those in contact with the person as well as appropriate cleaning of ultrasound equipment and the clinical environment. • As support people's access to healthcare facilities is limited during the pandemic, ultrasound providers should consider allowing participation during a portion of the ultrasound visit by phone or through a virtual platform, or by providing a photograph or video of the scan for the pregnant person to take home. • Pregnant people should receive education on fetal movement monitoring to reduce the likelihood of third trimester ultrasound scan. • It is recognized that due to reduced access to pregnancy care and missed ultrasound appointments earlier in pregnancy, that access to third trimester ultrasound may become more important for the estimation of fetal weight and assessment of fetal well-being. • For persons with mobility impairments or lack transportation to centres providing pregnancy ultrasound at key moments in early pregnancy, education on fetal movements and provision of additional ultrasound in the third trimester may be appropriate. • It is suggested that standard cleaning protocols be used for all ultrasound equipment according to American Institute of Ultrasound in Medicine (AIUM).
# COVID-19 Vaccination in Pregnancy
Widespread vaccination campaigns are underway and are viewed as a key component to controlling the COVID-19 pandemic. While initial safety studies universally excluded pregnant and lactating individuals, there is increasing real world evidence of both efficacy and safety in these populations [36]. The Better Outcomes Registry & Network (BORN) Ontario is evaluating COVID-19 vaccination in pregnant individuals in Ontario. BORN released an initial report, with data collected from December 14, 2020 to May 31, 2021, with preliminary results that do not suggest any pattern of increased risk for pregnancy (e.g. post-partum hemorrhage) and birth outcomes (e.g. stillbirth, preterm birth, 5-minute Apgar score <7, small for gestational age) among vaccinated pregnant individuals [37]. This, coupled with the increasing evidence of risk for those who contract COVID-19 during pregnancy, has led to recommendations that all pregnant individuals should have access to the vaccine [36,38]. An informed decision making discussion should include information on risks and benefits of the vaccine, an assessment of whether the vaccine's benefits would outweigh the potential risks to the person and/or fetus and a disclosure that there is limited evidence of the vaccine's effects in pregnant and lactating individuals. A thorough discussion with one's provider can ensure that each person is in a good position to make an informed choice on whether to be vaccinated. Shared decisionmaking tools have been developed to help pregnant individuals and their healthcare providers with this discussion. For example, PCMCH has developed a Patient Information Sheet tool titled, "I am pregnant or breastfeeding. Should I get the COVID-19 Vaccine?" that is available in English and French languages.
The National Advisory Committee on Immunization (NACI) preferentially recommends that a complete vaccine series with an mRNA (Moderna, Pfizer-BioNTech) COVID-19 vaccine should be offered to individuals who are pregnant [36].
# Management of High-Risk Pregnancy
The definition of a high-risk pregnancy varies considerably. Generally, it is a pregnancy in which the risk of an adverse outcome to the pregnant person, fetus or neonate is increased. The features rendering this pregnancy "high risk" may exist prior to pregnancy, may be related to physiologic characteristics (e.g., age, BMI), may directly link to the pregnancy itself (e.g., multiple gestations) or to factors that develop during the pregnancy (e.g., gestational diabetes, IUGR). There is also the possibility that a pregnancy is considered high risk as a result of the outcome of a previous birth (e.g., preterm birth, preeclampsia, birth by Caesarean birth). As many socio-economic and racial factors increase risk in pregnancy and exacerbate adverse pregnancy outcomes, providers and care environments must make an effort to address racial healthcare disparities and the under-recognition of health risks for racialized groups.
In general, each high-risk condition has a specific management protocol that has been developed, usually in conjunction with professional bodies such as the SOGC, the Association of Ontario Midwives and other professional organizations. While many of
# All pregnant individuals should have access to COVID-19 vaccination at any stage in pregnancy.
these guidelines and recommendations are based on evidence that is of low certainty (GRADE classification), they are used across the province to establish local and regional protocols for the management of these pregnancies.
While it is beyond the scope of this document to provide specific guidance on all conditions that confer risk in pregnancy, several guiding principles should inform the care of high-risk pregnancies during the COVID-19 pandemic.
Frequency and Form of Visits for High-Risk Pregnancies
High-risk pregnancies require greater levels of assessment and surveillance; therefore, it is inappropriate to restrict the frequency of visits in most cases. It is nonetheless recommended that care environments and providers should critically review their protocols and make adjustments based on clinical need as well as current COVID-19specific guidance. For example, where guidelines recommend a range of intervals between visits (e.g., SOGC guidelines on management of twin pregnancies suggest a visit interval of two to four weeks), and where no other risks are identified, the number of visits can be reduced by adhering to the longer end of the time interval.
It may be possible to decrease the number of in-person assessments while still maintaining the same standard of care. Virtual care may be used in situations where direct examination of the pregnant individual is not necessary. As there is generally an increased number of investigations in high-risk pregnancies, clustering of investigations and assessments can reduce the number of contacts. If ultrasound measurements and blood testing can be done locally, virtual interpretation, care and counseling may assist in the care of pregnancies at risk while reducing both in-person contacts and the need for the pregnant person to travel for care.
In many settings, multidisciplinary input is required in the management of high-risk pregnancies. In care environments that specifically serve high-risk pregnancies, pregnant individuals are frequently seen by a variety of care providers at a single visit. While these clinics are efficient by allowing the pregnant individual to have multidisciplinary input in a single visit, they are often high-volume clinics with long wait times, which may create challenges for physical distancing and exposure reduction. A blended model of in-person assessment by one or a few members of the multidisciplinary team and virtual care by others can be effectively used in many settings as the physical examination is generally not necessary by each member of the team.
The care of high-risk pregnancies will, in essence, remain unchanged but contacts can be reduced by use of virtual visits, clustering of care and avoidance of duplication of assessments.
The mainstay of assessing fetal well-being for high-risk pregnancies includes ultrasound estimate of fetal growth, the biophysical profile, doppler flow measurements and the non-stress test. Assessment of fetal well-being should continue to be performed but steps can be taken to reduce the number of unnecessary assessments. Consistent use of standardized fetal growth charts is recommended to reduce investigations and referrals for suspected growth restriction.
The biophysical profile (BPP) classically includes an ultrasound assessment of fetal well-being and a non-stress test. Performing both components increases the duration of the pregnant person's visit but both elements are not always necessary. When the BPP is normal, the NST is often unnecessary. Conversely an isolated determination of amniotic fluid volume (e.g., single deepest pocket) combined with a non-stress test has also been shown to reduce the amount of time taken for a fetal assessment without significantly reducing the ability to measure fetal wellbeing.
# Special Tests
There exist a number of specific laboratory tests that can improve the accuracy of clinical assessment for pregnancy risks and complications. Access to these tests in both low-and high-risk care environments can reduce the number of consultations, transfers and hospital admissions at all times, which is particularly important during the pandemic. Conditions with specific tests that should be available to reduce unnecessary exposure during the pandemic include:
• Preterm rupture of membranes: Diagnostic tests exist with a very high specificity for the presence of amniotic fluid. These more specific tests should be made available for use in place of less reliable tests. • Preterm labour: The fetal fibronectin assay is a test with a very high specificity that can exclude the diagnosis of preterm labour when uterine contractions are suspected or present between 24 and34 weeks gestation [9]. • Preeclampsia: Randomized controlled data has shown that the ratio of soluble FMS-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) (sFlt-1:PIGF) is a sensitive and specific marker for risk of preeclampsia [39]. Wider availability of commercially available tests for measurement of the SFlt-1:PIGF ratio would assist in more appropriate care and reduced referrals.
# Assessment of fetal well-being should continue to be performed but steps can be taken to reduce the number of unnecessary assessments through deliberate use of testing and/or special tests
# Perinatal Mood Disorders and Substance Use
Perinatal mood disorders are common and often under-recognized in pregnancy. The uncertainties created by the pandemic, along with the impacts of social isolation, job loss and societal change, will impact pregnant people significantly [40]. People with preexisting mental health and substance use issues will simultaneously experience possible worsening in their conditions along with decreased access to services and support. For Indigenous communities, rates of prenatal and postpartum mood disorders are higher than the general population [41].
HCPs should increase their screening and monitoring of pregnant people for perinatal mood disorders and substance use during the pandemic [42]. While it is routine to enquire about mental health and substance use in pregnancy, the impact of the pandemic should prompt providers to be more vigilant than ever. Formal screening using tools such as the EPDS, PHQ-9 or GAD-7 should occur at intake and again in later pregnancy and providers should enquire regularly about coping, mood and substance use (e.g., at every visit). Those experiencing perinatal mood disorders or substance use may require additional prenatal visits. While mental healthcare can lend itself to virtual care, special considerations and additional in-person visits may be warranted for those with psychosocial vulnerabilities. Providers should be conscious of historic harms to Indigenous populations as a result of mental health disorders (e.g., child apprehension) and apply principles of cultural safety when enquiring about, and responding to, perinatal mood disorders and substance use.
When mood disorders and substance use are detected, pregnant people should have prompt access to resources and interventions. Changes in care delivery along with redeployment to pandemic related activities of staff typically working in perinatal mental health (e.g., public health nurses seconded to testing and tracing programs) has meant that many pregnant people have experienced decreased instead of increased access during the early portions of the pandemic. As in other areas of care, innovation and creativity is needed to ensure quality programming can be offered in altered formats such as virtual counselling and education as well as virtual group therapy.
Pregnant and postpartum people, as well as those with pre-existing mental health conditions, are amongst the most vulnerable during the COVID-19 pandemic. Healthcare providers should prioritize the care of this population during the pandemic.
# Providers should increase their awareness of and screening for mood disorders and substance use and adjust the frequency and format of visits to allow for both early detection and intervention.
Where possible, mental health services should be delivered through virtual care, particularly where the condition is mild. Individual consideration should be given to faceto-face care when needed for those with more severe illness or where access to virtual care is limited. Care should be multifaceted and include education about COVID-19 as well as coping, self-care strategies, self-help and the development of social support networks. Existing tools and programs may be updated with COVID-19-specific information and access should be facilitated. Education in the prenatal period should include advice about managing and reducing the impact of maternal mental health disorders both in the immediate postpartum period and for the first year of the child's life. When medications are prescribed, access should be facilitated through such practices as longer prescription periods involving either expanded take-home practices (e.g., for methadone or buprenorphine treatment, sustained release anti-seizure medicines, or neuroleptic depot with informed consent) or periodic delivery of medicines to the home [43].
Substance use is of particular concern, as evidence to date demonstrates that the stressors brought on by the pandemic has increased substance use in both those with pre-existing use disorders and those without previous problematic use of substances, including tobacco, alcohol, cannabis and illicit drugs [43,44]. While guidance specific to both pregnancy and the COVID-19 pandemic does not yet exist, existing documents such as the SOGC Clinical Practice Guideline on Substance Use in Pregnancy can be supplemented by COVID-19 specific guidance targeted at the general population such as the COVID-19 Opioid Agonist Treatment Guidance for management of opioid agonist therapy with methadone and buprenorphine and the COVID-19 Alcohol Withdrawal Management Protocol [45,46].
Provision of perinatal mental health services should be considered an essential service and while format may need to be altered, these services should be continued and strengthened throughout the pandemic.
# Existing resources and techniques for supporting pregnant individuals with perinatal mood disorders and substance use can be modified to create formats that are accessible through virtual means or a reduced number of visits.
Given the likelihood of increased substance use and worsening of preexisting substance use disorders during the COVID-19 pandemic, all pregnant people should be actively screened for alcohol, cannabis, tobacco, prescription and recreational drug use at multiple points during the pregnancy.
Pre-existing pregnancy specific guidelines on substance use in pregnancy should be supplemented by general COVID-19 substance use guidance.
# Intimate Partner Violence
The UN has noted that "data shows that since the outbreak of COVID-19, reports of violence against women, and particularly domestic violence, have increased in several countries as security, health, and money worries create tensions and strains accentuated by the cramped and confined living conditions of lockdown." [47]. A Government of Canada survey in Spring 2020 revealed that "8% of Canadians reported that they were very or extremely concerned about the possibility of violence in the home. This percentage was higher for women (10%) than men (6%)." [7]. During periods of social distancing, lock-down and quarantine due to COVID-19, more victims are isolated with their abusers, removing times and opportunities to leave and seek help, exacerbating the patterns, frequency and degree of abuse [48]. Providing support for survivors of intimate partner violence (IPV), including shelters, have been deemed essential services in Ontario and these services have been maintained regardless of whether the province is in lockdown or phased recovery.
During prenatal visits, HCPs should follow their usual protocol, best practices or guidelines for the identification of IPV, while being mindful of the increased prevalence of IPV during the COVID-19 pandemic. HCPs should take the opportunity during prenatal visits to ask questions about lived experience at home and be alert to potential indicators (signs and symptoms, behavioural signs and risk factors) of IPV and should ask questions about IPV when present. While COVID-19 specific guidance does not exist, the VEGA Projects Family Violence Handbook: Intimate Partner Violence Section represents an up-to-date resource that can guide response to disclosures of IPV [49].
Existing hospital based Sexual Assault and Domestic Violence Treatment Centres remain available and are essential services. Indigenous people should have access to culturally relevant support for IPV [6].
It is important to recognize that virtual care may both diminish pregnant individuals' ability to disclose that they are subject to domestic violence. Virtual care may also increase the violence they suffer as it uses means (e.g., cell phones) that can be tracked, traced and controlled by their abusers, and they may have decreased access to safe conversations as the perpetrator may be simultaneously present in the home. Inperson visits (especially when infection control dictates pregnant individuals attend without their partner) may represent better opportunities to screen for IPV and provide services to those who cannot access services safely, or at all, through virtual/remote means.
Due to the increased rates of IPV during the pandemic, providers should remain vigilant through increased screening for domestic violence as well as maintain a heightened awareness of the signs and symptoms suggestive of IPV.
# Birth Planning and Counseling
# Prenatal Education
Prenatal education has been shown to improve health outcomes and remains an important aspect of pregnancy care even though access to in-person prenatal education has been limited by pandemic restrictions. Most public health units in Ontario offer online courses that can be accessed through the Ontario Prenatal Education Programs Directory. The Directory serves as a resource for prenatal education providers with evidenced-based key messages that can be provided to pregnant people and their supports. Providers should also direct pregnant people towards evidence-based prenatal education resources such as OMama, Pregnancy Info and Best Start . Prenatal education programs will need to address the specific impacts of COVID-19 on pregnancy care and birth. Indigenous people can access information regarding Indigenous prenatal online classes at the Native Youth Sexual Health Network. Pregnant individuals may be seeking culturally specific prenatal care and education or education specific to the needs of a racialized or disabled person.
It is important to recognize that prenatal education includes planning for the postpartum and newborn period as well as preparation for parenting. In-person supports during the postpartum and newborn period have also been limited by the pandemic. As a result, formal prenatal education as well as information provided by care providers should include information about important postpartum and newborn topics like breastfeeding and contraception.
# Planning for Birth
The changes brought about by the pandemic make explicit planning for many aspects of the birth essential. To address health disparities and work towards health equity in pregnancy care, providers should, where possible, connect the pregnant individual with a provider or group that can meet their culturally specific needs.
The location of the birth, including home and birth centre, depends on the preferred choice of the pregnant person and the medical needs for the pregnant person and the infant. Considerations for planning an out-of-hospital birth include appropriate risk screening with the midwife, access to adequate PPE and other infection prevention and control supplies, and timely local access to emergency transport when indicated [50].
Care providers should remain vigilant to the ways in which virtual/remote care may be difficult to safely access for survivors of IPV and in-person care should be used to provide safe alternatives when necessary.
# Prenatal education can be offered during the pandemic through virtual means. Discussion on specific COVID-19 education should be incorporated into prenatal education and prenatal care.
Pregnant people with symptomatic confirmed or suspected COVID-19 are recommended to labour and give birth in hospital [50]. This recommendation is in light of the challenges associated with ensuring appropriate PPE in the home setting as well as literature reporting increased rates of intrapartum abnormal fetal health surveillance [14].
HCPs should advise the pregnant individual on how to self-isolate to reduce symptomatic infections at the time of birth, recognizing that this may not be possible for all individuals [51]. For individuals with a scheduled birth (e.g., Caesarean birth, scheduled induction of labour) self-isolation should be considered 14 days prior to the anticipated date of birth. All pregnant people and support people may consider selfisolating at term, although this may be difficult to apply given the unpredictability of birth. Pregnant people may consider having a second support person who is self-isolating and ready to attend the birth in the event that their primary support person becomes ill.
# Induction of Labour
Timing and indications for induction of labour (IOL) can be achieved through shared decision-making with the pregnant person and their provider. IOL may be an important element of the birth plan and COVID-19 hospital protocols may influence its scheduling. More information on this topic can be found in the Maternal-Neonatal COVID-19 General Guideline published by the Provincial Council for Maternal and Child Health (PCMCH).
# Birth After Caesarean Section
There is no evidence to guide clinicians on how to counsel pregnant individuals seeking Trial of Labour After Caesarean Section (TOLAC) during COVID-19. It is recognized that special attention should be taken into consideration by the interprofessional team and the pregnant individual, including the indication for the initial Caesarean section and the history of previous vaginal births [52]. The key concern in management of the TOLAC candidate is avoiding an emergency Caesarean birth requiring a general anesthetic. The factors should be acknowledged and discussed as part of routine shared decision-making. The risks and benefits to both the pregnant individual and the fetus should be discussed. The impact of COVID-19 on our healthcare system may influence the individual's decision about mode and timing of birth.
# Birth Planning for High-Risk Pregnancies
Birth planning for high-risk pregnancies should not change during the COVID-19 pandemic. Each institution should review their policies, protocols and procedures and decide where flexibility could be applied [14]. Planning for high-risk pregnancy and birth may require a transfer of care. Planning for transfer to a different care environment or All pregnant individuals should explicitly plan for birth keeping in mind the impacts of COVID-19 on their care and care environments.
provider should be done in a culturally sensitive manner, taking into account geographical distances.
# Workplace Issues
HCPs are routinely called upon to advise on the safety of work during pregnancy and must be able to address questions and anxieties about working during the pandemic.
While most pregnant people have mild COVID-19, emerging data from Canada and international jurisdictions shows an increased risk of severe illness requiring hospital care and admission to the intensive care unit from COVID-19 in a subset of pregnant people compared to non-pregnant reproductive-aged people or women. There is no evidence that the immune modulations of pregnancy affect the rate or severity of COVID-19 infection. Normal pregnancy alone is not a risk factor for poor prognosis; therefore, SOGC states that pregnant workers can continue to work during the pandemic, taking into consideration work-related risk, individual risk (comorbidities) and local disease activity. Pregnancy-related comorbidities, such as gestational diabetes and gestational hypertension, should be considered risk factors for more severe disease [53]. Within their role as healthcare advisors, an HCP can recommend accommodations or absence from work for pregnant workers in situations where work-related exposure is substantive or individual risk for COVID-19-related morbidity is high. While implementing disease-reducing activities such as screening, physical distancing, hand hygiene and adequate PPE are the responsibility of the workplace, accommodation recommendations may reflect the importance of these measures for all pregnant workers but especially those at increased risk. When making recommendations about workplace absences or accommodations due to COVID-19 risk, HCPs must be cognizant that the financial impacts may extend beyond the absence in pregnancy as it may negatively impact access to parental leave financial support. This may lead pregnant people to choose to remain in a workplace where they do not feel safe.
Pregnant HCPs represent a group that may be at higher risk of occupational exposure. While, the SOGC guidance provides the same advice for all workers, guidance for pregnant HCPs varies across the world.
# Guidance suggests that pregnant people can continue to work during the pandemic taking into consideration work related risk, individual risk, and local disease activity. HCPs should continue to recommend appropriate workplace accommodations when risk is considered high.
Indications and options for IOL, TOLAC and high-risk pregnancies are unchanged by the pandemic. However, it should be acknowledged that the impacts of the pandemic may influence both the care environment and the pregnant person's preferences; shared decision-making should continue with increased attention to these factors.
The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) and the Royal College of Obstetricians & Gynaecologists (RCOG) have suggested that pregnant HCPs be allocated to duties that have a reduced exposure to individuals with or suspected COVID-19. While exclusion from the workplace is not necessary for pregnant HCPs, recommendations may include reassignment to duties with lower exposure risk. All pregnant HCPs who may require an N95 mask should be fit tested in the pregnancy, particularly if weight gain has been significant.
Testing for COVID-19 in the Pregnant Population Just like the general population, most pregnant people with COVID-19 infection will have mild symptoms; however, emerging evidence demonstrates an increased risk of severe illness requiring hospital care and admission to the intensive care unit.
The general approach to COVID-19 symptom screening, exposure screening and testing of pregnant individuals is similar to that for others seen in similar healthcare settings, whether it be in the community or the hospital.
# Testing of Symptomatic Individuals
When entering healthcare settings, all pregnant individuals should be screened for symptoms compatible with COVID-19 prior to every appointment or on arrival to the healthcare setting. Symptomatic pregnant people should be tested for COVID-19, as is recommended for all persons with compatible symptoms.
Whenever pregnant persons are reviewed by non-obstetric HCPs, (e.g., emergency department, assessment centre or community office staff) and determined to have symptoms compatible with COVID-19, it is imperative that appropriate notification is made to the obstetric care team so appropriate follow-up can be arranged. The obstetric care team should also be involved as soon as possible if admission is required due to a COVID-19 compatible illness or if there are any obstetric concerns at the time of the review.
Pregnant individuals who are in labour with symptoms associated with COVID-19 should have laboratory testing expedited to facilitate care with the most information possible available to the healthcare team. To facilitate expedited testing for patients in
# Pregnant HCPs may continue to work in clinical roles with proper infection control procedures and consideration of assignment to lower risk care environments.
Pregnant people should be screened and tested as per guidelines for the general population and should be considered a priority population if access to testing is limited. Testing should be expedited for labouring pregnant individuals and when a prerequisite of transfer to another facility.
labour, the laboratory should be contacted in advance of the specimen being submitted so appropriate prioritization can be organized. The laboratory requisition should also clearly state that the individual is pregnant and in labour. Testing of pregnant or postpartum people requiring inter-facility transfer should be similarly prioritized, particularly where negative testing is a prerequisite of transfer. Pregnant people transferred between facilities should be tested in accordance with provincial recommendations for transfer testing [54]. However, individuals who have previously tested positive for COVID-19. and have since recovered, do not need to be tested prior to or after transfer between facilities unless there has been a new high-risk exposure and/or symptoms [54]. Due to the potential implications for maternal care and the wellbeing of the fetus and newborn, pregnant persons should be a priority group for access to COVID-19 laboratory testing should resources be limited.
# Pre-admission Testing and Testing of Asymptomatic Individuals
Currently routine preadmission testing is not recommended for pregnant individuals as a select group. In accordance with current MOH guidelines, the approach to screening prior to operative procedures should be dictated by the local prevalence of COVID-19 in the community where the hospital is situated. Testing prior to a surgical procedure is not required in areas where community transmission is low. When testing is indicated prior to a surgical procedure during pregnancy, it should be conducted between 24 and 48 hours prior to the procedure date.
# Surveillance of COVID-19 Positive Pregnancies
The Better Outcomes Registry & Network (BORN) is Ontario's prescribed registry for maternal-newborn health and collects and uses data to facilitate and improve care. Existing evidence on impacts and management of COVID-19 in pregnancy and the early newborn period is evolving [55]. BORN is collecting data to support care providers, hospitals, midwifery practice groups, families and policy makers in learning about the impact of COVID-19 in pregnancy.
# Policies on pre-admission and pre-surgical testing as well as disease clearance should apply to pregnant people in the same way that they do to the general population
BORN Ontario has completed the first perinatal surveillance report on COVID-19 and pregnancy in Ontario. To date, many, but not all, of the birthing hospitals in Ontario have agreed to participate in this important data-collection strategy. Ongoing BORN reporting will link with the BORN Information System, which will allow us to learn more about risk factors and outcomes for pregnant people and neonates. Providers, hospitals, and groups are encouraged to participate in ongoing data collection through BORN.
# B. Care of the COVID-19 Suspected or Confirmed Pregnant Person
Pregnant people with suspected or confirmed COVID-19 will continue to require antenatal care, physical assessment and investigations. When symptoms remain mild, it is preferable to defer routine pregnancy care until the person is deemed cleared through resolution of symptoms and a period of self-isolation and/or negative testing. If inperson assessment of COVID-19 positive or suspected people is required, ideally the provider assessment and any necessary investigations can be performed at the same visit to avoid multiple exposures. Emerging data on pregnancy course, complications and outcomes for pregnant people with COVID-19 suggest a probable need for regular maternal and fetal assessment, thus increased surveillance and encounters may be necessary [56,57]. This may include additional virtual or in-patient visits for pregnant people and increased fetal ultrasound to assess fetal growth and well-being.
Data collection is urgently needed to provide credible information to facilitate and improve care and to help guide decision -making at a provincial level. Hospitals and midwifery practice groups are encouraged to contribute to the data collection for pregnant people with suspected or confirmed COVID-19 through BORN Ontario. Where data is not able to be collected through BORN (e.g. Indigenous Midwifery Programs), interim data collection should be implemented without delay.
Routine pregnancy care may be deferred until the pregnant person with COVID-19 is no longer infectious, provided it is safe to do so.
There is evidence showing an increased risk of severe infection with COVID-19 during pregnancy, therefore, increased surveillance for both the pregnant person and the fetus is warranted for the remainder of the pregnancy.
If possible, provision of pregnancy care including maternal and fetal assessments, as well as ultrasound, can be provided at the same visit to minimize multiple exposures to people and care environments.
# Use of Droplet/Contact PPE
The predominant mode of transmission of COVID-19 is through respiratory droplets and aerosols [58] during close, unprotected contact [59]. Droplet/Contact Precautions are recommended for the routine care of individuals with suspected or confirmed COVID-19. Additional personal protective equipment should be chosen based on point-of-care risk assessment, considering the planned tasks (including surgical procedures and any associated AGMP) and is outlined in the PHO technical brief. Regardless of the vaccination status of the HCP, Droplet/Contact precautions should remain the minimum requirement necessary when providing care to any patient suspected or confirmed to have COVID-19 [58,60].
It is recognized that differing policies may apply to those with suspected or confirmed COVID-19 than to asymptomatic persons. Nonetheless, pregnancy care is essential care and COVID-19 suspected and positive people must not be denied access to necessary care based on their COVID-19 status. All care providers and care environments must have access to the necessary PPE to provide this care.
Support People for Pregnant Persons with Suspected or Confirmed COVID-19 Presenting for Pregnancy Care
Guidance on the presence of support people during prenatal care (see Care of Pregnant Population section) is aimed primarily at asymptomatic people. The increased precautions and PPE required for suspected and COVD-19 pregnant people aim to reduce the number of people in care environments, waiting areas and clinical spaces. It is generally recommended that only the pregnant person is present for the visit; decisions on the presence of support people should be based on the needs of the pregnant person, and the risk to HCP and the support person accompanying that individual. These decisions should align with current PH guidance and institutional policies. A support person may join by phone or virtually when appropriate. Under certain circumstances, a support person may be permitted to join a visit in person with advance planning and appropriate precautions taken to protect all involved.
# Care Environment
In populations where there are very few pregnant persons with suspected or confirmed COVID-19, essential pregnancy care may be incorporated into existing care environments with appropriate planning and modification.
Droplet/ Contact precautions are recommended for all HCPs during the routine care of pregnant people with suspected or confirmed COVID-19.
Settings where there are many pregnant individuals with suspected or confirmed COVID-19, it may be necessary to create a dedicated clinic environment and team to provide care. The dedicated clinic environment may be a separate area of the clinic space that accessed through a dedicated entrance and/or elevator, a clinical area that is repurposed for the care of COVID-19 positive individuals or a dedicated area within the health care environment. Ideally, the clinical space will have all the needed equipment for pregnancy care and, if required, investigations such as ultrasound could be performed in the same space. Booking and timing of visits is important to minimize contact and waiting times. If volume of visits is high, it may be necessary for the care team to have additional support such as a patient navigator to ensure safety procedures are followed consistently. Care providers follow PPE protocols and don appropriate PPE and meets pregnant person Pregnant person arrives at meeting location and is escorted to visit room Pregnant person dons mask and performs hand hygiene Care providers ensure there is a designated restroom for pregnant person that has appropriate signage Care provider brings pregnant person to the visit room and places droplet contact sign on door Visit is conducted with electronic charting in the visit room Paper chart to be left outside the room to avoid contamination After visit is completed, pregnant person provided with information regarding next visit before leaving visit room Care provider reminds pregnant person to perform hand hygiene and guides patient to the exit Following visit, care provider places a sign on the door to prevent others from entering visit room Care provider doffs all PPE inside the room except mask in order to escort pregnant person to the exit Care provider alerts sanitation team to perform terminal cleaning twice of the visit room, restroom and equipment When assessing COVID-19 suspected or positive pregnant people, providers should not only provide pregnancy-specific care but also assess the severity of illness. Emergent assessment and possible hospital admission should be considered in the following situations:
• Shortness of breath (unable to walk across room, speak full sentence)
• Cough with blood • Chest pain • Dehydration • Decreased level of consciousness • Oxygen saturation < 94%
• Chest x-ray consistent with pneumonia (e.g., ground glass opacities)
As more information emerges regarding unusual presentations of COVID-19, HCPs should be aware that thromboembolic events may be a presentation of the disease and keep in mind that pregnancy is itself considered a hyper-coagulable state. COVID-19 may influence clinical decision-making on prophylaxis for thromboembolic disease in pregnancy [61].
# Stress and Stigma with COVID-19
Pregnant people affected by COVID-19 may have many challenges at home, including the need for general social distancing, self-isolation and caring for family members who are also COVID-19 positive. There is also stress associated with the potential impact of the COVID-19 viral infection on the developing fetus and pregnancy course. Due to prolonged home isolation, some pregnant individuals may have faced intimate partner violence (see section Intimate Partner Violence), food insecurity, wage insecurity and difficulty with access to medical services because of ability, lack of transport or other concerns. People with COVID-19 may experience feelings of shame and face discrimination in their community as a result of the infection. Providers should use prenatal encounters to screen for and identify mental health concerns, anxiety and depression, as well exacerbation of pre-existing maternal mental health conditions (see Section Perinatal Mood Disorders and Substance Abuse).
Dedicated care environments for care of COVID-19 positive pregnant people are suggested to minimize exposure of individuals and clinical spaces.
Symptoms of COVID-19 in a pregnant person may require in hospital assessment and possible in-patient admission.
# C. Care Environment Considerations During the Pandemic Infection Control and PPE
Outpatient settings that will be providing care to individuals who may have suspect or confirmed COVID-19 should be equipped with the personal protective equipment required to manage Droplet/Contact Precautions. This includes gowns, gloves, surgical/procedure masks and eye protection (either goggles or face shield). N95 respirators are also required if there are plans to perform aerosol-generating medical procedures. Prior to every interaction, HCPs must conduct a point-of-care risk assessment to determine the level of precautions required. In addition, information on personal protective equipment can be found on the Public Health Ontario (PHO) website under IPAC Recommendations for Use of Personal Protective Equipment for Care of Individuals with Suspect or Confirmed COVID-19.
A summary of required HCP precautions for various outpatient clinic interactions are included in the Occupational Health and Safety section of the MOH Guidance for Primary Care Providers in a Community Setting.
# Screening
According to COVID-19 Patient Screening Guidance Document, active and passive screening strategies should be used in the outpatient setting.
# Active Screening
Pre-screening prior to arrival in outpatient settings is a preferred strategy to identify symptomatic pregnant people or those with recent exposure. Individuals with symptoms compatible with COVID-19 should be referred to an assessment center, clinic or hospital as appropriate for testing. If possible, those with recent exposure or symptoms of COVID-19 should have their outpatient appointment deferred or completed virtually until outside of the incubation period, or symptoms resolve and a test is negative, respectively. For pregnant people who require in-person assessment, the outpatient setting should only complete the assessment if they are able to follow Droplet/Contact precautions. Arrangements should be made so that the individual can be identified, masked and transferred to a single-occupancy room as quickly as possible on arrival.
Pre-screening should not replace on-site screening. All pregnant people (and accompanying individuals, if applicable) should be screened for signs and symptoms compatible with COVID-19 and any exposures to COVID-19 on arrival at the healthcare setting. The staff conducting the screening should be protected by either a physical barrier (e.g., plexiglass), physical distancing (at least a two-metre distance) or PPE (a surgical/procedure mask and eye protection). Individuals identified as having symptoms of COVID-19 or exposure in the preceding 14 days should be provided a medical mask (i.e., surgical/procedure mask), if tolerated, and immediately transferred to a singleoccupancy room.
Screening should be done in accordance with the MOH COVID-19 Reference Document for Symptoms.
# Passive Screening
Signage should be posted at the entry points to the office/clinic and at the reception desk. This signage should direct individuals with symptoms to perform hand hygiene, put on a surgical/procedure mask and identify themselves to reception.
# Access to COVID-19 Assessment Centre/Testing
Testing should be performed when screening reveals a pregnant person with symptoms compatible with COVID-19. Outpatient settings should be aware of the local testing locations and protocols to provide instruction to those who require testing. Testing locations may include assessment centers, clinics and hospitals. Instructions should be provided to ensure safe arrangements are in place for travel to the testing facility and safe procedures are followed on arrival. This includes wearing a surgical/procedure mask, not taking public transit during travel, and performing hand hygiene, wearing a surgical/mask and self-identifying upon arrival at the testing facility.
# Modifications to Usual Visit and Frequency
Routine Pregnancy Assessment Schedule Throughout the pandemic, changes to the form and frequency of visits have been made in all areas of care to reduce exposing care providers and healthy pregnant individuals to the COVID-19 virus. Based on the WHO recommendation of a minimum of eight prenatal visits per pregnancy, alternate visit schedules have been proposed [62]. Some visits can be done virtually to limit the time of in-person exposure, particularly early in the pregnancy, although in-person assessments cannot be completely avoided. Covering all necessary information, as well as adding COVID-19 specific information into a modified schedule, may require additional time, particularly during virtual appointments. There is no evidence on the optimal length of an in-person visit to minimize risk of exposure while providing appropriate client care, but efforts should be made to limit the length of the visit.
The following is proposed as a minimum number of visits during pregnancy. It should be noted that due to the amount of education required, when the number of visits is reduced, they may need to be longer to ensure all essential care is provided. When local disease activity is low and good infection control practices are in place, routine frequency of care remains appropriate, especially when virtual care is included. Highrisk pregnancies should include an individualized plan of care to determine the schedule of visits.
# Recommended Minimum Visit Schedule
In-person and virtual visits can be alternated between first visit (before 12 weeks) up until 34 to 36 week visits. Visits at 38 weeks and onwards should be in person.
# Clustering of Testing/Visits to Minimize Exposure
When possible, testing should be clustered to limit the number of exposures. For instance, a single ultrasound done after 11 weeks can serve as a dating and NT ultrasound. Additionally, trimester specific, laboratory testing can be grouped at the same time (e.g., prenatal blood work with eFTS, gestational diabetes screening with type and screen in preparation for Rh immune globulin). When facilities such as clinic, lab and ultrasound, are co-located, scheduling investigations and assessments at the same time will reduce the number of visits and possibly overall exposure.
# Alternatives to In-person Visits
Virtual care in the form of phone or video visits allow providers to conduct assessments and education without exposure risk. Provincial and national professional organizations have created excellent resources, such as the Virtual Care Playbook [63] and the Virtual visit guide for midwives [64], for their members on the issues unique to providing virtual care. Providers must consider issues such as security of the platforms they are using, obtaining consent to provider virtual care and appropriate documentation requirements.
As well, ensure that pregnant people are in an appropriate, safe and confidential space for the assessment.
# Technology Access and Equity
While the COVID-19 pandemic has necessitated the rapid adoption of virtual care, not all pregnant individuals have the means to participate equally in virtual care platforms. While the majority of Ontarians have smartphones, not all may have access to sufficient data plans, high-quality Wi-Fi for a video call or enough voice minutes on their phone plan for telephone visits. For some, cultural barriers may exist to accessing virtual care. HCPs may need to adapt the schedule of virtual and in-person visits depending on the pregnant individual's ability to participate in virtual care. Lack of access to virtual care For most pregnancies, a minimum of eight antenatal appointments, with a combination of virtual and in-person care, can be adopted during the pandemic.
Investigations, including lab and ultrasound, should be clustered where possible to minimize contacts with the health care system.
Virtual care may replace some in-person in a blended model of care following guidance from professional organizations to ensure safety.
must not inadvertently intensify health disparities based on social determinants of health such as poverty, homelessness or cultural identity. In some rural and remote locations, inadequate access to broadband internet may impede virtual video visits and necessitate more reliance on telephone-based virtual care. Efforts must be made to minimize inequity in the quality of virtual care based on lack of access to internet services [65]. Efforts must be made to ensure adequate length and quality of calls for those reliant on telephone-based care [66].
Other groups, such as Deaf/hard of hearing individuals and those who require language interpretation, may be disadvantaged by virtual care unless accommodations are made for their needs. This may require the use of text-based platforms for the Deaf/hard of hearing and the use of platforms that allow for three-way audio or video calls for those who require language interpretation, including ASL.
Lack of Access to Care, Late to Care Pre-existing barriers to accessing prenatal care have been exacerbated by the COVID-19 pandemic. Marginalized groups -including, but not limited to, Black, Indigenous, racialized, newcomer, differently abled, refugee, 2SLGBTQ, homeless, incarcerated, sex workers, people with addictions and people with low socio-economic status -not only are at higher risk of poorer perinatal outcomes generally, but are more vulnerable to the impacts of the pandemic such as precarious employment and social isolation.
They are also at higher risk of contracting COVID-19.
Ontario made universal health care accessible to people without OHIP and removed the three-month waiting period for OHIP as an emergency measure during the pandemic. These were important steps to ensure that those without health insurance have access to care, including prenatal care. Still, many social determinants of health create barriers to timely access to prenatal care. During the pandemic, existing inequities can be amplified [4], meaning HCPs must be keenly aware of the disproportionate health impacts of the pandemic on populations who already carry a higher burden of perinatal morbidity and mortality. Awareness of these issues (and increased availability and adoption of cultural-safety and antiracism/implicit-bias training) must be a priority for healthcare providers to understand these underlying forces in health inequity. Modifications of the care schedule, method of care (virtual or in-person), length of visits and outreach (follow-up for missed appointments) to pregnant individuals must be made when taking these barriers to care into consideration. Efforts to make the care environment a safe space for those who have experienced healthcare-related trauma will improve access to prenatal care. Indigenous people often come late into care due to fear because of prior experiences of HCPs should assess the pregnant person's needs, means and ability to participate in virtual care and provide accommodations as needed. No pregnant person should be denied appropriate pregnancy care based on their inability to access technology.
racism in the healthcare system. They may be fearful of punitive measures being undertaken because of this, such as healthcare providers calling child protection, often resulting in infant apprehensions. Understanding and having compassion for the underlying layers of trauma is something all healthcare providers need to encompass in their care.
# Fear of Accessing Care
Some pregnant individuals may be reluctant to access in-person scheduled and acute care based on fear of exposure to COVID-19. HCPs, while being sensitive to these fears and providing access to resources for stress and anxiety, should provide reassurance about the safety measures in place in the care environment and the importance of in-person assessments to ensure the well-being of the pregnant individual and the fetus [67]. Assessments such as monitoring blood pressure, ensuring normal fetal growth, and receiving recommended vaccines are essential to the provision of prenatal care that leads to improved perinatal and neonatal outcomes [68]. Additionally, pregnant individuals who are symptomatic for COVID-19 should be reassured about the safety of testing centres and encouraged to access testing when indicated. Fear should not be a deterrent to presenting at a testing centre. Indigenous people often fear accessing care due to prior experiences of racism in the healthcare system. COVID-19 adds an additional layer to that fear.
# Rural and Remote Considerations
The realities of pregnancy and birth in rural and remote communities mean that rural pregnant people have reduced access to care and experience the cultural, financial and emotional burdens of travel for care. These stressors are amplified by the realities of the COVID-19 pandemic and all efforts must be made to ensure that pregnant individuals and their supports living in rural and remote communities have equitable access to quality prenatal care in face of changes in our patterns of care [69].
As a result of COVID-19-related restrictions, pregnant people in rural and remote communities have had decreased access to routine testing. This is particularly true in fly-in northern communities. Flights and other forms of travel have diminished, resulting
HCPs must understand systemic barriers to accessing care and the disproportionate health impacts of the pandemic on populations who already carry a higher burden of perinatal morbidity and mortality. Providers must make efforts to create safe spaces and modifications to care for those facing barriers.
HCPs should be aware of the impact of fear on accessing prenatal care, including COVID-19 testing, and provide reassurance, guidance and resources to minimize this impact.
in tests cancelled due to delays from collection to arrival at laboratories. As well, some testing (e.g., ultrasound) was provided by visiting providers who are no longer able to visit remote communities due to travel restrictions and isolation practices. In some instances, point-of-care (POC) testing may replace formal laboratory samples. For example, a POC glucose measurement can be done at the same time as the lab draw for gestational diabetes screening.
In rural and remote communities, decreased access to testing and increased turnaround times will result in a longer time between testing and clearance. As a result, pregnant individuals may experience longer periods of isolation even when able to remain in their home community. Increased virtual care and/or provider access to PPE may be required as a result. Rapid and POC testing, as they become more widely available, have the potential to reduce this impact.
Providing prenatal care through virtual means may benefit rural individuals by reducing their need to travel for in-person visits. As well, where pregnant people must leave their home community for birth, the expansion of virtual care may allow them to meet and form a relationship with their care team in the distant community earlier in the pregnancy rather than only at term. Providers must we aware, however, that virtual care is difficult to apply in many rural communities due to poor access to reliable, high-speed internet services and limited access to technology. Healthcare systems should be innovative and flexible in their support of virtual care (e.g., access to nursing station technology for virtual visits with urban providers).
While virtual care can decrease the need for pregnant people to leave their home communities, in-person care will still be required. The limitations on travel and resulting reduction in visiting care providers has highlighted the need to strengthen the prenatal care skill set of local providers. Efforts should be made to support healthcare providers located in rural and remote communities by providing the training, resources and regulatory ability to fill the gaps in care left in human health resources by pandemic restrictions.
In rural and remote communities, access to essential prenatal testing and diagnostics must be preserved. Where feasible, point -of -care testing should be made available and test timing should take into account transit times to urban laboratories.
Virtual care has the potential to improve access to prenatal care for rural and remote pregnant individuals, but providers must be aware of issues of access to and quality of technology in rural communities.
To date, many rural communities in Ontario have experienced low rates of COVID-19 infections. As a result, those who are required to travel for prenatal care, investigations and birth will experience anxiety about contracting the virus during the course of that care. Protections should be in place, and education and reassurance, provided such that essential care is not avoided. Pregnant people traveling from one community to another may experience periods of mandated isolation either when transferred out or upon returning to their home community (or both) as part of efforts to control spread of the virus. This may have significant impacts on not only the person in isolation but also their family and their entire community. Given the frequency of visits and testing during the course of routine prenatal care, a period of 14-day isolation following each visit or test could result in a pregnant person being in isolation for the majority of the pregnancy. This will inevitably lead to the choice to forgo care and/or defy isolation requirements.
Pregnant individuals in remote communities, especially those living in First Nation communities, may not have the options of applying recommendations on reducing disease transmission. For instance, they may not have reliable access to clean water for hand washing or may live in housing that is too crowded to allow for physical distancing. This will be especially true for COVID-19-positive or suspect people required to strictly self-isolate. When providing care to pregnant people in remote communities, providers should enquire directly about access to clean water and physical spaces that allow for isolation. Where they do not have necessary access, HCPs should work with local supports (e.g., hospitals, band councils, municipalities) to secure access to hand sanitizers, masks and other needed resources.
Where possible, care should be provided in a pregnant person's home community. Where travel for care is necessary, visits and testing should be bundled in such a way as to minimize travel and post-travel periods of selfisolation/quarantine.
When pregnant people are required to travel in and out of their home community for prenatal care and birth, isolation and quarantine policies should balance the needs of the community and the impact on the individual and their supports. Anxieties around risk of contracting the virus must be balanced against the necessity of the care being accessed in other communities and safeguards put in place.
During pregnancy care, providers should enquire directly about access to resources for transmission prevention, including safe housing and clean water.
# Evacuation for Birth
Pregnant people who must leave their home community to give birth already carry a significant burden of isolation and displacement around the time of birth. During the pandemic this burden has increased due to restrictions on support people as well as mandated periods of self-isolation. The stress and anxiety caused by this uncertainty should be addressed through increased screening/direct questioning, education and improved access to support, both formal and informal. The financial burden of travel for care has been amplified as a result of pandemic restrictions. While some financial support may be available, it is generally not sufficient to cover costs and not all rural and northern pregnant individuals have access to these financial supports. When prolonged periods of self-isolation are added to the travel time, costs mount considerably. As well, northerners often rely on informal supports such as staying with friends and family in urban communities. When these options become unavailable due to lockdown and phased recovery, options for food and housing such as hotels and restaurants also become less available.
The majority of pregnant people who face evacuation for birth (i.e., who must leave their home community at term and remain in a distant community until birth) are Indigenous people, leading to greater burdens and inequities to this already disadvantaged population. Policies and practices around evacuation for birth must be created in a culturally safe manner supported by existing educational programs around culturally safe care [70].
Rural hospitals and care providers may feel less equipped to deal with pregnant people who are COVID-19 suspect or positive due to restrictions provided by the physical environment or due to real or perceived lack of knowledge. To reduce spread of COVID-19 and minimize the impact on pregnant individuals, inter-facility transfers should be avoided, where possible. While COVID-19 alone should not be an indication for transfer [9], rural providers requesting transfer for COVID-19-positive or suspected pregnant individuals should be respected. Where transfer is not deemed necessary, virtual
Increased planning for and education around resources in the planned location of birth will be needed during times of lockdown and phased recovery. Providers should be aware of and explicitly address the emotional and financial costs of evacuation for birth.
Policies and practices around evacuation for birth must recognize that disproportionate burden carried by Indigenous communities and must be created in a culturally safe manner.
All rural care providers and environments should be supported in providing care to COVID-19 suspected or positive pregnant people with increased virtual support and education and transfer when appropriate.
support and education for the rural providers should be provided by expert teams in referral centres. Existing referral systems do not empower midwives and other nonphysician providers to facilitate necessary transfer. Midwives should be made part of the referral system so that seamless care can be provided for the pregnant person without adding additional burden to the provider.
# Care in Home and Non-Clinical Settings
Efforts should be made to minimize non-essential visits, which may include the reduction or elimination of planned antenatal visits in the pregnant person's home or in other non-clinical environments (e.g., shelters, hotels, public spaces). In some cases, these visits may be deemed necessary to provide prenatal care. This may be particularly important for those who would not otherwise access care. In these cases, efforts must be made for all members of the household or other non-clinical environment to be screened in advance of the visit for symptoms of COVID-19 and to limit the number of people present during the visit [50]. All members of the household or non-clinical environment who can wear masks are expected to do so and should be informed of this expectation prior to the visit. The provider must ensure access to adequate PPE and hand hygiene for themselves and appropriate cleaning supplies for surfaces and equipment for the visit. Providers must have sufficient PPE to properly doff and don between environments when traveling between care environments.
# D. Provider Considerations Communication During and About the Pandemic
The COVID-19 pandemic has brought about a significant and constantly evolving change in all pregnancy care environments. For many pregnant people, the uncertainty about what to expect during pregnancy visits and at the time of birth results in increased anxiety. It is important that information about any changes be clearly communicated to pregnant people and they be made aware of sources of up-to-date information.
Providers and care environments are encouraged to use a variety of means to share this information such as in-person communication, conversations during virtual visits, signage, written materials, clinic and hospital websites and social media. Communication with pregnant people should include discussion of ways in which the form and frequency of visits may have changed. It is also important to educate pregnant individuals about issues of security and confidentiality when using virtual platforms. Provincial and national organizations have created resources that can guide these Visits outside of the clinical care environment should be kept to a minimum while recognizing these visits may be necessary in certain situations. Adequate PPE for HCPs, pregnant individuals and their support people, and strict IPAC practices, must be used to make visits in non-clinical environments as safe as possible.
communications as well as provide sample language: Virtual Care Tools by OntarioMD and the Ontario Medical Association.
Pregnant people will have many questions about the potential impact of COVID-19 on their health, the health of their baby, their birth experience, and the safety of things such as workplaces and childcare for other children. HCPs should use a variety of means to provide information on these topics, including sharing websites and resources created for this purpose [71].
Changes to the care environment may have unintended impacts on communication between providers and pregnant people. Clear and empathetic communication is a priority even when care is provided through virtual means or while wearing PPE. Information should be available in community languages other than English and in visual or easy-to-understand formats as far as possible. Providers should remain cognizant of the ways in which PPE impacts non-verbal communication as well its impact on communities such as the deaf/Deaf/hard of hearing.
Sharing information with pregnant people and their care providers is essential to reduce unnecessary visits and duplication of investigations. All contact numbers should be double-checked to ensure they are correct before the pregnant person leaves care environments such as emergency departments, ultrasound facilities and labs as subsequent health care providers must be able to contact the person directly. It is recommended that pregnant people be given copies of their Ontario Perinatal Record, bloodwork, ultrasounds, etc. (paper or electronic) to carry with them so investigations do not get repeated unnecessarily. Indigenous people may or may not have access to regular means of communication, such as cell phones, in the same way as the rest of the population. Safe and sensitive follow-up should take into consideration how readily the person will be able to participate in the follow-up and no assumptions should be made.
HCPs and care environments should communicate with pregnant people about changes to care as well as provide information about COVID-19 in pregnancy. They are encouraged to do this through a variety of means, including websites and social media.
Clear and empathetic communication is a priority. Providers should be aware of the ways in which virtual care and PPE may impact communication.
Contact information should be collected and confirmed. Pregnant people at all gestational ages should be provided with copies of results to minimize repeat investigations.
# Staffing
Each care environment will be unique in how it provides space and personnel for care during the pandemic. Consideration should be given to a variety of factors when determining how staffing may change, including impact of virtual care, changes in flow of patients, screening requirements and cleaning of clinical spaces. Increased staffing may be necessary and staff may be required to perform duties outside of their typical roles. Illness and isolation requirements may have a significant impact on staff availability. Care environments should prepare emergency staffing plans to respond to possible increased absenteeism and create emergency contact lists. Care environments should establish and strengthen relationships with community partners including public health and municipal governments to coordinate pandemic response, provide consistent communication and share supplies. Healthcare employers should recognize that staff may experience anxiety about the impact of the pandemic on the workplace. Care environments should communicate clearly with their staff about what is known about COVID-19, the impact on the workplace, efforts being made to reduce disease transmission and emergency staffing plans.
# COVID-19 Related Stigma and Violence Directed Against HCPs
HCPs are subject to significant physical and psychological violence, particularly in the face of "work pressure and stress, social instability and the deterioration of personal interrelationships" [72]. Within pregnancy care environments, much of this violence has stemmed from frustration with support person policies and increased IPAC procedures and is exacerbated by the uncertainty and loss of control that pregnant people and their supports are experiencing. Additionally, HCPs have experienced stigma due to perceived increased risk of transmitting the disease, which has resulted in greater social isolation, negative impacts on their relationships with family, and decreased access to community resources and infrastructure. It is unsurprising that there have been increased reports of racialized violence against healthcare workers, particularly those from Asian communities that have been attributed to the impacts of the pandemic [73] [74].
Care environments should prepare for staffing impacts of the pandemic including by developing emergency staffing plans and by strengthening community partnerships.
Care environments should communicate clearly with staff about the impacts of COVID-19 on the work environment, including the details of pandemic staffing plans.
Workplace violence and stigma have been shown to have significant negative impact on staffing, working environments and organizational efficiency, which makes it imperative that violence and stigma, as well as factors that contribute to them, be addressed [75]. Pre-pandemic guidance such as the WHO Framework Guidelines for Addressing Workplace Violence in the Health Care Sector can be supplemented by specific guidance on reducing violence and stigma due to the pandemic. Care environments should address violence and stigma against healthcare workers through a multifaceted approach including:
• Creating a climate and policies that reject violence against health care workers • Creating a climate and policies that engage and empower HCWs to address violence and stigma • Reducing uncertainty and fear for pregnant people through clear communication within the care environment and with the community at large about changes in care practices • Participating in initiatives that increase community knowledge and address COVID-19 myths • Supporting initiatives that positively portray healthcare workers' contributions (e.g., Health Care Hero campaigns) • Ensuring workers have access to both formal and informal supports that recognize the increased stresses brought on by working during the pandemic
# E. Task Force Health Equity Context
Ontario is home to diverse pregnant and postpartum populations; inclusive of age, gender identity, race, ethnicity or culture, ability and other factors such as geographical location. These factors can greatly influence a person's unique needs and expectations around care management during pregnancy.
When appropriate, HCPs should consult with specialized organizations that support specific populations for assistance in appropriately tailoring these recommendations to the individuals under their care.
Indigenous populations have unique and diverse needs that arise out of being the original people of this land and being colonized and displaced from their home territories. Indigenous people suggest you ask them directly what their needs may be and make appropriate referrals when required.
COVID-19 related stigma and violence directed against healthcare workers cannot be tolerated. Care environments and workplaces should actively work to reduce stigma and violence through a multi-faceted approach.
In writing this guideline, attempts were made to align with emerging policy work on Indigenous cultural safety, vulnerable communities, and principles of diversity equity and inclusion by provincial and national associations, including the SOGC, the Association of Ontario Midwives and the Canadian Association of Perinatal and Women's Health Nurses [76,77,78,79]. The imperative for equity in this pregnancy care guideline comes from national and provincial legislation, regulation, policy and interpretation by PCMCH. The task force took the opportunity to consider vulnerable community pandemic experiences and how we could make representation, research and outcomes improvement processes and priorities more population-based. The task force acknowledges that individual, family and provider experience is essential to understanding population needs and impacts during the pandemic. This guidance reflects expert advice, stakeholder feedback, media scans and anecdotal experience. More sector work is needed to understand the diverse needs and outcomes of expectant and growing families in Ontario. PHO has stated social determinants of health play an important role in the risk of COVID-19 infection, especially when they impact the ability to perform physical distancing [80]. These determinants include:
• gender • socioeconomic position • race/ethnicity • occupation • Indigeneity • homelessness and incarceration
# Understanding and Identifying Vulnerable Populations
Canada's geography and diversity of populations can create challenges in delivering healthcare during a pandemic. [6] Community size and accompanying healthcare resources vary greatly across the country. COVID-19-specific advice for vulnerable populations can be found at: Planning advice for vulnerable populations, which was developed for pandemic influenza but may also be useful for COVID-19 [81].
According to the Government of Canada website, vulnerable communities include those with:
• Difficulty reading, speaking, understanding or communicating (including French language resources) • Difficulty accessing medical care or health advice Indigenous populations should be asked directly what their needs are and referrals made as required.
Providers and care environments should tailor these recommendations to the individuals under their care, consulting those who provide support to specific populations to ensure appropriateness.
• Difficulty doing preventive activities, like frequent hand washing and covering coughs and sneezes • Ongoing specialized medical care or needs specific medical supplies • Ongoing supervision needs or support for maintaining independence • Difficulty accessing transportation • Economic barriers • Unstable employment or inflexible working conditions • Social or geographic isolation, like in remote and isolated communities, or • Insecure, inadequate or nonexistent housing conditions [82].
Ontario's Action Plan for Vulnerable People adds additional guidance on those living in high-risk settings, including:
• Homes serving those with developmental disabilities • Shelters for survivors of gender-based violence and human trafficking, and • Children's residential settings, which would include Indigenous residential settings on and off reserve [83].
Based on client/patient and provider-reported feedback, the Task Force found COVID-19 is having direct and compounding mental and physical impacts on maternal and child health outcomes. The combination of family social isolation, structural barriers to early and regular prenatal care and disproportionate burden of illness in vulnerable populations may have a negative impact on birth outcomes for 2020 and 2021. At a systems level, the maternal and infant population may require the "vulnerable population" designation to ensure adequate planning and resource allocation in pandemic circumstances. Such allocation will need to include culturally safe health data collection, interpretation and public reporting of subpopulation maternal-newborn outcome indicators.
Our Task Force recognized the challenges and limitations of its structure and composition as well as knowledge base. We propose two items for future consideration: 1. Prioritization of staff and committee member health equity and diversity training, including Indigenous Cultural Safety Training for future similar projects; 2. A health equity template, an example of which is provided in the appendix, may help facilitate a more comprehensive embedding of health equity principles during the preparation of healthcare guidelines.
In addition to embedding equity throughout this guideline and recommendations, the task force is using the lessons learned to direct specific system-based recommendations to the MOH as well as to encourage PCMCH to continue to work towards explicitly embedding equity into all of their work.
# Wendy Carew Ontario Health North
# Wendy Katherine
Best Start: Health Nexus
# Contributors
A subcommittee was established to guide and inform the development of this document with a focus on ensuring that the perspectives and lived experiences of Indigenous, Black and people of colour are reflected in these recommendations. We thank these members for their additional time and thoughtful contributions to promote a decolonized, equitable and inclusive process.
The equity subcommittee included: Cynthia Maxwell, Elizabeth Brandeis, Ellen Blais, Katherine (Kate) Miller and Wendy Katherine.
Through the development of this guideline, the Task Force identified a number of additional concerns respecting the delivery of safe and equitable prenatal care for both patients and providers. The PCMCH Recommendations to Address Gaps in Prenatal Care System report, led by the equity subcommittee members, was released in January 2021. This report includes a series of recommendations that signal an opportunity to strengthen the healthcare system for all pregnant people and their families.
In addition to the contributions of the individual task force members, sections of this guideline were developed, reviewed or informed by the following individuals:
# Attiya Khan Family Advisor
# Lynne Giroux Eastern Ontario Health Unit
Naana Jumah Thunder Bay Regional Health Science Centre
# Shelley Dougan Prenatal Screening Ontario-BORN Ontario
Stephanie Black London Health Sciences Centre
# Appendix A: Equity Table
This template was adapted from the Health Equity Impact Assessment (HEIA) workbook, available at www.ontario.ca/healthequity. For the purposes of this task force guidance, the populations listed below correspond to reproductive age Ontarians and children.
Step | None | None |
ab8beba664702cb2421cf0f4cd31314d91041e6b | cma | None | This resource is intended to support rehabilitation and allied health providers across the care continuum who are working with patients of all ages recovering from symptoms of COVID-19. The recommendations in this document are intended to represent a biopsychosocial approach to care given the complex biological, physical, psychological, social, economic, and spiritual needs of patients. The purpose of this document is not to outline all treatment approaches, rather it is intended to highlight new practice considerations when working with patient's post-COVID. The recommendations in this document are based on current evidence and were established through consultation with practice directors, physicians, rehabilitation, and allied health staff. It is recognized that some patients may not have a confirmed diagnosis of COVID-19 but the treatment considerations outlined can be applied to anyone experiencing ongoing symptoms of COVID-19. This document is meant to guide clinicians in their practice, but treatment approaches should be adapted to meet the unique needs of each individual. Treatment approaches may also vary depending on the local context and services available in each zone.# Introduction
The majority of COVID-19 patients with mild symptoms will improve functionally in the 6-8 weeks following their illness. However, there may be some patients, including those experiencing long-term symptoms of COVID-19, who will benefit from rehabilitation and allied health services to aid in their recovery.
A variety of terms to describe symptoms after COVID-19 have emerged, including Long COVID, Post COVID Condition, Persistent Post COVID and more. It is important to clarify the terminology for the purposes of rehabilitation and recovery. Vu and McGill (2021) used the term post-COVID-19 condition to incorporate symptoms beyond the acute infection phase. The NICE rapid guideline (2022) in the UK describes two conditions: ongoing symptomatic COVID-19 with symptoms between 4-12 weeks after infection, and Post COVID-19 syndrome with symptoms present 12 weeks after illness and lasting at least 2 months. The World Health Organization (October 2021) developed a clinical case definition of Post COVID-19 through a Delphi consensus, this definition reflects the long term symptoms typically associated with what has been termed Long COVID.
"Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others (see Table 3 and Annex 2) which generally have an impact on everyday functioning. Symptoms may be new onset, following initial recovery from an acute COVID19 episode, or persist from the initial illness. Symptoms may also fluctuate or relapse over time. A separate definition may be applicable for children." (Page 1 World Health Organization, 2021) Recognizing that definitions and terminology continue to evolve, for the purpose of this document, the term "Post-COVID" is used to capture patients in the sub-acute phase of recovery including patients who required an acute care or intensive care admission and patients experiencing Long COVID or Post COVID-19 conditions.
Rehabilitation and allied health professionals provide a variety of roles across the continuum of care. One important role is to help patients improve their activity tolerance and function while providing education and resources to support self-management over the longer term. Another key role is to address other long-term impacts including psychological needs, social needs, spiritual well-being, and community re-engagement.
At present, there is limited evidence to guide rehabilitation best practices for patients recovering from COVID-19. As a result, caution may be required, particularly when prescribing exercise to patients who present with any of the following physical sequelae: 1) Post-exertional symptom exacerbation 2) Cardiac symptoms 3) History of Multisystem Inflammatory Syndrome in Children (MIS-C) 4) Significant dyspnea 5) Exertional oxygen desaturation 6) Dysautonomia and orthostatic intolerance 7) Coagulation dysfunction
The guidelines in this document address the physical sequelae mentioned above as well as treatment recommendations for other post-COVID sequelae including cognitive changes, speech & language impairments, social, psychological, and spiritual impacts. Clinicians are encouraged to use validated, psychosocial screening tools that are organizationally approved such as the social determinants of health module in Connect Care.
The recommendations are based on current evidence (as of June 2022), published expert opinions and consensus statements. More detailed information and references are available at the end of the document. Every effort will be made to update the recommendations in this document as new evidence becomes available.
- Task 1: "Normalize the uncertainty in prognosis". It is important to acknowledge the limitations to medical knowledge and diagnostic investigations. Although we would like to be able to provide more certainty on what may cause a given symptom or provide more certainty that a treatment will result in the desired outcome -in almost all cases total certainty is not possible. Normalizing that having uncertainty is a normal part of illness, while also acknowledging that there is more uncertainty about Long Covid than other conditions (because it is new, less researched, does not have a diagnostic test to confirm the diagnosis, etc.) may be helpful when paired with the other two tasks of this framework. Take care to not dismiss the importance and emotional impact of this uncertainty with patients.
- Task 2: "Address patients' emotions about uncertainty, acknowledging how difficult it may be for them not to know." Some patients and family may become focused upon seeking answers to the uncertainty. To a degree, this seeking knowledge to alleviate uncertainty is a normal and helpful behaviour. However, if the distress, emotional intensity, or focus on seeking answers becomes barriers to engaging in treatment, the patient or family may need to revisit their physician to discuss (A) the steps that were taken to arrive at the diagnosis; and/or (B) to explore their current mental health and coping. o Be cautious in the use of statements of reassurance, such was "the doctors have ruled out everything bad" because in the face of uncertainty, many such statements may be perceived as dismissive of their experiences and the impact Long Covid may be having on their lives and functioning. Instead, focus on statements of validation: "It makes sense to me how you could be feeling ____ given ____ happening" and helping the patient to identify actions within their control (such as engaging in treatment) which may help achieve what they want for the future. This is where practices such collaborative goal setting may be helpful.
- Task 3: "Help patients and families manage the effect of uncertainty on their ability to live in the here and now." An effective way to manage uncertainty regarding what the future (in relation to one's health and quality of life), is to focus on the current moment. Allied staff have a critical role to play in this, as many of the therapies or symptom treatment options outlined in this document help to address the symptoms which may be causing the greatest disturbance in the patient's usual functioning. Again, this is where the use of goal setting, pacing and encouraging selfmanagement strategies may be helpful.
# Tips for Supporting Self-Management:
Begin any program with the clinician explaining their role and allow time for the patient and family to introduce themselves and state what they are hoping to gain from the service or program. | This resource is intended to support rehabilitation and allied health providers across the care continuum who are working with patients of all ages recovering from symptoms of COVID-19. The recommendations in this document are intended to represent a biopsychosocial approach to care given the complex biological, physical, psychological, social, economic, and spiritual needs of patients. The purpose of this document is not to outline all treatment approaches, rather it is intended to highlight new practice considerations when working with patient's post-COVID. The recommendations in this document are based on current evidence and were established through consultation with practice directors, physicians, rehabilitation, and allied health staff. It is recognized that some patients may not have a confirmed diagnosis of COVID-19 but the treatment considerations outlined can be applied to anyone experiencing ongoing symptoms of COVID-19. This document is meant to guide clinicians in their practice, but treatment approaches should be adapted to meet the unique needs of each individual. Treatment approaches may also vary depending on the local context and services available in each zone.# Introduction
The majority of COVID-19 patients with mild symptoms will improve functionally in the 6-8 weeks following their illness. However, there may be some patients, including those experiencing long-term symptoms of COVID-19, who will benefit from rehabilitation and allied health services to aid in their recovery.
A variety of terms to describe symptoms after COVID-19 have emerged, including Long COVID, Post COVID Condition, Persistent Post COVID and more. It is important to clarify the terminology for the purposes of rehabilitation and recovery. Vu and McGill (2021) used the term post-COVID-19 condition to incorporate symptoms beyond the acute infection phase. The NICE rapid guideline (2022) in the UK describes two conditions: ongoing symptomatic COVID-19 with symptoms between 4-12 weeks after infection, and Post COVID-19 syndrome with symptoms present 12 weeks after illness and lasting at least 2 months. The World Health Organization (October 2021) developed a clinical case definition of Post COVID-19 through a Delphi consensus, this definition reflects the long term symptoms typically associated with what has been termed Long COVID.
"Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others (see Table 3 and Annex 2) which generally have an impact on everyday functioning. Symptoms may be new onset, following initial recovery from an acute COVID19 episode, or persist from the initial illness. Symptoms may also fluctuate or relapse over time. A separate definition may be applicable for children." (Page 1 World Health Organization, 2021) Recognizing that definitions and terminology continue to evolve, for the purpose of this document, the term "Post-COVID" is used to capture patients in the sub-acute phase of recovery including patients who required an acute care or intensive care admission and patients experiencing Long COVID or Post COVID-19 conditions.
Rehabilitation and allied health professionals provide a variety of roles across the continuum of care. One important role is to help patients improve their activity tolerance and function while providing education and resources to support self-management over the longer term. Another key role is to address other long-term impacts including psychological needs, social needs, spiritual well-being, and community re-engagement.
At present, there is limited evidence to guide rehabilitation best practices for patients recovering from COVID-19. As a result, caution may be required, particularly when prescribing exercise to patients who present with any of the following physical sequelae: 1) Post-exertional symptom exacerbation 2) Cardiac symptoms 3) History of Multisystem Inflammatory Syndrome in Children (MIS-C) 4) Significant dyspnea 5) Exertional oxygen desaturation 6) Dysautonomia and orthostatic intolerance 7) Coagulation dysfunction
The guidelines in this document address the physical sequelae mentioned above as well as treatment recommendations for other post-COVID sequelae including cognitive changes, speech & language impairments, social, psychological, and spiritual impacts. Clinicians are encouraged to use validated, psychosocial screening tools that are organizationally approved such as the social determinants of health module in Connect Care.
The recommendations are based on current evidence (as of June 2022), published expert opinions and consensus statements. More detailed information and references are available at the end of the document. Every effort will be made to update the recommendations in this document as new evidence becomes available.
o Task 1: "Normalize the uncertainty in prognosis". It is important to acknowledge the limitations to medical knowledge and diagnostic investigations. Although we would like to be able to provide more certainty on what may cause a given symptom or provide more certainty that a treatment will result in the desired outcome -in almost all cases total certainty is not possible. Normalizing that having uncertainty is a normal part of illness, while also acknowledging that there is more uncertainty about Long Covid than other conditions (because it is new, less researched, does not have a diagnostic test to confirm the diagnosis, etc.) may be helpful when paired with the other two tasks of this framework. Take care to not dismiss the importance and emotional impact of this uncertainty with patients.
o Task 2: "Address [the] patients' [and familys'] emotions about uncertainty, acknowledging how difficult it may be for them not to know." Some patients and family may become focused upon seeking answers to the uncertainty. To a degree, this seeking knowledge to alleviate uncertainty is a normal and helpful behaviour. However, if the distress, emotional intensity, or focus on seeking answers becomes barriers to engaging in treatment, the patient or family may need to revisit their physician to discuss (A) the steps that were taken to arrive at the diagnosis; and/or (B) to explore their current mental health and coping. o Be cautious in the use of statements of reassurance, such was "the doctors have ruled out everything bad" because in the face of uncertainty, many such statements may be perceived as dismissive of their experiences and the impact Long Covid may be having on their lives and functioning. Instead, focus on statements of validation: "It makes sense to me how you could be feeling ____ given ____ happening" and helping the patient to identify actions within their control (such as engaging in treatment) which may help achieve what they want for the future. This is where practices such collaborative goal setting may be helpful.
o Task 3: "Help patients and families manage the effect of uncertainty on their ability to live in the here and now." An effective way to manage uncertainty regarding what the future (in relation to one's health and quality of life), is to focus on the current moment. Allied staff have a critical role to play in this, as many of the therapies or symptom treatment options outlined in this document help to address the symptoms which may be causing the greatest disturbance in the patient's usual functioning. Again, this is where the use of goal setting, pacing and encouraging selfmanagement strategies may be helpful.
# Tips for Supporting Self-Management:
Begin any program with the clinician explaining their role and allow time for the patient and family to introduce themselves and state what they are hoping to gain from the service or program.
Acknowledge and validate the patient and family's concerns.
# Screening, Flags and Referrals
Recovery from COVID-19 can be different for everyone. It is important for clinicians to be aware of the common symptoms of COVID-19, as well as "red flag" symptoms which may contraindicate certain treatment approaches or warrant further medical investigation. For the purpose of this document, "yellow flags" are used to describe symptoms or presentations that may warrant increased caution and monitoring.
The following section is intended to provide guidance on common symptoms to watch for and when it might be appropriate to refer a patient to another member of the health care team. Please keep in mind, monitoring of symptoms should occur throughout the patient's rehabilitation episode of care.
This section focuses on screening for physical symptoms. It is important to take a bio-psychosocial-spiritual approach in responding to post-COVID care needs. Patients do better when we pay attention to their physical and psychological symptoms and needs, as well as their spiritual and social needs and considerations. It is also important to note that children often cannot describe or explain their symptoms; they will require families and clinicians to watch for and monitor trends in participation and behavior. Clinicians should also consider how recovery from COVID affects a patient's wellbeing, for this reason clinicians may wish to work with their teams to screen for psychosocial needs.
# Screening
To support clinicians in screening patients for common red flag symptoms, screening tools for post-COVID physical sequelae have been developed for adult and pediatric populations. These tools are separate from the Post Covid Functional Screen and Symptom Check List which is a general screening tool for Post Covid needs (Appendix A) and is often used in by service providers as part of their referral triage process.
These tools incorporate outcome measures that can be used to screen and assess patients for post-exertional symptom exacerbation, cardiac symptoms, significant dyspnea, exertional oxygen desaturation and dysautonomia. These tools are meant to serve as a guide. Clinicians are responsible and encouraged to use clinical judgement to determine the level of assessment required for each individual patient.
See Appendix B for the Adult Screening Tool for Post-COVID Physical Sequelae See Appendix C for the Pediatric Screening Tool for Post-COVID Physical Sequelae
# Red Flags, Yellow Flags and Referrals
The following section outlines the most common red and yellow flags that clinicians may encounter when working with post-COVID patients. If these symptoms are identified on screening/assessment, clinicians are encouraged to follow the recommendations outlined or direct patients to the appropriate next level of care.
# Red Flags
Post Exertional Symptom Exacerbation (PESE)
o If a patient screens positive for PESE on the Screening Tool for Post COVID Physical Sequelae, activity and/or exercise must be titrated below the level that symptoms are exacerbated (Appendix B and Appendix C). o Typical graded exercise (i.e. overload principal) may be detrimental. o Note: PESE can occur at any time. Continue to monitor symptoms and re-screen as appropriate. o See the Post Exertional Symptom Exacerbation section for additional treatment recommendations.
# Myocarditis or known cardiac pathology
o The management of myocarditis or cardiac pathology may vary depending on the patient's clinical presentation, age and activity level. Treatment decisions should be based on recommendations from the patient's cardiologist. o For young and active patients with symptomatic myocarditis, it is recommended that patients not exercise beyond basic functional mobility and ADLs for 3-6 months after their illness, unless otherwise prescribed by their cardiologist. Following this, graded return to exercise is advised (Barker-Davies, 2020). o See the Cardiac Symptoms section for additional treatment recommendations. o Increasing chest pain that is worsening -Urgent care
# History of Multisystem Inflammatory Syndrome in Children (MIS-C) -new
o Clinicians should be aware of MIS-C history and associated implications including decreased exercise capacity and cardiovascular risk See Alberta Health Services MIS-C Care Guide for more information. Treatment decisions should be based on recommendations from the patient's physician, and ongoing medical follow-up is typically warranted.
# Unexplained chest pain or tightness or increasing/worsening chest pain
o Further medical assessment is warranted. Refer back to primary care provider or urgent care (depending on clinical presentation).
# Heart palpitations
o Further medical assessment may be warranted. Refer back to primary care provider or urgent care (depending on clinical presentation).
Alternate cardiac presentations in children. Chest pain is not always associated with cardiac disease in children (Geggel, 2004 , 2003;Dempsey & Wagner. 1985;Bota & Rowe, 1995). These values are slightly different from the Alberta Primary Pathway and reflect the rehabilitation context of mild exertion. o For pediatric patients during mild exertion a fall in oxygen saturation below 92% is considered abnormal (Langley & Cunningham, 2017). o Consider referral back to primary care provider for further medical investigation (i.e. pulmonary function testing, cardiac investigation, etc.). o If lung pathology is identified, consider referring to Pulmonary Rehabilitation.
o During pregnancy, a saturation below 95% should be directed to urgent care. o See the Respiratory Symptoms section for additional information.
# Postural Orthostatic Tachycardia Syndrome (POTS)
o Sustained elevation of HR ≥30 bpm (adults) or ≥40 bpm (children) from baseline or ≥120bpm, in the first 10 minutes of being in an upright position. o Refer back to primary care provider for further investigation and diagnosis (i.e. tilt-
# Supplemental Oxygen Requirements
o Where patients are on supplemental oxygen, saturation levels should be monitored prior to, during and following exercise. o Patients on supplemental oxygen may have increased oxygen requirements on exertion or with activity. Check with the patient if they have been given target oxygen parameters by their physician. o See the Respiratory Symptoms section for additional treatment recommendations.
# Orthostatic Hypotension
o A fall in SBP of >20mm Hg or DBP >10 mm Hg from baseline within 3 minutes in an upright position for adults or 4 minutes for children.
o If symptoms of OH are extremely limiting, consider referral back to the primary care physician for pharmacological management.
# Resources:
Rehabilitation for Clients with Post COVID-19 Condition (Long COVID), Canadian Physiotherapy Association If patients do not have a primary care physician they can search: https://albertafindadoctor.ca/ or call Health Link (811)
# Post Exertional Symptom Exacerbation (PESE)
Fatigue and post-exertional malaise (PEM) are some of the most common symptoms reported after COVID-19 (Hannah Davis, 2020). Post-exertional malaise is also described as postexertional symptom exacerbation (PESE) which can be defined as the triggering or worsening of symptoms following physiological stress and/or cognitive activity (Mateo, 2020). Symptom exacerbation typically occurs 12 to 48 hours after activity and can last for days or even weeks.
Post-exertional malaise/symptom exacerbation is a hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disease characterized by profound fatigue, cognitive dysfunction, sleep abnormalities, autonomic manifestations, pain, and other symptoms that are made worse by exertion. ME/CFS may be suspected if symptoms are present for at least 6 months or more (Shepard, 2020).
A subset of questions from the DePaul Symptom Questionnaire have been validated for evaluating PEM in people with ME/CFS (Cotler et al., 2018). Recently, this tool has been used to evaluate the frequency and severity of PESE in post-COVID patients. This tool has been incorporated into the Screening Tool for Post-COVID Physical Sequelae which can be administered at any time during a patient's recovery from COVID-19 (Appendix B). A pediatric version has been adapted with permission but has not yet been validated (Appendix C)
# Treatment Considerations:
Treatment should be focused on patient and family education regarding activity pacing and energy conservation. See the Maximizing Energy section for more detailed information on pacing.
Patients may benefit from instruction in the use of diaphragmatic breathing and pursedlip breathing to promote parasympathetic activation and respiratory efficiency.
If a patient is demonstrating viral symptom recurrence (i.e. fatigue, cough, headache, shortness of breath, etc.), reduce the intensity of your intervention and complete and activity log to determine how to best support the patient in their recovery.
Cognitive and emotional load may contribute to symptom burden or exercise intolerance. Consider the patient's day to day needs including work or school when scheduling or planning rehabilitation appointments.
Appointment attendance and travel may contribute to symptom burden or exercise intolerance. Consider providing in-person care in reduced frequency, or through virtual care delivery (individual or group).
Patients with PESE or ME may take longer to recover between sessions. For this reason, it may be appropriate to consider shorter treatment sessions spread out over a longer period of time. Programs may need to consider their usual models of care (i.e. discharging patients after 6-8 weeks of therapy) as this may not be appropriate for this population.
Patients with PESE or ME may be unable to return to their regular work, academic or leisure activities. A multidisciplinary approach to the patient's treatment plan is strongly encouraged.
It is important to recognize patients may not fully recover from PESE or ME during their time in rehabilitation. Clinicians should promote self-management early in the treatment process to empower patients and families and to facilitate smooth transitions in care.
# Considerations for Activity Progression:
Be aware of the signs and symptoms of orthostatic intolerance and how to manage it (i.e. limit standing and encourage patients to lay down when needed).
For adult patients consider the use of a HR monitor and encourage patients to keep their HR below their anaerobic threshold (~60% of HR max). To calculate an estimated, use the following formula (220 -age) x 0.55 = anaerobic threshold in beats per minute.
o Keep in mind, the anaerobic threshold may be lower for severely ill patients and symptoms should always be used to guide intervention.
For adult and pediatric patients begin activity and exercise at or below a score of 2 on the BORG and only progress above a BORG of 2 if symptoms do not recur (symptom titrated exercise).
As the patient progresses and activity tolerance improves, consider in-person sessions focusing on gradual return to activity and exercise.
Treatments may begin with gentle stretching and strengthening exercises, progressing to aerobic activities as tolerated. Increases in activity intensity and duration should only be attempted if the patient has recovered after an hour and fatigue levels are normal.
A patient's activity tolerance may vary significantly from day-to-day. Clinicians will need to continuously monitor symptoms and adapt their treatment approach accordingly.
# Recommended Outcome Measures:
Borg Scale CR10 for Shortness of Breath and Fatigue o Scale ranging from 0-10, which provides clinical information on the patient experience on shortness of breath and fatigue. Borg Rating Of Perceived Exertion -Physiopedia (physio-pedia.com) o A Rating of perceived exertion using facial expressions for conveying exercise intensity for children and young adults (Chen et al., 2017).
# Resources:
Post
# Cardiac Symptoms
COVID-19 typically presents with signs and symptoms of a respiratory tract infection, although cardiac manifestations including arrhythmias, tachycardia, myocardial injury and heart failure are commonly reported (Pellicori et al, 2021;Ståhlberg et al, 2021).
Cardiac involvement should be considered in patients presenting with a history of new-onset chest pain/pressure, heart palpitations, breathlessness, or exercise induced dizziness or syncope. Collaboration with other health care providers including primary care, cardiologists and other specialists can help to ensure the best possible management of patients with cardiac manifestations following COVID-19.
# Treatment Considerations:
Patients and families should receive education on signs and symptoms to watch out for and when to seek urgent medical attention (i.e. sudden chest pain that persists for >15 minutes, chest pain associated with nausea or vomiting, loss of consciousness, tachycardia or dyspnea at rest, etc.).
Ensure patients perform a proper warm-up and cool-down (~5 minutes), before and after exercising.
Consider the use of a HR monitor and start exercise below the patient's anaerobic threshold (~60% of HR max). To calculate an estimate, use the following formula (220age) x 0.55 = HR below expected anaerobic threshold in beats per minute.
o Keep in mind, the anaerobic threshold may be lower for severely ill patients and symptoms should always be used to guide intervention.
o Tolerance should be evaluated for each patient before progressing the duration or intensity of exercise. Consider the FITT principles -frequency, intensity, type and time.
Monitor heart rate recovery (HRR) post exercise. HRR is defined as the difference between HR at peak exercise and exactly 1 minute into the recovery period. A HRR value ≤12 bpm is considered abnormal and may warrant further medical investigation (Jolly et al., 2011).
Monitor patient for abnormal responses to activity (i.e. arrhythmias, rapid increase or decrease in blood pressure, disproportionate breathlessness, lower extremity swelling, etc.).
Consider referral back to primary care provider or cardiologist if required.
For pediatric patients follow recommendations from the cardiologist.
# Resources:
The
# Respiratory Symptoms
Long term respiratory symptoms are present in up to 29% of COVID-19 survivors (Huang, 2021). Common respiratory symptoms include dyspnea (shortness of breath), exertional oxygen desaturation and chronic cough.
Dyspnea is one of the most common respiratory symptoms in this population. This may be due to lung damage, deconditioning, upper airway injury, breathing pattern disorders, cardiac impairment, fatigue, or anxiety and it is often a major limiting factor in rehabilitation. Having dyspnea in the acute phase of the illness (defined as day 7 after symptom onset), or having a history of asthma or chronic lung disease, is associated with a higher risk for prolonged or chronic dyspnea (Carvalho-Schneider et al., 2020;Cellai & O'Keefe, 2020).
Another concerning symptom from a rehabilitation perspective is exertional oxygen desaturation. Generally, oxygen saturation levels should be above 95% though this may differ in patients with known lung disease, where above 88% may be acceptable (Zhao et al., 2020). Lower oxygen saturation levels after exercise have been observed in patients with acute COVID-19 but it can also occur during the recovery phase making it an important safety consideration when working with post-COVID patients . Dempsey & Wagner, 1985;Bota & Rowe, 1995). These values are slightly different from the Alberta Primary Pathway and reflect the rehabilitation context of mild exertion. o For pediatric patients during mild exertion a fall in oxygen saturation below 92% is considered abnormal (Langley & Cunningham, 2017). o Consider referral back to primary care provider for further medical investigation (i.e. pulmonary function testing, cardiac investigation, etc.). o If lung pathology is identified, consider referring to Pulmonary Rehabilitation.
# Yellow Flag: Supplemental Oxygen Requirements
o Where patients are on supplemental oxygen, saturation levels should be monitored prior to, during and following exercise. o Patients on supplemental oxygen may have increased oxygen requirements on exertion or with activity. Check with the patient if they have been given target oxygen parameters by their physician.
# Dyspnea/Shortness of Breath Treatment Considerations:
Dysfunctional Breathing Patterns: Shortness of breath is a commonly reported persistent symptom, which may exist in the absence of underlying disease (Ionescu et al, 2021). Dysfunctional breathing patterns may present as hyperventilation, exertional hyperventilation, apical breathing pattern dominance, lack of breath control, and activity avoidance (Motiejunaite et al., 2021).
o Normal, quiet breathing is performed through the nose, with minimal accessory muscle involvement, at a rate of 12-20 breaths/minute.
o If your patient is presenting with difficulty controlling their breathing at rest or with exertion, consider performing a basic chest assessment to determine if your patient may benefit from breathing retraining.
Provide education on positions to ease shortness of breath (i.e. high side-lying, forward leaning, etc.).
# Review common breathing techniques:
o Pursed-lip breathing instructions: Breathe in through your nose and out through your mouth while pursing your lips, as if you were about to blow out candles on a cake.
Breathe in for about 2 seconds and breathe out for 4-6 seconds. In the early stages of rehabilitation (acute care and/or early inpatient rehabilitation, around 6-8 weeks post-COVID), patients should resume activity at a level of 3/10 on the modified Borg Scale (Spruit et al., 2020).
As activity tolerance improves, patients can be progressed to exercise at a level of up to 6/10 on the modified Borg Scale. Emphasis should be placed on breath control and when progressing activity, regular monitoring of symptoms should occur.
# Exertional Oxygen Desaturation
# Considerations for Assessment:
Currently, there are no validated tools to evaluate exertional oxygen desaturation in post-COVID patients. Regardless of which assessment tool used once desaturation is observed the test should be terminated to limit over exertion.
Patients should be advised to terminate any test if they develop adverse symptoms (i.e. severe breathlessness, chest pain or dizziness).
In adult patients the 1 minute sit-to-stand (1MSTS) test correlates well with the 6-minute walk (6MWT) test and has been validated on chronic interstitial lung disease and airway obstruction.
The 1MSTS test has been proposed as an appropriate method to evaluate exertional desaturation in post-COVID populations but testing should not take place outside a supervised setting unless the patient's resting SpO2 is ≥96% .
If the 1MSTS test is used, patients should be monitored for at least 1 minute following completion of the test to observe for exertional oxygen desaturation (Núñez-Cortés et al., 2021).
The 2 minute step test (TMST) also correlates well with the 6MWT, and may be used to assess for exertional desaturation, especially for individuals with mobility/strength limitations for whom the 1MSTS may be too difficult to complete (Hameed, 2021).
Assessment should include monitoring of hyperventilation or breathing pattern disorders. Hyperventilation can result in a variety of symptoms including dyspnea, chest pain, tachycardia, fatigue, dizziness, and syncope on exertion (Motiejunaite et al., 2021).
In pediatric patients the 6 minute walk test is recommended for children 5 years and up. Note differences in distances walked are age dependent (Ulrich et al., 2013).
# Treatment Considerations:
The use of pulse oximetry under clinical supervision has been recommended for post-COVID patients experiencing respiratory symptoms, especially during phases of activity progression . Patients and families can be educated on home pulse oximetry to support activity progression, safety, and self-management.
In the early stages of rehabilitation (acute care and/or early inpatient rehabilitation, around 6-8 weeks post-COVID), patients should resume activity at a level of 3/10 on the modified Borg Scale (Spruit et al, 2020).
If patients exhibit signs of exertional oxygen desaturation, the patient should be referred back to their primary care provider for further investigation.
o If medically cleared, treatment should focus on pacing and symptom titrated return to activity.
# Managing a Chronic Cough
Treatment Considerations: o In the acute care setting, airway clearance techniques such as active cycle of breathing, percussions and vibrations, assisted cough maneuvers, mechanical insufflation-exsufflation and/or mobilization may be indicated for patients with confirmed or suspected COVID-19 who develop exudative consolidation, mucous hypersecretion and/or difficulty clearing secretions (Thomas et al., 2020).
o For chronic productive coughs, educate on the importance of routine airway clearance and provide instruction on specific techniques which may include mobility/exercise, deep breathing and huff coughing, autogenic drainage, active cycle of breathing, and if indicated, positive expiratory pressure therapy (Thomas et al., 2020;McIlwaine, 2006).
# Recommended Outcome Measures:
Borg Scale CR10 for Shortness of Breath and Fatigue o Scale ranging from 0-10, which provides clinical information on the patient experience on shortness of breath and fatigue. Borg Rating Of Perceived Exertion -Physiopedia (physio-pedia.com) o A Rating of perceived exertion using facial expressions for conveying exercise intensity for children and young adults (Chen et al., 2017
# Dysautonomia & Orthostatic Intolerance
Dysautonomia is a term used to describe a range of clinical conditions characterized by dysfunction in the autonomic nervous system (Rocha et al., 2021). Recent evidence suggests post-COVID patients may experience dysautonomia in the form of orthostatic intolerance or postural orthostatic tachycardia syndrome (POTS) (Raj et al., 2021).
Orthostatic intolerance (OI) syndromes refer to conditions in which the upright position (most often the movement from lying or sitting to standing) causes symptomatic arterial hypotension. This occurs as a result of reduced blood volume or when the autonomic nervous system fails to responds to the challenges imposed by upright positioning (Brignole, 2007). OI symptoms can include lightheadedness, palpitations, tremulousness, and atypical chest pain (Raj et al., 2020). A common presentation of OI is orthostatic hypotension (OH) which is defined as a fall in systolic blood pressure (SBP) >20 mmHg or a fall in diastolic blood pressure (DBP) >10 mmHg from baseline within 3 minutes in an upright position (Lahrmann et al., 2006). Typically, this presents with signs of cerebral hypoperfusion including dizziness and presyncope (Brignole, 2007).
Postural orthostatic tachycardia syndrome (POTS) is characterized by sustained increase in heart rate ≥30 bpm (adults) or ≥40 bpm (children) or ≥120bpm, in the first 10 minutes of being in an upright position, without classical orthostatic hypotension associated and accompanied by orthostatic intolerance. Other symptoms such as dizziness, weakness, presyncope and heart palpitations are also common (Rocha et al., 2021). Orthostatic tachycardia can also present in the absence of orthostatic symptoms, which if accompanied by palpitations should be referred back to primary care (Ståhlberg et al., 2021).
Note: Many symptoms of orthostatic hypotension and POTS are difficult to differentiate from cardiac conditions. As a result, it is important to assess heart rate parameters and orthostatic hypotension if these conditions are suspected.
# Red Flag: Postural Orthostatic Tachycardia Syndrome (POTS)
o Sustained elevation of HR ≥30 bpm (adults) or ≥40 bpm (children) from baseline or ≥120bpm, in the first 10 minutes of being in an upright position accompanied by orthostatic symptoms. o Refer back to primary care provider for further investigation and diagnosis (i.e. tilt-table assessment, ECG, echocardiogram, cardiac MRI, etc.).
# Yellow Flag: Orthostatic Hypotension
o A fall in SBP of >20mm Hg or DBP >10 mm Hg from baseline within 3 minutes in an upright position. o If symptoms of OH are extremely limiting, consider referral back to the primary care physician for pharmacological management.
# Treatment Considerations:
Provide education on how to manage/prevent episodes of orthostatic hypotension or POTS (i.e. laying down until symptoms resolve, rising slowly after lying down, avoiding long periods of standing, drinking plenty of fluids, wearing support stocking or compressive clothing, etc.).
Consider a holistic treatment approach addressing topics such as: physical activity, mental well-being, pacing, sleep, nutrition, stress management, breathing and medication.
Provide education on breathing techniques (i.e. diaphragmatic breathing) and activity pacing to assist patients with return to activity.
If medically cleared by a physician, structured exercise including aerobic reconditioning and strength training may be considered for patients with POTS (Fu and Levine, 2018). This may or may not progress into an upright position.
Physical activity and exercise should be adjusted based on symptoms, which may fluctuate from day-to-day. This may be referred to as "symptom titrated physical activity" (National Institute of Health Research, 2021).
During the initial stages of rehabilitation, non-upright exercises (i.e. recumbent cycling, swimming, seated resistance training, etc.) may be more suitable for patients who have significant symptoms in standing (Dani et al., 2020).
Autonomic Conditioning Therapy (ACT) may help to reduce fatigue and improve symptoms of autonomic dysfunction in post-COVID patients (Putrino et al., 2021). Note that the classic Levine protocol may be too intense. It is recommended to start at or below a BORG of 2 before progressing to use heart rate determine progression (Putrino et al., 2021).
Dysautonomia has also been shown to impact a patient's cognitive function see cognitive section for treatment considerations.
# Recommended Outcome Measures:
Active Stand Test o Blood pressure and HR are measured after 5 minutes in supine, then immediately upon standing and at 2, 5 and 10 minutes. PoTS -Postural Tachycardia Syndrome (potsuk.org)
Resources:
# Joint and Muscle Pain
Joint pain (arthralgia) and muscle pain (myalgia) are common symptoms in the acute stages of COVID-19 but these symptoms are also displayed in the post-COVID population. Although prevalence varies, some research suggests up to 60% of post-COVID patients may experience persistent symptoms of joint and muscle pain (Galal et al., 2021). Treating arthralgia and myalgia is an important priority for rehabilitation professionals as these conditions can significantly impact function, return to regular activity and psychological well-being. The treatment strategies used to manage pain in the general population will still apply when working with patients after COVID-19 (Wang et al., 2020).
# Red Flag: Post-Infectious inflammatory arthritis
o Joint swelling, reduced range of motion, morning stiffness greater than 1 hour.
# Treatment Considerations:
Provide education on pain management strategies (i.e. heat, ice, joint protection strategies, etc.).
Consider gentle stretching, range of motion and strengthening activities.
Patients may benefit from medication including muscle relaxants or non-steroidal antiinflammatory (NSAID) medications.
If pain is not resolving or if patient presents with an exaggerated pain response, consider referring back to the primary care physician for further medical investigation.
Referral to chronic pain programs may also be warranted if symptoms persist beyond a reasonable time frame.
# Resources:
AHS Patient Education Resource: Symptoms: Joint and muscle pain (alberta.ca)
# Pelvic Health Concerns
Although pelvic health concerns are not commonly reported in the literature related to COVID-19, recent studies suggest post-COVID patients may experience increased urinary frequency, nocturia (>4 episodes/night) and incontinence (Dhar et al., 2020). Although the exact mechanism behind these changes is unknown, both respiratory dysfunction and hospitalization can have an impact on pelvic floor function. It is hypothesized that the residual respiratory symptoms of COVID-19, including chronic cough and shortness of breath, may contribute to pelvic floor dysfunction and worsening urinary or fecal incontinence and/or pelvic organ prolapse (Siracusa & Gray, 2020).
# Treatment Considerations:
Education Traditional pelvic floor strengthening programs can be easily individualized for the post-COVID population. If patients are experiencing proximal muscle fatigue, pelvic floor contraction sets can be prescribed with longer rest breaks and exercises can be performed in a semi-reclined or supine position to reduce the demand on the diaphragm and the pelvic floor (Siracusa & Gray, 2020).
Consider referring to a Physical Therapist who is authorized by Physiotherapy Alberta in the performance of pelvic floor rehabilitation. Physiotherapy Alberta College + Association : The Movement Specialists: Physiotherapist Directory
# Resources:
Pelvic floor information and exercises: Pelvic Floor First
# Activity & Exercise After COVID-19
"Physical activity" and "exercise" are two distinct terms which are often used interchangeably.
It is important to make a distinction between these terms as it may have impacts on rehabilitation recommendations for the post-COVID population. Physical activity is defined as any bodily movement produced by skeletal muscles that results in energy expenditure. It can be categorized into occupational activities, sports, conditioning, household or other activities (Caspersen et al., 1985). Participating in activities of daily living is considered to be a physical activity.
Exercise on the other hand, is a subset of physical activity that is planned, structured and repetitive with the objective being the improvement or maintenance of physical fitness (Caspersen et al., 1985). Exercise therapy used to treat health conditions would fall into this category and examples might include: aerobic training, strength, balance, range of motion exercises, etc.
In the post-COVID population, return to activity and exercise are important goals but exercise should not take precedent over return to regular activities of daily living. It's important to consult with patients and families to determine their functional goals and activities they want to focus on.
# Treatment Considerations:
Before beginning an exercise program, it is important to complete the Screening Tool for Post-COVID Physical Sequelae to identify any red flags or contraindications for exercise.
Both physical activity and exercise should be adjusted based on symptoms which may fluctuate from day-to-day. This may be referred to as "symptom titrated physical activity" (National Institute of Health Research, 2021).
If patients have limited tolerance or struggle with fatigue, the emphasis of treatment should be placed on energy conservation and return to activities of daily living prior to initiating a therapeutic exercise program.
Patients should only exercise if they feel recovered from the previous day and have no new onset or return of symptoms (Salman et al., 2021).
There is no clear evidence based guideline for returning patients to physical activity and exercise but a prudent approach would be gradual, individualized and based on subjective tolerance and symptoms (Salaman et al., 2021).
Patients and families should receive education on signs and symptoms to monitor during physical activity and exercise and when they should seek medical attention (i.e. chest pain, palpitations, disproportionate breathlessness, dizziness, etc.).
# Resources:
AHS
# Treatment Considerations:
# Principles and strategies for Energy Maximization
Acknowledge and validate the patient's experience. Most COVID 19 patients anticipated a short -term illness and are coming to terms with making lifestyle adjustments to manage their recovery. Patients can experience anxiety, shame and frustration resulting from the experiencing a prolonged recovery and an inability to return to their usual routine.
Collaborative goal setting conversations can be the first step in identifying patient-centered goals and priorities for allocating and maximizing energy. Once goals have been established, tracking current activities and energy levels (and other post exertional symptoms) can be a valuable tool to understand energy utilization patterns and occupational participation. Symptom tracking including Rate of Perceived Exertion or Activity and Symptom trackers can support the patient to develop an understanding of their current energy budget. Support patients to develop an awareness of their energy "budget" and the cost associated with their individual PESE triggers. Ensure your patients have considered not just the cost of physical tasks but also emotional and cognitive energy outputs.
Educate patients and families about the "Push and Crash" or "Boom and Bust" cycle and that there is often a causational relation to PESE/PEM. It is important to note that there can be a delay in experiencing a "crash" of 12-72 hours. Normalize patients' non-linear recovery experience and emphasize that progression of activity level should be based on avoidance of symptom exacerbation.
Reinforce that energy maximization strategies like pacing, are ways to avoid PESE and offers a way to reduce symptoms, regain control, and support improvement. It is important for patients and families to understand that participating in cognitively, emotionally, or spiritually demanding activities also requires energy and that thoughts and emotions can be a barrier to successful implementation of energy maximization techniques. A discussion of barriers to implementation can be integral to success.
# The Six P's of Energy Maximization
1. Pacing with precaution -Help patients identify their energy budget and problem solve around how they will pace themselves to stay within this budget. Breaking up activities and proactively building in frequent rest breaks are important features of pacing. 2. Positioning -Modify activities so they are more energy efficient. This can include the use of gadgets/aids and equipment as well as your body position during activities. Aids such as bathing or mobility aids may be useful in maximizing energy. 3. Planning -Using a journal/planner/agenda can assist with planning tasks on a daily or weekly basis as well as help reflection on energy reserves to avoid over exertion. Encourage development of sustainable routines with rest as the foundation and include activities that restore energy or rejuvenate the patient. 4. Prioritizing-Identify priorities for the day/ week; 'what matters most to you'. Help the patient consider which activities they must complete themselves and which could be delegated. 5. Problem solving -Look for new and energy efficient ways to engage in activities.
Recognizing and celebrate successes. 6. Permission -Encourage the patient to give themselves permission to do things differently than before COVID. It is important to be patient with yourself and acknowledge recovery can take time. Self -compassion skills can support this.
# Rules for rest
• Rest before you are fatigued. If you rest when you start to get tired rather than after you are exhausted you will require less recovery time. • Take short, frequent rests. They can add up to less overall rest time. Experiment with timing and length of rest. • Plan rest into your schedule first, then schedule activities around rest. Think of rest as an activity and plan it into your day. • Make rest a habit. To use budgeting terms, resting is making a deposit into your energy bank account.
# Progressing Activities
Develop a patient-centered, symptom-guided rehabilitation program with short and long term goals where progressions are not based on timelines but are titrated based on the avoidance of symptom exacerbation. In order to break the Push/Crash Cycle, patients must develop new activity patterns by:
1. Recognizing individual symptoms of fatigue (PESE) and triggers.
2. Finding a current activity budget (activity levels that do not result in PESE)
3. Adapting activity budgets (learning to work within your budget) 4. Expanding limits based base on absence of symptom exacerbation
# KEY MESSAGES:
Guided discussions including activity analysis can support patients to incorporate the 6 P's at the task/day/week levels. Increasing or adding new activities is not based solely on target dates but on the absence of PESE. Support the development of new routines with an emphasis on pacing and avoidance of push/ crash cycles. A key feature of maximizing energy is rest and restoration
# SPECIAL AREAS FOR CONSIDERATION:
Return to Work (RTW) or return to school for children, youth and young adults.
In an online survey of 3762 individuals whose illness lasted over 28 days, Davis et al (2021) found 45.2% required a reduced work schedule compared to pre-illness and an additional 22.3% were not working at all due to illness. By seven months, many patients had not yet recovered (mainly from systemic and neurological/cognitive symptoms) and had not returned to previous levels of work.
# Determining readiness
A successful return the work plan needs to be sustainable. Before looking at returning to work, it is important to consider if patients are managing home life within their energy budget. Managing home life can be characterized by the ability to minimize push/crash cycles while engage in most home life activities. Patients still need to be able to prepare meals, do laundry, shower and commute to work in addition to doing their paid occupation. Having a plan to mitigate the home life energy demands through the use of strategies such as delegation may allow for return to work despite not yet returning to full home life activities. This will depend on the patient's priorities. Consider having your patient begin progressively practicing return to work activities like waking up closer to their work hours and simulating job duties. Making a plan to reduce the anxiety of RTW is also important, as this can be a trigger for PESE.
Activity/ symptom logs can help determine if current activity levels are supportive of RTW. Ability to engage in cognitive, physical, and emotional activities without frequent and prolonged PESE as well as adequate sleep schedules are factors that support return to work. Once it is determined that there is a manageable home life plan, engaging in a job duty activity analysis can support making recommendations for appropriate accommodations (if needed) and return to work schedule. Job duty analysis can include developing a list the job demands (duties/ tasks) and identifying physical, cognitive and emotional PESE triggers. Once barriers/ challenges as well as strengths for return to work are identified, engage with patient (and employer as appropriate) to problem solve through these barriers and enhance strengths. using energy maximization strategies in their daily lives, they may find it useful to apply similar strategies in the work place. It is also important to consider that managing an illness takes energy and should be built this into RTW plan. Medical appointments should ideally be consider part of the work day. During the patient's first few weeks returning to work, it can be supportive to reduce the home life work load by delegating, planning ahead and prioritizing.
# Progressive return to work planning
People with Post COVID may require a more gradual RTW plan when compared to a musculoskeletal injury population. Progression should not be based on timelines but on ability to manage/ avoid PESE. If timelines are required, it is can be helpful to build an option in the plan to re-adjust timelines if progressions are not manageable. Avoid progressing more than one variable at a time (example: hours of work, days of work, duties). Working from home can reduce the energy demands of commuting.
# Sex and Intimacy
Post COVID patients have expressed barriers to sex/intimacy including fatigue, brain fog, erectile dysfunction and irregular periods. Open communication between partners is essential to support sexual wellness when recovering from Post-COVID. Communication can support shared problem solving and combats the tendency to isolate. Consider applying the 6 P's to sex/ intimacy. Planning intimacy for a time of day when ones energy is best, is a supportive strategy. As well, consider positions that are energy efficient. Pacing can be supportive as some extra time may be required to support arousal. Relaxation techniques can also support managing anxiety and help support setting the scene for intimacy and connection. It can also be supportive to look at alternatives to intercourse for intimacy.
# Recommended Outcome Measures:
•
# Sleep
Sleep quantity and quality are important factors in overall wellness. Insufficient sleep has been linked to a variety of negative health impacts including increased risk of obesity, cardiovascular disease and mood and cognitive disorders (Mendelkorn et al., 2021). Since the start of the pandemic, there has been an increased prevalence of sleep disturbances among the general population as well as COVID-19 survivors. According to current evidence, sleep disorders impact approximately 40% of general population and health care workforce, while up to 75% of patients with COVID-19 experience sleep disturbances. Often times, sleep related issues such as insomnia persist well beyond the acute phase of COVID-19 (Jahrami et al., 2021).
Supporting patients with sleep disorders is an important priority for rehabilitation professionals as impaired sleep can significantly impact participation and overall recovery.
Red Flags: High Risk STOP BANG screen score, recommend returning to primary care physician for referral for Level 3 (in home) sleep study.
Yellow Flags: Poor sleep, in combination with changes in appetite, feelings of low mood or incessant worrying may be indicators of depression or anxiety disorders and may warrant further screening or referral. Reports of off-label medication use or alcohol use may warrant further screening or referral.
# Treatment Considerations:
Consider using a sleep diary/journal as well as a daily routine journal to establish sleep habits as well as activity level during the day. It may be helpful to consider pre-COVID sleep habits as well.
Provide education on sleepiness versus fatigue. This can allow a better understanding of the lived experience is for each patient.
Consider providing resources on mind/body calming skills such as: mindfulness, guided imagery, progressive muscle relaxation, diaphragmatic breathing, etc. Achieving confidence with the skill prior to using it for sleep initiation is recommended.
# Cognition
Cognitive changes associated with COVID-19 include difficulty with attention/concentration, working memory and executive functioning. The term 'brain fog' is frequently used by patients to describe a loss of focus, vague memory problems or slowed processing or recall. Cognitive issues may be associated with encephalitis, stroke, hypoxia, or Post-Intensive Care Syndrome (PICS). One study of adult patients who required inpatient rehabilitation after prolonged hospitalization (mean age 64.5/ evaluated mean 43.2 days post-initial hospital admission) found 81% of patients had cognitive impairment. Working memory (55% of patients), set shifting (47%), divided attention (46%) and processing speed (40%) deficits were observed and were not significantly associated with length of time intubated, length of time since extubation, psychiatric diagnosis or preexisting cardiovascular disease. .
However, even non-hospitalized patients have demonstrated cognitive difficulties. In one study of adult patients who were never hospitalized and seen on average 4.7 months after onset of symptoms, 81% reported brain fog and performed worse on attention and working memory tasks than a demographically matched sample (Graham et al., 2021).
An Italian study by Buonsenso and colleagues (2021) with pediatric patients 162.5 ± 113.7 days post initial COVID-19 diagnosis found that persistent or delayed onset symptoms were not reported in 41.9% of patients, while 35.7% of patients reported one or two symptoms, and 22.5% reported three or more symptoms. The most commonly reported symptoms were fatigue (86.8%), insomnia (18.6%), nasal congestion/runny nose (12.4%), trouble concentrating (10.1%), myalgias (10.1%), weight loss (7.7%), joint pain/swelling (6.9%), skin rash (6.9%), constipation (6.2%), chest tightness (6.2%) and persistent cough (5.4%).
In addition to cognitive sequelae, psychiatric conditions such as depression and anxiety are expected to occur with higher prevalence in COVID-19 patients (Bailey et al., 2021). Mental health symptoms, and ongoing fatigue can also impact a patient's cognitive presentation. Thus, for many individuals it will be important for clinicians to provide education on lifestyle habits and routines; in conjunction with strategies and tools to manage cognitive changes.
# Functional Cognition
Treatment Considerations:
# Provide Education on Factors that can Affect Cognition
Patients can feel lost or hopeless if they feel that they are not in control of improving their cognitive abilities. Providing education and tools and empowering patients to create changes in their routine can help shift the onus of control.
• Discuss sleep habits and provide education on sleep hygiene. A sleep log may be helpful to increase self-awareness of habits and what is and is not working. Help patients realize that they may require more rest than before becoming ill. Children may require more rest than before becoming ill. • Educate patients and families on the link between rest/energy and how it can impact cognitive functioning. • Normalize the stress associated with long-term symptom management and propose tools. Educate patients on how stress can impact cognitive functioning. • Educate patients and families on energy maximization and pacing. Introduce tools such as the Pacing points system or Activity logs to increase self-awareness. • For children encourage parents to set small, manageable goals with their child. An initial goal that requires 10-20% of change (e.g. if child can currently read for 10 minutes, set a goal of 12 minutes). Increase these targets in small, manageable increments. Praise children for achieving their goals and use rewards as desired to encourage success
# Collaborate and Document Long-term Goals
Patients may show lapses in memory, concentration, and focus, from cognitive overload, direct consequences on the brain, persisting hypoxia, or fatigue. They may lose track of goals, plans, and steps. So reviewing and documenting their goals is important for organization and to monitor progress, especially when patients are uncertain, demoralized and have reduced memory or attention. Steps include:
• Help the patient keep track of learned information throughout sessions • Review major goals and frame these larger goals into short-term achievable steps • Provide and review homework and activities provided to your patient. Discuss feedback, the patient's experience and their perceived challenges. Involve family support as needed and emphasize the importance of accountability and follow-through. • Identify and reflect on progress and reflect on goal attainment.
# Managing Attention, Memory, Planning
Patients can get distracted, overwhelmed by details, and have trouble retaining specifics. They may also become overwhelmed by the whole experience of trying to manage therapies, on top of other roles. It's important to provide some structure to help manage this.
• Be structured -consider a written agenda for the session.
• Decrease cognitive load -focus on one thing at a time.
• Reduce distractors and try to work in a quiet environment.
• Take breaks and encourage your patient to learn to recognize opportunities for needed rest. • Encourage written notes -for the session, or items to follow later on, to limit distractions. • Take a minute at the start of the session to review the plan, take a minute at the end of the session to plan for practice, and the next step. • For memory, use brief keywords; lengthy descriptions are excessive.
# Cognition, Fatigue and Stress: "Brain Fog"
Everyone experiences some interference when we are stressed or tired, affecting how we use our thinking skills. When people are stressed or tired, they are more prone to lapses in memory and attention. They may feel this is a sign of cognitive deterioration. It is also important to remember thinking and concentration also takes effort, which is more obvious when people are recovering. Reading, using the computer, and similar activities are all more tiring during recovery, it is important to stop before you get fatigued.
• Normalize lapses -everyone has them. Post-COVID patients may report an increased frequency of these lapses. Reassure your patients that they will likely decrease as they feel more in control and use their tools. • Encourage coping skills -deep breathing, relaxation, and setting time to refocus.
• Encourage reminder tools for activities and for breaks (alarms, using an agenda).
• Review activity level, and breaks.
• Pacing and energy maximization.
• Encourage an exit plan for when patients become fatigued or overwhelmed by cognitive or social activities -"Know when it's time to go".
# School
School attendance may have been impacted by cognitive symptoms with attendance becoming sporadic or even stopping altogether. Staying out of school has negative impacts for children as it reduces opportunities for learning, social connection, and adherence to helpful structured routines.
Most schools can develop an individualized attendance plan to facilitate a full or gradual return to school as needed:
• Accommodations may include shortened school day, scheduling more frequent breaks, reducing workload, and allowing extra time for completion of schoolwork, temporarily eliminating or reducing homework, and developing a structured plan for catching up on missed assignments or schoolwork. • Identifying a member of staff as a designated support person at school is also important. • Support a gradual increase in school attendance (e.g. for a child who has completely stopped attending school start with 2 hours per day, gradually working up to half or full day as appropriate).
Use rewards and consequences to support planned school attendance. Rewards might involve use of a sticker chart for younger children or earning additional privileges for teens.
Consequences for not attending school as planned, may include loss of leisure screen time for the school day in question.
# Use Electronic or Written Aids
Patients often need reminders of specific details, and cues for planning and follow-through. Work with them to help use their preferred tools, or tools that family can support with. This can be written in a notepad, agenda, wall/fridge calendar, phone, or computer.
• Choose the tool they are most familiar with. Older adults often like pencil and paper, younger adults may prefer electronic tools. • Consider alarms (on phone or computer) to cue specific tasks, such as homework time, stretches or activity. • Use phone to record exercises or take photos as cues.
• For teens it may be helpful to use a phone to record exercises. Younger children may benefit from a picture based visual schedule. • Consider separating main goals, progress reports, and specific activity plans/exercises.
# Identify and Use Prior Strategies
Every individual comes to us with their own history and resources. Exploring and acknowledging these with your patients can be an important part of instilling hope and rebuilding self-agency.
• Does your patient like to plan in advance? Does your patient use self-talk to maintain focus, or put items out in preparation for tomorrow? Resuming old and helpful strategies increases control and self-direction. • Set aside time to plan and review or prepare steps for potential challenges.
o Managing physical or cognitive fatigue by setting breaks o Ensuring that family members know schedule so they can provide reminders if necessary o Review and practice homework.
• Work together with your patient, and their family, or other support people to identify potential solutions and next steps.
# Review and Aid Patient/Family Review
Patients and their families will often get focused on the challenges of the day, which makes it easy to overlook progress they have made. Sometimes, this can also be important if we are working on a goal but making little progress, to suggest a possible change in goals, or strategies.
• Make a regular time to review progress, perhaps five minutes of the start or end of the week. When family are involved, get permission to get their feedback.
• Review what is happening outside of therapy activities is well. What is changing or progressing in life?
# Catch Successes, Problem-Solve Lapses
Being ill, experiencing cognitive difficulties, having poor endurance and prolonged recovery is demoralizing. It's important to problem-solve difficulties, but also to identify the steps and strategies that either prevented difficulties or responded to them so they are no longer a barrier.
• Regularly review barriers and challenges, and both practical and motivational responses for these. Encourage your patient to generate these. • Encourage your patients to record challenges and record the steps they have taken to manage and prevent challenges, as a problem-solving and motivational tool.
# Reassurance and Increasing Independence
Being ill and relying on supports is demoralizing. Adult patients can develop some dependence and seek reassurance, so it is important to plan for independence and increasing self-reliance.
• When you are often being asked for reassurance, ask your patient -"What did we say before?" Encourage them to generate responses to their questions. • Encourage your patient to plan activities they value and describe any tools they will use.
• If necessary, cue them to schedule leisure, productive, and social activities. Encourage brief initial activities and have an exit plan if they get fatigued or overwhelmed partway through. "The success lies in starting, endurance comes later" • Support low intensity initial steps to their goals -participating in meal preparation, taking turns driving, as steps to independence. Flag the next steps.
# Long-term goals and Timing
Patients will be eager to resume activities that are challenging and represent normalcy and a return to their baseline. Sometimes persisting symptoms and fatigue will be a barrier to retuning to certain activities. Timing of the return to school, work, and driving should be guided by the medical/therapy team.
• Patients will benefit from being provided with reassurance that recovery takes time and that return to more complex activities must be timed appropriately.
• Inform patients that they may require medical clearance to return to driving or work. This will depend on the severity of their course of illness.
• Factors such as fatigue, and mental wellness may also help to inform readiness to return to higher level cognitive activities.
# Recommended Outcome Measures:
• For Adult patients in addition to traditional cognitive screens that identify mild cognitive impairment (such as SLUMS, ACE-III, or RUDAS) consider adding a screen that tests processing speed (such as Trail-Making or Symbol Digit Modality Test).
# Resources:
MHA
# Cognitive Communication
Cognitive and emotional disturbances observed in individuals recovering from COVID-19 can have a significant impact on their functional communication abilities.
Temporary and permanent brain damage can occur in patients with COVID-19 due to intermittent or chronic hypoxia (resulting from acute respiratory distress syndrome) or from inflammation and/or coagulation within the vascular system resulting from the immune system's response to the COVID-19 virus (Ramage, 2020).
Cognitive-communication disorders are defined as communication deficits (e.g. listening, speaking, reading, writing, social interaction) resulting from underlying cognitive impairments.
Cognitive impairments associated with COVID-19 include slowed speed of information processing, reduced orientation, attention and concentration difficulties, memory problems and executive functions. These impairments can result in a variety of communication deficits that include difficulties:
• Comprehending spoken or written information in a timely, reliable manner -slowed information processing may make it difficulty to keep up during a rapid conversation, especially when there are multiple speakers or when the environment is distracting. • Speaking or writing in clear, organized fashion -expression may be inefficient (i.e. low information content conveyed relative to the number of words produced) and disorganized (drifting from topic to topic, and containing tangential or irrelevant remarks). • Retrieving the right words in a timely manner • Interpreting and using abstract language (e.g. humour, metaphors) • Recalling conversations or steps to complete new tasks • Interacting in a socially appropriate manner -this can include a tendency to monopolize conversations, difficulties maintaining a conversational topic, exhibiting limited interest in conversational partners or failure to correctly interpret non-verbal forms of communication (e.g. tone of voice, facial expression).
Cognitive-communication impairments can have a significant impact on an individual's psychoemotional status, social participation and their success returning to previous life roles (MacDonald, 2017).
Referral to an SLP is indicated when a change in an individual's communicative ability is observed in any of the areas described above.
# Treatment Considerations:
Speech-language pathologists perform an essential role in the early identification and remediation of cognitive-communication disorders.
Treatment of cognitive-communication disorders should start as early as possible to enhance recovery, functional performance and quality of life of individuals recovering from COVID-19.
Cognitive-communication rehabilitation is most effective when provided by an interprofessional team.
Cognitive-communication rehabilitation domains can include comprehension, expression, attention, memory, social communication, problem solving, reasoning and self-awareness.
The following areas should be considered in developing an intervention plan to support individuals with cognitive-communication deficits:
# Voice and Upper Airway Respiratory Issues
Dysphonia and dyspnea are common early symptoms of COVD-19. These difficulties may persist or worsen beyond the acute phase of the infection. Some of these symptoms may require focused upper airway (laryngeal) diagnostic workup and intervention for both adults and children.
Post acute COVID-19 laryngeal injury and dysfunction may have a number of different etiologies. The causes may be neurogenic, structural, functional, or a combination of these. Examples of laryngeal sequelae are posterior glottic or subglottic stenosis, intubation granuloma, vocal fold paresis/paralysis, chronic laryngitis, vocal fold atrophy, muscle tension dysphonia, and paradoxical vocal fold motion. Symptoms can span a broad range of severity, acuity and functional impact. Laryngeal injury or dysfunction should be considered in patients presenting with stridor/inspiratory dyspnea (particularly post extubation), or new-onset and/or progressive dysphonia. Comprehensive diagnostic assessment including laryngoscopy is warranted prior to any intervention for these upper airway symptoms. An interdisciplinary team including voice/upper airway specialized ENT and SLP will continue to play an integral role in assessing and treating these patients, in coordination with primary care providers. Indeed, early otolaryngology evaluation for voice, airway and swallowing dysfunction remains critical as we seek to manage or prevent long-term laryngotracheal sequelae that could have lasting impacts on quality of life. (Neevel et al., 2021, p
# Treatment Considerations:
Patients and their families should receive general information on care of the voice (e.g. resting the voice as needed, avoiding straining or pushing the voice, avoiding prolonged loud voice use and optimizing hydration.) Structural abnormalities (e.g. posterior glottic or subglottic stenosis, intubation granuloma) may require surgical intervention). Chronic laryngitis may be managed medically.
Vocal fold paresis/paralysis may be managed with operative or in-office surgical procedures and adjuvant voice therapy. Children may need to wait until they are older for surgical intervention.
Vocal fold atrophy may be addressed with operative or in-office surgical procedures.
Voice therapy may be used to address milder atrophy or vocal deconditioning/vocal fatigue. Functional/muscle tension dysphonia is typically addressed and managed via voice therapy. Functional (upper airway) breathing disorders such as paradoxical vocal fold motion (PVFM) can be managed with behavioural intervention.
# Resources:
Prevalence of dysphonia in non-hospitalized patients with COVID-19 in Lombardy, the Italian epicenter of the pandemic.
Features of mild-to-moderate COVID-19 patients with dysphonia. Persistent dysphonia in hospitalized COVID-19 patients. Laryngeal complications of COVID-19. Postacute COVID-19 laryngeal injury and dysfunction.
# Eating, Feeding and Swallowing
Eating, feeding, and swallowing concerns may result from COVID-19 for patients and their families regardless of the initial severity of their condition. It occurs in people who have and those who have not required hospitalization. Difficulties range from aspiration during swallowing to reduced enjoyment of eating due to loss of taste and smell. Dysphagia (difficulty swallowing) is commonly observed in patients diagnosed with COVID-19 (Dawson et al., 2020) and is an independent predictor of severe COVID-19 infection (Pulia, 2021).
Acute respiratory distress syndrome (ARDS) is the most common symptom of COVID-19 observed in critically ill hospitalized patients. These patients are typically admitted to ICU and require invasive medical treatments to manage their respiratory failure (e.g. mechanical ventilation, proning, and extracorporeal membrane oxygenation (ECMO) for multi-organ failure). These treatments and the underlying physiological impairments are significant risk factors for the development of dysphagia, aspiration, and negative sequelae of aspiration. Difficulty coordinating respiration and swallowing is a primary cause of dysphagia in persons recovering from COVID-19 (Ranjini and Mohapatra, 2020).
In addition to respiratory complications, patients with COVID-19 are at risk of developing critical illness polyneuropathy and myopathy and other neurological complications such as stroke, encephalitis, and Guillain-Barré syndrome (Dziewas et al., 2020). All of these conditions are significant risk factors for dysphagia.
Research demonstrates that not identifying swallowing concerns can lead to poor patient outcomes, including respiratory morbidity and mortality (Macht, 2011), and increase the length and cost of hospital admissions (Ferraris, 2001). All hospitalized patients recovering from COVID-19 should be screened for swallowing concerns as soon as they are alert and ready to trial oral intake. Patients reporting or exhibiting signs of swallowing difficulty or risk factors for dysphagia should be referred to a dysphagia therapist for a comprehensive assessment.
Dysphagia therapists draw from knowledge of respiratory disorders, critical care, and neurology populations in the assessment and management of individuals recovering from COVID-19. This includes physiological factors related to aspiration risk (Steel and Cichero, 2014), aspiration pneumonia (Langmore 1998;2002), prolonged intubation (Skoretz, 2010), and tracheostomy (Macht, 2011).
# Pediatric Considerations
In pediatrics, children who have experienced multisystem inflammatory disease have been reported to have increased incidence of dysphagia which may be the result of the airway inflammatory process or secondary to intubation (Cheong et al., 2021). The recommendation was made that all children with Pediatric Inflammatory Multisystem Syndrome (PIMS) should be screened for dysphagia (Halfpenny et al., 2021).
Clinical considerations in managing swallowing concerns in individuals recovering from COVID-19 include:
• Lung damage is frequently observed in patients recovering from COVID-19 resulting in greater risk of suboptimal ventilation and a subsequent risk of abnormal coordination of the respiratory and swallowing cycle • Critically ill COVID-19 frequently needed to be maintained in a prone position for extended periods of time. This can increase their risk of aspiration, interfere with safe provision of oral hygiene and affect breath-swallow pattern and timing (Dawson et al., 2020) • Airway inflammation and tracheobronchitis are observed even in the absence of mechanical ventilation. • Delirium is frequently observed in patients with COVID-19 who have been admitted to hospital. • Oral hygiene is especially important for patients with COVID-19 as aspiration of oropharyngeal bacteria induces the expression of angiotensin-converting enzyme 2, a receptor for SARS-CoV-2, and the production of inflammatory cytokines in the lower respiratory tract. Consequently, poor oral hygiene can lead to COVID-19 aggravation (Takahashi et al., 2020). • The medical status of patients with COVID-19 may fluctuate dramatically and without warning during the acute care phase, necessitating close monitoring of overall status and impact on swallow function.
Risk factors for dysphagia include:
• prolonged intubation (> 48h) and/or repeated intubation • tracheostomy • diagnosis of acute or progressive neurological condition (e.g. traumatic brain injury, stroke, Parkinson disease) • dependency for self-care (e.g. feeding, oral hygiene) • critical care neuropathy and deconditioning • altered level of consciousness (sedation, delirium, impaired attention, impulsivity) • poor respiratory status including need for supplemental oxygen or increased respiratory rate • recent pneumonia, delirium, acute respiratory distress syndrome Treatment Considerations:
• An integrated multi-disciplinary team is required to assess and manage the complex etiology of eating, feeding and swallowing difficulties associated with COVID-19 and to manage concurrent demands related to respiratory health, nutrition, hydration, swallowing rehabilitation, medication requirements, and other health needs. • Individuals recovering from COVID-19 often experience persistent respiratory deficits (e.g. shortness of breath) and symptoms of physical and mental fatigue ("brain fog").
Respiratory issues can affect swallowing safety by impacting the ability to coordinate breathing and swallowing. Marked fluctuation in the respiratory status of patients recovering from COVID-19 is common and therefore close monitoring of swallow function is essential. • To manage fatigue and respiratory issues during mealtimes, the following strategies are recommended: o Eat smaller, more frequent meals throughout the day. o Take a rest break before meals to optimize energy. o Allow more time to eat meals -stop and rest if feeling short of breath or fatigued, take small bites/sips, try eating softer foods that require less chewing o Limit talking during meals to avoid shortness of breath. o Consider positioning: Sitting at a table in a supportive chair maximizes energy for both breathing and feeding. o Meal time aids are available to support weakness/ fatigue; if needed consult an OT. • Patients recovering from COVID-19 may experience changes in their smell or taste.
This can have a significant impact on appetite. The following strategies are recommended to support adequate nutrition and hydration and enhance the enjoyment of eating: o Increase the sensory experience of foods by selecting foods with a variety of textures and temperatures.
o Enhance the range of flavor by preparing foods that stimulate all of the tongue's taste receptors (e.g., saltiness, sweetness, bitterness, and sourness) o Make the presentation of foods as appetizing, as possible • Facilitate bolus transit and reduce throat irritation by alternating between bites of food and sips of liquid. Also consider blended or softer foods during recovery. • Instrumental assessment is strongly recommended for patients who have or had a tracheostomy and exhibit signs/symptoms of dysphagia or have dysphagia risk factors in their case history. Instrumental assessment is also strongly recommended for patients who are unable to tolerate any deflation of a cuffed tracheostomy. • Also refer to the Nutrition section of this document Telephone sessions are unlikely to adequately replace Face to Face (FTF) or synchronous videoconferencing, especially for moderate or severe dysphagia. However, videoconferencing can be used to triage patients, identify the need for urgent or FTF follow up, and provide education to aid in reducing risks of aspiration in the interim (See Dysphagia Assessment and Treatment During the COVID-19 Pandemic: Lessons Learned from the Transition to Telepractice ).
# Recommended Screening Tools and Outcome Measures:
Dysphagia Handicap Index o Self-report measure of the handicapping effect of dysphagia on the emotional, functional, and physical aspects of a person's life Eating Assessment Tool (EAT-10)
o Self-report measure of swallowing difficulties.
# Psychosocial Impacts
The amount of literature on the effects of the COVID pandemic on children and teens in general is starting to be quite substantial. The specific psychosocial effects on children and teens has been documented worldwide. In a recent study of adolescents and mental health (Donmez and Ucur, 2022) in Turkey, results showed that 49.9% of the participants had anxiety symptoms, 29.5% had depression symptoms, and 51.4% had irritability symptoms. Younger age was determined to be a potential risk factor for anxiety symptoms, and female gender was a potential risk factor for anxiety and depressive symptoms. Having a COVID-19 death in the family or home environment was also suggested to be a potential risk factor for depression and irritability symptoms, while television and internet exposure to COVID-19 information was found to be a potential risk factor for anxiety, depression, and irritability symptoms. A study by Caffo, Asto, and Scandroglio (2021) in Italy suggested some similar predictors in the negative effects on mental health in children and teens. Some of the factors suggested as predictors included social isolation, excessive screen time and social media exposure, higher levels of parental stress and poor parent-child relationship, low socioeconomic status, and presence of pre-existing (to COVID) mental health conditions or disabilities.
The amount of research specifically on the psychosocial effects of post COVID conditions on pediatric patients and families is still limited and diverse. In a review of post COVID research Zimmerman et al. (2021) found that, in children, the risk of coronavirus disease (COVID) being severe is low, the risk of persistent symptoms following infection with SARS-CoV-2 is uncertain, and symptoms of "long COVID" are poorly defined. They concluded that long-term or post-COVID infection associated symptoms are difficult to distinguish from pandemicassociated symptoms.
However, In North America, a 2021 report by the United States Department of Health and Human Services suggested that, following a COVID-19 diagnosis, adolescents were almost 4.5 times more likely to experience depression than younger children, aged 6 to 11 years old (37.9% versus 8.6%). The pre-existence of adverse childhood experiences (e.g., child abuse and neglect), death of a family member, addiction in families, and certain psychosocial events (e.g., criminality in family) substantially increased the likelihood of young people experiencing a mental health condition, post-COVID infection. Parental metal health concerns have also been found to be associated with their children's mental health
# Responding to Stress and Distress in Post-COVID Patients Practice Considerations:
It is important for all healthcare providers to take a bio-psycho-social-spiritual approach in responding to post-COVID care needs. Patients and their families do better when we pay attention to their physical and psychological symptoms and needs, as well as their spiritual and social needs and considerations.
Patients and caregivers may be stressed or distressed, and may experience multiple stressors individually, and as a family. Not all stressors cause distress. Supportive conversations are important to connect with people, and to understand their experience and needs. Broad sources of stress can include: o physical symptoms o loss of or greatly altered routines and meaningful participation o social needs and considerations (e.g. loss of income/finances, or relationship/role changes) o psychological impacts (e.g. new or re-developing mental health symptoms or illness) or concerns o spiritual impacts (e.g. suffering a loss of meaning and or a sense of connection)
or concerns The pandemic environment is itself a significant stressor, and those who have had COVID-19 may also have trauma-related symptoms
# Practice Tips:
Create a safe place for patients and their families to share and build trust and rapport Be curious: try to ask open ended questions in a narrative manner to find out what matters most to the patient Approach patients and families in a calm, caring manner, making eye contact and speaking at an unhurried pace. Be cognizant that not all cultural groups interact in this specific manner (For example, less direct eye contact is made with some cultural groups and signals that they are finished speaking, as opposed to having something to say). Use normalizing language, emphasizing that stress impacts people in different ways, and that different people cope with it in different ways. When working with children or youth, take care to confirm and validate the child's or teen's report of troubling symptoms, as well as related issues the family or caregivers may mention. This not only helps the patient and family feel heard but serves to ensure a correct understanding between the patient/family and health care worker. Use familiar wording and clear language that is appropriate for the age and developmental level of any children. Some of the more complex medical terminology and diagnoses may require explanation; Try to avoid using too much medical jargon and explain things in a way pediatric patients and their families will understand. Use active listening skills, such as summarizing or paraphrasing to ensure you and the patient, caregiver or family member are understanding each other. Offer practical suggestions, such as taking a few slow, deep breaths, to support patients to reduce anxiety. problems? Recognize that the impacts of the pandemic influence all of us in various ways. Note the strengths of the individual and provide patients and caregivers with information to support them in self-management of stress. Consider referral to another healthcare provider or program if appropriate to address a given need that is outside your scope of practice.
# Signs of Distress in Children and Teens:
Encourage Parents and Caregivers to monitor their children for signs of stress and mental health issues post COVID. Signs of stress and mental health challenges are not the same for every child or teen, but there are some common signs or symptoms associated with these issues that are different for certain age groups of pediatric patients:
Infants and younger children may show a decline in skills or regression in developmental level. Caregivers may need to monitor their child for: o an increase in fussiness or irritability, startling or crying more easily, or the child is difficult to console when upset.
o trouble falling asleep or waking up more often during the night.
o issues related to feeding/eating, such as nausea or vomiting, constipation or loose stools, or new complaints of stomach pain.
o an increase in anxiety when they have to be away from the family, clinginess, not wanting to socialize, or they fear going outside.
o an increase in aggressive behavior, such as hitting, biting, or more frequent or intense tantrums.
o bed-wetting after the child has successfully been potty-trained.
Older children and adolescents may show signs of distress, such as:
o changes in mood for the child that are unusual or uncharacteristic, such as increased irritability, feelings of hopelessness or anger, or more conflicts with friends, family, or school staff.
o changes in behavior, such as increased withdrawal from personal relationships or obligations (e.g., chores, appointments).
o A decrease of loss of interest in previously enjoyed activities or interests.
o an increase in sleep issues such as in time falling or staying asleep or feeling sleepy/tired all the time.
o changes in eating patterns/appetite, such as not eating a lot or feeling hungry all of the time. A marked increase or decrease in weight may also be cause for concern.
o changes in appearance, such as a decrease of basic personal hygiene activities.
o trouble with memory, thinking, or attention/concentration.
o decreased interest in schoolwork, or drop in academic effort or performance.
o an increase in risk-taking behaviors, such as using drugs or alcohol.
o expressed thoughts or comments about death or suicide, or engaged in selfharming behaviours (e.g., cutting, reckless behaviour).
# Parenting Tips and Considerations:
Encourage parents and caregivers to regularly check in with their child, asking them how they are doing/feeling, and reminding them that they are there to talk when the child or teen is ready.
Remind parents/caregivers that some children or adolescents may require more time or space to express themselves. Some may do better with gradual conversations and other activities besides talking (e.g., artwork), while others might be more comfortable with direct conversations or activities (e.g., counselling). Encourage parents to see themselves as a primary 'agent of change' in responding to psychological distress associated with post-COVID symptoms. Research indicates that an 'authoritative parenting style' is most effective in supporting children who are struggling with chronic illness: o In this parenting style, the parents are nurturing, responsive, and supportive, yet set firm limits for their children. o It is helpful for parents to adopt a position of understanding/acceptance of their child's symptoms, while focusing on explicit problem-solving strategies to address specific concerns.
Encourage parents to help the child or teen to talk with a trusted friend or family member if they do not wish to talk with the parent or primary caregiver about their problems.
During the pandemic contact restrictions, or due to post-COVID symptoms, children/teens may not be able to physically interact or talk in-person with their with peers/trusted adults. In such cases all attempts should be made to ensure the child/teen has access to other forms of interpersonal interaction, such as online play dates for younger children, or teleconfrences/online chats and text messaging for teens.
-Parents may need to communicate with their child's friends' caregivers/family to arrange such to ensure the child/teen feels connected to a support network, and has the time to socialize to some extent. -For older asdolescents and teens, parental support for communication with peers should also include some private communication to alllow their child to feel some independence and be able to interact freely with their peers, within some reasonable limits (e.g., a specific amount of 'screen time' per day with peers). Interactions may include online gaming with friends, which parents can also support within reasonable expectations (e.g., time limits per day of game time such as half an hour per day is recommended for adolescents and an hour for teens as opposed to unrestricted time. Remind parents/caregivers to monitor and maintain their own mental health. Many studies have associated parental mental health with their children's mental health. Thus, it is of significant importance for parents/primary caregivers to ensure they are maintaining their own mental health effectively, or utilizing health care or social services to help manage mental health conditions, in order to minimize impaxt on the children under their care.
# Other Practice Considerations:
Try to be aware of any cultural or language considerations that need to be considered in treatment and treatment planning with a pediatric patient or their family and caregivers. For example, English may not be the first language of immigrant families and translation services may need to be accessed to ensure effective communication with patients and caregivers.
-Sometimes the pediatric patient or another family member may take on the role of translator between the health care provider and family/caregivers. The translator may view this as an additional source of stress, adding to any other stressors. While it may be convenient for the patient to translate, it is not a replacement for a professional translator, or unit staff member that speaks the guage, versed in health care terminology who can ensure that there is a complete understanding of the patient's health care concerns with involved family members. -If the pediatric patient does end up having to be the primary translator beteween the health professional and the family/caregivers, frequent check-ins should be done with the child/teen to ensure that: the patient understands the information first, prior to translation to the family or caregivers; and the patient is comfortable and not overly stressed by the translator role.
# Resources:
Help
# Difference between Spirituality & Religion
Spirituality is a broader concept than religion: not all people identify as religious but the spiritual attributes of meaning, values, transcendence, connecting and becoming may be universal.
# Understanding Spiritual Distress
Spirituality addresses sources of wellbeing, needs and issues related to meaning, values, transcendence, connecting and becoming. The experience of COVID impacts all these spiritual dimensions. Questions of meaning may surface for patients. Visitation restrictions may have challenged health care providers' patient-centered values and patients' opportunities for connection with others. Individuals may have suffered disruptions to their beliefs about themselves, others and the health care system. The experience as a whole may have impacts on personal growth and development. These all may be expressions of spiritual distress.
# AHS Definition of Spiritual Distress
The loss of meaning and connection in relationship with self, others and Other, (what one considers ultimate/transcendent). The latter may or may not be a deity; it might be a philosophy, nature, the universe etc.
# Practice Considerations:
It is important to recognize that patients may express spiritual distress in both religious and in non-religious terms. Examples of Symptoms of Spiritual Distress: Loss of Meaning and Connection with Self o Symptom: loss or diminished sense of self e.g. "I don't feel like myself anymore," "I don't recognize myself anymore," "I feel numb," "I always thought I was a person of faith but now I'm not so sure." o Lament is a spiritual way to process to your own suffering through expressing grief or loss, desire, trust, and gratitude. Practicing lament in tough times can help you shift from "unbearable suffering" to "bearable suffering." It can help you express your emotions, without judgement; know that you are not alone in feeling this way; engage with your inner suffering and give voice to your questions.
o Breath Meditation is an awareness practice that helps bring you back to the present moment. This practice can help you develop a sense of grounding and connection; improve concentration; decrease anxiety and depression; and improve overall sense of wellbeing.
o Contemplative Reading is a practice that opens you to deeper connection and meaning/wisdom through reading short pieces of inspirational or sacred texts.
o Find the Feeling is a practice that helps you recognize, experience, and understand your emotions. It can help you become more comfortable with experiencing strong emotions. This practice can help you build emotional resilience.
o Labyrinth Walking helps you to be in the present moment through walking a single, winding path with one entrance that leads to a centre and back out. This practice can help you feel calm, focused and connected. Benefits of walking the labyrinth include: feelings of calmness and relaxation; improved focus; reduced anxiety and stress; and insight.
o Mantras are a spiritual practice in which a sacred word is repeated over and over. It is a form of meditation that can support spiritual wellness and coping and connect you with what is meaningful in your life.
o Taking and Sending is a spiritual practice that helps you see and acknowledge painful situations while creating meaningful connections with others. This practice can help you find courage through a deep sense of connection when things feel uncertain. In doing this practice, you may begin to feel care and love for yourself and others.
# Nutrition
Nutrition is an important aspect of recovery, especially after a serious illness. For individuals recovering from COVID-19, certain symptoms such as fatigue, shortness of breath, loss of taste or smell, or changes in swallowing can make it difficult to eat and drink. A summary of common post-COVID-19 nutrition-related side-effects that individuals may experience are summarized in Table 1. If a patient is experiencing any of these, a referral to a registered dietitian is recommended. Food insecurity may also be an issue for some people as they may be unable to return to work due to ongoing symptoms.
Children who miss school or social activities may not access food programs in place. Social isolation, government lockdown orders, difficulties getting to a grocery store, or limited food choices in one's community can significantly impair a patient's ability to access foods. The ability to afford basic needs, including food, will impact patients' recovery. Screen patients and connect them to supports and services. For immediate patient concerns regarding food access see: Free Food in Alberta Information for Albertans
As rehabilitation clinicians, it is important to be aware of the impacts COVID-19 may have on nutrition and the resources available to support patients in their recovery. The following section outlines several key nutrition resources that have been developed within AHS.
# Information on Referral to a Registered Dietitian:
Health Link has registered dietitians available to answer nutrition questions. If your patient has a nutrition question about COVID-19, they can call 811 or the Rehabilitation Advice Line (1-833-379-0563), to be referred to a Health Link dietitian.
To learn more about programs and services offered in each zone, visit Nutrition Services.
# Outpatient Caseload Management & Prioritization
Prioritizing caseloads can be challenging, especially when working with post-COVID patients.
The table below is intended to act as a guide for clinicians and leaders with the recognition that eligibility criteria and services vary significantly across the province. Programs may need to reflect on their criteria and service models in order to meet the needs of this unique population.
In addition to the
# Appendix A:
Post COVID Rehabilitation Screening Tool Sample Script: The purpose of this screening tool is to evaluate any functional concerns or lingering symptoms you may be experiencing as a result of COVID-19. This will help us determine what rehabilitation supports you may require moving forward. This survey will take 5-10 minutes to complete. If there are topics you do not wish to comment on or if you are not currently experiencing issues in an area, please indicate N/A. The first part of the survey will focus on your functional abilities and the second part of the survey will look at the symptoms you are currently experiencing.
# Considerations for Completion:
• The purpose of this screening tool is to identify rehabilitation needs of patients who have been diagnosed or were suspected to have COVID-19.
• This tool can be administered at any time during the patient's recovery but it is important to consider the natural progression of the illness when determining rehabilitation needs. Depending on the severity of symptoms & functional impairment, some patients may be better served by starting with a self-management program before being referred to more specialized rehabilitation.
• This tool can be completed by any health care provider (e.g. nursing / allied health / physician)
# Scoring/Evaluation:
Rehabilitation needs should be determined using a combination of the PCFS scale and the symptom checklist. The following is meant to act as a guide but as always, clinicians are encouraged to use their clinical judgement when directing patients to rehabilitation services. Healthcare providers are encouraged to factor in which resources and services are available in each situation to support their patient's unique needs. The majority of patients can self-manage with appropriate resources and supports.
# Resources for ALL patients (PCFS
# 3)…do you have chest pain at rest?"
☐ Absent ☐ Pre-existing: same ☐ Pre-existing: worse ☐ New since COVID-19: Stable/improving ☐ New since COVID-19: worse 4)…do you have chest pain with activity?" ☐ Absent ☐ Pre-existing: same ☐ Pre-existing: worse ☐ New since COVID-19: Stable/improving ☐ New since COVID-19: worse further cardiac investigation.
# Significant Dyspnea
*Consider recent medical clearance, baseline status and/or pre-existing conditions when determining if patient requires further medical investigation.
# Modified MRC Breathlessness Scale
(Select only one option among the five possible choices that describes your breathlessness related to activities.) Score of 4: Refer back to primary care physician for further investigation (i.e. PFT, chest x-ray, etc.).
# Score of ≤ 3:
Proceed with assessment for exertional oxygen desaturation.
# Grade
Degree of breathlessness related to activities If new or worsening to either question, complete the Active Stand Test to screen for orthostatic hypotension (OH) or postural orthostatic tachycardia syndrome (POTS).
During the Active Stand Test, blood pressure (BP) and heart rate (HR) should be measured after 5 minutes in supine, the immediately upon standing and at 2, 5 and 10 minutes.
# •
Orthostatic hypotension (OH) = A fall in systolic blood pressure (SBP) of >20mm Hg or diastolic blood pressure (DBP) > 10 mm Hg from baseline.
• Postural orthostatic tachycardia syndrome (POTS) = Sustained elevation of HR ≥ 30 bpm from baseline or ≥ 120 bpm, in the first 10 minutes of being in an upright position AND orthostatic symptoms. Consider the following questions, children can respond using the Pediatric BORG Scale (range 0-10) with faces. 1. How do you feel after playing tag with your friends? 2. How do you feel after hurrying or walking up a slight hill? 3. How do you feel after walking the length of the school yard? NOTE: the BORG should be completed by the child -based on their perception.
# BORG of 3 or higher on questions 2 and 3
Refer back to primary care physician for further investigation (i.e. PFT, chest x-ray, etc.). Score of less than 3 proceed with assessment for exertional oxygen desaturation.
# Exertional Oxygen Desaturation
*Consider recent medical clearance, baseline status and/or pre-existing conditions when determining if patient requires further medical investigation.
To assess for exertional oxygen desaturation, the PT involved should complete the 6 minute walk test (6MW with children ages 5 years and up). *Submaximal testing should not be completed with patients who screen positive for post exertional symptom exacerbation, consider informal assessment. Terminate testing if exertional oxygen desaturation is observed.
Note: Oxygen saturation (SpO2) should be monitored for the 10 minutes prior to the test, throughout test and for the duration of posttest vital assessment (6 minutes).
# Positive Screen
Refer to primary care physician for further investigation. If medically cleared continue with pacing. If "Yes" to any question, complete the Active Stand Test to screen for orthostatic hypotension (OH) or postural orthostatic tachycardia syndrome (POTS).
# Negative Screen
During the Active Stand Test, blood pressure (BP) and heart rate (HR) should be measured after 5 minutes in supine, the immediately upon standing and at 2, 5 and 10 minutes.
• Orthostatic hypotension (OH) = A fall in systolic blood pressure (SBP) of >20mm Hg or diastolic blood pressure (DBP) > 10 mm Hg from baseline.
• Postural orthostatic tachycardia syndrome (POTS) = Sustained elevation of HR ≥ 40 bpm from baseline or ≥ 120 bpm, in the first 10 minutes of being in an upright position AND orthostatic symptoms.
If patient screens positive for OH, provide education and proceed with symptom titrated activity and exercise.
If patient screens positive for POTS, refer back to primary care physician for further investigation.
Chen, Y. L., Chiou, W. K., Tzeng, Y. T., Lu, C. Y., & Chen, S. C. (2017). A rating of perceived exertion scale using facial expressions for conveying exercise intensity for children and young adults. | None | None |
7567c61422818b7a27e0d12b8f9a6beeb8f9e570 | cma | None | Purpose The purpose of this research was to generate recommendations on strategies to achieve patient-centered care (PCC) for ductal carcinoma in situ (DCIS). Methods Thirty clinicians (surgeons, medical/radiation oncologists, radiologists, nurses, navigators) who manage DCIS and 32 DCIS survivors aged 18 or older were nominated. Forty-six recommendations to support PCC for DCIS were derived from primary research, and rated in a two-round Delphi process from March to June 2018. Results A total of 29 clinicians and 27 women completed Round One, and 28 clinicians and 22 women completed Round Two. The 29 recommendations retained by both women and clinicians reflected the PCC domains of fostering patient-physician relationship (5), exchanging information (5), responding to emotions (1), managing uncertainty (4), making decisions (9), and enabling patient self-management ( 5). An additional 13 recommendations were retained by women only: fostering patient-physician relationship (1), exchanging information (3), responding to emotions (2), making decisions (3), and enabling patient self-management (4). Some recommendations refer to processes (i.e., ask questions about lifestyle or views about risks/outcomes to understand patient preferences); others to tools (i.e., communication aid). Panelists recommended a separate consensus process to refine the language that clinicians use when describing DCIS. Conclusions This is the first study to generate guidance on how to achieve PCC for DCIS. Organizations that deliver or oversee health care can use these recommendations on PCC for DCIS to plan, evaluate, or improve services. Ongoing research is needed to develop communication tools, and establish labels and language for DCIS that optimize communication.# Introduction
Approximately 15-25% of mammographically detected lesions are ductal carcinoma in situ (DCIS) . The incidence of DCIS is increasing globally concomitant with rising mammography rates . DCIS is a complex premalignant disease that includes a spectrum of abnormal cell types confined to the breast ducts with variable natural history, and risk of progression and recurrence . Approximately 20% of cases will progress to invasive disease so most women with DCIS will never develop breast cancer and have a favorable prognosis, although DCIS may be more aggressive in women less than 50 years of age and African American women . The 20-year breast cancer-specific mortality is 3.3% . However, tests to determine which women with DCIS will develop invasive disease remain in development , and trials to determine the clinical effectiveness and patient-derived endpoints of active surveillance for DCIS are in progress . Thus, the standard of care for most women is to undergo lumpectomy, in part to confirm a DCIS diagnosis, with consideration of adjuvant radiation and hormone therapy, or mastectomy, which may entail short-and long-term treatment-related complications .
Management of DCIS is challenging for women and their clinicians. Physicians surveyed in England and the United States indicated that explaining DCIS and justifying treatment to women were difficult . Other studies found variation in the language clinicians used to describe DCIS, with many referring to it as cancer, and variation in treatment patterns . Women with DCIS worldwide have reported suboptimal communication, poor health care experiences, and adverse health outcomes . In these studies, most women felt they were given unclear and conflicting information about whether they had cancer; were unaware of treatment options and implications; had inaccurate perceptions of the risk of invasive cancer, metastasis, recurrence, and survival; and experienced similar anxiety and depression as women with invasive breast cancer. Despite the challenges reported by patients and physicians, our scoping review of 51 studies published from 1997 to 2016 identified only two studies that developed interventions to support discussions about DCIS .
There is an urgent, widespread need to improve patient-clinician communication about DCIS. Patientcentered care (PCC) offers an approach for doing so. PCC is ideally suited for circumstances when there is limited evidence to support decision-making, when treatment outcomes are difficult to predict or may be adverse, or as is the case for DCIS, when two or more treatment options are suitable . PCC addresses patient values and preferences through information sharing, empathy, empowerment, and health promotion . McCormack et al. reviewed literature, observed medical encounters, interviewed patients, and engaged a 13-member expert panel to generate a PCC framework specific to cancer patients of 31 sub-domains within six interdependent domains: fostering patient-clinician relationships, exchanging information, addressing patient emotions, managing uncertainty, making decisions, and enabling patient self-management . PCC is a crucial element of high quality care because it has improved patient (knowledge, relationship with providers, service experience, satisfaction, treatment adherence, quality of life; and reduced anxiety, missed work, readmission rates, and mortality) and health system (appropriate health care utilization, cost-effective service delivery) outcomes .
No prior research has established guidance on PCC for DCIS. Lo et al. and Robinson et al. employed qualitative methods to explore the information needs of women diagnosed with DCIS; however, those studies did not capture the multidimensional nature of PCC or offer insight on the various strategies to support PCC for DCIS . The purpose of this research was to generate national consensus recommendations on strategies required to achieve PCC for DCIS. Broad adoption of those recommendations could lead to improved experiences and outcomes for women with DCIS and their clinicians.
# Methods
# Approach
The Delphi technique, a widely used approach for establishing expert consensus, was used to generate recommendations for strategies that support PCC for DCIS . This approach was chosen because we identified little evidence on strategies to achieve PCC for DCIS , necessitating a consensus approach. Potential recommendations were derived from our prior research including a review of published literature , and interviews with women with DCIS and clinicians who manage DCIS (to be published elsewhere), then rated in an online questionnaire by an expert panel through two rounds. Ratings are anonymous so that panelists are not unduly influenced by others. Conduct and reporting of this research complied with recommendations for the conduct of online surveys , and the Conducting and Reporting of Delphi Studies (CREDES) criteria to enhance rigor . A 9-member research team including health services researchers (ARG, RU) and breast cancer surgeons (FCW, NJLH, GG, LH, PM, MLQ, RW) provided input at all stages, further enhancing rigor. The University Health Network Research Ethics Board reviewed and approved this study.
# Expert panel sampling and recruitment
Delphi panels typically include 8 to 12 members ; however, research shows an increase in Delphi reliability with increasing panel size . We aimed to establish a 30-member clinician panel to achieve multidisciplinary and national representation, more heavily weighted with surgeons since the standard of treatment is surgery . We asked research team members based in different Canadian provinces to nominate surgeons, oncologists (medical, radiation), radiologists, nurses, and patient navigators specializing in breast cancer to achieve national representation. We did not include general practitioners representing primary care because diagnosis and treatment are most often communicated to women with DCIS by specialists. Nominated clinicians were contacted by email on November 29, 2017 with a brief description of the purpose, process, timing and expected commitment, and were asked to confirm their participation. We also invited women to participate since they could provide first-hand input on PCC for DCIS. Women aged 18 years and older treated for DCIS within the past 2 years from 5 provinces who had participated in prior focus groups were sent an email inviting them to complete the survey. We directly contacted women at 2 of 5 sites; at the remaining 3 sites, due to local research ethics board requirements, a site coordinator communicated with women.
# Survey development
Recommendations to be rated by panelists were derived from a prior scoping review of research published from 1997 to 2016 on DCIS communication experiences, needs, and interventions among DCIS patients or clinicians ; and qualitative interviews with 46 clinicians and focus groups involving 35 women with DCIS from across Canada (to be published). From results of the scoping review, interviews, and focus groups, ARG and two research assistants independently extracted facilitators and barriers, and suggestions to improve patient-clinician discussions about DCIS. Those were worded as recommendations, and organized in a table according to the McCormack et al. six-domain framework of PCC: fostering clinician-patient relationships, exchanging information, addressing patient emotions, managing uncertainty, making decisions, and enabling patient self-management . This PCC framework was chosen because it was specific to cancer, included the perspectives of women and clinicians, and had been rigorously developed. The table also displayed the source of each recommendation as one or more of scoping review, clinician interviews, or patient focus groups. The recommendation source document was reviewed by the other 8 members of the research team who offered suggestions for refining the wording of recommendations.
# Data collection and analysis
Recommendations were formatted as a Round One survey administered online using Google Forms. The survey prompted respondents to rate each recommendation on a 7-point Likert scale where 1 was strongly disagree and 7 was strongly agree. The survey was comprised of 46 recommendations on 6 web pages corresponding to McCormack et al. PCC categories . Free text options were included for comments on the wording or content of recommendations, and to suggest additional recommendations not already included in the survey. The survey was reviewed by the research team who offered suggestions to refine the wording and clarify of survey instructions, and to identify errors in spelling or survey functionality. An email with a link to the same survey and the recommendation source document was sent to clinician panelists on March 7, 2018, and women with DCIS panelists between April 5, 2018 and May 2, 2018. The survey of women with DCIS was delayed pending completion of focus groups at all five sites. We sent a reminder email at 2 and 4 weeks.
We calculated Likert scale response frequencies for each recommendation, and summarized comments and newly suggested recommendations. Standard Delphi protocol suggests that two rounds of rating with agreement by two-thirds of panelists will prevent respondent fatigue and drop-out . We conducted two rounds of rating; however, to yield unequivocal recommendations, more stringent consensus criteria were applied. Strong consensus for inclusion was defined as 80% or more of panelists agreed or strongly agreed by choosing 6 or 7, or 85% or more chose 5 or 6 or 7; strong consensus for exclusion was defined as 80% or more chose 1 or 2 or 3 or 4; with remaining recommendations categorized as unclear consensus.
The Round One summary report of anonymized results, including Likert rating and comments about the recommendation or its wording, was circulated to panelists by email with a link to the Round Two survey formatted similarly to the Round One survey for rating of recommendations that had not yet achieved consensus for inclusion or exclusion. The email was sent to clinician panelists on April 5, 2018 and to women with DCIS panelists on June 11, 2018, followed by a reminder at 2 and 4 weeks. We analyzed and summarized responses in a manner similar to Round One. Ultimately, items were categorized as recommendations if retained by both women and clinicians, additional considerations if retained by women only, and exclusions if they did not achieve consensus among either women or clinicians.
# Results
# Respondents
Of 49 clinician nominees, 31 accepted the invitation; a total of 32 women were invited to complete the survey.
# Initial recommendations
Supplementary File 1 presents all recommendations to support PCC for DCIS that emerged from prior research (n = 46) organized by PCC domains: fostering patient-physician relationship (n = 6), exchanging information (n = 11), responding to patient emotions (n = 3), managing uncertainty (n = 4), making decisions (n = 13), and enabling patient self-management (n = 9). The majority of recommendations were derived from clinician interviews (40, 87.0%) followed by patient focus groups (33, 71.7%) and the scoping review (10, 21.7%). A total of 8 (17.4%) recommendations were common to all three sources; 19 (41.3%) were common to both patients and clinicians. More recommendations were derived from clinicians for exchanging information (clinicians 11, patients 7), managing uncertainty (clinicians 4, patients 2), and making decisions (clinicians 13, patients 9). More recommendations were derived from patients for responding to emotions (patients 3, clinicians 1) and enabling self-management (patients 8, clinicians 7).
# Delphi results
Supplementary File 2 presents the rating results of Round One and Round Two. Figure 1 shows the number of recommendations included and excluded in each Round. In Round One, 27 of 46 recommendations were retained by all panelists. The Round Two survey included 20 recommendations: 13 retained by women only and 6 that did not achieve consensus in Round One, plus 1 newly suggested recommendation. Table 2 shows the final results. Twentynine recommendations were retained by both women and clinicians in the PCC domains of fostering patient-physician relationship (5), exchanging information (5), responding to emotions (1), managing uncertainty (4), making decisions (9), and enabling patient self-management ( 5). An additional 13 recommendations were retained by women only: fostering patient-physician relationship (1), exchanging information (3), responding to emotions (2), making decisions (3), and enabling patient self-management (4). A total of 5 recommendations did not achieve consensus among women or clinicians and were excluded.
# Future implications
# Discussion
This research generated national consensus recommendations on strategies to achieve PCC for DCIS, including 29 recommended by both women and clinicians, and 13 additional considerations endorsed by women only. Many recommendations, organized in the PCC domains of fostering a patient-physician relationship, exchanging information, responding to emotions, managing uncertainty, making decisions, and enabling patient self-management, refer to processes during the clinical consultation. Other recommendations refer to informational material or tools that could be used during or after consultation. Despite the benefits associated with PCC, and insight on the elements of PCC and how to achieve it, many patients do not experience PCC. A national survey in the United States in 2011 showed that, among 2718 responding adults aged 40 or greater with ten common medical conditions, there was considerable variation in whether patients experienced PCC . Suboptimal PCC was reported by half of 1794 American cancer survivors responding in 2013 to a national survey . A survey of 30,849 patients affiliated with 56 primary care sites in one Veterans Health Administration Region before and after medical home (model of coordinated, teambased primary care) implementation between 2010 and 2012 found no improvement in PCC . Therefore, insight is needed on how to achieve PCC. This may be particularly important for women due to gendered disparities in access to and quality of care. In 2016, a Commonwealth Fund national survey revealed that women were less likely than men to have medical needs addressed, access to a specialist, or report good patient-provider communication . A meta-review (28 reviews 2011-2017) identified patient (i.e., tailoring care to values and preferences, providing selfmanagement information, offering emotional support) and professional (i.e., education and training) interventions to achieve PCC . However, that review pertained to patients with various medical conditions. Our study was unique in that it generated insight on how to achieve PCC specifically for DCIS. These recommendations for PCC for DCIS supplement and are complementary to clinical quality indicators for DCIS diagnosis, radiology, treatment, and pathology developed by modified Delphi technique . Together, the clinical quality indicators and PCC recommendations can be used by organizations that deliver or oversee health care to plan services, or evaluate and improve services.
A key next step recommended by panelists was a separate consensus process to establish language that clinicians should use when describing DCIS, although consensus was not achieved on whether to refer to DCIS as something other than cancer. Research has found that significantly more women chose surgery when DCIS was referred to as noninvasive cancer compared with breast lesion or abnormal cells, women are increasingly choosing mastectomy and bilateral mastectomy rather than lumpectomy even though these treatments do not improve breast cancer-specific survival, and clinicians may be driven to over-diagnose and over-treat DCIS due to fear of litigation or missing disease, and feeling compelled to do something rather than nothing . Hence, changing the label for DCIS may be a strategy that avoids over-treatment or, until ongoing trials demonstrate the clinical effectiveness of active surveillance for DCIS , at the very least reduces confusion and anxiety among women diagnosed with DCIS, and concern about explaining DCIS among clinicians. Precedence for changing labels has been established for bladder, cervical, and thyroid cancers .
Another important next step recommended by panelists was to develop resources that support communication, reduce confusion and anxiety, and improve well-being following treatment. These included information for patients on DCIS pathobiology, natural history, treatment options, outcomes, and aftercare; a communication tool to support patient-clinician discussions; a patient decision aid; a Conversations about DCIS should include information and/or statistics about the risk of recurrence, metastasis, progression to invasive disease, and prognosis The risk of recurrence or progression with and without additional therapy should be quantified and presented in absolute terms over a 10-or 20-year time frame Clinicians should mention the possibility of invasive disease that biopsy may not detect when there is a reasonable possibility of sampling error Surgeons and oncologists should work closely together so that each conveys to the same patient consistent information about treatment options and risks "prescription" template detailing the clinical follow-up plan; and a web site listing credible online DCIS resources. We found two DCIS decision aids: one developed in Australia in 2010 for patients although it is not known if the content reflects all aspects of PCC considered important by women , and one developed in the United States specifically for use by clinicians as a risk calculator . However, while decision aids support patient engagement in their own care , numerous patient, clinician, and system-level barriers limit the implementation and impact of decision aids . Therefore, ongoing research is needed to develop these recommended resources and test their impact on PCC and other outcomes. This study featured both strengths and limitations. Recommendations reflected the views of multidisciplinary clinicians and women treated for DCIS representing different geographic regions from across Canada. Recommendations were evidence-and consensus-based because they were Clinicians should recommend a treatment option but explain why the option is best suited to patient and tumor characteristics Clinicians should ask questions about lifestyle and views about risks/ outcomes to gain a better understanding about patient preferences Clinicians and patients should work together to discuss the merits of treatment options and jointly make a decision about the best option but ultimately it is the patient's decision to make Clinicians should give patients a week to make a treatment decision Surgeons should refer patients before surgery for consultation with a radiation oncologist if considering lumpectomy, and offer referral to a plastic surgeon if considering mastectomy or lumpectomy Clinicians should explain that, even though patients may want mastectomy or prophylactic mastectomy, it may not be necessary Conversations about treatment options should include information about possible side effects that may occur after treatment such as worsened body image, anxiety, or depression A guideline of DCIS treatment options should be developed to facilitate patient-clinician discussions Educational resources should be made available for DCIS patients considering reconstruction after mastectomy Clinicians should explain that, even though DCIS is not cancer, treatment is necessary to achieve a bigger margin and prevent progression to invasive cancer if applicable to patient (women only) Clinicians may employ a decision aid when discussing treatment options with patients (women only) Regional breast centers should be developed that provide patients with access to various treatment options and supportive care resources so that treatment decisions are not based on avoiding travel time and associated costs (women only) Enabling patient self-management Setting expectations for follow-up; preparing for self-managing health and well-being
Patients should be aware of their follow-up plan before leaving the care of their surgeon Clinicians should provide patients with pamphlets on routine aftercare including exercise to aid in recovery Websites/external resources should offered to patients who seek more information on DCIS Clinicians should encourage patients to seek emotional support if needed at any point post-DCIS diagnosis and treatment A web site should be developed that lists credible online resources and organizations from which patients can acquire information or support DCIS-specific resources (i.e., pamphlets, support groups) should be developed and offered to patients (women only) Patients should be offered the opportunity to be linked with a patient navigator to provide information and education about DCIS (women only) A card with contact information for patient navigators (and other supportive resources), if available, should be provided to patients to address further questions (women only) Survivorship programs that accept or are specific to DCIS should be developed and offered (women only) drawn from a scoping review , and primary research involving interviews with clinicians and focus groups with women (to be published elsewhere). We optimized the Delphi process by using a large panel who were identified by nomination , and by using only two rounds to prevent respondent fatigue , and thus achieved relatively high response rates. We complied with research and reporting standards for online surveys , and Delphi studies . A 9-member research team reviewed recommendations at all stages, further enhancing rigor. A few issues may limit the interpretation and use of these findings. We did not discuss findings among panelists as is done for the modified Delphi process , which may have altered the number or nature of final recommendations. Participating women were volunteers, and their views on PCC may differ from other patients. Panelists may reflect the views of Canadian women with DCIS and clinicians and/or the characteristics of Canada's publicly funded health care system, so recommendations may not apply elsewhere. However, globally women have reported dissatisfaction and confusion with PCC for DCIS , and clinicians also reported that discussing DCIS with women is challenging , so these recommendations to support PCC for DCIS are likely broadly relevant.
In conclusion, a national consensus process involving women with DCIS and multidisciplinary clinicians who specialize in breast cancer generated recommendations for improving PCC for DCIS including the need for communication tools, and a separate consensus process to establish labels and language that clearly and accurately describe DCIS. | Purpose The purpose of this research was to generate recommendations on strategies to achieve patient-centered care (PCC) for ductal carcinoma in situ (DCIS). Methods Thirty clinicians (surgeons, medical/radiation oncologists, radiologists, nurses, navigators) who manage DCIS and 32 DCIS survivors aged 18 or older were nominated. Forty-six recommendations to support PCC for DCIS were derived from primary research, and rated in a two-round Delphi process from March to June 2018. Results A total of 29 clinicians and 27 women completed Round One, and 28 clinicians and 22 women completed Round Two. The 29 recommendations retained by both women and clinicians reflected the PCC domains of fostering patient-physician relationship (5), exchanging information (5), responding to emotions (1), managing uncertainty (4), making decisions (9), and enabling patient self-management ( 5). An additional 13 recommendations were retained by women only: fostering patient-physician relationship (1), exchanging information (3), responding to emotions (2), making decisions (3), and enabling patient self-management (4). Some recommendations refer to processes (i.e., ask questions about lifestyle or views about risks/outcomes to understand patient preferences); others to tools (i.e., communication aid). Panelists recommended a separate consensus process to refine the language that clinicians use when describing DCIS. Conclusions This is the first study to generate guidance on how to achieve PCC for DCIS. Organizations that deliver or oversee health care can use these recommendations on PCC for DCIS to plan, evaluate, or improve services. Ongoing research is needed to develop communication tools, and establish labels and language for DCIS that optimize communication.# Introduction
Approximately 15-25% of mammographically detected lesions are ductal carcinoma in situ (DCIS) [1]. The incidence of DCIS is increasing globally concomitant with rising mammography rates [1,2]. DCIS is a complex premalignant disease that includes a spectrum of abnormal cell types confined to the breast ducts with variable natural history, and risk of progression and recurrence [1]. Approximately 20% of cases will progress to invasive disease so most women with DCIS will never develop breast cancer and have a favorable prognosis, although DCIS may be more aggressive in women less than 50 years of age and African American women [2]. The 20-year breast cancer-specific mortality is 3.3% [2]. However, tests to determine which women with DCIS will develop invasive disease remain in development [3], and trials to determine the clinical effectiveness and patient-derived endpoints of active surveillance for DCIS are in progress [4][5][6]. Thus, the standard of care for most women is to undergo lumpectomy, in part to confirm a DCIS diagnosis, with consideration of adjuvant radiation and hormone therapy, or mastectomy, which may entail short-and long-term treatment-related complications [7,8].
Management of DCIS is challenging for women and their clinicians. Physicians surveyed in England and the United States indicated that explaining DCIS and justifying treatment to women were difficult [9,10]. Other studies found variation in the language clinicians used to describe DCIS, with many referring to it as cancer, and variation in treatment patterns [11,12]. Women with DCIS worldwide have reported suboptimal communication, poor health care experiences, and adverse health outcomes [13][14][15][16][17]. In these studies, most women felt they were given unclear and conflicting information about whether they had cancer; were unaware of treatment options and implications; had inaccurate perceptions of the risk of invasive cancer, metastasis, recurrence, and survival; and experienced similar anxiety and depression as women with invasive breast cancer. Despite the challenges reported by patients and physicians, our scoping review of 51 studies published from 1997 to 2016 identified only two studies that developed interventions to support discussions about DCIS [18].
There is an urgent, widespread need to improve patient-clinician communication about DCIS. Patientcentered care (PCC) offers an approach for doing so. PCC is ideally suited for circumstances when there is limited evidence to support decision-making, when treatment outcomes are difficult to predict or may be adverse, or as is the case for DCIS, when two or more treatment options are suitable [19]. PCC addresses patient values and preferences through information sharing, empathy, empowerment, and health promotion [20][21][22][23][24]. McCormack et al. reviewed literature, observed medical encounters, interviewed patients, and engaged a 13-member expert panel to generate a PCC framework specific to cancer patients of 31 sub-domains within six interdependent domains: fostering patient-clinician relationships, exchanging information, addressing patient emotions, managing uncertainty, making decisions, and enabling patient self-management [25]. PCC is a crucial element of high quality care because it has improved patient (knowledge, relationship with providers, service experience, satisfaction, treatment adherence, quality of life; and reduced anxiety, missed work, readmission rates, and mortality) and health system (appropriate health care utilization, cost-effective service delivery) outcomes [26][27][28][29].
No prior research has established guidance on PCC for DCIS. Lo et al. and Robinson et al. employed qualitative methods to explore the information needs of women diagnosed with DCIS; however, those studies did not capture the multidimensional nature of PCC or offer insight on the various strategies to support PCC for DCIS [30,31]. The purpose of this research was to generate national consensus recommendations on strategies required to achieve PCC for DCIS. Broad adoption of those recommendations could lead to improved experiences and outcomes for women with DCIS and their clinicians.
# Methods
# Approach
The Delphi technique, a widely used approach for establishing expert consensus, was used to generate recommendations for strategies that support PCC for DCIS [32][33][34]. This approach was chosen because we identified little evidence on strategies to achieve PCC for DCIS [18], necessitating a consensus approach. Potential recommendations were derived from our prior research including a review of published literature [18], and interviews with women with DCIS and clinicians who manage DCIS (to be published elsewhere), then rated in an online questionnaire by an expert panel through two rounds. Ratings are anonymous so that panelists are not unduly influenced by others. Conduct and reporting of this research complied with recommendations for the conduct of online surveys [35], and the Conducting and Reporting of Delphi Studies (CREDES) criteria to enhance rigor [36]. A 9-member research team including health services researchers (ARG, RU) and breast cancer surgeons (FCW, NJLH, GG, LH, PM, MLQ, RW) provided input at all stages, further enhancing rigor. The University Health Network Research Ethics Board reviewed and approved this study.
# Expert panel sampling and recruitment
Delphi panels typically include 8 to 12 members [32][33][34]; however, research shows an increase in Delphi reliability with increasing panel size [37]. We aimed to establish a 30-member clinician panel to achieve multidisciplinary and national representation, more heavily weighted with surgeons since the standard of treatment is surgery [7,8]. We asked research team members based in different Canadian provinces to nominate surgeons, oncologists (medical, radiation), radiologists, nurses, and patient navigators specializing in breast cancer to achieve national representation. We did not include general practitioners representing primary care because diagnosis and treatment are most often communicated to women with DCIS by specialists. Nominated clinicians were contacted by email on November 29, 2017 with a brief description of the purpose, process, timing and expected commitment, and were asked to confirm their participation. We also invited women to participate since they could provide first-hand input on PCC for DCIS. Women aged 18 years and older treated for DCIS within the past 2 years from 5 provinces who had participated in prior focus groups were sent an email inviting them to complete the survey. We directly contacted women at 2 of 5 sites; at the remaining 3 sites, due to local research ethics board requirements, a site coordinator communicated with women.
# Survey development
Recommendations to be rated by panelists were derived from a prior scoping review of research published from 1997 to 2016 on DCIS communication experiences, needs, and interventions among DCIS patients or clinicians [18]; and qualitative interviews with 46 clinicians and focus groups involving 35 women with DCIS from across Canada (to be published). From results of the scoping review, interviews, and focus groups, ARG and two research assistants independently extracted facilitators and barriers, and suggestions to improve patient-clinician discussions about DCIS. Those were worded as recommendations, and organized in a table according to the McCormack et al. six-domain framework of PCC: fostering clinician-patient relationships, exchanging information, addressing patient emotions, managing uncertainty, making decisions, and enabling patient self-management [25]. This PCC framework was chosen because it was specific to cancer, included the perspectives of women and clinicians, and had been rigorously developed. The table also displayed the source of each recommendation as one or more of scoping review, clinician interviews, or patient focus groups. The recommendation source document was reviewed by the other 8 members of the research team who offered suggestions for refining the wording of recommendations.
# Data collection and analysis
Recommendations were formatted as a Round One survey administered online using Google Forms. The survey prompted respondents to rate each recommendation on a 7-point Likert scale where 1 was strongly disagree and 7 was strongly agree. The survey was comprised of 46 recommendations on 6 web pages corresponding to McCormack et al. PCC categories [25]. Free text options were included for comments on the wording or content of recommendations, and to suggest additional recommendations not already included in the survey. The survey was reviewed by the research team who offered suggestions to refine the wording and clarify of survey instructions, and to identify errors in spelling or survey functionality. An email with a link to the same survey and the recommendation source document was sent to clinician panelists on March 7, 2018, and women with DCIS panelists between April 5, 2018 and May 2, 2018. The survey of women with DCIS was delayed pending completion of focus groups at all five sites. We sent a reminder email at 2 and 4 weeks.
We calculated Likert scale response frequencies for each recommendation, and summarized comments and newly suggested recommendations. Standard Delphi protocol suggests that two rounds of rating with agreement by two-thirds of panelists will prevent respondent fatigue and drop-out [32][33][34]. We conducted two rounds of rating; however, to yield unequivocal recommendations, more stringent consensus criteria were applied. Strong consensus for inclusion was defined as 80% or more of panelists agreed or strongly agreed by choosing 6 or 7, or 85% or more chose 5 or 6 or 7; strong consensus for exclusion was defined as 80% or more chose 1 or 2 or 3 or 4; with remaining recommendations categorized as unclear consensus.
The Round One summary report of anonymized results, including Likert rating and comments about the recommendation or its wording, was circulated to panelists by email with a link to the Round Two survey formatted similarly to the Round One survey for rating of recommendations that had not yet achieved consensus for inclusion or exclusion. The email was sent to clinician panelists on April 5, 2018 and to women with DCIS panelists on June 11, 2018, followed by a reminder at 2 and 4 weeks. We analyzed and summarized responses in a manner similar to Round One. Ultimately, items were categorized as recommendations if retained by both women and clinicians, additional considerations if retained by women only, and exclusions if they did not achieve consensus among either women or clinicians.
# Results
# Respondents
Of 49 clinician nominees, 31 accepted the invitation; a total of 32 women were invited to complete the survey.
# Initial recommendations
Supplementary File 1 presents all recommendations to support PCC for DCIS that emerged from prior research (n = 46) organized by PCC domains: fostering patient-physician relationship (n = 6), exchanging information (n = 11), responding to patient emotions (n = 3), managing uncertainty (n = 4), making decisions (n = 13), and enabling patient self-management (n = 9). The majority of recommendations were derived from clinician interviews (40, 87.0%) followed by patient focus groups (33, 71.7%) and the scoping review (10, 21.7%). A total of 8 (17.4%) recommendations were common to all three sources; 19 (41.3%) were common to both patients and clinicians. More recommendations were derived from clinicians for exchanging information (clinicians 11, patients 7), managing uncertainty (clinicians 4, patients 2), and making decisions (clinicians 13, patients 9). More recommendations were derived from patients for responding to emotions (patients 3, clinicians 1) and enabling self-management (patients 8, clinicians 7).
# Delphi results
Supplementary File 2 presents the rating results of Round One and Round Two. Figure 1 shows the number of recommendations included and excluded in each Round. In Round One, 27 of 46 recommendations were retained by all panelists. The Round Two survey included 20 recommendations: 13 retained by women only and 6 that did not achieve consensus in Round One, plus 1 newly suggested recommendation. Table 2 shows the final results. Twentynine recommendations were retained by both women and clinicians in the PCC domains of fostering patient-physician relationship (5), exchanging information (5), responding to emotions (1), managing uncertainty (4), making decisions (9), and enabling patient self-management ( 5). An additional 13 recommendations were retained by women only: fostering patient-physician relationship (1), exchanging information (3), responding to emotions (2), making decisions (3), and enabling patient self-management (4). A total of 5 recommendations did not achieve consensus among women or clinicians and were excluded.
# Future implications
# Discussion
This research generated national consensus recommendations on strategies to achieve PCC for DCIS, including 29 recommended by both women and clinicians, and 13 additional considerations endorsed by women only. Many recommendations, organized in the PCC domains of fostering a patient-physician relationship, exchanging information, responding to emotions, managing uncertainty, making decisions, and enabling patient self-management, refer to processes during the clinical consultation. Other recommendations refer to informational material or tools that could be used during or after consultation. Despite the benefits associated with PCC, and insight on the elements of PCC and how to achieve it, many patients do not experience PCC. A national survey in the United States in 2011 showed that, among 2718 responding adults aged 40 or greater with ten common medical conditions, there was considerable variation in whether patients experienced PCC [38]. Suboptimal PCC was reported by half of 1794 American cancer survivors responding in 2013 to a national survey [39]. A survey of 30,849 patients affiliated with 56 primary care sites in one Veterans Health Administration Region before and after medical home (model of coordinated, teambased primary care) implementation between 2010 and 2012 found no improvement in PCC [40]. Therefore, insight is needed on how to achieve PCC. This may be particularly important for women due to gendered disparities in access to and quality of care. In 2016, a Commonwealth Fund national survey revealed that women were less likely than men to have medical needs addressed, access to a specialist, or report good patient-provider communication [41,42]. A meta-review (28 reviews 2011-2017) identified patient (i.e., tailoring care to values and preferences, providing selfmanagement information, offering emotional support) and professional (i.e., education and training) interventions to achieve PCC [43]. However, that review pertained to patients with various medical conditions. Our study was unique in that it generated insight on how to achieve PCC specifically for DCIS. These recommendations for PCC for DCIS supplement and are complementary to clinical quality indicators for DCIS diagnosis, radiology, treatment, and pathology developed by modified Delphi technique [44]. Together, the clinical quality indicators and PCC recommendations can be used by organizations that deliver or oversee health care to plan services, or evaluate and improve services.
A key next step recommended by panelists was a separate consensus process to establish language that clinicians should use when describing DCIS, although consensus was not achieved on whether to refer to DCIS as something other than cancer. Research has found that significantly more women chose surgery when DCIS was referred to as noninvasive cancer compared with breast lesion or abnormal cells, women are increasingly choosing mastectomy and bilateral mastectomy rather than lumpectomy even though these treatments do not improve breast cancer-specific survival, and clinicians may be driven to over-diagnose and over-treat DCIS due to fear of litigation or missing disease, and feeling compelled to do something rather than nothing [45,46]. Hence, changing the label for DCIS may be a strategy that avoids over-treatment or, until ongoing trials demonstrate the clinical effectiveness of active surveillance for DCIS [4][5][6], at the very least reduces confusion and anxiety among women diagnosed with DCIS, and concern about explaining DCIS among clinicians. Precedence for changing labels has been established for bladder, cervical, and thyroid cancers [46].
Another important next step recommended by panelists was to develop resources that support communication, reduce confusion and anxiety, and improve well-being following treatment. These included information for patients on DCIS pathobiology, natural history, treatment options, outcomes, and aftercare; a communication tool to support patient-clinician discussions; a patient decision aid; a Conversations about DCIS should include information and/or statistics about the risk of recurrence, metastasis, progression to invasive disease, and prognosis The risk of recurrence or progression with and without additional therapy should be quantified and presented in absolute terms over a 10-or 20-year time frame Clinicians should mention the possibility of invasive disease that biopsy may not detect when there is a reasonable possibility of sampling error Surgeons and oncologists should work closely together so that each conveys to the same patient consistent information about treatment options and risks "prescription" template detailing the clinical follow-up plan; and a web site listing credible online DCIS resources. We found two DCIS decision aids: one developed in Australia in 2010 for patients although it is not known if the content reflects all aspects of PCC considered important by women [47], and one developed in the United States specifically for use by clinicians as a risk calculator [48]. However, while decision aids support patient engagement in their own care [49], numerous patient, clinician, and system-level barriers limit the implementation and impact of decision aids [50]. Therefore, ongoing research is needed to develop these recommended resources and test their impact on PCC and other outcomes. This study featured both strengths and limitations. Recommendations reflected the views of multidisciplinary clinicians and women treated for DCIS representing different geographic regions from across Canada. Recommendations were evidence-and consensus-based because they were Clinicians should recommend a treatment option but explain why the option is best suited to patient and tumor characteristics Clinicians should ask questions about lifestyle and views about risks/ outcomes to gain a better understanding about patient preferences Clinicians and patients should work together to discuss the merits of treatment options and jointly make a decision about the best option but ultimately it is the patient's decision to make Clinicians should give patients a week to make a treatment decision Surgeons should refer patients before surgery for consultation with a radiation oncologist if considering lumpectomy, and offer referral to a plastic surgeon if considering mastectomy or lumpectomy Clinicians should explain that, even though patients may want mastectomy or prophylactic mastectomy, it may not be necessary Conversations about treatment options should include information about possible side effects that may occur after treatment such as worsened body image, anxiety, or depression A guideline of DCIS treatment options should be developed to facilitate patient-clinician discussions Educational resources should be made available for DCIS patients considering reconstruction after mastectomy Clinicians should explain that, even though DCIS is not cancer, treatment is necessary to achieve a bigger margin and prevent progression to invasive cancer if applicable to patient (women only) Clinicians may employ a decision aid when discussing treatment options with patients (women only) Regional breast centers should be developed that provide patients with access to various treatment options and supportive care resources so that treatment decisions are not based on avoiding travel time and associated costs (women only) Enabling patient self-management Setting expectations for follow-up; preparing for self-managing health and well-being
Patients should be aware of their follow-up plan before leaving the care of their surgeon Clinicians should provide patients with pamphlets on routine aftercare including exercise to aid in recovery Websites/external resources should offered to patients who seek more information on DCIS Clinicians should encourage patients to seek emotional support if needed at any point post-DCIS diagnosis and treatment A web site should be developed that lists credible online resources and organizations from which patients can acquire information or support DCIS-specific resources (i.e., pamphlets, support groups) should be developed and offered to patients (women only) Patients should be offered the opportunity to be linked with a patient navigator to provide information and education about DCIS (women only) A card with contact information for patient navigators (and other supportive resources), if available, should be provided to patients to address further questions (women only) Survivorship programs that accept or are specific to DCIS should be developed and offered (women only) drawn from a scoping review [18], and primary research involving interviews with clinicians and focus groups with women (to be published elsewhere). We optimized the Delphi process by using a large panel who were identified by nomination [37], and by using only two rounds to prevent respondent fatigue [32][33][34], and thus achieved relatively high response rates. We complied with research and reporting standards for online surveys [35], and Delphi studies [36]. A 9-member research team reviewed recommendations at all stages, further enhancing rigor. A few issues may limit the interpretation and use of these findings. We did not discuss findings among panelists as is done for the modified Delphi process [32][33][34], which may have altered the number or nature of final recommendations. Participating women were volunteers, and their views on PCC may differ from other patients. Panelists may reflect the views of Canadian women with DCIS and clinicians and/or the characteristics of Canada's publicly funded health care system, so recommendations may not apply elsewhere. However, globally women have reported dissatisfaction and confusion with PCC for DCIS [13][14][15][16][17], and clinicians also reported that discussing DCIS with women is challenging [11,12], so these recommendations to support PCC for DCIS are likely broadly relevant.
In conclusion, a national consensus process involving women with DCIS and multidisciplinary clinicians who specialize in breast cancer generated recommendations for improving PCC for DCIS including the need for communication tools, and a separate consensus process to establish labels and language that clearly and accurately describe DCIS.
# Acknowledgements
The authors thank Claire Kim and Bryanna Nyhof for assistance in collecting data for this study.
#
Funding This study was funded by the Canadian Cancer Society.
# Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
# Ethical approval This research was approved by the University Health Network Research Ethics Board.
OpenAccess This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. | None | None |
8050b47feb2c319e52fbe63e2d72ffa57250e556 | cma | None | Special considerations for issues related to experiencing past 2SLGBTQ+ discrimination . . .# Table of Contents Introduction
The ability to render accessible, continuous, patientcentred, collaborative, and culturally competent care for Veterans (former members of the military) is important for family physicians and other primary care providers, especially as many may already have Veteran patients in their practice. Caring for Veterans who kept our nation secure through national service can be a rewarding and an enriching experience for family physicians. Additionally, some family physicians/ primary care teams may be uncertain about how best to manage Veterans' care 1 and would benefit from guidance and decision-making tools that can help them better serve Veterans and their health needs.
# Purpose of the Guide
The purpose of this guide is to highlight special considerations for family physicians and other primary care providers in caring for the Veteran population, including contextualizing this information within the College of Family Physicians of Canada TM (CFPC)'s Patient's Medical Home (PMH) 2 vision for the future of family practice in Canada. Family physicians have an essential role in caring for Veterans and in facilitating supportive cooperation between care providers to ensure Veterans receive the best care possible. This guide will share common themes to address the health needs of Veteran patients, providing key factors and context, practical tips, and rewards related to caring for Veterans.
While there are a variety of resources available to Veterans to enhance their health and other aspects of their well-being, there are many different organizations dedicated to Veterans' health across Canada, and the Veterans Affairs Canada (VAC) system can be complicated to navigate. The resources shared in this guide are intended to help primary care providers connect their Veteran patients to relevant resources and allow them to establish and maintain relationships with other care providers for optimal outcomes and follow-up.
# Background
The population of living Veterans in Canada is approximately 629,300, 3 representing almost one in 30 of the adult population in Canada. Former members of the military may have participated in a variety of operations throughout their military career, either abroad or within Canada, including wartime service or special duty area service, humanitarian relief and disaster response, and search and rescue. 4,5 The increase in Canadian military operations during and after the first Persian Gulf War in 1990 has resulted in family physicians caring for more Veterans experiencing the effects of military-related injuries/illness. 6 Only 19 per cent of Veterans in Canada access payment for treatment through VAC 3 ; it is therefore important that family physicians can adequately attend to the needs of all Veteran patients and have knowledge of the resources available to Veterans to help enhance their health and well-being. Being aware of and understanding the military context and potentially related health conditions can also help providers enhance communication and trust with their Veteran patients, and can notably improve the effectiveness of care and treatment. 7 Timely, convenient access to health care is a nationwide issue-in Canada, five million people do not have a family doctor. 8,9 On average, Veterans have a higher use rate of health care providers, including family physicians. Though their health care use is greater than that of the general population, considering Veterans' higher rates of chronic pain, mental health issues, and other conditions, their use is lower than expected. 10 While most Veterans have a family physician, 18 per cent of male Veterans and 13 per cent of female Veterans do not. 10 Veterans face similar barriers to accessing care as the rest of the population, with the additional difficulties of navigating the change from a military health care system to a less structured, civilian system. 10 Though the culture is evolving, a reluctance to admit emotional or physical pain, typical in military settings as a result of stigma, may also act as a barrier and prevent Veterans from seeking care. 10,11,12 Working with Veterans can be a rewarding experience for family physicians. Eligible Veterans have greater access to remuneration for a wide range of additional health care supports through VAC, which family physicians can help them access, potentially leading to better patient outcomes. While Canadian Armed Forces (CAF) members are released from service in all age groups, many Veterans are young or middle-aged upon release. 13 The average age of release is 42, 14 which offers family doctors an opportunity to provide continuous, collaborative care for Veteran patients over many years. This can have a substantial impact on Veterans' health throughout the course of their life post-service. 15 Relevant Factors in Providing Veteran Care and Tips for Family Physicians
# Military literacy and cultural competency considerations
Understanding and recognizing military experience and context as it relates to Veterans' health can facilitate better care and treatment for military Veterans. 1 Familiarity with military culture can help physicians understand how each Veteran's unique background may influence their preference for care as well as their medical condition, and can strengthen the patientprovider relationship. Recent evidence also indicates that health care providers' improved understanding of military culture positively affects quality of care delivery. 16 Veterans and their families encounter unique circumstances throughout their time in the military and in life after service. A feature of military service that distinguishes it from civilian employment is that members serve under unlimited liability, which means they are subject to being lawfully ordered into harm's way, in circumstances that may lead to death. 17 Veterans can feel a strong sense of identity linked to their military career 7 and make close connections with other members of the military, 18 which can make the transition to civilian life difficult. While for many Veterans this transition is often seamless, for others it can be challenging, 19 especially if dealing with a mental or physical health condition. 18 Frequent moves and periods of separation throughout a military career can also put pressure on family relationships and can sometimes present problems for adjustment to life after service, as captured in the CFPC's previous guides While VAC and the CAF work with CAF members in health planning before they complete their service, some individuals may not have revealed all health concerns prior to release. Health conditions that arise in service may impede normal adjustment after release, 18 and require follow-up, assessment, and treatment with a family physician. If CAF members are released involuntarily owing to health-related employment limitations (one in five), their health conditions have often already been diagnosed and are being treated. 18 Many transitioning members experience identity challenges after leaving service. 22 Military culture often encourages members to think in a collectivist mindset, which emphasizes placing the team before the self with an external locus of control and an emphasis on self-sacrifice. 23,24,25 Teambefore-self attitudes common in the military can sometimes result in Veterans downplaying their pain. 23 Employing active listening with Veteran patients to learn about their experiences in the military and creating a safe environment for them to talk about their military service are particularly important. Veterans may have concerns about disclosure of health issues in ways that could impact their VAC benefitsbuilding patient-provider trust is critical. Taking the time to understand the Veteran's background and their life in the military using open-ended questions can help patients feel understood, and can shed light on issues that may come up over time. When Veterans give their medical history, physicians should take note of the patient's understanding of how their medical issues are linked to their military experience. Physicians can help patients contact VAC and, with permission, can refer them to local VAC offices for remuneration for treatment depending on the medical condition. 18 3 Best Advice -Caring for Veterans
# Resources for supporting Veterans in transition to post-service life
- VAC Assistance Service 26 is a hotline that offers psychological support 24 hours a day. The toll-free number is 1-800-268-7708.
- The Veteran Family Program 27 is funded by VAC and offers supports to medically released Veterans and their families through a Veteran Family Program coordinator at centres across Canada. The program assists Veterans with their transition through delivery of additional information and referral services.
- The Operational Stress Injury Social Support 28 (OSISS) is a peer support network for Veterans, CAF members, and their families who are experiencing an operational stress injury (OSI). As Veterans transition to life after service, peer support and learning from fellow Veterans can be helpful while they adapt.
- The Veterans Transition Network 29 is a charity that provides supportive programs for Veterans across Canada but specifically focuses on those transitioning from military to civilian life. The network offers transition skills programs as well as peer support, and lists a variety of resources for Veterans and their families.
- Veterans support groups exist in various cities across Canada; local Royal Canadian Legions 30 (a nonprofit dedicated to serving Veterans, with community organizations throughout Canada) can offer support and may be able to help direct Veterans to support groups in their city.
# Veterans Affairs Canada referrals and forms
Veterans must apply through VAC to access payment for treatment benefits and care services. Wait times for approvals can sometimes be problematic for those living with various physical or mental health conditions. 12,31 After release, a lack of continuity of care and limited support during the transition to post-service life can amplify the difficulties of adjusting to civilian life. Family physicians can help promote a positive post-release transition for Veterans by taking them on as a priority population in their family practice, rather than having them access a clinic through a wait list. Veterans may delay seeking help after leaving service, by which time issues may become exacerbated, especially if there are barriers to accessing care.
When a Veteran applies to VAC for benefits they will be provided with support and forms for their family physician to fill out regarding their health problems.
A family physician's information regarding a patient's mental, physical, and social health is critical to informing VAC decisions regarding benefits. These forms are an important part of caring for Veterans and their families. 32 Patient access to VAC benefits also enables the family physician to provide better care, as this can improve the physician's options for treatment planning. With the patient's permission, physicians can also write a referral letter to VAC with relevant health information if they believe a patient would benefit from VAC programs. 32
# Tips for family physicians for completing VAC forms
- Before completing the form, ask your patient to list all notable instances from their time in the military including accidents, potential exposures, and where they were stationed. Family physicians can use this information to provide extensive detail on the form, which helps inform VAC in making a decision about the benefit. For example, listing all toxins the Veteran was exposed to can help provide a clearer picture for adjudicators.
- Physicians do not need to make a statement about causality of medical issues as related to service, VAC makes this determination. Respond to the question on the form. For example, note health problems the patient is facing and list their history.
- The Canadian Family Physician (CFP) article Forms for father 32 provides additional information regarding the forms process specific to family physicians.
# Special Considerations When Caring for Veterans
The following section will outline military-related physical and mental health conditions relevant to family physicians caring for Veterans, as well as practical guidance and resources to support the Veteran patient. These include post-traumatic stress disorder (PTSD) and other mental health conditions, Gulf War illness, mild traumatic brain injury (MTBI), health concerns related to past mefloquine use, musculoskeletal disorders (MSDs), chronic pain, hearing loss/tinnitus, and issues related to military sexual trauma and 2SLGBTQ+ discrimination.
# Best practices for managing chronic pain and musculoskeletal disorders
Approximately 20 per cent of the population in Canada lives with chronic pain, and the nature of military work puts Veterans at a greater risk than the general population of experiencing chronic pain.
# Resources for managing chronic pain and musculoskeletal disorders
- The Chronic Pain Centre of Excellence for Canadian Veterans 38 is a pan-Canadian network that conducts research on chronic pain and works with Veterans to translate this research into practice at pain clinics across Canada.
- The centre shares recent research 39 on chronic pain relevant to clinicians and their care of Veterans.
- Physicians can find a list of clinics 40 where this research is being implemented and where they can refer Veteran patients for evidence-based interdisciplinary care.
- VAC offers rehabilitation services, 41 which include assistance with physical and mental health issues related to service. Veterans can apply through their VAC account, where without requiring a medical release from service they can detail how their health has adversely affected their life.
- A sailor's pain 42 (a CFP article) provides a helpful, detailed approach to managing Veterans' MSDs, chronic pain, and disability.
# Best practices for treating mental health conditions in Veterans
Like many Canadians, Veterans can experience a decline in their mental health that impacts their ability to function. While 48 per cent of CAF Regular Force Veterans released from service from 1998 to 2018 rated their mental health as excellent or very good, a significant number also reported depression (26 per cent), anxiety (21 per cent), PTSD (24 per cent), and suicidal ideation (10 per cent over a 12-month period, 26 per cent lifetime). 43 o VAC offers a network of OSI clinics across the country to help diagnose, treat, and support eligible Veterans with service-related mental health conditions. These clinics work collaboratively with health care providers to help with continuity and follow-up.
- OSI Connect 58 is an app that helps Veterans with OSI learn about OSI and provides assistance through the OSI clinic network. Resources help patients with mental health issues and other conditions, including PTSD, depression, anxiety, sleep, and stress management.
- Mental Health First Aid Canada offers a course on Mental Health First Aid for the Veteran Community, 59 which was created to help Veterans and those caring for them provide support for someone experiencing poor or worsening mental health.
- This course can be helpful for Veterans and their loved ones, and for health professionals and those caring for Veterans. It is free for members of the Veteran community.
- For urgent support, Veterans can call the VAC Assistance Service, 26 open 24 hours a day for confidential help, at 1-800-268-7708.
- Lifespeak 60 is a Web-based platform designed to improve patients' health and other aspects of wellbeing through educational videos, podcasts, tips, action plans, and other resources. It is free for Veterans as part of VAC Assistance Service and can be used anonymously at any time.
- The CFPC Addiction Medicine Members Interest Group has produced the Practical Approach to Substance Use Disorders for the Family Physician, 61 which provides guidance in recognizing and treating common substance use disorders in family practice.
# Post-traumatic stress disorder (PTSD)
Psychological trauma is a psychiatric injury that can arise after exposure to intensely stressful events. 62 Veterans may experience PTSD as a result of events in their military career. Rates of military-related PTSD among Veterans are higher in direct correlation to members' exposure to potentially traumatic events during training, deployment-related combat, or humanitarian operations, or from their role as military police. 63 If not treated, PTSD can become chronic, and manifestations of PTSD can have negative consequences on a social, occupational, and/or interpersonal level. 62 Though it is one of the most common mental health conditions among civilian and military populations, PTSD is often underrecognized by primary care providers. 62 While PTSD related to Veterans' experience in the military is regularly diagnosed during service, some members may not seek treatment until after they have been released from the military. 64
Symptoms of PTSD can present in different ways, depending on factors such as age, gender, and age of exposure. Military-related PTSD symptoms can appear in tandem with other psychiatric disorders and physical health conditions such as chronic pain, medically unexplained symptoms, and addiction issues, and therefore can be challenging to recognize and diagnose. A trauma-informed approach to investigating PTSD is critical; trauma-informed family practices appreciate how psychological trauma can alter the way one thinks, feels, and acts. Traumainformed care operates on five guiding principles: safety, trustworthiness, choice, collaboration, and empowerment. 62
Five-point approach to trauma-informed care for family physicians 45,65 1. Bear witness to the patient's experience of trauma
- Recognize the impact of the trauma and its continuing effect on the patient.
- Help the patient feel they are in a safe space; acknowledge the patient's need for emotional and physical safety
- Ensure consistency and predictability of care; allow adequate time to care for the patient.
# Include patients in the healing process
- Present patients with choices and build collaborative patient-physician relationships to engage them in their care.
# Believe in the patient's strength and resilience
- Empower the patient using a strengths-based approach.
- Use practices that are sensitive to the patient's cultural, ethnic, personal, and social identity
- Display sensitivity to marginalization and systemic abuse.
Family physicians should investigate PTSD as a potential diagnosis if the Veteran has a history of exposure to potentially psychologically traumatic events. Approaches should be personalized to individual patients, and timing is an important consideration when asking about psychological trauma; the patient should be ready and have established a feeling of trust and safety with the provider. 62 In addition to the diagnostic criteria, the US Department of Veterans Affairs National Center for PTSD offers the Primary Care PTSD Screen for DSM-5, 66 a quick, five-item tool to screen for PTSD in primary care. Some Veterans may struggle to express their experiences due to common stigmas around seeking help within the military. 11,12,64 To cope with psychological trauma, some Veterans may develop issues that can affect other parts of their life, which could arise in relation to or outside PTSD. These include depression, anxiety, alcohol and drug use, or issues with relationships, work, and family. 67 Moral injury is the psychological, behavioural, and social result of events where an individual "may perpetrate, fail to prevent, or witness events that contradict deeply held moral beliefs and expectations." 69 It is a psychological injury that has a lasting effect on one's self-image and world view. 70 Moral injury overlaps with PTSD in many ways and is important to understand because of its common occurrence in military personnel and Veterans. Additionally, moral injury can be a barrier to recovery, as people with moral injuries may be reluctant to discuss their concerns because of shame or guilt. 71 The research on moral injury is in its early stages but the Centre of Excellence on PTSD offers several resources for understanding moral injury. 70
# Resources for managing and treating post-traumatic stress disorder in Veterans
- Veterans Affairs: Post-Traumatic Stress Disorder and War-Related Stress 67 This page by VAC provides a thorough background on PTSD and how it can affect Veterans specifically, from common reactions and symptoms to coping and dealing with PTSD. It also details typical treatment options and traumaassociated problems.
- Recognizing Post-Traumatic Stress Disorder in Primary Care 64 details primary care principles for recognizing and treating psychological trauma in patients, including how to make your practice traumainformed. The document also provides case examples of different presentations of PTSD and principles of trauma-informed care, as well as a primary care screening tool for PTSD.
- Horror comes home: Veterans with posttraumatic stress disorder 64 This article provides advice for family physicians treating PTSD in Veterans, including a helpful resource for diagnosing PTSD in Veterans.
# - Centre of Excellence on Post-Traumatic Stress Disorder and Related Mental Health Conditions 56
- The Canadian Centre of Excellence on PTSD and Related Mental Health Conditions establishes community relationships to create networks of support for Veterans, first responders, and their families. The centre engages in knowledge collection and translation for the practical use of research.
- Family physicians can also directly recommend these resources to their patients for help with PTSD:
- The Operational Stress Injury Social Support 28 (OSISS) program is a peer support network for Veterans, CAF members, and their families who are experiencing an OSI. Individuals can contact an OSISS coordinator through the website.
- PTSD Coach Canada mobile app 72 allows Veterans to learn about PTSD and offers resources to manage their symptoms.
- MDcme.ca is a Memorial University of Newfoundland Faculty of Medicine resource that offers accredited online medical education for primary care providers in Canada, including a course to help health care professionals recognize PTSD 73 and learn about appropriate treatments.
The Centre of Excellence on PTSD offers the tool kit, Understanding and Addressing Moral Injury: A Toolkit for Leaders. 74 Section 1 provides an overview of moral injury and concrete actions to address it.
# Best practices for managing military-related hearing loss/tinnitus
Hearing loss and tinnitus related to military service are common concerns for Veterans. 75 The prevalence of hearing loss in younger CAF members is much higher than in the comparable general population in Canada, and many persons with mild hearing loss do not recognize their condition. 75 Hearing loss and tinnitus rates in CAF members are unlikely to decrease because hearing protection in military occupations remains difficult to mitigate. 75 It is important to diagnose even mild hearing impairment, as hearing loss can have a negative impact on Veterans' quality of life and well-being, 75 including impeding social interactions and limiting the ability to hear sounds necessary for daily living and work life.
There are no objective tests to diagnose tinnitus 76 but there are ways to manage the symptoms. The US Department of Veterans Affairs uses a progressive management program 77 with a team of health care providers to produce individualized management plans to reduce the impact of tinnitus on patients' lives.
# Resources for treating Veterans with hearing loss/tinnitus
- VAC provides a thorough overview of tinnitus 78 and hearing loss 79 and their impacts on quality of life, as well as of pension-eligible military-related events that could lead to these disorders.
- Veterans can receive compensation for hearing loss and tinnitus through VAC disability benefits. 80 - Veterans can obtain access to treatment benefits 81 for hearing loss/tinnitus through their VAC health care card, which can cover home health, audiologist and other specialist visits, medical equipment, and other supports.
# Best practices for managing effects of mild traumatic brain injury
Mild traumatic brain injury (MTBI) is an injury that typically results from a severe impact to the head. It can cause a range of chronic physical, mental, emotional, and behavioural symptoms. 82 While family physicians are likely familiar with treating concussion in civilian populations, additional attention should be paid to MTBI history in Veterans. MTBI is more frequent in Iraq/Afghan War Veterans but it can also occur in non-deployed service members. In addition to blunt force trauma and combat-related blast injuries, exposure to blasts in training exercises (and, in snipers, exposure to very close and repeated recoil from rounds of high-caliber rounds) can also result in MTBI. 83,84 Though no diagnostic test can establish MTBI in patients, in Veterans with persistent symptoms physicians should ask about the patient's MTBI history and conduct a physical examination with special consideration of neurological functioning. 83 Brain injuries can heal without lasting damage but Veterans with cognitive and psychological symptoms should be referred for mental health treatment. Strong collaboration between the patient, the family physician, and the supporting health care team (including mental health care providers) can pave the way for optimal results, as well as physicians' consideration of the relationship between the patient's military service and the injury. 83
# Resources for treating Veterans with symptoms related to MTBI
- OSI Clinics, 58 mentioned above, can also be used by Veterans with MTBI. Physicians can refer patients to OSI clinics for treatment by reaching out to the closest VAC office, where case managers can help potential clients access services.
# - Persistent Symptoms Following Mild Traumatic Brain Injury (mTBI): A Resource for Clinicians and
Staff 82 provides more detail for clinicians and health care providers in treating symptoms of an MTBI and gives thorough explanations of MTBI related to military service.
# Special considerations for issues related to military sexual trauma
While issues related to sexual assault and harassment are not unique to the military, family physicians may encounter Veterans who experienced sexual trauma during their military service. Approximately 1.6 per cent of Regular Force members reported military-related experiences of sexual assault, with women impacted at a significantly higher rate (4.3 per cent) compared with men (1.1 per cent). Indigenous members were affected at a greater rate (3 per cent) than non-Indigenous members (1.5 per cent), as were members with disabilities (3 per cent) compared with those without disabilities (1.5 per cent). 85 Exposure to sexual harassment or assault during military service 86 is different from civilian sexual trauma, as it is a work-related injury and can involve a sense of moral injury due to institutional betrayal in addition to the sexual misconduct. 87,88 Veterans who experienced military sexual trauma (MST) may have resulting PTSD; studies from the United States indicate a strong link between the two. 86,89 Evidence-based psychotherapies can be effective for treating MST. 90 Family physicians should work collaboratively with the Veteran and the Veteran's VAC case manager to ensure referral to psychotherapists with military cultural competencies to ensure evidence-based treatments.
# Resources for treating patients who experienced military sexual trauma
- Veterans who experienced sexual trauma during their military service may be newly eligible for VAC benefits, 91 even if previously denied.
- The Department of National Defence Sexual Misconduct Response Centre offers a 24/7 phone line 92 (1-844-750-1648) where CAF members can call to receive free, confidential support from a Sexual Misconduct Response Centre counsellor who can also refer patients to resources and services for further assistance. While the service is not tailored to Veterans, Veterans may call to receive support.
- The Centre of Excellence on Post-Traumatic Stress Disorder has created a Military Sexual Misconduct and Military Sexual Trauma Fact Sheet 93 that explains what MST is, provides statistics on MST, and lists other important factors to consider regarding MST.
- VA Beyond MST app 94 is a self-help tool for survivors of MST that helps users develop coping skills and manage symptoms in order to improve their quality of life.
# Special considerations for issues related to experiencing past 2SLGBTQ+ discrimination
While members of the 2SLGBTQ+ community have been able to serve in the Canadian military since 1992, discrimination based on sexual orientation still affects many soldiers throughout their service. 95 For Veterans who served prior to 1992, experiencing adverse psychological, physical, and social impacts (depression, stress, substance use) due to having to hide one's sexual orientation, or harassment/dismissal because of their sexual orientation, was not uncommon. 96,97 In the civilian population, evidence has demonstrated that 2SLGBTQ+ individuals are at a greater risk for mental health conditions than heterosexual individuals. 98 Research indicates that 2SLGBTQ+ individuals in the military are also at a higher risk for mental health conditions such as depression. 99 Experiencing anti-2SLGBTQ+ discrimination can increase one's risk for mental health issues. 100,101 Past experiences of discrimination can also prevent 2SLGBTQ+ people from accessing health care, 98 and some needs may not be appropriately addressed if health care providers are unaware of a patient's sexual orientation. Family physicians treating 2SLGBTQ+ Veterans should strive to create safe, accepting spaces and help to facilitate culturally safe care in collaboration with local 2SLGBTQ+ outreach services, to which they can refer patients.
# Resources for managing issues related to experiencing past 2SLGBTQ+ discrimination
- Ontario HIV Treatment Network's report Facilitators and barriers to health care for lesbian, gay and bisexual (LGB) people 98 may also be able to provide support to physicians looking for more resources to help patients who have experienced past 2SLGBTQ+ discrimination.
- VAC has a 2SLGBTQ+ Veteran hotline for those with service-related injuries who have not applied for benefits: 1-800-487-7797. 105
- Rainbow Veterans is a Veterans group that offers support to members who experienced discrimination while in the CAF because of their sexual orientation.
# Current military Veteran health concerns
Below are a few examples of health issues of concern to military Veterans of Canada from all eras:
# Current Military Veteran Health Concerns Resources
# Cannabis for Medical Use
As of 2016 VAC reimburses Veterans for the medical use of cannabis. 106 Medical cannabis is increasingly used by Veterans in Canada; medical cannabis reimbursements account for one in five medical reimbursements by VAC. 107,108 Evidence is mixed on outcomes of cannabis use. Some research has shown an association between cannabis use and poorer health outcomes among the general population 109,110 and among Veterans. 111 Various studies have shown some minor benefits of cannabis use for chronic pain. 107 Though AUD and cannabis use often co-occur in Veterans, Veterans who use cannabis for medical reasons show lower alcohol use than nonmedical users. 112
- The CFPC has provided guidelines 113 and recommendations for physicians regarding authorizing cannabis for medical purposes, including authorizing use only after conventional treatments have failed. 114 Provincial health care provider regulators across Canada have also provided guidelines for cannabis authorization. A Clinical Practice Guidelines article from CFP 115 outlines considerations for prescribing medical cannabis in primary care settings, which advises limiting the use of medical cannabinoids but highlights specific circumstances in which there is evidence demonstrating its benefit.
- A recent practice guideline 116 summarized that cannabis provided small benefits for chronic pain relief, physical functioning, and sleep quality for those with chronic pain, and a small risk of transient harms, concluding that the evidence supports a weak recommendation for a cannabis trial. However, there are a number of evidence limitations for health care providers to consider when discussing cannabis use with Veterans. 117
# Gulf War Illness
After service in the Gulf War of 1990-1991, a number of CAF Veterans described various symptoms which they understood as resulting from exposures during their Gulf War service. Extensive research has been conducted and is ongoing to understand these health issues. Though research has not provided sufficient evidence for a medically diagnosable condition, the term Gulf War illness (or chronic multisymptom illness) is used for these issues. 22,118 Certain conditions have been reported more commonly in Gulf War Veterans than in non-Gulf War Veterans and civilians, including symptoms of fibromyalgia and chronic fatigue syndrome. 119 Some conditions reported under the umbrella of Gulf War illnesses include major depression, anxiety, asthma/bronchitis, chronic fatigue, and cognitive dysfunction, but many have medically unexplained symptoms.
Similar to the civilian population, Veterans can have diagnosable medical issues and medically unexplained symptoms, both of which can be treated using traditional approaches. In a comprehensive study on Gulf War illnesses, the National Academy of Medicine (formerly Institute of Medicine) in the United States recommends that providers employ a long-term, integrated approach to helping patients manage their symptoms.
- VAC provides a thorough overview of Gulf War illness, including relevant research in Canada.
- The U.S. Department of Veterans Affairs provides guidance 120 for clinicians on how to diagnose and treat those with Gulf War illness.
# Current Military Veteran Health Concerns Resources
# Past Mefloquine Use
Mefloquine is an antimalarial medication, and was the CAF's most commonly used antimalarial until evidence demonstrated that some patients were experiencing adverse psychiatric effects from its use, particularly patients with existing psychiatric illnesses. 121 Some patients report long-term effects from mefloquine use, although in 2017 the CAF released findings from the Surgeon General's review, which did not find evidence supporting this claim. 122 Patients reporting health issues should be treated for the symptoms they are experiencing. For example, physicians can establish a treatment plan for patients experiencing PTSD regardless of its cause.
- Veterans can apply to claim any medical condition with supporting documentation from their doctor.
- Chapter Five of the Surgeon General's 2017 report 122 on mefloquine examines the evidence for short-term and long-term adverse effects of mefloquine use.
# Polypharmacy
Polypharmacy-the use of five or more medications to manage symptoms-is common in Veterans with comorbid and complex physical and mental health conditions, especially in older adults. 123 Evidence suggests potential negative effects of polypharzmacy.
# Accessible care
A key feature of the PMH is its ability to improve access to care. 125 This includes timely access, virtual access, and access to a variety of specialty services. Since higher rates of chronic mental and physical health conditions are common in Veterans, it is essential that they can access care when needed. A PMH setting allows Veterans to access the most appropriate care provider available while maintaining continuity of care.
# Patient-and family-partnered care
Patients play an important role in their care; their perspectives and history factor into their health experience.
Taking the time to understand patients' feelings, background, and experiences can strengthen the trust between patient and provider. For Veterans, military service and experience can be an important part of their identity and are often related to their health and well-being. 22 Involving Veteran patients as partners in their care can help them feel that they have more opportunities to talk about their needs, and that they are active participants in the management of their health and treatment plans. 125 Families are often involved in the care of their loved ones, helping the patient through illness and providing reliable health information. 126 Veterans' families have also experienced the unique pressures of their family member's military career, including frequent moves, the stress of occupational risks posed to the serving member, and the adjustment from military to civilian life. 20 Involving families and caregivers in the Veteran's care process (with the patient's permission) can facilitate better communication and enhanced care for the patient while decreasing stress for the family. 127 Patients should determine their level of involvement as partners, but options such as allowing them to access their medical information, providing them with self-management tools, and offering evidencebased information about their care can improve patient satisfaction and the patient-provider relationship. 12
# Long-term care and Home Care Services
# Caring for Veterans in the Patient's Medical Neighbourhood
The Patient's Medical Neighbourhood (Neighbourhood) 132 is a broader network of care involving providers and services outside the family practice. In a Neighbourhood, family practices coordinate and share responsibility for patient care with other health care providers and community services (e.g., mental health and addiction services, pharmacy, social, and community supports, etc.). In caring for Veterans, a Neighbourhood setting can help connect Veterans with relevant resources in their community, such as 2SLGBTQ+ health care centres, personalize their care, improve patient outcomes, and encourage continuity as a result of the existing relationship between the family practice and providers in the Neighbourhood.
# Community adaptiveness and social accountability
A PMH adapts to the needs of the community and works to understand how patients experience the health care system differently, based on intersecting social determinants of health. Indigenous, female, 2SLGBTQ+, and disabled Veterans are disproportionately affected by mental and physical health conditions. 128,129,130 Physicians caring for Veterans in these populations in the PMH are aware of socioeconomic influences on Veterans' health and work to respond to these differences at the patient, practice, community, and policy level. 132 Family doctors can act as advocates for their patients and encourage government to establish policies that improve Veterans' health and other forms of well-being.
# Comprehensive team-based care with family physician leadership and continuity of care
An interprofessional primary care team approach offers a host of benefits to patients, including improved access to care, better continuity of care, and enhanced access to specialty resources. The interprofessional nature of PMH teams allows health professionals with expertise in different disciplines to effectively work together to deliver comprehensive and specialized care to patients. In a PMH, family physicians work collaboratively with nurses, psychologists, social workers, physiotherapists, and other health care providers to provide convenient access to a varied range of high-quality care services.
Within the general population in Canada there is a high prevalence of patients with comorbid, complex chronic conditions. 131 Team-based, patient-centred primary care is crucial for effective management of health conditions over the long term and can be especially beneficial in treating Veterans when combined with the additional resources available through VAC programs. Many VAC programs encourage collaboration with family physicians, including OSI clinics and rehabilitation services. Open communication between VAC providers and the family physician can broaden options for effective treatment planning and can facilitate optimal patient outcomes. 32 In PMH settings, interdisciplinary primary care teams are knowledgeable about community resources and engaged with local organizations. As some Veterans may be newly transitioning to life after service, a PMH referral to resources in their community can help them find peers undergoing similar experiences, direct them to selfmanagement resources, and encourage a personalized and holistic approach to their well-being.
# Conclusion
Caring for Veterans can be deeply rewarding for family physicians. As the physician-patient relationship is at the core of the profession, connecting with Veterans, learning about their military service, and understanding their perspectives can be an enriching experience.
Treating Veteran patients allows family physicians to care for those who served Canada's population and often made great sacrifices to do so.
Additionally, many Veterans have been released from service at a young age or in middle age; physicians' active management of health conditions can have a tremendous impact on their ability to remain healthy, active, working, and participating in social and family life over decades. Early management of conditions with the right interventions can have lasting effects on Veterans and their families. Veterans have greater access to a variety of services and support than the general population; eligible Veterans can receive VAC funding for interprofessional care. This can facilitate enhanced treatment planning for the physician.
While 20 per cent of the Veteran population uses VAC services, there are many more Veterans who have health issues that may not be service-related. 3 Nevertheless, the military context and an understanding of Veterans' background remain important. Learning about and recognizing Veterans' experience can greatly enhance the provider-patient relationship and improve patients' health outcomes in the long term. Additionally, many Veterans may not know they can access VAC or may fear being denied benefits; family physicians can play a substantial role in facilitating access to benefits for which they are eligible. Working collaboratively with Veterans, VAC, and other health care teams and providers, in alignment with the PMH vision's principles of care, family physicians can have a significant and long-lasting impact on the health and well-being of their Veteran patients. | Special considerations for issues related to experiencing past 2SLGBTQ+ discrimination . . .# Table of Contents Introduction
The ability to render accessible, continuous, patientcentred, collaborative, and culturally competent care for Veterans (former members of the military) is important for family physicians and other primary care providers, especially as many may already have Veteran patients in their practice. Caring for Veterans who kept our nation secure through national service can be a rewarding and an enriching experience for family physicians. Additionally, some family physicians/ primary care teams may be uncertain about how best to manage Veterans' care 1 and would benefit from guidance and decision-making tools that can help them better serve Veterans and their health needs.
# Purpose of the Guide
The purpose of this guide is to highlight special considerations for family physicians and other primary care providers in caring for the Veteran population, including contextualizing this information within the College of Family Physicians of Canada TM (CFPC)'s Patient's Medical Home (PMH) 2 vision for the future of family practice in Canada. Family physicians have an essential role in caring for Veterans and in facilitating supportive cooperation between care providers to ensure Veterans receive the best care possible. This guide will share common themes to address the health needs of Veteran patients, providing key factors and context, practical tips, and rewards related to caring for Veterans.
While there are a variety of resources available to Veterans to enhance their health and other aspects of their well-being, there are many different organizations dedicated to Veterans' health across Canada, and the Veterans Affairs Canada (VAC) system can be complicated to navigate. The resources shared in this guide are intended to help primary care providers connect their Veteran patients to relevant resources and allow them to establish and maintain relationships with other care providers for optimal outcomes and follow-up.
# Background
The population of living Veterans in Canada is approximately 629,300, 3 representing almost one in 30 of the adult population in Canada. Former members of the military may have participated in a variety of operations throughout their military career, either abroad or within Canada, including wartime service or special duty area service, humanitarian relief and disaster response, and search and rescue. 4,5 The increase in Canadian military operations during and after the first Persian Gulf War in 1990 has resulted in family physicians caring for more Veterans experiencing the effects of military-related injuries/illness. 6 Only 19 per cent of Veterans in Canada access payment for treatment through VAC 3 ; it is therefore important that family physicians can adequately attend to the needs of all Veteran patients and have knowledge of the resources available to Veterans to help enhance their health and well-being. Being aware of and understanding the military context and potentially related health conditions can also help providers enhance communication and trust with their Veteran patients, and can notably improve the effectiveness of care and treatment. 7 Timely, convenient access to health care is a nationwide issue-in Canada, five million people do not have a family doctor. 8,9 On average, Veterans have a higher use rate of health care providers, including family physicians. Though their health care use is greater than that of the general population, considering Veterans' higher rates of chronic pain, mental health issues, and other conditions, their use is lower than expected. 10 While most Veterans have a family physician, 18 per cent of male Veterans and 13 per cent of female Veterans do not. 10 Veterans face similar barriers to accessing care as the rest of the population, with the additional difficulties of navigating the change from a military health care system to a less structured, civilian system. 10 Though the culture is evolving, a reluctance to admit emotional or physical pain, typical in military settings as a result of stigma, may also act as a barrier and prevent Veterans from seeking care. 10,11,12 Working with Veterans can be a rewarding experience for family physicians. Eligible Veterans have greater access to remuneration for a wide range of additional health care supports through VAC, which family physicians can help them access, potentially leading to better patient outcomes. While Canadian Armed Forces (CAF) members are released from service in all age groups, many Veterans are young or middle-aged upon release. 13 The average age of release is 42, 14 which offers family doctors an opportunity to provide continuous, collaborative care for Veteran patients over many years. This can have a substantial impact on Veterans' health throughout the course of their life post-service. 15 Relevant Factors in Providing Veteran Care and Tips for Family Physicians
# Military literacy and cultural competency considerations
Understanding and recognizing military experience and context as it relates to Veterans' health can facilitate better care and treatment for military Veterans. 1 Familiarity with military culture can help physicians understand how each Veteran's unique background may influence their preference for care as well as their medical condition, and can strengthen the patientprovider relationship. Recent evidence also indicates that health care providers' improved understanding of military culture positively affects quality of care delivery. 16 Veterans and their families encounter unique circumstances throughout their time in the military and in life after service. A feature of military service that distinguishes it from civilian employment is that members serve under unlimited liability, which means they are subject to being lawfully ordered into harm's way, in circumstances that may lead to death. 17 Veterans can feel a strong sense of identity linked to their military career 7 and make close connections with other members of the military, 18 which can make the transition to civilian life difficult. While for many Veterans this transition is often seamless, for others it can be challenging, 19 especially if dealing with a mental or physical health condition. 18 Frequent moves and periods of separation throughout a military career can also put pressure on family relationships and can sometimes present problems for adjustment to life after service, as captured in the CFPC's previous guides While VAC and the CAF work with CAF members in health planning before they complete their service, some individuals may not have revealed all health concerns prior to release. Health conditions that arise in service may impede normal adjustment after release, 18 and require follow-up, assessment, and treatment with a family physician. If CAF members are released involuntarily owing to health-related employment limitations (one in five), their health conditions have often already been diagnosed and are being treated. 18 Many transitioning members experience identity challenges after leaving service. 22 Military culture often encourages members to think in a collectivist mindset, which emphasizes placing the team before the self with an external locus of control and an emphasis on self-sacrifice. 23,24,25 Teambefore-self attitudes common in the military can sometimes result in Veterans downplaying their pain. 23 Employing active listening with Veteran patients to learn about their experiences in the military and creating a safe environment for them to talk about their military service are particularly important. Veterans may have concerns about disclosure of health issues in ways that could impact their VAC benefitsbuilding patient-provider trust is critical. Taking the time to understand the Veteran's background and their life in the military using open-ended questions can help patients feel understood, and can shed light on issues that may come up over time. When Veterans give their medical history, physicians should take note of the patient's understanding of how their medical issues are linked to their military experience. Physicians can help patients contact VAC and, with permission, can refer them to local VAC offices for remuneration for treatment depending on the medical condition. 18 3 Best Advice -Caring for Veterans
# Resources for supporting Veterans in transition to post-service life
• VAC Assistance Service 26 is a hotline that offers psychological support 24 hours a day. The toll-free number is 1-800-268-7708.
• The Veteran Family Program 27 is funded by VAC and offers supports to medically released Veterans and their families through a Veteran Family Program coordinator at centres across Canada. The program assists Veterans with their transition through delivery of additional information and referral services.
• The Operational Stress Injury Social Support 28 (OSISS) is a peer support network for Veterans, CAF members, and their families who are experiencing an operational stress injury (OSI). As Veterans transition to life after service, peer support and learning from fellow Veterans can be helpful while they adapt.
• The Veterans Transition Network 29 is a charity that provides supportive programs for Veterans across Canada but specifically focuses on those transitioning from military to civilian life. The network offers transition skills programs as well as peer support, and lists a variety of resources for Veterans and their families.
• Veterans support groups exist in various cities across Canada; local Royal Canadian Legions 30 (a nonprofit dedicated to serving Veterans, with community organizations throughout Canada) can offer support and may be able to help direct Veterans to support groups in their city.
# Veterans Affairs Canada referrals and forms
Veterans must apply through VAC to access payment for treatment benefits and care services. Wait times for approvals can sometimes be problematic for those living with various physical or mental health conditions. 12,31 After release, a lack of continuity of care and limited support during the transition to post-service life can amplify the difficulties of adjusting to civilian life. Family physicians can help promote a positive post-release transition for Veterans by taking them on as a priority population in their family practice, rather than having them access a clinic through a wait list. Veterans may delay seeking help after leaving service, by which time issues may become exacerbated, especially if there are barriers to accessing care.
When a Veteran applies to VAC for benefits they will be provided with support and forms for their family physician to fill out regarding their health problems.
A family physician's information regarding a patient's mental, physical, and social health is critical to informing VAC decisions regarding benefits. These forms are an important part of caring for Veterans and their families. 32 Patient access to VAC benefits also enables the family physician to provide better care, as this can improve the physician's options for treatment planning. With the patient's permission, physicians can also write a referral letter to VAC with relevant health information if they believe a patient would benefit from VAC programs. 32
# Tips for family physicians for completing VAC forms
• Before completing the form, ask your patient to list all notable instances from their time in the military including accidents, potential exposures, and where they were stationed. Family physicians can use this information to provide extensive detail on the form, which helps inform VAC in making a decision about the benefit. For example, listing all toxins the Veteran was exposed to can help provide a clearer picture for adjudicators.
• Physicians do not need to make a statement about causality of medical issues as related to service, VAC makes this determination. Respond to the question on the form. For example, note health problems the patient is facing and list their history.
• The Canadian Family Physician (CFP) article Forms for father 32 provides additional information regarding the forms process specific to family physicians.
# Special Considerations When Caring for Veterans
The following section will outline military-related physical and mental health conditions relevant to family physicians caring for Veterans, as well as practical guidance and resources to support the Veteran patient. These include post-traumatic stress disorder (PTSD) and other mental health conditions, Gulf War illness, mild traumatic brain injury (MTBI), health concerns related to past mefloquine use, musculoskeletal disorders (MSDs), chronic pain, hearing loss/tinnitus, and issues related to military sexual trauma and 2SLGBTQ+ discrimination.
# Best practices for managing chronic pain and musculoskeletal disorders
Approximately 20 per cent of the population in Canada lives with chronic pain, and the nature of military work puts Veterans at a greater risk than the general population of experiencing chronic pain.
# Resources for managing chronic pain and musculoskeletal disorders
• The Chronic Pain Centre of Excellence for Canadian Veterans 38 is a pan-Canadian network that conducts research on chronic pain and works with Veterans to translate this research into practice at pain clinics across Canada.
o The centre shares recent research 39 on chronic pain relevant to clinicians and their care of Veterans.
o Physicians can find a list of clinics 40 where this research is being implemented and where they can refer Veteran patients for evidence-based interdisciplinary care.
• VAC offers rehabilitation services, 41 which include assistance with physical and mental health issues related to service. Veterans can apply through their VAC account, where without requiring a medical release from service they can detail how their health has adversely affected their life.
• A sailor's pain 42 (a CFP article) provides a helpful, detailed approach to managing Veterans' MSDs, chronic pain, and disability.
# Best practices for treating mental health conditions in Veterans
Like many Canadians, Veterans can experience a decline in their mental health that impacts their ability to function. While 48 per cent of CAF Regular Force Veterans released from service from 1998 to 2018 rated their mental health as excellent or very good, a significant number also reported depression (26 per cent), anxiety (21 per cent), PTSD (24 per cent), and suicidal ideation (10 per cent over a 12-month period, 26 per cent lifetime). 43 o VAC offers a network of OSI clinics across the country to help diagnose, treat, and support eligible Veterans with service-related mental health conditions. These clinics work collaboratively with health care providers to help with continuity and follow-up.
• OSI Connect 58 is an app that helps Veterans with OSI learn about OSI and provides assistance through the OSI clinic network. Resources help patients with mental health issues and other conditions, including PTSD, depression, anxiety, sleep, and stress management.
• Mental Health First Aid Canada offers a course on Mental Health First Aid for the Veteran Community, 59 which was created to help Veterans and those caring for them provide support for someone experiencing poor or worsening mental health.
o This course can be helpful for Veterans and their loved ones, and for health professionals and those caring for Veterans. It is free for members of the Veteran community.
• For urgent support, Veterans can call the VAC Assistance Service, 26 open 24 hours a day for confidential help, at 1-800-268-7708.
• Lifespeak 60 is a Web-based platform designed to improve patients' health and other aspects of wellbeing through educational videos, podcasts, tips, action plans, and other resources. It is free for Veterans as part of VAC Assistance Service and can be used anonymously at any time.
• The CFPC Addiction Medicine Members Interest Group has produced the Practical Approach to Substance Use Disorders for the Family Physician, 61 which provides guidance in recognizing and treating common substance use disorders in family practice.
# Post-traumatic stress disorder (PTSD)
Psychological trauma is a psychiatric injury that can arise after exposure to intensely stressful events. 62 Veterans may experience PTSD as a result of events in their military career. Rates of military-related PTSD among Veterans are higher in direct correlation to members' exposure to potentially traumatic events during training, deployment-related combat, or humanitarian operations, or from their role as military police. 63 If not treated, PTSD can become chronic, and manifestations of PTSD can have negative consequences on a social, occupational, and/or interpersonal level. 62 Though it is one of the most common mental health conditions among civilian and military populations, PTSD is often underrecognized by primary care providers. 62 While PTSD related to Veterans' experience in the military is regularly diagnosed during service, some members may not seek treatment until after they have been released from the military. 64
Symptoms of PTSD can present in different ways, depending on factors such as age, gender, and age of exposure. Military-related PTSD symptoms can appear in tandem with other psychiatric disorders and physical health conditions such as chronic pain, medically unexplained symptoms, and addiction issues, and therefore can be challenging to recognize and diagnose. A trauma-informed approach to investigating PTSD is critical; trauma-informed family practices appreciate how psychological trauma can alter the way one thinks, feels, and acts. Traumainformed care operates on five guiding principles: safety, trustworthiness, choice, collaboration, and empowerment. 62
Five-point approach to trauma-informed care for family physicians 45,65 1. Bear witness to the patient's experience of trauma
• Recognize the impact of the trauma and its continuing effect on the patient.
2. Help the patient feel they are in a safe space; acknowledge the patient's need for emotional and physical safety
• Ensure consistency and predictability of care; allow adequate time to care for the patient.
# Include patients in the healing process
• Present patients with choices and build collaborative patient-physician relationships to engage them in their care.
# Believe in the patient's strength and resilience
• Empower the patient using a strengths-based approach.
5. Use practices that are sensitive to the patient's cultural, ethnic, personal, and social identity
• Display sensitivity to marginalization and systemic abuse.
Family physicians should investigate PTSD as a potential diagnosis if the Veteran has a history of exposure to potentially psychologically traumatic events. Approaches should be personalized to individual patients, and timing is an important consideration when asking about psychological trauma; the patient should be ready and have established a feeling of trust and safety with the provider. 62 In addition to the diagnostic criteria, the US Department of Veterans Affairs National Center for PTSD offers the Primary Care PTSD Screen for DSM-5, 66 a quick, five-item tool to screen for PTSD in primary care. Some Veterans may struggle to express their experiences due to common stigmas around seeking help within the military. 11,12,64 To cope with psychological trauma, some Veterans may develop issues that can affect other parts of their life, which could arise in relation to or outside PTSD. These include depression, anxiety, alcohol and drug use, or issues with relationships, work, and family. 67 Moral injury is the psychological, behavioural, and social result of events where an individual "may perpetrate, fail to prevent, or witness events that contradict deeply held moral beliefs and expectations." 69 It is a psychological injury that has a lasting effect on one's self-image and world view. 70 Moral injury overlaps with PTSD in many ways and is important to understand because of its common occurrence in military personnel and Veterans. Additionally, moral injury can be a barrier to recovery, as people with moral injuries may be reluctant to discuss their concerns because of shame or guilt. 71 The research on moral injury is in its early stages but the Centre of Excellence on PTSD offers several resources for understanding moral injury. 70
# Resources for managing and treating post-traumatic stress disorder in Veterans
• Veterans Affairs: Post-Traumatic Stress Disorder and War-Related Stress 67 This page by VAC provides a thorough background on PTSD and how it can affect Veterans specifically, from common reactions and symptoms to coping and dealing with PTSD. It also details typical treatment options and traumaassociated problems.
• Recognizing Post-Traumatic Stress Disorder in Primary Care 64 details primary care principles for recognizing and treating psychological trauma in patients, including how to make your practice traumainformed. The document also provides case examples of different presentations of PTSD and principles of trauma-informed care, as well as a primary care screening tool for PTSD.
• Horror comes home: Veterans with posttraumatic stress disorder 64 This article provides advice for family physicians treating PTSD in Veterans, including a helpful resource for diagnosing PTSD in Veterans.
# • Centre of Excellence on Post-Traumatic Stress Disorder and Related Mental Health Conditions 56
o The Canadian Centre of Excellence on PTSD and Related Mental Health Conditions establishes community relationships to create networks of support for Veterans, first responders, and their families. The centre engages in knowledge collection and translation for the practical use of research.
• Family physicians can also directly recommend these resources to their patients for help with PTSD:
o The Operational Stress Injury Social Support 28 (OSISS) program is a peer support network for Veterans, CAF members, and their families who are experiencing an OSI. Individuals can contact an OSISS coordinator through the website.
o PTSD Coach Canada mobile app 72 allows Veterans to learn about PTSD and offers resources to manage their symptoms.
• MDcme.ca is a Memorial University of Newfoundland Faculty of Medicine resource that offers accredited online medical education for primary care providers in Canada, including a course to help health care professionals recognize PTSD 73 and learn about appropriate treatments.
The Centre of Excellence on PTSD offers the tool kit, Understanding and Addressing Moral Injury: A Toolkit for Leaders. 74 Section 1 provides an overview of moral injury and concrete actions to address it.
# Best practices for managing military-related hearing loss/tinnitus
Hearing loss and tinnitus related to military service are common concerns for Veterans. 75 The prevalence of hearing loss in younger CAF members is much higher than in the comparable general population in Canada, and many persons with mild hearing loss do not recognize their condition. 75 Hearing loss and tinnitus rates in CAF members are unlikely to decrease because hearing protection in military occupations remains difficult to mitigate. 75 It is important to diagnose even mild hearing impairment, as hearing loss can have a negative impact on Veterans' quality of life and well-being, 75 including impeding social interactions and limiting the ability to hear sounds necessary for daily living and work life.
There are no objective tests to diagnose tinnitus 76 but there are ways to manage the symptoms. The US Department of Veterans Affairs uses a progressive management program 77 with a team of health care providers to produce individualized management plans to reduce the impact of tinnitus on patients' lives.
# Resources for treating Veterans with hearing loss/tinnitus
• VAC provides a thorough overview of tinnitus 78 and hearing loss 79 and their impacts on quality of life, as well as of pension-eligible military-related events that could lead to these disorders.
• Veterans can receive compensation for hearing loss and tinnitus through VAC disability benefits. 80 • Veterans can obtain access to treatment benefits 81 for hearing loss/tinnitus through their VAC health care card, which can cover home health, audiologist and other specialist visits, medical equipment, and other supports.
# Best practices for managing effects of mild traumatic brain injury
Mild traumatic brain injury (MTBI) is an injury that typically results from a severe impact to the head. It can cause a range of chronic physical, mental, emotional, and behavioural symptoms. 82 While family physicians are likely familiar with treating concussion in civilian populations, additional attention should be paid to MTBI history in Veterans. MTBI is more frequent in Iraq/Afghan War Veterans but it can also occur in non-deployed service members. In addition to blunt force trauma and combat-related blast injuries, exposure to blasts in training exercises (and, in snipers, exposure to very close and repeated recoil from rounds of high-caliber rounds) can also result in MTBI. 83,84 Though no diagnostic test can establish MTBI in patients, in Veterans with persistent symptoms physicians should ask about the patient's MTBI history and conduct a physical examination with special consideration of neurological functioning. 83 Brain injuries can heal without lasting damage but Veterans with cognitive and psychological symptoms should be referred for mental health treatment. Strong collaboration between the patient, the family physician, and the supporting health care team (including mental health care providers) can pave the way for optimal results, as well as physicians' consideration of the relationship between the patient's military service and the injury. 83
# Resources for treating Veterans with symptoms related to MTBI
• OSI Clinics, 58 mentioned above, can also be used by Veterans with MTBI. Physicians can refer patients to OSI clinics for treatment by reaching out to the closest VAC office, where case managers can help potential clients access services.
# • Persistent Symptoms Following Mild Traumatic Brain Injury (mTBI): A Resource for Clinicians and
Staff 82 provides more detail for clinicians and health care providers in treating symptoms of an MTBI and gives thorough explanations of MTBI related to military service.
# Special considerations for issues related to military sexual trauma
While issues related to sexual assault and harassment are not unique to the military, family physicians may encounter Veterans who experienced sexual trauma during their military service. Approximately 1.6 per cent of Regular Force members reported military-related experiences of sexual assault, with women impacted at a significantly higher rate (4.3 per cent) compared with men (1.1 per cent). Indigenous members were affected at a greater rate (3 per cent) than non-Indigenous members (1.5 per cent), as were members with disabilities (3 per cent) compared with those without disabilities (1.5 per cent). 85 Exposure to sexual harassment or assault during military service 86 is different from civilian sexual trauma, as it is a work-related injury and can involve a sense of moral injury due to institutional betrayal in addition to the sexual misconduct. 87,88 Veterans who experienced military sexual trauma (MST) may have resulting PTSD; studies from the United States indicate a strong link between the two. 86,89 Evidence-based psychotherapies can be effective for treating MST. 90 Family physicians should work collaboratively with the Veteran and the Veteran's VAC case manager to ensure referral to psychotherapists with military cultural competencies to ensure evidence-based treatments.
# Resources for treating patients who experienced military sexual trauma
• Veterans who experienced sexual trauma during their military service may be newly eligible for VAC benefits, 91 even if previously denied.
• The Department of National Defence Sexual Misconduct Response Centre offers a 24/7 phone line 92 (1-844-750-1648) where CAF members can call to receive free, confidential support from a Sexual Misconduct Response Centre counsellor who can also refer patients to resources and services for further assistance. While the service is not tailored to Veterans, Veterans may call to receive support.
• The Centre of Excellence on Post-Traumatic Stress Disorder has created a Military Sexual Misconduct and Military Sexual Trauma Fact Sheet 93 that explains what MST is, provides statistics on MST, and lists other important factors to consider regarding MST.
• VA Beyond MST app 94 is a self-help tool for survivors of MST that helps users develop coping skills and manage symptoms in order to improve their quality of life.
# Special considerations for issues related to experiencing past 2SLGBTQ+ discrimination
While members of the 2SLGBTQ+ community have been able to serve in the Canadian military since 1992, discrimination based on sexual orientation still affects many soldiers throughout their service. 95 For Veterans who served prior to 1992, experiencing adverse psychological, physical, and social impacts (depression, stress, substance use) due to having to hide one's sexual orientation, or harassment/dismissal because of their sexual orientation, was not uncommon. 96,97 In the civilian population, evidence has demonstrated that 2SLGBTQ+ individuals are at a greater risk for mental health conditions than heterosexual individuals. 98 Research indicates that 2SLGBTQ+ individuals in the military are also at a higher risk for mental health conditions such as depression. 99 Experiencing anti-2SLGBTQ+ discrimination can increase one's risk for mental health issues. 100,101 Past experiences of discrimination can also prevent 2SLGBTQ+ people from accessing health care, 98 and some needs may not be appropriately addressed if health care providers are unaware of a patient's sexual orientation. Family physicians treating 2SLGBTQ+ Veterans should strive to create safe, accepting spaces and help to facilitate culturally safe care in collaboration with local 2SLGBTQ+ outreach services, to which they can refer patients.
# Resources for managing issues related to experiencing past 2SLGBTQ+ discrimination
• Ontario HIV Treatment Network's report Facilitators and barriers to health care for lesbian, gay and bisexual (LGB) people 98 may also be able to provide support to physicians looking for more resources to help patients who have experienced past 2SLGBTQ+ discrimination.
• VAC has a 2SLGBTQ+ Veteran hotline for those with service-related injuries who have not applied for benefits: 1-800-487-7797. 105
• Rainbow Veterans is a Veterans group that offers support to members who experienced discrimination while in the CAF because of their sexual orientation.
# Current military Veteran health concerns
Below are a few examples of health issues of concern to military Veterans of Canada from all eras:
# Current Military Veteran Health Concerns Resources
# Cannabis for Medical Use
As of 2016 VAC reimburses Veterans for the medical use of cannabis. 106 Medical cannabis is increasingly used by Veterans in Canada; medical cannabis reimbursements account for one in five medical reimbursements by VAC. 107,108 Evidence is mixed on outcomes of cannabis use. Some research has shown an association between cannabis use and poorer health outcomes among the general population 109,110 and among Veterans. 111 Various studies have shown some minor benefits of cannabis use for chronic pain. 107 Though AUD and cannabis use often co-occur in Veterans, Veterans who use cannabis for medical reasons show lower alcohol use than nonmedical users. 112
• The CFPC has provided guidelines 113 and recommendations for physicians regarding authorizing cannabis for medical purposes, including authorizing use only after conventional treatments have failed. 114 Provincial health care provider regulators across Canada have also provided guidelines for cannabis authorization. A Clinical Practice Guidelines article from CFP 115 outlines considerations for prescribing medical cannabis in primary care settings, which advises limiting the use of medical cannabinoids but highlights specific circumstances in which there is evidence demonstrating its benefit.
• A recent practice guideline 116 summarized that cannabis provided small benefits for chronic pain relief, physical functioning, and sleep quality for those with chronic pain, and a small risk of transient harms, concluding that the evidence supports a weak recommendation for a cannabis trial. However, there are a number of evidence limitations for health care providers to consider when discussing cannabis use with Veterans. 117
# Gulf War Illness
After service in the Gulf War of 1990-1991, a number of CAF Veterans described various symptoms which they understood as resulting from exposures during their Gulf War service. Extensive research has been conducted and is ongoing to understand these health issues. Though research has not provided sufficient evidence for a medically diagnosable condition, the term Gulf War illness (or chronic multisymptom illness) is used for these issues. 22,118 Certain conditions have been reported more commonly in Gulf War Veterans than in non-Gulf War Veterans and civilians, including symptoms of fibromyalgia and chronic fatigue syndrome. 119 Some conditions reported under the umbrella of Gulf War illnesses include major depression, anxiety, asthma/bronchitis, chronic fatigue, and cognitive dysfunction, but many have medically unexplained symptoms.
Similar to the civilian population, Veterans can have diagnosable medical issues and medically unexplained symptoms, both of which can be treated using traditional approaches. In a comprehensive study on Gulf War illnesses, the National Academy of Medicine (formerly Institute of Medicine) in the United States recommends that providers employ a long-term, integrated approach to helping patients manage their symptoms.
• VAC provides a thorough overview of Gulf War illness, including relevant research in Canada.
• The U.S. Department of Veterans Affairs provides guidance 120 for clinicians on how to diagnose and treat those with Gulf War illness.
# Current Military Veteran Health Concerns Resources
# Past Mefloquine Use
Mefloquine is an antimalarial medication, and was the CAF's most commonly used antimalarial until evidence demonstrated that some patients were experiencing adverse psychiatric effects from its use, particularly patients with existing psychiatric illnesses. 121 Some patients report long-term effects from mefloquine use, although in 2017 the CAF released findings from the Surgeon General's review, which did not find evidence supporting this claim. 122 Patients reporting health issues should be treated for the symptoms they are experiencing. For example, physicians can establish a treatment plan for patients experiencing PTSD regardless of its cause.
• Veterans can apply to claim any medical condition with supporting documentation from their doctor.
• Chapter Five of the Surgeon General's 2017 report 122 on mefloquine examines the evidence for short-term and long-term adverse effects of mefloquine use.
# Polypharmacy
Polypharmacy-the use of five or more medications to manage symptoms-is common in Veterans with comorbid and complex physical and mental health conditions, especially in older adults. 123 Evidence suggests potential negative effects of polypharzmacy.
# Accessible care
A key feature of the PMH is its ability to improve access to care. 125 This includes timely access, virtual access, and access to a variety of specialty services. Since higher rates of chronic mental and physical health conditions are common in Veterans, it is essential that they can access care when needed. A PMH setting allows Veterans to access the most appropriate care provider available while maintaining continuity of care.
# Patient-and family-partnered care
Patients play an important role in their care; their perspectives and history factor into their health experience.
Taking the time to understand patients' feelings, background, and experiences can strengthen the trust between patient and provider. For Veterans, military service and experience can be an important part of their identity and are often related to their health and well-being. 22 Involving Veteran patients as partners in their care can help them feel that they have more opportunities to talk about their needs, and that they are active participants in the management of their health and treatment plans. 125 Families are often involved in the care of their loved ones, helping the patient through illness and providing reliable health information. 126 Veterans' families have also experienced the unique pressures of their family member's military career, including frequent moves, the stress of occupational risks posed to the serving member, and the adjustment from military to civilian life. 20 Involving families and caregivers in the Veteran's care process (with the patient's permission) can facilitate better communication and enhanced care for the patient while decreasing stress for the family. 127 Patients should determine their level of involvement as partners, but options such as allowing them to access their medical information, providing them with self-management tools, and offering evidencebased information about their care can improve patient satisfaction and the patient-provider relationship. 12
# Long-term care and Home Care Services
# Caring for Veterans in the Patient's Medical Neighbourhood
The Patient's Medical Neighbourhood (Neighbourhood) 132 is a broader network of care involving providers and services outside the family practice. In a Neighbourhood, family practices coordinate and share responsibility for patient care with other health care providers and community services (e.g., mental health and addiction services, pharmacy, social, and community supports, etc.). In caring for Veterans, a Neighbourhood setting can help connect Veterans with relevant resources in their community, such as 2SLGBTQ+ health care centres, personalize their care, improve patient outcomes, and encourage continuity as a result of the existing relationship between the family practice and providers in the Neighbourhood.
# Community adaptiveness and social accountability
A PMH adapts to the needs of the community and works to understand how patients experience the health care system differently, based on intersecting social determinants of health. Indigenous, female, 2SLGBTQ+, and disabled Veterans are disproportionately affected by mental and physical health conditions. 128,129,130 Physicians caring for Veterans in these populations in the PMH are aware of socioeconomic influences on Veterans' health and work to respond to these differences at the patient, practice, community, and policy level. 132 Family doctors can act as advocates for their patients and encourage government to establish policies that improve Veterans' health and other forms of well-being.
# Comprehensive team-based care with family physician leadership and continuity of care
An interprofessional primary care team approach offers a host of benefits to patients, including improved access to care, better continuity of care, and enhanced access to specialty resources. The interprofessional nature of PMH teams allows health professionals with expertise in different disciplines to effectively work together to deliver comprehensive and specialized care to patients. In a PMH, family physicians work collaboratively with nurses, psychologists, social workers, physiotherapists, and other health care providers to provide convenient access to a varied range of high-quality care services.
Within the general population in Canada there is a high prevalence of patients with comorbid, complex chronic conditions. 131 Team-based, patient-centred primary care is crucial for effective management of health conditions over the long term and can be especially beneficial in treating Veterans when combined with the additional resources available through VAC programs. Many VAC programs encourage collaboration with family physicians, including OSI clinics and rehabilitation services. Open communication between VAC providers and the family physician can broaden options for effective treatment planning and can facilitate optimal patient outcomes. 32 In PMH settings, interdisciplinary primary care teams are knowledgeable about community resources and engaged with local organizations. As some Veterans may be newly transitioning to life after service, a PMH referral to resources in their community can help them find peers undergoing similar experiences, direct them to selfmanagement resources, and encourage a personalized and holistic approach to their well-being.
# Conclusion
Caring for Veterans can be deeply rewarding for family physicians. As the physician-patient relationship is at the core of the profession, connecting with Veterans, learning about their military service, and understanding their perspectives can be an enriching experience.
Treating Veteran patients allows family physicians to care for those who served Canada's population and often made great sacrifices to do so.
Additionally, many Veterans have been released from service at a young age or in middle age; physicians' active management of health conditions can have a tremendous impact on their ability to remain healthy, active, working, and participating in social and family life over decades. Early management of conditions with the right interventions can have lasting effects on Veterans and their families. Veterans have greater access to a variety of services and support than the general population; eligible Veterans can receive VAC funding for interprofessional care. This can facilitate enhanced treatment planning for the physician.
While 20 per cent of the Veteran population uses VAC services, there are many more Veterans who have health issues that may not be service-related. 3 Nevertheless, the military context and an understanding of Veterans' background remain important. Learning about and recognizing Veterans' experience can greatly enhance the provider-patient relationship and improve patients' health outcomes in the long term. Additionally, many Veterans may not know they can access VAC or may fear being denied benefits; family physicians can play a substantial role in facilitating access to benefits for which they are eligible. Working collaboratively with Veterans, VAC, and other health care teams and providers, in alignment with the PMH vision's principles of care, family physicians can have a significant and long-lasting impact on the health and well-being of their Veteran patients.
# Acknowledgements
| None | None |
509e9e394e35d7f7780f036e657dc2eae4f275fb | cma | None | # Background
On January 20, 2023, NACI published Guidance on COVID-19 vaccine booster doses: Initial considerations for 2023. This guidance consolidated and reinforced previously established booster dose recommendations and extended the fall booster program for those who had not yet received a 2022 recommended booster dose into 2023.
Since that time:
- Omicron sub-lineages continue to be the dominant strains of COVID-19 circulating in Canada. Viral sequencing is currently showing clear dominance of variants BQ.1 and BQ.1.1, while an increase in the XBB.1.5 recombinant sub-lineage is also being observed.
Based on neutralization studies, BQ- and XBB- sub-lineages are more immune evasive than earlier sub-lineages (such as BA.2 and BA.5), with XBB- described as the most immune evasive sub-lineage. - While there are fluctuations in COVID-19 transmission indicators (i.e., cases reported, hospitalizations, and deaths) and variation across provinces and territories, COVID-19 activity has been relatively stable with hospitalizations remaining at a relatively high level since the widespread circulation of Omicron in early 2022.
- Additional evidence has emerged on the performance and safety of bivalent vaccines, and the duration of protection of vaccination and hybrid immunity which help to inform the need for and benefit of additional booster doses.
NACI continues to monitor the rapidly evolving scientific data recognizing that the trajectory of the COVID-19 pandemic remains unclear. Updated recommendations will be made as needed.
NACI's recommendations remain aligned with the goals of the Canadian COVID-19 Pandemic Response that were last updated on February 14, 2022:
- To minimize serious illness and death while minimizing societal disruption as a result of the COVID-19 pandemic. - To transition away from the crisis phase towards a more sustainable approach to long term management of COVID-19.
# Methods
On February 6 and 7, 2023, NACI reviewed the available epidemiology and evidence on vaccine protection and hybrid immunity, including the performance of bivalent vaccines based on clinical trial data and real-world evidence from observational studies. Preliminary modelling data were also considered, as were ethics and acceptability considerations. NACI continues to apply the decision-making framework for booster doses in their deliberations. NACI approved these recommendations on February 19, 2023.
For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to National Advisory Committee on Immunization (NACI): Statements and publications and the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG)
Further information on NACI's process and procedures is available elsewhere (1,2) .
# Overview of Evidence
Available information as of February 5, 2023, is summarized below.
# Evolving epidemiology
- The evolutionary trajectory of SARS-CoV-2, including the emergence of novel variants of concern (VOCs), remains uncertain. - Omicron BQ.1 sub-lineages are currently the dominant strains circulating in Canada, while viral sequencing is also showing increases in the XBB.1.5 recombinant sub -lineage. - Recently circulating sub-lineages of Omicron (e.g., BQ*, XBB*) are more immune evasive than previous sub-lineages (e.g., BA.2, BA.4/5), based on the ability of recent sublineages to more efficiently evade neutralizing antibodies elicited from vaccination and past infection (3)(4)(5)(6)(7)(8)(9)(10) . - Rates of hospitalizations and deaths in Canada continue to be highest in unvaccinated individuals, particularly for adults 60 years of age and older, with risk increasing with age and highest among those ≥80 years, and lowest for those recently vaccinated (11) . - Seroepidemiologic studies demonstrate high levels of antibodies to vaccines and/or infection in the Canadian population (12) .
# Vaccine effectiveness and duration of vaccine protection of mRNA COVID-19 vaccine booster doses
Vaccine protection against infection and symptomatic disease with original monovalent COVID-19 vaccines has been shown to wane over time; however, protection against severe outcomes persists longer than protection against symptomatic disease (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) . Evidence suggests that a fourth dose of an original monovalent COVID-19 vaccine provides an increase in vaccine effectiveness (VE) against infection; however, waning of protection is observed over time, consistent with the waning of protection after two or three doses (25)(26)(27)(28)(29)(30) . VE against severe disease from booster doses is generally higher and more sustained than against infection. Due to the short follow-up period to date, there are no estimates available regarding waning following bivalent booster doses against infection or severe disease.
- Real-world effectiveness data from the US suggest that in adults, a booster dose of a BA.4/5 bivalent mRNA COVID-19 vaccine provides increased protection against both symptomatic disease and hospitalization, compared to those who did not receive a bivalent booster dose but received at least 2 previous doses of original monovalent vaccines in the past (31,32) . The relative VE of the bivalent booster increased with increased time since the original vaccine group received their last dose, due to increased waning over time in this group. From these observational studies, it cannot be determined if the benefit is due to the recent receipt of a booster dose and/or specifically the receipt of a bivalent booster. - Other clinical data comparing relative VE from a bivalent booster dose to an original monovalent booster dose are emerging. Although there are some limitations in these studies (often including earlier receipt of an original booster than a bivalent booster), the emerging evidence suggests that the bivalent vaccine performs at least as well as, and possibly better than, the original vaccine against circulating strains.
- Two recent studies by Lin et al. used linked administrative data from North Carolina to provide evidence regarding the VE of bivalent BA.4/5 booster doses compared to original monovalent booster doses. The first study of individuals ≥12 years of age assessed relative VE against severe outcomes of a single booster dose (original or bivalent BA.4/5, manufacturer not specified) compared to a previous original vaccine dose (primary series, or a first or second booster dose) during a period of 15-99 days after the booster dose. A single BA.4/5 bivalent mRNA booster dose provided greater and somewhat more sustained relative protection against severe outcomes than the relative protection from a single original mRNA booster dose. However, the original booster was administered and assessed over a three-month period occurring earlier than that of the bivalent booster, and other factors such as circulating variants and the extent of previous infection may have been different between the groups (33) . The second study (preprint) of children 5 to 11 years of age found that the relative VE against infection of a booster dose compared to only receiving two previous original vaccine doses was higher for those who received the BA.4/5 bivalent vaccine (manufacturer not specified) as a booster than the original vaccine as a booster. However, like the previous study, the original vaccine was given during an earlier period than the bivalent vaccine. As well, in some instances, the third dose may have been part of a 3-dose primary series recommended for immunocompromised individuals instead of a booster dose, and the distribution of those who are immunocompromised may have differed between the groups (34) . - Preliminary data from Ontario that was presented to NACI demonstrates that shortterm (<90 days) VE against severe outcomes in community dwelling adults aged ≥50 years was similar between those receiving original and bivalent mRNA vaccine booster doses and between the available vaccine products (Moderna Spikevax original or BA.1 bivalent and Pfizer-BioNTech Comirnaty original or BA.4/5 bivalent) during a period when BA.5 was the predominant Omicron sub-lineage and BQ.1 was emerging (35) .
- Preliminary data (preprint) from four Scandinavian countries used linked administrative data to evaluate the VE of a fourth dose (either original, BA.1 bivalent or BA.4/5 bivalent) up to 60 days after receipt of the booster dose relative to a third original vaccine dose. Regardless of product received, a fourth dose was associated with significantly reduced risks of hospitalization and death, compared to receiving only three doses. There was a trend towards increased protection against severe outcomes associated with a fourth dose of bivalent vaccine compared to a fourth dose of original vaccine, however effect estimates were imprecise with wide confidence intervals (CI) (36) . When comparing the BA.1 bivalent and BA.4/5 bivalent vaccines (manufacturer not specified), the BA.4/5 bivalent vaccine was associated with a somewhat lower relative risk of hospitalization compared to the BA.1 bivalent vaccine. However, this observation was based primarily on the comparative VE from Denmark. The VE estimate was not significant for Norway, and not estimable in the other two countries.
- A randomized clinical trial conducted by Moderna in the United Kingdom (preprint) compared those ≥16 years of age randomized to receive a bivalent BA.1 booster to those randomized to receive an original monovalent booster. Although the primary endpoint was immunogenicity, exploratory analyses revealed that the efficacy against symptomatic disease was somewhat higher for the bivalent booster than the original booster against sub-lineages BA.2 (relative VE of bivalent booster compared to original booster vaccine of 32.6%; 95% CI: -15.1 to 60.5%) and BA.4 (41.6%; 95% CI: -5.1 to 67.5%), but not against BA.5 (4.4%; 95% CI: -27.2 to 28.2%) (37) . - VE and duration of protection are still emerging for more recent variants (i.e., XBB.1.5 and BQ.1).
- A recent US study compared relative VE against symptomatic disease in immunocompetent adults who had and had not received a bivalent BA.4/5 booster among those who had previously received 2 to 4 original monovalent vaccine doses. Relative VE for the bivalent vaccine booster compared to past monovalent doses for at least 3 months after bivalent vaccination ranged from 37% to 52% (with somewhat lower VE with increasing age) against Omicron subvariants which were determined likely XBB/XBB.1.5-related and ranged from 40 to 49% against likely BA.5-related strains based on S-gene target status. The relative VE estimates for the bivalent BA.4/5 vaccine against XBB/XBB.1.5-related and BA.5related strains were similar (38) . - There are currently no available data regarding bivalent vaccine protection against severe disease caused by XBB/XBB.1.5.
# Safety of Omicron-containing bivalent mRNA COVID-19 vaccines
- Available evidence from Canada and internationally show that overall, the safety profile of the bivalent mRNA COVID-19 vaccine boosters is comparable to that of original mRNA COVID-19 vaccine boosters among individuals aged ≥5 years (39)(40)(41)(42)(43)(44)(45) . - The safety profile appears to be similar in those with or without previous SARS-CoV-2 infections. - A possible association between Pfizer-BioNTech Comirnaty bivalent BA.4/5 booster and ischemic stroke in persons ≥65 years of age has been identified by the US Vaccine Safety Datalink (VSD) (46,47) . This possible association has not been replicated in other surveillance systems used to monitor vaccine safety in the US or in other countries. As well, this potential safety signal has not been identified with the Moderna Spikevax bivalent BA.4/5 mRNA COVID-19 vaccine. To date, the totality of the US data suggests that it is very unlikely that the potential signal in VSD represents a true clinical risk (46)(47)(48) . This is supported by international data including from Canada, Israel, Europe, and Singapore where a similar signal has not been identified. Monitoring of the potential safety signal is ongoing. NACI updates its recommendations as needed.
# Hybrid immunity
- Hybrid immunity results from ≥1 exposure(s) from vaccination and ≥1 exposure(s) from SARS-CoV-2 infection (before or after vaccination). Previous infection and vaccination may provide superior protection (as measured by neutralization capacity) against VOCs, including Omicron, compared with primary vaccination only, or previous SARS-CoV-2 infection without vaccination. - In Canada, hybrid immunity population profiles differ by age group. A greater proportion of older adults are protected by vaccination only and have not been infected, as compared to younger ages. Adolescents and young adults have the highest proportion of hybrid immunity, and a large proportion of children have been infected but not vaccinated (12) .
- There are Canadian data suggesting that vaccine protection may reach a plateau for adults with hybrid immunity, with limited benefit demonstrated in receiving booster doses of the original mRNA COVID-19 vaccines against Omicron subvariants BA.2 infection/symptomatic disease in healthcare workers with hybrid immunity and against BA.1, BA.2 and BA.4/5 hospitalization in non-institutionalized elderly populations with hybrid immunity (15,49,50) . Additionally, VE is lower in adults without previous infection and has more pronounced waning over time compared to those with previous infection. - A systematic review and meta-regression study also found that protection against severe disease from hybrid immunity with primary series vaccination remained >95% until the end of available follow-up at 11 months after vaccination and up to 4 months based on available data from hybrid immunity with first booster vaccination. Based on statistical modelling projections, protection from hybrid immunity would be sustained at elevated levels to at least 12 months after primary series and at least 6 months after booster vaccination (51) . However, the analysis was based on studies on protection conferred by pre-Omicron SARS-CoV-2 strains and there was no consideration of the impact on protection due to circulation of more immune evasive Omicron subvariants. - These data suggest that future booster program efforts may achieve the greatest impact among those who have not yet been infected by the SARS-CoV-2 virus. Further study will be needed to determine whether the findings regarding the protection from hybrid immunity would apply broadly to Omicron-containing bivalent COVID-19 vaccines (although based on available evidence regarding the performance of bivalent vaccines, this is expected to be the case) and against new subvariants and VOCs.
# Ethics, equity, feasibility, and acceptability (EEFA)
- Given the considerable uncertainty regarding the trajectory of the COVID-19 pandemic, NACI based its recommendations on an evidence-informed framework and recommends booster doses focused on those at greatest risk of severe illness from COVID-19 at this time.
- COVID-19 vaccine uptake increases with age in Canada, but uptake with each subsequent dose has decreased suggesting acceptability has decreased over time. - There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions. - Supply of bivalent vaccines (BA.1 or BA.4/5) in Canada is expected to be sufficient to accommodate NACI's recommendations for booster doses.
# Other considerations
- Using assumptions based on recent VE studies, where waning protection against hospitalisations occurs most in older adults without hybrid immunity, modelling suggests that an additional booster dose in adults 65 years and older starting this spring could be expected to prevent hundreds or thousands of hospitalizations across the country this year if a booster dose restores protection to levels achieved shortly after the previous dose. Modelled estimates are dependent on various assumptions on aspects such as the durability of protection from bivalent booster doses, the rate of infection of future subvariants, and the ability of future subvariants to escape protection offered by the vaccines.
# Recommendations
Please see Table 1 for an explanation of strong versus discretionary NACI recommendations.
NACI continues to recommend a COVID-19 vaccine primary series as follows:
- Individuals 5 years of age and older should be immunized with a primary series of an authorized mRNA vaccine. (Strong NACI recommendation) 2. Children 6 months to under 5 years of age may be immunized with a primary series of an authorized mRNA vaccine. (Discretionary NACI recommendation)
Additional details including those pertaining to alternative vaccine products are available in the COVID-19 vaccine chapter in the Canadian Immunization Guide and NACI statements and publications. - Bivalent Omicron-containing mRNA COVID-19 vaccines are the preferred booster products. - No other recommendations for additional booster doses are being made at this time.
- NACI will continue to monitor the SARS-CoV-2 epidemiology and emerging evidence, including duration of vaccine protection from bivalent booster doses in the coming months to provide recommendations on the timing of subsequent booster doses if warranted. - Planning should consider that vaccine deployment may be recommended for broader population groups in the fall of 2023 depending on the COVID-19 pandemic context.
For further information on these recommendations, please refer to the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
NACI continues to monitor and assess the evidence as it emerges and will update its recommendations as needed.
# RESEARCH PRIORITIES
- Continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of COVID-19 vaccines, including bivalent mRNA booster doses, through clinical trials and studies in real-world settings, including the degree and duration of protection conferred by each booster dose against circulating variants. The research should also consider the clinical implications of previous SARS-CoV-2 infection; repeated immunization; and outcomes after any infection such as multisystem inflammatory syndrome in children (MIS-C), post-COVID-19 condition/post-acute COVID syndrome (long COVID), or infectioninduced myocarditis and/or pericarditis in older adult, adult, adolescent, and pediatric populations. 2. Further evaluations of the optimal interval between dose administration, as well as further evaluations of the optimal interval between previous SARS-CoV-2 infection and vaccine dose administration. 3. Vigilant monitoring and reporting of adverse events of special interest to support the rapid identification of potential vaccine safety signals and accurately inform potential risks associated with any future booster doses. Global collaboration should be prioritized to enable data sharing so decision makers around the world can weigh benefits and risks of additional booster doses of COVID-19 vaccines. 4. Continuous monitoring of COVID-19 epidemiology and VE in special populations at high risk of severe outcomes or long-term consequences of infection with COVID-19, including but not limited to those with co-morbidities, immunocompromising conditions, and pregnant populations. 5. Further evaluation on the optimal timing and trigger for the initiation of potential future booster dose recommendations, as well as evaluation of potential risks associated with providing booster doses earlier than necessary. 6. Continuous monitoring of vaccine coverage in Canada, for COVID-19 vaccines and other routine vaccines, particularly in the context of COVID-19 vaccine booster doses and including consideration of measures that may reduce the risk of disparities in vaccine confidence and uptake across different sub-populations.
# Implication
A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale f or an alternative approach is present.
A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable. | # Background
On January 20, 2023, NACI published Guidance on COVID-19 vaccine booster doses: Initial considerations for 2023. This guidance consolidated and reinforced previously established booster dose recommendations and extended the fall booster program for those who had not yet received a 2022 recommended booster dose into 2023.
Since that time:
• Omicron sub-lineages continue to be the dominant strains of COVID-19 circulating in Canada. Viral sequencing is currently showing clear dominance of variants BQ.1 and BQ.1.1, while an increase in the XBB.1.5 recombinant sub-lineage is also being observed.
Based on neutralization studies, BQ* and XBB* sub-lineages are more immune evasive than earlier sub-lineages (such as BA.2 and BA.5), with XBB* described as the most immune evasive sub-lineage. • While there are fluctuations in COVID-19 transmission indicators (i.e., cases reported, hospitalizations, and deaths) and variation across provinces and territories, COVID-19 activity has been relatively stable with hospitalizations remaining at a relatively high level since the widespread circulation of Omicron in early 2022.
• Additional evidence has emerged on the performance and safety of bivalent vaccines, and the duration of protection of vaccination and hybrid immunity which help to inform the need for and benefit of additional booster doses.
NACI continues to monitor the rapidly evolving scientific data recognizing that the trajectory of the COVID-19 pandemic remains unclear. Updated recommendations will be made as needed.
NACI's recommendations remain aligned with the goals of the Canadian COVID-19 Pandemic Response that were last updated on February 14, 2022:
• To minimize serious illness and death while minimizing societal disruption as a result of the COVID-19 pandemic. • To transition away from the crisis phase towards a more sustainable approach to long term management of COVID-19.
# Methods
On February 6 and 7, 2023, NACI reviewed the available epidemiology and evidence on vaccine protection and hybrid immunity, including the performance of bivalent vaccines based on clinical trial data and real-world evidence from observational studies. Preliminary modelling data were also considered, as were ethics and acceptability considerations. NACI continues to apply the decision-making framework for booster doses in their deliberations. NACI approved these recommendations on February 19, 2023.
For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to National Advisory Committee on Immunization (NACI): Statements and publications and the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG)
Further information on NACI's process and procedures is available elsewhere (1,2) .
# Overview of Evidence
Available information as of February 5, 2023, is summarized below.
# Evolving epidemiology
• The evolutionary trajectory of SARS-CoV-2, including the emergence of novel variants of concern (VOCs), remains uncertain. • Omicron BQ.1 sub-lineages are currently the dominant strains circulating in Canada, while viral sequencing is also showing increases in the XBB.1.5 recombinant sub -lineage. • Recently circulating sub-lineages of Omicron (e.g., BQ*, XBB*) are more immune evasive than previous sub-lineages (e.g., BA.2, BA.4/5), based on the ability of recent sublineages to more efficiently evade neutralizing antibodies elicited from vaccination and past infection (3)(4)(5)(6)(7)(8)(9)(10) . • Rates of hospitalizations and deaths in Canada continue to be highest in unvaccinated individuals, particularly for adults 60 years of age and older, with risk increasing with age and highest among those ≥80 years, and lowest for those recently vaccinated (11) . • Seroepidemiologic studies demonstrate high levels of antibodies to vaccines and/or infection in the Canadian population (12) .
# Vaccine effectiveness and duration of vaccine protection of mRNA COVID-19 vaccine booster doses
Vaccine protection against infection and symptomatic disease with original monovalent COVID-19 vaccines has been shown to wane over time; however, protection against severe outcomes persists longer than protection against symptomatic disease (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) . Evidence suggests that a fourth dose of an original monovalent COVID-19 vaccine provides an increase in vaccine effectiveness (VE) against infection; however, waning of protection is observed over time, consistent with the waning of protection after two or three doses (25)(26)(27)(28)(29)(30) . VE against severe disease from booster doses is generally higher and more sustained than against infection. Due to the short follow-up period to date, there are no estimates available regarding waning following bivalent booster doses against infection or severe disease.
• Real-world effectiveness data from the US suggest that in adults, a booster dose of a BA.4/5 bivalent mRNA COVID-19 vaccine provides increased protection against both symptomatic disease and hospitalization, compared to those who did not receive a bivalent booster dose but received at least 2 previous doses of original monovalent vaccines in the past (31,32) . The relative VE of the bivalent booster increased with increased time since the original vaccine group received their last dose, due to increased waning over time in this group. From these observational studies, it cannot be determined if the benefit is due to the recent receipt of a booster dose and/or specifically the receipt of a bivalent booster. • Other clinical data comparing relative VE from a bivalent booster dose to an original monovalent booster dose are emerging. Although there are some limitations in these studies (often including earlier receipt of an original booster than a bivalent booster), the emerging evidence suggests that the bivalent vaccine performs at least as well as, and possibly better than, the original vaccine against circulating strains.
• Two recent studies by Lin et al. used linked administrative data from North Carolina to provide evidence regarding the VE of bivalent BA.4/5 booster doses compared to original monovalent booster doses. ▪ The first study of individuals ≥12 years of age assessed relative VE against severe outcomes of a single booster dose (original or bivalent BA.4/5, manufacturer not specified) compared to a previous original vaccine dose (primary series, or a first or second booster dose) during a period of 15-99 days after the booster dose. A single BA.4/5 bivalent mRNA booster dose provided greater and somewhat more sustained relative protection against severe outcomes than the relative protection from a single original mRNA booster dose. However, the original booster was administered and assessed over a three-month period occurring earlier than that of the bivalent booster, and other factors such as circulating variants and the extent of previous infection may have been different between the groups (33) . ▪ The second study (preprint) of children 5 to 11 years of age found that the relative VE against infection of a booster dose compared to only receiving two previous original vaccine doses was higher for those who received the BA.4/5 bivalent vaccine (manufacturer not specified) as a booster than the original vaccine as a booster. However, like the previous study, the original vaccine was given during an earlier period than the bivalent vaccine. As well, in some instances, the third dose may have been part of a 3-dose primary series recommended for immunocompromised individuals instead of a booster dose, and the distribution of those who are immunocompromised may have differed between the groups (34) . • Preliminary data from Ontario that was presented to NACI demonstrates that shortterm (<90 days) VE against severe outcomes in community dwelling adults aged ≥50 years was similar between those receiving original and bivalent mRNA vaccine booster doses and between the available vaccine products (Moderna Spikevax original or BA.1 bivalent and Pfizer-BioNTech Comirnaty original or BA.4/5 bivalent) during a period when BA.5 was the predominant Omicron sub-lineage and BQ.1 was emerging (35) .
• Preliminary data (preprint) from four Scandinavian countries used linked administrative data to evaluate the VE of a fourth dose (either original, BA.1 bivalent or BA.4/5 bivalent) up to 60 days after receipt of the booster dose relative to a third original vaccine dose. Regardless of product received, a fourth dose was associated with significantly reduced risks of hospitalization and death, compared to receiving only three doses. There was a trend towards increased protection against severe outcomes associated with a fourth dose of bivalent vaccine compared to a fourth dose of original vaccine, however effect estimates were imprecise with wide confidence intervals (CI) (36) . When comparing the BA.1 bivalent and BA.4/5 bivalent vaccines (manufacturer not specified), the BA.4/5 bivalent vaccine was associated with a somewhat lower relative risk of hospitalization compared to the BA.1 bivalent vaccine. However, this observation was based primarily on the comparative VE from Denmark. The VE estimate was not significant for Norway, and not estimable in the other two countries.
• A randomized clinical trial conducted by Moderna in the United Kingdom (preprint) compared those ≥16 years of age randomized to receive a bivalent BA.1 booster to those randomized to receive an original monovalent booster. Although the primary endpoint was immunogenicity, exploratory analyses revealed that the efficacy against symptomatic disease was somewhat higher for the bivalent booster than the original booster against sub-lineages BA.2 (relative VE of bivalent booster compared to original booster vaccine of 32.6%; 95% CI: -15.1 to 60.5%) and BA.4 (41.6%; 95% CI: -5.1 to 67.5%), but not against BA.5 (4.4%; 95% CI: -27.2 to 28.2%) (37) . • VE and duration of protection are still emerging for more recent variants (i.e., XBB.1.5 and BQ.1).
• A recent US study compared relative VE against symptomatic disease in immunocompetent adults who had and had not received a bivalent BA.4/5 booster among those who had previously received 2 to 4 original monovalent vaccine doses. Relative VE for the bivalent vaccine booster compared to past monovalent doses for at least 3 months after bivalent vaccination ranged from 37% to 52% (with somewhat lower VE with increasing age) against Omicron subvariants which were determined likely XBB/XBB.1.5-related and ranged from 40 to 49% against likely BA.5-related strains based on S-gene target status. The relative VE estimates for the bivalent BA.4/5 vaccine against XBB/XBB.1.5-related and BA.5related strains were similar (38) . • There are currently no available data regarding bivalent vaccine protection against severe disease caused by XBB/XBB.1.5.
# Safety of Omicron-containing bivalent mRNA COVID-19 vaccines
• Available evidence from Canada and internationally show that overall, the safety profile of the bivalent mRNA COVID-19 vaccine boosters is comparable to that of original mRNA COVID-19 vaccine boosters among individuals aged ≥5 years (39)(40)(41)(42)(43)(44)(45) . • The safety profile appears to be similar in those with or without previous SARS-CoV-2 infections. • A possible association between Pfizer-BioNTech Comirnaty bivalent BA.4/5 booster and ischemic stroke in persons ≥65 years of age has been identified by the US Vaccine Safety Datalink (VSD) (46,47) . This possible association has not been replicated in other surveillance systems used to monitor vaccine safety in the US or in other countries. As well, this potential safety signal has not been identified with the Moderna Spikevax bivalent BA.4/5 mRNA COVID-19 vaccine. To date, the totality of the US data suggests that it is very unlikely that the potential signal in VSD represents a true clinical risk (46)(47)(48) . This is supported by international data including from Canada, Israel, Europe, and Singapore where a similar signal has not been identified. Monitoring of the potential safety signal is ongoing. NACI updates its recommendations as needed.
# Hybrid immunity
• Hybrid immunity results from ≥1 exposure(s) from vaccination and ≥1 exposure(s) from SARS-CoV-2 infection (before or after vaccination). Previous infection and vaccination may provide superior protection (as measured by neutralization capacity) against VOCs, including Omicron, compared with primary vaccination only, or previous SARS-CoV-2 infection without vaccination. • In Canada, hybrid immunity population profiles differ by age group. A greater proportion of older adults are protected by vaccination only and have not been infected, as compared to younger ages. Adolescents and young adults have the highest proportion of hybrid immunity, and a large proportion of children have been infected but not vaccinated (12) .
• There are Canadian data suggesting that vaccine protection may reach a plateau for adults with hybrid immunity, with limited benefit demonstrated in receiving booster doses of the original mRNA COVID-19 vaccines against Omicron subvariants BA.2 infection/symptomatic disease in healthcare workers with hybrid immunity and against BA.1, BA.2 and BA.4/5 hospitalization in non-institutionalized elderly populations with hybrid immunity (15,49,50) . Additionally, VE is lower in adults without previous infection and has more pronounced waning over time compared to those with previous infection. • A systematic review and meta-regression study also found that protection against severe disease from hybrid immunity with primary series vaccination remained >95% until the end of available follow-up at 11 months after vaccination and up to 4 months based on available data from hybrid immunity with first booster vaccination. Based on statistical modelling projections, protection from hybrid immunity would be sustained at elevated levels to at least 12 months after primary series and at least 6 months after booster vaccination (51) . However, the analysis was based on studies on protection conferred by pre-Omicron SARS-CoV-2 strains and there was no consideration of the impact on protection due to circulation of more immune evasive Omicron subvariants. • These data suggest that future booster program efforts may achieve the greatest impact among those who have not yet been infected by the SARS-CoV-2 virus. Further study will be needed to determine whether the findings regarding the protection from hybrid immunity would apply broadly to Omicron-containing bivalent COVID-19 vaccines (although based on available evidence regarding the performance of bivalent vaccines, this is expected to be the case) and against new subvariants and VOCs.
# Ethics, equity, feasibility, and acceptability (EEFA)
• Given the considerable uncertainty regarding the trajectory of the COVID-19 pandemic, NACI based its recommendations on an evidence-informed framework and recommends booster doses focused on those at greatest risk of severe illness from COVID-19 at this time.
• COVID-19 vaccine uptake increases with age in Canada, but uptake with each subsequent dose has decreased suggesting acceptability has decreased over time. • There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions. • Supply of bivalent vaccines (BA.1 or BA.4/5) in Canada is expected to be sufficient to accommodate NACI's recommendations for booster doses.
# Other considerations
• Using assumptions based on recent VE studies, where waning protection against hospitalisations occurs most in older adults without hybrid immunity, modelling suggests that an additional booster dose in adults 65 years and older starting this spring could be expected to prevent hundreds or thousands of hospitalizations across the country this year if a booster dose restores protection to levels achieved shortly after the previous dose. Modelled estimates are dependent on various assumptions on aspects such as the durability of protection from bivalent booster doses, the rate of infection of future subvariants, and the ability of future subvariants to escape protection offered by the vaccines.
# Recommendations
Please see Table 1 for an explanation of strong versus discretionary NACI recommendations.
NACI continues to recommend a COVID-19 vaccine primary series as follows:
1. Individuals 5 years of age and older should be immunized with a primary series of an authorized mRNA vaccine. (Strong NACI recommendation) 2. Children 6 months to under 5 years of age may be immunized with a primary series of an authorized mRNA vaccine. (Discretionary NACI recommendation)
Additional details including those pertaining to alternative vaccine products are available in the COVID-19 vaccine chapter in the Canadian Immunization Guide and NACI statements and publications. • Bivalent Omicron-containing mRNA COVID-19 vaccines are the preferred booster products. • No other recommendations for additional booster doses are being made at this time.
• NACI will continue to monitor the SARS-CoV-2 epidemiology and emerging evidence, including duration of vaccine protection from bivalent booster doses in the coming months to provide recommendations on the timing of subsequent booster doses if warranted. • Planning should consider that vaccine deployment may be recommended for broader population groups in the fall of 2023 depending on the COVID-19 pandemic context.
For further information on these recommendations, please refer to the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
NACI continues to monitor and assess the evidence as it emerges and will update its recommendations as needed.
# RESEARCH PRIORITIES
1. Continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of COVID-19 vaccines, including bivalent mRNA booster doses, through clinical trials and studies in real-world settings, including the degree and duration of protection conferred by each booster dose against circulating variants. The research should also consider the clinical implications of previous SARS-CoV-2 infection; repeated immunization; and outcomes after any infection such as multisystem inflammatory syndrome in children (MIS-C), post-COVID-19 condition/post-acute COVID syndrome (long COVID), or infectioninduced myocarditis and/or pericarditis in older adult, adult, adolescent, and pediatric populations. 2. Further evaluations of the optimal interval between dose administration, as well as further evaluations of the optimal interval between previous SARS-CoV-2 infection and vaccine dose administration. 3. Vigilant monitoring and reporting of adverse events of special interest to support the rapid identification of potential vaccine safety signals and accurately inform potential risks associated with any future booster doses. Global collaboration should be prioritized to enable data sharing so decision makers around the world can weigh benefits and risks of additional booster doses of COVID-19 vaccines. 4. Continuous monitoring of COVID-19 epidemiology and VE in special populations at high risk of severe outcomes or long-term consequences of infection with COVID-19, including but not limited to those with co-morbidities, immunocompromising conditions, and pregnant populations. 5. Further evaluation on the optimal timing and trigger for the initiation of potential future booster dose recommendations, as well as evaluation of potential risks associated with providing booster doses earlier than necessary. 6. Continuous monitoring of vaccine coverage in Canada, for COVID-19 vaccines and other routine vaccines, particularly in the context of COVID-19 vaccine booster doses and including consideration of measures that may reduce the risk of disparities in vaccine confidence and uptake across different sub-populations.
# Implication
A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale f or an alternative approach is present.
A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.
# ACKNOWLEDGMENTS
This statement was prepared by: E Wong, B Warshawsky, J Montroy, J Zafack, MC Tunis, R Harrison, S Wilson, and S Deeks, on behalf of NACI.
NACI gratefully acknowledges the contribution of: K Ramotar, C Mauviel, M Salvadori, R Krishnan, A Killikelly, E Tice, and the NACI Secretariat. | None | None |
0c86c39b2b1f9a16d42d3e61908100c3fa1e421f | cma | None | This Canadian Cardiovascular Society position statement is focused on the management of sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) that occurs in patients with structural heart disease (SHD), including previous myocardial infarction, dilated cardiomyopathy, and other forms of nonischemic cardiomyopathy. This patient population is rapidly increasing because of advances in care and improved overall survival of patients with all forms of SHD. In this position statement, the acute and long-term management of VT/VF are outlined, and the many unique aspects of care in this populationThis Canadian Cardiovascular Society position statement is focused on the acute and long-term management of sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) in patients with structural heart disease (SHD), defined by the presence of abnormal myocardium and scar. SHD includes conditions such as myocardial infarction (MI), dilated cardiomyopathies, hypertrophic cardiomyopathy, infiltrative cardiomyopathies (eg, sarcoidosis), and arrhythmogenic right ventricular cardiomyopathy# R ESUM E
Le pr esent enonc e de position de la Soci et e canadienne de cardiologie est ax e sur la prise en charge de la tachycardie ventriculaire (TV) et de la fibrillation ventriculaire (FV) soutenues qui surviennent chez les patients pr esentant une cardiopathie structurelle, par exemple des ant ec edents d'infarctus du myocarde, une cardiomyopathie dilat ee et d'autres formes de cardiomyopathie non isch emique. Cette population de patients augmente rapidement, en raison des avanc ees r ealis ees en matière de soins et de l'am elioration de la survie globale des patients pr esentant une cardiopathie structurelle sous une forme ou (ARVC). Almost all such patients have an indication for an implantable cardioverter-defibrillator (ICD). 1 Although many of the recommendations in this document can apply to patients with complex congenital heart disease, this population is not specifically addressed. The reader is referred to other published resources on the management of VT/VF in that population. 2,3 This statement is not intended to replace the guidelines for cardiopulmonary resuscitation, 4 but provides guidance for the ongoing care of patients with VT/VF after resuscitation. This statement is targeted at health professionals involved in the continuum of care of patients with SHD and VT/VF, including emergency medicine, critical care, internal medicine, and cardiology. The management of premature ventricular complexes and nonsustained VT in patients with SHD, and the management of VT/VF in patients with structurally normal hearts (including inherited arrhythmia syndromes) are beyond the scope of this statement.
# Position Statement Development
This position statement was written by a multidisciplinary panel of experts who care for patients with VT/VF (see Supplemental Table S1). The recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation standards with strength of recommendations classified as "strong" or "conditional." The recommendations are presented, along with their background and rationale.
# Definitions
Sustained VT is defined as an episode of VT lasting > 30 seconds or requiring intervention before 30 seconds. 5 Hemodynamically stable VT is defined as VT without signs or symptoms of organ hypoperfusion. Electrical storm (also known as VT/VF storm) is defined as the occurrence of 3 or more distinct episodes of VT/VF within 24 hours. Monomorphic VT has similar QRS complexes on the electrocardiogram (ECG), whereas polymorphic VT has changing beat-to-beat morphology. Torsade de pointes is polymorphic VT occurring in the setting of QT prolongation. VF is chaotic and does not have distinct QRS complexes on the ECG. Monomorphic VT might degenerate to polymorphic VT or VF. A summary of classification and mechanisms of VT and VF in patients with SHD is presented in Supplemental Table S2.
# Incidence and Prognosis of Sustained VT/VF in Patients With SHD
Ventricular arrhythmias can cause sudden cardiac death (SCD) or arrest, most frequently in those with previous MI. 6 The past decade saw a decreasing incidence of post-MI VT/ VF causing SCD, yet no change in the incidence of SCD in patients without ischemic heart disease. 7 The development of VT/VF in patients with SHD is associated with a higher risk of future episodes of VT/VF, of electrical storm, and of death. 8
# Initial Evaluation and Management of SHD Patients With Sustained VT/VF
Patients who present with VT/VF often have a preexisting diagnosis of SHD. However, VT/VF might be the initial indication of the presence of SHD for some patients. The initial evaluation must rapidly assess the need for acute intervention and identify potential etiologies or precipitating factors. When the patient is stabilized, the evaluation should include a complete history and examination, comprehensive laboratory testing, and assessment of cardiac function (Fig. 1).
A 12-lead ECG recorded during VT is important to localize VT and give insight into pathophysiology. An ECG performed after restoration of the underlying rhythm can be used to evaluate for reversible causes, such as ischemia and QT prolongation. Laboratory tests might identify precipitating RECOMMENDATION 1. We recommend that all patients presenting with VT/ VF undergo a comprehensive initial evaluation including a detailed history, physical examination, laboratory investigations, ECG, ICD interrogation (if present) and transthoracic echocardiography (Strong Recommendation, Low-Quality Evidence).
Values and preferences. A comprehensive initial evaluation can be performed quickly and at a reasonable cost. This evaluation is critical for guiding subsequent treatment.
Practical tip. If not previously diagnosed, most forms of SHD will be apparent after this initial evaluation. Unless a reversible cause is identified (such as acute MI), all patients with VT/VF and SHD should be referred for consideration of an ICD, if not already present, for the prevention of sudden death.
are emphasized. The initial evaluation, acute therapy, indications for chronic suppressive therapy, choices of chronic suppressive therapy, implantable cardioverter-defibrillator programming, alternative therapies, and psychosocial care are reviewed and recommendations for optimal care are provided. The target audience for this statement includes all health professionals involved in the continuum of care of patients with SHD and VT/VF. une autre. L' enonc e de position pr esente les grandes lignes de la prise en charge aiguë et à long terme de la TV et de la FV, et fait ressortir les nombreux aspects propres aux soins dont cette population a besoin. L' evaluation initiale, le traitement aigu, les indications commandant un traitement suppresseur prolong e, les options de traitement suppresseur prolong e, la programmation des d efibrillateurs cardioverteurs implantables, les th erapies parallèles et les soins psychosociaux sont examin es, et des recommandations concernant les soins optimaux sont formul ees. Ce document est destin e à tous les professionnels de la sant e qui interviennent dans le continuum des soins aux patients pr esentant une cardiopathie structurelle et une TV/FV.
factors, prognostic factors, and contraindications to specific antiarrhythmic drug (AAD) therapies (such as renal or hepatic dysfunction). Cardiac imaging is useful to determine the presence of underlying SHD and aid prognostication. Transthoracic echocardiography remains the first-line diagnostic imaging tool for assessment of ventricular function, wall motion abnormalities, and valvular disease. Nevertheless, it has limitations in identifying scar. Cardiac magnetic resonance (CMR) imaging, with gadolinium contrast, can support the diagnosis, particularly with nonischemic and infiltrative cardiomyopathies. 9,10 Emergent angiography should be performed for VT/VF in the setting of ST-elevation MI. Urgent angiography should also be considered in those who present with polymorphic VT/VF potentially due to acute ischemia. Other coronary imaging modalities can be considered if there is a lower index of suspicion of coronary disease. Monomorphic VT is rarely caused by acute ischemia, but coronary imaging might be warranted to establish the presence and severity of coronary artery disease.
Positron emission tomography can be useful in identifying patients with active inflammatory states, such as sarcoidosis, when other imaging modalities yield negative or equivocal findings. 11 Invasive electrophysiological testing of patients with wide complex tachycardia might be useful to distinguish VT from SVT or to diagnose bundle-branch reentry VT. 12
# Management of hemodynamically unstable VT/VF
Figure 2 illustrates the acute management of patients with VT/VF. In patients with unstable VT electrical cardioversion/defibrillation is indicated and advanced cardiac life support algorithms should be followed (Fig. 2A). 13,14 In
# Ini al Evalua on of Sustained VT/VF
# RECOMMENDATION
- We recommend that CMR imaging be performed in patients who present with VT/VF when the initial evaluation has failed to establish the etiology of the underlying heart disease (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. CMR imaging provides enhanced assessment of the presence, location, and quantity of myocardial scar in patients with SHD and can identify inflammatory conditions, such as myocarditis. Practical tip. In patients for whom the initial workup is not definitive, early use of CMR imaging has a high diagnostic and prognostic yield. patients with shock-refractory VF or VT, bolus intravenous (I.V.) amiodarone or lidocaine should be used. 15,16 Intravenous AAD dosing is summarized in Supplemental Table S3.
# Electrical storm
A Figure 2
. Initial management of sustained VT/VF. The initial management of VF and polymorphic VT is outlined in (A), whereas the initial management of monomorphic VT is outlined in (B). For unstable patients with VT/VF that recurs despite defibrillation/cardioversion or VT/VF that persists despite 1-2 attempts at defibrillation/cardioversion, intravenous (I.V.) amiodarone or lidocaine should be administered. For unstable VT/VF that recurs, the treatment should follow the electrical storm recommendations. See the accompanying text for drug dosing. ACLS, Advanced Cardiac Life Support; ACS, acute coronary syndrome; VF, ventricular fibrillation; VT, ventricular tachycardia.
# RECOMMENDATION
- We recommend the administration of I.V. amiodarone or lidocaine for acute treatment of patients with shockrefractory VT/VF (failure of at least 1 attempt at defibrillation) or patients with recurrent polymorphic VT/ VF, unless there is a strong suspicion of torsade de pointes (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. The outcome of unstable patients with VT/VF arrest is poor, particularly in out-ofhospital settings. There is likely a small benefit to these drugs, which outweigh their risks.
Practical tip. Simplified, rather than weight-based dosing is easier in the setting of unstable VT/VF. Amiodarone can be given as 300 mg I.V. push (150 mg I.V. push for those < 45 kg) with a subsequent dose of 150 mg I.V. push in the event of failure of another shock. Lidocaine can be given as 100 mg I.V. push (50 mg I.V. push if < 45 kg) with a subsequent dose of 50 mg I.V. push in the event of failure of another shock.
b-blockade with propranolol, given immediately and continued during the hospitalization, was superior to selective b1 blockade (metoprolol) for suppressing VT, in conjunction with usual care including I.V. amiodarone. 17 If initial management strategies fail, general anaesthesia can be considered. Dexmedetomidine and propofol are preferred sedating agents because of their sedative and sympatholytic effects. 18,19 Patients with an ICD and electrical storm should undergo early device interrogation; ICD programming can be adjusted (such as optimizing antitachycardia pacing ) or ICD therapy can be temporarily disabled, if appropriate.
Amiodarone is useful for electrical storm in patients with SHD, and a target loading dose of 1000-2000 mg I.V. over the first 24 hours is recommended (Supplemental Table S3). 20,21 Combinations of AADs with distinct mechanisms of action (eg, amiodarone and lidocaine) might prove effective for acute arrhythmia suppression in selected patients. Ablation should be considered in selected patients with drug-refractory electrical storm due to monomorphic VT. 22,23 For recurrent polymorphic VT or VF in the absence of acute ischemia, administration of I.V. magnesium can be considered. Treatment directed at acute heart failure should also be considered, because this can precipitate VT/VF. Refractory patients might benefit from thoracic epidural anaesthesia or percutaneous cardiac sympathetic denervation. For recurrent VT/VF with prolonged hemodynamic instability, mechanical circulatory support might be considered (the readers are referred to the reference list of a review for temporary mechanical support in critical cardiac care 24 ).
# Acute Treatment of Sustained Monomorphic VT Electrical Defibrilla on/Cardioversion + ACLS
- Recurrent or Shock refractory: IV amiodarone or lidocaine
# First line therapy:
- Electrical cardioversion or - IV Procainamide
# Second line therapy:
- IV amiodarone - IV lidocaine Values and preferences. The outcomes of patients with electrical storm are poor. As such, aggressive intervention is often required.
Practical tip. In patients with stable blood pressure, oral, short-acting, nonselective b-blockers should be used preferentially (such as propranolol 40 mg orally every 6 hours).
# Stable monomorphic VT
Electrical cardioversion or I.V. AADs can acutely treat stable monomorphic VT in patients with SHD (Fig. 2B). Procainamide is superior to amiodarone for conversion of hemodynamically tolerated monomorphic VT, with higher efficacy and fewer adverse effects. 25 Procainamide is also superior to lidocaine for acute termination of stable monomorphic VT. 26
# Polymorphic VT
Most patients with sustained polymorphic VT are unstable and should be acutely treated as per VF (Fig. 2) with aggressive early investigation and treatment of underlying causes, such as acute ischemia (most commonly), decompensated heart failure or other potential contributors (Supplemental Table S2). Polymorphic VT due to QT prolongation (torsade de pointes) can be related to drugs, electrolyte disturbance (hypokalemia/hypomagnesemia), or (rarely) concomitant long QT syndrome. Magnesium can be useful in patients with torsade de pointes regardless of measured serum magnesium levels, 27 but not for ischemiarelated ventricular arrhythmias. 28 Although no evidencebased dosing or targets exist for VT, it would be reasonable to target a serum potassium 4.0 mmol/L and serum magnesium 0.9-1.0 mmol/L. 6. Initiation of Long-Term Suppressive Therapy for Sustained VT/VF 6.1. Goals for initiating long-term suppressive therapy for VT/VF Although appropriate ICD shocks are often acutely lifesaving, they are associated with a subsequent increased mortality risk, even compared with VT/VF terminated with ATP therapy. Furthermore, ICD shocks can result in significant psychosocial morbidity (see section 11. Psychosocial Care of Patients With VT/VF). Treating VT/VF should aim to reduce VT/VF burden and ICD shocks. Optimization of ICD programming (see section 9. ICD Programming in Patients With Sustained VT/VF in the Setting of SHD) should be performed in all patients with VT/VF to minimize shocks. Suppression of VT/VF might be accomplished by use of AADs and/or catheter ablation, the latter predominantly indicated for monomorphic VT (Fig. 3).
# First episode of sustained VT/VF
The risk of recurrent VT/VF after a first event, without suppressive therapy is approximately 22% after 1 year and approximately 53% after 2 years. Catheter ablation after the first episode of monomorphic VT reduces recurrences of VT (hazard ratios 0.54-0.61 vs controls for recurrent VT at 1-2 years), but these studies did not routinely use active controls with AAD therapy (AAD use was only 32%-35%). In the most recent randomized trial, VT ablation did not reduce the composite outcome of death, VT hospitalization, or worsening heart failure, compared with ICD therapy alone. 33 No randomized trial has specifically evaluated the effect of AAD therapy after a first VT/VF episode, although these patients were represented in larger trials that assessed drug efficacy. Although usually unnecessary, suppressive therapy beyond b-blockade after a first VT/VF episode might be warranted despite the potential risks of therapy, particularly if the patient experienced significant morbidity with the index episode (Fig. 3). Importantly, ICD implantation should be performed with optimization of programming to minimize future shocks (see section 9. ICD Programming in Patients With Sustained VT/VF in the Setting of SHD).
# Recurrent sustained VT/VF
Recurrent episodes of VT/VF despite optimal medical therapy are associated with increased risks of electrical storm and mortality 29,31,34 and therefore treatment with AADs or catheter ablation is generally recommended (see Fig. 3 Values and preferences. Procainamide therapy can frequently terminate monomorphic VT without the need for cardioversion, but might interact with chronic AADs (such as amiodarone or sotalol). Cardioversion, although effective at terminating monomorphic VT, requires sedation and does not prevent recurrent VT. Selection of the preferred first-line approach should take into consideration local resources and expertise, as well as patient preference.
Practical tip. There are a wide variety of reported doses of I.V. procainamide used in the literature but a rapid infusion of 10 mg/kg over 20 minutes has good efficacy and a low rate of hypotension (Supplemental Table S3). The infusion can be slowed if hypotension is encountered. This can be followed by an ongoing infusion of 1-2 mg/min. Amiodarone I.V. (150 mg I.V. over 10 minutes, followed by an infusion of 1 mg/min for 6 hours, followed by 0.5 mg/min for 18 hours) or lidocaine (1 mg/kg I.V. push, followed by 1-2 mg/min infusion), can be given as second-line alternatives to procainamide.
# Electrical storm
Electrical storm has a 2-year recurrence rate of 45%-60%. 36,37 Chronic suppressive AAD therapy is almost always indicated. When AAD therapy is unsuccessful, catheter ablation for monomorphic VT can reduce VT recurrences. 22,23 Values and preferences. The poor prognosis and high recurrence rate of VT/VF in patients with electrical storm warrants long-term suppressive therapy to reduce the risk of recurrence.
Practical tip. After the acute treatment of electrical storm, in addition to b-blocker therapy, chronic suppressive therapy should be initiated/undertaken while in hospital. Amiodarone is the preferred AAD for patients with electrical storm.
# AAD Therapy for Long-Term Management of Sustained VT/VF
AADs (with the exception of b-blockers) are not known to improve survival in patients with SHD 38,39 and cannot replace ICD therapy, which has consistently resulted in survival benefit compared with AAD therapy for VT/VF. Nevertheless, in patients who are not candidates for ICD implantation, amiodarone might be useful for treatment of VT/VF. 40 7.1. b-Blockers b-Blocker therapy is recommended in patients with SHD for the prevention of VT/VF and sudden death, in conjunction with an ICD. 41,42 Clinical data support a modest AAD effect of b-blockers compared with placebo. 43,44
# Sotalol
Sotalol has better efficacy in reducing VT compared with placebo or b-blocker monotherapy but is less effective than amiodarone. 29,30 Practical considerations for the use of sotalol are outlined in Table 1. Sotalol has a side effect profile similar to other b-blockers with the added risk of QT prolongation. However, rates of sotalol discontinuation were higher than other b-blockers in an open-label randomized trial (23.5% vs 5.3% at 1 year). 29 Sotalol proarrhythmic risk might be higher in patients with advanced heart failure, 45 but its use might be appropriate in those with less severe heart failure or as an adjunct to an ICD. 29,30 Sotalol should be avoided in patients with a prolonged QT and should be used with caution in those with severe heart failure (left ventricular ejection fraction < 20% and/or New York Heart Association classification 3) or renal failure. Although sotalol was most commonly tested in randomized trials without concomitant use of other b-blocker therapy, 29,30 consideration can be given to using sotalol in conjunction with an evidence-based b-blocker (carvedilol, bisoprolol, - Amiodarone blocks the tubular secretion of creatinine by p-glycoprotein. This reduces the total clearance of creatinine resulting in a 5%-15% increase in serum creatinine concentrations in patients who start amiodarone therapy. metoprolol succinate, nebivolol) 35 for patients with heart failure and reduced ejection fraction.
# Amiodarone
Amiodarone is the most effective AAD for reducing VT/ VF recurrence in patients with SHD and an ICD. 29 It requires approximately 10 g (I.V.) to 20 g (oral) dose to achieve steady state and full antiarrhythmic effect (Table 1). Its main limitation is the risk of long-term adverse effects. The discontinuation rate for amiodarone at 1 year is approximately 10%-20%, and increases with time. 29,34 8. Catheter Ablation for the Treatment of Sustained VT in Patients With SHD
# Patient selection
Catheter ablation is effective for patients with monomorphic VT and SHD. Procedural success is generally highest for patients with hemodynamically tolerated monomorphic VT and those with higher left ventricular ejection fraction, 31,46 although substrate ablation techniques have improved ablation effectiveness in patients with worse ventricular systolic function. 47,48 There is a wide spectrum of SHD that leads to scar-related VT. Distribution, location, and heterogeneity of the underlying scar tissue are important determinants of procedural outcomes.
# Ischemic cardiomyopathy.
A randomized study in patients who have refractory monomorphic VT despite AAD therapy showed that catheter ablation is more effective than escalation of AAD therapy, particularly after failure of amiodarone treatment. 34 Catheter ablation may be considered for first-line suppressive therapy, 31,49 to reduce recurrent subsequent ICD therapies, although randomized comparisons with AADs in this setting are still under way.
# Nonischemic cardiomyopathy. Nonischemic cardiomyopathies include a heterogeneous group of cardiac diseases with heterogeneous myocardial scar distribution.
There are limited data regarding the relative efficacy of catheter ablation or AAD therapy in such patients. 50 Longterm success rates for ablation of monomorphic VT appear more modest compared with those in patients with ischemic cardiomyopathy (Supplemental Table S4), with a frequent need for epicardial ablation. 51,52 Accordingly, there is a higher threshold for the use of catheter ablation in this population.
# RECOMMENDATION
- If AAD therapy is chosen for suppressive therapy, we recommend that either sotalol or amiodarone be used as first-line AAD therapy for suppression of VT/VF in patients with SHD (Strong Recommendation, High-Quality Evidence).
Values and preferences. Although amiodarone is more effective in suppressing VT/VF compared with sotalol, it is associated with long-term toxicities, hence both agents are reasonable as first-line therapy. Each appears to be relatively safe in patients with SHD.
Practical tip. Sotalol, given its more favourable longterm toxicity profile, should be preferentially used. Sotalol can be used alone or in addition to preexisting bblocker therapy. However, amiodarone should be used for the treatment of electrical storm, because of its superior efficacy. See Supplemental Table S3 for guidance on drug selection and dosing.
# RECOMMENDATION
- We suggest that catheter ablation can be considered, in selected patients, as first-line suppressive therapy, in addition to b-blocker therapy, for patients with ischemic cardiomyopathy (previous MI) and monomorphic VT (Conditional Recommendation, Low-Quality Evidence).
Values and preferences. Catheter ablation, using an endocardial approach, has a low risk of complications and good efficacy for monomorphic VT suppression in ischemic cardiomyopathy. Furthermore, it avoids the side effects and long-term risks of AAD therapy.
Practical tip. First-line catheter ablation should be performed by skilled teams at centres that routinely perform VT ablation.
# RECOMMENDATION
# We recommend catheter ablation of monomorphic
VT in patients with ischemic cardiomyopathy (previous MI) in whom treatment with sotalol or amiodarone has been ineffective (Strong Recommendation, High-Quality Evidence).
Values and preferences. Catheter ablation has good efficacy at suppressing monomorphic VT in this population, and has a low risk of procedural complications.
Practical tip. After failure of amiodarone treatment, catheter ablation appears to be much more effective than escalation of AAD therapy (increasing the AAD dose, switching from sotalol to amiodarone, or combination AAD therapy). 8.1.3. Epicardial mapping and ablation. Percutaneous epicardial access facilitates mapping and ablation of epicardial myocardial substrate, but is associated with added risks. Epicardial mapping should be considered in patients in whom previous endocardial catheter ablation has failed and an epicardial substrate is suspected. Epicardial mapping during the first ablation procedure should be reserved for patients with ARVC or dilated cardiomyopathy, who commonly have an epicardial VT substrate.
# Complications
Catheter ablation of VT in patients with SHD is a complex procedure performed in a vulnerable patient. The procedure carries significant risks, which can be minimized with experience, technique, and patient optimization. In contemporary trials, reported procedural complication rates have been between 3% and 6%. 31,34,47,49,62 One analysis of administrative data suggested an acute complication rate of 9.9% and in-hospital mortality of 1.8%. 63
# ICD Programming in Patients With Sustained VT/VF in the Setting of SHD
The goals of ICD programming are to ensure appropriate therapy for VT/VF, to minimize inappropriate shocks, to minimize symptoms from VT/VF, and to prevent mortality (Table 2). Secondary goals include avoidance of arrhythmia induction and of nonessential therapies. 64,65 ICD shocks are associated with increased mortality, hospitalization, and health care costs compared with ATP therapy alone. 64,66 In patients with VT/VF, prolonged detection times reduce inappropriate therapy and nonessential appropriate therapy, with no increase in mortality or arrhythmic syncope. 65,67,68 Numerous trials support the use of ATP programming for fast VT (188-250 beats per minute). 10. Suppression of VT/VF When Initial Therapy Is Ineffective (Second-and Third-Line Therapy)
Initial suppressive therapies for VT/VF in patients with SHD are sotalol, amiodarone, or catheter ablation. After failure of one of these therapies, a trial of an alternate first-line therapy should be undertaken. Amiodarone and catheter ablation have similar efficacy after failure of sotalol treatment. 34 A significant proportion of patients will have recurrent VT/VF despite firstline therapy, and alternate strategies must be considered.
10.1. Second-and third-line antiarrhythmic therapy 10.1.1. Mexiletine. Mexiletine, a class I AAD with properties similar to I.V. lidocaine, has been reported in small cohort studies to have some efficacy in combination with amiodarone. 72,73 Nevertheless, the additional use of mexiletine with high-dose amiodarone (> 300 mg daily) is inferior to catheter ablation. 74 A pre-ICD era randomized trial of mexiletine showed increased mortality when used in patients with heart failure. 75 Thus mexiletine should be used with caution in patients with SHD and heart failure.
10.1.2. Dofetilide (not currently available in Canada). Dofetilide prolongs repolarization and has a risk of QT prolongation and proarrhythmia. However, it as been shown RECOMMENDATION 12. We recommend catheter ablation of monomorphic VT in patients with nonischemic cardiomyopathy in whom treatment with sotalol or amiodarone has been ineffective (Strong Recommendation, Low-Quality Evidence).
Values and preferences. The reduced efficacy of catheter ablation, and the increased complexity of the procedure in patients with nonischemic cardiomyopathies led to the recommendation that catheter ablation should be considered second-line in this population.
Practical tip. Catheter ablation in patients with nonischemic cardiomyopathy should be performed by skilled teams at centres that routinely perform VT ablation, including experience with epicardial ablation. to reduce VT/VF and ICD shocks in cohort studies. 76,77 In a cross-over study, dofetilide had efficacy similar to sotalol. 78 However, many patients who responded to one drug did not respond to the other.
10.1.3. Class 1C agents. Class 1C agents might lead to increased mortality risk in patients with ventricular scar/ dysfunction (in the absence of an ICD). 79 However, case series have reported successful combination therapy using sotalol and flecainide in patients with ARVC who had preserved left ventricular ejection fraction and refractory VT. 80,81
# Emerging and alternate ablation modalities
Several newer ablation approaches have been used for treatment-refractory monomorphic VT, including needle ablation, bipolar ablation, transvascular ethanol, and stereotactic radiotherapy. Each permits ablation of deep substrate, not easily reached from the endocardium.
# Cardiac sympathectomy
There is increasing evidence for the use of bilateral cardiac sympathetic denervation for the acute and long-term management of refractory VT/VF in patients with SHD. 86 This procedure is carried out via thorascopic surgery in a single or staged procedure.
# Psychosocial Care of Patients With VT/VF
Studies of the roles of psychosocial factors in the genesis and management of VT/VF are appearing with increasing frequency. Individuals experiencing VT/VF might be susceptible to poor mental health and reduced quality of life as they manage the symptoms of the VT/VF and those of its treatment.
# Preimplantation and stable postimplantation patients
Anxiety and depression are prevalent among patients with an ICD and particularly those who have experienced VT/ VF. 87 Preimplantation factors that contribute to this psychological distress include: premorbid psychological distress, ICD concerns, reduced perceived control, and type D (distressed) personality. 88 These factors place the patient at increased risk of complications/difficulties post implantation and at increased risk of mortality. Unfortunately, these symptoms often go undetected and untreated.
Optimal care pathways should include screening and treatment for psychological distress among patients with VT/VF and an ICD to safeguard health status. Managing psychological distress while living with an ICD is essential to improve outcomes.
In patients with VT/VF and SHD, special attention should be directed to reducing ICD shocks, because they are a significant cause of anxiety due to anticipation of shocks and associated pain. 89 The fear of shocks can have as much or more psychological effect on a patient as an actual shock. 90
# Special populations; ICD generator change in frail/ elderly patients
Patients might develop new or worsening illness subsequent to their initial ICD implantation and their goals of care might RECOMMENDATION 13. We suggest that mexiletine (given in addition to amiodarone) or dofetilide can be used in patients with SHD and refractory VT/VF who are not candidates or in whom therapy with sotalol, amiodarone, or catheter ablation has failed (Conditional Recommendation, Low-Quality Evidence).
Values and preferences. Despite the lack of evidence supporting the use of mexiletine and dofetilide, there are few other therapeutic alternatives in this setting.
Practical tip. Mexiletine has limited efficacy as monotherapy and should be given in addition to amiodarone. Dofetilide can be given as monotherapy.
# RECOMMENDATION
- We suggest that bipolar radiofrequency ablation, extendable/retractable radiofrequency needle ablation, stereotactic ablative radiotherapy, and sympathectomy may be considered for treatment of VT/VF after failure of one or more standard ablation procedures and after failure of amiodarone therapy (Conditional Recommendation, Low-Quality Evidence).
Values and preferences. Most of these techniques are emerging therapies, with sympathectomy having the most supporting evidence. Despite the limited data supporting these techniques, they might be beneficial in patients with refractory VT/VF.
# RECOMMENDATION
- We recommend frequent systematic assessment of psychological status in all patients with SHD and VT/ VF, and recommend referral for treatment of such distress when identified (Strong Recommendation, Low-Quality Evidence).
Values and preferences. The psychological effect of VT/VF and its therapies is substantial and can affect all facets of a patient's life. This effect might not be fully appreciated in routine care discussions and needs to be explicitly evaluated.
Practical tip. Simple screening tools, such as the Patient Health Questionnaire-2 (PHQ-2) and the Generalized Anxiety Disorder-2 (GAD-2) questionnaire are an effective way to screen psychological status (see the Psychological Status Screening Tools section of the Supplementary Material). If either of these are positive (score 3), a more in-depth assessment of psychological status is warranted.
Practical tip. These techniques should be used, by experienced operators, and preferably in the context of a research protocol. change to favour comfort over longevity. A significant proportion of these patients might be unaware of the option of deactivation of tachycardia therapy. Furthermore, they might overestimate the potential benefits of the ICD near the end of life, particularly as the risk of nonarrhythmic death increases (such as in advanced heart failure). 90
# End of life
The management of VT/VF at the end of life can be associated with significant patient and family distress. Clinicians need to ensure that patients are aware that deactivation of ICD tachyarrhythmia therapies is an option at any time, and is not akin to euthanasia, 91 and will not lead to immediate death. 92 These conversations are best carried out before ICD implantation, continued on a regular basis as part of routine device care, and then revisited at times of significant clinical decline. 93 ICD deactivation near the end of life can potentially minimize physical and psychological distress. Although patients might choose to maintain ICD therapies near the time of death, it is important to ensure that such patients have made well informed decisions in line with their goals of care. 94
# Conclusion/Future Directions/Knowledge Gaps
Implantable defibrillators have dramatically modified the prognosis and the management of ventricular arrhythmias in the presence of SHD. Further study is needed to minimize sudden death risk in the population, to understand when and which arrhythmia-suppressive therapy is best, and to understand the short-and long-term clinical outcomes of available therapies, as well as their effects on mortality, costeffectiveness, and quality of life.
# Disclosures
Please see Supplemental Table S1 for a complete list of disclosures.
# RECOMMENDATION
- In patients with VT/VF, we recommend ongoing incorporation of patient values and preferences in goals of care discussions, including ICD tachycardia therapy deactivation or ICD replacement with a pacemaker, particularly at times of ICD generator replacement or changes in clinical status (Strong Recommendation, Low-Quality Evidence).
Values and preferences. Despite the lack of systematic evidence supporting goals of care discussions, the importance of these discussions is paramount for patient-centred care.
Practical tip. Incorporating discussion of goals of care and ICD deactivation into routine device clinic standard of care promotes enhanced patient understanding of end of life options and facilitates patient decision-making. | This Canadian Cardiovascular Society position statement is focused on the management of sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) that occurs in patients with structural heart disease (SHD), including previous myocardial infarction, dilated cardiomyopathy, and other forms of nonischemic cardiomyopathy. This patient population is rapidly increasing because of advances in care and improved overall survival of patients with all forms of SHD. In this position statement, the acute and long-term management of VT/VF are outlined, and the many unique aspects of care in this populationThis Canadian Cardiovascular Society position statement is focused on the acute and long-term management of sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) in patients with structural heart disease (SHD), defined by the presence of abnormal myocardium and scar. SHD includes conditions such as myocardial infarction (MI), dilated cardiomyopathies, hypertrophic cardiomyopathy, infiltrative cardiomyopathies (eg, sarcoidosis), and arrhythmogenic right ventricular cardiomyopathy# R ESUM E
Le pr esent enonc e de position de la Soci et e canadienne de cardiologie est ax e sur la prise en charge de la tachycardie ventriculaire (TV) et de la fibrillation ventriculaire (FV) soutenues qui surviennent chez les patients pr esentant une cardiopathie structurelle, par exemple des ant ec edents d'infarctus du myocarde, une cardiomyopathie dilat ee et d'autres formes de cardiomyopathie non isch emique. Cette population de patients augmente rapidement, en raison des avanc ees r ealis ees en matière de soins et de l'am elioration de la survie globale des patients pr esentant une cardiopathie structurelle sous une forme ou (ARVC). Almost all such patients have an indication for an implantable cardioverter-defibrillator (ICD). 1 Although many of the recommendations in this document can apply to patients with complex congenital heart disease, this population is not specifically addressed. The reader is referred to other published resources on the management of VT/VF in that population. 2,3 This statement is not intended to replace the guidelines for cardiopulmonary resuscitation, 4 but provides guidance for the ongoing care of patients with VT/VF after resuscitation. This statement is targeted at health professionals involved in the continuum of care of patients with SHD and VT/VF, including emergency medicine, critical care, internal medicine, and cardiology. The management of premature ventricular complexes and nonsustained VT in patients with SHD, and the management of VT/VF in patients with structurally normal hearts (including inherited arrhythmia syndromes) are beyond the scope of this statement.
# Position Statement Development
This position statement was written by a multidisciplinary panel of experts who care for patients with VT/VF (see Supplemental Table S1). The recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation standards with strength of recommendations classified as "strong" or "conditional." The recommendations are presented, along with their background and rationale.
# Definitions
Sustained VT is defined as an episode of VT lasting > 30 seconds or requiring intervention before 30 seconds. 5 Hemodynamically stable VT is defined as VT without signs or symptoms of organ hypoperfusion. Electrical storm (also known as VT/VF storm) is defined as the occurrence of 3 or more distinct episodes of VT/VF within 24 hours. Monomorphic VT has similar QRS complexes on the electrocardiogram (ECG), whereas polymorphic VT has changing beat-to-beat morphology. Torsade de pointes is polymorphic VT occurring in the setting of QT prolongation. VF is chaotic and does not have distinct QRS complexes on the ECG. Monomorphic VT might degenerate to polymorphic VT or VF. A summary of classification and mechanisms of VT and VF in patients with SHD is presented in Supplemental Table S2.
# Incidence and Prognosis of Sustained VT/VF in Patients With SHD
Ventricular arrhythmias can cause sudden cardiac death (SCD) or arrest, most frequently in those with previous MI. 6 The past decade saw a decreasing incidence of post-MI VT/ VF causing SCD, yet no change in the incidence of SCD in patients without ischemic heart disease. 7 The development of VT/VF in patients with SHD is associated with a higher risk of future episodes of VT/VF, of electrical storm, and of death. 8
# Initial Evaluation and Management of SHD Patients With Sustained VT/VF
Patients who present with VT/VF often have a preexisting diagnosis of SHD. However, VT/VF might be the initial indication of the presence of SHD for some patients. The initial evaluation must rapidly assess the need for acute intervention and identify potential etiologies or precipitating factors. When the patient is stabilized, the evaluation should include a complete history and examination, comprehensive laboratory testing, and assessment of cardiac function (Fig. 1).
A 12-lead ECG recorded during VT is important to localize VT and give insight into pathophysiology. An ECG performed after restoration of the underlying rhythm can be used to evaluate for reversible causes, such as ischemia and QT prolongation. Laboratory tests might identify precipitating RECOMMENDATION 1. We recommend that all patients presenting with VT/ VF undergo a comprehensive initial evaluation including a detailed history, physical examination, laboratory investigations, ECG, ICD interrogation (if present) and transthoracic echocardiography (Strong Recommendation, Low-Quality Evidence).
Values and preferences. A comprehensive initial evaluation can be performed quickly and at a reasonable cost. This evaluation is critical for guiding subsequent treatment.
Practical tip. If not previously diagnosed, most forms of SHD will be apparent after this initial evaluation. Unless a reversible cause is identified (such as acute MI), all patients with VT/VF and SHD should be referred for consideration of an ICD, if not already present, for the prevention of sudden death.
are emphasized. The initial evaluation, acute therapy, indications for chronic suppressive therapy, choices of chronic suppressive therapy, implantable cardioverter-defibrillator programming, alternative therapies, and psychosocial care are reviewed and recommendations for optimal care are provided. The target audience for this statement includes all health professionals involved in the continuum of care of patients with SHD and VT/VF. une autre. L' enonc e de position pr esente les grandes lignes de la prise en charge aiguë et à long terme de la TV et de la FV, et fait ressortir les nombreux aspects propres aux soins dont cette population a besoin. L' evaluation initiale, le traitement aigu, les indications commandant un traitement suppresseur prolong e, les options de traitement suppresseur prolong e, la programmation des d efibrillateurs cardioverteurs implantables, les th erapies parallèles et les soins psychosociaux sont examin es, et des recommandations concernant les soins optimaux sont formul ees. Ce document est destin e à tous les professionnels de la sant e qui interviennent dans le continuum des soins aux patients pr esentant une cardiopathie structurelle et une TV/FV.
factors, prognostic factors, and contraindications to specific antiarrhythmic drug (AAD) therapies (such as renal or hepatic dysfunction). Cardiac imaging is useful to determine the presence of underlying SHD and aid prognostication. Transthoracic echocardiography remains the first-line diagnostic imaging tool for assessment of ventricular function, wall motion abnormalities, and valvular disease. Nevertheless, it has limitations in identifying scar. Cardiac magnetic resonance (CMR) imaging, with gadolinium contrast, can support the diagnosis, particularly with nonischemic and infiltrative cardiomyopathies. 9,10 Emergent angiography should be performed for VT/VF in the setting of ST-elevation MI. Urgent angiography should also be considered in those who present with polymorphic VT/VF potentially due to acute ischemia. Other coronary imaging modalities can be considered if there is a lower index of suspicion of coronary disease. Monomorphic VT is rarely caused by acute ischemia, but coronary imaging might be warranted to establish the presence and severity of coronary artery disease.
Positron emission tomography can be useful in identifying patients with active inflammatory states, such as sarcoidosis, when other imaging modalities yield negative or equivocal findings. 11 Invasive electrophysiological testing of patients with wide complex tachycardia might be useful to distinguish VT from SVT or to diagnose bundle-branch reentry VT. 12
# Management of hemodynamically unstable VT/VF
Figure 2 illustrates the acute management of patients with VT/VF. In patients with unstable VT electrical cardioversion/defibrillation is indicated and advanced cardiac life support algorithms should be followed (Fig. 2A). 13,14 In
# Ini al Evalua on of Sustained VT/VF
# RECOMMENDATION
2. We recommend that CMR imaging be performed in patients who present with VT/VF when the initial evaluation has failed to establish the etiology of the underlying heart disease (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. CMR imaging provides enhanced assessment of the presence, location, and quantity of myocardial scar in patients with SHD and can identify inflammatory conditions, such as myocarditis. Practical tip. In patients for whom the initial workup is not definitive, early use of CMR imaging has a high diagnostic and prognostic yield. patients with shock-refractory VF or VT, bolus intravenous (I.V.) amiodarone or lidocaine should be used. 15,16 Intravenous AAD dosing is summarized in Supplemental Table S3.
# Electrical storm
A Figure 2
. Initial management of sustained VT/VF. The initial management of VF and polymorphic VT is outlined in (A), whereas the initial management of monomorphic VT is outlined in (B). For unstable patients with VT/VF that recurs despite defibrillation/cardioversion or VT/VF that persists despite 1-2 attempts at defibrillation/cardioversion, intravenous (I.V.) amiodarone or lidocaine should be administered. For unstable VT/VF that recurs, the treatment should follow the electrical storm recommendations. See the accompanying text for drug dosing. ACLS, Advanced Cardiac Life Support; ACS, acute coronary syndrome; VF, ventricular fibrillation; VT, ventricular tachycardia.
# RECOMMENDATION
3. We recommend the administration of I.V. amiodarone or lidocaine for acute treatment of patients with shockrefractory VT/VF (failure of at least 1 attempt at defibrillation) or patients with recurrent polymorphic VT/ VF, unless there is a strong suspicion of torsade de pointes (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. The outcome of unstable patients with VT/VF arrest is poor, particularly in out-ofhospital settings. There is likely a small benefit to these drugs, which outweigh their risks.
Practical tip. Simplified, rather than weight-based dosing is easier in the setting of unstable VT/VF. Amiodarone can be given as 300 mg I.V. push (150 mg I.V. push for those < 45 kg) with a subsequent dose of 150 mg I.V. push in the event of failure of another shock. Lidocaine can be given as 100 mg I.V. push (50 mg I.V. push if < 45 kg) with a subsequent dose of 50 mg I.V. push in the event of failure of another shock.
b-blockade with propranolol, given immediately and continued during the hospitalization, was superior to selective b1 blockade (metoprolol) for suppressing VT, in conjunction with usual care including I.V. amiodarone. 17 If initial management strategies fail, general anaesthesia can be considered. Dexmedetomidine and propofol are preferred sedating agents because of their sedative and sympatholytic effects. 18,19 Patients with an ICD and electrical storm should undergo early device interrogation; ICD programming can be adjusted (such as optimizing antitachycardia pacing [ATP]) or ICD therapy can be temporarily disabled, if appropriate.
Amiodarone is useful for electrical storm in patients with SHD, and a target loading dose of 1000-2000 mg I.V. over the first 24 hours is recommended (Supplemental Table S3). 20,21 Combinations of AADs with distinct mechanisms of action (eg, amiodarone and lidocaine) might prove effective for acute arrhythmia suppression in selected patients. Ablation should be considered in selected patients with drug-refractory electrical storm due to monomorphic VT. 22,23 For recurrent polymorphic VT or VF in the absence of acute ischemia, administration of I.V. magnesium can be considered. Treatment directed at acute heart failure should also be considered, because this can precipitate VT/VF. Refractory patients might benefit from thoracic epidural anaesthesia or percutaneous cardiac sympathetic denervation. For recurrent VT/VF with prolonged hemodynamic instability, mechanical circulatory support might be considered (the readers are referred to the reference list of a review for temporary mechanical support in critical cardiac care 24 ).
# Acute Treatment of Sustained Monomorphic VT Electrical Defibrilla on/Cardioversion + ACLS
• Recurrent or Shock refractory: IV amiodarone or lidocaine
# First line therapy:
• Electrical cardioversion or • IV Procainamide
# Second line therapy:
• IV amiodarone • IV lidocaine Values and preferences. The outcomes of patients with electrical storm are poor. As such, aggressive intervention is often required.
Practical tip. In patients with stable blood pressure, oral, short-acting, nonselective b-blockers should be used preferentially (such as propranolol 40 mg orally every 6 hours).
# Stable monomorphic VT
Electrical cardioversion or I.V. AADs can acutely treat stable monomorphic VT in patients with SHD (Fig. 2B). Procainamide is superior to amiodarone for conversion of hemodynamically tolerated monomorphic VT, with higher efficacy and fewer adverse effects. 25 Procainamide is also superior to lidocaine for acute termination of stable monomorphic VT. 26
# Polymorphic VT
Most patients with sustained polymorphic VT are unstable and should be acutely treated as per VF (Fig. 2) with aggressive early investigation and treatment of underlying causes, such as acute ischemia (most commonly), decompensated heart failure or other potential contributors (Supplemental Table S2). Polymorphic VT due to QT prolongation (torsade de pointes) can be related to drugs, electrolyte disturbance (hypokalemia/hypomagnesemia), or (rarely) concomitant long QT syndrome. Magnesium can be useful in patients with torsade de pointes regardless of measured serum magnesium levels, 27 but not for ischemiarelated ventricular arrhythmias. 28 Although no evidencebased dosing or targets exist for VT, it would be reasonable to target a serum potassium 4.0 mmol/L and serum magnesium 0.9-1.0 mmol/L. 6. Initiation of Long-Term Suppressive Therapy for Sustained VT/VF 6.1. Goals for initiating long-term suppressive therapy for VT/VF Although appropriate ICD shocks are often acutely lifesaving, they are associated with a subsequent increased mortality risk, even compared with VT/VF terminated with ATP therapy. Furthermore, ICD shocks can result in significant psychosocial morbidity (see section 11. Psychosocial Care of Patients With VT/VF). Treating VT/VF should aim to reduce VT/VF burden and ICD shocks. Optimization of ICD programming (see section 9. ICD Programming in Patients With Sustained VT/VF in the Setting of SHD) should be performed in all patients with VT/VF to minimize shocks. Suppression of VT/VF might be accomplished by use of AADs and/or catheter ablation, the latter predominantly indicated for monomorphic VT (Fig. 3).
# First episode of sustained VT/VF
The risk of recurrent VT/VF after a first event, without suppressive therapy is approximately 22% after 1 year and approximately 53% after 2 years. [29][30][31] Catheter ablation after the first episode of monomorphic VT reduces recurrences of VT (hazard ratios 0.54-0.61 vs controls for recurrent VT at 1-2 years), [31][32][33] but these studies did not routinely use active controls with AAD therapy (AAD use was only 32%-35%). In the most recent randomized trial, VT ablation did not reduce the composite outcome of death, VT hospitalization, or worsening heart failure, compared with ICD therapy alone. 33 No randomized trial has specifically evaluated the effect of AAD therapy after a first VT/VF episode, although these patients were represented in larger trials that assessed drug efficacy. Although usually unnecessary, suppressive therapy beyond b-blockade after a first VT/VF episode might be warranted despite the potential risks of therapy, particularly if the patient experienced significant morbidity with the index episode (Fig. 3). Importantly, ICD implantation should be performed with optimization of programming to minimize future shocks (see section 9. ICD Programming in Patients With Sustained VT/VF in the Setting of SHD).
# Recurrent sustained VT/VF
Recurrent episodes of VT/VF despite optimal medical therapy are associated with increased risks of electrical storm and mortality 29,31,34 and therefore treatment with AADs or catheter ablation is generally recommended (see Fig. 3 Values and preferences. Procainamide therapy can frequently terminate monomorphic VT without the need for cardioversion, but might interact with chronic AADs (such as amiodarone or sotalol). Cardioversion, although effective at terminating monomorphic VT, requires sedation and does not prevent recurrent VT. Selection of the preferred first-line approach should take into consideration local resources and expertise, as well as patient preference.
Practical tip. There are a wide variety of reported doses of I.V. procainamide used in the literature but a rapid infusion of 10 mg/kg over 20 minutes has good efficacy and a low rate of hypotension (Supplemental Table S3). The infusion can be slowed if hypotension is encountered. This can be followed by an ongoing infusion of 1-2 mg/min. Amiodarone I.V. (150 mg I.V. over 10 minutes, followed by an infusion of 1 mg/min for 6 hours, followed by 0.5 mg/min for 18 hours) or lidocaine (1 mg/kg I.V. push, followed by 1-2 mg/min infusion), can be given as second-line alternatives to procainamide.
# Electrical storm
Electrical storm has a 2-year recurrence rate of 45%-60%. 36,37 Chronic suppressive AAD therapy is almost always indicated. When AAD therapy is unsuccessful, catheter ablation for monomorphic VT can reduce VT recurrences. 22,23 Values and preferences. The poor prognosis and high recurrence rate of VT/VF in patients with electrical storm warrants long-term suppressive therapy to reduce the risk of recurrence.
Practical tip. After the acute treatment of electrical storm, in addition to b-blocker therapy, chronic suppressive therapy should be initiated/undertaken while in hospital. Amiodarone is the preferred AAD for patients with electrical storm.
# AAD Therapy for Long-Term Management of Sustained VT/VF
AADs (with the exception of b-blockers) are not known to improve survival in patients with SHD 38,39 and cannot replace ICD therapy, which has consistently resulted in survival benefit compared with AAD therapy for VT/VF. Nevertheless, in patients who are not candidates for ICD implantation, amiodarone might be useful for treatment of VT/VF. 40 7.1. b-Blockers b-Blocker therapy is recommended in patients with SHD for the prevention of VT/VF and sudden death, in conjunction with an ICD. 41,42 Clinical data support a modest AAD effect of b-blockers compared with placebo. 43,44
# Sotalol
Sotalol has better efficacy in reducing VT compared with placebo or b-blocker monotherapy but is less effective than amiodarone. 29,30 Practical considerations for the use of sotalol are outlined in Table 1. Sotalol has a side effect profile similar to other b-blockers with the added risk of QT prolongation. However, rates of sotalol discontinuation were higher than other b-blockers in an open-label randomized trial (23.5% vs 5.3% at 1 year). 29 Sotalol proarrhythmic risk might be higher in patients with advanced heart failure, 45 but its use might be appropriate in those with less severe heart failure or as an adjunct to an ICD. 29,30 Sotalol should be avoided in patients with a prolonged QT and should be used with caution in those with severe heart failure (left ventricular ejection fraction < 20% and/or New York Heart Association classification 3) or renal failure. Although sotalol was most commonly tested in randomized trials without concomitant use of other b-blocker therapy, 29,30 consideration can be given to using sotalol in conjunction with an evidence-based b-blocker (carvedilol, bisoprolol, * Amiodarone blocks the tubular secretion of creatinine by p-glycoprotein. This reduces the total clearance of creatinine resulting in a 5%-15% increase in serum creatinine concentrations in patients who start amiodarone therapy. metoprolol succinate, nebivolol) 35 for patients with heart failure and reduced ejection fraction.
# Amiodarone
Amiodarone is the most effective AAD for reducing VT/ VF recurrence in patients with SHD and an ICD. 29 It requires approximately 10 g (I.V.) to 20 g (oral) dose to achieve steady state and full antiarrhythmic effect (Table 1). Its main limitation is the risk of long-term adverse effects. The discontinuation rate for amiodarone at 1 year is approximately 10%-20%, and increases with time. 29,34 8. Catheter Ablation for the Treatment of Sustained VT in Patients With SHD
# Patient selection
Catheter ablation is effective for patients with monomorphic VT and SHD. Procedural success is generally highest for patients with hemodynamically tolerated monomorphic VT and those with higher left ventricular ejection fraction, 31,46 although substrate ablation techniques have improved ablation effectiveness in patients with worse ventricular systolic function. 47,48 There is a wide spectrum of SHD that leads to scar-related VT. Distribution, location, and heterogeneity of the underlying scar tissue are important determinants of procedural outcomes.
# Ischemic cardiomyopathy.
A randomized study in patients who have refractory monomorphic VT despite AAD therapy showed that catheter ablation is more effective than escalation of AAD therapy, particularly after failure of amiodarone treatment. 34 Catheter ablation may be considered for first-line suppressive therapy, 31,49 to reduce recurrent subsequent ICD therapies, although randomized comparisons with AADs in this setting are still under way.
# Nonischemic cardiomyopathy. Nonischemic cardiomyopathies include a heterogeneous group of cardiac diseases with heterogeneous myocardial scar distribution.
There are limited data regarding the relative efficacy of catheter ablation or AAD therapy in such patients. 50 Longterm success rates for ablation of monomorphic VT appear more modest compared with those in patients with ischemic cardiomyopathy (Supplemental Table S4), with a frequent need for epicardial ablation. 51,52 Accordingly, there is a higher threshold for the use of catheter ablation in this population.
# RECOMMENDATION
9. If AAD therapy is chosen for suppressive therapy, we recommend that either sotalol or amiodarone be used as first-line AAD therapy for suppression of VT/VF in patients with SHD (Strong Recommendation, High-Quality Evidence).
Values and preferences. Although amiodarone is more effective in suppressing VT/VF compared with sotalol, it is associated with long-term toxicities, hence both agents are reasonable as first-line therapy. Each appears to be relatively safe in patients with SHD.
Practical tip. Sotalol, given its more favourable longterm toxicity profile, should be preferentially used. Sotalol can be used alone or in addition to preexisting bblocker therapy. However, amiodarone should be used for the treatment of electrical storm, because of its superior efficacy. See Supplemental Table S3 for guidance on drug selection and dosing.
# RECOMMENDATION
10. We suggest that catheter ablation can be considered, in selected patients, as first-line suppressive therapy, in addition to b-blocker therapy, for patients with ischemic cardiomyopathy (previous MI) and monomorphic VT (Conditional Recommendation, Low-Quality Evidence).
Values and preferences. Catheter ablation, using an endocardial approach, has a low risk of complications and good efficacy for monomorphic VT suppression in ischemic cardiomyopathy. Furthermore, it avoids the side effects and long-term risks of AAD therapy.
Practical tip. First-line catheter ablation should be performed by skilled teams at centres that routinely perform VT ablation.
# RECOMMENDATION
# We recommend catheter ablation of monomorphic
VT in patients with ischemic cardiomyopathy (previous MI) in whom treatment with sotalol or amiodarone has been ineffective (Strong Recommendation, High-Quality Evidence).
Values and preferences. Catheter ablation has good efficacy at suppressing monomorphic VT in this population, and has a low risk of procedural complications.
Practical tip. After failure of amiodarone treatment, catheter ablation appears to be much more effective than escalation of AAD therapy (increasing the AAD dose, switching from sotalol to amiodarone, or combination AAD therapy). 8.1.3. Epicardial mapping and ablation. Percutaneous epicardial access facilitates mapping and ablation of epicardial myocardial substrate, but is associated with added risks. Epicardial mapping should be considered in patients in whom previous endocardial catheter ablation has failed and an epicardial substrate is suspected. [53][54][55][56] Epicardial mapping during the first ablation procedure should be reserved for patients with ARVC or dilated cardiomyopathy, who commonly have an epicardial VT substrate. [57][58][59][60][61]
# Complications
Catheter ablation of VT in patients with SHD is a complex procedure performed in a vulnerable patient. The procedure carries significant risks, which can be minimized with experience, technique, and patient optimization. In contemporary trials, reported procedural complication rates have been between 3% and 6%. 31,34,47,49,62 One analysis of administrative data suggested an acute complication rate of 9.9% and in-hospital mortality of 1.8%. 63
# ICD Programming in Patients With Sustained VT/VF in the Setting of SHD
The goals of ICD programming are to ensure appropriate therapy for VT/VF, to minimize inappropriate shocks, to minimize symptoms from VT/VF, and to prevent mortality (Table 2). Secondary goals include avoidance of arrhythmia induction and of nonessential therapies. 64,65 ICD shocks are associated with increased mortality, hospitalization, and health care costs compared with ATP therapy alone. 64,66 In patients with VT/VF, prolonged detection times reduce inappropriate therapy and nonessential appropriate therapy, with no increase in mortality or arrhythmic syncope. 65,67,68 Numerous trials support the use of ATP programming for fast VT (188-250 beats per minute). [69][70][71] 10. Suppression of VT/VF When Initial Therapy Is Ineffective (Second-and Third-Line Therapy)
Initial suppressive therapies for VT/VF in patients with SHD are sotalol, amiodarone, or catheter ablation. After failure of one of these therapies, a trial of an alternate first-line therapy should be undertaken. Amiodarone and catheter ablation have similar efficacy after failure of sotalol treatment. 34 A significant proportion of patients will have recurrent VT/VF despite firstline therapy, and alternate strategies must be considered.
10.1. Second-and third-line antiarrhythmic therapy 10.1.1. Mexiletine. Mexiletine, a class I AAD with properties similar to I.V. lidocaine, has been reported in small cohort studies to have some efficacy in combination with amiodarone. 72,73 Nevertheless, the additional use of mexiletine with high-dose amiodarone (> 300 mg daily) is inferior to catheter ablation. 74 A pre-ICD era randomized trial of mexiletine showed increased mortality when used in patients with heart failure. 75 Thus mexiletine should be used with caution in patients with SHD and heart failure.
10.1.2. Dofetilide (not currently available in Canada). Dofetilide prolongs repolarization and has a risk of QT prolongation and proarrhythmia. However, it as been shown RECOMMENDATION 12. We recommend catheter ablation of monomorphic VT in patients with nonischemic cardiomyopathy in whom treatment with sotalol or amiodarone has been ineffective (Strong Recommendation, Low-Quality Evidence).
Values and preferences. The reduced efficacy of catheter ablation, and the increased complexity of the procedure in patients with nonischemic cardiomyopathies led to the recommendation that catheter ablation should be considered second-line in this population.
Practical tip. Catheter ablation in patients with nonischemic cardiomyopathy should be performed by skilled teams at centres that routinely perform VT ablation, including experience with epicardial ablation. to reduce VT/VF and ICD shocks in cohort studies. 76,77 In a cross-over study, dofetilide had efficacy similar to sotalol. 78 However, many patients who responded to one drug did not respond to the other.
10.1.3. Class 1C agents. Class 1C agents might lead to increased mortality risk in patients with ventricular scar/ dysfunction (in the absence of an ICD). 79 However, case series have reported successful combination therapy using sotalol and flecainide in patients with ARVC who had preserved left ventricular ejection fraction and refractory VT. 80,81
# Emerging and alternate ablation modalities
Several newer ablation approaches have been used for treatment-refractory monomorphic VT, including needle ablation, bipolar ablation, transvascular ethanol, and stereotactic radiotherapy. Each permits ablation of deep substrate, not easily reached from the endocardium. [82][83][84][85]
# Cardiac sympathectomy
There is increasing evidence for the use of bilateral cardiac sympathetic denervation for the acute and long-term management of refractory VT/VF in patients with SHD. 86 This procedure is carried out via thorascopic surgery in a single or staged procedure.
# Psychosocial Care of Patients With VT/VF
Studies of the roles of psychosocial factors in the genesis and management of VT/VF are appearing with increasing frequency. Individuals experiencing VT/VF might be susceptible to poor mental health and reduced quality of life as they manage the symptoms of the VT/VF and those of its treatment.
# Preimplantation and stable postimplantation patients
Anxiety and depression are prevalent among patients with an ICD and particularly those who have experienced VT/ VF. 87 Preimplantation factors that contribute to this psychological distress include: premorbid psychological distress, ICD concerns, reduced perceived control, and type D (distressed) personality. 88 These factors place the patient at increased risk of complications/difficulties post implantation and at increased risk of mortality. Unfortunately, these symptoms often go undetected and untreated.
Optimal care pathways should include screening and treatment for psychological distress among patients with VT/VF and an ICD to safeguard health status. Managing psychological distress while living with an ICD is essential to improve outcomes.
In patients with VT/VF and SHD, special attention should be directed to reducing ICD shocks, because they are a significant cause of anxiety due to anticipation of shocks and associated pain. 89 The fear of shocks can have as much or more psychological effect on a patient as an actual shock. 90
# Special populations; ICD generator change in frail/ elderly patients
Patients might develop new or worsening illness subsequent to their initial ICD implantation and their goals of care might RECOMMENDATION 13. We suggest that mexiletine (given in addition to amiodarone) or dofetilide can be used in patients with SHD and refractory VT/VF who are not candidates or in whom therapy with sotalol, amiodarone, or catheter ablation has failed (Conditional Recommendation, Low-Quality Evidence).
Values and preferences. Despite the lack of evidence supporting the use of mexiletine and dofetilide, there are few other therapeutic alternatives in this setting.
Practical tip. Mexiletine has limited efficacy as monotherapy and should be given in addition to amiodarone. Dofetilide can be given as monotherapy.
# RECOMMENDATION
14. We suggest that bipolar radiofrequency ablation, extendable/retractable radiofrequency needle ablation, stereotactic ablative radiotherapy, and sympathectomy may be considered for treatment of VT/VF after failure of one or more standard ablation procedures and after failure of amiodarone therapy (Conditional Recommendation, Low-Quality Evidence).
Values and preferences. Most of these techniques are emerging therapies, with sympathectomy having the most supporting evidence. Despite the limited data supporting these techniques, they might be beneficial in patients with refractory VT/VF.
# RECOMMENDATION
15. We recommend frequent systematic assessment of psychological status in all patients with SHD and VT/ VF, and recommend referral for treatment of such distress when identified (Strong Recommendation, Low-Quality Evidence).
Values and preferences. The psychological effect of VT/VF and its therapies is substantial and can affect all facets of a patient's life. This effect might not be fully appreciated in routine care discussions and needs to be explicitly evaluated.
Practical tip. Simple screening tools, such as the Patient Health Questionnaire-2 (PHQ-2) and the Generalized Anxiety Disorder-2 (GAD-2) questionnaire are an effective way to screen psychological status (see the Psychological Status Screening Tools section of the Supplementary Material). If either of these are positive (score 3), a more in-depth assessment of psychological status is warranted.
Practical tip. These techniques should be used, by experienced operators, and preferably in the context of a research protocol. change to favour comfort over longevity. A significant proportion of these patients might be unaware of the option of deactivation of tachycardia therapy. Furthermore, they might overestimate the potential benefits of the ICD near the end of life, particularly as the risk of nonarrhythmic death increases (such as in advanced heart failure). 90
# End of life
The management of VT/VF at the end of life can be associated with significant patient and family distress. Clinicians need to ensure that patients are aware that deactivation of ICD tachyarrhythmia therapies is an option at any time, and is not akin to euthanasia, 91 and will not lead to immediate death. 92 These conversations are best carried out before ICD implantation, continued on a regular basis as part of routine device care, and then revisited at times of significant clinical decline. 93 ICD deactivation near the end of life can potentially minimize physical and psychological distress. Although patients might choose to maintain ICD therapies near the time of death, it is important to ensure that such patients have made well informed decisions in line with their goals of care. 94
# Conclusion/Future Directions/Knowledge Gaps
Implantable defibrillators have dramatically modified the prognosis and the management of ventricular arrhythmias in the presence of SHD. Further study is needed to minimize sudden death risk in the population, to understand when and which arrhythmia-suppressive therapy is best, and to understand the short-and long-term clinical outcomes of available therapies, as well as their effects on mortality, costeffectiveness, and quality of life.
# Disclosures
Please see Supplemental Table S1 for a complete list of disclosures.
# RECOMMENDATION
16. In patients with VT/VF, we recommend ongoing incorporation of patient values and preferences in goals of care discussions, including ICD tachycardia therapy deactivation or ICD replacement with a pacemaker, particularly at times of ICD generator replacement or changes in clinical status (Strong Recommendation, Low-Quality Evidence).
Values and preferences. Despite the lack of systematic evidence supporting goals of care discussions, the importance of these discussions is paramount for patient-centred care.
Practical tip. Incorporating discussion of goals of care and ICD deactivation into routine device clinic standard of care promotes enhanced patient understanding of end of life options and facilitates patient decision-making.
# Acknowledgements
The authors thank Brittany Forrest from the Canadian Cardiovascular Society for her tireless efforts.
# Funding Sources
This position statement was funded by the Canadian Cardiovascular Society. | None | None |
f3853c4921765e86dcd8e77c2ee222a4c45a52c7 | cma | None | - Introduction 2. Principles 3. Current status of cardiac rehabilitation during COVID-19 4. Challenges and Obstacles of Care Delivery 5. Implementing Virtual Cardiac Rehabilitation 6. Practical tips from established virtual cardiac rehabilitation programs 7.# Introduction
Cardiac rehabilitation (CR) programs across Canada have suspended in-person services as a result of large-scale physical distancing recommendations designed to flatten the COVID-19 pandemic curve. As medically supervised or centre-based cardiac rehab (CBCR) is the mainstay of CR care delivery, this guideline-based therapy is at risk of being significantly underutilized. CBCR has unequivocally demonstrated reductions in hospital readmissions, secondary events, and mortality in cardiovascular disease patients. Significant consequences of CBCR suspension may include short-and longer-term adverse events, increased cardiacrelated emergency department visits and hospital admissions, and exposure of this vulnerable cardiac population to infection. This all places additional burdens on already strained acute care services. Prolonged closures or reduced access are likely to result in a significant waitlist expansion, perpetuating in-person care delivery delay.
Virtual CR (VCR) offers an alternate mechanism to CBCR, capable of delivering similar patient outcomes and safety profiles for those with low to moderate cardiac risk. 2 However, execution of this can be daunting, particularly for centres without previously established virtual care programs. Conversely, centres where some home-based/virtual programs are already available, the conversion of all CR participants to VCR brings new challenges, largely around greater resource requirements. A review of the challenges, limitations, and pragmatic guidance on the rapid transition to VCR is outlined below.
# Principles
- Protect CR staff and patients from undue exposure risk during the COVID-19 pandemic - Continue CR care delivery during the COVID-19 pandemic to prevent short-and longterm negative impacts on at-risk cardiovascular populations - Rapidly implement or expand VCR programming to replace lost capacity due to suspension of in-person CBCR services - Plan for potential capacity growth, based on scalable models of delivery - Initial focus on collation, utilization and re-purposing of existing resources, equipment, and technology over complex restructuring to allow for rapid deployment - Adapt VCR programs to ensure care delivery fits the needs of vulnerable populations in a variety of settings, including low-resource, urban and rural - Develop sustainable and pragmatic VCR programming to address the possibility of prolonged or recurrent restrictions on in-person care, and to improve access to and delivery of CR care during non-pandemic situations - Ensure virtual care privacy and safety standards pertaining to VCR delivery are reviewed and respected. Utilize available secure technologies
# Current status of cardiac rehabilitation during COVID-19
Prior to the COVID-19 pandemic, Canadian CR programs fell into one of three categories: 1. Those with no pre-existing VCR experience or programs 2. Those with several CR components delivered virtually (i.e. 'partial' or 'hybrid' VCR) 3. Those with well-established VCR programs integrated into their CBCR programs Prior to COVID-19, no programs existed as "stand-alone" virtual CR. Patient participation in VCR was determined by eligibility criteria based on risk stratification for cardiac events, and patient factors, such as access to required technology and self-motivation. The majority of programs limited participation to low-moderate risk patients, with higher risk patients enrolled in CBCR. Graded-exercise testing (GXT) informed the risk stratification process.
During the COVID-19 pandemic, up to 50% of all Canadian CR programs have ceased providing any care (unpublished data, personal communication, Dr. Paul Oh). Those that continued adapted to a lack of in-person intake assessments, a potential inability to perform routine GXT risk-stratification, and a lack of in-person exercise monitoring for those deemed to be at "high-risk" of cardiac events. These programs have also innovated using a virtual model to deliver all other CR care components.
The University of Ottawa Heart Institute (UOHI) in Ottawa, and the University Health Network (UHN) in Toronto were reasonably well-equipped for this scenario, due to previously established home and VCR programs. These centres can serve as blueprints, to assist other sites with initial VCR implementation, with readily available online resources. 7,8
# Challenges and Obstacles of Care Delivery
Several specific areas of concern surrounding the transition to VCR delivery include: a. Implementation Challenges i.
Lack of centre and patient experience with VCR delivery ii.
Access to affordable, effective required technology iii.
Potential CR staff redeployment b. Safe and standardized care delivery concerns i.
Limited guideline standards to use as benchmarks for implemented VCR programs ii.
Lack of evidence for entirely virtual programs (i.e. without access to in-person intake assessments, risk stratification by GXT, and the inclusion of high-risk patients) iii.
Variable technology platforms and literacy, limiting access to virtual care delivery 5. Implementing Virtual Cardiac Rehabilitation (VCR) (Figure 1) The risk of excluding patients considered high-risk by CR standards should be carefully balanced with potential benefits of appropriately guided participation iv)
VCR
The risks and benefits of participation should be discussed, and informed written consent obtained
# c) Resource Limited and Rural Centers i)
Programs with limited resources may require regular phone interactions and educational mail-outs ii)
Individual programs may consider purchasing tablets, smart phones or other electronic options for loan to participants to enhance a "one-on one" personal experience 6. Practical tips from established virtual cardiac rehabilitation programs a) Utilize tip sheets to help staff adjust to delivering their intervention virtually. ie.
%20cues.pdf b) Avoid becoming overwhelmed by the multitude of available resources by finding a single, comprehensive, verified online resource for patients and staff c) Encourage patients to attend at a minimum, intake assessments to discuss the merits of virtual CR d) Follow a shared decision-making process regarding VCR enrollment to ensure patients understand potential risks and benefits of participating virtually, versus choosing to delay care e) Utilize practical approaches to obtaining patient metrics. Examples include remote 6minute walk test for baseline exercise capacity, having patient use personal scales and blood pressure cuff f) Focus initial care on core components (lifestyle risk management, psychosocial support, medical advice, education) and simple exercise prescriptions aimed at encouraging low to moderate intensity physical activity. These goals should be achieved prior to implementing complex technologic virtual care systems, or considering higher intensity activities g) Provide group tele-/videoconferencing for educational sessions and patient support, when possible, to reduce resource intensive 1-on-1 sessions h) Formalize an evaluation process to assess the merits and efficacy of VCR. This will be enabled by use of CACPR registry software, available free of charge.
# Planning for the Ebb and Flow of an Uncertain Future
The COVID-19 pandemic is likely to result in varying degrees of care disruptions in the future. Once a virtual CR program has been established, centers should plan for an ebb and flow of care delivery restrictions due to physical distancing recommendations likely to follow the COVID-19 pandemic trajectory. Restrictions on care will fall into three general categories with each level requiring a specific strategy.
# Level 1
Minor restriction in regular services, due to persistent health and societal effects of COVID-19, despite low infection rates ○ Programs should plan to integrate VCR into CBCR, as it is likely programs may be required to operate at lower capacities to adhere to even low-level restrictions, thereby creating a hybrid model of care delivery ○ CR care should be individualized, with varying degrees or virtual and in-person care to optimize the risks and benefits to both patients and healthcare workers ○ Elements of the CR intervention, such as initial in-person assessment and exercise stress testing may be available, and should be encouraged assuming appropriate PPE is available
# Level 2
Major restriction in regular services due to COVID-19 outbreaks or high-risk of potential outbreaks ○ Programs should focus on the improvement and expansion of VCR ○ Alternative methods for key in-person elements such as initial assessment and exercise testing should be sought.
# Level 3
Complete inability to provide regular services due to closure of ambulatory facilities or essential staff reassignment ○ Programs should offer a limited form of VCR. This may be the provision of educational and care resources, with a focus on a higher degree of patient responsibility and less frequent or minimal care-team interactions
Corresponding Author: Dr David Bewick, 299 Metcalf Street Saint John, New Brunswick E2K 4P8 Canada Tel. þ1-506-633-2099 Fax: þ1-506-633-1487 E-mail: [email protected] Virtual cardiac rehabilitation (or VCR) is home-based cardiac rehabilitation (HBCR) delivered by virtual mechanisms. Virtual care refers to any remotely occurring interaction between patients and their care that uses communication technologies to facilitate or maximize the quality and effectiveness of care. This includes telephone and video-conferencing communication, email, mail, text or other messaging solutions, smartphone applications, online resources, online platforms and/or wearable devices.
# What is "virtual cardiac rehabilitation"?
# Setting up your virtual cardiac rehabilitation program: Guidance for Clinicians
# Decide who is ELIGIBLE for your virtual cardiac rehabilitation program
This includes patients who were typically excluded from VCR programs prior to the COVID-19 pandemic:
- Patients at "high-risk" of events, exercise-induced or otherwise
# In the beginning…
"Basic, safe and timely" care should initially be prioritized over "complex and comprehensive", particularly for those with no previously established virtual program.
# Once your program is established…
Shift focus to:
- ensuring traditional cardiac rehabilitation care delivery standards are met; - protocolized patient assessment, risk stratification and follow-up are defined; and - workflows are optimized.
# Determine the GOALS of your virtual cardiac rehabilitation program
Develop sustainable VCR solutions to account for care gaps that existed prior to and post COVID-19.
# Practical approaches to delivering cardiac rehabilitation during COVID-19 from the CCS COVID-19 Rapid Response Team
Our new "virtual reality" Risk stratification and exercise prescription is both challenging and paramount. The COVID-19 pandemic is likely to result in varying degrees of ongoing care disruptions. Once a virtual CR program has been established, centers should plan for an ebb and flow of care delivery restrictions due to physical distancing recommendations likely to follow the COVID-19 pandemic trajectory. Restrictions on care will fall into three general categories, with each requiring a specific strategy. | 1. Introduction 2. Principles 3. Current status of cardiac rehabilitation during COVID-19 4. Challenges and Obstacles of Care Delivery 5. Implementing Virtual Cardiac Rehabilitation 6. Practical tips from established virtual cardiac rehabilitation programs 7.# Introduction
Cardiac rehabilitation (CR) programs across Canada have suspended in-person services as a result of large-scale physical distancing recommendations designed to flatten the COVID-19 pandemic curve. As medically supervised or centre-based cardiac rehab (CBCR) is the mainstay of CR care delivery, this guideline-based therapy is at risk of being significantly underutilized. CBCR has unequivocally demonstrated reductions in hospital readmissions, secondary events, and mortality in cardiovascular disease patients. Significant consequences of CBCR suspension may include short-and longer-term adverse events, increased cardiacrelated emergency department visits and hospital admissions, and exposure of this vulnerable cardiac population to infection. This all places additional burdens on already strained acute care services. Prolonged closures or reduced access are likely to result in a significant waitlist expansion, perpetuating in-person care delivery delay.
Virtual CR (VCR) offers an alternate mechanism to CBCR, capable of delivering similar patient outcomes and safety profiles for those with low to moderate cardiac risk. 2 However, execution of this can be daunting, particularly for centres without previously established virtual care programs. Conversely, centres where some home-based/virtual programs are already available, the conversion of all CR participants to VCR brings new challenges, largely around greater resource requirements. A review of the challenges, limitations, and pragmatic guidance on the rapid transition to VCR is outlined below.
# Principles
• Protect CR staff and patients from undue exposure risk during the COVID-19 pandemic • Continue CR care delivery during the COVID-19 pandemic to prevent short-and longterm negative impacts on at-risk cardiovascular populations • Rapidly implement or expand VCR programming to replace lost capacity due to suspension of in-person CBCR services • Plan for potential capacity growth, based on scalable models of delivery • Initial focus on collation, utilization and re-purposing of existing resources, equipment, and technology over complex restructuring to allow for rapid deployment • Adapt VCR programs to ensure care delivery fits the needs of vulnerable populations in a variety of settings, including low-resource, urban and rural • Develop sustainable and pragmatic VCR programming to address the possibility of prolonged or recurrent restrictions on in-person care, and to improve access to and delivery of CR care during non-pandemic situations • Ensure virtual care privacy and safety standards pertaining to VCR delivery are reviewed and respected. Utilize available secure technologies
# Current status of cardiac rehabilitation during COVID-19
Prior to the COVID-19 pandemic, Canadian CR programs fell into one of three categories: 1. Those with no pre-existing VCR experience or programs 2. Those with several CR components delivered virtually (i.e. 'partial' or 'hybrid' VCR) 3. Those with well-established VCR programs integrated into their CBCR programs Prior to COVID-19, no programs existed as "stand-alone" virtual CR. Patient participation in VCR was determined by eligibility criteria based on risk stratification for cardiac events, and patient factors, such as access to required technology and self-motivation. The majority of programs limited participation to low-moderate risk patients, with higher risk patients enrolled in CBCR. Graded-exercise testing (GXT) informed the risk stratification process.
During the COVID-19 pandemic, up to 50% of all Canadian CR programs have ceased providing any care (unpublished data, personal communication, Dr. Paul Oh). Those that continued adapted to a lack of in-person intake assessments, a potential inability to perform routine GXT risk-stratification, and a lack of in-person exercise monitoring for those deemed to be at "high-risk" of cardiac events. These programs have also innovated using a virtual model to deliver all other CR care components.
The University of Ottawa Heart Institute (UOHI) in Ottawa, and the University Health Network (UHN) in Toronto were reasonably well-equipped for this scenario, due to previously established home and VCR programs. These centres can serve as blueprints, to assist other sites with initial VCR implementation, with readily available online resources. 7,8
# Challenges and Obstacles of Care Delivery
Several specific areas of concern surrounding the transition to VCR delivery include: a. Implementation Challenges i.
Lack of centre and patient experience with VCR delivery ii.
Access to affordable, effective required technology iii.
Potential CR staff redeployment b. Safe and standardized care delivery concerns i.
Limited guideline standards to use as benchmarks for implemented VCR programs ii.
Lack of evidence for entirely virtual programs (i.e. without access to in-person intake assessments, risk stratification by GXT, and the inclusion of high-risk patients) iii.
Variable technology platforms and literacy, limiting access to virtual care delivery 5. Implementing Virtual Cardiac Rehabilitation (VCR) (Figure 1) The risk of excluding patients considered high-risk by CR standards should be carefully balanced with potential benefits of appropriately guided participation iv)
VCR
The risks and benefits of participation should be discussed, and informed written consent obtained
# c) Resource Limited and Rural Centers i)
Programs with limited resources may require regular phone interactions and educational mail-outs ii)
Individual programs may consider purchasing tablets, smart phones or other electronic options for loan to participants to enhance a "one-on one" personal experience 6. Practical tips from established virtual cardiac rehabilitation programs a) Utilize tip sheets to help staff adjust to delivering their intervention virtually. ie.
https://cacpr.wildapricot.org/resources/Documents/UOHI%20CR%20Home%20Program %20cues.pdf b) Avoid becoming overwhelmed by the multitude of available resources by finding a single, comprehensive, verified online resource for patients and staff https://pwc.ottawaheart.ca/resources/covid-19 c) Encourage patients to attend at a minimum, intake assessments to discuss the merits of virtual CR d) Follow a shared decision-making process regarding VCR enrollment to ensure patients understand potential risks and benefits of participating virtually, versus choosing to delay care e) Utilize practical approaches to obtaining patient metrics. Examples include remote 6minute walk test for baseline exercise capacity, having patient use personal scales and blood pressure cuff f) Focus initial care on core components (lifestyle risk management, psychosocial support, medical advice, education) and simple exercise prescriptions aimed at encouraging low to moderate intensity physical activity. These goals should be achieved prior to implementing complex technologic virtual care systems, or considering higher intensity activities g) Provide group tele-/videoconferencing for educational sessions and patient support, when possible, to reduce resource intensive 1-on-1 sessions h) Formalize an evaluation process to assess the merits and efficacy of VCR. This will be enabled by use of CACPR registry software, available free of charge. https://cardiologica.org/7/?i=cr
# Planning for the Ebb and Flow of an Uncertain Future
The COVID-19 pandemic is likely to result in varying degrees of care disruptions in the future. Once a virtual CR program has been established, centers should plan for an ebb and flow of care delivery restrictions due to physical distancing recommendations likely to follow the COVID-19 pandemic trajectory. Restrictions on care will fall into three general categories with each level requiring a specific strategy.
# Level 1
Minor restriction in regular services, due to persistent health and societal effects of COVID-19, despite low infection rates ○ Programs should plan to integrate VCR into CBCR, as it is likely programs may be required to operate at lower capacities to adhere to even low-level restrictions, thereby creating a hybrid model of care delivery ○ CR care should be individualized, with varying degrees or virtual and in-person care to optimize the risks and benefits to both patients and healthcare workers ○ Elements of the CR intervention, such as initial in-person assessment and exercise stress testing may be available, and should be encouraged assuming appropriate PPE is available
# Level 2
Major restriction in regular services due to COVID-19 outbreaks or high-risk of potential outbreaks ○ Programs should focus on the improvement and expansion of VCR ○ Alternative methods for key in-person elements such as initial assessment and exercise testing should be sought.
# Level 3
Complete inability to provide regular services due to closure of ambulatory facilities or essential staff reassignment ○ Programs should offer a limited form of VCR. This may be the provision of educational and care resources, with a focus on a higher degree of patient responsibility and less frequent or minimal care-team interactions
#
Corresponding Author: Dr David Bewick, 299 Metcalf Street Saint John, New Brunswick E2K 4P8 Canada Tel. þ1-506-633-2099 Fax: þ1-506-633-1487 E-mail: [email protected] Virtual cardiac rehabilitation (or VCR) is home-based cardiac rehabilitation (HBCR) delivered by virtual mechanisms. Virtual care refers to any remotely occurring interaction between patients and their care that uses communication technologies to facilitate or maximize the quality and effectiveness of care. This includes telephone and video-conferencing communication, email, mail, text or other messaging solutions, smartphone applications, online resources, online platforms and/or wearable devices.
# What is "virtual cardiac rehabilitation"?
# Setting up your virtual cardiac rehabilitation program: Guidance for Clinicians
# Decide who is ELIGIBLE for your virtual cardiac rehabilitation program
This includes patients who were typically excluded from VCR programs prior to the COVID-19 pandemic:
• Patients at "high-risk" of events, exercise-induced or otherwise
# In the beginning…
"Basic, safe and timely" care should initially be prioritized over "complex and comprehensive", particularly for those with no previously established virtual program.
# Once your program is established…
Shift focus to:
• ensuring traditional cardiac rehabilitation care delivery standards are met; • protocolized patient assessment, risk stratification and follow-up are defined; and • workflows are optimized.
# Determine the GOALS of your virtual cardiac rehabilitation program
Develop sustainable VCR solutions to account for care gaps that existed prior to and post COVID-19.
# Practical approaches to delivering cardiac rehabilitation during COVID-19 from the CCS COVID-19 Rapid Response Team
Our new "virtual reality" Risk stratification and exercise prescription is both challenging and paramount. The COVID-19 pandemic is likely to result in varying degrees of ongoing care disruptions. Once a virtual CR program has been established, centers should plan for an ebb and flow of care delivery restrictions due to physical distancing recommendations likely to follow the COVID-19 pandemic trajectory. Restrictions on care will fall into three general categories, with each requiring a specific strategy. | None | None |
5fe1556c734bd89abeea6128248e8664d681afa4 | cma | None | Purpose Since the last Canadian Airway Focus Group (CAFG) guidelines were published in 2013, the published airway management literature has expanded substantially. The CAFG therefore re-convened to examine this literature and update practice recommendations. This second of two articles addresses airway evaluation, decision-making, and safe implementation of an airway management strategy when difficulty is anticipated. Source Canadian Airway Focus Group members, including anesthesia, emergency medicine, and critical care physicians were assigned topics to search. Searches were run in the Medline, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL The members of the Canadian Airway Focus Group are listed in Appendix.#
databases. Results were presented to the group and discussed during video conferences every two weeks from April 2018 to July 2020. These CAFG recommendations are based on the best available published evidence. Where high-quality evidence is lacking, statements are based on group consensus. Findings and key recommendations Prior to airway management, a documented strategy should be formulated for every patient, based on airway evaluation. Bedside examination should seek predictors of difficulty with facemask ventilation (FMV), tracheal intubation using videoor direct laryngoscopy (VL or DL), supraglottic airway use, as well as emergency front of neck airway access. Patient physiology and contextual issues should also be assessed. Predicted difficulty should prompt careful decision-making on how most safely to proceed with airway management. Awake tracheal intubation may provide an extra margin of safety when impossible VL or DL is predicted, when difficulty is predicted with more than one mode of airway management (e.g., tracheal intubation and FMV), or when predicted difficulty coincides with significant physiologic or contextual issues. If managing the patient after the induction of general anesthesia despite predicted difficulty, team briefing should include triggers for moving from one technique to the next, expert assistance should be sourced, and required equipment should be present. Unanticipated difficulty with airway management can always occur, so the airway manager should have a strategy for difficulty occurring in every patient, and the institution must make difficult airway equipment readily available. Tracheal extubation of the atrisk patient must also be carefully planned, including assessment of the patient's tolerance for withdrawal of airway support and whether re-intubation might be difficult.
# Résumé
Objectif Depuis la dernie`re publication des lignes directrices du Canadian Airway Focus Group (CAFG) en 2013, la litte´rature sur la prise en charge des voies ae´riennes s'est conside´rablement e´toffe´e. Le CAFG s'est donc re´uni a`nouveau pour examiner la litte´rature et mettre a`jour ses recommandations de pratique. Ce deuxie`me article traite de l'e´valuation des voies ae´riennes, de la prise de de´cision et de la mise en oeuvre se´curitaire d'une strate´gie de prise en charge des voies ae´riennes lorsque des difficulte´s sont anticipe´es. Sources Des sujets de recherche ont e´te´assigne´s aux membres du Canadian Airway Focus Group, qui compte des me´decins anesthe´sistes, urgentologues et intensivistes. Les recherches ont e´te´re´alise´es dans les bases de donne´es Medline, EMBASE, Cochrane Central Register of Controlled Trials et CINAHL. Les re´sultats ont e´teṕ re´sente´s au groupe et discute´s lors de vide´oconfe´rences toutes les deux semaines entre avril 2018 et juillet 2020. Les recommandations du CAFG sont fonde´es sur les meilleures donne´es probantes publie´es. Si les donne´es probantes de haute qualite´manquaient, les e´nonce´s se fondent alors sur le consensus du groupe. Constatations et recommandations clés Avant d'amorcer la prise en charge des voies ae´riennes, une strate´gie documente´e devrait eˆtre formule´e pour chaque patient, en fonction de l'e´valuation de ses voies ae´riennes. L'examen au chevet devrait rechercher les pre´dicteurs de difficulte´s pour la ventilation au masque, l'intubation trache´ale utilisant la vide´olaryngoscopie ou la laryngoscopie directe, l'utilisation d'un dispositif supraglottique, ainsi que pour la cricothyroı¨dotomie d'urgence. La physiologie du patient et ses proble´matiques contextuelles devraient e´galement eˆtre e´value´es. Les difficulte´s anticipe´es devraient inciter ap rendre des de´cisions e´claire´es sur la façon la plus se´curitaire de proce´der a`la prise en charge des voies ae´riennes. L'intubation trache´ale e´veille´e peut procurer une marge de se´curite´supple´mentaire lorsqu'on s'attend ac e que la vide´olaryngoscopie ou la laryngoscopie directe soient impossibles, lorsqu'on pre´voit des difficulte´s pour plus d'un mode de prise en charge des voies ae´riennes (p. ex., intubation trache´ale et ventilation au masque), ou lorsque la difficulte´pre´vue coı¨ncide avec des proble`mes physiologiques ou contextuels importants. En cas de choix de prise en charge des voies respiratoires du patient apre`s induction de l'anesthe´sie ge´ne´rale malgre´les difficulte´s pre´vues, les directives a`l'e´quipe devraient inclure les de´clencheurs pour passer d'une technique a`l'autre, l'aide d'experts disponibles et l'e´quipement requis disponible. Des difficulte´s impre´vues lors de la prise en charge des voies ae´riennes peuvent toujours survenir, de sorte que la personne responsable de la prise en charge des voies ae´riennes devrait avoir une strate´gie pour chaque patient, et l'e´tablissement doit rendre facilement disponible le mate´riel pour la prise en charge des voies ae´riennes difficiles. L'extubation trache´ale du patient a`risque doit e´galement eˆtre soigneusement planifie´e, y compris l'e´valuation de la tole´rance du patient lors du retrait du dispositif de soutien des voies ae´riennes et d'une re´intubation potentiellement difficile.
# Introduction
Significant morbidity related to airway management continues to be reported, with the failure to plan for difficulty a recurrent theme. Most published airway guidelines focus on management of the alreadyunconscious patient when difficulty with tracheal intubation is encountered. Although less frequently addressed, avoiding having to manage an unexpectedly difficult airway almost certainly has greater potential to prevent patient harm. Airway-related morbidity can be prevented by careful patient evaluation and formulation of an airway management strategy (a co-ordinated series of plans) before proceeding with airway management. Lack of an airway evaluation or the failure to change usual practice based on its findings has been associated with morbidity. 1 Airway evaluation includes examination for anatomic predictors of difficulty with tracheal intubation, facemask ventilation (FMV), supraglottic airway (SGA) use, and emergency front of neck airway access (eFONA). It should also include assessment of physiologic issues (e.g., apnea tolerance, aspiration risk, and altered hemodynamics) and the clinical context (e.g., case urgency, airway manager experience, equipment availability, and access to expert assistance). Airway evaluation should occur before starting airway management as well as before its discontinuation.
Video laryngoscopy (VL) has helped achieve more consistent glottic visualization and has improved firstattempt intubation success rates in the unconscious patient, especially in populations deemed to be at risk for difficult direct laryngoscopy (DL). 4 Nevertheless, there remain patients who, based on thorough airway evaluation, would likely be more safely managed with awake tracheal intubation. This article addresses airway evaluation and provides recommendations to help formulate and implement a safe airway management strategy when difficulty is anticipated. In part 1 of these updated twopart recommendations, 5 we address management of airway difficulties encountered in the unconscious patient, whether anticipated or not. Recommendations in both articles are meant to be broadly applicable to all specialties that have airway management in their practice mandate.
# Methods
The methods presented here are identical to those described in the companion part 1 article 5 and are reproduced here for the benefit of the reader. The Canadian Airway Focus Group (CAFG) is comprised of 17 members (see Appendix), with representation from across Canada as well as one member from each of New Zealand and Australia.
The CAFG membership includes anesthesiologists, emergency physicians, and critical care physicians. Topics for review were divided among the members, with most assigned to two members. Members reviewed the literature published from 2011 onwards.
A medical librarian helped design and conduct the literature searches. Though not constituting a formal systematic review, databases searched included Medline, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL. Non-English and non-French, animal, manikin, and cadaver studies were excluded from searches, as were case reports, editorials, and letters. Nevertheless, team members had the discretion to include such material where relevant.
The CAFG met every two weeks by video conference from April 2018 to July 2020 to review findings and arrive at consensus regarding recommendations. Consistent with other recent airway management guidelines, we did not assign levels of evidence or strength of recommendation. This follows from a lack of what is considered high-level evidence seen in other medical fields. Randomized controlled trials of airway devices typically address efficacy (often in a population of low-risk elective surgical patients) but when critical events are uncommon (as with airway management), they are unable to evaluate the safety of techniques or decision-making. 10 Information gleaned from large database studies is better able to capture uncommon events, 10 but analysis is limited to association rather than causation and the population studied may not represent all practice environments. Thus, although evidence-based to the extent possible, some of the recommendations are based largely on expert consensus.
After review by the CAFG, draft documents were sent to several airway experts internationally (see Acknowledgments) for informal review and comment.
# Definitions
The following definitions are used throughout the manuscript.
- Anticipated difficult airway. A difficult airway is predicted when the airway manager anticipates difficulty with any or all of FMV, tracheal intubation, SGA use, or eFONA. - Awake tracheal intubation. Awake tracheal intubation (ATI) refers to tracheal intubation of a patient who is sufficiently conscious to maintain a patent airway unassisted, to maintain adequate gas exchange by spontaneous ventilation, and to protect the airway against the aspiration of gastric contents or other foreign material. Awake tracheal intubation can occur via the nasal, oral, or front of neck routes, and is facilitated by topical, regional, or local infiltrative airway anesthesia. - At-risk tracheal extubation. The at-risk tracheal extubation is defined by the patient anticipated to be intolerant of tracheal extubation or who might be potentially difficult to re-intubate. Difficult reintubation might be anticipated based on pre-existing or de novo conditions (e.g., neck fusion or immobilization; upper airway edema).
# Prediction of difficulty with airway management
Predicting difficulty underlies the planning for safe airway management. Expert opinion appearing in audits of airwayrelated morbidity and closed legal claim studies suggest that the ''failure to prepare for failure'' by omitting, not documenting, or not acting on positive findings of an airway evaluation figures prominently in cases with poor outcomes. Canadian data, 3 and that from the USA, 2 reveal that most anesthesia airway-related closed claims involved patients presenting for elective surgery (78% and 63%, respectively). Comprehensive airway evaluation includes physical examination of the patient and review of relevant physiologic and contextual issues, pertinent diagnostic imaging studies, and any available records of previous airway management. A history of previous difficulty is more often correctly predictive of difficulty than the bedside examination. Alone or in combination, the various bedside screening tests of anatomic features have been criticized for their poor performance in correctly predicting when difficulty will indeed occur with airway management. 11,13,16 Nevertheless, the presence of certain anatomic features (Tables 1, 2, 3, 4, 5, 6, 7) should alert the airway manager to carefully consider the safest approach to airway management and which devices to have available; little downside will accrue if airway management turns out to be non-problematic. Conversely, when bedside screening suggests that no difficulty is expected, while more often correctly predictive of the actual outcome, 11,16,17 unanticipated difficulty can still occur, such that the airway manager must be ready with a strategy to address difficulty in all patients. Performing and documenting an airway evaluation is standard of care, and furthermore, acts as a cognitive prompt 18 to consider the potential for difficulty with every patient. The CAFG recommends that all patients undergo airway evaluation before the initiation of airway management and before the discontinuation of airway support (e.g., tracheal extubation).
# Published predictors of difficult airway management
Predictors of difficult tracheal intubation by DL and VL and other devices appear in Tables 1-3. Predictors of difficult FMV and difficult SGA use appear in Tables 4 and 5, respectively. Predictors of difficult eFONA have not been prospectively studied but appear on a presumptive basis in Table 6. The likelihood of actually encountering difficulty with any modality increases in proportion to the number of anatomic predictors of difficulty. There are currently few published studies looking at predictors of difficulty with tracheal intubation using VL; this is a gap in the literature that should be addressed. Physiologic and contextual factors that may also impact planning and implementation of airway management appear in Table 7.
# The enhanced airway evaluation
Patients with obstructing airway pathology may have distortions of upper or lower airway anatomy that cannot be identified by regular bedside screening tests. For the patient with known or suspected obstructing glottic or supraglottic airway pathology, awake nasal endoscopy or oral VL performed under local anesthesia immediately before airway management can help clarify the extent and location of the problem. 19 Subglottic pathology can be assessed by review of recent imaging studies. 20 Point-ofcare ultrasound is playing an increasing role in physiologic diagnosis and evaluation of targeted management of resuscitation before, during, or after airway management. 21 Another aspect to enhancing the airway exam in patients with significantly altered anatomy is to identify the location of the cricothyroid membrane (CTM). 22 If visual inspection or palpation fails to identify the CTM location with certainty, it should be identified using ultrasonography and marked, 22,23 with the patient's neck in an extended position. The patient can subsequently be positioned Table 1 Published predictors of difficult tracheal intubation using direct laryngoscopy Predictors of difficult laryngoscopy and tracheal intubation using direct laryngoscopy 16, - Age [ 46 yr
- Male sex
- Modified Mallampati grades 3 or 4
- Thyromental distance \ 6 cm
- Prominent, gapped, repaired, or fragile dentition - Visibility impaired by blood or secretions
- Higher neck skinfold thickness
- Larger tracheal tube inner diameter relative to scope outer diameter optimally for the intended airway technique; if eFONA is required, the patient can quickly be returned to the neckextended position to utilize the previously made marking. 24 6 Decision-making when difficult tracheal intubation is predicted
Few published studies or guidelines specifically address which patients with predictors of difficult tracheal intubation can safely be managed after the induction of general anesthesia. Nevertheless, cues can be taken from the UK's NAP4 study 1 and closed claims analyses. 2,3 In NAP4, ATI was judged to have been underutilized in patients with known difficult airways. Eighteen cooperative patients with predictors of both difficult tracheal intubation and difficult FMV underwent intubation attempts after 7 Physiologic and contextual issues that may impact airway management Physiologic issues that may impact airway management 53,54 - Apnea intolerance, based on: s Decreased functional residual capacity s Increased oxygen consumption s Baseline hypoxemia; decreased PaO 2 /FiO 2 ratio s Acid-base disturbance with respiratory compensation.
- Full stomach or other major risk factor for aspiration.
- Hemodynamic instability.
# Contextual issues that may impact airway management
- Adverse location (e.g., remote location, difficult access to patient, adverse lighting conditions) - Help/backup unavailable (e.g., because of time of day or remote location) - Airway manager inexperience with chosen or required technique - Lack of equipment - Team inexperienced with difficult airway management - Poor team communication induction of general anesthesia. All suffered complications and two patients died. 1 When difficulty is predicted, ATI enables patients to maintain their own airway patency, gas exchange, and protection of the lower airway against aspiration during tracheal intubation; thus, ATI potentially provides a safety benefit. Conversely, despite possessing predictors of difficult laryngoscopy or intubation, some patients might still be safely managed after induction of general anesthesia. When difficult laryngoscopy or intubation is predicted, deliberate consideration of the following four questions can help the airway manager decide whether ATI is indicated or if management might safely occur after induction (Fig. 1).
A. Does the patient clearly need awake tracheal intubation?
Significant and obvious anatomic deformities or pathologic alterations of the head and neck are often most safely managed with ATI. Examples include (but are not limited to) the patient with very limited mouth opening, a fixed flexion deformity of the head and neck, or a pathologically enlarged tongue. In such patients, there is often no chance that standard techniques such as DL, Macintosh blade video laryngoscopy (Mac-VL) or hyperangulated blade VL (HA-VL) are feasible. Alternatives to these standard techniques are likely to be less familiar to the airway manager or take longer to use, especially in the context of distorted anatomy. Thus, if managing the airway in apneic conditions after induction of general anesthesia, this could put the patient at risk of significant hypoxemia. In addition, anatomy altered to this extent will often also predict difficulty with fallback modes of ventilation such as FMV or SGA use (see next section). For these reasons, ATI is a safer option.
B. Is difficulty also predicted with fallback ventilation options?
When difficult tracheal intubation is predicted, no matter how effective the primary device chosen to facilitate Fig. 1 Flow diagram: Decision-making when difficult tracheal intubation is predicted. ATI = awake tracheal intubation; DL = direct laryngoscopy; FMV = face-mask ventilation; SGA = supraglottic airway; VL = video laryngoscopy. tracheal intubation may be, all have a failure rate. When this occurs, FMV or SGA ventilation will be needed between attempts. Unfortunately, when difficult or failed tracheal intubation has occurred, difficult FMV is more likely, and vice versa. 46,57 Similarly, failed SGA ventilation is associated with a higher incidence of difficult FMV. 49,52 This phenomenon has been referred to as the ''composite failure of airway management''. 55 Tracheal intubation and FMV are reported to have predictors of difficulty common to both modalities 44 (Table 4). Thus, when difficulty is predicted with one mode (e.g., tracheal intubation), the airway manager must be especially vigilant in assessing the patient for predicted difficulty with other modes (e.g., FMV, SGA ventilation, or front of neck airway access ). When significant difficulty is predicted with two or more modes, (e.g., tracheal intubation and FMV), ATI should be strongly considered as a potentially safer option.
C. Is there any physiologic compromise? Physiologic compromise (Table 7) complicates and distracts from difficult airway management. 53,54 It is also accentuated by induction of anesthesia that additionally risks hypoxemia, aspiration, or hemodynamic instability in those at risk. Separation of difficult airway management from induction of anesthesia is therefore of value; thus, ATI is likely the optimal choice for both safety and controlling the cognitive load of the airway manager.
Rarely, physiologic issues might be the sole indication for ATI, without any anatomic predictors of difficulty with airway management, as with a critically ill patient with significant lung parenchymal disease and a high shunt fraction. 58 D. Are there any complicating contextual issues? Contextual issues (Table 7) might also favour ATI when difficult tracheal intubation is predicted. For example, when an airway manager is practicing in a resource-austere setting without access to expert assistance or VL, the use of ATI for the predicted difficult airway patient might improve the margin of safety if patient transfer to a more fully equipped facility is not an option.
As indicated in Fig. 1, if all of the preceding questions are answered in the negative, airway management after induction of general anesthesia may be considered. Nevertheless, it must be emphasized that this decision remains one of clinical judgement and that the algorithm based on these questions has not been validated in a randomized-controlled trial. An airway manager's individual threshold for performing ATI or other patient or system factors might also impact the decision. Conversely, if the pathway through the Figure 1 flow diagram has suggested that ATI might be a safer option, a fifth question must then be addressed, as follows.
6.1 Can the patient cooperate with ATI and is there time?
Proceeding with ATI generally requires both a cooperative patient and time for its completion. If these are lacking, options become more limited. In some critically ill patients, physiologic disturbances or an alteration in sensorium can make compliance with ATI challenging. This may guide the airway manager towards tracheal intubation after the induction of general anesthesia if airway management must proceed at that time (Fig. 1). Under these circumstances, regardless of how the induction of general anesthesia proceeds (e.g., with or without an attempt to maintain spontaneous ventilation), ''double set-up'' (Table 8) preparations for eFONA are recommended in case of need. This decision must be balanced against the benefit of delaying tracheal intubation in favour of less invasive approaches for ventilation/oxygenation or further medical management, if this is an option.
When difficulty is predicted, tracheal intubation should only proceed after the induction of general anesthesia when the estimated margin of safety is equivalent to an awake technique. In the elective surgical setting, perceived time pressure or airway manager discomfort with performing ATI must not play a role in decision-making for the patient with a difficult airway. Rather, help might be sought from a colleague with more experience in performing ATI.
# Implementation of the planned strategy when difficult tracheal intubation is predicted
When difficult tracheal intubation is predicted, the following principles are common to implementing the plan, whether by ATI or after induction of general anesthesia:
- An additional experienced airway manager should be sourced. For more challenging situations, having this individual standing by in the room is advisable; - The airway manager should brief the assembled team on the intended strategy for securing the airway; - The briefing should include the planned response to failure of the intended technique; - An SGA must be available for use as a rescue technique in the event of failed tracheal intubation; - During the briefing, the airway manager should include triggers for declaring failure of one technique and proceeding to the next. At this time, all members of the team should be explicitly empowered to state when they believe a trigger has occurred.
# Awake tracheal intubation in the patient with anticipated difficult tracheal intubation
When performed by experienced airway managers, high success and low complication rates have been reported with ATI. All awake techniques are facilitated by one or more of topical, regional, or local infiltrative anesthesia, often aided by small doses of adjunctive systemic medications. Any discomfort with ATI is typically brief and patients are usually accepting of an airway manager's recommendation for airway management, especially when its safety aspects are discussed. 62 The Difficult Airway Society in the UK has recently published comprehensive guidelines on ATI. 63
# Topical airway anesthesia for awake tracheal intubation
Topically applied lidocaine provides good conditions for ATI and has a favourable safety profile compared with other agents. Used for ATI, a maximum dosage of 9 mgÁkg -1 (lean body weight) of topical lidocaine has been recommended by the DAS ATI guidelines, 63 although there have been reports of symptoms and signs of toxicity at this and lower doses in volunteers. 64 Thus, the lowest lidocaine dose compatible with adequate conditions for the procedure should be used. There is no published evidence to recommend one topicalization regime over another, nor is there evidence that percutaneous nerve blocks are superior to topical airway anesthesia.
# Adjunctive systemic medications during awake tracheal intubation
Systemic medications should complement topical airway anesthesia and should not be used to compensate for its ineffective application. The goal of therapy should be considered in choosing a systemic agent and its dosage. Anxiolysis and sometimes, amnesia, may be achieved with a benzodiazepine or dexmedetomidine 65,66 ; decreasing airway reflexes may be aided by opioids, such as a lowdose remifentanil infusion. Sedation is a secondary and arguably less desirable goal during ATI, as it may impair the patient's ability to cooperate with application of topical anesthesia. 67 The use of systemic medication in the patient undergoing ATI because of obstructing pathology must be carefully considered, recognizing that total loss of airway patency has been reported. 68 Reviews on the use of systemic medications during ATI have been published. 65,69 No single systemic agent has yet been definitively identified as the best to aid ATI, although dexmedetomidine has been established as an effective sedative for the purpose. 66,69 Airway managers' preferences and familiarity with the various drugs are important factors to help guide their choice of agent.
# Choice of device to facilitate awake tracheal intubation
ATI has traditionally been accomplished using a flexible bronchoscope (FB). More recently, HA-VL has also been reported to successfully facilitate ATI via the oral 70,71 and nasal 72 routes. While each class of device has benefits and limitations when used for ATI (Table 9), they appear to have comparable safety profiles. 73,74 If one technique fails, the other may prove successful. Both options require effective topical airway anesthesia for ATI. Note that awake VL will not be an option for some difficult anatomical presentations (Table 9). Nevertheless, it is important for the airway manager to appreciate that for many difficult airway situations, ATI can proceed with a variety of devices. 75 Other options to facilitate ATI include optical stylets, the concurrent use of VL and the FB, or awake placement of an SGA under topical anesthesia to provide a conduit for FB-aided intubation. 77 The latter is particularly effective in the setting of redundant upper airway tissue, as seen with significant obesity, patients with obstructive sleep apnea, and some children with predicted difficult airways. Blind passage of a tracheal tube through an SGA without being facilitated by a FB is not recommended for ATI.
The CAFG recommends that all airway managers should be competent in ATI. This includes effective application of topical airway anesthesia as well as the use Table 8 Components of the ''double set-up'' in airway management The ''double set-up'' in airway management: components
- Mark the location of the cricothyroid membrane with the patient's head and neck extended. Use ultrasound guidance if skilled. - Decide who will undertake eFONA. This should be someone other than the primary airway manager if possible. - Ensure equipment for the chosen eFONA technique is present in the room, opened, and ready to use. - Brief the team before induction, including the potential need for eFONA and triggers for proceeding with it. Rationale for the double set-up in airway management
- The double set-up will help focus everyone's attention on the anticipated airway management difficulty and patient risk. - Equipment and personnel are present in the room while the airway is being secured. - eFONA will be perceived as part of the plan, rather than the rescue of a failed plan. Timelier onset of eFONA may result.
eFONA = emergency front of neck airway access.
-f both the FB and VL for that purpose. Maintaining skills in ATI is important to ensure that airway manager discomfort is not a deterrent for performing an awake technique when clinically indicated.
# Failed awake intubation
Awake tracheal intubation may fail for a number of reasons, including inadequate topical anesthesia, excess sedation, adverse anatomy, or a lack of patient cooperation. The airway manager must carefully consider the next steps.
Simply proceeding with induction of general anesthesia after failed ATI has resulted in major morbidity and death. 1,81 Options include deferral of an elective surgical case, summoning more experienced help, or application of additional topical anesthesia. Simply deepening systemic sedation may be hazardous. For an urgent or emergency situation that cannot be deferred, tracheal intubation after the induction of general anesthesia must sometimes be undertaken, with a ''double set-up'' preparation for eFONA (please see section 6.2 and Table 8). Reports of complete airway obstruction occurring during attempted ATI have been published, 59,68,82,83 most often in the setting of advanced obstructing airway pathology. Possible causes include excess sedation, or a direct adverse effect of local anesthetic on upper airway patency. 84,85 The latter phenomenon does not imply that ATI should be avoided in patients with obstructing airway pathology, but rather, that the airway manager should be ready with an alternate plan, including rapidly proceeding with eFONA if a ''cannot ventilate, cannot oxygenate'' (CVCO) situation occurs. It should also be noted that if eFONA is anticipated to be difficult and prolonged (e.g., due to a thick neck, previous irradiation or overlying induration or infection), it should not be considered a viable fallback technique. In this situation, awake cricothyrotomy or tracheotomy under local infiltrative anesthesia (next section) may be the more prudent planned approach.
# Awake tracheotomy or awake cricothyrotomy
Elective FONA by tracheotomy or cricothyrotomy is a good option as a planned primary technique when great difficulty is predicted with airway management-e.g., with a friable airway cancer and/or severely narrowed airway. Requiring patient cooperation, local infiltrative anesthesia, and most often performed by a surgeon, this option might be chosen in the following situations, among others:
- For the patient presenting with advanced obstructing upper airway pathology that might cause significant technical difficulties during attempted awake oral or nasal intubation (e.g., a very friable, large base of tongue tumour); - When the glottic opening is very small (e.g., because of obstructing tumour burden) and FB-aided awake oral or nasal intubation would transiently completely occlude the patient's breathing during intubation, possibly causing panic and loss of patient cooperation; - When both oral and nasal routes are not available (e.g., because of substantial disruption by trauma or distortion by advanced upper airway pathology); - When a surgeon elects to do awake tracheotomy as an alternative to awake oral or nasal intubation if the - Enables a broad view of anatomy and good spatial awareness; facilitates a shared mental model with other team members. - The tracheal tube can be directed to and observed to pass between the vocal cords. - The ''pink-out'' that can occur if a FB abuts mucosa is avoided.
- Variously sized styleted tracheal tubes can be prepared; it is easier to substitute a smaller sized tracheal tube than re-load and re-insert a FB if the initial tube size is too large. - Space is created in the oropharynx with gentle lifting of the blade during VL. - As a familiar technique, VL may allow more rapid ATI than the FB.
- VL may not be an option with some anatomic and pathologic abnormalities (e.g., very limited mouth opening, fixed neck flexion deformity, enlarged tongue, or base of tongue masses). Use of flexible bronchoscopy for awake tracheal intubation - Passage of the FB and tracheal tube can occur by the nasal route, if necessary. - Navigation is possible in all planes around obstructing masses (e.g., a base of tongue lesion). - Advanced to just above the carina, the FB acts as a guide for tracheal tube advancement to, through, and beyond the larynx. The FB can also be used to confirm successful tracheal intubation and can be used to ensure correct tube positioning above the carina. - The FB can be used for some situations where anatomic constraints preclude use of awake VL. Thus, airway managers must also attain and maintain skills with the FB for ATI. - Using the FB routinely for ATI maintains skills in a critical technique. - Permits examination of the trachea to rule out injury, or to ensure a tracheal tube is placed distal to a known or suspected penetrating tracheal injury or fistula.
ATI = awake tracheal intubation; FB = flexible bronchoscope; VL = video laryngoscopy.
airway manager is not confident that ATI is a feasible option.
7.1.6 The ''impossible airway'' and awake institution of extracorporeal membrane oxygenation as a primary technique
An impossible airway might be predicted in clinical situations where all four of FMV, SGA use, tracheal intubation, and FONA are anticipated to fail. Failed FONA might occur with obstructing pathology distal to the thoracic inlet (or planned FONA site), or when anterior neck pathology precludes access to the trachea by cricothyrotomy or tracheotomy. In these circumstances, establishing awake veno-venous or veno-arterial extracorporeal membrane oxygenation (ECMO) prior to or as a replacement for airway intervention might represent a safer option to maintain oxygenation. 86 This underlying rationale, together with continually improving technology and expertise in ECMO, supports its use in the context of the impossible airway situation, although the currently supportive evidence appears chiefly as single case reports and case series, 90 with the attendant potential for positive publication bias. The decision to initiate ECMO prior to airway intervention should ideally occur by multidisciplinary consultation involving surgeons, anesthesiologists, perfusionists, and critical care staff, considering both diagnostic findings and clinical signs and symptoms such as stridor, dyspnea, and orthopnea. Even in experienced hands, establishing ECMO may be complicated and is time-consuming. Therefore, it has no role as a rescue technique for a failed airway encountered after the induction of general anesthesia. This is distinct from the use of veno-arterial ECMO in the cardiac arrest scenario, when extracorporeal cardiopulmonary resuscitation is possible when specific criteria are met. In this case, patients are often transitioned to mechanical circulatory support some time after cardiac arrest and, although in a low-flow state, they will have received continuous ventilation and oxygenation throughout.
# Management of the patient with anticipated difficult tracheal intubation after the induction of general anesthesia
If difficulty with management is predicted but the airway manager has elected to proceed with tracheal intubation after the induction of general anesthesia, close attention must be paid to details of implementation. Guiding principles are as follows:
- Position the patient optimally for the planned technique;
- Pre-oxygenate;
- Use apneic oxygenation throughout;
- Fully prepare equipment for the planned primary intubation approach; - Fully prepare equipment for alternate intubation techniques; - Prepare an appropriately sized second-generation SGA for rescue ventilation and oxygenation; - Brief the team on the planned progression of techniques, with objective triggers for transitioning to the next technique; - Review and communicate the exit strategy 5 to be used if tracheal intubation fails; - Ensure that an additional experienced airway manager has been sourced.
Further details appear below.
# Patient positioning
Appropriate patient positioning can help with technical aspects of airway management and by increasing safe apnea time.
- Positioning for laryngoscopy and intubation.
Published literature suggests optimal patient positioning for direct-and Mac-VL is the ''sniffing'' position. This is typically obtained by aligning the patient's tragus with their sternum in the horizontal plane, by flexing the lower neck and extending the head. 95 In the obese patient, similar alignment can be achieved in several ways, including commercial positioning devices, back-of-bed elevation, or by creating a ramp with folded sheets. There is currently insufficient evidence to recommend a specific patient position for the use of hyper-angulated videolaryngoscopes, which can be used in both the sniffing and neutral positions of the head and neck. The patient positioned in the neutral position with cervical spine immobilization is sub-optimally positioned for DL and Mac-VL, so that an experienced airway manager and alternate devices such as an HA-VL should be available. 105 - Positioning for FMV. Although the evidence is sparse, the sniffing position appears to be beneficial for improving upper airway patency 106 and facilitating FMV. 107 - Positioning for SGA insertion. Product monographs for SGAs typically espouse a sniffing position for insertion, with head extension and lower neck flexion. 108,109 Furthermore, a prospective study has indicated reduced neck mobility to be a risk factor for difficult SGA insertion. 52 With respect to ventilation once placed, a systematic review and meta-analysis by Kim and colleagues compared the performance of a variety of SGAs in the flexed, neutral, and extended positions. 110 Compared with the neutral position, the flexed position improved device seal but impaired ventilation as well as the view of the glottis obtainable with flexible endoscopy. Conversely, compared with the neutral position, the extended position worsened the device seal but had no effect on ventilation effectiveness or endoscopic view. These findings suggest that after insertion, SGAs should generally be used with the head and neck in the neutral position. - Positioning for eFONA. Although published evidence is lacking, full extension of the head and neck is likely the optimal position for eFONA. 4 This will be aided by placing a bolster or pillow under the patient's shoulders. There is some evidence that full neck extension may increase the height of the CTM by as much as 30%. 111 Pre-induction landmarking of the CTM (e.g., by ultrasound or palpation) should also occur in a position of full neck extension, as the CTM location may change significantly when re-positioning from a neutral to an extended position. 111
# Pre-oxygenation
The American Society of Anesthesiologists and Canadian Medical Protective Association closed claims publications revealed that many patients who sustained airway-related morbidity were healthy and presenting for elective surgery. 2,3 In some cases, harm might have been prevented or mitigated by closer attention to the use of pre-oxygenation and apneic oxygenation techniques to prolong the safe apnea time. Safe apnea time relates to the volume of the patient's functional residual capacity (FRC), effective de-nitrogenation of the FRC, and oxygen consumption. Of these, FRC and de-nitrogenation are modifiable. As described by Mosier in a recent editorial, three scenarios might be considered, based on the risk of oxygen desaturation with the onset of apnea 58 :
- Low to moderate risk of oxygen desaturation: Describing many elective surgical patients with a predicted ample FRC and low shunt fraction, the FRC should be de-nitrogenated by pre-oxygenation with 100% oxygen for three minutes of tidal volume breathing, eight vital capacity breaths over 60 sec, 112,113 or until the measured fraction of exhaled oxygen (FeO 2 ) exceeds 0.9. 114 More than one strategy has been described for standard pre-oxygenation: 1) use of a tightly applied cuffed face mask attached to an anesthetic circuit or manual resuscitator with O 2 flow C 10 LÁmin -1 , or 2) use of a nonrebreathing face mask with oxygen flow at ''flush rate'' (i.e., C 40
LÁmin -1 ). 115 The high flow rate helps match the patient's peak inspiratory flow rate, thus avoiding dilution by room air during peak demand. There is evidence that safe apnea time can be further extended with efforts to increase FRC, e.g., by patient positioning in the semi-seated (Fowler's), reverse Trendelenburg, or seated upright position, if hemodynamics allow. This is particularly applicable to morbidly obese patients and term parturients. In addition, gentle FMV between loss of consciousness and beginning laryngoscopy is advocated. - Moderate to high risk of oxygen desaturation: For the patient at higher risk of oxygen desaturation with the onset of apnea, such as those with lower FRC and increased shunt fraction, the optimal pre-oxygenation strategy likely involves use of positive end-expiratory pressure or non-invasive positive pressure ventilation (NIV) during pre-oxygenation, together with back up or reverse Trendelenburg positioning. The concurrent use of standard nasal cannulae with NIV can augment pre-oxygenation and subsequently provide apneic oxygenation during laryngoscopy and intubation, 129 although to avoid hazardous gastric insufflation, airway patency must be assured. Use of high-flow nasal oxygenation (HFNO) devices running high flows under a tightly sealed mask should be avoided, e.g., during FMV, for fear of rapid gastric distention or pulmonary hyperinflation and subsequent barotrauma. - High risk of oxygen desaturation due to refractory hypoxemia: The critically ill patient with substantial lung parenchymal disease and high shunt fraction is often refractory to pre-oxygenation and apneic oxygenation techniques, resulting in severely limited safe apnea time. The use of awake intubation and HFNO while maintaining spontaneous ventilation is one option to help address this scenario, if feasible.
The benefit of de-nitrogenation/pre-oxygenation is age dependent. Children have a relatively low FRC and high metabolic demand, which combine to create short apnea times despite pre-oxygenation. They often benefit from apneic oxygenation techniques to help maintain oxygenation during airway management. 130 The CAFG recommends universal pre-oxygenation before the induction of general anesthesia/rapid-sequence intubation (RSI), if feasible.
# Apneic oxygenation
The use of apneic oxygenation can be beneficial in prolonging the safe apnea time during airway management. Apneic oxygenation is most often accomplished with the use of standard nasal cannulae at flows of 5-15 LÁmin -1 or devices that provide heated and humidified oxygen at higher flows (40-70 LÁmin -1 in adults-i.e., HFNO). Apneic oxygenation is thought to work by a number of synergistic mechanisms, including mass flow of oxygen along a pressure gradient from the pharynx to the alveoli, turbulent supraglottic flow vortices and dead space flushing, as well as the effect of cardiac oscillations on intrathoracic pressure. Nevertheless, the airway manager must recognize that while oxygenation might be maintained, carbon dioxide clearance will be diminished during apneic oxygenation. Thus, caution and monitoring are required when allowing prolonged apnea in all patients, but especially those with increased intracranial pressure, metabolic acidosis, or pulmonary hypertension. 132 Apneic oxygenation by both standard nasal cannulae and HFNO has been studied in operating room (OR), emergency department (ED), and intensive care unit (ICU) settings. In general, compared with no apneic oxygenation, use of apneic oxygenation is effective in reducing oxygen desaturation during laryngoscopy in both adult and pediatric surgical patients. 132, Results are mixed in out-of-OR settings such as the ED or ICU, possibly relating to factors such as patient population (e.g., shunt physiology precluding oxygen uptake) or study design (e.g., a nonpatent airway during apnea before laryngoscopy). 132, The CAFG recommends that at a minimum, apneic oxygenation should be used for patients with anticipated difficult or prolonged laryngoscopy/tracheal intubation and/or for the patient with anticipated intolerance of apnea. It is essential to note that apneic oxygenation relies on a patent upper airway and will have no effect if the airway is obstructed.
# Maintenance or ablation of spontaneous ventilation?
General anesthesia with maintenance of spontaneous ventilation has been suggested to facilitate tracheal intubation when difficulty is anticipated. Nevertheless, despite the theoretical safety advantage afforded by the maintenance of inspiratory effort, 151 functional upper airway obstruction can occur with loss of consciousness, to a greater degree than occurs during natural sleep. 152 This follows from attenuation of upper airway dilator muscle activity, which makes the pharynx vulnerable to collapse. 153,154 The tendency of an airway to collapse with loss of consciousness is compounded by the negative intraluminal pressures generated during spontaneous inspiration within a narrowed airway. 153 Although inhalational induction is commonly used in pediatric patients, in adults it can take considerable time to reach a plane of general anesthesia sufficiently deep to allow for airway instrumentation without provoking reflex glottic closure. The NAP4 report highlighted the hazards of using inhalational induction in the adult patient with obstructing airway pathology. 1 The CAFG does not endorse use of inhalational induction of general anesthesia as a sole strategy for the adult patient with anticipated difficult laryngoscopy or tracheal intubation.
# Assessing for FMV efficacy prior to administration of a neuromuscular blocking agent
After the induction of general anesthesia, a trial of FMV prior to administering neuromuscular blocking agents (NMBAs) has been advocated, 155 with a view to potentially allowing the patient to awaken if FMV is unsuccessful. Nevertheless, in this situation, the effect of sedative-hypnotics may not dissipate or be reversible in sufficient time for the patient to resume spontaneous ventilation before significant hypoxemia occurs. 156 Thus, the more appropriate action when impossible FMV occurs would be to proceed with tracheal intubation or SGA insertion, both of which will be facilitated by neuromuscular blockade. Studies of pharmacologic paralysis (albeit almost always having been performed in patients without difficult airways) generally conclude that pharmacologic paralysis facilitates FMV, and virtually never makes it worse. With or without anticipated difficulty, if electing to proceed with tracheal intubation after the induction of general anesthesia, the CAFG did not find sufficient evidence to support a recommendation for a trial of FMV prior to NMBA administration.
# Use of short or intermediate-acting neuromuscular blockade
When difficulty with tracheal intubation is anticipated, the CAFG could not find evidence of an outcome benefit to justify recommending use of succinylcholine over an intermediate-acting non-depolarizing NMBA. Considerations in choosing a NMBA include the following:
- Pharmacologic modelling studies have indicated that succinylcholine may not necessarily wear off in time to allow resumption of spontaneous ventilation before hypoxemia occurs in the CVCO situation. 168,169 In addition, the residual effects of the sedative/induction agent may persist, also impairing a return to adequate spontaneous ventilation. - Similarly, a proportion of patients given sugammadex for reversal of rocuronium or vecuronium would also critically desaturate during the time required to draw up and administer the drug and for it to work, particularly if apnea intolerant. 169 In one simulation study of a CVCO situation, 170 a substantial time passed from a decision to use the drug, obtaining it, and its administration to the patient. Therefore, the immediate availability of sugammadex is recommended in all airway management locations. It should be noted that sugammadex will not necessarily reverse CVCO situations related to obstructing airway pathology. 171,172 - In critically ill patients where airway management is being performed as part of a resuscitation, expectations of a return to effective spontaneous ventilation is unrealistic when the clinical trajectory is rapidly deteriorating. Use of succinylcholine or a plan to reverse rocuronium if difficulty occurs is not a reliable plan if it is the only difficult airway strategy being deployed. - Use of an intermediate-acting NMBA to facilitate tracheal intubation will optimize conditions for the duration of airway management should more than one attempt be required, including change of device or operator.
# Choice of equipment
Resources allowing, the CAFG advocates for the routine use of VL (with appropriately selected blade type) for tracheal intubation, with or without anticipated difficulty. 5 Regardless of the chosen technique, the airway manager must attain and maintain competence with its use in lower acuity clinical or simulation settings. 173,174
# Difficulty encountered with a first attempt at tracheal intubation
Difficulty with tracheal intubation after the induction of general anesthesia will inevitably occur from time to time, whether predicted or not. The reader is referred to the accompanying part 1 article 5 for recommendations on management of this situation.
# Difficult tracheal intubation predicted-other options
When difficult tracheal intubation is predicted, most patients will be intubated either awake or after the induction of general anesthesia with additional preparation and precautions. Nevertheless, in some circumstances, the following options may be considered:
7.3.1 Avoiding predicted difficult tracheal intubation-use of regional or local anesthesia for a surgical case When difficult tracheal intubation is predicted, some surgical cases may be amenable to regional or local anesthesia, with the following caveats:
- As complications from the surgical procedure itself, administered local anesthetic or sedative medications could all present the need for airway management despite the use of a regional technique, a complete airway evaluation must still occur, and a management strategy determined. - The surgical procedure must be of a predictable duration, and the block must be shown to be effective before proceeding.
- Ideally, there should be easy access to the patient's airway intraoperatively. - Before proceeding, the team should be briefed on the patient's difficult airway status, together with the plan for intraoperative airway management if needed.
# Deferring management of the patient with predicted difficult tracheal intubation
Occasionally, it might be appropriate to defer airway management when difficult tracheal intubation is predicted. Examples of this include:
- Transferring an elective surgical patient to a more fully equipped hospital; - Transferring a pediatric surgical patient with known facial dysmorphism to a specialized pediatric hospital for management; - Rescheduling a semi-urgent surgical procedure from overnight hours until daytime staff have arrived; - Deferring tracheal intubation of a critically ill patient by temporizing with the use of non-invasive ventilation or HFNO while additional expertise and equipment is sourced, or until the patient is transferred to a different location (e.g., the OR) for the intubation.
# Use of an SGA in the patient with known or predicted difficult tracheal intubation
For the patient with predictors or a history of difficult tracheal intubation, the use of an SGA requires careful consideration. Three scenarios that might be considered include:
- For the case normally undertaken with tracheal intubation, electively choosing to proceed with an SGA simply to avoid a difficult tracheal intubation situation has been shown to be hazardous. 1 The CAFG recommends against this practice. Rather, the difficult intubation situation should be safely dealt with ''up front''. - For a case where an SGA would normally be used, using an SGA in a patient with anticipated difficult tracheal intubation is often successful, although the airway manager must recognize that the fallback option of defaulting to tracheal intubation should the SGA fail may not easily succeed. This might suggest consideration of initial tracheal intubation as the safer plan when general anesthesia is required. If using an SGA regardless, at the very least, there should be a predetermined plan for airway management should SGA ventilation fail. - Despite the above, SGA use is often (appropriately) recommended as a fallback option after failed tracheal intubation in the induced patient. 5,6 The SGA can be used to maintain oxygenation and temporize the situation pending the patient's awakening, while obtaining more equipment or expertise, or it might be used as a conduit to facilitate FB-aided intubation. In an urgent situation (e.g., failed tracheal intubation during emergency Cesarean delivery under general anesthesia), a risk to benefit analysis might justify continuing with the SGA.
8 Special situations
# The patient with a known or suspected highly infectious respiratory pathogen
Airway management guidelines for patients with known or suspected highly transmissible infections should follow core principles, with some modification. The contemporary experience of the COVID-19 pandemic caused by SARS-CoV-2 infection is but one example that may lead to respiratory failure requiring tracheal intubation. 175 - Team safety. The risk of transmission of a highly infectious pathogen such as SARS-CoV-2 to a healthcare worker in the immediate peri-intubation period depends on the pathogen and precautions taken. 176,177 Spread for most pathogens is assumed to occur by direct contact with droplet containing viral particles, and/or from aerosols generated during a patient cough or an airway procedure (i.e., aerosolgenerating medical procedure ). Whether it is an elective surgical patient who has tested positive for a highly infectious pathogen, a critically ill patient with unknown status, or a patient requiring tracheal intubation because of primary respiratory disease caused by a highly infectious pathogen, airway manager and team safety is paramount. Hastening to manage one of these patients without considering team safety may result in healthcare worker infections. The number of people in the room should be kept to a minimum, with a pre-assigned primary airway manager, an airway assistant, and ideally a third clinical support practitioner. - Personal protective equipment (PPE). While there has been significant controversy surrounding what defines ''safe'' PPE for practitioners caring for patients infected by a highly infectious pathogen, it remains possible that airway management poses a significant potential risk for clinicians. 178 During airway management involving AGMPs, an important risk period occurs while removing (doffing) PPE. Incorrectly donning PPE or using inadequate PPE also poses a risk to the airway manager. Airborne, contact, and droplet precaution PPE for practitioners directly performing or assisting in airway management includes an N95 respirator, eye shield, Association for the Advancement of Medical Instrumentation level 3 gown, neck cover, and gloves. 176,178 Training in donning and doffing PPE should be performed regularly and practitioners should be checked to ensure adequate PPE coverage before entering the patient care room.
The CAFG recommendations for airway management of the patient with a known or suspected respiratory infectious disease spread by droplet or airborne mechanism reflect other published consensus statements on the topic and are summarized in Table 10.
# The patient with obstructing airway pathology or a traumatized airway
The patient with known or suspected obstructing airway pathology, or with airway trauma, requires careful and skilled evaluation and planning. Obstructing pathology can occur from tumour, infection, edema, foreign body, or stenosis. Trauma can distort the expected anatomy and might involve a breach of integrity of the airway, sometimes in more than one location. If general anesthesia has been induced and the patient is apneic, patients in both categories may present significant technical difficulties with some or all of DL or VL, FMV and SGA use. When tracheal intubation is indicated and time and resources permit, enhancing the standard airway evaluation is advised. Patient cooperation allowing, nasal endoscopic evaluation of the pharynx and larynx will help clarify the nature and extent of glottic and supraglottic pathology or injury. 19 Any available computed tomography or magnetic Table 10 Airway management considerations for the patient with known or suspected respiratory infectious disease spread by droplet or aerosol CAFG recommendations for airway management of the patient with known or suspected highly infectious respiratory infectious disease spread by droplet or airborne mechanism Environment and preprocedure
- If out of the operating room/theatre, an airborne infection isolation room is preferred for tracheal intubation.
- A negative pressure environment is preferred regardless of location, but ventilation rate/air exchanges are more important than positive or negative pressurization. - Minimize team members in the room. The most experienced available airway manager should perform tracheal intubation. - Supervised personal protective equipment (PPE) donning should occur.
- Perform team briefing; use a checklist.
- Simulation-based team training is valuable.
# Equipment
- Place a viral filter between tracheal tube, face mask, or supraglottic airway (SGA) and more proximal ventilation equipment. - Sidestream capnography aspiration to be located proximal to the viral filter.
# - Use video laryngoscopy as primary technique:
s To increase first-pass success s To avoid close proximity to patient's face and respiratory tract s To enable a shared mental model and situation awareness of non-intubating team members.
- Consider using SGAs for airway rescue scenarios only-not as a planned technique. Second-generation devices are recommended for their higher seal pressures. - Take pre-packaged kits with required equipment into the room.
- Position a standby airway cart (?/-additional personnel in PPE as ''runners'') outside room.
# Pre-oxygenation
- Pre-oxygenate with a well-applied face mask.
- Add PEEP valve to bag-valve mask set-up, if using.
- Limit flow rates to the least required to obtain desired fraction of exhaled oxygen value (e.g., 0.9). This may not always be achievable. Induction
- Intravenous induction with NMB preferred.
- FMV discouraged while awaiting onset of NMB unless clinically significant hypoxemia has occurred or is expected. - Avoid apneic oxygenation with HFNO.
- If apneic oxygenation is used, consider use of low oxygen flows (e.g., 5 L min -1 ).
# Intubation
- Most experienced airway manager available should manage the airway.
- Ensure a styleted tracheal tube or bougie is available, as appropriate to the video laryngoscope blade in use.
- Institute positive pressure ventilation only after tracheal tube cuff inflation.
- If high airway pressures are encountered, ensure tracheal tube cuff pressure is 5 cm H 2 0 higher than peak inspiratory pressure.
# Unanticipated difficult airway
- Use FMV between intubation attempts only if needed to re-oxygenate the patient.
- If FMV is undertaken, use two-handed mask application with thenar eminence (''V-E'') grip to maximize seal and jaw lift effectiveness. - Use waveform capnography to confirm efficacy of rescue ventilation.
- Avoid excessive ventilation. Respiratory rate, volume and inspiratory pressure should ideally be guided by objective feedback (waveform capnography, pressure manometer). - For the elective surgical patient, if SGA rescue is used, consider using a second-generation device that supports FB-aided tracheal intubation. - If SGA rescue has occurred, then patient awakening is preferred: if not feasible, other options include FB-aided intubation through the SGA, or FONA during SGA-supported ventilation. Proceed with surgery only if considered safe. - Above all, the safety of the team must be prioritized.
# CVCO and eFONA
- Scalpel-bougie emergency FONA is the recommend technique.
- Transiently discontinue attempted FMV or SGA ventilation during incision of cricothyroid membrane.
resonance imaging scans should also be reviewed, especially for patients with pathology below the glottis, recognizing that for dynamic pathology, any imaging occurs at an unknown point in the patient's respiratory cycle. 20 Planning a safe approach to tracheal intubation of these patients should occur according to the principles described in Section 6 above, in consultation with all involved team members, including the surgical team. If difficulty is anticipated with two or more of tracheal intubation, FMV, and SGA ventilation, an awake approach (via a nasal, oral, or front of neck route) is advised.
The trauma patient with a blunt or penetrating injury to the airway must be assessed for how best to approach airway management, as well as for the potential for vascular or other injury. Patient cooperation and time allowing, securing the airway awake during spontaneous ventilation (e.g., by awake tracheotomy or awake oral or nasal intubation) enables avoidance of positive pressure ventilation above the level of a known or suspected airway breach, and its attendant risk of causing or exacerbating pneumothorax, pneumomediastinum or subcutaneous emphysema. There is also the potential for entering a tear, creating a false passage, or converting a partial tracheal disruption to a complete disruption during tracheal intubation. Thus, indirect visualization of the anatomy (e.g., using a FB until distal to the suspected or known level of breach) is recommended. Management of the traumatized airway has recently been well reviewed. 187 Successful use of an SGA as a primary technique has been described under combat conditions, 188 as well as in surgical patients with obstructing pathologies. 189 Such reports are limited to observational case series or single case reports; randomized-controlled trials are lacking. Thus, while an SGA might successfully rescue a failed intubation, the CAFG recommends securing the obstructed or traumatized airway by tracheal intubation or FONA, when resources allow. As indicated in section 7.1.6, some severe cases of obstructing pathology below the thoracic inlet might be most safely managed with institution of ECMO before the airway is managed. Multidisciplinary planning and management are required.
# The morbidly obese patient
The obese patient is at elevated risk during airway management. The NAP4 audit reported that patients with a body mass index (BMI) A co-existing thick neck (e.g., circumference and OSA 167 are associated with difficult
# Awake tracheal intubation
- Avoid awake intubation unless high risk of a CVCO situation with induction of general anesthesia/RSI.
- VL or flexible bronchoscopy can be used for awake tracheal intubation, skills allowing. Consider use of an SGA as a conduit for the FB. - Consider alternatives to local anesthetic nebulization or aerosolization for topical airway anesthesia, e.g., local anesthetic gels/ointments or nerve blocks.
# Intraoperative phase
- Avoid circuit disconnections.
- Place ventilator into standby mode if disconnection is needed.
- Disconnect circuit proximal to viral filter if feasible; if not, then consider temporarily clamping the tracheal tube, seeking to avoid damaging it or its pilot line.
# Extubation
- Tracheal extubation is an AGMP with potentially higher risk for aerosol generation than intubation 185 .
- Use pharmacologic measures to help prevent cough, agitation, or vomiting during or after extubation.
- Place a surgical or procedure mask on the patient before awake extubation and extubate while the mouth, nose, and nasal prongs are covered by the mask; leave the mask on the patient during subsequent transfer 186 . - Avoid airway exchange procedures if possible.
# Post-procedure
- Dispose of airway management equipment appropriately.
- Doff PPE under supervision.
AGMP = aerosol-generating medical procedure; CAFG = Canadian Airway Focus Group; CVCO = cannot ventilate, cannot oxygenate; eFONA = emergency front of neck airway access; FB = flexible bronchoscope; FMV = face-mask ventilation; FONA = front of neck airway access; NMB = neuromuscular blockade; PEEP = positive end-expiratory pressure; PPE = personal protective equipment; RSI = rapid-sequence intubation; SGA = supraglottic airway.
DL or intubation. Whether obesity alone predicts difficult laryngoscopy/intubation continues to be controversial, with some studies reporting an association, 15,29,31,39, and others not. 11,25,191, No studies have yet reported obesity to be a risk factor for difficult or failed VLfacilitated tracheal intubation, although one study has reported a thick neck to be associated with failed HA-VLfacilitated tracheal intubation. 33 In another study, a higher neck skinfold thickness was associated with longer times to successful intubation with a FB in anesthetized patients. 38 Obesity or a thick neck also predicts difficulty with SGA use in some, but not all 199 studies, and may predict difficulty with palpation of landmarks for eFONA.
Even more significant are physiologic challenges during airway management of the obese patient. 53 With reduced FRC, apnea is poorly tolerated, so that if difficulty is encountered in establishing ventilation, rapid oxygen desaturation must be anticipated.
Canadian Airway Focus Group recommendations for airway management of the obese and morbidly obese patient are as follows:
- The potential for technical difficulty with both tracheal intubation and other modes of ventilation, coinciding with likely apnea intolerance, suggests that the airway manager should carefully consider whether ATI might confer a safety benefit (Fig. 1). - Regardless of the chosen approach, close attention to patient positioning is recommended, with ramping to ensure the patient's tragus is aligned with the sternum. 96,98 ''Back up'' or reverse Trendelenburg positioning will help delay oxygen desaturation. If general anesthesia is elected, careful pre-oxygenation must occur, with a goal of achieving FeO 2 C 0.9. - Apneic oxygenation is recommended during laryngoscopy and intubation of all morbidly obese patients when managed after the induction of general anesthesia. - Given the anticipated short apnea time and potential for difficulty with fallback ventilation options, primary use of VL (with appropriately selected blade type) is recommended for tracheal intubation to help maximize first-pass success.
- Careful planning and documentation should occur before embarking on airway management of the obese patient. The team should be briefed on the strategy in the event that difficulty is encountered; this should include the triggers for moving to the next step in the plan. Given the potential for rapid oxygen desaturation, the airway manager should consider having a second experienced airway manager stand by for assistance if required.
8.4 The patient with an increased risk of aspiration
In the NAP4 audit, aspiration was the most common cause of airway management-related death and brain damage. 1 In an incident-reporting study from Australia and New Zealand, aspiration was associated with significant harm, with many of the cases occurring in fasted patients. 200 In the difficult airway patient, the risk of aspiration increases in conjunction with the potential for longer or multiple intubation attempts and/or gastric insufflation with FMV between attempts. Tracheal intubation is indicated when general anesthesia is required in the at-risk patient. Although secondgeneration SGAs with integrated drainage ports may confer some protection against aspiration, 204 neither an SGA or FMV would typically be used as an intended primary technique in this scenario. Nevertheless, these modalities can and should be used as needed to maintain oxygenation between intubation attempts.
Although better referred to as ''cricoid force'', cricoid pressure (CP) applied with a force of 10 N (i.e., 1 kg) before induction and 30 N (i.e., 3 kg) after loss of consciousness may reduce the risk of regurgitation and hence aspiration during RSI by occluding the hypopharynx behind the cricoid cartilage. 205 Nevertheless, especially if poorly applied, CP can also make tracheal intubation more challenging, 206 and it can also complicate SGA insertion. Evidence on the effectiveness of CP has been conflicting 207 and controversial, creating equipoise around its use. Birenbaum et al. recently published a large randomized non-inferiority trial (n = 3,472 at-risk patients) on the use of CP. 208 The primary outcome of aspiration did not differ between the actively applied CP (ten cases; 0.6%) and sham CP (nine cases; 0.5%) groups (relative risk of aspiration for the sham CP group compared with the actual CP group 0.9; 90% confidence interval, 0.39 to 1.99). In addition, glottic visualization and duration of intubation favoured the sham CP group. Despite the clinically equivalent occurrence of aspiration between groups, methodologically, the authors were unable to declare non-inferiority of sham CP because of a lower-thanexpected aspiration event rate. Other study limitations included the non-inclusion of obstetric, critical care, and ED patients, and there were few (\ 1% of the total) subjects with an anticipated difficult airway. Nevertheless, given that the original Sellick communication on CP was a small, non-randomized, unblinded, uncontrolled case series of 26 patients, 209 having the very large Birenbaum et al. study suggest no clinically important difference in the incidence of aspiration in an at-risk population is very helpful in advancing our understanding of CP.
Canadian Airway Focus Group recommendations for airway management of the patient with an anticipated difficult airway and an increased risk of aspiration are as follows:
- There may still be a role for correctly applied CP in some settings (e.g., obstetrics). Given the limited data available, the ultimate decision to use CP is at the discretion of the airway manager; - When a significantly elevated risk of aspiration coincides with an anticipated difficult airway, performing ATI with minimal sedation may confer a safety benefit; - If the airway manager decides to intubate the at-risk patient after the induction of general anesthesia, practical advice includes suctioning a nasogastric tube if already present (consider inserting one if not) before induction, placing the patient in the back up or reverse Trendelenburg position, and having two suction devices immediately available for oropharyngeal suctioning. Before induction, an in situ nasogastric tube should be attached to continuous low-pressure suction to prevent intra-gastric pressure accumulation following induction 210 ;
- Use of VL allows airway team members to assess the laryngeal view, the impact of CP (if used) on the view of the glottis, and provides heightened situational awareness during a critical time. Nevertheless, should massive regurgitation occur, the camera may be obscured. Thus, unless difficulty in glottic visualization is anticipated, use of Mac-VL is preferable in the patient at high risk of regurgitation, to allow direct, eye-to-glottis visualization if necessary; - If CP is deemed to be impeding either laryngoscopy or tracheal intubation, it should be removed; - The use of FMV with low inspiratory pressure during RSI, before or between attempts at tracheal intubation, can extend safe apnea time without oxygen desaturation; - If the planned tracheal intubation attempts fail, a second-generation SGA should be inserted, and the integrated drainage port used to drain the esophagus. If CP had been applied, it should be removed for insertion of the SGA and not reapplied.
# The patient with a bleeding upper airway
Bleeding in the upper airway and subsequent problems with airway management are important causes of airwayrelated morbidity and death. Bleeding in the upper airway is fundamentally different from other challenging airway situations in that flexible bronchoscopic and videolaryngoscopic intubation are often more difficult or impossible because of soiling with blood. In addition, because the stomach may be filled with blood, the use of an SGA is only suitable as a temporary measure, or as a guide to intubation. 213,214 Initial therapeutic measures include compression of the bleeding site, patient positioning (the patient will often only tolerate the sitting position), suctioning, oxygen delivery, and fluid resuscitation. Concomitantly, the airway should be evaluated for predictors of difficult or impossible DL, and the location of the CTM should be established. If laryngoscopy and intubation is predicted to be otherwise technically easy and the CTM is identified with certainty, then RSI can be employed, with two large bore rigid suction catheters ready. Otherwise, preparations should be made for an ATI with alternative techniques that can be used even if visibility of the airway is obscured by blood. 213 Such techniques include awake FONA, awake FB-guided intubation via an SGA as well as awake DL or Mac-VL, awake retrograde-, blind nasal-, oral digital-, lighted stylet-, and ultrasound-guided intubation. 213 Awake intubation with a FB or VL can still be attempted in this situation, but might fail, so the airway manager should be prepared to use one of the alternatives mentioned above. In addition, a ''double set-up'' to allow for eFONA should be prepared (Table 8) in case the airway is lost during attempted management.
Management of the bleeding airway has recently been reviewed in detail. 213,215 9 Tracheal extubation Published audits and closed legal claims continue to document the risks associated with tracheal extubation. Re-intubation in the ICU after failed extubation and tracheal tube exchange in the patient with a difficult airway have also caused patient morbidity. 216,217 Although such cases consistently account for up to 25% of total airway management-related morbidity, a substantially smaller proportion of all published articles on airway management relate to tracheal extubation, rather than intubation. 2 Fortunately, excellent guidelines 218 and narrative reviews 219,220 on tracheal extubation have been published. Intentional extubation is elective and thus allows for careful planning to occur (Fig. 2), including identification of at-risk patients after tracheal extubation.
# The at-risk tracheal extubation
The patient may be deemed at risk at the time of tracheal extubation in one or both of two ways: 1) failure to tolerate tracheal extubation, where the patient is at risk of failing to maintain gas exchange, airway patency, or airway protection after extubation; and 2) if tracheal reintubation might be difficult, either because the patient was originally difficult to intubate, or because of an interval event (Table 11).
In some cases, more objective risk stratification can occur before planned tracheal extubation. For example, the patient considered at risk of supraglottic or glottic airway edema might be assessed with a cuff leak test. 221, In a recent systematic review, the authors concluded that the absence of a cuff leak in an at-risk patient is associated with post-extubation stridor or need for re-intubation, but the presence of a leak does not necessarily rule out the occurrence of stridor or need for re-intubation. 228 Further assessment of the at-risk patient can occur by indirect visual evaluation of the glottis and supraglottic area using a VL 229 or FB before emergence from anesthesia or sedation begins.
Strategies to manage the at-risk patient upon tracheal extubation are presented in Table 12. 9.2 Lower risk (''routine'') tracheal extubation Even for the patient not identified as being at risk of morbidity, care must be taken with tracheal extubation. Routine extubation measures such as gas exchange and hemodynamics should be adequate and level of consciousness sufficient to enable airway patency and protection. The patient's neuromuscular function, temperature, and acid-base status should be near normal. Prior to extubation, the patient should be pre-oxygenated and the pharynx should be suctioned, especially if at risk of pooled pharyngeal blood, to avoid the potential of aspirated blood forming an occluding clot in the trachea. 2 Extubation at end-inspiration will help avoid immediate aspiration of blood or residual secretions. Additional CAFG recommendations for tracheal extubation are as follows: - As extubation of the surgical patient is often accompanied by airway manager fatigue and team distraction, a ''sterile cockpit'' concept of minimizing non-essential conversation during emergence and extubation of the surgical patient is advocated. - Supplemental oxygen delivery should occur during transportation of all recently extubated patients to highdependency nursing units including postanesthesia care units. Pulse oximetry monitoring should also be used.
Handover should routinely detail the type and ease of airway management. - In critical care or ED settings, if a consulting service has recommended tracheal extubation of an intubated patient, direct communication should occur between that service and critical care/ED attending staff about the rationale and timing of extubation. Documentation of intubating conditions/difficulty should be clearly available to consulting services to help guide the extubation plan.
# Extubation over an airway exchange catheter (AEC)
If tracheal intubation was or might now be challenging, short-term use of an AEC can be considered at extubation to assist re-intubation should it be required. Appropriately positioned and secured above the carina (e.g., at around 23 cm at the teeth in the adult patient), 11-or 14-French airway exchange catheters are reasonably well tolerated 236 and permit spontaneous ventilation, coughing, and talking. Although AECs can support oxygen insufflation and even jet ventilation, barotrauma and fatalities have been reported in these scenarios. Conventional methods of oxygen delivery such as face mask, nasal cannula, or HFNO 237 can still be used when an AEC is present; the CAFG recommends against any routine oxygen administration through an AEC. If unavoidable during an emergency, oxygen insufflation through an AEC should be limited to 2 LÁmin -1 , only as a temporizing measure until oxygenation is re-established by a conventional mode of delivery, 237 and close attention must be paid to ensuring that gas egress can occur. 240 An AEC can be left in situ after extubation of the difficult airway patient until the need for tracheal reintubation becomes unlikely. Although case specific, in one published ICU series, most patients requiring tracheal reintubation over an AEC underwent the procedure within two to ten hours after extubation. 236 The surgical patient will almost always have the AEC removed before leaving the post-anesthetic care unit. Although infrequently required, tracheal re-intubation over an AEC will be facilitated by the use of VL to both retract the tongue and - Other perioperative issues including hypothermia, altered acid-base status and uncontrolled pain.
# Potential causes of difficult tracheal re-intubation
- The original tracheal intubation was difficult.
- Interval development of airway edema.
- Anatomic changes as a result of a surgical intervention: s Upper airway surgery s Upper cervical spine fusion. enable monitoring of tracheal tube passage through the glottis. 241 In addition, prior passage of an intermediate catheter (e.g., the Aintree catheter; Cook Group Incorporated, Bloomington, IN, USA) over an 11-or 14-French AEC will facilitate passage of a tracheal tube through the adult larynx by reducing the size discrepancy between the outer diameter of the catheter and the inner diameter of the tracheal tube. 242 Of note, the Cook AECs (Cook Group Incorporated, Bloomington, IN, USA) are only licensed for immediate tracheal tube exchange in most countries. Therefore, leaving an AEC in situ for retaining airway access following extubation, though widely practiced, is technically an off-label application.
# Human factors and the anticipated difficult airway
The NAP4 study 1 and published closed legal claims 2,3 have indicated that airway management misadventure was often associated with inadequate evaluation and lack of a predetermined airway strategy. That is, airway managers simply did not anticipate difficulty or failed to modify their strategy appropriately despite predicted difficulty. The airway manager must be self-aware of potential human factor pitfalls to avoid. Table 13 presents some issues together with suggested mitigating strategies.
# Summary and key recommendations
Informed by publications of airway-related morbidity, guidelines should not only address management techniques for the difficult airway when encountered in the unconscious patient but also emphasize the need for detailed patient evaluation, planning, and communication. In this way, safe airway management decision-making and implementation can occur. Briefly summarized, our guiding principles and recommendations are as follows: significant physiologic (e.g., apnea intolerance or aspiration risk) or contextual issues; - Awake tracheal intubation can proceed via oral, nasal, or front of neck routes. In some cases, oral or nasal ATI can be facilitated by a variety of devices (e.g., flexible bronchoscopy or VL);
- If a lack of patient cooperation or time precludes ATI, and airway management after the induction of general anesthesia must proceed, it should proceed with ''double set-up'' preparation allowing for immediate eFONA;
Table 13 Potential human factor issues during patient evaluation and airway management decision-making, with suggested mitigation strategies Potential human factor issues during patient evaluation and airway management decision-making, with suggested mitigation strategies Issue Possible mitigation strategies: by the airway manager by the assembled team by the organization Failure to match planned strategy with the findings of airway evaluation (anatomy, physiology, and clinical context)
- Review your planned strategy for a high-risk or difficult case with a colleague.
- With predicted difficulty, before proceeding, ensure that all equipment for your airway strategy (i.e., planned primary and fallback techniques) is physically present, sized for the patient, and arranged in the order of anticipated use. This well help ensure you have thought through the situation.
- For all patients, brief the team on your chosen strategy, including your alternate plans if the intended technique fails, together with triggers for moving to an alternate plan.
- During the briefing, specifically empower team members to speak up if they think that a trigger has occurred.
- The organization should mandate inclusion of the airway strategy in the first surgical safety checklist.
- Airway management education programs should include material on safe decision-making, rather than only teaching ''hands-on'' skills.
Maintenance of competence. Use of ATI is decreasing 243 . When difficulty is predicted, lack of recent experience, confidence, or skills in ATI might tempt the airway manager to avoid its use despite indicators of it being the safest approach. Lack of suitable equipment might also be a factor in some cases.
- Enlist a colleague to help perform ATI: you will both benefit from the experience.
- Seek opportunities to perform ATIs, rather than using excuses to avoid them.
- If the patient's anatomy is amenable, consider using a more familiar device for ATI (e.g., VL).
- For the patient requiring ATI with obstructing pathology, a surgeon should be physically present to perform fallback eFONA.
- The organization should provide training and maintenance of competence workshops in ATI techniques, including use of the FB.
- Provide airway simulators or standard airway training manikins for individual practice at any time.
- Ensure equipment for all aspects of ATI is easily accessible at airway management locations.
- Package all equipment and local anesthetics needed for topical airway anesthesia together in easilyaccessed ''grab kits''.
''Production pressure'' to get a case done might lead to an unsafe decision to manage a difficult airway patient after the induction of general anesthesia, when ATI might be the safer approach.
- When sensing production pressure, (whether self-induced or from another source) push back by deliberately slowing to reflect on whether the pressure is adversely impacting your patient's safety.
- Pre-empt any pushback on planned ATI by using ''safest for the patient'' language.
- Increase team buy-in by early communication with the surgeon and team when ATI is needed for an operative case.
- Multidisciplinary team training or rounds on adverse airway events might help improve communication and cooperation for future difficult airway situations that involve multiple specialties.
''Normalization of deviance 3 '': the airway manager might have managed a series of patients after the induction of general anesthesia where despite predictors of difficulty, none occurred. On the basis of thus ''getting away with it'' over time, inducing such patients might become a clinician's normal practice, rather than even considering ATI.
- With significant predicted difficulty, if considering tracheal intubation after the induction of general anesthesia, as a thought exercise, satisfy yourself that it can occur with a margin of safety equal to or greater than ATI. If not, proceed with the ATI.
- Beware of ''gambler's fallacy'': the false belief that the outcome of the current case is less (or more) likely given results of previous events. Judge every case on its own, based on findings from the airway evaluation.
- Team members should be encouraged to speak up if uncomfortable with the airway manager's chosen approach. The ''PACE'' (probealert-challenge-emergency) or similar mnemonic can be used as a prompt by team members to question the planned approach.
- Appoint a hospital ''airway lead'' 244 in your department or hospital, tasked with ensuring a full array of difficult airway equipment is readily available across the institution, arranging airway education, including skills in ATI, and to help constructively debrief airway-related critical incidents and near-events.
ATI = awake tracheal intubation; eFONA = emergency front of neck airway access; FB = flexible bronchoscope; VL = video laryngoscopy.
- Management of the anticipated difficult airway after the induction of general anesthesia should only occur with an appropriate pre-determined strategy for difficulty if/ when encountered. A second airway manager should be sourced, the team briefed, and the required equipment brought to the room. Attention should be paid to patient positioning, pre-oxygenation, and apneic oxygenation; - Regardless of the chosen approach when difficulty is predicted, the airway manager must clearly communicate the planned management strategy to the team, including the triggers for moving from one technique to the next; - Extra care should be used in the planning and implementation of care for the patient with head and neck pathology, obesity, or increased aspiration risk; - Tracheal extubation of the at-risk patient must be carefully planned in terms of assessing whether the patient can tolerate extubation and whether reintubation might be difficult; - As unanticipated difficulty with airway management can occur despite none being predicted, the airway manager must be ready with a strategy for difficulty occurring in every patient, and the institution must make difficult airway equipment readily available and easily accessible; - As pandemic conditions add complexity to both routine and difficult airway decision-making and management, individual and institutional preparedness should be mandated.
Management of difficulty with airway management occurring in the already-unconscious patient is addressed in the part 1 companion article. 5 Author contributions See Appendix. | Purpose Since the last Canadian Airway Focus Group (CAFG) guidelines were published in 2013, the published airway management literature has expanded substantially. The CAFG therefore re-convened to examine this literature and update practice recommendations. This second of two articles addresses airway evaluation, decision-making, and safe implementation of an airway management strategy when difficulty is anticipated. Source Canadian Airway Focus Group members, including anesthesia, emergency medicine, and critical care physicians were assigned topics to search. Searches were run in the Medline, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL The members of the Canadian Airway Focus Group are listed in Appendix.#
databases. Results were presented to the group and discussed during video conferences every two weeks from April 2018 to July 2020. These CAFG recommendations are based on the best available published evidence. Where high-quality evidence is lacking, statements are based on group consensus. Findings and key recommendations Prior to airway management, a documented strategy should be formulated for every patient, based on airway evaluation. Bedside examination should seek predictors of difficulty with facemask ventilation (FMV), tracheal intubation using videoor direct laryngoscopy (VL or DL), supraglottic airway use, as well as emergency front of neck airway access. Patient physiology and contextual issues should also be assessed. Predicted difficulty should prompt careful decision-making on how most safely to proceed with airway management. Awake tracheal intubation may provide an extra margin of safety when impossible VL or DL is predicted, when difficulty is predicted with more than one mode of airway management (e.g., tracheal intubation and FMV), or when predicted difficulty coincides with significant physiologic or contextual issues. If managing the patient after the induction of general anesthesia despite predicted difficulty, team briefing should include triggers for moving from one technique to the next, expert assistance should be sourced, and required equipment should be present. Unanticipated difficulty with airway management can always occur, so the airway manager should have a strategy for difficulty occurring in every patient, and the institution must make difficult airway equipment readily available. Tracheal extubation of the atrisk patient must also be carefully planned, including assessment of the patient's tolerance for withdrawal of airway support and whether re-intubation might be difficult.
# Résumé
Objectif Depuis la dernie`re publication des lignes directrices du Canadian Airway Focus Group (CAFG) en 2013, la litte´rature sur la prise en charge des voies ae´riennes s'est conside´rablement e´toffe´e. Le CAFG s'est donc re´uni a`nouveau pour examiner la litte´rature et mettre a`jour ses recommandations de pratique. Ce deuxie`me article traite de l'e´valuation des voies ae´riennes, de la prise de de´cision et de la mise en oeuvre se´curitaire d'une strate´gie de prise en charge des voies ae´riennes lorsque des difficulte´s sont anticipe´es. Sources Des sujets de recherche ont e´te´assigne´s aux membres du Canadian Airway Focus Group, qui compte des me´decins anesthe´sistes, urgentologues et intensivistes. Les recherches ont e´te´re´alise´es dans les bases de donne´es Medline, EMBASE, Cochrane Central Register of Controlled Trials et CINAHL. Les re´sultats ont e´teṕ re´sente´s au groupe et discute´s lors de vide´oconfe´rences toutes les deux semaines entre avril 2018 et juillet 2020. Les recommandations du CAFG sont fonde´es sur les meilleures donne´es probantes publie´es. Si les donne´es probantes de haute qualite´manquaient, les e´nonce´s se fondent alors sur le consensus du groupe. Constatations et recommandations clés Avant d'amorcer la prise en charge des voies ae´riennes, une strate´gie documente´e devrait eˆtre formule´e pour chaque patient, en fonction de l'e´valuation de ses voies ae´riennes. L'examen au chevet devrait rechercher les pre´dicteurs de difficulte´s pour la ventilation au masque, l'intubation trache´ale utilisant la vide´olaryngoscopie ou la laryngoscopie directe, l'utilisation d'un dispositif supraglottique, ainsi que pour la cricothyroı¨dotomie d'urgence. La physiologie du patient et ses proble´matiques contextuelles devraient e´galement eˆtre e´value´es. Les difficulte´s anticipe´es devraient inciter ap rendre des de´cisions e´claire´es sur la façon la plus se´curitaire de proce´der a`la prise en charge des voies ae´riennes. L'intubation trache´ale e´veille´e peut procurer une marge de se´curite´supple´mentaire lorsqu'on s'attend ac e que la vide´olaryngoscopie ou la laryngoscopie directe soient impossibles, lorsqu'on pre´voit des difficulte´s pour plus d'un mode de prise en charge des voies ae´riennes (p. ex., intubation trache´ale et ventilation au masque), ou lorsque la difficulte´pre´vue coı¨ncide avec des proble`mes physiologiques ou contextuels importants. En cas de choix de prise en charge des voies respiratoires du patient apre`s induction de l'anesthe´sie ge´ne´rale malgre´les difficulte´s pre´vues, les directives a`l'e´quipe devraient inclure les de´clencheurs pour passer d'une technique a`l'autre, l'aide d'experts disponibles et l'e´quipement requis disponible. Des difficulte´s impre´vues lors de la prise en charge des voies ae´riennes peuvent toujours survenir, de sorte que la personne responsable de la prise en charge des voies ae´riennes devrait avoir une strate´gie pour chaque patient, et l'e´tablissement doit rendre facilement disponible le mate´riel pour la prise en charge des voies ae´riennes difficiles. L'extubation trache´ale du patient a`risque doit e´galement eˆtre soigneusement planifie´e, y compris l'e´valuation de la tole´rance du patient lors du retrait du dispositif de soutien des voies ae´riennes et d'une re´intubation potentiellement difficile.
# Introduction
Significant morbidity related to airway management continues to be reported, with the failure to plan for difficulty a recurrent theme. [1][2][3] Most published airway guidelines focus on management of the alreadyunconscious patient when difficulty with tracheal intubation is encountered. Although less frequently addressed, avoiding having to manage an unexpectedly difficult airway almost certainly has greater potential to prevent patient harm. Airway-related morbidity can be prevented by careful patient evaluation and formulation of an airway management strategy (a co-ordinated series of plans) before proceeding with airway management. Lack of an airway evaluation or the failure to change usual practice based on its findings has been associated with morbidity. 1 Airway evaluation includes examination for anatomic predictors of difficulty with tracheal intubation, facemask ventilation (FMV), supraglottic airway (SGA) use, and emergency front of neck airway access (eFONA). It should also include assessment of physiologic issues (e.g., apnea tolerance, aspiration risk, and altered hemodynamics) and the clinical context (e.g., case urgency, airway manager experience, equipment availability, and access to expert assistance). Airway evaluation should occur before starting airway management as well as before its discontinuation.
Video laryngoscopy (VL) has helped achieve more consistent glottic visualization and has improved firstattempt intubation success rates in the unconscious patient, especially in populations deemed to be at risk for difficult direct laryngoscopy (DL). 4 Nevertheless, there remain patients who, based on thorough airway evaluation, would likely be more safely managed with awake tracheal intubation. This article addresses airway evaluation and provides recommendations to help formulate and implement a safe airway management strategy when difficulty is anticipated. In part 1 of these updated twopart recommendations, 5 we address management of airway difficulties encountered in the unconscious patient, whether anticipated or not. Recommendations in both articles are meant to be broadly applicable to all specialties that have airway management in their practice mandate.
# Methods
The methods presented here are identical to those described in the companion part 1 article 5 and are reproduced here for the benefit of the reader. The Canadian Airway Focus Group (CAFG) is comprised of 17 members (see Appendix), with representation from across Canada as well as one member from each of New Zealand and Australia.
The CAFG membership includes anesthesiologists, emergency physicians, and critical care physicians. Topics for review were divided among the members, with most assigned to two members. Members reviewed the literature published from 2011 onwards.
A medical librarian helped design and conduct the literature searches. Though not constituting a formal systematic review, databases searched included Medline, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL. Non-English and non-French, animal, manikin, and cadaver studies were excluded from searches, as were case reports, editorials, and letters. Nevertheless, team members had the discretion to include such material where relevant.
The CAFG met every two weeks by video conference from April 2018 to July 2020 to review findings and arrive at consensus regarding recommendations. Consistent with other recent airway management guidelines, [6][7][8][9] we did not assign levels of evidence or strength of recommendation. This follows from a lack of what is considered high-level evidence seen in other medical fields. Randomized controlled trials of airway devices typically address efficacy (often in a population of low-risk elective surgical patients) but when critical events are uncommon (as with airway management), they are unable to evaluate the safety of techniques or decision-making. 10 Information gleaned from large database studies is better able to capture uncommon events, 10 but analysis is limited to association rather than causation and the population studied may not represent all practice environments. Thus, although evidence-based to the extent possible, some of the recommendations are based largely on expert consensus.
After review by the CAFG, draft documents were sent to several airway experts internationally (see Acknowledgments) for informal review and comment.
# Definitions
The following definitions are used throughout the manuscript.
• Anticipated difficult airway. A difficult airway is predicted when the airway manager anticipates difficulty with any or all of FMV, tracheal intubation, SGA use, or eFONA. • Awake tracheal intubation. Awake tracheal intubation (ATI) refers to tracheal intubation of a patient who is sufficiently conscious to maintain a patent airway unassisted, to maintain adequate gas exchange by spontaneous ventilation, and to protect the airway against the aspiration of gastric contents or other foreign material. Awake tracheal intubation can occur via the nasal, oral, or front of neck routes, and is facilitated by topical, regional, or local infiltrative airway anesthesia. • At-risk tracheal extubation. The at-risk tracheal extubation is defined by the patient anticipated to be intolerant of tracheal extubation or who might be potentially difficult to re-intubate. Difficult reintubation might be anticipated based on pre-existing or de novo conditions (e.g., neck fusion or immobilization; upper airway edema).
# Prediction of difficulty with airway management
Predicting difficulty underlies the planning for safe airway management. Expert opinion appearing in audits of airwayrelated morbidity and closed legal claim studies suggest that the ''failure to prepare for failure'' by omitting, not documenting, or not acting on positive findings of an airway evaluation figures prominently in cases with poor outcomes. [1][2][3] Canadian data, 3 and that from the USA, 2 reveal that most anesthesia airway-related closed claims involved patients presenting for elective surgery (78% and 63%, respectively). Comprehensive airway evaluation includes physical examination of the patient and review of relevant physiologic and contextual issues, pertinent diagnostic imaging studies, and any available records of previous airway management. A history of previous difficulty is more often correctly predictive of difficulty than the bedside examination. [11][12][13][14][15] Alone or in combination, the various bedside screening tests of anatomic features have been criticized for their poor performance in correctly predicting when difficulty will indeed occur with airway management. 11,13,16 Nevertheless, the presence of certain anatomic features (Tables 1, 2, 3, 4, 5, 6, 7) should alert the airway manager to carefully consider the safest approach to airway management and which devices to have available; little downside will accrue if airway management turns out to be non-problematic. Conversely, when bedside screening suggests that no difficulty is expected, while more often correctly predictive of the actual outcome, 11,16,17 unanticipated difficulty can still occur, such that the airway manager must be ready with a strategy to address difficulty in all patients. Performing and documenting an airway evaluation is standard of care, and furthermore, acts as a cognitive prompt 18 to consider the potential for difficulty with every patient. The CAFG recommends that all patients undergo airway evaluation before the initiation of airway management and before the discontinuation of airway support (e.g., tracheal extubation).
# Published predictors of difficult airway management
Predictors of difficult tracheal intubation by DL and VL and other devices appear in Tables 1-3. Predictors of difficult FMV and difficult SGA use appear in Tables 4 and 5, respectively. Predictors of difficult eFONA have not been prospectively studied but appear on a presumptive basis in Table 6. The likelihood of actually encountering difficulty with any modality increases in proportion to the number of anatomic predictors of difficulty. There are currently few published studies looking at predictors of difficulty with tracheal intubation using VL; this is a gap in the literature that should be addressed. Physiologic and contextual factors that may also impact planning and implementation of airway management appear in Table 7.
# The enhanced airway evaluation
Patients with obstructing airway pathology may have distortions of upper or lower airway anatomy that cannot be identified by regular bedside screening tests. For the patient with known or suspected obstructing glottic or supraglottic airway pathology, awake nasal endoscopy or oral VL performed under local anesthesia immediately before airway management can help clarify the extent and location of the problem. 19 Subglottic pathology can be assessed by review of recent imaging studies. 20 Point-ofcare ultrasound is playing an increasing role in physiologic diagnosis and evaluation of targeted management of resuscitation before, during, or after airway management. 21 Another aspect to enhancing the airway exam in patients with significantly altered anatomy is to identify the location of the cricothyroid membrane (CTM). 22 If visual inspection or palpation fails to identify the CTM location with certainty, it should be identified using ultrasonography and marked, 22,23 with the patient's neck in an extended position. The patient can subsequently be positioned Table 1 Published predictors of difficult tracheal intubation using direct laryngoscopy Predictors of difficult laryngoscopy and tracheal intubation using direct laryngoscopy [11][12][13]16,[25][26][27][28][29][30][31] • Age [ 46 yr
• Male sex
• Modified Mallampati grades 3 or 4
• Thyromental distance \ 6 cm
• Prominent, gapped, repaired, or fragile dentition • Visibility impaired by blood or secretions
•
• Higher neck skinfold thickness
• Larger tracheal tube inner diameter relative to scope outer diameter optimally for the intended airway technique; if eFONA is required, the patient can quickly be returned to the neckextended position to utilize the previously made marking. 24 6 Decision-making when difficult tracheal intubation is predicted
Few published studies or guidelines specifically address which patients with predictors of difficult tracheal intubation can safely be managed after the induction of general anesthesia. Nevertheless, cues can be taken from the UK's NAP4 study 1 and closed claims analyses. 2,3 In NAP4, ATI was judged to have been underutilized in patients with known difficult airways. Eighteen cooperative patients with predictors of both difficult tracheal intubation and difficult FMV underwent intubation attempts after 7 Physiologic and contextual issues that may impact airway management Physiologic issues that may impact airway management 53,54 • Apnea intolerance, based on: s Decreased functional residual capacity s Increased oxygen consumption s Baseline hypoxemia; decreased PaO 2 /FiO 2 ratio s Acid-base disturbance with respiratory compensation.
• Full stomach or other major risk factor for aspiration.
• Hemodynamic instability.
# Contextual issues that may impact airway management
• Adverse location (e.g., remote location, difficult access to patient, adverse lighting conditions) • Help/backup unavailable (e.g., because of time of day or remote location) • Airway manager inexperience with chosen or required technique • Lack of equipment • Team inexperienced with difficult airway management • Poor team communication induction of general anesthesia. All suffered complications and two patients died. 1 When difficulty is predicted, ATI enables patients to maintain their own airway patency, gas exchange, and protection of the lower airway against aspiration during tracheal intubation; thus, ATI potentially provides a safety benefit. Conversely, despite possessing predictors of difficult laryngoscopy or intubation, some patients might still be safely managed after induction of general anesthesia. When difficult laryngoscopy or intubation is predicted, deliberate consideration of the following four questions can help the airway manager decide whether ATI is indicated or if management might safely occur after induction (Fig. 1).
A. Does the patient clearly need awake tracheal intubation?
Significant and obvious anatomic deformities or pathologic alterations of the head and neck are often most safely managed with ATI. Examples include (but are not limited to) the patient with very limited mouth opening, a fixed flexion deformity of the head and neck, or a pathologically enlarged tongue. In such patients, there is often no chance that standard techniques such as DL, Macintosh blade video laryngoscopy (Mac-VL) or hyperangulated blade VL (HA-VL) are feasible. Alternatives to these standard techniques are likely to be less familiar to the airway manager or take longer to use, especially in the context of distorted anatomy. Thus, if managing the airway in apneic conditions after induction of general anesthesia, this could put the patient at risk of significant hypoxemia. In addition, anatomy altered to this extent will often also predict difficulty with fallback modes of ventilation such as FMV or SGA use (see next section). For these reasons, ATI is a safer option.
B. Is difficulty also predicted with fallback ventilation options?
When difficult tracheal intubation is predicted, no matter how effective the primary device chosen to facilitate Fig. 1 Flow diagram: Decision-making when difficult tracheal intubation is predicted. ATI = awake tracheal intubation; DL = direct laryngoscopy; FMV = face-mask ventilation; SGA = supraglottic airway; VL = video laryngoscopy. tracheal intubation may be, all have a failure rate. When this occurs, FMV or SGA ventilation will be needed between attempts. Unfortunately, when difficult or failed tracheal intubation has occurred, difficult FMV is more likely, [55][56][57] and vice versa. 46,57 Similarly, failed SGA ventilation is associated with a higher incidence of difficult FMV. 49,52 This phenomenon has been referred to as the ''composite failure of airway management''. 55 Tracheal intubation and FMV are reported to have predictors of difficulty common to both modalities 44 (Table 4). Thus, when difficulty is predicted with one mode (e.g., tracheal intubation), the airway manager must be especially vigilant in assessing the patient for predicted difficulty with other modes (e.g., FMV, SGA ventilation, or front of neck airway access [FONA]). When significant difficulty is predicted with two or more modes, (e.g., tracheal intubation and FMV), ATI should be strongly considered as a potentially safer option.
C. Is there any physiologic compromise? Physiologic compromise (Table 7) complicates and distracts from difficult airway management. 53,54 It is also accentuated by induction of anesthesia that additionally risks hypoxemia, aspiration, or hemodynamic instability in those at risk. Separation of difficult airway management from induction of anesthesia is therefore of value; thus, ATI is likely the optimal choice for both safety and controlling the cognitive load of the airway manager.
Rarely, physiologic issues might be the sole indication for ATI, without any anatomic predictors of difficulty with airway management, as with a critically ill patient with significant lung parenchymal disease and a high shunt fraction. 58 D. Are there any complicating contextual issues? Contextual issues (Table 7) might also favour ATI when difficult tracheal intubation is predicted. For example, when an airway manager is practicing in a resource-austere setting without access to expert assistance or VL, the use of ATI for the predicted difficult airway patient might improve the margin of safety if patient transfer to a more fully equipped facility is not an option.
As indicated in Fig. 1, if all of the preceding questions are answered in the negative, airway management after induction of general anesthesia may be considered. Nevertheless, it must be emphasized that this decision remains one of clinical judgement and that the algorithm based on these questions has not been validated in a randomized-controlled trial. An airway manager's individual threshold for performing ATI or other patient or system factors might also impact the decision. Conversely, if the pathway through the Figure 1 flow diagram has suggested that ATI might be a safer option, a fifth question must then be addressed, as follows.
6.1 Can the patient cooperate with ATI and is there time?
Proceeding with ATI generally requires both a cooperative patient and time for its completion. If these are lacking, options become more limited. In some critically ill patients, physiologic disturbances or an alteration in sensorium can make compliance with ATI challenging. This may guide the airway manager towards tracheal intubation after the induction of general anesthesia if airway management must proceed at that time (Fig. 1). Under these circumstances, regardless of how the induction of general anesthesia proceeds (e.g., with or without an attempt to maintain spontaneous ventilation), ''double set-up'' (Table 8) preparations for eFONA are recommended in case of need. This decision must be balanced against the benefit of delaying tracheal intubation in favour of less invasive approaches for ventilation/oxygenation or further medical management, if this is an option.
When difficulty is predicted, tracheal intubation should only proceed after the induction of general anesthesia when the estimated margin of safety is equivalent to an awake technique. In the elective surgical setting, perceived time pressure or airway manager discomfort with performing ATI must not play a role in decision-making for the patient with a difficult airway. Rather, help might be sought from a colleague with more experience in performing ATI.
# Implementation of the planned strategy when difficult tracheal intubation is predicted
When difficult tracheal intubation is predicted, the following principles are common to implementing the plan, whether by ATI or after induction of general anesthesia:
• An additional experienced airway manager should be sourced. For more challenging situations, having this individual standing by in the room is advisable; • The airway manager should brief the assembled team on the intended strategy for securing the airway; • The briefing should include the planned response to failure of the intended technique; • An SGA must be available for use as a rescue technique in the event of failed tracheal intubation; • During the briefing, the airway manager should include triggers for declaring failure of one technique and proceeding to the next. At this time, all members of the team should be explicitly empowered to state when they believe a trigger has occurred.
# Awake tracheal intubation in the patient with anticipated difficult tracheal intubation
When performed by experienced airway managers, high success and low complication rates have been reported with ATI. [59][60][61] All awake techniques are facilitated by one or more of topical, regional, or local infiltrative anesthesia, often aided by small doses of adjunctive systemic medications. Any discomfort with ATI is typically brief and patients are usually accepting of an airway manager's recommendation for airway management, especially when its safety aspects are discussed. 62 The Difficult Airway Society in the UK has recently published comprehensive guidelines on ATI. 63
# Topical airway anesthesia for awake tracheal intubation
Topically applied lidocaine provides good conditions for ATI and has a favourable safety profile compared with other agents. Used for ATI, a maximum dosage of 9 mgÁkg -1 (lean body weight) of topical lidocaine has been recommended by the DAS ATI guidelines, 63 although there have been reports of symptoms and signs of toxicity at this and lower doses in volunteers. 64 Thus, the lowest lidocaine dose compatible with adequate conditions for the procedure should be used. There is no published evidence to recommend one topicalization regime over another, nor is there evidence that percutaneous nerve blocks are superior to topical airway anesthesia.
# Adjunctive systemic medications during awake tracheal intubation
Systemic medications should complement topical airway anesthesia and should not be used to compensate for its ineffective application. The goal of therapy should be considered in choosing a systemic agent and its dosage. Anxiolysis and sometimes, amnesia, may be achieved with a benzodiazepine or dexmedetomidine 65,66 ; decreasing airway reflexes may be aided by opioids, such as a lowdose remifentanil infusion. Sedation is a secondary and arguably less desirable goal during ATI, as it may impair the patient's ability to cooperate with application of topical anesthesia. 67 The use of systemic medication in the patient undergoing ATI because of obstructing pathology must be carefully considered, recognizing that total loss of airway patency has been reported. 68 Reviews on the use of systemic medications during ATI have been published. 65,69 No single systemic agent has yet been definitively identified as the best to aid ATI, although dexmedetomidine has been established as an effective sedative for the purpose. 66,69 Airway managers' preferences and familiarity with the various drugs are important factors to help guide their choice of agent.
# Choice of device to facilitate awake tracheal intubation
ATI has traditionally been accomplished using a flexible bronchoscope (FB). More recently, HA-VL has also been reported to successfully facilitate ATI via the oral 70,71 and nasal 72 routes. While each class of device has benefits and limitations when used for ATI (Table 9), they appear to have comparable safety profiles. 73,74 If one technique fails, the other may prove successful. Both options require effective topical airway anesthesia for ATI. Note that awake VL will not be an option for some difficult anatomical presentations (Table 9). Nevertheless, it is important for the airway manager to appreciate that for many difficult airway situations, ATI can proceed with a variety of devices. 75 Other options to facilitate ATI include optical stylets, the concurrent use of VL and the FB, or awake placement of an SGA under topical anesthesia to provide a conduit for FB-aided intubation. 77 The latter is particularly effective in the setting of redundant upper airway tissue, as seen with significant obesity, patients with obstructive sleep apnea, and some children with predicted difficult airways. [78][79][80] Blind passage of a tracheal tube through an SGA without being facilitated by a FB is not recommended for ATI.
The CAFG recommends that all airway managers should be competent in ATI. This includes effective application of topical airway anesthesia as well as the use Table 8 Components of the ''double set-up'' in airway management The ''double set-up'' in airway management: components
• Mark the location of the cricothyroid membrane with the patient's head and neck extended. Use ultrasound guidance if skilled. • Decide who will undertake eFONA. This should be someone other than the primary airway manager if possible. • Ensure equipment for the chosen eFONA technique is present in the room, opened, and ready to use. • Brief the team before induction, including the potential need for eFONA and triggers for proceeding with it. Rationale for the double set-up in airway management
• The double set-up will help focus everyone's attention on the anticipated airway management difficulty and patient risk. • Equipment and personnel are present in the room while the airway is being secured. • eFONA will be perceived as part of the plan, rather than the rescue of a failed plan. Timelier onset of eFONA may result.
eFONA = emergency front of neck airway access.
of both the FB and VL for that purpose. Maintaining skills in ATI is important to ensure that airway manager discomfort is not a deterrent for performing an awake technique when clinically indicated.
# Failed awake intubation
Awake tracheal intubation may fail [59][60][61] for a number of reasons, including inadequate topical anesthesia, excess sedation, adverse anatomy, or a lack of patient cooperation. The airway manager must carefully consider the next steps.
Simply proceeding with induction of general anesthesia after failed ATI has resulted in major morbidity and death. 1,81 Options include deferral of an elective surgical case, summoning more experienced help, or application of additional topical anesthesia. Simply deepening systemic sedation may be hazardous. For an urgent or emergency situation that cannot be deferred, tracheal intubation after the induction of general anesthesia must sometimes be undertaken, with a ''double set-up'' preparation for eFONA (please see section 6.2 and Table 8). Reports of complete airway obstruction occurring during attempted ATI have been published, 59,68,82,83 most often in the setting of advanced obstructing airway pathology. Possible causes include excess sedation, or a direct adverse effect of local anesthetic on upper airway patency. 84,85 The latter phenomenon does not imply that ATI should be avoided in patients with obstructing airway pathology, but rather, that the airway manager should be ready with an alternate plan, including rapidly proceeding with eFONA if a ''cannot ventilate, cannot oxygenate'' (CVCO) situation occurs. It should also be noted that if eFONA is anticipated to be difficult and prolonged (e.g., due to a thick neck, previous irradiation or overlying induration or infection), it should not be considered a viable fallback technique. In this situation, awake cricothyrotomy or tracheotomy under local infiltrative anesthesia (next section) may be the more prudent planned approach.
# Awake tracheotomy or awake cricothyrotomy
Elective FONA by tracheotomy or cricothyrotomy is a good option as a planned primary technique when great difficulty is predicted with airway management-e.g., with a friable airway cancer and/or severely narrowed airway. Requiring patient cooperation, local infiltrative anesthesia, and most often performed by a surgeon, this option might be chosen in the following situations, among others:
• For the patient presenting with advanced obstructing upper airway pathology that might cause significant technical difficulties during attempted awake oral or nasal intubation (e.g., a very friable, large base of tongue tumour); • When the glottic opening is very small (e.g., because of obstructing tumour burden) and FB-aided awake oral or nasal intubation would transiently completely occlude the patient's breathing during intubation, possibly causing panic and loss of patient cooperation; • When both oral and nasal routes are not available (e.g., because of substantial disruption by trauma or distortion by advanced upper airway pathology); • When a surgeon elects to do awake tracheotomy as an alternative to awake oral or nasal intubation if the • Enables a broad view of anatomy and good spatial awareness; facilitates a shared mental model with other team members. • The tracheal tube can be directed to and observed to pass between the vocal cords. • The ''pink-out'' that can occur if a FB abuts mucosa is avoided.
• Variously sized styleted tracheal tubes can be prepared; it is easier to substitute a smaller sized tracheal tube than re-load and re-insert a FB if the initial tube size is too large. • Space is created in the oropharynx with gentle lifting of the blade during VL. • As a familiar technique, VL may allow more rapid ATI than the FB.
• VL may not be an option with some anatomic and pathologic abnormalities (e.g., very limited mouth opening, fixed neck flexion deformity, enlarged tongue, or base of tongue masses). Use of flexible bronchoscopy for awake tracheal intubation • Passage of the FB and tracheal tube can occur by the nasal route, if necessary. • Navigation is possible in all planes around obstructing masses (e.g., a base of tongue lesion). • Advanced to just above the carina, the FB acts as a guide for tracheal tube advancement to, through, and beyond the larynx. The FB can also be used to confirm successful tracheal intubation and can be used to ensure correct tube positioning above the carina. • The FB can be used for some situations where anatomic constraints preclude use of awake VL. Thus, airway managers must also attain and maintain skills with the FB for ATI. • Using the FB routinely for ATI maintains skills in a critical technique. • Permits examination of the trachea to rule out injury, or to ensure a tracheal tube is placed distal to a known or suspected penetrating tracheal injury or fistula.
ATI = awake tracheal intubation; FB = flexible bronchoscope; VL = video laryngoscopy.
airway manager is not confident that ATI is a feasible option.
7.1.6 The ''impossible airway'' and awake institution of extracorporeal membrane oxygenation as a primary technique
An impossible airway might be predicted in clinical situations where all four of FMV, SGA use, tracheal intubation, and FONA are anticipated to fail. Failed FONA might occur with obstructing pathology distal to the thoracic inlet (or planned FONA site), or when anterior neck pathology precludes access to the trachea by cricothyrotomy or tracheotomy. In these circumstances, establishing awake veno-venous or veno-arterial extracorporeal membrane oxygenation (ECMO) prior to or as a replacement for airway intervention might represent a safer option to maintain oxygenation. 86 This underlying rationale, together with continually improving technology and expertise in ECMO, supports its use in the context of the impossible airway situation, although the currently supportive evidence appears chiefly as single case reports [87][88][89] and case series, 90 with the attendant potential for positive publication bias. The decision to initiate ECMO prior to airway intervention should ideally occur by multidisciplinary consultation involving surgeons, anesthesiologists, perfusionists, and critical care staff, considering both diagnostic findings and clinical signs and symptoms such as stridor, dyspnea, and orthopnea. Even in experienced hands, establishing ECMO may be complicated and is time-consuming. Therefore, it has no role as a rescue technique for a failed airway encountered after the induction of general anesthesia. This is distinct from the use of veno-arterial ECMO in the cardiac arrest scenario, when extracorporeal cardiopulmonary resuscitation is possible when specific criteria are met. In this case, patients are often transitioned to mechanical circulatory support some time after cardiac arrest and, although in a low-flow state, they will have received continuous ventilation and oxygenation throughout.
# Management of the patient with anticipated difficult tracheal intubation after the induction of general anesthesia
If difficulty with management is predicted but the airway manager has elected to proceed with tracheal intubation after the induction of general anesthesia, close attention must be paid to details of implementation. Guiding principles are as follows:
• Position the patient optimally for the planned technique;
• Pre-oxygenate;
• Use apneic oxygenation throughout;
• Fully prepare equipment for the planned primary intubation approach; • Fully prepare equipment for alternate intubation techniques; • Prepare an appropriately sized second-generation SGA for rescue ventilation and oxygenation; • Brief the team on the planned progression of techniques, with objective triggers for transitioning to the next technique; • Review and communicate the exit strategy 5 to be used if tracheal intubation fails; • Ensure that an additional experienced airway manager has been sourced.
Further details appear below.
# Patient positioning
Appropriate patient positioning can help with technical aspects of airway management and by increasing safe apnea time.
• Positioning for laryngoscopy and intubation.
Published literature suggests optimal patient positioning for direct-and Mac-VL is the ''sniffing'' position. [91][92][93][94] This is typically obtained by aligning the patient's tragus with their sternum in the horizontal plane, by flexing the lower neck and extending the head. 95 In the obese patient, similar alignment can be achieved in several ways, including commercial positioning devices, back-of-bed elevation, or by creating a ramp with folded sheets. [96][97][98][99][100][101][102][103][104] There is currently insufficient evidence to recommend a specific patient position for the use of hyper-angulated videolaryngoscopes, which can be used in both the sniffing and neutral positions of the head and neck. The patient positioned in the neutral position with cervical spine immobilization is sub-optimally positioned for DL and Mac-VL, so that an experienced airway manager and alternate devices such as an HA-VL should be available. 105 • Positioning for FMV. Although the evidence is sparse, the sniffing position appears to be beneficial for improving upper airway patency 106 and facilitating FMV. 107 • Positioning for SGA insertion. Product monographs for SGAs typically espouse a sniffing position for insertion, with head extension and lower neck flexion. 108,109 Furthermore, a prospective study has indicated reduced neck mobility to be a risk factor for difficult SGA insertion. 52 With respect to ventilation once placed, a systematic review and meta-analysis by Kim and colleagues compared the performance of a variety of SGAs in the flexed, neutral, and extended positions. 110 Compared with the neutral position, the flexed position improved device seal but impaired ventilation as well as the view of the glottis obtainable with flexible endoscopy. Conversely, compared with the neutral position, the extended position worsened the device seal but had no effect on ventilation effectiveness or endoscopic view. These findings suggest that after insertion, SGAs should generally be used with the head and neck in the neutral position. • Positioning for eFONA. Although published evidence is lacking, full extension of the head and neck is likely the optimal position for eFONA. 4 This will be aided by placing a bolster or pillow under the patient's shoulders. There is some evidence that full neck extension may increase the height of the CTM by as much as 30%. 111 Pre-induction landmarking of the CTM (e.g., by ultrasound or palpation) should also occur in a position of full neck extension, as the CTM location may change significantly when re-positioning from a neutral to an extended position. 111
# Pre-oxygenation
The American Society of Anesthesiologists and Canadian Medical Protective Association closed claims publications revealed that many patients who sustained airway-related morbidity were healthy and presenting for elective surgery. 2,3 In some cases, harm might have been prevented or mitigated by closer attention to the use of pre-oxygenation and apneic oxygenation techniques to prolong the safe apnea time. Safe apnea time relates to the volume of the patient's functional residual capacity (FRC), effective de-nitrogenation of the FRC, and oxygen consumption. Of these, FRC and de-nitrogenation are modifiable. As described by Mosier in a recent editorial, three scenarios might be considered, based on the risk of oxygen desaturation with the onset of apnea 58 :
• Low to moderate risk of oxygen desaturation: Describing many elective surgical patients with a predicted ample FRC and low shunt fraction, the FRC should be de-nitrogenated by pre-oxygenation with 100% oxygen for three minutes of tidal volume breathing, eight vital capacity breaths over 60 sec, 112,113 or until the measured fraction of exhaled oxygen (FeO 2 ) exceeds 0.9. 114 More than one strategy has been described for standard pre-oxygenation: 1) use of a tightly applied cuffed face mask attached to an anesthetic circuit or manual resuscitator with O 2 flow C 10 LÁmin -1 , or 2) use of a nonrebreathing face mask with oxygen flow at ''flush rate'' (i.e., C 40
LÁmin -1 ). 115 The high flow rate helps match the patient's peak inspiratory flow rate, thus avoiding dilution by room air during peak demand. There is evidence that safe apnea time can be further extended with efforts to increase FRC, e.g., by patient positioning in the semi-seated (Fowler's), reverse Trendelenburg, or seated upright position, [116][117][118][119][120] if hemodynamics allow. This is particularly applicable to morbidly obese patients and term parturients. [121][122][123][124] In addition, gentle FMV between loss of consciousness and beginning laryngoscopy is advocated. • Moderate to high risk of oxygen desaturation: For the patient at higher risk of oxygen desaturation with the onset of apnea, such as those with lower FRC and increased shunt fraction, the optimal pre-oxygenation strategy likely involves use of positive end-expiratory pressure or non-invasive positive pressure ventilation (NIV) during pre-oxygenation, [125][126][127][128] together with back up or reverse Trendelenburg positioning. The concurrent use of standard nasal cannulae with NIV can augment pre-oxygenation and subsequently provide apneic oxygenation during laryngoscopy and intubation, 129 although to avoid hazardous gastric insufflation, airway patency must be assured. Use of high-flow nasal oxygenation (HFNO) devices running high flows under a tightly sealed mask should be avoided, e.g., during FMV, for fear of rapid gastric distention or pulmonary hyperinflation and subsequent barotrauma. • High risk of oxygen desaturation due to refractory hypoxemia: The critically ill patient with substantial lung parenchymal disease and high shunt fraction is often refractory to pre-oxygenation and apneic oxygenation techniques, resulting in severely limited safe apnea time. The use of awake intubation and HFNO while maintaining spontaneous ventilation is one option to help address this scenario, if feasible.
The benefit of de-nitrogenation/pre-oxygenation is age dependent. Children have a relatively low FRC and high metabolic demand, which combine to create short apnea times despite pre-oxygenation. They often benefit from apneic oxygenation techniques to help maintain oxygenation during airway management. 130 The CAFG recommends universal pre-oxygenation before the induction of general anesthesia/rapid-sequence intubation (RSI), if feasible.
# Apneic oxygenation
The use of apneic oxygenation can be beneficial in prolonging the safe apnea time during airway management. Apneic oxygenation is most often accomplished with the use of standard nasal cannulae at flows of 5-15 LÁmin -1 or devices that provide heated and humidified oxygen at higher flows (40-70 LÁmin -1 in adults-i.e., HFNO). Apneic oxygenation is thought to work by a number of synergistic mechanisms, including mass flow of oxygen along a pressure gradient from the pharynx to the alveoli, turbulent supraglottic flow vortices and dead space flushing, as well as the effect of cardiac oscillations on intrathoracic pressure. [131][132][133][134] Nevertheless, the airway manager must recognize that while oxygenation might be maintained, carbon dioxide clearance will be diminished during apneic oxygenation. Thus, caution and monitoring are required when allowing prolonged apnea in all patients, but especially those with increased intracranial pressure, metabolic acidosis, or pulmonary hypertension. 132 Apneic oxygenation by both standard nasal cannulae and HFNO has been studied in operating room (OR), emergency department (ED), and intensive care unit (ICU) settings. In general, compared with no apneic oxygenation, use of apneic oxygenation is effective in reducing oxygen desaturation during laryngoscopy in both adult and pediatric surgical patients. 132,[135][136][137][138][139][140][141] Results are mixed in out-of-OR settings such as the ED or ICU, possibly relating to factors such as patient population (e.g., shunt physiology precluding oxygen uptake) or study design (e.g., a nonpatent airway during apnea before laryngoscopy). 132,[142][143][144][145][146][147][148][149][150] The CAFG recommends that at a minimum, apneic oxygenation should be used for patients with anticipated difficult or prolonged laryngoscopy/tracheal intubation and/or for the patient with anticipated intolerance of apnea. It is essential to note that apneic oxygenation relies on a patent upper airway and will have no effect if the airway is obstructed.
# Maintenance or ablation of spontaneous ventilation?
General anesthesia with maintenance of spontaneous ventilation has been suggested to facilitate tracheal intubation when difficulty is anticipated. Nevertheless, despite the theoretical safety advantage afforded by the maintenance of inspiratory effort, 151 functional upper airway obstruction can occur with loss of consciousness, to a greater degree than occurs during natural sleep. 152 This follows from attenuation of upper airway dilator muscle activity, which makes the pharynx vulnerable to collapse. 153,154 The tendency of an airway to collapse with loss of consciousness is compounded by the negative intraluminal pressures generated during spontaneous inspiration within a narrowed airway. 153 Although inhalational induction is commonly used in pediatric patients, in adults it can take considerable time to reach a plane of general anesthesia sufficiently deep to allow for airway instrumentation without provoking reflex glottic closure. The NAP4 report highlighted the hazards of using inhalational induction in the adult patient with obstructing airway pathology. 1 The CAFG does not endorse use of inhalational induction of general anesthesia as a sole strategy for the adult patient with anticipated difficult laryngoscopy or tracheal intubation.
# Assessing for FMV efficacy prior to administration of a neuromuscular blocking agent
After the induction of general anesthesia, a trial of FMV prior to administering neuromuscular blocking agents (NMBAs) has been advocated, 155 with a view to potentially allowing the patient to awaken if FMV is unsuccessful. Nevertheless, in this situation, the effect of sedative-hypnotics may not dissipate or be reversible in sufficient time for the patient to resume spontaneous ventilation before significant hypoxemia occurs. 156 Thus, the more appropriate action when impossible FMV occurs would be to proceed with tracheal intubation or SGA insertion, both of which will be facilitated by neuromuscular blockade. [157][158][159] Studies of pharmacologic paralysis (albeit almost always having been performed in patients without difficult airways) generally conclude that pharmacologic paralysis facilitates FMV, and virtually never makes it worse. [160][161][162][163][164][165][166][167] With or without anticipated difficulty, if electing to proceed with tracheal intubation after the induction of general anesthesia, the CAFG did not find sufficient evidence to support a recommendation for a trial of FMV prior to NMBA administration.
# Use of short or intermediate-acting neuromuscular blockade
When difficulty with tracheal intubation is anticipated, the CAFG could not find evidence of an outcome benefit to justify recommending use of succinylcholine over an intermediate-acting non-depolarizing NMBA. Considerations in choosing a NMBA include the following:
• Pharmacologic modelling studies have indicated that succinylcholine may not necessarily wear off in time to allow resumption of spontaneous ventilation before hypoxemia occurs in the CVCO situation. 168,169 In addition, the residual effects of the sedative/induction agent may persist, also impairing a return to adequate spontaneous ventilation. • Similarly, a proportion of patients given sugammadex for reversal of rocuronium or vecuronium would also critically desaturate during the time required to draw up and administer the drug and for it to work, particularly if apnea intolerant. 169 In one simulation study of a CVCO situation, 170 a substantial time passed from a decision to use the drug, obtaining it, and its administration to the patient. Therefore, the immediate availability of sugammadex is recommended in all airway management locations. It should be noted that sugammadex will not necessarily reverse CVCO situations related to obstructing airway pathology. 171,172 • In critically ill patients where airway management is being performed as part of a resuscitation, expectations of a return to effective spontaneous ventilation is unrealistic when the clinical trajectory is rapidly deteriorating. Use of succinylcholine or a plan to reverse rocuronium if difficulty occurs is not a reliable plan if it is the only difficult airway strategy being deployed. • Use of an intermediate-acting NMBA to facilitate tracheal intubation will optimize conditions for the duration of airway management should more than one attempt be required, including change of device or operator.
# Choice of equipment
Resources allowing, the CAFG advocates for the routine use of VL (with appropriately selected blade type) for tracheal intubation, with or without anticipated difficulty. 5 Regardless of the chosen technique, the airway manager must attain and maintain competence with its use in lower acuity clinical or simulation settings. 173,174
# Difficulty encountered with a first attempt at tracheal intubation
Difficulty with tracheal intubation after the induction of general anesthesia will inevitably occur from time to time, whether predicted or not. The reader is referred to the accompanying part 1 article 5 for recommendations on management of this situation.
# Difficult tracheal intubation predicted-other options
When difficult tracheal intubation is predicted, most patients will be intubated either awake or after the induction of general anesthesia with additional preparation and precautions. Nevertheless, in some circumstances, the following options may be considered:
7.3.1 Avoiding predicted difficult tracheal intubation-use of regional or local anesthesia for a surgical case When difficult tracheal intubation is predicted, some surgical cases may be amenable to regional or local anesthesia, with the following caveats:
• As complications from the surgical procedure itself, administered local anesthetic or sedative medications could all present the need for airway management despite the use of a regional technique, a complete airway evaluation must still occur, and a management strategy determined. • The surgical procedure must be of a predictable duration, and the block must be shown to be effective before proceeding.
• Ideally, there should be easy access to the patient's airway intraoperatively. • Before proceeding, the team should be briefed on the patient's difficult airway status, together with the plan for intraoperative airway management if needed.
# Deferring management of the patient with predicted difficult tracheal intubation
Occasionally, it might be appropriate to defer airway management when difficult tracheal intubation is predicted. Examples of this include:
• Transferring an elective surgical patient to a more fully equipped hospital; • Transferring a pediatric surgical patient with known facial dysmorphism to a specialized pediatric hospital for management; • Rescheduling a semi-urgent surgical procedure from overnight hours until daytime staff have arrived; • Deferring tracheal intubation of a critically ill patient by temporizing with the use of non-invasive ventilation or HFNO while additional expertise and equipment is sourced, or until the patient is transferred to a different location (e.g., the OR) for the intubation.
# Use of an SGA in the patient with known or predicted difficult tracheal intubation
For the patient with predictors or a history of difficult tracheal intubation, the use of an SGA requires careful consideration. Three scenarios that might be considered include:
• For the case normally undertaken with tracheal intubation, electively choosing to proceed with an SGA simply to avoid a difficult tracheal intubation situation has been shown to be hazardous. 1 The CAFG recommends against this practice. Rather, the difficult intubation situation should be safely dealt with ''up front''. • For a case where an SGA would normally be used, using an SGA in a patient with anticipated difficult tracheal intubation is often successful, although the airway manager must recognize that the fallback option of defaulting to tracheal intubation should the SGA fail may not easily succeed. This might suggest consideration of initial tracheal intubation as the safer plan when general anesthesia is required. If using an SGA regardless, at the very least, there should be a predetermined plan for airway management should SGA ventilation fail. • Despite the above, SGA use is often (appropriately) recommended as a fallback option after failed tracheal intubation in the induced patient. 5,6 The SGA can be used to maintain oxygenation and temporize the situation pending the patient's awakening, while obtaining more equipment or expertise, or it might be used as a conduit to facilitate FB-aided intubation. In an urgent situation (e.g., failed tracheal intubation during emergency Cesarean delivery under general anesthesia), a risk to benefit analysis might justify continuing with the SGA.
8 Special situations
# The patient with a known or suspected highly infectious respiratory pathogen
Airway management guidelines for patients with known or suspected highly transmissible infections should follow core principles, with some modification. The contemporary experience of the COVID-19 pandemic caused by SARS-CoV-2 infection is but one example that may lead to respiratory failure requiring tracheal intubation. 175 • Team safety. The risk of transmission of a highly infectious pathogen such as SARS-CoV-2 to a healthcare worker in the immediate peri-intubation period depends on the pathogen and precautions taken. 176,177 Spread for most pathogens is assumed to occur by direct contact with droplet containing viral particles, and/or from aerosols generated during a patient cough or an airway procedure (i.e., aerosolgenerating medical procedure [AGMP]). Whether it is an elective surgical patient who has tested positive for a highly infectious pathogen, a critically ill patient with unknown status, or a patient requiring tracheal intubation because of primary respiratory disease caused by a highly infectious pathogen, airway manager and team safety is paramount. Hastening to manage one of these patients without considering team safety may result in healthcare worker infections. The number of people in the room should be kept to a minimum, with a pre-assigned primary airway manager, an airway assistant, and ideally a third clinical support practitioner. • Personal protective equipment (PPE). While there has been significant controversy surrounding what defines ''safe'' PPE for practitioners caring for patients infected by a highly infectious pathogen, it remains possible that airway management poses a significant potential risk for clinicians. 178 During airway management involving AGMPs, an important risk period occurs while removing (doffing) PPE. Incorrectly donning PPE or using inadequate PPE also poses a risk to the airway manager. Airborne, contact, and droplet precaution PPE for practitioners directly performing or assisting in airway management includes an N95 respirator, eye shield, Association for the Advancement of Medical Instrumentation level 3 gown, neck cover, and gloves. 176,178 Training in donning and doffing PPE should be performed regularly and practitioners should be checked to ensure adequate PPE coverage before entering the patient care room.
The CAFG recommendations for airway management of the patient with a known or suspected respiratory infectious disease spread by droplet or airborne mechanism reflect other published consensus statements on the topic [179][180][181][182][183][184] and are summarized in Table 10.
# The patient with obstructing airway pathology or a traumatized airway
The patient with known or suspected obstructing airway pathology, or with airway trauma, requires careful and skilled evaluation and planning. Obstructing pathology can occur from tumour, infection, edema, foreign body, or stenosis. Trauma can distort the expected anatomy and might involve a breach of integrity of the airway, sometimes in more than one location. If general anesthesia has been induced and the patient is apneic, patients in both categories may present significant technical difficulties with some or all of DL or VL, FMV and SGA use. When tracheal intubation is indicated and time and resources permit, enhancing the standard airway evaluation is advised. Patient cooperation allowing, nasal endoscopic evaluation of the pharynx and larynx will help clarify the nature and extent of glottic and supraglottic pathology or injury. 19 Any available computed tomography or magnetic Table 10 Airway management considerations for the patient with known or suspected respiratory infectious disease spread by droplet or aerosol CAFG recommendations for airway management of the patient with known or suspected highly infectious respiratory infectious disease spread by droplet or airborne mechanism Environment and preprocedure
• If out of the operating room/theatre, an airborne infection isolation room is preferred for tracheal intubation.
• A negative pressure environment is preferred regardless of location, but ventilation rate/air exchanges are more important than positive or negative pressurization. • Minimize team members in the room. The most experienced available airway manager should perform tracheal intubation. • Supervised personal protective equipment (PPE) donning should occur.
• Perform team briefing; use a checklist.
• Simulation-based team training is valuable.
# Equipment
• Place a viral filter between tracheal tube, face mask, or supraglottic airway (SGA) and more proximal ventilation equipment. • Sidestream capnography aspiration to be located proximal to the viral filter.
# • Use video laryngoscopy as primary technique:
s To increase first-pass success s To avoid close proximity to patient's face and respiratory tract s To enable a shared mental model and situation awareness of non-intubating team members.
• Consider using SGAs for airway rescue scenarios only-not as a planned technique. Second-generation devices are recommended for their higher seal pressures. • Take pre-packaged kits with required equipment into the room.
• Position a standby airway cart (?/-additional personnel in PPE as ''runners'') outside room.
# Pre-oxygenation
• Pre-oxygenate with a well-applied face mask.
• Add PEEP valve to bag-valve mask set-up, if using.
• Limit flow rates to the least required to obtain desired fraction of exhaled oxygen value (e.g., 0.9). This may not always be achievable. Induction
• Intravenous induction with NMB preferred.
• FMV discouraged while awaiting onset of NMB unless clinically significant hypoxemia has occurred or is expected. • Avoid apneic oxygenation with HFNO.
• If apneic oxygenation is used, consider use of low oxygen flows (e.g., 5 L min -1 ).
# Intubation
• Most experienced airway manager available should manage the airway.
• Ensure a styleted tracheal tube or bougie is available, as appropriate to the video laryngoscope blade in use.
• Institute positive pressure ventilation only after tracheal tube cuff inflation.
• If high airway pressures are encountered, ensure tracheal tube cuff pressure is 5 cm H 2 0 higher than peak inspiratory pressure.
# Unanticipated difficult airway
• Use FMV between intubation attempts only if needed to re-oxygenate the patient.
• If FMV is undertaken, use two-handed mask application with thenar eminence (''V-E'') grip to maximize seal and jaw lift effectiveness. • Use waveform capnography to confirm efficacy of rescue ventilation.
• Avoid excessive ventilation. Respiratory rate, volume and inspiratory pressure should ideally be guided by objective feedback (waveform capnography, pressure manometer). • For the elective surgical patient, if SGA rescue is used, consider using a second-generation device that supports FB-aided tracheal intubation. • If SGA rescue has occurred, then patient awakening is preferred: if not feasible, other options include FB-aided intubation through the SGA, or FONA during SGA-supported ventilation. Proceed with surgery only if considered safe. • Above all, the safety of the team must be prioritized.
# CVCO and eFONA
• Scalpel-bougie emergency FONA is the recommend technique.
• Transiently discontinue attempted FMV or SGA ventilation during incision of cricothyroid membrane.
resonance imaging scans should also be reviewed, especially for patients with pathology below the glottis, recognizing that for dynamic pathology, any imaging occurs at an unknown point in the patient's respiratory cycle. 20 Planning a safe approach to tracheal intubation of these patients should occur according to the principles described in Section 6 above, in consultation with all involved team members, including the surgical team. If difficulty is anticipated with two or more of tracheal intubation, FMV, and SGA ventilation, an awake approach (via a nasal, oral, or front of neck route) is advised.
The trauma patient with a blunt or penetrating injury to the airway must be assessed for how best to approach airway management, as well as for the potential for vascular or other injury. Patient cooperation and time allowing, securing the airway awake during spontaneous ventilation (e.g., by awake tracheotomy or awake oral or nasal intubation) enables avoidance of positive pressure ventilation above the level of a known or suspected airway breach, and its attendant risk of causing or exacerbating pneumothorax, pneumomediastinum or subcutaneous emphysema. There is also the potential for entering a tear, creating a false passage, or converting a partial tracheal disruption to a complete disruption during tracheal intubation. Thus, indirect visualization of the anatomy (e.g., using a FB until distal to the suspected or known level of breach) is recommended. Management of the traumatized airway has recently been well reviewed. 187 Successful use of an SGA as a primary technique has been described under combat conditions, 188 as well as in surgical patients with obstructing pathologies. 189 Such reports are limited to observational case series or single case reports; randomized-controlled trials are lacking. Thus, while an SGA might successfully rescue a failed intubation, the CAFG recommends securing the obstructed or traumatized airway by tracheal intubation or FONA, when resources allow. As indicated in section 7.1.6, some severe cases of obstructing pathology below the thoracic inlet might be most safely managed with institution of ECMO before the airway is managed. Multidisciplinary planning and management are required.
# The morbidly obese patient
The obese patient is at elevated risk during airway management. The NAP4 audit reported that patients with a body mass index (BMI)[30 kgÁm -2 were twice as likely to suffer a severe airway complication, and those with BMI [ 40 kgÁm -2 (morbidly obese) were four times as likely. 1 Patients were obese in 68% of difficult intubation claims in a recent analysis of the Anesthesia Closed Claims Project database. 2 A higher BMI is associated with difficult FMV. 25,28,40,[45][46][47][48] A co-existing thick neck [40][41][42] (e.g., circumference [ 40-50 cm), obstructive sleep apnea (OSA), 25,40,43,46,167 and/or a history of snoring 39,45,47,48 are also associated with difficult FMV. A thick neck 15,28,[190][191][192] and OSA 167 are associated with difficult
# Awake tracheal intubation
• Avoid awake intubation unless high risk of a CVCO situation with induction of general anesthesia/RSI.
• VL or flexible bronchoscopy can be used for awake tracheal intubation, skills allowing. Consider use of an SGA as a conduit for the FB. • Consider alternatives to local anesthetic nebulization or aerosolization for topical airway anesthesia, e.g., local anesthetic gels/ointments or nerve blocks.
# Intraoperative phase
• Avoid circuit disconnections.
• Place ventilator into standby mode if disconnection is needed.
• Disconnect circuit proximal to viral filter if feasible; if not, then consider temporarily clamping the tracheal tube, seeking to avoid damaging it or its pilot line.
# Extubation
• Tracheal extubation is an AGMP with potentially higher risk for aerosol generation than intubation 185 .
• Use pharmacologic measures to help prevent cough, agitation, or vomiting during or after extubation.
• Place a surgical or procedure mask on the patient before awake extubation and extubate while the mouth, nose, and nasal prongs are covered by the mask; leave the mask on the patient during subsequent transfer 186 . • Avoid airway exchange procedures if possible.
# Post-procedure
• Dispose of airway management equipment appropriately.
• Doff PPE under supervision.
AGMP = aerosol-generating medical procedure; CAFG = Canadian Airway Focus Group; CVCO = cannot ventilate, cannot oxygenate; eFONA = emergency front of neck airway access; FB = flexible bronchoscope; FMV = face-mask ventilation; FONA = front of neck airway access; NMB = neuromuscular blockade; PEEP = positive end-expiratory pressure; PPE = personal protective equipment; RSI = rapid-sequence intubation; SGA = supraglottic airway.
DL or intubation. Whether obesity alone predicts difficult laryngoscopy/intubation continues to be controversial, with some studies reporting an association, 15,29,31,39,[192][193][194][195] and others not. 11,25,191,[196][197][198] No studies have yet reported obesity to be a risk factor for difficult or failed VLfacilitated tracheal intubation, although one study has reported a thick neck to be associated with failed HA-VLfacilitated tracheal intubation. 33 In another study, a higher neck skinfold thickness was associated with longer times to successful intubation with a FB in anesthetized patients. 38 Obesity or a thick neck also predicts difficulty with SGA use in some, [49][50][51] but not all 199 studies, and may predict difficulty with palpation of landmarks for eFONA.
Even more significant are physiologic challenges during airway management of the obese patient. 53 With reduced FRC, apnea is poorly tolerated, so that if difficulty is encountered in establishing ventilation, rapid oxygen desaturation must be anticipated.
Canadian Airway Focus Group recommendations for airway management of the obese and morbidly obese patient are as follows:
• The potential for technical difficulty with both tracheal intubation and other modes of ventilation, coinciding with likely apnea intolerance, suggests that the airway manager should carefully consider whether ATI might confer a safety benefit (Fig. 1). • Regardless of the chosen approach, close attention to patient positioning is recommended, with ramping to ensure the patient's tragus is aligned with the sternum. 96,98 ''Back up'' or reverse Trendelenburg positioning will help delay oxygen desaturation. [116][117][118][119][120][121][122][123][124] If general anesthesia is elected, careful pre-oxygenation must occur, with a goal of achieving FeO 2 C 0.9. • Apneic oxygenation is recommended during laryngoscopy and intubation of all morbidly obese patients when managed after the induction of general anesthesia. • Given the anticipated short apnea time and potential for difficulty with fallback ventilation options, primary use of VL (with appropriately selected blade type) is recommended for tracheal intubation to help maximize first-pass success.
• Careful planning and documentation should occur before embarking on airway management of the obese patient. The team should be briefed on the strategy in the event that difficulty is encountered; this should include the triggers for moving to the next step in the plan. Given the potential for rapid oxygen desaturation, the airway manager should consider having a second experienced airway manager stand by for assistance if required.
8.4 The patient with an increased risk of aspiration
In the NAP4 audit, aspiration was the most common cause of airway management-related death and brain damage. 1 In an incident-reporting study from Australia and New Zealand, aspiration was associated with significant harm, with many of the cases occurring in fasted patients. 200 In the difficult airway patient, the risk of aspiration increases in conjunction with the potential for longer or multiple intubation attempts and/or gastric insufflation with FMV between attempts. [201][202][203] Tracheal intubation is indicated when general anesthesia is required in the at-risk patient. Although secondgeneration SGAs with integrated drainage ports may confer some protection against aspiration, 204 neither an SGA or FMV would typically be used as an intended primary technique in this scenario. Nevertheless, these modalities can and should be used as needed to maintain oxygenation between intubation attempts.
Although better referred to as ''cricoid force'', cricoid pressure (CP) applied with a force of 10 N (i.e., 1 kg) before induction and 30 N (i.e., 3 kg) after loss of consciousness may reduce the risk of regurgitation and hence aspiration during RSI by occluding the hypopharynx behind the cricoid cartilage. 205 Nevertheless, especially if poorly applied, CP can also make tracheal intubation more challenging, 206 and it can also complicate SGA insertion. Evidence on the effectiveness of CP has been conflicting 207 and controversial, creating equipoise around its use. Birenbaum et al. recently published a large randomized non-inferiority trial (n = 3,472 at-risk patients) on the use of CP. 208 The primary outcome of aspiration did not differ between the actively applied CP (ten cases; 0.6%) and sham CP (nine cases; 0.5%) groups (relative risk of aspiration for the sham CP group compared with the actual CP group 0.9; 90% confidence interval, 0.39 to 1.99). In addition, glottic visualization and duration of intubation favoured the sham CP group. Despite the clinically equivalent occurrence of aspiration between groups, methodologically, the authors were unable to declare non-inferiority of sham CP because of a lower-thanexpected aspiration event rate. Other study limitations included the non-inclusion of obstetric, critical care, and ED patients, and there were few (\ 1% of the total) subjects with an anticipated difficult airway. Nevertheless, given that the original Sellick communication on CP was a small, non-randomized, unblinded, uncontrolled case series of 26 patients, 209 having the very large Birenbaum et al. study suggest no clinically important difference in the incidence of aspiration in an at-risk population is very helpful in advancing our understanding of CP.
Canadian Airway Focus Group recommendations for airway management of the patient with an anticipated difficult airway and an increased risk of aspiration are as follows:
• There may still be a role for correctly applied CP in some settings (e.g., obstetrics). Given the limited data available, the ultimate decision to use CP is at the discretion of the airway manager; • When a significantly elevated risk of aspiration coincides with an anticipated difficult airway, performing ATI with minimal sedation may confer a safety benefit; • If the airway manager decides to intubate the at-risk patient after the induction of general anesthesia, practical advice includes suctioning a nasogastric tube if already present (consider inserting one if not) before induction, placing the patient in the back up or reverse Trendelenburg position, and having two suction devices immediately available for oropharyngeal suctioning. Before induction, an in situ nasogastric tube should be attached to continuous low-pressure suction to prevent intra-gastric pressure accumulation following induction 210 ;
• Use of VL allows airway team members to assess the laryngeal view, the impact of CP (if used) on the view of the glottis, and provides heightened situational awareness during a critical time. Nevertheless, should massive regurgitation occur, the camera may be obscured. Thus, unless difficulty in glottic visualization is anticipated, use of Mac-VL is preferable in the patient at high risk of regurgitation, to allow direct, eye-to-glottis visualization if necessary; • If CP is deemed to be impeding either laryngoscopy or tracheal intubation, it should be removed; • The use of FMV with low inspiratory pressure during RSI, before or between attempts at tracheal intubation, can extend safe apnea time without oxygen desaturation; • If the planned tracheal intubation attempts fail, a second-generation SGA should be inserted, and the integrated drainage port used to drain the esophagus. If CP had been applied, it should be removed for insertion of the SGA and not reapplied.
# The patient with a bleeding upper airway
Bleeding in the upper airway and subsequent problems with airway management are important causes of airwayrelated morbidity and death. [211][212][213] Bleeding in the upper airway is fundamentally different from other challenging airway situations in that flexible bronchoscopic and videolaryngoscopic intubation are often more difficult or impossible because of soiling with blood. In addition, because the stomach may be filled with blood, the use of an SGA is only suitable as a temporary measure, or as a guide to intubation. 213,214 Initial therapeutic measures include compression of the bleeding site, patient positioning (the patient will often only tolerate the sitting position), suctioning, oxygen delivery, and fluid resuscitation. Concomitantly, the airway should be evaluated for predictors of difficult or impossible DL, and the location of the CTM should be established. If laryngoscopy and intubation is predicted to be otherwise technically easy and the CTM is identified with certainty, then RSI can be employed, with two large bore rigid suction catheters ready. Otherwise, preparations should be made for an ATI with alternative techniques that can be used even if visibility of the airway is obscured by blood. 213 Such techniques include awake FONA, awake FB-guided intubation via an SGA as well as awake DL or Mac-VL, awake retrograde-, blind nasal-, oral digital-, lighted stylet-, and ultrasound-guided intubation. 213 Awake intubation with a FB or VL can still be attempted in this situation, but might fail, so the airway manager should be prepared to use one of the alternatives mentioned above. In addition, a ''double set-up'' to allow for eFONA should be prepared (Table 8) in case the airway is lost during attempted management.
Management of the bleeding airway has recently been reviewed in detail. 213,215 9 Tracheal extubation Published audits and closed legal claims continue to document the risks associated with tracheal extubation. Re-intubation in the ICU after failed extubation and tracheal tube exchange in the patient with a difficult airway have also caused patient morbidity. [1][2][3]216,217 Although such cases consistently account for up to 25% of total airway management-related morbidity, a substantially smaller proportion of all published articles on airway management relate to tracheal extubation, rather than intubation. 2 Fortunately, excellent guidelines 218 and narrative reviews 219,220 on tracheal extubation have been published. Intentional extubation is elective and thus allows for careful planning to occur (Fig. 2), including identification of at-risk patients after tracheal extubation.
# The at-risk tracheal extubation
The patient may be deemed at risk at the time of tracheal extubation in one or both of two ways: 1) failure to tolerate tracheal extubation, where the patient is at risk of failing to maintain gas exchange, airway patency, or airway protection after extubation; and 2) if tracheal reintubation might be difficult, either because the patient was originally difficult to intubate, or because of an interval event (Table 11).
In some cases, more objective risk stratification can occur before planned tracheal extubation. For example, the patient considered at risk of supraglottic or glottic airway edema might be assessed with a cuff leak test. 221,[226][227][228] In a recent systematic review, the authors concluded that the absence of a cuff leak in an at-risk patient is associated with post-extubation stridor or need for re-intubation, but the presence of a leak does not necessarily rule out the occurrence of stridor or need for re-intubation. 228 Further assessment of the at-risk patient can occur by indirect visual evaluation of the glottis and supraglottic area using a VL 229 or FB before emergence from anesthesia or sedation begins.
Strategies to manage the at-risk patient upon tracheal extubation are presented in Table 12. 9.2 Lower risk (''routine'') tracheal extubation Even for the patient not identified as being at risk of morbidity, care must be taken with tracheal extubation. Routine extubation measures such as gas exchange and hemodynamics should be adequate and level of consciousness sufficient to enable airway patency and protection. The patient's neuromuscular function, temperature, and acid-base status should be near normal. Prior to extubation, the patient should be pre-oxygenated and the pharynx should be suctioned, especially if at risk of pooled pharyngeal blood, to avoid the potential of aspirated blood forming an occluding clot in the trachea. 2 Extubation at end-inspiration will help avoid immediate aspiration of blood or residual secretions. Additional CAFG recommendations for tracheal extubation are as follows: • As extubation of the surgical patient is often accompanied by airway manager fatigue and team distraction, a ''sterile cockpit'' concept of minimizing non-essential conversation during emergence and extubation of the surgical patient is advocated. • Supplemental oxygen delivery should occur during transportation of all recently extubated patients to highdependency nursing units including postanesthesia care units. Pulse oximetry monitoring should also be used.
Handover should routinely detail the type and ease of airway management. • In critical care or ED settings, if a consulting service has recommended tracheal extubation of an intubated patient, direct communication should occur between that service and critical care/ED attending staff about the rationale and timing of extubation. Documentation of intubating conditions/difficulty should be clearly available to consulting services to help guide the extubation plan.
# Extubation over an airway exchange catheter (AEC)
If tracheal intubation was or might now be challenging, short-term use of an AEC can be considered at extubation to assist re-intubation should it be required. Appropriately positioned and secured above the carina (e.g., at around 23 cm at the teeth in the adult patient), 11-or 14-French airway exchange catheters are reasonably well tolerated 236 and permit spontaneous ventilation, coughing, and talking. Although AECs can support oxygen insufflation and even jet ventilation, barotrauma and fatalities have been reported in these scenarios. [237][238][239] Conventional methods of oxygen delivery such as face mask, nasal cannula, or HFNO 237 can still be used when an AEC is present; the CAFG recommends against any routine oxygen administration through an AEC. If unavoidable during an emergency, oxygen insufflation through an AEC should be limited to 2 LÁmin -1 , only as a temporizing measure until oxygenation is re-established by a conventional mode of delivery, 237 and close attention must be paid to ensuring that gas egress can occur. 240 An AEC can be left in situ after extubation of the difficult airway patient until the need for tracheal reintubation becomes unlikely. Although case specific, in one published ICU series, most patients requiring tracheal reintubation over an AEC underwent the procedure within two to ten hours after extubation. 236 The surgical patient will almost always have the AEC removed before leaving the post-anesthetic care unit. Although infrequently required, tracheal re-intubation over an AEC will be facilitated by the use of VL to both retract the tongue and • Other perioperative issues including hypothermia, altered acid-base status and uncontrolled pain.
# Potential causes of difficult tracheal re-intubation
• The original tracheal intubation was difficult.
• Interval development of airway edema.
• Anatomic changes as a result of a surgical intervention: s Upper airway surgery s Upper cervical spine fusion. enable monitoring of tracheal tube passage through the glottis. 241 In addition, prior passage of an intermediate catheter (e.g., the Aintree catheter; Cook Group Incorporated, Bloomington, IN, USA) over an 11-or 14-French AEC will facilitate passage of a tracheal tube through the adult larynx by reducing the size discrepancy between the outer diameter of the catheter and the inner diameter of the tracheal tube. 242 Of note, the Cook AECs (Cook Group Incorporated, Bloomington, IN, USA) are only licensed for immediate tracheal tube exchange in most countries. Therefore, leaving an AEC in situ for retaining airway access following extubation, though widely practiced, is technically an off-label application.
# Human factors and the anticipated difficult airway
The NAP4 study 1 and published closed legal claims 2,3 have indicated that airway management misadventure was often associated with inadequate evaluation and lack of a predetermined airway strategy. That is, airway managers simply did not anticipate difficulty or failed to modify their strategy appropriately despite predicted difficulty. The airway manager must be self-aware of potential human factor pitfalls to avoid. Table 13 presents some issues together with suggested mitigating strategies.
# Summary and key recommendations
Informed by publications of airway-related morbidity, [1][2][3] guidelines should not only address management techniques for the difficult airway when encountered in the unconscious patient but also emphasize the need for detailed patient evaluation, planning, and communication. In this way, safe airway management decision-making and implementation can occur. Briefly summarized, our guiding principles and recommendations are as follows: significant physiologic (e.g., apnea intolerance or aspiration risk) or contextual issues; • Awake tracheal intubation can proceed via oral, nasal, or front of neck routes. In some cases, oral or nasal ATI can be facilitated by a variety of devices (e.g., flexible bronchoscopy or VL);
•
• If a lack of patient cooperation or time precludes ATI, and airway management after the induction of general anesthesia must proceed, it should proceed with ''double set-up'' preparation allowing for immediate eFONA;
Table 13 Potential human factor issues during patient evaluation and airway management decision-making, with suggested mitigation strategies Potential human factor issues during patient evaluation and airway management decision-making, with suggested mitigation strategies Issue Possible mitigation strategies: by the airway manager by the assembled team by the organization Failure to match planned strategy with the findings of airway evaluation (anatomy, physiology, and clinical context)
• Review your planned strategy for a high-risk or difficult case with a colleague.
• With predicted difficulty, before proceeding, ensure that all equipment for your airway strategy (i.e., planned primary and fallback techniques) is physically present, sized for the patient, and arranged in the order of anticipated use. This well help ensure you have thought through the situation.
• For all patients, brief the team on your chosen strategy, including your alternate plans if the intended technique fails, together with triggers for moving to an alternate plan.
• During the briefing, specifically empower team members to speak up if they think that a trigger has occurred.
• The organization should mandate inclusion of the airway strategy in the first surgical safety checklist.
• Airway management education programs should include material on safe decision-making, rather than only teaching ''hands-on'' skills.
Maintenance of competence. Use of ATI is decreasing 243 . When difficulty is predicted, lack of recent experience, confidence, or skills in ATI might tempt the airway manager to avoid its use despite indicators of it being the safest approach. Lack of suitable equipment might also be a factor in some cases.
• Enlist a colleague to help perform ATI: you will both benefit from the experience.
• Seek opportunities to perform ATIs, rather than using excuses to avoid them.
• If the patient's anatomy is amenable, consider using a more familiar device for ATI (e.g., VL).
• For the patient requiring ATI with obstructing pathology, a surgeon should be physically present to perform fallback eFONA.
• The organization should provide training and maintenance of competence workshops in ATI techniques, including use of the FB.
• Provide airway simulators or standard airway training manikins for individual practice at any time.
• Ensure equipment for all aspects of ATI is easily accessible at airway management locations.
• Package all equipment and local anesthetics needed for topical airway anesthesia together in easilyaccessed ''grab kits''.
''Production pressure'' to get a case done might lead to an unsafe decision to manage a difficult airway patient after the induction of general anesthesia, when ATI might be the safer approach.
• When sensing production pressure, (whether self-induced or from another source) push back by deliberately slowing to reflect on whether the pressure is adversely impacting your patient's safety.
• Pre-empt any pushback on planned ATI by using ''safest for the patient'' language.
• Increase team buy-in by early communication with the surgeon and team when ATI is needed for an operative case.
• Multidisciplinary team training or rounds on adverse airway events might help improve communication and cooperation for future difficult airway situations that involve multiple specialties.
''Normalization of deviance 3 '': the airway manager might have managed a series of patients after the induction of general anesthesia where despite predictors of difficulty, none occurred. On the basis of thus ''getting away with it'' over time, inducing such patients might become a clinician's normal practice, rather than even considering ATI.
• With significant predicted difficulty, if considering tracheal intubation after the induction of general anesthesia, as a thought exercise, satisfy yourself that it can occur with a margin of safety equal to or greater than ATI. If not, proceed with the ATI.
• Beware of ''gambler's fallacy'': the false belief that the outcome of the current case is less (or more) likely given results of previous events. Judge every case on its own, based on findings from the airway evaluation.
• Team members should be encouraged to speak up if uncomfortable with the airway manager's chosen approach. The ''PACE'' (probealert-challenge-emergency) or similar mnemonic can be used as a prompt by team members to question the planned approach.
• Appoint a hospital ''airway lead'' 244 in your department or hospital, tasked with ensuring a full array of difficult airway equipment is readily available across the institution, arranging airway education, including skills in ATI, and to help constructively debrief airway-related critical incidents and near-events.
ATI = awake tracheal intubation; eFONA = emergency front of neck airway access; FB = flexible bronchoscope; VL = video laryngoscopy.
• Management of the anticipated difficult airway after the induction of general anesthesia should only occur with an appropriate pre-determined strategy for difficulty if/ when encountered. A second airway manager should be sourced, the team briefed, and the required equipment brought to the room. Attention should be paid to patient positioning, pre-oxygenation, and apneic oxygenation; • Regardless of the chosen approach when difficulty is predicted, the airway manager must clearly communicate the planned management strategy to the team, including the triggers for moving from one technique to the next; • Extra care should be used in the planning and implementation of care for the patient with head and neck pathology, obesity, or increased aspiration risk; • Tracheal extubation of the at-risk patient must be carefully planned in terms of assessing whether the patient can tolerate extubation and whether reintubation might be difficult; • As unanticipated difficulty with airway management can occur despite none being predicted, the airway manager must be ready with a strategy for difficulty occurring in every patient, and the institution must make difficult airway equipment readily available and easily accessible; • As pandemic conditions add complexity to both routine and difficult airway decision-making and management, individual and institutional preparedness should be mandated.
Management of difficulty with airway management occurring in the already-unconscious patient is addressed in the part 1 companion article. 5 Author contributions See Appendix.
#
Acknowledgements The members of the CAFG thank Brooke Ballantyne Scott, MLIS for invaluable assistance in conducting literature searches for this project. In addition, we wish to express our gratitude to the following clinicians for their review of this manuscript and very helpful suggestions: Drs. Loes Bruijstens, Tim Cook, Thomas Heidegger, and Michael Kristensen.
#
Disclosures See Appendix.
# Funding None.
Editorial responsibility This submission was handled by Dr. Hilary P. Grocott, former Editor-in-Chief, Canadian Journal of Anesthesia/Journal canadien d'anesthe´sie.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/ by-nc/4.0/. | None | None |
d49d95e2261354750c8bf0cc7674625b7c6c4f16 | cma | None | To provide an evidence-based approach to treatment of patients presenting with deep vein thrombosis (DVT).An estimated 45,000 patients in Canada are affected by DVT each year, with an incidence of approximately 1-2 cases per 1,000 persons annually. This translates to 2-4 DVTs per year in a typical, individual, Canadian family practice. Approximately one third of patients with DVT also develop symptomatic pulmonary embolism (PE), one third will suffer from post-thrombotic syndrome (PTS) and one third will have a recurrent DVT or PE within 10 years. Rapid diagnosis and treatment of DVT is essential to prevent these complications. Active malignancy, surgery (especially orthopedic), immobilization, and estrogen use/pregnancy are common transient provoking factors. However, up to 50% of first-time DVT is unprovoked (or "idiopathic").#
- Unless compression ultrasound (CUS) is rapidly available, patients with moderate-to-high suspicion of DVT (except those with a high risk of bleeding) should start anticoagulant therapy before the diagnosis is confirmed. Imaging confirmation should be obtained as soon as possible. - Outpatient management is preferred over hospital-based treatment except for patients with limb threatening DVT, high risk of bleeding, or patients who have additional indication for hospitalization. - Initial treatment should have an immediate anticoagulant effect. Therefore, warfarin monotherapy is not appropriate as a lone initial treatment. - For patients who cannot be therapeutically anticoagulated due to active bleeding or high bleeding risks such as severe liver disease or significant thrombocytopenia, consultation should be initiated with a hematologist or thrombosis specialist. Management may include placement of a retrievable inferior vena cava filter (IVC filter) if therapeutic anticoagulation cannot be safely provided in the acute setting .
# Anticoagulant Agents and Dosing:
In general, choice of anticoagulation in the acute treatment of DVT should take into consideration patient-specific factors. Guidelines recommend direct oral anticoagulant (DOAC) therapy (apixaban or rivaroxaban) or low molecular weight heparin (LMWH) followed by a DOAC (for dabigatran and edoxaban) over VKA therapy EXCEPT for patients with a diagnosis of antiphospholipid syndrome, severe renal impairment, drug interactions (concomitant medications metabolized through the CYP3A4 enzyme or P-glycoprotein), extremes of weight, or conditions that may impair oral absorption.
Other factors that should influence choice of anticoagulant include the requirement for lead in parenteral therapy prior to specific DOACs such as Dabigatran or Edoxaban, cost, once daily vs twice daily dosing, and patient preference.
LMWH is an option to be used as monotherapy for the full duration of treatment in patients with active cancer and those with DVT in pregnancy. Large phase 3 studies have demonstrated the efficacy and safety of these agents for the initial (apixaban and rivaroxaban) treatment of DVT, as well as for acute and extended treatment (all agents). Four DOACs have been approved in Canada for the treatment of patients with DVT. An initial 5-to 10-day course of LMWH is required prior to starting dabigatran and edoxaban but not with rivaroxaban and apixaban.
DOACs should not be used in pregnant or breastfeeding women or in those with severe renal dysfunction .
# Apixaban (Eliquis®):
Apixaban is an oral anticoagulant that works through direct inhibition of clotting factor Xa. Apixaban should be used with caution in patients with a creatinine clearance (CrCl) 15-29 mL/min) and is not recommended in those with a CrCl <15 mL/min or undergoing dialysis. The large randomized trials evaluating apixaban in patients with VTE and atrial fibrillation excluded patients with a CrCl <25 mL/min. Apixaban is dosed at 10 mg PO twice daily for the first 7 days, followed by 5 mg PO twice daily for the duration of treatment. For patients continuing on long-term treatment beyond 6 months, consideration can be given to reducing the dose to 2.5 mg PO BID.
# Rivaroxaban (Xarelto®):
Rivaroxaban is an oral anticoagulant that works through direct inhibition of clotting factor Xa. Rivaroxaban is dosed at 15 mg PO twice daily for the first 21 days, followed by 20 mg PO once daily for the duration of treatment. No dosing adjustment is recommended in those with CrCl 15-50 mL/min, however, caution is recommended for those with CrCl 15-30 mL/min. The large randomized trials evaluating rivaroxaban in patients with VTE and atrial fibrillation excluded patients with a CrCl <30 mL/min. Use is not recommended in patients with CrCl <15 mL/min. For patients continuing on long-term treatment beyond 6 months, consideration can be given to reducing the dose to 10 mg PO daily.
# Dabigatran (Pradaxa®):
Dabigatran is an oral anticoagulant that works through direct inhibition of clotting factor IIa (thrombin). Dabigatran requires a 5-to 10-day initial treatment period with a parenteral anticoagulant (usually LMWH). Dabigatran is dosed at 150 mg PO twice daily for the duration of treatment. Dose reduction has not been studied in this setting. Use is contraindicated with CrCl <30 mL/min).
# Edoxaban (Lixiana®):
Edoxaban is an oral anticoagulant that works through direct inhibition of clotting factor Xa. Studies excluded patients with CrCl ˂30 mL/min. Edoxaban requires a 5-to 10-day initial treatment period with a parenteral anticoagulant (usually LMWH). Edoxaban is dosed at 60 mg (or 30 mg in those with CrCl 30-50 mL/min, body weight less than or equal to 60 kg, or concomitant use of P-gp inhibitors) PO once daily for the duration of treatment. In patients with severe renal insufficiency (CrCl <30 mL/min), LMWH is generally avoided because of its dependence on renal clearance. However, for tinzaparin, available evidence demonstrates no accumulation in patients with CrCl down to 20 mL/min. There are limited data available in patients with an estimated CrCl <20 mL/min. Guidelines recommend against testing trough anti-factor Xa levels to monitor for accumulation to guide dose adjustment. Instead, the provider should consider product label-dose adjustments or switching to unfractionated heparin (UFH) due to a lack of good data showing a correlation between these levels and bleeding outcomes. Consultation in these cases with a hematologist or thrombosis expert is recommended.
# Unfractionated Heparin (UFH)
UFH use in the treatment of DVT is limited by a narrow therapeutic range, inter-individual variation in anticoagulant effect, need for laboratory monitoring, and the increased risk of HIT. The use of UFH should be limited to: (1) patients with severe renal insufficiency (CrCl <30 mL/min), in whom LMWHs should generally be avoided;
(2) patients at high risk for bleeding, in whom rapid reversal of the anticoagulant effect may be needed; and (3) patients who develop DVT within close time proximity to also receiving thrombolytic therapy.
If used intravenously, UFH should be given with an initial bolus of 5,000 U (or 80 U/kg), followed by an initial UFH infusion of 18-20 U/kg/hr adjusted to achieve a target activated partial thromboplastin time (aPTT) as defined by the local hospital laboratory. Dosing is best guided using standardized nomograms. If used subcutaneously, UFH dosed at 333 units/kg SC for the initial dose and then 250 units/kg SC twice daily is an alternative that does not require aPTT monitoring.
# Warfarin
Initial treatment with warfarin should be combined with an immediate-acting agent such as LMWH or UFH for at least 5 days and until the INR reaches at least 2.0 for two consecutive days. Initial dosing is best guided by using standardized nomograms; although initial dosing is typically 5 mg once daily, the therapeutic dose is highly variable. The elderly, infirm, and those with a low body weight typically require a lower dose; initial dosing with 2-3 mg daily should be considered. Conversely, relatively young, healthy, and large patients typically require a higher dose, and initial dosing with 7.5-10 mg daily should be considered. Frequent monitoring is required until a stable, in-range INR is reached, after which reduced frequency of testing (e.g. every 2-4 weeks) is appropriate. In suitable patients, point of care home INR testing and patient self-adjustment of warfarin therapy can be considered.
Warfarin is associated with many drug and food interactions that affect INR. Alcohol and a number of health supplements (e.g. St. John's Wort) can also change the INR. Alterations in concomitant medications and new concurrent illness should prompt more frequent INR testing. Patients should not restrict their intake of foods high in vitamin K but should be encouraged to maintain a consistent diet. Low intake of vitamin K can be associated with more unstable INR results.
# DURATION OF THERAPY:
The duration of treatment should be individualized and based on estimated risks of recurrent thrombosis and bleeding as well as the patient's preferences. In general, at least 3 months of anticoagulation is required for all patients. For more details, see the Clinical Guide: Venous Thromboembolism: Duration of Treatment.
# SPECIAL CONSIDERATIONS:
Massive lower extremity DVT:
Massive DVT is defined as iliofemoral thrombosis with severe symptoms, including phlegmasia cerulea dolens (severe cyanosis and swelling of the affected leg). In such patients, treatment with pharmacomechanical or catheter-directed thrombolysis (PCDT) within 14 days of symptom onset should be considered since it rapidly relieves venous obstruction. Two recent trials (ATTRACT, CAVA studies) did not find a significant difference in PTS rate with the use of catheter-directed thrombolysis (either ultrasound-accelerated or pharmacomechanical), though there may be a role for CDT in select patients with large iliofemoral DVT. There were more major bleeds with CDT than with standard therapy. As such this intervention should generally be reserved for low-risk bleeding patients with severe or limbthreatening DVT. Intravenous UFH should be used pre-and post-thrombolytic therapy. As with patients who do not receive PCDT, anticoagulation is indicated following PCDT for at least 3 months.
# Superficial vein thrombosis (SVT):
# Isolated distal DVT:
Isolated distal DVT is defined as thrombus involving the deep venous system of the lower limbs distal to the popliteal vein. In patients with isolated distal DVT, anticoagulation may be withheld in favour of serial imaging (repeat ultrasound once weekly for 2 weeks or sooner with worsening symptoms) to assess for proximal extension, as only 10-15% of distal DVT will extend proximally. This strategy is particularly pertinent for patients with a high risk of bleeding. Anticoagulation is generally suggested if the patient has severe symptoms, has risk factors for extension at initial assessment (thrombus greater than 5 cm in length, involvement of multiple deep veins, close to the popliteal vein, no reversible risk factor, previous VTE, in-patient, active cancer, or positive D-dimer), is unable or unwilling to return for serial studies, or has progression of the DVT on repeat imaging. If treatment is initiated, then the duration of anticoagulation should be least 3 months.
# Date of Version: 14November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide an evidence-based approach to treatment of patients presenting with deep vein thrombosis (DVT).An estimated 45,000 patients in Canada are affected by DVT each year, with an incidence of approximately 1-2 cases per 1,000 persons annually. This translates to 2-4 DVTs per year in a typical, individual, Canadian family practice. Approximately one third of patients with DVT also develop symptomatic pulmonary embolism (PE), one third will suffer from post-thrombotic syndrome (PTS) and one third will have a recurrent DVT or PE within 10 years. Rapid diagnosis and treatment of DVT is essential to prevent these complications. Active malignancy, surgery (especially orthopedic), immobilization, and estrogen use/pregnancy are common transient provoking factors. However, up to 50% of first-time DVT is unprovoked (or "idiopathic").#
• Unless compression ultrasound (CUS) is rapidly available, patients with moderate-to-high suspicion of DVT (except those with a high risk of bleeding) should start anticoagulant therapy before the diagnosis is confirmed. Imaging confirmation should be obtained as soon as possible. • Outpatient management is preferred over hospital-based treatment except for patients with limb threatening DVT, high risk of bleeding, or patients who have additional indication for hospitalization. • Initial treatment should have an immediate anticoagulant effect. Therefore, warfarin monotherapy is not appropriate as a lone initial treatment. • For patients who cannot be therapeutically anticoagulated due to active bleeding or high bleeding risks such as severe liver disease or significant thrombocytopenia, consultation should be initiated with a hematologist or thrombosis specialist. Management may include placement of a retrievable inferior vena cava filter (IVC filter) if therapeutic anticoagulation cannot be safely provided in the acute setting [see Clinical Guide Vena Cava Filter].
# Anticoagulant Agents and Dosing:
In general, choice of anticoagulation in the acute treatment of DVT should take into consideration patient-specific factors. Guidelines recommend direct oral anticoagulant (DOAC) therapy (apixaban or rivaroxaban) or low molecular weight heparin (LMWH) followed by a DOAC (for dabigatran and edoxaban) over VKA therapy EXCEPT for patients with a diagnosis of antiphospholipid syndrome, severe renal impairment, drug interactions (concomitant medications metabolized through the CYP3A4 enzyme or P-glycoprotein), extremes of weight, or conditions that may impair oral absorption.
Other factors that should influence choice of anticoagulant include the requirement for lead in parenteral therapy prior to specific DOACs such as Dabigatran or Edoxaban, cost, once daily vs twice daily dosing, and patient preference.
LMWH is an option to be used as monotherapy for the full duration of treatment in patients with active cancer and those with DVT in pregnancy. Large phase 3 studies have demonstrated the efficacy and safety of these agents for the initial (apixaban and rivaroxaban) treatment of DVT, as well as for acute and extended treatment (all agents). Four DOACs have been approved in Canada for the treatment of patients with DVT. An initial 5-to 10-day course of LMWH is required prior to starting dabigatran and edoxaban but not with rivaroxaban and apixaban.
DOACs should not be used in pregnant or breastfeeding women or in those with severe renal dysfunction [see Clinical Guides for Apixaban (Eliquis®), Rivaroxaban (Xarelto®), Dabigatran (Pradaxa®), and Edoxaban (Lixiana®)].
# Apixaban (Eliquis®):
Apixaban is an oral anticoagulant that works through direct inhibition of clotting factor Xa. Apixaban should be used with caution in patients with a creatinine clearance (CrCl) 15-29 mL/min) and is not recommended in those with a CrCl <15 mL/min or undergoing dialysis. The large randomized trials evaluating apixaban in patients with VTE and atrial fibrillation excluded patients with a CrCl <25 mL/min. Apixaban is dosed at 10 mg PO twice daily for the first 7 days, followed by 5 mg PO twice daily for the duration of treatment. For patients continuing on long-term treatment beyond 6 months, consideration can be given to reducing the dose to 2.5 mg PO BID.
# Rivaroxaban (Xarelto®):
Rivaroxaban is an oral anticoagulant that works through direct inhibition of clotting factor Xa. Rivaroxaban is dosed at 15 mg PO twice daily for the first 21 days, followed by 20 mg PO once daily for the duration of treatment. No dosing adjustment is recommended in those with CrCl 15-50 mL/min, however, caution is recommended for those with CrCl 15-30 mL/min. The large randomized trials evaluating rivaroxaban in patients with VTE and atrial fibrillation excluded patients with a CrCl <30 mL/min. Use is not recommended in patients with CrCl <15 mL/min. For patients continuing on long-term treatment beyond 6 months, consideration can be given to reducing the dose to 10 mg PO daily.
# Dabigatran (Pradaxa®):
Dabigatran is an oral anticoagulant that works through direct inhibition of clotting factor IIa (thrombin). Dabigatran requires a 5-to 10-day initial treatment period with a parenteral anticoagulant (usually LMWH). Dabigatran is dosed at 150 mg PO twice daily for the duration of treatment. Dose reduction has not been studied in this setting. Use is contraindicated with CrCl <30 mL/min).
# Edoxaban (Lixiana®):
Edoxaban is an oral anticoagulant that works through direct inhibition of clotting factor Xa. Studies excluded patients with CrCl ˂30 mL/min. Edoxaban requires a 5-to 10-day initial treatment period with a parenteral anticoagulant (usually LMWH). Edoxaban is dosed at 60 mg (or 30 mg in those with CrCl 30-50 mL/min, body weight less than or equal to 60 kg, or concomitant use of P-gp inhibitors) PO once daily for the duration of treatment. In patients with severe renal insufficiency (CrCl <30 mL/min), LMWH is generally avoided because of its dependence on renal clearance. However, for tinzaparin, available evidence demonstrates no accumulation in patients with CrCl down to 20 mL/min. There are limited data available in patients with an estimated CrCl <20 mL/min. Guidelines recommend against testing trough anti-factor Xa levels to monitor for accumulation to guide dose adjustment. Instead, the provider should consider product label-dose adjustments or switching to unfractionated heparin (UFH) due to a lack of good data showing a correlation between these levels and bleeding outcomes. Consultation in these cases with a hematologist or thrombosis expert is recommended.
# Unfractionated Heparin (UFH) [See Clinical Guide Unfractionated Heparin, Low molecular weight heparin, and Fondaparinux]
UFH use in the treatment of DVT is limited by a narrow therapeutic range, inter-individual variation in anticoagulant effect, need for laboratory monitoring, and the increased risk of HIT. The use of UFH should be limited to: (1) patients with severe renal insufficiency (CrCl <30 mL/min), in whom LMWHs should generally be avoided;
(2) patients at high risk for bleeding, in whom rapid reversal of the anticoagulant effect may be needed; and (3) patients who develop DVT within close time proximity to also receiving thrombolytic therapy.
If used intravenously, UFH should be given with an initial bolus of 5,000 U (or 80 U/kg), followed by an initial UFH infusion of 18-20 U/kg/hr adjusted to achieve a target activated partial thromboplastin time (aPTT) as defined by the local hospital laboratory. Dosing is best guided using standardized nomograms. If used subcutaneously, UFH dosed at 333 units/kg SC for the initial dose and then 250 units/kg SC twice daily is an alternative that does not require aPTT monitoring.
# Warfarin [See Clinical Guide Warfarin]
Initial treatment with warfarin should be combined with an immediate-acting agent such as LMWH or UFH for at least 5 days and until the INR reaches at least 2.0 for two consecutive days. Initial dosing is best guided by using standardized nomograms; although initial dosing is typically 5 mg once daily, the therapeutic dose is highly variable. The elderly, infirm, and those with a low body weight typically require a lower dose; initial dosing with 2-3 mg daily should be considered. Conversely, relatively young, healthy, and large patients typically require a higher dose, and initial dosing with 7.5-10 mg daily should be considered. Frequent monitoring is required until a stable, in-range INR is reached, after which reduced frequency of testing (e.g. every 2-4 weeks) is appropriate. In suitable patients, point of care home INR testing and patient self-adjustment of warfarin therapy can be considered.
Warfarin is associated with many drug and food interactions that affect INR. Alcohol and a number of health supplements (e.g. St. John's Wort) can also change the INR. Alterations in concomitant medications and new concurrent illness should prompt more frequent INR testing. Patients should not restrict their intake of foods high in vitamin K but should be encouraged to maintain a consistent diet. Low intake of vitamin K can be associated with more unstable INR results.
# DURATION OF THERAPY: [See Clinical Guide Venous Thromboembolism: Duration of Treatment]
The duration of treatment should be individualized and based on estimated risks of recurrent thrombosis and bleeding as well as the patient's preferences. In general, at least 3 months of anticoagulation is required for all patients. For more details, see the Clinical Guide: Venous Thromboembolism: Duration of Treatment.
# SPECIAL CONSIDERATIONS:
Massive lower extremity DVT:
Massive DVT is defined as iliofemoral thrombosis with severe symptoms, including phlegmasia cerulea dolens (severe cyanosis and swelling of the affected leg). In such patients, treatment with pharmacomechanical or catheter-directed thrombolysis (PCDT) within 14 days of symptom onset should be considered since it rapidly relieves venous obstruction. Two recent trials (ATTRACT, CAVA studies) did not find a significant difference in PTS rate with the use of catheter-directed thrombolysis (either ultrasound-accelerated or pharmacomechanical), though there may be a role for CDT in select patients with large iliofemoral DVT. There were more major bleeds with CDT than with standard therapy. As such this intervention should generally be reserved for low-risk bleeding patients with severe or limbthreatening DVT. Intravenous UFH should be used pre-and post-thrombolytic therapy. As with patients who do not receive PCDT, anticoagulation is indicated following PCDT for at least 3 months.
[
# Superficial vein thrombosis (SVT):
[See Clinical Guide Superficial Thrombophlebitis, Superficial Vein Thrombosis]
# Isolated distal DVT:
Isolated distal DVT is defined as thrombus involving the deep venous system of the lower limbs distal to the popliteal vein. In patients with isolated distal DVT, anticoagulation may be withheld in favour of serial imaging (repeat ultrasound once weekly for 2 weeks or sooner with worsening symptoms) to assess for proximal extension, as only 10-15% of distal DVT will extend proximally. This strategy is particularly pertinent for patients with a high risk of bleeding. Anticoagulation is generally suggested if the patient has severe symptoms, has risk factors for extension at initial assessment (thrombus greater than 5 cm in length, involvement of multiple deep veins, close to the popliteal vein, no reversible risk factor, previous VTE, in-patient, active cancer, or positive D-dimer), is unable or unwilling to return for serial studies, or has progression of the DVT on repeat imaging. If treatment is initiated, then the duration of anticoagulation should be least 3 months.
# Date of Version: 14November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
4286af020ad5ffe04cc8c8c3be91e49aa0dea936 | cma | None | To assist practitioners in managing patients with a suspected or confirmed deficiency in protein C, protein S or antithrombin (AT), in consultation with a thrombosis specialist.Protein C, protein S and AT are endogenous anticoagulants that help maintain hemostatic equilibrium. Deficiency in protein C, protein S or AT is associated with a prothrombotic state that leads to an increased risk for venous thromboembolism (VTE), mainly deep vein thrombosis (DVT) or pulmonary embolism (PE). Increased risk of arterial thrombosis has not been clearly established. Limited and weak data suggest that protein C or S deficiency might be associated with a slightly increased risk of arterial stroke, particularly in young adults; however, the clinical significance of this finding is not clear. A deficiency in protein C, protein S or AT can be inherited (as autosomal dominant traits), although such conditions are uncommon, occurring in 1 in 300 to 1 in 3000 people in the general population and in <5% of patients presenting with unprovoked (or idiopathic) DVT or PE. Acquired deficiencies of protein C, protein S, and AT are more common. For example, protein S levels are decreased during pregnancy and the post-partum period and in oral contraceptive users. Because protein C and protein S are dependent on vitamin K for their synthesis, their levels are reduced in patients who are receiving a vitamin K antagonist such as warfarin. A deficiency in AT can occur in patients with nephrotic syndrome and in those receiving L-asparaginase chemotherapy. Finally, deficiencies in all these proteins occur in patients with advanced liver disease and may occur in the presence of extensive, acute thrombosis.# WHEN SHOULD PATIENTS BE INVESTIGATED FOR A DEFICIENCY IN PROTEIN C, PROTEIN S AND AT?
Specialist advice should be sought before considering testing patients with DVT or PE for any thrombophilia. The reason for this conservative approach is that a confirmed positive test rarely affects patient management and may lead to inappropriate duration of therapy or inappropriate testing of relatives; a negative result may provide false reassurance as to the future risk of recurrence or the risk of a first DVT or PE in relatives. In addition, diagnosed deficiencies in clinically unaffected relatives may adversely affect the way they think about their health and may affect their life and disability insurance status.
# WHICH PATIENTS SHOULD NOT BE INVESTIGATED FOR A DEFICIENCY IN PROTEIN C, PROTEIN S OR AT?
- Most patients with VTE, even in unusual sites unless discussed with experts.
- Patients with thrombosis and a clinically identifiable provoking risk factor (e.g. surgery).
- Patients with arterial thrombosis, ischemic stroke or myocardial infarction.
- Patients with an acute DVT or PE (or with another acute illness), since they may have decreased protein C, protein S and AT levels in the acute setting, leading to the incorrect assumption that the patient has a deficiency.
- Patients already on anticoagulant therapy: o In those receiving a vitamin K antagonist such as warfarin, protein C and protein S levels will be substantially decreased, leading to the incorrect assumption that the patient has a deficiency. o In patients who are taking direct oral anticoagulants (DOACs), functional assays for protein C, protein S and AT may be impacted, thus rendering these tests inaccurate. o In patients who are taking unfractionated heparin (UFH), low molecular weight heparin (LMWH) or fondaparinux, antithrombin levels may be falsely low. - Women who are pregnant, postpartum, or taking an oral contraceptive, since they will have mildly to moderately decreased protein S levels.
# WHAT IF A PATIENT HAS A DEFICIENCY OF PROTEIN C, PROTEIN S OR AT (WITHOUT THROMBOSIS)?
- A provisional diagnosis of a deficiency in protein C, protein S and AT should be made in consultation with a specialist because of the potential for misdiagnosis due to false positive test results and the need for evidence-based patient and family counseling. - In a patient who is confirmed to have a deficiency of protein C, protein S or AT and has not had thrombosis, appropriate patient counseling should be given including risks of future VTE, symptoms of possible VTE, and the effect of pregnancy, oral contraceptive use, etc. on the risk of thrombosis. - In patients with protein C, protein S or AT deficiency, specialist advice should be sought related to thromboprophylaxis if there are situations of increased risk such as trauma, surgery or pregnancy.
# HOW TO MANAGE PATIENTS WITH THROMBOSIS AND A DEFICIENCY IN PROTEIN C, PROTEIN S OR AT:
In patients who develop acute DVT or PE and have a known deficiency in protein C, protein S or AT, consultation with a specialist is advised. The initial anticoagulant treatment is generally similar to that of patients who do not have a deficiency of protein C, protein S or AT, with important caveats indicated below. As in other patients, the duration of anticoagulation depends on the presence or absence of a provoking factor. Treatment duration is at least 3 months and, in many patients, longterm.
- AT deficiency: Since the anticoagulant action of UFH, LMWH and fondaparinux depends on inhibiting AT, patients with AT deficiency may be resistant to usual doses of these anticoagulants and, therefore, may require higher doses. This would be evident, for example, when the activated partial thromboplastin time (aPTT) is not prolonged despite usually adequate doses of UFH. The anti-Xa activity of UFH and LMWH can be reduced in patients with antithrombin deficiency. Alternative anticoagulants that are independent of AT (e.g. argatroban or direct oral anticoagulants ) may be considered. - Protein C deficiency: Acute DVT or PE can be managed with LMWH/UFH/fondaparinux and warfarin, as in patients without protein C deficiency. However, warfarin routinely reduces protein C levels. In patients who have protein C deficiency, warfarin will further reduce protein C levels quickly and this may produce a prothrombotic state that can lead to warfarin-induced skin necrosis. Therefore, initial treatment with LMWH/UFH/fondaparinux must overlap with warfarin for at least 5 days and until the international normalized ratio (INR) is ≥2.0 for at least two consecutive days before stopping the LMWH/UFH/fondaparinux. In patients with protein C deficiency, warfarin should not be started without coverage with a rapidly acting anticoagulant such as LMWH or UFH or fondaparinux. Loading doses of warfarin should not be used. - Protein S deficiency: Treatment of acute thrombosis is like that of protein C deficiency.
Given the low frequency of protein C, protein S and AT deficiency in the population, experience with DOACs in affected individuals is limited and the literature to limited mostly to case reports and posthoc analyses of clinical trials. One small nonrandomized study reported no adverse thrombotic events with DOAC use in 45 patients with a major thrombophilia and venous thromboembolism.
# HOW TO MANAGE PATIENTS WITH A DEFICIENCY OF PROTEIN C, PROTEIN S OR AT WHO NEED SURGERY:
Patients with these deficiencies may be at higher risk for perioperative VTE. In all such patients, consultation with a specialist is advised to provide appropriate thrombosis prophylaxis. In selected patients with AT deficiency, AT concentrate can be used to raise AT levels around the time of surgery. AT concentrate may also be used in selected patients with AT deficiency during pregnancy to prevent DVT or PE. Protein C concentrate is also available but there is no protein S concentrate.
# PEDIATRICS:
Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with thromboembolism and those with deficiencies of protein C, protein S or AT. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
# PREGNANCY:
See the Clinical Guide Pregnancy: Thromboprophylaxis for information about the prevention of pregnancy associated VTE in women with a deficiency of Protein C, Protein S or AT.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Pregnancy: Thromboprophylaxis
# REFERENCES:
Chiasakul T, et al. Inherited thrombophilia and the risk of arterial ischemic stroke: a systematic review and meta-analysis. J Am Heart Assoc 2019;8( 19
# Date of Version: 03July2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To assist practitioners in managing patients with a suspected or confirmed deficiency in protein C, protein S or antithrombin (AT), in consultation with a thrombosis specialist.Protein C, protein S and AT are endogenous anticoagulants that help maintain hemostatic equilibrium. Deficiency in protein C, protein S or AT is associated with a prothrombotic state that leads to an increased risk for venous thromboembolism (VTE), mainly deep vein thrombosis (DVT) or pulmonary embolism (PE). Increased risk of arterial thrombosis has not been clearly established. Limited and weak data suggest that protein C or S deficiency might be associated with a slightly increased risk of arterial stroke, particularly in young adults; however, the clinical significance of this finding is not clear. A deficiency in protein C, protein S or AT can be inherited (as autosomal dominant traits), although such conditions are uncommon, occurring in 1 in 300 to 1 in 3000 people in the general population and in <5% of patients presenting with unprovoked (or idiopathic) DVT or PE. Acquired deficiencies of protein C, protein S, and AT are more common. For example, protein S levels are decreased during pregnancy and the post-partum period and in oral contraceptive users. Because protein C and protein S are dependent on vitamin K for their synthesis, their levels are reduced in patients who are receiving a vitamin K antagonist such as warfarin. A deficiency in AT can occur in patients with nephrotic syndrome and in those receiving L-asparaginase chemotherapy. Finally, deficiencies in all these proteins occur in patients with advanced liver disease and may occur in the presence of extensive, acute thrombosis.# WHEN SHOULD PATIENTS BE INVESTIGATED FOR A DEFICIENCY IN PROTEIN C, PROTEIN S AND AT?
Specialist advice should be sought before considering testing patients with DVT or PE for any thrombophilia. The reason for this conservative approach is that a confirmed positive test rarely affects patient management and may lead to inappropriate duration of therapy or inappropriate testing of relatives; a negative result may provide false reassurance as to the future risk of recurrence or the risk of a first DVT or PE in relatives. In addition, diagnosed deficiencies in clinically unaffected relatives may adversely affect the way they think about their health and may affect their life and disability insurance status.
# WHICH PATIENTS SHOULD NOT BE INVESTIGATED FOR A DEFICIENCY IN PROTEIN C, PROTEIN S OR AT?
• Most patients with VTE, even in unusual sites unless discussed with experts.
• Patients with thrombosis and a clinically identifiable provoking risk factor (e.g. surgery).
• Patients with arterial thrombosis, ischemic stroke or myocardial infarction.
• Patients with an acute DVT or PE (or with another acute illness), since they may have decreased protein C, protein S and AT levels in the acute setting, leading to the incorrect assumption that the patient has a deficiency.
• Patients already on anticoagulant therapy: o In those receiving a vitamin K antagonist such as warfarin, protein C and protein S levels will be substantially decreased, leading to the incorrect assumption that the patient has a deficiency. o In patients who are taking direct oral anticoagulants (DOACs), functional assays for protein C, protein S and AT may be impacted, thus rendering these tests inaccurate. o In patients who are taking unfractionated heparin (UFH), low molecular weight heparin (LMWH) or fondaparinux, antithrombin levels may be falsely low. • Women who are pregnant, postpartum, or taking an oral contraceptive, since they will have mildly to moderately decreased protein S levels.
# WHAT IF A PATIENT HAS A DEFICIENCY OF PROTEIN C, PROTEIN S OR AT (WITHOUT THROMBOSIS)?
• A provisional diagnosis of a deficiency in protein C, protein S and AT should be made in consultation with a specialist because of the potential for misdiagnosis due to false positive test results and the need for evidence-based patient and family counseling. • In a patient who is confirmed to have a deficiency of protein C, protein S or AT and has not had thrombosis, appropriate patient counseling should be given including risks of future VTE, symptoms of possible VTE, and the effect of pregnancy, oral contraceptive use, etc. on the risk of thrombosis. • In patients with protein C, protein S or AT deficiency, specialist advice should be sought related to thromboprophylaxis if there are situations of increased risk such as trauma, surgery or pregnancy.
# HOW TO MANAGE PATIENTS WITH THROMBOSIS AND A DEFICIENCY IN PROTEIN C, PROTEIN S OR AT:
In patients who develop acute DVT or PE and have a known deficiency in protein C, protein S or AT, consultation with a specialist is advised. The initial anticoagulant treatment is generally similar to that of patients who do not have a deficiency of protein C, protein S or AT, with important caveats indicated below. As in other patients, the duration of anticoagulation depends on the presence or absence of a provoking factor. Treatment duration is at least 3 months and, in many patients, longterm.
• AT deficiency: Since the anticoagulant action of UFH, LMWH and fondaparinux depends on inhibiting AT, patients with AT deficiency may be resistant to usual doses of these anticoagulants and, therefore, may require higher doses. This would be evident, for example, when the activated partial thromboplastin time (aPTT) is not prolonged despite usually adequate doses of UFH. The anti-Xa activity of UFH and LMWH can be reduced in patients with antithrombin deficiency. Alternative anticoagulants that are independent of AT (e.g. argatroban or direct oral anticoagulants [DOACs]) may be considered. • Protein C deficiency: Acute DVT or PE can be managed with LMWH/UFH/fondaparinux and warfarin, as in patients without protein C deficiency. However, warfarin routinely reduces protein C levels. In patients who have protein C deficiency, warfarin will further reduce protein C levels quickly and this may produce a prothrombotic state that can lead to warfarin-induced skin necrosis. Therefore, initial treatment with LMWH/UFH/fondaparinux must overlap with warfarin for at least 5 days and until the international normalized ratio (INR) is ≥2.0 for at least two consecutive days before stopping the LMWH/UFH/fondaparinux. In patients with protein C deficiency, warfarin should not be started without coverage with a rapidly acting anticoagulant such as LMWH or UFH or fondaparinux. Loading doses of warfarin should not be used. • Protein S deficiency: Treatment of acute thrombosis is like that of protein C deficiency.
Given the low frequency of protein C, protein S and AT deficiency in the population, experience with DOACs in affected individuals is limited and the literature to limited mostly to case reports and posthoc analyses of clinical trials. One small nonrandomized study reported no adverse thrombotic events with DOAC use in 45 patients with a major thrombophilia and venous thromboembolism.
# HOW TO MANAGE PATIENTS WITH A DEFICIENCY OF PROTEIN C, PROTEIN S OR AT WHO NEED SURGERY:
Patients with these deficiencies may be at higher risk for perioperative VTE. In all such patients, consultation with a specialist is advised to provide appropriate thrombosis prophylaxis. In selected patients with AT deficiency, AT concentrate can be used to raise AT levels around the time of surgery. AT concentrate may also be used in selected patients with AT deficiency during pregnancy to prevent DVT or PE. Protein C concentrate is also available but there is no protein S concentrate.
# PEDIATRICS:
Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with thromboembolism and those with deficiencies of protein C, protein S or AT. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
# PREGNANCY:
See the Clinical Guide Pregnancy: Thromboprophylaxis for information about the prevention of pregnancy associated VTE in women with a deficiency of Protein C, Protein S or AT.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Pregnancy: Thromboprophylaxis
# REFERENCES:
Chiasakul T, et al. Inherited thrombophilia and the risk of arterial ischemic stroke: a systematic review and meta-analysis. J Am Heart Assoc 2019;8( 19
# Date of Version: 03July2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
c6bfa5e9d2d9948e0033966743a1e29662385c1b | cma | None | This progression of lung disease accounts for the bulk of morbidity and mortality (approximately 50% of adults have a Forced Expiratory Volume in 1 second <70%). The underlying lung disease complicated by difficult-to-treat infecting organisms is the primary reason for COVID-19 vulnerability. Other reasons for COVID-19 susceptibility and poor outcomes in people with CF: - Diabetes mellitus: Present in approximately 40% of adults with CF (dysglycemia is present in approximately 65%), and has been shown to be an independent factor for worse outcomes with COVID-19 infection. - Nutritional deficiency: Approximately 85% of people with CF are pancreatic insufficient, with resultant undernutrition in a large proportion of adults with CF. - Chronic liver disease: Affects approximately 30% of people with CF.#
- Post-transplantation: In Canada, around 1,500 people with CF have received solid organ transplants (predominantly lung) since 2019. People who have received a solid organ transplant take immunosuppressant medications, which are believed to increase risk of serious disease from COVID-19 infection.
There is a growing evidence base available to understand the risk related to COVID-19 infection in people with CF. A recent publication based on data obtained prior to the introduction of COVID-19 vaccines from 22 countries reported on 1452 individuals with CF and confirmed COVID-19 infection. Of those included in the study, 1 in 5 patients required hospitalization, 1 in 30 required intensive care unit (ICU) admission, and 1 in 75 died. 1 Among non-transplanted individuals, worse outcomes were reported for those of older age, non-white race, lower lung function, low body mass index, and concomitant diabetes; this provides direct support for the postulated comorbidities/clinical features listed above. The CF Registry Global Harmonization Group published findings from a global study on the impact of COVID-19 on children with CF. 2 The study included 105 children with CF under the age of 18 from 13 countries; while infection was mild in most cases, a higher number of hospitalizations was noted in individuals with pre-existing advanced lung disease or poor nutrition. 3 Impact of respiratory viruses in people with CF extrapolated from other data People with CF commonly experience infections with a number of respiratory viruses including influenza, adenovirus, respiratory syncytial virus (RSV), enteroviruses, and rhinoviruses. These infections are a common cause of pulmonary exacerbations (estimated at >50%), which drive symptom morbidity and hospitalizations, accelerate lung function decline, and increase mortality. Viral infections may also be associated with acquisition of Pseudomonas aeruginosa pulmonary infection, which is independently associated with the aforementioned negative outcomes.
A previous meta-analysis showed that 50 to 70% of people with CF testing positive for influenza A (H1N1) required hospitalization, as compared to 7 to 20% of the general population. 4 Approximately 40% of patients never recover to their previous baseline lung function after a CF pulmonary exacerbation.
There is every reason to implicate SARS-CoV-2 infection with similar, if not greater, adverse events. Individuals with other chronic lung diseases also are negatively impacted by viral infections, including chronic obstructive pulmonary disease, severe asthma, and bronchiectasis. Although high-quality evidence is not available, influenza immunization is routinely recommended for people with CF worldwide.
Is the COVID-19 vaccine efficacious and safe for people with CF?
As CF is considered to be a severe underlying medical condition, people with CF were excluded from the Pfizer-BioNTech, Moderna, and AstraZeneca COVID-19 vaccine trials. Data is currently limited as to whether COVID-19 vaccines are as efficacious for people with CF as they were found to be for the clinical trial participants. There are data to suggest that the currently available COVID-19 vaccines have efficacy 5 and there is no reason to believe that the antibody response to immunization should be lower in CF compared to the general population.
CF transmembrane conductance regulator (CFTR) gene mutations, which are the cause of CF, do not have clinically relevant impacts on the host and innate immunity. There is no evidence of blunted immune response to other immunizations (e.g., influenza), and immunizations are a routine part of CF care. As well, the relatively younger age of people with CF supports a robust immunological response (65 years of age).
# COVID-19 Vaccines for People with Cystic Fibrosis
Updated: April 18, 2023 3
People with CF are most often not on maintenance/routine medications that would potentially blunt an immune response to immunization (e.g., oral corticosteroids or immunosuppressive therapies). If a patient has received a lung transplant or other solid organ transplant, please refer to the respective clinical guidance for these individuals.
There is no reason to believe that there are specific safety concerns for immunization in people with CF. A study involving 424 people with CF from Italy aged 12 years and older demonstrated that mRNA-based vaccines against SARS-CoV-2 were well-tolerated and safe in the short-term. 6 Individuals with CF invariably have chronic lung disease, some more severe in nature. Therefore, if there was an anaphylactic reaction, there is the potential for more severe symptoms and complications. This would be similar to other patient populations with advanced lung disease (but perhaps less so in CF, as cardiovascular comorbidities are generally not present). As such, it is recommended that healthcare providers counseling people with CF follow the allergy contraindications and advice provided below closely, particularly for people with CF with most severe lung disease (i.e., FEV1 <40% predicted).
Are there any specific contraindications or exceptions for people with CF?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 7 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
People with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, revaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If revaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after revaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Otherwise, there are no specific contraindications or exceptions for people with CF from a disease perspective.
COVID-19 vaccines can be given concomitantly with, or any time before or after any other live or inactivated vaccine. Are there specific recommendations or considerations for safe and/or most effective administration?
Out of abundance of caution, it is recommended that immunization be delayed in the following circumstances: o If the patient is currently undergoing treatment, including antibiotics for a pulmonary exacerbation of CF; o If patient is hospitalized for a CF-related complication like a bowel obstruction or acute pancreatitis. | This progression of lung disease accounts for the bulk of morbidity and mortality (approximately 50% of adults have a Forced Expiratory Volume in 1 second [FEV1] <70%). The underlying lung disease complicated by difficult-to-treat infecting organisms is the primary reason for COVID-19 vulnerability. Other reasons for COVID-19 susceptibility and poor outcomes in people with CF: • Diabetes mellitus: Present in approximately 40% of adults with CF (dysglycemia is present in approximately 65%), and has been shown to be an independent factor for worse outcomes with COVID-19 infection. • Nutritional deficiency: Approximately 85% of people with CF are pancreatic insufficient, with resultant undernutrition in a large proportion of adults with CF. • Chronic liver disease: Affects approximately 30% of people with CF.#
• Post-transplantation: In Canada, around 1,500 people with CF have received solid organ transplants (predominantly lung) since 2019. People who have received a solid organ transplant take immunosuppressant medications, which are believed to increase risk of serious disease from COVID-19 infection.
There is a growing evidence base available to understand the risk related to COVID-19 infection in people with CF. A recent publication based on data obtained prior to the introduction of COVID-19 vaccines from 22 countries reported on 1452 individuals with CF and confirmed COVID-19 infection. Of those included in the study, 1 in 5 patients required hospitalization, 1 in 30 required intensive care unit (ICU) admission, and 1 in 75 died. 1 Among non-transplanted individuals, worse outcomes were reported for those of older age, non-white race, lower lung function, low body mass index, and concomitant diabetes; this provides direct support for the postulated comorbidities/clinical features listed above. The CF Registry Global Harmonization Group published findings from a global study on the impact of COVID-19 on children with CF. 2 The study included 105 children with CF under the age of 18 from 13 countries; while infection was mild in most cases, a higher number of hospitalizations was noted in individuals with pre-existing advanced lung disease or poor nutrition. 3 Impact of respiratory viruses in people with CF extrapolated from other data People with CF commonly experience infections with a number of respiratory viruses including influenza, adenovirus, respiratory syncytial virus (RSV), enteroviruses, and rhinoviruses. These infections are a common cause of pulmonary exacerbations (estimated at >50%), which drive symptom morbidity and hospitalizations, accelerate lung function decline, and increase mortality. Viral infections may also be associated with acquisition of Pseudomonas aeruginosa pulmonary infection, which is independently associated with the aforementioned negative outcomes.
A previous meta-analysis showed that 50 to 70% of people with CF testing positive for influenza A (H1N1) required hospitalization, as compared to 7 to 20% of the general population. 4 Approximately 40% of patients never recover to their previous baseline lung function after a CF pulmonary exacerbation.
There is every reason to implicate SARS-CoV-2 infection with similar, if not greater, adverse events. Individuals with other chronic lung diseases also are negatively impacted by viral infections, including chronic obstructive pulmonary disease, severe asthma, and bronchiectasis. Although high-quality evidence is not available, influenza immunization is routinely recommended for people with CF worldwide.
Is the COVID-19 vaccine efficacious and safe for people with CF?
As CF is considered to be a severe underlying medical condition, people with CF were excluded from the Pfizer-BioNTech, Moderna, and AstraZeneca COVID-19 vaccine trials. Data is currently limited as to whether COVID-19 vaccines are as efficacious for people with CF as they were found to be for the clinical trial participants. There are data to suggest that the currently available COVID-19 vaccines have efficacy 5 and there is no reason to believe that the antibody response to immunization should be lower in CF compared to the general population.
CF transmembrane conductance regulator (CFTR) gene mutations, which are the cause of CF, do not have clinically relevant impacts on the host and innate immunity. There is no evidence of blunted immune response to other immunizations (e.g., influenza), and immunizations are a routine part of CF care. As well, the relatively younger age of people with CF supports a robust immunological response (<5% of patients are >65 years of age).
# COVID-19 Vaccines for People with Cystic Fibrosis
Updated: April 18, 2023 3
People with CF are most often not on maintenance/routine medications that would potentially blunt an immune response to immunization (e.g., oral corticosteroids or immunosuppressive therapies). If a patient has received a lung transplant or other solid organ transplant, please refer to the respective clinical guidance for these individuals.
There is no reason to believe that there are specific safety concerns for immunization in people with CF. A study involving 424 people with CF from Italy aged 12 years and older demonstrated that mRNA-based vaccines against SARS-CoV-2 were well-tolerated and safe in the short-term. 6 Individuals with CF invariably have chronic lung disease, some more severe in nature. Therefore, if there was an anaphylactic reaction, there is the potential for more severe symptoms and complications. This would be similar to other patient populations with advanced lung disease (but perhaps less so in CF, as cardiovascular comorbidities are generally not present). As such, it is recommended that healthcare providers counseling people with CF follow the allergy contraindications and advice provided below closely, particularly for people with CF with most severe lung disease (i.e., FEV1 <40% predicted).
Are there any specific contraindications or exceptions for people with CF?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 7 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
People with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, revaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If revaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after revaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Otherwise, there are no specific contraindications or exceptions for people with CF from a disease perspective.
COVID-19 vaccines can be given concomitantly with, or any time before or after any other live or inactivated vaccine. [8][9][10][11] Are there specific recommendations or considerations for safe and/or most effective administration?
Out of abundance of caution, it is recommended that immunization be delayed in the following circumstances: o If the patient is currently undergoing treatment, including antibiotics for a pulmonary exacerbation of CF; o If patient is hospitalized for a CF-related complication like a bowel obstruction or acute pancreatitis. | None | None |
f76201d7076b27693eb8a2f0e92a98a60f3a224a | cma | None | To summarize evidence-based recommendations for the management of antithrombotic drugs in patients with surgical valve replacement (mechanical and bioprosthetic heart valves) and transaortic valve replacement (TAVR or TAVI).Surgical heart valve replacement (SAVR) can be done with either a bioprosthetic (tissue) or mechanical prosthesis. TAVI or TAVR is undertaken in a heart catheterization lab and the prosthetic aortic valve is deployed via catheter without an open-heart surgical sternotomy. Mitral valve replacement with a transcatheter approach is not currently available.# Bioprosthetic Valves
Long-term anticoagulation for patients with bioprosthetic valves is not indicated as the risk of thrombosis and thromboembolism is low (about 0.2%/year):
- In patients with a bioprosthetic mitral valve who are in sinus rhythm and have no other indications for anticoagulant therapy, 3 to 6 months of warfarin therapy (international normalized ratio target: 2.5) after valve replacement is suggested, to be followed by long-term acetylsalicylic acid (ASA) 81 mg daily. - In patients with a bioprosthetic aortic valve who are in sinus rhythm and have no other indications for anticoagulant therapy long-term ASA 81 mg daily may be considered for patients with low bleeding risk after 3 to 6 months of warfarin therapy (INR target: 2.5). - Patients with a bioprosthetic valve and atrial fibrillation should be considered for long-term anticoagulant therapy as outlined in the Clinical Guide, Stroke Prevention in Atrial Fibrillation.
# Mechanical Valves
There are 3 basic types of mechanical valves: 1. Bileaflet (e.g. On-X, St. Judes, most frequently seen today) 2. Tilting disc (e.g. Bjork-Shiley, infrequently seen today) 3. Ball-cage (e.g. Starr-Edwards, rarely seen today)
Patients with mechanical heart valves are at increased risk for embolic stroke and thrombosis of the valve itself and, therefore, require long-term anticoagulation. Even with anticoagulation, the risk of stroke/valve thrombosis is ~0.9%/year with mechanical mitral valves, ~0.5%/year for mechanical aortic valves, and ~1.2%/year in those with two mechanical valves.
In selecting the optimal anticoagulation for patients with a mechanical heart valve, it is also important to consider the risk of bleeding, the different INR targets depending on valve type and location, and the need for bridging anticoagulant therapy for surgical procedures.
On-X aortic mechanical valve implant has design features and construction materials thought to reduce thrombogenicity and flow turbulence compared to other valve designs; theoretically allowing a lower intensity INR target range to protect from valve thrombosis that could result in a lower rate of anticoagulant associated major bleeding. The safety of this lower target range INR (1.5 to 2.0) compared to the traditional target range INR (2.0 to 3.0) following placement of the On-X aortic valve implant was evaluated in the PROACT study. Patients with at least one additional risk factor for stroke were randomized after 3 months of warfarin anticoagulation with an INR target of 2.5 to either the lower INR target range or to continue with the traditional INR target range. All subjects received concurrent low dose ASA 81 mg/day. Follow up was planned for 5 to 8 yrs. Interim results of this trial published in 2014 with an average follow up of 3.8 years reported that the subjects in the lower INR target range group had a significantly lower rate of major bleeding compared to those in the traditional INR target range group (1.48% per year vs 3.26 % per year). There was no difference between the groups on the endpoints of stroke, transient ischemic attack, total neurological events and all-cause mortality. In the 2017 Focused Update of the Valvular Heart Disease Guidelines, the American College of Cardiology made a weak (class IIb) recommendation based on a single moderate quality randomized clinical trial that a lower target INR range of 1.5 to 2.0 plus ASA 81 mg/day may be reasonable after 3 months of an INR target of 2.5 (2.0 to 3.0).
# Transaortic Valves
TAVI or TAVR may be used as an alternative to surgical valve replacement when the risk of conventional open heart surgery is too high. There are currently 2 catheter-delivered valve systems in widespread clinical use to treat aortic stenosis. The SAPIEN valves (Edwards Lifesciences Inc., Irvine, CA) utilize a bovine pericardial valve mounted on a balloon-expandable stent which is placed entirely within the native diseased valve. The CoreValve ReValving System (Medtronic Inc, Minneapolis, MN) consists of a porcine pericardial valve mounted on a self-expanding stent which extends into the ascending aorta for stabilization.
Antithrombotic therapy after TAVI is not well established. It is based on expert consensus and on the original clinical trial protocols that examined indefinite low dose ASA 81 mg daily with an initial 1 to 6 months of a thienopyridine such as clopidogrel 75 mg daily. The addition of a thienopyridine was based on original studies showing that 7% to 40% of TAVI patients who receive antiplatelet therapy alone may develop valve thrombosis post procedure detected by computerized tomography. However, recent data suggest that there is less major or life-threatening bleeding with ASA alone, with no increase in thromboembolic events. As such, in the 2019 Position Statement for Transcatheter Aortic Valve Implantation, the Canadian Cardiovascular Society (CCS) suggests aspirin monotherapy after TAVI unless there is an indication for dual antiplatelet (i.e. recent percutaneous catheter intervention) (strong recommendation, medium quality evidence). TAVI patients with another indication for anticoagulation, such as atrial fibrillation, should receive an oral anticoagulant as per guideline (See Clinical Guide: Stroke Prevention in Atrial Fibrillation) in addition to ASA. The CCS caution against the use of triple therapy (ASA, antiplatelet agent, vitamin K antagonist (VKA), or direct oral anticoagulant (DOAC)) as triple therapy may render an excessively high bleeding risk in these patients. A recent study showed that among TAVI patients with an indication for long-term oral anticoagulation, oral anticoagulation with either VKA or DOAC alone compared with oral anticoagulation (VKA, DOAC) plus 3 months of clopidogrel was associated with a lower risk of all bleeding (21.7% vs 34.6% respectively). However, concerns regarding the classification of bleeding and the reliability of secondary outcome analyses that addressed thromboembolic risk have been highlighted. There are currently several ongoing trials that are examining DOACs or VKA use in TAVI patients with or without a long-term indication for oral anticoagulation. It should be noted that a trial that examined rivaroxaban 10 mg daily (with ASA at a dose of 75 to 100 mg daily for the first 3 months) or ASA at a dose of 75 to 100 mg daily (with clopidogrel at a dose of 75 mg daily for the first 3 months) in TAVI patients without an indication for long-term oral anticoagulation was stopped prematurely because of excess mortality in the rivaroxaban group.
# ANTITHROMBOTIC AGENTS AND DOSING FOR PATIENTS WITH MECHANICAL VALVES:
Warfarin Long-term warfarin therapy is indicated in all patients with mechanical heart valves. The target INR is dependent on the valve type and manufacturer (e.g. bileaflet or tilting disc, St. Jude or On-X) and location (e.g. aortic or mitral). See
# Direct Oral Anticoagulants
The direct factor inhibitor anticoagulants, such as apixaban, dabigatran, edoxaban, and rivaroxaban, are contraindicated in patients with mechanical heart valves. A randomized trial demonstrated that dabigatran is associated with more thrombosis and bleeding compared with warfarin in patients with mechanical heart valves. 2.5 (range 2.0-3.0) † Yes Aortic (On-X) First 3 months 2.5 (range 2.0-3.0) Yes Aortic (On-X) After 3 months 1.8 (range 1.5-2.0) ++ Yes Mitral (any manufacturer) 3.0 (range 2.5-3.5) Yes
Combined aortic and mitral 3.0 (range 2.5-3.5) Yes Pulmonic 2.5 (range 2.0-3.0) No Tricuspid 3.0 (range 2.5-3.5) No
Combined pulmonic and tricuspid 3.0 (range 2.5-3.5) No † Higher-intensity INR (target: 3.0) can be considered in selected patients with additional risk factors for stroke and in patients with ball-cage valves (e.g. Starr-Edwards). ++Higher-intensity INR (target 2.5) should be continued beyond 3 months for On-X aortic valves in patients who also have atrial fibrillation or additional risk factors for stroke. ‡ Co-administration of ASA should be considered in selected patients at low risk for bleeding.
# SPECIAL CONSIDERATIONS:
# Periprocedural Management
In patients with a mechanical heart valve who need an elective surgery or procedure, bridging with UFH or LMWH is indicated. . Interruption of warfarin in patients with mechanical heart valves is not recommended for minor procedures, such as cataract removal, dental procedures, and skin biopsies.
# Pregnancy in Women with Mechanical Heart Valves
Pregnant women with mechanical heart valves are at especially high risk of developing thrombotic complications; however, relatively little evidence is available to guide recommendations. These women should be managed by multidisciplinary teams experienced in the care of these patients. Women of childbearing age who have mechanical heart valves should receive preconception counseling regarding risks associated with prosthetic valves and the risks and benefits of antithrombotic therapy.
Therapeutic anticoagulation should continue throughout the pregnancy for all women with mechanical valves. Warfarin is effective in preventing thrombotic complications in pregnant women with mechanical valves, but is associated with risks of teratogenicity, mostly with use during the first trimester, fetal loss and, if used close to term, neonatal hemorrhage. It has been reported that warfarin at low doses is less likely to be associated with adverse fetal outcomes and current guidelines suggest that in women requiring 5 mg per day or less of warfarin, warfarin may be continued throughout the pregnancy while in those who require more than 5 mg per day, twice-daily LMWH monitored with regular anti-Xa testing and dose adjustment or intravenous unfractionated heparin can be considered instead of warfarin for the first trimester. It is important to note that warfarin embryopathy, miscarriage, and stillbirth have been reported in women taking less than 5 mg of warfarin per day. Therefore, in well-informed women who place a relatively higher value on avoiding teratogenic effects, monitored twice-daily LMWH may be considered throughout pregnancy. ASA 81 mg daily can be added during the second and third trimesters to further reduce the thrombotic risk. All pregnant women with mechanical valves should have planned deliveries and should be switched to unfractionated heparin prior to delivery, so as to minimize the time off anticoagulants in the peri-delivery period.
Whitlock RP, Sun JS, Fremes, SE, et al. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2Suppl):e576S-600S.
# Date of Version: 09September2020
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
# Pediatrics
There are few studies and no randomized controlled trials on the safety and efficacy of antithrombotic therapy post-heart valve placement in children. Children should be managed postvalve placement by a cardiologist and adult recommendations for management should be followed.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES | To summarize evidence-based recommendations for the management of antithrombotic drugs in patients with surgical valve replacement (mechanical and bioprosthetic heart valves) and transaortic valve replacement (TAVR or TAVI).Surgical heart valve replacement (SAVR) can be done with either a bioprosthetic (tissue) or mechanical prosthesis. TAVI or TAVR is undertaken in a heart catheterization lab and the prosthetic aortic valve is deployed via catheter without an open-heart surgical sternotomy. Mitral valve replacement with a transcatheter approach is not currently available.# Bioprosthetic Valves
Long-term anticoagulation for patients with bioprosthetic valves is not indicated as the risk of thrombosis and thromboembolism is low (about 0.2%/year):
• In patients with a bioprosthetic mitral valve who are in sinus rhythm and have no other indications for anticoagulant therapy, 3 to 6 months of warfarin therapy (international normalized ratio [INR] target: 2.5) after valve replacement is suggested, to be followed by long-term acetylsalicylic acid (ASA) 81 mg daily. • In patients with a bioprosthetic aortic valve who are in sinus rhythm and have no other indications for anticoagulant therapy long-term ASA 81 mg daily may be considered for patients with low bleeding risk after 3 to 6 months of warfarin therapy (INR target: 2.5). • Patients with a bioprosthetic valve and atrial fibrillation should be considered for long-term anticoagulant therapy as outlined in the Clinical Guide, Stroke Prevention in Atrial Fibrillation.
# Mechanical Valves
There are 3 basic types of mechanical valves: 1. Bileaflet (e.g. On-X, St. Judes, most frequently seen today) 2. Tilting disc (e.g. Bjork-Shiley, infrequently seen today) 3. Ball-cage (e.g. Starr-Edwards, rarely seen today)
Patients with mechanical heart valves are at increased risk for embolic stroke and thrombosis of the valve itself and, therefore, require long-term anticoagulation. Even with anticoagulation, the risk of stroke/valve thrombosis is ~0.9%/year with mechanical mitral valves, ~0.5%/year for mechanical aortic valves, and ~1.2%/year in those with two mechanical valves.
In selecting the optimal anticoagulation for patients with a mechanical heart valve, it is also important to consider the risk of bleeding, the different INR targets depending on valve type and location, and the need for bridging anticoagulant therapy for surgical procedures.
On-X aortic mechanical valve implant has design features and construction materials thought to reduce thrombogenicity and flow turbulence compared to other valve designs; theoretically allowing a lower intensity INR target range to protect from valve thrombosis that could result in a lower rate of anticoagulant associated major bleeding. The safety of this lower target range INR (1.5 to 2.0) compared to the traditional target range INR (2.0 to 3.0) following placement of the On-X aortic valve implant was evaluated in the PROACT study. Patients with at least one additional risk factor for stroke were randomized after 3 months of warfarin anticoagulation with an INR target of 2.5 to either the lower INR target range or to continue with the traditional INR target range. All subjects received concurrent low dose ASA 81 mg/day. Follow up was planned for 5 to 8 yrs. Interim results of this trial published in 2014 with an average follow up of 3.8 years reported that the subjects in the lower INR target range group had a significantly lower rate of major bleeding compared to those in the traditional INR target range group (1.48% per year vs 3.26 % per year). There was no difference between the groups on the endpoints of stroke, transient ischemic attack, total neurological events and all-cause mortality. In the 2017 Focused Update of the Valvular Heart Disease Guidelines, the American College of Cardiology made a weak (class IIb) recommendation based on a single moderate quality randomized clinical trial that a lower target INR range of 1.5 to 2.0 plus ASA 81 mg/day may be reasonable after 3 months of an INR target of 2.5 (2.0 to 3.0).
# Transaortic Valves
TAVI or TAVR may be used as an alternative to surgical valve replacement when the risk of conventional open heart surgery is too high. There are currently 2 catheter-delivered valve systems in widespread clinical use to treat aortic stenosis. The SAPIEN valves (Edwards Lifesciences Inc., Irvine, CA) utilize a bovine pericardial valve mounted on a balloon-expandable stent which is placed entirely within the native diseased valve. The CoreValve ReValving System (Medtronic Inc, Minneapolis, MN) consists of a porcine pericardial valve mounted on a self-expanding stent which extends into the ascending aorta for stabilization.
Antithrombotic therapy after TAVI is not well established. It is based on expert consensus and on the original clinical trial protocols that examined indefinite low dose ASA 81 mg daily with an initial 1 to 6 months of a thienopyridine such as clopidogrel 75 mg daily. The addition of a thienopyridine was based on original studies showing that 7% to 40% of TAVI patients who receive antiplatelet therapy alone may develop valve thrombosis post procedure detected by computerized tomography. However, recent data suggest that there is less major or life-threatening bleeding with ASA alone, with no increase in thromboembolic events. As such, in the 2019 Position Statement for Transcatheter Aortic Valve Implantation, the Canadian Cardiovascular Society (CCS) suggests aspirin monotherapy after TAVI unless there is an indication for dual antiplatelet (i.e. recent percutaneous catheter intervention) (strong recommendation, medium quality evidence). TAVI patients with another indication for anticoagulation, such as atrial fibrillation, should receive an oral anticoagulant as per guideline (See Clinical Guide: Stroke Prevention in Atrial Fibrillation) in addition to ASA. The CCS caution against the use of triple therapy (ASA, antiplatelet agent, vitamin K antagonist (VKA), or direct oral anticoagulant (DOAC)) as triple therapy may render an excessively high bleeding risk in these patients. A recent study showed that among TAVI patients with an indication for long-term oral anticoagulation, oral anticoagulation with either VKA or DOAC alone compared with oral anticoagulation (VKA, DOAC) plus 3 months of clopidogrel was associated with a lower risk of all bleeding (21.7% vs 34.6% respectively). However, concerns regarding the classification of bleeding and the reliability of secondary outcome analyses that addressed thromboembolic risk have been highlighted. There are currently several ongoing trials that are examining DOACs or VKA use in TAVI patients with or without a long-term indication for oral anticoagulation. It should be noted that a trial that examined rivaroxaban 10 mg daily (with ASA at a dose of 75 to 100 mg daily for the first 3 months) or ASA at a dose of 75 to 100 mg daily (with clopidogrel at a dose of 75 mg daily for the first 3 months) in TAVI patients without an indication for long-term oral anticoagulation was stopped prematurely because of excess mortality in the rivaroxaban group.
# ANTITHROMBOTIC AGENTS AND DOSING FOR PATIENTS WITH MECHANICAL VALVES:
Warfarin Long-term warfarin therapy is indicated in all patients with mechanical heart valves. The target INR is dependent on the valve type and manufacturer (e.g. bileaflet or tilting disc, St. Jude or On-X) and location (e.g. aortic or mitral). See
# Direct Oral Anticoagulants
The direct factor inhibitor anticoagulants, such as apixaban, dabigatran, edoxaban, and rivaroxaban, are contraindicated in patients with mechanical heart valves. A randomized trial demonstrated that dabigatran is associated with more thrombosis and bleeding compared with warfarin in patients with mechanical heart valves. 2.5 (range 2.0-3.0) † Yes Aortic (On-X) First 3 months 2.5 (range 2.0-3.0) Yes Aortic (On-X) After 3 months 1.8 (range 1.5-2.0) ++ Yes Mitral (any manufacturer) 3.0 (range 2.5-3.5) Yes
Combined aortic and mitral 3.0 (range 2.5-3.5) Yes Pulmonic 2.5 (range 2.0-3.0) No Tricuspid 3.0 (range 2.5-3.5) No
Combined pulmonic and tricuspid 3.0 (range 2.5-3.5) No † Higher-intensity INR (target: 3.0) can be considered in selected patients with additional risk factors for stroke and in patients with ball-cage valves (e.g. Starr-Edwards). ++Higher-intensity INR (target 2.5) should be continued beyond 3 months for On-X aortic valves in patients who also have atrial fibrillation or additional risk factors for stroke. ‡ Co-administration of ASA should be considered in selected patients at low risk for bleeding.
# SPECIAL CONSIDERATIONS:
# Periprocedural Management
In patients with a mechanical heart valve who need an elective surgery or procedure, bridging with UFH or LMWH is indicated. [See Clinical Guide Warfarin: Perioperative Management]. Interruption of warfarin in patients with mechanical heart valves is not recommended for minor procedures, such as cataract removal, dental procedures, and skin biopsies.
# Pregnancy in Women with Mechanical Heart Valves
Pregnant women with mechanical heart valves are at especially high risk of developing thrombotic complications; however, relatively little evidence is available to guide recommendations. These women should be managed by multidisciplinary teams experienced in the care of these patients. Women of childbearing age who have mechanical heart valves should receive preconception counseling regarding risks associated with prosthetic valves and the risks and benefits of antithrombotic therapy.
Therapeutic anticoagulation should continue throughout the pregnancy for all women with mechanical valves. Warfarin is effective in preventing thrombotic complications in pregnant women with mechanical valves, but is associated with risks of teratogenicity, mostly with use during the first trimester, fetal loss and, if used close to term, neonatal hemorrhage. It has been reported that warfarin at low doses is less likely to be associated with adverse fetal outcomes and current guidelines suggest that in women requiring 5 mg per day or less of warfarin, warfarin may be continued throughout the pregnancy while in those who require more than 5 mg per day, twice-daily LMWH monitored with regular anti-Xa testing and dose adjustment or intravenous unfractionated heparin can be considered instead of warfarin for the first trimester. It is important to note that warfarin embryopathy, miscarriage, and stillbirth have been reported in women taking less than 5 mg of warfarin per day. Therefore, in well-informed women who place a relatively higher value on avoiding teratogenic effects, monitored twice-daily LMWH may be considered throughout pregnancy. ASA 81 mg daily can be added during the second and third trimesters to further reduce the thrombotic risk. All pregnant women with mechanical valves should have planned deliveries and should be switched to unfractionated heparin prior to delivery, so as to minimize the time off anticoagulants in the peri-delivery period.
Whitlock RP, Sun JS, Fremes, SE, et al. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2Suppl):e576S-600S.
# Date of Version: 09September2020
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
# Pediatrics
There are few studies and no randomized controlled trials on the safety and efficacy of antithrombotic therapy post-heart valve placement in children. Children should be managed postvalve placement by a cardiologist and adult recommendations for management should be followed.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES
| None | None |
3065315418325fa9585a70dc17413cd2265a1e29 | cma | None | To outline the main clinical and laboratory features of the antiphospholipid antibody syndrome (APS) and to describe its anticoagulant management.APS is an acquired hypercoagulable state characterized by the persistent presence of autoantibodies against proteins bound to cell membrane phospholipids. It is associated with thrombosis (venous, arterial, or microvascular) and/or pregnancy complications such as recurrent miscarriage, late pregnancy loss, or pre-eclampsia. There may be accompanying features such as thrombocytopenia, livedo reticularis, renal disease and neurologic symptoms. APS may occur in the setting of underlying autoimmune disease such as systemic lupus erythematosus (secondary APS) or may occur in isolation (primary APS). The term 'obstetric APS' denotes the condition of APS with pregnancy morbidity but without thrombosis.# DIAGNOSIS:
The diagnosis of APS should be made carefully and in consultation with a specialist because of the potential for both false positive and false negative laboratory tests. In addition, a diagnosis of APS has important treatment implications because such patients may require long-term anticoagulant therapy. APS is diagnosed based on expert consensus criteria (revised Sapporo criteria) and requires the presence of at least one laboratory and one clinical criterion.
# Laboratory criteria:
If laboratory testing is undertaken in a patient with a history of recent thrombosis, it should be performed after a minimum of 3 months of anticoagulant therapy has been completed. A positive result requires confirmation and documentation of persistent positivity at least 3 months later.
Currently, 3 types of antibodies are accepted for the laboratory criteria for definite APS:
1) Lupus anticoagulant (LA) or non-specific inhibitor. These antibodies are present (positive) or absent (negative). Note that in laboratories that use a lupus-sensitive activated partial thromboplastin time (aPTT) reagent, LA can result in an elevated aPTT. The presence of LA is more strongly associated with thrombosis than the presence of other antibodies listed below. LA testing should not be performed in patients who are receiving heparin, low molecular weight heparin (LMWH), or direct oral anticoagulants (DOACs) given the potential for false positive or false negative results. LA testing should also be avoided in patients taking vitamin K antagonists (VKA) such as warfarin, and in patients with factor deficiencies, as these can also result in a false positive result. 2) Anticardiolipin (aCL) antibody (IgG or IgM) present in medium or high titre (i.e. >40 GPL units or >99 th percentile).
3) Anti-beta2 glycoprotein-I antibody (IgG or IgM) with a titre >99 th percentile.
Patients testing positive for all 3 antibodies ("triple positivity") appear to have the highest risk of thrombotic events.
Clinical criteria: 1) Vascular thrombosis:
- One or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed by objective criteria (i.e. unequivocal findings on appropriate imaging studies or histopathology of microvascular thrombosis). For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall. Superficial venous thrombosis is not part of the criteria.
# 2) Obstetrical complications:
- Three or more unexplained, consecutive spontaneous abortions before the 10th week of gestation, with exclusion of maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes, or - One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or - One or more premature births of a morphologically normal neonate before the 34th
week of gestation because of: (i) eclampsia or severe pre-eclampsia according to standard definitions or (ii) recognized features of placental insufficiency.
# ANTITHROMBOTIC THERAPY OF APS:
Due to the complexity and potential severity of APS, diagnosis, and treatment of patients with APS should be undertaken in consultation with a specialist.
# Acute venous thrombosis:
LMWH is preferred over unfractionated heparin (UFH) in patients with venous thrombosis whose baseline aPTT is prolonged by a LA because of the difficulties with monitoring UFH in this situation. Patients with a known high-risk APL profile (either triple positivity, or persistently positive lupus anticoagulant +/-moderate-to-high titre ACL IgG or beta-2-glycoprotein-I IgG antibodies) and those with arterial events should be treated with warfarin administered to a target INR of 2.0 to 3.0 (see "DOACs in APS" below). Whether DOACs can be used in lower risk patients is unknown although available evidence supports the safety of this approach (see below).
# Acute arterial thrombosis:
The treatment of patients with an acute arterial thrombosis is controversial as data are limited. However, most guidelines currently recommend anticoagulation therapy with warfarin in this setting.
A study assessed secondary ischemic stroke prevention with acetylsalicylic acid (ASA) 325 mg daily versus warfarin (international normalized ratio target of 1.4 -2.8). A subset of this study included patients with antiphospholipid antibodies present and found no difference between the two treatment arms. However, the antibodies were generally low titre and only measured once, making it unclear if these patients truly had APS. Antiplatelet therapy or anticoagulant therapy are seen as options in this setting but anticoagulant therapy with warfarin administered to a target INR of 2.0 to 3.0 is generally preferred.
# DOACs in APS:
Randomized clinical trials have found rivaroxaban to be less effective than warfarin administered to a target INR of 2.0 to 3.0 in preventing recurrent thrombosis in patients with APS. This includes patients with triple positivity and patients with a high-risk APL profile (persistent lupus anticoagulant positive +/-moderate-to-high titre ACL IgG or beta-2-glycoprotein-I IgG antibodies). In these studies, patients on rivaroxaban experienced more thrombotic episodes and bleeding than those on warfarin.
A patient-level data meta-analysis of 47 studies analyzed data of rivaroxaban (n = 290), apixaban (n = 13), and dabigatran (n = 144) users with APS. Recurrent thrombosis occurred 16.9% of rivaroxaban/apixaban users and 15% of dabigatran users at a mean follow up of 12.5 months. A prior history of arterial thrombosis was also associated with a higher risk of recurrent thrombosis.
Therefore, warfarin administered to a target INR of 2.0 to 3.0 is currently the preferred long-term anticoagulant for patients with a high-risk APL profile. Patients who decline warfarin or who cannot tolerate warfarin should be informed about the available evidence, possible reduced benefit of DOACs relative to warfarin, and referred to a hematologist or thrombosis specialist. There is uncertainty about which antithrombotic therapy is preferred for non-high-risk profiles and consultation with a hematologist or thrombosis specialist is recommended.
Long-term anticoagulant management: Since the risk of recurrent thrombosis in patients with APS is high, long-term anticoagulation is usually required. Consultation with a specialist is recommended for patients with APS. All patients with APS should have aggressive reduction of their modifiable cardiovascular risk factors. Patients who also have systemic lupus erythematosus may benefit from the addition of hydroxychloroquine. It is not known whether anticoagulation may be stopped safely if the laboratory criteria for APS are no longer present on later follow-up.
# Intensity of anticoagulant therapy:
Most patients with venous or arterial thrombosis and APS should receive conventional warfarin therapy, administered to achieve an INR range of 2.0-3.0. Randomized controlled trial data supports this suggestion.
There is limited data with regards to patients who develop recurrent thrombosis, despite conventional doses of warfarin and optimal time in therapeutic range. Treatment options include higher-intensity warfarin (INR range: 3.0-4.0), therapeutic-dose LMWH, or the combination of low dose ASA and convention warfarin therapy. In all cases the suspected recurrence should be objectively confirmed, and the adequacy of anticoagulation assessed before an event is labelled a recurrence, given the longterm implications of failure of therapeutic anticoagulation.
Laboratory monitoring of anticoagulant therapy: Some patients with APS have a prolongation in the INR before anticoagulant therapy is commenced. In such patients, alternate monitoring approaches may be necessary. Consultation with an expert is strongly suggested to prevent under-treatment. Point of care INR determinations appear to be particularly prone to error in patients with APS. Periodic reconfirmation of the reliability of test results is required for patients being monitored with point of care devices.
# SPECIAL CONSIDERATIONS:
Asymptomatic (without thrombosis) patients with positive antiphospholipid test results: Due to the widespread use of the aPTT in clinical practice, a LA may be detected in otherwise asymptomatic patients who do not have the clinical criteria for APS. A detailed clinical history should be taken to exclude thrombotic events that were previously missed. Although asymptomatic patients with both LA and other APS markers may be at increased risk for thrombotic complications, there is no consensus on the role of primary antithrombotic prophylaxis. These individuals should receive aggressive thromboprophylaxis in high-risk situations. APS may be associated with other manifestations such as immune thrombocytopenia and livedo reticularis; there is no evidence to support treatment with anticoagulants for those conditions alone. A small study examined use of ASA for primary prophylaxis in patients with APS and found no benefit.
Pregnant women with antiphospholipid antibodies: It is recommended that pregnant women who meet criteria for obstetric APS without a history of venous/arterial thrombosis receive prophylacticdose LMWH/UFH combined with low-dose ASA for the duration of their pregnancy; however, it is important to note that the efficacy and safety of such management has not been validated in welldesigned clinical trials. The role of prophylactic-dose LMWH/UFH and low-dose ASA in women with persistent antiphospholipid antibodies and a single late pregnancy loss has not been well studied. Low-dose ASA is often used in pregnant women with persistent antiphospholipid antibodies to reduce the risk of pre-eclampsia. Post-partum prophylaxis is also frequently used in these patients even in the absence of a prior history of thrombosis, although this practice is not evidence-based.
Catastrophic antiphospholipid antibody syndrome: Catastrophic antiphospholipid antibody syndrome (CAPS) is a rare clinical manifestation presenting with a fulminant onset of multiorgan microvascular thrombosis, oftentimes in patients without a prior history of APS. Management consists of aggressive anticoagulation, plasmapheresis, and immunosuppression. Despite treatment, there is a high rate of long-term morbidity and mortality. Diagnosis requires identification of one or more antiphospholipid antibodies but does not require tissue biopsy evidence of microvascular thrombosis in a compatible clinical setting. Management should occur in expert centers under the direction of experienced clinicians. Anti-complement therapy may be of benefit in selected patients and should be considered for critically ill patients and those not responding to "standard" therapies.
Pediatrics: For children with venous thromboembolism (VTE) in the setting of antiphospholipid antibodies, anticoagulation as per general recommendations for VTE management in children is recommended. Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with thromboembolism. When this is not possible, a combination of a neonatologist/pediatrician and a pediatric hematologist or an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Deep Vein Thrombosis (DVT): Treatment
# Date of Version: 25July2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To outline the main clinical and laboratory features of the antiphospholipid antibody syndrome (APS) and to describe its anticoagulant management.APS is an acquired hypercoagulable state characterized by the persistent presence of autoantibodies against proteins bound to cell membrane phospholipids. It is associated with thrombosis (venous, arterial, or microvascular) and/or pregnancy complications such as recurrent miscarriage, late pregnancy loss, or pre-eclampsia. There may be accompanying features such as thrombocytopenia, livedo reticularis, renal disease and neurologic symptoms. APS may occur in the setting of underlying autoimmune disease such as systemic lupus erythematosus (secondary APS) or may occur in isolation (primary APS). The term 'obstetric APS' denotes the condition of APS with pregnancy morbidity but without thrombosis.# DIAGNOSIS:
The diagnosis of APS should be made carefully and in consultation with a specialist because of the potential for both false positive and false negative laboratory tests. In addition, a diagnosis of APS has important treatment implications because such patients may require long-term anticoagulant therapy. APS is diagnosed based on expert consensus criteria (revised Sapporo criteria) and requires the presence of at least one laboratory and one clinical criterion.
# Laboratory criteria:
If laboratory testing is undertaken in a patient with a history of recent thrombosis, it should be performed after a minimum of 3 months of anticoagulant therapy has been completed. A positive result requires confirmation and documentation of persistent positivity at least 3 months later.
Currently, 3 types of antibodies are accepted for the laboratory criteria for definite APS:
1) Lupus anticoagulant (LA) or non-specific inhibitor. These antibodies are present (positive) or absent (negative). Note that in laboratories that use a lupus-sensitive activated partial thromboplastin time (aPTT) reagent, LA can result in an elevated aPTT. The presence of LA is more strongly associated with thrombosis than the presence of other antibodies listed below. LA testing should not be performed in patients who are receiving heparin, low molecular weight heparin (LMWH), or direct oral anticoagulants (DOACs) given the potential for false positive or false negative results. LA testing should also be avoided in patients taking vitamin K antagonists (VKA) such as warfarin, and in patients with factor deficiencies, as these can also result in a false positive result. 2) Anticardiolipin (aCL) antibody (IgG or IgM) present in medium or high titre (i.e. >40 GPL units or >99 th percentile).
3) Anti-beta2 glycoprotein-I antibody (IgG or IgM) with a titre >99 th percentile.
Patients testing positive for all 3 antibodies ("triple positivity") appear to have the highest risk of thrombotic events.
Clinical criteria: 1) Vascular thrombosis:
• One or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed by objective criteria (i.e. unequivocal findings on appropriate imaging studies or histopathology of microvascular thrombosis). For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall. Superficial venous thrombosis is not part of the criteria.
# 2) Obstetrical complications:
• Three or more unexplained, consecutive spontaneous abortions before the 10th week of gestation, with exclusion of maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes, or • One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or • One or more premature births of a morphologically normal neonate before the 34th
week of gestation because of: (i) eclampsia or severe pre-eclampsia according to standard definitions or (ii) recognized features of placental insufficiency.
# ANTITHROMBOTIC THERAPY OF APS:
Due to the complexity and potential severity of APS, diagnosis, and treatment of patients with APS should be undertaken in consultation with a specialist.
# Acute venous thrombosis:
LMWH is preferred over unfractionated heparin (UFH) in patients with venous thrombosis whose baseline aPTT is prolonged by a LA because of the difficulties with monitoring UFH in this situation. Patients with a known high-risk APL profile (either triple positivity, or persistently positive lupus anticoagulant +/-moderate-to-high titre ACL IgG or beta-2-glycoprotein-I IgG antibodies) and those with arterial events should be treated with warfarin administered to a target INR of 2.0 to 3.0 (see "DOACs in APS" below). Whether DOACs can be used in lower risk patients is unknown although available evidence supports the safety of this approach (see below).
# Acute arterial thrombosis:
The treatment of patients with an acute arterial thrombosis is controversial as data are limited. However, most guidelines currently recommend anticoagulation therapy with warfarin in this setting.
A study assessed secondary ischemic stroke prevention with acetylsalicylic acid (ASA) 325 mg daily versus warfarin (international normalized ratio [INR] target of 1.4 -2.8). A subset of this study included patients with antiphospholipid antibodies present and found no difference between the two treatment arms. However, the antibodies were generally low titre and only measured once, making it unclear if these patients truly had APS. Antiplatelet therapy or anticoagulant therapy are seen as options in this setting but anticoagulant therapy with warfarin administered to a target INR of 2.0 to 3.0 is generally preferred.
# DOACs in APS:
Randomized clinical trials have found rivaroxaban to be less effective than warfarin administered to a target INR of 2.0 to 3.0 in preventing recurrent thrombosis in patients with APS. This includes patients with triple positivity and patients with a high-risk APL profile (persistent lupus anticoagulant positive +/-moderate-to-high titre ACL IgG or beta-2-glycoprotein-I IgG antibodies). In these studies, patients on rivaroxaban experienced more thrombotic episodes and bleeding than those on warfarin.
A patient-level data meta-analysis of 47 studies analyzed data of rivaroxaban (n = 290), apixaban (n = 13), and dabigatran (n = 144) users with APS. Recurrent thrombosis occurred 16.9% of rivaroxaban/apixaban users and 15% of dabigatran users at a mean follow up of 12.5 months. A prior history of arterial thrombosis was also associated with a higher risk of recurrent thrombosis.
Therefore, warfarin administered to a target INR of 2.0 to 3.0 is currently the preferred long-term anticoagulant for patients with a high-risk APL profile. Patients who decline warfarin or who cannot tolerate warfarin should be informed about the available evidence, possible reduced benefit of DOACs relative to warfarin, and referred to a hematologist or thrombosis specialist. There is uncertainty about which antithrombotic therapy is preferred for non-high-risk profiles and consultation with a hematologist or thrombosis specialist is recommended.
Long-term anticoagulant management: Since the risk of recurrent thrombosis in patients with APS is high, long-term anticoagulation is usually required. Consultation with a specialist is recommended for patients with APS. All patients with APS should have aggressive reduction of their modifiable cardiovascular risk factors. Patients who also have systemic lupus erythematosus may benefit from the addition of hydroxychloroquine. It is not known whether anticoagulation may be stopped safely if the laboratory criteria for APS are no longer present on later follow-up.
# Intensity of anticoagulant therapy:
Most patients with venous or arterial thrombosis and APS should receive conventional warfarin therapy, administered to achieve an INR range of 2.0-3.0. Randomized controlled trial data supports this suggestion.
There is limited data with regards to patients who develop recurrent thrombosis, despite conventional doses of warfarin and optimal time in therapeutic range. Treatment options include higher-intensity warfarin (INR range: 3.0-4.0), therapeutic-dose LMWH, or the combination of low dose ASA and convention warfarin therapy. In all cases the suspected recurrence should be objectively confirmed, and the adequacy of anticoagulation assessed before an event is labelled a recurrence, given the longterm implications of failure of therapeutic anticoagulation.
Laboratory monitoring of anticoagulant therapy: Some patients with APS have a prolongation in the INR before anticoagulant therapy is commenced. In such patients, alternate monitoring approaches may be necessary. Consultation with an expert is strongly suggested to prevent under-treatment. Point of care INR determinations appear to be particularly prone to error in patients with APS. Periodic reconfirmation of the reliability of test results is required for patients being monitored with point of care devices.
# SPECIAL CONSIDERATIONS:
Asymptomatic (without thrombosis) patients with positive antiphospholipid test results: Due to the widespread use of the aPTT in clinical practice, a LA may be detected in otherwise asymptomatic patients who do not have the clinical criteria for APS. A detailed clinical history should be taken to exclude thrombotic events that were previously missed. Although asymptomatic patients with both LA and other APS markers may be at increased risk for thrombotic complications, there is no consensus on the role of primary antithrombotic prophylaxis. These individuals should receive aggressive thromboprophylaxis in high-risk situations. APS may be associated with other manifestations such as immune thrombocytopenia and livedo reticularis; there is no evidence to support treatment with anticoagulants for those conditions alone. A small study examined use of ASA for primary prophylaxis in patients with APS and found no benefit.
Pregnant women with antiphospholipid antibodies: It is recommended that pregnant women who meet criteria for obstetric APS without a history of venous/arterial thrombosis receive prophylacticdose LMWH/UFH combined with low-dose ASA for the duration of their pregnancy; however, it is important to note that the efficacy and safety of such management has not been validated in welldesigned clinical trials. The role of prophylactic-dose LMWH/UFH and low-dose ASA in women with persistent antiphospholipid antibodies and a single late pregnancy loss has not been well studied. Low-dose ASA is often used in pregnant women with persistent antiphospholipid antibodies to reduce the risk of pre-eclampsia. Post-partum prophylaxis is also frequently used in these patients even in the absence of a prior history of thrombosis, although this practice is not evidence-based.
Catastrophic antiphospholipid antibody syndrome: Catastrophic antiphospholipid antibody syndrome (CAPS) is a rare clinical manifestation presenting with a fulminant onset of multiorgan microvascular thrombosis, oftentimes in patients without a prior history of APS. Management consists of aggressive anticoagulation, plasmapheresis, and immunosuppression. Despite treatment, there is a high rate of long-term morbidity and mortality. Diagnosis requires identification of one or more antiphospholipid antibodies but does not require tissue biopsy evidence of microvascular thrombosis in a compatible clinical setting. Management should occur in expert centers under the direction of experienced clinicians. Anti-complement therapy may be of benefit in selected patients and should be considered for critically ill patients and those not responding to "standard" therapies.
Pediatrics: For children with venous thromboembolism (VTE) in the setting of antiphospholipid antibodies, anticoagulation as per general recommendations for VTE management in children is recommended. Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with thromboembolism. When this is not possible, a combination of a neonatologist/pediatrician and a pediatric hematologist or an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Deep Vein Thrombosis (DVT): Treatment
# Date of Version: 25July2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
4ffb34f62fc94ac563115113a8692fe2101d90e9 | cma | None | The Ontario COVID-19 Science Advisory Table is a group of scientific experts and health system leaders who evaluate and report on emerging evidence relevant to the COVID-19 pandemic, to inform Ontario's response. Our mandate is to provide weekly summaries of relevant scientific evidence for the COVID-19 Health Coordination Table of the Province of Ontario, integrating information from existing scientific tables, Ontario's universities and agencies, and the best global evidence. The Science Table summarizes its findings for the Health Coordination Table and the public in Science Briefs.Guidelines Working Group is a group of clinicians and scientists with recognized expertise in drugs, biologics, and clinical care. The Working Group evaluates existing scientific data, disease epidemiology, drug availability, and implementation issues in order to develop Clinical Practice Guidelines for the treatment of COVID-19 using drugs and biologics. The Working Group reports its findings to the public and the Science Table . Its findings are also summarized in Science Briefs.#
Prophylactic dose low molecular weight or unfractionated heparin are recommended in critically ill patients hospitalized with COVID-19. These patients should not receive therapeutic dose anticoagulation unless they have a separate indication for this treatment. Therapeutic dose anticoagulation in this patient population does not reduce the need for organ support and may increase bleeding events as compared to prophylactic dose anticoagulation.
# Moderately Ill Patients
Therapeutic dose low molecular weight or unfractionated heparin may be considered over prophylactic dose anticoagulation in moderately ill patients who are felt to be at low risk of bleeding. All other patients should receive prophylactic dose anticoagulation, unless they have a separate indication for therapeutic dose anticoagulation. Therapeutic dose anticoagulation may reduce the need for organ support (including the need for high-flow nasal oxygen) and appears to decrease thrombotic events in moderately ill patients compared to lower intensity anticoagulation. Its benefits on survival are unclear, and it may increase major bleeding events. Given the small absolute risk reduction for patient-important outcomes and the known harms, a strong recommendation for therapeutic dose anticoagulation in moderately ill patients cannot be made.
# Mildly Ill Patients
There is insufficient evidence to make a recommendation around anticoagulation for mildly ill patients.
# Lay Summary
Patients with COVID-19 may become ill because of a combination of viral infection and the inflammation produced by the body's immune system in response to that infection. Inflammation can lead to blood clots which damage their lungs, heart, kidney, and other vital organs.
# How Low Molecular Weight and Unfractionated Heparin Work
Unfractionated heparin is a blood thinner (also called an anticoagulant). Low molecular weight heparins (including drugs like dalteparin, enoxaparin and tinzaparin) are also anticoagulants, which come from unfractionated heparin that has been broken down into smaller pieces. These anticoagulant medications make it more difficult for blood to clot and can be given in different doses to prevent clots (prophylactic dose) or to treat clots (therapeutic dose). Additionally, there is some evidence from laboratory experiments not conducted in humans that unfractionated and low molecular weight heparins may reduce inflammation. Other laboratory experiments have shown that unfractionated heparin may prevent the SARS-CoV-2 virus from attacking cells.
# How We Came to Our Recommendations
To understand low molecular weight and unfractionated heparin's effects on patients admitted to hospital with COVID-19, we reviewed a multiplatform randomized controlled trial (RCT) -a study that coordinated three similar RCTs to provide information on a larger group of patients -and a multicentre RCT. The multiplatform and multicentre RCTs compared the effects of these medications for treatment (therapeutic doses) and prevention (prophylactic doses). These studies involved thousands of patients in many different countries. They looked at patients with moderate illness (who were on low flow oxygen) as well as patients with severe illness (who required breathing and/or circulation support, including high flow oxygen).
# Our Recommendation for Patients Admitted to Hospital with COVID-19 with Critical Illness
Patients admitted to hospital with severe COVID-19 illness do not benefit from treatment dose anticoagulation, and may suffer harm from severe bleeding or the need for a blood transfusion. They should not receive therapeutic dose anticoagulation unless they need it for another medical condition. Prevention dose anticoagulation should be offered to these patients.
# Our Recommendation for Patients Admitted to Hospital with COVID-19 with Moderate Illness
Therapeutic dose anticoagulation may be given to patients admitted to hospital with moderate COVID-19 illness who are felt to be at a low risk of bleeding, after a discussion between the patient and the treating physician. This treatment may reduce the number of days that these patients spend receiving "intensive care", including high doses of oxygen, a ventilator, and/or medications that increase their blood pressure or help their heart pump. Therapeutic dose anticoagulation may reduce mortality, but may also increase the chance of severe bleeding or the need for a blood transfusion. For these reasons, therapeutic dose anticoagulation may not be appropriate for all patients. Prevention dose anticoagulation should be offered to all patients not on therapeutic dose, to reduce the chance that they will develop blood clots.
# Our Recommendation for Patients with COVID-19 with Mild Illness
We do not have enough evidence to make a recommendation about anticoagulation for patients with mild COVID-19 illness, who are usually not admitted to hospital. In general, these patients do not receive anticoagulation unless they need it for another medical condition.
# Side Effects of Anticoagulation
The most common side effect of anticoagulant medications is bleeding. Higher doses of anticoagulants are more likely to cause bleeding. In moderately ill patients admitted to hospital with COVID-19 who have a low risk of bleeding, the benefits of therapeutic dose anticoagulation may outweigh the risk of bleeding. Other patients may receive lower, preventative doses of anticoagulation.
In critically ill patients admitted to hospital with COVID-19, the benefits of therapeutic dose anticoagulation do not outweigh the risks of bleeding. These patients do not benefit from a higher dose of anticoagulant treatment. They should receive lower, prevention doses of anticoagulation.
# Background
COVID-19-associated thrombosis, provoked by profound inflammation and viralmediated effects on cells, has been reported since the early days of the pandemic. 1 Despite the use of prophylactic dose anticoagulation, venous and arterial thrombosesincluding in situ pulmonary thrombosis, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, intravenous catheter thrombosis, and limb ischemiaare common in patients with COVID-19. A meta-analysis of studies utilizing various thromboprophylactic strategies reported venous thromboembolism in 5.5% of admitted non-critically ill patients and 18.7% of critically ill patients when patients were not screened for venous thrombosis with imaging, and rates of 23% and 45.6% in noncritically ill and critically ill patients respectively when routine screening was used. 2 Unfractionated and low molecular weight heparins are commonly used parenteral anticoagulants for the prevention and treatment of venous and arterial thromboembolism. Unfractionated heparin is a mixture of proteoglycans of various chain lengths which bind to anti-thrombin to inhibit coagulation factors. Low molecular weight heparins, including dalteparin, enoxaparin, and tinzaparin, are smaller chain length molecules fractionated from heparin which also bind to anti-thrombin and inhibit coagulation factors Xa and IIa.
In addition to their anticoagulant activity, heparins have anti-inflammatory and, possibly, antiviral activity. Anti-inflammatory effects occur through inhibition of neutrophil activation and function, interaction with vascular endothelium to prevent inflammatory mediator expression, prevention of vascular smooth muscle cell proliferation, 3 and anticoagulant activity. In vitro studies have demonstrated that unfractionated heparin may bind to the SARS-CoV-2 spike protein and act as a competitive inhibitor for viral entry into the host cell. 4 As such, it was hypothesized that an increased heparin dose in COVID-19 patients may improve outcomes through multiple mechanisms.
# Questions
Does anticoagulation improve outcomes, such as mortality, need for mechanical ventilation, and organ support-free days for patients with COVID-19?
What are the indications for therapeutic dose and prophylactic dose heparin in moderately and critically ill patients?
What is the risk of major bleeding in moderately and critically ill patients?
# Findings Overview of Key Trials
# Multiplatform Trial Including ATTACC, ACTIV-4a and REMAP-CAP
The randomized multiplatform trial including ATTACC, ACTIV-4a and REMAP-CAP compared therapeutic anticoagulation with usual care thromboprophylaxis (standard prophylactic or intermediate dose) in hospitalized COVID-19 patients. Enrollment was discontinued in the critically ill cohort on December 19, 2020, after an interim analysis showed that the statistical criterion for futility had been met. On January 22, 2021, enrollment in the non-critically ill cohort was discontinued on the advice of the data and safety monitoring boards after a planned analysis of data in accordance with the adaptive design. Papers describing both arms were published on August 4, 2021. 5,6 The multiplatform RCT used a composite primary outcome combining in-hospital mortality and days free of organ support. This outcome was an ordinal scale combining in-hospital mortality (assigned a value of -1) and days free of organ support (invasive or non-invasive mechanical ventilation, high flow nasal oxygen, vasopressor therapy, or extracorporeal membrane oxygenation (ECMO)) to day 21 (worst score of -1 and best score of 21). For example, a patient who died at day 18 would be assigned a score of -1 and a patient who survived and no longer required organ support at day 15 would be assigned a score of 6. The multiplatform RCT also considered other patientimportant outcomes such as survival to hospital discharge without thrombosis, bleeding, survival to hospital discharge, survival without organ support through 28 days, and survival without intubation; these were considered secondary outcomes.
The trial in the critically ill cohort enrolled 1,089 patients between April 21, 2020 and December 19, 2020 in 10 countries (United Kingdom, Ireland, Netherlands, Australia, New Zealand, Saudi Arabia, Canada, United States, Brazil and Mexico). The trial in the moderately ill cohort enrolled 2,219 patients between April 21, 2020 and January 22, 2021 in 9 countries (United States, Canada, United Kingdom, Brazil, Mexico, Nepal, Australia, Netherlands, and Spain). A substantial proportion of patients in this multiplatform trial did not receive other treatments with demonstrated evidence for benefit: only 60% of moderately ill patients were on corticosteroids (a therapy that is now nearly universally used in this population), 0.5% were on tocilizumab, and 36% were on remdesivir.
# RAPID Trial
The randomized multicentre RAPID trial comparing therapeutic anticoagulation with thromboprophylaxis (prophylactic standard dose) in moderately ill hospitalized COVID-19 patients completed enrollment on April 12, 2021, and was published in preprint form on July 12, 2021. 7 The RAPID trial's primary outcome was a composite of intensive care unit (ICU) admission, non-invasive (bilevel or continuous positive airway pressure) or invasive mechanical ventilation, or death up to 28 days. Secondary outcomes included: allcause death; the composite of any mechanical ventilation or all-cause death; ICU admission or all-cause death; ventilator-free days alive; organ support-free days alive; ICU-free days alive; hospital free days alive; renal replacement therapy; venous thromboembolism; arterial thromboembolism; and D-dimer level at 2 days ± 24 hours post-randomization.
The trial included 465 patients enrolled between May 29, 2020 and April 12, 2021 at 28 sites in 6 countries in 10 countries (Canada, Saudi Arabia, Brazil, United States, Ireland and United Arab Emirates). Patients were required to have D-dimer levels above the upper limit of normal (ULN) of the local hospital in the presence of an oxygen saturation ≤93% on room air, or ≥2 times the ULN irrespective of oxygen saturation. Compared to the multiplatform trial, more patients in the RAPID trial received other treatments with demonstrated evidence for benefit; 77% of patients were on steroids, 5% were on tocilizumab, and 13% were on remdesivir.
# Outcomes in Moderately Ill Patients
The multiplatform trial showed that therapeutic-dose anticoagulation increased organ support-free days as compared to usual care thromboprophylaxis with a posterior probability of 99.0% (median adjusted odds ratio 1.29, 95% credible interval (CrI) 1.04 to 1.61). A total of 76.4% of patients in the usual care thromboprophylaxis group survived to hospital discharge without requiring organ support during the first 21 days, compared with 80.2% in the therapeutic-dose group. The median adjusted absolute improvement in organ support-free survival to hospital discharge was 4.6% with therapeutic anticoagulation (95% CrI 0.7 to 8.1). There was no statistically significant difference between groups in the secondary endpoint of survival to hospital discharge, with 91.8% of patients in the usual care thromboprophylaxis surviving to hospital discharge as compared to 92.7% in the therapeutic dose anticoagulation Major bleeding occurred in 1.86% in the therapeutic anticoagulation arm as compared to 0.86% in the usual care thromboprophylaxis arm in the multiplatform trial, with a median adjusted proportional odds ratio for the secondary endpoint of freedom from major bleeding with therapeutic anticoagulation as compared to usual care thromboprophylaxis of 0.56 (95% CrI 0.27-1.11). Overt and symptomatic bleeding in a critical area or organ were rare with 9 events in the therapeutic anticoagulation group and 1 event in the usual care thromboprophylaxis group. There were 3 fatal bleeds in the therapeutic anticoagulation group and 1 fatal bleed in the usual care thromboprophylaxis group). Major bleeding occurred in 2 patients in the therapeutic heparin group and 4 patients in the prophylactic group (odds ratio 0.52; 95%-CI, 0.09 to 2.85) in the RAPID trial. There were no fatal bleeding events and no cases of intracranial hemorrhage in this trial.
A meta-analysis of RAPID and the multiplatform was performed, to evaluate safety and efficacy outcomes for moderately ill patients. There was no significant reduction in all-cause death (odds ratio, 0.74; 95%-CI, 0.54 to 1.02) with therapeutic heparin. There were significant reductions in the composite of death or invasive mechanical ventilation (odds ratio, 0.77; 95%-CI, 0.60 to 0.99), death or organ support (odds ratio, 0.77; 95%-CI, 0.63 to 0.93), death or major thrombotic event (odds ratio, 0.64; 95%-CI, 0.48 to 0.86), and major thrombotic events (odds ratio, 0.47; 95%-CI, 0.25 to 0.87). There were significant decreases in ventilator-free days alive (odds ratio, 1.30; 95%-CI 1.05 to 1.61) and organ support-free days alive (odds ratio 1.31, 95% 1.08 to 1.60) with therapeutic heparin. There was a non-significant increase in major bleeding. 7
# Outcomes in Critically Ill Patients
The multiplatform trial demonstrated that the median adjusted proportional odds ratio for the effect of therapeutic anticoagulation on organ support-free days was 0.87 (95% CrI 0.70-1.08), yielding a posterior probability of futility of 99.8% and a posterior probability of inferiority of 89.4%. The median value for organ supportfree days was 3 (interquartile range -1, 16) in participants randomized to therapeutic anticoagulation as compared to 5 (interquartile range -1, 16) in patients assigned to usual care thromboprophylaxis.
Major bleeding occurred in 3.1% of patients in the therapeutic anticoagulation group as compared to 2.4% of patients in the usual care thromboprophylaxis group in the multiplatform trial, with a median adjusted proportional odds ratio for the safety endpoint of major bleeding with therapeutic anticoagulation as compared to usual care thromboprophylaxis of 1.46 (95% CrI 0.61-3.49).
# Practical Considerations
Low molecular weight and unfractionated heparins are commonly used in the care of hospitalized patients. Protocols dealing with their use in specialized patient populations (e.g., renal failure, obesity) have been developed. In the Ontario context, we believe there are no specific concerns around cost, provincial supply, equity, feasibility, or acceptability associated with our recommendations.
# Should Therapeutic Dose Anticoagulation Be Continued or Initiated in Critically Ill Patients Who Show Clinical Improvement, and Are Now Considered Moderately Ill?
We recommend continuation of prophylactic dose anticoagulation in critically ill patients who improve and can be classified as moderately ill, unless they develop another indication for therapeutic dose anticoagulation. This strategy was used in the multiplatform trial protocol, and is likely to be perceived as feasible and acceptable by clinicians. Moreover, the putative anti-inflammatory effects of therapeutic dose anticoagulation, potentially important to prevent progression to critical illness, are likely less important in patients who are clinically improving. At this time, there is insufficient evidence to support "stepping up" to therapeutic dose anticoagulation for patients who have clinically improved from critical to moderate illness.
# Should Therapeutic Dose Anticoagulation Be Continued in Moderately Ill Patients Who Become Critically Ill?
Ontario COVID-19 Science Advisory Table Heparin Anticoagulation for Hospitalized Patients with COVID-19
We recommend continuation of therapeutic dose anticoagulation in moderately ill patients felt to be at low risk of bleeding who become critically ill, unless they develop a contraindication. This strategy was used in the multiplatform trial protocol, and is likely to be perceived as feasible and acceptable by clinicians. At this time, there is insufficient evidence to support "stepping down" to prophylactic dose anticoagulation at the time of transfer to a critical care setting.
# Should We Use Standard or Intensified Prophylactic Dose Low Molecular Weight or Unfractionated Heparin?
There is insufficient evidence at this time to recommend an intensified prophylactic dose of anticoagulation (also called "intermediate dose") in patients admitted to hospital with COVID-19. A multicentred RCT including 562 critically ill patients at 10 Iranian centres compared standard with intermediate dose anticoagulation (at a dose higher than standard prophylaxis, but lower than therapeutic anticoagulation) found no difference with respect to the composite endpoint of venous or arterial thrombosis, treatment with ECMO or 30 day mortality. Very low rates of venous thromboembolism were reported, however, and the study was underpowered. 14
# Should We Use Low Molecular Weight Heparin or Unfractionated Heparin?
Given the greater variability in anticoagulant response, increased laboratory monitoring requirements, and higher incidence of heparin induced thrombocytopenia with unfractionated heparin as compared to low molecular weight heparin, low molecular weight heparin is generally preferred over unfractionated heparin. 12 Intravenous unfractionated heparin may, however, be considered in patients with severe renal dysfunction (creatinine clearance less than 30 mL/min), who would benefit from a shorter acting anticoagulant (e.g., those with high bleeding risk, those who require brief periods of anticoagulant interruption), or in situations where subcutaneous medication absorption may be reduced or erratic (i.e., anasarca).
# Special Considerations with Pregnancy
While pregnant patients were excluded from the ACTIV-4a and RAPID trials (pregnancy not specified among exclusion criteria in ATTACC and REMAP-CAP trials), pregnant patients are at increased risk of morbidity and mortality due to COVID-19. 15 Low molecular weight and unfractionated heparins, due to their molecular size, do not cross the placenta. 16 Given the extensive experience and safety associated with these anticoagulants in pregnancy, we believe that the recommendations outlined in this document should apply to pregnant patients.
# Special Considerations with Breastfeeding
Unfractionated heparin, due to its molecular size, is not found in breastmilk. Small amounts of low molecular weight heparin may pass into breast milk, however, given their low bioavailability, do not result in an anticoagulant effect in the baby. Given the extensive experience and safety associated with both of these anticoagulants in lactation, we believe that the recommendations outlined in this document should apply to lactating patients.
# Recommendations
Please see the below section entitled "Methods Used for this Scientific Brief" for a description of COVID-19 illness severity criteria.
# Critically Ill Patients
Prophylactic dose low molecular weight or unfractionated heparin are recommended in critically ill patients hospitalized with COVID-19. These patients should not receive
Ontario COVID-19 Science Advisory Table Heparin Anticoagulation for Hospitalized Patients with COVID-19 therapeutic dose anticoagulation unless they have a separate indication for this treatment. Therapeutic dose anticoagulation in this patient population does not reduce the need for organ support and may increase bleeding events as compared to prophylactic dose anticoagulation.
The panel did not specifically review the indirect evidence for the use of prophylactic dose anticoagulation versus no anticoagulation in critically ill patients with COVID-19. Risk assessment models to estimate thrombotic risk in critically ill patients exist, but none have been specifically validated in patients with COVID-19. 8,9 However critically ill patients with COVID-19 are at higher risk of venous thromboembolism by virtue of having an acute infectious disease, organ failure, and may be considered to have a hypercoagulable state (given their high incidence of clinically evident thrombosis).
Many critically ill patients also have additional risk factors for thrombosis, including older age and immobility. For this reason, all critically ill patients are considered high risk for thrombosis, even after routine prophylactic anticoagulation; pharmacologic venous thromboembolism prophylaxis is accepted as standard of care, unless there are clear bleeding contraindications. 10,11 For this reason, prophylactic dose anticoagulation is likely to be perceived as feasible and acceptable by clinicians and patients, versus no anticoagulation. The rates of major bleeding in critically ill patients on prophylactic dose anticoagulation is approximately 5%; this is comparable to the findings of the multiplatform trial. 12
# Moderately Ill Patients
Therapeutic dose low molecular weight or unfractionated heparin may be considered over prophylactic dose anticoagulation in moderately ill patients who are felt to be at low risk of bleeding. All other patients should receive prophylactic dose anticoagulation, unless they have a separate indication for therapeutic dose anticoagulation. Therapeutic dose anticoagulation may reduce the need for organ support (including the need for high-flow nasal oxygen) and appears to decrease thrombotic events in moderately ill patients compared to lower intensity anticoagulation. Its benefits on survival are unclear, and it may increase major bleeding events. Given the small absolute risk reduction for patient-important outcomes and the known harms, a strong recommendation for therapeutic dose anticoagulation in moderately ill patients cannot be made at this time.
Risk assessment models to estimate bleeding risk in hospitalized patients exist, but none have been specifically validated in patients with COVID-19. 13 The cumulative incidence of major in-hospital bleeding within 14 days of admission in acutely ill hospitalized medical patients is approximately 1.2%. The panel defined patients at higher risk of bleeding as those who would have been excluded from the multiplatform trial: intracranial surgery or stroke within 3 months, history of intracerebral arteriovenous malformation, cerebral aneurysm or mass lesion of the central nervous system, intracranial malignancy, history of bleeding diatheses such as hemophilia, history of gastrointestinal bleeding within 3 months, thrombolysis within 1 week, epidural or spinal catheter, major surgery within 2 weeks, uncontrolled hypertension with systolic blood pressure over 200 mmHg or diastolic blood pressure over 120 mmHg, platelet count less than 50 x 10^9/L, INR over 2, baseline aPTT over 50 seconds, hemoglobin less than 80 g/L, acute or subacute bacterial endocarditis, or concurrent use of dual antiplatelet therapy.
A minority (⅓) of the guideline panel voted against the use of therapeutic dose anticoagulation versus prophylactic dose anticoagulation in moderately ill patients at low risk of bleeding. The majority (⅔) of the guideline panel voted for a conditional recommendation for therapeutic dose anticoagulation versus prophylactic dose anticoagulation in moderately ill patients at low risk of bleeding. The panel's ultimate recommendation is based on the perceived importance of both mortality and organ support free days to patients (in particular, avoiding intubation and possible transfer to another institution if a higher level of care is needed). There was a small absolute benefit for these outcomes, and the panel noted that The RAPID trial suggested that though therapeutic dose anticoagulation may reduce all-cause death, this benefit was not sustained when data from the RAPID trial and the multiplatform trial were metaanalyzed. They also noted that both the multiplatform trial's and the RAPID trial's definition of organ support free days included avoiding respiratory support via highflow nasal cannula, an outcome perceived to be less important to many patients. The panel's ultimate recommendation is also based on the perceived importance of survival to hospital discharge to patients, an outcome that showed minimal absolute benefit in the multiplatform trial.
It should be noted that the available evidence for anticoagulation reflects patients who largely did not receive other evidence-based therapies for COVID-19 such as tocilizumab, and remdesivir. The panel hypothesized that with improved, evidencebased therapy, the small absolute benefits of anticoagulation may be less pronounced, while its bleeding risks would remain the same. The panel also notes that the benefits of therapeutic anticoagulation may have been diluted in the multiplatform trial, and the harms of prophylactic anticoagulation may have been overstated, as 26.5% (227/855) of patients in the usual care group received intermediate dose thromboprophylaxis.
The panel did not specifically review the indirect evidence for the use of prophylactic dose anticoagulation versus no anticoagulation in moderately ill patients with COVID-19. Risk assessment models to estimate thrombotic risk in hospitalized patients exist, but none have been specifically validated in patients with COVID-19.8,9 Patients with COVID-19 are at higher risk of venous thromboembolism by virtue of having an acute infectious disease, and may be considered to have a hypercoagulable state (given their high incidence of clinically evident thrombosis). Many moderately ill patients also have additional risk factors for thrombosis, including age, immobility, and respiratory failure. For this reason, prophylactic dose anticoagulation is likely to be perceived as feasible and acceptable by clinicians and patients, versus no anticoagulation.
# Mildly Ill Patients
There is currently insufficient evidence to make a recommendation around anticoagulation for mildly ill patients.
# Methods Used for This Science Brief
We searched PubMed, Google Scholar, the COVID-19 Rapid Evidence Reviews, the Joanna Briggs Institute's COVID-19 Special Collection, LitCovid in PubMed, the Oxford COVID-19 Evidence Service, the World Health Organization's Global Literature on Coronavirus Disease, and other COVID-19 specific resources listed by the Guidelines International Network and the McMaster Health Forum. In addition, we retrieved reports citing relevant articles through Google Scholar and reviewed references from identified articles for additional studies. The search was last updated on August 20, 2021.
For therapeutic recommendations, we used the following definitions for severity:
# Critically Ill
Patients requiring ventilatory and/or circulatory support, including high-flow nasal oxygen, non-invasive ventilation, invasive mechanical ventilation, or ECMO. These patients are usually managed in an intensive care setting.
# Moderately Ill | The Ontario COVID-19 Science Advisory Table is a group of scientific experts and health system leaders who evaluate and report on emerging evidence relevant to the COVID-19 pandemic, to inform Ontario's response. Our mandate is to provide weekly summaries of relevant scientific evidence for the COVID-19 Health Coordination Table of the Province of Ontario, integrating information from existing scientific tables, Ontario's universities and agencies, and the best global evidence. The Science Table summarizes its findings for the Health Coordination Table and the public in Science Briefs.Guidelines Working Group is a group of clinicians and scientists with recognized expertise in drugs, biologics, and clinical care. The Working Group evaluates existing scientific data, disease epidemiology, drug availability, and implementation issues in order to develop Clinical Practice Guidelines for the treatment of COVID-19 using drugs and biologics. The Working Group reports its findings to the public and the Science Table . Its findings are also summarized in Science Briefs.#
Prophylactic dose low molecular weight or unfractionated heparin are recommended in critically ill patients hospitalized with COVID-19. These patients should not receive therapeutic dose anticoagulation unless they have a separate indication for this treatment. Therapeutic dose anticoagulation in this patient population does not reduce the need for organ support and may increase bleeding events as compared to prophylactic dose anticoagulation.
# Moderately Ill Patients
Therapeutic dose low molecular weight or unfractionated heparin may be considered over prophylactic dose anticoagulation in moderately ill patients who are felt to be at low risk of bleeding. All other patients should receive prophylactic dose anticoagulation, unless they have a separate indication for therapeutic dose anticoagulation. Therapeutic dose anticoagulation may reduce the need for organ support (including the need for high-flow nasal oxygen) and appears to decrease thrombotic events in moderately ill patients compared to lower intensity anticoagulation. Its benefits on survival are unclear, and it may increase major bleeding events. Given the small absolute risk reduction for patient-important outcomes and the known harms, a strong recommendation for therapeutic dose anticoagulation in moderately ill patients cannot be made.
# Mildly Ill Patients
There is insufficient evidence to make a recommendation around anticoagulation for mildly ill patients.
# Lay Summary
Patients with COVID-19 may become ill because of a combination of viral infection and the inflammation produced by the body's immune system in response to that infection. Inflammation can lead to blood clots which damage their lungs, heart, kidney, and other vital organs.
# How Low Molecular Weight and Unfractionated Heparin Work
Unfractionated heparin is a blood thinner (also called an anticoagulant). Low molecular weight heparins (including drugs like dalteparin, enoxaparin and tinzaparin) are also anticoagulants, which come from unfractionated heparin that has been broken down into smaller pieces. These anticoagulant medications make it more difficult for blood to clot and can be given in different doses to prevent clots (prophylactic dose) or to treat clots (therapeutic dose). Additionally, there is some evidence from laboratory experiments not conducted in humans that unfractionated and low molecular weight heparins may reduce inflammation. Other laboratory experiments have shown that unfractionated heparin may prevent the SARS-CoV-2 virus from attacking cells.
# How We Came to Our Recommendations
To understand low molecular weight and unfractionated heparin's effects on patients admitted to hospital with COVID-19, we reviewed a multiplatform randomized controlled trial (RCT) -a study that coordinated three similar RCTs to provide information on a larger group of patients -and a multicentre RCT. The multiplatform and multicentre RCTs compared the effects of these medications for treatment (therapeutic doses) and prevention (prophylactic doses). These studies involved thousands of patients in many different countries. They looked at patients with moderate illness (who were on low flow oxygen) as well as patients with severe illness (who required breathing and/or circulation support, including high flow oxygen).
# Our Recommendation for Patients Admitted to Hospital with COVID-19 with Critical Illness
Patients admitted to hospital with severe COVID-19 illness do not benefit from treatment dose anticoagulation, and may suffer harm from severe bleeding or the need for a blood transfusion. They should not receive therapeutic dose anticoagulation unless they need it for another medical condition. Prevention dose anticoagulation should be offered to these patients.
# Our Recommendation for Patients Admitted to Hospital with COVID-19 with Moderate Illness
Therapeutic dose anticoagulation may be given to patients admitted to hospital with moderate COVID-19 illness who are felt to be at a low risk of bleeding, after a discussion between the patient and the treating physician. This treatment may reduce the number of days that these patients spend receiving "intensive care", including high doses of oxygen, a ventilator, and/or medications that increase their blood pressure or help their heart pump. Therapeutic dose anticoagulation may reduce mortality, but may also increase the chance of severe bleeding or the need for a blood transfusion. For these reasons, therapeutic dose anticoagulation may not be appropriate for all patients. Prevention dose anticoagulation should be offered to all patients not on therapeutic dose, to reduce the chance that they will develop blood clots.
# Our Recommendation for Patients with COVID-19 with Mild Illness
We do not have enough evidence to make a recommendation about anticoagulation for patients with mild COVID-19 illness, who are usually not admitted to hospital. In general, these patients do not receive anticoagulation unless they need it for another medical condition.
# Side Effects of Anticoagulation
The most common side effect of anticoagulant medications is bleeding. Higher doses of anticoagulants are more likely to cause bleeding. In moderately ill patients admitted to hospital with COVID-19 who have a low risk of bleeding, the benefits of therapeutic dose anticoagulation may outweigh the risk of bleeding. Other patients may receive lower, preventative doses of anticoagulation.
In critically ill patients admitted to hospital with COVID-19, the benefits of therapeutic dose anticoagulation do not outweigh the risks of bleeding. These patients do not benefit from a higher dose of anticoagulant treatment. They should receive lower, prevention doses of anticoagulation.
# Background
COVID-19-associated thrombosis, provoked by profound inflammation and viralmediated effects on cells, has been reported since the early days of the pandemic. 1 Despite the use of prophylactic dose anticoagulation, venous and arterial thrombosesincluding in situ pulmonary thrombosis, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, intravenous catheter thrombosis, and limb ischemiaare common in patients with COVID-19. A meta-analysis of studies utilizing various thromboprophylactic strategies reported venous thromboembolism in 5.5% of admitted non-critically ill patients and 18.7% of critically ill patients when patients were not screened for venous thrombosis with imaging, and rates of 23% and 45.6% in noncritically ill and critically ill patients respectively when routine screening was used. 2 Unfractionated and low molecular weight heparins are commonly used parenteral anticoagulants for the prevention and treatment of venous and arterial thromboembolism. Unfractionated heparin is a mixture of proteoglycans of various chain lengths which bind to anti-thrombin to inhibit coagulation factors. Low molecular weight heparins, including dalteparin, enoxaparin, and tinzaparin, are smaller chain length molecules fractionated from heparin which also bind to anti-thrombin and inhibit coagulation factors Xa and IIa.
In addition to their anticoagulant activity, heparins have anti-inflammatory and, possibly, antiviral activity. Anti-inflammatory effects occur through inhibition of neutrophil activation and function, interaction with vascular endothelium to prevent inflammatory mediator expression, prevention of vascular smooth muscle cell proliferation, 3 and anticoagulant activity. In vitro studies have demonstrated that unfractionated heparin may bind to the SARS-CoV-2 spike protein and act as a competitive inhibitor for viral entry into the host cell. 4 As such, it was hypothesized that an increased heparin dose in COVID-19 patients may improve outcomes through multiple mechanisms.
# Questions
Does anticoagulation improve outcomes, such as mortality, need for mechanical ventilation, and organ support-free days for patients with COVID-19?
What are the indications for therapeutic dose and prophylactic dose heparin in moderately and critically ill patients?
What is the risk of major bleeding in moderately and critically ill patients?
# Findings Overview of Key Trials
# Multiplatform Trial Including ATTACC, ACTIV-4a and REMAP-CAP
The randomized multiplatform trial including ATTACC, ACTIV-4a and REMAP-CAP compared therapeutic anticoagulation with usual care thromboprophylaxis (standard prophylactic or intermediate dose) in hospitalized COVID-19 patients. Enrollment was discontinued in the critically ill cohort on December 19, 2020, after an interim analysis showed that the statistical criterion for futility had been met. On January 22, 2021, enrollment in the non-critically ill cohort was discontinued on the advice of the data and safety monitoring boards after a planned analysis of data in accordance with the adaptive design. Papers describing both arms were published on August 4, 2021. 5,6 The multiplatform RCT used a composite primary outcome combining in-hospital mortality and days free of organ support. This outcome was an ordinal scale combining in-hospital mortality (assigned a value of -1) and days free of organ support (invasive or non-invasive mechanical ventilation, high flow nasal oxygen, vasopressor therapy, or extracorporeal membrane oxygenation (ECMO)) to day 21 (worst score of -1 and best score of 21). For example, a patient who died at day 18 would be assigned a score of -1 and a patient who survived and no longer required organ support at day 15 would be assigned a score of 6. The multiplatform RCT also considered other patientimportant outcomes such as survival to hospital discharge without thrombosis, bleeding, survival to hospital discharge, survival without organ support through 28 days, and survival without intubation; these were considered secondary outcomes.
The trial in the critically ill cohort enrolled 1,089 patients between April 21, 2020 and December 19, 2020 in 10 countries (United Kingdom, Ireland, Netherlands, Australia, New Zealand, Saudi Arabia, Canada, United States, Brazil and Mexico). The trial in the moderately ill cohort enrolled 2,219 patients between April 21, 2020 and January 22, 2021 in 9 countries (United States, Canada, United Kingdom, Brazil, Mexico, Nepal, Australia, Netherlands, and Spain). A substantial proportion of patients in this multiplatform trial did not receive other treatments with demonstrated evidence for benefit: only 60% of moderately ill patients were on corticosteroids (a therapy that is now nearly universally used in this population), 0.5% were on tocilizumab, and 36% were on remdesivir.
# RAPID Trial
The randomized multicentre RAPID trial comparing therapeutic anticoagulation with thromboprophylaxis (prophylactic standard dose) in moderately ill hospitalized COVID-19 patients completed enrollment on April 12, 2021, and was published in preprint form on July 12, 2021. 7 The RAPID trial's primary outcome was a composite of intensive care unit (ICU) admission, non-invasive (bilevel or continuous positive airway pressure) or invasive mechanical ventilation, or death up to 28 days. Secondary outcomes included: allcause death; the composite of any mechanical ventilation or all-cause death; ICU admission or all-cause death; ventilator-free days alive; organ support-free days alive; ICU-free days alive; hospital free days alive; renal replacement therapy; venous thromboembolism; arterial thromboembolism; and D-dimer level at 2 days ± 24 hours post-randomization.
The trial included 465 patients enrolled between May 29, 2020 and April 12, 2021 at 28 sites in 6 countries in 10 countries (Canada, Saudi Arabia, Brazil, United States, Ireland and United Arab Emirates). Patients were required to have D-dimer levels above the upper limit of normal (ULN) of the local hospital in the presence of an oxygen saturation ≤93% on room air, or ≥2 times the ULN irrespective of oxygen saturation. Compared to the multiplatform trial, more patients in the RAPID trial received other treatments with demonstrated evidence for benefit; 77% of patients were on steroids, 5% were on tocilizumab, and 13% were on remdesivir.
# Outcomes in Moderately Ill Patients
The multiplatform trial showed that therapeutic-dose anticoagulation increased organ support-free days as compared to usual care thromboprophylaxis with a posterior probability of 99.0% (median adjusted odds ratio 1.29, 95% credible interval (CrI) 1.04 to 1.61). A total of 76.4% of patients in the usual care thromboprophylaxis group survived to hospital discharge without requiring organ support during the first 21 days, compared with 80.2% in the therapeutic-dose group. The median adjusted absolute improvement in organ support-free survival to hospital discharge was 4.6% with therapeutic anticoagulation (95% CrI 0.7 to 8.1). There was no statistically significant difference between groups in the secondary endpoint of survival to hospital discharge, with 91.8% of patients in the usual care thromboprophylaxis surviving to hospital discharge as compared to 92.7% in the therapeutic dose anticoagulation Major bleeding occurred in 1.86% in the therapeutic anticoagulation arm as compared to 0.86% in the usual care thromboprophylaxis arm in the multiplatform trial, with a median adjusted proportional odds ratio for the secondary endpoint of freedom from major bleeding with therapeutic anticoagulation as compared to usual care thromboprophylaxis of 0.56 (95% CrI 0.27-1.11). Overt and symptomatic bleeding in a critical area or organ were rare with 9 events in the therapeutic anticoagulation group and 1 event in the usual care thromboprophylaxis group. There were 3 fatal bleeds in the therapeutic anticoagulation group and 1 fatal bleed in the usual care thromboprophylaxis group). Major bleeding occurred in 2 patients in the therapeutic heparin group and 4 patients in the prophylactic group (odds ratio 0.52; 95%-CI, 0.09 to 2.85) in the RAPID trial. There were no fatal bleeding events and no cases of intracranial hemorrhage in this trial.
A meta-analysis of RAPID and the multiplatform was performed, to evaluate safety and efficacy outcomes for moderately ill patients. There was no significant reduction in all-cause death (odds ratio, 0.74; 95%-CI, 0.54 to 1.02) with therapeutic heparin. There were significant reductions in the composite of death or invasive mechanical ventilation (odds ratio, 0.77; 95%-CI, 0.60 to 0.99), death or organ support (odds ratio, 0.77; 95%-CI, 0.63 to 0.93), death or major thrombotic event (odds ratio, 0.64; 95%-CI, 0.48 to 0.86), and major thrombotic events (odds ratio, 0.47; 95%-CI, 0.25 to 0.87). There were significant decreases in ventilator-free days alive (odds ratio, 1.30; 95%-CI 1.05 to 1.61) and organ support-free days alive (odds ratio 1.31, 95% 1.08 to 1.60) with therapeutic heparin. There was a non-significant increase in major bleeding. 7
# Outcomes in Critically Ill Patients
The multiplatform trial demonstrated that the median adjusted proportional odds ratio for the effect of therapeutic anticoagulation on organ support-free days was 0.87 (95% CrI 0.70-1.08), yielding a posterior probability of futility of 99.8% and a posterior probability of inferiority of 89.4%. The median value for organ supportfree days was 3 (interquartile range -1, 16) in participants randomized to therapeutic anticoagulation as compared to 5 (interquartile range -1, 16) in patients assigned to usual care thromboprophylaxis.
Major bleeding occurred in 3.1% of patients in the therapeutic anticoagulation group as compared to 2.4% of patients in the usual care thromboprophylaxis group in the multiplatform trial, with a median adjusted proportional odds ratio for the safety endpoint of major bleeding with therapeutic anticoagulation as compared to usual care thromboprophylaxis of 1.46 (95% CrI 0.61-3.49).
# Practical Considerations
Low molecular weight and unfractionated heparins are commonly used in the care of hospitalized patients. Protocols dealing with their use in specialized patient populations (e.g., renal failure, obesity) have been developed. In the Ontario context, we believe there are no specific concerns around cost, provincial supply, equity, feasibility, or acceptability associated with our recommendations.
# Should Therapeutic Dose Anticoagulation Be Continued or Initiated in Critically Ill Patients Who Show Clinical Improvement, and Are Now Considered Moderately Ill?
We recommend continuation of prophylactic dose anticoagulation in critically ill patients who improve and can be classified as moderately ill, unless they develop another indication for therapeutic dose anticoagulation. This strategy was used in the multiplatform trial protocol, and is likely to be perceived as feasible and acceptable by clinicians. Moreover, the putative anti-inflammatory effects of therapeutic dose anticoagulation, potentially important to prevent progression to critical illness, are likely less important in patients who are clinically improving. At this time, there is insufficient evidence to support "stepping up" to therapeutic dose anticoagulation for patients who have clinically improved from critical to moderate illness.
# Should Therapeutic Dose Anticoagulation Be Continued in Moderately Ill Patients Who Become Critically Ill?
Ontario COVID-19 Science Advisory Table Heparin Anticoagulation for Hospitalized Patients with COVID-19
We recommend continuation of therapeutic dose anticoagulation in moderately ill patients felt to be at low risk of bleeding who become critically ill, unless they develop a contraindication. This strategy was used in the multiplatform trial protocol, and is likely to be perceived as feasible and acceptable by clinicians. At this time, there is insufficient evidence to support "stepping down" to prophylactic dose anticoagulation at the time of transfer to a critical care setting.
# Should We Use Standard or Intensified Prophylactic Dose Low Molecular Weight or Unfractionated Heparin?
There is insufficient evidence at this time to recommend an intensified prophylactic dose of anticoagulation (also called "intermediate dose") in patients admitted to hospital with COVID-19. A multicentred RCT including 562 critically ill patients at 10 Iranian centres compared standard with intermediate dose anticoagulation (at a dose higher than standard prophylaxis, but lower than therapeutic anticoagulation) found no difference with respect to the composite endpoint of venous or arterial thrombosis, treatment with ECMO or 30 day mortality. Very low rates of venous thromboembolism were reported, however, and the study was underpowered. 14
# Should We Use Low Molecular Weight Heparin or Unfractionated Heparin?
Given the greater variability in anticoagulant response, increased laboratory monitoring requirements, and higher incidence of heparin induced thrombocytopenia with unfractionated heparin as compared to low molecular weight heparin, low molecular weight heparin is generally preferred over unfractionated heparin. 12 Intravenous unfractionated heparin may, however, be considered in patients with severe renal dysfunction (creatinine clearance less than 30 mL/min), who would benefit from a shorter acting anticoagulant (e.g., those with high bleeding risk, those who require brief periods of anticoagulant interruption), or in situations where subcutaneous medication absorption may be reduced or erratic (i.e., anasarca).
# Special Considerations with Pregnancy
While pregnant patients were excluded from the ACTIV-4a and RAPID trials (pregnancy not specified among exclusion criteria in ATTACC and REMAP-CAP trials), pregnant patients are at increased risk of morbidity and mortality due to COVID-19. 15 Low molecular weight and unfractionated heparins, due to their molecular size, do not cross the placenta. 16 Given the extensive experience and safety associated with these anticoagulants in pregnancy, we believe that the recommendations outlined in this document should apply to pregnant patients.
# Special Considerations with Breastfeeding
Unfractionated heparin, due to its molecular size, is not found in breastmilk. Small amounts of low molecular weight heparin may pass into breast milk, however, given their low bioavailability, do not result in an anticoagulant effect in the baby. Given the extensive experience and safety associated with both of these anticoagulants in lactation, we believe that the recommendations outlined in this document should apply to lactating patients.
# Recommendations
Please see the below section entitled "Methods Used for this Scientific Brief" for a description of COVID-19 illness severity criteria.
# Critically Ill Patients
Prophylactic dose low molecular weight or unfractionated heparin are recommended in critically ill patients hospitalized with COVID-19. These patients should not receive
Ontario COVID-19 Science Advisory Table Heparin Anticoagulation for Hospitalized Patients with COVID-19 therapeutic dose anticoagulation unless they have a separate indication for this treatment. Therapeutic dose anticoagulation in this patient population does not reduce the need for organ support and may increase bleeding events as compared to prophylactic dose anticoagulation.
The panel did not specifically review the indirect evidence for the use of prophylactic dose anticoagulation versus no anticoagulation in critically ill patients with COVID-19. Risk assessment models to estimate thrombotic risk in critically ill patients exist, but none have been specifically validated in patients with COVID-19. 8,9 However critically ill patients with COVID-19 are at higher risk of venous thromboembolism by virtue of having an acute infectious disease, organ failure, and may be considered to have a hypercoagulable state (given their high incidence of clinically evident thrombosis).
Many critically ill patients also have additional risk factors for thrombosis, including older age and immobility. For this reason, all critically ill patients are considered high risk for thrombosis, even after routine prophylactic anticoagulation; pharmacologic venous thromboembolism prophylaxis is accepted as standard of care, unless there are clear bleeding contraindications. 10,11 For this reason, prophylactic dose anticoagulation is likely to be perceived as feasible and acceptable by clinicians and patients, versus no anticoagulation. The rates of major bleeding in critically ill patients on prophylactic dose anticoagulation is approximately 5%; this is comparable to the findings of the multiplatform trial. 12
# Moderately Ill Patients
Therapeutic dose low molecular weight or unfractionated heparin may be considered over prophylactic dose anticoagulation in moderately ill patients who are felt to be at low risk of bleeding. All other patients should receive prophylactic dose anticoagulation, unless they have a separate indication for therapeutic dose anticoagulation. Therapeutic dose anticoagulation may reduce the need for organ support (including the need for high-flow nasal oxygen) and appears to decrease thrombotic events in moderately ill patients compared to lower intensity anticoagulation. Its benefits on survival are unclear, and it may increase major bleeding events. Given the small absolute risk reduction for patient-important outcomes and the known harms, a strong recommendation for therapeutic dose anticoagulation in moderately ill patients cannot be made at this time.
Risk assessment models to estimate bleeding risk in hospitalized patients exist, but none have been specifically validated in patients with COVID-19. 13 The cumulative incidence of major in-hospital bleeding within 14 days of admission in acutely ill hospitalized medical patients is approximately 1.2%. The panel defined patients at higher risk of bleeding as those who would have been excluded from the multiplatform trial: intracranial surgery or stroke within 3 months, history of intracerebral arteriovenous malformation, cerebral aneurysm or mass lesion of the central nervous system, intracranial malignancy, history of bleeding diatheses such as hemophilia, history of gastrointestinal bleeding within 3 months, thrombolysis within 1 week, epidural or spinal catheter, major surgery within 2 weeks, uncontrolled hypertension with systolic blood pressure over 200 mmHg or diastolic blood pressure over 120 mmHg, platelet count less than 50 x 10^9/L, INR over 2, baseline aPTT over 50 seconds, hemoglobin less than 80 g/L, acute or subacute bacterial endocarditis, or concurrent use of dual antiplatelet therapy.
A minority (⅓) of the guideline panel voted against the use of therapeutic dose anticoagulation versus prophylactic dose anticoagulation in moderately ill patients at low risk of bleeding. The majority (⅔) of the guideline panel voted for a conditional recommendation for therapeutic dose anticoagulation versus prophylactic dose anticoagulation in moderately ill patients at low risk of bleeding. The panel's ultimate recommendation is based on the perceived importance of both mortality and organ support free days to patients (in particular, avoiding intubation and possible transfer to another institution if a higher level of care is needed). There was a small absolute benefit for these outcomes, and the panel noted that The RAPID trial suggested that though therapeutic dose anticoagulation may reduce all-cause death, this benefit was not sustained when data from the RAPID trial and the multiplatform trial were metaanalyzed. They also noted that both the multiplatform trial's and the RAPID trial's definition of organ support free days included avoiding respiratory support via highflow nasal cannula, an outcome perceived to be less important to many patients. The panel's ultimate recommendation is also based on the perceived importance of survival to hospital discharge to patients, an outcome that showed minimal absolute benefit in the multiplatform trial.
It should be noted that the available evidence for anticoagulation reflects patients who largely did not receive other evidence-based therapies for COVID-19 such as tocilizumab, and remdesivir. The panel hypothesized that with improved, evidencebased therapy, the small absolute benefits of anticoagulation may be less pronounced, while its bleeding risks would remain the same. The panel also notes that the benefits of therapeutic anticoagulation may have been diluted in the multiplatform trial, and the harms of prophylactic anticoagulation may have been overstated, as 26.5% (227/855) of patients in the usual care group received intermediate dose thromboprophylaxis.
The panel did not specifically review the indirect evidence for the use of prophylactic dose anticoagulation versus no anticoagulation in moderately ill patients with COVID-19. Risk assessment models to estimate thrombotic risk in hospitalized patients exist, but none have been specifically validated in patients with COVID-19.8,9 Patients with COVID-19 are at higher risk of venous thromboembolism by virtue of having an acute infectious disease, and may be considered to have a hypercoagulable state (given their high incidence of clinically evident thrombosis). Many moderately ill patients also have additional risk factors for thrombosis, including age, immobility, and respiratory failure. For this reason, prophylactic dose anticoagulation is likely to be perceived as feasible and acceptable by clinicians and patients, versus no anticoagulation.
# Mildly Ill Patients
There is currently insufficient evidence to make a recommendation around anticoagulation for mildly ill patients.
# Methods Used for This Science Brief
We searched PubMed, Google Scholar, the COVID-19 Rapid Evidence Reviews, the Joanna Briggs Institute's COVID-19 Special Collection, LitCovid in PubMed, the Oxford COVID-19 Evidence Service, the World Health Organization's Global Literature on Coronavirus Disease, and other COVID-19 specific resources listed by the Guidelines International Network and the McMaster Health Forum. In addition, we retrieved reports citing relevant articles through Google Scholar and reviewed references from identified articles for additional studies. The search was last updated on August 20, 2021.
For therapeutic recommendations, we used the following definitions for severity:
# Critically Ill
Patients requiring ventilatory and/or circulatory support, including high-flow nasal oxygen, non-invasive ventilation, invasive mechanical ventilation, or ECMO. These patients are usually managed in an intensive care setting.
# Moderately Ill
# Acknowledgements
The authors would like to acknowledge the important contributions of the Ontario COVID-19 Antimicrobial and Immunomodulatory Clinical Practice Guidelines Committee throughout the COVID-19 pandemic.
#
Patients newly requiring low-flow supplemental oxygen. These patients are usually managed in hospital wards.
# Mildly Ill
Patients who do not require new or additional supplemental oxygen from their baseline status, intravenous fluids, or other physiological support. These patients are usually managed in an ambulatory/outpatient setting.
# Author Contributions
SC wrote the first draft of the Science Brief. All authors contributed to the conception of the Science Brief, revised it critically for important intellectual content, and approved the final version.
The authors would like to thank all members of the Drugs and Biologics Clinical Practice Guideline Working Group for their contribution to this Science Brief. Members are listed here: https://covid19-sciencetable.ca/about/.
The Ontario COVID Drugs and Biologics Clinical Practice Guidelines and associated Science Briefs are currently available at https://antimicrobialstewardship.com and https://covid19-sciencetable.ca/sciencebrief/. | None | None |
21a99c57522e62bf2b4eaaa8ae48bb9a06954163 | cma | None | The affiliations of the members of the Ontario COVID-19 Science Advisory Table can be found at https:// covid19-sciencetable.ca/.#
publichealthontario.ca/en/health-topics/infection-prevention-control/routine-practices-additional-precautions The three pediatric transplant centers are The Hospital for Sick Children (Toronto, Ontario), Stollery Children's Hospital (Edmonton, Alberta) and CHU Sainte-Justine (Montreal, Quebec). # See Section on "What tests should be completed" and / Test-Information-Index/Hepatitis-of-Unknown-Origin-in-Children $ hepatitis_2022_05_03.pdf.
# Ontario COVID-19 Science Advisory Table
Severe Acute Hepatitis in Children of Unknown Etiology Science Brief are those of the authors and do not necessarily reflect the views of all of the members of the Ontario COVID-19 Science Advisory Table, its Working Groups, and its partners.
Clinicians need to be aware of how to recognize severity of acute hepatitis in children, what investigations to perform, and threshold to refer to a pediatric gastroenterologist or a liver transplant center. This document summarizes a pathway for the evaluation of children with severe acute hepatitis of unknown etiology and highlights the importance of immediately consulting with a pediatric gastroenterologist if the INR is elevated (greater or equal to than 1.5) and/or serum direct bilirubin is elevated to prioritize investigations and guide management.
# Summary
# Background
A series of reports originating in Alabama, United States and Scotland in spring 2022 identified a potential concern about an increase in cases of acute severe hepatitis of unknown etiology in children.
Surveillance has been implemented across many jurisdictions globally to identify cases, investigate etiologies, and monitor trends. Given that these reports were emerging during the COVID-19 pandemic, a potential relationship between SARS-CoV-2 infection and acute severe hepatitis is important to explore, among other etiologies. However, many patients have not had complete workups reported in the literature, limiting the epidemiological investigation to date.
# Questions
How is severe acute hepatitis of unknown etiology in children defined?
What are potential causes of severe acute hepatitis of unknown etiology in children?
What symptoms should make you suspect acute hepatitis in children?
What tests need to be prioritized and should be completed?
When should I refer?
# Findings
Acute severe hepatitis is the sudden onset of liver inflammation and the most severe condition in the spectrum of severe acute hepatitis is pediatric acute liver failure (PALF). There is a broad differential diagnoses for severe acute hepatitis and PALF and it is important to ensure a thorough workup is sent and treatable conditions are recognized early. It is essential that clinicians are able to recognize severe acute hepatitis, decide which diagnostic tests to initiate and when to refer to a pediatric liver specialist or center.
The presence of scleral icterus (yellow pigmentation of the white areas of the eye) or other signs of jaundice are more specific manifestations of severe hepatitis and symptoms that warrant urgent testing. Other less specific symptoms include dark urine and/or pale stools, skin irritation, easy bleeding/bruising, muscle aches, lethargic behaviour, loss of appetite, nausea and vomiting and fever. Recognition of these symptoms combined with a detailed medical history and followed by a combination of clinical, biochemical, radiological and histopathology studies can confirm a clinical diagnosis of acute severe hepatitis.
To date, there is insufficient data to determine whether there has been a recent increase in the incidence of acute severe hepatitis in children. Furthermore, current surveillance data has not conclusively identified a specific infectious or non-infectious cause. A potential role for SARS-CoV-2 or adenovirus infection has been raised but remains unproven at the present time. Several other hypotheses being explored include drug, toxin or environmental exposure or any combination of factors. There is no evidence of a link between any SARS-CoV-2 vaccine with severe acute hepatitis 3 The challenge is that that the baseline incidence of this condition is unknown and the incidence of severe acute hepatitis with the same definitions in prior comparable periods is not available in most jurisdictions. It is therefore difficult to determine whether there has been a true increase in incidence or whether heightened awareness and associated surveillance have led to the increased case identification. In a recent survey, 5 out of 17 European countries and 1 out of 7 non-European countries reported an increase compared with previous years, although limited details were provided on whether and how the numbers were substantiated. 4 Notably, recent data from the US did not find an increase in hepatitis-associated emergency department visits, hospitalizations or liver transplants compared to pre-COVID-19 pandemic baseline levels. 5 In addition, the incidence of pediatric acute liver failure (PALF; also referred to as fulminant liver failure or fulminant hepatitis), the most severe phenotype of severe acute hepatitis in children, remains uncertain, despite the availability of a clear definition. 6 INR values, the key indicator of liver synthetic function used to assess for PALF, were not provided in either of the 2 initial reports, 1,2 although data are emerging in more recent reports from transplant centers. 7 Given these gaps in the literature, it remains challenging to determine if the current cluster of cases represents a new increased signal of concern. Corresponding cases of severe hepatitis of unknown etiology have not been noted in adults. Nevertheless, a potential increased incidence of severe hepatitis and acute liver failure (as described below) warrants immediate attention and public health agencies worldwide have mandated clinicians to report cases to enable the goal of investigating possible etiologies and monitoring trends. Given the occurrence of these cases during the COVID-19 pandemic, it is important to assess for any possible relationship (or lack thereof) to the pandemic as covered in this document. In this regard, beyond the possibility of a specific new etiologic agent, it is necessary to explore if the pandemic influenced disease epidemiology or reporting patterns culminating in the genesis of the above reports. This document aims to provide background and guidance to clinicians who first encounter children with acute hepatitis, including recommended investigations to evaluate for possible etiologies (summarized below). 8 Ontario COVID-19 Science Advisory Table Severe Acute Hepatitis in Children of Unknown Etiology
# Questions
How is severe acute hepatitis of unknown etiology in children defined?
What are potential causes of severe acute hepatitis of unknown etiology in children?
What symptoms should make you suspect acute hepatitis in children?
What tests need to be prioritized and should be completed?
When should I refer?
# Findings
How is Severe Acute Hepatitis of Unknown Etiology in Children Defined?
Acute hepatitis is diagnosed from a combination of clinical, biochemical, and ideally histopathological data, used to confirm the presence and severity of inflammation of the liver. Most patients are previously healthy without clinically significant medical comorbidities, and present with symptoms (liver-specific like jaundice or abdominal distention, or non-liver-specific like nausea, diarrhea, abdominal pain, malaise, etc.) that lead to a clinician ordering bloodwork noteworthy for markedly elevated transaminases. Many have a preceding viral prodrome, often gastrointestinal symptoms including vomiting as a prominent feature.
Acute hepatitis presents along a spectrum of severity, ranging from asymptomatic liver enzyme elevation to PALF. PALF is the most severe condition in the spectrum of severe acute hepatitis. The definition of PALF proposed by the NIH-supported Pediatric Acute Liver Failure Study Group (PALFSG) highlighted distinctions from the longstanding definition in adults in that hepatic encephalopathy is not a defining feature.6 Rather, PALF is defined by biochemical evidence of acute liver injury and hepatic-based coagulopathy (uncorrectable INR ≥ 1.5 in the presence of clinical hepatic encephalopathy or INR ≥2.0 not corrected by IV vitamin K in a child without encephalopathy). PALF accounts for approximately 10-15% of pediatric liver transplants performed in Canada and the United States annually. 6 Publications from the PALF Study Group reported that more than 50% of patients were categorized as indeterminate (PALF-I), defined as absence of an identifiable etiology. 6 To date, of the 650 probable cases of severe acute hepatitis of unknown etiology identified by the WHO, at least 38 (6%) have required transplantation and nine (1%) deaths have been reported. 3 Recent data from the US has not found an increase in hepatitis-associated emergency department visits, hospitalizations or liver transplants compared to pre-COVID-19 pandemic baseline levels. 5 That said, within the reported number of cases, it is possible that some new etiologies could exist.
It is difficult to gauge the incidence of acute hepatitis in children as the true denominator for elevated serum ALT levels is unknown due to wide variability in the diagnostic and laboratory work up of symptomatic children.
# Surveillance Case Definition of Severe Acute Hepatitis of Unknown Etiology in Children
Triggered by the initial cases in Alabama and Scotland, public health agencies developed surveillance case definitions for this entity. As of June 13, 2022, the current probable case definition developed by WHO and used by many international jurisdictions includes a person who is 16 years or younger presenting with acute hepatitis (non-hepatitis virus A-E) AND serum liver transaminase (AST or ALT) level >500 IU/L, since October 1, 2021. 3,9 There are several aspects of the case definition that warrant further discussion:
- Surveillance definitions are not meant to be used as diagnostic definitions or for clinical purposes, they are often broad to enable case finding and explore associations. A sensitive (broad) case definition enables case finding, but will capture other etiologies (both known and unknown) -sensitivity is intentionally high, acknowledging lower specificity. The case definition in all jurisdictions excludes certain etiologies known to cause hepatitis (e.g., hepatotropic viruses -hepatitis A-E), but there is variability in the requirements for reporting cases of acute hepatitis caused by known etiologies.
- Direct comparisons of numbers between jurisdictions may not be accurate if different surveillance case definitions are being used. There are two notable differences in surveillance definitions between jurisdictions. These include 1) variation in the definition used for "severity", which ranges from biochemical markers alone (i.e., ALT > 500 IU/L) to requiring hospitalization and 2) variation with inclusion/exclusion of cases of acute hepatitis attributed to known etiologies (e.g., autoimmune hepatitis) with available targeted medical treatments. In Ontario, the current surveillance definition of a probable case includes the following: 1) A person who is 16 years and younger presenting with clinical evidence of severe acute hepatitis since October 2021 and requiring hospitalization, AND 2) elevated serum transaminase >500 IU/L (AST or ALT) or INR > 2.0, AND 3) excluding hepatitis caused or attributed to a hepatitis virus (A,B,C,D,E) or a known or expected presentation of a drug or medication; a genetic, congenital, or metabolic condition; an oncologic, vascular, or ischemia-related condition; or an acute worsening of chronic hepatitis. 10 However, cases identified as autoimmune hepatitis (AIH) and hemophagocytic lymphohistiocytosis (HLH) are required to be reported.
Understanding that the surveillance definition assists in detecting a potential signal of an increase in the incidence of severe acute hepatitis is critical to interpreting the reported numbers. However, these numbers have not historically been reported, so it is challenging to determine if there is in fact a signal of concern, unless appropriate methodology for case finding is followed and compared to prior corresponding periods of time. All these factors can lead to uncertainty when examining reported cases across the world.
# What Are Potential Causes of Severe Acute Hepatitis of Unknown Etiology in Children?
There is a broad differential for acute hepatitis 11,12 and PALF 13 in children, including infectious as well as non-infectious conditions. However, to date, there is no conclusive evidence attributing cases of severe acute hepatitis of unknown etiology to any one infectious or non-infectious condition. More robust data are needed to understand whether there is truly an increase in acute hepatitis in children and if so, the cause. Potential etiological hypotheses to date include adenovirus and SARS-CoV-2 infection, although data are limited and inconsistent to date. 8
# Evidence for Adenovirus
Adenovirus has been detected in some, but not all children reported as cases of severe acute hepatitis of unknown etiology. In the UK case series of 163 children, 126 were tested for adenovirus and 72% were positive on any specimen. 8 This corresponded to a time when there was evidence of increased adenovirus detection in the community. 8 In the Alabama case series, all 9 patients (100%) tested positive for adenovirus by polymerase chain reaction (PCR) on blood samples (initial viral load range = 991-70,680 copies/mL). 2 However, since these initial reports, several additional countries have reported cases where adenovirus has not been found (e.g., Israel), or found in a smaller proportion of cases (e.g., Spain, Netherlands, Japan). 3 It is important to recognize that adenovirus infections are very common in children.
There are more than 100 types of adenovirus divided into seven subgroups (A to G). 14 Most children have been infected by at least one adenovirus by the age of 5 years and the virus can be detected by PCR in up to 11% of healthy, asymptomatic children from throat samples. 15 Adenovirus may be incidentally detected due to persistence or asymptomatic shedding, limiting the utility of PCR detection alone in respiratory, stool or even blood samples, in attributing causality. While detection in the blood may be considered stronger evidence for a role in hepatitis, testing for adenovirus in blood samples using PCR is rarely performed in otherwise healthy children with uncomplicated infection (i.e., gastroenteritis), so the frequency with which adenovirus is found in the blood is unknown. For a hepatitis to be clearly attributed to a viral infection of the liver, evidence of viral inclusions should be seen on liver pathology, 16 as has been reported for adenovirus hepatitis. 17 Notably, the liver biopsies from patients in the Alabama case series (n=6) did not show viral inclusions, immunohistochemical evidence of adenovirus or viral particles, which raises significant questions around the role of adenovirus infection as a direct cause of this entity. However, an adenovirustriggered inflammatory or autoimmune process cannot be excluded. Notably, 6 of the Alabama cases tested positive for EBV DNA in blood by quantitative PCR, but all 5 who were tested for EBV IgM were negative, so these cases did not have acute EBV infection (no such resolution using serology is available for adenovirus).
Adenovirus 41, the strain that has been identified as a possible etiology in recent reports, 2 is most commonly associated with gastroenteritis, whereas the serotypes known to cause hepatitis (1,2,3,5 and 7) and other non-40/41 serotypes that have broader cell tropism, have not been identified in any cases to date. Patterns of circulating adenovirus in children without clinical hepatitis have not been reported in most series, making it difficult to assess whether the incidence of adenovirus 41 is elevated amongst those presenting with severe acute hepatitis compared to the general pediatric population in these jurisdictions.
# Evidence for SARS-CoV-2
The recent increase in infections worldwide due to SARS-CoV-2, particularly the Omicron variant, coincided with reported cases of hepatitis of unknown etiology.
For the majority of case series published and cases reported, SARS-CoV-2 has been infrequently isolated at the time of hepatitis presentation. In the UK case series (n=163), of 132 children tested, 24 (18%) tested positive by PCR, including 11 of the 97 cases (11%) from England. 8 Similarly, of the 188 cases from Europe tested for SARS-
CoV-2, 23 (12.2%) were positive. 18 However, when one considers both evidence of acute and previous infection, the strength of association may increase. In a preprint from India, 19 among 37 cases of hepatitis between April -July 2021, all were either infected with or had prior evidence of SARS-CoV-2 infection. Furthermore, from the European surveillance data, while serology results were only available on 26 cases, 19 (73.1%) were seropositive. 18 However, with the high circulating levels of SARS-CoV-2 in the community for over 2 years, it is possible that these findings may be similar to the prevalence of past/current SARS-CoV-2 infection at the population level in children.
There is pathophysiologic evidence to support a potential role for SARS-CoV-2 in causing hepatitis, as the virus has been shown to have an affinity for the liver. 20 SARS-CoV-2 can replicate in cholangiocytes (bile duct cells) and rare cases of severe acute hepatitis where viral-like particles have been seen on liver biopsy. 21 There have been several retrospective reports demonstrating hepatitis or liver impairment during acute SARS-CoV-2 infection in adults, 22,23 with liver test abnormalities estimated to occur in approximately 15% of all hospitalized adult patients. 24 However, the overall incidence of liver enzyme elevation in all those with SARS-CoV-2 infection is unknown, as most people do not have liver tests performed during acute infection. While less common in children, hepatitis has also been reported in the context of COVID-19. 19,25 A preprint report of a nationwide (US) retrospective cohort study from March 11, 2020 to March 11, 2022 of 245,675 children with a history of COVID-19 (≤10 years old, mean age: 6.0 ± 3.1 years), 26 found that children with COVID-19 had a higher risk of elevated AST or ALT (hazard ratio : 2.52; 95% confidence interval : 2.03-3.12) and bilirubin (HR: 3.35, 95% CI: 2.16-5.18) at six months after infection compared with a propensityscore matched cohort of those with other respiratory virus infections (n= 245,161).
Given that the majority of children have not demonstrated evidence of acute SARS-CoV-2 infection at the time of hepatitis presentation and the lack of evidence of viral infection in the livers that have been biopsied, a post-infectious cause for hepatitis has also been suggested. 27 SARS-CoV-2 has been associated with a number of postinfectious sequelae, including post-acute COVID-19 syndrome (PACS) and multisystem inflammatory syndrome (MIS-C). 28 Hepatitis has been reported with MIS-C, with one retrospective review reporting a 43% (n=19) prevalence in pediatric patients. 29 It is important to note that the hepatitis was mild in the majority of these patients (ALT < 146 in 14 of the 19 patients), and as a result, the majority of patients would not have met the current case definition for severe acute hepatitis of unknown etiology. Furthermore, the findings of hepatitis in MIS-C are inconsistent, with several systematic reviews and meta-analyses of MIS-C in children not mentioning the occurrence of abnormal liver findings or acute liver failure. Regardless, it has been suggested that acute hepatitis of unknown etiology could be a post-infectious inflammatory phenomenon related to the Omicron variant, with suggestion of a MIS-C-like immunological injury driven by a superantigen from SARS-CoV-2. 33,34 The mechanism remains unclear as to why this would be noted more commonly now that MIS-C appears to be occurring less frequently 35 and why the inflammation would be concentrated in the liver.
# Other Etiologies Considered
Beyond adenovirus and SARS-CoV-2: While adenovirus and SARS-CoV-2 are leading hypotheses, the etiology and pathogenic mechanisms of recent acute hepatitis cases are still under investigation, and there are several other hypotheses that continue to be explored. 8 These include drug, toxin or environmental exposure, a novel pathogen either acting alone or as a coinfection, or any combination of factors. One such combination under investigation includes the "priming hypothesis", suggesting that the severe hepatitis could be a consequence of an adenovirus infection with intestinal tropism in children who have previously been infected by SARS-CoV-2 and carrying viral reservoirs, leading to a more pronounced superantigen-mediated effect. 36 The many hypotheses still under investigation and incomplete workup of most cases to date (i.e., inconsistent adenovirus and SARS-CoV-2 testing without exclusion of other etiologies), highlight the need for robust surveillance and thorough workup of potential cases.
# No link with vaccines:
There is no evidence of a link between any SARS-CoV-2 vaccine with this acute hepatitis entity. The majority of cases have been among children who were less than 5 years of age and who were vaccine ineligible or who had not received a SARS-CoV-2 vaccine. Of the 163 cases reported in the UK, none had received a COVID-19 vaccine.
# Clinical Recommendations
What Symptoms Should Make You Suspect Hepatitis?
The presence of scleral icterus or other signs of jaundice are more specific manifestations of severe hepatitis and therefore warrant urgent laboratory testing. Dark urine and/or pale stools are also potentially attributable to hepatitis but less well defined and thus less specific. In addition to routine physical examination, the patient should be specifically assessed for:
Growth, development and nutritional status Evidence of bruising, bleeding excessively after venipuncture and petechiae to suspect evidence of coagulopathy Findings related to liver dysfunction such as jaundice, hepatomegaly alone or with splenomegaly, ascites, peripheral edema Evidence for hepatic encephalopathy, recognizing it may be difficult to assess in toddler and younger aged children. Stages of hepatic encephalopathy are defined slightly differently in children under the age of 4 years. 37 Findings suggestive of chronic liver disease include digital clubbing, palmar erythema, cutaneous xanthoma, and prominent abdominal vessels. If present, these suggest the presence of decompensation or complications of a pre-existing chronic liver condition that has not previously been diagnosed or recognized, rather than a true acute hepatitis or true PALF.
# What Tests Should Be Completed?
Initial blood work should include general laboratory tests (CBC and differential, blood glucose, electrolytes, urea, creatinine, amylase), tests of liver injury (AST, ALT, alkaline phosphatase, GGT), and tests of liver function (total and conjugated bilirubin, albumin, INR).
If AST or ALT > 500 IU/L or INR ≥ 1.5, the case should be discussed with a pediatric gastroenterologist or liver specialist for further direction based on the clinical scenario. 13 Additional immediate investigations should include an acetaminophen level (even if no history of ingestion), urine for toxicology screen and a complete infectious workup (which is outlined in the Public Health Ontario laboratory information sheet) 38 as summarized below. Consultation with a pediatric infectious disease specialist or microbiologist may be helpful to guide investigations based on laboratory test availability in the jurisdiction.
Respiratory Virus Testing (including SARS-CoV-2 and adenovirus): If performing a respiratory multiplex, confirm whether it includes all adenovirus serotypes. If not all serotypes are included, an adenovirus-specific PCR may be completed on the respiratory sample.
Stool testing for adenovirus and enterovirus: If performing a stool multiplex, ensure multiplex includes all adenovirus serotypes (some only test for the most common serotypes associated with gastroenteritis, i.e., serotypes 40/41)
Serology
# When Should I Refer?
While acute hepatitis often resolves with supportive care, the clinical course is unpredictable, and clinicians should be cognizant of a potential for rapid deterioration. Clinicians should consult a pediatric gastroenterologist if they have concerns and especially when they are seeing a child with ALT > 500 or INR ≥ 1.5, to discuss investigations, interim management strategies, anticipatory guidance, and frequency of next lab work. Prompt transfer to a Children's Hospital with a liver transplant program should always be discussed if:
Persistent or continued elevation of serial INR values and bilirubin levels after one IV vitamin K dosage Clinical concerns for hepatic encephalopathy (sleepiness, fatigue, altered mental status, movement abnormalities), GI bleeding, decreased urine output.
# Interpretation
For the majority of cases, acute hepatitis resolves with supportive care. Clinicians should consult a pediatric gastroenterologist for a child with AST > 500 IU/L or INR ≥ 1.5 to prioritize investigations, 9 discuss management (vitamin K), review anticipatory guidance (clinical monitoring, bleeding prevention), and indications for admission.
More data is needed to explore a potential relationship between suspected etiologies (including SARS-CoV-2 and adenovirus infection) and acute severe hepatitis.
# Methods Used for This Science Brief
A rapid review of PubMed and Google Scholar, as well as a cited literature search in Web of Science, was completed on May 30, 2022. Reports citing relevant articles and reference lists of identified articles were also reviewed during this time. Keywords used in this review were: acute hepatitis, children, and COVID-19, however, these were tailored for each database. Specific literature describing these topics was identified manually or through key informants by brief authors following these preliminary database searches.
# Author Contributions
VN, MS, UA and FR conceived the Science Brief. VN and MS wrote the first draft of the Science Brief. All authors revised the Science Brief critically for important intellectual content and approved the final version. | The affiliations of the members of the Ontario COVID-19 Science Advisory Table can be found at https:// covid19-sciencetable.ca/.#
publichealthontario.ca/en/health-topics/infection-prevention-control/routine-practices-additional-precautions ** The three pediatric transplant centers are The Hospital for Sick Children (Toronto, Ontario), Stollery Children's Hospital (Edmonton, Alberta) and CHU Sainte-Justine (Montreal, Quebec). # See Section on "What tests should be completed" and https://www.publichealthontario.ca/en/Laboratory-Services/ Test-Information-Index/Hepatitis-of-Unknown-Origin-in-Children $https://health.gov.on.ca/en/pro/programs/publichealth/acute_hepatitis/docs/CMOH_order_acute_ hepatitis_2022_05_03.pdf.
# Ontario COVID-19 Science Advisory Table
Severe Acute Hepatitis in Children of Unknown Etiology Science Brief are those of the authors and do not necessarily reflect the views of all of the members of the Ontario COVID-19 Science Advisory Table, its Working Groups, and its partners.
Clinicians need to be aware of how to recognize severity of acute hepatitis in children, what investigations to perform, and threshold to refer to a pediatric gastroenterologist or a liver transplant center. This document summarizes a pathway for the evaluation of children with severe acute hepatitis of unknown etiology and highlights the importance of immediately consulting with a pediatric gastroenterologist if the INR is elevated (greater or equal to than 1.5) and/or serum direct bilirubin is elevated to prioritize investigations and guide management.
# Summary
# Background
A series of reports originating in Alabama, United States and Scotland in spring 2022 identified a potential concern about an increase in cases of acute severe hepatitis of unknown etiology in children.
Surveillance has been implemented across many jurisdictions globally to identify cases, investigate etiologies, and monitor trends. Given that these reports were emerging during the COVID-19 pandemic, a potential relationship between SARS-CoV-2 infection and acute severe hepatitis is important to explore, among other etiologies. However, many patients have not had complete workups reported in the literature, limiting the epidemiological investigation to date.
# Questions
How is severe acute hepatitis of unknown etiology in children defined?
What are potential causes of severe acute hepatitis of unknown etiology in children?
What symptoms should make you suspect acute hepatitis in children?
What tests need to be prioritized and should be completed?
When should I refer?
# Findings
Acute severe hepatitis is the sudden onset of liver inflammation and the most severe condition in the spectrum of severe acute hepatitis is pediatric acute liver failure (PALF). There is a broad differential diagnoses for severe acute hepatitis and PALF and it is important to ensure a thorough workup is sent and treatable conditions are recognized early. It is essential that clinicians are able to recognize severe acute hepatitis, decide which diagnostic tests to initiate and when to refer to a pediatric liver specialist or center.
The presence of scleral icterus (yellow pigmentation of the white areas of the eye) or other signs of jaundice are more specific manifestations of severe hepatitis and symptoms that warrant urgent testing. Other less specific symptoms include dark urine and/or pale stools, skin irritation, easy bleeding/bruising, muscle aches, lethargic behaviour, loss of appetite, nausea and vomiting and fever. Recognition of these symptoms combined with a detailed medical history and followed by a combination of clinical, biochemical, radiological and histopathology studies can confirm a clinical diagnosis of acute severe hepatitis.
To date, there is insufficient data to determine whether there has been a recent increase in the incidence of acute severe hepatitis in children. Furthermore, current surveillance data has not conclusively identified a specific infectious or non-infectious cause. A potential role for SARS-CoV-2 or adenovirus infection has been raised but remains unproven at the present time. Several other hypotheses being explored include drug, toxin or environmental exposure or any combination of factors. There is no evidence of a link between any SARS-CoV-2 vaccine with severe acute hepatitis 3 The challenge is that that the baseline incidence of this condition is unknown and the incidence of severe acute hepatitis with the same definitions in prior comparable periods is not available in most jurisdictions. It is therefore difficult to determine whether there has been a true increase in incidence or whether heightened awareness and associated surveillance have led to the increased case identification. In a recent survey, 5 out of 17 European countries and 1 out of 7 non-European countries reported an increase compared with previous years, although limited details were provided on whether and how the numbers were substantiated. 4 Notably, recent data from the US did not find an increase in hepatitis-associated emergency department visits, hospitalizations or liver transplants compared to pre-COVID-19 pandemic baseline levels. 5 In addition, the incidence of pediatric acute liver failure (PALF; also referred to as fulminant liver failure or fulminant hepatitis), the most severe phenotype of severe acute hepatitis in children, remains uncertain, despite the availability of a clear definition. 6 INR values, the key indicator of liver synthetic function used to assess for PALF, were not provided in either of the 2 initial reports, 1,2 although data are emerging in more recent reports from transplant centers. 7 Given these gaps in the literature, it remains challenging to determine if the current cluster of cases represents a new increased signal of concern. Corresponding cases of severe hepatitis of unknown etiology have not been noted in adults. Nevertheless, a potential increased incidence of severe hepatitis and acute liver failure (as described below) warrants immediate attention and public health agencies worldwide have mandated clinicians to report cases to enable the goal of investigating possible etiologies and monitoring trends. Given the occurrence of these cases during the COVID-19 pandemic, it is important to assess for any possible relationship (or lack thereof) to the pandemic as covered in this document. In this regard, beyond the possibility of a specific new etiologic agent, it is necessary to explore if the pandemic influenced disease epidemiology or reporting patterns culminating in the genesis of the above reports. This document aims to provide background and guidance to clinicians who first encounter children with acute hepatitis, including recommended investigations to evaluate for possible etiologies (summarized below). 8 Ontario COVID-19 Science Advisory Table Severe Acute Hepatitis in Children of Unknown Etiology
# Questions
How is severe acute hepatitis of unknown etiology in children defined?
What are potential causes of severe acute hepatitis of unknown etiology in children?
What symptoms should make you suspect acute hepatitis in children?
What tests need to be prioritized and should be completed?
When should I refer?
# Findings
How is Severe Acute Hepatitis of Unknown Etiology in Children Defined?
Acute hepatitis is diagnosed from a combination of clinical, biochemical, and ideally histopathological data, used to confirm the presence and severity of inflammation of the liver. Most patients are previously healthy without clinically significant medical comorbidities, and present with symptoms (liver-specific like jaundice or abdominal distention, or non-liver-specific like nausea, diarrhea, abdominal pain, malaise, etc.) that lead to a clinician ordering bloodwork noteworthy for markedly elevated transaminases. Many have a preceding viral prodrome, often gastrointestinal symptoms including vomiting as a prominent feature.
Acute hepatitis presents along a spectrum of severity, ranging from asymptomatic liver enzyme elevation to PALF. PALF is the most severe condition in the spectrum of severe acute hepatitis. The definition of PALF proposed by the NIH-supported Pediatric Acute Liver Failure Study Group (PALFSG) highlighted distinctions from the longstanding definition in adults in that hepatic encephalopathy is not a defining feature.6 Rather, PALF is defined by biochemical evidence of acute liver injury and hepatic-based coagulopathy (uncorrectable INR ≥ 1.5 in the presence of clinical hepatic encephalopathy or INR ≥2.0 not corrected by IV vitamin K in a child without encephalopathy). PALF accounts for approximately 10-15% of pediatric liver transplants performed in Canada and the United States annually. 6 Publications from the PALF Study Group reported that more than 50% of patients were categorized as indeterminate (PALF-I), defined as absence of an identifiable etiology. 6 To date, of the 650 probable cases of severe acute hepatitis of unknown etiology identified by the WHO, at least 38 (6%) have required transplantation and nine (1%) deaths have been reported. 3 Recent data from the US has not found an increase in hepatitis-associated emergency department visits, hospitalizations or liver transplants compared to pre-COVID-19 pandemic baseline levels. 5 That said, within the reported number of cases, it is possible that some new etiologies could exist.
It is difficult to gauge the incidence of acute hepatitis in children as the true denominator for elevated serum ALT levels is unknown due to wide variability in the diagnostic and laboratory work up of symptomatic children.
# Surveillance Case Definition of Severe Acute Hepatitis of Unknown Etiology in Children
Triggered by the initial cases in Alabama and Scotland, public health agencies developed surveillance case definitions for this entity. As of June 13, 2022, the current probable case definition developed by WHO and used by many international jurisdictions includes a person who is 16 years or younger presenting with acute hepatitis (non-hepatitis virus A-E) AND serum liver transaminase (AST or ALT) level >500 IU/L, since October 1, 2021. 3,9 There are several aspects of the case definition that warrant further discussion:
1. Surveillance definitions are not meant to be used as diagnostic definitions or for clinical purposes, they are often broad to enable case finding and explore associations. A sensitive (broad) case definition enables case finding, but will capture other etiologies (both known and unknown) -sensitivity is intentionally high, acknowledging lower specificity. The case definition in all jurisdictions excludes certain etiologies known to cause hepatitis (e.g., hepatotropic viruses -hepatitis A-E), but there is variability in the requirements for reporting cases of acute hepatitis caused by known etiologies.
2. Direct comparisons of numbers between jurisdictions may not be accurate if different surveillance case definitions are being used. There are two notable differences in surveillance definitions between jurisdictions. These include 1) variation in the definition used for "severity", which ranges from biochemical markers alone (i.e., ALT > 500 IU/L) to requiring hospitalization and 2) variation with inclusion/exclusion of cases of acute hepatitis attributed to known etiologies (e.g., autoimmune hepatitis) with available targeted medical treatments. In Ontario, the current surveillance definition of a probable case includes the following: 1) A person who is 16 years and younger presenting with clinical evidence of severe acute hepatitis since October 2021 and requiring hospitalization, AND 2) elevated serum transaminase >500 IU/L (AST or ALT) or INR > 2.0, AND 3) excluding hepatitis caused or attributed to a hepatitis virus (A,B,C,D,E) or a known or expected presentation of a drug or medication; a genetic, congenital, or metabolic condition; an oncologic, vascular, or ischemia-related condition; or an acute worsening of chronic hepatitis. 10 However, cases identified as autoimmune hepatitis (AIH) and hemophagocytic lymphohistiocytosis (HLH) are required to be reported.
Understanding that the surveillance definition assists in detecting a potential signal of an increase in the incidence of severe acute hepatitis is critical to interpreting the reported numbers. However, these numbers have not historically been reported, so it is challenging to determine if there is in fact a signal of concern, unless appropriate methodology for case finding is followed and compared to prior corresponding periods of time. All these factors can lead to uncertainty when examining reported cases across the world.
# What Are Potential Causes of Severe Acute Hepatitis of Unknown Etiology in Children?
There is a broad differential for acute hepatitis 11,12 and PALF 13 in children, including infectious as well as non-infectious conditions. However, to date, there is no conclusive evidence attributing cases of severe acute hepatitis of unknown etiology to any one infectious or non-infectious condition. More robust data are needed to understand whether there is truly an increase in acute hepatitis in children and if so, the cause. Potential etiological hypotheses to date include adenovirus and SARS-CoV-2 infection, although data are limited and inconsistent to date. 8
# Evidence for Adenovirus
Adenovirus has been detected in some, but not all children reported as cases of severe acute hepatitis of unknown etiology. In the UK case series of 163 children, 126 were tested for adenovirus and 72% were positive on any specimen. 8 This corresponded to a time when there was evidence of increased adenovirus detection in the community. 8 In the Alabama case series, all 9 patients (100%) tested positive for adenovirus by polymerase chain reaction (PCR) on blood samples (initial viral load range = 991-70,680 copies/mL). 2 However, since these initial reports, several additional countries have reported cases where adenovirus has not been found (e.g., Israel), or found in a smaller proportion of cases (e.g., Spain, Netherlands, Japan). 3 It is important to recognize that adenovirus infections are very common in children.
There are more than 100 types of adenovirus divided into seven subgroups (A to G). 14 Most children have been infected by at least one adenovirus by the age of 5 years and the virus can be detected by PCR in up to 11% of healthy, asymptomatic children from throat samples. 15 Adenovirus may be incidentally detected due to persistence or asymptomatic shedding, limiting the utility of PCR detection alone in respiratory, stool or even blood samples, in attributing causality. While detection in the blood may be considered stronger evidence for a role in hepatitis, testing for adenovirus in blood samples using PCR is rarely performed in otherwise healthy children with uncomplicated infection (i.e., gastroenteritis), so the frequency with which adenovirus is found in the blood is unknown. For a hepatitis to be clearly attributed to a viral infection of the liver, evidence of viral inclusions should be seen on liver pathology, 16 as has been reported for adenovirus hepatitis. 17 Notably, the liver biopsies from patients in the Alabama case series (n=6) did not show viral inclusions, immunohistochemical evidence of adenovirus or viral particles, which raises significant questions around the role of adenovirus infection as a direct cause of this entity. However, an adenovirustriggered inflammatory or autoimmune process cannot be excluded. Notably, 6 of the Alabama cases tested positive for EBV DNA in blood by quantitative PCR, but all 5 who were tested for EBV IgM were negative, so these cases did not have acute EBV infection (no such resolution using serology is available for adenovirus).
Adenovirus 41, the strain that has been identified as a possible etiology in recent reports, 2 is most commonly associated with gastroenteritis, whereas the serotypes known to cause hepatitis (1,2,3,5 and 7) and other non-40/41 serotypes that have broader cell tropism, have not been identified in any cases to date. Patterns of circulating adenovirus in children without clinical hepatitis have not been reported in most series, making it difficult to assess whether the incidence of adenovirus 41 is elevated amongst those presenting with severe acute hepatitis compared to the general pediatric population in these jurisdictions.
# Evidence for SARS-CoV-2
The recent increase in infections worldwide due to SARS-CoV-2, particularly the Omicron variant, coincided with reported cases of hepatitis of unknown etiology.
For the majority of case series published and cases reported, SARS-CoV-2 has been infrequently isolated at the time of hepatitis presentation. In the UK case series (n=163), of 132 children tested, 24 (18%) tested positive by PCR, including 11 of the 97 cases (11%) from England. 8 Similarly, of the 188 cases from Europe tested for SARS-
CoV-2, 23 (12.2%) were positive. 18 However, when one considers both evidence of acute and previous infection, the strength of association may increase. In a preprint from India, 19 among 37 cases of hepatitis between April -July 2021, all were either infected with or had prior evidence of SARS-CoV-2 infection. Furthermore, from the European surveillance data, while serology results were only available on 26 cases, 19 (73.1%) were seropositive. 18 However, with the high circulating levels of SARS-CoV-2 in the community for over 2 years, it is possible that these findings may be similar to the prevalence of past/current SARS-CoV-2 infection at the population level in children.
There is pathophysiologic evidence to support a potential role for SARS-CoV-2 in causing hepatitis, as the virus has been shown to have an affinity for the liver. 20 SARS-CoV-2 can replicate in cholangiocytes (bile duct cells) and rare cases of severe acute hepatitis where viral-like particles have been seen on liver biopsy. 21 There have been several retrospective reports demonstrating hepatitis or liver impairment during acute SARS-CoV-2 infection in adults, 22,23 with liver test abnormalities estimated to occur in approximately 15% of all hospitalized adult patients. 24 However, the overall incidence of liver enzyme elevation in all those with SARS-CoV-2 infection is unknown, as most people do not have liver tests performed during acute infection. While less common in children, hepatitis has also been reported in the context of COVID-19. 19,25 A preprint report of a nationwide (US) retrospective cohort study from March 11, 2020 to March 11, 2022 of 245,675 children with a history of COVID-19 (≤10 years old, mean age: 6.0 ± 3.1 years), 26 found that children with COVID-19 had a higher risk of elevated AST or ALT (hazard ratio [HR]: 2.52; 95% confidence interval [CI]: 2.03-3.12) and bilirubin (HR: 3.35, 95% CI: 2.16-5.18) at six months after infection compared with a propensityscore matched cohort of those with other respiratory virus infections (n= 245,161).
Given that the majority of children have not demonstrated evidence of acute SARS-CoV-2 infection at the time of hepatitis presentation and the lack of evidence of viral infection in the livers that have been biopsied, a post-infectious cause for hepatitis has also been suggested. 27 SARS-CoV-2 has been associated with a number of postinfectious sequelae, including post-acute COVID-19 syndrome (PACS) and multisystem inflammatory syndrome (MIS-C). 28 Hepatitis has been reported with MIS-C, with one retrospective review reporting a 43% (n=19) prevalence in pediatric patients. 29 It is important to note that the hepatitis was mild in the majority of these patients (ALT < 146 in 14 of the 19 patients), and as a result, the majority of patients would not have met the current case definition for severe acute hepatitis of unknown etiology. Furthermore, the findings of hepatitis in MIS-C are inconsistent, with several systematic reviews and meta-analyses of MIS-C in children not mentioning the occurrence of abnormal liver findings or acute liver failure. [30][31][32] Regardless, it has been suggested that acute hepatitis of unknown etiology could be a post-infectious inflammatory phenomenon related to the Omicron variant, with suggestion of a MIS-C-like immunological injury driven by a superantigen from SARS-CoV-2. 33,34 The mechanism remains unclear as to why this would be noted more commonly now that MIS-C appears to be occurring less frequently 35 and why the inflammation would be concentrated in the liver.
# Other Etiologies Considered
Beyond adenovirus and SARS-CoV-2: While adenovirus and SARS-CoV-2 are leading hypotheses, the etiology and pathogenic mechanisms of recent acute hepatitis cases are still under investigation, and there are several other hypotheses that continue to be explored. 8 These include drug, toxin or environmental exposure, a novel pathogen either acting alone or as a coinfection, or any combination of factors. One such combination under investigation includes the "priming hypothesis", suggesting that the severe hepatitis could be a consequence of an adenovirus infection with intestinal tropism in children who have previously been infected by SARS-CoV-2 and carrying viral reservoirs, leading to a more pronounced superantigen-mediated effect. 36 The many hypotheses still under investigation and incomplete workup of most cases to date (i.e., inconsistent adenovirus and SARS-CoV-2 testing without exclusion of other etiologies), highlight the need for robust surveillance and thorough workup of potential cases.
# No link with vaccines:
There is no evidence of a link between any SARS-CoV-2 vaccine with this acute hepatitis entity. The majority of cases have been among children who were less than 5 years of age and who were vaccine ineligible or who had not received a SARS-CoV-2 vaccine. Of the 163 cases reported in the UK, none had received a COVID-19 vaccine.
# Clinical Recommendations
What Symptoms Should Make You Suspect Hepatitis?
The presence of scleral icterus or other signs of jaundice are more specific manifestations of severe hepatitis and therefore warrant urgent laboratory testing. Dark urine and/or pale stools are also potentially attributable to hepatitis but less well defined and thus less specific. In addition to routine physical examination, the patient should be specifically assessed for:
Growth, development and nutritional status Evidence of bruising, bleeding excessively after venipuncture and petechiae to suspect evidence of coagulopathy Findings related to liver dysfunction such as jaundice, hepatomegaly alone or with splenomegaly, ascites, peripheral edema Evidence for hepatic encephalopathy, recognizing it may be difficult to assess in toddler and younger aged children. Stages of hepatic encephalopathy are defined slightly differently in children under the age of 4 years. 37 Findings suggestive of chronic liver disease include digital clubbing, palmar erythema, cutaneous xanthoma, and prominent abdominal vessels. If present, these suggest the presence of decompensation or complications of a pre-existing chronic liver condition that has not previously been diagnosed or recognized, rather than a true acute hepatitis or true PALF.
# What Tests Should Be Completed?
Initial blood work should include general laboratory tests (CBC and differential, blood glucose, electrolytes, urea, creatinine, amylase), tests of liver injury (AST, ALT, alkaline phosphatase, GGT), and tests of liver function (total and conjugated bilirubin, albumin, INR).
If AST or ALT > 500 IU/L or INR ≥ 1.5, the case should be discussed with a pediatric gastroenterologist or liver specialist for further direction based on the clinical scenario. 13 Additional immediate investigations should include an acetaminophen level (even if no history of ingestion), urine for toxicology screen and a complete infectious workup (which is outlined in the Public Health Ontario laboratory information sheet) 38 as summarized below. Consultation with a pediatric infectious disease specialist or microbiologist may be helpful to guide investigations based on laboratory test availability in the jurisdiction.
Respiratory Virus Testing (including SARS-CoV-2 and adenovirus): If performing a respiratory multiplex, confirm whether it includes all adenovirus serotypes. If not all serotypes are included, an adenovirus-specific PCR may be completed on the respiratory sample.
Stool testing for adenovirus and enterovirus: If performing a stool multiplex, ensure multiplex includes all adenovirus serotypes (some only test for the most common serotypes associated with gastroenteritis, i.e., serotypes 40/41)
Serology
# When Should I Refer?
While acute hepatitis often resolves with supportive care, the clinical course is unpredictable, and clinicians should be cognizant of a potential for rapid deterioration. Clinicians should consult a pediatric gastroenterologist if they have concerns and especially when they are seeing a child with ALT > 500 or INR ≥ 1.5, to discuss investigations, interim management strategies, anticipatory guidance, and frequency of next lab work. Prompt transfer to a Children's Hospital with a liver transplant program should always be discussed if:
Persistent or continued elevation of serial INR values and bilirubin levels after one IV vitamin K dosage Clinical concerns for hepatic encephalopathy (sleepiness, fatigue, altered mental status, movement abnormalities), GI bleeding, decreased urine output.
# Interpretation
For the majority of cases, acute hepatitis resolves with supportive care. Clinicians should consult a pediatric gastroenterologist for a child with AST > 500 IU/L or INR ≥ 1.5 to prioritize investigations, 9 discuss management (vitamin K), review anticipatory guidance (clinical monitoring, bleeding prevention), and indications for admission.
More data is needed to explore a potential relationship between suspected etiologies (including SARS-CoV-2 and adenovirus infection) and acute severe hepatitis.
# Methods Used for This Science Brief
A rapid review of PubMed and Google Scholar, as well as a cited literature search in Web of Science, was completed on May 30, 2022. Reports citing relevant articles and reference lists of identified articles were also reviewed during this time. Keywords used in this review were: acute hepatitis, children, and COVID-19, however, these were tailored for each database. Specific literature describing these topics was identified manually or through key informants by brief authors following these preliminary database searches.
# Author Contributions
VN, MS, UA and FR conceived the Science Brief. VN and MS wrote the first draft of the Science Brief. All authors revised the Science Brief critically for important intellectual content and approved the final version. | None | None |
d7de09e043219dd5261ed799fc444d73f27c0b0c | cma | None | - Smallpox vaccine should be recommended as post-exposure prophylaxis (PEP) to pregnant women who are exposed to monkeypox in accordance with jurisdictional-specific direction on categories of exposures that qualify for PEP.
- Pregnant individuals with suspected monkeypox should be managed by an interdisciplinary team as there is a paucity of data on monkeypox in pregnancy, but signals of profound morbidity for the pregnancy exist.
# Epidemiology
Monkeypox virus belongs to the Orthopoxvirus genus in the family Poxviridae. The Orthopoxvirus genus also includes variola virus (causes smallpox), vaccinia virus (used in the smallpox vaccine) and cowpox. Monkeys, rodents and nonhuman primates can harbour the virus and infect people. 1 Monkeypox cases in humans have been increasing since its discovery in the 1950s, especially in the Democratic Republic of Congo (DRC), where it is now considered endemic. The age of infection has increased over time from young children to now more predominantly young adults and those of reproductive age. 2 While most cases occur in central Africa, cases outside of Africa have been reported periodically. The last outbreak in North America was reported in several American states in 2003 when community transmission resulted from contact with infected prairie dogs that had been housed with rodents imported from Ghana. 3 This outbreak was effectively contained with extensive education, laboratory testing and use of smallpox vaccines and treatments. 4
# Natural History
The incubation period of monkeypox is usually 7-14 days, but can range from 5-21 days. The prodromal illness begins with generalized symptoms including fever, headache, myalgias, backache, lymphadenopathy (as a point of distinction from smallpox and varicella which do not cause lymphadenopathy), drenching sweats, chills and fatigue. Within 1-10 days, the patient develops a rash. The rash typically progresses from macules to papules, to vesicles, then to pustules that finally crust. The rash may start on the face and then spread to other parts of the body. In general, the illness lasts 2-4 weeks. The Central African clade can cause death in 1 in 10 persons, but the West African Clade is much less severe. The reported cases in the recent outbreak are of the West African Clade (milder disease). 5,6 The WHO classifies severity of monkeypox based on number of skin lesions:
-Mild 250 skin lesions
# Investigation
The differential diagnoses for presentations of fever, rash and lymphadenopathy in pregnancy are broad, and include human immunodeficiency virus, syphilis, varicella, cytomegalovirus and parvovirus B19. Given the potential impact of these conditions on the fetus, they must be considered in the initial investigations for a suspected case of monkeypox in pregnancy. In addition, coxsackie virus (the pathogen causing hand, foot and mouth disease) can cause mouth, palmar and plantar vesicular lesions, but does not cause specific maternal/fetal morbidity.
To identify monkeypox, polymerase chain reaction (PCR) testing can be performed on oral secretions or a skin biopsy during the prodromal phase with early macular rash. There are high amounts of virus in the vesicular lesions that can be deroofed and the fluid swabbed for PCR testing during the vesicular phase. Nasopharyngeal swabs can also be sent for PCR and, depending on the clinical presentation, other specimens may be indicated. At present, testing is only occurring at reference laboratories and an epidemiological link to a known case is required for testing. Consultation with local medical microbiology experts is recommended.
# Transmission
The virus enters the body through broken skin, the respiratory tract or mucous membranes. Animal-to-human transmission can be through a bite, scratch, bush meat preparation, direct contact with a lesion or body fluids or indirect contact with body fluids such as bedding. Human-to-human contact is principally through large droplet transmission (prolonged face-to-face contact is required), as well as, direct contact with a lesion or body fluids or indirect contact with body fluids such as bedding. A more recent epidemiologic analysis from the DRC has raised questions about mode of transmission because, among the cohort studied, it was not clear whether all current cases had contact with an infected person. 7,8 There is limited information regarding asymptomatic shedding but the current research indicates viral shedding coincides with the onset of symptoms. Asymptomatic carriage and viral shedding prior to the onset of symptoms has not been reported. 7 Current recommendations from the Public Health Agency of Canada include airborne, droplet and contact precautions to be employed for suspected, probable and confirmed cases of monkeypox. 9
# Prevention
Smallpox vaccine has been reported to reduce the risk of monkeypox by 85% among previously vaccinated persons in Africa. Exposed persons should be vaccinated within 4 days of exposure if possible. Vaccination after 4 days, but before 14 days may not prevent infection but may attenuate symptoms. 3,5
# Treatment
There is no proven treatment for monkeypox at present. To control outbreaks, smallpox vaccine, antivirals (e.g., cidofovir and tecovirimat) and vaccinia immune globulin (VIG) can be used. 9 Cidofovir is classified as category C by the FDA because in animal studies embryotoxicity and teratogenicity were noted, including reduced fetal weight and increased incidence of fetal external, soft tissue and skeletal abnormalities. There is no available safety data for tecovirimat in pregnancy. While no studies of the vaccinia immunoglobulin are known, other immunoglobulins have been used extensively in pregnancy and felt to be safe. There are no contraindications to the use of the smallpox vaccine in emergency and exposure situations.
# Monkeypox and pregnancy 3, 5
We know that other orthopoxvirus infections, such as variola virus (smallpox) result in worse outcomes in pregnant compared to non-pregnant women (i.e., higher rate of hemorrhagic smallpox that carries a case-fatality rate of 70% for unvaccinated pregnant women). In addition, smallpox infection in pregnancy is associated with spontaneous abortion, stillbirth and preterm delivery. However, it is not known whether this holds true with monkeypox.
There are a limited number of reports from which to inform ourselves about monkeypox in pregnant women. As detailed below, of the 5 cases reported in the formal literature, 1 resulted in a live birth, 2 in miscarriages and 1 stillbirth and 1 neonatal death:
-In the DRC (formerly Zaire), there was a case of a woman who was 24 weeks pregnant when she developed monkeypox (culture-proven) and she delivered a 1,500 g female infant 6 weeks later (at 30 weeks) with a generalized skin rash resembling monkeypox. This infant died of malnutrition at 6 weeks of age. 3 -A case series by Mbala et al. 5 reported fetal outcomes for four pregnant women in the DRC. These four women were the only pregnant patients among 222 patients symptomatic from monkeypox. Of these four women, by WHO classification, one had mild disease, two had moderate disease and one had severe disease. The only live birth was from the woman with mild disease, who was infected in the early 2 nd trimester, while the other three patients had either miscarriages (2/4) or fetal demise (1/4). Monkeypox was detected on the fetal tissue of the 18 week fetal demise case along with visible skin lesions on the infant. 5 If monkeypox is diagnosed in a pregnant patient, a multidisciplinary team including maternal-fetal medicine and infectious diseases or reproductive infectious diseases should be assembled.
# Smallpox vaccine in pregnancy
There has been an evolution of the smallpox vaccine over time with an attenuation of viral replication potential. The first-and second-generations (e.g., ACAM 2000®) of vaccines are live-attenuated vaccines with replication potential, but the third-generation vaccine (e.g., Imvamune®) uses non-replicating virus which de facto cannot cause vaccinia in the recipient.
Importantly, this third-generation vaccine only became licensed in 2019-2020 and therefore most data that we have related to the use of smallpox vaccine in pregnancy is based on first-and second-generation technology that uses a live-attenuated vaccinia virus with replicating potential. Badell et al conducted a systematic review that included 37 articles dating back into the 19 th century. 10 No adverse maternal outcomes were described for those vaccinated. This systematic review focused on three primary outcomes:
- Spontaneous abortion: no association was found between the use of the smallpox vaccine and spontaneous abortion even when analysis was restricted to studies considering first trimester exposure (RR 1.03, 95% CI 0.76-1.41) o Congenital defects: no increased risk of congenital anomaly for fetuses exposed to the smallpox vaccine (RR 1.25 95% CI 0.99-1.56). Of five studies restricted to first trimester exposure, four demonstrated no increased risk of congenital anomalies and one demonstrated an increased risk with no specific pattern of congenital anomaly associated with the smallpox vaccination. o Fetal vaccinia: Of the 37 articles, 18 articles included fetal outcomes of 12,201 pregnant women vaccinated against smallpox and no cases of fetal vaccinia were reported. In 19 articles, 21 cases of fetal vaccinia were described between 1809 to present.
The vaccine that is available for use in the current outbreak in Canada is a third-generation vaccine (Imvamune®) that is non-replicating. No clinical trials have been conducted in pregnant individuals, although approximately 300 pregnancies have been reported to the manufacturer with no safety issues identified. Similarly, the available developmental and reproductive toxicity (DART) data has not identified safety issues in animal studies. No data is available to determine whether Imvamune® is excreted in breastmilk, but given that it is non-replicating, it is unlikely. Therefore, there is no biological concern with using this vaccine in pregnancy.
Based on a small number of case reports and our experience with other viruses from the same family in pregnancy (i.e., smallpox), we believe that the risk of monkeypox to the pregnant woman and fetus could be significant. While data specific to the use of Imvamune in pregnancy are limited, the experience of using less-attenuated smallpox vaccines during pregnancy from 1809 to present is reassuring. Further, the rare risk of fetal vaccinia infection is felt to be completely obviated by use of a third-generation live-attenuated, non-replicating vaccine such as Imvamune®.
Hence, the smallpox vaccine should be recommended as post-exposure prophylaxis (PEP) to pregnant women, who are exposed to monkeypox, in accordance with jurisdictional-specific direction on categories of exposures that qualify for PEP.
# Maternal-to-Child-transmission
Based on the few cases of monkeypox in pregnancy that have been reported, vertical transmission appears possible.
In the five cases reported by Jameison 3 and Mbala, 5 two had supportive evidence of in utero transmission. The rate and gestational age at which it occurs is unclear and the fetal consequences are yet to be delineated. Almost nothing is known about genital tract shedding and perinatal monkeypox transmission.
# Mode of Delivery
For antenatal monkeypox resolved by the time of delivery, mode of delivery should be determined based on obstetrical factors exclusively. There is no evidence that cesarean delivery will prevent neonatal monkeypox in the context of maternal monkeypox infection. In the context of active isolated genital lesions, cesarean delivery could be considered.
# Peripartum Considerations
Infant and newborn monkeybox disease appears to have serious morbidity. Horizontal transmission in the newborn period is of concern. It is advised to engage a multidisciplinary team including infection prevention and control experts, as well as, pediatric infectious diseases specialists to make decisions with respect to co-habitation of a newborn and mother who is actively infected with monkeypox. Where an infant appears uninfected at birth, strong consideration should be given to temporary separation of mother and infant in an attempt to prevent newborn infection. The length of time of separation will depend on individual factors (e.g stage of disease at delivery) and should be decided in consultation with a multidisciplinary team.
# Breastfeeding
It is unknown whether monkeypox can be transmitted through breast-feeding or breastmilk. With active maternal disease, avoidance of breastfeeding until resolution of symptoms may be considered. Multidisciplinary discussions should guide management of individualized cases. 11
# Precautions for patient interactions
For anyone presenting with unexplained fever, rash or prominent lymphadenopathy, monkeypox should be considered on the differential diagnosis, and appropriate contact, droplet and airborne precautions should be used. Testing, treatment and public health notification should be carried out in accordance with jurisdiction-specific protocols. | #
1. Smallpox vaccine should be recommended as post-exposure prophylaxis (PEP) to pregnant women who are exposed to monkeypox in accordance with jurisdictional-specific direction on categories of exposures that qualify for PEP.
2. Pregnant individuals with suspected monkeypox should be managed by an interdisciplinary team as there is a paucity of data on monkeypox in pregnancy, but signals of profound morbidity for the pregnancy exist.
# Epidemiology
Monkeypox virus belongs to the Orthopoxvirus genus in the family Poxviridae. The Orthopoxvirus genus also includes variola virus (causes smallpox), vaccinia virus (used in the smallpox vaccine) and cowpox. Monkeys, rodents and nonhuman primates can harbour the virus and infect people. 1 Monkeypox cases in humans have been increasing since its discovery in the 1950s, especially in the Democratic Republic of Congo (DRC), where it is now considered endemic. The age of infection has increased over time from young children to now more predominantly young adults and those of reproductive age. 2 While most cases occur in central Africa, cases outside of Africa have been reported periodically. The last outbreak in North America was reported in several American states in 2003 when community transmission resulted from contact with infected prairie dogs that had been housed with rodents imported from Ghana. 3 This outbreak was effectively contained with extensive education, laboratory testing and use of smallpox vaccines and treatments. 4
# Natural History
The incubation period of monkeypox is usually 7-14 days, but can range from 5-21 days. The prodromal illness begins with generalized symptoms including fever, headache, myalgias, backache, lymphadenopathy (as a point of distinction from smallpox and varicella which do not cause lymphadenopathy), drenching sweats, chills and fatigue. Within 1-10 days, the patient develops a rash. The rash typically progresses from macules to papules, to vesicles, then to pustules that finally crust. The rash may start on the face and then spread to other parts of the body. In general, the illness lasts 2-4 weeks. The Central African clade can cause death in 1 in 10 persons, but the West African Clade is much less severe. The reported cases in the recent outbreak are of the West African Clade (milder disease). 5,6 The WHO classifies severity of monkeypox based on number of skin lesions:
-Mild <25 skin lesions -Moderate 25-99 skin lesions -Severe 100-250 skin lesions -Grave >250 skin lesions
# Investigation
The differential diagnoses for presentations of fever, rash and lymphadenopathy in pregnancy are broad, and include human immunodeficiency virus, syphilis, varicella, cytomegalovirus and parvovirus B19. Given the potential impact of these conditions on the fetus, they must be considered in the initial investigations for a suspected case of monkeypox in pregnancy. In addition, coxsackie virus (the pathogen causing hand, foot and mouth disease) can cause mouth, palmar and plantar vesicular lesions, but does not cause specific maternal/fetal morbidity.
To identify monkeypox, polymerase chain reaction (PCR) testing can be performed on oral secretions or a skin biopsy during the prodromal phase with early macular rash. There are high amounts of virus in the vesicular lesions that can be deroofed and the fluid swabbed for PCR testing during the vesicular phase. Nasopharyngeal swabs can also be sent for PCR and, depending on the clinical presentation, other specimens may be indicated. At present, testing is only occurring at reference laboratories and an epidemiological link to a known case is required for testing. Consultation with local medical microbiology experts is recommended.
# Transmission
The virus enters the body through broken skin, the respiratory tract or mucous membranes. Animal-to-human transmission can be through a bite, scratch, bush meat preparation, direct contact with a lesion or body fluids or indirect contact with body fluids such as bedding. Human-to-human contact is principally through large droplet transmission (prolonged face-to-face contact is required), as well as, direct contact with a lesion or body fluids or indirect contact with body fluids such as bedding. A more recent epidemiologic analysis from the DRC has raised questions about mode of transmission because, among the cohort studied, it was not clear whether all current cases had contact with an infected person. 7,8 There is limited information regarding asymptomatic shedding but the current research indicates viral shedding coincides with the onset of symptoms. Asymptomatic carriage and viral shedding prior to the onset of symptoms has not been reported. 7 Current recommendations from the Public Health Agency of Canada include airborne, droplet and contact precautions to be employed for suspected, probable and confirmed cases of monkeypox. 9
# Prevention
Smallpox vaccine has been reported to reduce the risk of monkeypox by 85% among previously vaccinated persons in Africa. Exposed persons should be vaccinated within 4 days of exposure if possible. Vaccination after 4 days, but before 14 days may not prevent infection but may attenuate symptoms. 3,5
# Treatment
There is no proven treatment for monkeypox at present. To control outbreaks, smallpox vaccine, antivirals (e.g., cidofovir and tecovirimat) and vaccinia immune globulin (VIG) can be used. 9 Cidofovir is classified as category C by the FDA because in animal studies embryotoxicity and teratogenicity were noted, including reduced fetal weight and increased incidence of fetal external, soft tissue and skeletal abnormalities. There is no available safety data for tecovirimat in pregnancy. While no studies of the vaccinia immunoglobulin are known, other immunoglobulins have been used extensively in pregnancy and felt to be safe. There are no contraindications to the use of the smallpox vaccine in emergency and exposure situations.
# Monkeypox and pregnancy 3, 5
We know that other orthopoxvirus infections, such as variola virus (smallpox) result in worse outcomes in pregnant compared to non-pregnant women (i.e., higher rate of hemorrhagic smallpox that carries a case-fatality rate of 70% for unvaccinated pregnant women). In addition, smallpox infection in pregnancy is associated with spontaneous abortion, stillbirth and preterm delivery. However, it is not known whether this holds true with monkeypox.
There are a limited number of reports from which to inform ourselves about monkeypox in pregnant women. As detailed below, of the 5 cases reported in the formal literature, 1 resulted in a live birth, 2 in miscarriages and 1 stillbirth and 1 neonatal death:
-In the DRC (formerly Zaire), there was a case of a woman who was 24 weeks pregnant when she developed monkeypox (culture-proven) and she delivered a 1,500 g female infant 6 weeks later (at 30 weeks) with a generalized skin rash resembling monkeypox. This infant died of malnutrition at 6 weeks of age. 3 -A case series by Mbala et al. 5 reported fetal outcomes for four pregnant women in the DRC. These four women were the only pregnant patients among 222 patients symptomatic from monkeypox. Of these four women, by WHO classification, one had mild disease, two had moderate disease and one had severe disease. The only live birth was from the woman with mild disease, who was infected in the early 2 nd trimester, while the other three patients had either miscarriages (2/4) or fetal demise (1/4). Monkeypox was detected on the fetal tissue of the 18 week fetal demise case along with visible skin lesions on the infant. 5 If monkeypox is diagnosed in a pregnant patient, a multidisciplinary team including maternal-fetal medicine and infectious diseases or reproductive infectious diseases should be assembled.
# Smallpox vaccine in pregnancy
There has been an evolution of the smallpox vaccine over time with an attenuation of viral replication potential. The first-and second-generations (e.g., ACAM 2000®) of vaccines are live-attenuated vaccines with replication potential, but the third-generation vaccine (e.g., Imvamune®) uses non-replicating virus which de facto cannot cause vaccinia in the recipient.
Importantly, this third-generation vaccine only became licensed in 2019-2020 and therefore most data that we have related to the use of smallpox vaccine in pregnancy is based on first-and second-generation technology that uses a live-attenuated vaccinia virus with replicating potential. Badell et al conducted a systematic review that included 37 articles dating back into the 19 th century. 10 No adverse maternal outcomes were described for those vaccinated. This systematic review focused on three primary outcomes:
o Spontaneous abortion: no association was found between the use of the smallpox vaccine and spontaneous abortion even when analysis was restricted to studies considering first trimester exposure (RR 1.03, 95% CI 0.76-1.41) o Congenital defects: no increased risk of congenital anomaly for fetuses exposed to the smallpox vaccine (RR 1.25 95% CI 0.99-1.56). Of five studies restricted to first trimester exposure, four demonstrated no increased risk of congenital anomalies and one demonstrated an increased risk with no specific pattern of congenital anomaly associated with the smallpox vaccination. o Fetal vaccinia: Of the 37 articles, 18 articles included fetal outcomes of 12,201 pregnant women vaccinated against smallpox and no cases of fetal vaccinia were reported. In 19 articles, 21 cases of fetal vaccinia were described between 1809 to present.
The vaccine that is available for use in the current outbreak in Canada is a third-generation vaccine (Imvamune®) that is non-replicating. No clinical trials have been conducted in pregnant individuals, although approximately 300 pregnancies have been reported to the manufacturer with no safety issues identified. Similarly, the available developmental and reproductive toxicity (DART) data has not identified safety issues in animal studies. No data is available to determine whether Imvamune® is excreted in breastmilk, but given that it is non-replicating, it is unlikely. Therefore, there is no biological concern with using this vaccine in pregnancy.
Based on a small number of case reports and our experience with other viruses from the same family in pregnancy (i.e., smallpox), we believe that the risk of monkeypox to the pregnant woman and fetus could be significant. While data specific to the use of Imvamune in pregnancy are limited, the experience of using less-attenuated smallpox vaccines during pregnancy from 1809 to present is reassuring. Further, the rare risk of fetal vaccinia infection is felt to be completely obviated by use of a third-generation live-attenuated, non-replicating vaccine such as Imvamune®.
Hence, the smallpox vaccine should be recommended as post-exposure prophylaxis (PEP) to pregnant women, who are exposed to monkeypox, in accordance with jurisdictional-specific direction on categories of exposures that qualify for PEP.
# Maternal-to-Child-transmission
Based on the few cases of monkeypox in pregnancy that have been reported, vertical transmission appears possible.
In the five cases reported by Jameison 3 and Mbala, 5 two had supportive evidence of in utero transmission. The rate and gestational age at which it occurs is unclear and the fetal consequences are yet to be delineated. Almost nothing is known about genital tract shedding and perinatal monkeypox transmission.
# Mode of Delivery
For antenatal monkeypox resolved by the time of delivery, mode of delivery should be determined based on obstetrical factors exclusively. There is no evidence that cesarean delivery will prevent neonatal monkeypox in the context of maternal monkeypox infection. In the context of active isolated genital lesions, cesarean delivery could be considered.
# Peripartum Considerations
Infant and newborn monkeybox disease appears to have serious morbidity. Horizontal transmission in the newborn period is of concern. It is advised to engage a multidisciplinary team including infection prevention and control experts, as well as, pediatric infectious diseases specialists to make decisions with respect to co-habitation of a newborn and mother who is actively infected with monkeypox. Where an infant appears uninfected at birth, strong consideration should be given to temporary separation of mother and infant in an attempt to prevent newborn infection. The length of time of separation will depend on individual factors (e.g stage of disease at delivery) and should be decided in consultation with a multidisciplinary team.
# Breastfeeding
It is unknown whether monkeypox can be transmitted through breast-feeding or breastmilk. With active maternal disease, avoidance of breastfeeding until resolution of symptoms may be considered. Multidisciplinary discussions should guide management of individualized cases. 11
# Precautions for patient interactions
For anyone presenting with unexplained fever, rash or prominent lymphadenopathy, monkeypox should be considered on the differential diagnosis, and appropriate contact, droplet and airborne precautions should be used. Testing, treatment and public health notification should be carried out in accordance with jurisdiction-specific protocols. | None | None |
e73b421f4bae7f20257a1e990da2bbe104c03803 | cma | None | arkinson disease is chronic and progressive in nature, decreasing the quality of life for both patients with the disease and their caregivers and placing an onerous economic burden on society. 1 The first Canadian guideline on Parkinson disease was published in 2012. 2 Since that guideline, there have been substantial advances in the literature on the disease, particularly with respect to diagnostic criteria and treatment options. Parkinson Canada undertook to update the existing guideline to reflect these advances, as well as to add information on palliative care. With the aim of enhancing care for all Canadians with Parkinson disease, this guideline is based on the best published evidence, involves expert consensus when there is a lack of evidence, offers practical clinical advice, takes patient choice and informed decision-making into account and is relevant to the Canadian health care system. The guideline has been divided into 5 main sections to improve the ease of use: communication, diagnosis and progression, treatment, nonmotor features and palliative care. The full guideline is available in Appendix 1, at www.cmaj.ca/lookup/ suppl/#
- Advanced therapies like deep brain stimulation and intrajejunal levodopa-carbidopa gel infusion are now routinely used in Parkinson disease to manage motor symptoms and fluctuations.
- Evidence exists to support early institution of exercise at the time of diagnosis of Parkinson disease, in addition to the clear benefit now shown in those with well-established disease.
- Palliative care requirements of people with Parkinson disease should be considered throughout all phases of the disease, which includes an option of medical assistance in dying. evidence that they thought would warrant making an update to a recommendation. For those recommendations still considered valid, the experts were asked if they were aware of any new evidence that would change the grade or strength of evidence.
The Knowledge Synthesis Group used components of the ADAPTE process as the basis for the update. 3 Literature searches included those in English from 2006 to December 2016, using the following databases: National Guideline Clearinghouse, the Guidelines International Network, National Library of Guidelines, CPG Infobase, Trip Medical Database, Google Scholar, Embase and Ovid MEDLINE (including Epub Ahead of Print, In-Process and Other Nonindexed Citations), Cochrane Library (limited to Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and the Health Technology Assessment database). Research undertaken only in animals and opinion pieces were removed from the results.
The Knowledge Synthesis Group first searched for clinical practice guidelines on the care of patients with Parkinson disease. If no sufficiently high-quality guidelines or no guidelines were identified, then a staged approach to identification of evidence was implemented, where first moderate-to high-quality systematic reviews were systematically searched for and used as evidence. In the absence of such reviews, or if there were no systematic reviews, then randomized controlled trials (RCTs) were searched for.
The Knowledge Synthesis Group used the Appraisal of Guidelines for Research & Evaluation (AGREE II) instrument to assess the rigour of clinical practice guidelines, 4 the 16-point A MeaSurement Tool to Assess Systematic Reviews (AMSTAR 2) 5 to assess systematic reviews, and the Cochrane Risk of Bias tool to assess RCTs. 6 The Knowledge Synthesis group developed packages of information (including strengths of evidence, citations and summaries of new studies) and compiled them in the form of summaries for distribution to working groups of panel members with relevant expertise (e.g., treatment, communication, etc.) in preparation for a consensus meeting.
Before the consensus meeting, the guideline panel identified several additional topics that were thought to be important and that had not been initially captured because of the stringent topic search conducted. These included depression and Parkinson disease (the initial search had been restricted to amitriptyline, as it was the only antidepressant included in the original guideline), pimavanserin and rotigotine. The Knowledge Synthesis Group extracted data from systematic reviews for these topics, and produced additional summaries to be distributed in advance of the consensus meeting.
Many recommendations from the 2006 National Institute for Health and Care Excellence (NICE) guideline 7 had been adapted for inclusion in the 2012 Canadian guideline. An updated version of the NICE guideline was not identified in the literature search, as its publication date was initially scheduled for June 2017 (published in July 2017). 8 However, a draft version of the updated NICE guideline was available from October 2016 and was included in the materials supplied to the guideline panel for the consensus meeting.
A full-day meeting with 29 guideline panel members was held on Apr. 8, 2017 (Supplement Table 5 in Appendix 1). The working groups reviewed the relevant summaries and the full text of the new literature on their topic. Each working group chair presented their group's recommendations to the entire guideline panel; this served as the basis for the initial voting matrix for each recommendation. An open voting process and summary discussion method identified 5 main areas on which to base the guideline update: communication, diagnosis and progression, treatment, nonmotor features and a new section on palliative care.
Working group members used recommendations from the clinical practice guidelines identified during the literature search to update or create new recommendations. (At the meeting, some recommendations that required updating were identified that had not been raised by the original survey of experts.) If no appropriate recommendation was found in the available clinical practice guidelines, the guideline panel discussed the topic and referred it to the Knowledge Synthesis Group for a follow-up search of systematic reviews and, if necessary, RCTs.
The guideline panel made substantial effort to maintain the phrasing of any recommendation extracted from another guideline, although some were modified slightly to achieve standardized terminology or to make the recommendation more specific. The source for each recommendation extracted from another guideline is cited at the end of the recommendation. When the recommendation was created de novo by the working groups from systematic review or RCT evidence or expert opinion, the recommendation is denoted as "CAN." The classifications for determining the level of evidence used across the guidelines differed slightly, but the recommendation grade was maintained from the original source (i.e., if a recommendation had a grade of B in its source guideline, it was retained as grade B in this guideline update) (Box 1).
After the meeting, we created a voting matrix, organized into the 5 main themes with subsections. We conducted Web-based voting using SurveyMonkey (www.surveymonkey.com) to ensure that the majority (> 75%) agreed on each of the recommendation points. One recommendation did not reach 75% agreement but was considered to be an essential topic to include. The section leads subsequently modified the wording of this recommendation and the newly worded recommendation was approved by the guideline panel. More information on the methods used to develop this guideline is available in Appendix 1.
# Management of competing interests
All guideline panel members agreed to terms of reference that included disclosure of all perceived and actual competing interests to the entire panel at the beginning and end of the guideline development process. Panellists with competing interests were permitted to participate in panel discussions, and later in the voting matrix, without restriction.
# Recommendations
The complete list of recommendations appears in Tables 1 to 5; a description of the underlying evidence for each recommendation is available in Appendix 1.This synopsis provides information on selected recommendations, along with the grade of and source for the recommendation. (When the term "CAN" is used as a source, it refers to a recommendation that was developed de novo for this guideline and was not adapted from another source.)
# COMMUNICATION
n People with Parkinson disease should be encouraged to participate in choices about their own care.
n Communication should be in verbal and written form.
n Discussions should aim to achieve a balance between providing realistic information and promoting optimism.
n Families and caregivers should be informed about the condition and available support services.
# DIAGNOSIS AND PROGRESSION
n Parkinson disease should be suspected in anyone with tremor, sti ness, slowness, balance problems or gait disorders.
n CT or MRI brain scanning should not be routinely used to diagnose Parkinson disease.
n Patients, especially young, who request genetic testing should be assessed by a movement disorders specialist.
n No therapies are e ective for slowing or stopping brain degeneration in Parkinson disease.
# NONMOTOR FEATURES
n Botulinum toxin A helps control drooling.
n Drug therapy for low blood pressure includes midodrine, udrocortisone and domperidone.
n Management of depression should be tailored to the individual and their current therapy.
n Dementia should not exclude a diagnosis of Parkinson disease, even if present early.
n Rapid eye movement sleep behaviour disorder can pre-date the diagnosis of Parkinson disease.
# PALLIATIVE CARE
n The palliative care needs of people with Parkinson disease should be considered throughout all phases of the disease.
n If the patient asks, the option of medical assistance in dying should be discussed.
# TREATMENT
n Levodopa is the most e ective medication and may be used early.
n A regular exercise regimen begun early has proven bene t.
# C1
Communication with people with PD should be aimed at empowering them to participate in the judgments and choices about their own care.
# NICE 7 D C2
Discussions should be aimed at achieving a balance between the provision of honest, realistic information about the condition and the promotion of a feeling of optimism.
# NICE 7 D C3
Because people with PD may develop impaired cognitive ability, a communication deficit or depression, they should be provided with both verbal and written communication throughout the course of the disease -which should be individually tailored and reinforced as necessary -and consistent communication from the professionals involved.
# NICE 7 D GPP C4
Families and caregivers should be given information about the condition, their entitlements to care assessment and the support services available.
# Communication
Communication with people with Parkinson disease should be aimed at empowering them to participate in the judgments and choices about their own care (grade: D; source: NICE 7 ).
Discussions should be aimed at achieving a balance between the provision of honest, realistic information about the condition and the promotion of a feeling of optimism (grade: D; source: NICE 7 ).
Because people with Parkinson disease may develop impaired cognitive ability, a communication deficit or depression, they should be provided with both verbal and written communication throughout the course of the disease -which should be individ ually tailored and reinforced as necessary -and consistent com munication from the professionals involved (grade: D, good prac tice point; source: NICE 7 ).
Families and caregivers should be given information about the condition, their entitlements to care assessment and the support services available (grade: D, good practice point; source: NICE 7 ).
Good communication is at the heart of every interaction between people with Parkinson disease, their caregivers and health professionals. Health care professionals committed to clear and empathic communication can make a meaningful difference to their patients. When people with Parkinson disease know what health care professionals recommend and why, they can participate in shared decision-making. Communication should be supported by the provision of evidence-based information, offered in a form that is tailored to the needs of the individual. Where possible, written materi al should be provided that includes instructions for medication use. Parkinson disease affects people living with the illness and their caregivers and family. It is important that they all have access to the same information and services.
# C9
Clinicians should be aware of the poor specificity of a clinical diagnosis of PD in the early stages of the disease, and consider this uncertainty when giving information to the patient and when planning management.
SIGN 13 C C10 Patients should be offered long-term, regular follow-up to review the diagnosis of PD. This should include a review of the ongoing benefits in those started on dopamine replacement therapy.
SIGN 13 GPP
# C11
Patients initially considered to have a possible diagnosis of PD may benefit from a trial of dopamine replacement therapy to assist with an accurate diagnosis.
SIGN 13
# GPP C12
Patients with suspected PD, with substantial disability or exclusion criteria or red flags as per the MDS diagnostic criteria, should be seen by a clinician with sufficient expertise in movement disorders to make the diagnosis.
SIGN 13 C GPP
# C13
Acute challenge testing with either levodopa or apomorphine should not be used in the diagnosis of PD. Patients with suspected PD should be considered for a trial of chronic levodopa treatment.
# SIGN 13 A C14
Objective olfactory testing is not recommended in the diagnosis of PD. SIGN 13 B C15 Routine use of functional imaging is not recommended for the differential diagnosis of PD and Parkinson plus disorders such as progressive supranuclear palsy and multiple system atrophy.
# SIGN 13 C C16
PET scanning is not recommended as part of the diagnostic work-up of parkinsonian syndromes, except within a research framework.
# SIGN 13 GPP C17
123 I-FP-CIT SPECT scanning should be considered as an aid to clinical diagnosis in patients where there is uncertainty between PD and nondegenerative parkinsonism or tremor disorders.
SIGN 13 B
# C18
Computed tomography or MRI brain scanning should not be routinely applied in the diagnosis of idiopathic PD. SIGN 13 C C19 Vitamin E should not be used as a neuroprotective therapy for people with PD. Co-enzyme Q10 should not be used as a neuroprotective therapy for people with PD.
NICE 8 A C20 Levodopa (grade: GPP), amantadine (grade: GPP), dopamine agonists (pramipexole, ropinirole, rotigotine, apomorphine, bromocriptine) (grade: A), or MAO inhibitors (selegiline, rasagiline) (grade: A) should not be used as neuroprotective therapies for people with PD, except in the context of clinical trials.
# CAN Varied
# C21
Genetic testing for monogenic parkinsonism is not recommended in routine clinical practice. SIGN 13
# GPP C22
Patients who request genetic testing, particularly those with young-onset parkinsonism, should be assessed in a specialist movement disorders clinic for consideration of counselling and testing.
# General considerations
# C23
People with PD should have regular access to the following:
- Clinical monitoring and medication adjustment - A continuing point of contact for support, including home visits, when appropriate - A reliable source of information about clinical and social matters of concern to people with PD and their caregivers, which may be provided by a PD nurse specialist.
# NICE C C24
Antiparkinsonian medication should not be withdrawn abruptly or allowed to fail suddenly owing to poor absorption (e.g., gastroenteritis, abdominal surgery), to avoid the potential for acute akinesia or neuroleptic malignant syndrome.
# NICE D GPP C25
The practice of withdrawing patients from their antiparkinsonian drugs (so-called "drug holidays") to reduce motor complications should not be undertaken because of the risk of neuroleptic malignant syndrome.
# NICE D GPP C26
In view of the risks of sudden changes in antiparkinsonian medication, people with PD who are admitted to hospital or care homes should have their medication: i) given at the appropriate times, which in some cases may mean allowing self-medication; ii) adjusted by, or adjusted only after discussion with, a specialist in the management of PD.
# NICE D GPP C27
Surveillance for dopamine dysregulation syndrome should be undertaken in patients receiving levodopa or intermittent apomorphine.
# SIGN 13 GPP C28
When starting dopamine agonist therapy, people and their family members and caregivers (as appropriate) should be given verbal and written information about the following, and the discussion should be recorded as having taken place:
- The increased risk of developing impulse control disorders when taking dopamine agonist therapy, and that these may be concealed by the person affected - The different types of impulse control disorders (e.g., compulsive gambling, hypersexuality, binge eating and obsessive shopping) - Who to contact if impulse control disorders develop - The possibility that if problematic impulse control disorders develop, dopamine agonist therapy will be reviewed and may be reduced or stopped.
# NICE GPP C29
It should be recognized that impulse control disorders can develop in a person with PD who is on any dopaminergic therapy at any stage in the disease course.
# NICE GPP
# Pharmacologic therapy in early PD
# C30
Before starting treatment for people with PD, the following should be discussed:
# C39
There is insufficient evidence to support the use of amantadine in the treatment of patients with early PD.
SIGN 13 A
# Rehabilitation
# C56
Consideration should be given to referring people who are in the early stages of PD to a physiotherapist with experience of the disease for assessment, education and advice, including information about physical activity.
# NICE 8 B C57
Physiotherapy specific to PD should be offered to people who are experiencing balance or motor function problems.
# NICE 8 A C58
Consideration should be given to referring people who are in the early stages of PD to an occupational therapist with experience of PD for assessment, education and advice on motor and nonmotor symptoms.
# NICE 8 B C59
Occupational therapy specific to PD should be offered to people who are having difficulties with activities of daily living.
NICE 7 A
# Diagnosis and progression
Parkinson disease should be suspected in people presenting with tremor, stiffness, slowness, balance problems or gait disorders (grade: D, good practice point; source: NICE 7 ).
Parkinson disease can be diagnosed using the Movement Disorder Society Clinical Diagnostic Criteria (grade: good practice point; source: CAN).
Parkinson disease is characterized by a constellation of clinical manifestations, which include slowness of movement (bradykinesia), rest tremor, rigidity and postural instability. The diagnosis of Parkinson disease is still based predominantly on its clinical features; in 2015, the Movement Disorder Society 9 published new criteria for clinically established and probable Parkinson disease. Typical Parkinson disease must be differentiated from secondary parkinsonism or tremor resulting from neuroleptic drug exposure, essential tremor or structural changes in the brain, such as from normal pressure hydrocephalus, multiple small vessel disease strokes (i.e., vascular parkinsonism) and other neurodegenerative forms of parkinsonism, for example (Figure 1).
Patients initially considered to have a possible diagnosis of Parkin son disease may benefit from a trial of dopamine replacement ther apy to assist with an accurate diagnosis (grade: good practice point; source: SIGN 13 ).
A clear response to dopamine replacement therapy (e.g., levodopa/carbidopa 600 mg/d) in an individual with Parkinson disease could help to reinforce that an accurate diagnosis has been established.
# Routine use of functional imaging is not recommended for the dif ferential diagnosis of Parkinson disease and Parkinson plus disor
ders such as progressive supranuclear palsy and multiple system atrophy (grade: C; source: SIGN 13 ).
Positron emission tomography scanning is not recommended as part of the diagnostic workup of parkinsonian syndromes, except within a research framework (grade: good practice point; source: SIGN 13 ).
123 Iioflupane ( 123 IFPCIT) singlephoton emission computed tomography (SPECT) scanning should be considered as an aid to clinical diagnosis in patients where there is uncertainty between Parkinson disease and nondegenerative parkinsonism or tremor disorders (grade: B; source: SIGN 13 ).
Computed tomography or magnetic resonance imaging brain scanning should not be routinely applied in the diagnosis of idio pathic Parkinson disease (grade: C; source: SIGN 13 ).
Imaging modalities have been extensively researched over the years for a more accurate diagnosis of Parkinson disease, in the differential diagnosis of parkinsonian disorders, as well as in the consideration of a possible progression marker for typical Parkinson disease. However, to date, no single test has been shown to have sufficient sensitivity and specificity to accomplish all 3 objectives.
# Autonomic dysfunction C67
Botulinum toxin A is efficacious for the symptomatic control of sialorrhea in PD. MDS 16 A C68 General measures for treating urinary urgency and incontinence include before bedtime, avoiding coffee and limiting water ingestion. When symptoms appear suddenly, exclude urinary tract infection.
- Nocturia: reduce intake of fluid after 6 pm. Sleep with head-up tilt of bed to reduce urine production. - Nighttime dopaminergic therapy should be optimized.
- For urinary urgency (overactive bladder), anticholinergic or antispasmodic drugs may be useful, but care must be taken regarding central adverse effects. - Botulinum toxin type A injected in the detrusor muscle.
EFNS 15 GPP C69 For orthostatic hypotension, general measures would include the following:
- Avoid aggravating factors such as large meals, alcohol, exposure to a warm environment and drugs known to cause orthostatic hypotension, such as diuretics or antihypertensive drugs.
Levodopa and dopamine agonists may also worsen orthostatic hypotension. - Increase salt intake in symptomatic orthostatic hypotension.
- Ensure head-up tilt of the bed at night. - Wear elastic stockings.
- Highlight postprandial effects. In some patients, hypotension occurs only postprandially.
Warning the patient about this effect and taking frequent small meals may be helpful.
EFNS 15 GPP C70 For orthostatic hypotension, drug therapy includes the addition of:
- Midodrine - Fludrocortisone - Domperidone.
# EFNS 14 EFNS 14 CAN
A GPP GPP
# C71
For gastrointestinal motility problems in PD, general measures for treating constipation should be applied:
- Increased intake of fluid and fibre is recommended (grade: GPP).
- Increased physical activity can be beneficial (grade: GPP).
- Polyethylene glycol solution (macrogol) is recommended (grade: A).
- Fibre supplements such as psyllium (grade: B) or methylcellulose and osmotic laxatives (e.g., lactulose) are recommended (grade: GPP). - Short-term irritant laxatives for selected patients are recommended (grade: GPP).
- The use of drugs with anticholinergics activity should be reduced or discontinued (grade: GPP).
- Domperidone should be added (grade: B). EFNS 14 Varied C72 For individuals with PD and erectile dysfunction:
- Drugs associated with erectile dysfunction (e.g., α-blockers) or anorgasmia (e.g., selective serotonin reuptake inhibitors) should be discontinued. Dopaminergic therapy can have both negative and positive effects on this symptom (grade: GPP). - Sildenafil 50-100 mg, 1 h before sex, can be tried in patients with PD with these problems (grade: B). - Other drugs of this class, such as tadalafil (10 mg, 30 min-12 h before sex) or vardenafil (10 mg, 1 h before sex) can be alternative choices (grade: GPP). - In some patients, apomorphine injections (5-10 min before sex) can also be an alternative treatment (grade: GPP). - Intracavernous injections of papaverine or alprostadil can be considered in selected patients (grade: GPP).
# EFNS 15 Varied
Cognitive impairment
# C73
The diagnoses of dementia associated with PD and of mild cognitive impairment in PD can be made using the Movement Disorder Society Clinical Diagnostic Criteria. These require reports of subjective cognitive decline and difficulties on psychometric testing.
# CAN GPP C74
For PD dementia, cholinesterase inhibitors could be added: rivastigmine (grade: A), donepezil (grade: A), or galantamine (grade: C). There may be idiosyncrasy in clinical response and adverse effects, so it is worth trying an alternative agent (grade: GPP). Memantine can be added or substituted if cholinesterase inhibitors are not tolerated or lack efficacy (grade: C).
# EFNS 14 Varied
# C75
No interventions have been proven to reduce the risk of progression of PD from mild cognitive impairment to dementia but lifestyle modifications, such as engaging in cognitive and social activities and physical exercise, are encouraged.
# CAN GPP
# C84
Clinicians should be aware that there are difficulties in diagnosing mild depression in people with PD because the clinical features of depression overlap with the motor features of PD.
# NICE 7 D GPP C85
Self-rating or clinician-rated scales may be used to screen for depression in patients with PD.
- Diagnosis of depression should not be made on the basis of rating scale score alone.
- Assessment or formulation of depression should be carried out via clinical interview, with a focus on low mood, and with due caution in relation to interpretation of cognitive or somatic symptoms that may be symptoms of PD rather than depression. - Relatives or caregivers who know the patient well should be invited to provide supplementary information to assist the diagnosis, particularly in the context of cognitive impairment.
C GPP GPP GPP C86
The management of depression in people with PD should be tailored to the individual -in particular, to their co-existing therapy.
# NICE 7 D GPP
# Psychosis
# C87
All people with PD and psychosis should receive a general medical evaluation and treatment for any precipitating condition.
# NICE 7 D GPP C88
For patients with PD and psychosis, polypharmacy should be reduced.
- Anticholinergic antidepressants should be reduced or stopped; anxiolytics or sedatives should be reduced or stopped. - Antiparkinsonian drugs should be reduced. Anticholinergics should be stopped, amantadine should be stopped, dopamine agonists should be reduced or stopped, MAO-B and COMT inhibitors should be reduced or stopped and, lastly, levodopa should be reduced.
# EFNS 14 GPP
Genetic testing for monogenic parkinsonism is not recommended in routine clinical practice (grade: good practice point; source: SIGN 13 ).
To date, there is no established therapy for any of the genetic risk factors that have been convincingly identified in the development of either early-onset, monogenic parkinsonism or for the "complex disease-type," late-onset Parkinson disease variant; this is one reason why genetic testing is not recommended in routine clinical practice at this time.
# Treatment
Many symptomatic treatments are available for Parkinson disease. These include medications, surgical procedures, physiotherapy, occupational therapy and other support services. These treatments can have a substantial impact on improving an affected individual's quality of life and should be made available. Despite the increase in nonpharmacologic treatments, individuals with Parkinson disease become more reliant on their medication to maintain their ability to function as the
# C93
People with PD and their family members and caregivers (as appropriate) should be offered opportunities to discuss the prognosis of their condition. These discussions should promote people's priorities, shared decision-making and patient-centred care.
# NICE 8 D C94
People with PD and their family members and caregivers should be given appropriate verbal and written information about the following, and it should be recorded that the discussion has taken place:
- Progression of PD - Possible future adverse effects of medicines for PD - Advance care planning, including orders for advanced decisions to refuse treatment and do not attempt resuscitation, and lasting power of attorney for finance and health and social care - Options for future management - What could happen at the end of life - Available support services; for example, personal care, equipment and practical support, financial support and advice, care at home and respite care.
# NICE 8 D C95
When discussing palliative care, it should be recognized that family members and caregivers may have different information needs from the person with PD.
# NICE 8 D C96
Consideration should be given to referring people at any stage of PD to the palliative care team to give them and their family members or caregivers (as appropriate) the opportunity to discuss palliative care and care at the end of life. disease progresses. A balance between the adverse effects of the medication and the benefit often becomes more difficult with time (Table 6).
# Levodopa
Levodopa may be used as a symptomatic treatment for people with early Parkinson disease (grade: A; source: NICE 7 ).
Levodopa remains the most effective medication for the treatment of motor symptoms and there is no reason to delay its use for those with bothersome motor symptoms.
# Dopamine agonists
Dopamine agonists may be used as a symptomatic treatment for people with early Parkinson disease (grade: A; source: NICE 7 ).
A dopamine agonist should be titrated to a clinically efficacious dose. If adverse effects prevent this, another agonist or a drug from another class should be used in its place (grade: D, good practice point; source: NICE 7 ).
Although dopamine agonists are effective in the initial treatment of Parkinson disease, the risk of adverse effects is higher than with levodopa. In patients older than 70 years, dopamine agonists should be used with even more caution, if at all. There is no good evidence that one dopamine agonist is superior to another regarding control of motor symptoms in Parkinson disease, but only nonergot dopamine agonists should be used because of the risk of pulmonary and cardiac fibrosis seen with the older ergot agonists (e.g., bromocriptine). A transdermally administered dopamine agonist (rotigotine) is now available in Canada and has the conven ience of a single, daily, nonoral administration. Subcutaneous apomorphine infusions or injections may be con sidered for the management of severe motor complications, but should be provided only in units that have sufficient experience and resources (grade: C; source: SIGN 13 ).
Apomorphine is a nonergot dopamine agonist that can be administered in the form of subcutaneous injection. Health Canada has recently approved the latter formulation for the acute, intermittent treatment of "off" episodes. However, training is required for patients and caregivers.
When starting dopamine agonist therapy, people and their family members and caregivers (as appropriate) should be given verbal and written information about the following, and the discussion should be recorded as having taken place:
- The increased risk of developing impulse control disorders when taking dopamine agonist therapy, and that these may be concealed by the person affected. - The different types of impulse control disorders (e.g., compul sive gambling, hypersexuality, binge eating and obsessive shopping). - Who to contact if impulse control disorders develop.
- The possibility that if problematic impulse control disorders develop, dopamine agonist therapy will be reviewed and may be reduced or stopped (grade: good practice point; source: NICE 8 ).
It should be recognized that impulse control disorders can develop in a person with Parkinson disease who is on any dopaminergic therapy at any stage in the disease course (grade: good practice point; source: NICE 8 ).
While impulse control disorders can develop at any time when dopaminergic therapies are used, it occurs in nearly half of those taking dopamine agonists over a prolonged period. 10
# Device-aided therapies
Deep brain stimulation of the subthalamic nucleus or the globus pallidus interna is effective against motor fluctuations and dyskin esia (grade: A; source: EFNS 14 ).
Deep brain stimulation is currently the surgical treatment of choice in appropriately selected patients with substantial motor complications when optimized medical treatment has failed in treating motor symptoms (such as motor fluctuations or dyskinesia).
Intrajejunal levodopacarbidopa enteric gel administered through percutaneous gastrostomy may be considered for the reduction of offtime or to reduce dyskinesia (grade: C; source: EFNS 14 ).
The intrajejunal levodopa-carbidopa gel infusion through a percutaneous enteral tube is now available in Canada. It is accessible under limited use in tertiary movement disorders centres and can substantially reduce off-times when compared with standard oral levodopa. 14
# Rehabilitation
Consideration should be given to referring people who are in the early stages of Parkinson disease to a physiotherapist with experi ence of the disease for assessment, education and advice, includ ing information about physical activity (grade: B; source: NICE 8 ).
# Nonmotor features
Autonomic dysfunction is a common complication of Parkinson disease and can include cardiovascular, gastrointestinal, urogenital and thermoregulatory problems. These have a substantial negative impact on quality of life; however, the quality of evidence to guide management is poor.
Botulinum toxin A is efficacious for the symptomatic control of sial orrhea in Parkinson disease (grade: A; source: MDS 16 ).
Sialorrhea can be cosmetically disturbing and can contribute to functional disability. Botulinum toxin A injections into the salivary glands have been shown to be efficacious to treat sialorrhea. 16 For orthostatic hypotension, drug therapy includes the addition of:
- midodrine (grade: A; source: EFNS 14 The management of depression in people with Parkinson disease should be tailored to the individual -in particular, to their co existing therapy (grade: D, good practice point; source: NICE 7 ).
Depression frequently manifests even before the onset of motor symptoms of Parkinson disease and becomes more prominent and increasingly challenging to treat with disease progression. Unfortunately, there continues to be a paucity of high-quality research trials to support the choice of symptomatic therapies. The principles guiding the use of antidepressants in Parkinson disease are similar to those guiding their use in other medically ill populations in general: start low and go slow, with the effective dose often being less than that recommended for the general population.
# Palliative care
There is growing information with respect to palliative care in Parkinson disease and the guideline panel therefore thought that the topic was an important addition to the new guideline. End-of-life choices, including advance care planning with an open and frank discussion with the patient and the person designated as decision-maker, should be initiated early in the disease process. Conversations occurring in the ambulatory setting are likely to be more productive and less crisis driven than leaving such conversations until an acute stay in hospital.
# Implementation
Parkinson Canada will assist in disseminating print and electronic versions of the guideline to health care providers, individuals with Parkinson disease and their families, as well as post the full guideline on its website. As part of the Parkinson Canada affiliation with the Neurological Health Charities Canada, the guideline will be used to assist in advocacy efforts to federal and provincial governments to improve the care of individuals with Parkinson disease, as well as other brain diseases.
A clear barrier to the implementation of this guideline is a lack of adequate access to health care providers with expertise in dealing with individuals with Parkinson disease. This includes not only specialty physicians but also nurses, speech, occupational and physical therapists with adequate training to deal with these patients who have this very complex condition. Access to palliative care treatment is also lacking for Canadians with neurodegenerative disease and should be addressed at local and national levels of care delivery.
Deep brain stimulation therapy and intrajejunal levodopacarbidopa enteric gel therapy are expensive and complex to use, and most centres have limited budgetary or human resources with respect to the number of procedures they can perform and continue to manage.
The cost of care for neurodegenerative diseases in general will increase as our population ages. The limits that our publicly funded health care system can provide must be addressed, but are outside the scope of this guideline. Parkinson Canada, as well as patients and their families, will continue to play an important role in advocating for more resources and the dissemination of knowledge to improve the care and support of all of those affected by this disease.
# Other guidelines
This guideline draws on the recommendations of the Scottish Intercollegiate Guidelines Network, 13 the European Federation of Neurological Societies, 14,15 the Movement Disorder Society, 16 the National Institute for Health and Clinical Excellence 7,8 and the American Academy practice parameters. 17 We used knowledge taken from these other guidelines to form the basis of this guideline update, and we chose the recommendations for their relevance to our Canadian health care system.
# Gaps in knowledge
There remain important knowledge gaps with respect to many areas of Parkinson disease. Understanding the pathophysiology of the disease will allow for the development of more effective and potentially disease-modifying treatments. Even if we do not yet fully understand disease-causing mechanisms, having good biomarkers for Parkinson disease will accelerate the development of new therapies. Progress has been made in our understanding and management of nonmotor features of Parkinson disease, but evidence for optimal treatment, especially for this area in Parkinson disease, is lacking, as can be appreciated by the low grade of many recommendations in this section.
# Conclusion
Important strides have been made in improving our understanding of Parkinson disease, as well as its treatment. Management of the disease remains complex, and all members of the health care team need access to the most up-to-date information available. Effectively communicating information among all members of the health care team and the patient is essential for optimal care delivery, yet obstacles remain. The cost of care for Parkinson disease and neurodegenerative diseases in general will increase as our population ages. Decisions about the limits that our publicly funded health care system can provide need to be addressed.
Contributors: All of the authors contributed to the conception and design of the work, and the acquisition, analysis, and interpretation of data. David Grimes drafted the manuscript. All of the authors revised it critically for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work. | arkinson disease is chronic and progressive in nature, decreasing the quality of life for both patients with the disease and their caregivers and placing an onerous economic burden on society. 1 The first Canadian guideline on Parkinson disease was published in 2012. 2 Since that guideline, there have been substantial advances in the literature on the disease, particularly with respect to diagnostic criteria and treatment options. Parkinson Canada undertook to update the existing guideline to reflect these advances, as well as to add information on palliative care. With the aim of enhancing care for all Canadians with Parkinson disease, this guideline is based on the best published evidence, involves expert consensus when there is a lack of evidence, offers practical clinical advice, takes patient choice and informed decision-making into account and is relevant to the Canadian health care system. The guideline has been divided into 5 main sections to improve the ease of use: communication, diagnosis and progression, treatment, nonmotor features and palliative care. The full guideline is available in Appendix 1, at www.cmaj.ca/lookup/ suppl/#
• Advanced therapies like deep brain stimulation and intrajejunal levodopa-carbidopa gel infusion are now routinely used in Parkinson disease to manage motor symptoms and fluctuations.
• Evidence exists to support early institution of exercise at the time of diagnosis of Parkinson disease, in addition to the clear benefit now shown in those with well-established disease.
• Palliative care requirements of people with Parkinson disease should be considered throughout all phases of the disease, which includes an option of medical assistance in dying. evidence that they thought would warrant making an update to a recommendation. For those recommendations still considered valid, the experts were asked if they were aware of any new evidence that would change the grade or strength of evidence.
The Knowledge Synthesis Group used components of the ADAPTE process as the basis for the update. 3 Literature searches included those in English from 2006 to December 2016, using the following databases: National Guideline Clearinghouse, the Guidelines International Network, National Library of Guidelines, CPG Infobase, Trip Medical Database, Google Scholar, Embase and Ovid MEDLINE (including Epub Ahead of Print, In-Process and Other Nonindexed Citations), Cochrane Library (limited to Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and the Health Technology Assessment database). Research undertaken only in animals and opinion pieces were removed from the results.
The Knowledge Synthesis Group first searched for clinical practice guidelines on the care of patients with Parkinson disease. If no sufficiently high-quality guidelines or no guidelines were identified, then a staged approach to identification of evidence was implemented, where first moderate-to high-quality systematic reviews were systematically searched for and used as evidence. In the absence of such reviews, or if there were no systematic reviews, then randomized controlled trials (RCTs) were searched for.
The Knowledge Synthesis Group used the Appraisal of Guidelines for Research & Evaluation (AGREE II) instrument to assess the rigour of clinical practice guidelines, 4 the 16-point A MeaSurement Tool to Assess Systematic Reviews (AMSTAR 2) 5 to assess systematic reviews, and the Cochrane Risk of Bias tool to assess RCTs. 6 The Knowledge Synthesis group developed packages of information (including strengths of evidence, citations and summaries of new studies) and compiled them in the form of summaries for distribution to working groups of panel members with relevant expertise (e.g., treatment, communication, etc.) in preparation for a consensus meeting.
Before the consensus meeting, the guideline panel identified several additional topics that were thought to be important and that had not been initially captured because of the stringent topic search conducted. These included depression and Parkinson disease (the initial search had been restricted to amitriptyline, as it was the only antidepressant included in the original guideline), pimavanserin and rotigotine. The Knowledge Synthesis Group extracted data from systematic reviews for these topics, and produced additional summaries to be distributed in advance of the consensus meeting.
Many recommendations from the 2006 National Institute for Health and Care Excellence (NICE) guideline 7 had been adapted for inclusion in the 2012 Canadian guideline. An updated version of the NICE guideline was not identified in the literature search, as its publication date was initially scheduled for June 2017 (published in July 2017). 8 However, a draft version of the updated NICE guideline was available from October 2016 and was included in the materials supplied to the guideline panel for the consensus meeting.
A full-day meeting with 29 guideline panel members was held on Apr. 8, 2017 (Supplement Table 5 in Appendix 1). The working groups reviewed the relevant summaries and the full text of the new literature on their topic. Each working group chair presented their group's recommendations to the entire guideline panel; this served as the basis for the initial voting matrix for each recommendation. An open voting process and summary discussion method identified 5 main areas on which to base the guideline update: communication, diagnosis and progression, treatment, nonmotor features and a new section on palliative care.
Working group members used recommendations from the clinical practice guidelines identified during the literature search to update or create new recommendations. (At the meeting, some recommendations that required updating were identified that had not been raised by the original survey of experts.) If no appropriate recommendation was found in the available clinical practice guidelines, the guideline panel discussed the topic and referred it to the Knowledge Synthesis Group for a follow-up search of systematic reviews and, if necessary, RCTs.
The guideline panel made substantial effort to maintain the phrasing of any recommendation extracted from another guideline, although some were modified slightly to achieve standardized terminology or to make the recommendation more specific. The source for each recommendation extracted from another guideline is cited at the end of the recommendation. When the recommendation was created de novo by the working groups from systematic review or RCT evidence or expert opinion, the recommendation is denoted as "CAN." The classifications for determining the level of evidence used across the guidelines differed slightly, but the recommendation grade was maintained from the original source (i.e., if a recommendation had a grade of B in its source guideline, it was retained as grade B in this guideline update) (Box 1).
After the meeting, we created a voting matrix, organized into the 5 main themes with subsections. We conducted Web-based voting using SurveyMonkey (www.surveymonkey.com) to ensure that the majority (> 75%) agreed on each of the recommendation points. One recommendation did not reach 75% agreement but was considered to be an essential topic to include. The section leads subsequently modified the wording of this recommendation and the newly worded recommendation was approved by the guideline panel. More information on the methods used to develop this guideline is available in Appendix 1.
# Management of competing interests
All guideline panel members agreed to terms of reference that included disclosure of all perceived and actual competing interests to the entire panel at the beginning and end of the guideline development process. Panellists with competing interests were permitted to participate in panel discussions, and later in the voting matrix, without restriction.
# Recommendations
The complete list of recommendations appears in Tables 1 to 5; a description of the underlying evidence for each recommendation is available in Appendix 1.This synopsis provides information on selected recommendations, along with the grade of and source for the recommendation. (When the term "CAN" is used as a source, it refers to a recommendation that was developed de novo for this guideline and was not adapted from another source.)
# COMMUNICATION
n People with Parkinson disease should be encouraged to participate in choices about their own care.
n Communication should be in verbal and written form.
n Discussions should aim to achieve a balance between providing realistic information and promoting optimism.
n Families and caregivers should be informed about the condition and available support services.
# DIAGNOSIS AND PROGRESSION
n Parkinson disease should be suspected in anyone with tremor, sti ness, slowness, balance problems or gait disorders.
n CT or MRI brain scanning should not be routinely used to diagnose Parkinson disease.
n Patients, especially young, who request genetic testing should be assessed by a movement disorders specialist.
n No therapies are e ective for slowing or stopping brain degeneration in Parkinson disease.
# NONMOTOR FEATURES
n Botulinum toxin A helps control drooling.
n Drug therapy for low blood pressure includes midodrine, udrocortisone and domperidone.
n Management of depression should be tailored to the individual and their current therapy.
n Dementia should not exclude a diagnosis of Parkinson disease, even if present early.
n Rapid eye movement sleep behaviour disorder can pre-date the diagnosis of Parkinson disease.
# PALLIATIVE CARE
n The palliative care needs of people with Parkinson disease should be considered throughout all phases of the disease.
n If the patient asks, the option of medical assistance in dying should be discussed.
# TREATMENT
n Levodopa is the most e ective medication and may be used early.
n A regular exercise regimen begun early has proven bene t.
# C1
Communication with people with PD should be aimed at empowering them to participate in the judgments and choices about their own care.
# NICE 7 D C2
Discussions should be aimed at achieving a balance between the provision of honest, realistic information about the condition and the promotion of a feeling of optimism.
# NICE 7 D C3
Because people with PD may develop impaired cognitive ability, a communication deficit or depression, they should be provided with both verbal and written communication throughout the course of the disease -which should be individually tailored and reinforced as necessary -and consistent communication from the professionals involved.
# NICE 7 D GPP C4
Families and caregivers should be given information about the condition, their entitlements to care assessment and the support services available.
# Communication
Communication with people with Parkinson disease should be aimed at empowering them to participate in the judgments and choices about their own care (grade: D; source: NICE 7 ).
Discussions should be aimed at achieving a balance between the provision of honest, realistic information about the condition and the promotion of a feeling of optimism (grade: D; source: NICE 7 ).
Because people with Parkinson disease may develop impaired cognitive ability, a communication deficit or depression, they should be provided with both verbal and written communication throughout the course of the disease -which should be individ ually tailored and reinforced as necessary -and consistent com munication from the professionals involved (grade: D, good prac tice point; source: NICE 7 ).
Families and caregivers should be given information about the condition, their entitlements to care assessment and the support services available (grade: D, good practice point; source: NICE 7 ).
Good communication is at the heart of every interaction between people with Parkinson disease, their caregivers and health professionals. Health care professionals committed to clear and empathic communication can make a meaningful difference to their patients. When people with Parkinson disease know what health care professionals recommend and why, they can participate in shared decision-making. Communication should be supported by the provision of evidence-based information, offered in a form that is tailored to the needs of the individual. Where possible, written materi al should be provided that includes instructions for medication use. Parkinson disease affects people living with the illness and their caregivers and family. It is important that they all have access to the same information and services.
# C9
Clinicians should be aware of the poor specificity of a clinical diagnosis of PD in the early stages of the disease, and consider this uncertainty when giving information to the patient and when planning management.
SIGN 13 C C10 Patients should be offered long-term, regular follow-up to review the diagnosis of PD. This should include a review of the ongoing benefits in those started on dopamine replacement therapy.
SIGN 13 GPP
# C11
Patients initially considered to have a possible diagnosis of PD may benefit from a trial of dopamine replacement therapy to assist with an accurate diagnosis.
SIGN 13
# GPP C12
Patients with suspected PD, with substantial disability or exclusion criteria or red flags as per the MDS diagnostic criteria, should be seen by a clinician with sufficient expertise in movement disorders to make the diagnosis.
SIGN 13 C GPP
# C13
Acute challenge testing with either levodopa or apomorphine should not be used in the diagnosis of PD. Patients with suspected PD should be considered for a trial of chronic levodopa treatment.
# SIGN 13 A C14
Objective olfactory testing is not recommended in the diagnosis of PD. SIGN 13 B C15 Routine use of functional imaging is not recommended for the differential diagnosis of PD and Parkinson plus disorders such as progressive supranuclear palsy and multiple system atrophy.
# SIGN 13 C C16
PET scanning is not recommended as part of the diagnostic work-up of parkinsonian syndromes, except within a research framework.
# SIGN 13 GPP C17
123 I-FP-CIT SPECT scanning should be considered as an aid to clinical diagnosis in patients where there is uncertainty between PD and nondegenerative parkinsonism or tremor disorders.
SIGN 13 B
# C18
Computed tomography or MRI brain scanning should not be routinely applied in the diagnosis of idiopathic PD. SIGN 13 C C19 Vitamin E should not be used as a neuroprotective therapy for people with PD. Co-enzyme Q10 should not be used as a neuroprotective therapy for people with PD.
NICE 8 A C20 Levodopa (grade: GPP), amantadine (grade: GPP), dopamine agonists (pramipexole, ropinirole, rotigotine, apomorphine, bromocriptine) (grade: A), or MAO inhibitors (selegiline, rasagiline) (grade: A) should not be used as neuroprotective therapies for people with PD, except in the context of clinical trials.
# CAN Varied
# C21
Genetic testing for monogenic parkinsonism is not recommended in routine clinical practice. SIGN 13
# GPP C22
Patients who request genetic testing, particularly those with young-onset parkinsonism, should be assessed in a specialist movement disorders clinic for consideration of counselling and testing.
# General considerations
# C23
People with PD should have regular access to the following:
• Clinical monitoring and medication adjustment • A continuing point of contact for support, including home visits, when appropriate • A reliable source of information about clinical and social matters of concern to people with PD and their caregivers, which may be provided by a PD nurse specialist.
# NICE C C24
Antiparkinsonian medication should not be withdrawn abruptly or allowed to fail suddenly owing to poor absorption (e.g., gastroenteritis, abdominal surgery), to avoid the potential for acute akinesia or neuroleptic malignant syndrome.
# NICE D GPP C25
The practice of withdrawing patients from their antiparkinsonian drugs (so-called "drug holidays") to reduce motor complications should not be undertaken because of the risk of neuroleptic malignant syndrome.
# NICE D GPP C26
In view of the risks of sudden changes in antiparkinsonian medication, people with PD who are admitted to hospital or care homes should have their medication: i) given at the appropriate times, which in some cases may mean allowing self-medication; ii) adjusted by, or adjusted only after discussion with, a specialist in the management of PD.
# NICE D GPP C27
Surveillance for dopamine dysregulation syndrome should be undertaken in patients receiving levodopa or intermittent apomorphine.
# SIGN 13 GPP C28
When starting dopamine agonist therapy, people and their family members and caregivers (as appropriate) should be given verbal and written information about the following, and the discussion should be recorded as having taken place:
• The increased risk of developing impulse control disorders when taking dopamine agonist therapy, and that these may be concealed by the person affected • The different types of impulse control disorders (e.g., compulsive gambling, hypersexuality, binge eating and obsessive shopping) • Who to contact if impulse control disorders develop • The possibility that if problematic impulse control disorders develop, dopamine agonist therapy will be reviewed and may be reduced or stopped.
# NICE GPP C29
It should be recognized that impulse control disorders can develop in a person with PD who is on any dopaminergic therapy at any stage in the disease course.
# NICE GPP
# Pharmacologic therapy in early PD
# C30
Before starting treatment for people with PD, the following should be discussed:
•
# C39
There is insufficient evidence to support the use of amantadine in the treatment of patients with early PD.
SIGN 13 A
# Rehabilitation
# C56
Consideration should be given to referring people who are in the early stages of PD to a physiotherapist with experience of the disease for assessment, education and advice, including information about physical activity.
# NICE 8 B C57
Physiotherapy specific to PD should be offered to people who are experiencing balance or motor function problems.
# NICE 8 A C58
Consideration should be given to referring people who are in the early stages of PD to an occupational therapist with experience of PD for assessment, education and advice on motor and nonmotor symptoms.
# NICE 8 B C59
Occupational therapy specific to PD should be offered to people who are having difficulties with activities of daily living.
NICE 7 A
# Diagnosis and progression
Parkinson disease should be suspected in people presenting with tremor, stiffness, slowness, balance problems or gait disorders (grade: D, good practice point; source: NICE 7 ).
Parkinson disease can be diagnosed using the Movement Disorder Society Clinical Diagnostic Criteria (grade: good practice point; source: CAN).
Parkinson disease is characterized by a constellation of clinical manifestations, which include slowness of movement (bradykinesia), rest tremor, rigidity and postural instability. The diagnosis of Parkinson disease is still based predominantly on its clinical features; in 2015, the Movement Disorder Society 9 published new criteria for clinically established and probable Parkinson disease. Typical Parkinson disease must be differentiated from secondary parkinsonism or tremor resulting from neuroleptic drug exposure, essential tremor or structural changes in the brain, such as from normal pressure hydrocephalus, multiple small vessel disease strokes (i.e., vascular parkinsonism) and other neurodegenerative forms of parkinsonism, for example (Figure 1).
Patients initially considered to have a possible diagnosis of Parkin son disease may benefit from a trial of dopamine replacement ther apy to assist with an accurate diagnosis (grade: good practice point; source: SIGN 13 ).
A clear response to dopamine replacement therapy (e.g., levodopa/carbidopa 600 mg/d) in an individual with Parkinson disease could help to reinforce that an accurate diagnosis has been established.
# Routine use of functional imaging is not recommended for the dif ferential diagnosis of Parkinson disease and Parkinson plus disor
ders such as progressive supranuclear palsy and multiple system atrophy (grade: C; source: SIGN 13 ).
Positron emission tomography scanning is not recommended as part of the diagnostic workup of parkinsonian syndromes, except within a research framework (grade: good practice point; source: SIGN 13 ).
123 Iioflupane ( 123 IFPCIT) singlephoton emission computed tomography (SPECT) scanning should be considered as an aid to clinical diagnosis in patients where there is uncertainty between Parkinson disease and nondegenerative parkinsonism or tremor disorders (grade: B; source: SIGN 13 ).
Computed tomography or magnetic resonance imaging brain scanning should not be routinely applied in the diagnosis of idio pathic Parkinson disease (grade: C; source: SIGN 13 ).
Imaging modalities have been extensively researched over the years for a more accurate diagnosis of Parkinson disease, in the differential diagnosis of parkinsonian disorders, as well as in the consideration of a possible progression marker for typical Parkinson disease. However, to date, no single test has been shown to have sufficient sensitivity and specificity to accomplish all 3 objectives.
# Autonomic dysfunction C67
Botulinum toxin A is efficacious for the symptomatic control of sialorrhea in PD. MDS 16 A C68 General measures for treating urinary urgency and incontinence include before bedtime, avoiding coffee and limiting water ingestion. When symptoms appear suddenly, exclude urinary tract infection.
• Nocturia: reduce intake of fluid after 6 pm. Sleep with head-up tilt of bed to reduce urine production. • Nighttime dopaminergic therapy should be optimized.
• For urinary urgency (overactive bladder), anticholinergic or antispasmodic drugs may be useful, but care must be taken regarding central adverse effects. • Botulinum toxin type A injected in the detrusor muscle.
EFNS 15 GPP C69 For orthostatic hypotension, general measures would include the following:
• Avoid aggravating factors such as large meals, alcohol, exposure to a warm environment and drugs known to cause orthostatic hypotension, such as diuretics or antihypertensive drugs.
Levodopa and dopamine agonists may also worsen orthostatic hypotension. • Increase salt intake in symptomatic orthostatic hypotension.
• Ensure head-up tilt of the bed at night. • Wear elastic stockings.
• Highlight postprandial effects. In some patients, hypotension occurs only postprandially.
Warning the patient about this effect and taking frequent small meals may be helpful.
EFNS 15 GPP C70 For orthostatic hypotension, drug therapy includes the addition of:
• Midodrine • Fludrocortisone • Domperidone.
# EFNS 14 EFNS 14 CAN
A GPP GPP
# C71
For gastrointestinal motility problems in PD, general measures for treating constipation should be applied:
• Increased intake of fluid and fibre is recommended (grade: GPP).
• Increased physical activity can be beneficial (grade: GPP).
• Polyethylene glycol solution (macrogol) is recommended (grade: A).
• Fibre supplements such as psyllium (grade: B) or methylcellulose and osmotic laxatives (e.g., lactulose) are recommended (grade: GPP). • Short-term irritant laxatives for selected patients are recommended (grade: GPP).
• The use of drugs with anticholinergics activity should be reduced or discontinued (grade: GPP).
• Domperidone should be added (grade: B). EFNS 14 Varied C72 For individuals with PD and erectile dysfunction:
• Drugs associated with erectile dysfunction (e.g., α-blockers) or anorgasmia (e.g., selective serotonin reuptake inhibitors) should be discontinued. Dopaminergic therapy can have both negative and positive effects on this symptom (grade: GPP). • Sildenafil 50-100 mg, 1 h before sex, can be tried in patients with PD with these problems (grade: B). • Other drugs of this class, such as tadalafil (10 mg, 30 min-12 h before sex) or vardenafil (10 mg, 1 h before sex) can be alternative choices (grade: GPP). • In some patients, apomorphine injections (5-10 min before sex) can also be an alternative treatment (grade: GPP). • Intracavernous injections of papaverine or alprostadil can be considered in selected patients (grade: GPP).
# EFNS 15 Varied
Cognitive impairment
# C73
The diagnoses of dementia associated with PD and of mild cognitive impairment in PD can be made using the Movement Disorder Society Clinical Diagnostic Criteria. These require reports of subjective cognitive decline and difficulties on psychometric testing.
# CAN GPP C74
For PD dementia, cholinesterase inhibitors could be added: rivastigmine (grade: A), donepezil (grade: A), or galantamine (grade: C). There may be idiosyncrasy in clinical response and adverse effects, so it is worth trying an alternative agent (grade: GPP). Memantine can be added or substituted if cholinesterase inhibitors are not tolerated or lack efficacy (grade: C).
# EFNS 14 Varied
# C75
No interventions have been proven to reduce the risk of progression of PD from mild cognitive impairment to dementia but lifestyle modifications, such as engaging in cognitive and social activities and physical exercise, are encouraged.
# CAN GPP
# C84
Clinicians should be aware that there are difficulties in diagnosing mild depression in people with PD because the clinical features of depression overlap with the motor features of PD.
# NICE 7 D GPP C85
Self-rating or clinician-rated scales may be used to screen for depression in patients with PD.
• Diagnosis of depression should not be made on the basis of rating scale score alone.
• Assessment or formulation of depression should be carried out via clinical interview, with a focus on low mood, and with due caution in relation to interpretation of cognitive or somatic symptoms that may be symptoms of PD rather than depression. • Relatives or caregivers who know the patient well should be invited to provide supplementary information to assist the diagnosis, particularly in the context of cognitive impairment.
C GPP GPP GPP C86
The management of depression in people with PD should be tailored to the individual -in particular, to their co-existing therapy.
# NICE 7 D GPP
# Psychosis
# C87
All people with PD and psychosis should receive a general medical evaluation and treatment for any precipitating condition.
# NICE 7 D GPP C88
For patients with PD and psychosis, polypharmacy should be reduced.
• Anticholinergic antidepressants should be reduced or stopped; anxiolytics or sedatives should be reduced or stopped. • Antiparkinsonian drugs should be reduced. Anticholinergics should be stopped, amantadine should be stopped, dopamine agonists should be reduced or stopped, MAO-B and COMT inhibitors should be reduced or stopped and, lastly, levodopa should be reduced.
# EFNS 14 GPP
Genetic testing for monogenic parkinsonism is not recommended in routine clinical practice (grade: good practice point; source: SIGN 13 ).
To date, there is no established therapy for any of the genetic risk factors that have been convincingly identified in the development of either early-onset, monogenic parkinsonism or for the "complex disease-type," late-onset Parkinson disease variant; this is one reason why genetic testing is not recommended in routine clinical practice at this time.
# Treatment
Many symptomatic treatments are available for Parkinson disease. These include medications, surgical procedures, physiotherapy, occupational therapy and other support services. These treatments can have a substantial impact on improving an affected individual's quality of life and should be made available. Despite the increase in nonpharmacologic treatments, individuals with Parkinson disease become more reliant on their medication to maintain their ability to function as the
# C93
People with PD and their family members and caregivers (as appropriate) should be offered opportunities to discuss the prognosis of their condition. These discussions should promote people's priorities, shared decision-making and patient-centred care.
# NICE 8 D C94
People with PD and their family members and caregivers should be given appropriate verbal and written information about the following, and it should be recorded that the discussion has taken place:
• Progression of PD • Possible future adverse effects of medicines for PD • Advance care planning, including orders for advanced decisions to refuse treatment and do not attempt resuscitation, and lasting power of attorney for finance and health and social care • Options for future management • What could happen at the end of life • Available support services; for example, personal care, equipment and practical support, financial support and advice, care at home and respite care.
# NICE 8 D C95
When discussing palliative care, it should be recognized that family members and caregivers may have different information needs from the person with PD.
# NICE 8 D C96
Consideration should be given to referring people at any stage of PD to the palliative care team to give them and their family members or caregivers (as appropriate) the opportunity to discuss palliative care and care at the end of life. disease progresses. A balance between the adverse effects of the medication and the benefit often becomes more difficult with time (Table 6).
# Levodopa
Levodopa may be used as a symptomatic treatment for people with early Parkinson disease (grade: A; source: NICE 7 ).
Levodopa remains the most effective medication for the treatment of motor symptoms and there is no reason to delay its use for those with bothersome motor symptoms.
# Dopamine agonists
Dopamine agonists may be used as a symptomatic treatment for people with early Parkinson disease (grade: A; source: NICE 7 ).
A dopamine agonist should be titrated to a clinically efficacious dose. If adverse effects prevent this, another agonist or a drug from another class should be used in its place (grade: D, good practice point; source: NICE 7 ).
Although dopamine agonists are effective in the initial treatment of Parkinson disease, the risk of adverse effects is higher than with levodopa. In patients older than 70 years, dopamine agonists should be used with even more caution, if at all. There is no good evidence that one dopamine agonist is superior to another regarding control of motor symptoms in Parkinson disease, but only nonergot dopamine agonists should be used because of the risk of pulmonary and cardiac fibrosis seen with the older ergot agonists (e.g., bromocriptine). A transdermally administered dopamine agonist (rotigotine) is now available in Canada and has the conven ience of a single, daily, nonoral administration. Subcutaneous apomorphine infusions or injections may be con sidered for the management of severe motor complications, but should be provided only in units that have sufficient experience and resources (grade: C; source: SIGN 13 ).
Apomorphine is a nonergot dopamine agonist that can be administered in the form of subcutaneous injection. Health Canada has recently approved the latter formulation for the acute, intermittent treatment of "off" episodes. However, training is required for patients and caregivers.
When starting dopamine agonist therapy, people and their family members and caregivers (as appropriate) should be given verbal and written information about the following, and the discussion should be recorded as having taken place:
• The increased risk of developing impulse control disorders when taking dopamine agonist therapy, and that these may be concealed by the person affected. • The different types of impulse control disorders (e.g., compul sive gambling, hypersexuality, binge eating and obsessive shopping). • Who to contact if impulse control disorders develop.
• The possibility that if problematic impulse control disorders develop, dopamine agonist therapy will be reviewed and may be reduced or stopped (grade: good practice point; source: NICE 8 ).
It should be recognized that impulse control disorders can develop in a person with Parkinson disease who is on any dopaminergic therapy at any stage in the disease course (grade: good practice point; source: NICE 8 ).
While impulse control disorders can develop at any time when dopaminergic therapies are used, it occurs in nearly half of those taking dopamine agonists over a prolonged period. 10
# Device-aided therapies
Deep brain stimulation of the subthalamic nucleus or the globus pallidus interna is effective against motor fluctuations and dyskin esia (grade: A; source: EFNS 14 ).
Deep brain stimulation is currently the surgical treatment of choice in appropriately selected patients with substantial motor complications when optimized medical treatment has failed in treating motor symptoms (such as motor fluctuations or dyskinesia).
Intrajejunal levodopacarbidopa enteric gel administered through percutaneous gastrostomy may be considered for the reduction of offtime or to reduce dyskinesia (grade: C; source: EFNS 14 ).
The intrajejunal levodopa-carbidopa gel infusion through a percutaneous enteral tube is now available in Canada. It is accessible under limited use in tertiary movement disorders centres and can substantially reduce off-times when compared with standard oral levodopa. 14
# Rehabilitation
Consideration should be given to referring people who are in the early stages of Parkinson disease to a physiotherapist with experi ence of the disease for assessment, education and advice, includ ing information about physical activity (grade: B; source: NICE 8 ).
# Nonmotor features
Autonomic dysfunction is a common complication of Parkinson disease and can include cardiovascular, gastrointestinal, urogenital and thermoregulatory problems. These have a substantial negative impact on quality of life; however, the quality of evidence to guide management is poor.
Botulinum toxin A is efficacious for the symptomatic control of sial orrhea in Parkinson disease (grade: A; source: MDS 16 ).
Sialorrhea can be cosmetically disturbing and can contribute to functional disability. Botulinum toxin A injections into the salivary glands have been shown to be efficacious to treat sialorrhea. 16 For orthostatic hypotension, drug therapy includes the addition of:
• midodrine (grade: A; source: EFNS 14 The management of depression in people with Parkinson disease should be tailored to the individual -in particular, to their co existing therapy (grade: D, good practice point; source: NICE 7 ).
Depression frequently manifests even before the onset of motor symptoms of Parkinson disease and becomes more prominent and increasingly challenging to treat with disease progression. Unfortunately, there continues to be a paucity of high-quality research trials to support the choice of symptomatic therapies. The principles guiding the use of antidepressants in Parkinson disease are similar to those guiding their use in other medically ill populations in general: start low and go slow, with the effective dose often being less than that recommended for the general population.
# Palliative care
There is growing information with respect to palliative care in Parkinson disease and the guideline panel therefore thought that the topic was an important addition to the new guideline. End-of-life choices, including advance care planning with an open and frank discussion with the patient and the person designated as decision-maker, should be initiated early in the disease process. Conversations occurring in the ambulatory setting are likely to be more productive and less crisis driven than leaving such conversations until an acute stay in hospital.
# Implementation
Parkinson Canada will assist in disseminating print and electronic versions of the guideline to health care providers, individuals with Parkinson disease and their families, as well as post the full guideline on its website. As part of the Parkinson Canada affiliation with the Neurological Health Charities Canada, the guideline will be used to assist in advocacy efforts to federal and provincial governments to improve the care of individuals with Parkinson disease, as well as other brain diseases.
A clear barrier to the implementation of this guideline is a lack of adequate access to health care providers with expertise in dealing with individuals with Parkinson disease. This includes not only specialty physicians but also nurses, speech, occupational and physical therapists with adequate training to deal with these patients who have this very complex condition. Access to palliative care treatment is also lacking for Canadians with neurodegenerative disease and should be addressed at local and national levels of care delivery.
Deep brain stimulation therapy and intrajejunal levodopacarbidopa enteric gel therapy are expensive and complex to use, and most centres have limited budgetary or human resources with respect to the number of procedures they can perform and continue to manage.
The cost of care for neurodegenerative diseases in general will increase as our population ages. The limits that our publicly funded health care system can provide must be addressed, but are outside the scope of this guideline. Parkinson Canada, as well as patients and their families, will continue to play an important role in advocating for more resources and the dissemination of knowledge to improve the care and support of all of those affected by this disease.
# Other guidelines
This guideline draws on the recommendations of the Scottish Intercollegiate Guidelines Network, 13 the European Federation of Neurological Societies, 14,15 the Movement Disorder Society, 16 the National Institute for Health and Clinical Excellence 7,8 and the American Academy practice parameters. 17 We used knowledge taken from these other guidelines to form the basis of this guideline update, and we chose the recommendations for their relevance to our Canadian health care system.
# Gaps in knowledge
There remain important knowledge gaps with respect to many areas of Parkinson disease. Understanding the pathophysiology of the disease will allow for the development of more effective and potentially disease-modifying treatments. Even if we do not yet fully understand disease-causing mechanisms, having good biomarkers for Parkinson disease will accelerate the development of new therapies. Progress has been made in our understanding and management of nonmotor features of Parkinson disease, but evidence for optimal treatment, especially for this area in Parkinson disease, is lacking, as can be appreciated by the low grade of many recommendations in this section.
# Conclusion
Important strides have been made in improving our understanding of Parkinson disease, as well as its treatment. Management of the disease remains complex, and all members of the health care team need access to the most up-to-date information available. Effectively communicating information among all members of the health care team and the patient is essential for optimal care delivery, yet obstacles remain. The cost of care for Parkinson disease and neurodegenerative diseases in general will increase as our population ages. Decisions about the limits that our publicly funded health care system can provide need to be addressed.
#
Contributors: All of the authors contributed to the conception and design of the work, and the acquisition, analysis, and interpretation of data. David Grimes drafted the manuscript. All of the authors revised it critically for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work.
Funding: This guideline update was supported by a grant from Parkinson Canada with no participants or authors receiving any personal funding for their creation.
# Acknowledgements:
The authors thank the panel of health care professionals who contributed their expertise. The authors also thank their patients and caregivers, who continue to educate and inspire them, as well as the Knowledge Synthesis Group at The Ottawa Hospital, who played a critical role in developing the methods needed for the guideline.
Correspondence to: David Grimes, [email protected] | None | None |
4cd809e4e8d781359c4b80ceec7c6e5412fd8dcb | cma | None | Note: This document adapts prior pandemic and Influenza-Like Illness (ILI) guidance to the current COVID-19 crisis. This document has been developed by the Provincial Critical Care Adult COVID-19 Working Group.This material is intended for general information only and is provided on an "as is", "where is" basis. Although reasonable efforts were made to confirm the accuracy of the information, Alberta Health Services does not make any representation or warranty, express, implied or statutory, as to the accuracy, reliability, completeness, applicability or fitness for a particular purpose of such information. AHS staff who require legal advice regarding copyright should contact the Corporate & Commercial Division within AHS Legal & Privacy for further assistance. Alberta Health Services expressly disclaims all liability for the use of these materials, and for any claims, actions, demands or suits arising from such use.The links in this document are updated regularly and should be periodically reviewed.# Intention for use:
- To guide all providers of critical care in Alberta as to the basic care of adult critically ill patients with suspected, probable or confirmed COVID-19 infection to ensure such patients receive optimal, consistent and equitable care throughout the ICUs of Alberta. o Recognize that the application of the guidance in this document will need to be adapted to the characteristics of each individual unit, zone and department. o This guideline is not meant to be applied to patient groups outside of critical care units. o "Humidity should be preferentially provided via in-line HME devices. Active/heated humidity systems should only be used when necessary (e.g., to manage difficult secretions or to provide inhaled epoprostenol) and only when such a system is part of a fixed integral part of a particular ventilator"
# AHS COVID-19 Website
# Table of Contents
- Replace prostacyclin with epoprostenol April 13, 2020
Robertson/Morrissey/Bagshaw/Zuege based on feedback from Provincial Working Group, feedback from the provincial critical care community and updated AHS Guidance documents.
# Surveillance
Case Description for COVID-19 COVID-19 is an infectious syndrome caused by SARS-CoV-2, a novel coronavirus. COVID-19 is believed to be spread primarily via respiratory droplets (similar to influenza and other coronaviruses such as MERS and SARS) and/or contact (e.g., contaminated hands to mucous membranes). Numerous genetic variants of SARS-CoV-2 are now known to exist in addition to the original 'wild' type. Some variants may have differences in transmissibility and/or pathogenicity.
# Clinical Presentation
- Individuals infected with the virus that causes COVID-19 may have few or no symptoms and may range from mild to severe, life-threatening illness, with manifestations including fever greater than 38°C (>90% of cases), new onset or exacerbation of chronic cough (80% of cases), shortness of breath (20% of cases), difficulty breathing, sore throat or runny nose. Canadian SPRINT-SARI Characteristic Data March 2021 - Severe disease from COVID-19 infection can cause viral pneumonia and respiratory failure, sepsis, septic shock and multi-organ failure or death.
- Susceptibility is assumed to be universal.
- The virus appears to cause more severe disease in older adults (greater than 60 years of age) and individuals with underlying comorbidities (e.g., cardiovascular, renal and liver disorders, diabetes and chronic respiratory diseases) or immune compromising conditions.
- There is evolving understanding of the immune response in COVID-19 disease, and the possibility of reinfection with SARS-CoV-2 has not been excluded. - All patients are to be assessed initially for symptoms and risk factors associated with respiratory communicable disease using Form 21615: Communicable Disease (Respiratory) Initial Screening Form (or equivalent electronic version).
- The initial assessment will then inform the use of AHS Acute Care COVID-19 Expanded Testing Algorithm.
- Ongoing assessment of admitted patients is to be completed using When an AGMP is in progress the following poster may be utilized: AGMP Poster There is no settle time required after AGMP is complete 5. Due to the high risk of aerosol generation, critically ill patients with suspected, probable or confirmed positive COVID-19 will be admitted to single patient rooms when available.
- Negative pressure (airborne isolation) rooms are not required and should be reserved for patients with disease processes requiring airborne isolation but may be utilized if available.
- If all single patient rooms are occupied, then attempt to cohort COVID-19 patients in one area with a minimum 2-meter separation between patients. IP&C guidance on cohorting of patients should be reviewed.
Of note, given the presence of SARS-CoV-2 variants, before considering cohorting patients with COVID-19 in the same room, the viral subtype must be identified (eg wild type or variant) for both patients being considered for cohorting. Viruses from all COVID-positive patients in Alberta are being subtyped with turn-around times currently being approximately 6 days. Viral subtyping results are not currently available within existing electronic medical records (though this is being actively explored).
- Strain typing of COVID-19 must be considered when cohorting.
- Patients with unknown COVID-19 strain are not to be cohorted.
- ii. If the patient is intubated, an ETA should be collected as soon as possible and sent for respiratory viral testing (irrespective of whether an NPS has been collected).
- If the patient is not intubated and has not had an NPS sent for respiratory viral testing, then an NPS should be collected as soon as possible.
- If there is a clinical possibility of other more unusual pathogens (e.g., as in an immunosuppressed patient), consideration should be given to performing bronchoalveolar lavage (BAL) recognizing that bronchoscopy is an aerosol generating medical procedure (AGMP).
- Bronchoscopy solely for the purposes of microbial sampling in an otherwise uncomplicated patient is not recommended. 8. If patient is intubated: a. Transport using an in-line filter, in-line suction catheter and heat moisture exchange filter (HMEF). b. Use of transport ventilators (with filtering systems) is preferred to minimize the need for manual bagging. If use of a transport ventilator is not possible, use a manual bagging unit (with PEEP valve). c. RRT will manage airway and oxygen requirements. d. Clean and disinfect transport ventilator after use and discard breathing circuit.
- If patient is not intubated: a. Transport with non-humidified (dry) oxygen supply -respiratory to identify the most appropriate oxygen delivery mask. b. Patients receiving oxygen by any type of nasal cannula should be given a procedure mask to wear if tolerated.
- Clean O2 cylinder(s) and transport stretcher with disinfectant wipes before returning to general circulation.
# Staffing Considerations
The principle is to minimize the number of staff involved directly with the patient while providing quality patient care.
- The nurse in charge and the respiratory therapy supervisor are responsible to determine patient assignments and will coordinate care of all patients in the unit with the principle in mind that the total number of staff caring for a COVID-19 patient should be kept to a minimum. If possible, cohort staff so that RNs and RRTs caring for COVID-19 patients are not caring for non-COVID-19 patients. Geographical cohorting of COVID-19 patients may assist with staff assignments if appropriate to facilitate.
- All members of the healthcare team, inclusive of MRHP, NPs, RNs, RRTs, allied health, and support staff will continue to perform their usual duties. They must review and adhere to all appropriate isolation precautions prior to entering rooms.
- For students (medical or otherwise) working within an ICU, please check with current educational institution guidelines for any restrictions to practice or exposures.
- Individuals who are unable to competently adhere to the IP&C recommendations for COVID-19 (e.g., skin condition that precludes proper hand hygiene practices) should not provide care to patients who are under investigation for COVID-19, or those who have suspected, probable or confirmed COVID-19. Staff who are unable to be Fit Tested for N95 respirators should not care for COVID-19 patients that are intubated or those that require any AGMP.
- During a pandemic there may be a need to move towards team-based models of care delivery during surge. Although the structure of each team model (staff mix, staff to patient ratio) are site specific, there are common facilitating elements to team based model functionality.
# Resources for Team-Based Care Models during Pandemic
# Infection, Prevention and Control
Suspected, probable or confirmed positive COVID-19 cases in the ICU should be managed with contact and droplet precautions. Use N95 respirators for all aerosol generating medical procedures (Aerosol Generating Medical Procedure GuidanceTool) and for all suspected, probable or confirmed positive COVID-19 intubated patients.
Interim IPC Recommendations COVID-19
- All staff providing care must be successfully N95 fit tested and masks must be seal checked when applying.
- Continuous masking and eye protection must be adhered to in patient care areas.
# PPE Guidance:
The following link contains all up to date information on PPE and should be reviewed periodically: Personal Protective Equipment (PPE).
Applying N95 respirators: All health care workers must have been fit tested within the last two years. Hold mask in your hand and pull both elastic ties, bottom first, over your hand for ease of putting mask on. Test to ensure that mask is secure and that there are no leaks. Discard immediately outside of room after use. Do not touch the outside of the mask while discarding as it is considered contaminated.
Proper wearing of an N95 respirator includes:
- Putting on the respirator before entering the patient's room.
- Molding the metal bar over the nose.
- Ensuring an airtight seal on the face, over top of the nose and under the chin. - Donning eye protection after N95 for AGMP.
- Leaving the room and changing the respirator when it becomes moist.
- Removing the respirator after leaving the patient's room by touching elastic only.
- Not wearing respirator around the neck.
# Personal Protective Equipment (PPE) Guidance to Help Make Continuous Masking Work for You
Eye protection (disposable face shields/goggles): Face shields or goggles are to be worn upon entering the patient room. Personal eyewear (glasses) is not sufficient. Face shields are single use. Discard face shields outside of the room after use. If googles are re-used they must be fully wiped down with disinfectant wipes prior to re-use.
Gloves: Always perform hand hygiene prior to putting on gloves and after removal.
# General ICU Care
- Reduce all clinically unnecessary entries into the room.
See Appendix E for strategies to conserve personal protective equipment (PPE). 1. Point of Care Risk Assessment (PCRA) should be completed by all health care workers before initiating any resuscitation. 2. The AHS Scientific Advisory Committee has determined that the provision of chest compressions alone is not considered to be an aerosol generating medical procedure (AGMP) and only requires contact and droplet PPE.
- Assume patient is COVID-19 positive, unless otherwise identified/known.
- Consideration that the location of resuscitation may influence response and team processes (i.e. Critical Care Unit vs. Inpatient Unit or Emergency Department (ED)).
- Minimize number of participants in the resuscitation area during resuscitation. 6. Minimize equipment in the resuscitation area wherever possible. 7. If CPR is indicated, chest compressions alone can be initiated safely by a provider wearing contact/droplet PPE. 8. Contact and droplet precautions (including a fit-tested N95 respirator) shall be donned prior to initiating any AGMP (including manual ventilation and airway management) by all response team members, even if there is a perceived delay in resuscitation efforts. 9. Routine practices, such as defibrillation are otherwise unchanged from non-COVID-19 patients.
Communication:
- Current paging/notification processes should be followed.
- Clear identification of isolation requirements should be made to the response team on arrival. - Clear communication of current GOC status should be made to the responding resuscitation team members on arrival, where available/known. - Upon arrival to the code, team members should quickly clarify roles and which members will be working inside versus outside the room.
Arrival to Code Blue:
- Ensure that PPE is readily available for responding team members and that there is an available "safety/logistics officer' to monitor donning/doffing. Since the availability of suitable PPE in enough quantities at the site of the arrest may not be guaranteed, the use of PPE pre-made kits should be considered, to travel with the response team or to be stored with code carts (where possible). - Chest compressions alone are not an AGMP and an N95 respirator is not required to initiate hands-only CPR. Healthcare workers completing manual chest compressions are directed to continue to wear recommended PPE in alignment with our continuous masking directive, the point-of-care risk assessment, with the addition of contact and droplet precautions for patients with suspected, probable or confirmed positive COVID-19. Outside the room:
- RN/HCW "runner", to assist with supply of equipment stored on the unit and the activation of other HCWs, if required. - "Logistic/Safety Officer", who should be a senior HCW, to regulate access to the patient's room, monitor proper PPE donning and doffing, ensure that protocols and the opening and closing of doors is followed and communicate with the ICU prior to the initiation of patient transport.
Modifications to Advanced Cardiac Life Support (ACLS) in COVID-19 Patients:
- Intubate patients early and hold CPR during intubation to minimize aerosolization of particles and optimize intubation success. - The best pharmacotherapy for induction and intubation will be determined by the MRHP on a case-by-case basis but in general should include strategies that minimize chances of cough or aerosol generation via use of agents inducing deep sedation and often use of neuromuscular blockade when clinically appropriate (e.g. no signs predicting difficult intubation). - Manual bagging of non-intubated patients using a BVM should be avoided if possible. If necessary because of unsuccessful initial intubation, use two experienced practitioners to establish an intact seal and minimize the risk of aerosolization. - Avoid disconnections between the ETT and resuscitation bag. If required due to gas trapping, the plan to disconnect should be announced loudly in advance and the ETT should only be disconnected beyond the HEPA filter.
Post-Arrest: to minimize the need for manual bagging. - Transportation to a critical care unit should follow guidelines listed in Section D of this document. - For patients being transported to an ICU or an advanced care unit in a facility, consideration should be given to testing that can be safely completed on route to minimize the need for additional transports (e.g. CT scan).
Charting Considerations:
- Computer code narrator may be utilized with existing computers within the room or immediately outside the resuscitation room.
- No portable computer devices should be brought into the room.
- All efforts to maintain a clean paper chart should be taken.
- Papers are not a means of transmission. Handle all paper with clean hands, clean any shared items (like chart binders, pens or binders) with a low-level disinfectant wipe. o Transcribing for purposes of infection prevention will not be required.
# Respiratory Care
The basic principles are to always use personal protective equipment in addition to appropriate isolation precautions and minimize the use of aerosol-generating procedures.
For Non-Intubated Patients:
- Provide O2 as ordered with continuous SpO2 monitoring. 2. For patients receiving oxygen by any type of nasal cannula outside of single rooms should be given a procedure mask to wear, so to reduce others' exposure to cough/sneeze droplet spread, if tolerated. 3. Patients should be cared for with the head of bed elevated 30-45 degrees. 4. Minimize use of sedative and analgesic therapies (other than for palliative care). 5. No peak flow monitoring. 6. Nebulization should be avoided and be used only as an exception. Memorandum: Restricted use of Nebulized Treatment for Covid-19 7. Bronchodilator delivery via MDI via spacer is preferred if patients can effectively utilize. 8. If patient is on HHHF or NIV, aerosolization should be administered via in-line devices, rather than disconnection and delivery of MDI. 9. The evidence base for the efficacy and safety of awake prone positioning of nonintubated COVID-19 patients with hypoxemic respiratory failure is not well established and hence this practice is not recommended for routine or generalized application in this population of patients in the ICU. This does not preclude the selected use of this procedure based on best clinical judgement. Clinical trials of awake prone positioning are active and enrolling in various facilities in Alberta and consideration for trial participation is strongly encouraged. The following trials are currently underway in Alberta:
- COVI-PRONE CLINICAL TRIAL - CORONA
If this procedure is used, given uncertain efficacy and safety and the observation of significant failure rates with the need for more advanced management, there should be careful consideration of appropriate patient selection (fully awake and cooperative without hemodynamic instability or current signs of impending respiratory failure), initial tolerance and ongoing close monitoring needs. Patients should be closely monitored for evidence of clinical deterioration.
Heated Humidified High Flow Oxygen therapy devices (AIRVO, Optiflow or Vapotherm):
- Aerosolization of respiratory secretions may result from high flow heated humidity oxygen therapy devices and use of this therapy is considered a continuous AGMP. - The clinical efficacy in clinical trials of heated high flow oxygen therapy to support patients with significant acute hypoxemic respiratory failure is mixed with significant failure rates and the need for more advanced management.
- As such, the selective use of this procedure in the ICU for this population may be considered based on best clinical judgement. Patients should be closely monitored for evidence of clinical deterioration. - If used in patients with suspected or confirmed COVID-19 infection, treatment must be performed in a single patient room with the door closed and with staff using appropriate contact and droplet precautions, including use of N95 respirators.
Non-Invasive Ventilation (CPAP or BIPAP):
- Non-invasive positive pressure ventilation (NIV) may result in aerosolization of respiratory secretions and is considered a continuous AGMP. - The clinical efficacy of NIV in clinical trials of patients with significant acute hypoxemic respiratory failure is unproven with significant failure rates and the need for more advanced management. - As such, NIV is not recommended for routine use in suspected or confirmed COVID-19 patients with hypoxemic respiratory failure in the ICU. This does not preclude the selected use of this procedure based on best clinical judgement in patients presenting with patterns more suggestive of cardiogenic pulmonary edema or obstructive lung disease. - Patients with hemodynamic instability, multi-organ failure, or abnormal mental status are at high risk for failure and should not receive NIV. - Pro-active intubation under less emergent conditions is the preferred strategy and should be considered. - If NIV is used in patients with suspected, probable or confirmed COVID-19 infection, NIV treatment must be performed in a single patient room with the door closed and with staff using appropriate contact and droplet precautions, including use of N95 respirators. - During the COVID-19 pandemic, nocturnal CPAP will not be routinely used for hospitalized patients with OSA since it is an AGMP. Chronic CPAP or NIV should be continued only when deemed essential (i.e. life-sustaining). Consult pulmonary medicine as needed to help define the necessity of use during hospitalization. If therapy is deemed non-essential while the patient is admitted, then consider routinely reassessing to determine when it may safely be resumed.
# AHS Scientific Rapid Response Report: Oxygen Therapy Recommendations
Tracheostomy care and management in the non-ventilated patient:
Patients spontaneously breathing via a tracheostomy and remaining on contact and droplet precautions for COVID-19 should:
- Continue to be managed in single patient rooms with use of appropriate PPE.
- Provide humidity as indicated and per current practice.
- Closed suction systems are recommended for these patients.
If single patient rooms are unavailable, patients cohorting may be considered. See guidance. IP&C Cohorting Recommendations for COVID-19 in Acute Care Intubation Guidelines:
Moderate to severe hypoxemic respiratory failure/ARDS usually requires support with endotracheal intubation and mechanical ventilation. NIV and high-flow oxygen therapies frequently fail to adequately support such patients making intubation necessary. Close monitoring is crucial in order to detect failure of non-invasive support means so that intubation can be performed in a timely and controlled manner using all optimal infection prevention strategies.
- Endotracheal intubation should, ideally, be performed by the most experienced MRHP available.
- Minimize number of people involved. Close the room door. Nursing and RRT support ideally should be provided by the same individuals assigned to patient.
- In units with adjustable room airflow rates, increase the rate of airflow (or put the room in "bronchoscopy mode") prior to intubation.
- Don full PPE including N95 respirator, face shield, gown and gloves. Proper application of PPE should be verified by an independent observer prior to entry into the patient room.
- Consider the additional use of goggles given the potential for expectorated secretions to flow around front-covering face shields and contact ocular mucus membranes with coughing and during head turns of the intubator. If goggles are re-used, they must be fully wiped down with disinfectant wipes prior to re-use.
- Patients with hypoxemic respiratory failure usually have poor oxygenation reserves. Pre-oxygenate as much as possible using non-invasive oxygen.
Reserve use of bag-valve-mask ventilation via facemask to situations where noninvasive oxygen delivery is failing (to reduce aerosolization risks).
- The best pharmacotherapy for induction and intubation will be determined by the MRHP on a case-by-case basis but in general should include strategies that minimize chances of cough or aerosol generation via use of agents inducing deep sedation and often use of neuromuscular blockade when clinically appropriate (e.g. no signs predicting difficult intubation).
- Consider use of visual technological devices (e.g., video laryngoscope) for the initial attempt at intubation (to reduce the risk of aerosol contact by reducing the need to look directly down the airway); however, MRHP should use the technique most familiar to them that will ensure the greatest probability of successful intubation.
AHS Scientific Advisory Rapid Evidence Report: Video Laryngoscopy 9. Place in-line suction catheter on in all patients. Use either HMEF or heated humidity systems (if they are fixed integral system of a particular ventilator).
- In patients not already diagnosed with COVID-19, if sputum samples have not already been collected, collect ETA while all infection control precautions are already in place for intubation.
- If difficult airway cart or other stand-by equipment is brought to the area, do not bring entire cart/equipment into the room -bring in only the necessary equipment as it is needed.
See additional intubation guidance and tools in Appendix C.
For Intubated Patients: 2. In patients with refractory hypoxemia (e.g., Pa02/Fi02 ratio < 150 after attempting all the above strategies), consider the following additional strategies: a. Non-conventional modes of ventilation, such as Airway Pressure Release Ventilation (APRV). b. Inhaled epoprostenol: i. Provided per local policy. Dosing 10 -50 ng/kg/min. An active humidification system is required to use this therapy. ii. Use only in intubated patients. iii. Patients who do not demonstrate a physiological response (increase in PaO2 of ≥20% from baseline) after 30 minutes should be discontinued from inhaled epoprostenol therapy. iv. A daily assessment should be performed in an attempt to discontinue inhaled epoprostenol therapy.
- If advanced ICU respiratory care (defined as the use of all of the above measures possible to apply) has failed to improve oxygenation or can only be accomplished by applying mechanical ventilation that is not lung protective, consider consulting the ECLS Team (Edmonton for Northern Alberta, Calgary for Southern Alberta).
To initiate a referral: a. For Calgary, Central and South Zones, page the on-call CVICU Intensivist at the Foothills Medical Centre (403) 944-1110. b. For Edmonton (sites other than UAH) and North Zones, page the on-call Intensivist for the UAH General Systems ICU. c. For the UAH site, page the on-call Mazankowski CVICU Intensivist.
An early consultative process is recommended as ideally potential ECLS candidates should be first transferred to the ECLS referral center and then, if deemed suitable candidates, cannulated.
Consider referral to ECLS team when the following criteria are met:
- PaO2:FIO2 ratio 3 hours with inability to maintain lung protective ventilation (LPV) as defined in section 1 above. - PaO2:FiO2 6 hours even with maintenance of lung protective ventilation. - An arterial blood pH of 6 hours. - Endotracheal intubation and high-pressure mechanical ventilation for less than 7 days. - Near maximization of conventional therapies.
- No severe life-limiting chronic illnesses. Expected life expectancy of at least 2 years of independent functioning, should the patient survive.
ECLS Recommendations for COVID-19 4. If a patient is not deemed a suitable candidate for ECLS support and continued care is pursued, consider:
- Permissive hypoxemia -accept Sp02 85-90%, Pa02 50-60.
- Target Hemoglobin >85 g/L (maximize oxygen carrying capacity).
- Target temperature <37.5 C (reduce oxygen demand). Extubation Guidelines:
Extubation of patients is an AGMP. Careful consideration should be given to the safety of HCWs during the extubation procedure and to reduced reintubation rates.
- Ensure readiness for extubation - Extubate from spontaneous or pressure support with low PEEP.
- FiO2 ≤ 0.50.
- Patient should be ready for extubation onto low-flow oxygen.
- Per usual practice, ensure cuff leak.
- Apply PPE per AGMP.
- Two staff members are recommended during extubation to monitor safety given the time to apply PPE should any assistance be required.
- Strategies should be employed to minimize coughing - Oral suctioning may be performed with care taken not to precipitate coughing. - Medication to minimize coughing may be employed such as use of intravenous opioids, lidocaine or dexmedetomidine.
- Post ventilation handling of ventilator: Follow site specific protocols for cleaning and disposal.
# Medical Care
Goals of care discussions should occur early in admission consistent with our regular practice. Streamlined Goals of Care Designation decision-making for COVID-19
Other standard practices of medical care will apply such as nutrition in the ICU and ventilator acquired pneumonia prevention protocols.
Currently there are no robust evidence-based effective direct antiviral therapies for the treatment of the novel coronavirus, SARS-CoV-2, and supportive care remains the mainstay of therapy for infected individuals. For patients presenting with an ILI where SARS-CoV-2 is one possible etiology, it is important to recognize the possibility of additional common viral and bacterial pathogens to underlie the patient's presentation, even in the presence of exposure to COVID-19 infected individuals or relevant travel exposures.
Current Guidance for the Management of Adult Hospitalized Patients with COVID-19
# Microbial Testing
Even in patients with proven COVID-19 infection, particularly in patients with severe disease, bacterial and/or other viral co-pathogens may be present.
All patients evolving severe illness should be tested for the full spectrum of respiratory viruses (including SARS-CoV-2) and bacterial pathogens.
This should include:
i In all patients, an NPS and/or ETA for respiratory viruses (including SARS-CoV-2) (see admission testing Section C above).
ii In intubated patients, an ETA sample for bacterial culture.
iii For non-intubated patients NPS will be used for diagnosis of SARS-CoV-2, and in those able to produce sputum, expectorated sputum can be sent for bacterial culture. Sputum induction is not recommended in non-intubated patients (to reduce exposure risks).
iv Blood cultures x 2 drawn from separate lines/sites.
v Sampling of pleural fluid as appropriate if present is significant quantities.
Bronchoscopy solely for the purposes of microbial sampling in otherwise uncomplicated patients is not recommended (unproven benefit; high risk procedure). If there is a clinical possibility of other more unusual pathogens (e.g., as in an immunosuppressed patient), consideration could be given to performing bronchoalveolar lavage (BAL) recognizing that bronchoscopy is an AGMP. If necessary, bronchoscopy should be performed only in intubated patients and avoided in non-intubated patients with COVID-19 in order to minimize the risk of aerosolization.
# Empiric Antimicrobial Therapy
Antibiotics will generally have a limited role in managing patients with proven COVID-19 though they are indicated for Initial empiric management of patients with severe pneumonia while COVID-19 is being confirmed and bacterial superinfection is being excluded.
Patients evolving severe illness should be empirically treated with intravenous antibacterials along with consideration for oseltamivir (seasonally depending on circulation of influenza) pending results of initial microbial testing. Appropriate antibacterials should take into consideration patient presentation (isolated respiratory vs more generalized illness), allergies, prior or high risk for colonization with ARO (e.g., MRSA), local microbial resistance patterns and comorbid disease that might influence antibiotic use (e.g., conduction delay). As per current guidelines for community-acquired pneumonia management, initial empiric antibacterial coverage should include an agent to cover atypical microbes (e.g., macrolide, respiratory quinolone or tetracycline) and typical bacterial species. Initial empiric therapy should be de-escalated or discontinued as microbiology results return as appropriate.
COVID-19 Specific Antiviral Therapy
# Systemic Corticosteroids
The RECOVERY (and other) trials have provided new rigorous evidence to support use of treatment with dexamethasone 6 mg delivered intravenously or enterally once daily for up to 10 days to reduce 28-day mortality in patients with COVID-19 who are receiving respiratory support. This recommendation is limited to patients who are receiving respiratory support (i.e., supplemental oxygen and/or invasive mechanical ventilation) with the greatest mortality benefit seen in those requiring invasive mechanical ventilation.
# Immune Modulating Therapies
Severe COVID disease is often associated with ARDS and cytokine release. There is an evolving evidence base exploring the use of IL-6 receptor antagonists for the treatment of patients with severe COVID-19 disease.
AHS has approved tocilizumab for the treatment of severe COVID-19 pneumonia, restricted as follows:
- Patient was admitted to hospital due to COVID-19 seven or fewer days ago OR patient developed symptoms due to hospital-acquired COVID-19, while in hospital for other reasons, seven or fewer days ago AND 2. The patient is experiencing significant respiratory failure, due to COVID-19 pneumonia, which requires: a. Invasive or non-invasive ventilation (e.g. Continuous Positive Airway Pressure or Bilevel Positive Airway Pressure) OR b. Supplemental oxygen to achieve a minimal SpO2 of 90%, in the form of one of the following: i. Heated high flow oxygen with FiO2 > 0.5 (e.g. Optiflow, Airvo) ii. Oxygen delivered via nasal prong at a rate > 6 L/minute iii. Mask delivered oxygen with FiO2 > 0.5 (e.g. non-rebreather or Venturi mask) AND 3. No more than 24 hours has elapsed since initiation of ventilation as defined above or since the patient met the oxygen thresholds stated above AND 4. The patient has not received another dose of tocilizumab for the same indication at any point during their current hospitalization.
# Appendix D
# Timing
- Prone positioning of a patient should always occur in a planned fashion o Patients benefit most from prone positioning when used for 14-16 consecutive hours per day o The initial decision to prone should be made early, in consideration of clinical indicators and staff availability o Efforts should be made to plan subsequent prone and supine (unproning) positioning to occur during daytime hours (or when staffing is maximal) - Unplanned prone positioning may be done when a patient acutely deteriorates. This may be more common in the first 24 hours of patient admission to the intensive care unit.
# Requirements
- Team size will be determined by each site and guided by the size of the patient and members of the prone positioning team - The attending physician or assigned delegate must be present for the initial prone positioning procedure. - The attending physician or assigned delegate must always be aware of any subsequent prone/supine positioning maneuvers, and available for support as needed. Follow local processes. - At a minimum prone positioning of a patient can be accomplished by 5 team members o One respiratory therapist -primary responsibility is management of the airway o One registered ICU nurse -primary responsibilities are the lines, catheters, tubes and drips o Three additional healthcare workers Can be ICU or non-ICU staff including RRT/RN/HCA/allied health workers/physicians.
# Equipment
- 2 -Flat sheets - 1 -Proning head cushion and one pillow case to cover cushion/plastic bag - 1 -Absorbent pad - 3 -pillows - Skin protection dressing (duoderm, mefix, etc.)
- Proning checklist
# Care of the Proned Patient
- Refer to existing local policy and procedure for detailed information - Patients may be in prone position for up to 20 hours per day (of which at least 14-16 hours should be continuous, as directed by attending physicians' orders) - Continue with regular clinical, physiologic and laboratory assessments:
- Follow oxygenation and hemodynamic status closely to monitor for deterioration -as patients can experience transient deterioration in gas-exchange shortly after proning prior to improvement o Chest and heart sounds can be assessed by slipping stethoscope under patient's chest (if using a special care bed this will be easier if air pressure is decreased in the area to be assessed) - Minimize sedation and paralytics as patient condition allows, as ordered by the attending physician - Head turns and arm repositioning are done q2h to prevent skin break down, contractures, and nerve compression
- Use a support under the patients face (e.g., gel horseshoe, foam cushion, or folded pillow) to ensure the downward eye is free from pressure. Apply eye lubrication q2h to prevent eye damage. - Keep the bed in reverse Trendelenburg whenever possible to prevent venous congestion of the head and neck. - Avoid over extension of the neck with positioning. Facilitate PT/PROM exercises as tolerated.
# FAQs
- CRRT -Can be run while in prone position. The patient should have an easily visible line (jugular). - CPR -CPR can be performed while in the prone position while awaiting team to flip.
- Paralysis -Neuromuscular blockade is strongly suggested prior to a trial of prone positioning. Femoral lines -Caution needs to be exercised if patients have venous or arterial femoral lines as these are not visualized while patients are in prone position.
staff members to enter patient room.
- Staff already in isolation should be utilized to complete ECG and blood draws vs a lab tech entering.
- Adjust alarm parameters to reduce non-relevant alarms.
- Utilize bed functions such as turn assist, rotation, percussion and vibration.
- Utilize the function of overhead lifts and repositioning slings to reduce the number of staff for repositioning. Single person techniques should be reviewed and utilized in possible.
- During prone positioning, only team members directly involved in the turn need to be in the room.
- Minimize patient washes and linen changes if appropriate.
- RN & RRT to remove garbage when full to reduce frequency of housekeeping entering the room. Garbage must be properly disposed of. o Minimize the frequency of blood draws and review at rounds each day o Bundle order times of required bloodwork o Before redrawing determine if required order can be added to previously drawn bloodwork.
- Do not order routine CXR or ECG -order only as needed when clinically indicated.
- Minimize off unit procedures or interventions. Review the need for off -unit care with the care team. Deliver care at the bedside as much as possible.
- Nursing in collaboration with pharmacy to adjust medication administration times so that regularly scheduled medications can be administered in a cluster vs staggered administration. Suggest alignment with feeding tube water flushes.
- Physician assessments should be kept to one per 24 hours unless clinical indication requires further assessment. This includes Residents, Fellows and Attending Physicians.
# Care of the Adult Critically Ill COVID-19 Patient - 42
- To reduce the frequency of entry into isolation room consider utilizing MRI tubing as an extension to regular IV tubing and have IV pumps located outside of the patient room.
# Caution and Guidelines
- ACLS and critical medication bolus cannot be infused via extension tubing.
- Patients who are highly dependent on the infusion to achieve set RASS and hemodynamic goals should have infusions in the room.
- Lines must be marked with color tabs to make them visible.
- Lines should be located in areas that are not going to result in injury to staff or dislodgment of line.
- Extension tubing can only be connected to central line.
- Line cannot be touching the floor.
- MRI tubing must be labeled with all medications infusing through it.
- Ensure that lines are positioned to reduce risk of occlusion.
- Use triple lumens or manifolds to connect medications before attaching to MRI tubing.
- MRI tubing must be primed with all medications prior to connection
The use of tocilizumab as above is restricted to a SINGLE DOSE per patient, based on the following weight-based dosing: 40 or less kg: 8 mg/kg 40 kg to 65 or less kg: 400 mg 65 kg to 90 or less kg: 600 mg Greater than 90 kg: 800 mg
# Venous Thromboembolism (VTE) Prevention
Patients admitted to critical care with COVID-19 are at significant risk of thrombotic complications such as VTE. Standard prevention therapy is recommended for all COVID-19 positive patients with a preference for low molecular weight heparin (LMWH) administered at standard doses. Pneumatic Compression Stockings (PCS) should be used when pharmacological interventions are contraindicated.
There is no high-quality evidence to suggest vitamin D at supplemental or higher doses is effective in the prevention or treatment of COVID-19.
# Scientific Advisory Group -Rapid Evidence Brief -Vitamin D Clinical Trials
Consideration should be given to enrollment in any locally active clinical trials (epidemiologic or treatment related) if available. Contact the local research coordinator or MRHP as appropriate. - PPE conservation strategies are to be initiated immediately.
# Handling of Patient Care Items and Equipment
- PPE usage should be restricted to direct patient care use only.
- PPE should not be used for simulation, orientation and education purpose unless it is expired.
Considerations to maximize time spent in isolation room 1. Reduce doffing of PPE and leaving room to collect supplies.
- Keep stock in rooms that is not excessive.
- RN and RRT to discuss patient care supply requirements during shift handover.
- Staff to determine required supplies before going into room for care and procedures.
- Use call bell for supply runners rather than leaving isolation.
- Utilize supply runners as 'clean staff' to assist isolation staff to fetch required supplies. This could be staff that has been redeployed to critical care including students.
# Group documentation together.
- Utilize existing computers in room for charting.
- Charting does not need to be completed in real time.
- Utilize whiteboards or glass doors for interim documentation with a dry erase marker for later translation into the health record.
- If staffing allows, utilize a staff to transcribe outside the room while care provider remains in the room. - RRT & RN to share tasks and responsibilities and determine if it is necessary for 2 | Note: This document adapts prior pandemic and Influenza-Like Illness (ILI) guidance to the current COVID-19 crisis. This document has been developed by the Provincial Critical Care Adult COVID-19 Working Group.This material is intended for general information only and is provided on an "as is", "where is" basis. Although reasonable efforts were made to confirm the accuracy of the information, Alberta Health Services does not make any representation or warranty, express, implied or statutory, as to the accuracy, reliability, completeness, applicability or fitness for a particular purpose of such information. AHS staff who require legal advice regarding copyright should contact the Corporate & Commercial Division within AHS Legal & Privacy for further assistance. Alberta Health Services expressly disclaims all liability for the use of these materials, and for any claims, actions, demands or suits arising from such use.The links in this document are updated regularly and should be periodically reviewed.# Intention for use:
o To guide all providers of critical care in Alberta as to the basic care of adult critically ill patients with suspected, probable or confirmed COVID-19 infection to ensure such patients receive optimal, consistent and equitable care throughout the ICUs of Alberta. o Recognize that the application of the guidance in this document will need to be adapted to the characteristics of each individual unit, zone and department. o This guideline is not meant to be applied to patient groups outside of critical care units. o "Humidity should be preferentially provided via in-line HME devices. Active/heated humidity systems should only be used when necessary (e.g., to manage difficult secretions or to provide inhaled epoprostenol) and only when such a system is part of a fixed integral part of a particular ventilator"
# AHS COVID-19 Website
# Table of Contents
• Replace prostacyclin with epoprostenol April 13, 2020
Robertson/Morrissey/Bagshaw/Zuege based on feedback from Provincial Working Group, feedback from the provincial critical care community and updated AHS Guidance documents.
# Surveillance
Case Description for COVID-19 COVID-19 is an infectious syndrome caused by SARS-CoV-2, a novel coronavirus. COVID-19 is believed to be spread primarily via respiratory droplets (similar to influenza and other coronaviruses such as MERS and SARS) and/or contact (e.g., contaminated hands to mucous membranes). Numerous genetic variants of SARS-CoV-2 are now known to exist in addition to the original 'wild' type. Some variants may have differences in transmissibility and/or pathogenicity.
# Clinical Presentation
• Individuals infected with the virus that causes COVID-19 may have few or no symptoms and may range from mild to severe, life-threatening illness, with manifestations including fever greater than 38°C (>90% of cases), new onset or exacerbation of chronic cough (80% of cases), shortness of breath (20% of cases), difficulty breathing, sore throat or runny nose. Canadian SPRINT-SARI Characteristic Data March 2021 • Severe disease from COVID-19 infection can cause viral pneumonia and respiratory failure, sepsis, septic shock and multi-organ failure or death.
• Susceptibility is assumed to be universal.
• The virus appears to cause more severe disease in older adults (greater than 60 years of age) and individuals with underlying comorbidities (e.g., cardiovascular, renal and liver disorders, diabetes and chronic respiratory diseases) or immune compromising conditions.
• There is evolving understanding of the immune response in COVID-19 disease, and the possibility of reinfection with SARS-CoV-2 has not been excluded. • All patients are to be assessed initially for symptoms and risk factors associated with respiratory communicable disease using Form 21615: Communicable Disease (Respiratory) Initial Screening Form (or equivalent electronic version).
• The initial assessment will then inform the use of AHS Acute Care COVID-19 Expanded Testing Algorithm.
• Ongoing assessment of admitted patients is to be completed using When an AGMP is in progress the following poster may be utilized: AGMP Poster **There is no settle time required after AGMP is complete ** 5. Due to the high risk of aerosol generation, critically ill patients with suspected, probable or confirmed positive COVID-19 will be admitted to single patient rooms when available.
6. Negative pressure (airborne isolation) rooms are not required and should be reserved for patients with disease processes requiring airborne isolation but may be utilized if available.
7. If all single patient rooms are occupied, then attempt to cohort COVID-19 patients in one area with a minimum 2-meter separation between patients. IP&C guidance on cohorting of patients should be reviewed.
Of note, given the presence of SARS-CoV-2 variants, before considering cohorting patients with COVID-19 in the same room, the viral subtype must be identified (eg wild type or variant) for both patients being considered for cohorting. Viruses from all COVID-positive patients in Alberta are being subtyped with turn-around times currently being approximately 6 days. Viral subtyping results are not currently available within existing electronic medical records (though this is being actively explored).
• Strain typing of COVID-19 must be considered when cohorting.
• Patients with unknown COVID-19 strain are not to be cohorted.
• ii. If the patient is intubated, an ETA should be collected as soon as possible and sent for respiratory viral testing (irrespective of whether an NPS has been collected).
4. If the patient is not intubated and has not had an NPS sent for respiratory viral testing, then an NPS should be collected as soon as possible.
5. If there is a clinical possibility of other more unusual pathogens (e.g., as in an immunosuppressed patient), consideration should be given to performing bronchoalveolar lavage (BAL) recognizing that bronchoscopy is an aerosol generating medical procedure (AGMP).
6. Bronchoscopy solely for the purposes of microbial sampling in an otherwise uncomplicated patient is not recommended. 8. If patient is intubated: a. Transport using an in-line filter, in-line suction catheter and heat moisture exchange filter (HMEF). b. Use of transport ventilators (with filtering systems) is preferred to minimize the need for manual bagging. If use of a transport ventilator is not possible, use a manual bagging unit (with PEEP valve). c. RRT will manage airway and oxygen requirements. d. Clean and disinfect transport ventilator after use and discard breathing circuit.
9. If patient is not intubated: a. Transport with non-humidified (dry) oxygen supply -respiratory to identify the most appropriate oxygen delivery mask. b. Patients receiving oxygen by any type of nasal cannula should be given a procedure mask to wear if tolerated.
10. Clean O2 cylinder(s) and transport stretcher with disinfectant wipes before returning to general circulation.
# Staffing Considerations
The principle is to minimize the number of staff involved directly with the patient while providing quality patient care.
1. The nurse in charge and the respiratory therapy supervisor are responsible to determine patient assignments and will coordinate care of all patients in the unit with the principle in mind that the total number of staff caring for a COVID-19 patient should be kept to a minimum. If possible, cohort staff so that RNs and RRTs caring for COVID-19 patients are not caring for non-COVID-19 patients. Geographical cohorting of COVID-19 patients may assist with staff assignments if appropriate to facilitate.
2. All members of the healthcare team, inclusive of MRHP, NPs, RNs, RRTs, allied health, and support staff will continue to perform their usual duties. They must review and adhere to all appropriate isolation precautions prior to entering rooms.
3. For students (medical or otherwise) working within an ICU, please check with current educational institution guidelines for any restrictions to practice or exposures.
4. Individuals who are unable to competently adhere to the IP&C recommendations for COVID-19 (e.g., skin condition that precludes proper hand hygiene practices) should not provide care to patients who are under investigation for COVID-19, or those who have suspected, probable or confirmed COVID-19. Staff who are unable to be Fit Tested for N95 respirators should not care for COVID-19 patients that are intubated or those that require any AGMP.
5. During a pandemic there may be a need to move towards team-based models of care delivery during surge. Although the structure of each team model (staff mix, staff to patient ratio) are site specific, there are common facilitating elements to team based model functionality.
# Resources for Team-Based Care Models during Pandemic
# Infection, Prevention and Control
Suspected, probable or confirmed positive COVID-19 cases in the ICU should be managed with contact and droplet precautions. Use N95 respirators for all aerosol generating medical procedures (Aerosol Generating Medical Procedure GuidanceTool) and for all suspected, probable or confirmed positive COVID-19 intubated patients.
Interim IPC Recommendations COVID-19
1. All staff providing care must be successfully N95 fit tested and masks must be seal checked when applying.
2. Continuous masking and eye protection must be adhered to in patient care areas.
# PPE Guidance:
The following link contains all up to date information on PPE and should be reviewed periodically: Personal Protective Equipment (PPE).
Applying N95 respirators: All health care workers must have been fit tested within the last two years. Hold mask in your hand and pull both elastic ties, bottom first, over your hand for ease of putting mask on. Test to ensure that mask is secure and that there are no leaks. Discard immediately outside of room after use. Do not touch the outside of the mask while discarding as it is considered contaminated.
Proper wearing of an N95 respirator includes:
• Putting on the respirator before entering the patient's room.
• Molding the metal bar over the nose.
• Ensuring an airtight seal on the face, over top of the nose and under the chin. • Donning eye protection after N95 for AGMP.
• Leaving the room and changing the respirator when it becomes moist.
• Removing the respirator after leaving the patient's room by touching elastic only.
• Not wearing respirator around the neck.
# Personal Protective Equipment (PPE) Guidance to Help Make Continuous Masking Work for You
Eye protection (disposable face shields/goggles): Face shields or goggles are to be worn upon entering the patient room. Personal eyewear (glasses) is not sufficient. Face shields are single use. Discard face shields outside of the room after use. If googles are re-used they must be fully wiped down with disinfectant wipes prior to re-use.
Gloves: Always perform hand hygiene prior to putting on gloves and after removal.
# General ICU Care
1. Reduce all clinically unnecessary entries into the room.
See Appendix E for strategies to conserve personal protective equipment (PPE). 1. Point of Care Risk Assessment (PCRA) should be completed by all health care workers before initiating any resuscitation. 2. The AHS Scientific Advisory Committee has determined that the provision of chest compressions alone is not considered to be an aerosol generating medical procedure (AGMP) and only requires contact and droplet PPE.
3. Assume patient is COVID-19 positive, unless otherwise identified/known.
4. Consideration that the location of resuscitation may influence response and team processes (i.e. Critical Care Unit vs. Inpatient Unit or Emergency Department (ED)).
5. Minimize number of participants in the resuscitation area during resuscitation. 6. Minimize equipment in the resuscitation area wherever possible. 7. If CPR is indicated, chest compressions alone can be initiated safely by a provider wearing contact/droplet PPE. 8. Contact and droplet precautions (including a fit-tested N95 respirator) shall be donned prior to initiating any AGMP (including manual ventilation and airway management) by all response team members, even if there is a perceived delay in resuscitation efforts. 9. Routine practices, such as defibrillation are otherwise unchanged from non-COVID-19 patients.
Communication:
• Current paging/notification processes should be followed.
• Clear identification of isolation requirements should be made to the response team on arrival. • Clear communication of current GOC status should be made to the responding resuscitation team members on arrival, where available/known. • Upon arrival to the code, team members should quickly clarify roles and which members will be working inside versus outside the room.
Arrival to Code Blue:
• Ensure that PPE is readily available for responding team members and that there is an available "safety/logistics officer' to monitor donning/doffing. Since the availability of suitable PPE in enough quantities at the site of the arrest may not be guaranteed, the use of PPE pre-made kits should be considered, to travel with the response team or to be stored with code carts (where possible). • Chest compressions alone are not an AGMP and an N95 respirator is not required to initiate hands-only CPR. Healthcare workers completing manual chest compressions are directed to continue to wear recommended PPE in alignment with our continuous masking directive, the point-of-care risk assessment, with the addition of contact and droplet precautions for patients with suspected, probable or confirmed positive COVID-19. Outside the room:
• RN/HCW "runner", to assist with supply of equipment stored on the unit and the activation of other HCWs, if required. • "Logistic/Safety Officer", who should be a senior HCW, to regulate access to the patient's room, monitor proper PPE donning and doffing, ensure that protocols and the opening and closing of doors is followed and communicate with the ICU prior to the initiation of patient transport.
Modifications to Advanced Cardiac Life Support (ACLS) in COVID-19 Patients:
• Intubate patients early and hold CPR during intubation to minimize aerosolization of particles and optimize intubation success. • The best pharmacotherapy for induction and intubation will be determined by the MRHP on a case-by-case basis but in general should include strategies that minimize chances of cough or aerosol generation via use of agents inducing deep sedation and often use of neuromuscular blockade when clinically appropriate (e.g. no signs predicting difficult intubation). • Manual bagging of non-intubated patients using a BVM should be avoided if possible. If necessary because of unsuccessful initial intubation, use two experienced practitioners to establish an intact seal and minimize the risk of aerosolization. • Avoid disconnections between the ETT and resuscitation bag. If required due to gas trapping, the plan to disconnect should be announced loudly in advance and the ETT should only be disconnected beyond the HEPA filter.
Post-Arrest: to minimize the need for manual bagging. • Transportation to a critical care unit should follow guidelines listed in Section D of this document. • For patients being transported to an ICU or an advanced care unit in a facility, consideration should be given to testing that can be safely completed on route to minimize the need for additional transports (e.g. CT scan).
•
Charting Considerations:
• Computer code narrator may be utilized with existing computers within the room or immediately outside the resuscitation room.
• No portable computer devices should be brought into the room.
• All efforts to maintain a clean paper chart should be taken.
o Papers are not a means of transmission. Handle all paper with clean hands, clean any shared items (like chart binders, pens or binders) with a low-level disinfectant wipe. o Transcribing for purposes of infection prevention will not be required.
# Respiratory Care
The basic principles are to always use personal protective equipment in addition to appropriate isolation precautions and minimize the use of aerosol-generating procedures.
For Non-Intubated Patients:
1. Provide O2 as ordered with continuous SpO2 monitoring. 2. For patients receiving oxygen by any type of nasal cannula outside of single rooms should be given a procedure mask to wear, so to reduce others' exposure to cough/sneeze droplet spread, if tolerated. 3. Patients should be cared for with the head of bed elevated 30-45 degrees. 4. Minimize use of sedative and analgesic therapies (other than for palliative care). 5. No peak flow monitoring. 6. Nebulization should be avoided and be used only as an exception. Memorandum: Restricted use of Nebulized Treatment for Covid-19 7. Bronchodilator delivery via MDI via spacer is preferred if patients can effectively utilize. 8. If patient is on HHHF or NIV, aerosolization should be administered via in-line devices, rather than disconnection and delivery of MDI. 9. The evidence base for the efficacy and safety of awake prone positioning of nonintubated COVID-19 patients with hypoxemic respiratory failure is not well established and hence this practice is not recommended for routine or generalized application in this population of patients in the ICU. This does not preclude the selected use of this procedure based on best clinical judgement. Clinical trials of awake prone positioning are active and enrolling in various facilities in Alberta and consideration for trial participation is strongly encouraged. The following trials are currently underway in Alberta:
• COVI-PRONE CLINICAL TRIAL • CORONA
If this procedure is used, given uncertain efficacy and safety and the observation of significant failure rates with the need for more advanced management, there should be careful consideration of appropriate patient selection (fully awake and cooperative without hemodynamic instability or current signs of impending respiratory failure), initial tolerance and ongoing close monitoring needs. Patients should be closely monitored for evidence of clinical deterioration.
Heated Humidified High Flow Oxygen therapy devices (AIRVO, Optiflow or Vapotherm):
• Aerosolization of respiratory secretions may result from high flow heated humidity oxygen therapy devices and use of this therapy is considered a continuous AGMP. • The clinical efficacy in clinical trials of heated high flow oxygen therapy to support patients with significant acute hypoxemic respiratory failure is mixed with significant failure rates and the need for more advanced management.
• As such, the selective use of this procedure in the ICU for this population may be considered based on best clinical judgement. Patients should be closely monitored for evidence of clinical deterioration. • If used in patients with suspected or confirmed COVID-19 infection, treatment must be performed in a single patient room with the door closed and with staff using appropriate contact and droplet precautions, including use of N95 respirators.
Non-Invasive Ventilation (CPAP or BIPAP):
• Non-invasive positive pressure ventilation (NIV) may result in aerosolization of respiratory secretions and is considered a continuous AGMP. • The clinical efficacy of NIV in clinical trials of patients with significant acute hypoxemic respiratory failure is unproven with significant failure rates and the need for more advanced management. • As such, NIV is not recommended for routine use in suspected or confirmed COVID-19 patients with hypoxemic respiratory failure in the ICU. This does not preclude the selected use of this procedure based on best clinical judgement in patients presenting with patterns more suggestive of cardiogenic pulmonary edema or obstructive lung disease. • Patients with hemodynamic instability, multi-organ failure, or abnormal mental status are at high risk for failure and should not receive NIV. • Pro-active intubation under less emergent conditions is the preferred strategy and should be considered. • If NIV is used in patients with suspected, probable or confirmed COVID-19 infection, NIV treatment must be performed in a single patient room with the door closed and with staff using appropriate contact and droplet precautions, including use of N95 respirators. • During the COVID-19 pandemic, nocturnal CPAP will not be routinely used for hospitalized patients with OSA since it is an AGMP. Chronic CPAP or NIV should be continued only when deemed essential (i.e. life-sustaining). Consult pulmonary medicine as needed to help define the necessity of use during hospitalization. If therapy is deemed non-essential while the patient is admitted, then consider routinely reassessing to determine when it may safely be resumed.
# AHS Scientific Rapid Response Report: Oxygen Therapy Recommendations
Tracheostomy care and management in the non-ventilated patient:
Patients spontaneously breathing via a tracheostomy and remaining on contact and droplet precautions for COVID-19 should:
• Continue to be managed in single patient rooms with use of appropriate PPE.
• Provide humidity as indicated and per current practice.
• Closed suction systems are recommended for these patients.
If single patient rooms are unavailable, patients cohorting may be considered. See guidance. IP&C Cohorting Recommendations for COVID-19 in Acute Care Intubation Guidelines:
Moderate to severe hypoxemic respiratory failure/ARDS usually requires support with endotracheal intubation and mechanical ventilation. NIV and high-flow oxygen therapies frequently fail to adequately support such patients making intubation necessary. Close monitoring is crucial in order to detect failure of non-invasive support means so that intubation can be performed in a timely and controlled manner using all optimal infection prevention strategies.
1. Endotracheal intubation should, ideally, be performed by the most experienced MRHP available.
2. Minimize number of people involved. Close the room door. Nursing and RRT support ideally should be provided by the same individuals assigned to patient.
3. In units with adjustable room airflow rates, increase the rate of airflow (or put the room in "bronchoscopy mode") prior to intubation.
4. Don full PPE including N95 respirator, face shield, gown and gloves. Proper application of PPE should be verified by an independent observer prior to entry into the patient room.
5. Consider the additional use of goggles given the potential for expectorated secretions to flow around front-covering face shields and contact ocular mucus membranes with coughing and during head turns of the intubator. If goggles are re-used, they must be fully wiped down with disinfectant wipes prior to re-use.
6. Patients with hypoxemic respiratory failure usually have poor oxygenation reserves. Pre-oxygenate as much as possible using non-invasive oxygen.
Reserve use of bag-valve-mask ventilation via facemask to situations where noninvasive oxygen delivery is failing (to reduce aerosolization risks).
7. The best pharmacotherapy for induction and intubation will be determined by the MRHP on a case-by-case basis but in general should include strategies that minimize chances of cough or aerosol generation via use of agents inducing deep sedation and often use of neuromuscular blockade when clinically appropriate (e.g. no signs predicting difficult intubation).
8. Consider use of visual technological devices (e.g., video laryngoscope) for the initial attempt at intubation (to reduce the risk of aerosol contact by reducing the need to look directly down the airway); however, MRHP should use the technique most familiar to them that will ensure the greatest probability of successful intubation.
AHS Scientific Advisory Rapid Evidence Report: Video Laryngoscopy 9. Place in-line suction catheter on in all patients. Use either HMEF or heated humidity systems (if they are fixed integral system of a particular ventilator).
10. In patients not already diagnosed with COVID-19, if sputum samples have not already been collected, collect ETA while all infection control precautions are already in place for intubation.
11. If difficult airway cart or other stand-by equipment is brought to the area, do not bring entire cart/equipment into the room -bring in only the necessary equipment as it is needed.
See additional intubation guidance and tools in Appendix C.
For Intubated Patients: 2. In patients with refractory hypoxemia (e.g., Pa02/Fi02 ratio < 150 after attempting all the above strategies), consider the following additional strategies: a. Non-conventional modes of ventilation, such as Airway Pressure Release Ventilation (APRV). b. Inhaled epoprostenol: i. Provided per local policy. Dosing 10 -50 ng/kg/min. An active humidification system is required to use this therapy. ii. Use only in intubated patients. iii. Patients who do not demonstrate a physiological response (increase in PaO2 of ≥20% from baseline) after 30 minutes should be discontinued from inhaled epoprostenol therapy. iv. A daily assessment should be performed in an attempt to discontinue inhaled epoprostenol therapy.
3. If advanced ICU respiratory care (defined as the use of all of the above measures possible to apply) has failed to improve oxygenation or can only be accomplished by applying mechanical ventilation that is not lung protective, consider consulting the ECLS Team (Edmonton for Northern Alberta, Calgary for Southern Alberta).
To initiate a referral: a. For Calgary, Central and South Zones, page the on-call CVICU Intensivist at the Foothills Medical Centre (403) 944-1110. b. For Edmonton (sites other than UAH) and North Zones, page the on-call Intensivist for the UAH General Systems ICU. c. For the UAH site, page the on-call Mazankowski CVICU Intensivist.
An early consultative process is recommended as ideally potential ECLS candidates should be first transferred to the ECLS referral center and then, if deemed suitable candidates, cannulated.
Consider referral to ECLS team when the following criteria are met:
• PaO2:FIO2 ratio < 120 mm Hg for > 3 hours with inability to maintain lung protective ventilation (LPV) as defined in section 1 above. • PaO2:FiO2 < 100 mm Hg for > 6 hours even with maintenance of lung protective ventilation. • An arterial blood pH of < 7.25 with a partial pressure of arterial carbon dioxide [PaCO2] of ≥ 60 mm Hg for > 6 hours. • Endotracheal intubation and high-pressure mechanical ventilation for less than 7 days. • Near maximization of conventional therapies.
• No severe life-limiting chronic illnesses. Expected life expectancy of at least 2 years of independent functioning, should the patient survive.
ECLS Recommendations for COVID-19 4. If a patient is not deemed a suitable candidate for ECLS support and continued care is pursued, consider:
• Permissive hypoxemia -accept Sp02 85-90%, Pa02 50-60.
• Target Hemoglobin >85 g/L (maximize oxygen carrying capacity).
• Target temperature <37.5 C (reduce oxygen demand). Extubation Guidelines:
Extubation of patients is an AGMP. Careful consideration should be given to the safety of HCWs during the extubation procedure and to reduced reintubation rates.
1. Ensure readiness for extubation • Extubate from spontaneous or pressure support with low PEEP.
• FiO2 ≤ 0.50.
• Patient should be ready for extubation onto low-flow oxygen.
• Per usual practice, ensure cuff leak.
2. Apply PPE per AGMP.
3. Two staff members are recommended during extubation to monitor safety given the time to apply PPE should any assistance be required.
4. Strategies should be employed to minimize coughing • Oral suctioning may be performed with care taken not to precipitate coughing. • Medication to minimize coughing may be employed such as use of intravenous opioids, lidocaine or dexmedetomidine.
5. Post ventilation handling of ventilator: Follow site specific protocols for cleaning and disposal.
# Medical Care
Goals of care discussions should occur early in admission consistent with our regular practice. Streamlined Goals of Care Designation decision-making for COVID-19
Other standard practices of medical care will apply such as nutrition in the ICU and ventilator acquired pneumonia prevention protocols.
Currently there are no robust evidence-based effective direct antiviral therapies for the treatment of the novel coronavirus, SARS-CoV-2, and supportive care remains the mainstay of therapy for infected individuals. For patients presenting with an ILI where SARS-CoV-2 is one possible etiology, it is important to recognize the possibility of additional common viral and bacterial pathogens to underlie the patient's presentation, even in the presence of exposure to COVID-19 infected individuals or relevant travel exposures.
Current Guidance for the Management of Adult Hospitalized Patients with COVID-19
# Microbial Testing
Even in patients with proven COVID-19 infection, particularly in patients with severe disease, bacterial and/or other viral co-pathogens may be present.
All patients evolving severe illness should be tested for the full spectrum of respiratory viruses (including SARS-CoV-2) and bacterial pathogens.
This should include:
i In all patients, an NPS and/or ETA for respiratory viruses (including SARS-CoV-2) (see admission testing Section C above).
ii In intubated patients, an ETA sample for bacterial culture.
iii For non-intubated patients NPS will be used for diagnosis of SARS-CoV-2, and in those able to produce sputum, expectorated sputum can be sent for bacterial culture. Sputum induction is not recommended in non-intubated patients (to reduce exposure risks).
iv Blood cultures x 2 drawn from separate lines/sites.
v Sampling of pleural fluid as appropriate if present is significant quantities.
Bronchoscopy solely for the purposes of microbial sampling in otherwise uncomplicated patients is not recommended (unproven benefit; high risk procedure). If there is a clinical possibility of other more unusual pathogens (e.g., as in an immunosuppressed patient), consideration could be given to performing bronchoalveolar lavage (BAL) recognizing that bronchoscopy is an AGMP. If necessary, bronchoscopy should be performed only in intubated patients and avoided in non-intubated patients with COVID-19 in order to minimize the risk of aerosolization.
# Empiric Antimicrobial Therapy
Antibiotics will generally have a limited role in managing patients with proven COVID-19 though they are indicated for Initial empiric management of patients with severe pneumonia while COVID-19 is being confirmed and bacterial superinfection is being excluded.
Patients evolving severe illness should be empirically treated with intravenous antibacterials along with consideration for oseltamivir (seasonally depending on circulation of influenza) pending results of initial microbial testing. Appropriate antibacterials should take into consideration patient presentation (isolated respiratory vs more generalized illness), allergies, prior or high risk for colonization with ARO (e.g., MRSA), local microbial resistance patterns and comorbid disease that might influence antibiotic use (e.g., conduction delay). As per current guidelines for community-acquired pneumonia management, initial empiric antibacterial coverage should include an agent to cover atypical microbes (e.g., macrolide, respiratory quinolone or tetracycline) and typical bacterial species. Initial empiric therapy should be de-escalated or discontinued as microbiology results return as appropriate.
COVID-19 Specific Antiviral Therapy
# Systemic Corticosteroids
The RECOVERY (and other) trials have provided new rigorous evidence to support use of treatment with dexamethasone 6 mg delivered intravenously or enterally once daily for up to 10 days to reduce 28-day mortality in patients with COVID-19 who are receiving respiratory support. This recommendation is limited to patients who are receiving respiratory support (i.e., supplemental oxygen and/or invasive mechanical ventilation) with the greatest mortality benefit seen in those requiring invasive mechanical ventilation.
# Immune Modulating Therapies
Severe COVID disease is often associated with ARDS and cytokine release. There is an evolving evidence base exploring the use of IL-6 receptor antagonists for the treatment of patients with severe COVID-19 disease.
AHS has approved tocilizumab for the treatment of severe COVID-19 pneumonia, restricted as follows:
1. Patient was admitted to hospital due to COVID-19 seven or fewer days ago OR patient developed symptoms due to hospital-acquired COVID-19, while in hospital for other reasons, seven or fewer days ago AND 2. The patient is experiencing significant respiratory failure, due to COVID-19 pneumonia, which requires: a. Invasive or non-invasive ventilation (e.g. Continuous Positive Airway Pressure or Bilevel Positive Airway Pressure) OR b. Supplemental oxygen to achieve a minimal SpO2 of 90%, in the form of one of the following: i. Heated high flow oxygen with FiO2 > 0.5 (e.g. Optiflow, Airvo) ii. Oxygen delivered via nasal prong at a rate > 6 L/minute iii. Mask delivered oxygen with FiO2 > 0.5 (e.g. non-rebreather or Venturi mask) AND 3. No more than 24 hours has elapsed since initiation of ventilation as defined above or since the patient met the oxygen thresholds stated above AND 4. The patient has not received another dose of tocilizumab for the same indication at any point during their current hospitalization.
# Appendix D
# Timing
• Prone positioning of a patient should always occur in a planned fashion o Patients benefit most from prone positioning when used for 14-16 consecutive hours per day o The initial decision to prone should be made early, in consideration of clinical indicators and staff availability o Efforts should be made to plan subsequent prone and supine (unproning) positioning to occur during daytime hours (or when staffing is maximal) • Unplanned prone positioning may be done when a patient acutely deteriorates. This may be more common in the first 24 hours of patient admission to the intensive care unit.
# Requirements
• Team size will be determined by each site and guided by the size of the patient and members of the prone positioning team • The attending physician or assigned delegate must be present for the initial prone positioning procedure. • The attending physician or assigned delegate must always be aware of any subsequent prone/supine positioning maneuvers, and available for support as needed. Follow local processes. • At a minimum prone positioning of a patient can be accomplished by 5 team members o One respiratory therapist -primary responsibility is management of the airway o One registered ICU nurse -primary responsibilities are the lines, catheters, tubes and drips o Three additional healthcare workers Can be ICU or non-ICU staff including RRT/RN/HCA/allied health workers/physicians.
# Equipment
• 2 -Flat sheets • 1 -Proning head cushion and one pillow case to cover cushion/plastic bag • 1 -Absorbent pad • 3 -pillows • Skin protection dressing (duoderm, mefix, etc.)
• Proning checklist
# Care of the Proned Patient
• Refer to existing local policy and procedure for detailed information • Patients may be in prone position for up to 20 hours per day (of which at least 14-16 hours should be continuous, as directed by attending physicians' orders) • Continue with regular clinical, physiologic and laboratory assessments:
o Follow oxygenation and hemodynamic status closely to monitor for deterioration -as patients can experience transient deterioration in gas-exchange shortly after proning prior to improvement o Chest and heart sounds can be assessed by slipping stethoscope under patient's chest (if using a special care bed this will be easier if air pressure is decreased in the area to be assessed) • Minimize sedation and paralytics as patient condition allows, as ordered by the attending physician • Head turns and arm repositioning are done q2h to prevent skin break down, contractures, and nerve compression
• Use a support under the patients face (e.g., gel horseshoe, foam cushion, or folded pillow) to ensure the downward eye is free from pressure. Apply eye lubrication q2h to prevent eye damage. • Keep the bed in reverse Trendelenburg whenever possible to prevent venous congestion of the head and neck. • Avoid over extension of the neck with positioning. Facilitate PT/PROM exercises as tolerated.
# FAQs
• CRRT -Can be run while in prone position. The patient should have an easily visible line (jugular). • CPR -CPR can be performed while in the prone position while awaiting team to flip.
• Paralysis -Neuromuscular blockade is strongly suggested prior to a trial of prone positioning. Femoral lines -Caution needs to be exercised if patients have venous or arterial femoral lines as these are not visualized while patients are in prone position.
staff members to enter patient room.
• Staff already in isolation should be utilized to complete ECG and blood draws vs a lab tech entering.
• Adjust alarm parameters to reduce non-relevant alarms.
• Utilize bed functions such as turn assist, rotation, percussion and vibration.
• Utilize the function of overhead lifts and repositioning slings to reduce the number of staff for repositioning. Single person techniques should be reviewed and utilized in possible.
# •
• During prone positioning, only team members directly involved in the turn need to be in the room.
• Minimize patient washes and linen changes if appropriate.
• RN & RRT to remove garbage when full to reduce frequency of housekeeping entering the room. Garbage must be properly disposed of. o Minimize the frequency of blood draws and review at rounds each day o Bundle order times of required bloodwork o Before redrawing determine if required order can be added to previously drawn bloodwork.
• Do not order routine CXR or ECG -order only as needed when clinically indicated.
• Minimize off unit procedures or interventions. Review the need for off -unit care with the care team. Deliver care at the bedside as much as possible.
• Nursing in collaboration with pharmacy to adjust medication administration times so that regularly scheduled medications can be administered in a cluster vs staggered administration. Suggest alignment with feeding tube water flushes.
• Physician assessments should be kept to one per 24 hours unless clinical indication requires further assessment. This includes Residents, Fellows and Attending Physicians.
# Care of the Adult Critically Ill COVID-19 Patient • 42
3. To reduce the frequency of entry into isolation room consider utilizing MRI tubing as an extension to regular IV tubing and have IV pumps located outside of the patient room.
# Caution and Guidelines
• ACLS and critical medication bolus cannot be infused via extension tubing.
• Patients who are highly dependent on the infusion to achieve set RASS and hemodynamic goals should have infusions in the room.
• Lines must be marked with color tabs to make them visible.
• Lines should be located in areas that are not going to result in injury to staff or dislodgment of line.
• Extension tubing can only be connected to central line.
• Line cannot be touching the floor.
• MRI tubing must be labeled with all medications infusing through it.
• Ensure that lines are positioned to reduce risk of occlusion.
• Use triple lumens or manifolds to connect medications before attaching to MRI tubing.
• MRI tubing must be primed with all medications prior to connection
#
The use of tocilizumab as above is restricted to a SINGLE DOSE per patient, based on the following weight-based dosing: 40 or less kg: 8 mg/kg 40 kg to 65 or less kg: 400 mg 65 kg to 90 or less kg: 600 mg Greater than 90 kg: 800 mg
# Venous Thromboembolism (VTE) Prevention
Patients admitted to critical care with COVID-19 are at significant risk of thrombotic complications such as VTE. Standard prevention therapy is recommended for all COVID-19 positive patients with a preference for low molecular weight heparin (LMWH) administered at standard doses. Pneumatic Compression Stockings (PCS) should be used when pharmacological interventions are contraindicated.
There is no high-quality evidence to suggest vitamin D at supplemental or higher doses is effective in the prevention or treatment of COVID-19.
# Scientific Advisory Group -Rapid Evidence Brief -Vitamin D Clinical Trials
Consideration should be given to enrollment in any locally active clinical trials (epidemiologic or treatment related) if available. Contact the local research coordinator or MRHP as appropriate. • PPE conservation strategies are to be initiated immediately.
# Handling of Patient Care Items and Equipment
• PPE usage should be restricted to direct patient care use only.
• PPE should not be used for simulation, orientation and education purpose unless it is expired.
Considerations to maximize time spent in isolation room 1. Reduce doffing of PPE and leaving room to collect supplies.
• Keep stock in rooms that is not excessive.
• RN and RRT to discuss patient care supply requirements during shift handover.
• Staff to determine required supplies before going into room for care and procedures.
• Use call bell for supply runners rather than leaving isolation.
• Utilize supply runners as 'clean staff' to assist isolation staff to fetch required supplies. This could be staff that has been redeployed to critical care including students.
# Group documentation together.
• Utilize existing computers in room for charting.
• Charting does not need to be completed in real time.
• Utilize whiteboards or glass doors for interim documentation with a dry erase marker for later translation into the health record.
• If staffing allows, utilize a staff to transcribe outside the room while care provider remains in the room. • RRT & RN to share tasks and responsibilities and determine if it is necessary for 2 | None | None |
be454e960422278e6d286a51a69684f97c2c2bdb | cma | None | # PREAMBLE
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidencebased recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# INTRODUCTION
On January 25, 2022, NACI published updated recommendations on the use of the Pfizer-BioNTech Comirnaty (10 mcg) COVID-19 vaccine in children 5 to 11 years of age, including strengthening their recommendation to strongly recommend a 2-dose primary series. In children 5 to 11 years of age who are moderately to severely immunocompromised, a 3-dose primary series is recommended.
# Since this guidance:
-Health Canada authorized the use of the Moderna Spikevax (50 mcg) COVID-19 vaccine for children 6 to 11 years of age; -Additional safety surveillance data on the use of mRNA vaccine booster Moderna Spikevax (50 mcg and 100 mcg) and Pfizer-BioNTech Comirnaty (30 mcg) among individuals aged 18 years and older has emerged; and -Additional safety surveillance data on the 2-dose primary series of Pfizer-BioNTech Comirnaty (10 mcg) in children 5 to 11 years of age is available, further supporting that the product is well tolerated and providing preliminary estimates on the risk of myocarditis and/or pericarditis in children 5 to 11 years of age.
NACI has reviewed the evolving evidence and has updated evidence-informed recommendations on the use of COVID-19 vaccines in pediatric populations. NACI continues to review the evidence on the use of COVID-19 vaccines and will update its recommendations as needed. Details of NACI's evidence-informed recommendation development process can be found elsewhere (1,2) . Tromethamine (Tris or trometamol) is used as a buffer in vaccines and medications, including those for use in children, to improve stability and prevent pH fluctuations in the solution. No safety concerns have been identified with tromethamine (3) . While tromethamine has been identified as a potential allergen, a review of existing evidence did not identify any cases of allergic reactions to tromethamine in children (4) .
b
Regardless of storage condition, vaccines should not be used after date of expiry printed on the vial and cartons. c Frozen is -25°C to -15°C; Refrigerated is +2°C to +8°C; Room temperature is +15°C to +25°C. d Once vials are thawed, they should not be refrozen. Thaw in refrigerated conditions between +2° to +8°C (36° to 46°F) for 2 hours and 30 minutes. After thawing, let vial stand at room temperature for 15 minutes before administering. Alternatively, thaw at room temperature for 1 hour. e During storage, minimize exposure to room light, and avoid exposure to direct sunlight and ultraviolet light. Vials must be kept frozen and protected from light, in the original cartons, until ready to thaw.
For complete prescribing information for the pediatric and adult formulations of the Moderna Spikevax and Pfizer-BioNTech COVID-19 vaccines, consult the product leaflets or information contained within Health Canada's authorized product monographs available through the Drug Product Database.
# Schedule
Refer to Table 2 for a summary of immunization schedules for authorized COVID-19 vaccines among children 5 to 11 or 6 to 11 years of age. There is emerging evidence that longer intervals between the first and second doses of COVID-19 vaccines result in more robust and durable immune response and higher vaccine effectiveness. NACI will continue to monitor the evidence and update this interval as needed.
# RECOMMENDATIONS
# NACI recommends that a complete series with an mRNA COVID-19 vaccine should be offered to children in the authorized age groups without contraindications to the vaccine, with a dosing interval of at least 8 weeks between the first and second dose. (Strong NACI Recommendation)
For children 6 to 11 years of age (which is the age group in which the Moderna Spikevax 50 mcg primary series vaccine is authorized):
- Moderna Spikevax (50 mcg dose) may be offered as an alternative to Pfizer-BioNTech Comirnaty (10 mcg dose), however the use of Pfizer-BioNTech Comirnaty (10 mcg dose) is preferred to Moderna Spikevax (50 mcg dose) to start or continue the primary vaccine series.
- Although risk of myocarditis/pericarditis with the Moderna Spikevax (50 mcg) in children 6 to 11 years of age is unknown, with a primary series in adolescents and young adults the rare risk of myocarditis/pericarditis with Moderna Spikevax (100 mcg) was higher than with Pfizer-BioNTech Comirnaty (30 mcg).
- Indirect data from adult populations (≥18 years of age) suggest Moderna Spikevax (100 mcg) may result in higher vaccine effectiveness after a 2-dose primary series compared to Pfizer-BioNTech Comirnaty (30 mcg) and is associated with a higher seroconversion rate among adult immunocompromised patients (5) . Given this potential benefit, administration of the Moderna Spikevax (50 mcg) vaccine as a 3-dose primary series may be considered for some immunocompromised individuals 6 to 11 years of age, as outlined in the product monograph. Each dose would be provided 4 to 8 weeks apart, as per the NACI recommended schedule for immunocompromised populations.
Rationale and summary of evidence In the Phase 2/3 clinical trial on Moderna Spikevax, 3,007 children 6 to 11 years of age received the Moderna Spikevax COVID-19 vaccine (50 mcg), and 995 received the placebo; both groups were followed a median of 51 days since dose 2. The trial was conducted in the US and Canada when the Delta variant was predominant (data cut-off November 10, 2021). Interim findings did not indicate any safety concerns and preliminary efficacy against symptomatic COVID-19 was 88% starting 14 days after dose 1, which is comparable to efficacy after Pfizer-BioNTech Comirnaty among children 5 to 11 years of age. No cases of myocarditis/pericarditis or any other serious adverse events (SAEs) were reported among phase 2/3 trial participants that received the Moderna Spikevax COVID-19 vaccine (50 mcg). Any rare, or very rare adverse event (AEs) that occurs at the frequency less often than 1 in 1,000 to 1 in 10,000 would likely not be detected with this trial size (3,007 participants received the vaccine). Among individuals 12 to 29 years of age, safety surveillance data shows a lower reported rate of myocarditis/pericarditis following (6)(7)(8)(9)(10)(11) Pfizer-BioNTech Comirnaty (30 mcg) compared to Moderna Spikevax (100 mcg) primary series, as well as following the Pfizer-BioNTech Comirnaty (30 mcg) booster compared to the Moderna Spikevax (50 mcg) booster, among individuals 18 years of age and older. Safety surveillance data on the risk of myocarditis or pericarditis within 7 days following immunization with the Pfizer-BioNTech Comirnaty COVID-19 vaccine (10 mcg) from the US show that among males after the 2 nd dose, the risk may be substantially lower in children 5 to 11 years of age following Pfizer-BioNTech Comirnaty 10 mcg vaccine (4.3 cases per million doses) compared to adolescents following Pfizer-BioNTech Comirnaty 30 mcg (12,13)
# Trial design
The Moderna Spikevax COVID-19 vaccine was evaluated in an ongoing, randomized, observerblind, placebo-controlled Phase 1/2/3 clinical trial in healthy children from 6 months to 11 years of age (P204) (14) . Based on the reactogenicity and immunogenicity observed in the initial cohort of children 6 to 11 years of age in the open-label Phase 1 trial, a dose of 50 mcg was selected for the Phase 2/3 trial for this age group. A total of 4,011 participants 6 to 11 years of age were randomized 3:1 to receive either two doses of the vaccine (50 mcg mRNA) or placebo, 28 days apart. At time of reporting, median follow-up of participants was 51 days since dose 2. Follow-up is planned for up to approximately 12 months following the second dose. The trial was conducted at a time of predominant Delta variant of concern circulation (data cut off: November 10, 2021).
# Study population
All pediatric study participants for the Phase 2/3 trial were recruited from the US and Canada. Individuals with known history of SARS-CoV-2 infection within 2 weeks prior to administration of vaccine or known close contact with anyone with laboratory-confirmed SARS-CoV-2 infection or COVID-19 within 2 weeks prior to administration of vaccine were excluded from the trial. Individuals with known immunodeficiency or immunocompromised conditions were excluded from the trial.
# Immunogenicity comparator group
The immunogenicity comparator group for the children (6 to 11 years) was a randomly selected subset (n=295) of participants aged 18 to ≤25 years from the earlier Phase 2/3 study P301 who received two doses of the Moderna Spikevax COVID-19 vaccine (100 mcg), 28 days apart.
# Demographics
Demographic characteristics were similar among vaccine and placebo groups in the P204 trial. Overall, 49.2% of participants were female, with a median age at vaccination of 8.0 years (range: 5-11 years) in the vaccine group and 9.0 (range: 6-11 years) in the placebo group. About twothirds of participants were white (65.5%), with participants from other race/ethnic groups each comprising significantly less of the study population: Multiracial (10.8%), Black or African American (10.0% overall), Asian (9.9%), and all other groups comprising <2% of participants. All race and ethnicity groups had similar proportions in the vaccine and placebo groups. A total of 20% of participants were defined as obese. A total of 4 participants 6 to 11 years of age with known HIV were enrolled in the trial (all in the vaccine group), and 10 participants had cardiac disorders. The prevalence of SARS-CoV-2 infection or prior infection at baseline (determined by a positive RT-PCR or serological assay) in the vaccine and placebo groups in the safety population was comparable at 8.5% and 8.7%, respectively.
# Safety
Safety evidence for participants is based on the phase 2/3 randomized, observer-blind, placebocontrolled expansion study of children (focused on the cohort 6 years to 11 years of age) who received 2 intramuscular injections of Moderna Spikevax 50 mcg (n=3,007) or placebo (n=995) approximately 28 days apart. Data on solicited local and systemic reactions were collected daily for 7 days following each injection. Participants (6 to 11 years of age) were monitored for unsolicited adverse events for up to 28 days following each dose and follow-up is ongoing. Median duration of safety follow-up after second vaccination for study participants in the blinded phase was 51 days.
# Local reactions
Local reactions were increased in frequency in vaccine recipients (93.7% for dose 1, 95.3% for dose 2) compared to placebo recipients (48.3% for dose 1, 50.6% for dose 2). Most solicited local reactions were grade 1 or grade 2. Grade 3 reactions were more common in the vaccine recipients than in the placebo recipients (5.6% vs 0.8% respectively). The most frequent grade 3 reaction was injection site pain. There were no grade 4 solicited local adverse reactions in either group. The majority of solicited local reactions occurred within the first 1 to 2 days after any dose and persisted for a median of 3 days. Local reactions were very common and mostly mild to moderate in severity. In the vaccine recipient group, solicited local adverse reactions that persisted beyond 7 days after injection were injection site pain (0.8% dose 1, 0.5% dose 2), erythema (0.5% dose 1, 0.3% dose 2) injection site swelling (0.4% dose 1, 0.2% dose 2) and axillary/groin swelling or tenderness (1.7% dose 1, 0.7% dose 2). See Table 1 for the frequency of solicited local AEs for the Moderna Spikevax COVID-19 vaccine among children 6 to 11 years of age.
# Systemic reactions
Systemic events were increased in frequency in vaccine recipients compared to placebo recipients, with frequencies increasing with the number of doses in vaccine recipients (57.9% after dose 1 compared to 78.1% after dose 2 in vaccine recipients, and 52.2% after dose 1 and 50.1% after dose 2 in placebo recipients). Headache (31.2% and 54.3% after dose 1 and 2 respectively in vaccine recipients, and 30.8% and 28.4% after dose 1 and 2 respectively in placebo recipients), fatigue (43.2% and 64.5% after dose 1 and 2 respectively in vaccine recipients, and 33.6% and 34.6% after dose 1 and 2 respectively in placebo recipients), myalgias (14.6% and 28.2% after dose 1 and 2 respectively in vaccine recipients, and 9.7% and 10.8% after dose 1 and 2 respectively in placebo recipients), nausea/vomiting (10.8% and 24.0% after dose 1 and 2 respectively in vaccine recipients, and 10.8% and 10.0% after dose 1 and 2 respectively in placebo recipients) and chills (10.3% and 30.3% after dose 1 and 2 respectively in vaccine recipients, and 6.7% and 7.6% after dose 1 and 2 respectively in placebo recipients) were very common after dose 1 and dose 2 in vaccine recipients. Arthralgias were common after the first dose (8.7% in vaccine recipients and 7.6% in placebo recipients) and very common after the second dose in vaccine recipients (16.1% in vaccine recipients and 8.7% in placebo recipients). Fever was common after the first dose (3.3% in vaccine recipients and 1.5% in placebo recipients) and very common after the second dose in vaccine recipients (23.9% in vaccine recipients and 2.0% in placebo recipients). Grade 3 events were more common in the vaccine recipients (1.8% after dose 1, 12.2% after dose 2) than the placebo recipients (1.3% and 1.4% respectively). There were no grade 4 events in the vaccine recipients. See Table 2 for the frequency of solicited systemic AEs for the Moderna Spikevax COVID-19 vaccine among children 6 to 11 years of age.
# Serious adverse events and other adverse events of interest
There were no serious AEs assessed as related to the study interventions, either the vaccine or placebo, no deaths, no cases of MIS-C, and no cases of myocarditis or pericarditis reported during the study period. Monitoring for serious adverse events and medically attended adverse events will continue throughout the study period (up to 12 months following the second dose).
# Immunogenicity
An immunobridging analysis evaluating SARS-CoV-2 50% neutralising titres (ID50) and seroresponse rates 28 days after dose 2 was conducted in subset of children 6 to 11 years of age (Study P204; N=320) and in participants aged 18 through ≤25 from the Phase 3 efficacy study (Study P301; N=295). Subjects had no immunologic or virologic evidence of prior SARS-CoV-2 infection at baseline. The geometric mean ratio (GMR) of the neutralising antibody titres in children 6 to 11 years of age compared to the 18-to 25-year-olds was 1.2 (95% CI: 1.1, 1.4). The difference in seroresponse rate was 0.1% (95% CI: -1.9, 2.1%). Both pre-specified non-inferiority criteria (lower bound of the 95% CI for GMR greater than 0.67 and lower bound of the 95% CI of the seroresponse rate difference greater than -10%) were met. Immunogenicity data was also assessed following dose 1 in the same subset of participants; at day 29 from baseline, and GMR was similar across the two groups (108.1 in children 6 to 11 years of age, compared to 96.7 in adults 18 to 25 years of age).
Samples from a randomly selected subset of 20 participants 6 to 11 years of age were assessed for neutralization titres against the Delta variant and Omicron variant. Among children 6-11 years of age, the level of neutralizing antibodies against Omicron 28 days after dose 2 were 22.1 fold lower than those against D614G. However, the neutralizing antibody response against both Omicron and D614G among children 6 to 11 years of age was higher than among adults 18 years of age and older (15) .
As no correlate of protection has been established for any COVID-19 outcome at this time, it is unknown how reported immune responses are related to prevention of SARS-CoV-2 infection or disease or the ability to transmit infection to others.
# Efficacy
The evaluable efficacy population consisted of 2,687 participants randomized to receive vaccine and 880 participants randomized to receive placebo, all of whom had a negative baseline SARS-CoV-2 serostatus. As of November 10, 2021 (data cut-off for analysis), a total of 25 confirmed, symptomatic cases of COVID-19 were identified starting 14 days after dose 1 (7 in vaccine group, 18 in placebo group) in participants 6 to 11 years of age. The estimated efficacy of the vaccine against confirmed COVID-19 from 14 days after dose 1 was 88.0% (95% CI: 70.0 to 95.8%). The estimated efficacy against SARS-CoV-2 infection from 14 days after dose 1 (regardless of symptoms) and against asymptomatic SARS-CoV-2 infection was 74.0% (95% CI: 57.9 to 84.1%) and 62.5% (95% CI: 30.9 to 79.4%), respectively. However, these estimates of vaccine efficacy should be interpreted with caution. The definition of asymptomatic infection was based on either a positive RT-PCR result (generally performed as a result of symptoms) or a positive serology result based on samples collected at pre-specified times (Days 1, 29, 43, 57, 209 and 394). Therefore, the identification of asymptomatic cases based on positive serology do not correspond to identification of infection at a discrete point in time, but rather could reflect infection acquired at any time after collection of negative serology sample at baseline. Most confirmed cases in study participants were identified at a time when the Delta variant was the predominant circulating strain in the US and Canada. However, no sequence analysis was reported on case isolates to determine whether they were caused by the Delta variant or another variant.
There were too few cases identified beginning 14 days after dose 2 to generate estimates of vaccine efficacy for dose 2, however it is important to note the majority of participants (99.4%) randomized to receive vaccine received 2 doses, and therefore estimates of efficacy beginning 14 days after dose 1 cannot only be attributed to protection conferred from the first dose alone. There were no subgroup analyses (e.g., age, sex, race/ethnicity, presence of underlying medical conditions) presented for vaccine efficacy against any outcome.
None of the identified cases met the pre-defined criteria for a severe case of COVID-19, therefore the data did not include estimates of vaccine efficacy against severe outcomes such as hospitalization, MIS-C or death.
# APPENDIX B: FREQUENCY OF SOLICITED ADVERSE EVENTS FOLLOWING IMMUNIZATION FOR COVID-19 IN CLINICAL TRIALS
# Very common Very common Common Common
Abbreviations: AEFI: adverse event following immunization; NS: not solicited a Very common = occur in 10% or more of vaccine recipients, common = occur in 1 to less than 10% of vaccine recipients, uncommon= occur in 0.1% to less than 1% of vaccine recipients. b AEFIs were solicited within 7 days after each dose in a Phase 2/3 clinical trial. The information in this table is up to date as of February 10, 2022. For updated information, please consult the Spikevax product monograph. | # PREAMBLE
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidencebased recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# INTRODUCTION
On January 25, 2022, NACI published updated recommendations on the use of the Pfizer-BioNTech Comirnaty (10 mcg) COVID-19 vaccine in children 5 to 11 years of age, including strengthening their recommendation to strongly recommend a 2-dose primary series. In children 5 to 11 years of age who are moderately to severely immunocompromised, a 3-dose primary series is recommended.
# Since this guidance:
-Health Canada authorized the use of the Moderna Spikevax (50 mcg) COVID-19 vaccine for children 6 to 11 years of age; -Additional safety surveillance data on the use of mRNA vaccine booster Moderna Spikevax (50 mcg and 100 mcg) and Pfizer-BioNTech Comirnaty (30 mcg) among individuals aged 18 years and older has emerged; and -Additional safety surveillance data on the 2-dose primary series of Pfizer-BioNTech Comirnaty (10 mcg) in children 5 to 11 years of age is available, further supporting that the product is well tolerated and providing preliminary estimates on the risk of myocarditis and/or pericarditis in children 5 to 11 years of age.
NACI has reviewed the evolving evidence and has updated evidence-informed recommendations on the use of COVID-19 vaccines in pediatric populations. NACI continues to review the evidence on the use of COVID-19 vaccines and will update its recommendations as needed. Details of NACI's evidence-informed recommendation development process can be found elsewhere (1,2) . Tromethamine (Tris or trometamol) is used as a buffer in vaccines and medications, including those for use in children, to improve stability and prevent pH fluctuations in the solution. No safety concerns have been identified with tromethamine (3) . While tromethamine has been identified as a potential allergen, a review of existing evidence did not identify any cases of allergic reactions to tromethamine in children (4) .
b
Regardless of storage condition, vaccines should not be used after date of expiry printed on the vial and cartons. c Frozen is -25°C to -15°C; Refrigerated is +2°C to +8°C; Room temperature is +15°C to +25°C. d Once vials are thawed, they should not be refrozen. Thaw in refrigerated conditions between +2° to +8°C (36° to 46°F) for 2 hours and 30 minutes. After thawing, let vial stand at room temperature for 15 minutes before administering. Alternatively, thaw at room temperature for 1 hour. e During storage, minimize exposure to room light, and avoid exposure to direct sunlight and ultraviolet light. Vials must be kept frozen and protected from light, in the original cartons, until ready to thaw.
For complete prescribing information for the pediatric and adult formulations of the Moderna Spikevax and Pfizer-BioNTech COVID-19 vaccines, consult the product leaflets or information contained within Health Canada's authorized product monographs available through the Drug Product Database.
# Schedule
Refer to Table 2 for a summary of immunization schedules for authorized COVID-19 vaccines among children 5 to 11 or 6 to 11 years of age. There is emerging evidence that longer intervals between the first and second doses of COVID-19 vaccines result in more robust and durable immune response and higher vaccine effectiveness. NACI will continue to monitor the evidence and update this interval as needed.
# RECOMMENDATIONS
# NACI recommends that a complete series with an mRNA COVID-19 vaccine should be offered to children in the authorized age groups without contraindications to the vaccine, with a dosing interval of at least 8 weeks between the first and second dose. (Strong NACI Recommendation)
For children 6 to 11 years of age (which is the age group in which the Moderna Spikevax 50 mcg primary series vaccine is authorized):
Moderna Spikevax (50 mcg dose) may be offered as an alternative to Pfizer-BioNTech Comirnaty (10 mcg dose), however the use of Pfizer-BioNTech Comirnaty (10 mcg dose) is preferred to Moderna Spikevax (50 mcg dose) to start or continue the primary vaccine series.
Although risk of myocarditis/pericarditis with the Moderna Spikevax (50 mcg) in children 6 to 11 years of age is unknown, with a primary series in adolescents and young adults the rare risk of myocarditis/pericarditis with Moderna Spikevax (100 mcg) was higher than with Pfizer-BioNTech Comirnaty (30 mcg).
Indirect data from adult populations (≥18 years of age) suggest Moderna Spikevax (100 mcg) may result in higher vaccine effectiveness after a 2-dose primary series compared to Pfizer-BioNTech Comirnaty (30 mcg) and is associated with a higher seroconversion rate among adult immunocompromised patients (5) . Given this potential benefit, administration of the Moderna Spikevax (50 mcg) vaccine as a 3-dose primary series may be considered for some immunocompromised individuals 6 to 11 years of age, as outlined in the product monograph. Each dose would be provided 4 to 8 weeks apart, as per the NACI recommended schedule for immunocompromised populations.
Rationale and summary of evidence In the Phase 2/3 clinical trial on Moderna Spikevax, 3,007 children 6 to 11 years of age received the Moderna Spikevax COVID-19 vaccine (50 mcg), and 995 received the placebo; both groups were followed a median of 51 days since dose 2. The trial was conducted in the US and Canada when the Delta variant was predominant (data cut-off November 10, 2021). Interim findings did not indicate any safety concerns and preliminary efficacy against symptomatic COVID-19 was 88% starting 14 days after dose 1, which is comparable to efficacy after Pfizer-BioNTech Comirnaty among children 5 to 11 years of age. No cases of myocarditis/pericarditis or any other serious adverse events (SAEs) were reported among phase 2/3 trial participants that received the Moderna Spikevax COVID-19 vaccine (50 mcg). Any rare, or very rare adverse event (AEs) that occurs at the frequency less often than 1 in 1,000 to 1 in 10,000 would likely not be detected with this trial size (3,007 participants received the vaccine). Among individuals 12 to 29 years of age, safety surveillance data shows a lower reported rate of myocarditis/pericarditis following (6)(7)(8)(9)(10)(11) Pfizer-BioNTech Comirnaty (30 mcg) compared to Moderna Spikevax (100 mcg) primary series, as well as following the Pfizer-BioNTech Comirnaty (30 mcg) booster compared to the Moderna Spikevax (50 mcg) booster, among individuals 18 years of age and older. Safety surveillance data on the risk of myocarditis or pericarditis within 7 days following immunization with the Pfizer-BioNTech Comirnaty COVID-19 vaccine (10 mcg) from the US show that among males after the 2 nd dose, the risk may be substantially lower in children 5 to 11 years of age following Pfizer-BioNTech Comirnaty 10 mcg vaccine (4.3 cases per million doses) compared to adolescents following Pfizer-BioNTech Comirnaty 30 mcg (12,13)
# Trial design
The Moderna Spikevax COVID-19 vaccine was evaluated in an ongoing, randomized, observerblind, placebo-controlled Phase 1/2/3 clinical trial in healthy children from 6 months to 11 years of age (P204) (14) . Based on the reactogenicity and immunogenicity observed in the initial cohort of children 6 to 11 years of age in the open-label Phase 1 trial, a dose of 50 mcg was selected for the Phase 2/3 trial for this age group. A total of 4,011 participants 6 to 11 years of age were randomized 3:1 to receive either two doses of the vaccine (50 mcg mRNA) or placebo, 28 days apart. At time of reporting, median follow-up of participants was 51 days since dose 2. Follow-up is planned for up to approximately 12 months following the second dose. The trial was conducted at a time of predominant Delta variant of concern circulation (data cut off: November 10, 2021).
# Study population
All pediatric study participants for the Phase 2/3 trial were recruited from the US and Canada. Individuals with known history of SARS-CoV-2 infection within 2 weeks prior to administration of vaccine or known close contact with anyone with laboratory-confirmed SARS-CoV-2 infection or COVID-19 within 2 weeks prior to administration of vaccine were excluded from the trial. Individuals with known immunodeficiency or immunocompromised conditions were excluded from the trial.
# Immunogenicity comparator group
The immunogenicity comparator group for the children (6 to 11 years) was a randomly selected subset (n=295) of participants aged 18 to ≤25 years from the earlier Phase 2/3 study P301 who received two doses of the Moderna Spikevax COVID-19 vaccine (100 mcg), 28 days apart.
# Demographics
Demographic characteristics were similar among vaccine and placebo groups in the P204 trial. Overall, 49.2% of participants were female, with a median age at vaccination of 8.0 years (range: 5-11 years) in the vaccine group and 9.0 (range: 6-11 years) in the placebo group. About twothirds of participants were white (65.5%), with participants from other race/ethnic groups each comprising significantly less of the study population: Multiracial (10.8%), Black or African American (10.0% overall), Asian (9.9%), and all other groups comprising <2% of participants. All race and ethnicity groups had similar proportions in the vaccine and placebo groups. A total of 20% of participants were defined as obese. A total of 4 participants 6 to 11 years of age with known HIV were enrolled in the trial (all in the vaccine group), and 10 participants had cardiac disorders. The prevalence of SARS-CoV-2 infection or prior infection at baseline (determined by a positive RT-PCR or serological assay) in the vaccine and placebo groups in the safety population was comparable at 8.5% and 8.7%, respectively.
# Safety
Safety evidence for participants is based on the phase 2/3 randomized, observer-blind, placebocontrolled expansion study of children (focused on the cohort 6 years to 11 years of age) who received 2 intramuscular injections of Moderna Spikevax 50 mcg (n=3,007) or placebo (n=995) approximately 28 days apart. Data on solicited local and systemic reactions were collected daily for 7 days following each injection. Participants (6 to 11 years of age) were monitored for unsolicited adverse events for up to 28 days following each dose and follow-up is ongoing. Median duration of safety follow-up after second vaccination for study participants in the blinded phase was 51 days.
# Local reactions
Local reactions were increased in frequency in vaccine recipients (93.7% for dose 1, 95.3% for dose 2) compared to placebo recipients (48.3% for dose 1, 50.6% for dose 2). Most solicited local reactions were grade 1 or grade 2. Grade 3 reactions were more common in the vaccine recipients than in the placebo recipients (5.6% vs 0.8% respectively). The most frequent grade 3 reaction was injection site pain. There were no grade 4 solicited local adverse reactions in either group. The majority of solicited local reactions occurred within the first 1 to 2 days after any dose and persisted for a median of 3 days. Local reactions were very common and mostly mild to moderate in severity. In the vaccine recipient group, solicited local adverse reactions that persisted beyond 7 days after injection were injection site pain (0.8% dose 1, 0.5% dose 2), erythema (0.5% dose 1, 0.3% dose 2) injection site swelling (0.4% dose 1, 0.2% dose 2) and axillary/groin swelling or tenderness (1.7% dose 1, 0.7% dose 2). See Table 1 for the frequency of solicited local AEs for the Moderna Spikevax COVID-19 vaccine among children 6 to 11 years of age.
# Systemic reactions
Systemic events were increased in frequency in vaccine recipients compared to placebo recipients, with frequencies increasing with the number of doses in vaccine recipients (57.9% after dose 1 compared to 78.1% after dose 2 in vaccine recipients, and 52.2% after dose 1 and 50.1% after dose 2 in placebo recipients). Headache (31.2% and 54.3% after dose 1 and 2 respectively in vaccine recipients, and 30.8% and 28.4% after dose 1 and 2 respectively in placebo recipients), fatigue (43.2% and 64.5% after dose 1 and 2 respectively in vaccine recipients, and 33.6% and 34.6% after dose 1 and 2 respectively in placebo recipients), myalgias (14.6% and 28.2% after dose 1 and 2 respectively in vaccine recipients, and 9.7% and 10.8% after dose 1 and 2 respectively in placebo recipients), nausea/vomiting (10.8% and 24.0% after dose 1 and 2 respectively in vaccine recipients, and 10.8% and 10.0% after dose 1 and 2 respectively in placebo recipients) and chills (10.3% and 30.3% after dose 1 and 2 respectively in vaccine recipients, and 6.7% and 7.6% after dose 1 and 2 respectively in placebo recipients) were very common after dose 1 and dose 2 in vaccine recipients. Arthralgias were common after the first dose (8.7% in vaccine recipients and 7.6% in placebo recipients) and very common after the second dose in vaccine recipients (16.1% in vaccine recipients and 8.7% in placebo recipients). Fever was common after the first dose (3.3% in vaccine recipients and 1.5% in placebo recipients) and very common after the second dose in vaccine recipients (23.9% in vaccine recipients and 2.0% in placebo recipients). Grade 3 events were more common in the vaccine recipients (1.8% after dose 1, 12.2% after dose 2) than the placebo recipients (1.3% and 1.4% respectively). There were no grade 4 events in the vaccine recipients. See Table 2 for the frequency of solicited systemic AEs for the Moderna Spikevax COVID-19 vaccine among children 6 to 11 years of age.
# Serious adverse events and other adverse events of interest
There were no serious AEs assessed as related to the study interventions, either the vaccine or placebo, no deaths, no cases of MIS-C, and no cases of myocarditis or pericarditis reported during the study period. Monitoring for serious adverse events and medically attended adverse events will continue throughout the study period (up to 12 months following the second dose).
# Immunogenicity
An immunobridging analysis evaluating SARS-CoV-2 50% neutralising titres (ID50) and seroresponse rates 28 days after dose 2 was conducted in subset of children 6 to 11 years of age (Study P204; N=320) and in participants aged 18 through ≤25 from the Phase 3 efficacy study (Study P301; N=295). Subjects had no immunologic or virologic evidence of prior SARS-CoV-2 infection at baseline. The geometric mean ratio (GMR) of the neutralising antibody titres in children 6 to 11 years of age compared to the 18-to 25-year-olds was 1.2 (95% CI: 1.1, 1.4). The difference in seroresponse rate was 0.1% (95% CI: -1.9, 2.1%). Both pre-specified non-inferiority criteria (lower bound of the 95% CI for GMR greater than 0.67 and lower bound of the 95% CI of the seroresponse rate difference greater than -10%) were met. Immunogenicity data was also assessed following dose 1 in the same subset of participants; at day 29 from baseline, and GMR was similar across the two groups (108.1 in children 6 to 11 years of age, compared to 96.7 in adults 18 to 25 years of age).
Samples from a randomly selected subset of 20 participants 6 to 11 years of age were assessed for neutralization titres against the Delta variant and Omicron variant. Among children 6-11 years of age, the level of neutralizing antibodies against Omicron 28 days after dose 2 were 22.1 fold lower than those against D614G. However, the neutralizing antibody response against both Omicron and D614G among children 6 to 11 years of age was higher than among adults 18 years of age and older (15) .
As no correlate of protection has been established for any COVID-19 outcome at this time, it is unknown how reported immune responses are related to prevention of SARS-CoV-2 infection or disease or the ability to transmit infection to others.
# Efficacy
The evaluable efficacy population consisted of 2,687 participants randomized to receive vaccine and 880 participants randomized to receive placebo, all of whom had a negative baseline SARS-CoV-2 serostatus. As of November 10, 2021 (data cut-off for analysis), a total of 25 confirmed, symptomatic cases of COVID-19 were identified starting 14 days after dose 1 (7 in vaccine group, 18 in placebo group) in participants 6 to 11 years of age. The estimated efficacy of the vaccine against confirmed COVID-19 from 14 days after dose 1 was 88.0% (95% CI: 70.0 to 95.8%). The estimated efficacy against SARS-CoV-2 infection from 14 days after dose 1 (regardless of symptoms) and against asymptomatic SARS-CoV-2 infection was 74.0% (95% CI: 57.9 to 84.1%) and 62.5% (95% CI: 30.9 to 79.4%), respectively. However, these estimates of vaccine efficacy should be interpreted with caution. The definition of asymptomatic infection was based on either a positive RT-PCR result (generally performed as a result of symptoms) or a positive serology result based on samples collected at pre-specified times (Days 1, 29, 43, 57, 209 and 394). Therefore, the identification of asymptomatic cases based on positive serology do not correspond to identification of infection at a discrete point in time, but rather could reflect infection acquired at any time after collection of negative serology sample at baseline. Most confirmed cases in study participants were identified at a time when the Delta variant was the predominant circulating strain in the US and Canada. However, no sequence analysis was reported on case isolates to determine whether they were caused by the Delta variant or another variant.
There were too few cases identified beginning 14 days after dose 2 to generate estimates of vaccine efficacy for dose 2, however it is important to note the majority of participants (99.4%) randomized to receive vaccine received 2 doses, and therefore estimates of efficacy beginning 14 days after dose 1 cannot only be attributed to protection conferred from the first dose alone. There were no subgroup analyses (e.g., age, sex, race/ethnicity, presence of underlying medical conditions) presented for vaccine efficacy against any outcome.
None of the identified cases met the pre-defined criteria for a severe case of COVID-19, therefore the data did not include estimates of vaccine efficacy against severe outcomes such as hospitalization, MIS-C or death.
# APPENDIX B: FREQUENCY OF SOLICITED ADVERSE EVENTS FOLLOWING IMMUNIZATION FOR COVID-19 IN CLINICAL TRIALS
# Very common Very common Common Common
Abbreviations: AEFI: adverse event following immunization; NS: not solicited a Very common = occur in 10% or more of vaccine recipients, common = occur in 1 to less than 10% of vaccine recipients, uncommon= occur in 0.1% to less than 1% of vaccine recipients. b AEFIs were solicited within 7 days after each dose in a Phase 2/3 clinical trial. The information in this table is up to date as of February 10, 2022. For updated information, please consult the Spikevax product monograph. | None | None |
5f9fef55aa87870a744f4a80736f436731350033 | cma | None | No material available at www.caddra.ca (the "Materials") may be copied, reproduced, republished, uploaded, posted, transmitted, or distributed in any way, except that you may: (a) Download one copy of the Materials on any single computer for your personal or medical practice use only, provided you keep intact all copyright and other proprietary notices. Where stipulated, specific "tools and patient handouts", developed for physicians and other medical professionals to use in their practice, may be reproduced by medical professionals or on the advice of medical professionals; (b) Give a presentation using the Materials, so long as: (i) the purpose of the presentation or distribution is for public education; (ii) you keep intact all copyright and other proprietary notices in the Materials; and (iii) the presentation or distribution is completely noncommercial and you or your organization receive no monetary compensation. If monetary compensation is involved, you must provide notice to CADDRA at least ten (10) business days before the presentation and request permission. Modification of the Materials or use of the Materials for any other purpose, without the prior written consent of CADDRA, is a violation of CADDRA's copyright and other proprietary rights.# Contents of CADDRA ADHD ASSESSMENT eTOOLKIT (USB key)
Step
# PREFACE
# CANADIAN ADHD PRACTICE GUIDELINES INTRODUCTION
The purpose of the Canadian ADHD Practice Guidelines is to improve the quality of health care and outcomes for all individuals with Attention Deficit Hyperactivity Disorder (ADHD) in Canada.
The Guidelines:
- Cover the lifespan of the disorder.
- Are based on published evidence.
- Involve expert consensus when evidence is lacking.
- Offer practical clinical advice.
- Provide assessment, treatment and follow-up questionnaires.
- Include templates for requesting accommodations.
- Recommend optimizing care on an individual basis.
- Assist healthcare providers to empower their patients to make informed choices in a collaborative process of care.
- Contain information specific to the Canadian healthcare system.
The Guidelines are targeted at health care professionals but may also be of use to additional stakeholders (policy makers, funding bodies, educators) and individuals with ADHD and their families. The tools included in the Guidelines were selected based on their validity, reliability and accessibility. These Guidelines were developed to provide information and user-friendly tools to support Canadian health care professionals in diagnosing and treating ADHD across the lifespan. These Guidelines are not intended to replicate or replace the many excellent textbooks on ADHD.
# The evolution of the 4th Edition
The Canadian ADHD Practice Guidelines are produced and funded by CADDRA -Canadian ADHD Resource Alliance, a national, independent, not-for-profit association whose members are drawn from family practice, pediatrics, psychiatry (child, adolescent and adult), psychology and other health professions.
# The Guidelines have been in constant review for over ten years
The fourth edition of the Canadian ADHD Practice Guidelines evolved from earlier editions published in 2006, 2008, and 2011. A multidisciplinary team that included ADHD specialists, pediatricians, psychiatrists, psychologists, family physicians, pharmacists, nurses, educators and community stakeholders from across Canada and from the US contributed to its writing and review.
# Disclosures and Funding
Conflicts of interest were recorded for all individuals that were a part of the process and are included in the Guidelines. As has been the case since the 1 st edition of the Canadian ADHD Guidelines, all authors have donated their time and shared their expertise without receiving any financial contribution. The final draft of the 4th edition was independently reviewed by a range of relevant stakeholders (e.g., adult psychiatrist, child and adolescent psychiatrist, psychologist, patient advocate/nurse, family physician). The Guidelines development process was fully funded by CADDRA and occurred without external financial grants.
# Endorsements
These Guidelines are endorsed by the Centre for ADHD Awareness, Canada (CADDAC).
# CADDRA GUIDELINES -CORE PRINCIPLES
These Guiding Principles were developed and approved by the CADDRA Board.
# Principles for Assessment and Diagnosis
- The clinician has to be fully licensed and adequately trained in order to ensure Diagnostic and Statistical Manual, Fifth Edition (DSM-5) diagnostic criteria for ADHD are fully met . 2. The assessment needs to reflect an understanding of multi-systemic issues that may confound or complicate the ADHD diagnosis (e.g., the educational/vocational, psychosocial, psychiatric and medical interfaces). 3. Symptoms and functional impairment need to be assessed. Using valid, reliable and sensitive instruments helps to evaluate frequency, severity, and outcome. 4. Regular documentation of symptoms and functional impairment, if possible at each visit, helps to track progress and monitor outcome. 5. Establishing collaborative treatment goals with the patient (and their family when appropriate) ensures that outcomes are patient-centered. 6. The results of the assessment need to be communicated to the patient and their family with clarity and compassion.
# Acronyms
# ADHD
# CHAPTER 1: DIAGNOSIS OF ADHD
Attention Deficit Hyperactivity Disorder (ADHD) is typically a chronic, often lifelong, condition. The impact and presentation of ADHD can change over time and often requires lifelong monitoring and treatment . Clinicians who follow individual patients and their families should be knowledgeable about how ADHD presents and causes functional impairment across the lifespan.
Although the term Attention Deficit Disorder was first introduced in 1980 in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) , symptoms of inattention, hyperactivity and impulsivity have been described in children over the last 200 years . A historical perspective reveals that Melchior Adam Weikard is credited with first describing a disorder similar to ADHD in 1775 , followed by Sir Alexander Crichton's description in 1798 ; Heinrich Hoffman M.D. created the character of "Fidgety Phil", used as a popular allegory for children with ADHD, in 1844 ; and Dr. George Frederic Still described a condition remarkably similar to ADHD in the English medical journal the Lancet in 1902 . In 1937, psychiatrist Charles Bradley administered Benzedrine sulfate, an amphetamine, to "problem" children at a home in Providence, Rhode Island to alleviate headaches but noticed an unexpected behavioural effect: improved school performance, social interactions, and emotional responses .
The Diagnostic and Statistical Manual of Mental Disorders, Second edition (DSM-II) described the disorder "hyperkinetic reaction of childhood (or adolescence)" in 1968 .
ADHD is now defined as a neurodevelopmental disorder. Characterization of ADHD has evolved through several revisions over the years, the most recent one being in the Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5) in 2013 . ADHD is usually seen in early childhood, but not necessarily diagnosed at that time. It is thought to be a lifelong disorder. More than 50% of individuals diagnosed in childhood and adolescence continue to have significant and impairing symptoms in adult life .
The general prevalence of ADHD is estimated at between 5-9% for children and adolescents and 3-5% for adults . The disorder is not confined to the USA or Canada but is prevalent worldwide .
There is a common public misconception, reinforced by much of the media, that ADHD is over-diagnosed. However, a recent meta-analysis confirmed stable rates of the prevalence of ADHD over the past 30 years .
The etiology of ADHD remains under investigation. ADHD is highly heritable . Parents with ADHD have a better than 50% chance of having a child with ADHD, and about 25% of children with ADHD have parents who meet the formal diagnostic criteria for ADHD . Twin studies have placed the heritability of ADHD at 76% with the risk of ADHD in first-degree relatives of diagnosed individuals being somewhere between 30 to 40% . This includes children of adults with ADHD, their siblings or their parents.
The genetics of ADHD are complex . Many different genes have been identified as linked to ADHD (DRD4, DAT) but, as ADHD is a heterogeneous disorder, it is most likely related to complex genetic etiologies .
The ongoing genome wide studies are likely to shed light on this issue in the future . Other etiological factors have been linked to ADHD, such as tobacco/alcohol use during pregnancy. Low birth weight and psychosocial adversity should be considered as possible contributors to ADHD symptomatology in an individual . Neuronal networks associated with ADHD have been reviewed in neuroimaging studies and the dysfunction of fronto-striatal pathways (dorsolateral and anterior cingulate) is often targeted as a possible underlying neural mechanism . A landmark study on ADHD, the Multimodal Treatment of Attention Deficit Hyperactivity Disorder (MTA) study , found that 70% of school-aged children with ADHD have at least one other psychiatric disorder such as anxiety, Oppositional Defiant Disorder, Obsessive Compulsive Disorder, Tic Disorder or depression.
# Making a Diagnosis in Primary Care
Patients with ADHD can be managed in a primary care setting . According to DSM-5, the diagnostic tasks are to ensure:
- Current symptoms present sufficiently (see Table 1.1).
- Age of onset of these symptoms is by age 12.
- Impairment in two or more roles due to these symptoms has been present for the last six months or more.
- A lack of alternate explanation for the symptoms or impairment, including a broad range of alternate medical (including mental health) and circumstantial conditions.
However, the following situations may require further consultation:
- Medical (physical) or psychiatric comorbidities are present and contributing significant morbidity or diagnostic uncertainty (refer to chapter 2).
- Failure to respond to recommended treatment algorithms (refer to chapter 5).
- Patient/family reluctance to accept diagnosis and/or treatment.
Note: Overall psychiatric health should always be considered and a risk assessment done at the onset.
There are several tools available to assist in the diagnosis of mental health problems. Examples of these general screeners are the Weiss Symptom Record (WSR) , the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder Item-7 (GAD-7) as well as the Screen for Child Anxiety Related Disorders (SCARED) and the Kutcher Adolescent Depression Scale (KADS) . As always, therapeutic decisions should be based on a thorough evaluation of the patient with the most prominent or critical issues addressed first. This chapter provides information on how to systematically assess patients with ADHDconsistent features. Often fails to give close attention to details or makes careless mistakes in school work
Often fidgets with hands or feet or squirms in seat 2.
Often has difficulty sustaining attention in tasks or play activities Often leaves seat in classroom when remaining seated is expected 3.
Often does not seem to listen when spoken to directly Often runs about or climbs excessively in situations where it is inappropriate 4.
Often does not follow through on instructions and fails to finish school work
Often has difficulty playing or engaging in leisure activities quietly
Often has difficulty organizing tasks and activities Often is "on the go" or often acts as if "driven by a motor" 6.
Often avoids, dislikes, or reluctantly engages in tasks requiring sustained mental effort Often talks excessively 7.
Often loses things necessary for activities (e.g. school assignments, pencils, or books)
Often blurts out answers to questions before the questions have been completed 8.
Often is distracted by extraneous stimuli Often has difficulty awaiting turn 9.
Often is forgetful in daily activities Often interrupts or intrudes on others (e.g. butts into conversations/games)
Reproduced with permission from American Psychiatric Association Publishing Other Specified ADHD / Unspecified ADHD: Symptoms causing impairment but full criteria for ADHD are not met. *Total number of symptoms are less in adults (17+): 5 of 9 instead of 6 of 9
Chapter One of the Canadian ADHD Practice Guidelines and the CADDRA ADHD Assessment Toolkit have been designed to give frontline workers a convenient yet comprehensive step-by-step approach to the assessment and diagnosis of ADHD throughout the lifespan. The forms, assessment tools, and handouts referred to in the diagnostic algorithms are free to download from www.caddra.ca and to print and duplicate for your personal or practice use.
Rating scales and questionnaires can be used as an efficient way to obtain information from the patient and collateral sources, but are not sufficient for a diagnosis as other conditions may screen positive on ADHD rating scales (e.g. overlapping symptoms of depression or anxiety, or the presence of medical conditions like sleep apnea or anemia). A careful and thorough assessment reduces the risk of a false diagnosis of ADHD . These instruments, however, are effective screening tools and can be employed to document change over time and track treatment effects.
# Update on strategies for the diagnosis of ADHD
Establishing a diagnosis is an essential step in identifying pathology and developing a personalized treatment plan. Thus, clinicians are interested in keeping abreast of advances in diagnostic strategies. To address this need, a literature review spanning the past 10 years (2006-2016) on the diagnosis of ADHD was conducted. Only reviews, meta-analyses and randomized controlled trials were selected.
At this time, there is no evidence that any strategies beyond those described in the CADDRA Guidelines and recommended in the toolkit (namely the clinical interview in combination with rating scales), offer substantial benefit in the diagnosis of ADHD. The clinical interview and evaluation continues to be the mainstay of ADHD diagnosis.
Although rating scales alone are not sufficient to diagnose ADHD because of issues such as the variability of interpretation of questions by respondent, their use to enrich the process of evaluation is widely recommended .
Direct behavioural observation (i.e. observing the child in the classroom) is recommended by most sources , and has been complemented by standardized coding systems. However, it is associated with a high cost and may be possible where health professionals are also school personnel , but is generally limited to research settings.
While, neuropsychological and psychoeducational evaluations are frequently recommended, these are most useful in situations of diagnostic uncertainty and should be interpreted in the context of a broader clinical evaluation given issues of sensitivity and specificity. Certain neuropsychological tests (Wide Range Assessment of Memory and Learning, California Verbal Learning Test, Wisconsin Card Sorting Test) have been recommended as particularly appropriate measures of ADHD . However, neuropsychological tests of executive function have low ecological validity. Not all individuals with ADHD, although functionally impaired by their ADHD, show impairment levels in standardized test data alone .
Furthermore, testing results should not be required to demonstrate below "average" functioning for a disability to be recognized and for the student to qualify for services and accommodations. Neuropsychological or psychoeducational testing should not be used to determine the severity of ADHD or quantify the impact of ADHD on cognitive or academic functioning as they do not accurately measure the nature of "real world" cognitive or academic impairments that characterize ADHD.
Computerized cognitive assessments (e.g. Conners' Continuous Performance Test, Test of Variables of Attention, Gordon Diagnostic System) have also been developed that specifically assess attention and response inhibition but are associated with a degree of overlap between individuals with ADHD and controls .
Neuroimaging has identified structural alterations and dysfunctions in ADHD using population and research studies, but has no direct clinical application at this time .
Electroencephalography has been the focus of many publications . Children with ADHD may have an increase in absolute and relative theta and decreases in absolute and relative alpha and beta . This continues to distinguish adolescents and adults with ADHD . Having said this, EEG testing Is not a validated diagnostic tool for ADHD and CADDRA does not endorse its use for this purpose.
Red Flags for ADHD
Organizational skill problems (time management difficulties, missed appointments, frequent late and unfinished projects).
- Erratic work/academic performance.
- Anger control problems.
- Family/marital problems.
- Difficulty in maintaining organized household routines, sleeping patterns and other self-regulating activities.
- Difficulty managing finances.
- Addictions such as substance use, compulsive shopping, sexual addiction, overeating, compulsive exercise, video gaming or gambling.
- Frequent accidents either through recklessness or inattention.
- Problems with driving (speeding tickets, serious accidents, license revoked).
- Having a direct relative who has ADHD.
- Having to reduce course load, or having difficulty completing assignments in school.
- Low self-esteem or chronic under-achievement.
# STEP 1: INITIAL INFORMATION GATHERING
# Reasons for Assessment or Referral
Individuals may come to you, or are referred, for a wide variety of reasons:
- Someone close to the individual (e.g., a relative, teacher, employer, colleague or friend) has learned about ADHD and recognizes these traits in the person.
The individual (typically an adolescent or an adult) has learned about ADHD and recognizes the relevant symptoms.
- A relative has already been diagnosed with ADHD and this diagnosis triggers an awareness of ADHD within the individual (e.g., a child is diagnosed and one or both parents think they may also have ADHD).
- There are functional difficulties that the individual presents with (such as behavioural or attention problems, academic issues, difficulty with paperwork, time management, driving, smoking or marital problems) and the clinician postulates ADHD as a possible explanation.
- Symptoms are attributed to another psychiatric diagnosis (mania, depression, anxiety, substance use disorder) but in fact could be related to ADHD. Some clinicians may be wary of an individual self-referring with a possible ADHD diagnosis. They may suspect that the person is looking for drugs, accommodations or an explanation/excuse for other problems. Clinical experience indicates this is an infrequent occurrence.
# Practice Point
- Review the individual's strengths and NOT just their areas of relative weakness.
- Establish a rapport with the individual and their family that makes future contacts easier and can aid intervention planning.
- Ensure that each interview ends with a statement about the coping skills that the individual and/or family have successfully used to work with difficult circumstances.
- Outline and affirm the importance and value of the individual and their family's efforts to succeed.
- Remember that self-referral neither guarantees nor eliminates a diagnosis of ADHD.
# Presenting Complaint and Documentation Initiation
Review with the individual and their family any concerns, the reason(s) for referral and the individual's/family's hopes for the assessment. Psychometric evaluations included in the CADDRA toolkit are designed to track the person's progress and assist with efficient and structured clinician charting. The diagnosis of ADHD cannot be done through the CADDRA toolkit alone but in conjunction with a diagnostic interview and attention to medical history, psychosocial elements and clinical presentation.
# SUGGESTED ACTION -AT THE END OF STEP 1
- Give the individual the relevant inventories necessary for the next visit (see appropriate 'Diagnosis and Treatment Flowchart' for the age group).
- Ask the individual and/or family to provide any relevant prior documentation (e.g., school report cards, previous assessments, etc.). Good school performance does not necessarily rule out ADHD. Individuals with ADHD may not accurately recall symptoms . Therefore, collateral information may assist in diagnosis.
The CADDRA Toolkit provides several forms (all available in the public domain), see flowcharts. An ADHD assessment should always include a general mental health screening (to consider comorbidities and differential diagnoses). In addition to a diagnostic interview, the CADDRA Toolkit contains optional assessment tools such as the CADDRA ADHD Assessment Form and the Weiss Symptom Record II (WSR II). The step-by-step flowcharts in this chapter apply after general mental health screening has been completed and ADHD is suspected. All the tools documented in this flowchart are free to download and use. Other assessment tools can be used in place of those proposed below.
# Practice Point
Communicating with the child or adolescent's school is crucial to collect information and implement appropriate measures. If parent(s) object to involving the school, the physician should let the parent(s) know that that an understanding of any ADHD-related difficulties in the classroom is needed to make a full assessment. In adults, collateral information provided by observer reports, such as from family members or partners, are important assessment tools.
Inconsistent reports (i.e. disagreement between parents, teachers, and partners) may require further exploration to better understand any discrepancy and may require referral.
# STEP 2: MEDICAL REVIEW
Objectives:
- Collect the documentation from past records when available.
- Score and review completed forms from Step 1.
- Complete the physical examination (or document that a physical examination was completed by a colleague) and review medical history to ensure that there are no other medical causes that could mimic or modulate ADHD symptoms.
- Discuss the possible complications / outcomes of having ADHD (e.g. accidents, poor sleep, nutrition, and substance abuse).
Ensure that there are no medical contraindications to the use of medications for treating ADHD (see chapter 5).
# SUGGESTED ACTION -AT THE END OF STEP 2
- Order any relevant clinical tests based on the physical findings to rule out medical causes and risk factors.
# STEP 3: ADHD-SPECIFIC INTERVIEW
# Objectives:
A complete childhood developmental history is an important part of a comprehensive assessment. Because accurate recollection of childhood symptoms and developmental history is difficult to obtain in adults, it is suggested to obtain, when possible, the point of view of a parent or a close family member who knows the individual's early history. The CADDRA ADHD Assessment Form offers an optional ADHD interview format and is available in the CADDRA eToolkit. The Diva 2.0 Diagnostic Interview for ADHD in Adults is another tool that can be downloaded at www.divacenter.eu in various languages .
In order to do a complete review, explore:
- Perinatal history (birth weight, complications, maternal alcohol and tobacco usage during pregnancy).
- Developmental milestones.
- Medical history (i.e. illnesses, concussions, seizures etc.)
- Impact of symptoms on learning, socialization and independent functioning.
Temperament.
- Symptoms of ADHD prior to the age of 12.
- Presence of any life events that were of emotional concern in childhood (e.g., abuse, bullying, divorce, loss, deaths, attachment issues).
- Content review of the completed forms with the individual and their family.
# Practice Point
- Review the person's strengths uncovered in the previous steps.
- Do not rely on ADHD symptoms observed during the interview as obvious symptoms of motor hyperactivity, impulsivity and inattention may not present in a one-to-one or novel situation. If observed during the clinical interview, this often suggests that the symptoms are more severe.
- Remember that a diagnosis of ADHD is made on symptoms and impairments reported rather than only on direct physician observation.
- Question not only the nature of the impairment and symptoms but the triggers that allow them to become apparent.
- Separate out symptoms caused by psychosocial stressors. This can be very difficult, particularly when the patient has suffered significant loss or trauma. It's important to differentiate any acute onset symptoms that may have been caused by recent stressors, such as loss or trauma, from the more chronic neurobiological symptoms of ADHD.
# SUGGESTED ACTION -AT THE END OF STEP 3
- Order any tests if necessary. If indicated, make referrals for further specialty assessments such as psychology, occupational therapy, speech language pathology, psychiatry or other medical specialists.
- Request a psychoeducational assessment if a learning disability or other cognitive challenges are suspected.
- Continue to emphasize the need to learn about ADHD and ensure that individuals and their families are aware of relevant websites for more information, such as: o CADDAC www.caddac.ca (Canada) o CHADD www.chadd.org (USA)
# STEP 4: FEEDBACK & TREATMENT RECOMMENDATIONS
# Feedback of the Diagnosis (if not previously done)
- Review all completed rating scales to determine if they meet criteria for ADHD.
- Review the developmental history, identifying impairments that are often associated with ADHD.
- For children/adolescents, review the CADDRA Teacher Assessment Form.
- Review all other available documentation, such as report cards and prior assessments.
- Give feedback related to the interview and collateral sources.
- Based on the findings above, present the diagnosis and any other concerns that might be relevant.
# Dispelling Myths
Many individuals and their families come into an assessment for ADHD with false information or beliefs. Some examples are:
- They are just lazy and looking for an excuse.
- I don't want my child to take medication that could change their personality.
- I am not the one with the problem, my spouse/employer/parent/teacher/school system is the problem.
- I had it as a child but it went away.
- I don't have all of the clinical symptoms.
- ADHD is just a fad.
- Plus, many more…
# Feedback of the Treatment Plan
- Address the feelings, questions and reactions to the ADHD diagnosis of the person with ADHD and their family.
- Explain the impact of the diagnosis in social/school/vocational settings. Documentation of the official diagnosis may be critical to receive various school interventions, benefits (e.g. special funding) and accommodations.
- Review the areas of impairment, trying to narrow down the primary symptoms that are troubling the patient.
Provide further education about ADHD (e.g. the CADDRA Information handout).
- Discuss psychosocial treatments (Chapter 4) and pharmacological treatment options (Chapter 5).
# Implementation of Treatment
- Treatment is often multimodal and should be individualized.
- Refer to chapters 4 and 5 for specific treatment guidelines.
# Follow-up
Regular and frequent follow-up is important until ADHD is stabilized. Once stabilized, active individualized monitoring based on a chronic disease management model should occur. Frequency of follow-up is dependent on patient characteristics such as medical complications, compliance, response to treatment, social supports and lifestyle factors.
The CADDRA Clinician ADHD Baseline/Follow-up and CADDRA Patient ADHD Medication forms can help streamline these visits.
# Practice Point
Regular monitoring includes completion of a growth chart for children plus rating scales, collection of vital signs, and side effects profiles whatever the age of the patient.
# PREVALENCE OF COMORBIDITIES
When making an ADHD diagnosis, it is very important to note that, in the majority of cases, ADHD does not exist in isolation . An evaluation for ADHD requires screening for possible comorbid disorders and consideration of biological, social, and psychological factors. Consideration of a second opinion or referral to an ADHD specialist should be made if the patient has a clinical history that is complex or if you are contemplating pharmacological treatment beyond those recommended in these Guidelines .
Most individuals with ADHD have co-occurring conditions that may complicate the clinical presentation. Often these comorbid disorders need to be dealt with concomitantly . In some circumstances, as described later in this chapter, one may need to prioritize which condition to treat first.
# From the Literature:
- 50-90% of children with ADHD have at least one comorbid condition .
- Approximately half of all children with ADHD have at least two comorbidities .
- 85% of adults with ADHD meet criteria for a comorbid condition .
The literature offers multiple potential explanations for the existence of comorbidities and/or overlapping symptoms between ADHD and other disorders .
The main explanations are :
- One disorder is a precursor to another;
- One disorder is a risk factor for the development of the other;
- The disorders share the same related risk factors; or - There is a common underlying symptomatic basis for one or more of the behaviours in common. Comorbidity can contribute to the failure to diagnose ADHD in adults and children . In addition, follow-up studies of children with ADHD and comorbidity show that these children have a poorer outcome than children with ADHD alone, as evidenced by significantly greater social, emotional and psychological difficulties . The most common comorbidities identified in the Multimodal Treatment Study of ADHD and in other comorbidity studies have been remarkably consistent (e.g. Oppositional Defiant Disorder, Learning Disorders, Anxiety Disorders, Substance Use Disorders).
# Disorder-based Differentiation
Differential diagnosis is the process of differentiating between two or more conditions that share similar signs or symptoms while comorbid disorders are disorders that occur together with ADHD (either causallyrelated or independent and occur concurrent with ADHD). A careful assessment of other possible diagnoses should be undertaken at the time of evaluation. As ADHD does not have a symptom that is pathognomonic for the condition, there can be numerous overlaps with other disorders.
A thorough history and full functional review accompanied by a physical examination may highlight underlying physical conditions. While most individuals with ADHD do not need laboratory investigations as part of their diagnostic assessment, in certain instances, a laboratory work up or specific tests are needed to eliminate a suspected pathology.
Some special medical investigations may be required, such as polysomnography , electroencephalogram , or brain imaging . Psychological testing may be required to address a suspected learning disability or other cognitive challenges. The clinical evaluation of a child with ADHD includes an evaluation of potentially adverse psychosocial factors such as a disruptive family environment , child abuse or neglect and attachment issues . These may complicate the presentation of ADHD. - Neurofibromatosis
Medications that may have psychomotor side effects:
- Medication with cognitive dulling side effect (e.g. mood stabilizers).
- Medication with psychomotor activation (e.g. decongestants, beta-agonists like asthma medication).
# Common Comorbidities
In this chapter, we will briefly describe key comorbidities that can present alongside ADHD and the auxiliary treatments that they require.
# ADHD, Comorbidity & Development
- ADHD in its different presentations (combined, inattentive or hyperactive-impulsive), and the most common comorbid disorders, change over time and by developmental stage .
The most common comorbid disorders in early childhood are oppositional defiant disorder (ODD) , language disorders , and anxiety disorders .
- Many children with ADHD have a Specific Learning Disorder .
- ADHD may be two to three times more common in children with developmental disabilities or borderline IQ and intellectual disabilities .
In the mid-school-age years, symptoms of anxiety or tic disorders become more common .
- Mood disorders and substance use disorders tend to be more observable by early adolescence compared to childhood .
- In adulthood, anxiety, major mood disorders (depression or bipolar disorder) and substance use disorders are commonly seen with ADHD .
# OPPOSITIONAL DEFIANT DISORDER
Behavioural problems (including oppositionality, aggression and delinquency) are among the most common comorbid presentations in children with ADHD . The presence of comorbid Oppositional Defiant Disorder (ODD) with ADHD is likely to generate substantial impairment and is expected to result in increased referrals for treatment . ODD rarely presents as an isolated diagnosis. Distinguishing between normal adolescent self-assertion and ODD may not always be easy. The impulsivity and irritability associated with ADHD is sometimes mistaken for the willfulness of ODD. In some individuals, ODD may continue into adulthood .
# Symptoms
DSM-5 symptom classification of ODD helps distinguish between the reactive-irritable symptoms that overlap with ADHD manifestations and the provocative-vindictive symptoms . The provocative-vindictive symptoms are less common and are often conceptualized as a reaction to insecurity or low self-esteem and may reflect reaction to a dysfunctional environment. The anxiety/depressive symptoms are associated with the irritable symptom construct of the DSM-5 .
DSM-5 provides three symptom clusters (mood related, provocative or vindictive) of ODD. It is useful to examine each symptom in light of its overlapping characteristics with ADHD.
# Treatment
Treatment of comorbid ODD with ADHD should be multimodal . In patients with comorbid ODD with ADHD, it is advisable that the first step is optimization of pharmacotherapy of ADHD, which may stabilize the reactive-irritable symptoms . This should be followed by augmentation with psychosocial treatment, including Parent Management Training (PMT), Cognitive-Behavioral Therapy (CBT) or Collaborative and Proactive Solutions (CPS) . It is important to distinguish ODD from conduct disorder (CD). Children with ODD have recurring negativistic, defiant, hostile and disobedient behaviour, especially toward authority figures, whereas those with CD repeatedly violate the basic rights of others or ageappropriate societal norms, as defined by a pattern of repeated aggression, lying, stealing, and truancy . The onset of both disorders can be prepubertal, thus making early identification, diagnosis, and treatment crucial. In one study, ODD was found to be a precursor to conduct disorder in approximately 50% of the cases .
# Key Points
- Some patients with ADHD and ODD may respond adequately to stimulant or non-stimulant (atomoxetine, guanfacine XR) medications . Since many cases are likely to require augmentation with either psychosocial treatment and/or off-label use of another medication (for example; atypical antipsychotics) , referral to specialized care may be required in complex cases.
- Effective treatment may reduce the risk of more severe conditions in adolescent and adult years, such as CD, substance use disorder and depression .
# CONDUCT DISORDER/AGGRESSION
Conduct Disorder (CD) comorbid with ADHD is a severe, persistent condition that is frequently preceded by ODD . When CD has pre-pubertal onset (before the age of 10 years old), the prognosis is considered worse than for the group of children that have adolescent-limited CD . DSM-5 also emphasizes that limited pro-social emotions (lack of remorse or guilt; callousness and lack of empathy); being unconcerned about performance; and shallow or deficient affect are poor prognostic indicators and increase the risk for the development of antisocial personality disorders in adulthood . Furthermore, co-occurrence of ADHD and CD is often a precursor of nicotine use disorder, substance use disorder, anxiety, and depression .
Research shows that ADHD and CD represent two complex and distinct entities that can be associated . Children with either of these conditions in isolation present with different core symptoms and perform differently on objective measures of ADHD symptoms than those with ADHD + CD . Children with ADHD + CD show the poorest outcome within each individual group .
# Symptoms
The following table serves to help clinicians identify behavioural symptoms that may be seen in ADHD and may respond to specific treatments for ADHD. CD specific symptoms may require a multi-systemic approach and may also need to involve the legal system.
# Treatment
Pharmacotherapy for patients with a combination of ADHD, CD and aggression using both stimulant and non-stimulant medications has been found to be useful . Although medications are usually effective in reducing the symptoms of ADHD and impulsive aggression , these patients typically receive more benefit from multimodal treatment .
Medications should initially be used to treat the most severe underlying disorder, but in some complex situations targeting specific symptoms could be appropriate. For example, patients with CD may show aggression before and during the course of treatment, making it imperative to document their aggressive behaviours before the introduction of medication and to make these behaviours an explicit target of therapeutic strategies. Clinicians should assess pharmacological treatment tolerability as some medications may augment irritability and aggression .
Conduct problems may be reduced by the most widely used evidence-based treatments for ADHD (e.g. stimulant and nonstimulant medication and psychosocial treatment) . However, treatment of the ADHD may not be sufficient to resolve all symptoms. Optimization of medication as part of a multimodal treatment approach indicated that psychosocial treatments including individual and family interventions are often required . Specialists in this area might use mood stabilizers or an atypical anti-psychotic (both are off-label). Other treatments (besides optimizing ADHD medication and psychosocial treatments) are controversial and referral to a specialist is recommended .
# Key Points
The essential characteristic of CD is repetitive and persistent behavior manifested by violation of others' fundamental rights or violation of social rules/norms.
- Psychosocial treatment, such as parenting and problem-solving skills training, and family and/or individual therapy, is often needed to improve patient outcomes.
- Pharmacological treatment of comorbid ADHD and CD may require combination of an ADHD medication and a medication that targets aggression.
- CD with ADHD represents a complex diagnostic entity that may require specialized interventions.
# ANTISOCIAL PERSONALITY DISORDER
Antisocial Personality Disorder (ASPD) is diagnosed when a pattern of antisocial behaviour has occurred since age 15. CD is, therefore, a precursor to ASPD. Many people with ASPD have a history of ADHD but most people with ADHD do not develop ASPD .
# Symptoms
Many of the ASPD symptoms have an impulsive component. It is therefore clinically indicated to carefully assess for ADHD in patients with ASPD. However, targeting and treating ADHD symptoms may not resolve ASPD symptoms as they are crystalized in the personality but may facilitate a structured intervention for the ASPD.
# Treatment
Both disorders must be treated separately using the efficacious treatments for each specific condition. Since some patients with ASPD may exhibit drug seeking behavior (for secondary gain) or concurrent substance use disorders , clinicians may be sometimes reluctant to consider psychostimulant treatments for these patients, even if the ADHD is significant. Non-stimulant medications have not been systematically investigated in these patients but offer a treatment option for some underlying ADHD-related symptoms.
# Key Points
- ADHD is a treatable risk factor for ASPD.
- Both conditions require specific interventions and education may help to improve impulsive behaviours but ASPD traits need to be addressed separately.
- ASPD with ADHD represents a complex diagnostic entity and may require specialized interventions.
# BORDERLINE PERSONALITY DISORDER
According to the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) , the lifetime prevalence of Borderline Personality Disorder (BPD) was reported to be 33.69% in those with ADHD versus 5.17% in the general population, suggesting an association between the two disorders. The most common symptom between ADHD and BPD is impulsivity .
# Symptoms
BPD and ADHD have shared and overlapping symptoms. The following table assists the clinician in distinguishing symptoms that are more specific to BPD from those that may overlap with ADHD.
# Treatment
There are no studies establishing the optimal treatment for individuals with ADHD and BPD. The available literature suggests treating the two entities as separate phenomena . In addition, there is no current evidence to propose that an improvement in ADHD leads to a resolution of BPD, signifying that the personality features require specific treatments . However, most treatment strategies for BPD aim to control impulsive behaviours (often with medication), emotion dysregulation and distress tolerance . Currently, Dialectical Behavioral Therapy (DBT) is the most commonly recognized treatment for BPD . While all patients with core impulsivity are at risk of medication misuse, physicians must use their judgment and not necessarily deny patients with BPD effective treatments for ADHD.
# Key Points
- BPD with ADHD represents a complex diagnostic entity that requires specific mode of interventions.
- Psychosocial interventions like DBT have been shown to be effective for BPD and should be used in combination with psychopharmacology in the presence of ADHD.
- Stabilizing impulsive behaviours and optimizing emotion regulation should be the main goals of the combined psychosocial and pharmacological interventions.
- BPD with ADHD represents a complex diagnostic entity and may require specialized interventions.
# ADDICTIONS
In some individuals with ADHD, the need for rapid feedback, the desire for immediate reward and the high adrenaline riskseeking behaviours may render them vulnerable to addictions. These addictions may be to shopping, sex, pornography, internet and gambling, in addition to possible substance use disorders . Management principles for addictions and ADHD should include a specific intervention for the addictive behaviour and a specific treatment for the ADHD, ideally concurrently .
# SUBSTANCE USE DISORDER
Compared to typically developing individuals, people with ADHD have a two-fold risk for substance abuse and dependence . The literature suggests that one-quarter of adults with substance use disorder (SUD) and one-half of adolescents with SUD have ADHD . Several studies suggest a higher rate of SUD in adults with ADHD than in the general population, and ADHD itself is a risk factor for SUD . Among ADHD patients with a comorbid behavior disorder, those with either comorbid CD or Bipolar Disorder have the greatest likelihood of developing SUD .
Individuals with ADHD are at significant risk of using substances (e.g. nicotine, cocaine and cannabis) and of starting use earlier than the general population . Moreover, the accompanying poor self-esteem and impulsivity associated with ADHD may be conducive to the development of SUD.
Marijuana continues to be the most commonly abused agent in individuals with ADHD . Abuse can include alcoholism, smoking and other drugs . Furthermore, substance use problems may increase the severity of ADHD symptoms. On the other hand, it is also true that patients with these substance use problems may present with attention, behaviour and self-control symptoms that can mimic ADHD. A referral to a specialist may be required before establishing an ADHD diagnosis when a patient is actively using illicit substances.
# Treatment
The best approach to treatment sequencing in individuals with ADHD and comorbid substance use disorder is concurrent intervention with specific interventions for each disorder . Some researchers suggest that ADHD and SUD-related craving share neurobiological similarities, and that treatment of ADHD may reduce craving for substances and subsequently reduce the risk for relapse to substance use . An aggregate of the literature seems to suggest that early stimulant treatment reduces or delays the onset of SUDs and perhaps cigarette smoking into adolescence; however, the protective effect may be lost in adulthood .
The treatment needs of individuals with ADHD and SUD need to be considered simultaneously; however, if SUD is severe, sequential treatment may be considered with immediate attention paid to the stabilization of the addiction. Depending on the severity and duration of the SUD, individuals may require residential or inpatient treatment. Day treatment can be a more cost-effective option if patients are ready and motivated for change . Depending on the type of substance being used, prescribing psychostimulants in the presence of active substance abuse requires careful monitoring for medical interactions and should take into account the potential risk of misuse and abuse .
Although patients commonly report subjective calming with cannabis and other improved symptoms (increased appetite, better sleep), there is no evidence that cannabis is an effective treatment for ADHD or that it improves attention and productivity. In fact, there is evidence that cannabis can impair cognition and exacerbate motivation issues .
Methylphenidate does not have the same abuse liability as cocaine due to slower dissociation from the site of action, slower uptake into the striatum, and slower binding and dissociation with the dopamine transporter protein relative to cocaine . However, it is important to remember that the route of administration may alter the abuse liability of a substance. The oral administration of psychostimulants has been shown to decrease the likability of a substance while parenteral usage (injected, snorted) has been shown to be associated with euphoria . Individuals with ADHD and either SUD or CD are at highest risk for diversion and misuse and are more likely to both misuse and divert their stimulant medication . Both immediate-release and, to a lesser degree, extended-release preparations of stimulant medications can be diverted or misused, with extended release preparations having less potential for parenteral usage . Nonstimulants such as atomoxetine and guanfacine XR do not have abuse potential.
# Key Points
- In most cases, ADHD and SUD need to be treated concurrently and independently when comorbid.
- Psychostimulants taken orally do not have the same abuse liability as illicit stimulants (e.g. cocaine) due to slower dissociation from the site of action, slower uptake into the striatum, and slower binding and dissociation with the dopamine transporter protein.
- Non-stimulant and long-acting psychostimulants have less abuse potential than immediate-release preparations of psychostimulants.
# ANXIETY DISORDER
As many as a third of children and half of adults with ADHD have comorbid anxiety . Individuals with ADHD often develop symptoms of anxiety due to chronic difficulties related to their ADHD symptoms. For instance, the experience of repeatedly forgetting may lead to realistic worries that one will forget. Compensatory checking may mistakenly be interpreted as evidence of a primary anxiety disorder.
# Symptoms
The table of specific versus commonly seen symptoms may help clinicians distinguish ADHD from anxiety disorders.
# Treatment
If ADHD exists with anxiety, a general rule of thumb is to treat the most impairing condition first . Psychostimulant treatment may increase anxiety especially during treatment initiation, or when increasing dosages of medication . A slower than usual titration schedule may be preferred in these cases. If the anxiety becomes too intense, then the ADHD medication should be reduced or withdrawn, and the anxiety should be treated until the symptoms are stabilized and only then should the ADHD medications be started. Any of the ADHD stimulants can be successfully used when anxiety is comorbid with ADHD . A randomized-controlled pediatric study showed that the non-stimulant atomoxetine can be beneficial in patients with co-occurring ADHD and anxiety disorders . Guanfacine XR was found to be well tolerated in pediatric subjects with anxiety disorder .
# Key Points
- ADHD-associated impairments can induce anxiety symptoms that are different from a specific anxiety disorder.
- Anxiety disorders and ADHD often coexist, and the most impairing condition should be treated first.
Stimulants and non-stimulants can be used for ADHD in the context of anxiety.
- Titration of psychostimulants may need to be initiated at a slower pace and monitored more carefully with patients prone to anxiety.
# MAJOR DEPRESSIVE DISORDER
There is considerable overlap between the clinical presentations of Major Depressive Disorder (MDD) and ADHD. MDD patients (without ADHD) may have depressive episodes presenting with inattention, short-term memory problems, irritability, impulsivity, difficulty sleeping, trouble concentrating, restlessness and fidgetiness . A critical point to explore is the "since when" question, as a reported recent drop in mood is qualitatively different from the lifelong demoralization that may be seen in ADHD .
# Symptoms
Patients with primary ADHD often have to deal with failure and attacks to their self-esteem, frequently at a very young age, and may become demoralized and depressed as a result. In this case, they may present with both disorders. However, patients with ADHD may look like they have a mood disorder when they do not. Lack of motivation may mimic anhedonia and chronic difficulty going to sleep and restless sleep may mimic insomnia secondary to MDD. Patients with ADHD commonly have dysregulated mood (dysphoria, irritability), but it is not typical for ADHD in the absence of a mood disorder to be associated with entrenched, depressed affect or anhedonia.
# Treatment
When a patient with ADHD also suffers from MDD, treatment of the most disabling condition should be undertaken first. It is important to note that if the depressive episode is part of a Bipolar Disorder, the treatment algorithm should follow that of Bipolar Disorder (see section on Bipolar Disorder). In some patients, antidepressants with catecholaminergic activity, such as bupropion, can be useful to treat both MDD and ADHD. Typically, the combination of an antidepressant (e.g SSRIs) with psychostimulants may be necessary to achieve remission. SSRIs are considered safe to use in combination with stimulants. However, drug interactions involving the CYP450/2D6 (e.g., involving fluoxetine, paroxetine), when combined with the amphetamine class or atomoxetine, require caution and monitoring.
If the MDD continues to be impairing or worsens, referral or specialized care in depression is recommended. In severe depression, and in subjects at risk of self-harm, intervention for depression and specialized referral must be carried out as a priority.
# Key Points
- If a patient presents with mild depression and ADHD, then treatment of ADHD may be considered first.
In cases of depression or severe suicidal risk, treatment for depression must be the priority.
- Concurrent treatment of ADHD and major depression is often required, and concomitant use of antidepressants and ADHD medications are commonly used.
# BIPOLAR DISORDER
The diagnosis of Bipolar Disorder (BD) in the context of ADHD is challenging. Many symptoms of BD overlap with ADHD symptoms. The definitive epidemiological relationship between both disorders remains controversial. The following table may guide clinicians in differential diagnosis. However, if Bipolar Disorder is suspected, a referral to specialized care should be considered.
# Symptoms
# Treatment
Treatment of comorbid ADHD and BD should usually start with managing and stabilizing the BD symptoms first .
The management of ADHD with BD is usually more complicated than managing ADHD alone and often requires the use of mood stabilizers and/or atypical antipsychotics . There is a small risk of switching from euthymia or depression to mania when a bipolar patient is prescribed stimulant medication . If this occurs, the stimulant should be adjusted (reduced) or discontinued, and treatment of BD should be prioritized. Once the patient's mood is stabilized, stimulant medication may cautiously be re-instituted (start low and go slow) .
# Key Points
The co-occurrence of BD and ADHD may be difficult to diagnose and manage. A referral to a specialist should be considered.
- Treatments should be aimed at stabilizing the Bipolar Disorder first and then treating ADHD.
- Stimulants have been shown to be safe and effective in patients with BP once their symptoms have been stabilized.
# DISRUPTIVE MOOD DYSREGULATION DISORDER
The diagnostic criteria for Disruptive Mood Dysregulation Disorder (DMDD) includes severe recurrent disproportional temper outbursts (verbal and/or physical) occurring three or more times a week in at least two different settings for 12 months or more . Diagnoses are generally made between the ages of 6 and 10 and cannot first be made before the age of six years or after the age of 18 years . Between temper outbursts, the mood of the patient with DMDD appears to be irritable/dysphoric .
DMDD is currently considered a presentation of childhood depression and this diagnosis was created to address concerns about the potential for the over diagnosis of, and treatment for, bipolar disorder in children . A study of some 3,258 participants aged 3 to 17 showed a prevalence rate for bipolar disorder of 0.8% to 3.3% with the highest rate in preschoolers. DMDD was also found to be very comorbid (62% to 92%). The highest rates of comorbidity occurred with depressive disorder (odds ratio 9.9 to 23.5) and ODD (52.9% to 100%). Rate of co-occurrence with ADHD had odds ratios which ranged from 2.9 to 12.
# Symptoms Table 2.9 Disruptive Mood Dysregulation Disorder (DMDD) Differentiation OVERLAPPING SYMPTOMS WITH ADHD DMDD DISTINCT FEATURES Irritable mood episodes (explosive outbursts)
Inter-episode dysphoria Psychomotor agitation
Minor triggers with extreme rage attacks Chronic course Young age of onset
# Treatment
A combination of medications and psychosocial interventions is needed to treat ADHD + DMDD. Many of the medications effective for treating ADHD have been shown to be effective for DMDD .
# Key Point
- DMDD is a new DSM-5 diagnosis. Research regarding its treatment and relationship to ADHD is underway.
# OBSESSIVE-COMPULSIVE DISORDER
The lifetime prevalence of Obsessive Compulsive Disorder (OCD) in the general population is 1-3% . Reported rates of ADHD-OCD co-occurrence are highly inconsistent in the literature . If OCD and ADHD present together, there is an increased risk of Tic Disorders and Tourette Syndrome also being present . ADHD patients often develop behavioural patterns, like repetitive checking of tasks, as coping strategies to compensate for the symptoms of ADHD. Whether these behaviours are secondary to ADHD or are indicative of OCD needs to be considered.
# Treatment
Treatment of OCD and ADHD should be carried out simultaneously. While there are no controlled studies, a 2014 review reported no evidence showing a worsening of OCD symptoms with the concurrent use of psychostimulant medications.
# Key Points
- Psychostimulants do not usually lead to an exacerbation of OCD symptoms .
- The presence of OCD comorbidity does not change the treatment approach to either disorder.
# TOURETTE SYNDROME AND TIC DISORDERS
ADHD is highly comorbid with tics and Tourette Syndrome (TS) (50-90%) , so patients with tics should be screened for ADHD. In a 2014 study, four clusters of individuals were identified: pure TS (49.8%), TS + ADHD (22.2%), TS + OCD (21.5%) and TS + ADHD + OCD (6.5%) . A commonality to all groups was emotional lability. All groups had significant behavioral problems compared to normal controls. The presence of OCD is considered to be more impairing than the presence of ADHD and is more likely to increase the rate of other co-morbidities , though there are no current long-term studies on treatment outcome for these four groups. When tics co-occur with ADHD, the tics themselves are generally less impairing than ADHD .
# Treatment
Recent research studies suggest that treatment interventions for TS include education about tics and related disorders, clinical monitoring, pharmacological and/or psychological treatments, and school interventions for children and adolescents . Stimulant medication is a safe and effective treatment for ADHD + Tic Disorder but requires careful monitoring of potential tic worsening ; the alpha-2-adrenergic agonists, clonidine and guanfacine XR, have shown promise in the treatment of tics, particularly in combination with ADHD . In patients where stimulants may cause tic exacerbation, atomoxetine may be also considered as an option as it will rarely cause worsening of symptoms .
Recent studies indicate that on a population level stimulants do not seem to raise the risk of tics, and that the exacerbation of tics when stimulants are started is often coincidental, having to do with the waxing and waning nature of tics .
Non-pharmacological treatments for Tic Disorder include Habit Reversal Therapy and Comprehensive Behaviour Intervention for Tics (CBIT) and may be considered as first-line treatments when available.
# Key Points
- Tics and TS are highly comorbid with ADHD.
The presence of tics or TS is not a contraindication to the use of stimulants in ADHD but careful monitoring is required.
- Stimulants do not typically raise the risk of tics but may rarely do so in some individuals.
# EATING DISORDERS
Bulimia nervosa is more prevalent in patients with ADHD versus patients without ADHD . ADHD is more prevalent in anorexia nervosa purging type . Females with ADHD are 3.6 times more likely to meet the diagnosis of eating disorders compared to females without ADHD . The prevalence rate of ADHD in eating disorders is 11.4% . This would suggest that females with ADHD in particular should be screened for an eating disorder, and vice versa. Clinicians should be alert as patients with anorexia that may not have ADHD may seek stimulant medication (feigning symptoms of ADHD) for the purpose of weight loss. Obesity has also been reported among patients with ADHD, especially in the adult population .
One of the proposed mechanisms underlying weight issues in patients with ADHD could be the impulsive behaviours leading to binge eating . Impulsivity is greater in individuals with comorbid eating disorders than in individuals with ADHD alone . It is important to recognize that obesity is a risk factor for sleep apnea , a condition that may mimic or aggravate ADHD symptoms. Therefore, the longitudinal course of symptoms is of crucial importance before making a diagnosis of ADHD in obese patients with sleep apnea. . Binge Eating Disorder is a newly recognized disorder in DSM-5 and its relationship with ADHD is currently unclear.
# Key Points
- The diagnosis and treatment of ADHD in the presence of anorexia nervosa can be complicated.
- Treatment of ADHD could contribute to behavioral control in the context of binge eating.
- A growing body of literature points to ADHD as a risk for obesity.
# AUTISM SPECTRUM DISORDER
Until the publication of the DSM-5, Autism Spectrum Disorder (ASD) was an exclusionary criterion in making the diagnosis of ADHD, and the two diagnoses could not be made concurrently. Because of this, the relationship of ADHD and ASD remains unclear and is currently being researched. Prior research has suggested as many as 30 to 70% of patients with ASD may meet criteria for ADHD . Many individuals with ADHD also show high level of social deficits and ASD type symptoms .
# Symptoms
# Treatment
Treatment of ADHD in patients with ASD is effective and significantly improves functioning. There have been only a small number of Randomized Controlled Trials (RCTs) that have looked at treatment of ADHD symptoms in subjects with comorbid ASD but these have shown promising results .
RCTs with methylphenidate in comorbid samples have shown a response rate of 50% (versus 70-80% response rate for psychostimulants in ADHD without comorbid ASD) . Additionally, patients with ADHD and ASD may be more sensitive to side effects such as irritability, hyper focus, and stereotypies than those without ASD . Clinical experience indicates that medications should be started at low doses and titrated more cautiously than usual in this population .
Both risperidone and aripiprazole (off-label use) have shown efficacy in controlling hyperactivity in this population, but generally have a less favorable side effect profile (metabolic changes, weight gain) than psychostimulants .
One RCT of atomoxetine in individuals with ADHD and ASD showed positive results in improving hyperactivity, impulsivity and inattention and was generally well tolerated; however, overall improvement in clinical and functional improvement was limited . Extended release guanfacine has recently been found to be effective for reducing hyperactivity in children with ASD .
# Key Points
- ADHD patients should be screened for ASD and vice-versa.
- Treatment of ADHD in patients with ASD can be very effective and help overall functioning.
- Treatment of comorbid ADHD and ASD with standard ADHD medication is often effective but may have lower effect sizes and higher risks of side effects.
# SPECIFIC LEARNING DISORDER
# Symptoms
Children/adolescents with ADHD frequently fall below their typically developing peers in their scores on standardized achievement tests. Teachers and parents often express concerns about a child's level of productivity and may label this child/adolescent as "lazy" or "unmotivated". There are several trajectories that can culminate in underachievement. One of the possibilities is that the individual has both ADHD and a Specific Learning Disorder (SLD). Indeed, research indicates that the comorbidity of ADHD and SLD is as high as 45% . It is important to note that the comorbidity range suggested to be between 31% and 45% can vary greatly depending on how SLD is diagnosed .
Even without comorbid SLD, people with ADHD may still have a great deal of difficulty academically in terms of listening and reading comprehension and written expression (as well as with performance deficits such as following instructions, listening in the classroom, or staying on task) . Additionally, individuals with ADHD often have executive function difficulties in the areas of initiation, organization, planning, self-directed activity, and ability to complete multistep tasks .The degree of difficulty individuals experience varies, with some individuals greatly impaired and their academic achievement subsequently falling well below their abilities. Learning disorders and executive function deficits are also developmental. That is, they may become more overt as cognitive demands in school increase . Note: SLD is a clinical diagnosis that is not necessarily synonymous with 'learning disabilities' as identified within the education system: that is, not all children with learning disabilities/difficulties identified by the school system would meet a DSM-5 clinical diagnosis of SLD. By contrast, those with a DSM-5 diagnosis of SLD would be expected to meet the educational definition .
# Diagnostic Assessment
In terms of assessment, practitioners should always: a) Screen for academic skills deficits among students with ADHD and for ADHD symptoms among students with SLD. b) Assess academic functioning across subject areas (e.g., reading, math, writing) when evaluating students with ADHD. c) Carefully evaluate whether interventions for ADHD enhance academic functioning.
Given the relatively high comorbidity rate between ADHD and SLD, students who are evaluated for one of these disorders should always be screened for possible symptoms of the other disorder. The CADDRA Teacher Assessment Forms screens for academic performance problems in addition to ADHD. If the screening suggests the possibility of an SLD, then a letter should be sent to the school, with the parent's approval, to notify them and suggest that the school may wish to consult with support staff and/or the board psychology practitioners for further investigation and school programming.
In adults, as in children, ADHD can occur along with specific problems in reading, math or with written expression .
Assessing whether these difficulties have caused previous problems in school and continue to cause residual difficulty can usually identify these. The childhood history should reveal previous concerns of ADHD. It is additionally important to determine if the patient is inattentive only in the area in which learning deficits present a challenge.
# Management
Learning disabilities require intensive, direct instruction, and modifications/accommodations . Comprehensive intervention services for students with comorbid ADHD and SLD will require empirically supported treatment strategies that address both disorders and that are implemented across school and home settings. Although some school boards across Canada do not currently recognize ADHD as qualifying a student as a 'special needs student', this perspective is changing. Clinicians wishing to advocate for accommodations for their ADHD patient may wish to use the CADDRA Educational Accommodation Template.
# SPECIAL PRESENTATIONS
# Intellectual Giftedness
Research has shown that having a high IQ does not preclude the possibility that one might have ADHD . However, the co-occurrence of ADHD and intellectual giftedness remains controversial and under-investigated. Most previous discussions in the literature have been based largely on anecdotal comments, opinions and small clinical samples. Moreover, DSM-5 does not mention ADHD in the context of intellectual giftedness .
Misdiagnosis of ADHD in the context of intellectual giftedness can occur in two ways: intellectually gifted individuals with high energy and over-excitability in school contexts (particularly in those with little academic stimulation) may be misdiagnosed as having ADHD; alternatively, intellectually gifted individuals who meet full diagnostic criteria for ADHD but who can concentrate for long periods of time, may not be diagnosed with ADHD . Moreover, intellectually gifted individuals with ADHD may also meet criteria for SLD and other comorbidities . Thus, it is important for practitioners to recognize that intellectual giftedness in individuals with ADHD should be documented.
A high IQ may help individuals with ADHD cope with symptoms. Therefore, in some cases, clinically relevant impairment among gifted IQ children may not develop until later in elementary school or even in high school . However, although ADHD may not be diagnosed until later it is not any less impairing. Diagnosis and treatment is critical at any age.
# Symptoms
There are overlapping symptoms shared by individuals with high IQs and individuals with ADHD which may make differential diagnosis challenging. Frequently, bright children are referred to psychologists or pediatricians because they exhibit certain behaviors commonly associated with a diagnosis of ADHD (e.g., restlessness, inattention, impulsivity, high activity level, day-dreaming). A child may be diagnosed with ADHD when in fact the child is gifted and reacting to an inappropriate curriculum . The process of completing a differential diagnosis requires specific questions to clarify what is shared and what is unique to either ADHD or giftedness or whether the child is twice exceptional.
In general, intellectually gifted individuals with ADHD show a similar pattern of cognitive, social, psychiatric, and behavioral characteristics as those with ADHD in the context of average IQ . However, the individual's strengths and difficulties may interact so that one presentation obscures the other .
Practitioners will need to undertake a thorough medical, developmental and educational history, as well as a comprehensive clinical and psychological evaluation, to ascertain an individual's behavior in different contexts and situations. The National Commission on Twice Exceptional Students concludes that the 'identification of twice-exceptional learners requires comprehensive assessment in both the areas of giftedness and disabilities . When possible, the assessment and identification should be conducted by professionals from both disciplines (i.e., ADHD, giftedness) and ideally by those with knowledge and experience with individuals with twice-exceptionality.
# Psychological Trauma
The interaction between psychological trauma and ADHD can be complex. Post-trauma symptoms of hyperarousal, hypervigilance, and dissociation can confound ADHD assessment. Although there is conflicting evidence, a history of psychological trauma may increase the risk of being diagnosed with ADHD .
Various explanatory hypotheses are being explored in the literature to explain the interaction between trauma-related symptoms and ADHD symptoms . First, ADHD may place children at greater risk for exposure to psychological trauma . Conversely, Post Traumatic Stress Disorder (PTSD) symptoms may mimic symptoms of ADHD . Additionally, some initial animal research suggests the individual response to trauma (i.e. externalizing vs. internalizing) may be influenced by genetic predispositions . Under this latter hypothesis, trauma exposure merely exacerbates a prepotent genetic propensity towards having ADHD.
Although increased care should be taken to ensure the effects of historic trauma are considered during the assessment process, a history of trauma exposure does not automatically preclude the diagnosis of ADHD in an individual who otherwise meets DSM-5 criteria for ADHD. Further, in the absence of research evidence to the contrary, clinicians are encouraged to follow the normal ADHD treatment protocols described elsewhere in these guidelines.
Clinicians are advised to: a) screen for history of psychological trauma and where indicated, ensure appropriate trauma-informed support and interventions are mobilized; and b) assess for ADHD based on DSM criteria, and treat in accordance with these guidelines.
# Developmental Coordination Disorder
The prevalence rate of Developmental Coordination Disorder (DCD) in the general population is 1.7% in 7-to 8-year-olds . There is no reported prevalence of the co-occurrence of ADHD + DCD, in large part because DCD is often still unrecognized. Clinicians are urged to do simple assessments of balance as part of the routine workup of ADHD including: observations of gait, throwing and catching a ball, balancing on one foot (first identifying dominance) and fine motor tasks such as writing, use of scissors or drawing .
Balance problems, dyslexia, and poor handwriting in comorbid patients may be related to cerebellar dysfunction and may be associated with DCD . Occupational therapy assessment is warranted to provide recommendations .
Having the person learn keyboarding can often be beneficial. Relevant software programs (e.g. voice recognition) can also help to overcome problems.
# Epilepsy
Studies have suggested a higher incidence of symptoms of ADHD in children with epilepsy (20% to 50% of patients) than in the general population . There is a strong trend towards a higher incidence of epilepsy among children with ADHD than among children without ADHD and epilepsy in children with ADHD appears to be more severe than in those without ADHD . Anti-epileptic medications side effects, which can impair attention and learning, may be confused with ADHD symptoms. Therefore, improving seizure control with anti-epileptic medications that have less potential for behavioural or cognitive side effects should be a priority. In those patients with a formal diagnosis of ADHD in the presence of epilepsy, a pharmacological intervention as part of a biopsychosocial approach to treatment could be considered. No strong evidence exists that psychostimulants increase the severity or frequency of seizures in patients with stable epilepsy .
# Key Points
- When choosing an anti-epileptic medication, one that has less potential for behavioural or cognitive side effects should be preferred in the context of comorbid ADHD.
- Use of psychostimulants could be appropriate in patients with epilepsy provided seizures are well controlled by antiepileptic medications.
- Consideration needs to be given to metabolic drug interaction between ADHD medications and anti-epileptics.
# Brain Injury
Individuals with ADHD of all ages are at risk for physical injuries because they are impulsive, hyperactive and/or inattentive. Children and teenagers with ADHD are three times more likely to experience a moderate or severe brain injury than their peers without ADHD . Any injury to the brain, particularly to the frontal lobes, can produce a syndrome known as Secondary ADHD (S-ADHD) , also referred to as acquired ADHD. Recent literature has shown that the brain correlates of S-ADHD include the lesions in right putamen, thalamus and orbital frontal gyrus .
Children and adolescents with a moderate or severe brain injury have between a 20 to 48% chance of developing S-ADHD . S-ADHD can be treated using the same principles and medication as ADHD, but the research literature supporting this treatment is not as extensive or compelling as it is for ADHD.
Given that concussion and brain injuries are relatively common, and symptoms of persistent impairment could mimic or exacerbate the symptoms of ADHD, it is recommended that all patients being assessed for ADHD should be questioned as to whether they have ever suffered a concussion or brain injury. The literature on the association between ADHD and nontraumatic acquired brain injuries such as fetal alcohol syndrome, stroke or treatment with neuro-toxic medications is less clear, but many of these types of patients who develop ADHD symptoms may respond to standard treatments . Patients with brain injury may be more sensitive to medication and thus starting off at lower doses during medication titration trials is recommended .
# Key Points
- Assessment for ADHD includes inquiring if the person has suffered a concussion or brain injury.
- Patients with S-ADHD due to traumatic brain injury can be treated with same approaches and medication as regular ADHD although lower starting doses may be considered.
# Sleep
Sleep problems, particularly the symptoms of insomnia (i.e., difficulties falling asleep and staying asleep, and early morning awakenings), are very commonly reported by individuals with ADHD. In fact, at least 50% of children and adults with ADHD report significant sleep problems . While there is a high rate of reported sleep problems in individuals with ADHD, there have been inconsistent findings when objective measures of sleep, such as actigraphy and polysomnography, have been used in research . Across studies examining sleep in children with ADHD, the main finding is that individuals with ADHD have more restless sleep than their peers, which can lead to fragmented sleep. There have been no consistent differences found in terms of sleep variables such as sleep duration or sleep architecture (i.e., differences in the amount of REM sleep or NREM sleep) in individuals with ADHD . There is consistent evidence that stimulant medications used to treat ADHD symptoms could make falling asleep more difficult, which can potentially result in shorter night sleep . Shorter and/or fragmented sleep can result in problems with daytime functioning. There is also growing evidence for possible differences in circadian rhythms, which could make individuals with ADHD more vulnerable to delayed-phase sleep disorder and other types of sleep problems .
Research has clearly shown that insufficient sleep in children and adults can result in difficulties with attention, emotional and behavioural regulation, cognitive functioning (e.g., memory), and academic performance . It would be logical to assume that individuals with ADHD may be even more affected by insufficient sleep given their existing vulnerabilities in these areas. However, very little research has been conducted to determine if this is the case, but in the few existing studies, there is some evidence for this assumption. For example, in one study, sleep restriction negatively impacted both typically developing children and children with ADHD, but only the ADHD group moved into the clinical range on an attention task .
While there is a need for more research to better understand the relationship between sleep and ADHD , it is clear that we need to be attentive to sleep problems when conducting assessments and/or developing treatment plans for individuals with ADHD. First, we need to think of differentials in our diagnostic formulations. For example, sleep apnea can mimic or aggravate ADHD symptoms . Also, given that medications used to treat ADHD can impact sleep, it is important for sleep to be monitored when an individual is taking these medications. It is also likely that sleep problems could exacerbate ADHD symptoms, and therefore, sleep problems should be addressed in the treatment plan.
# Treatment
While there is little evidence for pharmacological treatment of sleep problems in individuals with ADHD , there is a growing body of literature that demonstrates that behavioural sleep interventions can be effective for children with ADHD, even when taking stimulant medication . Many individuals with ADHD take melatonin to help with their sleep problems, and the very small body of research has demonstrated that this may be an effective intervention . However, given that there is limited research, and the fact that behavioural interventions have been shown to be effective, it is recommended that the first line of treatment is behavioural interventions for sleep problems in individuals with ADHD. For a comprehensive overview of assessment and management of sleep problems in individuals with ADHD please see or .
# Key Points
- Differential diagnosis needs to be considered in diagnostic formulations (e.g., sleep apnea can mimic ADHD symptoms).
# Incontinence
ADHD and incontinence (nocturnal enuresis, daytime urinary incontinence, and fecal incontinence) are strongly associated with each other. Children with ADHD are two to three times more likely to have enuresis than those without ADHD . In typically developing samples, the rate of enuresis is 4.45% in boys and 2.5% in girls, with prevalence rates decreasing with age. The trend is similar for fecal incontinence and daytime urinary incontinence . Likewise, children with nocturnal enuresis are more likely to have ADHD than those without incontinence .
# Treatment
In most cases, ADHD and issues of incontinence need to be investigated and managed separately. However, recent studies have found that successful treatment of ADHD with stimulant medication can result in resolution of incontinence in some children . Enuresis treatment must begin with the correction of any underlying medical cause. Daytime enuresis may be improved with medication. Nighttime enuresis often requires individualized management. In a double-blind study, atomoxetine has been associated with a significant increase in dry nights in children with nocturnal enuresis .
# CHAPTER 3: SPECIAL CONSIDERATIONS ACROSS THE LIFESPAN
ADHD is a persistent disorder, with functional impairment and treatment needs varying through the lifespan for many. It is important for clinicians to be aware of these differences to better serve individuals with ADHD. Below is a summary of the functional impairments commonly seen across different age groups for individuals with ADHD.
# OVERVIEW Preschool children
Hyperactivity in preschoolers tends to be temporally and situationally stable and is highly heritable . However, clinicians should remember that inattention and hyperactivity in preschoolers can be influenced by a number of factors. These can include intellectual impairment, expressive language issues, and their response to child abuse and neglect as well as conflictual environments .
Epidemiological data indicates that approximately 2-7.9% of children from three to five years of age have ADHD . The American Academy of Pediatrics has suggested that ADHD can be diagnosed in children as early as age four . Nonpharmacological approaches should be the first-line treatment for preschool children .
# School-aged children
ADHD is one of the most common psychiatric disorders diagnosed in children. Prevalence rates range from 3 to 9% of school-age children . A recent meta-analysis determined that the prevalence rate for children and adolescents was 7.25% .
Research indicates that girls may be consistently under-identified and under-diagnosed . Commonly seen differences between boys and girls with ADHD exist during this period :
- Boys may be three times more likely to be identified; girls are consistently under-identified and underdiagnosed.
- Girls with ADHD have lower levels of disruptive symptoms than boys with ADHD.
Childhood is usually the time where ADHD is diagnosed for most individuals. Challenges may occur in all areas of the child's life including at school, at home and during social activities. Interventions are aimed at minimizing the functional impairment that can occur and are part of what is known as a multimodal approach to treating ADHD.
There can be associated problems with ADHD, such as learning difficulties or low self-esteem, which must be managed in addition to the ADHD symptoms. The clinician must utilize the resources available in the team or in the community to provide additional supports for the child and the family. This may be through referral to other professionals such as a psychologist, occupational therapist, social worker, educational aid, resource teacher or behavioural consultant. Examples of useful accommodations for school-aged children can be found at www.caddac.ca under the 'Understanding ADHD In Education' tab.
# Adolescents
Prevalence rates of ADHD in the adolescent population range from 6-12% . Between 50% and 80% of youth diagnosed with ADHD in childhood maintain significant symptoms and meet diagnostic criteria for the disorder in adolescence . Males are three times more likely to be diagnosed with ADHD than females . This discrepancy starts to lessen over time nearing adulthood.
As children grow into adolescents, it is important to work with both the individual and their parents together. This acknowledges the emerging autonomy of the adolescent. Clinicians should not rely exclusively on the parent as an intermediary. It is important to use language that adolescents can understand and avoid the use of excessive medical jargon. Adolescents should at some point be seen alone and during that time the clinician should develop rapport directly with the adolescent and obtain a history of risk factors such as reckless driving, smoking, drug use, sexual activity, family or interpersonal conflicts, illegal activities and issues of bullying. A review of their peer relationships helps to assess their social development and to flag any risky behaviour. Peers tend to be in trouble together.
Adolescents with ADHD are not always the best historians. They frequently do not have full insight into their condition and they may have a self-centered perception and a tendency to deflect blame onto others . Gathering collateral information from key people who know the adolescent can be very helpful. Even though there can be considerable variability in ratings completed by adolescents, serial ratings (see CADDRA ADHD Assessment eToolkit) done by the same individual provide valid measures of treatment outcomes compared to pre-treatment.
Many of the symptoms seen in adolescence are like those seen during childhood but they can affect an adolescent's life in many different areas. Difficulties in school usually continue and often, because of increasing school challenges, become worse. Inattention, lack of focus, impulsivity and forgetfulness can impact assignments and grades. Even athletic and extracurricular activities can be negatively affected. Adolescence is also a developmental period where risk-taking can increase dramatically. Clinicians need to be aware of the very significant negative outcomes that can occur when ADHD during adolescence is untreated (see Accidents/Risks in Adolescence later in this chapter).
Adherence to medication and to psychosocial interventions can be very poor in adolescence. Studies indicate 48-90% of adolescents stop taking their medications , though the use of once-daily dosing improves adherence . Psychoeducation is a very useful tool for augmenting adherence by making the adolescent a partner in treatment . Knowledge of the individual's acceptance level of their diagnosis will help determine if intervention is required to address resistance. Using motivational interviewing techniques can be helpful with adolescents who will not adhere to treatment .
# College/University Students
The prevalence of ADHD among post-secondary students is between 2-12% . Young people with ADHD attending university programs may present with varying histories, such as:
- Students already diagnosed and treated in childhood may want to adapt their ADHD treatment to their studying schedule. This may be a challenge as students may require treatment coverage further into the evening or night.
- Some students may have stopped taking their medication and may want to restart their treatment as they face increasing cognitive demands of the university curriculum.
- Similarly, some individuals who may never have been diagnosed before seek consult for the first time while facing difficulties coping with the high cognitive demands of university classes.
Young adults presenting for the first time for a diagnosis of ADHD should be carefully assessed. Some reports in the literature suggest a subset of students may exaggerate their symptoms to obtain accommodations/benefits or to obtain medications to enhance performance, to sell or to use for recreational purposes . A recent study found that some female college students endorsed having used ADHD specific stimulant outside a doctor's prescription for weight loss .
Life-time prevalence rates of non-prescribed stimulant use in college and university students range from 5%-43% .
Despite a minority of misusers, students with ADHD will benefit from access to treatments and accommodations. The CADDRA Assessment eToolkit includes an educational accommodation letter template and CADDAC provides a detailed chart of appropriate accommodations linked to specific impairments in the post-secondary environment on its website (www.caddac.ca).
# PRACTICE POINT
Information gathered from standardized rating scales help identify ADHD symptoms, comorbid disorders and associated impairments. If necessary, standardized cognitive evaluation focusing on attention and other executive dysfunction may help quantify IQ, identify specific cognitive dysfunction and, importantly, diagnose Specific Learning Disorders.
When assessing ADHD in post-secondary students, an assessment may require multiple visits and comprises a review of (when available):
- Parental/guardian reports of symptoms during childhood.
- School report cards.
- Reports from current collateral informants. Some reports suggest misuse or diversion of stimulants is associated with SUD and CD, so these conditions should be carefully screened for .
Additional school services and accommodations in the university setting can be very useful (e.g., separate testing environments, longer testing times, reduced homework and provision of a note taker).
# Adults
Many adults go undiagnosed and untreated for ADHD. In a study published by Kessler et al., the prevalence of ADHD in adults (20-to 64-year-olds) was 4.4%. Some adults may present to healthcare professionals seeking an assessment for ADHD with no prior diagnosis. This occurs for a variety of reasons, including:
- Parents of children who have recently been assessed for ADHD begin to wonder if they may have the same diagnosis.
- Individuals who have heard or read about ADHD in adulthood and can relate to the symptomatology.
- A subset of adults who have not experienced significant symptoms or struggles prior to adulthood. Lack of challenges prior to adulthood may be due to significant supports, structure and routines earlier in life, and/or an above average IQ . With increasing responsibilities and demands, and with diminished "scaffolding" in adulthood, many of these individuals begin to experience significant symptoms and associated impairment .
In adults with ADHD initially diagnosed during childhood, a significant number discontinue their medication management during adolescence . This may be due to medication side effects, independence needs, healthcare discontinuity, social stigma , or symptom remission . However, due to the re-emergence of symptoms and associated impairment in adulthood, they may seek re-assessment of their ADHD and choose to resume treatment.
Most adults with ADHD (85%) suffer from a comorbid mental health condition . Thus, many adults with undiagnosed ADHD may present to their primary care physician and/or mental health professional seeking treatment for what may appear to be a primary mood, anxiety or other mental health disorder. Others may get medical attention for substance use or high-risk behaviour consequences, trauma or unplanned pregnancies. It is important to know which of these individuals should be screened for possible underlying ADHD. Missing this diagnosis can result in years of trials with antidepressants, mood stabilizers and anxiolytics without adequate symptom response.
Examples of useful workplace accommodation and information for employees and employers can be found on the CADDAC website (www.caddac.ca). CADDRA has a template for requesting occupational accommodations in the eToolkit.
# Older adults
Results from a large epidemiological study have demonstrated that ADHD symptoms can persist in older adulthood, with an estimated prevalence of about 3% .
However, there is relative paucity of data available on the aging ADHD population compared to younger age groups. Small observational studies have characterized the presence, impact, and treatment of ADHD in adults over the age of 50 years .
Undiagnosed ADHD in older patients can lead to lifelong functional and psychosocial impairments. In addition, the presence of comorbidities including depression and cognitive impairment can make diagnosing an older patient's ADHD complex. Furthermore, diagnosis of ADHD in older adults can be tricky because some ADHD symptoms are seen in the normal aging process, or are similar to certain symptoms of minimal cognitive impairment or dementia, thus leading to the incorrect assumption that older adults with ADHD are undergoing a neurodegenerative disease process .
It is therefore crucial to raise clinician awareness about ADHD in older adults. Detailed history-taking (longitudinal cognitive difficulties since childhood) and neuropsychological testing may help the clinician to make a diagnosis of ADHD . In summary, diagnosis in older adults requires identification of past and current symptoms/impairments, and differential diagnosis should include other neuropsychiatric conditions. The first-line medications for ADHD recommended in these guidelines remain the treatment of choice for older adults when their medical condition permits their use. It is important to note that very few clinical drug trials have included participants with ADHD over age 65. However, appropriate treatment with specific medication for ADHD might improve functional outcomes for older adults with ADHD, including those with comorbid dementia . An important consideration in treatment is drug interactions since older adults often take multiple medications. Medication and psychotherapy trials with older adults are needed to determine best treatment approaches.
# IMPACT/FUNCTIONAL DISABILITY ACROSS THE LIFESPAN
ADHD can impact all aspects of an individual's life, both personally and systemically. In a 33-year follow-up study, children with ADHD were found to have a greater risk of poor long-term outcomes as adults in almost every aspect of life compared to their non-ADHD counterparts .
The core difficulties in executive functioning seen in many individuals with ADHD cause varying degrees of functional impairment depending upon the demands made on the individual by their environment and the supports available. Variable factors include family and school or occupational resources, as well as personal responsibilities, coping strategies, cognitive capacity and reflective insight of the individual.
Individual -Regardless of academic, personal, occupational, professional or financial success, many individuals with ADHD struggle with low self-esteem . Some often describe negative beliefs or expectations of their own abilities. Some describe an "imposter complex" whereby they have trouble taking credit for their success. This may be due to lifelong inconsistent performance and a history of negative feedback for perceived failures.
Family -Due to the high heritability of ADHD there is seldom only one individual with ADHD within a family unit. In addition, untreated ADHD may be a significant explanation for a higher rate of separation and divorce in these individuals . Other impacts on the individual or the family can include: parental stress; parental emotional/mental health problems; sibling conflict; disruption to family cohesion; and less time available to spend on family activities . In a survey of 500 individuals with ADHD compared to 501 matched controls it was found that the annual US household income losses due to ADHD were $77 Billion USD per year and up to $15,000 per household per year . The literature supports the fact that ADHD runs in families and where appropriate, other family members should be screened or encouraged to seek out assessment. Parents, siblings and extended family members may have ADHD and therefore have problems with organization, consistency, impulsivity and emotional lability. In addition, having a child with a disability may increase the likelihood of substance abuse, depression and anxiety in parents . Parental psychopathology can have a significant impact on the parents' ability to structure, monitor and generally help their child . Identifying this psychopathology and referring the parents for appropriate treatment will improve the psychiatric state of the parent(s) and their parenting ability, and thus be of great help to the child or adolescent and their family. It is important for the parent(s) to be treated at the same time as the child or adolescent. This "all in the family" approach to intervention is good for the child/adolescent as it shows that the parent can empathize with their experiences. When parents learn skills to control their own lives, it is easier to institute structure in the child's life .
School -Individuals with untreated/undertreated ADHD are more likely to be expelled or be truant, may have lower grades than expected, and also disrupt others' education . This may impact the individual's future social and economic status.
Occupation -Adults suffering from ADHD have higher absenteeism and lower productivity in the job setting . They are also more likely to impulsively quit or change jobs, or be fired . Specific ADHD treatment may diminish this risk (87).
Healthcare and Society -A population-based, historical cohort study followed 4,880 individuals from 1987 to 1995 and compared the nine-year median medical cost per person: ADHD medical costs were US$4,306, whereas non-ADHD medical costs were US$1,944 (p<0.01) . Individuals with ADHD have a 33% increased rate of emergency room visits and may be more vulnerable to motor vehicle accidents with some studies suggesting a rate that is two to four times as high . Compared to children without ADHD, children with ADHD may be more likely to sustain injuries that are severe, and that involve the head or multiple body regions . The increased rate of accidents in individuals with untreated/undertreated ADHD has economic impacts on the healthcare system, as well as economic and social effects within the family (e.g., reduced income, missing education) .
# ACCIDENTS/RISKS
Accidents/risk in childhood ADHD in children has been linked to a two times greater risk for accidental injuries of all types, for more severe injuries, as well as for repeated injuries . Comorbidity of ODD/aggression with ADHD in children is thought to exacerbate these risks .
Children admitted to hospitals due to accidental injuries are three times more likely to have ADHD (approx. 30%) than are children admitted for other reasons. Factors that have been associated with these elevated risks are inattention, impulsivity and risk-taking behaviours, motor incoordination, comorbidity with ODD/CD, anxiety, and depression, and parental characteristics such as reduced parental monitoring of the child's activities. Medication can decrease injuries .
# PRACTICE POINT
Promote safety in the home and outside, especially for the hyperactive/impulsive child. To reduce risks, children with ADHD may need supervision of activities, such as walking to school, that peers may not require.
Points to discuss with parents:
- Provide physical safety (e.g. safety proofing, ample outdoor places that can be safely used and supervised, opportunities for physical movement).
- Assure adequate supervision, and reinforce behaviours where the child shows risk management (e.g. wearing a helmet/protective gear, asking permission, wanting advice, following rules, reading instructions, showing good judgment).
- Children with ADHD benefit from physical activity and may find opportunities for success in play or sport.
- Balance must be struck between providing safe environments and overprotection.
- It is also important to create a calm, structured, positive approach to child rearing to not only optimize appropriate developmental progression, but also allow for a more acceptable response to limit setting.
- Above all, it is crucial that parents retain an enjoyable relationship with their child that encourages their self-esteem. Doing things that the child excels at or enjoys is very important. Parenting should include not only structure and guidance, but fun. The school must create a similar environment.
# Accidents/risk in adolescence
Adolescence is a developmental period when a significant percentage of individuals start to engage in activities that have associated risk . Adolescents who have ADHD are at higher risk than the general population for experiencing the negative outcomes of risky behaviours . Impulsivity, in particular, can negatively impact an adolescent's executive functioning. There is much evidence that untreated ADHD can lead to higher rates of accidents, school failure and dropout, driving accidents and family conflict/fighting .
Sexual activity starts for some during adolescence. Both male and female adolescents who have ADHD are at increased risk for early sexual activity, sexual transmitted diseases and multiple sexual partners . Females with ADHD are at risk of higher rates of teenage pregnancy compared to adolescents without ADHD . Information should be provided about risky sexual activities and use of birth control methods should be encouraged where appropriate.
Adolescence is frequently the time where experimentation with alcohol and drugs begins. Adolescents with ADHD have higher risk than the general population to start using earlier and to develop more severe difficulties with substances . Comorbidity of ADHD and SUD commonly starts in adolescence .
Abstinence from illicit drug use is ideal, though a harm reduction approach may be a useful option. Another group of substances that should be asked about are beverages containing excessive caffeine, including for example "energy drinks".
# Accidents/risk in adulthood
Many of the risky behaviours that are problematic in childhood and adolescence continue to impact individuals with ADHD into adulthood. In a recent study, the adjusted mortality rate ratio (MRR) was greater for individuals diagnosed with ADHD, and increased with delay in diagnosis. The adjusted MRR was 1.86 when diagnosis occurred before six years of age and increased to 4.25 when diagnosis was delayed to 18 years or older . The cause-specific mortality for suicide was significantly higher among ADHD cases (SMR = 4.83). This study concluded that childhood ADHD is a chronic health problem, with significant risk for mortality, persistence of ADHD, and long-term morbidity in adulthood.
Richards et al. assessed negative driving outcomes in individuals with ADHD, reporting more driving anger and aggression expressed using vehicles, as well as less adaptive and constructive anger expression compared to peers without ADHD. College student drivers with ADHD rated themselves as more angry, risky, and unsafe behind the wheel, and reported more struggles with concentration and vehicular control .
# DRIVING
ADHD symptoms can negatively impact the ability to drive safely for both adolescents and adults . Not all patients with ADHD who drive have significant driving problems. However, the epidemiological data suggest that ADHD drivers as a whole have an increased risk . It is important that all adolescents with ADHD have driver training and that their driving risks be minimized (e.g. curfews, staying off major highways, absolutely no drugs or alcohol while driving). Driving assessments can be done and an example of such is the Jerome Driving Questionnaire (JDQ), which is provided in the CADDRA Assessment eToolkit).
Clinical studies indicate that young drivers with untreated or sub-optimally treated ADHD have between two to four times as many motor vehicle collisions and moving violations than a comparable non-ADHD population . These driving problems are seen independent of comorbidity. The problem profile commonly includes speeding, distractibility and driving anger or road rage. The presence of ADHD and comorbid substance use disorders magnifies driving risk .
Neurodevelopmental immaturities in executive functioning (resulting in problems with attention, impulse control and emotional regulation), combined with a lack of driving experience, can lead to problem driving styles in young people in general . On-road data demonstrates the benefits of long-term use of stimulant medication in reducing motor vehicle collisions in older adults .
Simulator and on-road observation studies suggest that methylphenidate, dexamphetamine and atomoxetine improve driving behaviours in ADHD populations . At the time of writing (March 2017) there are no current studies evaluating other agents for treating ADHD. Clinicians should monitor individual response to medications, both for improvement as well as worsening of driving abilities. For example, agents like guanfacine or clonidine may be sedative initially and worsen driving in the initial titration period. In addition, some medications may not last until late evening or adherence with the use of an "as needed" short-acting stimulant medication is particularly poor in the evening, which is the time of maximum driving risk for young drivers.
Restrictions on cell phone and manual transmission use, as well as on nighttime and weekend driving, may all improve driving performance. Psychosocial and legislative interventions may prove to be more effective preventative public health measures in the long run .
# EVALUATION OF DRIVING RISK AND DOCUMENTATION
Discussion with young drivers and their families should include information on functional impairment and driving risks . Problems with speeding, following too close, road rage, inattention and distractibility when driving should be reviewed. When developing a therapeutic alliance with a family, it may be useful to encourage contracts between young drivers and their families where adherence with medications and other issues such as good school performance are exchanged for access to a motor vehicle. Documentation of discussions regarding driving safety, along with use of a driving style and behavior assessment, would demonstrate that the clinician is exercising due diligence for their ADHD patients around driving safety issues. The Canadian Medical Association (CMA) Guidelines on Fitness to Operate a Motor vehicle continue to remind physicians that if ADHD drivers have a demonstrated problem with driving and are non-compliant with treatment recommendations, doctors have a duty to report their concerns to the Provincial Ministries of Transportation . Reporting in Alberta, Quebec and Nova Scotia is discretionary . The latest CMA guidelines continue to recommend the same reporting requirements and have an updated reference list on ADHD and driving.
# CHAPTER 4: PSYCHOSOCIAL TREATMENT OF ADHD
Until recently, symptom control was the main priority in the assessment and treatment of ADHD . In recent years, the clinical focus has shifted towards functional impairments and outcomes, with improvement of overall life quality as the main goal . ADHD can impact many aspects of an individual's daily life such as social and emotional functioning, academic/work-related success, relationships, marriage, family life and even physical health . This is true for individuals with ADHD across the lifespan. Generally considered to be a chronic lifetime disorder, ADHD requires a comprehensive, collaborative and multimodal treatment approach tailored to meet the unique needs of the person with ADHD.
Research studies and clinical experience show that a multimodal approach (incorporating psychosocial interventions together with medication) improves not just core ADHD symptoms but the overall quality of life by improving the resultant functioning impairments . Medications are an important aspect of treatment and assist the facilitation of changes in these areas by improving focus, self-regulation and decreasing impulsivity/hyperactivity and thus allowing the individual to use psychosocial strategies more effectively .
Psychosocial treatment is the therapeutic approach preferred by many individuals over medications and is recommended as a first line for preschoolers by the American Academy of Pediatrics and the Choosing Wisely Canada campaign (choosingwiselycanada.org). Psychosocial interventions play a particularly crucial role during key life transitions, for instance in the transition from adolescence to adulthood . It is important to incorporate a patient-/familycentered approach to ADHD treatment, by considering individual/family treatment preferences Although front-line clinicians may see time constraints and perceived lack of expertise as barriers to implementation of psychosocial treatments , these individuals are in fact ideally placed to assess and provide treatment for ADHD beyond traditional pharmacological approaches. Primary care practitioners are in the unique position of being able to diagnose, treat and follow individuals with ADHD across the lifespan . They can provide or support some of these interventions in a timely manner either on their own (with community resource supports) or in co-ordination with other medical specialists, health-care providers and professionals from the educational system.
A solid therapeutic alliance is best achieved by spending time listening to a patient's concerns and understanding their perspective and goals. CADDRA wishes to highlight this principal as being the core foundation for all effective treatment approaches.
# PSYCHOEDUCATION
The overall purpose of psychoeducation is to educate and empower patients and their families by providing information on ADHD (e.g., impact on daily functioning, treatment options, strategies for optimizing functioning).
# PRACTICE POINT
CADDRA Guide to ADHD Psychoeducation can be downloaded from the CADDRA website from the Resources section. This guide provides a quick overview of the components of psychoeducation along with a summary of strategies and interventions that can be recommended to individuals with ADHD and their families.
# Key Elements of Psychoeducation Discover
Find out what the patient and family already know, or think they know, about ADHD . This may help guide your approach to diagnosis and treatment.
# Demystify
Take the time to discuss some of the societal myths commonly associated with ADHD. For example, the following myths are adapted from the "Take Ten Series" from the CanLearn Society, Calgary.
# MYTHS FACTS
ADHD is not a real condition ADHD is a neurobiological condition that is associated with inattention, hyperactivity and/or impulsivity, along with several related difficulties, inappropriate for an individual's age.
# ADHD is over-diagnosed
A US 2014 national survey found that healthcare practitioners are carefully diagnosing children. The vast majority (9 out of 10) of the 2,976 children diagnosed with ADHD had been diagnosed by practitioners using best practice guidelines . Possible explanations for increased diagnosis of ADHD include improved healthcare practitioner and parental awareness; more screening by pediatricians and other primary care givers; decreased stigma about ADHD; availability of better treatment options, and more awareness of suspected environmental causes such as prenatal exposure to toxins or high blood lead levels .
# All children with ADHD have disruptive behavioural problems
Approximately 50 percent of children with ADHD demonstrate significant problems with disruptive behaviour .
# ADHD results from ineffective teaching and/or poor parenting
ADHD is primarily biological and genetic in its origins. Environmental factors such as teaching and parenting quality, however, can minimize or intensify the difficulties experienced by an individual with ADHD .
# Children with ADHD can never pay attention or complete their work
Inconsistency is a pervasive characteristic of ADHD. Sometimes, and under some circumstances, individuals with ADHD can focus and concentrate, while at other times they experience extreme difficulty. They are, for example, often able to hyper focus on stimulating activities, like video games, or creative activities such as Lego or drawing.
# CONTINUED…
# All children with ADHD are hyperactive
A person with ADHD may not necessarily demonstrate hyperactivity. In fact, some individuals with ADHD may appear to lack energy and seem quiet and reserved.
# ADHD only occurs in boys
Boys are four to nine times more likely to be diagnosed ; however, the disorder occurs in both boys and girls. Girls are more prone to inattentive type ADHD , which is marked by disorganized and unfocused behaviour rather than the disruptive, impulsive conduct typically seen in boys. Girls with ADHD tend to have higher rates of overall distress, anxiety and depression compared to boys with ADHD .
# Food allergies, refined sugar, food additives and poor diet cause ADHD
The actual correlation between ADHD and diet has not been proven . Good nutrition and general health are always important. An unhealthy lifestyle, including poor diet, can influence attention and functioning .
# Medication alone can manage ADHD
While there is no cure for ADHD, medication can have positive effects on symptoms of inattention, impulsivity and hyperactivity. A "multimodal" or comprehensive approach is most beneficial and includes appropriate diagnosis, personal and family understanding of the disorder, behavioural interventions and educational supports.
# Individuals with ADHD are lazy or lack willpower
Everyone finds it easier to focus on a topic or activity that catches their attention. Many people with ADHD have some domains of activity (such as sports, music, video games, art, mechanical activities and areas of work) in which they can focus very well. As a result, their inability to focus in other areas is often misunderstood.
There is a test that can diagnose for ADHD ADHD is a clinical diagnosis that should be arrived at through a comprehensive evaluation of the history and presentation. This is true of many other medical conditions (e.g. migraine).
# Everyone has ADHD because everybody is inattentive sometimes, especially these days.
The core symptoms of ADHD can occur in everyone occasionally (e.g. forgetting items). People with ADHD, however, experience significantly greater numbers of these symptoms (meeting a threshold of at least 6/9 symptoms for children, 5/9 for adults (17+)), with greater frequency and more significant difficulties and impairment (e.g., job loss, academic underachievement).
# Instill Hope
Families will respond positively when told evidence-based treatments and interventions do exist. This in turn will promote the therapeutic alliance and a positive outcome.
# Educate
The first step is to educate individuals and families about the nature of ADHD and its symptoms. If relevant, explain the concept of emotional dysregulation. This refers to the fact that many individuals with ADHD can experience difficulty selfmodulating and regulating emotions, often referred to as "a short fuse". They can impulsively over-react verbally or physically, causing significant conflicts.
Explain the rationale behind your treatment approach (e.g. the use of pharmacological or psychosocial interventions and the risks and benefits of each). For example, ADHD medications can improve focus and decrease impulsivity/hyperactivity, allowing individuals to make better use of psychosocial strategies . Provide handouts and information on relevant websites, community resources, parent training and support/social skills groups, etc.
# Empathize | No material available at www.caddra.ca (the "Materials") may be copied, reproduced, republished, uploaded, posted, transmitted, or distributed in any way, except that you may: (a) Download one copy of the Materials on any single computer for your personal or medical practice use only, provided you keep intact all copyright and other proprietary notices. Where stipulated, specific "tools and patient handouts", developed for physicians and other medical professionals to use in their practice, may be reproduced by medical professionals or on the advice of medical professionals; (b) Give a presentation using the Materials, so long as: (i) the purpose of the presentation or distribution is for public education; (ii) you keep intact all copyright and other proprietary notices in the Materials; and (iii) the presentation or distribution is completely noncommercial and you or your organization receive no monetary compensation. If monetary compensation is involved, you must provide notice to CADDRA at least ten (10) business days before the presentation and request permission. Modification of the Materials or use of the Materials for any other purpose, without the prior written consent of CADDRA, is a violation of CADDRA's copyright and other proprietary rights.# Contents of CADDRA ADHD ASSESSMENT eTOOLKIT (USB key)
Step
# PREFACE
# CANADIAN ADHD PRACTICE GUIDELINES INTRODUCTION
The purpose of the Canadian ADHD Practice Guidelines is to improve the quality of health care and outcomes for all individuals with Attention Deficit Hyperactivity Disorder (ADHD) in Canada.
The Guidelines:
• Cover the lifespan of the disorder.
• Are based on published evidence.
• Involve expert consensus when evidence is lacking.
• Offer practical clinical advice.
• Provide assessment, treatment and follow-up questionnaires.
• Include templates for requesting accommodations.
• Recommend optimizing care on an individual basis.
• Assist healthcare providers to empower their patients to make informed choices in a collaborative process of care.
• Contain information specific to the Canadian healthcare system.
The Guidelines are targeted at health care professionals but may also be of use to additional stakeholders (policy makers, funding bodies, educators) and individuals with ADHD and their families. The tools included in the Guidelines were selected based on their validity, reliability and accessibility. These Guidelines were developed to provide information and user-friendly tools to support Canadian health care professionals in diagnosing and treating ADHD across the lifespan. These Guidelines are not intended to replicate or replace the many excellent textbooks on ADHD.
# The evolution of the 4th Edition
The Canadian ADHD Practice Guidelines are produced and funded by CADDRA -Canadian ADHD Resource Alliance, a national, independent, not-for-profit association whose members are drawn from family practice, pediatrics, psychiatry (child, adolescent and adult), psychology and other health professions.
# The Guidelines have been in constant review for over ten years
The fourth edition of the Canadian ADHD Practice Guidelines evolved from earlier editions published in 2006, 2008, and 2011. A multidisciplinary team that included ADHD specialists, pediatricians, psychiatrists, psychologists, family physicians, pharmacists, nurses, educators and community stakeholders from across Canada and from the US contributed to its writing and review.
# Disclosures and Funding
Conflicts of interest were recorded for all individuals that were a part of the process and are included in the Guidelines. As has been the case since the 1 st edition of the Canadian ADHD Guidelines, all authors have donated their time and shared their expertise without receiving any financial contribution. The final draft of the 4th edition was independently reviewed by a range of relevant stakeholders (e.g., adult psychiatrist, child and adolescent psychiatrist, psychologist, patient advocate/nurse, family physician). The Guidelines development process was fully funded by CADDRA and occurred without external financial grants.
# Endorsements
These Guidelines are endorsed by the Centre for ADHD Awareness, Canada (CADDAC).
# 2
# CADDRA GUIDELINES -CORE PRINCIPLES
These Guiding Principles were developed and approved by the CADDRA Board.
# Principles for Assessment and Diagnosis
1. The clinician has to be fully licensed and adequately trained in order to ensure Diagnostic and Statistical Manual, Fifth Edition (DSM-5) diagnostic criteria for ADHD are fully met [1]. 2. The assessment needs to reflect an understanding of multi-systemic issues that may confound or complicate the ADHD diagnosis (e.g., the educational/vocational, psychosocial, psychiatric and medical interfaces). 3. Symptoms and functional impairment need to be assessed. Using valid, reliable and sensitive instruments helps to evaluate frequency, severity, and outcome. 4. Regular documentation of symptoms and functional impairment, if possible at each visit, helps to track progress and monitor outcome. 5. Establishing collaborative treatment goals with the patient (and their family when appropriate) ensures that outcomes are patient-centered. 6. The results of the assessment need to be communicated to the patient and their family with clarity and compassion.
# Acronyms
# ADHD
# CHAPTER 1: DIAGNOSIS OF ADHD
Attention Deficit Hyperactivity Disorder (ADHD) is typically a chronic, often lifelong, condition. The impact and presentation of ADHD can change over time [2] and often requires lifelong monitoring and treatment [3]. Clinicians who follow individual patients and their families should be knowledgeable about how ADHD presents and causes functional impairment across the lifespan.
Although the term Attention Deficit Disorder was first introduced in 1980 in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) [4], symptoms of inattention, hyperactivity and impulsivity have been described in children over the last 200 years [5]. A historical perspective reveals that Melchior Adam Weikard is credited with first describing a disorder similar to ADHD in 1775 [6], followed by Sir Alexander Crichton's description in 1798 [5]; Heinrich Hoffman M.D. created the character of "Fidgety Phil", used as a popular allegory for children with ADHD, in 1844 [5]; and Dr. George Frederic Still described a condition remarkably similar to ADHD in the English medical journal the Lancet in 1902 [5]. In 1937, psychiatrist Charles Bradley administered Benzedrine sulfate, an amphetamine, to "problem" children at a home in Providence, Rhode Island to alleviate headaches but noticed an unexpected behavioural effect: improved school performance, social interactions, and emotional responses [7].
The Diagnostic and Statistical Manual of Mental Disorders, Second edition (DSM-II) described the disorder "hyperkinetic reaction of childhood (or adolescence)" in 1968 [8].
ADHD is now defined as a neurodevelopmental disorder. Characterization of ADHD has evolved through several revisions over the years, the most recent one being in the Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5) in 2013 [1]. ADHD is usually seen in early childhood, but not necessarily diagnosed at that time. It is thought to be a lifelong disorder. More than 50% of individuals diagnosed in childhood and adolescence continue to have significant and impairing symptoms in adult life [9,10].
The general prevalence of ADHD is estimated at between 5-9% for children and adolescents and 3-5% for adults [11,12]. The disorder is not confined to the USA or Canada but is prevalent worldwide [13].
There is a common public misconception, reinforced by much of the media, that ADHD is over-diagnosed. However, a recent meta-analysis confirmed stable rates of the prevalence of ADHD over the past 30 years [14].
The etiology of ADHD remains under investigation. ADHD is highly heritable [15]. Parents with ADHD have a better than 50% chance of having a child with ADHD, and about 25% of children with ADHD have parents who meet the formal diagnostic criteria for ADHD [16]. Twin studies have placed the heritability of ADHD at 76% [17] with the risk of ADHD in first-degree relatives of diagnosed individuals being somewhere between 30 to 40% [18]. This includes children of adults with ADHD, their siblings or their parents.
The genetics of ADHD are complex [19]. Many different genes have been identified as linked to ADHD (DRD4, DAT) but, as ADHD is a heterogeneous disorder, it is most likely related to complex genetic etiologies [17].
The ongoing genome wide studies are likely to shed light on this issue in the future [20,21]. Other etiological factors have been linked to ADHD, such as tobacco/alcohol use during pregnancy. Low birth weight and psychosocial adversity should be considered as possible contributors to ADHD symptomatology in an individual [22]. Neuronal networks associated with ADHD have been reviewed in neuroimaging studies and the dysfunction of fronto-striatal pathways (dorsolateral and anterior cingulate) is often targeted as a possible underlying neural mechanism [23]. A landmark study on ADHD, the Multimodal Treatment of Attention Deficit Hyperactivity Disorder (MTA) study [24], found that 70% of school-aged children with ADHD have at least one other psychiatric disorder such as anxiety, Oppositional Defiant Disorder, Obsessive Compulsive Disorder, Tic Disorder or depression.
# Making a Diagnosis in Primary Care
Patients with ADHD can be managed in a primary care setting [25]. According to DSM-5, the diagnostic tasks are to ensure:
• Current symptoms present sufficiently (see Table 1.1).
• Age of onset of these symptoms is by age 12.
• Impairment in two or more roles due to these symptoms has been present for the last six months or more.
• A lack of alternate explanation for the symptoms or impairment, including a broad range of alternate medical (including mental health) and circumstantial conditions.
However, the following situations may require further consultation:
• Medical (physical) or psychiatric comorbidities are present and contributing significant morbidity or diagnostic uncertainty (refer to chapter 2).
• Failure to respond to recommended treatment algorithms (refer to chapter 5).
• Patient/family reluctance to accept diagnosis and/or treatment.
Note: Overall psychiatric health should always be considered and a risk assessment done at the onset.
There are several tools available to assist in the diagnosis of mental health problems. Examples of these general screeners are the Weiss Symptom Record (WSR) [26], the Patient Health Questionnaire (PHQ-9) [27] and the Generalized Anxiety Disorder Item-7 (GAD-7) [28] as well as the Screen for Child Anxiety Related Disorders (SCARED) [29] and the Kutcher Adolescent Depression Scale (KADS) [30]. As always, therapeutic decisions should be based on a thorough evaluation of the patient with the most prominent or critical issues addressed first. This chapter provides information on how to systematically assess patients with ADHDconsistent features. Often fails to give close attention to details or makes careless mistakes in school work
Often fidgets with hands or feet or squirms in seat 2.
Often has difficulty sustaining attention in tasks or play activities Often leaves seat in classroom when remaining seated is expected 3.
Often does not seem to listen when spoken to directly Often runs about or climbs excessively in situations where it is inappropriate 4.
Often does not follow through on instructions and fails to finish school work
Often has difficulty playing or engaging in leisure activities quietly
# 5.
Often has difficulty organizing tasks and activities Often is "on the go" or often acts as if "driven by a motor" 6.
Often avoids, dislikes, or reluctantly engages in tasks requiring sustained mental effort Often talks excessively 7.
Often loses things necessary for activities (e.g. school assignments, pencils, or books)
Often blurts out answers to questions before the questions have been completed 8.
Often is distracted by extraneous stimuli Often has difficulty awaiting turn 9.
Often is forgetful in daily activities Often interrupts or intrudes on others (e.g. butts into conversations/games)
Reproduced with permission from American Psychiatric Association Publishing Other Specified ADHD / Unspecified ADHD: Symptoms causing impairment but full criteria for ADHD are not met. *Total number of symptoms are less in adults (17+): 5 of 9 instead of 6 of 9
Chapter One of the Canadian ADHD Practice Guidelines and the CADDRA ADHD Assessment Toolkit have been designed to give frontline workers a convenient yet comprehensive step-by-step approach to the assessment and diagnosis of ADHD throughout the lifespan. The forms, assessment tools, and handouts referred to in the diagnostic algorithms are free to download from www.caddra.ca and to print and duplicate for your personal or practice use.
Rating scales and questionnaires can be used as an efficient way to obtain information from the patient and collateral sources, but are not sufficient for a diagnosis as other conditions may screen positive on ADHD rating scales (e.g. overlapping symptoms of depression or anxiety, or the presence of medical conditions like sleep apnea or anemia). A careful and thorough assessment reduces the risk of a false diagnosis of ADHD [31]. These instruments, however, are effective screening tools and can be employed to document change over time and track treatment effects.
# Update on strategies for the diagnosis of ADHD
Establishing a diagnosis is an essential step in identifying pathology and developing a personalized treatment plan. Thus, clinicians are interested in keeping abreast of advances in diagnostic strategies. To address this need, a literature review spanning the past 10 years (2006-2016) on the diagnosis of ADHD was conducted. Only reviews, meta-analyses and randomized controlled trials were selected.
At this time, there is no evidence that any strategies beyond those described in the CADDRA Guidelines and recommended in the toolkit (namely the clinical interview in combination with rating scales), offer substantial benefit in the diagnosis of ADHD. The clinical interview and evaluation continues to be the mainstay of ADHD diagnosis.
Although rating scales alone are not sufficient to diagnose ADHD because of issues such as the variability of interpretation of questions by respondent, their use to enrich the process of evaluation is widely recommended [32].
Direct behavioural observation (i.e. observing the child in the classroom) is recommended by most sources [32,33], and has been complemented by standardized coding systems. However, it is associated with a high cost and may be possible where health professionals are also school personnel [32], but is generally limited to research settings.
While, neuropsychological and psychoeducational evaluations are frequently recommended, these are most useful in situations of diagnostic uncertainty [34] and should be interpreted in the context of a broader clinical evaluation given issues of sensitivity and specificity. Certain neuropsychological tests (Wide Range Assessment of Memory and Learning, California Verbal Learning Test, Wisconsin Card Sorting Test) have been recommended as particularly appropriate measures of ADHD [32]. However, neuropsychological tests of executive function have low ecological validity. Not all individuals with ADHD, although functionally impaired by their ADHD, show impairment levels in standardized test data alone [35][36][37].
Furthermore, testing results should not be required to demonstrate below "average" functioning for a disability to be recognized and for the student to qualify for services and accommodations. Neuropsychological or psychoeducational testing should not be used to determine the severity of ADHD or quantify the impact of ADHD on cognitive or academic functioning as they do not accurately measure the nature of "real world" cognitive or academic impairments that characterize ADHD.
Computerized cognitive assessments (e.g. Conners' Continuous Performance Test, Test of Variables of Attention, Gordon Diagnostic System) have also been developed that specifically assess attention and response inhibition [32] but are associated with a degree of overlap between individuals with ADHD and controls [38].
Neuroimaging has identified structural alterations and dysfunctions in ADHD using population and research studies, but has no direct clinical application at this time [39].
Electroencephalography has been the focus of many publications [40]. Children with ADHD may have an increase in absolute and relative theta and decreases in absolute and relative alpha and beta [40,41]. This continues to distinguish adolescents and adults with ADHD [40,41]. Having said this, EEG testing Is not a validated diagnostic tool for ADHD and CADDRA does not endorse its use for this purpose.
Red Flags for ADHD [3,[42][43][44] •
Organizational skill problems (time management difficulties, missed appointments, frequent late and unfinished projects).
• Erratic work/academic performance.
• Anger control problems.
• Family/marital problems.
• Difficulty in maintaining organized household routines, sleeping patterns and other self-regulating activities.
• Difficulty managing finances.
• Addictions such as substance use, compulsive shopping, sexual addiction, overeating, compulsive exercise, video gaming or gambling.
• Frequent accidents either through recklessness or inattention.
• Problems with driving (speeding tickets, serious accidents, license revoked).
• Having a direct relative who has ADHD.
• Having to reduce course load, or having difficulty completing assignments in school.
• Low self-esteem or chronic under-achievement.
# STEP 1: INITIAL INFORMATION GATHERING
# Reasons for Assessment or Referral
Individuals may come to you, or are referred, for a wide variety of reasons:
• Someone close to the individual (e.g., a relative, teacher, employer, colleague or friend) has learned about ADHD and recognizes these traits in the person.
•
The individual (typically an adolescent or an adult) has learned about ADHD and recognizes the relevant symptoms.
• A relative has already been diagnosed with ADHD and this diagnosis triggers an awareness of ADHD within the individual (e.g., a child is diagnosed and one or both parents think they may also have ADHD).
• There are functional difficulties that the individual presents with (such as behavioural or attention problems, academic issues, difficulty with paperwork, time management, driving, smoking or marital problems) and the clinician postulates ADHD as a possible explanation.
• Symptoms are attributed to another psychiatric diagnosis (mania, depression, anxiety, substance use disorder) but in fact could be related to ADHD. Some clinicians may be wary of an individual self-referring with a possible ADHD diagnosis. They may suspect that the person is looking for drugs, accommodations or an explanation/excuse for other problems. Clinical experience indicates this is an infrequent occurrence.
# Practice Point
• Review the individual's strengths and NOT just their areas of relative weakness.
• Establish a rapport with the individual and their family that makes future contacts easier and can aid intervention planning.
• Ensure that each interview ends with a statement about the coping skills that the individual and/or family have successfully used to work with difficult circumstances.
• Outline and affirm the importance and value of the individual and their family's efforts to succeed.
• Remember that self-referral neither guarantees nor eliminates a diagnosis of ADHD.
# Presenting Complaint and Documentation Initiation
Review with the individual and their family any concerns, the reason(s) for referral and the individual's/family's hopes for the assessment. Psychometric evaluations included in the CADDRA toolkit are designed to track the person's progress and assist with efficient and structured clinician charting. The diagnosis of ADHD cannot be done through the CADDRA toolkit alone but in conjunction with a diagnostic interview and attention to medical history, psychosocial elements and clinical presentation.
# SUGGESTED ACTION -AT THE END OF STEP 1
• Give the individual the relevant inventories necessary for the next visit (see appropriate 'Diagnosis and Treatment Flowchart' for the age group).
• Ask the individual and/or family to provide any relevant prior documentation (e.g., school report cards, previous assessments, etc.). Good school performance does not necessarily rule out ADHD. Individuals with ADHD may not accurately recall symptoms [45]. Therefore, collateral information may assist in diagnosis.
The CADDRA Toolkit provides several forms (all available in the public domain), see flowcharts. An ADHD assessment should always include a general mental health screening (to consider comorbidities and differential diagnoses). In addition to a diagnostic interview, the CADDRA Toolkit contains optional assessment tools such as the CADDRA ADHD Assessment Form and the Weiss Symptom Record II (WSR II). The step-by-step flowcharts in this chapter apply after general mental health screening has been completed and ADHD is suspected. All the tools documented in this flowchart are free to download and use. Other assessment tools can be used in place of those proposed below.
# Practice Point
Communicating with the child or adolescent's school is crucial to collect information and implement appropriate measures. If parent(s) object to involving the school, the physician should let the parent(s) know that that an understanding of any ADHD-related difficulties in the classroom is needed to make a full assessment. In adults, collateral information provided by observer reports, such as from family members or partners, are important assessment tools.
Inconsistent reports (i.e. disagreement between parents, teachers, and partners) may require further exploration to better understand any discrepancy and may require referral.
# STEP 2: MEDICAL REVIEW
Objectives:
• Collect the documentation from past records when available.
• Score and review completed forms from Step 1.
• Complete the physical examination (or document that a physical examination was completed by a colleague) and review medical history to ensure that there are no other medical causes that could mimic or modulate ADHD symptoms.
• Discuss the possible complications / outcomes of having ADHD (e.g. accidents, poor sleep, nutrition, and substance abuse).
# •
Ensure that there are no medical contraindications to the use of medications for treating ADHD (see chapter 5).
# SUGGESTED ACTION -AT THE END OF STEP 2
• Order any relevant clinical tests based on the physical findings to rule out medical causes and risk factors.
# STEP 3: ADHD-SPECIFIC INTERVIEW
# Objectives:
A complete childhood developmental history is an important part of a comprehensive assessment. Because accurate recollection of childhood symptoms and developmental history is difficult to obtain in adults, it is suggested to obtain, when possible, the point of view of a parent or a close family member who knows the individual's early history. The CADDRA ADHD Assessment Form offers an optional ADHD interview format and is available in the CADDRA eToolkit. The Diva 2.0 Diagnostic Interview for ADHD in Adults is another tool that can be downloaded at www.divacenter.eu in various languages [46].
In order to do a complete review, explore:
• Perinatal history (birth weight, complications, maternal alcohol and tobacco usage during pregnancy).
• Developmental milestones.
• Medical history (i.e. illnesses, concussions, seizures etc.)
• Impact of symptoms on learning, socialization and independent functioning.
# •
Temperament.
• Symptoms of ADHD prior to the age of 12.
• Presence of any life events that were of emotional concern in childhood (e.g., abuse, bullying, divorce, loss, deaths, attachment issues).
• Content review of the completed forms with the individual and their family.
# Practice Point
• Review the person's strengths uncovered in the previous steps.
• Do not rely on ADHD symptoms observed during the interview as obvious symptoms of motor hyperactivity, impulsivity and inattention may not present in a one-to-one or novel situation. If observed during the clinical interview, this often suggests that the symptoms are more severe.
• Remember that a diagnosis of ADHD is made on symptoms and impairments reported rather than only on direct physician observation.
• Question not only the nature of the impairment and symptoms but the triggers that allow them to become apparent.
• Separate out symptoms caused by psychosocial stressors. This can be very difficult, particularly when the patient has suffered significant loss or trauma. It's important to differentiate any acute onset symptoms that may have been caused by recent stressors, such as loss or trauma, from the more chronic neurobiological symptoms of ADHD.
# SUGGESTED ACTION -AT THE END OF STEP 3
• Order any tests if necessary. If indicated, make referrals for further specialty assessments such as psychology, occupational therapy, speech language pathology, psychiatry or other medical specialists.
• Request a psychoeducational assessment if a learning disability or other cognitive challenges are suspected.
• Continue to emphasize the need to learn about ADHD and ensure that individuals and their families are aware of relevant websites for more information, such as: o CADDAC www.caddac.ca (Canada) o CHADD www.chadd.org (USA)
# STEP 4: FEEDBACK & TREATMENT RECOMMENDATIONS
# Feedback of the Diagnosis (if not previously done)
• Review all completed rating scales to determine if they meet criteria for ADHD.
• Review the developmental history, identifying impairments that are often associated with ADHD.
• For children/adolescents, review the CADDRA Teacher Assessment Form.
• Review all other available documentation, such as report cards and prior assessments.
• Give feedback related to the interview and collateral sources.
• Based on the findings above, present the diagnosis and any other concerns that might be relevant.
# Dispelling Myths
Many individuals and their families come into an assessment for ADHD with false information or beliefs. Some examples are:
• They are just lazy and looking for an excuse.
• I don't want my child to take medication that could change their personality.
• I am not the one with the problem, my spouse/employer/parent/teacher/school system is the problem.
• I had it as a child but it went away.
• I don't have all of the clinical symptoms.
• ADHD is just a fad.
• Plus, many more…
# Feedback of the Treatment Plan
• Address the feelings, questions and reactions to the ADHD diagnosis of the person with ADHD and their family.
• Explain the impact of the diagnosis in social/school/vocational settings. Documentation of the official diagnosis may be critical to receive various school interventions, benefits (e.g. special funding) and accommodations.
• Review the areas of impairment, trying to narrow down the primary symptoms that are troubling the patient.
# •
Provide further education about ADHD (e.g. the CADDRA Information handout).
• Discuss psychosocial treatments (Chapter 4) and pharmacological treatment options (Chapter 5).
# Implementation of Treatment
• Treatment is often multimodal and should be individualized.
• Refer to chapters 4 and 5 for specific treatment guidelines.
# Follow-up
Regular and frequent follow-up is important until ADHD is stabilized. Once stabilized, active individualized monitoring based on a chronic disease management model should occur. Frequency of follow-up is dependent on patient characteristics such as medical complications, compliance, response to treatment, social supports and lifestyle factors.
The CADDRA Clinician ADHD Baseline/Follow-up and CADDRA Patient ADHD Medication forms can help streamline these visits.
# Practice Point
Regular monitoring includes completion of a growth chart for children plus rating scales, collection of vital signs, and side effects profiles whatever the age of the patient.
# PREVALENCE OF COMORBIDITIES
When making an ADHD diagnosis, it is very important to note that, in the majority of cases, ADHD does not exist in isolation [47]. An evaluation for ADHD requires screening for possible comorbid disorders and consideration of biological, social, and psychological factors. Consideration of a second opinion or referral to an ADHD specialist should be made if the patient has a clinical history that is complex or if you are contemplating pharmacological treatment beyond those recommended in these Guidelines [48].
Most individuals with ADHD have co-occurring conditions that may complicate the clinical presentation. Often these comorbid disorders need to be dealt with concomitantly [49]. In some circumstances, as described later in this chapter, one may need to prioritize which condition to treat first.
# From the Literature:
• 50-90% of children with ADHD have at least one comorbid condition [47].
• Approximately half of all children with ADHD have at least two comorbidities [47].
• 85% of adults with ADHD meet criteria for a comorbid condition [50,51].
The literature offers multiple potential explanations for the existence of comorbidities and/or overlapping symptoms between ADHD and other disorders [52].
The main explanations are [53,54]:
• One disorder is a precursor to another;
• One disorder is a risk factor for the development of the other;
• The disorders share the same related risk factors; or • There is a common underlying symptomatic basis for one or more of the behaviours in common. Comorbidity can contribute to the failure to diagnose ADHD in adults and children [47]. In addition, follow-up studies of children with ADHD and comorbidity show that these children have a poorer outcome than children with ADHD alone, as evidenced by significantly greater social, emotional and psychological difficulties [55]. The most common comorbidities identified in the Multimodal Treatment Study of ADHD [56] and in other comorbidity studies [57][58][59] have been remarkably consistent (e.g. Oppositional Defiant Disorder, Learning Disorders, Anxiety Disorders, Substance Use Disorders).
# Disorder-based Differentiation
Differential diagnosis is the process of differentiating between two or more conditions that share similar signs or symptoms while comorbid disorders are disorders that occur together with ADHD (either causallyrelated or independent and occur concurrent with ADHD). A careful assessment of other possible diagnoses should be undertaken at the time of evaluation. As ADHD does not have a symptom that is pathognomonic for the condition, there can be numerous overlaps with other disorders.
A thorough history and full functional review accompanied by a physical examination may highlight underlying physical conditions. While most individuals with ADHD do not need laboratory investigations as part of their diagnostic assessment, in certain instances, a laboratory work up or specific tests are needed to eliminate a suspected pathology.
Some special medical investigations may be required, such as polysomnography [60], electroencephalogram [61], or brain imaging [62,63]. Psychological testing may be required to address a suspected learning disability [64] or other cognitive challenges. The clinical evaluation of a child with ADHD includes an evaluation of potentially adverse psychosocial factors such as a disruptive family environment [65], child abuse or neglect [66,67] and attachment issues [68]. These may complicate the presentation of ADHD. • Neurofibromatosis
Medications that may have psychomotor side effects:
• Medication with cognitive dulling side effect (e.g. mood stabilizers).
• Medication with psychomotor activation (e.g. decongestants, beta-agonists like asthma medication).
# Common Comorbidities
In this chapter, we will briefly describe key comorbidities that can present alongside ADHD and the auxiliary treatments that they require.
# ADHD, Comorbidity & Development
• ADHD in its different presentations (combined, inattentive or hyperactive-impulsive), and the most common comorbid disorders, change over time and by developmental stage [69].
•
The most common comorbid disorders in early childhood are oppositional defiant disorder (ODD) [24,70], language disorders [71], and anxiety disorders [72].
• Many children with ADHD have a Specific Learning Disorder [73].
• ADHD may be two to three times more common in children with developmental disabilities or borderline IQ and intellectual disabilities [74].
# •
In the mid-school-age years, symptoms of anxiety or tic disorders become more common [75].
• Mood disorders and substance use disorders tend to be more observable by early adolescence compared to childhood [76][77][78].
• In adulthood, anxiety, major mood disorders (depression or bipolar disorder) [34] and substance use disorders are commonly seen with ADHD [79][80][81].
# OPPOSITIONAL DEFIANT DISORDER
Behavioural problems (including oppositionality, aggression and delinquency) are among the most common comorbid presentations in children with ADHD [82]. The presence of comorbid Oppositional Defiant Disorder (ODD) with ADHD is likely to generate substantial impairment and is expected to result in increased referrals for treatment [83]. ODD rarely presents as an isolated diagnosis. Distinguishing between normal adolescent self-assertion and ODD may not always be easy. The impulsivity and irritability associated with ADHD is sometimes mistaken for the willfulness of ODD. In some individuals, ODD may continue into adulthood [84].
# Symptoms
DSM-5 symptom classification of ODD helps distinguish between the reactive-irritable symptoms that overlap with ADHD manifestations and the provocative-vindictive symptoms [85]. The provocative-vindictive symptoms are less common and are often conceptualized as a reaction to insecurity or low self-esteem and may reflect reaction to a dysfunctional environment. The anxiety/depressive symptoms are associated with the irritable symptom construct of the DSM-5 [86].
DSM-5 provides three symptom clusters (mood related, provocative or vindictive) of ODD. It is useful to examine each symptom in light of its overlapping characteristics with ADHD.
# Treatment
Treatment of comorbid ODD with ADHD should be multimodal [1]. In patients with comorbid ODD with ADHD, it is advisable that the first step is optimization of pharmacotherapy of ADHD, which may stabilize the reactive-irritable symptoms [88]. This should be followed by augmentation with psychosocial treatment, including Parent Management Training (PMT), Cognitive-Behavioral Therapy (CBT) or Collaborative and Proactive Solutions (CPS) [89]. It is important to distinguish ODD from conduct disorder (CD). Children with ODD have recurring negativistic, defiant, hostile and disobedient behaviour, especially toward authority figures, whereas those with CD repeatedly violate the basic rights of others or ageappropriate societal norms, as defined by a pattern of repeated aggression, lying, stealing, and truancy [90]. The onset of both disorders can be prepubertal, thus making early identification, diagnosis, and treatment crucial. In one study, ODD was found to be a precursor to conduct disorder in approximately 50% of the cases [91].
# Key Points
• Some patients with ADHD and ODD may respond adequately to stimulant or non-stimulant (atomoxetine, guanfacine XR) medications [92,93]. Since many cases are likely to require augmentation with either psychosocial treatment and/or off-label use of another medication (for example; atypical antipsychotics) [94,95], referral to specialized care may be required in complex cases.
• Effective treatment may reduce the risk of more severe conditions in adolescent and adult years, such as CD, substance use disorder and depression [96].
# CONDUCT DISORDER/AGGRESSION
Conduct Disorder (CD) comorbid with ADHD is a severe, persistent condition that is frequently preceded by ODD [84,97,98]. When CD has pre-pubertal onset (before the age of 10 years old), the prognosis is considered worse than for the group of children that have adolescent-limited CD [78]. DSM-5 also emphasizes that limited pro-social emotions (lack of remorse or guilt; callousness and lack of empathy); being unconcerned about performance; and shallow or deficient affect are poor prognostic indicators and increase the risk for the development of antisocial personality disorders in adulthood [84]. Furthermore, co-occurrence of ADHD and CD is often a precursor of nicotine use disorder, substance use disorder, anxiety, and depression [78,99].
Research shows that ADHD and CD represent two complex and distinct entities that can be associated [100]. Children with either of these conditions in isolation present with different core symptoms and perform differently on objective measures of ADHD symptoms than those with ADHD + CD [101,102]. Children with ADHD + CD show the poorest outcome within each individual group [103,104].
# Symptoms
The following table serves to help clinicians identify behavioural symptoms that may be seen in ADHD and may respond to specific treatments for ADHD. CD specific symptoms may require a multi-systemic approach and may also need to involve the legal system.
# Treatment
Pharmacotherapy for patients with a combination of ADHD, CD and aggression using both stimulant and non-stimulant medications has been found to be useful [105,106]. Although medications are usually effective in reducing the symptoms of ADHD and impulsive aggression [56,107], these patients typically receive more benefit from multimodal treatment [99].
Medications should initially be used to treat the most severe underlying disorder, but in some complex situations targeting specific symptoms could be appropriate. For example, patients with CD may show aggression before and during the course of treatment, making it imperative to document their aggressive behaviours before the introduction of medication and to make these behaviours an explicit target of therapeutic strategies. Clinicians should assess pharmacological treatment tolerability as some medications may augment irritability and aggression [108].
Conduct problems may be reduced by the most widely used evidence-based treatments for ADHD (e.g. stimulant and nonstimulant medication and psychosocial treatment) [107,109]. However, treatment of the ADHD may not be sufficient to resolve all symptoms. Optimization of medication as part of a multimodal treatment approach indicated that psychosocial treatments including individual and family interventions are often required [110]. Specialists in this area might use mood stabilizers or an atypical anti-psychotic (both are off-label). Other treatments (besides optimizing ADHD medication and psychosocial treatments) are controversial and referral to a specialist is recommended [111,112].
# Key Points
•
The essential characteristic of CD is repetitive and persistent behavior manifested by violation of others' fundamental rights or violation of social rules/norms.
• Psychosocial treatment, such as parenting and problem-solving skills training, and family and/or individual therapy, is often needed to improve patient outcomes.
• Pharmacological treatment of comorbid ADHD and CD may require combination of an ADHD medication and a medication that targets aggression.
• CD with ADHD represents a complex diagnostic entity that may require specialized interventions.
# ANTISOCIAL PERSONALITY DISORDER
Antisocial Personality Disorder (ASPD) is diagnosed when a pattern of antisocial behaviour has occurred since age 15. CD is, therefore, a precursor to ASPD. Many people with ASPD have a history of ADHD but most people with ADHD do not develop ASPD [113].
# Symptoms
Many of the ASPD symptoms have an impulsive component. It is therefore clinically indicated to carefully assess for ADHD in patients with ASPD. However, targeting and treating ADHD symptoms may not resolve ASPD symptoms as they are crystalized in the personality but may facilitate a structured intervention for the ASPD.
# Treatment
Both disorders must be treated separately using the efficacious treatments for each specific condition. Since some patients with ASPD may exhibit drug seeking behavior (for secondary gain) or concurrent substance use disorders [114], clinicians may be sometimes reluctant to consider psychostimulant treatments for these patients, even if the ADHD is significant. Non-stimulant medications have not been systematically investigated in these patients but offer a treatment option for some underlying ADHD-related symptoms.
# Key Points
• ADHD is a treatable risk factor for ASPD.
• Both conditions require specific interventions and education may help to improve impulsive behaviours but ASPD traits need to be addressed separately.
• ASPD with ADHD represents a complex diagnostic entity and may require specialized interventions.
# BORDERLINE PERSONALITY DISORDER
According to the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) [115], the lifetime prevalence of Borderline Personality Disorder (BPD) was reported to be 33.69% in those with ADHD versus 5.17% in the general population, suggesting an association between the two disorders. The most common symptom between ADHD and BPD is impulsivity [116,117].
# Symptoms
BPD and ADHD have shared and overlapping symptoms. The following table assists the clinician in distinguishing symptoms that are more specific to BPD from those that may overlap with ADHD.
# Treatment
There are no studies establishing the optimal treatment for individuals with ADHD and BPD. The available literature suggests treating the two entities as separate phenomena [118]. In addition, there is no current evidence to propose that an improvement in ADHD leads to a resolution of BPD, signifying that the personality features require specific treatments [119]. However, most treatment strategies for BPD aim to control impulsive behaviours (often with medication), emotion dysregulation and distress tolerance [120]. Currently, Dialectical Behavioral Therapy (DBT) is the most commonly recognized treatment for BPD [121]. While all patients with core impulsivity are at risk of medication misuse, physicians must use their judgment and not necessarily deny patients with BPD effective treatments for ADHD.
# Key Points
• BPD with ADHD represents a complex diagnostic entity that requires specific mode of interventions.
• Psychosocial interventions like DBT have been shown to be effective for BPD and should be used in combination with psychopharmacology in the presence of ADHD.
• Stabilizing impulsive behaviours and optimizing emotion regulation should be the main goals of the combined psychosocial and pharmacological interventions.
• BPD with ADHD represents a complex diagnostic entity and may require specialized interventions.
# ADDICTIONS
In some individuals with ADHD, the need for rapid feedback, the desire for immediate reward and the high adrenaline riskseeking behaviours may render them vulnerable to addictions. These addictions may be to shopping, sex, pornography, internet and gambling, in addition to possible substance use disorders [122][123][124]. Management principles for addictions and ADHD should include a specific intervention for the addictive behaviour and a specific treatment for the ADHD, ideally concurrently [125].
# SUBSTANCE USE DISORDER
Compared to typically developing individuals, people with ADHD have a two-fold risk for substance abuse and dependence [126,127]. The literature suggests that one-quarter of adults with substance use disorder (SUD) [128] and one-half of adolescents with SUD have ADHD [129]. Several studies suggest a higher rate of SUD in adults with ADHD than in the general population, and ADHD itself is a risk factor for SUD [130,131]. Among ADHD patients with a comorbid behavior disorder, those with either comorbid CD or Bipolar Disorder have the greatest likelihood of developing SUD [114,[132][133][134][135].
Individuals with ADHD are at significant risk of using substances (e.g. nicotine, cocaine and cannabis) and of starting use earlier than the general population [134]. Moreover, the accompanying poor self-esteem and impulsivity associated with ADHD may be conducive to the development of SUD.
Marijuana continues to be the most commonly abused agent in individuals with ADHD [136]. Abuse can include alcoholism, smoking and other drugs [126]. Furthermore, substance use problems may increase the severity of ADHD symptoms. On the other hand, it is also true that patients with these substance use problems may present with attention, behaviour and self-control symptoms that can mimic ADHD. A referral to a specialist may be required before establishing an ADHD diagnosis when a patient is actively using illicit substances.
# Treatment
The best approach to treatment sequencing in individuals with ADHD and comorbid substance use disorder is concurrent intervention with specific interventions for each disorder [125]. Some researchers suggest that ADHD and SUD-related craving share neurobiological similarities, and that treatment of ADHD may reduce craving for substances and subsequently reduce the risk for relapse to substance use [137]. An aggregate of the literature seems to suggest that early stimulant treatment reduces or delays the onset of SUDs and perhaps cigarette smoking into adolescence; however, the protective effect may be lost in adulthood [138].
The treatment needs of individuals with ADHD and SUD need to be considered simultaneously; however, if SUD is severe, sequential treatment may be considered with immediate attention paid to the stabilization of the addiction. Depending on the severity and duration of the SUD, individuals may require residential or inpatient treatment. Day treatment can be a more cost-effective option if patients are ready and motivated for change [139,140]. Depending on the type of substance being used, prescribing psychostimulants in the presence of active substance abuse requires careful monitoring for medical interactions and should take into account the potential risk of misuse and abuse [97, 129, 133-135, 141, 142].
Although patients commonly report subjective calming with cannabis and other improved symptoms (increased appetite, better sleep), there is no evidence that cannabis is an effective treatment for ADHD or that it improves attention and productivity. In fact, there is evidence that cannabis can impair cognition and exacerbate motivation issues [143].
Methylphenidate does not have the same abuse liability as cocaine due to slower dissociation from the site of action, slower uptake into the striatum, and slower binding and dissociation with the dopamine transporter protein relative to cocaine [144]. However, it is important to remember that the route of administration may alter the abuse liability of a substance. The oral administration of psychostimulants has been shown to decrease the likability of a substance while parenteral usage (injected, snorted) has been shown to be associated with euphoria [144]. Individuals with ADHD and either SUD or CD are at highest risk for diversion and misuse and are more likely to both misuse and divert their stimulant medication [145]. Both immediate-release and, to a lesser degree, extended-release preparations of stimulant medications can be diverted or misused, with extended release preparations having less potential for parenteral usage [55,145]. Nonstimulants such as atomoxetine and guanfacine XR do not have abuse potential.
# Key Points
• In most cases, ADHD and SUD need to be treated concurrently and independently when comorbid.
• Psychostimulants taken orally do not have the same abuse liability as illicit stimulants (e.g. cocaine) due to slower dissociation from the site of action, slower uptake into the striatum, and slower binding and dissociation with the dopamine transporter protein.
• Non-stimulant and long-acting psychostimulants have less abuse potential than immediate-release preparations of psychostimulants.
# ANXIETY DISORDER
As many as a third of children and half of adults with ADHD have comorbid anxiety [146]. Individuals with ADHD often develop symptoms of anxiety due to chronic difficulties related to their ADHD symptoms. For instance, the experience of repeatedly forgetting may lead to realistic worries that one will forget. Compensatory checking may mistakenly be interpreted as evidence of a primary anxiety disorder.
# Symptoms
The table of specific versus commonly seen symptoms may help clinicians distinguish ADHD from anxiety disorders.
# Treatment
If ADHD exists with anxiety, a general rule of thumb is to treat the most impairing condition first [147]. Psychostimulant treatment may increase anxiety especially during treatment initiation, or when increasing dosages of medication [148]. A slower than usual titration schedule may be preferred in these cases. If the anxiety becomes too intense, then the ADHD medication should be reduced or withdrawn, and the anxiety should be treated until the symptoms are stabilized and only then should the ADHD medications be started. Any of the ADHD stimulants can be successfully used when anxiety is comorbid with ADHD [107]. A randomized-controlled pediatric study showed that the non-stimulant atomoxetine can be beneficial in patients with co-occurring ADHD and anxiety disorders [149]. Guanfacine XR was found to be well tolerated in pediatric subjects with anxiety disorder [150].
# Key Points
• ADHD-associated impairments can induce anxiety symptoms that are different from a specific anxiety disorder.
• Anxiety disorders and ADHD often coexist, and the most impairing condition should be treated first.
# •
Stimulants and non-stimulants can be used for ADHD in the context of anxiety.
• Titration of psychostimulants may need to be initiated at a slower pace and monitored more carefully with patients prone to anxiety.
# MAJOR DEPRESSIVE DISORDER
There is considerable overlap between the clinical presentations of Major Depressive Disorder (MDD) and ADHD. MDD patients (without ADHD) may have depressive episodes presenting with inattention, short-term memory problems, irritability, impulsivity, difficulty sleeping, trouble concentrating, restlessness and fidgetiness [141]. A critical point to explore is the "since when" question, as a reported recent drop in mood is qualitatively different from the lifelong demoralization that may be seen in ADHD [ 151].
# Symptoms
Patients with primary ADHD often have to deal with failure and attacks to their self-esteem, frequently at a very young age, and may become demoralized and depressed as a result. In this case, they may present with both disorders. However, patients with ADHD may look like they have a mood disorder when they do not. Lack of motivation may mimic anhedonia and chronic difficulty going to sleep and restless sleep may mimic insomnia secondary to MDD. Patients with ADHD commonly have dysregulated mood (dysphoria, irritability), but it is not typical for ADHD in the absence of a mood disorder to be associated with entrenched, depressed affect or anhedonia.
# Treatment
When a patient with ADHD also suffers from MDD, treatment of the most disabling condition should be undertaken first. It is important to note that if the depressive episode is part of a Bipolar Disorder, the treatment algorithm should follow that of Bipolar Disorder (see section on Bipolar Disorder). In some patients, antidepressants with catecholaminergic activity, such as bupropion, can be useful to treat both MDD and ADHD. Typically, the combination of an antidepressant (e.g SSRIs) with psychostimulants may be necessary to achieve remission. SSRIs are considered safe to use in combination with stimulants. However, drug interactions involving the CYP450/2D6 (e.g., involving fluoxetine, paroxetine), when combined with the amphetamine class or atomoxetine, require caution and monitoring.
If the MDD continues to be impairing or worsens, referral or specialized care in depression is recommended. In severe depression, and in subjects at risk of self-harm, intervention for depression and specialized referral must be carried out as a priority.
# Key Points
• If a patient presents with mild depression and ADHD, then treatment of ADHD may be considered first.
# •
In cases of depression or severe suicidal risk, treatment for depression must be the priority.
• Concurrent treatment of ADHD and major depression is often required, and concomitant use of antidepressants and ADHD medications are commonly used.
# BIPOLAR DISORDER
The diagnosis of Bipolar Disorder (BD) in the context of ADHD is challenging. Many symptoms of BD overlap with ADHD symptoms. The definitive epidemiological relationship between both disorders remains controversial. The following table may guide clinicians in differential diagnosis. However, if Bipolar Disorder is suspected, a referral to specialized care should be considered.
# Symptoms
# Treatment
Treatment of comorbid ADHD and BD should usually start with managing and stabilizing the BD symptoms first [152].
The management of ADHD with BD is usually more complicated than managing ADHD alone and often requires the use of mood stabilizers and/or atypical antipsychotics [119]. There is a small risk of switching from euthymia or depression to mania when a bipolar patient is prescribed stimulant medication [153]. If this occurs, the stimulant should be adjusted (reduced) or discontinued, and treatment of BD should be prioritized. Once the patient's mood is stabilized, stimulant medication may cautiously be re-instituted (start low and go slow) [141,154].
# Key Points
•
The co-occurrence of BD and ADHD may be difficult to diagnose and manage. A referral to a specialist should be considered.
• Treatments should be aimed at stabilizing the Bipolar Disorder first and then treating ADHD.
• Stimulants have been shown to be safe and effective in patients with BP once their symptoms have been stabilized.
# DISRUPTIVE MOOD DYSREGULATION DISORDER
The diagnostic criteria for Disruptive Mood Dysregulation Disorder (DMDD) includes severe recurrent disproportional temper outbursts (verbal and/or physical) occurring three or more times a week in at least two different settings for 12 months or more [1]. Diagnoses are generally made between the ages of 6 and 10 and cannot first be made before the age of six years or after the age of 18 years [1]. Between temper outbursts, the mood of the patient with DMDD appears to be irritable/dysphoric [155].
DMDD is currently considered a presentation of childhood depression and this diagnosis was created to address concerns about the potential for the over diagnosis of, and treatment for, bipolar disorder in children [1]. A study of some 3,258 participants aged 3 to 17 [156] showed a prevalence rate for bipolar disorder of 0.8% to 3.3% with the highest rate in preschoolers. DMDD was also found to be very comorbid (62% to 92%). The highest rates of comorbidity occurred with depressive disorder (odds ratio 9.9 to 23.5) and ODD (52.9% to 100%). Rate of co-occurrence with ADHD had odds ratios which ranged from 2.9 to 12.
# Symptoms Table 2.9 Disruptive Mood Dysregulation Disorder (DMDD) Differentiation OVERLAPPING SYMPTOMS WITH ADHD DMDD DISTINCT FEATURES Irritable mood episodes (explosive outbursts)
Inter-episode dysphoria Psychomotor agitation
Minor triggers with extreme rage attacks Chronic course Young age of onset
# Treatment
A combination of medications and psychosocial interventions is needed to treat ADHD + DMDD. Many of the medications effective for treating ADHD have been shown to be effective for DMDD [157].
# Key Point
• DMDD is a new DSM-5 diagnosis. Research regarding its treatment and relationship to ADHD is underway.
# OBSESSIVE-COMPULSIVE DISORDER
The lifetime prevalence of Obsessive Compulsive Disorder (OCD) in the general population is 1-3% [158]. Reported rates of ADHD-OCD co-occurrence are highly inconsistent in the literature [159]. If OCD and ADHD present together, there is an increased risk of Tic Disorders and Tourette Syndrome also being present [160]. ADHD patients often develop behavioural patterns, like repetitive checking of tasks, as coping strategies to compensate for the symptoms of ADHD. Whether these behaviours are secondary to ADHD or are indicative of OCD needs to be considered.
# Treatment
Treatment of OCD and ADHD should be carried out simultaneously. While there are no controlled studies, a 2014 review [161] reported no evidence showing a worsening of OCD symptoms with the concurrent use of psychostimulant medications.
# Key Points
• Psychostimulants do not usually lead to an exacerbation of OCD symptoms [161].
• The presence of OCD comorbidity does not change the treatment approach to either disorder.
# TOURETTE SYNDROME AND TIC DISORDERS
ADHD is highly comorbid with tics and Tourette Syndrome (TS) (50-90%) [162], so patients with tics should be screened for ADHD. In a 2014 study, four clusters of individuals were identified: pure TS (49.8%), TS + ADHD (22.2%), TS + OCD (21.5%) and TS + ADHD + OCD (6.5%) [162]. A commonality to all groups was emotional lability. All groups had significant behavioral problems compared to normal controls. The presence of OCD is considered to be more impairing than the presence of ADHD and is more likely to increase the rate of other co-morbidities [162], though there are no current long-term studies on treatment outcome for these four groups. When tics co-occur with ADHD, the tics themselves are generally less impairing than ADHD [163][164][165][166].
# Treatment
Recent research studies suggest that treatment interventions for TS include education about tics and related disorders, clinical monitoring, pharmacological and/or psychological treatments, and school interventions for children and adolescents [167]. Stimulant medication is a safe and effective treatment for ADHD + Tic Disorder but requires careful monitoring of potential tic worsening [168]; the alpha-2-adrenergic agonists, clonidine and guanfacine XR, have shown promise in the treatment of tics, particularly in combination with ADHD [169]. In patients where stimulants may cause tic exacerbation, atomoxetine may be also considered as an option as it will rarely cause worsening of symptoms [170].
Recent studies indicate that on a population level stimulants do not seem to raise the risk of tics, and that the exacerbation of tics when stimulants are started is often coincidental, having to do with the waxing and waning nature of tics [163,171].
Non-pharmacological treatments for Tic Disorder include Habit Reversal Therapy and Comprehensive Behaviour Intervention for Tics (CBIT) [172,173] and may be considered as first-line treatments when available.
# Key Points
• Tics and TS are highly comorbid with ADHD.
# •
The presence of tics or TS is not a contraindication to the use of stimulants in ADHD but careful monitoring is required.
• Stimulants do not typically raise the risk of tics but may rarely do so in some individuals.
# EATING DISORDERS
Bulimia nervosa is more prevalent in patients with ADHD versus patients without ADHD [174]. ADHD is more prevalent in anorexia nervosa purging type [175]. Females with ADHD are 3.6 times more likely to meet the diagnosis of eating disorders compared to females without ADHD [176]. The prevalence rate of ADHD in eating disorders is 11.4% [177]. This would suggest that females with ADHD in particular should be screened for an eating disorder, and vice versa. Clinicians should be alert as patients with anorexia that may not have ADHD may seek stimulant medication (feigning symptoms of ADHD) for the purpose of weight loss. Obesity has also been reported among patients with ADHD, especially in the adult population [178,179].
One of the proposed mechanisms underlying weight issues in patients with ADHD could be the impulsive behaviours leading to binge eating [180]. Impulsivity is greater in individuals with comorbid eating disorders than in individuals with ADHD alone [181]. It is important to recognize that obesity is a risk factor for sleep apnea [182], a condition that may mimic or aggravate ADHD symptoms. Therefore, the longitudinal course of symptoms is of crucial importance before making a diagnosis of ADHD in obese patients with sleep apnea. [183]. Binge Eating Disorder is a newly recognized disorder in DSM-5 and its relationship with ADHD is currently unclear.
# Key Points
• The diagnosis and treatment of ADHD in the presence of anorexia nervosa can be complicated.
• Treatment of ADHD could contribute to behavioral control in the context of binge eating.
• A growing body of literature points to ADHD as a risk for obesity.
# AUTISM SPECTRUM DISORDER
Until the publication of the DSM-5, Autism Spectrum Disorder (ASD) was an exclusionary criterion in making the diagnosis of ADHD, and the two diagnoses could not be made concurrently. Because of this, the relationship of ADHD and ASD remains unclear and is currently being researched. Prior research has suggested as many as 30 to 70% of patients with ASD may meet criteria for ADHD [184][185][186][187][188][189]. Many individuals with ADHD also show high level of social deficits and ASD type symptoms [190][191][192][193][194].
# Symptoms
# Treatment
Treatment of ADHD in patients with ASD is effective and significantly improves functioning. There have been only a small number of Randomized Controlled Trials (RCTs) that have looked at treatment of ADHD symptoms in subjects with comorbid ASD but these have shown promising results [195,196].
RCTs with methylphenidate in comorbid samples have shown a response rate of 50% (versus 70-80% response rate for psychostimulants in ADHD without comorbid ASD) [197,198]. Additionally, patients with ADHD and ASD may be more sensitive to side effects such as irritability, hyper focus, and stereotypies than those without ASD [199]. Clinical experience indicates that medications should be started at low doses and titrated more cautiously than usual in this population [199].
Both risperidone and aripiprazole (off-label use) have shown efficacy in controlling hyperactivity in this population, but generally have a less favorable side effect profile (metabolic changes, weight gain) than psychostimulants [200,201].
One RCT of atomoxetine in individuals with ADHD and ASD showed positive results in improving hyperactivity, impulsivity and inattention and was generally well tolerated; however, overall improvement in clinical and functional improvement was limited [202]. Extended release guanfacine has recently been found to be effective for reducing hyperactivity in children with ASD [203].
# Key Points
• ADHD patients should be screened for ASD and vice-versa.
• Treatment of ADHD in patients with ASD can be very effective and help overall functioning.
• Treatment of comorbid ADHD and ASD with standard ADHD medication is often effective but may have lower effect sizes and higher risks of side effects.
# SPECIFIC LEARNING DISORDER
# Symptoms
Children/adolescents with ADHD frequently fall below their typically developing peers in their scores on standardized achievement tests. Teachers and parents often express concerns about a child's level of productivity and may label this child/adolescent as "lazy" or "unmotivated". There are several trajectories that can culminate in underachievement. One of the possibilities is that the individual has both ADHD and a Specific Learning Disorder (SLD). Indeed, research indicates that the comorbidity of ADHD and SLD is as high as 45% [64]. It is important to note that the comorbidity range suggested to be between 31% and 45% can vary greatly depending on how SLD is diagnosed [204].
Even without comorbid SLD, people with ADHD may still have a great deal of difficulty academically in terms of listening and reading comprehension and written expression (as well as with performance deficits such as following instructions, listening in the classroom, or staying on task) [205][206][207][208][209][210]. Additionally, individuals with ADHD often have executive function difficulties in the areas of initiation, organization, planning, self-directed activity, and ability to complete multistep tasks [211].The degree of difficulty individuals experience varies, with some individuals greatly impaired and their academic achievement subsequently falling well below their abilities. Learning disorders and executive function deficits are also developmental. That is, they may become more overt as cognitive demands in school increase [211]. Note: SLD is a clinical diagnosis that is not necessarily synonymous with 'learning disabilities' as identified within the education system: that is, not all children with learning disabilities/difficulties identified by the school system would meet a DSM-5 clinical diagnosis of SLD. By contrast, those with a DSM-5 diagnosis of SLD would be expected to meet the educational definition [212].
# Diagnostic Assessment
In terms of assessment, practitioners should always: a) Screen for academic skills deficits among students with ADHD and for ADHD symptoms among students with SLD. b) Assess academic functioning across subject areas (e.g., reading, math, writing) when evaluating students with ADHD. c) Carefully evaluate whether interventions for ADHD enhance academic functioning.
Given the relatively high comorbidity rate between ADHD and SLD, students who are evaluated for one of these disorders should always be screened for possible symptoms of the other disorder. The CADDRA Teacher Assessment Forms screens for academic performance problems in addition to ADHD. If the screening suggests the possibility of an SLD, then a letter should be sent to the school, with the parent's approval, to notify them and suggest that the school may wish to consult with support staff and/or the board psychology practitioners for further investigation and school programming.
In adults, as in children, ADHD can occur along with specific problems in reading, math or with written expression [213].
Assessing whether these difficulties have caused previous problems in school and continue to cause residual difficulty can usually identify these. The childhood history should reveal previous concerns of ADHD. It is additionally important to determine if the patient is inattentive only in the area in which learning deficits present a challenge.
# Management
Learning disabilities require intensive, direct instruction, and modifications/accommodations [64]. Comprehensive intervention services for students with comorbid ADHD and SLD will require empirically supported treatment strategies that address both disorders and that are implemented across school and home settings. Although some school boards across Canada do not currently recognize ADHD as qualifying a student as a 'special needs student', this perspective is changing. Clinicians wishing to advocate for accommodations for their ADHD patient may wish to use the CADDRA Educational Accommodation Template.
# SPECIAL PRESENTATIONS
# Intellectual Giftedness
Research has shown that having a high IQ does not preclude the possibility that one might have ADHD [214,215]. However, the co-occurrence of ADHD and intellectual giftedness remains controversial and under-investigated. Most previous discussions in the literature have been based largely on anecdotal comments, opinions and small clinical samples. Moreover, DSM-5 does not mention ADHD in the context of intellectual giftedness [1].
Misdiagnosis of ADHD in the context of intellectual giftedness can occur in two ways: intellectually gifted individuals with high energy and over-excitability in school contexts (particularly in those with little academic stimulation) may be misdiagnosed as having ADHD; alternatively, intellectually gifted individuals who meet full diagnostic criteria for ADHD but who can concentrate for long periods of time, may not be diagnosed with ADHD [216]. Moreover, intellectually gifted individuals with ADHD may also meet criteria for SLD and other comorbidities [217]. Thus, it is important for practitioners to recognize that intellectual giftedness in individuals with ADHD should be documented.
A high IQ may help individuals with ADHD cope with symptoms. Therefore, in some cases, clinically relevant impairment among gifted IQ children may not develop until later in elementary school or even in high school [214]. However, although ADHD may not be diagnosed until later it is not any less impairing. Diagnosis and treatment is critical at any age.
# Symptoms
There are overlapping symptoms shared by individuals with high IQs and individuals with ADHD which may make differential diagnosis challenging. Frequently, bright children are referred to psychologists or pediatricians because they exhibit certain behaviors commonly associated with a diagnosis of ADHD (e.g., restlessness, inattention, impulsivity, high activity level, day-dreaming). A child may be diagnosed with ADHD when in fact the child is gifted and reacting to an inappropriate curriculum [218]. The process of completing a differential diagnosis requires specific questions to clarify what is shared and what is unique to either ADHD or giftedness or whether the child is twice exceptional.
In general, intellectually gifted individuals with ADHD show a similar pattern of cognitive, social, psychiatric, and behavioral characteristics as those with ADHD in the context of average IQ [214,217]. However, the individual's strengths and difficulties may interact so that one presentation obscures the other [219].
Practitioners will need to undertake a thorough medical, developmental and educational history, as well as a comprehensive clinical and psychological evaluation, to ascertain an individual's behavior in different contexts and situations. The National Commission on Twice Exceptional Students concludes that the 'identification of twice-exceptional learners requires comprehensive assessment in both the areas of giftedness and disabilities [220]. When possible, the assessment and identification should be conducted by professionals from both disciplines (i.e., ADHD, giftedness) and ideally by those with knowledge and experience with individuals with twice-exceptionality.
# Psychological Trauma
The interaction between psychological trauma and ADHD can be complex. Post-trauma symptoms of hyperarousal, hypervigilance, and dissociation can confound ADHD assessment. Although there is conflicting evidence, a history of psychological trauma may increase the risk of being diagnosed with ADHD [221,222].
Various explanatory hypotheses are being explored in the literature to explain the interaction between trauma-related symptoms and ADHD symptoms [223]. First, ADHD may place children at greater risk for exposure to psychological trauma [224]. Conversely, Post Traumatic Stress Disorder (PTSD) symptoms may mimic symptoms of ADHD [225]. Additionally, some initial animal research suggests the individual response to trauma (i.e. externalizing vs. internalizing) may be influenced by genetic predispositions [226]. Under this latter hypothesis, trauma exposure merely exacerbates a prepotent genetic propensity towards having ADHD.
Although increased care should be taken to ensure the effects of historic trauma are considered during the assessment process, a history of trauma exposure does not automatically preclude the diagnosis of ADHD in an individual who otherwise meets DSM-5 criteria for ADHD. Further, in the absence of research evidence to the contrary, clinicians are encouraged to follow the normal ADHD treatment protocols described elsewhere in these guidelines.
Clinicians are advised to: a) screen for history of psychological trauma and where indicated, ensure appropriate trauma-informed support and interventions are mobilized; and b) assess for ADHD based on DSM criteria, and treat in accordance with these guidelines.
# Developmental Coordination Disorder
The prevalence rate of Developmental Coordination Disorder (DCD) in the general population is 1.7% in 7-to 8-year-olds [227]. There is no reported prevalence of the co-occurrence of ADHD + DCD, in large part because DCD is often still unrecognized. Clinicians are urged to do simple assessments of balance as part of the routine workup of ADHD including: observations of gait, throwing and catching a ball, balancing on one foot (first identifying dominance) and fine motor tasks such as writing, use of scissors or drawing [228].
Balance problems, dyslexia, and poor handwriting in comorbid patients may be related to cerebellar dysfunction and may be associated with DCD [229,230]. Occupational therapy assessment is warranted to provide recommendations [231].
Having the person learn keyboarding can often be beneficial. Relevant software programs (e.g. voice recognition) can also help to overcome problems.
# Epilepsy
Studies have suggested a higher incidence of symptoms of ADHD in children with epilepsy (20% to 50% of patients) than in the general population [232]. There is a strong trend towards a higher incidence of epilepsy among children with ADHD than among children without ADHD [233] and epilepsy in children with ADHD appears to be more severe than in those without ADHD [233]. Anti-epileptic medications side effects, which can impair attention and learning, may be confused with ADHD symptoms. Therefore, improving seizure control with anti-epileptic medications that have less potential for behavioural or cognitive side effects should be a priority. In those patients with a formal diagnosis of ADHD in the presence of epilepsy, a pharmacological intervention as part of a biopsychosocial approach to treatment could be considered. No strong evidence exists that psychostimulants increase the severity or frequency of seizures in patients with stable epilepsy [234,235].
# Key Points
• When choosing an anti-epileptic medication, one that has less potential for behavioural or cognitive side effects should be preferred in the context of comorbid ADHD.
• Use of psychostimulants could be appropriate in patients with epilepsy provided seizures are well controlled by antiepileptic medications.
• Consideration needs to be given to metabolic drug interaction between ADHD medications and anti-epileptics.
# Brain Injury
Individuals with ADHD of all ages are at risk for physical injuries because they are impulsive, hyperactive and/or inattentive. Children and teenagers with ADHD are three times more likely to experience a moderate or severe brain injury than their peers without ADHD [236,237]. Any injury to the brain, particularly to the frontal lobes, can produce a syndrome known as Secondary ADHD (S-ADHD) [238], also referred to as acquired ADHD. Recent literature has shown that the brain correlates of S-ADHD include the lesions in right putamen, thalamus and orbital frontal gyrus [238].
Children and adolescents with a moderate or severe brain injury have between a 20 to 48% chance of developing S-ADHD [236,237]. S-ADHD can be treated using the same principles and medication as ADHD, but the research literature supporting this treatment is not as extensive or compelling as it is for ADHD.
Given that concussion and brain injuries are relatively common, and symptoms of persistent impairment could mimic or exacerbate the symptoms of ADHD, it is recommended that all patients being assessed for ADHD should be questioned as to whether they have ever suffered a concussion or brain injury. The literature on the association between ADHD and nontraumatic acquired brain injuries such as fetal alcohol syndrome, stroke or treatment with neuro-toxic medications is less clear, but many of these types of patients who develop ADHD symptoms may respond to standard treatments [239]. Patients with brain injury may be more sensitive to medication and thus starting off at lower doses during medication titration trials is recommended [240].
# Key Points
• Assessment for ADHD includes inquiring if the person has suffered a concussion or brain injury.
• Patients with S-ADHD due to traumatic brain injury can be treated with same approaches and medication as regular ADHD although lower starting doses may be considered.
# Sleep
Sleep problems, particularly the symptoms of insomnia (i.e., difficulties falling asleep and staying asleep, and early morning awakenings), are very commonly reported by individuals with ADHD. In fact, at least 50% of children and adults with ADHD report significant sleep problems [241]. While there is a high rate of reported sleep problems in individuals with ADHD, there have been inconsistent findings when objective measures of sleep, such as actigraphy and polysomnography, have been used in research [242]. Across studies examining sleep in children with ADHD, the main finding is that individuals with ADHD have more restless sleep than their peers, which can lead to fragmented sleep. There have been no consistent differences found in terms of sleep variables such as sleep duration [243] or sleep architecture (i.e., differences in the amount of REM sleep or NREM sleep) in individuals with ADHD [244]. There is consistent evidence that stimulant medications used to treat ADHD symptoms could make falling asleep more difficult, which can potentially result in shorter night sleep [245]. Shorter and/or fragmented sleep can result in problems with daytime functioning. There is also growing evidence for possible differences in circadian rhythms, which could make individuals with ADHD more vulnerable to delayed-phase sleep disorder and other types of sleep problems [246].
Research has clearly shown that insufficient sleep in children and adults can result in difficulties with attention, emotional and behavioural regulation, cognitive functioning (e.g., memory), and academic performance [247][248][249]. It would be logical to assume that individuals with ADHD may be even more affected by insufficient sleep given their existing vulnerabilities in these areas. However, very little research has been conducted to determine if this is the case, but in the few existing studies, there is some evidence for this assumption. For example, in one study, sleep restriction negatively impacted both typically developing children and children with ADHD, but only the ADHD group moved into the clinical range on an attention task [250].
While there is a need for more research to better understand the relationship between sleep and ADHD [251], it is clear that we need to be attentive to sleep problems when conducting assessments and/or developing treatment plans for individuals with ADHD. First, we need to think of differentials in our diagnostic formulations. For example, sleep apnea can mimic or aggravate ADHD symptoms [252,253]. Also, given that medications used to treat ADHD can impact sleep, it is important for sleep to be monitored when an individual is taking these medications. It is also likely that sleep problems could exacerbate ADHD symptoms, and therefore, sleep problems should be addressed in the treatment plan.
# Treatment
While there is little evidence for pharmacological treatment of sleep problems in individuals with ADHD [254], there is a growing body of literature that demonstrates that behavioural sleep interventions can be effective for children with ADHD, even when taking stimulant medication [255]. Many individuals with ADHD take melatonin to help with their sleep problems, and the very small body of research has demonstrated that this may be an effective intervention [256,257]. However, given that there is limited research, and the fact that behavioural interventions have been shown to be effective, it is recommended that the first line of treatment is behavioural interventions for sleep problems in individuals with ADHD. For a comprehensive overview of assessment and management of sleep problems in individuals with ADHD please see [258] or [259].
# Key Points
• Differential diagnosis needs to be considered in diagnostic formulations (e.g., sleep apnea can mimic ADHD symptoms).
# Incontinence
ADHD and incontinence (nocturnal enuresis, daytime urinary incontinence, and fecal incontinence) are strongly associated with each other. Children with ADHD are two to three times more likely to have enuresis than those without ADHD [260]. In typically developing samples, the rate of enuresis is 4.45% in boys and 2.5% in girls, with prevalence rates decreasing with age. The trend is similar for fecal incontinence [260] and daytime urinary incontinence [261]. Likewise, children with nocturnal enuresis are more likely to have ADHD than those without incontinence [262].
# Treatment
In most cases, ADHD and issues of incontinence need to be investigated and managed separately. However, recent studies have found that successful treatment of ADHD with stimulant medication can result in resolution of incontinence in some children [263,264]. Enuresis treatment must begin with the correction of any underlying medical cause. Daytime enuresis may be improved with medication. Nighttime enuresis often requires individualized management. In a double-blind study, atomoxetine has been associated with a significant increase in dry nights in children with nocturnal enuresis [265].
# CHAPTER 3: SPECIAL CONSIDERATIONS ACROSS THE LIFESPAN
ADHD is a persistent disorder, with functional impairment and treatment needs varying through the lifespan for many. It is important for clinicians to be aware of these differences to better serve individuals with ADHD. Below is a summary of the functional impairments commonly seen across different age groups for individuals with ADHD.
# OVERVIEW Preschool children
Hyperactivity in preschoolers tends to be temporally and situationally stable [266] and is highly heritable [267]. However, clinicians should remember that inattention and hyperactivity in preschoolers can be influenced by a number of factors. These can include intellectual impairment, expressive language issues, and their response to child abuse and neglect as well as conflictual environments [268].
Epidemiological data indicates that approximately 2-7.9% of children from three to five years of age have ADHD [269]. The American Academy of Pediatrics has suggested that ADHD can be diagnosed in children as early as age four [270]. Nonpharmacological approaches should be the first-line treatment for preschool children [72,271].
# School-aged children
ADHD is one of the most common psychiatric disorders diagnosed in children. Prevalence rates range from 3 to 9% of school-age children [11,272]. A recent meta-analysis determined that the prevalence rate for children and adolescents was 7.25% [273].
Research indicates that girls may be consistently under-identified and under-diagnosed [31]. Commonly seen differences between boys and girls with ADHD exist during this period [274][275][276][277]:
• Boys may be three times more likely to be identified; girls are consistently under-identified and underdiagnosed.
• Girls with ADHD have lower levels of disruptive symptoms than boys with ADHD.
Childhood is usually the time where ADHD is diagnosed for most individuals. Challenges may occur in all areas of the child's life including at school, at home and during social activities. Interventions are aimed at minimizing the functional impairment that can occur and are part of what is known as a multimodal approach to treating ADHD.
There can be associated problems with ADHD, such as learning difficulties or low self-esteem, which must be managed in addition to the ADHD symptoms. The clinician must utilize the resources available in the team or in the community to provide additional supports for the child and the family. This may be through referral to other professionals such as a psychologist, occupational therapist, social worker, educational aid, resource teacher or behavioural consultant. Examples of useful accommodations for school-aged children can be found at www.caddac.ca under the 'Understanding ADHD In Education' tab.
# Adolescents
Prevalence rates of ADHD in the adolescent population range from 6-12% [278,279]. Between 50% and 80% of youth diagnosed with ADHD in childhood maintain significant symptoms and meet diagnostic criteria for the disorder in adolescence [87]. Males are three times more likely to be diagnosed with ADHD than females [276]. This discrepancy starts to lessen over time nearing adulthood.
As children grow into adolescents, it is important to work with both the individual and their parents together. This acknowledges the emerging autonomy of the adolescent. Clinicians should not rely exclusively on the parent as an intermediary. It is important to use language that adolescents can understand and avoid the use of excessive medical jargon. Adolescents should at some point be seen alone and during that time the clinician should develop rapport directly with the adolescent and obtain a history of risk factors such as reckless driving, smoking, drug use, sexual activity, family or interpersonal conflicts, illegal activities and issues of bullying. A review of their peer relationships helps to assess their social development and to flag any risky behaviour. Peers tend to be in trouble together.
Adolescents with ADHD are not always the best historians. They frequently do not have full insight into their condition and they may have a self-centered perception and a tendency to deflect blame onto others [280]. Gathering collateral information from key people who know the adolescent can be very helpful. Even though there can be considerable variability in ratings completed by adolescents, serial ratings (see CADDRA ADHD Assessment eToolkit) done by the same individual provide valid measures of treatment outcomes compared to pre-treatment.
Many of the symptoms seen in adolescence are like those seen during childhood but they can affect an adolescent's life in many different areas. Difficulties in school usually continue and often, because of increasing school challenges, become worse. Inattention, lack of focus, impulsivity and forgetfulness can impact assignments and grades. Even athletic and extracurricular activities can be negatively affected. Adolescence is also a developmental period where risk-taking can increase dramatically. Clinicians need to be aware of the very significant negative outcomes that can occur when ADHD during adolescence is untreated (see Accidents/Risks in Adolescence later in this chapter).
Adherence to medication and to psychosocial interventions can be very poor in adolescence. Studies indicate 48-90% of adolescents stop taking their medications [24] [281], though the use of once-daily dosing improves adherence [282]. Psychoeducation is a very useful tool for augmenting adherence by making the adolescent a partner in treatment [283]. Knowledge of the individual's acceptance level of their diagnosis will help determine if intervention is required to address resistance. Using motivational interviewing techniques can be helpful with adolescents who will not adhere to treatment [284].
# College/University Students
The prevalence of ADHD among post-secondary students is between 2-12% [285]. Young people with ADHD attending university programs may present with varying histories, such as:
• Students already diagnosed and treated in childhood may want to adapt their ADHD treatment to their studying schedule. This may be a challenge as students may require treatment coverage further into the evening or night.
• Some students may have stopped taking their medication and may want to restart their treatment as they face increasing cognitive demands of the university curriculum.
• Similarly, some individuals who may never have been diagnosed before seek consult for the first time while facing difficulties coping with the high cognitive demands of university classes.
Young adults presenting for the first time for a diagnosis of ADHD should be carefully assessed. Some reports in the literature suggest a subset of students may exaggerate their symptoms to obtain accommodations/benefits or to obtain medications to enhance performance, to sell or to use for recreational purposes [286]. A recent study found that some female college students endorsed having used ADHD specific stimulant outside a doctor's prescription for weight loss [287,288].
Life-time prevalence rates of non-prescribed stimulant use in college and university students range from 5%-43% [289].
Despite a minority of misusers, students with ADHD will benefit from access to treatments and accommodations. The CADDRA Assessment eToolkit includes an educational accommodation letter template and CADDAC provides a detailed chart of appropriate accommodations linked to specific impairments in the post-secondary environment on its website (www.caddac.ca).
# PRACTICE POINT
Information gathered from standardized rating scales help identify ADHD symptoms, comorbid disorders and associated impairments. If necessary, standardized cognitive evaluation focusing on attention and other executive dysfunction may help quantify IQ, identify specific cognitive dysfunction and, importantly, diagnose Specific Learning Disorders.
When assessing ADHD in post-secondary students, an assessment may require multiple visits and comprises a review of (when available):
• Parental/guardian reports of symptoms during childhood.
• School report cards.
• Reports from current collateral informants. Some reports suggest misuse or diversion of stimulants is associated with SUD and CD, so these conditions should be carefully screened for [290].
Additional school services and accommodations in the university setting can be very useful (e.g., separate testing environments, longer testing times, reduced homework and provision of a note taker).
# Adults
Many adults go undiagnosed and untreated for ADHD. In a study published by Kessler et al., [47] the prevalence of ADHD in adults (20-to 64-year-olds) was 4.4%. Some adults may present to healthcare professionals seeking an assessment for ADHD with no prior diagnosis. This occurs for a variety of reasons, including:
• Parents of children who have recently been assessed for ADHD begin to wonder if they may have the same diagnosis.
• Individuals who have heard or read about ADHD in adulthood and can relate to the symptomatology.
• A subset of adults who have not experienced significant symptoms or struggles prior to adulthood. Lack of challenges prior to adulthood may be due to significant supports, structure and routines earlier in life, and/or an above average IQ [291]. With increasing responsibilities and demands, and with diminished "scaffolding" in adulthood, many of these individuals begin to experience significant symptoms and associated impairment [291].
In adults with ADHD initially diagnosed during childhood, a significant number discontinue their medication management during adolescence [281]. This may be due to medication side effects, independence needs, healthcare discontinuity, social stigma , or symptom remission [292]. However, due to the re-emergence of symptoms and associated impairment in adulthood, they may seek re-assessment of their ADHD and choose to resume treatment.
Most adults with ADHD (85%) suffer from a comorbid mental health condition [50]. Thus, many adults with undiagnosed ADHD may present to their primary care physician and/or mental health professional seeking treatment for what may appear to be a primary mood, anxiety or other mental health disorder. Others may get medical attention for substance use or high-risk behaviour consequences, trauma or unplanned pregnancies. It is important to know which of these individuals should be screened for possible underlying ADHD. Missing this diagnosis can result in years of trials with antidepressants, mood stabilizers and anxiolytics without adequate symptom response.
Examples of useful workplace accommodation and information for employees and employers can be found on the CADDAC website (www.caddac.ca). CADDRA has a template for requesting occupational accommodations in the eToolkit.
# Older adults
Results from a large epidemiological study have demonstrated that ADHD symptoms can persist in older adulthood, with an estimated prevalence of about 3% [293].
However, there is relative paucity of data available on the aging ADHD population compared to younger age groups. Small observational studies have characterized the presence, impact, and treatment of ADHD in adults over the age of 50 years [294].
Undiagnosed ADHD in older patients can lead to lifelong functional and psychosocial impairments. In addition, the presence of comorbidities including depression and cognitive impairment can make diagnosing an older patient's ADHD complex. Furthermore, diagnosis of ADHD in older adults can be tricky because some ADHD symptoms are seen in the normal aging process, or are similar to certain symptoms of minimal cognitive impairment or dementia, thus leading to the incorrect assumption that older adults with ADHD are undergoing a neurodegenerative disease process [295].
It is therefore crucial to raise clinician awareness about ADHD in older adults. Detailed history-taking (longitudinal cognitive difficulties since childhood) and neuropsychological testing may help the clinician to make a diagnosis of ADHD [296]. In summary, diagnosis in older adults requires identification of past and current symptoms/impairments, and differential diagnosis should include other neuropsychiatric conditions. The first-line medications for ADHD recommended in these guidelines remain the treatment of choice for older adults when their medical condition permits their use. It is important to note that very few clinical drug trials have included participants with ADHD over age 65. However, appropriate treatment with specific medication for ADHD might improve functional outcomes for older adults with ADHD, including those with comorbid dementia [297]. An important consideration in treatment is drug interactions since older adults often take multiple medications. Medication and psychotherapy trials with older adults are needed to determine best treatment approaches.
# IMPACT/FUNCTIONAL DISABILITY ACROSS THE LIFESPAN
ADHD can impact all aspects of an individual's life, both personally and systemically. In a 33-year follow-up study, children with ADHD were found to have a greater risk of poor long-term outcomes as adults in almost every aspect of life compared to their non-ADHD counterparts [298].
The core difficulties in executive functioning seen in many individuals with ADHD [299] cause varying degrees of functional impairment depending upon the demands made on the individual by their environment and the supports available. Variable factors include family and school or occupational resources, as well as personal responsibilities, coping strategies, cognitive capacity and reflective insight of the individual.
Individual -Regardless of academic, personal, occupational, professional or financial success, many individuals with ADHD struggle with low self-esteem [300]. Some often describe negative beliefs or expectations of their own abilities. Some describe an "imposter complex" whereby they have trouble taking credit for their success. This may be due to lifelong inconsistent performance and a history of negative feedback for perceived failures.
Family -Due to the high heritability of ADHD [15] there is seldom only one individual with ADHD within a family unit. In addition, untreated ADHD may be a significant explanation for a higher rate of separation and divorce in these individuals [301]. Other impacts on the individual or the family can include: parental stress; parental emotional/mental health problems; sibling conflict; disruption to family cohesion; and less time available to spend on family activities [302]. In a survey of 500 individuals with ADHD compared to 501 matched controls it was found that the annual US household income losses due to ADHD were $77 Billion USD per year and up to $15,000 per household per year [303]. The literature supports the fact that ADHD runs in families [318] and where appropriate, other family members should be screened or encouraged to seek out assessment. Parents, siblings and extended family members may have ADHD and therefore have problems with organization, consistency, impulsivity and emotional lability. In addition, having a child with a disability may increase the likelihood of substance abuse, depression and anxiety in parents [319]. Parental psychopathology can have a significant impact on the parents' ability to structure, monitor and generally help their child [141,320]. Identifying this psychopathology and referring the parents for appropriate treatment will improve the psychiatric state of the parent(s) and their parenting ability, and thus be of great help to the child or adolescent and their family. It is important for the parent(s) to be treated at the same time as the child or adolescent. This "all in the family" approach to intervention is good for the child/adolescent as it shows that the parent can empathize with their experiences. When parents learn skills to control their own lives, it is easier to institute structure in the child's life [321][322][323].
School -Individuals with untreated/undertreated ADHD are more likely to be expelled or be truant, may have lower grades than expected, and also disrupt others' education [304]. This may impact the individual's future social and economic status.
Occupation -Adults suffering from ADHD have higher absenteeism and lower productivity in the job setting [305]. They are also more likely to impulsively quit or change jobs, or be fired [306]. Specific ADHD treatment may diminish this risk (87).
Healthcare and Society -A population-based, historical cohort study followed 4,880 individuals from 1987 to 1995 and compared the nine-year median medical cost per person: ADHD medical costs were US$4,306, whereas non-ADHD medical costs were US$1,944 (p<0.01) [307]. Individuals with ADHD have a 33% increased rate of emergency room visits [307] and may be more vulnerable to motor vehicle accidents with some studies suggesting a rate that is two to four times as high [42]. Compared to children without ADHD, children with ADHD may be more likely to sustain injuries that are severe, and that involve the head or multiple body regions [308]. The increased rate of accidents in individuals with untreated/undertreated ADHD has economic impacts on the healthcare system, as well as economic and social effects within the family (e.g., reduced income, missing education) [309].
# ACCIDENTS/RISKS
Accidents/risk in childhood ADHD in children has been linked to a two times greater risk for accidental injuries of all types, for more severe injuries, as well as for repeated injuries [310]. Comorbidity of ODD/aggression with ADHD in children is thought to exacerbate these risks [87].
Children admitted to hospitals due to accidental injuries are three times more likely to have ADHD (approx. 30%) than are children admitted for other reasons. Factors that have been associated with these elevated risks are inattention, impulsivity and risk-taking behaviours, motor incoordination, comorbidity with ODD/CD, anxiety, and depression, and parental characteristics such as reduced parental monitoring of the child's activities. Medication can decrease injuries [87].
# PRACTICE POINT
Promote safety in the home and outside, especially for the hyperactive/impulsive child. To reduce risks, children with ADHD may need supervision of activities, such as walking to school, that peers may not require.
Points to discuss with parents:
• Provide physical safety (e.g. safety proofing, ample outdoor places that can be safely used and supervised, opportunities for physical movement).
• Assure adequate supervision, and reinforce behaviours where the child shows risk management (e.g. wearing a helmet/protective gear, asking permission, wanting advice, following rules, reading instructions, showing good judgment).
• Children with ADHD benefit from physical activity and may find opportunities for success in play or sport.
• Balance must be struck between providing safe environments and overprotection.
• It is also important to create a calm, structured, positive approach to child rearing to not only optimize appropriate developmental progression, but also allow for a more acceptable response to limit setting.
• Above all, it is crucial that parents retain an enjoyable relationship with their child that encourages their self-esteem. Doing things that the child excels at or enjoys is very important. Parenting should include not only structure and guidance, but fun. The school must create a similar environment.
# Accidents/risk in adolescence
Adolescence is a developmental period when a significant percentage of individuals start to engage in activities that have associated risk [311]. Adolescents who have ADHD are at higher risk than the general population for experiencing the negative outcomes of risky behaviours [312]. Impulsivity, in particular, can negatively impact an adolescent's executive functioning. There is much evidence that untreated ADHD can lead to higher rates of accidents, school failure and dropout, driving accidents and family conflict/fighting [313].
Sexual activity starts for some during adolescence. Both male and female adolescents who have ADHD are at increased risk for early sexual activity, sexual transmitted diseases and multiple sexual partners [314]. Females with ADHD are at risk of higher rates of teenage pregnancy compared to adolescents without ADHD [314,315]. Information should be provided about risky sexual activities and use of birth control methods should be encouraged where appropriate.
Adolescence is frequently the time where experimentation with alcohol and drugs begins. Adolescents with ADHD have higher risk than the general population to start using earlier and to develop more severe difficulties with substances [131]. Comorbidity of ADHD and SUD commonly starts in adolescence [316].
Abstinence from illicit drug use is ideal, though a harm reduction approach may be a useful option. Another group of substances that should be asked about are beverages containing excessive caffeine, including for example "energy drinks".
# Accidents/risk in adulthood
Many of the risky behaviours that are problematic in childhood and adolescence continue to impact individuals with ADHD into adulthood. In a recent study, the adjusted mortality rate ratio (MRR) was greater for individuals diagnosed with ADHD, and increased with delay in diagnosis. The adjusted MRR was 1.86 when diagnosis occurred before six years of age and increased to 4.25 when diagnosis was delayed to 18 years or older [317]. The cause-specific mortality for suicide was significantly higher among ADHD cases (SMR = 4.83). This study concluded that childhood ADHD is a chronic health problem, with significant risk for mortality, persistence of ADHD, and long-term morbidity in adulthood.
Richards et al. [42] assessed negative driving outcomes in individuals with ADHD, reporting more driving anger and aggression expressed using vehicles, as well as less adaptive and constructive anger expression compared to peers without ADHD. College student drivers with ADHD rated themselves as more angry, risky, and unsafe behind the wheel, and reported more struggles with concentration and vehicular control [318].
# DRIVING
ADHD symptoms can negatively impact the ability to drive safely for both adolescents and adults [319]. Not all patients with ADHD who drive have significant driving problems. However, the epidemiological data suggest that ADHD drivers as a whole have an increased risk [329,330]. It is important that all adolescents with ADHD have driver training and that their driving risks be minimized (e.g. curfews, staying off major highways, absolutely no drugs or alcohol while driving). Driving assessments can be done and an example of such is the Jerome Driving Questionnaire (JDQ), which is provided in the CADDRA Assessment eToolkit).
Clinical studies indicate that young drivers with untreated or sub-optimally treated ADHD have between two to four times as many motor vehicle collisions and moving violations than a comparable non-ADHD population [320]. These driving problems are seen independent of comorbidity. The problem profile commonly includes speeding, distractibility and driving anger or road rage. The presence of ADHD and comorbid substance use disorders magnifies driving risk [321,322].
Neurodevelopmental immaturities in executive functioning (resulting in problems with attention, impulse control and emotional regulation), combined with a lack of driving experience, can lead to problem driving styles in young people in general [323]. On-road data demonstrates the benefits of long-term use of stimulant medication in reducing motor vehicle collisions in older adults [324].
Simulator and on-road observation studies suggest that methylphenidate, dexamphetamine and atomoxetine improve driving behaviours in ADHD populations [325,326]. At the time of writing (March 2017) there are no current studies evaluating other agents for treating ADHD. Clinicians should monitor individual response to medications, both for improvement as well as worsening of driving abilities. For example, agents like guanfacine or clonidine may be sedative initially and worsen driving in the initial titration period. In addition, some medications may not last until late evening or adherence with the use of an "as needed" short-acting stimulant medication is particularly poor in the evening, which is the time of maximum driving risk for young drivers.
Restrictions on cell phone and manual transmission use, as well as on nighttime and weekend driving, may all improve driving performance. Psychosocial and legislative interventions may prove to be more effective preventative public health measures in the long run [327,328].
# EVALUATION OF DRIVING RISK AND DOCUMENTATION
Discussion with young drivers and their families should include information on functional impairment and driving risks [87]. Problems with speeding, following too close, road rage, inattention and distractibility when driving should be reviewed. When developing a therapeutic alliance with a family, it may be useful to encourage contracts between young drivers and their families where adherence with medications and other issues such as good school performance are exchanged for access to a motor vehicle. Documentation of discussions regarding driving safety, along with use of a driving style and behavior assessment, would demonstrate that the clinician is exercising due diligence for their ADHD patients around driving safety issues. The Canadian Medical Association (CMA) Guidelines on Fitness to Operate a Motor vehicle continue to remind physicians that if ADHD drivers have a demonstrated problem with driving and are non-compliant with treatment recommendations, doctors have a duty to report their concerns to the Provincial Ministries of Transportation [329]. Reporting in Alberta, Quebec and Nova Scotia is discretionary [329]. The latest CMA guidelines continue to recommend the same reporting requirements and have an updated reference list on ADHD and driving.
# CHAPTER 4: PSYCHOSOCIAL TREATMENT OF ADHD
Until recently, symptom control was the main priority in the assessment and treatment of ADHD [330]. In recent years, the clinical focus has shifted towards functional impairments and outcomes, with improvement of overall life quality as the main goal [330,331]. ADHD can impact many aspects of an individual's daily life such as social and emotional functioning, academic/work-related success, relationships, marriage, family life and even physical health [332]. This is true for individuals with ADHD across the lifespan. Generally considered to be a chronic lifetime disorder, ADHD requires a comprehensive, collaborative and multimodal treatment approach [333] tailored to meet the unique needs of the person with ADHD.
Research studies and clinical experience show that a multimodal approach (incorporating psychosocial interventions together with medication) improves not just core ADHD symptoms but the overall quality of life by improving the resultant functioning impairments [330,331,334]. Medications are an important aspect of treatment and assist the facilitation of changes in these areas by improving focus, self-regulation and decreasing impulsivity/hyperactivity and thus allowing the individual to use psychosocial strategies more effectively [335,336].
Psychosocial treatment is the therapeutic approach preferred by many individuals over medications and is recommended as a first line for preschoolers by the American Academy of Pediatrics and the Choosing Wisely Canada campaign (choosingwiselycanada.org). Psychosocial interventions play a particularly crucial role during key life transitions, for instance in the transition from adolescence to adulthood [291,[337][338][339]. It is important to incorporate a patient-/familycentered approach to ADHD treatment, by considering individual/family treatment preferences [340][341][342] Although front-line clinicians may see time constraints and perceived lack of expertise as barriers to implementation of psychosocial treatments [343], these individuals are in fact ideally placed to assess and provide treatment for ADHD beyond traditional pharmacological approaches. Primary care practitioners are in the unique position of being able to diagnose, treat and follow individuals with ADHD across the lifespan [344]. They can provide or support some of these interventions in a timely manner either on their own (with community resource supports) or in co-ordination with other medical specialists, health-care providers and professionals from the educational system.
A solid therapeutic alliance is best achieved by spending time listening to a patient's concerns and understanding their perspective and goals. CADDRA wishes to highlight this principal as being the core foundation for all effective treatment approaches.
# PSYCHOEDUCATION
The overall purpose of psychoeducation is to educate and empower patients and their families by providing information on ADHD (e.g., impact on daily functioning, treatment options, strategies for optimizing functioning).
# PRACTICE POINT
CADDRA Guide to ADHD Psychoeducation can be downloaded from the CADDRA website from the Resources section. This guide provides a quick overview of the components of psychoeducation along with a summary of strategies and interventions that can be recommended to individuals with ADHD and their families.
# Key Elements of Psychoeducation Discover
Find out what the patient and family already know, or think they know, about ADHD [345]. This may help guide your approach to diagnosis and treatment.
# Demystify
Take the time to discuss some of the societal myths commonly associated with ADHD. For example, the following myths are adapted from the "Take Ten Series" from the CanLearn Society, Calgary.
# MYTHS FACTS
ADHD is not a real condition ADHD is a neurobiological condition that is associated with inattention, hyperactivity and/or impulsivity, along with several related difficulties, inappropriate for an individual's age.
# ADHD is over-diagnosed
A US 2014 national survey found that healthcare practitioners are carefully diagnosing children. The vast majority (9 out of 10) of the 2,976 children diagnosed with ADHD had been diagnosed by practitioners using best practice guidelines [346]. Possible explanations for increased diagnosis of ADHD include improved healthcare practitioner and parental awareness; more screening by pediatricians and other primary care givers; decreased stigma about ADHD; availability of better treatment options, and more awareness of suspected environmental causes such as prenatal exposure to toxins or high blood lead levels [347].
# All children with ADHD have disruptive behavioural problems
Approximately 50 percent of children with ADHD demonstrate significant problems with disruptive behaviour [348,349].
# ADHD results from ineffective teaching and/or poor parenting
ADHD is primarily biological and genetic in its origins. Environmental factors such as teaching and parenting quality, however, can minimize or intensify the difficulties experienced by an individual with ADHD [16].
# Children with ADHD can never pay attention or complete their work
Inconsistency is a pervasive characteristic of ADHD. Sometimes, and under some circumstances, individuals with ADHD can focus and concentrate, while at other times they experience extreme difficulty. They are, for example, often able to hyper focus on stimulating activities, like video games, or creative activities such as Lego or drawing.
# CONTINUED…
# All children with ADHD are hyperactive
A person with ADHD may not necessarily demonstrate hyperactivity. In fact, some individuals with ADHD may appear to lack energy and seem quiet and reserved.
# ADHD only occurs in boys
Boys are four to nine times more likely to be diagnosed [277]; however, the disorder occurs in both boys and girls. Girls are more prone to inattentive type ADHD [276], which is marked by disorganized and unfocused behaviour rather than the disruptive, impulsive conduct typically seen in boys. Girls with ADHD tend to have higher rates of overall distress, anxiety and depression compared to boys with ADHD [275].
# Food allergies, refined sugar, food additives and poor diet cause ADHD
The actual correlation between ADHD and diet has not been proven [350]. Good nutrition and general health are always important. An unhealthy lifestyle, including poor diet, can influence attention and functioning [351].
# Medication alone can manage ADHD
While there is no cure for ADHD, medication can have positive effects on symptoms of inattention, impulsivity and hyperactivity. A "multimodal" or comprehensive approach is most beneficial and includes appropriate diagnosis, personal and family understanding of the disorder, behavioural interventions and educational supports.
# Individuals with ADHD are lazy or lack willpower
Everyone finds it easier to focus on a topic or activity that catches their attention. Many people with ADHD have some domains of activity (such as sports, music, video games, art, mechanical activities and areas of work) in which they can focus very well. As a result, their inability to focus in other areas is often misunderstood.
There is a test that can diagnose for ADHD ADHD is a clinical diagnosis that should be arrived at through a comprehensive evaluation of the history and presentation. This is true of many other medical conditions (e.g. migraine).
# Everyone has ADHD because everybody is inattentive sometimes, especially these days.
The core symptoms of ADHD can occur in everyone occasionally (e.g. forgetting items). People with ADHD, however, experience significantly greater numbers of these symptoms (meeting a threshold of at least 6/9 symptoms for children, 5/9 for adults (17+)), with greater frequency and more significant difficulties and impairment (e.g., job loss, academic underachievement).
# Instill Hope
Families will respond positively when told evidence-based treatments and interventions do exist. This in turn will promote the therapeutic alliance and a positive outcome.
# Educate
The first step is to educate individuals and families about the nature of ADHD and its symptoms. If relevant, explain the concept of emotional dysregulation. This refers to the fact that many individuals with ADHD can experience difficulty selfmodulating and regulating emotions, often referred to as "a short fuse". They can impulsively over-react verbally or physically, causing significant conflicts.
Explain the rationale behind your treatment approach (e.g. the use of pharmacological or psychosocial interventions and the risks and benefits of each). For example, ADHD medications can improve focus and decrease impulsivity/hyperactivity, allowing individuals to make better use of psychosocial strategies [335]. Provide handouts and information on relevant websites, community resources, parent training and support/social skills groups, etc.
# Empathize
Acknowledge feelings of discouragement and frustration (e.g. "that must make you feel so sad, mad…"). Empathize with the challenges of living and coping with ADHD every day, of raising a child with ADHD or living with a spouse, grandparent etc. who has ADHD. Keep in mind that ADHD is a highly hereditary disorder and therefore often multigenerational [107,352,353].
# Encourage, Guide and Motivate
Because an assessment often focuses on areas of difficulties, the process may be an overly negative experience for some.
Identifying strengths during the assessment and follow-up may mitigate this and establish a solid therapeutic alliance.
Encourage individuals and families to nurture strengths and talents (e.g. encourage skills in areas such as sports, music, arts or drama). Families can showcase their children's achievements; attend their games, recitals, productions; hang their art, display trophies etc. Existing strengths and talents can be leveraged as part of the therapeutic intervention.
# Be Culturally and Gender Sensitive
Ethnic, gender and cultural issues may shape the perception and beliefs about ADHD and its treatment. For example, some cultures may have lower acceptance and higher stigma associated with ADHD. Demystifying ADHD may be especially crucial in those circumstances.
# Promote a Balanced Lifestyle
Individuals with ADHD often struggle with their daily needs (e.g. sleep, meals and personal hygiene) and need assistance creating a balanced lifestyle by developing healthy habits and routines including regular exercise, consistent sleep hygiene, and nutritious eating. The clinician can instruct a patient to make self-care a priority.
Promote regular exercise to decrease stress and frustration, improve focus and cognitive clarity, increase endorphins, improve mood and restore a sense of well-being [354][355][356][357]. Aerobic exercise has been shown to improve core symptoms of ADHD plus anxiety, often a concurrent comorbidity [358].
Outline consistent sleep hygiene. ADHD is often associated with delayed sleep phases [359]. Describe sleep patterns and outline consistent sleep hygiene routines.
Encourage good nutrition, meal planning, grocery lists, consistent meal times, and eating as a family. Eating pathology such as binge eating has been associated with ADHD [183,360]. Encourage active practice of relaxation techniques such as meditation, deep breathing exercises, yoga or music. These can be helpful, although research is limited [361].
# Give Online Resources / Local Community Resources / Book Lists
The CADDRA toolkit includes the CADDRA ADHD Information Handout.
Other online resources:
•
The Centre for ADHD Awareness Canada (CADDAC) provides information and resources for individuals with ADHD, their families, educators and other stakeholders. www.caddac.ca
• Quebec-based physician and CADDRA member Dr. Annick Vincent provides information in both English and French through www.attentiondeficit-info.com
• PANDA is a French-language network of associations that work together to meet the needs of individuals with ADHD and their families. www.associationpanda.qc.ca
# •
Children and Adults with Attention-Deficit/Hyperactivity Disorder (CHADD), is an American organization providing education, advocacy and support for individuals with ADHD. In addition to its website, CHADD also publishes a variety of printed materials to keep members and professionals current on research advances, medications and treatments affecting individuals with ADHD. www.chadd.com
• ADHD Families, based in Alberta, Canada, provides information and resources for families on ADHD. www.adhdfamilies.ca
# PSYCHOSOCIAL INTERVENTIONS OVERVIEW
Understanding that ADHD is not just a school/post-secondary/workplace problem is crucial for optimized management and improved quality of life. Recognizing that ADHD symptoms significantly impact an individual's and family's functioning from the time they get up in the morning until they go to bed at night, every single day of the week, including weekends, is vital for a successful outcome.
# What can be done at home?
Improved functioning within unstructured environments such as home life, social situations, extracurricular activities, may require the development of planning and organization skills, which are often sub-optimal in ADHD individuals in general. Individuals lacking these skills commonly feel overwhelmed, resulting in stress, frustration, anger, panic, and loss of selfesteem, as well as significant family relationship conflict, chaos, and dysfunction [362,363].
Promoting a structured lifestyle and home life is key to success [364]. Emphasize the importance of having a home life that is organized, predictable, consistent, calm, and focused on positive outcomes. Providing such external structure and modelling expected behaviours is essential for increasing self-esteem, improving self-control and ensuring more harmony in family life and relationships. Keep in mind that ADHD can be multi-generational, some families will experience more difficulty creating a structured environment than others will.
# Rationale Strategies
Because of poor sustained attention and difficulty following multi-step directions, communication needs to be clear and direct.
• Get eye and/or gentle physical contact before giving one or two clear instructions. • Get the person to repeat the instructions before proceeding.
# BEHAVIOURAL INTERVENTIONS
# Rationale Strategies
Individuals with ADHD have a higher rate of emotional dysregulation (i.e. short fuse, easily frustrated) and this can cause significant family/spouse/partner/child/peer conflicts [44,[365][366][367]. These deficits lead to detrimental effects in several aspects of daily life [368,369]. Individuals with ADHD prefer immediate, small rewards over a larger delayed reward [370].
• Use a positive approach and calm tone of voice. Avoid yelling and arguing. • Encourage calming techniques to de-escalate conflict. Example:
Teach "stop and think" [344]. Help them put on their brakes by taking deep breaths. • Use praise, "catch them being good" (doing chores, playing nicely).
• Set clear attainable goals and limits (specific homework routine, bedtime routine, chores, etc.) and tie them to earning privileges, special outings, etc.' • Use positive incentives and natural consequences; "When you...(do homework ) ...then you ...(may go play )"; if…then [371]. • Use empathy statements such as "I understand" / "however" can be useful. • Recommend that adults model emotional self-regulation and encourage a balanced lifestyle (nutritious meal planning, exercise, hobbies and sleep hygiene). • Schedule family and partner time.
• Keep choices limited to two or three options.
• Make rewards meaningful and timed in close proximity to the desired behaviour.
# ENVIRONMENTAL INTERVENTIONS Rationale Strategies
Transition times, homework times and daily routines are difficult for individuals with ADHD, therefore, external scaffolding is crucial to establish daily expectations and structure and promote success. [372,373].
• Implement structure and routines.
• Parents/partners must be united, consistent, firm and fair.
Follow through with agreed consequences.
• Help them prioritize instead of procrastinating.
• Post visual reminders (rules, lists, reminders, sticky notes, calendars) in prominent locations, using different colors to accentuate/prioritize.
• Use timers/apps for deadlines (routines, homework, chores, paying bills, limiting electronics).
# CONTINUED…
• Keep labeled, different coloured folders or containers in prominent locations for items (keys, electronics, household items).
• Find work area best suitable to individual, e.g. dining room table, quiet areas.
• Chunk tasks (divide larger tasks into smaller ones) and assign specific deadlines to each step.
• Allow planned frequent movement breaks during prolonged tasks.
• Allow white noise, a fan or background music during homework, work or at bedtime.
# What can be done at school?
Many individuals with ADHD struggle most at school. School interventions can be either proactive or reactive. Proactive interventions (e.g., visual cues and prompts) are directed at anticipating and reducing the likelihood of the child with ADHD engaging in disruptive behaviours. Schools should provide instructional and environmental accommodations for all students with ADHD. For some students, the proactive interventions may not be sufficient and behavioural approaches will be required. These reactive interventions consequence target behaviour by reinforcing positive behaviour (e.g., token economy) and ignoring or punishing negative behaviour (e.g., timeout; response costs) [331,334]. It is important to monitor the actual outcomes of these "reactive" interventions as they may inadvertently increase disruptive behaviour [374].
Sharing information about ADHD and its impact with the family and the school is a way to begin promoting success at school. The following strategies focus on instruction, behaviour and environment within the classroom that can enhance success.
# Table 4.3 School Interventions INSTRUCTIONAL INTERVENTIONS Rationale
Strategies Students with ADHD often have difficulty with the "language" in the classroom [209,375,376]. Students with ADHD may have difficulties following instructions (particularly if they are multi-step instructions) or interpreting pragmatic language [377].
• Give clear and precise directions.
• Get the student's attention before providing instructions.
• Check the student's understanding by having the student repeat instructions and provide clarification as needed.
• Use direct requests -"when-then".
# BEHAVIOURAL INTERVENTIONS Rationale
Strategies Students with ADHD are more responsive to consistent, immediate reinforcement. With behavior modification, parents, teachers and children learn specific techniques that will help improve children's behavior. Approaches identify goals and target behaviors to be modified; emphasize consistency and routine; boost individual self-esteem through verbal recognition and tangible rewards; and identify incentives that are developmentally appropriate. It is critical that goals are developed through collaboration with the student and their family. Incentives need to be meaningful to the individual.
• Provide immediate and frequent feedback.
• Provide students with positive feedback and encouragement more frequently than negative feedback.
• Provide students with specific feedback -"thank you for putting your hand up to ask a question".
• Use visual cues in the classroom or on the desk for transitions.
• Use visual prompts/pictures or lists for task initiation and task completion.
• Chunk and break down steps to initiate tasks.
• Reduce the amount of work required to show knowledge i.e. rather than asking a child to do 10 addition questions, requiring them to do 5.
• Providing clear expectations and structure in the classroom.
• Allow for acceptable opportunities for movement: "walking passes".
# ENVIRONMENTAL INTERVENTIONS Rationale
Strategies Students with ADHD often require changes in their physical environment that will decrease the likelihood of distractors and allow for more opportunities for teacher monitoring and interaction.
• Preferential seating away from distractions.
• Proximity to the teacher.
• A quiet place in the classroom for calming down or working.
• Being seated beside a "more attentive" buddy.
• Increase change and introduce novelty.
# ACADEMIC INTERVENTIONS Rationale
Strategies Students with ADHD may have co-morbid learning needs (e.g., fine motor difficulties, slower processing speed, weaker working memory) in addition to problems with distractibility that require specific accommodations in the classroom.
• Actively engage the student by providing work at the appropriate academic level.
• Allow extended time (1.5 x) to complete quizzes, tests and exams.
• Permit student to write quizzes, tests and exams in a quiet room.
• Allow ear-plugs/ head-phones to help reduce external noises during tests.
• Provide a scribe or note taker or access to assistive technology.
• Assign homework as necessary but monitor quantity.
# EXECUTIVE FUNCTION INTERVENTIONS Rationale
Strategies Increase in classroom demands are frequently accompanied by increased struggles with organization, time management, prioritization and task completion. Executive function deficits have a significant and negative impact on academic progress and productivity. As the student moves into later grades the most common service provided are academic accommodations (e.g., testing accommodations preferential seating, copies of class notes etc.) which are not designed to develop or improve skills but rather that the expectations are being changed to permit the student a better chance at advancement [331].
• Find a tutor or academic coach.
• Seek a structured classroom.
• Establish a routine.
• Keep an assignment notebook.
• Develop an organization notebook.
• Organize what needs to be taken to school the night before.
• Monitor and prompt to get started on tasks.
• Teach awareness of time; time management. • Use graphic organizer for long-term projects.
# POST SECONDARY INTERVENTIONS Rationale
Strategies Students with ADHD in college and university are often very challenged by executive function deficits and other comorbidities such as anxiety and depression, which places significant demands on the student's ability to maintain consistent and efficient pace. Students are easily overwhelmed when supports are not in place which begins a cycle of frustration and failure [378].
• Encouraging students to contact the Accessibility/Disability Centres.
• Allow extended time for assignments, especially if numerous assignments are all due at the same time.
• Allow extended time on tests/exams.
• Organizational apps to keep notes, lists, ideas and more e.g. Evernote and Simplenote, Mind Manager.
• Technological support to better organize thinking, taking notes, writing, e.g. Livescribe, AudioNote, One Note, SoundNote, Audiotorium and Screen Record.
• Concept Mapping can be achieved on the computer by using graphic organizers (e.g., Inspiration, Writers Companion, Draft Builder).
• Access to preferential seating in lectures (close to the lecturer, away from visual or auditory distractions such as cycling heating/cooling units).
• Access to a scribe or note taker to take notes for those courses where it is necessary to focus on the lecture rather than switching attention between lecture and note-taking to ensure lecture notes are adequate and thorough enough to review for tests/exams.
# CONTINUED…
• Obtaining advance copies of lecture notes, overheads, etc. so that the student can focus on the lecture rather than read what's on the board, take notes, and listen all at the same time.
• Use videotape lectures if granted permission and review them later to reinforce class work.
• Devices such as a tablet as well as apps that help with writing such as planning (e.g., Inspiration); drafting (e.g., Dragon Dictation, iPad Dictation); and note-taking (e.g., Notability).
• Work with accessibility/disability staff to review and chunk assignments, check details, assist with time management and due dates and review progress.
• Access to 'prompt' sheets/memory aids with outline of steps, formulas etc.
• Coaching to identify strengths, negotiate problems, and work on specific goals.
# What can be done in the workplace? Table 4.4 Workplace Interventions
# WORKPLACE INTERVENTIONS
# Rationale Strategies
Setting individuals up for success in the work environment is critical. Individuals with ADHD often prefer to not disclose their ADHD in the work place given the stigma attached to ADHD and the fear of being judged as incompetent [379].
• Identify accommodation needs.
• Request accommodations supports (Suggest using the CADDRA Template letter and adapting to your patient's situation).
• Suggest regular and frequent meetings with manager and support collaborative approach.
• Set goals, learn to prioritize, review progress on a regular basis.
• Identify time management techniques that work for individual (i.e. using a planner, apps).
• Declutter and create work friendly environment.
• Use organizational Apps (i.e. Evernote, Omnifocus, Todoist).
• Explore productivity Websites (e.g. 43folders.com, zenhabits.net).
• Get assistance from an ADHD Coach.
• Review workplace strategies and accommodations at www.caddac.ca.
# MANUALIZED INTERVENTIONS
# Parent Management Training Models
For preschool-aged children, parent management training models, including parent-child interaction therapy (PCIT), the Incredible Years series, the New Forest Program, Triple P (Positive Parenting Program), and Helping the Noncompliant Child, [380] are effective in decreasing symptoms of ADHD and disruptive behaviour disorders. Parents are actively involved in all of these interventions, sometimes without the child and sometimes in parent-child interactions. According to the American Academy of Pediatrics [381], all share similar behavioral principles, most consistently engaging parents as partners to: (1) reinforce positive behaviors; (2) ignore low-level provocative behaviors; and (3) provide clear, consistent, safe responses to unacceptable behaviors.
# Social Skills Training
Many children with ADHD may be socially awkward. They may wish to be more social but their impulsivity may detract from their ability to make friends [382]. Sometimes they miss social cues or misunderstand social conventions like when to ask to join in or when not to interrupt. It is important to note that there is a spectrum of impairment in social skills. Some levels of impairment may be due just to ADHD, but for others there may be sufficient impairment in social skills and related problems to warrant an evaluation for a possible Autism Spectrum Disorder (ASD) diagnosis. Making friends is an important skill set that both the school and parents can facilitate. Good friendships can be a protective factor in reducing some of the negative outcomes associated with ADHD [383].
Social Skills Training (SST) generally focuses on teaching children how to perceive and interpret subtle social cues and problem-solve in social interactions while being reinforced for appropriate skills display within a group setting [384,385]. Traditional SST involves a group of children receiving training, and parents are informed of the skills taught each week. These traditional approaches may have difficulty with encouraging treated children's generalization of knowledge to outof-session contexts and with changing peers' negative biases toward children with ADHD [386]. In fact, a Cochrane review of the effects of SST interventions on children's social competences, general behaviour, ADHD symptoms and performance in school showed no statistically significant treatment effects on social skills, teacher-rated behavior or on the ADHD symptoms [384]. Other SST programs involve simultaneous parent or teacher training as friendship coaches [387] and may hold promise in providing children with in vivo reminders during real-world peer interactions, and in helping to alter peers' behaviours toward children with ADHD [ 386].
# Cognitive Behavioural Therapy
Cognitive Behavioural Therapy (CBT) focuses on the interaction between an individual's cognition, emotion and behaviour [388,389]. In CBT specifically targeted for ADHD, such issues as time management and organizational skills are primarily addressed.
CBT is recognized as an effective psychological treatment for adults with ADHD [390,391]. One recent study has suggested that this therapy has a functional effect on the brain of adults with ADHD (specifically, the fronto-parietal network and cerebellum). These are the same regions affected by stimulant medications often used to treat ADHD [392].
Another study found CBT treatment for ADHD was effective but CBT plus medication resulted in greater improvement than CBT alone [393].
Studies on treatment outcomes of CBT in children and adolescents with ADHD have been mixed [394]. Adolescents with ADHD and anxiety/depression appear to benefit more than those with Oppositional Defiant Disorder [395]. Group CBT, along with medication, has been associated with reducing ADHD symptoms in adolescents [396].
# Mindfulness Training
Mindfulness training is a cognitive-based therapy, often including mindful meditation, designed to increase mindful attention to one's own thoughts and actions (i.e., training individuals to focus on the present and to inhibit distracting thoughts and stimuli). Neuroimaging studies have shown that mindfulness training appears related to structural changes in the amygdala and increased grey matter volume in the hippocampus [397][398][399]. It has been found to lessen ADHD symptoms such as hyperactivity/impulsivity and attention problems, emotional dysregulation, while increasing selfdirectedness and self-regulation. These and other improvements in mood, anxiety, and social behaviour have been reported in children, adolescents and adults with ADHD, with the improvements being maintained over time. Mindfulness may also be a useful tool for parents to improve their interactions with their children with ADHD [400][401][402][403][404][405][406].
# INTRODUCTION
Medications are part of an integrated and multimodal treatment plan that may include educational and psychosocial interventions. As with all pharmacological treatments in medicine, risk/benefit ratios need consideration before initiating any medication. Among the factors to be considered, the high morbidity of ADHD makes it important that we also weigh the risk of not treating ADHD [407]. ADHD has been associated with decreased social, educational, vocational and self-care functioning, as well as higher rates of accidental injury [317]. The burden of untreated ADHD also includes the time and energy it requires individuals, and those that support them, to cope with ADHD-related challenges [408].
It is important to clearly identify all areas of impairment due to ADHD at the onset of treatment, and regularly re-evaluate the ongoing impact of the condition. It is also important to systematically identify other potential causes of impaired functioning in a patient. Sleep deprivation, poor nutrition, lack of routines, psychosocial issues and comorbid disorders can affect outcome and should always be considered when assessing the patient's condition and when measuring clinical response.
Medication treatment should target symptoms that cause impairment. Clinicians are invited to use the documents in the CADDRA Assessment eToolkit in order to allow efficient and regular tracking of symptoms and impairments. Those tools are free to use and can be shared between patients, families, teachers and physicians in helping to guide an informed and evidence based treatment plan. Patients and their families should be aware that such questionnaires can help measure symptom frequency and associated impairment. However, just as a thermometer records a fever but does not identify the many reasons it could be occurring, ADHD symptom scales do not tell you if ADHD is the specific reason the symptoms are occurring. Clinical judgment is important to uncover if symptoms are due to, or modulated by, another disorder, both before starting treatment, and during treatment.
As with any chronic medical condition, follow up is important if medication continues to be taken. Medication may be reduced, temporarily interrupted or completely stopped, either because ADHD symptoms have improved and the patient does not need it anymore, or because the patient experiences unacceptable side effects or a lack of response. However, in some cases, medications are stopped for non-clinical reasons such as stigma or lack of financial coverage or other lack of access to care.
# MEDICATION CLASSIFICATION
For purposes of medication selection, CADDRA categorizes ADHD medications as described below. CADDRA recommends that clinicians first consider viable first-line therapy choices, then second-line therapies, and only then third-line medications may be considered. However, physician discretion and clinical judgement determines final choice as ADHD treatment needs to be individualized.
# First-Line Treatments
Long-acting psychostimulants are first-line treatment agents. First-line pharmacological treatments for ADHD are medications approved by Health Canada that have the best evidence base, risk-benefit profile, effectiveness as measured by effect size, and duration of effect. Additionally, sustained-release preparations maintain privacy for patients and families in the context of the school, work and social situations. CADDRA recognizes that long-acting ADHD medications use diminishes the need for multiple dosages and therefore augments compliance, symptom coverage and treatment response [409]. In addition, compared to immediate-release psychostimulants, use of long-acting psychostimulants may diminish diversion and rebound and is often associated with better tolerability [410].
It is important to note that both classes of stimulant medication (methylphenidate and amphetamines) have similar efficacy and tolerability profiles at the population level. However, at the individual level, patients may respond to, or tolerate one class better than the other [411,412]. CADDRA therefore recommends an adequate trial of both classes of long-acting psychostimulants before engaging in a trial of a second-line treatment.
# Second-Line Treatments
Atomoxetine, guanfacine XR and short/intermediate acting psychostimulants are second-line treatment agents. Second-line treatments are medications approved by Health Canada for the treatment of ADHD but may have lower effect sizes, sub-optimal duration of action compared to first-line treatment, or reduced tolerability and risk-benefit profile [409,413]. They can be used for patients who experience significant side effects, have had suboptimal response with first-time medications, or do not have access to first-line medications [414]. Non-stimulants may also be used in combination with first-line agents as a potential augmentation for first-line treatment suboptimal responders [415]. Second-line non-stimulant agents also are appropriate where stimulant agents are contraindicated, such as in cases where there is high risk of stimulant misuse [133].
# Third-Line Treatments
Bupropion, clonidine, imipramine and modafinil are examples of third-line treatment agents. Atypical antipsychotics are among agents used for comorbidities commonly seen with ADHD, often in combination with other agents. They are medications whose use is off-label, or have higher risks, or a higher side-effect profile or a lower efficacy profile. Third line pharmacological treatments are generally reserved for treatment-resistant cases and may require specialized care. Exceeding product-monograph recommended maximum dosages is a third-line treatment option and may be considered after regular dosages of different options have been tried.
# STEPPED APPROACH TO PRESCRIBING
# STEP 1 -Setting Treatment Objectives
# Figure 5.1 Stepped Approach to Prescribing
Once ADHD is diagnosed, in collaboration with the patient and collateral informants, the next step is to identify ADHD symptoms and functional challenges as treatment targets. Consider targets in multiple domains including home, school, work, etc. Good treatment objectives are Specific, Measureable, Attainable, Relevant and Timely (SMART).
# 55
# STEP 2 -Medication Selection
When medication is discussed, use principles of informed consent to ensure the patient and family (where applicable) are adequately educated when addressing medication questions, particularly regarding clinical indications, reasonable goals of treatment, dosing strategies, degree of efficacy, side effects and adherence issues. Both patient related and medication related factors should be considered in the selection of a specific medication for the treatment of ADHD. These factors are outlined below.
# Medication Selection: Patient-related factors Age and individual Variation
• There are no age-specific match criteria -In general, ADHD medications could be used across the lifespan, although not every medication has received an "official" approval for all ages through the process required by the Therapeutic Products Directorate (TPD) of the Canadian government. Some ADHD medications (e.g. guanfancine XR), are lacking in trials and evidence in some age groups. Treatment before the age of six, if necessary, should be within the context of specialized care [270].
• There is no maximum age to treat ADHD -if the general health and cardiovascular status of the patient permits use of those treatments. See chapter three for special considerations in treatment in older adults with ADHD.
• Women of childbearing age -the effects of ADHD medications on the foetus and on the baby while breastfeeding are unknown and require careful weighing of any potential benefits and risks.
• Children and some adult patients may experience difficulty swallowing pills -Although this can often be improved by teaching swallowing techniques, it should also be noted that some medications can be sprinkled on soft food or diluted in liquid or are available in a chewable form (See section on delivery).
• No specific clinical profile can predict which medication will be better.
• Adherence to treatment -ADHD-related forgetfulness may cause difficulty adhering to a plan that requires multiple daily doses. Once daily doses are more helpful.
• Predicted compliance -Medications that cannot be stopped suddenly (e.g. alpha-2 agonist class agents) should be used with caution in patients who have compliance issues. Compliance can be improved with psychoeducation, regular support and follow-up.
• Weight of the patient does not predict optimal dosage for psychostimulants.
• At this time, there is insufficient evidence that symptom profile, family history or genetic testing can help predict which medication will work best for an individual in clinical practice. While patients respond differently, all medications approved for use in ADHD by Health Canada can reduce both inattention as well as impulsive/hyperactive symptoms of ADHD.
# Duration of Effect Required by Timing of Symptoms
With time, or with change in environmental supports or demands, the burden of ADHD may change. Medication use can be titrated to meet increased demands or to cover longer periods of daytime impairment. When considering duration of effect of the medication, it is important to remember that ADHD may impact all aspects of the patient's daily life, not just in the classroom or workplace. Attention and self-control are also important outside of school and work. Thus, the severity of impairment from ADHD will vary from individual to individual and between different developmental stages and ages.
The decision about when to administer treatment during the day and how long the effect of that treatment needs to last must be explored by the clinician in consultation with the patient and patient's family. This decision must be made considering the context of the individual's experience. The numerous ways ADHD symptoms can impact a person's daily life -at home, at school, at work, at play -makes it important to not only optimize treatment for core symptoms and to minimize side effects but to consider WHEN treatment is required.
In considering patient preferences regarding duration of effect it is also important to keep in mind that the level of insight regarding the functional impact of having ADHD varies from patient to patient. For example, an adolescent patient may only be concerned about the impact of ADHD on academic functioning during the day and may be unaware of its impact on their driving or evening risk-taking activities.
To improve the overall quality of life for the majority of individuals, regardless of age, the duration of effect of the medication usually needs to extend beyond the classroom/work settings into the evening, weekend and holidays. Similarly, a patient may realize that the best option may be to have individualized treatment based on day-to-day variation. This may be critical for tasks such as driving, where the maximal risk period for young drivers may be during the evenings and at weekends. It is important to remember that the duration of effect for a specific medication can vary from patient to patient. Clinical experience indicates that, for some patients, the duration of effect is shorter or longer than what is stated in the product monograph.
# Concurrent Psychiatric & Medical Issues Psychiatric Comorbidities
When there is a co-occurring psychiatric disorder along with ADHD, it is generally advised that the most impairing disorder be treated first. A variety of considerations may be important in determining sequence of treatment including diagnostic certainty, patient preference, the disorder with greatest impairment, or the disorder most likely to respond to treatment. However, psychosis, severe mood disorder, substance use disorder and all types of bipolar disorders should be identified and treated prior to ADHD, as these may complicate treatment. If the patient is expressing suicidal or violent thoughts these need to be addressed as a priority.
It is common for patients to have mood and anxiety distress secondary to ADHD. Treatment strategies should take into account those issues. Often, an effective ADHD treatment may contribute to reduce mood and anxiety related to ADHDassociated impairments. Although stimulants are thought to upregulate sympathetic nervous system activity, they are often compatible with anxiety disorders. For a more detailed discussion of comorbid conditions please refer to Chapter 2.
When treating comorbid psychiatric conditions, physicians should try to select medications that impair cognition less since this may aggravate ADHD symptoms, and consider potential drug-drug interactions. Treatment of ADHD combined with comorbid psychiatric disorders often involves polypharmacotherapy, increasing the risk for pharmacological interactions and side effects.
# Medical Precautions with ADHD Medications
It is important for clinicians to be aware of any medical risk the patient may have that affects suitability for an ADHD medication. Although some pre-existing conditions like tics and sleep problems may be positively affected by ADHD medications, in some cases they can be aggravated.
# Weight and Height
Weight and height require initial and ongoing measurement in children and adolescents. Referencing percentile charts and growth charts is recommended.
# Cardiovascular Issues
ADHD medications can affect blood pressure and heart rate. Personal history of unexplained light headedness, shortness of breath, or other possible cardiac symptoms, as well as any family history of suspected cardiac sudden death should lead to workup prior to initiation of stimulant treatments. Blood pressure and heart rate should be measured initially before starting ADHD medication and during followup. To understand the effect of ADHD pharmacology on blood pressure or heart rate, it is important to take measurements while medication is present in the patient's system.
To assess the effects of stimulants on vital signs, it may be useful to take measures before a dose is taken and compare to measures while the dose is active.
# PRACTICE POINTS
• Prescribers should thoroughly weigh the risks versus benefits of treating ADHD patients.
• Psychostimulants have been broadly prescribed for more than a half-century, with considerable safety data in the general population.
• A detailed medical history is recommended to identify potential cardiovascular risks of psychostimulants.
• Routine ECG monitoring, either before drug administration or after starting therapy, is not recommended in young patients with no history of heart disease or normal physical examination.
• Blood pressure and heart rate should be measured initially before starting ADHD medication and during follow-up.
• Cardiology consultation should be considered in patients with established or suspected heart disease.
# Special Section on Potential Cardiovascular Risks of Psychostimulants
Psychostimulant medications are generally safe and well tolerated in children, adolescents, and adults with ADHD. However, there has been controversy regarding the cardiovascular safety of these drugs, particularly the potential risk of arrhythmias. The direct consequence of small increases in systemic adrenergic activity lead to the expected cardiovascular effects of small increases in blood pressure and heart rate, which are statistically significant, but rarely clinically important [416][417][418][419]. However, some individuals may have much stronger sympathetic effects.
In 2006, the FDA and Health Canada raised concerns about ADHD medications after identifying 27 cases of sudden death in children from Adverse Event Reporting System (AERS) data between 1992 and 2004, and Health Canada withdrew market authorization for some medications. Following incorporation of the number of patient-years of prescribed medication into the interpretation of the AERS data and a detailed review, market authorization was reinstated, but warnings were added to ADHD medications labels.
There has been epidemiologic evidence related to ADHD medications and sudden cardiac death subsequent to the 2006 labeling that is reviewed below. It should be noted that this labeling does not constitute a recommendation for routine ECG screening prior to initiating ADHD medication in patients without identifiable risk factors for cardiac disease from history and examination. Population-based ECG screening is a controversial topic, with costs, benefits and feasibility that are highly dependent on the health care jurisdiction in which they are applied.
Using AERS data adjusted for drug exposure, the frequency of reported sudden death per year of ADHD therapy ranges from 0.2 to 0.5 per 100,000 patient-years [420][421][422][423], compared to a recognized baseline risk of 1.2 to 1.3 per 100,000 patient-years in the ostensibly normal paediatric population [424]. It is recognized that adverse events are usually underreported by 75 to 90%, although true underreporting for an event as dramatic as sudden death is not known. To study such low event rates, administrative databases have been used. Using Florida Medicaid beneficiary data on patients 3 to 20 years of age over 10 years in over two million individuals, rates of cardiac death or cardiac hospitalization were similar for ADHD patients prescribed psychostimulants as compared to the general paediatric population [425]. An administrative database study of children and young adults funded by the Agency for Healthcare Research and Quality and the FDA (>2.5 million person-years including 373,667 person-years of ADHD drug use) showed no increased risk of sudden death or stroke in patients with compared to without ADHD drug prescription [426]. In a third claims records database study, neither current nor previous stimulant use was related to cardiovascular symptoms or events [427]. A study of over 440,000 adults, with over 150,000 ADHD medication users, found no evidence of an increased risk of MI, sudden cardiac death or stroke [426].
On the other hand, two studies have identified associations of ADHD medication use with sudden death. A case-control study assessed matched groups of 564 children aged 7-19 years from state mortality data over an 11-year period, comparing those who had suffered sudden unexplained death to those who had died as passengers in motor vehicle accidents. Ten (1.8 %) of the sudden unexplained death cases were treated with a stimulant at the time of their death, compared with only two (0.4 %) of the motor vehicle accident victims. However, the histories related to the sudden unexplained death cases may have been subject to a recall bias, and in the absence of autopsy information, assigning cause of death in young individuals with sudden unexplained cardiac arrest is difficult [428]. In an administrative database study of Medicaid and commercial insurers, 43,999 new adult methylphenidate users were matched to 175,955 nonusers, and had a significant hazard ratio of 1.84 for sudden death or ventricular arrhythmias. Dosage was inversely associated with risk, and this lack of an expected dose-response relationship suggested that the association might not be a causal one. In addition, ventricular arrhythmias and sudden death are not synonymous and may arise by very different mechanisms, especially in persons without structural heart disease [429].
Taken as a whole, subsequent studies support the 2006 assertion that, when adjusted for medication exposure, sudden death rates in ADHD patients do not appear to differ from the general population. The AERS data had also demonstrated that sudden deaths in patients receiving ADHD medications has similar associations to those seen in sudden death within the general population, including male and teenage preponderance, occurrence during exertion, family history of sudden death or life-threatening ventricular arrhythmias, and pathology findings of cardiomyopathy, valvular defects or coronary anomalies. Despite the similarities to sudden death victims in the general population, and the absence of any identified incremental risk, ADHD medication labelling continues to advise that they "should generally not be used in patients with known structural cardiac abnormalities". "Structural abnormalities" are in general meant to encompass LV dysfunction, scarring, hypertrophy, and significant valvular disease, although the term is not precisely defined. Such patients where identified will benefit from expert cardiac assessment. Although they may have sudden death risks above the normal population, these risks are likely unrelated to ADHD medication use. The very low absolute risk of sudden death in these patients should be considered when weighing the benefits and potential risks of therapy for a disorder with substantial morbidity such as ADHD.
Even for patients with long QT syndrome, where the risk of arrhythmias with increased sympathetic activity is established, a recent report of a small series of children with LQTS and ADHD treated with stimulants concomitant with beta blockade demonstrated no adverse outcomes over 56 patient years. The study [430] was published along with a particularly pointed editorial entitled "People with long QT syndrome who have attention deficit hyperactivity disorder deserve to be treated properly" [431]. Specialty consultation is important to address whether patients with arrhythmia contraindications can be treated with ADHD medications.
It should be noted that in a subset of patients, ADHD and structural and/or hereditary heart disease may be intrinsically related to each other based on a common syndrome (e.g. Velocardiofacial Syndrome) [432] in association with complex congenital heart disease or [146] its surgical repair [433,434]. Patients with congenital heart disease have an increased prevalence of ADHD, and can benefit from ADHD therapies, including medication [435]. Drugs used in the treatment of ADHD do lead to a small increase in heart rate, (average 5-10 beats/min), and systolic blood pressure (average 4-6 mmHg [436]. It is uncommon, but some patients will have much higher effects from stimulant treatment. These effects can be evaluated by comparing heart rate and blood pressure before and on treatment -in the case of stimulants this can also be evaluated before a dose and after the dose the same day. In adult patients with hypertension or coronary heart disease, caution is advised and a closer monitoring of heart rate and blood pressure is recommended in these cases. 1 Psychostimulant medications are used cautiously in patients with anxiety disorders but the CADDRA ADHD Practice Guidelines Committee agrees that the benefits of psychostimulants to treat ADHD often exceeds the risk 2 Psychostimulant medications are used cautiously in tic spectrum disorders but the Committee agrees that use can be indicated if there is sufficient impairment of the concurrent ADHD. In these cases, the medications for ADHD are often combined with other drugs for tics (e.g., atypical neuroleptics or alpha-2 agonists). 3 Atomoxetine may be used in combination with inhaled beta2 agonists like salbutamol, but should be used with caution in patients being treated with oral or intravenous beta2 agonists Note: This table summarizes key information and cannot be considered exhaustive. Physicians should refer to Product Monographs for complete prescribing information.
# Psychiatric and Medical Precautions or Contraindications
# Physician, Family and Patient Attitudes
All patients and their families need to be educated about the potential benefits and drawbacks of treatment with ADHD medications. It is important to have a comprehensive discussion regarding all treatment options. Patients may be reluctant to start a specific product or class of ADHD medication for a variety of reasons.
# Psychological Biases, Misunderstandings and Side Effects
Psychological biases against the use of ADHD medications may be due to misinformation regarding side effects, stigma, or in the cases of parents, guilt about having 'caused' the problem through 'bad' parenting.
Patients may have questions and worries about side effects. They may be afraid that medication will cause them to "lose their sparkle" or their brain will become "lazy". A frank discussion about therapeutic and side effects may help patients make better choices. All medications may cause side effects. It should be stressed that most side effects settle after two or three weeks of continuous use and alternative options will be sought if a person feels they are impaired by a prescription.
A common reason for non-adherence is related to a lack of physician awareness or understanding of side effects, or patients' reluctance to explain their discomfort. Patients should be informed about how to determine if their medication dosage is too high. For example, they might experience feeling too "wired", too irritable or excessively focused, or experiencing restricted affect, sometimes called a "zombie effect".
Please note: If negative symptoms are experienced at the time when medications would be expected to be wearing off, or with sudden cessation of pharmacotherapy, it is likely that those symptoms are not from an excessively high dose but from withdrawal, where the medication is wearing off too quickly.
# Previous Experience with ADHD Medication
Some patients may have past experience with ADHD medication. That experience, positive or negative, may colour their attitudes towards the suggested course of treatment. For instance, they may have suffered the disappointment that comes with over-estimation of the effectiveness of medication, especially without concurrent educational and psychosocial interventions.
A family history of prior positive response to ADHD treatment should also be considered as well as any negative experience on specific medications. Although there is no evidence indicating that a family member's response indicates a greater likelihood of patient response, it is understandable that a positive response to a specific treatment in a family member could increase positive expectations for this treatment while the contrary can occur for a negative outcome.
When a patient mentions that they have a friend or a family member on ADHD medication, clinicians can inquire about their perception of the medication efficacy and tolerability. They may also inquire if the patient themselves "tried" the medication outside a treatment regime; patients may not spontaneously provide this information unless asked.
# Medication Selection: Medication-related factors
See the following section for medication-specific differences. These differences allow for matching of medication characteristics to patient needs and preferences.
# Drug Interactions
# Affordability, Accessibility and Reimbursement (Public/Private)
All patients should have access to optimum treatment. Unfortunately, some medications are beyond the financial reach of a significant number of patients without extended health insurance. Some medications can be supported through special access programs, but entrance can be limited by the procedures required or the constricted time for which medication is supplied.
Third party insurers cover most ADHD medications; however, patients may have to rely on generic formulations that may not be as effective (refer to the section in this chapter about generics). CADDRA continues to advocate for a resolution of this problem at the government level. Clinicians need to be informed about the cost of medications and the patient's coverage or ability to afford them before deciding what to prescribe.
Most Canadians have some access to reimbursement for prescription medications through private insurance plans (thirdparty insurance), the provincial / territorial drug benefit programs or federal programs for certain groups. Because healthcare falls within provincial and territorial jurisdiction, the funding available for ADHD medication varies considerably depending on an individual's address. An online guide to provincial reimbursement for prescription medications in Canada can be found here: http://bit.ly/PublicDrugBenefit.
# Special Considerations Combining Medications for Adjunct Effects
Common scenarios for adjunct prescribing in addition to an ADHD medication include adding an ADHD agent with a different mechanism, a short acting ADHD agent to cover uncovered portions of the day, or an agent to address concurrent mood, sleep, or anxiety disorders. The clinician should query a drug metabolic interaction database to understand how metabolism of either agent may be impacted (e.g. fluoxetine and atomoxetine) through an interaction of the cytochrome P450/2D6. Separately, clinicians should consider whether agents have additive effects that may preclude their combination or require careful monitoring -such as sedative or sympathetic effects. Special monitoring or consultation may be required to maximize the safety of unstudied combinations.
Only guanfacine XR has been approved by Health Canada for the adjunctive treatment of ADHD in combination with psychostimulants. However, other combinations are frequently used in clinical practice (e.g. atomoxetine and psychostimulants).
# Potential for Abuse, Misuse and Diversion
Individuals who abuse stimulants to achieve a "high" typically administer them via parenteral routes. Others misuse psychostimulants trying to mask fatigue, believing that the non-medical use of stimulants will increase academic performance.
Short-acting formulations of stimulants have a much higher risk of misuse/ diversion than the longer-acting stimulants due to their pharmacokinetic profile and easy crushability.
All professionals involved in treating ADHD patients should be alert to the signs of abuse, diversion and misuse and consider these behaviours as significant and not benign. For more information about the signs of diversion and misuse, please see Health Canada 2006, Abuse and Diversion of Controlled Substances: A Guide for Health Professionals [437].
# Generic Formulations
To be considered "bioequivalent", Health Canada only requires the maximum concentration (Cmax) and area-under-the-curve (AUC) of a generic product to be similar to the reference (brand-named) product. These are appropriate measures for most medications. However, the duration of effect may be more related to the length of the ascending concentration curve (time to maximum concentration -Tmax) than to the Cmax or AUC. For example, a generic brand for Concerta® available in Canada has a distribution curve that looks more like Ritalin SR than Concerta®, with an earlier Tmax and a shorter duration of effect than Concerta®. However, both are considered "bioequivalent" by Health Canada.
# PRACTICE POINT
The decision to switch to a generic formulation is an individual-based decision and the CADDRA Guidelines Committee strongly advocates that the patient/family be advised of the switch, told to check for clinical changes in efficacy or tolerability and report any changes to their pharmacist and doctor.
Therefore, the CADDRA Guidelines Committee considers this generic formulation substituted for the methylphenidate OROS® tablets to be a different drug because:
• Clinical studies and experience have shown a clinical difference between the generic and the original product [438].
•
The delivery system of the generic formulation differs from the original product.
•
The generic tablets may be easily crushed, therefore potentially increasing the risk for abuse by snorting or intravenous use.
# Practice Point
It is important that patients are given a realistic view of what they can expect from medication. They need to understand that each person has a different risk/benefit profile ranging from those who cannot tolerate or benefit from medication at all to those who have full remission with no side effects.
While research allows us to provide patients with a great deal of information about their medication options, patients and parents must be made to understand that every person is unique. A dosage that is effective for one patient might not work for another.
It is important to point out that agreeing to a "trial" of medication is not a decision to use it forever. A trial is an experiment that carries minimal if any risks that would extend beyond a very brief period of time, and can be discontinued at any point.
Key points for a successful medication trial:
• Involve the patient and their family • Identify the specific ADHD symptoms that impair function to define treatment goals • Select treatment options and clinical tools to measure change • Start with first line treatment options and take the time to adjust doses balancing clinical efficacy and side effects • Follow titration protocol outlined in the medication charts by age-group • Measure response at planned intervals • If response is unsatisfactory, explore why and try a different treatment option until symptom control is optimized • Follow-up and re-assess efficacy and need for treatment regularly Note: It is not a valid trial if patient is not adhering to doses prescribed, taking other interfering medications, or physician is not tracking changes.
# Key Points When Selecting an ADHD Medication Which medication is indicated in the patient's age group?
The first choice should be a medication that has an approved indication by Health Canada for ADHD within the specified age group. Even though some ADHD medications are not officially approved by Health Canada for a specific age group, doctors may decide to use them based on scientific evidence and expert consensus.
# What impairments does the patient have and at what time(s) of the day?
Is it mainly during school or work hours, meetings, exam times, leisure times, driving periods, morning routines, etc.? Ensure the medication is taken so that it is effective when most needed for the patient's individual needs.
# What medication does the patient prefer?
Has the patient ever taken any medications before or heard of something they might want to try? Patients may respond better to the medications they most strongly believe in. This also addresses the belief that patients must be educated, and they should have a partnership in the treatment agenda.
# Is a family member on medication for ADHD?
If yes, then consider trying the same medication first if the family member's clinical response is positive. Patients may be more inclined to try a medication that worked well in someone they know, whether it is a family member or not. The inverse is also true; patients may be more reluctant to try a medication if they know someone who experienced strong side effects with a specific product. Note: Currently, there is not sufficient evidence to recommend a routine pharmacogeneticsbased approach. However, the field is involving and this approach may be helpful in situations where it is difficult to find the optimal medication for a particular patient. However, in clinical practice, family response to certain types of medication may guide in medication selection.
# Does the patient have third party coverage or do they plan to pay for the medication?
Many of the current medications are expensive so there should be an open discussion related to government plans, third party insurance coverage, direct payment, co-payment plans and limited benefit plans. An online guide to provincial reimbursement for prescription medications in Canada can be found here: http://bit.ly/PublicDrugBenefit.
# Does the patient have trouble swallowing a pill?
If yes, that could indicate the need for medications that can be dissolved or sprinkled (e.g. Adderall, Biphentin, Foquest, Vyvanse), or chewed (Vyvanse Chewable Tablet). One should attempt to teach the individual to swallow a capsule if age appropriate and not limited by medical conditions. www.pillswallowing.com
# Does the patient have comorbid disorders that require more complex interventions?
If yes, a decision will need to be made as to which disorder to treat first. If it is ADHD, then initiate the ADHD medication and see what residual symptoms are left over that require further management. Anticipation of drug-drug interaction issues should be made when choosing the medication. Complex and comorbid presentations require specialist consultation.
# STEP 3 -Titration & Monitoring Establish a schedule for visits and contact with the patient and family
It is useful to take a structured approach to measuring treatment response beyond patient and family report. For example, target treatment could be to improve the person's capacity to be able to stay on-task for X amount of time. In evaluating this, particularly in younger patients, collateral information from the teacher and others may help measure efficacy. An adolescent may target their ability to sustain attention during their less interesting and less structured tasks. An adult may use a specific target that needs to change (e.g., their level of procrastination at work).
Formal observational rating scales are available to quantify specific medication changes, particularly at school and home.
The CADDRA toolkit includes questionnaires and forms (Clinician ADHD Baseline/Follow-up Form and the CADDRA Patient ADHD Medication Form) that can be used to evaluate change.
During the titration phase, regular contact with the patient reporting in either by phone, email, fax or visit is recommended. Ideally, the patient would be seen for a review of medication doses during the titration period and to check physical health, vital signs, side effects, family functioning, patient and family well-being, and coping strategy management.
Please note: The recommended starting doses and schedule for dose increases noted in the medication charts that follow are meant as a guide that should be followed in most cases. Specific exceptions may be made under clinician discretion. In addition, the CADDRA Guide to ADHD Pharmacological Treatments in Canada Chart can be found in the Resources Section on the CADDRA website (www.caddra.ca).
A general rule is to start low and go slow but continue to increase the dose until the desired goals of treatment have been reached or side effects preclude dose increases or when maximum recommended dosage is reached. Optimal treatment means that the symptoms have decreased and that there is improvement in general functioning. Optimal dose is that dose above which there is no further improvement. Sometimes side effects limit the dose titration. The threshold maximum dosage of medication in this document is consistent with the off-label standards established by the American Academy of Child and Adolescent Psychiatry [439], published clinical trials [440] and consensus-based within the CADDRA Guidelines committee. Exceeding CADDRA's recommended maximum dosage is a third-line treatment option and should be done cautiously after regular dosages of different options have been tried.
It is useful to alert the patient in advance that there may be variations in their experience of effect of ADHD medications. In general, a stimulant medication's effects are likely to be stable at a given dose after one to three weeks [93], and for atomoxetine after four to six weeks [441] and full response may not even take effect until after three months on a particular dose. Individual variation occurs, however, and should be addressed individually to achieve dose optimization. Under dosing can occur when full optimization is not adopted as a treatment goal. Some patients report loss of effect from stimulant treatments over time. In some cases, taking breaks from stimulant treatment intermittently has reportedly allowed for the maintenance of effects at lower doses. Research on this is underway [442].
# STEP 4 -Ongoing Follow-up
Long-term follow-up of individuals with ADHD should follow a chronic disease model which involves [443]:
• Pro-active, integrated care that is easily navigated by the patient: it is crucial to treat ADHD proactively before long-term negative consequences occur (e.g.: school drop-out, delinquency, job loss, divorce, substances use issues, comorbidities).
• Active involvement of patients in own care and advocacy: patients should be a partner in ADHD management. Furthermore, patients may serve as role models for other patients; services such as support groups may be useful.
• Multimodal treatment approaches supported by evidence-based guidelines: medication is an important aspect of ADHD management and should be accompanied by psychosocial approaches. This integrated approach may attenuate the high attrition rate of medication compliance. Furthermore, regular encounters with mental health providers may also allow for a stronger therapeutic alliance. The frequency of visits may vary from one patient to another. Many factors may play a role: e.g. patient engagement, symptoms stability and environmental support. During the stabilization period, regular (e.g. every two to four weeks) may be required while once stabilized, less frequent visits (e.g. every three to six months) may be sufficient.
• Provider education and resources: health care providers, teachers and other stakeholders require ongoing education on the management of ADHD. Resources like CADDAC, CADDRA and other organizations are essential to meet educational needs.
• Access to specialist expertise: in complex cases, health care providers may have to refer to specialized care and access in a timely manner is an important aspect of long-term ADHD management.
# MANAGING SIDE EFFECTS
Medications used to manage ADHD, like other psychopharmacologic agents, may produce a wide range of adverse effects. Usually, those side effects are mild and temporary if dosage is appropriate and medications are taken as prescribed. Most side effects appear when the medication is started or when dosages are modified. Often, they disappear over time (side effect tolerance), particularly when taken regularly.
ADHD medications are generally well tolerated overall, but one cannot predict the sensitivity of an individual person.
Patients and their families should be advised that unwanted physical side effects, emotional or behaviour changes might occur while on or just after stopping psychotropic medication.
Analyzing timing of the side effects profile may help manage them. Clinicians should monitor for adverse changes in growth, sleep, nutrition, pre-existing conditions, blood pressure, heart rate, mood or anxiety distress, thought pattern, and behaviour.
The aim is to find a positive balance between clinical benefit versus adverse effects. Positive clinical outcome should not be shadowed by the inconvenience of the side effects. See chapter 2 on comorbidity for special considerations in supporting individuals with histories of comorbid mental health conditions.
# Common Side Effects
# When to Reduce the Dose, or Stop a Medication
Medication can be reduced or interrupted for different reasons. Patients could forget to renew their prescription. Patients may be reluctant to take the medication because of side effects while others could wonder if the medication is still appropriate. Some patients observe a reduction of ADHD symptoms over time and may even report that they feel that the medication dose is now "too high". It is good clinical practice to re-evaluate if medication is still needed. Adjusting dosages up or down should occur under the supervision of the health care provider.
Safety may be improved by educating a patient how to reduce the dose or stop if they are uncomfortable. Adverse mood or personality changes induced by medication may not be as likely to resolve as physical discomforts such as sleep and appetite problems. It may be helpful to educate patients that if they are uncomfortable or if they do not feel "like themselves" they should contact their health care provider and reduce the dose or stop the medication.
If side effects require a period off medication ("drug holiday") or a reduced dose, it could be done during vacation periods, i.e. summer vacations or on long weekends, which minimize impact on critical role performance. Attention should be given to whether tapering off or on the agent is needed for an individual to have less withdrawal effects such as fatigue, or initiation effects such as sympathetic nervous symptom side effects. Clinically, it is observed that interrupting psychostimulants every weekend may in fact increase side effects.
Non-stimulant medications (e.g. atomoxetine, guanfacine XR, buproprion) need to be taken continuously for clinical effect. When discontinuing Alpha-2 agonist medications in particular, they should be tapered due to the significant danger of withdrawal effects (e.g. a hypertensive crisis for guanfacine XR and clonidine).
# How to Stop Medication
Some individuals may experience withdrawal from psychostimulants agents when they are stopped, particularly if dosages are high. If individuals are at robust doses, tapering these agents may avoid withdrawal. Atomoxetine is less likely to produce this withdrawal.
Alpha-2 agonists (e.g. guanfacine XR (GXR), clonidine) should not be interrupted abruptly and should always be tapered down progressively (e.g., tapered in decrements of no more than 1mg every three to seven days) due to the risk of rapid increase in blood pressure if stopped abruptly. Clinicians should prescribe the different dosages for the diminution of GXR and advise their patients that GXR pills should not be cut in half to reduce dosing since this would disturb the delivery system and increase immediate release, thus increasing side effects and reducing the duration of clinical effect.
# Choosing to Change to a Different Medication
When a patient benefits from a medication indicated for ADHD but has adverse effects, the kind and severity of adverse effect and its timing (e.g., if it occurs at peak concentration or when the dose is reduced at the end of the effect) is useful to consider before changing to alternate treatment. As a general guide, when adverse effects are more than mild or pose risk, changing to a different class of medication or managing an underlying vulnerability is advisable. However, where mild adverse effects occur or if the side effects seem related to the delivery system, a product with a different pattern of release of the same active ingredient may resolve the discomfort. Changes in release pattern may improve side effects that occur at a specific time of day -which conceptually could be due to peaks or valleys in the serum level. With stimulants, changing from one long acting form to another, or having the patient spread out initial dosing during the day into portions can achieve this. With atomoxetine, daily versus twice daily doses may be differently tolerated.
# Side Effects Management Techniques
# Somatic effects:
Many medications used to treat ADHD work through the catecholaminergic system. This is thought to explain many of the peripheral nervous system effects of stimulants, atomoxetine and guanfacine XR. Clinicians should expect and monitor potential variations in heart rate and blood pressure (increasing for psychostimulants and atomoxetine while decreasing for guanfacine XR), dry mouth, headache, decreased appetite, initial insomnia vs. daily sedation, gastrointestinal upset, and other perturbations of peripheral nervous system function. Key points to understand about these effects include:
• Physical side effects sometimes improve or resolve over a several-day period at steady daily dosing.
• Minimizing caffeine and other sympathomimetic agents sometimes eliminates or reduces side effects.
• Adverse effects of medications are reversible.
• Vulnerability and severity may be higher in pre-existing conditions impacted by peripheral CNS function like peripheral vascular disease, tic disorders, narrow angle glaucoma, or urinary dysfunction.
Stabilization of many comorbid conditions will facilitate ADHD medication administration, and collaboration with other clinicians may be important to stabilize and monitor conditions that sympathetic agents may exacerbate such as hypertension or narrow angle glaucoma. Tics may be exacerbated by psychostimulants, but in some cases tics improve with treatment of ADHD. In all cases of possible symptom exacerbation, risk assessment should be personalized.
# Appetite and growth effects
Medication-related growth delay may prompt treatment reduction or interruption during some periods like weekends or holidays or a switch to a non-stimulant treatment in children, as some studies associate stimulant treatment with effects on weight and height [90,444].
In cases of appetite reduction:
• Nutrition should be maximized during periods when appetite-suppression is not in effect (e.g. breakfast and after medication has worn off in the evening).
• Reduce portions but increase snack times, including mandatory snack time in the evening.
• Consider nutritional supplements or meal replacements.
• Consider dose reduction, change to alternate agent, or drug holidays for low body mass index or familial short stature.
# Matching coverage to daily patterns
In some cases, reports of adverse experiences may reflect suboptimal onset or duration of medication coverage, prompting changes in dosing patterns or agent. For example, stimulants may induce insomnia, prompting administration of medication as early as possible in the morning or use of a shorter acting agent. "Rebound" of symptoms is reported, where symptoms return or appear worse than when untreated. This should prompt a change in coverage or change in medication level during the period of concern. For example, in the case of a long-acting agent taken in the morning, this might be divided into two doses taken 20 to 30 minutes apart to ensure they wear off over a longer time period, or a lower dose of a short acting stimulant can be overlapped with the tail end of the long-acting stimulant.
# Managing Changing Medication Effects Over time
Some patients will report onset of new adverse effects, or loss of benefit from medication over time. If the treatment is well established over months prior to such a change in response to medicine, a broad differential diagnosis of new conditions should be considered.
# Points to consider:
• Some individuals report less effect from medications when switched from a brand name product to a generic formulation.
• Some clinical reports state that some individuals find that taking breaks from the stimulant medication may have a "rejuvenating" effect. This phenomenon is not well studied, but it is advisable to have patients take such breaks rather than to increase dose in a previously effective treatment.
• A pattern of escalating doses over time may reflect "tolerance" or may suggest that the specific treatment targets may not reflect what ADHD medication can do to help. It has been noted that some patients confuse the energetic, mood or pleasure side effects of a stimulant with the attention and behaviour control clinical effects. While the energetic side effect tends to be reduced over time, the improvement of sustained attention is usually still there. Escalating doses and other atypical responses to medication should prompt consideration that the treatment goals or treatment itself may be inappropriate for the individual.
# UNSATISFACTORY RESPONSE TO TREATMENT
CADDRA recommends reviewing the DATER diagram prior to considering whether second and third line therapies be considered. A
All -Have all medications within the higher line(s) of treatment (when clinically indicated and reasonable) been attempted? If not, explore why.
T Time -Has enough time been given to examine patient response and for side effects to resolve? E Examine -Has the patient-doctor team determined specific targets for treatment and means to measure changes? Select standardized measures to examine response and plan examination of response from many perspectives (e.g., teacher, parent, spouse and self-report).
R Review -Has the diagnostic process reviewed potential comorbidity, psychosocial complications and lifestyle issues?
Generally, if the patient does not respond optimally to monotherapy with at least one medication from each of the two psychostimulant classes (methylphenidate and amphetamine), augmentation strategies may be employed. a. Use of second line medications such as guanfacine XR may be an option, as this has been systematically studied in 6-17 years old patients with ADHD [445]. b. Third line options like off-label use of buproprion, clonidine, modafinil or imipramine may also be helpful, but in this case a specialist referral should be made. This is essential for ensuring optimal risk management, deciding that first-and second-line treatments have been optimally managed, and avoiding any contraindications.
When a switch in medication is required, if the situation allows, consider switching medication during long vacations or during the summer to avoid periods of non-response or possible side effects that may impair academic or work performance in the short-term. If there is partial or no response to treatment, it is important to review both the diagnosis (including comorbidities) and treatment plan to ensure compliance to treatment as well as to check if there are external factors that could complicate the clinical picture. Patients' responses to medication cannot be predicted based solely on the clinical symptoms displayed. Some patients may respond preferentially to one versus the other class of medications. If response or side effects to one class of medication are not optimal, another class of ADHD medication should be tried. In particular, if a patient does not have an adequate response to one class of stimulant, a switch to the other class of stimulant should be considered (e.g. methylphenidate to amphetamines or vice-versa).
There are several reasons why one ADHD medication may be substituted for another:
a. Peak and trough effects: change delivery mechanism, for example the immediate-release mechanism for a more sustained one.
b. End-of-dose rebound effects: change the immediate-release mechanism for a more sustained one or take an additional, short acting dose of the same psychostimulant just before the rebound routinely occurs.
c. Adverse effects don't allow dosage to be optimized: change the release mechanism, change the molecule, or add an adjunctive medication*.
d. Drug-to-drug interaction following usual titration strategies. If side effects occur, decide between reducing the psychostimulant versus the non-stimulant dosage. * *Note: Guanfacine XR is the only medication with a specific indication as an adjunctive therapy to psychostimulants for the treatment of ADHD in children and adolescents aged 6-17 years with a sub-optimal response to psychostimulants. Long-term combination of a psychostimulant with guanfacine XR in adults -or with atomoxetine -are off-label [138].
# Practice Point Best Time to Switch Medication in School-Age Children?
The summer or winter vacation may be the best time to switch medications for children. Be wary of switching meds at the beginning of a new school year with a new teacher. It is better to let the child continue on the current medication until after the first report card period, and then switch. In this way, the teacher can also provide feedback on the effect of the change.
# INFORMATION ON SPECIFIC MEDICATIONS
ADHD medications are not all the same. Their content (active ingredients) and formulation can affect response for a specific person. Medical treatment for ADHD needs to be individualized.
# ADHD Medication Chart
The CADDRA ADHD Medication Chart provides information on the dosage and appearance of ADHD medications and is a useful tool when discussing medication options with individuals and their families.
# Practice Point
• Medication effects are based on average population studies.
• Efficacy and tolerability can vary for individuals.
• Treatment should always be individualized and reviewed over time, to better target patients' needs.
# Psychostimulants
Based on their active ingredients, the psychostimulants are divided in two classes: amphetamines-based and methylphenidate-based products. Both classes are available in short, intermediary and long-acting preparations.
Long-acting psychostimulants are first line treatments for ADHD. A patient's response to one class of stimulant does not predict their response to the other class [411,412]. Thus, failure to respond to one class of stimulant should typically lead to a trial of the other class before moving to second-line treatments.
The CADDRA Guidelines Committee recommends that short or intermediate acting psychostimulants be used as second line treatments because:
• Multi-dosing may reduce adherence to treatment [446].
• Their duration of effect is shorter than that of long-acting versions and they are therefore prone to having peak/valley effects that may reduce symptom coverage and be associated with more side effects [447].
• Their potential of abuse is higher since short acting tablets are crushable, therefore increasing the potential risk for abuse by snorting or intravenous use [448].
Short or intermediate acting psychostimulants may be useful in specific situations where there is need for a medication with shorter duration of action:
• When a top-up of the once-daily medication is required.
• When coverage is required only for a few hours in the day.
• When more flexibility in the dosing schedule is necessary.
Due to their specific delivery systems, the abuse potential of pro-drug, osmotic pump and beads delivery systems are significantly reduced in comparison to short-acting medications due to the product formulation [449,450].
# Amphetamine (AMP)-based products
Amphetamines (AMP) are thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extra neuronal space [451], thereby increasing these neurotransmitters' availability in the synaptic cleft. AMP has a well-established safety and efficacy profile for the treatment of ADHD [452,453]. In Canada, AMP based products are subject to controlled substances regulation and are available in various delivery systems allowing short, intermediary and long-acting duration of effect.
NOTE: Mixed amphetamine salts: A focused review of sudden unexplained deaths was carried out by Health Canada in 2006 and the medication's safety has been assured [454].
# Methylphenidate (MPH)-based products
Methylphenidate hydrochloride (MPH) is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron, with a preferential effect on dopamine, thereby increasing these neurotransmitters' levels in the synaptic cleft [456]. MPH has a well-established safety and efficacy profile for the treatment of ADHD [174,410,457]. In Canada, MPH based products are subject to controlled substances regulation and are available in various delivery systems allowing short, intermediary and long-acting duration of effect [458].
# Can you tell if a patient has ADHD by their response to medication?
No. Psychotropic medications may have effects on individuals whether they have a clinical syndrome for which the agent was studied or not. As example, psychostimulants can improve attention and vigilance in patients with ADHD but also in patients with sleep apnea, diurnal hypersomnolence and depression [465].
# Can a medication trial be used to diagnose ADHD?
No. A positive response does not prove that ADHD is the cause of the inattention. A negative response does not rule out ADHD as patients may respond to one ADHD medication and not another.
# Can you predict which ADHD medication will help based on specific symptoms?
No. While individual patients respond differently, all medications approved for use in ADHD by Health Canada can reduce both inattention as well as impulsive/hyperactive symptoms described in the DSM definition of ADHD.
# Can medication choice be predicted by testing or laboratory studies?
There is insufficient evidence to support use of brain scans or EEG, or genetic or metabolic screening to predict which agent will be most effective or best tolerated for a specific individual with ADHD.
It is appealing to think that someone could base the choice of a specific ADHD medication on the results of genetic testing. At this time, use of pharmacogenetics is not generally recommended in clinical practice. However, pharmacogenetics is emerging as a potential future source of additional information regarding possible treatment direction in treatment-resistant cases.
# Do non-stimulants have a lower risk of side effects compared to stimulants?
No. Non-stimulants may have risks different from those associated with stimulants. While non-stimulants are less likely to be misused or abused than stimulants [133], non-stimulant medications used to treat ADHD may also have other potential risks such as sympathomimetic physical effects for ATX or hypotension or reduced heart rate for GXR.
# Should patients be started on a short-acting medication before taking a long-acting medication?
No. This practice is not recommended. There may be administrative reasons for why this approach must be taken (e.g., a provincial drug formulary). However, there is no scientific data to support this practice. Clinical and side effect response to short and long acting medications may vary in an individual so experience on short-and longacting agents should not be assumed to be predictive of each other. Furthermore, initiating a medication that is less effective, less tolerable, and with peak and valley effects may preclude the patient from pursuing medical treatment. In addition, the mandatory step of starting a short-acting psychostimulant first increases the cost on the medical system by increasing not only the number of appointments needed to adjust the medication, but could also increase the total number of visits to the emergency room as there is evidence to suggest that patients on short-acting ADHD psychostimulants consult more often at the emergency room for physical traumas than those on long-acting stimulants [466].
# Can you tell if a medication is working by how the patient "feels"?
No. Ability to self-observe is variable with age and between individuals, and this variation should be considered in the monitoring of medication effects. Also, some patients may confuse the perceived stimulating energizing effect of a stimulant (that is a side effect and will attenuate over time) from the real clinical effect of being able to better self-control attention, movements and behaviours (targeted effect, that should be stable over time).
Long-acting medication use is often associated with less peaks and valleys effects and some patients who have tried short-acting stimulants first can confuse the lack of "feeling that the medication is onboard" with lack of efficacy.
# Can you tell how a medication is working by patient report alone?
Yes and no. Clinicians should be aware that studies often demonstrate discord between collateral/observer and personal reports of ADHD symptoms in some individuals [467]. Sufficient personal and, whenever possible, collateral information help to monitor symptom pattern and function before and during treatment. Using specific age-appropriate questions that the patient understands and can report on is advisable.
# Are there other medications used in treating ADHD?
Other medications like modafinil, bupropion and desipramine have shown some efficacy in ADHD [441] and are considered third-line treatments for this disorder. Since their use is off-label, clinicians usually consult with an ADHD specialist when these medications are considered.
# PRACTICE POINT
# What is Pharmacogenetics?
Refers to individual differences in response to Pharmacological treatment due to genetic variation. There is some suggestion that this may be useful in regard to titrating ADHD medication.
# Should I use pharmacogenetics in treating ADHD?
One RCT involving adults with depression has shown that the use of pharmacogenetics can improve remission rates; however, more research is needed to support these findings. Also, there is currently no published research on the impact of pharmacogenetics on treatment outcomes for individuals with ADHD.
The current consensus of the CADDRA board is that no evidence, at this point, to recommend pharmacogenetics for standard practice in the management of ADHD. Although pharmacogenetics can provide information on rates of metabolism, it is possible to obtain the same information clinically. Also, findings lack sensitivity because while metabolization rates certainly effect treatment response, these rates represent only a small portion of the myriad factors that affect treatment response (e.g., comorbidities). Therefore, the limited utility of this information, at this point, needs to be weighed against the increased costs, usually to the patient.
# CHAPTER 6: TREATMENTS REQUIRING FURTHER RESEARCH
Individuals suffering from ADHD and their parents often request information regarding alternatives to medications indicated for ADHD. Thus, the clinician needs to be aware of the data regarding the efficacy and side-effects of these alternatives in order to respond to these requests. The aim of this section of the CADDRA guideline was to review available information on alternatives to treatments typically used for the treatment of ADHD in a systematic fashion in order to allow clinicians to respond to these queries in an informed manner.
The methodology involved a systematic literature review. Publications spanning the past 10 years were searched using the electronic databases PubMed, PsycInfo, Embase and CINAHL. This process yielded 754 research articles found on the first iteration of the search (as of June 21st, 2016). Once the selection was narrowed to include clinical trials, meta-analyses and reviews the final database included 186 articles. Of these 186 articles, research articles on omega-3 supplementation, neurofeedback and dietary means other than omega-3 fatty acids yielded the most results, with 45, 43 and 19 articles respectively. Each of these approaches are discussed separately in the following paragraphs.
# Omega-3 fatty acids
Omega-3 fatty acids (OFA) have been extensively studied as an alternative to pharmacological treatment of ADHD.
Western diet is rich in omega-6 fatty acids. Arachidonic acid, an omega-6 fatty acid, is found in cell membranes and is a precursor to inflammatory molecules such as prostaglandins and thromboxane. On the other hand, omega-3 fatty acids have anti-inflammatory properties. Unlike omega-6 acids, omega-3 fatty acids cannot be synthesised by humans and must be integrated in a person's diet for adequate daily intake. It is believed that a high omega-6 to omega-3 ratio promotes neuroinflammation. Omega-6 inflammatory mediators alter the structure of cell membrane phospholipids and the proteins imbedded in it therefore altering cell membrane fluidity, ultimately hampering the effective neurotransmission of serotonin and dopamine. Adding omega-3 to diet increases its concentration in the cell membrane therefore improving transmission of neurotransmitters by diminishing neuroinflammation, especially in the frontal cortex [468]. Furthermore, some studies have found that omega-3 levels are lower in the blood of children with ADHD [468][469][470].
Most randomized clinical trials (RCT) included in this review conclude that the benefits of omega-3 supplementation are modest at best when compared to treatment as usual [468,471,472], while others state they have no effect on the cognition of either the general population or those with neurodevelopmental disorders [473,474]. Furthermore, supplementation of children with lower levels of omega 3 did not result in a significant reduction of ADHD symptoms [469].
Based on current evidence, omega-3 supplementation is not recommended as a replacement to treatment as usual in people with significant ADHD symptoms although the literature suggests that omega 3 supplementation may possibly be a useful adjunct [475].
# Nutritional Supplements
Dietary interventions as alternatives to standard treatment of ADHD can be broadly divided into two categories : those that remove a particular kind of food (elimination diets) and others that increase the intake of a particular one [476]. Research on elimination diets consists mostly of eliminating either artificial food colorants, sugar or diets that eliminate all but a few food items (''few food diets'') [476]. Interventions where a particular food was increased postulate that children with ADHD may be lacking a particular kind of nutrient. Nutrients studied were mostly amino acids, essential fatty acids, vitamins and minerals [476].
The literature review identified 13 articles on dietary interventions; these consisted largely of studies of dietary supplementation, rather than restriction. The effects of amino acids (phosphatidylserine), broad-based preparations of micronutrients and zinc were studied in the articles reviewed. Only one article specifically studied a restrictive elimination diet.
Phosphatidylserine (PS) monotherapy, the object of 2 RCTs, is a fat-soluble amino acid derivative that is mostly found in the cell membrane of organs with high metabolic activity e.g. the brain. It is considered to be one of the most important brain nutrients as it influences many neurotransmitter systems, including those involved in ADHD (dopamine and norepinephrine). One double-blind RCT assessing effectiveness of supplementation with 200 mg of PS for the treatment of ADHD found an improvement of ADHD symptoms and short-term auditory memory in children [477]. Another double blind RCT was designed to determine its safety. Three hundred milligrams of PS administered daily for 15 weeks detected no difference in safety or side effects compared to placebo [478].
Broad-based preparations of micronutrients include vitamin D, B9 (folate), B12 and essential minerals such as zinc. These vitamins and minerals are known to act as essential cofactors in the synthesis of monoaminergic neurotransmitters [476,479]. One double-blind placebo-controlled RCT claiming to be the first to investigate the efficacy and safety of such a preparation found that micronutrient treatment induced statistically significant improvements in ADHD symptoms as well as being a safe alternative to ADHD treatment [479]. Another randomized double-blind placebo-controlled trial found that supplementary nutrition given mostly to 14 and 15 year olds might have a protective effect against worsening behaviour when assessed using the Conners' Teachers Rating Scale, but less clearly when using school discipline records [480].
Children's behaviour in the control group worsened without supplementation, yet children in the intervention group showed a reduction in problematic behaviour [480]. These trials do not allow us to determine which specific nutrient might be of particular relevance in the treatment of ADHD. Overall, the paucity of such trials shows that there is no robust evidence that high dose vitamin and minerals supplementation significantly improves ADHD symptomatology [476].
Zinc is an essential micronutrient that has a major role in synaptic transmission. It increases the affinity of methylphenidate for the dopamine transporter and inhibits dopamine uptake through binding to the dopamine transporter [481]. Few double blind RCTs have investigated the effect of Zinc in ADHD [481]. This review identified one double blind RCT which found that zinc was not more effective than placebo in either monotherapy or in combination with stimulants [482].
The rationale for restrictive elimination diets is that eliminating artificial food colourants and other additives implicated in hypersensitivity reactions will result in improving brain function [483]. One RCT found considerable improvement in ADHD symptomatology [483] during the first phase of the study; however, the control group intervention consisted of dietary instructions while the active group had a restrictive diet and only the rater was blinded. Hence the conclusions cannot be considered unbiased. Furthermore, restrictive diets are difficult to implement in children and adults [476,483] and may not be a realistic alternative to standard treatment.
# Neurofeedback
Neurofeedback (NF) consists of measuring the brain wave activity of participants in real time and rewarding them when EEG readings show brain activity that is correlated with focus, attention and problem-solving [484]. Usually, theta and beta brain waves in the right prefrontal cortex are measured. Beta waves are associated with thinking, focusing and sustained attention whereas theta waves are linked to distractibility [484]. ADHD is believed to be caused by dysfunction in the right prefrontal cortex [484]. Therefore, it is hypothesized that lowering the theta-beta ratio in this region is a means of increasing focus [484]. Slow cortical potential protocol (SCP) and theta-beta ratio (TBR) are the most frequent treatment protocols [485].
Initial non randomized placebo-controlled studies showed positive outcomes of NF are mostly specific to inattention and impulsivity with large effect sizes for inattention and impulsivity but medium effect sizes for hyperactivity [486]. It is important to note that these effect sizes were obtained in semi-active control protocols (such as a waiting-list control group). However, under randomized placebo control conditions no study has shown significant effect sizes [487][488][489]. Most proximal raters to the treatment condition (e.g. parents) tend to over-estimate the effect of NF when compared to more distal, blinded raters (e.g. teachers, research staff) [490]. On the other hand, treatment effects are limited yet tend to be durable over time (when evaluated again at 6 month follow-up) [491].
Although some authors propose that NF can be an efficacious alternative to treatment-as-usual in children who cannot tolerate the side effects of medication or do not pursue pharmacological treatment for any reason [491,492] other, more recent studies, cast doubt on the specificity and efficacy of NF as treatment of ADHD altogether [493].
Further research of NF should be conducted with more rigorous research designs and include more subjects [494]. In light of the data available at this stage, we conclude there is insufficient data to recommend NF as a standard treatment for ADHD.
# Chiropractic Care
A systematic review published in a major chiropractic journal concluded that there is currently insufficient evidence to support chiropractic care for the treatment of ADHD [495].
# PRACTICE POINT
Overall, this review concludes that:
• There is insufficient evidence to recommend neurofeedback, computer-assisted cognitive training [496](e.g.
Cogmed), dietary restriction or dietary supplementation as alternatives to standard treatments.
• While not in themselves harmful, these interventions may be expensive, time consuming and may divert individuals affected with ADHD away from more effective treatment.
In most alternative methods studied in this review, there seems to be a proximity bias in studies such that the closer the rater is to the participant being evaluated the more favourable the effect of treatment seems to be. Parents, and sometimes teachers, tend to notice subtle changes in the child's behavior that can account for the modest effects observed.
On the other hand, most large-scale studies and those that use a double-blind design, do not confirm these subtle changes and find no significant effects attributable to these interventions.
Further, these interventions may be expensive, time consuming and may divert individuals affected with ADHD away from more effective treatment.
# Diagnosis and Treatment -Adults
# Canadian Medication Tables per Age Group
9
Dexedrine® Spansule® may last 6-8 hours 10 Ritalin® SR may help cover the noon period but clinical experience suggests an effect similar to short-acting preparations. An increased dose could be spread out to include q2pm dose with a daily maximum of 60 mg Note: These tables summarize key information and cannot be considered exhaustive. Physicians should refer to Product Monographs for complete prescribing information.
# METHYLPHENIDATE HYDROCHLORIDE (MPH) BASED PRODUCTS -SHORT-ACTING AND INTERMEDIARY-ACTING MEDICATIONS BRAND NAME
# Non-Stimulants
The action onset of non-stimulants is often slower than stimulants and the maximum treatment effect may not be reached for six to eight weeks for atomoxetine (ATX) and four weeks for guanfacine XR (GXR) [459,460]. The clinical changes are gradual. Non-stimulants are not suitable in clinical cases where a rapid onset of action is needed or as an "as needed" treatment plan. The CADDRA Guidelines Committee recommends starting low and titrating slowly, every 14 days, depending on clinical response. If higher doses or off-label use are contemplated, a referral to an ADHD specialist should be made. If the doses exceed one pill a day, the cost of medication increases.
# CHARACTERISTICS
• No known abuse potential • Can be given once-a-day in the morning or evening, or as a morning and evening split dose which is sometimes optimal to reduce side effects (but this increases costs) • Capsules should be swallowed whole and unopened as the content can cause significant nausea and stomach upset in some patients • Contents are an ocular irritant. If the contents get in the eye, the eye should be flushed immediately and medical attention should be sought, if needed • Safety profile has been established, including risk factors related to cardiovascular conduction irregularity like those of stimulant drugs • Rare cases of reversible alteration in hepatic enzyme have been noted. Although no special monitoring protocol is required (i.e. blood tests), patients should be advised of the clinical symptoms of hepatic dysfunction. • Poor metabolizers (i.e., 7% Caucasians and 2% African Americans) are unlikely to have toxic effects given the slow titration schedule • In children, calibrate the dose of ATX to the patient's weight • Rare reports of suicidal ideation have been reported. One suicide attempt (overdose) was identified but no completed suicides have occurred [51,466]. Clinicians need to carefully monitor suicidal ideation, especially in the early treatment phase, not unlike with many antidepressant medications • Considering that GXR has a lower response rate than psychostimulants and requires close follow-up due to its side effects profile [64], the CADDRA Guidelines Committee recommends it as a second line treatment. But in specific circumstances where psychostimulants are not recommended, GXR could be a first choice and referral to an ADHD specialist may be made • Treatment adherence is essential because of the potential risk for rebound hypertension • GXR is indicated for combined treatment with psychostimulants for children aged 6 to 17 with ADHD who do not achieve optimal response on stimulants alone. The CADDRA Guidelines Committee recommends first trying AMP and MPH medications • Consider for children who need 24h symptom coverage • Consider for children who have comorbid tic spectrum disorders [65] or significant comorbid anxiety, oppositional behaviours, aggression or where atypical neuroleptics or other alpha 2 agonists might have been used • Monotherapy might be beneficial if not responsive or have intolerable side effects to stimulant medications (e.g., worsening sleep or elevated pulse/blood pressure) • No literature is available for adult ADHD, therefore all prescriptions for patients over 17-yearsold are off-label use and should be supervised by an ADHD specialist DOSAGES
# GUANFACINE HYDROCHLORIDE EXTENDED-RELEASE TABLETS (GXR) BRAND NAME
• Intuniv XR® is available in Canada in four doses (1, 2, 3 and 4mg)
# CHARACTERISTICS
• GXR is not classed amongst the psychostimulants and is not a controlled substance • No known abuse potential • Side effects profile of guanfacine is unique. Somnolence, sedation may occur, particularly at the initiation and after dose adjustments. • Unlike stimulant drugs and atomoxetine, it may reduce pulse and blood pressure. These parameters should be monitored closely while titrating the dose up or down • Adherence to treatment is essential as abruptly stopping GXR may significantly increase pulse and blood pressure [467]. Intuniv XR® can be given once-a-day in the morning or evening, or as a morning and evening split dose which is sometimes optimal to reduce side effects (but this strategy increases costs) • Intuniv XR ® tablets should be swallowed whole since cutting or crushing the pill will alter the slow release mechanism and increase side effects • Use caution when administering to patients taking medications like CYP3A4/5 inhibitors (e.g. ketoconazole), CYP3A4 inducers, valproic acid, heart rate-lowering and QT-prolonging drugs • GXR should not be administered with high fat meals • It is recommended not to use grapefruit products with this medication • Intuniv XR® does not require any blood tests or ECG before starting treatment when using as monotherapy and if there is NOT a positive cardiac history (which should be asked before initiating any medication for ADHD) • To help maintain adequate blood pressure, patients should be advised to avoid dehydration
# CONTRIBUTOR DISCLOSURES
# Conflict of Interest Declarations (2 years)
Dr. Doron Almagor: Shire (Advisory Board, Grants, Speaker, Other: Clinical Trial); Purdue Pharma (Advisory Board, Grants, Speaker); Janssen-Ortho (Advisory Board, Grants, Speaker); Highland Therapeutics (Advisory Board); AVIR Pharma (Consultant); Knight Therapeutics (Consultant).
Dr. Lauri Alto: Purdue Pharma (Advisory Board); Shire (Advisory Board); Janssen-Ortho (Advisory Board, Speaker); Ironshore Pharmaceuticals (Advisory Board). | None | None |
ade1b01d70a4e6d35a607130926e261e893d3284 | cma | None | # Background
The Canadian Partnership for Cancer (CPAC) reports that approximately 7,600 Canadians aged 15 to 39 years are diagnosed with cancer every year 1 Although the most frequent cancers in adolescent and young adults (AYAs) are thyroid cancer, breast cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, testicular cancer and melanoma, all tumour groups present in young adults. 1 While there has been an increase in the age-standardized incidence rate of cancer for the AYA population, most AYAs diagnosed with cancer in Canada will survive their disease today. 1 AYAs diagnosed with cancer face unique challenges during and after their cancer diagnosis. Ferrari et al state that, "AYA patients seem to be in a sort of no-man's land, halfway between the two different worlds of pediatric and adult medical oncology and bearing the brunt, in terms of inclusion in clinical trials and quality of professional care, of the lack of integration between these two worlds." 2 Besides differences in tumour biology, limited progress in survival, lower clinical trial participation rates, and insufficient awareness of cancer symptoms among patients and professionals, AYA cancer patients have distinct psychosocial and supportive care needs compared with pediatric and adult cancer populations. 3 Late adolescence and young adulthood is a developmentally complex period of life, during which individuals are working to establish their own identity, develop a positive body image and sexual identity, detach from their parents, increase their involvement with peers, find a life partner, make decisions about higher education and careers, and possibly have their own family. 4 A cancer diagnosis can temporarily or permanently derail these plans.
In recognition of the lack of information about AYAs diagnosed with cancer in Canada and the obligation to address their unmet needs, a Canadian framework for the care and support of AYAs with cancer was jointly published by CPAC and the Adolescent and Young Adults with Cancer National Network in 2019. 5 The purpose of this framework was to articulate a national vision for high quality care and survivorship support of AYAs diagnosed with cancer and to provide specific individual-, service-, and system-level key actions to achieve the vision. Thus, the framework inspired the development of this provincial guideline, which endeavors to align its recommendations with the frameworks four strategic priorities to:
- Integrate an AYA-centered experience throughout care and survivorship; - Deliver interdisciplinary, integrated and comprehensive care and survivorship support that address the unique needs of AYAs with cancer; - Increase access to cutting-edge approaches to care and survivorship support for AYAs with cancer; and, - Drive evidence-based improvements for AYAs with cancer. This guideline has been developed as a supportive care guideline and not as a treatment guideline. The purpose of the guideline is to increase awareness of unique issues in AYA oncology and to recommend standards of care and interventions unique to the AYA population. Fundamentally, this guideline describes the optimal safe and high-quality care for all Albertan AYAs with cancer. Specific Guideline Resource Unit treatments or clinical procedures at the patient level are the domain of the Provincial Tumour Teams and treating teams. Operationalization of these guidelines is the domain of the AYA Oncology Steering Committee and treating teams and will likely look different across healthcare facilities.
# Guideline Questions
In AYAs diagnosed with cancer:
# Search Strategy
PubMed database was searched for relevant studies, guidelines, and consensus documents. The specific search strategies, search terms, and search results, are presented in Appendix A. Evidence tables are available upon request. Online resources from oncology-based health organizations and guideline developers were also systematically searched, and relevant frameworks, care manuals, and guidelines from the following organizations were considered in the development of our recommendations: Canadian Partnership Against Cancer (CPAC), CanTeen Australia, Clinical Oncology Society of Australia (COSA), and the National Comprehensive Cancer Network (NCCN).
# Target Population
This guideline's recommendations are applicable to AYAs who have been diagnosed with cancer. We defined this population as persons aged 15 to 39 years, which is in line with The Canadian Framework for the Care and Support of Adolescents and Young Adults. 5 However, we recognize that based on their development status, persons chronologically less than 15 and older than 39 years may be best served through the recommendations of this guideline.
# Target Audience
This guideline is directed at healthcare professionals who are involved in the care of AYAs who have been diagnosed with cancer, as well as for AYAs with cancer and their families and caregivers. c) Using a shared decision-making process, healthcare professionals should inform AYAs and discuss the potential risks and benefit for AYAs and their families to participate in clinical trials, as well as enrollment on tumour banking and biologic protocols. 5,11,12 Discussions and decisions about participation in research and clinical trials should be documented in the patient care plan. 5,11 (Level of Evidence: V, Strength of Recommendation: A)
- Refer to Alberta Clinical Trials and ClinicalTrials.gov databases for a list of current clinical studies being conducted in Alberta and around the World. ) Developmentally-appropriate care should be delivered and/or supported by a multidisciplinary team populated with age-and disease-specific medical and psychosocial experts able to effectively communicate and provide evidence-based care. 5,13 - Refer to the Children's Oncology Group (COG) 24 and National Comprehensive Cancer Network (NCCN) 6 for published recommendations for late effect screening in AYA cancer survivors.
f) Treating clinicians should work with patients to identify potential factors contributing to nonadherence with treatment regimens. 8 It is recommended that adherence assessment and monitoring occur at every clinic visit. 25,26 (Level of Evidence: V, Strength of Recommendation: A) g) All AYAs should be provided access to systematic and standardized symptom management for side effects related to cancer treatment. 6 (Level of Evidence: V, Strength of Recommendation: A) (4) Oncofertility a) All AYAs with cancer that require treatment that could compromise future fertility must be informed of the likely risk and options to protect or preserve fertility before treatment begins. 27 (Level of Evidence: V, Strength of Recommendation: B)
- Discussion can occur simultaneously with staging and the formulation of a treatment plan and should be documented in the medical record. 28 Appendix B provides common examples of effect of radiotherapy and systemic therapy on fertility. - Involving family members in these discussions may be beneficial.
- If the clinician is unable to discuss risks and treatment options, a referral to a colleague, or an AYA oncology specialist should be initiated for further discussion, or a referral directly to the fertility clinic may be completed.
b) Referral to a fertility clinic should be offered to AYAs as soon as possible following diagnosis 27 unless the risk of infertility from the cancer or treatment is 0 percent and documented. (Level of Evidence: V, Strength of Recommendation: B)
Guideline Resource Unit c) A discussion and/or referral related to fertility should be considered when the patient returns for follow up after completion of therapy and/or if pregnancy is being considered. 28 a) All AYAs should receive psychosocial screening as part of the new patient intake process. 30 When indicated, a full psychosocial assessment is recommended. The goal of this process is to identify, assess, support, and intervene to address common concerns associated with having cancer during the AYA years. While there are numerous scales to assess psychosocial outcomes in cancer, few have been specifically validated for AYAs with cancer. 31 Screening should include practical issues (housing, transport, finances), and for educational, family/social, emotional, physical, sexual, spiritual, and informational concerns. 30,32,33 b) Based on results from the psychosocial screening and/or initial comprehensive assessment, healthcare professionals should: (Level of Evidence: V, Strength of Recommendation: B)
- Provide AYAs and their families with information about psychosocial supports and services. 6,8
- Provide information about and encourage the use of about peer support to assist AYAs establishing and maintaining relationships with their peers, as well as other AYAs with cancer through mediums such as face-to-face meetings, camp and retreat programs, online support groups, and social networking opportunities. 5,6,8,34 - Address any physical/medical issues that may impact psychosocial wellbeing, including alcohol and drug use during treatment, the impact of treatment on fertility, sexuality and sexual function, physical function, and appearance. 6,8,16,35 - AYAs experiencing coping, transition, mood or other mental health issues, should be referred early to a psychosocial clinician (social worker, psychologist, or spiritual care provider) and/or psychiatrist. 6 - Refer AYAs to a social worker and/or occupational therapist to ensure they have access to the full range of educational, vocational, and employment support services for which they are eligible. 6,34,36 - Refer AYAs experiencing challenges with their spirituality/faith to faith-based resources or activities, including to spiritual care providers. 6,8 c) Healthcare professionals should routinely reassess the psychosocial supports of their AYA patients as they are likely to change over the patient cancer experience. 5, - Intervention for consequences of cancer and treatment (e.g., medical problems, symptoms, emotional distress, financial and social concerns). - Coordination of care between primary care providers and specialists to ensure that all the survivor's health needs are met. 53 - Survivorship care planning. 54 - A consistent primary care physician for ongoing primary healthcare, health maintenance, and treatment of intercurrent illness. 6,51,55 - Assessment of sexuality and fertility related to the cancer and treatment should be considered part of routine follow up care. 6,56,57 - Offer of referral to an occupational therapy or a vocational specialist who can support reentering the workforce or returning to school. 34,36,58 c) Develop and provide to AYA cancer survivors and key healthcare professionals an individualized survivorship plan that includes 6,8 (Level of Evidence: V, Strength of Recommendation: B):
- Summary of treatment received.
- Information regarding follow-up care, surveillance, and screening recommendations.
- Information on post-treatment needs, including information regarding treatment-related effects and health risks when possible. - Delineation regarding roles of oncologists, primary care physicians in survivorship care and the timing of transfer if appropriate. - Healthy lifestyle recommendations (e.g., smoking cessation, physical activity).
# (7) Palliative Care
Alberta Health Services (AHS) adopts the World Health Organization (WHO) definition of palliative care that is, "an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual." 59 a) Clinicians caring for AYAs should screen for those who may benefit from an early, integrated palliative approach to care. Early, systematic integration of palliative care into standard oncology practice is recommended. Opportunities for screening include: symptom burden and patient concern, transitions points in care or indicators of advanced disease trajectory, requests from patient or family/caregiver for palliative care services or information, and based on clinical judgement. 63 - Symptom, distress, and functional status management (e.g., pain, dyspnea, fatigue, sleep disturbance, mood, nausea, or constipation). - Exploration of understanding and education about illness and prognosis.
- Clarification of treatment goals.
- Assessment and support of coping needs.
- Assistance with medical decision making.
- Coordination with other care providers.
- Provision of referrals to other care providers as indicated. c) All AYAs should be given the opportunity to participate in Advance Care Planning as a part of routine care, started early in a longitudinal relationship with a healthcare provider and revisited when the health or wishes of the AYA change.
Healthcare professionals referring to this appendix should exercise independent clinical judgment in the context of case-specific circumstances to frame discussions about fertility risk related to cancer treatment, including whether there is potential for recovery of fertility over time.
# Radiation Therapy
Temporary sterilization can occur in females of reproductive age at single-fraction doses to the ovary of 1.7-6.4 Gy with permanent sterilization occurring after 3.2-10 Gy. The effect of fractionated RT on ovarian function is shown in Table 1. Ovarian damage is also associated with whole abdomen dosages of 20-30 Gy (primary or premature secondary ovarian failure), as is direct or scattered irradiation from the spinal part of craniospinal irradiation. In males, multiple small fractions of radiation therapy are more toxic to spermatogenesis than a large, single fraction. Table 2 summarize the fractionated dose-related effect of spermatogenesis and Leydig cell function. In addition to testicular irradiation, the testes may be affected (transient elevation in FSH and oligospermia) by scatter from abdominal RT (>20 Gy).
# Systemic Therapy
The tables below list patients as being at high risk (>70%), intermediate risk (30-70%), or low risk (<30%) of infertility based on different types of systemic therapy. iii Very low risk can be considered <10%. This classification, while not precise, acts a critical starting point to promote uniform discussions with patients and families. iv
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Provincial Tumour Teams. Members include surgical oncologists, radiation oncologists, medical oncologists, dermatologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Tumour Teams and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2020. In 2023, the guideline was revised to include Appendix B: Fertility Risk Classification.
# Levels of Evidence
# I
Evidence | # Background
The Canadian Partnership for Cancer (CPAC) reports that approximately 7,600 Canadians aged 15 to 39 years are diagnosed with cancer every year 1 Although the most frequent cancers in adolescent and young adults (AYAs) are thyroid cancer, breast cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, testicular cancer and melanoma, all tumour groups present in young adults. 1 While there has been an increase in the age-standardized incidence rate of cancer for the AYA population, most AYAs diagnosed with cancer in Canada will survive their disease today. 1 AYAs diagnosed with cancer face unique challenges during and after their cancer diagnosis. Ferrari et al state that, "AYA patients seem to be in a sort of no-man's land, halfway between the two different worlds of pediatric and adult medical oncology and bearing the brunt, in terms of inclusion in clinical trials and quality of professional care, of the lack of integration between these two worlds." 2 Besides differences in tumour biology, limited progress in survival, lower clinical trial participation rates, and insufficient awareness of cancer symptoms among patients and professionals, AYA cancer patients have distinct psychosocial and supportive care needs compared with pediatric and adult cancer populations. 3 Late adolescence and young adulthood is a developmentally complex period of life, during which individuals are working to establish their own identity, develop a positive body image and sexual identity, detach from their parents, increase their involvement with peers, find a life partner, make decisions about higher education and careers, and possibly have their own family. 4 A cancer diagnosis can temporarily or permanently derail these plans.
In recognition of the lack of information about AYAs diagnosed with cancer in Canada and the obligation to address their unmet needs, a Canadian framework for the care and support of AYAs with cancer was jointly published by CPAC and the Adolescent and Young Adults with Cancer National Network in 2019. 5 The purpose of this framework was to articulate a national vision for high quality care and survivorship support of AYAs diagnosed with cancer and to provide specific individual-, service-, and system-level key actions to achieve the vision. Thus, the framework inspired the development of this provincial guideline, which endeavors to align its recommendations with the frameworks four strategic priorities to:
• Integrate an AYA-centered experience throughout care and survivorship; • Deliver interdisciplinary, integrated and comprehensive care and survivorship support that address the unique needs of AYAs with cancer; • Increase access to cutting-edge approaches to care and survivorship support for AYAs with cancer; and, • Drive evidence-based improvements for AYAs with cancer. This guideline has been developed as a supportive care guideline and not as a treatment guideline. The purpose of the guideline is to increase awareness of unique issues in AYA oncology and to recommend standards of care and interventions unique to the AYA population. Fundamentally, this guideline describes the optimal safe and high-quality care for all Albertan AYAs with cancer. Specific Guideline Resource Unit treatments or clinical procedures at the patient level are the domain of the Provincial Tumour Teams and treating teams. Operationalization of these guidelines is the domain of the AYA Oncology Steering Committee and treating teams and will likely look different across healthcare facilities.
# Guideline Questions
In AYAs diagnosed with cancer:
# Search Strategy
PubMed database was searched for relevant studies, guidelines, and consensus documents. The specific search strategies, search terms, and search results, are presented in Appendix A. Evidence tables are available upon request. Online resources from oncology-based health organizations and guideline developers were also systematically searched, and relevant frameworks, care manuals, and guidelines from the following organizations were considered in the development of our recommendations: Canadian Partnership Against Cancer (CPAC), CanTeen Australia, Clinical Oncology Society of Australia (COSA), and the National Comprehensive Cancer Network (NCCN).
# Target Population
This guideline's recommendations are applicable to AYAs who have been diagnosed with cancer. We defined this population as persons aged 15 to 39 years, which is in line with The Canadian Framework for the Care and Support of Adolescents and Young Adults. 5 However, we recognize that based on their development status, persons chronologically less than 15 and older than 39 years may be best served through the recommendations of this guideline.
# Target Audience
This guideline is directed at healthcare professionals who are involved in the care of AYAs who have been diagnosed with cancer, as well as for AYAs with cancer and their families and caregivers. c) Using a shared decision-making process, healthcare professionals should inform AYAs and discuss the potential risks and benefit for AYAs and their families to participate in clinical trials, as well as enrollment on tumour banking and biologic protocols. 5,11,12 Discussions and decisions about participation in research and clinical trials should be documented in the patient care plan. 5,11 (Level of Evidence: V, Strength of Recommendation: A)
• Refer to Alberta Clinical Trials and ClinicalTrials.gov databases for a list of current clinical studies being conducted in Alberta and around the World. ) Developmentally-appropriate care should be delivered and/or supported by a multidisciplinary team populated with age-and disease-specific medical and psychosocial experts able to effectively communicate and provide evidence-based care. 5,13 • Refer to the Children's Oncology Group (COG) 24 and National Comprehensive Cancer Network (NCCN) 6 for published recommendations for late effect screening in AYA cancer survivors.
f) Treating clinicians should work with patients to identify potential factors contributing to nonadherence with treatment regimens. 8 It is recommended that adherence assessment and monitoring occur at every clinic visit. 25,26 (Level of Evidence: V, Strength of Recommendation: A) g) All AYAs should be provided access to systematic and standardized symptom management for side effects related to cancer treatment. 6 (Level of Evidence: V, Strength of Recommendation: A) (4) Oncofertility a) All AYAs with cancer that require treatment that could compromise future fertility must be informed of the likely risk and options to protect or preserve fertility before treatment begins. 27 (Level of Evidence: V, Strength of Recommendation: B)
• Discussion can occur simultaneously with staging and the formulation of a treatment plan and should be documented in the medical record. 28 Appendix B provides common examples of effect of radiotherapy and systemic therapy on fertility. • Involving family members in these discussions may be beneficial.
• If the clinician is unable to discuss risks and treatment options, a referral to a colleague, or an AYA oncology specialist should be initiated for further discussion, or a referral directly to the fertility clinic may be completed.
b) Referral to a fertility clinic should be offered to AYAs as soon as possible following diagnosis 27 unless the risk of infertility from the cancer or treatment is 0 percent and documented. (Level of Evidence: V, Strength of Recommendation: B)
Guideline Resource Unit c) A discussion and/or referral related to fertility should be considered when the patient returns for follow up after completion of therapy and/or if pregnancy is being considered. 28 a) All AYAs should receive psychosocial screening as part of the new patient intake process. 30 When indicated, a full psychosocial assessment is recommended. The goal of this process is to identify, assess, support, and intervene to address common concerns associated with having cancer during the AYA years. While there are numerous scales to assess psychosocial outcomes in cancer, few have been specifically validated for AYAs with cancer. 31 Screening should include practical issues (housing, transport, finances), and for educational, family/social, emotional, physical, sexual, spiritual, and informational concerns. 30,32,33 b) Based on results from the psychosocial screening and/or initial comprehensive assessment, healthcare professionals should: (Level of Evidence: V, Strength of Recommendation: B)
• Provide AYAs and their families with information about psychosocial supports and services. 6,8
• Provide information about and encourage the use of about peer support to assist AYAs establishing and maintaining relationships with their peers, as well as other AYAs with cancer through mediums such as face-to-face meetings, camp and retreat programs, online support groups, and social networking opportunities. 5,6,8,34 • Address any physical/medical issues that may impact psychosocial wellbeing, including alcohol and drug use during treatment, the impact of treatment on fertility, sexuality and sexual function, physical function, and appearance. 6,8,16,35 • AYAs experiencing coping, transition, mood or other mental health issues, should be referred early to a psychosocial clinician (social worker, psychologist, or spiritual care provider) and/or psychiatrist. 6 • Refer AYAs to a social worker and/or occupational therapist to ensure they have access to the full range of educational, vocational, and employment support services for which they are eligible. 6,34,36 • Refer AYAs experiencing challenges with their spirituality/faith to faith-based resources or activities, including to spiritual care providers. 6,8 c) Healthcare professionals should routinely reassess the psychosocial supports of their AYA patients as they are likely to change over the patient cancer experience. 5,[37][38][39] • Intervention for consequences of cancer and treatment (e.g., medical problems, symptoms, emotional distress, financial and social concerns). • Coordination of care between primary care providers and specialists to ensure that all the survivor's health needs are met. 53 • Survivorship care planning. 54 • A consistent primary care physician for ongoing primary healthcare, health maintenance, and treatment of intercurrent illness. 6,51,55 • Assessment of sexuality and fertility related to the cancer and treatment should be considered part of routine follow up care. 6,56,57 • Offer of referral to an occupational therapy or a vocational specialist who can support reentering the workforce or returning to school. 34,36,58 c) Develop and provide to AYA cancer survivors and key healthcare professionals an individualized survivorship plan that includes 6,8 (Level of Evidence: V, Strength of Recommendation: B):
• Summary of treatment received.
• Information regarding follow-up care, surveillance, and screening recommendations.
• Information on post-treatment needs, including information regarding treatment-related effects and health risks when possible. • Delineation regarding roles of oncologists, primary care physicians in survivorship care and the timing of transfer if appropriate. • Healthy lifestyle recommendations (e.g., smoking cessation, physical activity).
# (7) Palliative Care
Alberta Health Services (AHS) adopts the World Health Organization (WHO) definition of palliative care that is, "an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual." 59 a) Clinicians caring for AYAs should screen for those who may benefit from an early, integrated palliative approach to care. Early, systematic integration of palliative care into standard oncology practice is recommended. [60][61][62] Opportunities for screening include: symptom burden and patient concern, transitions points in care or indicators of advanced disease trajectory, requests from patient or family/caregiver for palliative care services or information, and based on clinical judgement. 63 • Symptom, distress, and functional status management (e.g., pain, dyspnea, fatigue, sleep disturbance, mood, nausea, or constipation). • Exploration of understanding and education about illness and prognosis.
• Clarification of treatment goals.
• Assessment and support of coping needs.
• Assistance with medical decision making.
• Coordination with other care providers.
• Provision of referrals to other care providers as indicated. c) All AYAs should be given the opportunity to participate in Advance Care Planning as a part of routine care, started early in a longitudinal relationship with a healthcare provider and revisited when the health or wishes of the AYA change. [64][65][66]
#
Healthcare professionals referring to this appendix should exercise independent clinical judgment in the context of case-specific circumstances to frame discussions about fertility risk related to cancer treatment, including whether there is potential for recovery of fertility over time.
# Radiation Therapy
Temporary sterilization can occur in females of reproductive age at single-fraction doses to the ovary of 1.7-6.4 Gy with permanent sterilization occurring after 3.2-10 Gy. The effect of fractionated RT on ovarian function is shown in Table 1. Ovarian damage is also associated with whole abdomen dosages of 20-30 Gy (primary or premature secondary ovarian failure), as is direct or scattered irradiation from the spinal part of craniospinal irradiation. In males, multiple small fractions of radiation therapy are more toxic to spermatogenesis than a large, single fraction. Table 2 summarize the fractionated dose-related effect of spermatogenesis and Leydig cell function. In addition to testicular irradiation, the testes may be affected (transient elevation in FSH and oligospermia) by scatter from abdominal RT (>20 Gy).
# Systemic Therapy
The tables below list patients as being at high risk (>70%), intermediate risk (30-70%), or low risk (<30%) of infertility based on different types of systemic therapy. iii Very low risk can be considered <10%. This classification, while not precise, acts a critical starting point to promote uniform discussions with patients and families. iv
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Provincial Tumour Teams. Members include surgical oncologists, radiation oncologists, medical oncologists, dermatologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Tumour Teams and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2020. In 2023, the guideline was revised to include Appendix B: Fertility Risk Classification.
# Levels of Evidence
# I
Evidence | None | None |
Subsets and Splits