Vaccines: SARS-CoV-2 (COVID-19)

How to Cite This Chapter: Komorowski AS, Mourad O, Loeb M. Vaccines: SARS-CoV-2 (COVID-19). McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/B31.II.18.53.14. Accessed May 08, 2021.
Last Updated: April 29, 2021
Last Reviewed: April 29, 2021
Chapter Information

Authors’ note: Emergency Use Authorizations (EUAs) and approvals for different vaccinations to prevent coronavirus disease 2019 (COVID-19) are changing on a rapid basis and differ between jurisdictions. The textbook chapter that follows summarizes vaccines offered EUAs or approvals in Canada as of the date of the last update of this chapter. The judgment of professional and international organizations assessing the same body of evidence differs across jurisdictions, which may reflect different confidence in the data and different values and preferences associated with different outcomes.

Epidemiology, symptoms, diagnosis, and treatment of COVID-19: see Coronavirus Disease 2019 (COVID-19).

Vaccine PlatformsTop

mRNA vaccines currently approved for use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) consist of an mRNA molecule encapsulated in a lipid nanoparticle. The mRNA molecule itself encodes for the SARS-CoV-2 spike glycoprotein. The lipid nanoparticle is cationic and contains cholesterol for stability. Cholesterol is necessary to protect the mRNA from degradation once injected and allows its uptake into the cell, where endosomal release of the mRNA occurs. The mRNA is then translated into protein by ribosomes in a process that occurs outside—and independently—of the host cell nucleus. The resultant noninfectious SARS-CoV-2 spike glycoproteins are subsequently presented on the host cell surface for immune recognition by circulating lymphocytes. After being used by the cytoplasmic ribosomes to produce the spike glycoprotein, the mRNA is degraded. Of note, it is not biologically plausible for the mRNA component of the vaccine to integrate into human DNA, as human cells lack the reverse transcriptase and integrase enzymes required to accomplish this task.

Viral vector vaccines currently approved for use against SARS-CoV-2 consist of a recombinant, replication-deficient animal virus encoding for the SARS-CoV-2 spike glycoprotein. Upon injection, the viral vector is taken up into target cells and cellular ribosomes translate the recombinant sequence into the trimeric prefusion SARS-CoV-2 spike glycoprotein. The resultant noninfectious SARS-CoV-2 spike glycoproteins are subsequently presented on the host cell surface for immune recognition by circulating lymphocytes.

General ConsiderationsTop

1. Role of vaccination in those with previous SARS-CoV-2 infection: Current Canadian National Advisory Committee on Immunization (NACI) guidance is that vaccination should be recommended to those with previous clinical or microbiologic evidence of SARS-CoV-2 infection, as there is possible evidence of SARS-CoV-2 reinfection and of waning antibody titers from natural infection.

2. Role of microbiologic testing prior to administration of SARS-CoV-2 vaccines: Testing with polymerase chain reaction (PCR), rapid antigen detection tests, or serology is not required prior to immunization with a SARS-CoV-2 vaccine.

3. Postvaccination serologic testing: Serology is not required after immunization with a SARS-CoV-2 vaccine in order to document seroconversion.

4. Concern for infection with SARS-CoV-2 after immunization with a SARS-CoV-2 vaccine: Receipt of a vaccine will not interfere with PCR or rapid antigen testing for SARS-CoV-2 in the case that a clinician suspects infection with a circulating strain of SARS-CoV-2 in a previously vaccinated patient. Microbiologic testing can also distinguish between adverse events following immunization and natural infection with SARS-CoV-2.

5. Vaccine efficacy against SARS-CoV-2 variants of concern (VOCs): SARS-CoV-2 has a high baseline rate of mutation due to its RNA genome, allowing “escape mutants” to be produced, which are no longer bound by neutralizing antibodies from prior vaccination. Three major SARS-CoV-2 VOCs have thus far been identified: B.1.1.7, first identified in the United Kingdom; B.1.351, first identified in South Africa; and P.1, first identified in Japan and Brazil. Research is ongoing to determine the effect of VOCs on vaccine efficacy, and results will be updated as they become available in the “vaccine efficacy” subsection of each Health Canada–approved vaccine found below.

6. Prevention of transmission of SARS-CoV-2 by vaccination: Vaccinated individuals may harbor the virus in the nasopharyngeal mucosa but remain asymptomatic due to the vaccine effectively responding to the SARS-CoV-2 antigens. There is an emerging body of evidence that SARS-CoV-2 vaccines may reduce the viral load shed from the nasopharynx of vaccinated individuals asymptomatically harboring the virus in the nasopharynx.

7. Comparison of efficacy for SARS-CoV-2 vaccines: Different randomized controlled trials of SARS-CoV-2 vaccines have different efficacy endpoints and populations in which they were studied. Summary of these trials: Table 8.9-1.

Vaccines Currently Approved for Use in CanadaTop

Tozinameran (Pfizer-BioNTech) mRNA Vaccine

Tozinameran (marketed by Pfizer-BioNTech, previously known in developmental stages as “BNT162b2”) contains mRNA encoding for the SARS-CoV-2 spike glycoprotein encapsulated in lipid nanoparticles.

1. Indications: Tozinameran is recommended for the prevention of SARS-CoV-2 infection in patients aged ≥16 years.

2. Contraindications: Tozinameran is contraindicated in those with allergy or hypersensitivity to vaccine components. The nonmedicinal ingredients used in tozinameran are 1,2-distearoyl-sn-glycero-3-phosphocholine, ALC-0315, ALC-0159, cholesterol, dibasic sodium phosphate dihydrate, monobasic potassium phosphate, potassium chloride, sodium chloride, sucrose, and water for injection.

3. Special populations:

1) Children aged <16 years: The safety and efficacy of tozinameran has not yet been established in this population. The NACI recommends that in cases where a risk-benefit analysis has been undertaken and where informed consent has been obtained, tozinameran may be offered to individuals 12 to 15 years of age at very high risk of severe outcomes with COVID-19 (ie, in congregate living facilities or with preexisting conditions known to be associated with increased mortality risk in COVID-19).

2) Pregnant patients: The safety and efficacy of tozinameran has not yet been established in this population. A phase II/III study (ClinicalTrials.gov identifier: NCT04754594) in this population is underway.

3) Breastfeeding patients: It is unknown whether tozinameran is excreted in human breast milk, and therefore a risk to the breastfed child cannot be excluded or established.

4) Immunocompromised patients: Patients on immunosuppressive medications or those with immune compromise may have a diminished serologic response to vaccination.

4. Immunization schedule:

1) Tozinameran is given after dilution as a 0.3-mL IM injection in the deltoid muscle on days 0 and 21.

2) There is no information available with respect to missed doses and their effect on immune response to tozinameran. According to current guidance from the US Centers for Disease Control and Prevention (CDC), if a second dose is administered between days 17 and 21, it is considered within the recommended dosing schedule. If the second dose is administered prior to day 17, an additional dose should not be given. If >21 days have elapsed since the first dose, the second dose should be administered at the earliest convenience; in such a case, the primary series does not need to be repeated.

3) In the event of limited vaccine supply, the NACI recommends a pragmatic approach that maximizes the number of individuals deriving benefit from the initial dose of the vaccine series. As such, the interval between doses may be extended up to 112 days (16 weeks) as a temporary measure.

4) As the interchangeability of SARS-CoV-2 vaccines marketed by different manufacturers has not been established, it is currently recommended that a single manufacturer’s vaccine be used to initiate and complete the primary vaccination series.

5. Vaccine efficacy:

1) Short-term efficacy: Tozinameran was 95% effective (95% CI, 90.3-97.6) at preventing SARS-CoV-2 infection ≥7 days after the second dose (in participants without clinical or microbiologic evidence of infection at baseline).Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the short duration of follow-up (indirectness). Polack FP, Thomas SJ, Kitchin N, et al; C4591001 Clinical Trial Group. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020 Dec 10. doi: 10.1056/NEJMoa2034577. Epub ahead of print. PMID: 33301246. Vaccine efficacy was consistent across age, sex, race, and ethnicity demographics.

An Israeli study involving 1,193,236 participants showed similar efficacy data: at ≥7 days after the second dose, tozinameran was 92% effective (95% CI, 88-95) at preventing symptomatic SARS-CoV-2 infection; 88% effective (95% CI, 55-100) at preventing hospitalization; and 92% effective (95% CI, 75-100) at preventing severe COVID-19. Efficacy was also seen after administration of the first dose: tozinameran was 72% effective at preventing COVID-19–related death (95% CI, 19-100) for days 14 to 20 after the first dose.Evidence 2Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the short duration of follow-up (indirectness). Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N Engl J Med. 2021 Feb 24. doi: 10.1056/NEJMoa2101765. Epub ahead of print. PMID: 33626250.

2) Long-term efficacy: There is no current information regarding the durability of long-term efficacy or safety in individuals who have received the vaccine. This information is legally required to be collected and reported as part of postauthorization monitoring.

3) Role in preventing transmission: A study of vaccinated health-care workers that has yet to undergo peer review analyzed the effect of a single dose of tozinameran on PCR detection of asymptomatic SARS-CoV-2 infection in the nasopharynx. A 4-fold decrease in PCR detection was noted in health-care workers ≥12 days after having received their first dose relative to unvaccinated health-care workers (P = .004).Evidence 3Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the method of determination of transmissibility (indirectness). Weekes M, Jones NK, Rivett L, et al. Single-dose BNT162b2 vaccine protects against asymptomatic SARS-CoV-2 infection. Authorea. Published online February 24, 2021. doi: 10.22541/au.161420511.12987747/v1

4) Efficacy against SARS-CoV-2 VOCs: Tozinameran human serum neutralization assays (n = 8) against 3 key mutations found in the B.1.1.7 VOC have indicated consistently high neutralizing antibody titers from specific key mutations found therein.Evidence 4Low Quality of Evidence (low confidence that we know the true effects of the intervention). Quality of Evidence lowered due to the risk of bias from low sample size and indirectness. Xie X, Liu Y, Liu J, et al. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera. Nat Med. 2021 Feb 8. doi: 10.1038/s41591-021-01270-4. Epub ahead of print. PMID: 33558724. Liu Y, Liu J, Xia H, et al. Neutralizing Activity of BNT162b2-Elicited Serum - Preliminary Report. N Engl J Med. 2021 Feb 17. doi: 10.1056/NEJMc2102017. Epub ahead of print. PMID: 33596352. There was a 2-fold decrease in neutralizing antibody titers against key spike protein mutations from the B.1.351 VOC; however, titers remained above the levels that would signal a need to change the SARS-CoV-2 strains present in the vaccine.Evidence 5Low Quality of Evidence (low confidence that we know the true effects of the intervention). Quality of Evidence lowered due to the risk of bias from low sample size and indirectness. Xie X, Liu Y, Liu J, et al. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera. Nat Med. 2021 Feb 8. doi: 10.1038/s41591-021-01270-4. Epub ahead of print. PMID: 33558724. Liu Y, Liu J, Xia H, et al. Neutralizing Activity of BNT162b2-Elicited Serum - Preliminary Report. N Engl J Med. 2021 Feb 17. doi: 10.1056/NEJMc2102017. Epub ahead of print. PMID: 33596352. The effect of the full sequence length of the P.1 VOC has yet to be examined.

6. Adverse events: Adverse events stratified by dose and reported in the phase III clinical trial of tozinameran: Table 8.9-2.

Adverse events were more common after the second dose of the vaccine. Serious adverse events were reported by <1% of the clinical trial participants.

7. Shipping and storage:

1) Shipping: In order to preserve the efficacy of tozinameran, its temperature must be maintained between −80 and −60 degrees Celsius. The vaccine is shipped in multiple-dose vials within an insulated thermal shipping container on dry ice.

2) Storage: Tozinameran must be maintained between −80 and −60 degrees Celsius until it is ready to be thawed for patient use. Undiluted multiple-dose vials may be thawed in the refrigerator at 2 to 8 degrees Celsius and may be stored there for ≤5 days. If the vaccine is required for immediate use, it may be thawed at room temperature (≤25 degrees Celsius) for ≤30 minutes. Instructions for dilution and preparation of a thawed multiple-dose vial: covid-vaccine.canada.ca. Once diluted, the multiple-dose vial must be used within 6 hours or discarded. Vials should never be refrozen once thawed.

mRNA-1273 (Moderna) Vaccine

The mRNA-1273 vaccine (marketed by Moderna, and hereinafter referred to as “mRNA-1273 vaccine”) contains mRNA encoding for the SARS-CoV-2 spike glycoprotein encapsulated in lipid nanoparticles.

1. Indications: The mRNA-1273 vaccine is recommended for the prevention of SARS-CoV-2 infection in patients aged ≥18 years.

2. Contraindications: The mRNA-1273 vaccine is contraindicated in those with allergy or hypersensitivity to vaccine components. The nonmedicinal ingredients used in the mRNA-1273 vaccine are 1,2-distearoyl-sn-glycero-3-phosphocholine, acetic acid, cholesterol, lipid SM-102, polyethylene glycol 2000, sodium acetate, sucrose, tromethamine, tromethamine hydrochloride, and water for injection.

3. Special populations:

1) Children aged <18 years: The safety and efficacy of the mRNA-1273 vaccine has not yet been established in this population; a phase III study (TeenCOVE study; ClinicalTrials.gov identifier: NCT04649151) in this population is underway.

2) Pregnant patients: The safety and efficacy of the mRNA-1273 vaccine has not yet been established in this population. If a pregnant woman has been vaccinated with the mRNA-1273 vaccine, these patients should be encouraged to enroll in a postauthorization registry and monitoring program (contact Moderna Medical Information at 1-866-663-3762).

3) Breastfeeding patients: It is unknown whether the mRNA-1273 vaccine is excreted in human breast milk, and therefore a risk to the breastfed child cannot be excluded or established.

4) Immunocompromised patients: Patients on immunosuppressive medications or those with immune compromise may have a diminished serologic response to vaccination.

4. Immunization schedule:

1) The mRNA-1273 vaccine is given as a 0.5-mL IM injection in the deltoid muscle on days 0 and 28. The mRNA-1273 vaccine does not require reconstitution or dilution prior to administration.

2) There is no information available with respect to missed doses and their effect on immune response. According to current guidance from the NACI, if a second dose is administered between days 21 and 28, it is considered within the recommended dosing schedule. If >28 days have elapsed since the first dose, the second dose should be administered at the earliest convenience; in such a case, the primary series does not need to be repeated.

3) In the event of limited vaccine supply, the NACI recommends a pragmatic approach that maximizes the number of individuals deriving benefit from the initial dose of the vaccine series. As such, the interval between doses may be extended up to 112 days (16 weeks) as a temporary measure.

4) As the interchangeability of SARS-CoV-2 vaccines marketed by different manufacturers has not been established, it is currently recommended that a single manufacturer’s vaccine be used to initiate and complete the primary vaccination series.

5. Vaccine efficacy:

1) Short-term efficacy: The mRNA-1273 vaccine was 94.5% effective (95% CI, 86.5-97.8) at preventing SARS-CoV-2 infection ≥14 days after the second dose (in participants without clinical or microbiologic evidence of infection at baseline).Evidence 6Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the short duration of follow-up (indirectness). Baden LR, El Sahly HM, Essink B, et al; COVE Study Group. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2020 Dec 30:NEJMoa2035389. doi: 10.1056/NEJMoa2035389. Epub ahead of print. PMID: 33378609; PMCID: PMC7787219. Vaccine efficacy was consistent across age, sex, race, and ethnicity demographics.

2) Long-term efficacy: There is no current information regarding the durability of long-term efficacy or safety in individuals who have received the vaccine. This information is legally required to be collected and reported as part of postauthorization monitoring.

3) Role in preventing transmission: Data are currently insufficient to draw conclusions as to whether individuals vaccinated with the mRNA-1273 vaccine are less likely to transmit SARS-CoV-2 to unvaccinated individuals.

4) Efficacy against SARS-CoV-2 VOCs: mRNA-1273 human serum neutralization assays against the B.1.1.7 (UK) VOC illustrate a consistently high neutralizing antibody titers from the full set of mutations or from specific key mutations found therein.Evidence 7Low Quality of Evidence (low confidence that we know the true effects of the intervention). Quality of Evidence lowered due to the risk of bias from low sample size and indirectness. Wu K, Werner AP, Koch M, et al. Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine - Preliminary Report. N Engl J Med. 2021 Feb 17. doi: 10.1056/NEJMc2102179. Epub ahead of print. PMID: 33596346. Neutralizing antibody titers against the B.1.351 (South African) VOC showed a 6-fold decrease; however, titers remained above the levels shown to protect nonhuman primates in wild-type virus challenge experiments.Evidence 8Low Quality of Evidence (low confidence that we know the true effects of the intervention). Quality of Evidence lowered due to risk of bias from low sample size and indirectness. Wu K, Werner AP, Koch M, et al. Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine - Preliminary Report. N Engl J Med. 2021 Feb 17. doi: 10.1056/NEJMc2102179. Epub ahead of print. PMID: 33596346. The effect of the P.1 (Brazilian) VOC on neutralizing antibodies produced by mRNA-1273 vaccination, as well as on unvaccinated individuals in general, has not yet been studied.

6. Adverse events: Adverse events stratified by dose and reported in the phase III clinical trial of the mRNA-1273 vaccine: Table 8.9-3.

Adverse events were more common after the second dose of the vaccine. Most serious adverse events were reported by <2% of the clinical trial participants. In study participants ≥65 years of age, serious adverse events with an incidence ≥2% occurred exclusively after administration of the second dose of vaccine.

7. Shipping and storage:

1) Shipping: The mRNA-1273 vaccine should be maintained at temperatures between −25 and −15 degrees Celsius during shipping. It is shipped in multiple-dose vials.

2) Storage: The mRNA-1273 vaccine should not be stored on dry ice. During storage, it should be protected from light. Multiple-dose vials may be stored between 2 and 8 degrees Celsius for up to 30 days prior to first use. Vials may be thawed prior to use for 2.5 hours at 2 to 8 degrees Celsius; alternatively, they may be thawed for 1 hour at 15 to 25 degrees Celsius. Once the vial has been punctured with a needle, it should be used within 6 hours or discarded. Vials should never be refrozen once thawed.

AZD1222 ChAdOx1-S (Oxford-AstraZeneca and COVISHIELD) Vaccines

The AZD1222 ChAdOx1-S vaccine (marketed by AstraZeneca and Verity Pharmaceuticals) consists of a recombinant, replication-deficient chimpanzee adenovirus encoding for the SARS-CoV-2 spike glycoprotein. Each vaccine dose contains 5 × 1010 viral particles. There are 2 formulations of this vaccine approved by Health Canada: one produced by AstraZeneca and another by Verity Pharmaceuticals in partnership with AstraZeneca. For the purposes of this chapter, both formulations will hereinafter be referred to jointly as “AZD1222.”

1. Indications: The AZD1222 vaccine is recommended for the prevention of SARS-CoV-2 infection in patients aged ≥18 years.

While the vaccine has been approved for patients aged >18 years, current NACI recommendations suggest restricting the vaccine to patients aged >30 years to minimize the risk of vaccine-induced immune thrombotic thrombocytopenia (VITT). Some provinces have chosen a different age cutoff based on the current epidemiology of SARS-CoV-2 outbreaks in their jurisdictions.

2. Contraindications: The AZD1222 vaccine is contraindicated in those with allergy or hypersensitivity to vaccine components. The nonmedicinal ingredients used in the AZD1222 vaccine are ethanol, EDTA, L-histidine, L-histidine hydrochloride monohydrate, magnesium chloride hexahydrate, polysorbate 80, sodium chloride, sucrose, and water for injection.

3. Special populations:

1) Children aged <18 years: The safety and efficacy of the AZD1222 vaccine has not yet been established in this population.

2) Pregnant patients: The safety and efficacy of the AZD1222 vaccine has not yet been established in this population.

3) Breastfeeding patients: It is unknown whether the AZD1222 vaccine is excreted in human breast milk, and therefore a risk to the breastfed child cannot be excluded or established.

4) Immunocompromised patients: Patients on immunosuppressive medications or those with immune compromise may have a diminished serologic response to vaccination.

4. Immunization schedule:

1) The AZD1222 vaccine is given as a 0.5-mL IM injection in the deltoid muscle, with the first dose given on day 0, and the second dose given between days 28 and 84. There is some evidence that the AZD1222 vaccine may be more efficacious when the dosing interval is prolonged (ie, 84 days as opposed to 28 days). In patients who had a longer interval (≥12 weeks) between doses, vaccine efficacy was 81.3% (95% CI, 60.3-91.2), compared with those with a short interval between doses (<6 weeks), in whom vaccine efficacy was 55.1% (95% CI, 33.0-69.9).Evidence 9Low Quality of Evidence (low confidence that we know the true effects of the intervention). Quality of Evidence lowered due to the risk of bias from low indirectness (lack of follow-up), inconsistency (dosing error), and imprecision (small proportion of patients ≥65 years of age, a clinically relevant demographic). Voysey M, Costa Clemens SA, Madhi SA, et al; Oxford COVID Vaccine Trial Group. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. Lancet. 2021 Feb 19:S0140-6736(21)00432-3. doi: 10.1016/S0140-6736(21)00432-3. Epub ahead of print. PMID: 33617777; PMCID: PMC7894131. The AZD1222 vaccine does not require reconstitution or dilution prior to administration.

2) There is no information available with respect to missed doses and their effect on immune response. The NACI has not yet made recommendations with respect to missed doses as of the date of the last update of this chapter.

3) In the event of limited vaccine supply, the NACI recommends a pragmatic approach that maximizes the number of individuals deriving benefit from the initial dose of the vaccine series. As such, the interval between doses may be extended up to 112 days (16 weeks).

4) As the interchangeability of SARS-CoV-2 vaccines marketed by different manufacturers has not been established, it is currently recommended that a single manufacturer’s vaccine be used to initiate and complete the primary vaccination series.

5. Vaccine efficacy:

1) Short-term efficacy: Participants in the pooled efficacy analysis for AZD1222 either received 2 standard doses (5 × 1010 viral particles per dose), or 1 reduced dose (2.2 × 1010 viral particles per dose) followed by 1 standard dose. The reduced dose/standard dose regimen was the result of a difference in concentration determination in one of the studies. Of those trial participants who received 2 standard doses, the AZD1222 vaccine was 62.1% effective (95% CI, 39.96-76.08) at preventing symptomatic, PCR-confirmed SARS-CoV-2 infection ≥15 days after the second dose.Evidence 10Low Quality of Evidence (low confidence that we know the true effects of the intervention). Quality of Evidence lowered due to the risk of bias from low indirectness (lack of follow-up), inconsistency (dosing error), and imprecision (small proportion of patients ≥65 years of age, a clinically relevant demographic). Voysey M, Clemens SAC, Madhi SA, et al; Oxford COVID Vaccine Trial Group. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021 Jan 9;397(10269):99-111. doi: 10.1016/S0140-6736(20)32661-1. Epub 2020 Dec 8. Erratum in: Lancet. 2021 Jan 9;397(10269):98. PMID: 33306989; PMCID: PMC7723445. There were no hospitalizations for COVID-19 (data cutoff December 7, 2020) in participants ≥15 days after receipt of the second dose.Evidence 11Low Quality of Evidence (low confidence that we know the true effects of the intervention). Quality of Evidence lowered due to the risk of bias from low indirectness (lack of follow-up), inconsistency (dosing error), and imprecision (small proportion of patients ≥65 years of age, a clinically relevant demographic). Voysey M, Clemens SAC, Madhi SA, et al; Oxford COVID Vaccine Trial Group. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021 Jan 9;397(10269):99-111. doi: 10.1016/S0140-6736(20)32661-1. Epub 2020 Dec 8. Erratum in: Lancet. 2021 Jan 9;397(10269):98. PMID: 33306989; PMCID: PMC7723445. Short-term efficacy data should be interpreted with caution for AZD1222, as the trial population used for vaccine efficacy calculation excluded 51% of participants; an unexpected significant difference in vaccine efficacy was found between the participants who received the reduced dose/standard dose (90.0%; 95% CI, 67.4-97.0) versus those who received 2 standard doses; there was wide variability in dosing interval between study participants; and only 9.7% of clinical trial participants were ≥65 years of age.

2) Long-term efficacy: There is no current information regarding the durability of long-term efficacy or safety in individuals who have received the vaccine. This information is legally required to be collected and reported as part of postauthorization monitoring.

3) Role in preventing transmission: Two standard AZD1222 doses reduce SARS-CoV-2 PCR positivity rates in the nasopharynx by 54.1% (95% CI, 44.7-69.1).Evidence 12Low Quality of Evidence (low confidence that we know the true effects of the intervention). Quality of Evidence lowered due to the risk of bias from low indirectness (lack of follow-up), inconsistency (dosing error), and imprecision (small proportion of patients ≥65 years of age, a clinically relevant demographic). Voysey M, Costa Clemens SA, Madhi SA, et al; Oxford COVID Vaccine Trial Group. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. Lancet. 2021 Feb 19:S0140-6736(21)00432-3. doi: 10.1016/S0140-6736(21)00432-3. Epub ahead of print. PMID: 33617777; PMCID: PMC7894131.

4) Efficacy against SARS-CoV-2 VOCs: Non–peer-reviewed data from AZD1222 human serum neutralization assays against the B.1.1.7 VOC illustrate a 9-fold decrease in neutralizing antibody titers compared with a canonical strain of the virus; notably, vaccine efficacy against the B.1.1.7 VOC remained high at 74.6% (95% CI, 41.6-88.9).Evidence 13Low Quality of Evidence (low confidence that we know the true effects of the intervention). Quality of Evidence lowered due to inconsistency (dosing error) and imprecision (small proportion of patients ≥65 years of age, a clinically relevant demographic). Emary KRW, Golubchik T, Aley PK, et al; COVID-19 Genomics UK (COG-UK) Consortium and Oxford COVID Vaccine Trial Group. Efficacy of ChAdOx1 nCoV-19 (AZD1222) Vaccine Against SARS-CoV-2 VOC 202012/01 (B.1.1.7). SSRN. Published online February 4, 2021. doi: http://dx.doi.org/10.2139/ssrn.3779160. Non–peer-reviewed data with respect to the B.1.351 VOC indicate that vaccine efficacy in individuals infected with SARS-CoV-2 B.1.351 is 10.4% (95% CI, 76.8-54.8), suggesting no protection against mild or moderate COVID-19 with B.1.351 infection.Evidence 14Low Quality of Evidence (low confidence that we know the true effects of the intervention). Quality of Evidence lowered due to inconsistency (dosing error) and imprecision (small proportion of patients ≥65 years of age, a clinically relevant demographic factor). Madhi SA, Baillie V, Cutland CL, et al. Safety and efficacy of the ChAdOx1 nCoV-19 (AZD1222) Covid-19 vaccine against the B.1.351 variant in South Africa. medRxiv. Published online February 12, 2021. doi: https://doi.org/10.1101/2021.02.10.21251247. The effect of the P.1 VOC on neutralizing antibodies produced by AZD1222 vaccination has not yet been studied.

6. Adverse events: Adverse events stratified by dose and reported in the phase III clinical trial of the AZD1222 vaccine: Table 8.9-4.

Adverse events were more common after the first dose of the vaccine. Serious adverse events were reported by 0.7% of the clinical trial participants who received AZD1222. Two serious adverse events may have been related to AZD1222: pyrexia (n = 1), occurring 2 days after dose 1, and transverse myelitis (n = 1), occurring 14 days after dose 2.

There is an evolving body of evidence to suggest that AZD1222 increases the risk for the development of VITT. Its incidence is projected to occur at a rate between 1 per 26,000 and 1 per 250,000 vaccinations. This disorder resembles heparin-induced thrombocytopenia (HIT) and occurs between 4 and 20 days after injection of the dose. Further information can be found in the Thrombosis Canada guidelines at www.thrombosiscanada.ca.

7. Shipping and storage:

1) Shipping: The AZD1222 vaccine should be maintained at temperatures between 2 and 8 degrees Celsius during shipping and should not be frozen. It is shipped in multiple-dose vials.

2) Storage: The AZD1222 vaccine should not be stored frozen. Multiple-dose vials may be stored between 2 and 8 degrees Celsius. During refrigerated storage, unopened vials should be protected from light. Opened vials may be maintained at room temperature (max allowable temperature, 30 degrees Celsius) for up to 6 hours. Vials may be refrigerated (2-8 degrees Celsius) after opening for a maximum of 48 hours. If an opened vial is maintained at room temperature for a cumulative time of >6 hours or at refrigeration temperature for a cumulative time of >48 hours, it should be discarded.

Ad26.COV2.S (Johnson & Johnson/Janssen) Vaccine

The Ad26.COV2.S vaccine (marketed by Johnson & Johnson/Janssen Inc.) consists of a recombinant, replication-deficient adenovirus type 26 encoding for the SARS-CoV-2 spike glycoprotein in a stabilized conformation. The vaccine is produced in the PER.C6 TetR cell line. Each vaccine dose contains 5 × 1010 viral particles.

1. Indications: The Ad26.COV2.S vaccine is recommended for the prevention of SARS-CoV-2 infection in patients aged ≥18 years.

2. Contraindications: The Ad26.COV2.S vaccine is contraindicated in those with allergy or hypersensitivity to vaccine components. The nonmedicinal ingredients used in the Ad26.COV2.S vaccine are 2-hydroxypropyl-beta-cyclodextrin, citric acid monohydrate, ethanol, hydrochloric acid, polysorbate 80, sodium chloride, sodium hydroxide, trisodium citrate dihydrate, and water for injection.

3. Special populations:

1) Children aged <18 years: The safety and efficacy of the Ad26.COV2.S vaccine has not yet been established in this population.

2) Pregnant patients: The safety and efficacy of the Ad26.COV2.S vaccine has not yet been established in this population. Pregnant women who have been vaccinated with the Ad26.COV2.S vaccine should be encouraged to enroll in a postauthorization registry and monitoring program (c-viper.pregistry.com).

3) Breastfeeding patients: It is unknown whether the Ad26.COV2.S vaccine is excreted in human breast milk, and therefore a risk to the breastfed child cannot be excluded or established.

4) Immunocompromised patients: Patients on immunosuppressive medications or those with immune compromise may have a diminished serologic response to vaccination. Two populations of immunosuppressed patients were included in the phase III clinical trial of Ad26.COV2.S: those on chronic, low-dose immunosuppression (≤20 mg prednisone equivalent) and those with stable HIV infection.

4. Immunization schedule:

1) The Ad26.COV2.S vaccine is given as a single 0.5-mL IM injection in the deltoid muscle on day 0. The Ad26.COV2.S vaccine does not require reconstitution or dilution prior to administration.

2) As the interchangeability of SARS-CoV-2 vaccines marketed by different manufacturers has not been established, it is currently recommended that a single manufacturer’s vaccine be used to initiate and complete the primary vaccination series.

5. Vaccine efficacy:

1) Short-term efficacy: The Ad26.COV2.S vaccine was 66.9% effective (95% CI, 59.0-73.4) at preventing moderate to severe/critical COVID-19 ≥14 days after vaccination and 66.1% effective (95% CI, 55.0-74.8) at preventing moderate to severe/critical COVID-19 ≥28 days after vaccination. When stratified by severe and critical COVID-19 cases only, Ad26.COV2.S was 76.7% effective (95% CI, 54.6-89.1) at preventing such cases ≥14 days from vaccination and 85.4% effective (95% CI, 54.2-96.9) at preventing such cases ≥28 days from vaccination. There were no hospitalizations for COVID-19 in vaccinated trial participants in whom SARS-CoV-2 was detected ≥28 days after vaccination. There were no COVID-19–related deaths in trial participants who received the Ad26.COV2.S vaccine.Evidence 15Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the short duration of follow-up (indirectness). Product Monograph including Patient Medication Information: Janssen COVID-19 Vaccine: SARS-CoV02 Vaccine (Ad26.COV2.S, recombinant). Published March 5, 2021. Accessed March 5, 2021. https://covid-vaccine.canada.ca/janssen-covid-19-vaccine/product-details [Under resources for health care professionals]. Sadoff J, Gray G, Vandebosch A, et al; ENSEMBLE Study Group. Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19. N Engl J Med. 2021 Apr 21. doi: 10.1056/NEJMoa2101544. Epub ahead of print. PMID: 33882225

2) Long-term efficacy: There is no current information regarding the durability of long-term efficacy or safety in individuals who have received the vaccine. This information is legally required to be collected and reported as part of postauthorization monitoring.

3) Role in preventing transmission: Data are currently insufficient to draw conclusions as to whether individuals vaccinated with the Ad26.COV2.S vaccine are less likely to transmit SARS-CoV-2 to unvaccinated individuals.

4) Efficacy against SARS-CoV-2 VOCs: Ad26.COV2.S human serum neutralization assays against the B.1.1.7 VOC illustrate a 9-fold decrease in neutralizing antibody titers compared with a canonical strain of the virus at ≥28 days post vaccination; there was, however, only a 3.3-fold decrease in neutralizing antibody titers by ≥70 days post vaccination. Subgroup analysis of vaccine efficacy at the South African trial site, where the B.1.351 VOC predominates as a circulating strain, shows a vaccine efficacy of 64% (95% CI, 41.2-78.7), in line with overall trial results.Evidence 16Low Quality of Evidence (low confidence that we know the true effects of the intervention). Quality of Evidence lowered due to imprecision (use of entire study population to infer vaccine efficacy against VOC). Vaccines and Related Biological Products Advisory Committee Meeting: February 26, 2021. FDA Briefing Document: Janssen Ad26.COV2.S Vaccine for the Prevention of COVID-19COVID Vaccine Ad26.COV2.S VAC31518 (JNJ-78436735). Published February 26, 2021. Accessed March 6, 2021. https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-february-26-2021-meeting-announcement The effect of the B1.351 and P.1 VOCs on neutralizing antibodies produced by Ad26.COV2.S vaccination has not yet been studied.

6. Adverse events: Adverse events stratified by dose and reported in the phase III clinical trial of the Ad26.COV2.S vaccine: Table 8.9-5.

Thirteen percent of trial participants receiving Ad26.COV2.S had an unsolicited adverse event, the majority of which were low-grade reactogenicity events. Serious adverse events were reported by 0.4% of the clinical trial participants who received Ad26.COV2.S. Three serious adverse events were considered related to Ad26.COV2.S: fever, headache, and asthenia (n = 1); severe injection site pain nonresponsive to analgesics with symptoms ongoing at 10 weeks (n = 1); and type IV hypersensitivity reaction progressing to lip angioedema and resolving within 5 weeks (n = 1).

7. Shipping and storage:

1) Shipping: The Ad26.COV2.S vaccine should be maintained at temperatures between 2 and 8 degrees Celsius during shipping and should not be frozen. It is shipped in multiple-dose vials.

2) Storage: The Ad26.COV2.S vaccine should not be stored frozen. Multiple-dose vials may be stored between 2 and 8 degrees Celsius. During refrigerated storage, unopened vials should be protected from light. Unopened vials may be maintained at room temperature (max allowable temperature, 25 degrees Celsius) for up to 12 hours. Once opened, vials may be kept refrigerated (2-8 degrees Celsius) for up to 6 hours or at room temperature (max allowable temperature, 25 degrees Celsius) for up to 3 hours. If an opened vial is maintained at room temperature for a cumulative time of >3 hours or at refrigeration temperature for a cumulative time of >6 hours, it should be discarded.

TablesTop

Table 8.9-1. Summary of SARS-CoV-2 vaccines currently approved in Canada

Vaccine type

Population

Primary endpoint

Vaccine efficacy

Hospitalizationsa

Deathsa

Tozinameran (Pfizer-BioNTech)

mRNA

– Age >16 years

– Excluded if prior SARS-CoV-2 infection or if immunocompromised

Preventing COVID-19–related death 14-20 days after 1st dose

Dose 1: 72% (95% CI, 19-100)

0

0

Preventing SARS-CoV-2 infection ≥7 days after 2nd dose

Dose 2: 95% (95% CI, 90.3-97.6)

mRNA-1273 (Moderna)

mRNA

– Age >18 years

– Excluded if prior SARS-CoV-2 infection or if pregnant or immunocompromised

Preventing SARS-CoV-2 infection ≥14 days after 2nd dose

94.5% (95% CI, 86.5-97.8)

0

0

AZD1222 (Oxford-AstraZeneca and COVISHIELD)

Recombinant adenovirus

– Age 18-65 years

– Excluded if prior SARS-CoV-2 infection or if positive NAAT within 14 days of 2nd vaccination

Preventing symptomatic SARS-CoV-2 infection 14 days after 2nd dose

62.1% (95% CI, 39.96-76.08)

≥21 days after 1st dose: 0

≥21 days after 1st dose: 0

Ad26.COV2.S (Johnson & Johnson)

Recombinant adenovirus

– Age >18 years

– Excluded if after prior SARS-CoV-2 infection or if pregnant or immunocompromised

Preventing moderate to severe COVID-19

– 14 days: 66.9% (95% CI, 59.0-73.4)

– 28 days: 66.1% (95% CI, 55.0-74.8)

≥28 days post vaccination: 0

≥28 days post vaccination: 0

Preventing severe to critical COVID-19

– 14 days: 76.7% (95% CI, 54.6-89.1)

– 28 days: 85.4% (95% CI, 54.2-96.9)

a Outcomes in experimental arm.

COVID-19, coronavirus disease 2019; NAAT, nucleic acid amplification test; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Table 8.9-2. Adverse events with administration of tozinameran, stratified by age of clinical trial participants

Adverse events within 7 days of administration; study participants aged 18-55 years

Adverse event reported

Dose 1 (%)

Dose 2 (%)

Local erythema

4.5

5.9

Local swelling

5.8

6.3

Pain at injection site

83.1

77.8

Temperature ≥38°C

3.7

15.8

Fatigue

47.4

59.4

Headache

41.9

51.7

Chills

14.0

35.1

Vomiting

1.2

1.9

Diarrhea

11.1

10.4

New or worsened myalgia

21.3

37.3

New or worsened arthralgia

11.0

21.9

Adverse events within 7 days of administration; study participants aged ≥56 years

Adverse event reported

Dose 1 (%)

Dose 2 (%)

Local erythema

4.7

7.2

Local swelling

6.5

7.5

Pain at injection site

71.1

66.1

Temperature ≥38°C

1.4

10.9

Fatigue

34.1

50.5

Headache

25.2

39.0

Chills

6.3

22.7

Vomiting

0.5

0.7

Diarrhea

8.2

8.3

New or worsened myalgia

13.9

28.7

New or worsened arthralgia

8.6

18.9

Adapted from N Engl J Med. 2020 Dec 10. doi: 10.1056/NEJMoa2034577 and the Pfizer-BioNTech COVID-19 Vaccine [COVID-19 mRNA Vaccine] Product Monograph.

Table 8.9-3. Adverse events with administration of the mRNA-1273 vaccine, stratified by age of clinical trial participants

Adverse events within 7 days of administration; study participants aged 18-64 years

Adverse event reported

Dose 1 (%)

Dose 2 (%)

Local erythema

3.0

8.9

Local swelling

6.7

12.6

Pain at injection site

86.9

89.9

Axillary tenderness/swelling

11.6

16.2

Fatigue

38.4

67.6

Headache

35.3

62.8

Chills

9.2

48.6

Nausea/vomiting

9.4

21.4

Fever

0.9

17.4

Myalgia

23.7

61.6

Arthralgia

16.6

45.5

Adverse events within 7 days of administration; study participants aged ≥65 years

Adverse event reported

Dose 1 (%)

Dose 2 (%)

Local erythema

2.3

7.5

Local swelling

4.4

10.8

Pain at injection site

74.0

83.2

Axillary tenderness/swelling

6.1

8.5

Fatigue

33.3

58.3

Headache

24.5

46.2

Chills

5.4

30.9

Nausea/vomiting

5.2

11.8

Fever

0.3

10.0

Myalgia

19.7

47.1

Arthralgia

16.4

35.0

Adapted from N Engl J Med. 2020 Dec 30. doi: 10.1056/NEJMoa2035389 and Product Monograph: Moderna COVID-19 Vaccine, mRNA-1273 SARS-CoV-2 vaccine.

Table 8.9-3. Adverse events with administration of the mRNA-1273 vaccine, stratified by age of clinical trial participants

Adverse events within 7 days of administration; study participants aged 18-64 years

Adverse event reported

Dose 1 (%)

Dose 2 (%)

Local erythema

3.0

8.9

Local swelling

6.7

12.6

Pain at injection site

86.9

89.9

Axillary tenderness/swelling

11.6

16.2

Fatigue

38.4

67.6

Headache

35.3

62.8

Chills

9.2

48.6

Nausea/vomiting

9.4

21.4

Fever

0.9

17.4

Myalgia

23.7

61.6

Arthralgia

16.6

45.5

Adverse events within 7 days of administration; study participants aged ≥65 years

Adverse event reported

Dose 1 (%)

Dose 2 (%)

Local erythema

2.3

7.5

Local swelling

4.4

10.8

Pain at injection site

74.0

83.2

Axillary tenderness/swelling

6.1

8.5

Fatigue

33.3

58.3

Headache

24.5

46.2

Chills

5.4

30.9

Nausea/vomiting

5.2

11.8

Fever

0.3

10.0

Myalgia

19.7

47.1

Arthralgia

16.4

35.0

Adapted from N Engl J Med. 2020 Dec 30. doi: 10.1056/NEJMoa2035389 and Product Monograph: Moderna COVID-19 Vaccine, mRNA-1273 SARS-CoV-2 vaccine.

Table 8.9-4. Adverse events with administration of the AZD1222 vaccine, stratified by age of clinical trial participants

Adverse events within 7 days of administration; study participants aged 18-64 years from COV001, COV002, and COV003 studies

Adverse event reported

Dose 1 (%)

Dose 2 (%)

Local erythema

2.6

1.1

Local swelling

2.9

0.9

Pain at injection site

60.3

34.4

Local pruritus

6.5

4.2

Fatigue

64.6

43.0

Headache

61.1

38.3

Chills

37.2

6.5

Nausea

23.9

9.7

Fever

11.6

0.7

Myalgia

52.3

25.6

Arthralgia

28.0

11.6

Adverse events within 7 days of administration; study participants aged ≥65 years from COV001, COV002, and COV003 studies

Adverse event reported

Dose 1 (%)

Dose 2 (%)

Local erythema

2.3

0.4

Local swelling

2.0

0.8

Pain at injection site

22.8

10.2

Local pruritus

3.5

2.3

Fatigue

40.9

27.0

Headache

31.8

19.9

Chills

10.8

2.0

Nausea

8.0

5.5

Fever

1.0

0.0

Myalgia

22.6

13.7

Arthralgia

13.0

7.4

Adapted from Lancet. 2021 Jan 9;397(10269):99-111. doi: 10.1016/S0140-6736(20)32661-1 and Product Monograph: AstraZeneca COVID-19 Vaccine, ChAdOx1-S [recombinant].

Table 8.9-5. Adverse events with administration of the Ad26.COV2.S vaccine versus placebo, stratified by age of clinical trial participants

Adverse events within 7 days of administration; study participants aged 18-59 years

Adverse event reported

Percentage (%)

Local erythema

9.0

Local swelling

7.0

Pain at injection site

58.6

Fatigue

43.8

Headache

44.4

Nausea

15.5

Fever

12.8

Myalgia

39.1

Adverse events within 7 days of administration; study participants aged ≥60 years

Adverse event reported

Percentage (%)

Local erythema

4.6

Local swelling

2.7

Pain at injection site

33.3

Fatigue

29.7

Headache

30.4

Nausea

12.3

Fever

3.1

Myalgia

24.0

Adapted from Product Monograph including Patient Medication Information: Janssen COVID-19 Vaccine: SARS-CoV-2 Vaccine (Ad26.COV2.S, recombinant).

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