Archived 6: Recommendations on the use of COVID-19 vaccines [2021-03-16]

Notice to reader

This is an archived version. Please refer to the most current version of this statement.
We also have a table of updates of our latest changes.

Publication date: March 16, 2021

On this page

Table of updates

This evergreen document will be updated as COVID-19 vaccines are authorized for use in Canada, and as evidence on these vaccines and COVID-19 evolves. This table summarizes the latest changes to this current version. Please refer to the Table of updates for a full list of updates to previous versions.
Section Update Date
Introduction Health Canada authorized two manufacturers to produce the vaccine developed by AstraZeneca and Oxford University: AstraZeneca and Serum Institute of India (SII). NACI has not specifically reviewed evidence for the SII vaccine, but Health Canada has deemed SII and AstraZeneca vaccines to be comparable. 2021-03-16
Vaccines Table 1. COVID-19 vaccines authorized for use in Canada has been updated to reflect the change in the Pfizer BioNTech COVID-19 product monograph regarding storage requirements. 2021-03-16
Schedule Table 2. Recommended immunization schedule, by COVID-19 vaccine has been updated to reflect NACI’s current recommendation for extending the interval for the second dose of COVID-19 vaccines up to four months after the first. The rationale for the intervals included in this table has been included. 2021-03-16
Storage Requirements Storage requirements for the Pfizer BioNTech COVID-19 vaccine have been updated to reflect changes in the product monograph which allow vials to also be stored at -25°C to -15°C for up to 2 weeks. 2021-03-16
Recommendations The recommendation on the use of the AstraZeneca COVID-19 vaccine has been updated to include use in those 65 years of age and older. This update is based on results of observational studies of vaccine effectiveness from the United Kingdom released since NACI’s previous recommendations for the use of this vaccine in those 18 to 64 years of age. The rationale for this updated recommendation for the use of AstraZeneca COVID-19 vaccine in those ≥18 years of age has been added. 2021-03-16
Recommendations The recent recommendation made by NACI on extending the interval for the second dose of COVID-19 vaccines up to four months after the first, summarized in a separate document, is now included. The rationale for this recommendation has been summarized. 2021-03-16
Management options for COVID-19 vaccines authorized for use in Canada Table 4 has been updated with observational data for AstraZeneca COVID-19 vaccine effectiveness in individuals ≥ 65 years of age. 2021-03-16
Research Priorities Three additional research priorities have been added under the Efficacy, Effectiveness, Immunogenicity and Safety section. 2021-03-16
Appendix C A summary and review of evidence on the effectiveness of the AstraZeneca COVID-19 vaccine, based on observational studies published as pre-prints, has been added to the appendix on the Evidence Summary for AstraZeneca vaccine. 2021-03-16

Preamble

The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.

In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.

The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.

This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge.

This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Summary

The following highlights key, current information for immunization providers on COVID-19 vaccine. The evidence on COVID-19 disease and vaccines is evolving. Evidence from clinical trial data is limited due to limitations in the size and duration of follow-up of trial populations; however, studies are ongoing. NACI will continue to monitor the data and update its recommendations as needed. Please refer to the remainder of the Statement for details.

What

Disease

Currently authorized vaccines (Pfizer BioNTech COVID-19, Moderna COVID-19, AstraZeneca COVID-19 vaccine)

Who

NACI makes the following recommendations:

A complete vaccine series with a currently authorized COVID-19 vaccine should be offered to:

A complete vaccine series with a currently authorized COVID-19 vaccine may be offered to:

For some specific populations who were either excluded from, or were represented by small numbers of participants in clinical trials, NACI recommends that a complete vaccine series with a currently authorized COVID-19 vaccine may be offered, if a risk assessment deems that the benefits of vaccination outweigh the potential risks for the individual (e.g., where the risk of severe outcomes of COVID-19 and/or risk of exposure to SARS-CoV-2 is high) or for the fetus/infant (in the case of pregnancy/breastfeeding) and if informed consent includes discussion about the insufficient evidence in these populations:

These recommendations may change as more evidence on safety and/or efficacy/effectiveness in these populations becomes available.

NACI also recommends that:

NACI continues to recommend the following elements to guide ethical decision-making, as outlined in NACI's guidance on Key Populations for Early COVID-19 Immunization:

How

Why

Introduction

The goal of Canada's pandemic response is to minimize serious illness and death while minimizing societal disruption as a result of the COVID-19 pandemic. Safe and effective COVID-19 vaccines could help achieve this goal. Clinical trials of numerous candidate COVID-19 vaccines are currently underway.

This guidance document will provide recommendations on the use of authorized COVID-19 vaccines as they are approved for use in Canada, and as evidence on authorized vaccines evolves.

COVID-19 vaccines currently authorized for use in Canada:

The evidence on COVID-19 and COVID-19 vaccines has been rapidly evolving. To date, NACI has published the following evidence-informed guidance:

  1. Research priorities for COVID-19 vaccines to support public health decisions to inform clinical trials of candidate COVID-19 vaccines to protect against infection, serious illness, and deaths caused by SARS-CoV-2.
  2. Preliminary guidance on key populations for early COVID-19 immunization to plan for the efficient, effective, and equitable allocation of an eventual COVID-19 vaccine when limited initial vaccine supply will necessitate the immunization of some populations earlier than others.
  3. Guidance on the prioritization of initial doses of COVID-19 vaccine(s) for the efficient and equitable prioritization of initial doses of COVID-19 vaccines to assist with the planning for allocation of the first COVID-19 immunization programs.
  4. Guidance on the prioritization of key populations for COVID-19 immunization to provide guidance for the equitable, ethical, and efficient allocation of authorized COVID-19 vaccines in the context of staggered arrival of vaccine supply that will necessitate offering vaccines to some populations earlier than others.
  5. Rapid response: Extended dose intervals for COVID-19 vaccines to optimize early vaccine rollout and population protection in Canada to maximize the number of individuals benefiting from the first dose of vaccine by extending the interval for the second dose up to four months after the first.
  6. Recommendations on the use of COVID-19 vaccine initially published on December 12, 2020 and updated iteratively as new evidence becomes available and the authorization of additional COVID-19 vaccines. This statement reflects the most up to date guidance.

Guidance objective

The objective of this advisory committee statement is to provide guidance on the effective and equitable use of COVID-19 vaccines authorized for use in Canada in the context of staggered authorization of these vaccines. This evergreen document will be updated as COVID-19 vaccines are authorized for use in Canada, and as evidence on these vaccines evolves. In this guidance document, the evidence and rationale for recommendations as well as current knowledge gaps (e.g. due to the size and short-term follow up in ongoing clinical trials) will be summarized. Clinical trial details on vaccine characteristics for specific COVID-19 vaccines will be included in appendices.

Methods

Details of NACI's recommendation development process can be found elsewhere.Footnote 2Footnote 3

In brief, the broad stages in the preparation of this NACI advisory committee statement included:

In order to develop comprehensive, appropriate immunization program recommendations, NACI considers a number of factors. In addition to critically appraising evidence on burden of disease and vaccine characteristics such as safety, efficacy, immunogenicity and effectiveness, NACI uses a published, peer-reviewed framework and evidence-informed tools to ensure that issues related to ethics, equity, feasibility, and acceptability (EEFA) are systematically assessed and integrated into its guidanceFootnote 3. The NACI Secretariat applied this framework with accompanying evidence-informed tools (Ethics Integrated Filters, Equity Matrix, Feasibility Matrix, Acceptability Matrix) to systematically consider these programmatic factors for the development of clear, comprehensive, appropriate recommendations for timely, transparent decision-making. For details on the development and application of NACI's EEFA Framework and evidence-informed tools (including the Ethics Integrated Filters, Equity Matrix, Feasibility Matrix, and Acceptability Matrix), please see A framework for the systematic consideration of ethics, equity, feasibility, and acceptability in vaccine program recommendations.

For this advisory committee statement, NACI used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework to develop population-focused recommendations. Further information on this framework can be found in the GRADE handbook.

NACI reviewed and approved the key policy questions used to guide recommendation development on November 25, 2020 and rated the outcomes for their importance for decision-making. The Canadian Immunization Committee (CIC) provided feedback on the key policy questions to ensure alignment with program needs. Important ethical considerations relating to the key policy questions were presented on November 26, 2020, December 15, 2020 and January 26, 2021 to the PHAC Public Health Ethics Consultative Group, who provided an assessment of ethical considerations that are relevant to the development of recommendations. Knowledge synthesis and quality appraisal were performed by the NACI Secretariat for unpublished clinical trial evidence and were informed by NACI's rating of the outcomes. Unpublished data from Phase 1, 2, and 3 clinical trials were presented to the High Consequence Infectious Disease Working Group and NACI for discussion. Proposed recommendations were then presented and approved at emergency NACI meetings. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the text.

Key Dates:

Epidemiology

Information on COVID-19 is continually evolving. The following section will describe the current basis of knowledge, with an emphasis on the best available Canadian data where possible. To access the most recent updates to specific elements, please refer to the links below.

Disease description

Infectious agent

COVID-19 is caused by the SARS-CoV-2, which was first recognized in Wuhan, China in December 2019.

Transmission

Current evidence suggests that COVID-19 is spread through respiratory droplets and aerosols created when an infected person coughs, sneezes, sings, shouts, or talks. A person may be infectious for up to three days before showing symptoms. More information on the transmission of COVID-19 can be found on the PHAC webpages for COVID-19: Main modes of transmission and COVID-19 signs, symptoms and severity of disease: A clinician guide.

Risk factors

Anyone can be infected with SARS-CoV-2. However, some populations are at increased risk of exposure to the virus (e.g., due to living or occupational settings), and some populations are at increased risk of severe disease and outcomes (e.g., hospitalization and death) due to various biological (e.g. advanced age, pre-existing medical conditions) and social (e.g., socioeconomic status, belonging to a racialized population) factors that may intersect. Exposure and risk of severe disease factors may overlap, further increasing risk. Any combination of these factors, as well as varying access to health care services, has the potential for disproportionate consequences for specific populations characterized by increased rates of infection and disease, severe illness, hospitalizations, and/or deaths.

Please see NACI's Advisory Committee Statement on Key Populations for Early COVID-19 Immunization and the Equity MatrixFootnote 4 for a summary of inequities associated with COVID-19, potential reasons for and intersections between these inequities, and suggested interventions to reduce inequities and improve access to vaccines.

More information on the risk factors associated with COVID-19 can be found on PHAC webpages for People who are at high risk for severe illness from COVID-19 and Vulnerable populations and COVID-19.

Spectrum of clinical illness

The median incubation period for COVID-19 has been estimated to be 5 to 6 days from exposure to symptom onset, with most individuals (97.5%) developing symptoms within 11.5 days of exposure.

Clinical presentation and symptoms of COVID-19 vary in frequency and severity. To date, there is no list of symptoms that has been validated to have high specificity or sensitivity for COVID-19.

More information on the spectrum of clinical illness is available on the PHAC webpage for COVID-19 signs, symptoms and severity of disease: A clinician guide.

Disease incidence

Global

Updated international data on COVID-19 cases and deaths is available at: Interactive data visualizations of COVID-19.

Weekly epidemiological updates highlighting key global, regional and country-level data on COVID-19 cases and deaths are available from the World Health Organization (WHO) at: Coronavirus disease (COVID-19) Weekly Epidemiological Update and Weekly Operational Update.

National

Updated national, provincial and territorial-level data on COVID-19 cases and deaths in Canada over time is available from the PHAC webpage on Coronavirus disease (COVID-19): Outbreak update.

Vaccines

The following section summarizes information about COVID-19 vaccines authorized for use in Canada. More detailed vaccine-specific information is included in Appendices A through D. The current landscape of all candidate COVID-19 vaccines in clinical evaluation can be found on the WHO webpage Draft landscape of COVID-19 candidate vaccines. Under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19, Health Canada can make regulatory decisions for COVID-19 vaccines that have completed Phase 3 clinical trials for authorized use in Canada.

Most vaccine candidates in development that may become authorized for use in Canada use various technologies to deliver SARS-CoV-2 spike protein to vaccine recipients. This protein is expressed on the surface of the SARS-CoV-2 virus and is a major target for binding and neutralizing antibodies as well as cell-mediated immune responses.

mRNA vaccines

COVID-19 vaccines that use messenger RNA (mRNA) platforms contain modified nucleotides that code for the SARS-CoV-2 spike protein. A lipid nanoparticle formulation delivers the mRNA into the recipient's cells. Once inside the cytoplasm of a cell, the mRNA provides instructions to the cell's protein production machinery to produce the trans-membrane spike protein antigen that becomes anchored on the cell's external surface. The mRNA does not enter the nucleus of the cell and does not interact with, or alter, human DNA. The immune system is engaged by both the transmembrane spike protein and immune receptors carrying spike antigens to induce humoral and cellular immune responses. The mRNA, lipid nanoparticle, and spike protein are degraded or excreted within days to weeks from time of immunization. mRNA vaccines are not live vaccines and cannot cause infection in the host.

Non-replicating viral vector vaccines

COVID-19 vaccines based on viral vector platforms use a modified virus to carry genes that encode SARS-CoV-2 spike proteins into the host cells. The vector virus is a type of adenovirus that has been modified to carry COVID-19 genes and to prevent replication. These modifications are intended to prevent the viral vector from causing disease. (i.e., they are non-replicating). Once inside the cell, the SARS-CoV-2 spike protein genes are transcribed into mRNA in the nucleus and translated into proteins in the cytosol of the cell. The AstraZeneca vaccine uses a modified chimpanzee adenovirus vector (ChAd).

Preparations of COVID-19 vaccines authorized for use in Canada

Table 1: COVID-19 vaccines authorized for use in Canada
Product Brand Name Pfizer-BioNTech COVID-19 Vaccine Moderna COVID-19 Vaccine AstraZeneca COVID-19 Vaccine or SII
Type of vaccine mRNA mRNA Non-replicating viral vector (ChAd)
Date of authorization in Canada December 9, 2020 December 23, 2020 February 26, 2021
Authorized ages for use 16 years of age and older 18 years of age and older 18 years of age and older
Dose 0.3 mL (30 mcg of mRNA)Footnote a 0.5 mL (100 mcg of mRNA) 0.5 mL (5 x 1010 viral particles)
ScheduleFootnote b 2 Doses, 3 weeks apart 2 Doses, 4 weeks apart 2 Doses, 4 to 12 weeks apart
Route of administration IM IM IM
Nature of the antigen Transmembrane prefusion spike protein Transmembrane prefusion spike protein Transmembrane spike protein
Adjuvant (if present) None None None
Primary storage requirements pre-puncture -80°C to -60°CFootnote c
or
-25°C to -15°C for up to 2 weeksFootnote d
-25°C to -15°CFootnote cFootnote e +2ºC to +8ºC
Storage requirements pre-punctureFootnote c 120 hours (5 days) at +2°C to +8°C and/or
2 hours up to +25°C
30 days at +2°C to +8°C
and/or
12 hours at +8°C to +25°C
+2ºC to +8ºC
Diluent Yes No No
Usage limit post-puncture 6 hours at +2°C to +25°CFootnote f 6 hours at +2°C to +25°C 6 hours at room temperature (up to +30ºC)
or
48 hours at +2ºC to +8ºC
Formats available Multi-dose vial (6 doses)Footnote a, preservative-free Multi-dose vial (10 doses), preservative-free Multi-dose vial
(8-and 10-dose presentations), preservative-free

Footnotes

Footnote a

After dilution, one vial contains 6 doses of 0.3 mL each. However, vial labels and cartons may state that after dilution, a vial contains 5 doses of 0.3 mL. Information in the product monograph supersedes the number of doses stated on vial labels and cartons. Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. If standard syringes and needles are used, there may not be sufficient volume to extract a 6th dose from a single vial. Refer to the product monograph available through Health Canada's Drug Product Database for choice of diluent, dilution instructions and type of syringes which can be used to extract 6 doses from a single vial.

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Footnote b

Authorized schedule. For NACI recommendations on intervals between doses refer to Table 2 for details

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Footnote c

Protected from light during storage

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Footnote d

Vials stored at -25°C to -15°C for up to 2 weeks may be returned one time to the recommended storage condition of -80°C to -60°C. Total cumulative time the vials are stored at -25°C to -15°C should be tracked and should not exceed 2 weeks.

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Footnote e

Do not store on dry ice or below -40ºC

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Footnote f

After dilution, vaccine must be used within 6 hours

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Abbreviations:

  • ChAd: Chimpanzee adenovirus
  • IM: Intramuscular
  • mRNA: Messenger ribonucleic acid

Efficacy and effectiveness

Due to the availability of only short-term clinical trial data, the duration of COVID-19 vaccine efficacy, and vaccine effectiveness, are currently unknown. However, studies are ongoing.

The following section highlights key efficacy data for authorized COVID-19 vaccines (Pfizer-BioNTech COVID-19 vaccine, Moderna COVID-19 vaccine) and viral vector based COVID-19 vaccine (AstraZeneca COVID-19 vaccine) only. For additional details regarding trial design, including study population, length of follow-up, and efficacy for the authorized vaccines, refer to the evidence summary in Appendix A (for the Pfizer-BioNTech COVID-19 vaccine), Appendix B (for the Moderna COVID-19 vaccine), and Appendix C (for the AstraZeneca COVID-19 vaccine).

Efficacy against symptomatic COVID-19 disease

The currently authorized mRNA COVID-19 vaccines have been shown to be highly efficacious in the short term against confirmed symptomatic COVID-19 disease (presence of one or more symptoms plus laboratory confirmation of SARS-CoV-2 infection) from one to two weeks after receiving the full two-dose series. The authorized mRNA vaccines are similarly efficacious in adults with one or more comorbidities, as well as in younger adults and older adults. However, evidence in adults of a much more advanced age (e.g., 85 years and older) and in long-term care facilities is limited. In clinical trials, AstraZeneca COVID-19 viral vector vaccine has shown moderate short-term efficacy against symptomatic COVID-19 disease (presence of at least one pre-defined COVID-19 symptom plus laboratory confirmation of SARS-CoV-2 infection) in adults 18-64 years of age, at least two weeks after receiving the full series of two standard doses of the vaccine. Clinical trial data show that efficacy increased as the interval between doses increased. At present, there are insufficient clinical trial data in adults ≥65 years of age to assess vaccine is efficacy in this age group. The vaccine is similarly efficacious in adults ≥18 years of age with and without pre-defined comorbidities (presence of one or more mild to moderate and controlled cardiovascular disease, respiratory disease, diabetes or obesity).

In the absence of sufficient data from clinical trials to date on the efficacy of the AstraZeneca COVID-19 vaccine in those 65 years of age and older, a review of three observational studies in the UK published as pre-prints on real-world vaccine effectiveness in this age group has been conducted to inform NACI’s recommendations in this age group. The findings of this review are summarized in Appendix C. These studies provide effectiveness estimates following the first dose of AstraZeneca vaccine and have shown a reduction in the risk of symptomatic disease and hospitalization that appears to reach a comparable level to that observed among persons of similar age who received one dose of mRNA vaccine and also to efficacy estimates in the AstraZeneca COVID-19 vaccine clinical trials among adults 18 to 64 years of age.

The clinical trial data demonstrates that the authorized mRNA COVID-19 vaccines are efficacious over the short-term in individuals with or without evidence of prior SARS-CoV-2 infection. However, participants with laboratory-confirmed SARS-CoV-2 infection prior to enrollment were excluded from the trials and the number of trial participants with evidence of previous infection (as defined by trial protocol) who had confirmed symptomatic COVID-19 disease during the trials were small; therefore, the efficacy in this population and how it compares to those without evidence of previous infection is unknown at this time.

The first dose of the authorized COVID-19 vaccines has been shown to offer at least short-term protection against confirmed COVID-19 disease. For mRNA vaccines, the highest efficacy is seen after the second dose is administered. There is currently no available evidence on medium- and long-term efficacy of the authorized COVID-19 vaccines, however trials are ongoing and this Statement will be updated as evidence emerges.

Efficacy against severe disease

There are limited data to be able to assess the efficacy of the authorized COVID-19 vaccines against hospitalizations or deaths specifically, but studies are ongoing and further evidence is expected.

The authorized COVID-19 vaccines appear to be efficacious against hospitalizations for the AstraZeneca vaccine or severe COVID-19 outcomes for mRNA vaccines (severe outcomes were defined as laboratory-confirmed COVID-19 with one of the following additional features: clinical signs at rest that are indicative of severe systemic illness; respiratory failure; evidence of shock; significant acute renal, hepatic, or neurologic dysfunction; admission to an intensive care unit; or death). However, the follow-up time for this outcome was short in trials for all vaccines and the number of severe cases that have been observed to date was small in the Pfizer-BioNTech clinical trial and very small in the AstraZeneca clinic trial.   At the present time, there are insufficient data to estimate the efficacy of the viral vector vaccine against severe COVID-19 disease.

Efficacy against asymptomatic infection and transmission

Preliminary data from the ongoing Moderna COVID-19 vaccine trial showed a lower prevalence of SARS-CoV-2 positivity by PCR in asymptomatic participants at one particular time point (before Dose 2), and therefore viral shedding, in the group that received the vaccine compared to the placebo group. However, the current data is insufficient to draw conclusions. Exploratory analyses for the viral vector vaccine have not demonstrated efficacy against confirmed SARS-CoV-2 asymptomatic infection, however the number of asymptomatic infections was small. Studies are ongoing for these vaccines.

Efficacy against variants of concern

Data about the efficacy of authorized mRNA COVID-19 vaccines (Pfizer-BioNTech COVID-19 vaccine, Moderna COVID-19 vaccine) and viral vector-based COVID-19 vaccine (AstraZeneca COVID-19 vaccine) against VOC is evolving. NACI will continue to monitor the evidence and update recommendations as needed.

Immunogenicity

No immunological correlate of protection has been determined for SARS-COV-2; therefore, all immunological evidence in support of vaccine efficacy is indirect and cannot directly be used to estimate efficacy.

There are several key knowledge gaps that affect the understanding of immune responses to COVID-19 vaccine:

Due to limitations in the number of participants and duration of follow up from COVID-19 clinical trial data, long-term evidence on immunogenicity is unknown. However, studies are ongoing.

The following section highlights key immunogenicity data for the authorized mRNA COVID-19 vaccines (Pfizer-BioNTech COVID-19 vaccine and Moderna COVID-19 vaccine) and viral vector based COVID-19 vaccine (AstraZeneca COVID-19 vaccine) only. For additional details regarding trial design, including study population and length of follow-up, and immunogenicity for these authorized vaccines refer to the evidence summaries in Appendix A (for the Pfizer-BioNTech COVID-19 vaccine), Appendix B (for the Moderna COVID-19 vaccine), and Appendix C (for the AstraZeneca COVID-19 vaccine).

Humoral immune responses

All authorized COVID-19 vaccines induce humoral immune responses, including binding and neutralizing antibody responses. Humoral responses peaked after the second dose of mRNA vaccine, and after the second dose of AstraZeneca COVID-19 vaccine in participants who were not previously infected. Some vaccines induce higher immune responses in younger populations, see Appendix A, Appendix B, and Appendix C for details.

Viral vector-based vaccines may induce anti-vector immune responses, which may impact future vaccine efficacy and effectiveness and may vary by age, dose, and interval between doses.

Cellular immune responses

All authorized COVID-19 vaccines have been shown to produce cellular immune responses. Cellular immune responses increased after the second dose of mRNA COVID-19 vaccine, while responses for AstraZeneca COVID-19 vaccine were maintained or decreased after the second dose. Refer to Appendix A, Appendix B, and Appendix C for details.

Vaccine administration

For additional vaccine product-specific information, consult the product leaflet or information contained within the product monograph available through Health Canada's Drug Product Database. Refer to Vaccine Administration Practices in the Canadian Immunization Guide (CIG), Part 1 - Key Immunization Information for additional general information.

As for the routine administration of all vaccines, COVID-19 vaccines should be administered in settings capable of managing anaphylaxis. Refer to Anaphylaxis and other Acute Reactions Following Vaccination in the CIG, Part 2 — Vaccine Safety for information on the management of anaphylaxis post-vaccination.

Dose, route of administration, and schedule

Dose
Pfizer-BioNTech COVID-19 vaccine

Each dose is 0.3 mL after dilution, containing 30 mcg of SARS-CoV-2 spike protein mRNA.

The dose for the Pfizer-BioNTech COVID-19 vaccine (0.3 mL) is unique compared to that of most routine vaccinations. Special precaution should be taken to ensure the correct dose is taken from the multi-dose vial.

Moderna COVID-19 vaccine

Each dose is 0.5 mL, containing 100 mcg of SARS-CoV-2 spike protein mRNA.

No dilution is required.

AstraZeneca COVID-19 vaccine

Each dose is 0.5 mL, containing 5 x 1010 particles of SARS-CoV-2 spike protein.

No dilution is required.

Route of administration

COVID-19 vaccines are given as an intramuscular (IM) injection into the deltoid muscle.

Refer to Vaccine Administration Practices in the CIG, Part 1 — Key Immunization Information for additional information.

Schedule

Refer to Table 2 for a summary of immunization schedules for authorized COVID-19 vaccines.

Table 2: Recommended immunization schedule, by COVID-19 vaccine
Vaccine product (manufacturer) Immunization schedule Minimum interval Authorized interval Extended intervalFootnote a
Pfizer-BioNTech COVID-19
(Pfizer-BioNTech)
2-dose schedule 19 daysFootnote b 21 daysFootnote c 16 weeks
Moderna COVID-19
(Moderna)
2-dose schedule 21 daysFootnote d 28 days 16 weeks
AztraZeneca
COVID-19
(AstraZeneca)
2-dose schedule 28 days 4 to 12 weeksFootnote e 16 weeksFootnote e

Footnotes

Footnote a

Based on emerging evidence of the protection provided by the first dose of a two-dose series for COVID-19 vaccines currently authorized in Canada, NACI recommends that in the context of limited COVID-19 vaccine supply and ongoing pandemic disease, jurisdictions should maximize the number of individuals benefiting from the first dose of vaccine by extending the second dose of COVID-19 vaccine up to four months after the first. NACI will continue to monitor the evidence and update this interval as needed.

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Footnote b

The basis for this minimum interval is that the per-protocol design for the Pfizer-BioNTech COVID-19 vaccine clinical trial was 19-23 days

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Footnote c

An alternate interval of 28 days may be more feasible to implement. This interval is consistent with the minimum interval required for many other routine immunizations and the authorized interval for the Moderna COVID-19 vaccine. The majority of participants in the Pfizer-BioNTech clinical trial received the second dose 21 to 27 days apart

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Footnote d

The basis for this minimum interval is that the majority of participants in the Moderna COVID-19 vaccine clinical trial received the second dose 21 to 42 days after the first, as per the pre-defined window

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Footnote e

The AstraZeneca COVID-19 vaccine clinical trial demonstrated optimal efficacy when the interval between the first and second doses was ≥12 weeks

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Refer to Timing of Vaccine Administration in the CIG, Part 1 — Key Immunization Information for additional general information.

Extended intervals for COVID-19 vaccines to optimize early vaccine roll-out and population protection

Currently, no data on a maximum interval between doses or on medium- or long-term efficacy of COVID-19 vaccines are available.

In general, interruption of a vaccine series resulting in a greater than recommended interval between doses does not require restarting the series as delays between doses do not result in a reduction in final antibody concentrations for most multi-dose (prime-boost) products. For many other multi-dose vaccines provided in adulthood using other vaccine technologies, the greatest proportion of short-term protection is achieved with the first dose with additional doses primarily intended to extend protection over the longer term. However, the follow-up time in COVID-19 vaccine clinical trials is short, the duration of protection after one or both is unknown, and mRNA and viral vector-based vaccines represent relatively new vaccine technologies.

Morbidity and mortality from COVID-19 is ongoing. Extending the interval to the second dose of a COVID-19 vaccine maximizes vaccine supply to immunize the largest number of people as quickly as possible. Principles of immunology indicate that a minimum interval of four months between priming and boosting doses of a vaccine series results in a better, more durable response. Please refer to NACI’s Rapid response: Extended dose intervals for COVID-19 vaccines to optimize early vaccine rollout and population protection in Canada for a summary of the evidence.

Follow-up of vaccine effectiveness in individuals for whom the second dose is delayed or who have otherwise missed their second dose (e.g., missed a follow-up immunization appointment) will be important to inform future recommendations and ensure completion of the vaccine series as soon as possible. NACI will continue to monitor the evidence and update recommendations as needed.

Booster doses and re-immunization

There is currently no evidence on the need for booster doses of COVID-19 vaccine after the vaccine series is complete. Given the emergence of variants of concern against which vaccine effectiveness may be decreased, additional vaccine doses may be necessary. NACI will continue to monitor the evidence and update recommendations as needed.

Interchangeability

NACI recommends that the vaccine series be completed with the same COVID-19 vaccine product.

Currently, no data exist on the interchangeability of COVID-19 vaccines. However, the spike proteins encoded by either of the authorized mRNA vaccines have the same sequence and are stabilized in the same manner to remain in the pre-fusion conformation, though other vaccine components like the lipid nanoparticle and the mRNA sequence may be different. The spike protein encoded by the authorized viral vector vaccine is not stabilized in any specific conformation. Vaccines of different types (e.g., mRNA, viral vector) should be considered different vaccines and should not be used in the same series.

If the vaccine product used for a previously received dose is not known, or not available, attempts should be made to complete the vaccine series with a similar type of COVID-19 vaccine (e.g., mRNA vaccine and mRNA vaccine). It is not recommended that vaccines of different types (e.g., mRNA vaccine and viral vector vaccine) be used in the same series. In the context of limited COVID-19 vaccine supply and the absence of evidence on interchangeability of COVID-19 vaccines, the previous dose may be counted, and the series need not be restarted.

At this time, it is not recommended that vaccines of different types (e.g., mRNA vaccine and viral vector vaccine) be used in the same series. Active surveillance of effectiveness and safety of a mixed schedule will be important and these recommendations may change as further evidence becomes available. Accurate recording of vaccines received will be critical. NACI will continue to monitor the evidence and update recommendations as needed.

Refer to Principles of Vaccine Interchangeability in the CIG, Part 1 — Key Immunization Information for additional general information.

Post-vaccination counseling

NACI recommends that prophylactic oral analgesics or antipyretics (e.g., acetaminophen or ibuprofen) should not be routinely used before or at the time of vaccination, but their use is not a contraindication to vaccination. Oral analgesics or antipyretics may be considered for the management of adverse events (e.g., pain or fever, respectively), if they occur after vaccination.

Analgesics and antipyretics were used in clinical trials of COVID-19 vaccine for the management of pain and/or fever after vaccination. There is currently no evidence on the benefit from administration of oral analgesics for the prevention of immunization injection pain or systemic reactions. All vaccine recipients should be instructed to seek medical care if they develop signs or symptoms of an allergic reaction after their observation period ends and they have left the immunization clinic/venue.

All vaccine recipients who develop symptoms compatible with COVID-19 should be tested for SARS-CoV-2 to document breakthrough illness, particularly in the context of the emergence of variants of concern.

Refer to Vaccine Administration Practices in the CIG, Part 1 — Key Immunization Information for additional information on pre- and post-vaccination counseling.

Serological testing

Serologic testing is not needed before or after immunization with COVID-19 vaccine.

Storage requirements

Pfizer-BioNTech COVID-19 vaccine

Frozen vials prior to use

The Pfizer-BioNTech COVID-19 vaccine must be stored at ultra-low temperatures of -80°C to -60°C and protected from light, in the original packaging, until ready to use.

Refer to the re-icing guidelines (available at Pfizer-BioNTech COVID-19 Vaccine) for instructions regarding the use of the manufacturer's original thermal container for temporary storage.

Vials may also be stored at -25°C to -15°C for up to 2 weeks. Vials must be kept frozen and protected from light, in the original cartons, until ready to use. Vials stored at -25°C to -15°C for up to 2 weeks may be returned one time to the recommended storage condition of -80°C to -60°C. Total cumulative time the vials are stored at -25°C to -15°C should be tracked and should not exceed 2 weeks.

Thawed, unpunctured vials (prior to dilution)

The Pfizer-BioNTech COVID-19 vaccine may be thawed and stored at +2°C to +8°C for up to 120 hours (5 days) or at room temperature (up to +25°C) for no more than 2 hours. During storage, minimize exposure to room light, and avoid exposure to direct sunlight and ultraviolet light. Thawed vials can be handled in room light conditions.

Do not refreeze thawed vials.

Thawed, punctured vials (after dilution)

The Pfizer-BioNTech COVID-19 vaccine must be stored between +2°C to +25°C and used within 6 hours from the time of dilution. During storage, minimize exposure to room light, and avoid exposure to direct sunlight and ultraviolet light. After dilution, the vaccine vials can be handled in room light conditions.

Moderna COVID-19 vaccine

Frozen vials prior to use

The Moderna COVID-19 vaccine should be stored at temperatures of -25ºC to - 15ºC and protected from light in the original packaging. Do not store on dry ice or below -40ºC.

Thawed, unpunctured vials

If not punctured, the Moderna COVID-19 vaccine can be thawed and stored at +2°C to +8°C for up to 30 days, or at +8°C to +25°C for up to 12 hours.

Do not refreeze thawed vials.

Thawed, punctured vials

The Moderna COVID-19 vaccine can be stored between +2°C to below +25°C but must be discarded after 6 hours from the time of first puncture. During storage, vials should be protected from light.

AstraZeneca COVID-19 vaccine

Unopened multidose vial

The AstraZeneca vaccine can be stored between +2ºC to +8ºC and protected from light in the original packaging. Do not freeze.

Opened multidose vial

After first opening, chemical and physical in-use stability has been demonstrated from the time of vial puncture to administration for no more than 6 hours at room temperature (up to +30ºC) or 48 hours in a refrigerator (+2ºC to +8ºC).

After the first puncture, the vial can be re-refrigerated, but the cumulative storage time at room temperature must not exceed 6 hours, and the total cumulative storage time must not exceed 48 hours. After this time, the vial must be discarded.

For more information, consult the product leaflet or information contained within the product monograph available through Health Canada's Drug Product Database. Refer to Storage and Handling of Immunizing Agents in the CIG, Part 1 — Key Immunization Information for additional general information.

Simultaneous administration with other vaccines

NACI recommends that COVID-19 vaccines should not be given simultaneously with other vaccines (live or inactivated).

Currently, no data exist on the simultaneous administration of COVID-19 vaccine with other vaccines. In the absence of evidence, attempts should be made to avoid simultaneous administration to maximize benefits of COVID-19 vaccination while minimizing any risks of harm, including the potential for immune interference or the erroneous attribution of an adverse event following immunization (AEFI) to a particular vaccine. However, if a COVID-19 vaccine is inadvertently administered at the same time as another vaccine, neither dose should be repeated.

In the absence of evidence, it would be prudent to wait for a period of at least 28 days after each vaccine dose of an mRNA or viral vector COVID-19 vaccine before the administration of another vaccine (except in the case where another vaccine is required for post-exposure prophylaxis) due to the elicitation of an inflammatory cytokine response. It would be prudent to wait for a period of at least 14 days after the administration of another vaccine before administrating a COVID-19 vaccine to prevent erroneous attribution of an AEFI to a particular vaccine.

Refer to Timing of Vaccine Administration in the CIG, Part 1 — Key Immunization Information for additional general information on simultaneous administration of other vaccines in general.

Vaccine safety and adverse events following immunization (AEFI)

Due to limitations in the number of participants and duration of follow-up from COVID-19 clinical trials, medium- and long-term evidence on vaccine safety is limited. Clinical trials of the authorized COVID-19 vaccines excluded individuals with a history of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine. However, studies are ongoing.

The following section highlights key safety and AEFI data for the authorized COVID-19 vaccines. For additional details regarding trial design, including study population and length of follow-up, and safety for the COVID-19 vaccines authorized for use in Canada, refer to the evidence summaries in Appendix A (for the Pfizer-BioNTech COVID-19 vaccine), Appendix B (for the Moderna COVID-19 vaccine) and Appendix C (for the AstraZeneca COVID-19 vaccine). Refer to Appendix D for a summary of the frequency of AEFI for the different COVID-19 vaccine products.

Refer to Part 2 - Vaccine Safety in the CIG for definitions of AEFIs and additional general information.

Very common and common adverse events

Common adverse events are defined as those that occur in 1% to less than 10% of vaccine recipients; very common adverse events occur in 10% or more of vaccine recipients. Please see Appendix D for a summary of adverse events identified in clinical trials of authorized COVID-19 vaccines.

Local

Pain at the injection site is very common after administration of the currently authorized COVID-19 vaccine. More than 50% of recipients experienced injection site pain. Redness and swelling are common or very common after administration. Localized axillary swelling and tenderness was a solicited adverse event in the Moderna COVID-19 clinical trial and was very common after administration with that vaccine. Local adverse events are usually mild or moderate and resolve within a few days of vaccination. For the authorized mRNA COVID-19 vaccines, pain at the injection site was slightly more frequent in younger adults compared to older adults. For AstraZeneca COVID-19 vaccine, local reactions were milder and reported less frequently after the second vaccine dose in all age groups.

Systemic

Fatigue, headache, muscle pain, chills, and joint pain are all either common or very common after the administration of the currently authorized COVID-19 vaccines. Fever was very common after administration of the second dose of the mRNA COVID-19 vaccines and common after any dose of AstraZeneca COVID-19 vaccine. More than a quarter of vaccine recipients experienced headache, and/or fatigue after any dose. For the mRNA COVID-19 vaccines, systemic adverse events are usually mild or moderate intensity and resolve within a few days of vaccination. Systemic reactions are more frequent after the second vaccine dose and in younger adults. For AstraZeneca COVID-19 vaccine, systemic reactions are milder and reported less frequently after the second vaccine dose in all age groups.

Uncommon, rare, and very rare adverse events

Uncommon adverse events occur in 0.1% to less than 1% of vaccine recipients. Rare and very rare adverse events occur in 0.01% to less than 0.1% and less than 0.01% of vaccine recipients, respectively. The probability of detection of very rare adverse events in clinical trials is low given clinical trial population sizes; therefore, ongoing pharmacovigilance is essential.

mNRA COVID-19 vaccines

To date, the available data does not indicate that vaccination of SARS-CoV-2 naïve individuals with authorized COVID-19 vaccines will elicit enhanced or altered disease upon subsequent infection by SARS-CoV-2 (e.g., vaccine-enhanced disease); however, further study is needed.

Lymphadenopathy was not a solicited adverse event (unless indicated, see Appendix D) but was uncommonly reported after administration of the Pfizer-BioNTech and AstraZeneca COVID-19 vaccines.

No other solicited uncommon, rare, or very rare adverse events were reported among vaccinated participants in the clinical trials at this time.

Guidance on reporting adverse events following immunization (AEFI)

Vaccine providers are asked to report AEFIs through local public health departments and to follow AEFI reporting requirements that are specific to their province or territory. In general, any serious (defined as resulting in hospitalization, permanent disability or death) or unexpected adverse event that is temporally related to vaccination should be reported.

In addition to provincial or territorial reporting requirements, the Brighton Collaboration has developed a list of Adverse Events of Special Interest (AESI) that are of particular interest and should be reported. Refer to Brighton Collaboration: COVID-19 for the list with definitions.

There may be additional very rare AEFIs that have not been detected through clinical trials to date.

Refer to Adverse Events Following Immunization (AEFI) in the CIG, Part 2 — Vaccine Safety for additional information on definitions, reporting, investigating and managing, and causality assessments for AEFIs.

Refer to Reporting Adverse Events Following Immunization (AEFI) in Canada for additional information on the completion and submission of AEFI reports.

Contraindications and precautions

Rare anaphylactic reactions have been reported following immunization with mRNA COVID-19 vaccines; investigations are ongoing to identify the allergen(s) responsible and the recommendations will be updated as evidence becomes available.

Table 3 lists potential non-medicinal ingredients in authorized COVID-19 vaccines that have been associated with allergic reactions in other products. These reactions have occurred rarely, and ranged from mild cutaneous reactions to anaphylaxis. Anaphylaxis is typically a rare, severe, life-threatening allergic reaction typically with a rapid onset that involves multiple organ systems and can progress rapidly. Symptoms and signs of anaphylaxis may include, but are not limited to generalized urticaria; wheezing; swelling of the mouth, tongue, and throat; difficulty breathing; vomiting; diarrhea; hypotension; decreased level of consciousness; and shock. It is important to note that other, less serious reactions may mimic allergic reactions (e.g., vasovagal syncope) and vaccination is not contraindicated in these cases.

Table 3: Ingredients of authorized COVID-19 vaccines that have been associated with allergic reactions in other products
Vaccine product (manufacturer) Potential allergen included in the vaccine or its container Other products where the potential allergen may be found*
Pfizer-BioNTech COVID-19
(Pfizer-BioNTech)
polyethylene glycol (PEG)Footnote aFootnote bFootnote c Over the counter (e.g., cough syrup, laxatives), and prescription medications, medical bowel preparation products for colonoscopy, skin care products, dermal fillers, cosmetics, contact lens care solutions, products such as ultrasound gelFootnote d.
Moderna COVID-19
(Moderna)
PEG Footnote aFootnote bFootnote c Over the counter (e.g. cough syrup, laxatives), and prescription medications, medical bowel preparation products for colonoscopy, skin care products, dermal fillers, cosmetics, contact lens care solutions, products such as ultrasound gelFootnote d.
tromethamineFootnote e
(trometamol or Tris)
Component in contrast media, oral and parenteral medications.
AstraZeneca COVID-19
(AstraZeneca)
polysorbate 80Footnote c medical preparations (e.g., vitamin oils, tablets, and anticancer agents), cosmeticsFootnote dFootnote f

Footnotes

Note

N.B. This is not a complete list of products.

Footnote a

Medications that contain PEG are described in Stone CA, et al., DOI:10.1016/j.jaip.2018.12.003

Return to footnote a referrer

Footnote b

A review of immediate type hypersensitivity reactions to PEG is available in Wenande et al, DOI: 10.1111/cea.12760

Return to footnote b referrer

Footnote c

There is a potential of cross-reactive hypersensitivity between PEG and polysorbates

Return to footnote c referrer

Footnote d

PEG is an additive in some food and drinks but allergic reactions to PEG in food or drinks have not been documented.

Return to footnote d referrer

Footnote e

One case report of anaphylaxis to tromethamine has been described (Lukawska et al, DOI: 10.1016/j.jaip.2018.08.035).

Return to footnote e referrer

Footnote f

Case reports of anaphylaxis to polysorbate 80 have been described (Badiu et al, DOI: 10.1136/bcr.02.2012.5797, Palacios Castaño et al, DOI: 10.18176/jiaci.0109).

Return to footnote f referrer

Contraindications

An authorized COVID-19 vaccine should not be offered routinely to individuals with a history of severe allergic reaction (e.g., anaphylaxis) after previous administration of a COVID-19 vaccine using a similar platform (mRNA or viral vector). If a risk assessment deems that the benefits outweigh the potential risks for the individual; and if informed consent is provided, an authorized COVID-19 vaccine using a different platform may be considered for re-immunization (i.e., individuals with anaphylaxis post mRNA vaccine may be offered a viral vector vaccine and individuals with anaphylaxis post viral vector vaccine may be offered a mRNA vaccine).

An authorized COVID-19 vaccine should not be routinely offered to individuals with a proven severe allergic reaction (e.g., anaphylaxis) to any component of the specific COVID-19 vaccine or its container.

For a comprehensive list of components in the vaccine and packaging, please consult the product leaflet or information contained within the product monograph available through Health Canada's Drug Product Database.

Precautions

If a risk assessment deems that the benefits outweigh the potential risks for the individual; and if informed consent is provided; vaccination may be considered in individuals with mild to moderate immediate allergic reactions (defined as limited in the scope of symptoms and involvement of organ systems or even localized to the site of administration) after a previous dose of authorized COVID-19 vaccines or any of its components. Assessment by a physician or nurse with expertise in immunization may be warranted prior to re-immunization. Most instances of anaphylaxis to a vaccine begin within 30 minutes after administration of the vaccine. Therefore, if vaccination is chosen, an extended period of observation post-vaccination of at least 30 minutes should be provided for the aforementioned individuals.

Individuals with proven severe allergic reaction (e.g., anaphylaxis) to injectable therapy not related to a component of authorized COVID-19 vaccines (e.g. intramuscular, intravenous, or subcutaneous vaccines or therapies) may be routinely vaccinated and do not need to be assessed. Most instances of anaphylaxis to a vaccine begin within 30 minutes after administration of the vaccine. Therefore, an extended period of observation post-vaccination of 30 minutes should be provided for the aforementioned individuals.

Individuals with a history of allergy not related to a component of authorized COVID-19 vaccines or other injectable therapy (e.g. foods, oral drugs, insect venom or environmental allergens) can receive COVID-19 vaccines without any special precautions. Individuals should be observed for a minimum of 15 minutes following vaccination.

In individuals with bleeding disorders, the condition should be managed prior to immunization to minimize the risk of bleeding. Individuals receiving long-term anticoagulation are not considered to be at higher risk of bleeding complications following immunization and may be safely immunized without discontinuation of their anticoagulation therapy.

Vaccination of individuals who may be currently infected with SARS-CoV-2 is not known to have a detrimental effect on the illness. However, vaccination should be deferred in symptomatic individuals with confirmed or suspected SARS-CoV-2 infection, or those with respiratory symptoms, in order to avoid attributing any complications resulting from SARS-CoV-2 infection to vaccine-related AEFI and to minimize the risk of COVID-19 transmission at an immunization clinic/venue. If any persons are identified with symptoms on arrival at the venue, they should be instructed to follow current local public health measures.

As a precautionary measure and in light of the need to be able to monitor for COVID-19 vaccine adverse events without potential confounding from symptoms of COVID-19 or other co-existing illnesses, it would be prudent to wait until all symptoms of an acute illness are completely resolved before vaccinating with an authorized COVID-19 vaccine.

Refer to Contraindications, Precautions and Concerns in the CIG, Part 2 - Vaccine Safety for additional general information.

Drug interactions

There have been no drug interactions studies performed to date.

For more information about potential interactions with products containing anti-SARS-CoV-2 antibodies, refer to section Blood products, human immunoglobulin and timing of immunization, in this Statement.

Tuberculin skin testing (TST) or interferon gamma release assay (IGRA)

There is a theoretical risk that mRNA or viral vector vaccines may temporarily affect cell-mediated immunity, resulting in false-negative TST or IGRA test results. If tuberculin skin testing or an IGRA test is required, it should be administered and read before immunization or delayed for at least 4 weeks after vaccination. Vaccination with COVID-19 vaccines may take place at any time after all steps of tuberculin skin testing have been completed.

In cases where an opportunity to perform the TST or IGRA test might be missed, the testing should not be delayed since these are theoretical considerations. However, re-testing (at least 4 weeks post immunization) of individuals with negative results for whom there is high suspicion of TB infection may be prudent in order to avoid missing cases due to potentially false-negative results.

Blood products, human immunoglobulin and timing of immunization

NACI recommends that COVID-19 vaccines should not be given simultaneously with monoclonal antibodies or convalescent plasma.

To date, there is insufficient evidence on the receipt of both a COVID-19 vaccine and anti-SARS-CoV-2 monoclonal antibodies or convalescent plasma for treatment or prevention. Therefore, timing of administration and potential interference between these two products are currently unknown. Administration of these products close together may result in decreased effectiveness of a COVID-19 vaccine and/or anti-SARS-CoV-2 monoclonal antibodies because the monoclonal antibodies have high affinity for the spike protein expressed by the vaccines, which could prevent the production of antibodies stimulated by the vaccine.

In the post-exposure setting, expert clinical opinion should be sought on a case-by-case basis when deciding whether anti-SARS-CoV-2 monoclonal antibodies would be appropriate to administer after receipt of COVID-19 vaccine, taking into consideration the risk of exposure and the risk of severe COVID-19 disease in the individual.

To date, there is also insufficient evidence on the receipt of both a COVID-19 vaccine and any monoclonal antibodies or convalescent plasma for treatment or prevention of non-COVID-19 disease. Therefore, timing of administration and potential interference between these two products are currently unknown and expert clinical opinion should be sought on a case-by-case basis.

Recommendations

Following the thorough review of available evidence summarized above, as well as the systematic assessment of ethics, equity, feasibility and acceptability considerations with the EEFA FrameworkFootnote 3 as summarized in NACI's Guidance on Key Populations for Early COVID-19 Immunization, NACI makes the following recommendations for public health program level decision-making for the effective and equitable use of COVID-19 vaccines authorized for use in Canada.

NACI will continue to carefully monitor the scientific developments related to COVID-19 and COVID-19 vaccines, as well as ongoing vaccine pharmacovigilance, and will update recommendations as evidence evolves.

Please note:

Please see Table 5 for a more detailed explanation of the strength of NACI recommendations.

Recommendations on authorized COVID-19 vaccines for public health program level decision-making

(i.e., Provinces/Territories making decisions for publicly funded immunization programs)

These recommendations apply only to COVID-19 vaccines currently authorized and currently available for use in Canada (Pfizer-BioNTech COVID-19 vaccine; Moderna COVID-19 vaccine; AstraZeneca COVID-19 vaccine). In considering these recommendations and for the purposes of publicly funded program implementation, provinces and territories may consider local programmatic factors (e.g., logistical and operational contexts, resources) and local epidemiology (e.g., transmission of SARS-CoV-2 variants of concern).

1. NACI recommends that a complete COVID-19 vaccine series should be offered to individuals in the authorized age group without contraindications to the vaccine. In the context of limited vaccine supply, initial doses of mRNA COVID-19 vaccine should be prioritized for those at highest risk of severe illness and death from COVID-19 and highest risk of exposure to COVID-19.Footnote 1 (Strong NACI Recommendation)

  1. Due to suggested superior efficacy, mRNA COVID-19 vaccine is preferentially recommended for individuals in the authorized age group without contraindications, especially in those at highest risk of severe illness and death and highest risk of exposure to COVID-19 who are prioritized for early COVID-19 immunization.
  2. In the context of limited vaccine supply, AstraZeneca COVID-19 vaccine may be offered to individuals 18 years of age and older without contraindications if:
    1. the advantages of earlier vaccination outweigh the limitations of vaccinating with a less efficacious vaccine;
    2. the ease of transport, storage and handling of this vaccine facilitates access to vaccination which may otherwise be challenging; and
    3. informed consent includes discussion about current vaccine options and the timing of future vaccine options

(Discretionary NACI Recommendation)

When considering which groups to offer the AstraZeneca COVID-19 vaccine to when an authorized mRNA COVID-19 vaccine is unavailable or inaccessible, the assessment may vary between jurisdictions and groups and will depend on:

Refer to the Management options table for COVID-19 vaccines authorized for use in Canada for a summary of evidence and factors for jurisdictions to consider when implementing COVID-19 immunization programs.

Summary of evidence and rationale:

2. Based on emerging evidence of the protection provided by the first dose of a two-dose series for COVID-19 vaccines currently authorized in Canada, NACI recommends that in the context of limited COVID-19 vaccine supply and ongoing pandemic disease, jurisdictions should maximize the number of individuals benefiting from the first dose of vaccine by extending the second dose of COVID-19 vaccine up to four months after the first. NACI will continue to monitor the evidence on effectiveness of an extended dose interval and will adjust recommendations as needed. (Strong NACI Recommendation)

Summary of evidence and rationale:

3. NACI recommends that all individuals should continue to practice recommended public health measures for prevention and control of SARS-CoV-2 infection and transmission regardless of vaccination with COVID-19 vaccine, at this time. (Strong NACI Recommendation)

Summary of evidence and rationale:

4. NACI recommends that a complete series with a COVID-19 vaccine may be offered to individuals in the authorized age group without contraindications to the vaccine who have had previously PCR-confirmed SARS-CoV-2 infection. In the context of limited vaccine supply, initial doses may be prioritized for those who have not had a previously PCR-confirmed SARS-CoV-2 infection. (Discretionary NACI Recommendation)

Summary of evidence and rationale:

NACI also makes the following recommendations for COVID-19 immunization in some specific populations who were either excluded from or were represented by small numbers of participants in clinical trials. Vaccine may be offered to some individuals in these populations in some circumstances on a case-by-case basis with a risk-benefit analysis (where the risk of exposure and/or severe COVID-19 disease outweighs the risk of vaccination), and with transparency about the insufficiency of evidence. Preference for mRNA COVID-19 vaccine (as outlined in Recommendation #1, above), if available, also applies to the populations described below. These recommendations may change as more evidence becomes available.

Immunosuppressed persons

5. NACI recommends that a complete COVID-19 vaccine series may be offered to individuals who are immunosuppressed due to disease or treatment in the authorized age group in this population, if a risk assessment deems that the benefits outweigh the potential risks for the individual, and if informed consent includes discussion about the absence of evidence on the use of COVID-19 vaccines in this population and the possibility that individuals who are immunosuppressed may have a diminished immune response to any of the authorized COVID-19 vaccines. (Discretionary NACI Recommendation)

Summary of evidence and rationale:

Refer to Immunization of Immunocompromised Persons in the CIG, Part 3 — Vaccination of Specific Populations for definitions and general additional information.

Persons with an autoimmune condition

6. NACI recommends that a complete vaccine series with a COVID-19 vaccine may be offered to individuals with an autoimmune condition in the authorized age group in these populations if a risk assessment deems that the benefits outweigh the potential risks for the individual, and if informed consent includes discussion about the insufficiency of evidence on the use of COVID-19 vaccines in these populations. (Discretionary NACI Recommendation)

Summary of evidence and rationale:

Refer to Immunization in Persons with Chronic Diseases in the related section in the CIG, Part 3 — Vaccination of Specific Populations for additional general information on autoimmune conditions.

Pregnancy and breastfeeding

7. NACI recommends that a complete vaccine series with a COVID-19 vaccine may be offered to pregnant individuals in the authorized age group if a risk assessment deems that the benefits outweigh the potential risks for the individual and the fetus, and if informed consent includes discussion about the absence of evidence on the use of COVID-19 vaccines in this population. (Discretionary NACI Recommendation)

8. NACI recommends that a complete vaccine series with a COVID-19 vaccine may be offered to individuals in the authorized age group who are breastfeeding, if a risk assessment deems that the benefits outweigh the potential risks for the individual and the infant, and if informed consent includes discussion about the absence of evidence on the use of COVID-19 vaccines in this population. (Discretionary NACI Recommendation)

Summary of evidence and rationale:

Refer to Immunization in Pregnancy and Breastfeeding, Part 3 — Vaccination of Specific Populations of the CIG for additional general information.

Children and adolescents

9. NACI recommends that COVID-19 vaccines should not be offered routinely to individuals who are not in the authorized age group. (Strong NACI Recommendation)

a. However, a complete vaccine series with a Pfizer-BioNTech may be offered to individuals 12-15 years of age who are at very high risk of severe outcomes of COVID-19 (e.g., due to a pre-existing medical condition known to be associated with increased risk of hospitalization or mortality) or are at increased risk of exposure (e.g., due to living in a congregate care facility), if a risk assessment deems that the benefits outweigh the potential risks for the individual, and if informed consent with the individual and the parent or guardian includes discussion about the insufficiency of evidence on the use of COVID-19 vaccines in this population. (Discretionary NACI Recommendation)

Summary of evidence and rationale:

NACI continues to recommend the following:

Refer to Vaccine Safety and Pharmacovigilance in the CIG, Part 2 - Vaccine Safety for additional information.

NACI continues to recommend the following elements to guide ethical decision-making, as outlined in NACI's guidance on Key Populations for Early COVID-19 Immunization:

Management options for COVID-19 vaccines authorized for use in Canada

There are currently three authorized COVID-19 vaccines in Canada for the prevention of symptomatic COVID-19 that use two different vaccine platforms. To assist with the decision on which vaccine to offer to different populations or groups, a comparison of the relative merits of both have been summarized in Table 4 below. Caution should be taken when comparing vaccines due to differences in studies conducted for each vaccine (e.g., different endpoints, different analyses).

Table 4: Management options for types of COVID-19 vaccines authorized for use in Canada
Factor for consideration Considerations (Summary of available evidence and issues for consideration)
mRNA COVID-19 Vaccines Viral vector COVID-19 Vaccine

Efficacy and Effectiveness*

*N.B. This table currently reflects only effectiveness for one dose of the AstraZeneca vaccine in those 65 years of age and over.

Efficacy against symptomatic illness after dose 2

  • Pfizer-BioNTech and Moderna mRNA vaccines have high short-term efficacy (approximately 94%).
  • Data suggests the Pfizer/BioNTech vaccine is 95% efficacious in individuals ≥65 years of age.
  • Data suggests the Moderna vaccine is 86% efficacious in individuals ≥65 years of age.

Efficacy against symptomatic illness after dose 2

  • AstraZeneca SD/SD vaccine is 62% efficacious in participants 18 to 64 years of age.
  • Current data from clinical trials are insufficient to determine the efficacy of the AstraZeneca vaccine in individuals ≥65 years of age.
  • The interval between the first and second dose of the AstraZeneca vaccine may impact efficacy of the vaccine, with lower efficacy if the interval is less than 12 weeks.

Effectiveness against symptomatic illness and hospitalization

  • Observational data in individuals ≥65 years of age have shown a reduction in the risk of symptomatic disease and hospitalization with one dose of AstraZeneca vaccine that appears to reach a comparable level to that observed in the clinical trials among adults 18-64 years of age.

Efficacy against asymptomatic infection
A preliminary analysis of limited data in an ongoing trial suggests the Moderna COVID-19 vaccine may be efficacious in preventing asymptomatic infection, however data is still being collected and the final analysis is not complete. There is no data on asymptomatic infection for Pfizer-BioNTech COVID-19 vaccine.

Efficacy against asymptomatic infection
An exploratory ad hoc analysis of limited data suggests the AstraZeneca vaccine may not be efficacious in preventing asymptomatic infection.

Re-vaccination

  • It is not yet clear if booster doses (e.g., annual vaccination) will be required to provide long-term protection against symptomatic COVID-19 disease, in particular with the emergence of variants of concern.
  • Re-vaccinating those who initially received an mRNA vaccine with the same or another mRNA vaccine is currently being investigated but is thought to be safe and effective.
  • The efficacy and safety of re-vaccinating those who initially received mRNA vaccine with a different COVID-19 vaccine are unknown at this time.

Re-vaccination

  • It is not yet clear if booster doses (e.g., annual vaccination) will be required to provide long-term protection against symptomatic COVID-19 disease, in particular with the emergence of variants of concern
  • Re-vaccination with a booster dose of the AstraZeneca vaccine may reduce vaccine effectiveness due to the possible development of immunity to the viral vector which may interfere with the immune response to subsequent doses.
  • The efficacy and safety of re-vaccinating those who initially received AstraZeneca vaccine with a different COVID-19 vaccine are unknown at this time.

Immunogenicity

Humoral response

  • Humoral responses for both mRNA COVID-19 vaccines peaked after a second dose, including elicitation of neutralizing antibodies. However, as a correlate of protection is not known, these humoral responses cannot be interpreted as corresponding with protection.
  • Humoral responses had similar trends in individuals 18 to 55 years of age and individuals 65 to 85 years of age.

Humoral response

  • Humoral responses peaked after a second dose, including elicitation of neutralizing antibodies, for seronegative vaccine recipients. For seropositive vaccine recipients, humoral responses peaked at the first dose and maintained or decreased at the second dose.
  • For the AstraZeneca vaccine, humoral responses were lower in individuals ≥65 years of age and older, compared to individuals 18 to 64 years of age in unpublished data presented to NACI. Conflicting results have been shown for other age groups in recently published dataFootnote 11.
  • However, as a correlate of protection is not known, these humoral responses cannot be interpreted as corresponding with vaccine protection.

Cellular response

  • Both mRNA vaccines have been shown to produce a cellular immune response by one to two weeks after administration of a second dose.
  • Increases in cellular immune responses response were seen in both younger and older adults.
  • As no immunological correlate of protection has been determined for SARS-CoV-2, these cellular responses cannot be interpreted as corresponding with vaccine protection.

Cellular response

  • AstraZeneca vaccine has been shown to produce cellular immune responses that did not appear to increase after the second dose.
  • Cellular immune responses do not appear to differ between age groups.
  • As no immunological correlate of protection has been determined for SARS-CoV-2, these cellular responses cannot be interpreted as corresponding with vaccine protection.

Safety

Technology

  • mRNA vaccines use a new technology (which has been studied in experimental vaccines); however, all COVID-19 vaccines undergo the same rigorous review and approval process as routine vaccines.

Technology

  • Viral vector vaccines use a relatively new technology (the authorized Ebola vaccine uses this technology); however, all COVID-19 vaccines undergo the same rigorous review and approval process as routine vaccines.

Safety Signals

  • There have been no serious safety signals identified with either mRNA vaccine.
  • For both vaccines, some solicited adverse events are reported to be very common (defined as 10% or more) among vaccine recipients; however, they are mild or moderate and transient, resolving within a few days. These include: pain at the injection site, fatigue, headache, muscle pain, chills, joint pain, and fever. Some adverse events, including fever, are more frequent after the second dose.

Safety Signals

  • There have been no serious safety signals identified with the AstraZeneca vaccine.
  • Some solicited adverse events are reported to be very common (defined as 10% or more) among vaccine; however, they are mild or moderate and transient, resolving within a few days. These include: pain at the injection site, fatigue, headache, muscle pain, chills, joint pain, and fever. Some adverse events are less frequent after the second dose.
Ethics and Equity
  • mRNA vaccines have high short-term efficacy in all authorized age groups and Canada anticipates to have enough doses of mRNA vaccines for every individual in Canada in 2021.
  • Vaccines that are more efficacious may be directed to those who are most at risk of severe disease and exposure to limit the exacerbation of existing inequities.
  • The impact of not offering a less efficacious vaccine earlier to populations who would otherwise have to wait to receive an mRNA vaccine in areas with a high risk of transmission and infection, should take into consideration trust, justice, and the risk of doing harm vs good.
  • Offering any COVID-19 vaccine to those who would otherwise have to wait to receive one could enhance equity.
  • If protection against COVID-19 disease cannot be boosted for those that received a lower efficacy vaccine first, significant inequities could be created for those who receive the AstraZeneca vaccine compared to mRNA vaccines, depending on which population groups received the AstraZeneca vaccine.
  • The AstraZeneca vaccines may offer an option for individuals who are allergic to mRNA vaccine ingredients or their containers. The impact of offering a less efficacious vaccine earlier to some populations should take into consideration trust, justice and the risk of doing harm vs good.

Feasibility

Vaccine schedule

  • Both mRNA vaccines are given as a two-dose series.
  • The mRNA vaccines have an authorized schedule of 21 or 28 days between dose one and dose two. NACI has recommended an extended interval between the first and second dose of up to 4 months to maximize the number of individuals who can be vaccinated as quickly as possible with available vaccine supplies. This could allow for more individuals to receive one dose of the vaccine and have some protection against symptomatic COVID-19 disease.

Vaccine schedule

  • The AstraZeneca vaccine is given as a two-dose series.
  • The interval between the first and second dose of the AstraZeneca vaccine seems to impact efficacy of the vaccine, with lower efficacy if the interval is less than 12 weeks.
  • NACI has recommended an extended interval between the first and second dose of up to 4 months to maximize the number of individuals who can be vaccinated as quickly as possible with available vaccine supplies

Storage requirements

  • The mRNA vaccines have more challenging transport and storage requirements, requiring frozen or ultra-frozen cold chains. Significant efforts have been undertaken to address these logistical complexities. The storage requirements for these vaccines increase the logistical complexity of offering these vaccines in some venues to increase access for various populations.

Storage requirements

  • The AZ vaccine is easier to transport, store and handle than mRNA vaccines, and as a result, could be easier to use for wider distribution via pharmacies and primary healthcare providers.
  • The AstraZeneca vaccine requires storage and transport at +2 to +8°C, which uses standard cold chain infrastructure widely available in provinces and territories.
  • The storage requirements for this vaccine could increase access to the vaccine for some populations.

Acceptability

  • It is possible that individuals will favor mRNA vaccines since they have higher proven efficacy. Fewer cases of COVID-19 are expected after vaccination with a vaccine with high efficacy. The relatively low incidence of cases post-vaccination could positively affect acceptability of COVID-19 vaccines and vaccines in general.
  • It is possible that individuals will favor the AstraZeneca vaccine if it offers an earlier opportunity to receive a COVID-19 vaccine and is more convenient to access if it is available at more convenient locations due to ease of transport, storage and handling.
  • A greater number of COVID-19 cases are expected after vaccination with a vaccine that has lower efficacy. The relatively higher incidence of cases post-vaccination could negatively affect the public's acceptability of COVID-19 vaccines and vaccines in general.

Concerns about vaccine safety and effectiveness are the two most cited reasons for vaccine refusalFootnote 7

  • In a survey of Canadians conducted between December 16 and 22, 2020Footnote 8, the following results were reported:
    • Intention to get vaccinated when it becomes available and recommended is similar for a safe vaccine vs. an effective vaccine (65% vs 63% agreed, n=2,125)
    • For those who will wait to get the vaccine once it is available: 80% will wait to ensure the safety of the vaccine, 64% will wait to ensure the effectiveness of the vaccine (n=691)
  • In a survey of health care providers conducted on Dec 4-13, 2020Footnote 9, the: most important factors reported to influence the decision to receive vaccine were vaccine safety (95.5%), followed by vaccine effectiveness (86.7%)% (n=14,336)

Research priorities

COVID-19 disease and associated vaccines are novel; therefore, research is warranted in many areas. Research to address the following outstanding questions (not ordered in terms of importance) is encouraged, drawing from both short-term and long-term data, where available:

New and emerging research priorities

Efficacy, effectiveness, immunogenicity and safety

  1. What is the population effectiveness (against infection/transmission, hospitalization and death) and medium and long-term duration of protection of a single dose or a complete series of each COVID-19 vaccine approved in Canada?
  2. What is the efficacy, effectiveness, immunogenicity, and safety of COVID-19 vaccines across diverse population groups (e.g., adults of advanced age, those with high-risk medical conditions including autoimmune conditions and transplant recipients, individuals with social or occupational vulnerabilities, individuals who are pregnant or breastfeeding, children/adolescents, frailty)?
  3. What is the efficacy, effectiveness, immunogenicity and safety of COVID-19 vaccines in individuals who have had a previous laboratory evidence of SARS-CoV-2 infection?
    1. Is there a discernable difference between seronegative and seropositive people in any of the above parameters?
    2. Does previous exposure to SARS-COV-2 impact efficacy, effectiveness, immunogenicity or safety of COVID-19 vaccines?
    3. Can a single-dose vaccine series be as effective and safe in individuals with previously proven COVID-19 disease?
    4. Are there any emerging safety signals with COVID-19 immunization that are not predicted by the current understanding of the safety profile of similar vaccines?
    5. Does vaccination following prior SARS-CoV-2 infection or vaccination of SARS-CoV-2 naïve individuals elicit enhanced or altered disease upon subsequent infection by SARS-CoV-2 or other endemic coronaviruses?
  4. What is the efficacy, effectiveness, immunogenicity and safety of COVID-19 vaccines (including potential boosters) against SARS-CoV-2 variants of concern?
  5. What is the correlate of protection for SARS-CoV-2? How are immune responses induced by natural infection similar or different from those induced by vaccines against COVID-19? Is SARS-CoV-2 natural infection (symptomatic or asymptomatic) associated with protection against re-infection or severe disease?
  6. Further immunological evidence is needed in the following areas to inform efficacy predictions:
    1. How do immune responses change over time; what is the durability of immune responses against SARS-COV-2 over the long-term? What is the impact of vaccine dose or interval on durability?
    2. Which immune responses are most important for protection from infection (adaptive or innate immunity), severe disease or transmissibility? What is the role of humoral vs. cellular immunity in preventing immune escape of viral variants?
    3. Are immunoglobulin (Ig)A/IgG/IgM antibodies protective against SARS-CoV-2 and what is the correlate of protection?
  7. What level of COVID-19 vaccination coverage is required to achieve various public health milestones, including: coverage to reduce the burden on the health care system to a manageable degree, achieve herd immunity to protect non-vaccinated individuals, and remove PHM controls. What vaccine characteristics play the largest role on these milestones (i.e., efficacy, durability, uptake)?
  8. What is the background level of Canadian vaccine-vector-specific responses (i.e., anti-Chimpanzee adenovirus)? Are these responses higher in some groups? Will these responses interfere with vaccine efficacy of these highly seropositive groups? What is the duration of anti-vector interference immunity following viral vector vaccines?
  9. How will viral variants impact the efficacy, effectiveness, immunogenicity and safety of a vaccine with respect to death, severe disease, symptomatic disease, asymptomatic disease, infectivity and transmission? What is the effect of using booster vaccines containing heterologous antigens and what is the optimal timing for booster vaccination?
  10. Are any components of the COVID-19 vaccine at high risk of inducing an anaphylactic reaction?
  11. What is the incidence of rare, serious adverse events following immunization with COVID-19 vaccines?
  12. Does endemic coronavirus infection history impact the course of SARS-CoV-2 disease? Is there cross-protection or interference from antibodies/exposure to human seasonal coronaviruses when exposed to SARS-CoV-2 or vaccinated against SARS-CoV-2?
  13. Are there any negative interactions between COVID-19 vaccination and other medications? What is the recommended timing between COVID-19 vaccines and anti-SARS-CoV-2 prophylactic or therapeutic antibodies or convalescent plasma?
  14. Does vaccination have an impact on the transmissibility of SARS-CoV-2 in individuals with asymptomatic infection?
  15. What is the role of seasonal attenuation of SARS-CoV-2?
  16. How does vaccination impact individual-level variation in transmission (e.g., superspreaders)?
  17. What is the epidemiology of SARS-CoV-2 variants of concern over time and across the country and its regions? What are the transmissibility and virulence (including hospitalizations and deaths) of the variants of concern?
  18. What are the epidemiological characteristics of breakthrough illness (e.g., vaccine recipient characteristics, SARS-CoV-2 variants of concern)?

Vaccine administration

  1. Are any COVID-19 vaccines interchangeable to complete a regular vaccine series? What is the efficacy, effectiveness, immunogenicity and safety of a mixed dose schedule or a mixed dose booster series?
  2. What are the minimum, maximum, and optimal intervals between doses of a two-dose COVID-19 vaccine schedule that continue to provide protection against disease?
  3. Are any other vaccines (e.g., Bacillus Calmette-Guérin) protective against COVID-19 through off-target effects?
  4. Can COVID-19 vaccine be simultaneously administered with other, non-COVID-19 vaccines (either live or inactivated vaccines)? If not, what is the minimum interval between administrations?
  5. Can COVID-19 vaccines be given in individuals who have received convalescent plasma or anti-SARS-CoV-2 spike protein monoclonal antibodies? If so, what is the minimum interval required for vaccine administration following receipt of convalescent plasma or monoclonal antibodies?

Standing research priorities

COVID-19 infection and disease

  1. What is the epidemiological profile of COVID-19 (e.g., communicable period, all risk groups)?
    1. What is the disease distribution and spectrum of clinical illness for COVID-19, including burden of illness and risk by age, sex and other demographic variables associated with higher risk?
    2. What are the transmission dynamics of COVID-19, including degree of asymptomatic transmission, role of children in transmission, vertical transmissibility, onset and duration of viral shedding and communicable period, impact of changing weather conditions, and trends over time?
    3. What are the rates of COVID-19 co-infections with other respiratory pathogens and what is the impact on pathogenesis and clinical outcomes?
  2. Can COVID-19 vaccine be used to protect household contacts of a case from infection? Does COVID-19 vaccination decrease infectiousness and clinical illness in individuals that have already acquired infection? Is COVID-19 vaccination effective in interrupting transmission?

Ethics, equity, feasibility and acceptability

  1. What is the acceptability of (a) publicly funded COVID-19 vaccines and other vaccines over time and over different epidemiological contexts among key populations, marginalized populations, providers and policy-makers in different epidemiological contexts across the country?
    1. What factors affect acceptability of immunization with a COVID-19 vaccine in these groups?
    2. What factors affect acceptability of immunization in general?
    3. How will acceptability of prioritized key populations for early immunization with COVID-19 vaccines evolve in different epidemiological contexts across the country?
    4. What strategies can improve acceptability of a COVID-19 vaccine in these groups?
  2. How can vaccine allocation decisions be communicated to individuals and communities in order to maintain trust in public health authorities?
  3. What COVID-19 vaccination strategies or implementation strategies can reduce health inequities in populations directly targeted by vaccination and in populations not directly targeted by immunization?
  4. Can a different COVID-19 vaccine be used to complete a primary series or as a booster dose? How are returning travelers managed if they have initiated but not completed a COVID-19 vaccine series abroad?

Health-related quality of life and well-being

  1. What is the health-related quality of life or well-being of COVID-19 patients and caregivers over time (e.g., health utilities, patient-reported outcomes, patient-reported experiences measures)?
  2. What is the impact of COVID-19 vaccination on health-related quality of life or well-being on individuals?

Surveillance issues

Ongoing and systematic data collection, analysis, interpretation and timely dissemination is fundamental to planning, implementation, evaluation, and evidence-informed decision-making. To support such efforts, NACI encourages surveillance improvements in the following areas:

1. Epidemiology

2. Laboratory (e.g., strain characterization)

3. Vaccine (coverage, effectiveness, safety)

Table 5: Strength of NACI recommendations
Strength of NACI recommendation
based on factors not isolated to strength of evidence
(e.g., public health need)
Strong Discretionary
Wording "should/should not be offered" "may/may not be offered"
Rationale Known/anticipated advantages outweigh known/anticipated disadvantages ("should"),
or Known/Anticipated disadvantages outweigh known/anticipated advantages ("should not")
Known/anticipated advantages are closely balanced with known/anticipated disadvantages, or uncertainty in the evidence of advantages and disadvantages exists
Implication A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present. A discretionary recommendation may/may not be offered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.

List of abbreviations

AE
Adverse event
AEFI
Adverse event following immunization
CDC
Centres for Disease Control and Prevention (United States)
ChAd
Chimpanzee Adenovirus
CI
Confidence interval
CIC
Canadian Immunization Committee
CIG
Canadian Immunization Guide
COVID-19
Coronavirus disease 2019
EEFA
Ethics, Equity, Feasibility, and Acceptability
GRADE
Grading of Recommendations, Assessment, Development and Evaluation
HIV
Human immunodeficiency virus
IM
Intramuscular
Ig
Immunoglobulin
IGRA
Interferon gamma release assay
JCVI
Joint Committee on Vaccination and Immunisation (UK)
MenACWY
Quadrivalent meningococcal vaccine
mRNA
messenger ribonucleic acid
NACI
National Advisory Committee on Immunization
NITAG
National Immunization Technical Advisory Group
PCR
Polymerase chain reaction
PHAC
Public Health Agency of Canada
SAE
Serious adverse events
SAGE
Strategic Advisory Group of Experts on Immunization (WHO)
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SD
Standard dose
SII
Serum Institute India
SOC
System organ class
TST
Tuberculin skin test
UK
United Kingdom
VOC
Variants of Concern
VPD
Vaccine preventable disease
WHO
World Health Organization

Acknowledgments

This statement was prepared by: SJ Ismail, K Young, MC Tunis, A Killikelly, R Stirling, O Baclic, J Zafack, M Salvadori, N Forbes, L Coward, C Jensen, R Krishnan, Y-E Chung, B Warshawsky, E Wong, K Farrah, A Sinilaite, MW Yeung, S Deeks, and C Quach on behalf of the High Consequence Infectious Disease Working Group (HCID WG) and was approved by NACI.

NACI gratefully acknowledges the contribution of: C Mauviel, V Ferrante, S Pierre, E Tice, A Sinilaite, L Whitmore, J Shurgold, J Vachon, J Macri, J Mielczarek, R Goddard, B Sader, M Patel, A House, and A Nam, and the PHAC Public Health Ethics Consultative Group.

NACI

Members:  C Quach (Chair), S Deeks (Vice-Chair), J Bettinger, N Dayneka, P De Wals, E Dubé, V Dubey, S Gantt, R Harrison, K Hildebrand, K Klein, J Papenburg, C Rotstein, B Sander, S Smith, and S Wilson.

Liaison representatives:  LM Bucci (Canadian Public Health Association), E Castillo (Society of Obstetricians and Gynaecologists of Canada), A Cohn (Centers for Disease Control and Prevention, United States), L Dupuis (Canadian Nurses Association), J Emili (College of Family Physicians of Canada), D Fell (Canadian Association for Immunization Research and Evaluation), M Lavoie (Council of Chief Medical Officers of Health), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), and A Pham-Huy (Association of Medical Microbiology and Infectious Disease Canada).

Ex-officio representatives:  D Danoff (Marketed Health Products Directorate, HC), E Henry (Centre for Immunization and Respiratory Infectious Diseases [CIRID], PHAC), M Lacroix (Public Health Ethics Consultative Group, PHAC), J Pennock (CIRID, PHAC), R Pless (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada), G Poliquin (National Microbiology Laboratory, PHAC), V Beswick-Escanlar (National Defence and the Canadian Armed Forces), and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada).

NACI High Consequence Infectious Disease Working Group

Members: C Quach (Chair), S Deeks (Vice-Chair), Y-G Bui, K Dooling, R Harrison, K Hildebrand, M Miller, M Murti, J Papenburg, R Pless, S Ramanathan, N Stall, and S Vaughan.

PHAC Participants: N Abraham, P Doyon-Plourde, K Farrah, V Ferrante, N Forbes, SJ Ismail, A Killikelly, A Nam, M Patel, A Sinilaite, E Tice, MC Tunis, MW Yeung, K Young, and L Zhao.

Appendix A: Evidence summary for Pfizer-BioNTech COVID-19 vaccine

Study C4591001 is the pivotal Phase 1/2/3 trial for the Pfizer-BioNTech COVID-19 vaccine. Evidence on immunogenicity is available for adults 18 to 55 and 65 to 85 years of age. Evidence on the safety and efficacy of the vaccine is available for adults 16 years of age and older. Studies did not include participants from long term care facilities. The Phase 2/3 portion of the trial involved approximately 44,000 study participants randomized (1:1) to receive either the vaccine or placebo. The data presented below are for an interim analysis, therefore the time of follow-up is not consistent but was less than four months after the second dose (maximum of 14 weeks) for all participants.

Evidence from the ongoing Phase 2/3 trial were published recently, after NACI's review of the evidenceFootnote 10.

Efficacy

Severe outcomes due to COVID-19

There are no efficacy data for hospitalizations and deaths specifically, however data exists for efficacy against severe COVID-19 outcomes, defined as laboratory-confirmed COVID-19 with one of the following additional features: clinical signs at rest that are indicative of severe systemic illness; respiratory failure; evidence of shock; significant acute renal, hepatic, or neurologic dysfunction; admission to an intensive care unit; or deathFootnote 11.

There may be a protective effect against severe COVID-19 outcomes when receiving at least one dose of vaccine (overall vaccine efficacy of 88.9%, 95% CI: 20.1 to 99.7%), based on one case identified in the vaccine group (N=21,669) and nine cases in the placebo group (N=21,686). Vaccine efficacy against severe COVID-19 disease was also examined after receipt of Dose 2 (from 7 days and 14 days after Dose 2), but there were an insufficient number of events reported (one severe outcome in the vaccine group and three in the placebo group for each outcome) to determine whether the vaccine was efficacious in reducing severe outcomes with any precision (i.e., the resulting point estimates had wide confidence intervals that included zero).

Symptomatic COVID-19 disease

The estimated vaccine efficacy at least 7 days after Dose 2 was 94.6% (95% CI: 89.9 to 97.3%), with 9 confirmed symptomatic COVID-19 cases, as defined in trial protocolFootnote 10 identified among vaccine recipients (N=19,965) compared to 169 cases among placebo recipients (N=20,172). The vaccine efficacy at least 14 days after Dose 2 in this population was comparable (94.4%, 95% CI: 89.1 to 97.3%). Results were similar when estimating the efficacy specifically in individuals without evidence of prior SARS-CoV-2 infection at 95.0% (95% CI: 90.3 to 97.6%) with 8 confirmed cases among vaccine recipients (N=18,198) compared to 162 cases among placebo recipients (N=18,325).

When study participants without evidence of prior SARS-CoV-2 infection were stratified by age, vaccine efficacy against COVID-19 from 7 days after Dose 2 was between 93.7% (>55 years) and 95.6% (16 to 55 years). In individuals ≥65 years of age, vaccine efficacy was 94.7% (95% CI: 66.7 to 99.9%), while in participants ≥75 years of age, the observed vaccine efficacy was 100% compared to placebo, but with a wide confidence interval including zero which resulted from an insufficient number of events reported (0 vs 5 cases, 95% CI: -13.1 to 100.0%). The estimated vaccine efficacy against confirmed COVID-19 from 7 days after Dose 2 was greater than 91% (between 91.7% and 100.0%) in all subgroups stratified by "at risk" status (e.g., presence of a 1 or more comorbidities). The estimated vaccine efficacy against confirmed COVID-19 from 7 days after Dose 2 was greater than 89% for all races (89.3 to 100%) and 94% for all ethnicities included in the sub-analysis (94.4 to 95.4%).

After Dose 1 but prior to administration of Dose 2, 39 COVID-19 cases were identified in the vaccine group (n=21,669) compared to 82 in the placebo group (n=21,686) for an overall estimated vaccine efficacy of 52.4% (95% CI: 29.5 to 68.4%). If the analysis was restricted to cases identified only in the time period >14 days after dose 1 to before dose 2 the estimated vaccine efficacy increased to 92.3% (95% CI: 69 to 98%).

Table 6: Pfizer-BioNTech vaccine efficacy against the first occurrence of symptomatic COVID-19 disease after dose 1Footnote a
Time period of interest Events in vaccine group (N=21,669) Events in placebo group (N=21,686) Estimate of vaccine efficacy (95% confidence interval)
After dose 1 to before dose 2 39 82 52.4% (29.5 to 68.4%)
>14 days after dose 1 to before dose 2Footnote b 2 27 92.3% (69 to 98%)
1

In the all-available efficacy population consisting of randomized study participants who received at least one dose of the study intervention (i.e., vaccine or placebo)

Return to first footnote a referrer of Table 6a

2

Comité sur l'immunisation du Québec. Stratégie de vaccination contre la COVID-19 : report de la 2e dose en contexte de pénurie. Institut national de Santé Publique du Québec, 18 décembre 2020 (in French only).

Return to second footnote b referrer of Table 6a

There is no analysis provided for efficacy specifically in individuals with prior evidence of SARS-CoV-2 infection.

Asymptomatic infection and transmission

There are no efficacy data for these outcomes at this time.

Immunogenicity

Humoral immune responses

Both SARS-CoV-2 binding and neutralizing antibodies induced by this vaccine had similar trends across both age groups studied (N=195). Maximal immune responses were seen on day 28, 7 days after the second dose. Binding and neutralizing antibodies were both induced by one dose of vaccine and boosted by the second dose of vaccine. The immune response elicited by one dose accounted for 10-20% of the maximal immune response. Up to day 35, older adults (65-85 years of age) had a lower immune response compared to younger adults (18-55 years of age). After the peak on day 28, immune responses decreased until the final evaluation point on day 52, 30 days after dose 2 in younger adults, while no decrease was observed in older adults. At all time points and age groups, immune responses were higher than placebo.

Cellular immune responses

Both CD4+ and CD8+ T-cells specific to SARS-CoV-2 were induced by the vaccine, as demonstrated by the increase in these cell population percentages from day 1 to day 28. Increases were seen in both younger adults (18-55 years of age) and older adults (65-85 years of age). The characterization of these cells indicates a Th-1 biased cellular immune response. Intermediate time points were not reported.

Vaccine safety and adverse events following immunization

Safety evidence is based on interim analyses of 37,586 participants with a median of two months of follow-up (range: <2 weeks to <14 weeks) after Dose 2. About 19,000 participants had at least 2 months of follow-up, including about 9,500 who received the vaccine. Participants who inadvertently received the vaccine (n=12) or placebo (n=11) while pregnant are being followed.

Local reactions

In vaccine recipients, frequency of local reactions was similar after Dose 1 and Dose 2. Pain at the injection site was very common (occurred in 66.1 to 83.1%, dependent on age and whether it was Dose 1 or Dose 2 administered). Most local reactions among vaccine recipients were mild or moderate in severity, with any severe reactions being reported by ≤0.6% of participants. No Grade 4 local reactions were reported. Across both age groups, local reactions after either dose had a median onset between zero and 2 days post-vaccination and a median duration of 1 to 2 days.

Systemic reactions

Systemic events were generally increased in frequency and severity in vaccine recipients compared to placebo recipients, and in the younger age group (16-55 years old) compared with the older age group (≥56 years old), with frequencies and severity increasing with the number of doses (Dose 1 compared to Dose 2). Fatigue (34.1 to 59.4%), headache (25.2 to 51.7%), and muscle pain (13.9 to 37.3%) were very common in all age groups and after Dose 1 and Dose 2, respectively. Fever was common after the first dose (3.7% of 16-55 year olds, 1.4% of >55 year olds) but was very common after the second dose (15.8% of 16-55 year olds, 10.9% of >55 year olds). Joint pain was very common or common in all age groups (11.0 to 21.9% of 16-55 year olds, 8.6 to 18.9% of >55 year olds). Diarrhea was very common or common in both age groups (10.0 to 11.0% of 16-55 year olds, 8.0% of >55 year olds), but was similar to rates seen in the placebo group and did not appear to differ between Dose 1 and Dose 2.

Across age groups, the median onset day for most systemic events after either dose of vaccine was 1 to 2 days post-vaccination, with a median duration of 1 day. The majority of systemic events were mild or moderate in severity.

Overall, the frequency of any severe systemic event after Dose 1 was ≤0.9%. After Dose 2, severe systemic events had frequencies of <2% with the exception of fatigue (3.8%) and headache (2.0%). The proportion of participants that experience severe fever (>38.9°C to 40.0°C) increased between Dose 1 (0.2%) and Dose 2 (0.8%). Grade 4 fever (>40.0°C) was reported for 2 participants in each of the vaccine and placebo groups.

Severe or serious adverse events

In total, 1.1% and 0.1% of participants in the vaccine group experienced at least one severe AE and one life-threatening adverse events (AE), respectively, compared to 0.7% and 0.1% of participants in the placebo group. There were no clinically meaningful differences in AEs by category observed by age, sex, or race/ethnicity.

The proportions of participants who reported at least 1 serious adverse event (SAE) were similar in the vaccine group (0.5%) and in the placebo group (0.4%). Three of the SAEs in the vaccine group and none in the placebo group were assessed by the investigator as related to study intervention: 1 SAE each of shoulder injury related to vaccine administration, ventricular arrhythmia, and lymphadenopathy. No clinically meaningful differences in SAEs were observed by age, sex, or race/ethnicity. After either vaccine dose, no participant reported an immediate allergic reaction to vaccine.

Other serious adverse events

Lymphadenopathy

Lymphadenopathy was not a solicited AE. Among participants (n=37,586) who were followed for <2 weeks to <14 weeks after Dose 2, AEs of lymphadenopathy were reported in 0.3% (n=64) participants (0.5% [n=54] in the younger age group and 0.1% [n=10] in the older age group) in the vaccine group and 6 participants (0.0%) in the placebo group. Among the AEs of lymphadenopathy in the vaccine group, the majority (47 of 64) were judged by the investigator as related to the vaccine. Most lymphadenopathy events were reported within 2 to 4 days after vaccination. The average duration of these events was approximately 10 days, with 11 events ongoing at the time of the data cut-off.

Appendicitis

Among participants who were followed <2 weeks to <14 weeks after Dose 2, there were a total of 12 participants with SAEs of appendicitis; 8 of which were in the vaccine group. Six of those 8 occurred in younger adults and 2 occurred in older adults. None of the cases were assessed as related to the vaccine by the investigators. The rate in either age group was not estimated to be greater than expected compared to baseline rates.

Death

There were 6 participants who died as of 14 November 2020, the data cut-off date for the interim analysis. This included 2 participants in the vaccine group and 4 participants in the placebo group. None of these deaths in the vaccinated group were assessed by the investigator as related to the vaccine.

Appendix B: Evidence summary for Moderna COVID-19 vaccine

Pivotal Phase 1, 2, and 3 trials are being conducted for the Moderna COVID-19 vaccine. Evidence on efficacy, immunogenicity, and safety is available for adults ≥18 years of age. Studies did not include participants from long term care facilities. The Phase 3 portion of the trial involved 30,413 study participants randomized (1:1) to receive either the vaccine (2 doses of 100 mcg) or placebo. The data presented below are for an interim analysis, therefore the time of follow-up is not consistent but was a median of two months after the second dose (maximum of 14 weeks) for all participants.

Efficacy

Severe outcomes due to COVID-19

There are no efficacy data for hospitalizations and deaths specifically, however data exists for efficacy against severe COVID-19 outcomes, as defined in the trial protocolFootnote 12.

The efficacy of the Moderna COVID-19 vaccine to protect against severe COVID-19 cases occurring at least 14 days after the second injection was in 28,207 study participants (14,073 participants in the placebo group and 14,134 participants in the Moderna COVID-19 vaccine group). There were 30 confirmed severe COVID-19 cases in the placebo group compared to 0 cases in mRNA-1273 vaccine recipients, for an estimated vaccine efficacy of 100.0% (95% CI: not evaluable to 100.0%).

Symptomatic COVID-19 disease

The primary efficacy outcome examined the efficacy of Moderna COVID-19 vaccine to protect against confirmed symptomatic COVID-19 starting 14 days after Dose 2 in study participants 18 years of age or older without prior evidence of SARS-CoV-2 infection at baseline. This analysis included 28,207 study participants (14,073 participants in the placebo group and 14,134 participants in the Moderna COVID-19 vaccine group), with a median time of follow-up after receiving the second injection of 63 days. There were 185 confirmed COVID-19 casesFootnote 13 occurring at least 14 days after the second injection among placebo recipients compared to 11 cases among Moderna COVID-19 vaccine recipients, for an estimated vaccine efficacy of 94.1% (95% confidence interval, CI: 89.3 to 96.8%).

A subgroup analysis of the interim primary efficacy outcome was conducted in three age groups: 18 to <65 years of age (10,521 participants in the placebo group and 10,551 participants in the Moderna COVID-19 vaccine group), ≥65 years of age (3,552 participants in the placebo group and 3,583 participants in the Moderna COVID-19 vaccine group), and a further subgroup of study participants ≥75 years of age (688 participants in the placebo group and 630 participants in the Moderna COVID-19 vaccine group).

In study participants 18 to <65 years, there were 156 confirmed COVID-19 cases occurring at least 14 days after the second injection among placebo recipients compared to 7 cases among mRNA-1273 vaccine recipients, for an estimated vaccine efficacy of 95.6% (95% CI: 90.6 to 97.9%). The corresponding incidence rate per 1,000 person-years (total time at risk in each treatment group) was 64.63 in the placebo group and 2.88 in the Moderna COVID-19 vaccine group. In study participants ≥65 years of age there were 29 confirmed COVID-19 cases among placebo recipients compared to 4 cases among Moderna COVID-19 vaccine recipients, corresponding to a somewhat lower point estimate of vaccine efficacy of 86.4% (95% CI: 61.4 to 95.2%). The corresponding incidence rate per 1,000 person-years was 33.73 in the placebo group and 4.60 in the Moderna COVID-19 vaccine group. In the subgroup of study participants ≥75 years of age there were 7 confirmed COVID-19 cases among placebo recipients compared to 0 cases among Moderna COVID-19 vaccine recipients, for a corresponding vaccine efficacy of 100.0% (95% CI: not evaluable to 100.0%), but this must be interpreted with caution as there were few events identified in this age group.

The efficacy of the Moderna COVID-19 vaccine to protect against confirmed COVID-19 cases occurring at least 14 days after the second injection was also assessed in participants most at risk for severe complications of COVID-19. In study participants 18 to <65 years of age and at risk for severe complications of COVID-19 (2,118 participants in the placebo group and 2,155 participants in the Moderna COVID-19 vaccine group) there were 35 confirmed COVID-19 cases in the placebo group compared to 2 cases among Moderna COVID-19 vaccine recipients, for an estimated vaccine efficacy of 94.4% (95% CI: 76.9 to 98.7%). In study participants 18 to <65 years of age, but not at risk for severe complications of COVID-19 (8,403 participants in the placebo group and 8,396 participants in the Moderna COVID-19 vaccine group) the estimated vaccine efficacy was 95.9% (95% CI: 90.0 to 98.3%) based on 121 confirmed COVID-19 cases in the placebo group and 5 cases among Moderna COVID-19 vaccine recipients. Vaccine efficacy estimates were also calculated for select individual co-morbid conditions; however, as of November 7, 2020 the number of identified events in these subgroups (n=0 to 11) were too small for meaningful analysis.

A secondary analysis of vaccine efficacy to protect against the first occurrence of confirmed COVID-19 starting 14 days after Dose 2 regardless of prior SARS-CoV-2 infection, as determined by serologic titre, involved the full analysis set (randomly assigned study participants who received at least one injection). There were 30,351 study participants 18 years of age or older (15,170 participants in the placebo group and 15,181 participants in the Moderna COVID-19 vaccine group). There were 187 confirmed COVID-19 cases among placebo recipients compared to 12 cases among Moderna COVID-19 vaccine recipients, for an estimated vaccine efficacy of 93.6% (95% CI: 88.6 to 96.5%). However, there was a small proportion of study participants enrolled (n=679/29,148; 2.3%) with positive SARS-CoV-2 infection status at baseline.

In participants who had only received one dose of vaccine at the time of data analysis (placebo group: n=1,079; vaccine group: n=996), vaccine efficacy was 80.2% (95% CI: 55.2 to 92.5%). Limiting the analysis to 14 or more days after Dose 1, efficacy rose to 92.1% (95% CI: 68.8 to 99.1%). However, there are limited data on the efficacy of Dose 1 alone beyond 28 days post-vaccination.

Table 7: Moderna vaccine efficacy against the first occurrence of symptomatic COVID-19 disease after dose 1Footnote a
Time period of interest Events in vaccine group (N=996) Events in placebo group (N=1,079) Estimate of vaccine efficacy (95% confidence interval)
After dose 1 7 39 80.2% (55.2 to 92.5%)
>14 days after dose 1 to before dose 2 2 28 92.1% (68.8 to 99.1%)
a

In the modified intention-to-treat population consisting of randomized study participants who had received only one dose of their assigned intervention (i.e., vaccine or placebo) at the time of analysis

Return to first footnote a referrer of Table 7a

Asymptomatic infection and transmission

Nasopharyngeal swabs for SARS-CoV-2 virus were collected for all participants at specified intervals before Dose 1 and before Dose 2. There were 14 participants in the vaccine arm who were previously seronegative before administration of Dose 1 who had asymptomatic infection at the second time point, compared to 38 participants in the placebo arm. No formal efficacy data are available; however, assessment of this outcome is ongoing.

Immunogenicity

Humoral immune responses

Antibodies that bind the spike protein were induced in vaccine recipients by day 15 (15 days after dose 1) and reach maximum levels on day 43 (15 days after dose 2). Maximal binding antibody responses approximate the levels of the highest affinity samples of convalescent sera. Binding antibodies reached elevated levels on day 36 (7 days after dose 2) and persisted but decreased through day 119 (90 days after dose 2), the last day for which data is available.

Binding antibodies induced by 1 dose of the vaccine (i.e., on day 29) were 10-20% of the elevated responses seen on day 36. It is unknown how binding antibody responses change over time.

Binding antibody responses through day 36 seems to be approximately equivalent across age groups. The data may suggest an age-dependent binding antibody durability. Antibody responses for age 70 or below decreased more slowly than for those above 70.

Neutralizing antibodies weren't induced to the level of convalescent sera until day 36, 7 days after dose 2 for all age groups. Neutralizing antibody responses through day 36 seems to be approximately equivalent across age groups.

Neutralizing antibody responses on Day 119 represent a larger proportion of the maximum on day 43, compared to binding antibody responses. This may indicate increased durability of neutralizing antibody responses compared to binding antibody responses. These neutralizing data may also suggest an age-dependent neutralizing antibody durability as antibody responses on day 119 for each cohort were inversely proportional to the age of the cohort.

Cellular immune responses

Both CD4+ and CD8+ T-cells specific to SARS-CoV-2 were induced by the vaccine. Maximal induction of both CD4+ and CD8+ T cells was observed on day 43, 14 days after dose 2. The percentage of CD8+T cells was lower for all age groups compared to CD4+ T cells. By comparing the percentage of cells that express Th-1 (IFN gamma, IL-2, TNF) vs Th-2 (IL-4 and IL-13) it was demonstrated that this vaccine induces a Th1-biased cellular immune response.

Vaccine safety and adverse events following immunization

Safety evidence is based on interim analyses of 30,351 participants with a median follow-up time of 63 days after Dose 2 (92 days after Dose 1). 23,276 participants had at least one month of follow-up after Dose 2 (12,021 individuals received the vaccine) and 7,667 individuals had at least 2 months of follow-up after Dose 2 (3,894 individuals received the vaccine)Footnote 13. Participants who inadvertently received the vaccine (n=6) or placebo (n=7) while pregnant are being followed.

Solicited local reactions

In vaccine recipients, frequency of local reactions increased from Dose 1 to Dose 2. Pain at the injection site was very common (occurred in 83.7% of vaccine recipients after Dose 1 and in 88.42% of vaccine recipients after Dose 2). Redness was common (2.8 to 8.6%) and swelling was common to very common (6.1 to 12.2%). Grade 3 (severe) reactions were reported by 3.5% and 7.0% of vaccine recipients after Dose 1 and Dose 2, respectivelyFootnote 13. No Grade 4 local reactions were reported. The majority of local reactions after either dose occurred within the first 1 to 2 days post-vaccination and had a median duration of 1 to 3 days.

Localized axillary swelling and tenderness was solicited and occurred in less than 5% of placebo recipients after any dose, and 10.2% and 14.2% of vaccine recipients after Dose 1 and 2, respectively. Among vaccine recipients, the incidence of severe (Grade 3) axillary swelling and tenderness increased from Dose 1 to Dose 2 (0.3 to 0.5%), whereas in the placebo group it decreased from Dose 1 to Dose 2 (0.2 to 0.1%)Footnote 13.

Solicited systemic reactions

Systemic events generally had a higher frequency and severity in vaccine recipients compared to placebo recipients, with frequency and severity increasing with the number of doses (Dose 1 compared to Dose 2). In vaccine recipients, fatigue (37.2 to 65.3%), headache (32.6 to 58.6%), muscle pain (22.7 to 58.0%), and arthralgia (16.6 to 42.8%) were very common in all age groups and after Dose 1 and Dose 2, respectively. Chills and nausea/vomiting were very common or common (8.3 to 44.2% and 8.3 to 19.0%, respectively). Fever was uncommon after the first dose (0.8%) but was very common after the second dose (15.5%).

Grade 3 reactions were reported by 2.9% and 15.7% of vaccine recipients after Dose 1 and Dose 2, respectivelyFootnote 13. After Dose 2, Grade 3 fever (1.3%), headache (4.3%), fatigue (9.4%), myalgia (8.7%), arthralgia (5.1%), and chills (1.3%) were common. The proportion of vaccine recipients that experience Grade 3 fever (>38.9°C to 40.0°C) increased between Dose 1 (<0.1%; n=11) and Dose 2 (1.3%; n=202). Among placebo recipients only 2.7% reported Grade 3 adverse events after either dose.

The incidence of any Grade 4 events was <0.1% after both doses in both vaccine (6 to 12 events) and placebo (2 to 4 events) recipients. Grade 4 fever (>40.0°C) was reported for 4 placebo recipients and 4 vaccine recipients after Dose 1, and 2 placebo recipients and 12 vaccine recipients after Dose 2. The majority of systemic reactions after either dose occurred within the first 1 to 2 days post-vaccination and had a median duration of 1 to 2 days.

Unsolicited severe or serious adverse events

During the first 28 days after any dose, 1.45% and 0.5% of participants in the vaccine group (Dose 1 and Dose 2, respectively) reported unsolicited severe and serious AEs (SAEs), compared to 1.3% and 0.6% of participants in the placebo group. There was no apparent effect of age on the relative incidence of SAEs in the vaccinated or placebo group.

Three SAEs in vaccinated individuals were considered by the study sponsor to be related to the trial intervention: two cases of facial swelling and one case of nausea and vomiting with headaches and fever.

Four additional SAEs in vaccine recipients and five SAEs in placebo recipients were considered to be related to the trial intervention by trial investigatorsFootnote 13. Of the SAEs considered related to the Moderna vaccine, 2 cases of autoimmune diseases were reported: one rheumatoid arthritis in a participant known with hypothyroidism, that was unresolved at the time of the report and one autonomic dysfunction in a participant known with hypothyroidism, also unresolved at the time of the report. In the placebo group, one participant (known to have chronic back pain) developed polymyalgia rheumatica, which was resolving.

No clinically meaningful differences in SAEs were observed by age. Sex and race/ethnicity were not assessed. After either vaccine dose, no participant in the Phase 3 study reported an immediate allergic reaction to vaccine.

Other serious adverse events

Death

A total of 13 deaths were reported, 6 in the vaccine group and 7 in the placebo group. None of these deaths were assessed to be related to any study intervention or COVID-19.

Appendix C: Evidence summary for AstraZeneca COVID-19 vaccine

Results from four clinical trials (two Phase 1/2, one Phase 2/3, and one Phase 3) were available at time of authorization for the AstraZeneca COVID-19 vaccine. Results from an ongoing Phase 3 trial in the US are not available at time of writing. Evidence on efficacy, immunogenicity, and safety is available for adults ≥18 years of age. The Phase 2/3 trial (COV002) trial and Phase 3 trial (COV003) assessed efficacy, safety and immunogenicity of the vaccine. The Phase 2/3 trial was based in the United Kingdom, (UK) while the Phase 3 trial was based in Brazil. These two studies underwent a series of protocol amendments and logistical challenges during the conduct of the trials that resulted in significant changes to the trials' methodology. There were changes from a single to a two-dose vaccine regimen, the use of both a low dose/standard dose (LD/SD) (in COV002 only, due to dosing error) and standard dose/standard dose (SD/SD) vaccine regimen, and the recruitment of progressively older study participants (56-69 and then ≥70 years of age) after the initial focus on adults 18-55 years of age. In the SD/SD vaccine regimen, study participants were randomized (1:1) to receive either the AstraZeneca COVID-19 vaccine, AZD1222 (5 x 1010 viral particles per 0.5 mL dose) or control injection. The participants randomized to the control group were administered two doses of quadrivalent meningococcal vaccine (MenACWY) (COV002) or MenACWY for Dose 1 and placebo for Dose 2 (COV003).

There were significant differences in the baseline characteristics of participants in the Phase 2/3 and Phase 3 trials. In addition, the clinical trials prioritized the recruitment of health care professionals and other adults with high potential for exposure to SARS-CoV-2, including health care and social setting workers.

Evidence from the AstraZeneca COVID-19 vaccine trials has been publishedFootnote 14.

Efficacy

The estimates of vaccine efficacy for the AstraZeneca COVID-19 vaccine (AZD1222) come from the Phase 2/3 and Phase 3 trials. As of a data cut-off date of November 4, 2020 the primary analysis population (study participants who received either the LD/SD or SD/SD regimens) for the primary outcome included 11,636 participants seronegative at baseline (5,807 in the vaccine group, 5,829 in the control group). Of this population, 8,895 study participants (4,440 vaccine recipients and 4,455 controls) received the SD/SD regimen. As of a data cut-off date of December 7, 2020, the SD/SD population had increased to include 12,158 study participants (6,085 vaccine recipients and 6,073 controls). Unless otherwise noted, all data presented in this summary is based on the SD/SD vaccine regimen and as of a data cut-off date of December 7, 2020.

Symptomatic COVID-19 disease

The primary efficacy outcome assessed in the two trials was prevention of the first occurrence of confirmed COVID-19 beginning ≥15 days after Dose 2, based on assessments of cases by an Adjudication Committee blinded to participant group assignment, and analysed in the combined LD/SD and SD/SD regimen population. Assessment in the subgroup that only received SD/SD was a pre-specified secondary analysis in the clinical trial. Symptomatic COVID-19 was defined as having at least one of the following symptoms (objective fever ≥37.8 C, cough, shortness of breath, and anosmia or ageusia) AND a swab positive for SARS-CoV-2 by RT-PCR AND confirmed by an Adjudication Committee.

Based on data as of December 7, 2020, there were 12,158 study participants 18 years of age or older without prior evidence of SARS-CoV-2 infection at baseline (6,085 vaccine recipients and 6,073 controls) included as part of the SD/SD regimen analysis. The estimated vaccine efficacy against confirmed COVID-19 cases occurring at ≥15 days after Dose 2 in study participants receiving the SD/SD vaccine regimen was 62.5% (95% CI: 50.7 to 71.4%), based on identification of 71/6,085 (1.2%) cases in vaccine recipients and 186/6,073 (3.1%) in controls. The estimated vaccine efficacy by age was 63.1% (51.1 to 72.1%) in study participants 18-64 years of age and 50.7% (-65.8 to 85.4%) in participants ≥65 years of age. An ad-hoc subgroup analysis performed to examine the potential confounding effect of age and dosing interval on estimates of vaccine efficacy in the COV002 (UK) clinical trial generated an estimate of vaccine efficacy in study participants 18-55 years of age who received the SD/SD dosing regimen. Based on the interim data as of November 4, 2020, this subgroup analysis found an estimated vaccine efficacy of 59.3% (95% CI: 25.1 to 77.9%) in this age group. This analysis included study participants with any interval duration between doses.

Symptomatic COVID-19 by interval

As of December 7, 2020, the majority of study participants in the COV002 (UK) and COV003 (Brazil) clinical trials received the two doses of the SD/SD regimen within a 4-8 week (UK: 45.6%, Brazil: 87.2%) or a 9-12-week interval (UK: 34.4%; Brazil: 10.5%). About 1 in 5 study participants in the UK clinical trial (18.9%) received the SD/SD regimen with a >12-week interval between vaccine doses, and in the Brazil trial it was less than 1 in 50 study participants (1.8%). A very small proportion of study participants received the SD/SD regimen with a <4-week interval between doses (UK: 1.0%, Brazil: 0.4%).

An exploratory analysis examined the potential effect of the interval between the administration of the first and second vaccine doses on vaccine efficacy in study participants receiving the SD/SD vaccine regimen. Table 8 summarizes the estimates of vaccine efficacy against confirmed COVID-19 cases occurring at ≥15 days after dose 2 by dosing interval. There is a suggestion of an increase in the point estimate of vaccine efficacy with increasing intervals between the first and second dose of vaccine. However, it is important to note that the confidence intervals around these point estimates overlap.

Table 8: Estimates of vaccine efficacy against the first occurrence of confirmed COVID-19 beginning ≥15 days after Dose 2 in all participants, by dosing interval (SD/SD seronegative baseline efficacy setFootnote a)
Dosing interval Event in vaccine group (AZD1222) n/N (%) Events in control group (MenACWY) n/N (%) Vaccine efficacy
(95% CI)
4-12 weeks 67/5,473 (1.2) 162/5,422 (3.0) 59.6% (46.4 to 69.6%)
4-8 weeks 52/4,188 (1.2) 113/4,098 (2.8) 55.7% (38.5 to 68.1%)
9-12 weeks 15/1,285 (1.2) 49/1,324 (3.7) 69.0% (44.8 to 82.6%)
>12 weeks 4/571 (0.7) 22/599 (3.7) 81.6% (47.0 to 93.6%)

Footnotes

Footnote a

Participants without prior evidence of SARS-CoV-2 infection at baseline; all SD/SD vaccine recipients (or respective controls)

Return to footnote a referrer

In a subgroup analysis in study participants who received the SD/SD vaccine regimen, vaccine efficacy against confirmed COVID-19 cases occurring at ≥15 days after dose 2 was estimated by dosing interval and age group. These ad-hoc subgroup analyses were performed in participants 18-55 years of age from the COV002 (UK) clinical trial and in all study participants who received the SD/SD regimen (from COV002 and COV003), dichotomized into groups 18-64 years and ≥65 years of age.

The ad-hoc subgroup analysis performed to examine the potential confounding effect of age and dosing interval on estimates of vaccine efficacy in the COV002 (UK) clinical trial generated an estimate of vaccine efficacy in study participants 18-55 years of age who received the SD/SD regimen at an interval of >8 weeks between doses. Based on the interim data as of November 4, 2020, this subgroup analysis found an estimated vaccine efficacy of 65.6% (95% CI: 24.5 to 84.4%). In the updated dataset as of December 7, 2020, there were 1,375 study participants ≥65 years of age (699 in the vaccine group and 676 in the control group). Efficacy estimates for participants ≥65 years for the overall 4-12-week dosing interval and the 4-8-week interval have wide confidence intervals that include zero. Estimates of vaccine efficacy could not be calculated for participants ≥65 years for the 9-12-week and >12-week dosing intervals due to a lack of older study participants who received the SD/SD regimen during these dosing intervals (Table 9).

Table 9: Estimates of vaccine efficacy against the first occurrence of confirmed COVID-19 beginning ≥15 days after Dose 2, by dosing interval and age group (SD/SD seronegative baseline efficacy setFootnote a)
Dosing interval and
age group
Event in vaccine group (AZD1222) n/N (%) Events in control group (MenACWY) n/N (%) Vaccine efficacy
(95% CI)
4-12 weeks
18-64 years 63/4,790 (1.2) 156/4,760 (3.0) 60.5% (47.1 to 70.5%)
≥65 years 4/683 (0.6) 6/662 (0.9) 43.2% (-99.3 to 83.8%)
4 - 8 weeks
18-64 years 48/3,506 (1.4) 107/3,439 (3.1) 56.6% (39.1 to 69.1%)
≥65 years 4/682 (0.6) 6/659 (0.9) 43.4% (-98.5 to 83.9%)
9-12 weeks
18-64 years 15/1,284 (1.2) 49/1,321 (3.7) 69.0% (44.8 to 82.6%)
≥65 years 0/1 (0) 0/3 (0) No estimate
>12 weeks
18-64 years 4/571 (0.7) 22/599 (3.7) 81.6% (47.0 to 93.6%)
≥65 years 0/0 (0) 0/0 (0) No estimate

Footnotes

Footnote a

Participants without prior evidence of SARS-CoV-2 infection at baseline; all SD/SD vaccine recipients (or respective controls)

Return to footnote a referrer

Symptomatic COVID-19 by presence of co-morbidity

Efficacy was also assessed based on the presence of comorbidity, which was defined as the presence of one or more of the following mild to moderate and controlled medical conditions at baseline: cardiovascular disease, respiratory disease, diabetes, or obesity (BMI ≥30 kg/m2) based on a data cut-off date of November 4, 2020. For this exploratory analysis, included study participants who were SARS-CoV-2 seronegative at baseline and received the SD/SD regimen. The estimated vaccine efficacy against confirmed COVID-19 cases occurring at ≥15 days after Dose 2 in study participants without comorbidities was 58.0% (95% CI: 25.8 to 76.2%), based on 17/2,825 (0.6%) cases identified in the vaccine group compared to 39/2,774 (1.4%) cases in the control group. The corresponding estimate of vaccine efficacy in study participants with comorbidities was 67.1% (95% CI: 33.2 to 83.8%), based on the identification of 10/1,611 (0.6%) cases in the vaccine group compared to 32/1,670 (1.9%) cases in the control group.

Symptomatic COVID-19 after one dose

Efficacy at various time points after one dose of AstraZeneca COVID-19 vaccine was assessed as a secondary/exploratory analysis based on data as of the interim analysis cut-off date of November 4, 2020 (Table12). The analysis involved study participants who were SARS-CoV-2 seronegative at baseline and received SD vaccine as their initial vaccine dose. The median duration of follow-up after Dose 1 was 115 days (range: 41-149 days). Note that approximately 80% of study participants in the vaccine arm received the second dose of the vaccine; therefore, several estimates of vaccine efficacy are not solely due to the one dose of SD vaccine.

Table 10: Estimates of vaccine efficacy against the first occurrence of confirmed COVID-19 beginning after Dose 1, (SD/SD seronegative baseline efficacy setFootnote a)
Time period of interest Events in vaccine group (AZD1222) Events in control group (MenACWY) Estimate of vaccine efficacy
(95% confidence interval)
After Dose 1 92
(N=8,008)
185
(N=8,013)
50.5% (36.5 to 61.5%)
≥22 days after Dose 1 51
(N=6,307)
141
(N=6,297)
64.1% (50.5 to 73.9%).
≥22 after Dose 1 but before Dose 2 15
(N=6,310)
52
(N=6,296)
71.3% (49.0 to 83.8%)

Footnotes

Footnote a

Participants without prior evidence of SARS-CoV-2 infection at baseline; all SD/SD vaccine recipients (or respective controls)

Return to footnote a referrer

Severe outcomes due to COVID-19

Severe COVID-19 disease

Severe COVID-19 disease, defined as study participants who met the confirmed COVID-19 case definition and were assigned a severity score of ≥6 on the World Health Organization Clinical Progression Scale (e.g., clinical severity requiring hospitalization, and may include intubation and mechanical ventilation, and death), was assessed as a secondary analysis of vaccine efficacy. Analysis included study participants who had been followed for ≥15 days since Dose 2, who were seronegative for SARS-CoV-2 at baseline, and received both doses of the SD/SD regimen. As of December 7, 2020, there were 6,085 study participants in the vaccine group and 6,073 participants in the control group. There was 1 case of severe COVID-19 disease identified in a study participant in the control group who received the control intervention within the 4-12-week dosing interval. This participant also required ICU admission and eventually died. An additional severe case occurred >21 days after the first dose and ≤14 days after the second dose in a study participant in the control group.

Hospitalizations

Vaccine efficacy against COVID-19 associated hospitalizations was assessed at multiple time points (Table 11). Assessment included study participants who were seronegative for SARS-CoV-2 at baseline and received both doses of the SD/SD regimen. After Dose 2 (median follow-up duration: 36 days, range: 1-79 days, based on data as of November 4, 2020), there were 7 hospitalizations due to COVID-19 identified in study participants who received the SD/SD regimen within the 4-12-week dosing interval, all in participants in the control group. There were no hospitalizations in the vaccine group ≥22 days after Dose 1; however, there were 2 cases hospitalized due to COVID-19 identified in the vaccine group and 16 in the control group ≥15 days after Dose 1, resulting in an estimate of vaccine efficacy of 87.6% (95% CI: 46.0 to 97.2%). The 2 hospitalizations in the vaccine group were 1 and 10 days post vaccination (median follow up: 115 days, range: 41-149).

Table 11: Estimates of vaccine efficacy against hospitalization, by dosing interval (SD/SD seronegative baseline efficacy setFootnote a)
Time period of interest Event in vaccine group (AZD1222) n/N (%) Events in control group (MenACWY) n/N (%) Vaccine efficacy
(95% CI)
≥22 days after Dose 1Footnote b 0/6,307 (0.0) 9/6,297 (0.1) 100% (95% CI: 49.6 to NE)
≥15 days after Dose 2Footnote c 0/6,085 (0.0) 7/6,073 (0.1) N/A

Footnotes

Footnote a

Participants without prior evidence of SARS-CoV-2 infection at baseline; all SD/SD vaccine recipients (or respective controls)

Return to footnote a referrer

Footnote b

Based on data as of November 4, 2020

Return to footnote b referrer

Footnote c

Based on data as of December 7, 2020

Return to footnote c referrer

Deaths

As of the updated data cut-off date of December 7, 2020, there has been a single death due to COVID-19 identified in a study participant in the control group.

Asymptomatic infection and transmission

This was an exploratory analysis conducted only in clinical trial COV002 (UK). As part of the study protocol, beginning one week after receipt of Dose 1, study participants were asked to provide weekly self-administered nose or throat swabs for RT-PCR testing. Participants were asked to report symptoms when they appeared; however, the presence or absence of symptoms at the time of sample collection was not routinely collected. An asymptomatic infection was defined as a study participant with a swab virologically confirmed for SARS-CoV-2 and who reported no clinical trial-defined symptoms of confirmed COVID-19. Study participants with virologically confirmed SARS-CoV-2 infection, but who did not report whether or not they had symptoms were classified as "unknown symptoms".

Table 12: Estimates of vaccine efficacy against asymptomatic infection, by dosing interval (SD/SD seronegative baseline efficacy setFootnote a)
Dosing interval Event in vaccine group (AZD1222) n/N (%) Events in control group (MenACWY) n/N (%) Vaccine efficacy
(95% CI)
≥22 days after Dose 1Footnote b
  14/3,060 (0.5%) 15/3,064 (0.5%) 6.6% (-93.5 to 54.9%)
≥15 days after Dose 2Footnote c
Any interval 8/2,377 (0.3%) 11/2,340 (0.5%) 26.9% (-81.5 to 70.6%)
4-12 weeks N/A N/A 37.7% (-90.1 to 79.6%)
>12 weeks N/A N/A -4.3% (-416.5 to 79.0%)

Footnotes

Footnote a

Participants without prior evidence of SARS-CoV-2 infection at baseline; all SD/SD vaccine recipients (or respective controls)

Return to footnote a referrer

Footnote b

Based on data as of November 4, 2020

Return to footnote b referrer

Footnote c

Based on data as of December 7, 2020

Return to footnote c referrer

An additional ad-hoc analysis combining study participants with SARS-CoV-2 asymptomatic infection or associated with unknown symptoms also failed to demonstrate the efficacy of the SD/SD regimen (3.9%, 95% CI: -72.1 to 46.4%), based on the identification of 22 cases in the vaccine group and 23 cases in the control group ≥15 days after Dose 2.

Immunogenicity

Approximately 15% of the overall safety analysis set was targeted for inclusion in the immunogenicity analysis set. These analyses combined evidence from SD/SD and LD/SD dosing regimens, and may not completely align with the data from individual studies.

Humoral immune responses

Antibody responses, both binding and neutralizing, differed for seronegative and seropositive vaccine recipients. Vaccine recipients who were seropositive at baseline demonstrated high antibody titres 28 days after Dose 1 compared to seronegative recipients. Seronegative recipients demonstrated an increase in their immune responses 28 days after Dose 2. By contrast, seropositive recipients had decreased immune responses after Dose 2 compared to responses after Dose 1. However, immune responses for seropositive recipients at all time points were higher than those for seronegative recipients. The mechanism behind these differences, and their potential impact on vaccine efficacy and effectiveness remains unclear. A recently published article contains additional evidence on humoral responsesFootnote 6.

Antibody responses, both binding and neutralizing, were lower in older adults (65+) than in younger adults after both the first and second dose of vaccine. Without a correlate of protection, the significance of these differences in antibody responses is unclear.

Cellular immune responses

Cellular immune responses were elicited by this vaccine. The first dose elicited Th-1 biased CD4+ T cells in both younger and older age groups. Younger vaccine recipients exhibited higher cellular immune responses than older age groups. Notably, the second vaccine dose did not augment cellular immune responses. The mechanism and the impact on vaccine efficacy and effectiveness remains unclear.

Anti-vector immune responses

It is unclear to what extent pre-existing immunity to any adenovirus-based vaccine vector exists in the Canadian population and what impact that could have on adenovirus based vaccine safety and efficacy. It is also unclear as to what extent immunization with adenovirus-based vaccines elicits anti-vector immune responses and what impact that could have on homologous or heterologous booster doses with adenovirus-based vaccines. Evidence for a viral vector vaccine based on human adenovirus 5 (not authorized in Canada) indicated that vaccine recipients with high pre-existing immunity to the adenovirus vector had lower anti-SARS-CoV-2 immune responsesFootnote 15. The AstraZeneca COVID-19 vaccine uses a modified chimpanzee adenovirus vector (ChAd). AstraZeneca found no correlation between anti-ChAd neutralizing antibody responses and anti-SARS-CoV-2 immune responses. It also found that neutralizing antibody levels were not boosted after the second dose. However, neutralization is not the only anti-vector immune response that could impact vaccine-induced immunity. It remains unclear if immune responses to the ChAd vector will impact the efficacy or effectiveness of this vaccine.

Vaccine safety and adverse events following immunization

Safety evidence is based on interim analyses of 23,745 participants who received at least one dose of the vaccine. The safety analyses were conducted in different analysis sets. Solicited adverse events occurring within 7 days after any dose were assessed among 2648 vaccine recipients who received at least one dose (SD) and 2497 control recipients. Approximately one third of study participants received their second vaccine dose within 6 weeks of receiving Dose 1. The majority (~90%) of study participants in the safety cohort were less than 65 years of age. The median duration of follow-up was 105 days post-Dose 1 and 62 days post-Dose 2.

Solicited local reactions

Solicited local injection site AEs were reported by 74.7% of evaluated participants within the first 7 days following any vaccine dose. Pain and tenderness were most frequently reported (54.2% and 63.7%, respectively) followed by warmth (17.7%), bruising (17.3%), redness (14.0%), pruritus (12.7%), and swelling (10.0%). The majority of solicited local reactions among vaccine recipients were mild or moderate in severity, with any grade 3 or 4 reactions being reported by ≤9.5% of participants. No Grade 4 AEs were reported. Local reactions were generally milder and reported less frequently after the second dose of the vaccine. By dose interval, the reactogenicity of the vaccine was lower in participants who received the second dose within 6 weeks following Dose 1 (38.0% versus 58.3% to 74.3% when Dose 2 was provided after ≥6 weeks).

Solicited systemic reactions

Solicited systemic AEs were reported by 73.0% of evaluated participants within the first 7 days following any vaccine dose. The most common systemic solicited systemic AEs were fatigue (53.1%) and headache (52.6%). Other frequently reported systemic solicited AEs were muscle pain (44.0%), malaise (44.2%), feverishness (33.6%), chills (31.9%), joint pain (26.4%), nausea (21.9%) and fever ≥38.0°C (7.9%). Overall, the frequency of any grade 3 or 4 reaction was ≤8.3%. The single reported Grade 4 event was fever > 40°C. Across study groups, AEs were milder and reported less frequently after the second vaccine dose. By dose interval, the reactogenicity of the vaccine was lower in participants who received the second dose at <6 weeks following Dose 1 (37.6% versus. 49.2% to 67.1% when Dose 2 was provided after at ≥6 weeks).

Unsolicited serious adverse events

SAE were reported by less than 1% of study participants and was similar between the vaccine and control groups (0.7% and 0.8%, respectively). There were no clear imbalances by System Organ Class (SOC). The most frequently reported SAEs by SOC were 'Infections and Infestations' (0.1% vs 0.2%) and 'Injury, poisoning and procedural complications' (<0.1% vs 0.1%).

Two SAEs (pyrexia, transverse myelitis) in the vaccine recipients were considered related to the vaccine by the study investigators. The case of pyrexia (40.5°) occurred 2 days after dose 1 and resolved the same day following the administration of acetaminophen. The event of transverse myelitis occurred in a 37-year-old female with a family history of Charcot-Marie-Tooth type 1a (mother and brother). The participant received two doses of study intervention 77 days apart. Two weeks after the second dose, the participant developed sensory changes and clumsiness. Magnetic resonance imaging showed a lesion consistent with transverse myelitis or anterior spinal infarction. A third SAE was originally identified (C-reactive protein increase); However, after the cut-off date, causality for the SAE of C-reactive protein increase was updated by the investigator to be not treatment related.

Other serious adverse events

Demyelinating events

An event of multiple sclerosis occurred in a 37-year-old female who developed sensory symptoms about 10 days after first (and only) vaccination. The clinical episode had a duration of 3 weeks. Further follow up with MRI of spine and brain showed an acute spinal lesion and older cerebral lesions, revealing pre-existing, but previously unrecognized, multiple sclerosis.

Death

A total of 6 deaths were reported among study participants (2 in the vaccine group and 4 in the control group). The cause of death among vaccine recipients included malignant neoplasm and fungal pneumonia, with neither considered to be related to the study intervention by the investigators.

Effectiveness in individuals ≥65 years of age 

In the absence of sufficient data from clinical trials to date on the efficacy of the AstraZeneca COVID-19 vaccine in those 65 years of age and older, a review of three observational studies in the UK published as pre-prints on real-world vaccine effectiveness in this age group has been conducted to inform NACI’s recommendations in this age group. The findings of this review are summarized below. 

All three observational studies assessed one dose of either the Pfizer-BioNTech or the AstraZeneca vaccines in the United Kingdom. The results below pertain only to the AstraZeneca portion of the studies. The studies were conducted during the period when SARS-CoV-2 B.1.1.7 variant was rapidly becoming the dominant circulating strain in their respective geographic regions. Approximately 50% of laboratory samples were found to have a profile consistent with the B.1.1.7 variant in early December, 2020 in England, and 43% in Scotland in early January, 2021. By mid to late February, the SARS-CoV-2 B.1.1.7 variant represented almost 100% of circulating strains in England, and was considered the dominant strain in Scotland.

Overall summary of evidence:

In adults 65 years of age and over, observational data available from pre-prints from the United Kingdom have shown a reduction in the risk of symptomatic disease and hospitalization starting from two weeks following one dose of AstraZeneca vaccine that appears to be comparable to those observed in the pivotal Phase 2/3 clinical trials among adults less than 65 years of age.

Detailed summary of each study:

  1. Hyams et al., Assessing the Effectiveness of BNT162b2 and ChAdOx1nCoV-19 COVID-19 Vaccination in Prevention of Hospitalisations in Elderly and Frail Adults: A Single Centre Test Negative Case-Control Study. SSRN-Lancet preprint. March 3, 2021.

    https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3796835

Description: Test-negative case control study of hospitalized people ≥80 years of age (many of whom were frail with comorbidities) in two hospitals in Bristol, United Kingdom. Vaccination was determined by record linkage and adjustment was conducted for a number of factors. Vaccine effectiveness against hospitalization was assessed in those who had been vaccinated ≥14 days before symptom onset.

Results: One-dose vaccine effectiveness of 80.4% (95% CI: 36.4 – 94.5) against hospitalization occurring within 14 or more days (maximum 53 days) after one dose of AstraZeneca COVID-19 vaccine among patients ≥80 years of age.

Review:

The authors performed a sensitivity analysis of those with symptom onset < 14 days after vaccination and did not find an effect, which is expected as this is too early for the vaccine to work, and adds strength to differences they note 14 days or more after vaccination.

  1. Lopez Bernal et al., Early effectiveness of COVID-19 vaccination with BNT162b2 mRNA vaccine and ChAdOx1 adenovirus vector vaccine on symptomatic disease, hospitalisations and mortality in older adults in England. medRxiv. Preprint March 2, 2021.

    https://www.medrxiv.org/content/10.1101/2021.03.01.21252652v1

Description: Test negative-case control study using linked surveillance data in the United Kingdom among patients ≥70 years of age. PCR tests were within 10 days of onset of symptoms. For those who were vaccinated, cases and controls were assessed by time since vaccination to onset of symptoms, controlling for a number of factors. The impact of vaccination on hospitalization in individuals ≥80 years of age was also assessed in those who tested positive

Results: One-dose vaccine effectiveness against symptomatic PCR confirmed SARS-CoV-2 infection in the adjusted analysis was 22% (95% CI: 11 – 32) 14 to 20 days after vaccination and gradually rose up to 73% (95% CI: 27 – 90) 35 or more days (maximum 48 days) after vaccination. As well as the effect against symptomatic disease, in individuals who were ≥80 years of age there was an additional 37% protection against hospitalization within 14 days of a positive test in those 14 or more days from their first dose of vaccine compared to those who were unvaccinated.

Review:

  1. Vasileiou et al. Effectiveness of first dose COVID-19 vaccines against hospital admissions in Scotland effectiveness findings from Scotland: national prospective cohort study of 5.4 million people. SSRN-Lancet preprint. February 19, 2021.

    https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3789264

Description: A prospective observational cohort study using record linkage between databases, including vaccination, hospitalization and laboratory records for the population in Scotland, with adjustment for a number of factors. Although the study included those ≥18 years of age, the AstraZeneca vaccine was mostly administered to participants aged 65 years and older. Age-specific vaccine effectiveness is provided but did not distinguish between the Pfizer-BioNTech and AstraZeneca vaccines, which were both studied, although those ≥80 years of age mainly received the AstraZeneca vaccine.

Results: The effectiveness of one dose of the AstraZeneca vaccine against hospitalization was 74% (95% CI: 66 – 81) 14 to 20 days after vaccination and rose up to 94% (95% CI: 73 – 99) 28 to 34 days after vaccination. In patients ≥80 years of age, the authors found a peak vaccine effectiveness (VE) of 81% (95% CI: 65 – 90) against hospitalization within 28 to 34 days after one dose of vaccine that was mainly the AstraZeneca vaccine.

Review:

Due to concerns with methodological weaknesses in this study, NACI did not use these results to inform its recommendations. Methodological weaknesses include:

Appendix D: Frequency of solicited adverse eventsFootnote a following immunization for COVID-19 vaccines

Table 13: Frequency of solicited local adverse eventsFootnote a

AEFI
Pfizer-BioNTech COVID-19 Vaccine Moderna COVID-19 Vaccine AstraZeneca COVID-19 Vaccine
Vaccine Placebo control Vaccine Placebo control Vaccine Placebo control
Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2
Pain at injection site Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common
Tenderness NS NS NS NS NS NS NS NS Very Common Very Common Very Common Very Common
Redness Common Common Common Rare Common Common Uncommon Uncommon Common Common Common Uncommon
Swelling Common Common Rare Rare Common Very Common Uncommon Uncommon Common Common Common Common
LymphadenopathyFootnote b/ Axillary swelling and tenderness NS NS NS NS Very Common Very Common Common Common NS NS NS NS
Warmth NS NS NS NS NS NS NS NS Very Common Very Common Very Common Very Common
Pruritis NS NS NS NS NS NS NS NS Common Common Common Common
Induration NS NS NS NS NS NS NS NS Common Uncommon Common Common

Footnotes

Footnote a

Very common = occur in 10% or more of vaccine recipients, common = occur in 1 to less than 10% of vaccine recipients, uncommon= occur in 0.1% to less than 1% of vaccine recipients

Return to footnote a referrer

Footnote b

Lymphadenopathy was not a solicited adverse event for the Pfizer BioNTech COVID-19 vaccine or AstraZeneca COVID-19 vaccine and was reported as an unsolicited adverse event. Please see Appendix A and C for more details.

Return to footnote b referrer

Abbreviations:

  • AEFI: adverse event following immunization
  • MenACWY: Quadrivalent meningococcal vaccine
  • NS: not solicited
Table 14: Frequency of solicited systemic adverse eventsFootnote a
AEFI Pfizer-BioNTech COVID-19 Vaccine Moderna COVID-19 Vaccine AstraZeneca COVID-19 Vaccine
Vaccine Placebo control Vaccine Placebo control Vaccine Placebo control
Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2
Fatigue Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common
Headache Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common
Muscle Pain Very Common Very Common Common Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common Very Common
Chills Very Common Very Common Common Common Common Very Common Common Common Very Common Common Common Common
Joint Pain Common Very Common Common Common Very Common Very Common Very Common Very Common Very Common Very Common Common Common
FeverFootnote b Common Very Common Uncommon Uncommon Uncommon Very Common Uncommon Uncommon Very Common Uncommon Uncommon Uncommon
FeverishnessFootnote b NS NS NS NS NS NS NS NS Very Common Very Common Common Common
Diarrhea Common Common Common Common NS NS NS NS NS NS NS NS
Nausea and/or VomitingFootnote c Uncommon Common Uncommon Uncommon Common Very Common Common Common Very Common/
Common
 Common/
Uncommon
Very Common/
Uncommon
Very Common/
Uncommon

Footnotes

Footnote a

Very common = occur in 10% or more of vaccine recipients, common = occur in 1 to less than 10% of vaccine recipients, uncommon= occur in 0.1% to less than 1% of vaccine recipients

Return to footnote a referrer

Footnote b

Fever was objectively reported as having a temperature ≥38°C/100.4°F. Feverishness was a subjective, self-reported feeling of having fever.

Return to footnote b referrer

Footnote c

If two frequencies are reported the first reflects frequency of nausea and the second reflects the frequency of vomiting.

Return to footnote c referrer

Abbreviations:

  • AEFI: adverse event following immunization
  • MenACWY: Quadrivalent meningococcal vaccine
  • NS: not solicited

References

Footnote 1

National Advisory Committee on Immunization (NACI). Guidance on the prioritization of key populations for COVID-19 immunization February 2021. Available at: https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-prioritization-key-populations-covid-19-vaccination.html

Return to footnote 1 referrer

Footnote 2

Ismail SJ, Langley JM, Harris TM, et al. Canada's National Advisory Committee on Immunization (NACI): Evidence-based decision-making on vaccines and immunization. Vaccine. 2010;28:A58-63. doi:10.1016/j.vaccine.2010.02.035.

Return to footnote 2 referrer

Footnote 3

Ismail SJ, Hardy K, Tunis MC, et al. A framework for the systematic consideration of ethics, equity, feasibility, and acceptability in vaccine program recommendations. Vaccine. 2020;38:5861-76. doi:10.1016/j.vaccine.2020.05.051.

Return to footnote 3 referrer

Footnote 4

Ismail SJ, Tunis MC, Zhao L, et al. Navigating inequities: a roadmap out of the pandemic. BMJ Glob Health. 2021 Jan;6(1):e004087. doi: 10.1136/bmjgh-2020-004087.

Return to footnote 4 referrer

Footnote 5

Wingert A, Pillay J, Gates M, et al. Risk factors for severe outcomes of COVID-19: a rapid review. medRxiv. 2020. doi:10.1101/2020.08.27.201834344.

Return to footnote 5 referrer

Footnote 6

Ramasamy MN, Minassian AM, Ewer KJ, et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet. 2021;396:1979-93. doi:S0140-6736(20)32466-1.

Return to footnote 6 referrer

Footnote 7

Corrin T. Evergreen rapid review on COVID-19 vaccine knowledge, attitudes, and behaviors - Update 1. Ottawa (ON): Public Health Agency of Canada; 2020. [Unpublished]

Return to footnote 7 referrer

Footnote 8

COVID-19 Snapshot Monitoring (COSMO Canada). (2020, December; Wave 10). Available at: https://impact.canada.ca/en/challenges/cosmo-canada

Return to footnote 8 referrer

Footnote 9

Immunization Promotion and Partnerships Unit. COVID-19 vaccine resource and training needs survey for health care providers. Ottawa (ON): Public Health Agency of Canada; 2020. [Unpublished].

Return to footnote 9 referrer

Footnote 10

Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383:2603-15. doi:10.1056/NEJMoa2034577.

Return to footnote 10 referrer

Footnote 11

United States Food and Drug Administration. Development and licensure of vaccines to prevent COVID-19: Guidance for industry. 2020 June. Available at: https://www.fda.gov/media/139638/download

Return to footnote 11 referrer

Footnote 12

Moderna. A phase 3, randomized, stratified, observer-blind, placebo-controlled study to evaluate the efficacy, safety, and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine in adults aged 18 years and older. 2020. Available at: https://www.modernatx.com/sites/default/files/mRNA-1273-P301-Protocol.pdf

Return to footnote 12 referrer

Footnote 13

Moderna. Vaccines and Related Biological Products Advisory Committee Meeting December 17, 2020. FDA Briefing Document. Moderna COVID-19 Vaccine. Available at: https://www.fda.gov/media/144434/download 2020.

Return to footnote 13 referrer

Footnote 14

Voysey M, Clemens SAC, Madhi SA, et al. 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;397:99-111 doi:S0140-6736(20)32661-1.

Return to footnote 14 referrer

Footnote 15

Zhu FC, Guan XH, Li YH, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020;396:479-88 doi:S0140-6736(20)31605-6.

Return to footnote 15 referrer

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