Archived 2: Recommendations on the use of COVID-19 vaccines [2020-12-23]

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This is an archived version.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: December 23, 2020

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 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

Vaccine(s)

All sub-sections under Vaccines have been updated to include evidence or information from the product monograph related to the Moderna COVID-19 vaccine. This includes:

  • Table 1. COVID-19 vaccine(s) authorized for use in Canada
  • Dose, Route of administration, and Schedule
  • Efficacy and Immunogenicity
  • Storage requirements
  • Vaccine safety and adverse events following immunization

2020-12-23

Interchangeability

Additional information on the interchangeability of mRNA vaccines and guidance in case of limited supply or unavailability of a particular product has been incorporated under the NACI recommendation on interchangeability.

2020-12-23

Dose, route of administration, and schedule

Additional clarifying information on the schedule for a complete mRNA COVID-19 vaccine series has been added.

2020-12-23

Recommendations

Recommendations on COVID-19 vaccine now include use of the Moderna COVID-19 vaccine, and the rationales have been updated with evidence from Moderna COVID-19 vaccine clinical trials

2020-12-23

Recommendations

The recommendations for immunosuppressed individuals and those with autoimmune conditions have been split into two separate recommendations and further rationale for the recommendations has been provided.

2020-12-23

Recommendations

Additional information has been added to the rationale for the recommendation on pregnancy and breastfeeding and now recommends that it would be prudent to delay pregnancy by at least 28 days after the completion of a two-dose series of mRNA COVID-19 vaccines.

2020-12-23

Appendix B

Evidence on the efficacy, immunogenicity, and safety of the Moderna COVID-19 vaccine has been added in a new appendix

2020-12-23

Appendix C

Application of the EEFA Framework: Ethical analysis of the options for the delivery of a second dose of COVID-19 vaccine in the context of a limited vaccine supply has been added in a new appendix

2020-12-23

Appendix D

Frequency of Solicited Adverse Events Following Immunization for COVID-19 vaccine has been added in a new appendix

2020-12-23

Contraindications and Precautions

Reinforced existing recommendation that the authorized COVID-19 vaccines are contraindicated in individuals with a history of anaphylaxis after previous administration of the vaccine and included a new table with vaccine components that are potential allergens known to cause type 1 hypersensitivity reactions

  • New Table 3. Potential allergens known to cause type 1 hypersensitivity reactions

2020-12-12

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 and is disseminating this document 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 vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) 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 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:

COVID-19 vaccine should not be offered routinely to the following populations excluded from clinical trials until further evidence is available. However, if a risk assessment deems that the benefits of vaccine outweigh the potential risks for the individual (e.g. where the risk of severe outcomes of COVID-19 and 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 this population, then a complete series of authorized COVID-19 vaccine may be offered to individuals in the following populations:

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 vaccine(s) 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. Recommendations on the use of COVID-19 Vaccine, published on December 12, 2020 with evidence available to date, including information on the Pfizer-BioNTech COVID-19 vaccine authorized on December 9, 2020. This advisory committee statement updates that recent guidance with new evidence available and the authorization of the Moderna COVID-19 vaccine on December 23, 2020.

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 1Footnote 2

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

  1. Knowledge synthesis
  2. Synthesis of the body of evidence of benefits and harms, considering the quality of the synthesized evidence and magnitude and certainty of effects observed across the studies
  3. Translation of evidence into recommendations

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 2. 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 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 an emergency NACI meeting. 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 3 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 vaccine(s).

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.

Vaccine(s)

The following section summarizes information about COVID-19 vaccines authorized for use in Canada. More detailed vaccine-specific information is included in the appendices. 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.

Preparation(s) of COVID-19 vaccines authorized for use in Canada

Table 1: COVID-19 vaccine(s) authorized for use in Canada
Product Brand Name (Manufacturer) Pfizer-BioNTech COVID-19 Vaccine
(Pfizer-BioNTech)
Moderna COVID-19 Vaccine (Moderna)
Type of vaccine COVID-19 mRNA COVID-19 mRNA
Date of authorization in Canada December 9, 2020 December 23, 2020
Authorized ages for use 16 years of age and older 18 years of age and older
Dose 0.3 mL (30 mcg of mRNA )Footnote 1  0.5 mL (100 mcg of mRNA)
ScheduleFootnote 2 2 Doses, 21 days apart (alternate schedule 28 days apart) 2 Doses, 28 days apart
Route of administration IM IM
Nature of the antigen Prefusion spike protein Prefusion spike protein
Adjuvant (if present) None None
Primary storage requirements pre-puncture -80°C to -60°CFootnote 3 -25°C to -15°CFootnote 3Footnote 4
Storage requirements
pre-punctureFootnote 3
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
Diluent Yes No
Usage limit post-puncture 6 hours at +2°C to +25°CFootnote 5 6 hours at +2°C to +25°C
Formats available Multi-dose vial (5 doses)Footnote 1, preservative-free Multi-dose vial (10 doses), preservative-free

Footnotes

Footnote 1

After dilution. Refer to the product monograph available through Health Canada's Drug Product Database for choice of diluent and dilution

Return to footnote 1 referrer

Footnote 2

Authorized or alternate schedule. Refer to Table 2 for details

Return to footnote 2 referrer

Footnote 3

Protected from light during storage

Return to footnote 3 referrer

Footnote 4

Do not store on dry ice or below -40ºC

Return to footnote 4 referrer

Footnote 5

After dilution, vaccine must be used within 6 hours

Return to footnote 5 referrer

Abbreviations:

  • 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) 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) and Appendix B (for the Moderna 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. These authorized 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.

The clinical trial data demonstrates that the authorized 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. 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 mRNA COVID-19 vaccines, however trials are ongoing and this Statement will be updated as evidence emerges.

Efficacy against severe disease

There are no data yet to be able to assess the efficacy of the authorized mRNA COVID-19 vaccines against hospitalizations or deaths specifically.

The authorized COVID-19 vaccines appear to be efficacious 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 death). However, the follow-up time for this outcome was short in trials of both mRNA vaccines and the number of severe cases that have been observed to date in one of the vaccine trials (Pfizer-BioNTech COVID-19 vaccine) is small.

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 and studies are ongoing.

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, medium (longer than 3 months) and 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) 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) and Appendix B (for the Moderna COVID-19 vaccine).

Humoral immune responses

The peak humoral immune response to both authorized mRNA COVID-19 vaccines occurred one to two weeks after administration of the second dose, based on a small number of participants. The antibody response decreased from peak levels, but was detectable after the full series for the latest date of follow-up; four weeks (Pfizer-BioNTech COVID-19 vaccine) to 3 months (Moderna COVID-19 vaccine). Evidence beyond these time intervals, after completion for these vaccines, is not available at this time. The immune response (neutralizing antibodies) elicited by one dose accounted for a portion of the maximum response seen after the second dose, with evidence of boosting after the second dose. In general, immune responses in older adults were equivalent or lower than immune responses in younger adults.

Cellular immune responses

The authorized mRNA COVID-19 vaccines have been shown to produce a cellular immune response by one to two weeks after administration of the second dose. Increases in this response were seen in both younger and older adults. Refer to Appendix A and Appendix B 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.

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.

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 Alternate interval
Pfizer-BioNTech COVID-19
(Pfizer-BioNTech)
2-dose schedule 19 days 21 days 28 days
Moderna COVID-19
(Moderna)
2-dose schedule 21 days 28 days None

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

The authorized COVID-19 vaccines are efficacious against symptomatic laboratory-confirmed COVID-19 disease when provided as a two-dose schedule. The majority of participants in the Pfizer-BioNTech COVID-19 vaccine clinical trial received the second dose 21 to 27 days apart. The per-protocol design was 19 to 23 days. 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 Moderna COVID-19 vaccine clinical trial received the second dose 21 to 42 days after the first, as per the pre-defined window. A harmonized approach to the scheduling of COVID-19 vaccines 28 days apart could prevent erroneous administration of other vaccine doses at less than the recommended minimal interval.

Delay in receipt of dose 2 in a COVID-19 vaccine series

If administration of the second dose of a COVID-19 vaccine is delayed, the second dose should be provided as soon as possible. Currently, no data on a maximum interval between doses or on medium- or long-term efficacy of COVID-19 vaccines are available and peak humoral response occurs after second dose.

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 products. However, the follow-up time in COVID-19 vaccine clinical trials is short and maximum protection may not be attained until the complete vaccine series has been administered. Therefore, every effort should be made to vaccinate with the second dose according to the recommended schedule.

Data for both authorized products suggest vaccine efficacy begins between the first and second dose (i.e., after the first dose). Data from the Pfizer-BioNTech clinical trial suggests a vaccine efficacy of 52% (95% confidence interval [CI], 29.5 to 68.4) between the first and second dose, indicating early protection by the vaccine; this efficacy is likely underestimated as cases occurring immediately after dose one were included. Evidence from the Moderna clinical trial also suggests there is protection after one dose, with a vaccine efficacy of 80.2% (95% CI 55.2 to 92.5) before the second dose is administered. Efficacy starting as soon as 12 or 14 days after the first dose was reported. There are no data available on the medium- or long-term duration of protection offered by one dose of the vaccineFootnote 8. Humoral responses for both mRNA COVID-19 vaccines peak after a second dose, and then decline by week 4 or 3 months (end of assessment period).

If, due to logistical constraints, jurisdictions cannot complete the two-dose COVID-19 vaccine series as close as possible to the authorized or alternative schedules outlined in Table 2, they may refer to Appendix C for a summary of considerations and options on ethics, equity, feasibility and acceptability summarized in NACI's Core Ethical Dimensions Filter of the EEFA FrameworkFootnote 2 and the accompanying ethics analysis.

Active 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 vaccination 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.

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 confirmation, though other vaccine components like the lipid nanoparticle and the mRNA sequence may be different.

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). 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. Active surveillance of effectiveness and safety of this mixed schedule will be important in these individuals. 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.

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 packaged with the vaccine for instructions regarding the use of the manufacturer's original thermal container for temporary storage.

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.

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 the administration of the complete two-dose vaccine series of an mRNA 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. However, studies are ongoing.

The following section highlights key safety and AEFI data for the authorized mRNA COVID-19 vaccines. For additional details regarding trial design, including study population and length of follow-up, and safety for the mRNA COVID-19 vaccines, refer to the evidence summaries in Appendix A (for the Pfizer-BioNTech COVID-19 vaccine) and Appendix B (for the Moderna 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 vaccinees; very common adverse events occur in 10% or more of vaccinees. Please see Appendix D for a summary of adverse events identified in clinical trials of authorized mRNA COVID-19 vaccines.

mRNA COVID-19 vaccine
Local

Pain at the injection site is very common after administration of the currently authorized COVID-19 vaccine. More than 80% 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. Pain at the injection site was slightly more frequent in younger adults compared to older adults.

Systemic

Fatigue, headache, muscle pain, chills, and joint pain are all either common or very common after the administration of the currently authorized mRNA COVID-19 vaccines. Fever was very common after administration of the second dose of the currently authorized mRNA COVID-19 vaccines. More than a quarter of vaccine recipients after any dose experienced headache, and/or fatigue. 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.

Uncommon, rare, and very rare adverse events

Uncommon adverse events occur in 0.1% to less than 1% of vaccinees. Rare and very rare adverse events occur in 0.01% to less than 0.1% and less than 0.01% of vaccines, 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 but was uncommonly reported after administration of the Pfizer-BioNTech COVID-19 vaccine.

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

Contraindications

The authorized COVID-19 vaccine is contraindicated in individuals with a history of anaphylaxis after previous administration of the vaccine. Vaccine is also contraindicated in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its packaging. 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. Individuals with a history of severe allergic reaction to a component of the COVID-19 vaccine should not receive the COVID-19 vaccine.

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.

Potential non-medicinal ingredients in the vaccines known to cause type 1 hypersensitivity reactions ranging from mild cutaneous reactions to anaphylaxis are summarized in Table 3.

Table 3: Potential allergens known to cause type 1 hypersensitivity reactions
Vaccine product (manufacturer) Potential allergen included in the vaccine or its containerFootnote 1 Other products where the allergen may be foundFootnote 1
Pfizer-BioNTech COVID-19
(Pfizer-BioNTech)
polyethylene glycol (PEG) Bowel preparation products for colonoscopy, laxatives, cough syrup, cosmetics, contact lens care solutions, skin care products, and as an additive in some food and drinks
Moderna COVID-19
(Moderna)
polyethylene glycol (PEG) Bowel preparation products for colonoscopy, laxatives, cough syrup, cosmetics, contact lens care solutions, skin care products, and as an additive in some food and drinks

Footnotes

Footnote 1

N.B. This may not be a complete list.

Return to footnote 1 referrer

In situations of suspected hypersensitivity or non-anaphylactic allergy to COVID-19 vaccine components, investigation is indicated which may lead to vaccination in a controlled setting. Consultation with an allergist is advised. Most instances of anaphylaxis to a vaccine begin within 30 minutes after administration of vaccine. Therefore, if there is a specific concern about a possible allergy to a component of the COVID-19 vaccine being administered, an extended period of observation post-vaccination of 30 minutes may be warranted. Recommendations for the post-vaccination observation period for other vaccines during the pandemic, such as for influenza vaccine, should continue to be followed.

Refer to Anaphylaxis and Other Acute Reactions Following Vaccination in the CIG, Part 2 - Vaccine Safety for additional information on the management of anaphylaxis post-vaccination in a community setting.

Precautions

In individuals with bleeding disorders, the condition should be optimally 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 infection with SARS-CoV-2 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.

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 2 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 4 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 in Canada (Pfizer-BioNTech COVID-19 vaccine; Moderna 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).

1. NACI recommends that a complete vaccine series with a COVID-19 vaccine 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 COVID-19 vaccine should be prioritized for the key populations outlined in NACI's Guidance on the Prioritization of Initial Doses of COVID-19 Vaccine(s). (Strong NACI Recommendation)

Summary of evidence and rationale:

2. 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:

3. 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. These recommendations may change as more evidence becomes available.

Immunosuppressed persons

4. NACI recommends that COVID-19 vaccine should not be routinely offered to individuals who are immunosuppressed due to disease or treatment until further evidence is available (Strong NACI Recommendation). However, a complete series with a COVID-19 vaccine may be offered to individuals 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 vaccine in this population. (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

5. NACI recommends that COVID-19 vaccine should not be routinely offered to individuals with an autoimmune condition until further evidence is available (Strong NACI Recommendation). However, a complete series with a COVID-19 vaccine may be offered to individuals 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 vaccine 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 disorders and chronic inflammatory diseases.

Pregnancy and breastfeeding

6. NACI recommends that COVID-19 vaccine should not be routinely offered to individuals who are pregnant until after completion of pregnancy, until further evidence is available (Strong NACI Recommendation). However, a complete 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 vaccine in this population. (Discretionary NACI Recommendation)

7. NACI recommends that COVID-19 vaccine should not be routinely offered to individuals who are breastfeeding, until further evidence is available (Strong NACI Recommendation). However, a complete 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 vaccine 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

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

8a. However, a complete 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) and 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:

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 and medium and long-term duration of protection of a complete series of COVID-19 vaccine?
  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, 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. 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?
    2. 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. Is SARS-CoV-2 natural infection (symptomatic or asymptomatic) associated with protection against re-infection or severe disease? How are immune responses induced by natural infection similar or different from those induced by vaccines against COVID-19?
  5. 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?
    2. Which immune responses are most important for protection from infection (adaptive or innate immunity), severe disease or transmissibility?
    3. Are immunoglobulin (Ig)A/IgG/IgM antibodies protective against SARS-CoV-2 and what is the correlate of protection?
    4. Is there a cell-mediated immunity correlate of protection against SARS-CoV-2?
  6. What level of COVID-19 vaccination coverage is required to achieve herd immunity and is herd immunity achievable given the available vaccine(s)' characteristics?
  7. What is the efficacy, effectiveness, and immunogenicity of a single dose of COVID-19 vaccine(s) authorized as a two-dose series? How long is the duration of protection for an incomplete series?
  8. What is the background level of Canadian vaccine-vector-specific responses? Are these responses higher in some groups? Will these responses interfere with vaccine efficacy of these highly seropositive groups?
  9. Are any components of the COVID-19 vaccine at high risk of inducing an anaphylactic reaction?
  10. What is the incidence of rare, serious adverse events following immunization with COVID-19 vaccines?
  11. 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?
  12. 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?

Vaccine administration

  1. Are COVID-19 vaccines of similar or different platforms interchangeable?
  2. What are the minimum and maximum 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 vaccine(s) 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 vaccine(s) 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 4: 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
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
mRNA
messenger ribonucleic acid
NACI
National Advisory Committee on Immunization
PCR
Polymerase chain reaction
PHAC
Public Health Agency of Canada
SAE
Serious adverse events
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
WHO
World Health Organization

Acknowledgments

This statement was prepared by: Dr. SJ Ismail, Ms. K Young, Dr. MC Tunis, Dr. A Killikelly, Dr. R. Stirling, Dr. O Baclic, Dr. M. Salvadori, Dr. N Forbes, Ms. L Coward, Dr. R Krishnan, Ms. Y-E Chung, Ms. A Sinilaite, Ms. MW Yeung, Dr. S Deeks, and Dr. 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: Ms. S. Pierre, Mrs. C. Jensen, Ms. A Sinilaite, Ms. L Whitmore, Mr. J Shurgold, Ms. J Vachon, Ms. J Macri, Ms. J Mielczarek, Ms. M Matthieu-Higgins, Ms. V Ferrante, Ms. R Goddard, Mr. B Sader, Dr B Warshawsky, Mr. M Patel, Ms. A House, Ms. E Wong, and Dr. AA Nam, and the PHAC Public Health Ethics Consultative Group

NACI

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

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

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

NACI High Consequence Infectious Disease Working Group

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

PHAC Participants: Dr. N Abraham, Ms. P Doyon-Plourde, Ms. V Ferrante, Dr. N Forbes, Dr. SJ Ismail, Dr. A Killikelly, Ms. M Matthieu-Higgins, Dr. A Nam, Mr. M Patel, Ms. A Sinilaite, Dr. MC Tunis, Ms. MW Yeung, Ms. K Young, and Dr. 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 8.

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 7.

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 7 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=21,314) compared to 82 in the placebo group (n=21,258) for an overall estimated vaccine efficacy of 52.4% (95% CI: 29.5 to 68.4%). Overall, 98.2% of participants who were randomized completed the two-dose series. Vaccine efficacy was not assessed in individuals who only received one dose.

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 (SAEs)

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 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 9.

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 9 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%) in participants who were not considered at risk. However, most participants did receive a second dose, therefore there are limited data on the efficacy of Dose 1 alone beyond 28 days post-vaccination.

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 on day 119 were 30-20% of maximal responses reached on day 43 for those age groups below 70. Whereas antibody responses on day 119 were 3% of maximal immune responses reached on day 43 for those age groups above 70 years.

Neutralizing antibodies weren't induced to the level of convalescent sera until day 36, 7 days after dose 7 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 12. 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 12. 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 12.

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 12. 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 12. 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: Application of the EEFA framework – Ethical analysis of options for the delivery of a second dose of COVId-19 vaccine in the context of a limited vaccine supply

The purpose of the EEFA (Ethics, Equity Feasibility, Acceptability) FrameworkFootnote 2 is to provide evidence-informed tools for the systematic consideration of programmatic factors in order to develop clear, comprehensive recommendations for timely, transparent decision-making. The application of the Core Ethical Dimensions Filter, an evidence-informed tool that is part of the EEFA Framework, ensures that guidance upholds and integrates core ethical dimensions for public health (respect for persons and communities, beneficence and non-maleficence, justice, and trust). This Filter incorporates the other evidence-informed tools of the EEFA Framework to assess equity, feasibility and acceptability considerations. As part of the Core Ethical Dimensions Filter, if a major risk is identified, an in-depth scenario-based ethics analysis is conducted using the following steps:

  1. Identify issue and context
  2. Identify ethical considerations
  3. Identify and assess options
  4. Select best course of action and implement
  5. Evaluate

In the context of a limited initial supply of COVID-19 vaccines, the National Advisory Committee on Immunization (NACI) has identified a risk to adherence of the recommendation to offer a complete two-dose series with an authorized COVID-19 vaccine product according to the schedule summarized in Table 2 of this advisory committee statement. As such, the NACI Secretariat has conducted the first three steps of the ethics analysis described above, incorporating the results of a consultation with the Public Health Ethics Consultative Group (PHECG) on December 15, 2020. If, due to logistical constraints, jurisdictions cannot vaccinate individuals with two doses of an authorized COVID-19 vaccine product as close as possible to the authorized or alternate schedules outlined in Table 2, they may refer to this ethics analysis to assess their options, select the best course of action to implement, and evaluate.

Scenario-based ethics analysis

Step 1: Identify issue and context

The NACI recommends that a complete vaccine series with an authorized COVID-19 vaccine should be offered to individuals in the authorized age group without contraindications to the vaccine. (Strong NACI Recommendation). NACI further recommends that the vaccine series should be completed with the same COVID-19 vaccine product. The two vaccine doses should be administered according to the authorized or alternate intervals, as outlined in Table 2 of the NACI Advisory Committee Statement. The rationale and evidence for these recommendations are summarized in the guidance document. Though the evidence continues to evolve, the balance of evidence at this time supports NACI's recommendations. NACI will continue to monitor the evidence and update recommendations as needed.

Issue: In the context of limited initial vaccine supply and uncertain subsequent vaccine supply, should provinces and territories immediately distribute all doses of COVID-19 vaccines without reserving half of the initial doses (to ensure completion of the two-dose vaccine series in accordance with the recommended interval in initial vaccine recipients) in order to vaccinate a greater number of people in a shorter timeframe with the first dose?

Step 2: Identify the ethical considerations (using the Core Ethical Dimensions Filter of the EEFA FrameworkFootnote 2)
Core Ethical Dimension for Public Health
(and Description)
Considerations

Respect for persons and communities

(Right to exercise informed choice based on all available evidence)

  • Individual autonomy, choice and perspectives of unique and diverse populations need to be respected. Keeping doses in reserve to ensure completion of a vaccine series enhances autonomy and respect for persons and communities.
  • The public also expects that public health authorities will fulfill their responsibility to determine which course of action is in the best interest of the public when making recommendations. There is an obligation to be truthful and honest with those impacted.
  • If schedule deviations are intentionally anticipated, there should be a clear and strong rationale available to the affected population.
  • NACI's guidance is transparent about what is known and unknown regarding COVID-19 vaccines. This is included in the rationale for its recommendations to offer a complete two-dose vaccine series.
  • Informed consent of those receiving vaccine will be vital.
    • If half the initial doses are kept on reserve so that all initial vaccine recipients can receive both doses in accordance with the recommended interval, individuals can make a comparatively better informed choice than would be the case if no doses were kept in reserve.
      • Evidence on the safety and efficacy available from clinical trials could be provided with assurance if a second dose would be provided on schedule.
      • It is likely that the preference of individuals wishing to be vaccinated would be to complete the vaccine series within the recommended interval for optimal protection.
    • If all doses are immediately distributed without reserving doses to complete the vaccine series in accordance with the recommended interval, then the ability to make an informed choice will be limited to deciding whether to accept one dose of the vaccine in the face of considerable uncertainty about:
      • the timing of a second shipment of the authorized vaccine; and
      • safety and efficacy:
        1. the duration and comparative protection offered by one vs two doses of the authorized vaccine,
        2. the effectiveness of two doses that are given at a longer interval than the recommended interval,
        3. the safety and effectiveness of a mixed schedule with different vaccine products

In such circumstances, it is uncertain whether individuals offered the vaccine with no guarantee of on time second dose will have the ability to make a meaningfully informed choice.

Beneficence and non-maleficence

(Promotion of well-being, minimize risk of harm vs benefits)

  • If half the initial doses are kept on reserve so that all initial vaccine recipients can receive both doses in accordance with the recommended interval, this will maximize benefit and minimize risks for those vaccinated in high-risk key populationsFootnote 10Footnote 11 that have been identified to receive initial doses of COVID-19 vaccine by NACI.
  • If all doses are immediately distributed without reserving doses to complete the vaccine series in accordance with the recommended interval, there may be at least a short-term benefit to a greater number of individuals identified as high risk key populationsFootnote 10Footnote 11 with a broader distribution of the vaccine. This will promote the health of the population and minimize the overall burden of disease as much as possible immediately, in the face of significant morbidity and mortality. The timing of administration of this first dose will likely be more impactful if administered at a time when transmission of SARS-CoV-2 is highest. However, there is a possible risk of harm in the longer term if subsequent vaccine supply does not arrive as planned with limited evidence on the efficacy of one dose compared to two doses, no evidence on interchangeability, and the potential for a wasted precious resource if one dose is found not to offer sufficient protection. Other risks of harm include:
    • Risk of increased vaccine hesitancy for COVID-19 vaccines and vaccines in general
      • Decreased acceptability for vaccine if vaccinated individuals get disease
      • Decreased trust in public health officials making recommendations
      • Decreased compliance to complete other vaccine series in accordance with recommended intervals
    • Risk of behaviours associated with a false sense of security in individuals vaccinated with an incomplete series
    • Potential consequences of distributing the vaccine in a manner that is not consistent with the recommendations from the manufacturer
    • Risk of anxiety in the vaccinated individual related to uncertainties in degree of protection and vaccine availability for a second dose

Proportionality

(Measures should be proportionate to the level of risk and benefits gained)

  • If half the initial doses are kept on reserve so that all initial vaccine recipients can receive both doses in accordance with the recommended interval, the level of risk is proportionate to the benefits gained particularly for those vaccinated in the high-risk key populations identified by NACIFootnote 10Footnote 11.
  • If all doses are immediately distributed without reserving doses to complete the vaccine series in accordance with the recommended interval and subsequent supply is insufficient, the level of risk may not be proportionate to the anticipated benefits given the uncertainty of supply for a second dose, limited comparative evidence on the level and duration of protection offered by one vs two doses, and the absence of evidence on interchangeability of vaccine doses.

Effectiveness

(Reasonable likelihood that the action will achieve goals and will be feasible)

  • If half the initial doses are kept on reserve so that all initial vaccine recipients can receive both doses in accordance with the recommended interval, this may be more likely to achieve Canada's pandemic response goal: "To minimize serious illness and overall deaths while minimizing societal disruption as a result of the COVID-19 pandemic." Though there is insufficient evidence for medium to long-term efficacy for a two-dose schedule, the evidence for duration of protection from a two-dose schedule is comparatively more than evidence of protection from a one-dose schedule. Higher efficacy and maximum immune response were observed after the second COVID-19 vaccine dose.
  • If all doses are immediately distributed without reserving doses to complete the vaccine series in accordance with the recommended interval, the likelihood that this action would achieve Canada's pandemic response goal may be diminished, due to the uncertainty in the efficacy of one dose beyond the time when the second dose should be given, as well as the uncertainty in arrival of subsequent vaccine supply. If successive shipments of vaccine are delayed, diminished, or do not arrive, this could lead to the following scenarios where the effectiveness is uncertain:
    • Provision of a second dose at an extended interval
    • Provision of a second dose with another mRNA vaccine (presuming availability)
    • Inability to provide a second dose because of a lack of vaccine supply or because the individual who received the initial dose is lost to follow up (which may be more likely in this scenario)
  • However, if evidence evolves to suggest comparative protection with a single dose, delayed dose, or interchangeability of vaccines, then this option would more quickly achieve Canada's pandemic response goal with vaccination of double the number of vaccine recipients initially.

Precaution

(Take prudent action in the face of scientific uncertainty)

  • Given the higher degree of scientific uncertainty surrounding a one-dose vs two-dose schedule or a mixed schedule with different vaccine products at this time, the most prudent action would be to reserve half the initial doses so that initial vaccine recipients can receive both doses in accordance with the recommended interval, until more evidence becomes available.
  • Additional evidence on the efficacy of one dose, the duration of protection of one dose, interchangeability of vaccine products, maximum intervals between doses, and security of anticipated supply could mitigate risks of distributing all doses immediately without reserving doses to complete the vaccination schedule in accordance with the recommended interval.

Reciprocity

(Minimize the disproportionate burden faced by those taking on additional risk to protect the public)

  • Healthcare providers and staff of congregate living settings that provide care for seniors are among the key populations identified to receive initial dosesFootnote 11 of COVID-19 vaccine.
  • If half the initial doses are kept on reserve so that all initial vaccine recipients can receive both doses in accordance with the recommended interval, this would minimize the risks to these individuals who take on an additional burden and increased risk to provide care to protect the public and those who are most vulnerable to severe COVID-19 disease. Vaccinating with both doses on schedule enables those who receive the vaccine to receive the greatest possible protection, based on the best scientific evidence available.
  • If all doses are immediately distributed without reserving doses to complete the vaccine series in accordance with the recommended interval, double the number of healthcare providers and staff of congregate living settings that provide care for seniors could be vaccinated in the initial stages of vaccine roll out. However, there is a risk that these individuals will not be protected to the same degree and for the same length of time as if they had been vaccinated with two doses in accordance with the recommended interval. 

Justice

(Treat people and groups with equal concern and respect)

  • Distributive justice

(Fair and feasible distribution of resource)

  • If half the initial doses are kept on reserve so that all initial vaccine recipients can receive both doses in accordance with the recommended interval:
    • Those vaccinated in the high-risk groups identified as key populations for early immunization by NACI(10 ) with the guiding principle of equity will achieve maximum protection given the current state of evidence, which supports the principle of equity.
    • If initial vaccine supply is not sufficient to vaccinate all individuals in high risk groups identified as key populations for early immunization by NACI, then health equity principles may be undermined especially when local disease burden is high and there is some evidence of short-term protection with one dose of vaccine may be less logistically feasible initially due to storage requirements of reserved doses and security of these doses.
    • Fair and feasible distribution of resources will require consideration of when, where, and how follow up with individuals will be done to complete the vaccine series.
  • If all doses are immediately distributed without reserving doses to complete the vaccine series in accordance with the recommended interval:
    • This may provide greater access to a greater number of individuals providing at least some short-term protection, which could increase equity when local disease burden is high. However, health equity principles may be undermined if protection is not adequate and subsequent supply is insufficient, putting key populations at high risk of infection and disease.
    • High-risk groups prioritized for early immunizationFootnote 10 could perceive that they are not worthy of receiving the complete vaccine schedule, leading to further stigmatization and disadvantage.
    • This may be more logistically feasible initially for vaccine rollout, however tracking of individuals for follow up dosing may be challenging and resource-intense. Logistical considerations would include:
      • Fair and feasible distribution of resources will require consideration of when, where and how follow up with individuals will be done, as well as the capacity of immunizers to deliver vaccine quickly and concurrently to manage individuals on delayed schedules.
      • Whether an alternate vaccine product would be available in the setting for the second dose (e.g. Moderna COVID-19 vaccine may be destined for remote and isolated communities due to different storage and handling conditions)

Trust

(Long term reliability, integrity, sustainable and mutually fair relationship with individuals and communities)

  • Transparency is a key element for fostering public trust. Decision-makers should document, and must be prepared to justify, the decisions that they make.
  • All plans and decisions must, as much as possible, be made with an appeal to reasons that are mutually agreed upon and work toward collaboratively derived goals.
  • Trust may be impacted by taking a programming risk management decision without supporting scientific evidence.
  • Conformity and consistency of COVID-19 immunization programs across jurisdictions in Canada is important, especially in the context of ongoing changes to and differences in recommendations in the pandemic context.
  • Providing an incomplete schedule early on could erode trust in the necessity of the complete series overall. This is of particular concern given the current state of trust in COVID-19 vaccines and vaccines generally.
  • Decisions and care should be taken to create opportunities that minimize moral distress, and maximize integrity and well-being.
  • If half the initial doses are kept on reserve so that all initial vaccine recipients can receive both doses in accordance with the recommended interval:
    • This may have a negative impact on public trust due to a perception that only a small number of individuals are getting preferential access despite availability of additional doses. This risk can be mitigated with open communication about the rationale.
  • If all doses are immediately distributed without reserving doses to complete the vaccine series in accordance with the recommended interval:
    • This may have a negative impact on public trust in the COVID-19 immunization program, the COVID-19 response, and vaccines in general.
    • Perceptions that certain key populations are "guinea pigs" may be perpetuated. This is of particular concern as many of the key populations prioritized for early immunizationFootnote 10Footnote 11 experience social inequities and stigmatization and have been subject to inappropriate research historically.
    • The lack of consistency in approaches between jurisdictions in the initial phases of roll-out of the COVID-19 immunization program could erode public trust in the recommendations and process.

Step 3: Identify and assess options

In assessing the different options in the initial phase of vaccine roll out, provinces and territories should consider the ethical considerations outlined above in Step 2, as well as the following elements in their local contexts:

Conclusion:

Provinces and territories will have to determine the best course of action based on their own analysis and logistical contexts, including risks and unintended consequences that may occur as a result of delaying the second dose of vaccine, and in consideration of the in-depth ethical analysis provided here, recognizing that decisions made by provincial/territorial jurisdictions have impact throughout the country. Transparency in decision-making will be vital to foster continued trust. This ethics analysis may evolve as more evidence (e.g. effectiveness and duration of protection from the first dose of COVID-19 vaccine) emerges and as the certainty of vaccine supply increases. Research and evaluation in this area is encouraged.

Appendix D: Frequency of Solicited Adverse EventsFootnote 1 Following Immunization for COVID-19 vaccines

Step 2: Identify the ethical considerations (using the Core Ethical Dimensions Filter of the EEFA FrameworkFootnote 2)
AEFI Pfizer-BioNTech COVID-19 Vaccine Moderna COVID-19 Vaccine
Vaccine Placebo control Vaccine Placebo control
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

Redness

Common

Common

Common

Rare

Common

Common

Uncommon

Uncommon

Swelling

Common

Common

Rare

Rare

Common

Very Common

Uncommon

Uncommon

Lymphadenopathy/Anxillary swelling and tenderness

NSFootnote 2

NSFootnote 2

NSFootnote 2

NSFootnote 2

Very Common

Very Common

Common

Common

Fatigue

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

Muscle Pain

Very Common

Very Common

Common

Common

Very Common

Very Common

Very Common

Very Common

Chills

Very Common

Very Common

Common

Common

Common

Very Common

Common

Common

Joint Pain

Common

Very Common

Common

Common

Very Common

Very Common

Very Common

Very Common

Fever

Common

Very Common

Uncommon

Uncommon

Uncommon

Very Common

Uncommon

Uncommon

Diarrhea

Common

Common

Common

Common

NS

NS

NS

NS

Nausea and/or Vomiting

Uncommon

Common

Uncommon

Uncommon

Common

Very Common

Common

Common

Abbreviations: NS: not solicited

Table Footnotes

Footnote 1

Very common = occur in >10% or more of vaccinees, common = occur in 1 to less than <10% of vaccinees, uncommon = occur in 0.1% to less than 1% of vaccineest

Return to footnote 1 referrer

Footnote 2

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

Return to footnote 2 referrer

References

Footnote 1

Ismail SJ, Langley JM, Harris TM, Warshawsky BF, Desai S, FarhangMehr M. 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 1 referrer

Footnote 2

Ismail SJ, Hardy K, Tunis MC, Young K, Sicard N, Quach, C. A framework for the systematic consideration of ethics, equity, feasibility, and acceptability in vaccine program recommendations. [published online June 10, 2020]. Vaccine. DOI: 10.1016/j.vaccine.2020.05.051

Return to footnote 2 referrer

Footnote 3

Ismail SJ, Tunis MC, Zhao L, Quach C. Navigating inequities: a roadmap out of the pandemic. BMJ Global Health. 2020 Dec. Forthcoming.

Return to footnote 3 referrer

Footnote 4

Zhao L, Ismail SJ, Tunis MC. Ranking the relative importance of immunization strategies for novel coronavirus disease 2019 (COVID-19): a rapid survey of stakeholders. medRxiv. 2020. DOI: 10.1101/2020.09.16.20196295

Return to footnote 4 referrer

Footnote 5

Impact and Innovation Unit. (2020, August 17; wave 7). COVID-19 Snapshot Monitoring (COSMO Canada). Impact Canada.

Return to footnote 5 referrer

Footnote 6

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 6 referrer

Footnote 7

United States Food and Drug Administration. Development and Licensure of Vaccines to Prevent COVID Guidance for Industry. June 2020. Available at: https://www.fda.gov/media/139638/download

Return to footnote 7 referrer

Footnote 8

Polack FP, Thomas SJ, Kitchin N, et al., Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine. December 10, 2020. DOI: 10.1056/NEJMoa2034577

Return to footnote 8 referrer

Footnote 9

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 [cited 12 December 2020].Available at: https://www.modernatx.com/sites/default/files/mRNA-1273-P301-Protocol.pdf

Return to footnote 9 referrer

Footnote 10

National Advisory Committee on Immunization. Preliminary guidance on key populations for early COVID-19 immunization. November 2020. Available at: https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-key-populations-early-covid-19-immunization.html

Return to footnote 10 referrer

Footnote 11

National Advisory Committee on Immunization. Guidance on the prioritization of initial doses of COVID-19 vaccine(s). December 2020. Available at: https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/guidance-prioritization-initial-doses-covid-19-vaccines.html

Return to footnote 11 referrer

Footnote 12

ModernaTX. Vaccines and Related Biological Products Advisory Committee Meeting December 17, 2020. December 2020. Available at: https://www.fda.gov/media/144434/download

Return to footnote 12 referrer

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