Archived 10: Extended dose intervals for COVID-19 vaccines to optimize early vaccine rollout and population protection in Canada in the context of limited vaccine supply [2021-04-07]

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This is an archived version. Please refer to the most current version of the recommendations on the use of COVID-19 vaccines.

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Preamble

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

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

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

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

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

Introduction

Since COVID-19 vaccines were first authorized in Canada in December 2020, the National Advisory Committee on Immunization (NACI) has been providing evidence-informed guidance on the recommended interval between vaccine doses. On January 12, 2021, NACI provided advice on extending intervals for mRNA vaccines to six weeks. In February 2021, the Public Health Agency of Canada (PHAC) asked NACI to address the following context and question: Due to limited vaccine supply and logistical challenges, jurisdictions need to implement COVID-19 mRNA vaccine intervals beyond six weeks. Given emerging evidence as mRNA vaccines are rolled out to populations in Canada and elsewhere in the world, what extended interval would be recommended in order to balance individual protection and population impact? Are extended intervals a particular concern for any key populations?

A rapid response statement was published on March 3, 2021 to advise on NACI's decision regarding extended intervals in the context of limited vaccine supply. The current statement provides a more detailed overview of NACI's considerations, including evidence available through daily scanning as of March 26, 2021 as well as some additional studies that became available after that date with regard to mRNA vaccines and AstraZeneca.

Guidance objective

The objective of this statement is to provide guidance for the equitable, ethical, and efficient allocation of authorized COVID-19 vaccines in the context of staggered arrival of vaccine supply. This guidance builds on the foundational framework of NACI's Recommendations on the use of COVID-19 vaccines. 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. The goal of Canada's COVID-19 immunization response is to enable as many Canadians as possible to be immunized against COVID-19 as quickly as possible, while ensuring that high-risk populations are prioritized.

Methods

After receiving a request from PHAC and Chief Medical Officers of Health from across the country seeking advice about intervals between doses of COVID-19 vaccines given limited vaccine supply, NACI reviewed available evidence on extended intervals for COVID-19 vaccines in full Committee meetings (February 8, 2021; February 24-25, 2021; March 25, 2021; March 30, 3021) and Working Group meetings (February 19, 2021). This included evidence available from published peer-reviewed studies, pre-prints, and data available from population-based assessments from within and outside of Canada. The Public Health Ethics Consultative Group had been previously consulted by NACI (on December 15, 2020 and January 26, 2021) about the ethical implications of delaying the second dose in a COVID-19 vaccine series. On March 1, 2021, NACI voted on and approved the revised recommendations and between March 25 and 28, 2021 NACI members revisited the recommendations with regard to specific population groups. In arriving at its decisions, NACI considered the following factors, which are outlined in this document:

Table 1 summarizes studies that provide vaccine effectiveness (VE) estimates with one dose of COVID-19 vaccine. Daily literature scans for articles in Table 1 were conducted using the following sources: PubMed, Scopus, BioRxiv, MedRxiv, ArXiv, SSRN, Research Square, and cross-referenced with the COVID-19 information centers run by Lancet, BMJ, Elsevier, Nature, Wiley, Epistemonikos' L·OVE, and McMaster PLUS. Table 1 contains literature available in the scan up to March 26, 2021, 11:00 am EST. A first level rapid screening of titles was performed in Distiller by a single reviewer using a combination of manual review and DistillerAI's natural language processing technology. A second reviewer screened full text results of potentially relevant articles to identify those related to vaccine efficacy or effectiveness of the first dose. All articles in Table 1 were abstracted by one author and reviewed by a second author. Only articles that provide a clear VE estimate and were available before 11:00 am EST March 26, 2021 are included in Table 1. Some additional studies that became available after that time are referred to in the text only.

Evidence

Efficacy and effectiveness of the first dose of the available COVID-19 vaccines

Review of available data on efficacy and effectiveness of a single dose of mRNA vaccine was a critical factor in assessing the impact of extending the interval to the second dose. Evidence regarding efficacy and effectiveness of one dose of COVID-19 vaccines is summarized below. Additional details regarding evidence available up to March 26, 2021 are summarized in Table 1.

Data from the two clinical trials for mRNA vaccines (Pfizer-BioNTechFootnote 1 and ModernaFootnote 2) provide evidence that indicates that efficacy against symptomatic disease begins as early as 12 to 14 days after the first dose. Excluding the first 14 days before vaccines are expected to offer protection, both vaccines showed an efficacy of 92% up until the second doseFootnote 3Footnote 4 (the second dose was generally administered at approximately 21 days after the first dose for the Pfizer-BioNTech product and at approximately 28 days for the Moderna product). From the AstraZeneca clinical trial publication, one dose of the vaccine was found to have 76% efficacy between 22 and 90 days after administrationFootnote 5.

Since publication of the clinical trials to March 26, 2021, studies with clear VE data have become available from Israel (5 studiesFootnote 6Footnote 7Footnote 8Footnote 9Footnote 10, one of which was re-analyzedFootnote 11), Canada (several study designs and target populations in two provincesFootnote 12Footnote 13Footnote 14), the United States (3 studiesFootnote 15Footnote 16Footnote 17), the United Kingdom (9 studiesFootnote 18Footnote 19Footnote 20Footnote 21Footnote 22Footnote 23Footnote 24Footnote 25Footnote 26Footnote 27, some with multiple components) and Denmark (1 studyFootnote 28). Most of these studies are currently only available as unpublished preprints, and therefore have not been peer reviewed. The available one dose data reflects the vaccination programs and products being used at the time in each country as follows:

As can be seen from Table 1 and the summary below, VE of one dose of COVID-19 vaccines varied considerably as did study design, study size, study population, outcome (asymptomatic and/or symptomatic PCR-confirmed SARS-CoV-2, COVID-19 hospitalizations or deaths) and outcome dates (symptom onset date, specimen collection date, laboratory result date, hospitalization and death dates). VE estimates may also be impacted by the duration of follow-up and the time period of the study. Observational studies are subject to biases that may influence their results. In addition, many of the studies are preprints, which have not been peer reviewed. Some methodologic considerations with regard to studies available before the March 26, 2021 cut-off are highlighted in Table 1 and a review of general methodological considerations are summarized below.

The preponderance of one dose data pertains to mRNA vaccines (mostly Pfizer-BioNTech); the results summarized below pertain to one dose of mRNA vaccines unless AstraZeneca is specified and unless information regarding the second dose is provided. They do not include studies in long-term care home residents which are covered in Section 7 (Impact on specific populations groups).

The following studies provide additional information about symptomatic and/or asymptomatic infection:

For the AstraZeneca vaccine, the one-dose effectiveness data (58%Footnote 26 to 68%Footnote 44), one-dose efficacy from the clinical trial (76%)Footnote 5, and two-dose efficacy (63%)Footnote 5 appear to be similar. For the mRNA vaccines, the one-dose effectiveness data is lower (generally between 60 and 80%, with some lower and higher estimates) than the one-dose efficacy from the clinical trials (92%)Footnote 3Footnote 4 and lower than the two-dose effectiveness data (88% to 95%Footnote 25Footnote 6Footnote 31Footnote 30) and two-dose efficacy data (94%Footnote 2 to 95%Footnote 1).

One dose of both Pfizer-BioNTech and AstraZeneca vaccines provided very good protection against more serious outcomes, particularly hospitalizationFootnote 26Footnote 23Footnote 19, with one study also showing very good protection against deaths for the Pfizer-BioNTech vaccineFootnote 26.

VE estimates, which are obtained from observational studies, are typically lower than vaccine efficacy estimates from clinical trials. For the studies on one dose effectiveness of COVID-19 vaccines, differences between observational data and clinical trial data may be due to the following:

In addition, the following methodologic considerations could explain some of the differences between observational studies and clinical trials and should be noted when assessing the effectiveness data:

Duration of protection following the first dose of the available COVID-19 vaccines

Data and exploratory modeling from the AstraZeneca clinical trial publication indicated that the protection from one dose did not wane up to 90 days from vaccinationFootnote 5. Effectiveness data from Canada and the UK demonstrates protection from the mRNA vaccines based on analyses extending to about 8 weeks from vaccinationFootnote 14Footnote 23Footnote 25Footnote 26. Experience with other multi-dose vaccines after a single dose suggests protection could last for six months or longer in adolescents and adultsFootnote 32 (e.g., hepatitis A and human papillomavirus vaccines). Longer-term follow-up of clinical trial participants and populations receiving vaccinations in public programs will assist in determining the duration of protection following both one and two doses of COVID-19 vaccines.

Impact of extending the interval between the priming and boosting doses on the immune response and vaccine efficacy after the second dose

As a general vaccination principle, interruption of a vaccine series resulting in an extended interval between doses does not require restarting the vaccine series, regardless of the interval between dosesFootnote 33. Principles of vaccinology support at least a three-week interval between doses in a multi-dose primary series to avoid immune interference in the primary response to the vaccineFootnote 34. Furthermore, a longer interval between the priming and boosting doses allows maturation of the memory B cells, resulting in a higher and more durable responseFootnote 34.

Data from the AstraZeneca COVID-19 vaccine clinical trial showed maximum efficacy when the interval was extended to ≥12 weeks, with efficacy at <6 weeks between doses of 55.1% (95% CI: 33.0 to 69.9%) and efficacy at ≥12 weeks of 81.3% (60.3 to 91.2%)Footnote 5.

Impact of rapidly vaccinating more people with the available supply of COVID-19 vaccines

Extending the interval between the first and second doses will allow many more people to be vaccinated rapidly with the available supply of vaccines. Based on the expected supply of mRNA vaccines alone, 90% of older adults (50 years of age and over) and 75% of younger adults (16 to 49 years of age) could be offered a dose of mRNA vaccine by the middle of June 2021. Second doses could be offered as soon as all eligible individuals had been offered their first dose, or prioritized earlier for certain cohorts or specific population groups if indicated based on emerging data.

Vaccines that reduce both symptomatic and asymptomatic infection are expected to also reduce transmission of SARS-CoV-2. A number of the studies in this review found that the Pfizer-BioNTech vaccine was effective against SARS-CoV-2 infection (which is symptomatic or asymptomatic infection combinedFootnote 6Footnote 8Footnote 10Footnote 11Footnote 12Footnote 13Footnote 14Footnote 16Footnote 18Footnote 20Footnote 21Footnote 22Footnote 24Footnote 27Footnote 28).

Tande et al. assessed asymptomatic individuals undergoing pre-procedural screening and found a VE of 79% (95% CI: 63 to 88%) from >10 days after the first dose to the second dose of the Pfizer-BioNTech or Moderna vaccines (compared to unvaccinated people)Footnote 17. In addition, a recently released preprint from Israel showed 90.4% (95% CI: 89.1 to 91.5%) VE against asymptomatic infection based on two doses of the Pfizer-BioNTech vaccineFootnote 31. The clinical trial results for the ModernaFootnote 2 and JanssenFootnote 35 vaccines suggested that one dose of these vaccines may decrease asymptomatic infection. The AstraZeneca vaccine has not been shown to reduce asymptomatic infection, which appears to be due to poor efficacy against preventing asymptomatic infection with the B.1.1.7 variantFootnote 36; its ability to prevent transmission is unknown.

Vaccination of larger numbers of people with vaccines that prevent infection and transmission will not only protect the vaccinated individual but those around them as well (indirect protection). In addition, extending the interval between doses in order to more rapidly vaccinate an increased number of people is likely to decrease the overall circulation of the virus in the community contributing to community protection.

Modelling information on the impact of extending the interval between the first and second doses of COVID-19 vaccines

Public Health Agency of Canada model

An internal PHAC model, examining dose intervals between 12 and 24 weeks, suggested that accelerating vaccine coverage by extending dose intervals of mRNA vaccines could have short-term (12 months) public health benefits in reducing symptomatic disease, hospitalizations, and deaths compared to a 6-week interval while vaccine supply is constrained. The model used the following assumptions for effectiveness after the first dose: effectiveness against all infections representing 90% of effectiveness against symptomatic disease (e.g., 60.3% effectiveness against infection / 67% effectiveness against disease); effectiveness against symptomatic disease of 67% in adults aged 20-64 years and 58% in adults 65+ years; effectiveness against hospitalizations of 80% for all ages, and effectiveness against deaths of 85% for all ages. In addition, the model employed the following assumptions:

The model projected that a extending the dose interval would reduce overall symptomatic disease, hospitalizations, and deaths in the population while vaccine supply is constrained. Projected benefits were driven by accelerating access to vaccines in adults aged 20-74 years. A 16-week interval was projected to have the largest reductions in severe outcomes of hospitalizations and deaths in individuals 75+ years. A 24-week interval was projected to have the largest reductions in hospitalizations and deaths in individuals aged 20-74 years.

Sensitivity analysis indicated that dose intervals as long as 24 weeks would reduce symptomatic disease and hospitalizations across first dose effectiveness against disease and hospitalization values of 50% to 85%. All extended intervals were projected to reduce deaths while effectiveness against death was at least 65% but increased deaths when effectiveness was less than 65%. An effectiveness against death less than 65% could still reduce deaths if the third wave was more severe than the base case scenario.

Sensitivity analysis projected that extending the mRNA dose interval as far as 24 weeks would still have short-term public health benefits in reducing symptomatic disease, hospitalizations, and deaths if first dose protection was lost at a rate of 4% per week. A 24-week interval was no longer projected to reduce deaths under a scenario in which first dose protection was lost at a rate of 8% per week, though 12-week and 16-week intervals were still projected to reduce symptomatic disease, hospitalizations, and deaths.

Models available in publications or pre-prints

A multi-model comparison included five external vaccine modelling studies on alternate dosing strategies available as publications or pre-prints as of February 14, 2021Footnote 37Footnote 38Footnote 39Footnote 40Footnote 41. The studies were on mRNA vaccines and examined different delay intervals, single dose strategies, strategies where some subpopulations received one dose while others received two doses, and strategies that reserved some proportion of supply for two doses while the remainder were for one dose. One modelFootnote 37 directly compared different extended dosing intervals (up to 15 weeks) against no delay.

External modelling suggested that extended dosing intervals (between 9 to 12 weeks) can reduce infections, hospitalizations and deaths compared to no delays when vaccine supply is limitedFootnote 37. The population benefits come from providing greater vaccine coverage to more people, even when the level of protection of one dose is not as high as the protection offered by two doses.

Study results were dependent on particular model inputs used. Of note, the single dose effectiveness appeared influential - if a high single dose effectiveness was applied, then the extended interval strategy was preferred over no delay; however, if a low single dose effectiveness was applied, then the strategy of no delay was preferred. Studies considered single dose effectiveness between 72% to 80% as high and between 18% to 55% as lowFootnote 37Footnote 38Footnote 39. Model inputs on waning may also be influential - if the vaccine began to wane many weeks after the first dose, then the extended interval strategy was preferred; however, if the waning began soon after the first dose, then the strategy of no delay was preferredFootnote 37. Vaccine coverage and background transmission may also influence the preferred vaccine strategyFootnote 38.

Overall, internal and external modelling indicate the benefits of extending dose intervals by reducing symptomatic disease, hospitalizations, and deaths while vaccine supply is constrained.

Impact of extending the interval between doses of COVID-19 vaccines on variants of concern

The impact of extending the interval between doses on the emergence and/or circulation of variants of concern is unknown. There is currently no evidence that an extended interval between doses will either increase or decrease the emergence of variants of concern, although preventing transmission in the community by vaccination may decrease the chance of the emergence and/or spread of variants as suggested in a recent publicationFootnote 42. COVID-19 mRNA vaccines and the AstraZeneca vaccine have shown promising early results against variant B.1.1.7 based on effectiveness studies in the UK (Pfizer-BioNTech and AstraZenecaFootnote 26) and Israel (Pfizer-BioNtechFootnote 31) where this is the dominant strain. Two doses of the AstraZeneca vaccine were not found to be efficacious against the B.1.351 variant in a randomized clinical trial conducted in South AfricaFootnote 43, however a recent press release stated that two doses of the Pfizer-BioNTech vaccine were efficacious against B.1.351. Ongoing monitoring, including genetic sequencing of PCR positive samples in previously vaccinated people, will be required to assess the effectiveness of one and two doses of COVID-19 vaccines against variants of concern.

Manufacturers are currently exploring the need for, and development of, booster doses specific to variants of concern. Additional information may be available about updated formulations of the vaccines to inform the second dose recommendations by the time that dose is indicated.

Impact on specific population groups

Older adults

The following studies assessed one dose VE in older adults:

In assessing VE in long-term care homes, it should be noted that the extent to which indirect protection from also vaccinating health care workers and visitors (in addition to direct protection) is contributing to these VE estimates is not known.

Immunogenicity studies are also available to assess antibody response in older adults. However, it is difficult to interpret immunogenicity studies as the mechanism by which vaccines protect against COVID-19 is not certain and there is currently no correlate of protection.

Underlying medical conditions

Vaccine efficacy following a complete series of COVID-19 vaccines among immunocompromised patients is not known, as these patients were excluded from clinical trials. Effectiveness studies with clear data are not available regarding underlying medical conditions. Three immunogenicity studies are available, noting the limitations of interpreting immunogenicity studies due to the unknowns about the immune mechanism for protection against COVID-19 and no available correlate of protection.

It should be noted that a number of populations known to be at higher risk of severe COVID-19 outcomes have not been studied with regard to immunogenicity or effectiveness.

Ethics, equity, feasibility, and acceptability of extending the interval to the second dose of COVID-19 vaccines authorized as a two-dose series

NACI applies the ethics, equity, feasibility, and acceptability (EEFA) Framework for the systematic consideration of factors critical for comprehensive immunization program decision-making and successful implementation of recommendationsFootnote 53. This framework empowers the Committee to review and balance available evidence and transparently summarize the rationale for appropriate, timely COVID-19 immunization program recommendations. Key considerations for ethics, equity, feasibility and acceptability of the recommendation to extend the interval to the second dose are summarized below.

Recommendation

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 Framework, NACI makes the following recommendation 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 2 for a more detailed explanation of the strength of NACI recommendations.

Based on emerging evidence of the protection provided by the first dose of a two-dose series for COVID-19 vaccines currently authorized in Canada, NACI recommends that in the context of limited COVID-19 vaccine supply and ongoing pandemic disease, jurisdictions should maximize the number of individuals benefiting from the first dose of vaccine by extending the second dose of COVID-19 vaccine up to four months after the first. Second doses should be offered as soon as possible after all eligible populations have been offered first doses, with priority given to those at highest risk of severe illness and death from COVID-19 disease. Vaccinated people (with one or two doses) should continue to follow recommended public health measures. NACI will continue to monitor the evidence on effectiveness of an extended dose interval and will adjust recommendations as needed. (Strong NACI Recommendation)

Jurisdictions may choose to shorten the time between the first and second dose of a two-dose series for COVID-19 vaccines in specific population groups based on their local epidemiology, vaccine supply and vaccine delivery mechanisms.

Summary of evidence and rationale:

As summarized in more detail above, NACI developed its recommendations utilizing multiple sources of evidence in support of an extended interval of up to four months if needed to offer all currently eligible populations rapid vaccination. While studies have not yet accumulated data up to four months after the first dose, the AstraZeneca vaccine modelled one-dose efficacy of 76% up to 90 days from vaccination, and effectiveness data for one dose of mRNA vaccines have extended up to two months. Vaccinology principles support a better immune response with longer intervals between priming and boosting doses. Modelling demonstrated that longer intervals would have substantial population-level benefits. With anticipated vaccine supplies of mRNA vaccines alone, extending the interval to the second dose would allow over 90% of older adults (50 years of age and over) and 75% of younger adults (16 to 49 years of age) to be vaccinated by the middle of June, 2021, with second doses following afterwards. Compared to shorter intervals between doses, extending the interval between doses results in faster direct protection to substantially more of the population, along with the possibility of more rapid indirect and community protection. Second doses should be offered as soon as possible after all eligible populations have been offered first doses. Vaccinated individuals (with one or two doses) should continue to follow public health recommendation regarding COVID-19 prevention measures. Monitoring of VE and efficacy studies is ongoing and recommendations will be adjusted, including offering early vaccinations to some cohorts or population groups if needed.

Tables

Table 1: Summary of efficacy and effectiveness data from the first dose of COVID-19 vaccines
Source Description Protection from the first dose of COVID-19 vaccines
Clinical trials
Polack F.P et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. Published New England Journal of Medicine. December 10, 2020

Letter to the editor of the New England Journal of Medicine in response to Polack et al by Skowronski D and De Serres G.
  • Re-analysis of symptomatic illness from the clinical trial of the Pfizer-BioNTech vaccine removing the first 14 days when the vaccine is not expected to have an impact
The initial analysis by Polack et al. showed the efficacy between the first and second dose to be 52% (95% CI: 29.5 to 68.4)

Re-analysis by Skowronski and De Serres used data submitted to the Food and Drug Administration (FDA) to remove the first 14 days when the vaccine is not expected to be protective and found a 92.6% (95% CI: 69.0 to 98.3%) one-dose efficacy from 14 days after dose 1 until dose 2 at approximately 21 days.
Vaccine and Related Biological Products Advisory Committee Meeting FDA briefing document - Moderna COVID-19 - December 17, 2020

Baden LR et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. Published New England Journal of Medicine. December 30, 2020
  • Symptomatic illness from the clinical trial of the Moderna vaccine
  • Asymptomatic infection from the clinical trial of the Moderna vaccine based on swab results when receiving the first dose and then again at the time of the second dose
92.1% (95% CI: 68.8 to 99.1%) for those who only received one dose more than 14 days after that dose - data provided FDA briefing

94.3% calculated efficacy based on published data indicating 2 cases in the vaccine group and 35 cases in the placebo group from 14 days after dose 1 until dose 2 at approximately 28 days - data provided in Baden et al.

61% reduction based on those who had no initial evidence of infection at the first dose but a positive swab on the day of the second dose (15 people had asymptomatic infection in the group that received one dose of Moderna vaccine, compared to 39 people in the placebo group) - data provided in Baden et al.

Note: The first 14 days when the vaccine is not expected to be protective is included in this estimate, so the result may have been higher if the first 14 days could be removed.
Voysey M et al. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. Published The Lancet. February 19, 2021
  • Symptomatic illness from clinical trial of the AstraZeneca vaccine
An exploratory analysis found that a single standard dose of the AstraZeneca vaccines was 76.0% (95% CI: 59.3 to 85.9%) from days 22 to 90 after vaccination. Modelling did not demonstrate waning during that 3-month time period.
Israel: Effectiveness data
Chodick G et al. The effectiveness of the first dose of BNT162b2 vaccine in reducing SARS-CoV-2 infection 13-24 days after immunization: real-world evidence. Preprint MedRxiv. January 29, 2021

Reanalysis by Hunter PR and Brainard J. Estimating the effectiveness of the Pfizer COVID-19 BNT162b2 vaccine after a single dose. A reanalysis of a study of 'real-world' vaccination outcomes from Israel. Preprint MedRxiv. February 3, 2021
  • Retrospective cohort study from Maccabi Healthcare Services in Israel assessing incidence rates of PCR positive cases by specimen collection date from date of vaccination using Pfizer-BioNTech vaccine. Compared cumulative incidence rates from days 13 to 24 to days 1 to 12 post vaccination in 503,875 people.
  • The data was re-analyzed to determine the incidence rates per day post-vaccination. They calculated the VE per day from days 13 to 24, comparing an actual and expected number of cases per day (with the expected based on the pooled incidence from days 1 to 12).
Initial analysis showed 51% (95% CI: -7.2 to 78.0%) reduction in laboratory-confirmed infection (regardless of symptoms) in the 13 to 24 day period after vaccination compared to the 1 to 12 day period after vaccination. However, VE was only notable from 18 days post-vaccination so analysis over the entire 13 to 24 days underestimated VE.

Re-analysis of the data showed effectiveness as high as 91% (90% credible interval: 83 to 98%) on day 21 post-vaccination with a single dose of Pfizer-BioNTech vaccine.
Dagan N et al., BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. Published New England Journal of Medicine. February 24, 2021. A large prospective cohort study from Clalit Health Services in Israel using the Pfizer-BioNTech vaccine. Matched 596,618 vaccinated individuals to an equal number of unvaccinated individuals on a number of variables including age, sex, sector, neighbourhood, history of influenza vaccine, pregnancy and number of coexisting conditions and assessed various outcomes in three time intervals after vaccination (14 to 20 days after dose one; 21 to 27 days after dose one, with the second dose administered around day 21; and 7 or more days after the second dose). VE that reflects one dose (14 to 20 days - first bold number) or possibly reflects one dose but also including some second dose effect (21 to 27 days - second bold number) was as follows:
  • Asymptomatic infection (exploratory) - 29% (95% CI: 17 to 39%), 52% (95% CI: 41 to 60%)
  • Documented infection (PCR positive - 57% of cases were symptomatic): 46% (95% CI: 40 to 51%), 60% (95% CI: 53 to 66%)
  • Symptomatic illness: 57% (95% CI: 50 to 63%), 66% (95% CI: 57 to 73%)
  • Hospitalization: 74% (95% CI: 56 to 86%), 78% (95% CI: 61 to 91%)
  • Severe disease: 62% (95% CI: 39 to 80%), 80% (95% CI: 59 to 94%)
  • Deaths: 72% (95% CI: 19 to 100%), 84% (95% CI: 44 to 100%)


Note: As this analysis is based on dates of specimen collection, this will underestimate the impact in each time period as specimen collection dates are generally later than symptom onset date. For hospitalization and deaths, this analysis used dates of these events, and not date of onset or specimen collection date in those who subsequently had these events. Using dates of these events, the VE in the early period appears higher than would have been expected based on the time required for the vaccine to be protective and prevent subsequent hospitalizations and deaths.
Aran D. Estimating real-world COVID-19 vaccine effectiveness in Israel using aggregated counts. Preprint MedRxiv. February 23, 2021 Using administrative data from the Ministry of Health in Israel, this study assessed the number of vaccinated individuals with the Pfizer-BioNTech vaccine (<60 and > 60 years) for positive cases (symptomatic and asymptomatic), COVID-19 hospitalizations, COVID-19 severe diseases over 5 time periods: 1-13 days after first dose, 14-20 days after first dose, 0-6 days after second dose (second dose generally administered around day 21 from the first dose), 7-13 days after second dose and 14 and more days after second dose. Expected numbers of positive cases were estimated based on daily vaccination and general incidence rates, adjusting for number of cases that would have occurred without vaccination and across various incidence rates. For all outcomes, effectiveness was mainly noted beginning in the 0-6 days after the second dose (generally given on day 21 from the first dose). Given the delay in the outcomes (laboratory confirmation, hospitalization and severe disease), a portion of the effectiveness in this period is likely attributed to the first dose. This is particularly true for hospitalizations and severe disease (assuming what is reported is the date of these events).

Mid-range estimates for 14-20 days after first dose and 0-6 days after second dose were as follows:
  • Positive cases >60 years of age: 0% and 73%
  • Positive cases <60 years of age: 12% and 77%
  • Hospitalization cases >60 years of age: 0% and 81%
  • Hospitalization cases <60 years of age: 34% and 81%
  • Severe cases >60 years of age: 1% and 81%
  • Severe cases <60 years of age: 44% and 85%
Amit S et al. Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients. Published correspondence. February 18, 2021

Supplementary material
Retrospective cohort study from the Sheba Medical Centre in Israel comparing the rates of positive SARS-CoV-2 tests and symptomatic laboratory-confirmed COVID-19 among unvaccinated (1,895) and vaccinated (7214 with at least one dose, of which 6037 received two doses) health care workers. Vaccinated health care workers were within 1 to 14 and 15 to 28 days after first dose of Pfizer-BioNTech vaccine. The later time period was further broken down in the supplementary material into days 15 to 21 and days 22 to 28. Most received a second dose around day 21 or 22. Reduction in the rate of SARS-CoV-2 infection in vaccinated health care workers (symptomatic and asymptomatic) compared with unvaccinated health care workers was:
  • 65% (95% CI: 43 to 79%) from days 15 to 21 after first vaccination, and
  • 86% (95 CI: 70 to 94%) from days 22 to 28 after first vaccination (which includes time after second dose)

Reduction in the rate of symptomatic COVID-19 in vaccinated health care workers compared with unvaccinated health care workers was:

  • 76% (95% CI: 51 to 88%) from days 15 to 21 after first vaccination, and
  • 94% (95% CI: 76 to 99%) from days 22 to 28 after first vaccination (which includes time after second dose)

Note: It is not clear what date is based on. Likely specimen collection date.

Zacay G. Zacay et al., BNT162b2 Vaccine Effectiveness in Preventing Asymptomatic Infection with SARS-CoV-2 Virus: A Nationwide Historical Cohort Study. SSRN-Lancet preprint. March 3, 2021. Prospective cohort study of VE against PCR- confiormed infection in 6,286 individuals who were frequently tested in the Meuhedet Health Maintenance Organization (many of whom may have been health care workers) (2,941 received two doses of the Pfizer-BioNTech vaccine, 1,445 received one dose and 1,900 were not vaccinated). The included individuals had at least two PCR tests during November 2020, at least two PCR tests during December 2020, and at least one PCR test during January 2021, all of which were previously negative VE against PCR positive SARS-CoV-2 (with or without symptoms) from >≥14 days after dose 1 until the receipt of dose 2 was estimated to be 61% (CI 49%-71%) and 82% (71%-89%) for the period from 1 to 6 days after the second dose.

Note: The VE per day is not shown in this study and previous studies note that it increases across the time period from ≥14 days after vaccination to the second dose. B.1.1.7 was the dominant circulating strain.
Canada: Effectiveness data
Institut national de santé publique du Québec (INSPQ). Preliminary Data on Vaccine Effectiveness and Supplementary Opinion on the Strategy for Vaccination Against COVID-19 in Quebec in a Context of Shortage. February 12, 2021 and updated, as per Personal Communication Gaston De Serres following presentation to NACI on February 24, 2021 Analysis of surveillance data from residents in long-term care facilities (LTCF) and health care workers (HCWs) in Quebec. In Quebec, about 70% of doses in both target groups were Pfizer-BioNTech and the remainder was Moderna. Vaccinations began on December 14, 2020 and this study used data until February 10, 2021.

Following presentation to NACI on February 24, 2021 additional follow-up data were provided, extending to February 15, 2021 (63 days of follow-up), and restricting to HCWs 20 to 64 years of age and LTCF residents 65 years of age and over. Additional sensitivity analysis was also undertaken, restricting the analysis period from January 3 to February 15, 2021 (43 days of follow-up) to address potential variation over the holiday period.
VE against SARS-CoV-2 after one dose of mRNA vaccines in vaccinated compared to unvaccinated HCWs increased to almost 80% at the end of the observation period.

Using the screening method to compare percentage of health care workers with SARS-CoV-2 who were vaccinated ≥2 weeks before to the overall vaccination rates in health care workers, VE against SARS-CoV-2 ranged from 71% to 82% (depending on selected denominator).

Compared to the first nine days after vaccination, VE against SARS-CoV-2 in HCWs was 79.6% 28 days or more after one dose of mRNA vaccination. Update following February 24, 2021 NACI presentation: from December 14, VE in HCWs from days 21 to 63 after single-dose vaccination was 80% (95% CI: 77 to 82%) and from January 3 VE in HCWs from days 21 to 43 after single-dose vaccination was 83% (95%CI: 79 to 86%).

Compared to the first nine days after vaccination, VE against SARS-CoV-2 was 80.3% 21 to 27 days after vaccination with one dose of mRNA vaccine in LTCF residents. Update following February 24, 2021 NACI presentation: from December 14, VE in LTCF residents from days 21 to 63 after single-dose vaccination was 88% (95% CI: 85 to 90%) and from January 3 VE in LTCF residents from days 21 to 43 after single-dose vaccination was 90% (95%CI: 87 to 93%)

Note: SARS-CoV-2 rates were declining in the general population as well but to a lesser extent than among HCWs or LTCF residents.
Personal Communication, as per Danuta M Skowronski, Lead for Influenza & Emerging Respiratory Pathogens, BC Centre for Disease Control following presentation to NACI on February 24, 2021
  • Following presentation to NACI on February 24, 2021 updated analysis of surveillance data from health care workers (HCWs) 20 to 64 years of age and long term care facility (LTCF) residents 65 years of age and over were shared from British Columbia (BC).
  • Vaccination of HCWs began December 15 and of LTCF residents began December 23, 2020 in BC.
  • In BC, first doses among HCWs and LTCF residents included in cohort analyses of VE were compromised of about 80% and 60% Pfizer-BioNTech, respectively.
  • Follow-up extended to February 15, 2021 (62 and 54 days of follow-up for HCWs and LTCF residents, respectively). Additional sensitivity analysis was also undertaken, restricting the analysis period from January 3 to February 15, 2021 (43 days of follow-up) to address potential variation over the holiday period.
Using the screening method to compare percentage of HCWs SARS-CoV-2 cases who were vaccinated ≥2 weeks before to the overall vaccination rates in HCWs, VE against SARS-CoV-2 ranged from 74 to 79% (depending on selected denominator) when second dose recipients were excluded.

Compared to the first nine days after vaccination, from December 15, VE against SARS-CoV-2 in HCWs from days 21 to 62 after single-dose vaccination was 81% (95% CI: 73 to 86%) and from January 3 VE in HCWs from days 21 to 43 after single-dose vaccination was 89% (95%CI: 82 to 93%).

Compared to the first nine days after vaccination, from December 23, VE against SARS-CoV-2 in LTCF residents from days 21 to 54 after single-dose vaccination was 87% (95%CI: 79 to 92%) and from January 3 VE in LTCF residents from days 21 to 43 after single-dose vaccination was 80% (95%CI: 65 to 88%).

Note: SARS-CoV-2 rates were declining in the general population as well but to a lesser extent than among HCWs or LTCF residents.
United States: Effectiveness data
Pawlowski C et al. FDA-approved COVID-19 vaccines are effective per real-world evidence synthesized across a multi-state health system. Preprint MedRxiv. February 27, 2021. Retrospective cohort study of vaccinated (31,069) and propensity matched non-vaccinated (31,069) members of the Mayo clinic health system in the United States where the Pfizer-BioNTech and Moderna vaccines are available, assessing PCR positive specimens. Propensity matching was based on geography, demographics and record of previous PCR testing. VE based on a positive SARS-CoV-2 PCR test at time periods that are likely to represent the effect of one dose ranged from 69.2% (95% CI: 54.1 to 79.8%) from days 15 to 21 after vaccination to 74.2% (95% CI: 58.4 to 84.7%) from days 22 to 28 after vaccination.
Tande et al., Impact of the COVID-19 Vaccine on Asymptomatic Infection Among Patients Undergoing Pre-Procedural COVID-19 Molecular Screening. Clinical Infectious Diseases. March 10, 2021. Retrospective cohort study of consecutive asymptomatic patients (39,156) undergoing pre-symptomatic screening before surgical and select medical procedures (48 to 72 hours before the procedure) from December 17, 2020 to February 8 2021 using electronic health records to capture vaccination, test results, demographics from Mayo clinic associated sites in the United States. Participants were not symptomatic at time of screening but were not followed for future symptoms.
The Pfizer-BioNTech and Moderna vaccines were used and the analysis was adjusted for age, sex, race/ethnicity, residence, and repeat screening. The VE was assessed by number of doses and time period from vaccination.
Compared to unvaccinated, the VE against asymptomatic disease for Pfizer and Moderna combined in the adjusted analysis was:
  • 79% (95% CI: 63 to 88%) from >10 days after dose one to before dose 2
  • 80% (95% CI: 56 to 91%) after dose 2

Results for Pfizer-BioNTech alone were similar.

Note: It is possible that there is unmeasured confounding despite adjustments that contributed to the lower rate of test positivity within the vaccinated group.

Britton A et al. Effectiveness of the Pfizer-BioNTech COVID-19 Vaccine Among Residents of
Two Skilled Nursing Facilities Experiencing COVID-19 Outbreaks -
Connecticut, December 2020-February 2021 MMWR. March 15, 2021
Investigation of outbreaks in two skilled nursing homes in Connecticut, United States (142 residents and 321 residents).

Weekly surveillance testing was done to identify the outbreak and then once or twice weekly testing of residents and staff, as well as testing of symptomatic residents and staff and exposed residents.

Test information, vaccination information and co-morbidities determined for residents, and time since vaccination determined. Case date was symptom onset date or SARS-CoV-2 test result, whichever came first. Person years were determined from vaccination date or admission date, whichever came later.

Time to event analysis was necessary to adjust for change in risk due to the dynamics of the outbreak
Vaccination >14 days after first dose to 7 days after second dose resulted in a vaccine effectiveness of 63% (95% CI: 33 to 79%).

Sensitivity analysis showed that VE was 66% (95% CI: 29 to 83%) >14 days after the first dose to the time of the second dose.
United Kingdom: Effectiveness data
Hall VJ et al., Effectiveness of BNT162b2 mRNA Vaccine Against Infection and COVID-19 Vaccine Coverage in Healthcare Workers in England, Multicentre Prospective Cohort Study (the SIREN Study). Preprint The Lancet February 22, 2021. Analysis of vaccinated (with the Pfizer- BioNTech vaccine) and unvaccinated health care workers who underwent regular screening for SARS-CoV-2 in the UK, including every other week PCR testing and some who had twice weekly rapid tests confirmed by PCR. 23,324 health care workers met inclusion criteria from 104 hospitals. In those without past COVID-19 and assessing SARS-CoV-2 infection rates by PCR (with or without symptoms), a single dose of Pfizer-BioNTech vaccine was 72% (95% CI: 58 to 86%) effective at ≥21 days after vaccination. The effect was first noted on day 10 and plateaued after 21 days.

Note that updated data was published by Public Health England showing no evidence of a decline in effectiveness with good protection out to the period between 58 and 81 daysFootnote 26.
Vasileiou E et al., Effectiveness of First Dose of COVID-19 Vaccines Against Hospital Admissions in Scotland: National Prospective Cohort Study of 5.4 Million People. SSRN-Lancet preprint. February 19, 2021. Prospective cohort study using national linked administrative data from Scotland (5.4 million people) to assess COVID-19 hospitalizations comparing unvaccinated and vaccinated individuals by time from vaccination after a single dose of either the Pfizer- BioNTech or AstraZeneca vaccine. Hospital admission was defined as: COVID-19 as the main cause of admission or hospitalization within 28 days of a positive PCR SARS-CoV-2 test. Covariates were controlled for using a number of analyses. VE against hospitalization using Pfizer-BioNTech peaked at:
  • 85% (95% CI: 76 to 91%) 28 to 34 days after one dose.

VE against hospitalization using AstraZeneca peaked at:

  • 94% (95% CI: 73 to 99%) 28 to 34 days after one dose

Note: For the AstraZeneca vaccine, the VE against hospitalization was high (70%, 95% CI: 63 to 76%) even within 7 to 13 days after one dose, which would be too early to have an impact on hospitalization, making the results challenging to interpret.

Lopez Bernal J. et al., Early effectiveness of COVID-19 vaccination with BNT162b2 mRNA vaccine and ChAdOx1 adenovirus vector vaccine on symptomatic disease, hospitalisations and mortality in older adults in the UK: a test negative case control study. Preprint. March 1, 2021 and
Public Health England. Vaccine effectiveness report. March 17, 2021
Test negative-case control study using linked surveillance data in the UK. Assessed the Pfizer-BioNTech and AstraZeneca vaccines in those ≥70 years of age (over 7.5 million). PCR tests were within 10 days of onset of symptoms. For those who were vaccinated, cases (PCR positive) and controls (PCR negative) were assessed by time since vaccination to onset of symptoms. Controlled for covariates such as age, gender, deprivation and ethnicity, geography, period of time and care home status. A post-hoc analysis using days 4-9 post-vaccination as the baseline was conducted. The impact of vaccination on hospitalization and deaths for cases was assessed. For the Pfizer-BioNTech vaccine in those ≥80 years of age, with vaccination before January 4, 2021 VE against symptomatic COVID-19 was:
  • 61% (95% CI: 45 to 71%) 42 or more days (maximum ~75 days) after vaccination using the test negative design
  • 72% (95% CI: 60 to 80%) 42 or more days (maximum ~75 days) after one dose of vaccine compared to the 4-9 days post-vaccination
For the Pfizer-BioNTech vaccine in those ≥70 years of age, with vaccination from January 4, 2021 to February 21, 2021, VE against symptomatic COVID-19 was:
  • 61% (95% CI: 51 to 69%) 28 to 34 days and 57% (95% CI: 36 to 71%) 35 or more days (maximum ~48 days) after vaccination using the test negative design
For the AstraZeneca vaccine in those ≥70 years of age, with vaccination from January 4, 2021 to February 21, 2021 VE was:
  • 60% (95% CI: 41% to 73%) 28 to 34 days and 73% (95% CI: 27 to 90%) 35 or more days (maximum ~48 days) after vaccination using the test negative design; Note: the latter estimate is based on small numbers of cases
Hospitalization within 14 days of a positive test and death within 21 days of a positive test for those ≥80 years of age:
  • For those who did get symptomatic disease and tested positive 14 or more days after vaccination, there was an additional 43% and 37% protection against hospitalization with the Pfizer-BioNTech and AstraZeneca vaccines, respectively.
  • For those who did get symptomatic disease and tested positive 14 or more days after vaccination, there was an additional 51% protection against death with the Pfizer-BioNTech vaccine (data not available for AstraZeneca).
The report from Public Health England covering the same period noted VE against symptomatic disease in those ≥70 years of age of:
  • 58% (95% CI: 49 to 65%) for Pfizer-BioNTech from 28 days post-vaccination; and
  • 58% (95% CI: 38 to 72%) for AstraZeneca from 35 days after vaccination
For those ≥80 years of age, hospitalizations were reduced by 80% for both vaccines combined and deaths were reduced by 85% for the Pfizer-BioNTech vaccine (not assessed for AstraZeneca).
Weekes M et al., Single-dose BNT162b2 vaccine protects against asymptomatic SARS-CoV-2 infection. Preprint Authorea. February 24, 2021. A prospective cohort studies of health care workers in Cambridge University hospitals in the UK assessing the Pfizer-BioNTech vaccine. Health care workers were screened weekly for SARS-CoV-2 and percent positivity and cycle threshold values over two consecutive week periods were reported based on unvaccinated workers and those vaccinated <12 days or >12 days before a PCR positive test. Comparing unvaccinated, vaccinated < 12 days and vaccinated >12 days, percent positivity for asymptomatic workers was 0.8%, 0.37% and 0.20% - representing a four-fold decrease in risk from unvaccinated to >12 days after vaccination and a calculated VE of 75%.

Assessing both symptomatic and asymptomatic workers, percent positivity was 1.71% in unvaccinated and 0.40% those vaccinated >12 days previously - representing a 4.3- fold reduction in risk and a calculated VE of 76.6%.

Note: Study does not indicate if they excluded previously positive health care workers and VE calculated from rates provided in the study.
Hyams C, et al. Assessing the Effectiveness of BNT162b2 and ChAdOx1nCoV-19 COVID-19 Vaccination in Prevention of Hospitalisations in Elderly and Frail Adults: A Single Centre Test Negative Case-Control Study. Preprint - The Lancet. March 3, 2021 Test-negative case control study of 466 hospitalized people ≥80 years of age (many of whom were frail with comorbidities) in two hospitals in Bristol, UK. Patients admitted with two or more signs of respiratory illness, or a confirmed clinical or radiological diagnosis of acute lower respiratory disease were selected for inclusion (466 eligible people ≥80 years of age). Cases were PCR positive and controls were PCR negative. Vaccination was determined by record linkage. VE was assessed for the Pfizer-BioNTech and AstraZeneca in those who had been vaccinated ≥14 days before symptom onset. For Pfizer-BioNTech the VE for hospitalization with a positive laboratory test and symptom onset ≥14 days after vaccination (maximum 80 days):
  • 71.4% (95% CI: 43.1 to 86.2%) for the entire time period from December 8, 2020
  • 79.3% (95% CI: 47.0 to 92.5%) for a later time period beginning January 4, 2021, which covers the same period as the AstraZeneca distribution
For AstraZeneca the VE for hospitalization with a positive laboratory test and symptom onset ≥14 days after vaccination (maximum 53 days):
  • 80.4% (95% CI: 36.4 to 94.5%) for the later time period beginning January 4, 2021
Note: Separate analyses seemed to have been conducted for AstraZeneca and Pfizer-BioNTech but it is unclear how the study subjects for each analysis were assigned.
Menni C et al. Vaccine after Effects and Post-Vaccine Infection in a Real World Setting: Results from the COVID Symptom Study App. SSRN-Lancet Preprint. March 4, 2021. Prospective cohort study of people using an app to report vaccination status and details (date of vaccination, Pfizer-BioNTech or AstraZeneca), adverse events post-vaccination, symptoms, testing and test results on a daily basis in the UK. 42,866 people vaccinated with Pfizer-BioNTech and 16,773 people vaccinated with AstraZeneca who had at least one test (PCR or lateral flow rapid test) were included in this part of the analysis. Rates of positive tests were compared among vaccinated people (by date since first vaccination) and unvaccinated people who had a test on the same day. Rates were adjusted for age, sex, body mass index, smoking, race/ethnicity, health care status and the presence of comorbidities. Information was available for 42,866 people who received the Pfizer-BioNTech vaccine and 16,773 people who received the AstraZeneca vaccine. For the Pfizer-BioNTech vaccine, VE based on self-reported test results and vaccination status with one dose was:
  • 57% (95% CI: 38 to 71%) 12 to 21 days after vaccination
  • 68% (95% CI: 47 to 81%) 21 to 30 days after vaccination
  • 70% (95% CI: 57 to 100%) more than 30 days after vaccination
For the AstraZeneca vaccine, VE based on self-reported test results and vaccination status was:
  • 42% (95% CI: 17 to 71%) 12 to 21 days after vaccination
Note: Data is self-reported which may affect validity.
Lumley SF et al. An observational cohort study on the incidence of SARS-CoV-2 infection and B.1.1.7 variant infection inhealthcare workers by antibody and vaccination status. MedRxiv. March 12, 2021 A longitudinal cohort study of 13,109 healthcare workers (HCWs) in four hospitals and associated facilities in Oxfordshire, UK who received Pfizer-BioNTech or AstraZeneca vaccine (8,285 received the Pfizer-BioNTech vaccine [1,407 two doses] and 2,738 the Oxford-AstraZeneca vaccine [49 two doses]). Asymptomatic swabbing was offered every two weeks and serology every two months. VE against symptomatic and asymptomatic PCR-confirmed SARS-CoV-2 infection was estimated using Poisson regression adjusted for age, sex and temporal changes in incidence and role. At >14 days following vaccination in previously seronegative HCWs compared to unvaccinated seronegative HCWs:
  • PCR-confirmed symptomatic infection was 67% (95% CI: 48 to 79%) lower
  • any PCR-positive result (with or without symptoms) was 64% (95% CI: 50 to 74%) lower
Shah ASV et al., Effect of vaccination on transmission of COVID-19: an observational study in healthcare workers and their households. medRxiv. March 21, 2021. A cohort study using record linkage from multiple national data sets of 144,525 healthcare workers (HCWs) and 194,362 household members in Scotland. 78.3% of healthcare workers received at least one dose of the Pfizer-BioNTech or AstraZeneca vaccine and 25.1% received two doses. Cox regression models were used to estimate hazard ratios for the effect of vaccination (≥14 days) on SARS-CoV-2 PCR positive cases and hospitalization (within 28 days of a positive PCR test or PCR positive while in hospital). Co-variates included age, sex, deprivation index, ethnicity, comorbidities, health care worker roles, occupation and part-time status. Compared to unvaccinated health care workers, VE against PCR positive SARS-CoV-2 ≥14 days after vaccination was 55% (95% CI: 51 to 58%) and against hospitalization was 84% (95% CI: 73 to 91%).
Azamgarhi et al., Experience of COVID-19 Vaccination of Healthcare Workers in a Hospital Setting. ResearchSquare Preprint. March 9, 2021. Single centre hospital in the UK assessing VE against PCR positive disease in health care worker who were screened every two weeks.
1,373 out of 2,257 health care workers were vaccinated using the Pfizer-BioNTech vaccine.
Health care workers were classified as unvaccinated, vaccinated between days 0 and 13 and vaccinated 14 or more days in the past.
Outcome was time to symptoms or to PCR positive test if asymptomatic. Adjusted for age, sex, staff group and ethnicity.
VE against PCR positive disease comparing those vaccinated 14 or more days previously and unvaccinated health care workers was 80% (95% CI: 21 to 95%). Based on 45 new cases and follow-up to 42 days post vaccination.
Denmark: Effectiveness data
Moustsen-Helms et al., Vaccine effectiveness after 1st and 2nd dose of the BNT162b2 mRNA Covid-19 Vaccine in long-term care facility residents and healthcare workers - a Danish cohort study. medRxiv. March 9, 2021. Registry- and population-based observational cohort study using linkages to vaccination and laboratory data bases.
Studied all long term care facility residents (39,040) and all frontline health care workers (331,039) using PCR-confirmed outcomes (symptomatic and asymptomatic). Compared rates in unvaccinated to those vaccinated at various intervals related to first and second dose of the Pfizer-BioNTech vaccine in Denmark.
Days between first and second doses were 24 (IQR 20 to 52) and 25 (IQR 20 to 51) for long-term care home residents and health care workers, respectively.
VE for nursing home residents (adjusted for calendar time and unadjusted):
  • 21% (95% CI: - 0.11 to 44%) and 60% (95% CI: 46 to 71%) >14 days after vaccination to dose 2
  • 52% (95% CI: 27 to 69%) and 80% (95% CI: 70 to 88%) 0-7 days after dose 2
  • 64% (95% CI: 14 to 84%) and 96% (95% CI: 91 to 98%) >7 days after dose 2
VE for health care workers (adjusted for calendar time and unadjusted):
  • 17% (95% CI: 4 to 28%) and 50% (95% CI: 29 to 66%) >14 days after vaccination to dose 2
  • 46% (95% CI: 28 to 59%) and 77% (95% CI: 57 to 90%) 0-7 days after dose 2
  • 90% (95% CI: 82 to 95%) and 97% (95% CI: 90 to 100%) >7 days after dose 2
Note: The VE was negative in the first time period after vaccination (0-14 days) which was made worse by adjusting for calendar time, indicating potential methodologic bias which may underestimate the vaccine effectiveness.

Additional studies that assessed one-dose of a COVID-19 vaccine were reviewed but were not included in the analysis because they did not provide a definitive VE estimateFootnote 56Footnote 57Footnote 58Footnote 59Footnote 60.

Table 2: 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

Abbreviation
Term
CI
Confidence interval
EEFA
Ethics, equity, feasibility, and acceptability
HCW
Health care worker
LTCF
Long-term care facility
mRNA
Messenger ribonucleic acid
NACI
National Advisory Committee on Immunization
PCR
Polymerase chain reaction
PHAC
Public Health Agency of Canada
VE
Vaccine effectiveness

Acknowledgments

This statement was prepared by: B Warshawsky, M Salvadori, O Baclic, A Nam, MW Yeung, R Ximenes, K Farrah, YE Chung, M Tunis, S Deeks, and C Quach on behalf of NACI.

NACI gratefully acknowledges the contribution of: Dr. N Andrews, Dr. G De Serres, V Ferrante, Dr. A Iorio, Dr. S Ismail Dr. L Linkins, Dr. J Little, Dr. T Piggott, K Ramotar, Dr. D Skowronski, E Wong, K Young, and the NACI Secretariat.

NACI

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

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

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

NACI High Consequence Infectious Disease Working Group

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

PHAC Participants: N Abraham, O. Baclic, YE Chung, L Coward, P Doyon-Plourde, K Farrah, V Ferrante, N Forbes, SJ Ismail, C. Jensen, A Killikelly, R Krishnan, A Nam, M Patel, M Salvadori, A Sinilaite, R Stirling, E Tice, M Tunis, Ms. E Wong, MW Yeung, K Young, J Zafack, and B Warshawsky.

Footnotes

Footnote 1

Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020 Dec 31;383(27):2603,2615. doi: 10.1056/NEJMoa2034577.

Return to footnote 1 referrer

Footnote 2

Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021 Feb 4;384(5):403,416. doi: 10.1056/NEJMoa2035389.

Return to footnote 2 referrer

Footnote 3

Skowronski DM, De Serres G. Safety and efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2021 Feb 17;384(11):10.1056/NEJMc2036242#sa1. doi: 10.1056/NEJMc2036242.

Return to footnote 3 referrer

Footnote 4

Moderna. Vaccines and Related Biological Products Advisory Committee Meeting December 17, 2020. FDA Briefing Document. Moderna COVID-19 Vaccine [Internet].; 2020 Dec [cited 2020 Dec 23]. Available from: https://www.fda.gov/media/144434/download.

Return to footnote 4 referrer

Footnote 5

Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, Aley PK, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021 Jan 9;397(10269):99,111. doi: 10.1016/S0140-6736(20)32661-1.

Return to footnote 5 referrer

Footnote 6

Amit S, Regev-Yochay G, Afek A, Kreiss Y, Leshem E. Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients. The Lancet. 2021 Mar 6;397(10277):875,877. doi: 10.1016/S0140-6736(21)00448-7.

Return to footnote 6 referrer

Footnote 7

Aran D. Estimating real-world COVID-19 vaccine effectiveness in Israel using aggregated counts. medRxiv. 2021 Feb 23. doi: https://doi.org/10.1101/2021.02.05.21251139.

Return to footnote 7 referrer

Footnote 8

Chodick G, Tene L, Patalon T, Gazit S, Tov AB, Cohen D, et al. The effectiveness of the first dose of BNT162b2 vaccine in reducing SARS-CoV-2 infection 13-24 days after immunization: real-world evidence. medRxiv. 2021 Jan 29. doi: https://doi.org/10.1101/2021.01.27.21250612.

Return to footnote 8 referrer

Footnote 9

Dagan N, Barda N, Kepten E, Miron O, Perchik S, Katz MA, et al. BNT162b2 mRNA Covid-19 Vaccine in a nationwide mass vaccination setting. N Engl J Med. 2021 Feb 24. doi: 10.1056/NEJMoa2101765.

Return to footnote 9 referrer

Footnote 10

Zacay G, Shasha D, Bareket R, Kadim I, Sikron FH, Tsamir J, et al. BNT162b2 vaccine effectiveness in preventing asymptomatic infection with SARS-CoV-2 virus: A nationwide historical cohort study. SSRN- Lancet prepublication. 2021 Mar 3. https://dx.doi.org/10.2139/ssrn.3796868.

Return to footnote 10 referrer

Footnote 11

Hunter PR, Brainard J. Estimating the effectiveness of the Pfizer COVID-19 BNT162b2 vaccine after a single dose. A reanalysis of a study of 'real-world' vaccination outcomes from Israel. medRxiv. 2021 Feb 3. doi: https://doi.org/10.1101/2021.02.01.21250957.

Return to footnote 11 referrer

Footnote 12

Comité sur l'immunisation du Québec. Preliminary data on vaccine effectiveness and supplementary opinion on the strategy for vaccination against COVID-19 in Quebec in a context of shortage [Internet]. Québec (QC): Institut national de santé publique du Québec (INSPQ) [updated 2021 Mar 18; cited 2021 Mar 18]. Available from: https://www.inspq.qc.ca/en/publications/3111-vaccine-effectiveness-strategy-vaccination-shortage-covid19.

Return to footnote 12 referrer

Footnote 13

Personal communication, as per Danuta M Skowronski, Lead for Influenza & Emerging Respiratory Pathogens, BC Centre for Disease Control following presentation to NACI on February 24, 2021.

Return to footnote 13 referrer

Footnote 14

Personal communication, as per Gaston De Serres (l'Institut national de santé publique du Québec) following presentation to NACI on February 24, 2021

Return to footnote 14 referrer

Footnote 15

Britton A, Jacobs Slifka KM, Edens C, Nanduri SA, Bart SM, Shang N, et al. Effectiveness of the Pfizer-BioNTech COVID-19 Vaccine among residents of two skilled nursing facilities experiencing COVID-19 outbreaks - Connecticut, December 2020-February 2021. MMWR Morb Mortal Wkly Rep. 2021 Mar 19;70(11):396,401. doi: 10.15585/mmwr.mm7011e3.

Return to footnote 15 referrer

Footnote 16

Pawlowski C, Lenehan P, Puranik A, Agarwal V, Venkatakrishnan AJ, Niesen MJM, et al. FDA-authorized COVID-19 vaccines are effective per real-world evidence synthesized across a multi-state health system. medRxiv. 2021 Feb 27. doi: https://doi.org/10.1101/2021.02.15.21251623.

Return to footnote 16 referrer

Footnote 17

Tande AJ, Pollock BD, Shah ND, Farrugia G, Virk A, Swift M, et al. Impact of the COVID-19 vaccine on asymptomatic infection among patients undergoing pre-procedural COVID-19 molecular screening. Clin Infect Dis. 2021 Mar 10;ciab229. doi: 10.1093/cid/ciab229.

Return to footnote 17 referrer

Footnote 18

Weekes M, Jones NK, Rivett L, Workman C, Ferris M, Shaw A, et al. Single-dose BNT162b2 vaccine protects against asymptomatic SARS-CoV-2 infection. Authorea. 2021 Feb 24. doi: 10.22541/au.161420511.12987747/v1.

Return to footnote 18 referrer

Footnote 19

Vasileiou E, Simpson CR, Robertson C, Shi T, Kerr S, Agrawal U, et al. Effectiveness of first dose of COVID-19 vaccines against hospital admissions in Scotland: national prospective cohort study of 5.4 million people. SSRN- Lancet prepublication. 2021 Feb 19. https://dx.doi.org/10.2139/ssrn.3789264.

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Footnote 20

Shah ASV, Gribben C, Bishop J, Hanlon P, Caldwell D, Wood R, et al. Effect of vaccination on transmission of COVID-19: an observational study in healthcare workers and their households. medRxiv. 2021 Mar 21. doi: 10.1101/2021.03.11.21253275.

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Footnote 21

Menni C, Klaser K, May A, Polidori L, Capdevila J, Louca P, et al. Vaccine after effects and post-vaccine infection in a real world setting: Results from the COVID Symptom Study App. SSRN- Lancet prepublication. 2021 Mar 4. https://dx.doi.org/10.2139/ssrn.3795344.

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Footnote 22

Lumley SF, Rodger G, Constantinides B, Sanderson N, Chau KK, Street TL, et al. An observational cohort study on the incidence of SARS-CoV-2 infection and B.1.1.7 variant infection in healthcare workers by antibody and vaccination status. medRxiv. 2021 Mar 12. doi: 10.1101/2021.03.09.21253218.

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Footnote 23

Hyams C, Marlow R, Maseko Z, King J, Ward L, Fox K, et al. Assessing the effectiveness of BNT162b2 and ChAdOx1nCoV-19 COVID-19 vaccination in prevention of hospitalisations in elderly and frail adults: A single centre test negative case-control study. SSRN- Lancet prepublication. 2021 Mar 3. doi: https://dx.doi.org/10.2139/ssrn.3796835.

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Footnote 24

Hall VJ, Foulkes S, Saei A, Andrews N, Oguti B, Charlett A, et al. Effectiveness of BNT162b2 mRNA vaccine against infection and COVID-19 vaccine coverage in healthcare workers in England, multicentre prospective cohort study (the SIREN Study). SSRN- Lancet prepublication. 2021 Mar 9. doi: 10.21203/rs.3.rs-257937/v1.

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Footnote 25

Lopez Bernal J, Andrews N, Gower C, Stowe J, Robertson C, Tessier E, et al. Early effectiveness of COVID-19 vaccination with BNT162b2 mRNA vaccine and ChAdOx1 adenovirus vector vaccine on symptomatic disease, hospitalisations and mortality in older adults in England. medRxiv. 2021 Mar 2. doi: https://doi.org/10.1101/2021.03.01.21252652.

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Footnote 26

Public Health England vaccine effectiveness report [Internet]. London (UK): Public Health England; 2021 March 17 [cited 2021 March 18]. Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/971017/SP_PH__VE_report_20210317_CC_JLB.pdf.

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Footnote 27

Azamgarhi T, Hodgkinson M, Shah A, Skinner J, Briggs T, Hauptmannova I, et al. Experience of COVID-19 vaccination of healthcare workers in a hospital setting. Research Square preprint. 2021 Mar 9. doi: 10.21203/rs.3.rs-257937/v1.

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Footnote 28

Moustsen-Helms I, Emborg H, Nielsen J, Nielsen KF, Krause TG, Mølbak K, et al. Vaccine effectiveness after 1st and 2nd dose of the BNT162b2 mRNA Covid-19 Vaccine in long-term care facility residents and healthcare workers - a Danish cohort study. medRxiv. 2021 Mar 9. doi: 10.1101/2021.03.08.21252200.

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Footnote 29

Guijarro C, Galán I, Martínez-Ponce D, Pérez-Fernández E, José Goyanes M, Castilla V, et al. Dramatic drop of new SARS-CoV-2 infections among health care workers after the first dose of the BNT162b2 mRNA Covid-19 Vaccine. medRxiv. 2021 Cold Spring Harbor Laboratory Press:2021.03.24.21254238.

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Footnote 30

Thompson MG, Burgess JL, Naleway AL, Tyner HL, Yoon SK, Meece J, et al. Interim estimates of vaccine effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines in preventing SARS-CoV-2 infection among health care personnel, first responders, and other essential and frontline workers - eight U.S. locations, December 2020-March 2021. MMWR Morb Mortal Wkly Rep. ePub: 29 March 2021. doi: http://dx.doi.org/10.15585/mmwr.mm7013e3.

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Footnote 31

Haas EJ, Angulo FJ, McLaughlin JM, Anis E, Singer SR, Khan F, et al. Nationwide vaccination campaign with BNT162b2 in Israel demonstrates high vaccine effectiveness and marked declines in incidence of SARS-CoV-2 infections and COVID-19 cases, hospitalizations, and deaths. SSRN- Lancet prepublication. 2021 Mar 24. https://ssrn.com/abstract=381138.

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Footnote 32

Plotkin SA, Halsey N. Accelerate coronavirus disease 2019 (COVID-19) vaccine rollout by delaying the second dose of mRNA vaccines. Clin Infect Dis. 2021 Jan 27;ciab068. doi: 10.1093/cid/ciab068.

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Footnote 33

Public Health Agency of Canada (PHAC). Canadian Immunization Guide [Internet]. Ottawa (ON): PHAC [updated 2021 Mar 26; cited 2021 Mar 31]. Available from: https://www.canada.ca/en/public-health/services/canadian-immunization-guide.html.

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Footnote 34

Plotkin SA, Orenstein WA, Offit PA. Plotkin's vaccines. 7th ed. ed. Philadelphia, PA: Elsevier; 2018.

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Footnote 35

FDA Briefing Document. Janssen Ad26.COV2.S Vaccine for the prevention of COVID-19. Vaccines and Related Biological Products Advisory Committee Meeting February 26, 2021. [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2021 [cited 2021 March 17]. Available from: https://www.fda.gov/media/146217/download.

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Footnote 36

Emary KRW, Golubchik T, Aley PK, Ariani CV, Angus B, Bibi S, et al. Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial. Lancet. 2021 Mar 30. doi:https://doi.org/10.1016/S0140-6736(21)00628-0.

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Footnote 37

Moghadas SM, Vilches TN, Zhang K, Nourbakhsh S, Sah P, Fitzpatrick MC, et al. Evaluation of COVID-19 vaccination strategies with a delayed second dose. medRxiv. 2021 Jan 29. doi: https://doi.org/10.1101/2021.01.27.21250619.

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Footnote 38

Matrajt L, Eaton J, Leung T, Dimitrov D, Schiffer JT, Swan DA, et al. Optimizing vaccine allocation for COVID-19 vaccines: critical role of single-dose vaccination. medRxiv. 2021 Mar 3. doi: https://doi.org/10.1101/2020.12.31.20249099.

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Footnote 39

Paltiel AD, Zheng A, Schwartz JL. Speed versus efficacy: Quantifying potential tradeoffs in COVID-19 vaccine deployment. Ann Intern Med. 2021 Jan 5;M20-7866. doi: 10.7326/M20-7866.

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Footnote 40

Tuite AR, Zhu L, Fisman DN, Salomon JA. Alternative dose allocation strategies to increase benefits from constrained COVID-19 vaccine supply. Ann Intern Med. 2021 Jan 5;M20-8137. doi: 10.7326/M20-8137.

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Footnote 41

Graham J. Modelling decay of population immunity with proposed second dose deferral strategy. medRxiv. 2021 Jan 6. doi: https://doi.org/10.1101/2021.01.05.21249293.

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Footnote 42

Cobey S, Larremore DB, Grad YH, Lipsitch M. Concerns about SARS-CoV-2 evolution should not hold back efforts to expand vaccination. Nature Reviews Immunology. 2021 04/01.

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Footnote 43

Madhi SA, Baillie V, Cutland CL, Voysey M, Koen AL, Fairlie L, et al. Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. N Engl J Med. 2021 Mar 16. doi: 10.1056/NEJMoa2102214.

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Footnote 44

Shrotri M, Krutikov M, Palmer T, Giddings R, Azmi B, Subbarao S, et al. Vaccine effectiveness of the first dose of ChAdOx1 nCoV-19 and BNT162b2 against SARS-CoV-2 infection in residents of Long-Term Care Facilities (VIVALDI study). medRxiv. 2021 Mar 26. doi: https://doi.org/10.1101/2021.03.26.21254391

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Footnote 45

Ward H, Cooke G, Whitaker M, Redd R, Eales O, Brown JC, et al. REACT-2 Round 5: increasing prevalence of SARS-CoV-2 antibodies demonstrate impact of the second wave and of vaccine roll-out in England. medRxiv. 2021 Mar 1. doi: 10.1101/2021.02.26.21252512.

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Footnote 46

Brockman MA, Mwimanzi F, Sang Y, Ng K, Agafitei O, Ennis S, et al. Weak humoral immune reactivity among residents of long-term care facilities following one dose of the BNT162b2 mRNA COVID-19 vaccine. medRxiv. 2021 Mar 24. doi: https://doi.org/10.1101/2021.03.17.21253773.

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Footnote 47

Müller L, Andrée M, Moskorz W, Drexler I, Walotka L, Grothmann R, et al. Age-dependent immune response to the Biontech/Pfizer BNT162b2 COVID-19 vaccination. medRxiv. 2021 Cold Spring Harbor Laboratory Press:2021.03.03.21251066.

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Footnote 48

Whitaker H, Elgohari S, Rowe C, Otter A, Brooks T, Linley E, et al. Impact of COVID-19 vaccination program on seroprevalence in blood donors in England, 2021. SSRN. 2021 Mar 16. https://papers.ssrn.com/abstract=3803380.

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Footnote 49

Subbarao S, Warrener LA, Hoschler K, Perry KR, Shute J, Whitaker H, et al. Robust antibody responses in 70-80-year-olds 3 weeks after the first or second doses of Pfizer/BioNTech COVID-19 vaccine, United Kingdom, January to February 2021. Euro Surveill. 2021 Mar 25. doi: 10.2807/1560-7917.ES.2021.26.12.2100329.

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Footnote 50

Boyarsky BJ, Werbel WA, Avery RK, Tobian AAR, Massie AB, Segev DL, et al. Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients. JAMA. 2021 Mar 15. doi: 10.1001/jama.2021.4385.

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Footnote 51

Monin-Aldama L, Laing AG, Muñoz-Ruiz M, McKenzie DR, Barrio IdMd, Alaguthurai T, et al. Interim results of the safety and immune-efficacy of 1 versus 2 doses of COVID-19 vaccine BNT162b2 for cancer patients in the context of the UK vaccine priority guidelines. medRxiv. 2021 Mar 17. doi: 10.1101/2021.03.17.21253131

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Footnote 52

Benotmane I, Gautier-Vargas G, Cognard N, Olagne J, Heibel F, Braun-Parvez L, et al. Weak anti-SARS-CoV-2 antibody response after the first injection of an mRNA COVID-19 vaccine in kidney transplant recipients. medRxiv. 2021 Cold Spring Harbor Laboratory Press:2021.03.08.21252741.

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Footnote 53

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. Vaccine. 2020 Aug 10;38(36):5861,5876. doi: 10.1016/j.vaccine.2020.05.051.

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Footnote 54

Collier DA, Ferreira IA, Datir R, Meng B, Bergamaschi L, Collaboration C, et al. Age-related heterogeneity in neutralising antibody responses to SARS-CoV-2 following BNT162b2 vaccination. The Lancet Preprint. 2021 Feb 11.

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Footnote 55

Janssen Inc. Product monograph including patient medication information. Janssen COVID-19 Vaccine. SARS-CoV-2 Vaccine [Ad26.COV2.S, recombinant]. Suspension for intramuscular injection [Internet]. Ottawa (ON): Health Canada; 2021 Mar 5 [cited 2021 Mar 30]. Available from: https://covid-vaccine.canada.ca/info/pdf/janssen-covid-19-vaccine-pm-en.pdf.

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Footnote 56

Benenson S, Oster Y, Cohen MJ, Nir-Paz R. BNT162b2 mRNA Covid-19 vaccine effectiveness among health care workers. N Engl J Med. 2021 Mar 23. doi: 10.1056/NEJMc2101951.

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Footnote 57

Hollinghurst J, North L, Perry M, Akbari A, Gravenor MB, Lyons RA, et al. COVID-19 infection risk amongst 14,104 vaccinated care home residents: A national observational longitudinal cohort study in Wales, United Kingdom, December 2020 to March 2021. medRxiv. 2021 Mar 24. doi: 10.1101/2021.03.19.21253940.

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Footnote 58

Daniel W, Nivet M, Warner J, Podolsky DK. Early evidence of the effect of SARS-CoV-2 vaccine at one medical center. N Engl J Med. 2021 Mar 23. doi: 10.1056/NEJMc2102153.

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Footnote 59

Keehner J, Horton LE, Pfeffer MA, Longhurst CA, Schooley RT, Currier JS, et al. SARS-CoV-2 infection after vaccination in health care workers in California. N Engl J Med. 2021 Mar 23. doi: 10.1056/NEJMc2101927.

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Footnote 60

Yelin I, Katz R, Herzel E, Berman-Zilberstein T, Ben-Tov A, Kuint J, et al. Associations of the BNT162b2 COVID-19 vaccine effectiveness with patient age and comorbidities. medRxiv. 2021 Mar 17. doi: 10.1101/2021.03.16.21253686.

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