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]

On this page

• Preamble
• Introduction
• Methods
• Evidence
  • Efficacy and effectiveness of the first dose of the available COVID-19 vaccines
  • Duration of protection following the first dose of the available 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
  • Impact of rapidly vaccinating more people with the available supply of COVID-19 vaccines
  • Modelling information on the impact of extending the interval between the first and second doses of COVID-19 vaccines
  • Impact of extending the interval between doses of COVID-19 vaccines on variants of concern
  • Impact on specific population groups
  • Ethics, equity, feasibility, and acceptability of extending the interval to the second dose of COVID-19 vaccines authorized as a two-dose series
• Recommendation
• Tables
  • Table 1: Summary of efficacy and effectiveness data from the first dose of COVID-19 vaccines
  • Table 2: Strength of NACI recommendations
• List of abbreviations
• References

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:

• Efficacy and effectiveness of the first dose of the available COVID-19 vaccines
• Duration of protection following the first dose of the available COVID-19 vaccines
• Impact of extending the interval between the priming and boosting doses on the immune response and vaccine efficacy
• Impact of more rapidly vaccinating a greater number of people with the available supply of COVID-19 vaccines
• Modelling information on the impact of extending the interval between the first and second doses of COVID-19 vaccines
• Impact of extending the interval between doses of COVID-19 vaccines on variants of concern
• Impact on specific population groups
• Ethics, equity, feasibility, and acceptability of extending the interval to the second dose of COVID-19 vaccines authorized as a two-dose series.

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-BioNTech^{Footnote 1} and Moderna^{Footnote 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 dose^{Footnote 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 administration^{Footnote 5}.

Since publication of the clinical trials to March 26, 2021, studies with clear VE data have become available from Israel (5 studies^{Footnote 6Footnote 7Footnote 8Footnote 9Footnote 10}, one of which was re-analyzed^{Footnote 11}), Canada (several study designs and target populations in two provinces^{Footnote 12Footnote 13Footnote 14}), the United States (3 studies^{Footnote 15Footnote 16Footnote 17}), the United Kingdom (9 studies^{Footnote 18Footnote 19Footnote 20Footnote 21Footnote 22Footnote 23Footnote 24Footnote 25Footnote 26Footnote 27}, some with multiple components) and Denmark (1 study^{Footnote 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:

• Israel: Israel was using the Pfizer-BioNTech vaccine with the second dose administered approximately 21 days after the first dose. Therefore, one dose data is available only up to the time the second dose was administered.
• Canada: The Pfizer-BioNTech vaccine was authorized on December 9, 2020 and the Moderna vaccine was authorized on December 23, 2020. From December 2020 to early April 2021, approximately 75% of Canada's vaccines were supplied as Pfizer-BioNTech and 25% as Moderna. Data from Quebec is based on one dose, as the second dose was delayed for at least three months almost from the start of the provincial program. In British Columbia, provincial policy deferred the second dose to 5-6 weeks following the first dose; second-dose recipients were excluded to reflect the effect of a single dose.
• United States: The United States was administering both the Pfizer-BioNTech and Moderna vaccines with approximately a 21- and 28-day interval between doses, respectively. Therefore, one dose data is available only up to the time the second dose was administered.
• United Kingdom: The United Kingdom (UK) used only Pfizer-BioNTech from December 8, 2020 to January 3, 2021 and both AstraZeneca and Pfizer-BioNTech were used from January 4, 2021 onwards. Both products were given with an extended interval of 12 weeks between doses, except for a small number of people who received two doses of the Pfizer-BioNTech vaccine at shorter intervals.
• Denmark: Based on the one included study^{Footnote 28}, Denmark appears to have a two-dose schedule.

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).

• Symptomatic disease:
  • A large study from the UK found VE against symptomatic disease for both the Pfizer-BioNTech and AstraZeneca vaccines of 58% in adults ≥70 years of age^{Footnote 26}. Data from health care worker from four hospitals and associated facilities in the United Kingdom found a VE of 67% (combined results for Pfizer-BioNTech and AstraZeneca)^{Footnote 22}.
  • In studies in Israel, estimates of VE against symptomatic disease for Pfizer-BioNTech ranged from 57% in the general population^{Footnote 9} to 76% in health care workers^{Footnote 6}.
• Asymptomatic infection:
  • VE of 79% was reported in one study based on patients tested before medical or surgical procedures at Mayo clinic sites in the United States^{Footnote 17}.
  • VE of 75% was calculated based on test positivity in health care workers screened weekly in the UK^{Footnote 18}.
  • An exploratory analysis from Israel found a lower rate of 29%^{Footnote 9}, however there were methodological limitations noted in the study (see Table 1).
• PCR positive SARS-CoV-2 (symptomatic or asymptomatic): Many studies assessed this outcome with results as follows:
  • 55% in Scottish health care workers^{Footnote 20};
  • 61% in the Meuhedet Health Maintenance Organization in Israel^{Footnote 10};
  • 64% in health care workers in Oxfordshire, United Kingdom^{Footnote 22};
  • 65% in the Sheba Medical Centre in Israel^{Footnote 6};
  • 69% in the Mayo clinic health system in the United States^{Footnote 16};
  • 72% in health care workers in the SIREN study in the UK^{Footnote 24};
  • 77% calculated from test positivity in health care workers screened weekly in the UK ^{Footnote 18};
  • 80% in health care workers in a single hospital in the UK^{Footnote 27};
  • 70 to 90% in health care workers in Canada using Pfizer-BioNTech and Moderna^{Footnote 12Footnote 13Footnote 14}; and
  • 91% in the Maccabi Healthcare Services organization in Israel^{Footnote 8Footnote 11}.

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

• A study of frontline health care providers in Denmark found a 17% VE when adjusted for calendar time and 50% unadjusted vaccine effectiveness; methodologic limitations were noted in this study (see Table 1)^{Footnote 28}.
• A study of self-reported laboratory results found VE of 42% for AstraZeneca and 57% to 70% for Pfizer-BioNTech^{Footnote 21}.
• A study using administrative data from Israel found unusually low VE against positive cases for those > 60 and <60 years of age (0 and 12%) 14-20 days after the first dose, which was much higher 0-6 days after the second dose (73 and 77%) which may reflect, in part, a first dose effect^{Footnote 7}.
• A preprint released after March 26 (therefore not included in Table 1) describes vaccination of 2,116 health care workers in a medium-size hospital in Spain (including 30% of health care workers who were previously positive). New SARS-CoV-2 infections declined by 62% in the 2-4 weeks after the first dose of the Pfizer-BioNTech vaccine and virtually disappeared after the second dose. Community infection rates were also declining at the time but much less dramatically^{Footnote 29}.
• A study published after March 26 (therefore not included in Table 1) involved self-swabbing of 3,950 frontline workers in eight locations in the United States once weekly for 13 weeks as well as after symptom onset, and found a VE of one dose of Pfizer-BioNTech and/or Moderna of 80% (95% CI: 59 to 90%)^{Footnote 30}.
• Hospitalizations and deaths: VE estimates against hospitalizations were generally higher than for symptomatic and/or asymptomatic PCR positive SARS-CoV-2.
  • In mostly frail elderly patients in Bristol, UK, the Pfizer-BioNTech vaccine was 71 to 79% effective against hospitalizations and the AstraZeneca vaccine was 80% effective^{Footnote 23}.
  • A study from Israel using administrative data found VE of 81% 0-6 days after the second dose which likely represents the effect from the first dose^{Footnote 7}. See Table 1 for methodological considerations.
  • A study of health care workers from Scotland showed a VE against hospitalization of 84%^{Footnote 20}.
  • A study using national data for the population in Scotland found a VE of 85% for the Pfizer-BioNTech vaccine and 94% for AstraZeneca; some methodologic issues were noted with this study (see Table 1)^{Footnote 19}.
  • A study in the Clalit Health Services organization in Israel showed VE against hospitalization, severe disease and death of 74%, 62% and 72%, respectively, however methodologic issues were noted with these estimates^{Footnote 9} (see Table 1).
  • The largest study from Public Health England likely provides the most reliable estimates and showed that the Pfizer-BioNTech and AstraZeneca vaccines were approximately 80% effective against preventing hospitalizations in those ≥80 years of age, and the Pfizer-BioNTech vaccine was approximately 85% effective against preventing death in the same age group (the AstraZeneca vaccine was not studied against deaths)^{Footnote 26}.
• See Section 7 on specific population groups for data on residents in long-term care facilities.

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 hospitalization^{Footnote 26Footnote 23Footnote 19}, with one study also showing very good protection against deaths for the Pfizer-BioNTech vaccine^{Footnote 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:

• Observational studies include populations generally excluded from clinical trials (e.g., elderly residents in long-term care facilities).
• Both symptomatic and asymptomatic infection are often being studied in observational studies, whereas the clinical trials looked mainly at symptomatic disease.
• It is also possible that relaxing of public health measures and precautions by vaccinated people in the real world may be increasing their risk of infection, leading to lower VE estimates.

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:

• Unlike the clinical trials that assessed symptom onset dates, many of the effectiveness studies^{Footnote 8Footnote 10Footnote 12Footnote 13Footnote 14Footnote 16Footnote 18Footnote 20Footnote 22Footnote 24Footnote 27Footnote 28} used dates related to specimen collection or positive PCR results. Because specimen-related dates are often later than symptom onset dates, the impact of the first dose may only be noted later in the 14-to-21 day window, therefore underestimating the vaccine impact in that time period.
• Some studies assessing hospitalization or severe disease used the date of hospitalization or onset of severe disease^{Footnote 7Footnote 9Footnote 19} instead of the date of symptom onset in those who subsequently required hospitalization or developed severe disease. Two of these studies^{Footnote 9Footnote 19} noted unexpectedly high VE against hospitalization and/or severe disease in the early periods before the vaccine is expected to offer protection against infection and much sooner than the vaccine is expected to offer protection against hospital admission or onset of severe illness, raising methodological concerns.
• Unlike the clinical trials, most of the population included in effectiveness studies were not screened by PCR before entering the study (although those known to be previously positive were excluded in some studies). As a result, some subjects found to be PCR positive after vaccination may have acquired their infection before vaccination or in the earlier period after vaccination before the vaccine is expected to offer protection, which would underestimate the impact of the vaccine. The exceptions to this were the SIREN study by Hall et al.^{Footnote 24} and the study by Lumley et al.^{Footnote 22}, which screened all health care workers on a regular basis and assessed VE in only those who had no prior COVID-19.
• Studies that compare infection rates in the early post-vaccination period with the later period may be affected by the decreasing trends in community rates at the time^{Footnote 12Footnote 13Footnote 14}, which could overestimate VE in these studies.

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 vaccination^{Footnote 5}. Effectiveness data from Canada and the UK demonstrates protection from the mRNA vaccines based on analyses extending to about 8 weeks from vaccination^{Footnote 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 adults^{Footnote 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 doses^{Footnote 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 vaccine^{Footnote 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 response^{Footnote 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 combined^{Footnote 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 vaccine^{Footnote 31}. The clinical trial results for the Moderna^{Footnote 2} and Janssen^{Footnote 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 variant^{Footnote 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:

• mRNA vaccines were prioritized in descending order of age groups (given the risk of severe outcomes) until age 55 years and then vaccine was offered to those 20 to 54 years of age in no particular order;
• Coverage rates for adults aged 20-64 years and 65+ years were 65% and 80%, respectively
• The daily vaccination capacity was 150,000 doses in the first quarter (January to March, 2021) and increased to 350,000, 450,000, and 525,000 in the second quarter (April to June, 2021) and 525,000 (June to December, 2021);
• Given the limited evidence regarding waning protection for COVID-19 vaccines, first dose protection was lost at a rate of 1% per week (additional scenarios were run to test 4% and 8% loss per week).

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, 2021^{Footnote 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 model^{Footnote 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 limited^{Footnote 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 low^{Footnote 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 preferred^{Footnote 37}. Vaccine coverage and background transmission may also influence the preferred vaccine strategy^{Footnote 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 publication^{Footnote 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 AstraZeneca^{Footnote 26}) and Israel (Pfizer-BioNtech^{Footnote 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 Africa^{Footnote 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 a large study from Public Health England, VE of one dose of Pfizer-BioNTech or AstraZeneca vaccines against symptomatic disease in those ≥70 years of age was 58% with approximately 80% protection against hospitalization in those ≥80 years of age^{Footnote 26}. In addition, the Pfizer-BioNTech vaccine provided approximately 85% protection against death in those ≥80 years of age^{Footnote 26}.
• In mostly frail elderly patients in Bristol, United Kingdom, the Pfizer-BioNTech vaccines was 71 to 79% effective against hospitalizations and the AstraZeneca vaccine was 80% effective^{Footnote 23}.
• Surveillance-based data from long-term care facilities in British Columbia^{Footnote 13} and Quebec (INSPQ)^{Footnote 12Footnote 14} showed protection of 80 to 90% against PCR positive SARS-CoV-2 using Pfizer-BioNTech or Moderna vaccines in residents, noting that health care workers were also vaccinated which could provide indirect protection to residents as well.
• A study from Denmark found low VE against PCR-confirmed outcomes (symptomatic and asymptomatic combined) using the Pfizer-BioNTech vaccine in the adjusted analysis (21%, after adjustment for calendar time) from day 14 after the first dose to the second dose on approximately day 24, with higher VE of 60% in the unadjusted analysis, although methodological limitations were noted in this study (see Table 1)^{Footnote 28}.
• VE of 63% against SARS-CoV-2 infection, regardless of symptoms, using the Pfizer-BioNTech vaccine was noted in two outbreaks in skilled nursing facilities in the United States^{Footnote 15}.
• A more recently released preprint from the UK (Vivaldi study) (became available after March 26 therefore is not included in Table 1) assessed VE against PCR-positive SARS-CoV-2 among 10,412 residents from 310 long-term care facilities. The vast majority (85%) of PCR positive tests were identified following routine screening of residents; 7.5% of residents with a positive test were symptomatic at the time of routine testing. VE reached 65% (95% CI: 29 to 83%) for Pfizer-BioNTech and 68% (95% CI: 34 to 85%) for AstraZeneca, both between days 35 to 48 after vaccination^{Footnote 44}.

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.

• Based on home testing using lateral flow immunoassays, the percentage of participants with an IgG positive test was lower ≥21 days after one dose of the Pfizer-BioNTech vaccine in those ≥70 years of age, compared to younger age groups. IgG positivity was similarly high across all age groups after two doses of vaccine^{Footnote 45}.
• A small study using one dose of the Pfizer-BioNTech vaccine from British Columbia also showed lower binding and neutralizing antibody titres (based on a pseudovirus surrogate neutralization assay) among 12 residents of long term care homes compared to 18 health care workers^{Footnote 46}.
• A small study in the UK showed 8 of 15 (53%) subjects over 80 years of age reached the threshold titre for neutralizing antibodies three weeks after a first dose of the Pfizer-BioNTech vaccine, compared to 8 of 8 subjects under 80 years of age. All subjects developed a response after the second dose given three weeks after the firs^{Footnote 54}t.
• A study in a retirement home in Germany assessed immunogenicity in 93 participants <60 years of age (mean age 42 years) compared to 83 participants >80 years of age (mean age 88 years), 17-19 days after the first dose and 17 days after the second dose of the Pfizer-BioNTech vaccine. For the older group, 65.9% of participants and 10.6% of participants had spike specific IgG antibodies below the cut-off value after the first and second dose respectively, compared to 4.4% and 0% in the younger group. Both age groups showed low percentage of people developing neutralizing antibodies after the first dose (16.1% in the younger group and 1.2% in the older group). After the second dose, 97.8% of the younger group had a neutralizing antibodies compared to 68.7% of the older age group^{Footnote 47}.
• A survey of blood donors in England found that 75.8% (95% CI: 71.2 to 79.9%) of blood donors 70 to 84 years of age had antibodies against SARS-CoV-2 (with only 5.6% testing positive due to disease, as determined by antibodies against nucleoprotein)^{Footnote 48}.
• A study from the UK of adults aged 70-90 years assessed immunogenicity using five different tests (two assessing nucleoprotein to determine past SARS-CoV-2 infection and three assessing spike protein, to indicate vaccine response in those who are nucleoprotein negative) three weeks after first and second doses of Pfizer-BioNTech vaccination. Of the 92 individuals without evidence of previous infection (nucleoprotein negative) 77%, 77% and 95% were seropositive 3 weeks after one dose, depending on the spike protein assay used. Antibody levels were lower in those ≥80 years of age, compared to the younger age group. All 86 two-dose vaccine recipients were seropositive against spike protein in all three assays, with higher titres^{Footnote 49}.

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.

• A study of 436 solid organ transplant recipients showed that only 17% (95% CI: 14 to 21%) of people developed an antibody response a median of 20 days after one dose of the Pfizer-BioNTech or Moderna vaccines. Participants were more likely to have a detectable antibody level with the Moderna vaccine compared to the Pfizer-BioNTech vaccine, if they were not receiving anti-metabolite maintenance immunosuppression or if they were younger. The study did not assess the response after a second dose^{Footnote 50}.
• A study of 151 cancer patients (who had an average age of 73 years) compared to 54 younger healthier controls (40.5 years of age; most of whom were health care workers) found low antibody response 3 and 5 weeks after one dose of the Pfizer-BioNTech vaccine in those with solid tumors (that subsequently increased significantly after a booster dose at 21 days) and even lower antibody response in those with hematological malignancies. T cell responses were better than antibody responses in patients with both types of cancer. This study also assessed results of nose and throat swabs tested for SARS-CoV-2 by PCR in some patients (noting that there was limited compliance with this portion of the study). Up to day 21 post-vaccination, six patients were positive, two of whom died, while no new positive results were noted after day 21 post-vaccination^{Footnote 51}.
• A study of 241 kidney transplant recipients in France found that 10.8% had an antibody response 28 days after their first dose of Moderna vaccine. Patients who seroconverted had a longer time after their transplant, were receiving less immunosuppressive therapy and had better kidney function^{Footnote 52}.

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 recommendations^{Footnote 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.

• Ethics: Given the evolution of evidence on the level of protection offered by one dose of authorized COVID-19 vaccines, the balance of risks and benefits favours extending the interval between doses, especially in the context of high disease burden. This option could more quickly achieve Canada's immunization and pandemic response goals of enabling as many Canadians to be immunized against COVID-19 as quickly as possible, and minimizing serious illness and overall deaths while minimizing societal disruption as a result of the COVID-19 pandemic. In situations where informed consent included assumptions about second dose timing, jurisdictions may consider offering second doses at shorter intervals for those who provided consent for the vaccine series prior to the extended-interval recommendation.
• Equity: Extending the interval between doses allows many more eligible people to be vaccinated earlier, which considerably enhances equity compared to leaving large groups of people unvaccinated until the summer. However, some individuals who would have received two doses without the delayed second dose may become infected and symptomatic in the interval between the first and second dose, although these individuals are likely to experience less severe disease compared to if they had not been vaccinated^{Footnote 20Footnote 26}.
• Feasibility: The same number of doses need to be administered if vaccines are offered with an extended interval between doses or with a shorter interval, so extending the interval to the second dose will not require more vaccine administration capacity. Attention will need to be paid to ensure that people return for their second dose when it is offered, and this may be more logistically challenging with a longer interval. It should be noted that the second dose should be offered as soon as possible once first dose administration to all eligible populations approaches completion. The anticipated vaccine supply should support an interval of less than four months between doses.
• Acceptability: To minimize any adverse impact on public trust due to the off-label use of the COVID-19 vaccines and the change from the previous recommendation, transparent and clear communication with the public and those offered vaccines regarding the rationale for this recommendation will be important and should include the:
  • individual benefit for most people who will be receiving earlier vaccination that will provide good protection from COVID-19 disease and very good protection against its complications,
  • more robust and durable immune response that can be expected when a second dose is administered with a longer interval, and
  • the potential to provide indirect and community protection more rapidly.

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:

• 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 be offered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.

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:

• Morbidity and mortality from COVID-19 is ongoing and vaccine supply is limited. Extending the interval to the second dose allows vaccination of the largest number of people as quickly as possible, providing more people with direct protection and the possibility of indirect and community protection.
• An extended interval of up to four months allows as many eligible populations as possible to be offered vaccination with one dose before proceeding to offering second doses. However, as soon as all eligible groups have been offered their first dose of vaccine, second doses should be offered. The interval between first and second dose should not be extended any longer than needed to offer first doses of vaccine to all eligible individuals.
• This recommendation applies to all two-dose COVID-19 vaccines currently authorized for use and available in Canada.
• Should adolescents and/or children less than 16 years of age become eligible for vaccination in the near future, NACI will assess how these age groups are prioritized relative to those needing their second dose.
• Current evidence summarized in this document suggests very good vaccine efficacy against symptomatic COVID-19 from one dose of COVID-19 vaccines (92% efficacy for the mRNA vaccines^{Footnote 3Footnote 4}; 76% efficacy for the AstraZeneca vaccine^{Footnote 5}), with good effectiveness shown in observational studies (generally between 60 and 80%, with some lower and higher estimates) against symptomatic disease and/or asymptomatic infection, as well as very good effectiveness against hospitalization (approximately 80%) and death (approximately 85% based on one study from the UK^{Footnote 26}). While two doses of mRNA vaccines have shown excellent efficacy and effectiveness, one dose of mRNA vaccines appear to perform similarly to one or two doses of the AstraZeneca vaccine^{Footnote 5} and the single-dose Janssen vaccine^{Footnote 55}.
• Effectiveness has been documented for up to two months after the first dose of the mRNA vaccines, and the AstraZeneca clinical trial publication modelled one-dose efficacy up to 90 days after vaccination^{Footnote 5}.
• Informed expert opinion based on principles of immunology indicate that a longer interval between priming and boosting doses of a vaccine series results in a better, more durable response^{Footnote 34}. The AstraZeneca COVID-19 vaccine clinical trial demonstrated optimal efficacy when the interval between the first and second doses was ≥12 weeks^{Footnote 5}.
• In situations where informed consent included assumptions about second dose timing, jurisdictions may consider offering second doses at shorter intervals for those who provided consent for the vaccine series prior to implementation of this recommendation.
• Because of ongoing disease transmission and less than complete individual protection from vaccination in either one-dose or two-dose vaccinated people, ongoing compliance with public health measures (masking, physical distancing and limiting social interactions as per public health guidance) should continue at this time.
• The VE of the first dose will be monitored closely and the decisions regarding the second dose will be continuously assessed based on surveillance and effectiveness data and post-implementation study designs. In addition, effectiveness against variants of concern will also be monitored closely. If indicated based on these data, recommendations will be revised to offer earlier second doses to some cohorts or population groups.

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

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 estimate^{Footnote 56Footnote 57Footnote 58Footnote 59Footnote 60}.

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.