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. 2022 Nov 30;75(11):1980-1992.
doi: 10.1093/cid/ciac290.

Two-Dose Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine Effectiveness With Mixed Schedules and Extended Dosing Intervals: Test-Negative Design Studies From British Columbia and Quebec, Canada

Danuta M Skowronski  1   2 , Yossi Febriani  3 , Manale Ouakki  4 , Solmaz Setayeshgar  1 , Shiraz El Adam  1 , Macy Zou  5 , Denis Talbot  3   6 , Natalie Prystajecky  7   8 , John R Tyson  7 , Rodica Gilca  3   4   6 , Nicholas Brousseau  3   4   6 , Geneviève Deceuninck  3 , Eleni Galanis  1   2 , Chris D Fjell  7 , Hind Sbihi  2   5 , Elise Fortin  4   6   9 , Sapha Barkati  10 , Chantal Sauvageau  3   4   6 , Monika Naus  1   2 , David M Patrick  1   2 , Bonnie Henry  2   11 , Linda M N Hoang  7   8 , Philippe De Wals  3   4   6 , Christophe Garenc  3   4 , Alex Carignan  12 , Mélanie Drolet  3   6 , Agatha N Jassem  7   8 , Manish Sadarangani  13   14 , Marc Brisson  3   6 , Mel Krajden  7   8 , Gaston De Serres  3   4   6
Affiliations

Two-Dose Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine Effectiveness With Mixed Schedules and Extended Dosing Intervals: Test-Negative Design Studies From British Columbia and Quebec, Canada

Danuta M Skowronski et al. Clin Infect Dis. .

Erratum in

Abstract

Background: The Canadian coronavirus disease 2019 (COVID-19) immunization strategy deferred second doses and allowed mixed schedules. We compared 2-dose vaccine effectiveness (VE) by vaccine type (mRNA and/or ChAdOx1), interval between doses, and time since second dose in 2 of Canada's larger provinces.

Methods: Two-dose VE against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or hospitalization among adults ≥18 years, including due to Alpha, Gamma, and Delta variants of concern (VOCs), was assessed ≥14 days postvaccination by test-negative design studies separately conducted in British Columbia and Quebec, Canada, between 30 May and 27 November (epi-weeks 22-47) 2021.

Results: In both provinces, all homologous or heterologous mRNA and/or ChAdOx1 2-dose schedules were associated with ≥90% reduction in SARS-CoV-2 hospitalization risk for ≥7 months. With slight decline from a peak of >90%, VE against infection was ≥80% for ≥6 months following homologous mRNA vaccination, lower by ∼10% when both doses were ChAdOx1 but comparably high following heterologous ChAdOx1 + mRNA receipt. Findings were similar by age group, sex, and VOC. VE was significantly higher with longer 7-8-week versus manufacturer-specified 3-4-week intervals between mRNA doses.

Conclusions: Two doses of any mRNA and/or ChAdOx1 combination gave substantial and sustained protection against SARS-CoV-2 hospitalization, spanning Delta-dominant circulation. ChAdOx1 VE against infection was improved by heterologous mRNA series completion. A 7-8-week interval between first and second doses improved mRNA VE and may be the optimal schedule outside periods of intense epidemic surge. Findings support interchangeability and extended intervals between SARS-CoV-2 vaccine doses, with potential global implications for low-coverage areas and, going forward, for children.

Keywords: SARS-CoV-2; heterologous; test-negative design; vaccine effectiveness; waning.

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Conflict of interest statement

Potential conflicts of interest. G. D. S. received a grant paid to his institution for a meningococcal seroprevalence study from Pfizer in 2016. M. K. received grants/contracts paid to his institution from Roche (related to human papillomavirus), Hologic (related to human papillomavirus), and Siemens (related to human papillomavirus), unrelated to this work. M. S. has been an investigator on projects, unrelated to the current work, funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo, and VBI Vaccines. All funds have been paid to his institute, and he has not received any personal payments. M. S. is also the Chair/Deputy Chair of 2 Data Safety Monitoring Boards (DSMBs) for coronavirus disease 2019 (COVID-19) vaccine trials, involving different vaccines. R. G. received honoraria for an RSV Coordinators Workshop funded by AbbVie (payment to author). A. N. J. has received funding for other severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing and COVID-19 vaccine projects, paid to her institution and unrelated to the current work, from Genome BC, the Public Health Agency of Canada and the Canada Foundation for Innovation. D. M. S. reports contracts or grants, paid to her institution and unrelated to the current work, from Michael Smith Foundation for Health Research, Public Health Agency of Canada, and the Canadian Institutes of Health Research. G. D. reports a grant or contract paid to his institution from the Ministère de la Santé et des Services Sociaux du Québec. E. G. reports that their spouse is employed by QHR Tech, an electronic medical records company (no payments to author and author owns no stock in the company). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Adjusted 2-dose VE against infection and hospitalization (overall and Delta-specific), by vaccine type, in adults ≥18 years old: British Columbia and Quebec, Canada, epi-weeks 22–47 (30 May–27 November) of 2021. Shown are adjusted VE and 95% CIs against infection (blue) and hospitalization (orange) ≥14 days after the second dose by vaccine type, overall (A) and for the Delta variant of concern (B) among adults ≥18 years old in the provinces of BC and Quebec, Canada. In Quebec, VE against Delta hospitalization was assessed only between epi-weeks 31 and 47 because no hospitalized Delta variant cases were identified prior to that period. For additional details, including corresponding sample sizes and precise unadjusted and adjusted estimates with 95% CIs (and adjustment covariates specified), see Supplementary Table 5 (overall) and Supplementary Tables 9 and 10 (Alpha, Gamma, and Delta variants of concern). Abbreviations: BC, British Columbia; ChAdOx1, chimpanzee adenoviral vectored vaccine; CI, confidence interval; mRNA, messenger RNA; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; VE, vaccine effectiveness.
Figure 2.
Figure 2.
Adjusted 2-dose VE against infection and hospitalization, by age group, sex, and vaccine type in adults ≥18 years old: British Columbia and Quebec, Canada, epi-weeks 22–47 (30 May–27 November) of 2021. Shown are adjusted VE estimates and 95% CIs against infection (blue) and hospitalization (orange) ≥14 days after the second dose by age group (A) and sex (B) and by vaccine type in BC and Quebec, Canada. In Quebec, adjusted VE against hospitalization in ≥70-year-old adults required collapse of epi-week categories (triweekly) owing to sample-size considerations. For additional details, including corresponding sample sizes and precise unadjusted and adjusted estimates with 95% CIs (and adjustment covariates specified), see Supplementary Tables 6–8. Abbreviations: BC, British Columbia; ChAdOx1, chimpanzee adenoviral vectored vaccine; CI, confidence interval; mRNA, messenger RNA; NE, not estimable or total span of CI is ≥100%; QC, Quebec; VE, vaccine effectiveness.
Figure 3.
Figure 3.
Adjusted 2-dose mRNA and ChAdOx1 VE against infection and hospitalization by time since vaccination, in adults ≥18 years old: British Columbia and Quebec, Canada, epi-weeks 22–47 (30 May–27 November) of 2021. Shown are adjusted VE estimates and 95% CIs against infection (blue) and hospitalization (orange) by time between receipt of the second dose and specimen collection, among adults ≥18 years old in BC (solid lines) and Quebec (dashed lines). Panel A displays estimates for those who received any 2 mRNA vaccines and panel B displays estimates for those who received 2 ChAdOx1 vaccines. Due to sparse data, mRNA estimates are not displayed beyond the eighth month postvaccination against hospitalization in Quebec or beyond the seventh month postvaccination for ChAdOx1 in either province. Displayed are the point estimates against hospitalization for BC and against infection for Quebec. For additional details including all corresponding sample sizes and precise unadjusted and adjusted estimates with 95% CIs (and adjustment covariates specified), see Supplementary Table 12 (including details by mRNA vaccine type and for mixed product schedules). The corresponding information by age subgroups is displayed in Supplementary Table 13 and for Delta-specific VE in Supplementary Table 14 (also by mRNA vaccine type and for mixed products). Abbreviations: BC, British Columbia; ChAdOx1, chimpanzee adenoviral vectored vaccine; CI, confidence interval; d, days; mRNA, messenger RNA; VE, vaccine effectiveness; w, weeks.
Figure 4.
Figure 4.
Adjusted 2-dose VE against infection and hospitalization, by time since mRNA vaccination, in adults ≥70 years old: British Columbia and Quebec, Canada. Shown are adjusted VE estimates and 95% CIs against infection (blue) and hospitalization (orange) by time between receipt of the second dose of any mRNA vaccine and specimen collection, among adults ≥70 years old in BC (solid lines) and Quebec (dashed lines). In Quebec, adjusted VE against hospitalization required collapse of epi-week categories (triweekly) owing to sample size considerations. Displayed are the point estimates against hospitalization for BC and against infection for Quebec. For additional details including all corresponding sample sizes and precise unadjusted and adjusted estimates with 95% CIs (and adjustment covariates specified), see Supplementary Table 13 (including details by type of mRNA vaccine). Abbreviations: BC, British Columbia; CI, confidence interval; d, days; mRNA, messenger RNA; VE, vaccine effectiveness; w, weeks.
Figure 5.
Figure 5.
Adjusted 2-dose VE against infection and hospitalization, by interval between doses, mRNA and ChAdOx1 vaccines, in adults ≥18 years old: British Columbia and Quebec, Canada. Shown are adjusted VE estimates and 95% CIs against infection (blue) and hospitalization (orange) at ≥14 days after the second dose, by interval between the first and second dose among adults ≥18 years old who were vaccinated with any 2 mRNA vaccines (A) or 2 ChAdOx1 vaccines (B) in British Columbia and Quebec. For additional details including corresponding sample sizes and precise unadjusted and adjusted estimates with 95% CIs (and adjustment covariates specified), see Supplementary Table 15 (including details by type of mRNA vaccine). Abbreviations: ChAdOx1, chimpanzee adenoviral vectored vaccine; CI, confidence interval; d, days; mRNA, messenger RNA; NE, not estimable or total span of CI is ≥100%; VE, vaccine effectiveness; w, weeks.
Figure 6.
Figure 6.
Adjusted 2-dose BNT162b2 VE against infection by interval between doses and time since second dose, in adults ≥18 years old: British Columbia and Quebec, Canada. Shown are adjusted VE estimates and 95% CIs against infection by interval between the first and second BNT162b2 dose (3–4 weeks in purple; 5–6 weeks in dashed gold; 7+ weeks in green) and time since the second dose among adults ≥18 years old in the provinces of British Columbia and Quebec. For additional details including corresponding sample sizes and precise unadjusted and adjusted estimates with 95% CIs (and adjustment covariates specified), see Supplementary Table 16 (including both types of mRNA vaccine and ChAdOx1). Abbreviations: ChAdOx1, chimpanzee adenoviral vectored vaccine; CI, confidence interval; d, days; mRNA, messenger RNA; VE, vaccine effectiveness; V1, dose 1; V2, dose 2; w, weeks.
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