key: cord-0766185-q73hyvhf authors: Skowronski, Danuta M; Febriani, Yossi; Ouakki, Manale; Setayeshgar, Solmaz; El Adam, Shiraz; Zou, Macy; Talbot, Denis; Prystajecky, Natalie; Tyson, John R; Gilca, Rodica; Brousseau, Nicholas; Deceuninck, Geneviève; Galanis, Eleni; Fjell, Chris D; Sbihi, Hind; Fortin, Elise; Barkati, Sapha; Sauvageau, Chantal; Naus, Monika; Patrick, David M; Henry, Bonnie; Hoang, Linda M N; De Wals, Philippe; Garenc, Christophe; Carignan, Alex; Drolet, Mélanie; Jassem, Agatha N; Sadarangani, Manish; Brisson, Marc; Krajden, Mel; De Serres, Gaston title: Two-dose SARS-CoV-2 vaccine effectiveness with mixed schedules and extended dosing intervals: test-negative design studies from British Columbia and Quebec, Canada date: 2022-04-19 journal: Clin Infect Dis DOI: 10.1093/cid/ciac290 sha: 4fb01fa3de441fec61065ea523c7722780b414a4 doc_id: 766185 cord_uid: q73hyvhf BACKGROUND: The Canadian COVID-19 immunization strategy deferred second doses and allowed mixed schedules. We compared two-dose vaccine effectiveness (VE) by vaccine type (mRNA and/or ChAdOx1), interval between doses, and time since second dose in two of Canada’s larger provinces. METHODS: Two-dose VE against SARS-CoV-2 infection or hospitalization among adults ≥18-years-old, including due to Alpha, Gamma and Delta variants of concern (VOC), was assessed at ≥14 days post-vaccination by test-negative design studies separately conducted in British Columbia and Quebec, Canada between May 30 and November 27 (epi-weeks 22-47), 2021. RESULTS: In both provinces, all homologous or heterologous mRNA and/or ChAdOx1 two-dose schedules were associated with ≥90% reduction in SARS-CoV-2 hospitalization risk for at least 7 months. With slight decline from a peak of >90%, VE against infection was ≥80% for at least 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 vs. manufacturer-specified 3–4-week interval 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. Soon after authorization of the first mRNA vaccine (BNT162b2, Pfizer-BioNTech) against SARS-CoV-2 on December 9 (epi-week 50) of 2020 in Canada, experts in the provinces of British Columbia (BC) and Quebec simultaneously (epi-week 51) submitted briefing notes recommending that second doses of SARS-CoV-2 vaccines be deferred at least until optimal single-dose coverage of high-risk priority groups could be assured. For excerpt from the BC Centre for Disease Control expert briefing note (December 13, 2020), see page 3. For the full Quebec Immunization Committee expert briefing note, see: Original While acknowledging the ongoing importance of second doses, these briefing notes advocated their delayed administration in order to extend substantial single-dose protection to as many priority group members as possible, as fast as possible, while vaccine supplies remained constrained globally. Core ethical and vaccine principles were invoked in support and briefing notes in both provinces also reassuringly addressed the interchangeability of SARS-CoV-2 vaccines if the withholding of homologous doses, as recommended by the manufacturer to complete the series, was not possible under a population strategy of second-dose deferral. Underpinning the recommendation to defer the second dose was joint provincial re-analysis of the BNT162b2 (Pfizer-BioNTech) randomized controlled trial (RCT) data. Those RCT data became publicly available in the Pfizer-BioNTech Vaccines and Related Biological Products Advisory Committee (VRBAC) Briefing Document when it was web-posted on December 10, 2020. a Provincial experts used the data reported in Figure 13 of the Pfizer-BioNTech VRBAC document to show that single-dose BNT162b2 efficacy against symptomatic SARS-CoV-2 infection exceeded 90% when the typical lag period between vaccine receipt and development of the primary antibody response was properly taken into account (14 days for most vaccines), something the original RCT investigators had not presented. Single-dose mRNA-1273 efficacy also exceeding 90% was subsequently reported by Moderna investigators themselves in their VRBAC submission of December 17, 2020 (authorized in Canada on December 23, 2020). b Recognizing the implications for other jurisdictions, lead authors of the BC and Quebec briefing notes disseminated their re-analyses broadly to health authorities nationally and internationally. They drafted a Letter to the Editor c of the New England Journal of Medicine in response to the original Pfizer-BioNTech RCT publication d , providing the re-analyses, rationale and concluding recommendation that other countries (e.g. United States) also consider seconddose deferral as a matter of national security. The Letter to the Editor was submitted on December 24, 2020, and published February 17, 2021. Thereafter, on March 3, 2021 Canada's National Advisory Committee on Immunization (NACI) endorsed second dose deferral, recommending an even longer interval of 16 weeks between first and second doses. A timeline of SARS-CoV-2 vaccine developments including provincial (BC and Quebec) and national (NACI) recommendations and program modifications relevant to the current work is shown in Supplementary Abbreviations: BCCDC, BC Centre for Disease Control; ChAdOx1, Chimpanzee adenoviral vectored vaccine; mRNA, messenger RNA; NACI, National Advisory Committee on Immunization; V1, vaccine dose 1; V2, vaccine dose 2 a Consult relevant provincial and national websites for further updated information. A full listing of NACI recommendations can be found here: https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-onimmunization-naci.html b Since authorization, the Canadian NACI recommendation included an alternate schedule of 28 days between dose 1 and dose 2 for BNT162b2 [1, 2] . c Revised interval applies to all authorized/available vaccines at the time d As also articulated by the World health Organization (WHO) on January 8, 2021 [33] e As also articulated by the United Kingdom Joint Committee on Vaccination and Immunisation (JCVI) on December 30, 2020 (up to 12-week interval) [34] f COVISHIELD (Serum Institute of India) considered comparable by Health Canada regulators [35] g NACI initially recommended against the use of ChAdOx1 in individuals ≥ 65 years old due to limited efficacy data, removing this restriction in its March 16, 2021 statement as effectiveness data from observational studies accrued [35] h On May 3, 2021 (epi-week 18), Health Canada authorized another viral vector vaccine by Janssen for adults ≥ 18 years as a one-dose schedule [36] . This product was not generally available during the study period and is excluded from analyses reported here. i To maximize the number fully-vaccinated by fall and enable healthcare worker vaccination requirements, first announced August 12, 2021 (epi-week 32) and in effect October 12, 2021 (epi-week 41) for long-term care/assisted living workers [37] . 18. National Advisory Committee on Immunization (NACI). In variant-specific analyses, cases were categorized as Alpha, Gamma, or Delta variants of concern (VOC) a,b . In both provinces, the methods and sampling frame for genetic characterization of viruses evolved in response to changing epidemic patterns, case load and laboratory capacity. NA=Not available a Percentage of cases viruses by epidemiological period (column %) b Percentage of total case viruses for which genetic characterization information available, overall and each epidemiological period (row %). c Percentage of total case viruses for which genetic characterization information not available, overall and each epidemiological period (row %). d As explained in Supplementary Material 1, in BC all case viruses for which genetic characterization was not available were assumed to be Delta from epi-week 35 until the end of the analysis period. In Quebec, all case viruses for which genetic characterization was not available were assumed to be Delta from epi-week 36 until the end of the analysis period. e Percentage of genetically characterized viruses that were the specified variant of concern (VOC) overall and by epidemiological period (row %). f In British Columbia, non-VOC tallies include 22 without the 484K substitution and 30 with 484K substitution, the latter last detected in epi-week 34. g Percentage of genetically characterized viruses that were the specified variant of concern (VOC) overall and by epidemiological period (row % (4) 8 (1) 2 (7) 2506 (11) 27-30 (July 4-July 31) 199 (1) 6 (2) 56818 (7) 168 (2) 5 (2) 42599 (7) 27 (1) 1 (2) 12301 (7) 6 (1) 0 (0) 2468 (11) Reference VE=vaccine effectiveness; 95%CI=95% confidence interval; NE = not estimable or total span of CI is ≥100% a Unless otherwise specified, VE estimates adjusted for age group (18-49, 50-69, 70-79, ≥80 years); sex (male, female); individual epidemiological week (epi-weeks 22-47, categorical); and region (5 categories in each province). b In Quebec, VE against hospitalizations due to Delta variant assessed only between epi-weeks 31-47 because no hospitalized Delta variant cases were identified prior to that period. c In BC, adjusted VE against Alpha infections was restricted to a study period spanning from epi-weeks 22-35 owing to sample size considerations and otherwise adjusted as in footnote 1 above. d In Quebec, adjusted VE against Alpha infections was restricted to a study period spanning from epi-weeks 22-38 owing to sample size considerations and otherwise adjusted as in footnote 1 above. e In BC, adjusted VE against Alpha hospitalizations was restricted to a study period spanning from epi-week 22-35 and adjusted as in footnote 1 above except for calendar time undertaken bi-weekly between epi-weeks 22-35 (categorical) owing to sample size considerations. f In Quebec, VE against Alpha hospitalizations assessed only between epi-weeks 22-38, and adjusted for calendar time by four-week periods for epi-weeks 22-33 and five-week periods for epi-weeks 34-38. Archived 1: Recommendations on the use of COVID-19 vaccine(s) National Advisory Committee on Immunization (NACI) British Columbia (BC) Government, Ministry of Health. COVID-19: Year to date summary Ministère de la Santé et des Services sociaux. Pandémie de la COVID-19 -Toutes les doses des vaccins reçues seront utilisées afin d'immuniser un maximum de personnes possible Avis du Comité sur l'immunisation du Québec sur la stratégie de vaccination contre la COVID-19: report de la 2e dose en contexte de pénurie Archived 3: Recommendations on the use of COVID-19 vaccine(s) Pandémie de la COVID-19 -Le Québec prend les moyens pour vacciner le plus de personnes vulnérables rapidement possible British Columbia (BC) Government, Ministry of Health Victoria: BC Ministry of Health Archived 4: Recommendations on the use of COVID-19 vaccine(s) 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 Update to Communicable Disease Control Manual, Chapter 2: Immunization, Part 4 -Biological Products & Appendix E -Management of Biologicals Pandémie de la COVID-19 -Un intervalle de 16 semaines entre les deux doses de vaccin 94) 97 (97, 98) Unvaccinated 2594 77553 Reference 1066 148143 Reference Two mRNA-1273 (Moderna) vaccines -3 weeks) since second dose 21-34 day (3-4 week) interval between doses 95) 34 day (3-4 week) interval between doses 78) 35-48 day (5-6 week) interval between doses NE = not estimable or total span of CI is ≥100% 21-34 day (3-4 week) interval between doses 96) 95 (93, 96) 34 day (3-4 week) interval between doses 7+ week) interval between doses 90) 49-62 day (7+ week) interval between doses 77) 72 (62, 80) 49-62 day (7+ week) interval between doses 80+ years); sex (male, female); individual epidemiological week (epi-weeks 22-47, categorical)