key: cord-0751965-t5jsjwl5
authors: Carazo, Sara; Talbot, Denis; Boulianne, Nicole; Brisson, Marc; Gilca, Rodica; Deceuninck, Geneviève; Brousseau, Nicholas; Drolet, Mélanie; Ouakki, Manale; Sauvageau, Chantal; Barkati, Sapha; Fortin, Élise; Carignan, Alex; De Wals, Philippe; Skowronski, Danuta M; De Serres, Gaston
title: Single-dose mRNA vaccine effectiveness against SARS-CoV-2 in healthcare workers extending 16 weeks post-vaccination: a test-negative design from Quebec, Canada
date: 2021-08-30
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab739
sha: 5f5c2b597d9a65ba5b463e2db1e1b62c0997dde1
doc_id: 751965
cord_uid: t5jsjwl5

INTRODUCTION: In Canada, first and second doses of mRNA vaccines against SARS-CoV-2 were uniquely spaced 16 weeks apart, but the duration of single-dose protection remains uncertain. We estimated one- and two-dose mRNA vaccine effectiveness (VE) among healthcare workers (HCWs) in Quebec, Canada including protection against varying outcome severity, variants of concern (VOC), and the stability of single-dose protection out to 16 weeks post-vaccination. METHODS: A test-negative design compared vaccination among SARS-CoV-2 test-positive and weekly-matched (10:1), randomly-sampled, test-negative HCWs using linked surveillance and immunization databases. Vaccine status was defined by one dose ≥14 days or two doses ≥7 days before illness onset or specimen collection. Adjusted VE was estimated by conditional logistic regression. RESULTS: Primary analysis included 5,316 cases and 53,160 controls. Single-dose VE was 70% (95%CI: 68-73) against SARS-CoV-2 infection, 73% (95%CI: 71-75) against COVID-19 illness and 97% (95%CI: 92-99) against associated hospitalization. Two-dose VE was 86% (95%CI: 81-90) and 93% (95%CI: 89-95), respectively, with no associated hospitalizations. VE was higher for non-VOC than VOC (73% Alpha) among single-dose (77%, 95%CI: 73-81 versus 63%, 95%CI: 57-67) but not two-dose recipients (87%, 95%CI: 57-96 versus 94%, 95%CI: 89-96). Across 16 weeks, no decline in single-dose VE was observed with appropriate stratification based upon prioritized vaccination determined by higher versus lower likelihood of direct patient contact. CONCLUSION: One mRNA vaccine dose provided substantial and sustained protection to HCWs extending at least four months post-vaccination. In circumstances of vaccine shortage, delaying the second dose may be a pertinent public health strategy to consider.

In December 2020, two mRNA vaccines against SARS-CoV-2 were authorized in Canada based upon a schedule of two doses spaced 3 weeks (BNT162b2 (Pfizer-BioNTech)) or 4 weeks (mRNA-1273 (Moderna)) apart [1] . Phase III randomized-controlled trials showed vaccine efficacy that exceeded 90% for both products beginning from 14 days after a single dose but did not inform protection beyond 3-4 weeks post-vaccination [2] [3] [4] [5] . Healthcare workers (HCWs) were amongst the first prioritized for COVID-19 vaccination and several observational studies have since reported vaccine effectiveness (VE) after a single dose but most had short follow-up periods, the longest extending 8 weeks post-vaccination [6] [7] [8] [9] [10] .

In the context of limited vaccine supply, the Quebec Immunization Committee (QIC) recommended that the province of Quebec, Canada defer the second dose of vaccine in order to optimize first-dose coverage and provide protection to as many high-risk individuals as possible against COVID-related hospitalizations and deaths [11] . The QIC did not pre-specify the interval for second-dose administration, relying upon real-time monitoring of single-dose VE and adaptation in the event of waning protection [12] . The vaccination campaign in Quebec began December 14, 2020 , and initially targeted longterm care facility (LTCF) residents and HCWs with direct patient contact. On March 3, 2021 , the Canadian National Advisory Committee on Immunization and the Quebec Ministry of Health set the interval between doses at 16 weeks based upon expected vaccine supply, ethical considerations and short-term but reassuring VE findings [13, 14] .

Herein, we compare one-and two-dose mRNA VE against SARS-CoV-2, including varying outcome severity and variants of concern (VOC), among HCWs in Quebec and assess the stability of single-dose protection across 16 weeks post-vaccination.

A c c e p t e d M a n u s c r i p t 6 

The study used a test-negative design: HCWs who tested RT-PCR positive for SARS-CoV-2 during the study period were cases; HCWs who tested RT-PCR negative were controls.

The case reference date was defined hierarchically as the date of symptom onset (83.5%) or if not available, then the date of specimen collection (16.5%). The control reference date was defined by specimen collection date. To account for time-varying likelihoods of SARS-CoV-2 exposure and vaccination [15] , a density sampling approach was used with 10 randomly-sampled controls per case matched by week of reference date. A HCW could be sampled several times as a control over the study period (but only once per week) and could subsequently be included as a case. All cases were censored at their reference date.

The study population included all salaried health care workers publicly-funded by the Ministry of Health (e.g. hospital, LTCF, community clinic staff), as well as staff of private facilities under agreement with the Ministry (Supplementary_Figure_S1). Neither physicians who are funded on a fee-for-service basis through a separate source (Medicare) nor HCWs in private-pay settings (e.g. certain clinics, private seniors' residences, pharmacies) are included within this database.

Participants were excluded if: they were a confirmed SARS-CoV-2 case (RT-PCR confirmed or epidemiologically-linked) before January 17, 2021; were missing a unique personal identifying number (PIN) used for data linkage; had an invalid vaccination date (before December 14 th ); or were <18 or ≥75 years old. HCWs in child and youth A c c e p t e d M a n u s c r i p t 7 protection centers or those hired temporarily for pandemic work by Ministerial order were also excluded. Finally, AstraZeneca vaccine recipients were excluded from the date of vaccination because their limited number precluded VE estimation.

Using the unique PIN, the cohort of all publicly-funded HCWs in the province was linked with: 1) the provincial database of all SARS-CoV-2 infections reported to public health since pandemic start, including associated clinical details collected during case investigation by public health authorities; 2) the administrative hospitalization database and the chronic disease surveillance system, which integrates information on pre-existing medical conditions; 3) the Quebec provincial immunization registry which is a census of all Quebec residents insured under the universal publicly-funded health care system, including whether or not vaccinated, vaccination date(s) and type of vaccine received; 4) the provincial centralized laboratory database, including the dates, results and reason for all RT-PCR tests for SARS-CoV-2 across the province; and 5) VOC PCR screening assay results used to identify signature mutations (69-70 deletion, N501Y, E484K) to genetically characterize and categorize viruses. VOC screening was undertaken on a convenience sample of 10% of SARS-CoV-2 positive specimens in January 2021; on nearly 100% of specimens in February and March; and on about 85% of specimens from April 2021 onwards when the VOC prevalence exceeded 90% [16] . As of June 6, 2021, 89% of identified VOC cases were the Alpha variant (Pango lineage:

The study period included HCWs with specimen reference date between January 17 (epidemiological week 3) and June 5 (week 22), 2021 (Figure 1 ), taking into account the M a n u s c r i p t 8 immunization start-date and a several-week lag for vaccine effect. Data were extracted on June 17 th 2021, allowing additional 14-day lag to capture associated hospitalizations.

Vaccination status was defined in relation to the reference date. In primary analysis, a participant was deemed a single-or two-dose vaccinee if the doses were received ≥14 days or ≥7 days before the reference date (with day of vaccination being day 0), respectively, requiring ≥3 weeks between doses. HCWs who received no vaccine doses at any time on or before the reference date were considered unvaccinated whereas those who received the first dose <14 days or second dose <7 days prior were excluded.

RT-PCR confirmed SARS-CoV-2 outcomes of varying severity were explored, including: any infection; symptomatic infection of any severity (specified hereafter as COVID-19);

and COVID-19-related hospitalization (occurring within 30 days of illness onset).

Odds ratios (OR) and their 95% confidence intervals (95%CI) among one-and two-dose vaccinees relative to unvaccinated HCWs were estimated by multivariate conditional logistic regression using the matching week as strata and adjusting for potential confounders. VE and 95% CIs were derived as: ( ) .

Adjustment variables included: age group; sex; job category; healthcare setting; region of the healthcare setting (18 in Quebec); and presence of 17 possible comorbidities associated with increased COVID-19 hospitalization risk (known for ~90% of HCWs) [18] .

In addition to overall primary analyses by outcome severity, sensitivity analyses included: (a) stratifying by HCW priority group based upon those targeted before 

Of the 342,138 HCWs in the initial cohort, 333,832 (97.6%) were successfully linked with the immunization registry. One-dose VE against COVID-19 was 76-78% between 2-and 7-weeks post-vaccination, declining slightly to about 70% between 9-and 16-weeks post-vaccination (<1% were vaccinated >16 weeks prior) ( Figure 2 ). Follow-up after two doses was too short for corresponding interval analyses. A c c e p t e d M a n u s c r i p t 13 respectively, but these involved only short follow-up periods. In two US studies, singledose VE among HCWs, vaccinated according to the manufacturer's schedule, was 78% against any infection [6] , and 74% against symptomatic infection [7] , with two dose VE of 97% and 94%, respectively [6, 7] . Similarly, in an Israeli HCW cohort, single-dose VE was 75% against any SARS-CoV-2 infection from 15-28 days post-vaccination [9] . In Italy, 

We would like to thank Louis Rochette for his work on preparing the healthcare workers' dataset.

This work was supported by the Ministère de la santé et des services sociaux du Québec.

DT is supported by a "Chercheur-boursier" junior-1 career award from the Fonds de recherche 

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