key: cord-0992080-sa97rfnx
authors: Skowronski, D. M.; Setayeshgar, S.; Zou, M.; Prystajecky, N.; Tyson, J. R.; Galanis, E.; Naus, M.; Patrick, D. M.; Sbihi, H.; El Adam, S.; Henry, B.; Hoang, L. M. N.; Sadarangani, M.; Jassem, A. N.; Krajden, M.
title: Single-dose mRNA vaccine effectiveness against SARS-CoV-2, including P.1 and B.1.1.7 variants: a test-negative design in adults 70 years and older in British Columbia, Canada
date: 2021-06-09
journal: nan
DOI: 10.1101/2021.06.07.21258332
sha: 6bb1d50e1c7c46f6afaa42873a3977ccaaabb861
doc_id: 992080
cord_uid: sa97rfnx

Introduction: Randomized-controlled trials of mRNA vaccine protection against SARS-CoV-2 included relatively few elderly participants. We assess singe-dose mRNA vaccine effectiveness (VE) in adults [≥]70-years-old in British Columbia (BC), Canada where the second dose was deferred by up to 16 weeks and where a spring 2021 wave uniquely included co-dominant circulation of B.1.1.7 and P.1 variants of concern (VOC). Methods: Analyses included community-dwelling adults [≥]70-years-old with specimen collection between April 4 (epidemiological week 14) and May 1 (week 17). Adjusted VE was estimated by test-negative design through provincial laboratory and immunization data linkage. Cases were RT-PCR test-positive for SARS-CoV-2 and controls were test-negative. Vaccine status was defined by receipt of a single-dose [≥]21 days before specimen collection, but a range of intervals was assessed. In variant-specific analyses, test-positive cases were restricted to those genetically-characterized as B.1.1.7, P.1 or non-VOC. Results: VE analyses included 16,993 specimens: 1,226 (7.2%) test-positive cases and 15,767 test-negative controls. Of 1,131 (92%) viruses genetically categorized, 509 (45%), 314 (28%) and 276 (24%) were B.1.1.7, P.1 and non-VOC lineages, respectively. VE was negligible at 14% (95% CI 0-26) during the period 0-13 days post-vaccination but increased from 43% (95% CI 30-53) at 14-20 days to 75% (95% CI 63-83) at 35-41 days post-vaccination. VE at [≥]21 days was 65% (95% CI 58-71) overall: 72% (95% CI 58-81), 67% (95% CI 57-75) and 61% (95% CI 45-72) for non-VOC, B.1.1.7 and P.1, respectively. Conclusions: A single dose of mRNA vaccine reduced the risk of SARS-CoV-2 in adults [≥]70-years-old by about two-thirds, with protection only minimally reduced against B.1.1.7 and P.1 variants. Substantial single-dose protection in older adults reinforces the option to defer the second dose when vaccine supply is scarce and broader first-dose coverage is needed.

The first mRNA vaccines against COVID-19 (Pfizer-BioNTech; Moderna) were authorized in Canada in December, 2020 [1] [2] [3] . In randomized-controlled trials of both products, two doses spaced 3-4 weeks apart were 94-95% efficacious against symptomatic, laboratory-confirmed SARS-CoV-2 infection [2, 3] . When RCT data were re-analyzed applying the usual two-week lag for vaccine effect, a single dose of either product was also substantially protective at 92-93% [3, 4] . Participants in these trials, however, were generally young and healthy with not more than 5% ≥75-years-old [2, 3] .

In the context of elevated epidemic activity and scarce vaccine supply, some jurisdictions have extended the interval between first and second SARS-CoV-2 vaccine doses to enable more people to benefit from substantial single-dose protection. In the United Kingdom an interval of up to 12 weeks was recommended on December 30, 2020 [5] . In Canada, an even longer interval of up to 16 weeks was recommended beginning March 3, 2021 (epidemiological week 9) [6] . As in most provinces, British Columbia (BC), initially prioritized available mRNA vaccines to long-term care facility (LTCF) residents and frontline healthcare workers. This was associated with dramatic reduction in reported LTCF outbreaks and associated cases [6, 7] . However, high vaccine coverage (>90%), including a majority (>60%) who were twice-immunized before week 9 made it difficult to distinguish first-from second-dose and direct from indirect vaccine effects in that relatively closed setting.

Community vaccination in BC subsequently followed an age-based strategy that first prioritized older adults ≥90, 80-89 and 70-79 years beginning around week 10 . Although viral vector vaccines are also authorized in Canada [1] , they were not prominently used in these age groups. In All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 9, 2021. the spring 2021, BC experienced its most substantial pandemic wave to date, including a majority of viruses that were characterized as variants of concern (VOC), and uniquely including co-dominant circulation of P.1 and B.1.1.7 [9] . A publicly-funded, mostly symptom-based approach for SARS-CoV-2 diagnostic testing is broadly accessible in BC. In that context, we applied a test-negative design (TND) to estimate the vaccine effectiveness (VE) of a single dose of mRNA vaccine against SARS-CoV-2, including variant-specific estimates, among communitydwelling adults ≥70-years-old in BC.

There are about 673,000 adults ≥70-years-old in BC (13% of the total 5.1 million population)

including ~437,000 (65%) 70-79 years, 188,000 (28%) 80-89 years and 48,000 (7%) ≥90 years old with slightly more than half who are women (54%) [8] .

The spring 2021 wave peaked in BC in week 14 and gradually subsided with province-wide restrictions; however, weekly case reports continued to exceed the peak week of prior waves until week 17 [7] . The analysis period of the current study spanned weeks 14 to 17 (April 4-May 1), taking into account vaccine roll-out and several-week delay for vaccine effect as well as community SARS-CoV-2 activity that remained elevated during this period.

VE was assessed by TND with multivariable logistic regression used to estimate the adjusted odds ratio (ORadj) for vaccination among test-positive cases versus test-negative controls. VE and 95%

confidence intervals (CI) were derived as (1-ORadj) x 100%. The following covariates were All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. included in adjusted models: age group, sex, epidemiological week and health authority (HA) of residence, or if the latter were not available then the HA of the clinician associated with the test.

Specimens collected between weeks 14-17 and tested by RT-PCR for SARS-CoV-2 were eligible. Vaccination information was obtained from the provincial immunization registry (PIR), a centralized database that captures, also in real-time, all SARS-CoV-2 vaccinations in BC, along with client and vaccination details. Individual-level linkage between PLOVER and PIR datasets was achieved through unique personal identifiers.

Individuals could contribute a single test-positive specimen. In variant-specific analyses, testpositive cases were restricted to those in whom a VOC was detected, classified as P.1, B.1.1.7 or non-VOC as defined in Supplementary Material S1. Three approaches were used for testnegative control selection. In the first specimen-based approach, all negative specimens from a single individual could contribute; however, specimens collected on the same day were counted only once or excluded if discordant. In the second individual-based approach, only the single latest negative specimen per individual could contribute. In an alternative individual-based approach, only one randomly-selected negative specimen per individual could contribute. We All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. further explored with and without exclusion of negative specimens collected within three weeks before a positive specimen.

Clients with record of a single dose of mRNA vaccine on or before the date of specimen collection were considered vaccinated; those without such record were considered unvaccinated.

Because our VE analyses are timed on specimen collection rather than onset date we incorporate additional lag beyond the usual two week grace period for vaccine effect. Among communitydwelling adults ≥70-years-old with both dates available in PLOVER, the mean and median interval between onset and specimen collection date was 4 and 3 days, respectively, with interquartile range of 1-5 days. We base primary VE analyses on vaccine receipt at least three weeks before specimen collection date (≥21 days) but assess intervals of 0-13, 14-20, 21-27, 28-41 and ≥42 days.

Specimens missing information for age, sex, HA, specimen collection date, vaccine date or type were excluded as were those with missing or inconclusive RT-PCR results. Cases with collection date before the start of the analysis period were excluded, identified through further linkage with the notifiable disease list of confirmed COVID-19 cases reported by the HAs and maintained by the BCCDC. Specimens that were tested outside of public funding were excluded because of systematically lower likelihood of test-positivity [7] . Clients who received more than one vaccine dose were excluded as were those who received a viral vector vaccine [1] . Finally, any specimens identified within PLOVER and/or the PIR or notifiable disease list from LTCF, assisted-living or independent-living facilities were excluded.

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The copyright holder for this preprint this version posted June 9, 2021. ; https://doi.org/10.1101/2021.06.07.21258332 doi: medRxiv preprint

Data linkages and analyses were conducted under a surveillance mandate, authorized by the Provincial Health Officer under the Public Health Act, and exempt from research ethics board review.

In total, 16,993 SARS-CoV-2 specimens contributed to VE analyses, including 1,226 (7.2%) testpositive cases and 15,767 test-negative controls ( Figure S2 ). Viruses from 1,131/1,226 (92%) cases were genetically categorized with respect to VOC status, of which 509 (45%) and 314 (28%) were B.1.1.7 and P.1, respectively (Tables S1, S6; and S7). An additional 4 (<1%) viruses belonged to the B.1.351 lineage and another 12 (1%) could not be differentiated as P.1 or B.1.351 while 16 viruses (1%) were B.1.617.1/2; these were excluded from variant-specific VE analyses (Table S1) . Of the remainder, 276 (24%) were designated non-VOC. The distributions of VOC and non-VOC by participant sub-group were similar ( Figure S1 ).

Decrease in test-positivity and case tallies by successive week of the analysis period mirrored provincial surveillance patterns (Figure 1 ; Table 1 ) [7] . The distributions of test-negative controls by age, sex and HA were generally representative of the BC source population (Table 1) 

Among vaccinated cases and controls, 85% and 90%, respectively, had received their first dose by week 14 (Figure 1) . Among test-negative controls, vaccine coverage was comparable to the provincial average for community-dwelling adults ≥70 years overall (74% vs. 75%), and by week All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

VE estimates did not vary by the approach used to select test-negative controls and we therefore present VE based on all-specimen inclusion (approach 1) ( Table S2) . VE findings are illustrated in Figure 2 with details in Tables S2-S7. VE was negligible at 14% (95% CI 0-26) during the period 0-13 days post-vaccination but increased by one week interval thereafter from 43% (95% CI 30-53) at 14-20 days to 75% (95% CI 63-83) at 35-41 days post-vaccination (Figure 2 ). VE is also displayed for ≥42 days but warrants cautious interpretation given a minority of vaccinated participants belonged within that extended interval ( Table 1) . Summary VE at ≥21 days was 65% (95% CI 58-71) and was similar (within 10% absolute) in participant sub-group analyses, differing by 10% in women (70%; 95%

CI 61-76) vs. men (60%; 95% CI 48-70) (Figure 2 ; Tables S2-S5) .

At ≥21 days since vaccination, a single dose of mRNA vaccine was also significantly protective in variant-specific analyses, with VE of 72% (95% CI 58-81), 67% (95% CI 57-75) and 61%

(95% CI 45-72) for non-VOC, B.1.1.7 and P.1, respectively.

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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 9, 2021. ; https://doi.org/10.1101/2021.06.07.21258332 doi: medRxiv preprint

We report substantial protection provided by a single dose of mRNA vaccine against SARS-CoV-2 infection in adults ≥70-years-old. VE increased when longer intervals were used to define vaccine status, becoming statistically significant at 40% after a two-week lag, 60% after threeweek, 70% after four-week and 75% after 5-week interval between vaccination and specimen collection. While delayed immunological response in the elderly may be hypothesized to explain this prolonged timeline to protection [10] , a methodological explanation also exists, namely misclassification of cases as vaccine-preventable at too-short intervals when based on specimen collection rather than onset date. We underscore the need for studies to extend the interval used to define vaccine status when outcomes are timed on events such as specimen collection or testing that occur later or with more variability than the typical two-week interval from vaccination to onset date used in clinical trials. Our primary VE estimate of 65% based on RT-PCR detection of infection at ≥3 weeks between vaccination and specimen collection may also be an underestimate. Our findings suggest, however, that a single dose of mRNA vaccine prevented about two out of three SARS-CoV-2 infections in older adults. Such protection is particularly meaningful considering that it was provided during a period of peak pandemic risk, when VOCs were predominantly contributing to the epidemic in BC.

Our VE estimates were robust in sensitivity and subgroup analyses, varying only by about 10% (absolute) based on sex (10% lower in men) and VOC (11% lower for P.1 versus non-VOC).

With overlapping confidence intervals, these comparisons are not definitive but signal the need for further evaluation, notably in younger adults among whom sex differences may be more biologically-mediated [11] , and VOC circulation more prominent [9] . In BC, where P.1 and B.1.1.7 have uniquely co-dominated during a substantial spring wave [9] , the finding of their All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 9, 2021. ; https://doi.org/10.1101/2021.06.07.21258332 doi: medRxiv preprint comparable VE in older adults is important. This observation aligns well with immunogenicity findings elsewhere reporting comparable reductions in infection-and vaccine-induced neutralizing antibody for P.1 and B.1.1.7 [12] . Whereas more severe reductions in immunity or effectiveness have been reported for other VOC such as B.1.351 or B.1.617 [12] [13] [14] , we had toofew detections for their separate VE analysis here. Despite some shared substitutions such as E484K between P.1 and B.1.351, they may not be equal in their potential for vaccine escape. To better correlate molecular markers with immunological and epidemiological measures of vaccine protection, and to inform the need for vaccine update, VE analyses should be stratified as finely as possible by genetic sub-cluster.

Our findings may be compared to other similar studies in older adults although underlying differences (e.g. methods, populations, vaccine status and outcome definitions, mix of circulating viruses) need to be taken into account. Using the TND to assess VE among adults ≥70 years in [16] , also similar to our estimates among adults 80-89years-old of 54% (95% CI 32-70) and 75% (95% CI 55-86), respectively, at those intervals. In a recent pre-print also from Canada, Chung et al use the TND to assess mRNA VE against symptomatic infection for the population of Ontario with primary analysis based on an interval of ≥14 days between vaccination and specimen collection [17] . In sub-analysis of adults ≥70 years (excluding care-home residents), authors report VE of 40% (95% CI 29-49) which is lower than All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Given both time-varying vaccine coverage and disease risk, adjustment for confounding by calendar-time is critical in observational study designs. To address that concern, we restricted our analysis to a narrow window (weeks 14-17) when vaccine coverage and community risk were both high and relatively stable, further adjusting by epidemiological week to address variation.

We also explored several approaches for selecting test-negative controls with similar results, also likely reflecting the narrow analysis period we chose. The main limitation of our analysis, as elsewhere, is our reliance on general laboratory submissions and clinical or surveillance data that were originally collected for a different purpose and are subject to missing information and misclassification, as well as selection bias. Although foremost symptom-based, the clinical testing indications for COVID-19 are broad, discretionary and variable. To attempt standardization of the likelihood of test-positivity among sampled specimens we excluded those identified as having been collected from congregate settings or for non-clinical screening purposes. Such exclusions, however, may have been incomplete or introduced other unintended biases. We were limited in the covariates we could include in our model and cannot rule out residual bias and confounding.

As a form of validity check, we assessed VE during the 0-13-day period when little or no vaccine effect is anticipated, confirming negligible VE as expected. For similar reasons, we compared All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 9, 2021. ; https://doi.org/10.1101/2021.06.07.21258332 doi: medRxiv preprint vaccine coverage and other characteristics of our test-negative controls to that of the general source population ≥70-years-old in BC, and this was reassuringly concordant. Our findings also align well with other observational studies in older adults each of which are, however, subject to similar issues. Because the PLOVER database from which we sampled does not reliably capture symptoms or onset dates, we assessed VE against any infection without symptom or severity specification. VE estimates against more severe outcomes are anticipated to be higher than we report for infection per se [15] [16] [17] . Finally, we were limited in our ability to assess VE over the long-term or to compare to younger age groups prioritized later for vaccination, but those analyses are underway.

In conclusion, a single dose of mRNA vaccine reduced the risk of SARS-CoV-2 infection by about two-thirds in community-dwelling adults ≥70-years-old. Such protection is particularly important because it was observed during a period of peak pandemic risk when VOC, predominantly the B.1.1.7 and P.1 lineages, comprised at least 70% of characterized viruses.

Substantial single-dose protection in older adults reinforces the option to defer second doses when vaccine supply is scarce and broader first-dose coverage is needed.

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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 9, 2021. ; https://doi.org/10.1101/2021.06.07.21258332 doi: medRxiv preprint

Authors thank the following from the BC Centre for Disease Control: Chris Fjell for his leadership and management of the Public Health Laboratory Operations Viewer and Reporter (PLOVER); Yayuk Joffres for quality control of laboratory data; Yin Chang for laboratory data management; May Ahmed for her surveillance-related insights; Shinhye Kim for research coordination support and Samantha Kaweski for laboratory coordination support. We thank the Provincial Public Health Information Systems (PPHIS) team for contributions related to the provincial immunization registry (PIR). We thank the many frontline, regional and provincial practitioners, including clinical, laboratory and public health providers, epidemiologists, Medical Health Officers, laboratory staff, vaccinators and others who provided the epidemiological, virological and genetic characterization data underpinning these analyses.

Funding was provided in part by the Michael Smith Foundation for Health Research. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Single-dose recipients only without regard to interval between vaccination and specimen collection. Includes mRNA vaccine receipt only; viral vector vaccine recipients excluded. 2 As per Approach 1 for control selection: includes all test-negative specimens. 3 P value compares percentage vaccinated by characteristic. 4 Interval between first dose of vaccine and specimen collection date

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