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Effectiveness of mRNA-based vaccines during the emergence of SARS-CoV-2 Omicron variant

Abstract Background We evaluated effectiveness of mRNA-based vaccines following emergence of SARS-CoV-2 Omicron variant. Methods Recipients of a third dose of BNT162b2 or mRNA-1273 ≥ 180 days after the primary series were matched to primary series recipients and unvaccinated persons. Participants were followed from December 1, 2021 to March 12, 2022. Outcomes were documented SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 death. Effectiveness was calculated from 100-day risks estimated with the Kaplan-Meier estimator. Results BNT162b2 and mRNA-1273 groups respectively included 221,267 and 187,507 third dose recipients matched to equal numbers of primary series recipients and unvaccinated persons. Compared to no vaccination, effectiveness of a third dose of BNT162b2 was 47.8% (95% confidence interval [CI]: 45.2-50.3), 81.8% (95% CI 79.2-84.2), and 89.6% (95% CI 85.0-93.6) against documented infection, hospitalization, and death, respectively. Effectiveness of a third dose of BNT162b2 compared to the primary series was 30.1% (95% CI 26.2-33.7), 61.4% (95% CI 55.0-67.1), and 78.8% (95% CI 67.9-87.5) against documented infection, hospitalization, and death, respectively. Effectiveness of a third dose of mRNA-1273 compared to no vaccination was 61.9% (95% CI 59.4-64.4), 87.9% (95% CI 85.3-90.2), and 91.4% (95% CI 86.4-95.6) against documented infection, hospitalization, and death, respectively. Effectiveness of a third dose of mRNA-1273 compared to the primary series was 37.1% (95% CI 32.2-41.7), 63.5% (95% CI 53.7-71.6), and 75.0% (95% CI 55.4-88.0) against documented infection, hospitalization, and death, respectively. Conclusions BNT162b2 and mRNA-1273 were effective against COVID-19 following emergence of Omicron variant. A third dose provided additional protection over the primary series.

. The spread of the SARS-CoV-2 delta variant, resurgence of 4 and concern about waning antibody levels among vaccinated persons led US Food and Drug 5 Administration (FDA) to authorize a third dose of BNT162b2 (Pfizer-BioNTech) and mRNA-6 1273 (Moderna) 6 months after completing the primary series for vaccinated persons at high risk 7 of severe disease or exposure to 6]. Soon after, several states expanded eligibility 8 of booster doses to all adults as part of a continued effort to control . On 9 November 19, 2021 FDA expanded eligibility for booster vaccine doses to all individuals 18 10 years and older after completing the primary vaccine series [10]; eligibility was adjusted to 11 everyone 12 years and older for recipients of BNT162b2 [11]. By April 1, 2022, US Centers for 12 Disease Control and Prevention (CDC) estimated that more than 65% of the US population was 13 fully vaccinated, and 45% of fully vaccinated persons had received an additional dose of vaccine 14 [12]. 15 The emergence and rapid dissemination of the SARS-CoV-2 Omicron variant in 16 December 2021 raised new questions about the effectiveness of mRNA-based vaccines against 17 this novel strain. Early reports from South Africa and the US CDC suggest protection against 18 Omicron variant, though these studies were limited to hospitalized individuals [13,14]. 19 Additional studies in frontline healthcare workers and for self-reported symptomatic  following the emergence of Omicron variant have indicated continued effectiveness of mRNA-21 based vaccines [15,16]. The effectiveness of mRNA-based vaccines across the clinical spectrum 19 compared to persons who only completed the primary series [17,18]. However, these studies 3 predated the emergence of Omicron variant; vaccine effectiveness of mRNA-based vaccines in 4 the era of Omicron variant predominance has yet to be fully evaluated in the United States. 5 We leveraged electronic health records from the Veterans Health Administration (VHA), 6 to estimate the effectiveness of BNT162b2 and mRNA-1273 vaccines in preventing post-7 vaccination COVID-19 infection following the emergence of Omicron variant.

9
VHA is the largest integrated health system in the United States, providing healthcare and US county of residence. Third dose recipients and primary series recipients were matched on 4 an additional covariate corresponding to the calendar week in which the second dose of vaccine 5 was received. To account for healthcare seeking behavior, subgroups were also matched on 6 number of SARS-CoV-2 PCR tests received before the study start date. CoV-2 infection within 21 days before admission to an inpatient unit in an acute care VHA 10 facility), and COVID-19 death (defined as death within 30 days after documented SARS-CoV-2 11 infection). For each outcome and vaccine, individuals were followed from recruitment until the 12 earliest date of outcome, death, or end of the study period. Follow up of primary series recipients 13 was also halted if a third vaccine dose was received during follow up.
14 The Kaplan-Meier estimator was used to calculate the 100-day cumulative incidence 15 (risk) of outcomes for each subgroup and vaccine. Vaccine effectiveness (1risk ratio) was 16 calculated for three measures: primary series compared to unvaccinated, third dose compared to 17 unvaccinated, and primary series compared to third dose. Non-parametric bootstrapping with 18 1,000 samples was used to calculate 95% confidence intervals. All analyses were performed in R   (Table 1). Participants were older 9 persons, mostly male, and non-Hispanic White. Most (>80%) participants did not undergo 10 SARS-CoV-2 PCR testing before the start of follow up. About a quarter of study participants in 11 each group had an Elixhauser comorbidity score of 10 or greater. Among vaccinated participants, 12 more than 50% had completed the primary series at least 250 days before the study start date.

13
The median time that had elapsed from receipt of the third dose before start of follow up was 48 14 days for the BNT162b2 group and 28 days for the mRNA-1273 group.

11
Our findings are subject to several limitations. Clinical records for patients who received 12 care in facilities external to VHA might not be available in VHA databases unless these services 13 were ordered by VHA providers and paid for by VHA; therefore, these testing episodes and 14 outcomes would be missed in our analysis. Although VHA issued national testing guidelines, 15 differences across VHA facilities in testing assays and local policies or approaches to testing 16 may contribute to variability in detection of vaccine breakthrough events; some events might 17 have been missed or misclassified. Our study population consists of predominantly older 18 (median age 75 years), male persons (98%) receiving care at VHA facilities; therefore, our 19 results might not be generalizable to the larger US population. Positive PCR tests in hospitalized 20 persons and decedents may be incidental findings not associated with severe COVID-19 21 infection; misclassification might affect the accuracy of our estimates for these outcomes.

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Though we sought to control for health-seeking behavior as well as demographic and clinical   against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a 5 nationwide vaccination campaign in Israel: an observational study using national surveillance 6 data. Lancet 2021; 397 (10287)   Shaded areas describe 95% confidence intervals.