Effectiveness of messenger RNA vaccines against infection with SARS-CoV-2 during the periods of Delta and Omicron variant predominance in Japan: the Vaccine Effectiveness, Networking, and Universal Safety (VENUS) study

Vaccination against infection with SARS-CoV-2 in the general population of Japan began on April 12, 2021, and booster vaccination (the third dose) began on December 1, 2021. The Alpha (B.1.1.7) variant was gradually replaced by the Delta (B.1.617.2) variant beginning in June 2021, and the Delta variant accounted for approximately 80% of infections in Japan in August 2021 (). The Delta variant predominated until the Omicron (B.1.1.529) variant surged in January 2022 (; ). Although several case-control studies have been conducted to assess vaccine effectiveness (VE) in hospital settings, no population-based cohort studies have been conducted in Japan to date (; ; ). We launched the Vaccine Effectiveness, Networking, and Universal Safety (VENUS) study to utilize data, including cases of COVID-19 and vaccination records at an individual level, from municipalities in Japan. This is the first report of COVID-19 VE based on an analysis of the VENUS study data.

We conducted this population-based cohort study to assess the effectiveness of messenger RNA (mRNA) vaccines (BNT162b2 or mRNA-1273) in the population aged 16–64 years in a municipality in the Chugoku region. We used data from the Health Center Real-time Information-sharing System on COVID-19 (), which included cases of COVID-19, and from the Vaccination Record System, which included COVID-19 vaccination records linked to each resident. The data included information on all residents in the municipality. To account for the circulation of the Delta and Omicron variants, we conducted analyses for two study periods: the Delta-predominant (July 1–December 31, 2021) and Omicron-predominant (January 1–March 29, 2022) periods. We included individuals aged 16–64 years without previous COVID-19 at the start of each period. Vaccination status of each individual was categorized according to the number of doses (unvaccinated; 14 days after the first dose to 13 days after the second dose; 14 days after the second dose to 13 days after the third dose; and 14 days after the third dose). Infection was defined by a positive SARS-CoV-2 nucleic acid amplification or antigen test result, regardless of symptoms. Symptomatic infection was defined by a positive SARS-CoV-2 test result along with COVID-19-related symptoms. Cox proportional hazards models were used to estimate the hazard ratios with 95% confidence intervals (CIs) of the outcomes. Vaccination status was included as a time-dependent covariate, and age and sex were included as covariates. VE was calculated as (1−hazard ratio) × 100%. We performed additional analyses to assess the effectiveness of the third dose of BNT162b2 or mRNA-1273 after the BNT162b2 primary series. All statistical analyses were performed using R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria).

Overall, 105,618 and 105,267 individuals aged 16–64 years were included for the Delta- and Omicron-predominant periods, respectively (Table 1). The median age was 44 years (interquartile range 31–53 years), and 52.2% of both cohorts were male. Among individuals who received a third dose, 47.9% were vaccinated with a vaccine different from that received in their primary series. The VEs against infection and symptomatic infection 14 days after the second dose were 83.8% (95% CI: 75.3–89.3%) and 89.8% (95% CI: 80.5–94.7%), respectively, during the Delta-predominant period and 15.8% (95% CI: 7.9–23.1%) and 21.2% (95% CI: 11.0–30.3%), respectively, during the Omicron-predominant period (Table 2). During the Omicron-predominant period, the VEs against infection and symptomatic infection 14 days after the third dose were 56.5% (95% CI: 46.0–65.0%) and 71.8% (95% CI: 60.1–80.1%), respectively, compared with unvaccinated and 48.3% (95% CI: 36.4–57.9%) and 64.2% (95% CI: 49.9–74.4%), respectively, compared with 14 days after the second dose. At ≥14 days after a third dose of BNT162b2 or mRNA-1273 (after the BNT162b2 primary series) compared with unvaccinated, the VEs were 51.8% (95% CI: 39.0–61.8%) and 73.5% (95% CI: 53.8–84.8%), respectively, against infection; and 67.7% (95% CI: 53.0–77.8%) and 77.9% (95% CI: 50.0–90.2%), respectively, against symptomatic infection.

A third dose of an mRNA vaccine increased VE in the general population. The effectiveness of a second dose was lower during the Omicron-predominant period than during the Delta-predominant period due to waning immunity and high transmissibility of the Omicron variant; however, a third dose provided adequate effectiveness against infection and symptomatic infection. Specifically, after the BNT162 primary series, the effectiveness of a third dose of mRNA-1273 was higher than that of a third dose of BNT162b2. Our results are consistent with those of previous studies. In a previous study in Japan with a test-negative case-control design, the VE of the second dose was 88.7% against symptomatic infection with SARS-CoV-2 from July-September 2021 (). Test-negative case-control studies found a VE of two doses of mRNA-1273 vaccine of 13.9% (95% CI: 10.5–17.1%) against the Omicron variant in the United States () and a VE of three doses of BNT162b2 and mRNA-1273 vaccines of 67.2% and 73.9%, respectively, against symptomatic infections with the Omicron variant in England (). Although our population-based study has a potential for residual confounding, and the generalizability of the results may be limited due to the fact that the study was conducted in one local municipality, the results are similar to those of previous studies.

This research was supported by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP21nf0101635. AMED played no role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication.

The study was approved by the Kyushu University Institutional Review Board for Clinical Research (No. 2021-399).

WM, CI, FM, and HF designed the study. MM, FM, and HF collected the data. WM performed analysis; the data was interpreted by all authors. WM drafted the original manuscript. All authors reviewed and edited the manuscript. The study was supervised by CI and HF. All authors have read the manuscript and have approved its submission for publication.