Association between mRNA COVID-19 vaccine boosters and mortality in Japan: The VENUS study

ABSTRACT

Although previous studies have shown no increased mortality risk after the primary series of COVID-19 mRNA vaccines, reports on booster doses are lacking. This study aimed to evaluate mortality risk after the mRNA vaccine boosters in addition to the primary series. This nested case-control study included two age-specific cohorts (18–64 and ≥65 years as of February 1, 2021) in two municipalities. All deaths were identified and matched five controls for each case at each date of death (index date) with risk set sampling according to municipality, age, and sex. The adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for mRNA vaccines (first to fifth doses) were estimated by comparing with no vaccination within 21 and 42 days before the index date using a conditional logistic regression model. The 18–64-years cohort comprised 431 cases (mean age, 57.0 years; men, 58.2%) and 2,155 controls (mean age, 56.0; men, 58.2%), whereas the ≥65-years cohort comprised 12,166 cases (84.0; 50.2%) and 60,830 controls (84.0, 50.2%). The aORs (95% CI) in 0–21 days after the third and fourth doses in the 18–64-years cohort were 0.62 (0.24, 1.62) and 0.38 (0.08, 1.84), respectively. The aORs (95% CI) after the third to fifth doses in the ≥65 years cohort were 0.36 (0.31, 0.43), 0.30 (0.25, 0.37), and 0.26 (0.20, 0.33), respectively. In conclusion, booster doses of mRNA vaccines do not increase mortality risk. These findings could help subsequent vaccine campaigns and alleviate vaccine hesitancy.

KEYWORDS:

• COVID-19 vaccine
• vaccine safety
• mortality
• mRNA vaccine
• nested case-control study

Author contributions

WM developed the original protocol, and all authors reviewed and edited the protocol. MM, FM, and HF collected data. CI performed the data analysis. All authors interpreted the results of the analyses. WM drafted the original manuscript. All authors have reviewed and edited the manuscript. All the authors have read the manuscript and approved its submission for publication.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data cannot be made available for privacy or ethical reasons.

Additional information

Funding

The development of the database for the VENUS Study was supported by AMED [grant number: JP21nf0101635]. The statistical analysis using the VENUS Study was supported by the National Center for Global Health and Medicine Intramural Research Fund [grant number: 21A2010]. The publication of this paper was supported by AMED [grant Number: JP24fk0108709]. The funders played no role in the study design, collection, analysis, interpretation of data, writing of the report, or in the decision to submit the article for publication.