COVID-19 Booster Vaccination and Increased Mortality: Detection of a Safety Signal in a Non-Elderly Population

Background/PurposeCOVID-19 mRNA vaccines have been reported to prevent severe disease in high-risk populations. In Japan, booster doses of up to the seventh dose are publicly funded; however, the safety and benefits of frequent vaccinations in younger adults remain unclear. This study analyzed all-cause mortality by age group and number of vaccine doses, focusing on associations between frequent boosters (≥5 doses) and mortality.MethodsThe resident registry and vaccination records from Hamamatsu City (2021–2024) and Matsudo City (2021–2025) were linked to analyze all-cause mortality by age and number of vaccine doses. Three age groups were examined: 20–49, 50–64, and 65–89 years. Mortality rates were calculated using person-years, and each death was attributed to the most recent vaccine dose received.ResultsOlder adults (65–89 years) receiving ≥5 doses had lower all-cause mortality, although this may partly reflect healthy vaccinee bias, as healthier individuals were more likely to continue vaccination. In contrast, younger adults (20–49 years) showed a marked increase in mortality with ≥5 doses, and those aged 50–64 exhibited elevated mortality with six doses. These patterns suggest that selective vaccination of high-risk individuals does not fully account for the observed trends. While frequent vaccination was associated with reduced mortality in older adults but increased mortality in younger adults.ConclusionsObservational data indicated age- and dose-dependent differences in all-cause mortality after COVID-19 vaccination. Although additional doses may reduce mortality in older adults, frequent boosters in younger adults may pose potential risks. The causality cannot be established, and the underlying mechanisms remain unclear. These findings emphasize the need for careful risk–benefit assessments in younger populations and underscore the importance of nationwide confounder-adjusted analyses to inform optimized booster strategies, including vaccine type, dosing intervals, and immunological factors.