2024–2025 COVID-19 mRNA Vaccine Effectiveness Against Severe Disease

BACKGROUND: This study evaluated the effectiveness of the 2024-2025 coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccine against COVID-19 emergency department (ED) visits and hospitalizations. METHODS: Using electronic health records from a large South Carolina health system, we emulated a target trial comparing adults aged 18 years and older who did and did not receive the 2024-2025 COVID-19 mRNA vaccine. Vaccinated individuals during September 1, 2024-March 15, 2025, were risk-set matched 1:2 to unvaccinated individuals on demographic and clinical covariates using propensity score matching. Primary outcomes were time to COVID-19 ED or more severe care and time to hospitalization through April 16, 2025, analyzed using Cox proportional hazards models. RESULTS: The final matched cohort included 30,080 individuals, including 10,029 vaccinated participants. Mean age was 65.5 years, 36.5% male, 66.7% Caucasian; 85.6% had a pre-existing condition. Vaccine effectiveness against ED or more severe care was 41.3% (95% CI, 17.2%-58.4%) and 46.1% (95% CI, 13.6%-66.3%) against hospitalization. CONCLUSIONS: The 2024-2025 mRNA COVID-19 vaccine provided moderate protection against COVID-19 ED visits and hospitalizations among an older population with a high burden of pre-existing conditions, supporting continued efforts to improve vaccine uptake in higher-risk adults.