COVID-19 Vaccination Linked to Lower Hospitalization and Death Risk: NEJM Study

Although early randomized trials demonstrated high vaccine efficacy, the evolving SARS-CoV-2 variants, increasing background immunity, and declining vaccine uptake have raised questions about the continued benefit of annual booster doses. To address this, Miao Cai of the Department of Veterans Affairs (VA) St. Louis Health Care System and colleagues evaluated the effectiveness of the 2024–2025 vaccine formulation in preventing severe Covid-19 outcomes in a contemporary real-world setting.

The investigators conducted an observational study using electronic health records from the U.S. Department of Veterans Affairs. The analysis emulated a pragmatic target trial design and included 164,132 veterans who received the Covid-19 and influenza vaccines on the same day and 131,839 veterans who received the influenza vaccine alone as an active comparator group between September 3 and December 31, 2024. Participants were followed for 180 days or until the occurrence of an outcome. Inverse-probability-weighted models were used to estimate vaccine effectiveness.

Key Clinical Findings of the Study Include:

• Emergency Care Reduction: The study of the 2024–2025 vaccine showed a 29.3% effectiveness (95% confidence interval [CI], 19.1 to 39.2) against Covid-19–related ED visits, preventing approximately 18.3 incidents per 10,000 individuals.
• Hospitalization Prevention: In the study, the updated formulation achieved a 39.2% effectiveness (95% CI, 21.6 to 54.5) in reducing Covid-19–associated inpatient admissions compared to the influenza-only group.
• Mortality Mitigation: The most profound protection was observed against mortality, with a 64.0% reduction in Covid-19–associated deaths (95% CI, 23.0 to 85.8) over the six-month observation period.
• Broad Clinical Utility: A significant protection against severe outcomes remained consistent across all evaluated patient demographics, including those aged over 75 and individuals with immunocompromised status or significant chronic illnesses.
• Temporal Durability: Although the composite effectiveness against Covid-19 declined from 37.1% in the first two months to 21.4% at six months, the vaccine maintained a meaningful clinical defense throughout the follow-up.

The results suggest that the 2024–2025 Covid-19 vaccine provides significant incremental protection against serious clinical outcomes, including hospitalization and death, across diverse and high-risk patient populations. These findings support the continued clinical value of annual vaccinations for maintaining a robust defense against severe disease in the current epidemiologic landscape.

The authors conclude that these results provide essential contemporary evidence of the vaccine's continued effectiveness against severe disease, supporting the clinical value of recommending annual boosters to patients within the current epidemiological context.

While the authors acknowledge that the study’s observational design and demographic focus on older male veterans may limit broader applicability and causal conclusions, they highlight a critical need for future research to explore the mechanisms of declining immunity and strategies to improve the durability of vaccine protection.

Reference

Cai M, Xie Y, Al-Aly Z. Association of 2024–2025 Covid-19 Vaccine with Covid-19 Outcomes in U.S. Veterans. N Engl J Med 2025; 393: 1612-23.