High-Dose Influenza Vaccine Reduces Hospitalizations in Older Adults

Key Highlights

• High-dose influenza vaccine was associated with a lower absolute risk of hospitalization for influenza or pneumonia than the standard-dose vaccine.
• Relative vaccine effectiveness was 23.7% for preventing hospitalizations for influenza or pneumonia and 31.8% for preventing hospitalizations for influenza.
• Serious adverse events and mortality rates were similar between study groups.

In a new study, published in The New England Journal of Medicine, researchers evaluated whether the enhanced antigen content of the high-dose formulation confers greater protection against severe clinical outcomes in adults aged 65 to 79 years. While high-dose vaccines have demonstrated improved immunogenicity, their effectiveness against hospitalizations in this population has been less defined.

Researchers conducted an open-label, active-controlled randomized trial during the 2023-2024 and 2024-2025 influenza seasons. Community-dwelling adults aged 65 to 79 years were randomly assigned 1:1 to receive a high- or standard-dose quadrivalent inactivated influenza vaccine. All clinical outcomes were captured through the integrated electronic health registries within Galica, Spain. The primary outcome was hospitalization for influenza or pneumonia occurring at least 14 days after vaccination through May 31 of the following year. Secondary outcomes included hospitalizations for cardiorespiratory causes, all-cause hospitalizations, and all-cause mortality.

Study Findings

A total of 133,882 participants were included in the intention-to-treat analysis, with balanced baseline characteristics and a mean age of 72.3 years. Hospitalization for influenza or pneumonia occurred in 174 of 67,093 participants (0.26%) in the high-dose group and 227 of 66,789 participants (0.34%) in the standard-dose group, corresponding to a relative vaccine effectiveness of 23.7% (95% CI, 6.6-37.7).

Hospitalization for influenza alone occurred in 63 participants (0.09%) in the high-dose group and in 92 (0.14%) in the standard-dose group, yielding a relative vaccine effectiveness of 31.8% (95% CI, 5.0–51.3). Rates of serious adverse events, including deaths, were similar in both groups, and no unexpected safety signals emerged.

Clinical Implications

According to the study authors, the findings suggest that a high-dose inactivated influenza vaccine may reduce hospitalizations for influenza or pneumonia among adults aged 65 to 79 years, with additional protective effects seen for influenza-specific admissions. Although the number of primary events did not meet the threshold required for formal hypothesis testing, the direction and magnitude of effect were consistent with the previous literature, supporting enhanced protection from high-dose formulations.

The authors noted several limitations, including the open-label design, lack of systematic influenza testing, and conduct within a single Spanish region, which may limit generalizability. The lower-than-expected incidence of influenza also reduced statistical power for confirmatory analyses.

Expert Commentary

“Among community-dwelling adults 65 to 79 years of age, there appeared to be fewer hospitalizations for influenza or pneumonia with the high-dose inactivated influenza vaccine than with the standard dose,” the researchers concluded.

Reference

Pardo-Seco J, Rodríguez-Tenreiro-Sánchez C, Giné-Vázquez I, et al. High-dose influenza vaccine to reduce hospitalizations. N Engl J Med. 2025;393(23):2303-2312. doi:10.1056/NEJMoa2509834