High-Dose Influenza Vaccine to Reduce Hospitalizations
Jacobo Pardo-Seco, Carmen Rodríguez-Tenreiro-Sánchez, Iago Giné-Vázquez, et al
N Engl J Med Published August 30, 2025
DOI: 10.1056/NEJMoa2509834
Abstract
BACKGROUND
Superior protection against laboratory-confirmed influenza has been proved for high-dose inactivated influenza vaccine, as compared with the standard dose, among adults 65 years of age or older. However, data on the relative effectiveness of the high-dose vaccine against severe clinical outcomes, including hospitalizations, are limited.
METHODS
We conducted a pragmatic, registry-based, open-label, randomized, active-controlled trial to evaluate the relative effectiveness of high-dose inactivated influenza vaccine, as compared with the standard dose, against severe clinical outcomes among community-dwelling adults 65 to 79 years of age. The trial was performed during two influenza seasons (2023–2024 and 2024–2025) with regional health registry data in Galicia, Spain. In each influenza season, the participants were randomly assigned in a 1:1 ratio to receive high-dose inactivated influenza vaccine or the standard dose. The primary end point was a composite of hospitalization for influenza or pneumonia from 14 days after vaccination to May 31 of the following year.
RESULTS
A total of 103,169 unique participants underwent randomization; 31,307 participants were enrolled in both seasons and were counted for each. During the 2023–2024 and 2024–2025 seasons, 59,490 and 74,986 participants, respectively, underwent randomization. Among the participants, the mean (±SD) age was 72.3±4.3 years, and 53.6% were men. A primary end-point event occurred in 174 of 67,093 participants (absolute risk, 0.26%) in the high-dose group and in 227 of 66,789 (absolute risk, 0.34%) in the standard-dose group (relative vaccine effectiveness, 23.7%; 95% confidence interval [CI], 6.6 to 37.7). Hospitalization for influenza occurred in 63 of 67,093 participants (absolute risk, 0.09%) in the high-dose group and in 92 of 66,789 (absolute risk, 0.14%) in the standard-dose group (relative vaccine effectiveness, 31.8%; 95% CI, 5.0 to 51.3). The incidence of serious adverse events appeared to be similar in the two trial groups.
CONCLUSIONS
Among community-dwelling adults 65 to 79 years of age, there appeared to be fewer hospitalizations for influenza or pneumonia with high-dose inactivated influenza vaccine than with the standard dose. (Funded by Sanofi; GALFLU ClinicalTrials.gov number NCT06141655; EudraCT number, 2023-506977-36-00.)
