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. 2025 Aug 30.
doi: 10.1056/NEJMoa2509834. Online ahead of print.

High-Dose Influenza Vaccine to Reduce Hospitalizations

Jacobo Pardo-Seco  1   2   3   4   5 , Carmen Rodríguez-Tenreiro-Sánchez  1   2   3   6   7 , Iago Giné-Vázquez  1   2   3 , Narmeen Mallah  1   2   8   9 , Susana Mirás-Carballal  10 , Marta Piñeiro-Sotelo  10 , Martín Cribeiro-González  11 , Mónica Conde-Pájaro  10 , Juan-Manuel González-Pérez  12 , Irene Rivero-Calle  1   2   3   6   7 , Xabier Bello  1   2   3   4   5 , Josefina Lorena Razzini  1   2   3   6   7 , Ana Dacosta-Urbieta  1   2   3   6   7 , Antonio Salas  1   3   4   5 , Rebecca C Harris  13 , Matthew M Loiacono  14   15 , Robertus van Aalst  14 , Joan Manel Farre  16 , Marine Dufournet  17 , Niklas Dyrby Johansen  18   19 , Daniel Modin  18   19 , Tor Biering-Sørensen  18   19   20   21 , Carmen Durán-Parrondo  10 , Federico Martinón-Torres  1   2   3   6   7 ; GALFLU Trial Team
Affiliations

High-Dose Influenza Vaccine to Reduce Hospitalizations

Jacobo Pardo-Seco et al. N Engl J Med. .

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.).

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