Research Summary

High-Dose vs Standard-Dose Influenza Vaccine in Older Adults

Miranda Manier, BA

Key Highlights

  • High-dose influenza vaccine did not significantly reduce influenza- or pneumonia-related hospitalizations compared with standard-dose in adults ≥65 years.
  • Relative vaccine effectiveness against influenza hospitalization was 43.6%.
  • No differences were observed for pneumonia hospitalizations, all-cause hospitalizations, or all-cause mortality.
  • Serious adverse events were similar between vaccine groups.

In a large pragmatic randomized trial of older adults in Denmark, Niklas Dyrby Johansen, MD, PhD, and colleagues found that the high-dose inactivated influenza vaccine did not result in significantly fewer hospitalizations for influenza or pneumonia than the standard-dose vaccine. While the high-dose formulation reduced influenza-related hospitalizations compared with the standard dose, there was no overall benefit observed for pneumonia, cardiorespiratory disease, or all-cause outcomes.

Seasonal influenza vaccination is recommended for older adults because of their higher risk of complications, but uncertainty remains over whether high-dose vaccines meaningfully reduce severe outcomes compared with standard-dose formulations. Prior studies have suggested improved immunogenicity with the high-dose vaccine, but data from large, randomized trials focusing on hospitalization endpoints have been limited. This study aimed to address that evidence gap.

The trial enrolled 332,438 adults aged 65 years and older during the 2022–2025 influenza seasons. Participants were randomized in a 1:1 ratio to receive either the high-dose or standard-dose inactivated influenza vaccine. Outcomes were measured using nationwide administrative health registries. The primary endpoint was hospitalization for influenza or pneumonia occurring from 14 days after vaccination through the end of May of the following year.

Among the participants, the mean age was 73.7 years, and 48.6% were women. A total of 1138 participants (0.68%) in the high-dose group and 1210 (0.73%) in the standard-dose group experienced the primary endpoint, corresponding to a relative vaccine effectiveness of 5.9% (95.2% CI, –2.1 to 13.4; P = .14). Hospitalization for influenza occurred in 0.06% of high-dose recipients compared with 0.11% of standard-dose recipients (relative effectiveness, 43.6%; 95.2% CI, 27.5–56.3). Hospitalization for pneumonia occurred in 0.63% of both groups (relative effectiveness, 0.5%; 95.2% CI, –8.6 to 8.8). The relative effectiveness for hospitalization due to cardiorespiratory disease was 5.7% (95.2% CI, 1.4–9.9). Hospitalization for any cause occurred in 9.38% of high-dose recipients and 9.58% of standard-dose recipients (relative effectiveness, 2.1%; 95.2% CI, –0.1 to 4.3). Death from any cause occurred in 0.67% and 0.66%, respectively (relative effectiveness, –2.5%; 95.2% CI, –11.6 to 5.9). Serious adverse events were similar in the two groups.

 “In this trial, a high-dose inactivated influenza vaccine did not result in a significantly lower incidence of hospitalization for influenza or pneumonia than a standard dose among older adults,” Johansen and colleagues concluded.

Reference
Johansen ND, Modin D, Loiacono MM, et al. High-dose influenza vaccine effectiveness against hospitalization in older adults. N Engl J Med. Published online August 30, 2025. doi:10.1056/NEJMoa2509907