Clinical question: In adults aged 65 years and older, is high-dose influenza vaccine more effective than standard-dose vaccine in preventing severe clinical outcomes of influenza infection?
Background: Elderly adults are at increased risk for influenza infection and its complications, including hospitalization and death. Available studies indicate a superior benefit of high-dose influenza vaccine (HDIV) compared to standard-dose influenza vaccine (SDIV) against lab-confirmed influenza, as the higher doses boost the attenuated immune response in this population. The Centers for Disease Control and Prevention preferentially recommends HDIV for adults aged 65 years and older. However, no randomized trials have investigated the relative efficacy of HDIV for severe clinical outcomes such as hospitalization in the general elderly population.
Synopsis: 466,320 individually randomized community-dwelling adults aged 65 and older in Spain and Denmark received a single high dose (four times the standard dose) or standard dose of influenza vaccine each influenza season. The trial occurred between 2022 and 2025, with patients evenly divided between both groups. The primary endpoint was hospitalization for influenza or pneumonia, and secondary endpoints included hospitalization for cardiorespiratory disease, laboratory-confirmed influenza hospitalization, all-cause hospitalization, and all-cause mortality. Participants were followed from 14 days after immunization until May 31 of the following year, and data were retrieved from healthcare databases. The analysis showed definitive evidence of superior efficacy of HDIV for hospitalization for influenza or pneumonia (0.56% in the HDIV group versus 0.62% in the SDIV group, with relative vaccine efficacy of 8.8%). All secondary endpoints were reduced in the high-dose versus standard-dose influenza vaccine groups, except for mortality, which was similar between both groups. Serious adverse events were also similar between the two vaccination groups.
Bottom line: HDIV is more effective than SDIV in preventing severe clinical outcomes of influenza infection, such as hospitalization for influenza. HDIV should be utilized universally in the elderly to improve global vaccine policy and lessen the burden of influenza complications.
Citation: Johansen ND, et al. Effectiveness of high-dose influenza vaccine against hospitalisations in older adults (FLUNITY-HD): an individual-level pooled analysis. Lancet. 2025;406(10518):2425-2434. doi:10.1016/S0140-6736(25)01742-8.
Dr. Sowunmi is a med-peds hospitalist at the Cleveland Clinic and an assistant professor of internal medicine and pediatrics at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, both in Cleveland.