pragmatic individually randomized trial to evaluate the effectiveness of high-dose vs standard-dose influenza vaccine in older adults: Rationale and design of the DANFLU-2 trial.

BACKGROUND: The high-dose inactivated influenza vaccine (HD-IIV) has been shown to reduce the incidence of influenza infection compared with standard-dose inactivated influenza vaccine (SD-IIV); however, its effectiveness in preventing severe respiratory and cardiovascular outcomes in the older general population has not yet been assessed in a fully powered individually randomized trial. METHODS: DANFLU-2 is an ongoing pragmatic, registry-based, open-label, active-controlled, individually randomized trial conducted in Denmark during the 2022/2023, 2023/2024, and 2024/2025 influenza seasons. Utilizing innovative electronic recruitment strategies and an online informed consent process, the trial has enrolled 332,438 older adults ≥65 years; enrollment was completed in October 2024. Participants were randomly allocated in a 1:1 ratio to either HD-IIV or SD-IIV. Baseline, endpoint, and safety data are primarily obtained from the nationwide Danish administrative health registries. The primary endpoint is hospitalization for influenza or pneumonia with the trial also powered to assess the first secondary endpoint of hospitalization for any cardio-respiratory disease. The additional secondary endpoints of all-cause hospitalization and mortality will be tested hierarchically. Key ancillary analyses include cost-effectiveness and health care resource consumption assessments as well as a home self-swab sub-cohort. DISCUSSION: DANFLU-2 is the largest individually randomized influenza vaccine trial ever conducted and will provide critical, high-quality evidence on the effectiveness of HD-IIV against cardio-respiratory hospitalizations and mortality in the older general population. TRIAL REGISTRATION: Clinicaltrials.gov: NCT05517174, registered August 24, 2022, https://clinicaltrials.gov/study/NCT05517174.