Effectiveness of high-dose vs. standard-dose quadrivalent influenza vaccine against recurrent hospitalisations and mortality in relation to influenza circulation: a post-hoc analysis of the DANFLU-1 randomised clinical trial

OBJECTIVES:To evaluate the relative effectiveness of high-dose quadrivalent influenza vaccine (QIV-HD) vs. standard-dose quadrivalent influenza vaccine (QIV-SD) against recurrent hospitalisations and its potential variation in relation to influenza circulation. METHODS:We did a post-hoc analysis of a pragmatic, open-label, randomised trial of QIV-HD vs. QIV-SD conducted during the 2021-2022 influenza season among adults aged 65-79 years. Participants were enrolled in October-November, 2021 and followed for outcomes from 14 days post-vaccination until May 31, 2022. We investigated the following outcomes: Hospitalisations for pneumonia or influenza, respiratory hospitalisations, cardio-respiratory hospitalisations, cardiovascular hospitalisations, all-cause hospitalisations, and all-cause death. Outcomes were analysed as recurrent events. Cumulative numbers of events were assessed weekly. Cumulative relative effectiveness estimates were calculated and descriptively compared to influenza circulation. The trial is registered at Clinicaltrials.gov: NCT05048589. RESULTS:Among 12,477 randomly assigned participants, receiving QIV-HD was associated with lower incidence rates of hospitalisations for pneumonia or influenza (10 vs. 33 events, IRR 0.30 [95% CI 0.14-0.64], p=0.002) and all-cause hospitalisations (647 vs. 742 events, IRR 0.87 [95% CI 0.76-0.99], p=0.032) compared with QIV-SD. Trends favouring QIV-HD were consistently observed over time including in the period prior to active influenza transmission; i.e. while the first week with a ≥10% influenza test positivity rate was calendar week 10, 2022, the first statistically significant reduction in hospitalisations for pneumonia or influenza was already observed by calendar week 3, 2022 (5 vs. 15 events, IRR 0.33 [95% CI 0.11-0.94], p=0.037). CONCLUSION:In a post-hoc analysis, QIV-HD was associated with lower incidence rates of hospitalisations for pneumonia or influenza and all-cause hospitalisations compared with QIV-SD, with trends evident independent of influenza circulation levels. Our exploratory results correspond to a number needed to treat of 65 (95% CI 35-840) persons vaccinated with QIV-HD compared with QIV-SD to prevent one additional all-cause hospitalisation per season. Further research is needed to confirm these hypothesis-generating findings.