Relative effectiveness of high-dose versus standard-dose influenza vaccine against hospitalizations and mortality according to frailty score: A post-hoc analysis of the DANFLU-1 randomized trial.

BACKGROUND Frailty is a risk factor for adverse influenza-related outcomes. We assessed the effectiveness of high-dose (HD-IIV) versus standard-dose (SD-IIV) influenza vaccination according to frailty score (FS). METHODS This was a post-hoc analysis of the randomized feasibility trial of HD-IIV versus SD-IIV conducted during the 2021-2022 influenza season in older adults aged 65-79 years. We assessed prespecified outcomes including hospitalizations and mortality as time to first and recurrent events. Frailty was defined according to the Hospital Frailty Risk Score. RESULTS Among 12,477 included participants (mean age 71.7 years, 47.1% female), 10,689 (85.7%) were categorized as having low frailty (<5 points) and 1,784 (14.3%) had intermediate or high frailty (≥5 points). HD-IIV versus SD-IIV was associated with a lower risk of first and recurrent hospitalizations for pneumonia or influenza regardless of FS (Low frailty: 22 events, HR 0.37, 95% CI 0.15- 0.96; 25 recurrent events, IRR 0.31, 95% CI 0.11- 0.84. Intermediate or high frailty: 16 events, HR 0.33, 95% CI 0.11-1.01; 18 recurrent events, IRR 0.28, 95% CI 0.09-0.92. Pinteraction 0.92 and 0.93, respectively). FS modified the association of HD-IIV versus SD-IIV with all-cause mortality (Pinteraction 0.022), with an association with reduced risk in participants with low frailty only (43 events, HR 0.26, 95% CI 0.13 to 0.55). CONCLUSION HD-IIV was associated with a lower risk of first and recurrent hospitalizations for pneumonia and influenza compared with SD-IIV and may be preferred for older adults irrespective of frailty status. FS modified the association of HD-IIV versus SD-IIV with all-cause mortality.