Relative effectiveness of the high-dose versus standard-dose influenza vaccines for the prevention of laboratory-confirmed influenza among Italian older adults during three recent seasons

Objectives This study aimed to assess the relative vaccine effectiveness (rVE) of high-dose (HD-IIV) versus standard-dose (SD-IIV) inactivated influenza vaccines against laboratory-confirmed influenza among older adults in Liguria (Italy), Europe’s oldest region. Methods An integrated analysis of inpatient and outpatient data collected between the 2022/2023 and 2024/2025 seasons was performed using a test-negative approach. Adults aged ≥60 years vaccinated with either HD-IIV or SD-IIV and molecularly tested for influenza were eligible. For the base-case, rVE was estimated through conditional logistic regression. Alternative approaches, including the inverse probability of treatment weighting (IPTW), were used in sensitivity analyses. Results Among 1238 vaccinated older adults included in the analysis, influenza positivity prevalence was lower ( P = 0.022) in HD-IIV (6.6%; 46/693) than SD-IIV (10.3%; 56/545) recipients. rVE of HD-IIV versus SD-IIV was 29% (95% CI: −22%, 59%) among subjects aged ≥60 years. Among adults aged ≥80 years, for whom HD-IIV was preferentially recommended, HD-IIV was more effective than SD-IIV by 54% (95% CI: 10%, 76%). IPTW-derived estimates were similar in both ≥60-year-olds (32%; 95% CI: −20%, 61%) and ≥80-year-olds (53%; 95% CI: 7%, 77%). Conclusions Italian older adults, especially the oldest old, vaccinated with HD-IIV experienced fewer influenza episodes than those immunized with SD-IIV.