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 1,238 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.