Following an extremely low incidence of influenza during the first waves of the ongoing COVID-19 pandemic, the 2021/22 Northern Hemisphere winter season saw a resurgence of influenza virus circulation. The aim of this study was to describe epidemiology of severe acute respiratory infections (SARIs) among Italian adults and estimate the 2021/22 season influenza vaccine effectiveness. For this purpose, a test-negative case-control study was conducted in a geographically representative sample of Italian hospitals. Of 753 SARI patients analyzed, 2.5% (N = 19) tested positive for influenza, most of which belonged to the A(H3N2) subtype. Phylogenetic analysis showed that these belonged to the subclade 3C.2a1b.2a.2, which was antigenically different from the 2021/22 A(H3N2) vaccine component. Most (89.5%) cases were registered among non-vaccinated individuals, suggesting a protective effect of influenza vaccination. Due to a limited number of cases, vaccine effectiveness estimated through the Firth’s penalized logistic regression was highly imprecise, being 83.4% (95% CI: 25.8–97.4%) and 83.1% (95% CI: 22.2–97.3%) against any influenza type A and A(H3N2), respectively. Exclusion of SARS-CoV-2-positive controls from the model did not significantly change the base-case estimates. Within the study limitations, influenza vaccination appeared to be effective against laboratory-confirmed SARI.
