A Case–Control Study on the Effectiveness of Tick-Borne Encephalitis Vaccination Against Hospitalizations in an Endemic Area in Northeastern Italy

<b>Background</b>: Tick-borne encephalitis (TBE) is a severe viral infection of the central nervous system transmitted by tick bites. Vaccination represents the only effective preventive measure, yet data on TBE vaccine effectiveness in Italy are lacking. This study aimed to evaluate TBE vaccine effectiveness and vaccination coverage in the province of Udine, an endemic area in the Friuli Venezia Giulia region of Northern Italy. <b>Methods</b>: We conducted a case-control study using linked anonymized health databases of the region, including vaccination, laboratory, and hospital admission records from 2017 to 2025. Cases were defined as residents hospitalized with a diagnosis of TBE (ICD-9-CM 063.x or 321.2) and a positive anti-TBE IgM result in serum or cerebrospinal fluid. Controls were residents tested for anti-TBE IgM during the same period but not hospitalized for TBE. Vaccination history was retrieved from the regional vaccination registry. Vaccine effectiveness was estimated through logistic regression models comparing vaccinated and unvaccinated individuals. <b>Results</b>: Between 2017 and 2025, 21 confirmed TBE hospitalizations were recorded (mean annual incidence: 0.45/100,000 inhabitants). The mean hospital stay was 13.8. Among 6065 individuals tested for anti-TBE IgM, 95.2% of cases and 81.8% of controls were unvaccinated. The estimated odds ratio of TBE hospitalization for individuals with ≥3 vaccine doses versus unvaccinated was 0.11 (95% CI: 0.02-0.88). Vaccination coverage in 2025 reached about 10% of the provincial population, with markedly higher coverage (up to 34%) in mountain districts compared with lowland areas (<5%). <b>Conclusions</b>: Although limited by small sample size, this study provides the first real-world evidence of TBE vaccine effectiveness in an Italian endemic area. Vaccination is an effective preventive measure. Given the regional epidemiology and expected increase in tick activity due to climate change, strengthening vaccination uptake and public awareness in endemic districts is strongly recommended.