Background: We conducted a multicenter test-negative study to estimate vaccine effectiveness (VE) against medically-attended, laboratory-confirmed influenza in primary care, Europe, 2024/25.

Research design and methods: Specimens were collected from patients with acute respiratory infection. All or a random sample of viruses were sequenced. VE was (1-odds ratio) × 100, adjusted for confounders.

Results: We included 7275 cases and 17,516 controls (weeks 40-2024-18-2025). Overall VE was 46% (95%CI: 40-52), lowest in adults ≥ 65 years at 28% (95%CI: 12-42). VE against influenza A(H1N1)pdm09 was 30% (95%CI: 19-40); ranging 16-34% by age and vaccination target group. Most (88%) circulating clades were 5a.2a, distinct from the vaccine clade. VE was 28% (95%CI: 7-45) against 5a.2a (C.1.9), and 6% (95%CI: -62-45) against the vaccine-matched clade 5a.2a.1 (D). VE against influenza A(H3N2) was 38% (95%CI: 26-49); ranging 20-66% by age and target group. Circulating viruses belonged to the vaccine clade 2a.3a.1, with 88% subclade (J.2). VE against influenza B was 76% (95%CI: 69-81); ranging 70-80% by age and target group; all viruses belonged to vaccine clade V1A.3a.2, with diverse subclades.

Conclusions: Influenza vaccination protected approximately one in two vaccinated individuals against medically-attended infection in primary care in Europe, 2024/25, varying by (sub)type and age.