Effectiveness of influenza vaccination to prevent severe disease: a systematic review and meta-analysis of test-negative design studies

Background Seasonal influenza vaccination may be effective against severe influenza disease. Objectives To assess evidence on the real-world effectiveness of influenza vaccination in preventing severe influenza-related outcomes. Methods Data sources: PubMed, Ovid, and Cochrane CENTRAL from inception to September 24, 2024. Study eligibility criteria Observational test-negative design studies reporting influenza vaccine effectiveness (IVE) against influenza-associated hospitalisation, death, pneumonia, intensive care unit admission, or ventilatory support. Participants Hospitalized adults and children with laboratory-confirmed influenza and inpatient controls who tested negative for influenza infection. Interventions Influenza vaccination. Assessment of risk of bias Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development, and Evaluation were used to assess study quality and evidence certainty. Methods of data synthesis We extracted study characteristics and ORs or IVE estimates and corresponding 95% CI. Both crude and adjusted estimates were considered and analysed using a random-effects model. We calculated the pooled IVE overall and by season, age group, circulating strains, vaccine type, and match between the vaccine and circulating strains. Results Overall, 7727 publications were identified, 461 reviewed, and 165 included. Pooled IVE was 42% (95% CI: 39-44) against influenza-associated hospitalisation (very low certainty), 36% (95% CI: 24-46) against death (no certainty), 51% (95% CI: 36-63) against pneumonia (low certainty), 52% (95% CI: 38-63) against intensive care unit admission (very low certainty), and 55% (95% CI: 44-64) against ventilatory support (low certainty). IVE varied by age and was generally higher (up to 2-fold) in children compared to adults. Higher IVE was observed against influenza A(H1N1) compared to A(H3N2) and in seasons with good vaccine match. Hospitalisation IVE was slightly higher for quadrivalent (45% (95% CI: 32-56)) compared to trivalent (36% (95% CI: 27-43)) vaccine. Conclusions Seasonal influenza vaccination moderately reduces severe influenza-related outcomes, particularly in children, against A(H1N1), and with a good vaccine-strain match. PROSPERO registration CRD42023476003. Copyright © 2025 The Author(s).