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.