Real-world effectiveness of seasonal influenza vaccination and age as effect modifier: A systematic review, meta-analysis and meta-regression of test-negative design studies

•Influenza vaccines provided moderate protection against influenza-related outpatient visit and hospitalization.•The effectiveness varied substantially by influenza type/subtype, with highest effectiveness against A/H1N1 and lowest against A/H3N2.•Both young adults and elderly manifested significantly decreased influenza vaccine effectiveness compared with children. Under the global risk of epidemic rebound of influenza after COVID-19 outbreak, the study aimed to provide a comprehensive evaluation of the seasonal influenza vaccine effectiveness (IVE) and to explore the potential effect modifiers. We searched for test-negative design studies with IVE estimates published between January 1, 2017 and December 31, 2022. We estimated pooled IVE using random-effects meta-analysis, and conducted meta-regression with study site, age, sex and comorbidity as explanatory variables. We identified 2429 publications and included 191 in the meta-analysis. The pooled IVE was 41.4 % (95 % CI: 39.2–43.5 %) against any influenza. For specific strains, the IVE was 55.4 % (95 % CI: 52.7–58.1 %) against A/H1N1, 26.8 % (95 % CI: 23.5–29.9 %) against A/H3N2, 47.2 % (95 % CI: 38.1–54.9 %) against B/Yamagata, and 40.6 % (95 % CI: 23.7–53.7 %) against B/Victoria, and the effectiveness against A/H3N2 was significantly lower than A/H1N1 (p