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

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 < 0.0001) and B/Yamagata (p < 0.0001). The pooled IVE was 39.2 % (95 % CI: 36.5-41.9 %) in preventing influenza-associated outpatient visit and 43.7 % (95 % CI: 39.7-47.4 %) in preventing influenza-related hospitalization. The IVE against any influenza was 48.6 % (95 % CI: 44.7-52.2 %) for children aged < 18 years, 36.7 % (95 % CI: 31.9-41.1 %) for adults aged 18-64 years, and 30.6 % (95 % CI: 26.2-34.8 %) for elderly aged ≥65 years. Meta-regression revealed that the IVE was associated with the average age of study participants, in which both young adults [relative odds ratio (ROR) = 1.225, 95 % confidence interval (CI): 1.099-1.365, p = 0.0002] and elderly (ROR = 1.245, 95 % CI: 1.083-1.431, p = 0.002) manifested a significantly decreased effectiveness compared with children.Influenza vaccines provided moderate protection against laboratory-confirmed influenza and related outpatient visit and hospitalization. However, the effectiveness may vary substantially by virus type and age group, suggesting the necessity to tailor vaccination strategies especially for older individuals and against the A/H3N2 strain, and to promote annual immunization and annual analysis of vaccine effectiveness.