Sex Differences in the Immunogenicity and Efficacy of Seasonal Influenza Vaccines: A Meta-analysis of Randomized-Controlled Trials

Abstract Background Sex impacts individuals’ response to vaccination. However, most vaccine studies do not report these differences disaggregated by sex. The aim of this study was to assess sex differences in the immunogenicity and efficacy of influenza vaccine. Methods We performed a meta-analysis using phase III randomized-controlled trials data conducted between 2010-2018. Using heamagglutination inhibition antibody titers for each strain, differences in geometric mean ratios (GMR) were calculated by sex. Risk ratios (RR) comparing seroconversion proportions were pooled for females and males using random-effects models. Vaccine efficacy (VE) was assessed. Data were analyzed by age group (18-64 vs. ≥65 years). Findings A total of 33,092 healthy adults from 19 studies were included for immunogenicity analysis, and 6,740 from one study for VE. Whereas no sex differences in immunogenicity were found in adults < 65 years old, older females had a significantly greater chance to seroconvert compared to older males for all strains: RRH1N1 1·17 [1·12, 1·23]; RRH3N2 1·09 [1·05, 1·14]; RRVictoria 1·23 [1·14, 1·31]; RRYamagata 1·22 [1·14, 1·30]. GMRs were also higher in older females for all strains compared to older males. VE in preventing lab-confirmed influenza was higher in older females compared to older males with VEs of 27·32% (1·15, 46·56) and 6·06% (-37·68, 35·90), respectively. Conclusion Our results suggest a higher immunogenicity and VE in females compared to males in older adults. These differences in immunogenicity and VE support the disaggregation of vaccine data by sex in clinical trials and observational studies.