Humoral immune response to mRNA-based influenza vaccines in older adults: a systematic review and meta-analysis of randomized controlled trials

BACKGROUND: Influenza causes substantial morbidity and mortality in older adults, and conventional inactivated vaccines often elicit suboptimal immune responses in this population. Recent phase II/III randomized controlled trials (RCTs) have evaluated mRNA-based influenza vaccines, but a quantitative synthesis of their immunogenicity in adults aged ≥65 years is lacking. OBJECTIVE: To determine whether mRNA influenza vaccines yield higher seroconversion rates (SCRs) at 29 days post-vaccination compared to licensed inactivated vaccines in adults aged ≥65 years. DESIGN: Systematic review and meta-analysis of RCTs. SETTINGS: Hospital, out-patient and community-based RCTs conducted in the USA. METHODS: We searched PubMed, Scopus, Web of Science, and Google Scholar from database inception to July 2025 for RCTs reporting SCR at 29 days post-mRNA influenza vaccination in adults aged ≥65 years. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were estimated using a random-effects model. MAIN OUTCOME MEASURE: SCR at day 29 post-vaccination for each influenza strain (A/H1N1, A/H3N2, B/Victoria, B/Yamagata). SAMPLE SIZE: Seven RCTs out of 4 studies comprising 7,114 participants aged ≥65 years were included. RESULTS: >80%). Sensitivity analyses omitting one study at a time confirmed robustness of the pooled estimates. Funnel plots and Egger's test indicated possible small-study effects. Meta-regression found no significant association between vaccine dose and effect size. RISK OF BIAS: Visual inspection of Begg's funnel plots for the A/H1N1, A/H3N2, and B/Victoria strains revealed asymmetry, suggesting the possibility of publication bias. HETEROGENEITY: There was significant heterogeneity among studies for A/H1N1, A/H3N2, and B/Victoria strains but not B/Yamagata strain. CONCLUSION: In adults aged ≥65 years, mRNA influenza vaccines elicit substantially higher seroconversion rates across all four seasonal strains compared with licensed inactivated vaccines, suggesting a promising strategy to enhance immune protection in this high-risk population. Findings should be interpreted with caution given the small number of studies available. LIMITATIONS: Low number of studies included limits full assessment of heterogeneity and bias. REGISTRATION: PROSPERO CRD420251108768.