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: Across the seven RCTs (100% RCTs), mRNA vaccines achieved significantly higher SCRs than controls: A/H1N1 (RR 3.41; 95% CI 2.8-4.2), A/H3N2 (RR 3.54; 95% CI 2.9-4.3), B/Victoria (RR 2.83; 95% CI 2.3-3.5), and B/Yamagata (RR 3.34; 95% CI 2.7-4.2). Heterogeneity was high for all strains (I²>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.