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 (I
2
>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