Safety and heterogeneity of mRNA-based seasonal Influenza vaccines: A systematic review and meta-analysis of randomized controlled trials

BACKGROUND: Messenger RNA (mRNA)-based influenza vaccines represent a promising advancement in seasonal influenza prevention. However, comprehensive evaluation of their serious safety profile is essential as these vaccines progress toward widespread clinical use. While individual randomized controlled trials (RCTs) have reported low rates of serious adverse outcomes, pooled evidence is limited. OBJECTIVE: This systematic review and meta-analysis of RCTs aim to assess the risk of serious adverse events (SAEs) and adverse events of special interest (AESIs) associated with mRNA-based seasonal influenza vaccines in adults. DESIGN: Systematic review and meta-analysis SETTING: All RCTs included in the meta-analysis were carried out in the USA. METHODS: A systematic literature search was done until December 2025. RCTs evaluating mRNA-based influenza vaccines in adults and reporting participant-level data for SAEs and/or AESIs were included. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled. MAIN OUTCOME MEASURES: Risks of SAEs and AESIs associated with mRNA-based seasonal influenza vaccines in adults, expressed as pooled risk ratios with 95% CIs. SAMPLE SIZE: Seven RCTs (containing 12 datasets) were included in this meta-analysis. The total number of cases in the intervention and comparator groups were 23,754 and 22,806 respectively. RESULTS: The pooled analysis demonstrated no increased risk of SAEs (RR=0.90, 95% CI: 0.64–1.27, P =.56) and AESI (RR=0.76, 95% CI: 0.41–1.36, P =.35) among mRNA vaccine recipients compared with controls. RISK OF BIAS: Based on funnel plots, there is no evidence of systematic asymmetry or absence of smaller studies with null or adverse findings. Risk-of-bias assessment using the Cochrane traffic-light framework indicated low risk across all domains in all included RCTs. HETEROGENEITY: The heterogeneity was low-to-moderate (τ 2 =0.08; I 2 =27.79%; H 2 =1.38) for SAEs and the Q-test indicated statistically significant heterogeneity (Q=14.46, P =.21). For AESIs, heterogeneity was absent (τ 2 =0.00; I 2 =0.00%; H 2 =1.00), with no evidence of between-study variability by the Q-test (Q=4.70, P =.94). CONCLUSIONS: Pooled evidence shows that mRNA-based seasonal influenza vaccines are not associated with an increased risk of SAEs or AESIs compared with established influenza vaccines or placebo. LIMITATIONS: Low absolute number of AESIs limiting detection of extremely rare events, limited long-term follow-up beyond early and intermediate risk windows, and potential differences between trial populations and real-world vaccine recipients. REGISTRATION: CRD420251271174