Navigating the Transition to RNA-Based Influenza Vaccines: A State-of-the-Art Review

Seasonal influenza and the ongoing emergence of zoonotic influenza viruses, including highly pathogenic avian influenza A (H5N1), remain substantial global public health threats, underscoring the need for rapidly adaptable vaccine platforms. This state-of-the-art review critically evaluates the clinical development of RNA-based influenza vaccines through a comprehensive assessment of ClinicalTrials.gov records and peer-reviewed literature. Candidates were examined across four domains: seasonal influenza vaccines, pre-pandemic influenza vaccines, combination respiratory vaccines, and self-amplifying RNA (saRNA) platforms. Clinical evidence indicates that mRNA influenza vaccines consistently elicit robust humoral immune responses and, in late-stage trials, have demonstrated improved relative efficacy against influenza A compared with conventional influenza vaccines. Reactogenicity is generally more frequent with mRNA vaccines, particularly with respect to transient mild-to-moderate systemic adverse events. However, serious adverse events remain uncommon and broadly comparable to those observed with licensed comparator vaccines. Pre-pandemic and multicomponent mRNA vaccine candidates similarly demonstrate strong immunogenicity, supporting the potential of RNA platforms for both seasonal vaccination and pandemic preparedness. Clinical development of saRNA influenza vaccines has progressed through early-phase trials, although publicly available clinical data remain limited. Regulatory milestones in 2026, including U.S. approval of mRNA-1010 (mFlusiva), the first approved mRNA-based seasonal influenza vaccine, and European Union authorization of mRNA-1083 (mCOMBRIAX), an mRNA-based influenza-COVID-19 combination vaccine, represent important steps in the clinical transition and implementation of RNA-based influenza vaccination.