Available seasonal influenza vaccines, most of which are still produced in eggs, have several limitations. Messenger RNA (mRNA) technology has emerged as a transformative approach capable of overcoming some of these shortcomings. This overview synthesizes clinical trials evaluating the immunogenicity, efficacy, and safety of standalone and combination mRNA influenza vaccines. Moderna's mRNA-1010 (now approved in the United States) and Pfizer's modified-nucleoside RNA candidate (modRNA) represent the most advanced standalone platforms, while Moderna's combination influenza and COVID-19 vaccine, mRNA-1083, was recently granted European authorization. Following iterative platform optimization, these vaccines induce robust humoral and cell-mediated responses, especially against influenza A strains, characterized by extended germinal center reactions, continuous somatic hypermutation, enhanced Fc-mediated effector functions, and strong T helper 1 engagement. In phase III relative efficacy trials, an optimized mRNA-1010 formulation achieved superiority over standard-dose vaccines with a relative efficacy of 26.6% (95% CI: 16.7%, 35.4%) in adults aged ≥50 years. Pfizer's first-generation quadrivalent modRNA candidate showed 34.5% (95% CI: 7.4%, 53.9%) relative efficacy against a standard-dose comparator in younger adults aged 18-64 years, but failed to demonstrate non-inferiority in older adults (≥65 years), showing a relative efficacy of -5.8% (95% CI: -47.2%, 23.8%). However, whether mRNA platforms offer incremental benefits over enhanced formulations (such as high-dose, adjuvanted, or recombinant vaccines), which are the preferred options in some countries for older adults, remains to be established. The safety profile aligns with licensed COVID-19 mRNA vaccines; although reactogenicity is higher than with conventional vaccines, adverse reactions are predominantly mild-to-moderate and transient. Operationally, transitioning to single-dose pre-filled syringes alongside expanding refrigerated stability data significantly mitigates historical cold-chain bottlenecks. However, while standalone and combination mRNA platforms represent a major technological advance, real-world implementation challenges may affect their broader global health impact.
