DESPITE the widespread availability of licensed vaccines, influenza continues to impose a substantial global burden, with around one billion cases occurring annually. Traditional seasonal vaccines, produced using egg-, cell-based, or recombinant protein platforms, have demonstrated variable effectiveness, ranging between 19% and 60% across the past 15 years in the United States. Messenger RNA (mRNA) technology offers a promising alternative, with the potential to improve antigenic match to circulating strains and avoid mutations seen with egg-based production.
The investigational mRNA-1010 influenza vaccine has undergone extensive clinical evaluation in a series of trials involving over 14,000 adults. Its original formulation, which encodes for hemagglutinin (HA) proteins of WHO-recommended strains, was assessed for safety, immunogenicity, and efficacy. The phase 3 P301 trial confirmed an acceptable safety profile and demonstrated robust immune responses, particularly against influenza A strains. However, it did not meet immunogenicity endpoints for influenza B strains. A parallel phase 3 efficacy trial (P302) similarly found greater effectiveness against influenza A, with diminished efficacy for B strains.
These findings mirror challenges seen with other licensed vaccines, potentially due to immunological history or inherent differences in antigenicity. Nevertheless, immune correlate analysis from the P301 trial supported the use of Day 29 hemagglutination inhibition (HAI) antibody titres as predictive of protection – reinforcing their role as a clinical endpoint for evaluating mRNA-based influenza vaccines. While the original mRNA-1010 formulation showed promise, the observed limitations led to the development of an optimised version.
The revised mRNA-1010 formulation, evaluated in a subsequent trial (P303), met all primary immunogenicity goals and demonstrated superior immune responses against all four vaccine strains compared with standard-dose and high-dose vaccines. Importantly, the safety profile remained consistent, with no evidence of increased serious adverse events.
These results support the continued investigation of mRNA-based influenza vaccines and underscore the value of this platform in potentially improving seasonal vaccine effectiveness. An ongoing phase 3 efficacy trial of the optimised mRNA-1010 formulation (P304) may provide further evidence for its role in influenza prevention.
Reference
Kandinov B et al. An mRNA-based seasonal influenza vaccine in adults: results of two phase 3 randomized clinical trials and correlate of protection analysis of hemagglutination inhibition titers. Hum Vaccin Immunother. 2025;21(1):2484088.
