Immunogenicity and Efficacy of a Quadrivalent mRNA Influenza Vaccine in Adults: Results From a Phase 3 Trial

Background

Current inactivated influenza vaccines provide suboptimal protection, particularly against drifted strains. The mRNA vaccine platform, validated during the COVID-19 pandemic, offers potential advantages including rapid manufacturing and superior immunogenicity. mRNA-1010 is a lipid nanoparticle-encapsulated quadrivalent mRNA vaccine encoding hemagglutinin glycoproteins of four influenza strains recommended by the WHO. We report results from the pivotal phase 3 efficacy trial.

Methods

This observer-blind, randomized, active-controlled phase 3 trial was conducted at 98 sites across 22 countries during the 2024-2025 influenza season. A total of 23,152 adults aged 18 to 64 years were randomized 1:1 to receive a single dose of mRNA-1010 or a licensed quadrivalent inactivated influenza vaccine (QIV). The co-primary endpoints were geometric mean titer (GMT) ratios for hemagglutination inhibition antibodies at day 29 (superiority) and vaccine efficacy against RT-PCR-confirmed influenza illness (non-inferiority margin of 10 percentage points).

Results

mRNA-1010 elicited significantly higher GMT ratios compared with QIV for all four strains: A/H1N1 (2.8; 95% CI, 2.4-3.2), A/H3N2 (3.1; 95% CI, 2.7-3.6), B/Victoria (2.3; 95% CI, 2.0-2.7), and B/Yamagata (2.1; 95% CI, 1.8-2.4), all meeting the superiority criterion. Vaccine efficacy against RT-PCR-confirmed influenza was 51.3% (95% CI, 42.1-59.1) for mRNA-1010 versus 45.8% (95% CI, 36.2-54.0) for QIV, meeting the non-inferiority criterion (lower bound of difference: -1.2%). Solicited adverse events were more common with mRNA-1010 (injection-site pain: 78% vs. 62%; fatigue: 38% vs. 24%) but were predominantly mild and self-limited. No serious vaccine-related adverse events were reported.

Conclusions

The quadrivalent mRNA influenza vaccine generates significantly stronger immune responses against all four influenza strains compared with standard inactivated vaccine, with clinically meaningful and non-inferior efficacy against confirmed influenza illness in adults.