Research Summary

Efficacy, Safety of a Quadrivalent Modified mRNA Influenza Vaccine in the United States, South Africa, and the Philippines

Edited by:
Ashton L. Stahl

Key Highlights:

  • The modified mRNA (modRNA) vaccine demonstrated 34.5% relative efficacy versus a licensed inactivated vaccine.
  • Superior immunogenicity was observed for A/H3N2 and A/H1N1 strains.
  • Reactogenicity was higher with the modRNA vaccine but was mostly mild to moderate.

A modified mRNA (modRNA) vaccine achieved statistically significant superiority in preventing a laboratory-confirmed influenza-like illness, driven largely by circulating A/H3N2 and A/H1N1 strains during the 2022–2023 season, according to the results of a phase 3 trial published in The New England Journal of Medicine.

In their study, which was conducted across the United States, South Africa, and the Philippines, Fitz-Patrick and colleagues assessed the efficacy, immunogenicity, and safety of a quadrivalent modRNA influenza vaccine compared with a standard, inactivated quadrivalent vaccine.

The researchers randomized 18,476 healthy adults aged 18–64 years to receive either the modRNA vaccine or a licensed inactivated comparator. The primary end point was relative efficacy, which was based on first episodes of laboratory-confirmed influenza-like illness occurring at least 14 days postvaccination. Immunogenicity was measured using hemagglutination inhibition assays. Safety assessments included local and systemic reactions within 7 days, adverse events within 1 month, and serious adverse events within 6 months.

Study Findings

The trial enrolled 9225 participants in the modRNA vaccine group and 9251 in the control vaccine group. A total of 57 influenza-like illness cases occurred in the modRNA group versus 87 in the control group, yielding a relative efficacy of 34.5% (95% CI, 7.4–53.9). This outcome met criteria for both noninferiority and superiority. Most influenza-like illness cases were attributable to A/H3N2 and A/H1N1; almost no B strains were detected.

Immunogenicity analyses showed that the modRNA vaccine met noninferiority criteria for A/H3N2 and A/H1N1 strains in geometric mean titers and seroconversion but did not meet these criteria for B/Yamagata or B/Victoria. T-cell responses, including CD4+ and CD8+ activation, were higher with the modRNA vaccine at 1 week and remained elevated through 6 months.

Reactogenicity was more common with the modRNA vaccine (local reactions 70.1% vs. 43.1%; systemic events 65.8% vs. 48.7%). Fever occurred in 5.6% of modRNA recipients and 1.7% of control recipients. Adverse event rates and serious adverse events were similar between groups, with no confirmed myocarditis or pericarditis and no vaccine-related deaths.

Clinical Implications

According to the study authors, these findings suggest that the modRNA platform may offer enhanced efficacy against circulating A strains, supported by stronger antibody and T-cell responses. The authors noted that the vaccine’s increased reactogenicity did not translate to clinically meaningful differences in severe adverse events. They also emphasized that the trial’s single-season scope limits conclusions about efficacy against influenza B strains.

Expert Commentary

“Our randomized trial showed that the modRNA vaccine provided both similar and improved prevention of a first episode of laboratory-confirmed influenza in adults between 18 and 64 years of age, demonstrating the promise of the modRNA platform for seasonal influenza prevention,” the researchers concluded.

Reference
Fitz-Patrick D, McVinnie DS, Jackson LA, et al. Efficacy, immunogenicity, and safety of modified mRNA influenza vaccine. N Engl J Med. 2025;393:2001-2011. doi:10.1056/NEJMoa2416779