Quadrivalent modRNA Influenza Vaccine Shows Superior Efficacy to Licensed Inactivated Vaccine in Phase 3 Trial

A quadrivalent nucleoside-modified messenger RNA (modRNA) influenza vaccine demonstrated statistically superior efficacy to a licensed inactivated quadrivalent influenza vaccine in preventing laboratory-confirmed influenza-like illness among adults aged 18 to 64 years, according to findings from a phase 3 randomized trial published in the New England Journal of Medicine.

The multicountry trial enrolled 18 476 healthy or medically stable adults during the 2022–2023 influenza season across 242 sites in the US, 5 in South Africa, and 1 in the Philippines. Participants were randomized 1:1 to receive either a single 30-µg dose of the modRNA vaccine or a licensed inactivated comparator (FLUZONE). The primary outcome was relative vaccine efficacy against laboratory-confirmed influenza associated with influenza-like illness occurring ≥14 days after vaccination.

"This randomized trial showed that the modRNA vaccine provided both similar and improved prevention of a first episode of laboratory-confirmed influenza in adults between the ages of 18 and 64 years," investigators wrote.

Efficacy Findings

By the prespecified data cutoff (March 17, 2023), 57 cases of influenza-like illness occurred in the modRNA group and 87 in the control group. The modRNA vaccine met criteria for both noninferiority and superiority:

• Relative efficacy: 34.5% (95% CI, 7.4–53.9)
• Modified intention-to-treat analysis: 33.6% (95% CI, 12.5–49.8)
• End-of-season analysis: 28.7% (95% CI, 0.1–49.4)

Influenza A strains (A/H3N2 and A/H1N1) accounted for all matched cases, consistent with season-specific surveillance. No matched influenza B cases were identified.

Immunogenicity

In approximately 4000 participants in the immunogenicity subgroup, the modRNA vaccine elicited immune responses meeting noninferiority criteria for influenza A strains:

• Hemagglutination-inhibition (HAI) geometric mean ratios:
  Noninferior for A/H3N2 and A/H1N1; not met for B/Yamagata or B/Victoria.
• Seroresponse rates:
  Noninferior for A/H3N2 and A/H1N1; not met for B strains.

Postvaccination HAI titers at 4 weeks were higher for influenza A strains with the modRNA vaccine, whereas titers to B strains were similar or lower compared with the control vaccine.

Cell-mediated immune responses also favored the modRNA vaccine. According to the results, geometric mean factor increases for CD4 and CD8 T-cell responses were consistently higher 1 week after vaccination and remained elevated through 6 months.

Safety and Reactogenicity

Reactogenicity was more frequent with the modRNA vaccine. In the electronic diary subgroup (n=6127):

• Local reactions: 70.1% (modRNA) vs 43.1% (control)
• Systemic events: 65.8% vs 48.7%
• Fever: 5.6% vs 1.7%

Most events were mild or moderate. Pain, fatigue, and headache were the most common reactions, and severe events were infrequent and comparable between groups.

Across 18 388 participants in the safety dataset:

• Adverse events ≤4 weeks: 6.7% (modRNA) vs 4.9% (control)
• Serious adverse events: ~1% in each group
• No confirmed myocarditis or pericarditis
• No vaccine-related deaths reported

One modRNA recipient experienced a grade 3 injection-site reaction and grade 4 anaphylactic reaction that did not meet clinical criteria for anaphylaxis.

Clinical Implications

Authors noted that, in a season dominated by influenza A strains, the modRNA platform demonstrated improved efficacy and stronger A-strain immunogenicity relative to a licensed comparator. The absence of matched influenza B cases limits interpretation of protection against B strains, a limitation highlighted by modest HAI response differences.

The trial also underscores potential advantages of modRNA influenza vaccines, including shorter manufacturing timelines, avoidance of egg-adaptive mutations, and scalability.

"The modRNA platform offers promise for the development of influenza vaccines and may improve upon existing products," researchers concluded.

Study Limitations

Limitations included reliance on relative efficacy rather than absolute placebo-controlled efficacy, limited evaluation of B-strain protection, and exclusion of adults ≥65 years, children, pregnant persons, and immunocompromised individuals.

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