By Jake Scott, MD

Synopsis: In a Phase III randomized controlled trial of adults aged 18 to 64 years, a quadrivalent nucleoside-modified messenger ribonucleic acid (mRNA) (modRNA) influenza vaccine demonstrated 34.5% relative efficacy against laboratory-confirmed influenza-like illness compared with a licensed inactivated influenza vaccine, meeting criteria for both noninferiority and superiority. The modRNA platform showed enhanced immunogenicity against influenza A strains and strong T-cell responses but did not meet noninferiority criteria for immunogenicity against influenza B strains (although clinical efficacy against B strains could not be determined due to low case counts). The modRNA vaccine was associated with increased reactogenicity but demonstrated an acceptable safety profile, supporting the potential of mRNA technology for next-generation influenza vaccines.

Source: Fitz-Patrick D, McVinnie DS, Jackson LA, et al. Efficacy, immunogenicity, and safety of modified mRNA influenza vaccine. N Engl J Med. 2025;393(20):2001-2011.

Seasonal influenza remains a formidable public health challenge despite decades of vaccination efforts. During the 2022-2023 season alone, influenza caused an estimated 130,000 hospitalizations and more than 5,500 deaths among U.S. adults aged 18 to 64 years.¹ Although vaccination prevented an estimated 2.8 million illnesses and 22,000 hospitalizations in this age group, overall vaccine effectiveness against influenza has been suboptimal, ranging from 10% to 60% across seasons from 2004 to 2023.² The nucleoside-modified messenger ribonucleic acid (modRNA) platform offers theoretical advantages over traditional egg-based influenza vaccines: elimination of egg-adaptive mutations that can diminish effectiveness (particularly for H3N2), direct matching to circulating strains, and shorter manufacturing timelines.³

Fitz-Patrick and colleagues conducted a Phase III randomized, observer-blinded trial across 242 sites in the United States, five sites in South Africa, and one site in the Philippines during the 2022-2023 Northern Hemisphere influenza season. The trial enrolled healthy or medically stable adults aged 18 to 64 years who had not received any influenza vaccine within six months before enrollment. Participants were randomized 1:1 to receive either the quadrivalent modRNA vaccine encoding hemagglutinins from four World Health Organization (WHO)-recommended influenza strains (30 mcg dose) or the licensed inactivated comparator vaccine (Fluzone, Sanofi Pasteur).

The primary endpoint was relative vaccine efficacy, defined as the reduction in the percentage of participants with laboratory-confirmed influenza associated with influenza-like illness occurring at least 14 days after vaccination with the modRNA vaccine compared with the control vaccine. Noninferiority was declared if the lower boundary of the 95% confidence interval (CI) for relative vaccine efficacy exceeded −10 percentage points, and superiority if it exceeded 0 percentage points.

A total of 18,476 participants underwent randomization (9,225 to the modRNA group and 9,251 to the control group); of these, 9,191 received the modRNA vaccine and 9,197 received the control vaccine. The mean age was 43 years, 41.9% were men, and 25.1% had at least one risk factor for severe influenza. At the primary data-cutoff date, 57 cases of influenza-like illness had accrued in the modRNA group compared with 87 cases in the control group, yielding a relative vaccine efficacy of 34.5% (95% CI, 7.4 to 53.9). This result met criteria for both noninferiority and superiority. The end-of-season analysis showed relative vaccine efficacy of 28.7% (95% CI, 0.1 to 49.4). Given that licensed influenza vaccines demonstrated approximately 44% to 54% effectiveness during the 2022-2023 season, the authors extrapolated that the modRNA vaccine’s absolute efficacy may have ranged from 60% to 67%.

Cases were overwhelmingly caused by influenza A strains (specifically A/H3N2 and A/H1N1), with almost no influenza B cases, consistent with surveillance data showing 95.4% of that season’s cases were influenza A. No antigenically matched influenza B cases occurred in either group; only two cases of unknown B strains were reported, both in the modRNA group. B/Yamagata lineage viruses have not been confirmed in global circulation since March 2020, limiting the potential for efficacy assessment against this lineage.

Immunogenicity assessments revealed a divergent pattern by strain. On hemagglutination inhibition (HAI) assay, geometric mean ratios (modRNA-to-control) at four weeks post-vaccination met noninferiority criteria for A/H3N2 and A/H1N1 strains but not for B/Yamagata or B/Victoria strains. Similarly, seroconversion differences met noninferiority criteria for influenza A strains but not B strains. Because hierarchical testing required meeting noninferiority for all four strains on egg-derived virus HAI assays before proceeding to cell-derived assays, the immunogenicity hypothesis testing was truncated after the B strain results. The authors note that HAI assays historically have underperformed in detecting B-strain responses, a limitation recognized since the 1980s, suggesting uncertainty regarding the assay’s ability to predict clinical protection against influenza B.⁴

Cell-mediated immunity, evaluated in a peripheral-blood mononuclear cell (PBMC) subgroup of approximately 125 participants, told a more favorable story. The geometric mean factor increase in CD4+ and CD8+ T-cell expression of interferon-γ was consistently higher in the modRNA group than the control group across all four strains at one week, four weeks, and six months after vaccination. This advantage was particularly pronounced for CD8+ T-cell responses to B strains. Given that CD8+ T cells can target conserved viral epitopes and limit disease severity, this suggests the modRNA platform may elicit qualitatively different immunity even when antibody responses appear weaker.

Reactogenicity was more frequent with the modRNA vaccine. Among participants in the electronic diary subgroup, local reactions occurred in 70.1% of modRNA recipients vs. 43.1% of control recipients, and systemic events in 65.8% vs. 48.7%. Pain was the most common local reaction; fatigue and headache were the most common systemic events. Fever (≤ 40.0°C) occurred in 5.6% of modRNA recipients vs. 1.7% of control recipients. Events were predominantly mild to moderate, with no clinically meaningful differences in severe events between groups. Most reactions resolved within one to two days.

Serious adverse event frequencies were similar between groups (approximately 1.0% each) through six months. One modRNA recipient experienced vaccine-related serious adverse events (a grade 3 injection-site reaction and a grade 4 anaphylactic reaction that did not meet standard clinical criteria for anaphylaxis). No confirmed cases of myocarditis or pericarditis occurred in either group. Sixteen deaths occurred during follow-up (seven modRNA, nine control); none were considered vaccine-related.

Commentary

This trial represents a milestone in influenza vaccine development, providing the first Phase III clinical efficacy data for an messenger ribonucleic acid (mRNA) influenza vaccine compared with a licensed standard-of-care comparator. The demonstration of superiority, not merely noninferiority, suggests the modRNA platform offers meaningful advantages over traditional inactivated vaccines against influenza A strains, likely by circumventing the egg-adaptive mutations that historically hamper H3N2 vaccine effectiveness. However, this enhanced efficacy comes with a trade-off of increased reactogenicity, including higher rates of injection site pain, systemic symptoms, and fever compared to the inactivated vaccine.

The trial’s use of relative rather than absolute efficacy as the primary endpoint reflects the ethical difficulty of using placebo when effective vaccines exist. While this design choice complicates interpretation, comparing head-to-head against a licensed vaccine is arguably more clinically relevant for regulatory decisions. The authors’ extrapolation to 60% to 67% absolute efficacy, while speculative, would represent the upper range of observed influenza vaccine effectiveness in recent seasons.

The divergence between influenza A and B strain performance is the most important finding requiring explanation. The modRNA vaccine showed clear advantages against A strains on both efficacy and immunogenicity measures yet failed to demonstrate immunogenicity noninferiority for B strains. It remains unclear whether this reflects intrinsic platform limitations, suboptimal antigen design for B strains in this formulation, or the known low sensitivity of HAI assays for detecting B-strain antibody responses. The enhanced CD8+ T-cell responses to B strains observed in the PBMC subgroup offer some hope that cell-mediated immunity might partially compensate for weaker antibody responses, but this hypothesis remains clinically untested given the absence of B strain cases.

The reactogenicity profile is consistent with mRNA vaccine class effects observed with COVID-19 vaccines: more local and systemic reactions than traditional vaccines, but generally mild, transient, and acceptable.⁵ For a vaccine targeting generally healthy adults, this trade-off seems reasonable given the efficacy gains. The absence of myocarditis or pericarditis cases is reassuring, although the study was not powered to detect rare events. A large French cohort study published this month, analyzing 28 million adults aged 18 to 59 years over four years, found mRNA-vaccinated individuals had lower all-cause mortality than unvaccinated individuals, adding to long-term safety reassurance for this age demographic.⁶

Several limitations bear mention. The single-season design in an A-dominant year precluded assessment of B strain clinical efficacy. The study population (adults 18 to 64 years of age without immunocompromise or pregnancy) does not encompass groups at highest risk for severe influenza, including older adults and young children. While the trial included sites in South Africa and the Philippines, the heavy geographic concentration in the United States limits generalizability.

These data arrive at a complicated moment for mRNA vaccine development. In August 2025, the U.S. Department of Health and Human Services (HHS) terminated 22 mRNA vaccine development investments under the Biomedical Advanced Research and Development Authority (BARDA), including Moderna’s H5N1 pandemic influenza program.⁷ The rationale cited by HHS leadership, that mRNA vaccines fail to stop transmission, applies to intramuscularly administered vaccines regardless of platform. This study’s demonstration of superior clinical protection against laboratory-confirmed influenza, along with T-cell responses persisting at six months, argues for continued investment in the technology. The mRNA platform’s advantages (no egg-adaptive mutations, rapid strain updates, and the ability to scale manufacturing within weeks of pathogen sequencing) remain compelling, and this trial provides clinical evidence to support them.

Jake Scott, MD, is Clinical Associate Professor of Infectious Diseases and Geographic Medicine, Stanford University.

References

1. Fitz-Patrick D, McVinnie DS, Jackson LA, et al. Efficacy, immunogenicity, and safety of modified mRNA influenza vaccine. N Engl J Med. 2025;393(20):2001-2011.

2. Centers for Disease Control and Prevention. CDC Seasonal Flu Vaccine Effectiveness Studies. May 30, 2025. https://www.cdc.gov/flu-vaccines-work/php/effectiveness-studies/index.html

3. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines — A new era in vaccinology. Nat Rev Drug Discov. 2018;17(4):261-279.

4. Monto AS, Maassab HF. Ether treatment of type B influenza virus antigen for the hemagglutination inhibition test. J Clin Microbiol. 1981;13(1):54-57.

5. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383(27):2603-2615.

6. Semenzato L, Le Vu S, Botton J, et al. COVID-19 mRNA vaccination and 4-year all-cause mortality among adults aged 18 to 59 years in France. JAMA Netw Open. 2025;8(12):e2546822.

7. Schnirring L. HHS cancels funding for Moderna’s candidate H5 avian flu and pandemic vaccines. CIDRAP News. May 29, 2025. https://www.cidrap.umn.edu/avian-influenza-bird-flu/hhs-cancels-funding-moderna-s-candidate-h5-avian-flu-and-pandemic-vaccines