Published May 6, 2026
N Engl J Med 2026;394:1803-1813
DOI: 10.1056/NEJMoa2516491
Abstract
Background
Seasonal influenza causes substantial illness and death in adults 50 years of age or older, even with current vaccines. An investigational messenger RNA (mRNA)–based vaccine called mRNA-1010 encodes hemagglutinin glycoproteins from World Health Organization–recommended influenza strains.
Methods
In this phase 3, double-blind, active-controlled trial, we randomly assigned adults 50 years of age or older to receive trivalent mRNA-1010 (37.5 μg, which includes 12.5 μg of each strain) or a licensed standard-dose comparator. The primary efficacy end point was relative vaccine efficacy against reverse-transcriptase–polymerase-chain-reaction (RT-PCR)–confirmed, protocol-defined influenza-like illness caused by influenza A or B, from at least 14 days after vaccination through the end of the influenza season. Hypothesis testing was conducted hierarchically to assess noninferiority (lower boundary of the 95% confidence interval [CI], >−10%), superiority (lower boundary of the 95% CI, >0%), and a higher level of superiority (lower boundary of the 95% CI, >9.1%).
Results
A total of 40,703 participants received mRNA-1010 (20,350 participants) or the standard-dose comparator (20,353 participants); the median follow-up was 181 days (range, 1 to 227). RT-PCR–confirmed, protocol-defined influenza-like illness was observed in 411 of 20,179 recipients of mRNA-1010 (2.0%) and 557 of 20,124 recipients of the standard-dose comparator (2.8%), which corresponds to a relative vaccine efficacy of 26.6% (95% CI, 16.7 to 35.4), thereby meeting the criteria for noninferiority, superiority, and higher-level superiority. Solicited adverse reactions were more frequent with mRNA-1010 than with the standard-dose comparator (injection-site pain in 65.8% vs. 29.8%, fatigue in 45.1% vs. 20.3%, headache in 37.8% vs. 18.0%, and myalgia in 35.4% vs. 11.6%); most reactions were mild to moderate and transient. Serious adverse events were reported in 2.2% of the recipients of mRNA-1010 (with three events considered by the investigator to be vaccine-related) and in 1.9% of the recipients of the standard-dose comparator (with two events considered by the investigator to be vaccine-related).
Conclusions
In this trial, mRNA-1010 was superior to standard-dose licensed vaccines for prevention of RT-PCR–confirmed, protocol-defined influenza-like illness in adults 50 years of age or older. Solicited adverse reactions were more frequent with mRNA-1010. (Funded by Blackstone Life Sciences and Moderna; Fluent ClinicalTrials.gov number, NCT06602024.)
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Notes
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
Supported by Blackstone Life Sciences and Moderna.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the participants in the trial and their families; the members of the data and safety monitoring board for their hard work, support, and guidance of the trial; Agi Buchanan, M.D., Ph.D., Andrei Avanesov, Ph.D., Ren Chen, Ph.D., Haritha Singireddy, M.S., Brianna Fidler, M.A., Elissa Malkin, D.O., M.P.H., Chelsea Canan, Ph.D., M.P.H., and Peg Mutty, B.S., of Moderna, for helpful discussions; Alana Simorellis, Ph.D., of Moderna, for writing and editorial support with an earlier version of the manuscript; and Aliscia Daniels, Ph.D., of MEDiSTRAVA, for medical writing and editorial assistance with an earlier version of the manuscript, in accordance with Good Publication Practice (GPP3) guidelines, funded by Moderna, and under the direction of the authors.
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Copyright © 2026 Massachusetts Medical Society. All rights reserved.
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History
Published online: May 6, 2026
Published in issue: May 7, 2026
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- Moderna’s mRNA flu vaccine outperforms standard shot, study finds, BMJ, 393, (s895), (2026).https://doi.org/10.1136/bmj.s895
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Facts Only
A phase 3, double-blind, active-controlled trial compared mRNA-1010, an mRNA-based influenza vaccine, to a standard-dose licensed vaccine in adults 50 years or older.
The trial included 40,703 participants, with 20,350 receiving mRNA-1010 and 20,353 receiving the comparator vaccine.
The primary efficacy endpoint was relative vaccine efficacy against RT-PCR-confirmed influenza-like illness caused by influenza A or B.
mRNA-1010 demonstrated a relative vaccine efficacy of 26.6% (95% CI, 16.7 to 35.4).
Solicited adverse reactions were more frequent with mRNA-1010, including injection-site pain (65.8% vs. 29.8%), fatigue (45.1% vs. 20.3%), headache (37.8% vs. 18.0%), and myalgia (35.4% vs. 11.6%).
Serious adverse events occurred in 2.2% of mRNA-1010 recipients and 1.9% of comparator recipients.
The trial was funded by Blackstone Life Sciences and Moderna.
The study was published in the *New England Journal of Medicine* on May 6, 2026.
The trial is registered under ClinicalTrials.gov number NCT06602024.
Executive Summary
A phase 3 clinical trial evaluated the efficacy and safety of mRNA-1010, an mRNA-based seasonal influenza vaccine, compared to a standard-dose licensed vaccine in adults aged 50 and older. The study involved 40,703 participants, with half receiving mRNA-1010 and the other half the comparator vaccine. Results showed that mRNA-1010 demonstrated a relative vaccine efficacy of 26.6% against RT-PCR-confirmed influenza-like illness, meeting criteria for noninferiority, superiority, and higher-level superiority. However, solicited adverse reactions, such as injection-site pain, fatigue, headache, and myalgia, were more frequent with mRNA-1010, though most were mild to moderate. Serious adverse events were rare and comparable between the two groups. The trial was funded by Blackstone Life Sciences and Moderna, with the findings published in the *New England Journal of Medicine*.
The study highlights the potential of mRNA technology in improving influenza vaccine efficacy, particularly in older adults, a population at higher risk for severe outcomes. While the mRNA vaccine showed better protection, the trade-off includes more frequent but generally mild side effects. The results contribute to ongoing discussions about the role of mRNA vaccines beyond COVID-19, though further research may be needed to assess long-term safety and broader applicability.
Full Take
**ACADEMIC MODE**
This study presents a robust phase 3 trial of mRNA-1010, an mRNA-based influenza vaccine, demonstrating its superiority over standard-dose vaccines in adults aged 50 and older. The methodology is sound, with a large sample size (40,703 participants), double-blinding, and active controls, which strengthens the internal validity. The primary endpoint—RT-PCR-confirmed influenza-like illness—is clinically relevant, and the hierarchical testing for noninferiority, superiority, and higher-level superiority provides a clear framework for interpreting efficacy.
However, peer reviewers might flag the higher frequency of solicited adverse reactions with mRNA-1010, though these were mostly mild to moderate. The study’s funding by Blackstone Life Sciences and Moderna raises questions about potential conflicts of interest, though the authors disclose this transparently. The findings align with prior research on mRNA vaccines, suggesting their broader applicability beyond COVID-19, but long-term safety data and real-world effectiveness remain areas for further investigation.
**Real-world implications:** If these results hold, mRNA-1010 could become a preferred option for older adults, balancing improved efficacy against manageable side effects. Follow-up studies should assess durability of protection, cross-strain efficacy, and cost-effectiveness compared to traditional vaccines.
**Bridge questions:** How would mRNA-1010 perform in younger populations or against drifted influenza strains? What mechanisms underlie its superior efficacy, and could these insights improve other vaccines? Would broader adoption of mRNA flu vaccines reduce seasonal morbidity in high-risk groups?
**Patterns detected:** None. The study adheres to rigorous scientific standards, with transparent reporting of limitations and funding sources.
Sentinel — Human
This text exhibits the formal, precise structure and statistical rigor characteristic of human-authored, peer-reviewed medical research, suggesting a high degree of human provenance.