Recently published results from a phase 3 study demonstrate that an investigational messenger RNA (mRNA)-based vaccine called mRNA-1010 provided better clinical protection against influenza than the standard-dose vaccines.1
Previous studies have demonstrated that mRNA-based influenza vaccines can generate robust immune responses.2 However, it was unclear whether this would improve clinical protection against influenza.
In a recent study published in The New England Journal of Medicine, investigators sought to answer this question by comparing mRNA-1010 directly with licensed standard-dose influenza vaccines. The study included more than 40,000 adults aged 50 years or older.
Investigators observed 411 cases of laboratory-confirmed influenza in the mRNA-1010 group, compared with 557 in the standard-dose vaccine group. This translated into a relative vaccine efficacy of 26.6%, meaning that mRNA-1010 reduced the risk of influenza by about one-quarter compared with a licensed standard-dose influenza vaccine.
“I think this is an important proof of concept for the field. We already knew that mRNA influenza vaccines could induce strong immune responses. This study demonstrates that these immune responses can translate into a meaningful improvement in protection against influenza disease,” said lead author Isabel Leroux-Roels, MD, PhD, Associate Professor at Ghent University and Head of the Center for Vaccinology at Ghent University Hospital in Belgium.
However, there is a trade-off.
The mRNA vaccine showed higher reactogenicity compared with the standard-dose vaccines, with increased reports of injection site pain, fatigue, headache, and muscle aches. These side effects were mostly mild to moderate and transient. Notably, no new safety concerns were observed.
COVID-19 established mRNA as a vaccine platform, but success with one pathogen does not automatically translate to another, and influenza is a particularly interesting target for mRNA because vaccine composition must be adapted every year. This study provides evidence that mRNA technology can work for seasonal influenza.
The platform offers several potential advantages, including rapid, scalable manufacturing and greater flexibility to update vaccine composition. Unlike traditional egg-based influenza vaccines, mRNA vaccines also avoid egg-adaptive mutations that can alter the antigenicity of the vaccine strain, particularly for A/H3N2. This advantage is not unique to mRNA, as cell-based and recombinant influenza vaccines also avoid egg adaptation.
“The vaccine for the 2024 to 2025 flu season was well-matched, so this vaccine was tested under favorable conditions and still beat the egg-based comparator,” said Sara H. Mirza, MD, FCCP, Associate Professor in the Division of Pulmonary and Critical Care at the University of Michigan in Ann Arbor. “The season I worry about is the drifted one, and this trial cannot tell us about that. What it does tell us is that the platform works and can be updated in two or three months instead of six. That is where I feel this paper is opening a door.”
Moving forward, it will be important to assess the vaccine’s performance across multiple seasons, including the effects of repeated annual vaccination with an mRNA-based vaccine, Dr. Mirza said. In addition, the study compared mRNA-1010 with a standard-dose influenza vaccine but not with the enhanced influenza vaccines preferentially recommended for adults aged 65 years and older in the United States, such as high-dose, adjuvanted, or recombinant influenza vaccines. Head-to-head comparisons with those vaccines will therefore be important to better define the potential role of mRNA-based influenza vaccination in older adults.
Dr. Mirza also said that future research needs to be adequately powered for the outcomes that matter clinically: hospitalization, emergency department visits, need for ventilation, and death. Because these outcomes are relatively uncommon, she said, such evidence will likely come primarily from large, postlicensure, real-world effectiveness studies rather than traditional randomized clinical trials.
References
1. Leroux-Roels I, Huang G, Ferguson M, et al. Efficacy and safety of an mRNA seasonal influenza vaccine in adults. N Engl J Med. 2026;394(18):1803-1813. doi:10.1056/NEJMoa2516491
2. Soens M, Ananworanich J, Hicks B, et al. A phase 3 randomized safety and immunogenicity trial of mRNA-1010 seasonal influenza vaccine in adults. Vaccine. 2025;50:126847. doi:10.1016/j.vaccine.2025.126847
