mRNA flu vaccine: what the 26.6% advantage really means

The first FDA-approved mRNA flu vaccine is no longer an experimental concept. Moderna’s mFlusiva has been approved in the United States for adults 50 and older: traditional approval for ages 50–64 and accelerated approval for adults 65 and older, with a confirmatory postmarketing study required for the older group.

The number attracting the most attention is 26.6%. It is also the easiest number to misread. It does not mean that the vaccine prevents influenza in an additional 26.6 people out of every 100. It is a relative advantage over an already licensed standard-dose flu vaccine.

What the trial actually tested

The phase 3 study, published in the New England Journal of Medicine, enrolled adults 50 years of age or older. A total of 40,703 participants received a study vaccine: roughly half received the mRNA vaccine mRNA-1010, now marketed as mFlusiva, and half received a licensed standard-dose seasonal influenza vaccine. Median follow-up was 181 days, covering the 2024–2025 Northern Hemisphere influenza season.

The primary endpoint was not simply a positive test or any respiratory illness. Participants had to meet a protocol-defined set of influenza-like symptoms, and infection had to be confirmed by RT-PCR. Cases were counted from 14 days after vaccination through the end of the influenza season.

Among participants included in the primary efficacy analysis, 411 of 20,179 mRNA-1010 recipients developed confirmed influenza-like illness, about 2.0%. In the standard-vaccine group, there were 557 cases among 20,124 participants, about 2.8%. That produced a relative vaccine efficacy of 26.6% compared with the control vaccine, with a 95% confidence interval of 16.7% to 35.4%.

The absolute difference was much smaller: using the exact event proportions, it was about 0.7 percentage points over one season. Both numbers are correct, but they answer different questions. The 26.6% figure describes the reduction relative to another vaccine; the roughly 0.7-point difference describes how far apart the two groups actually were in this trial.

How an mRNA flu vaccine works

mFlusiva contains neither influenza virus nor premanufactured influenza protein. Lipid nanoparticles carry mRNA instructions that tell cells to make hemagglutinin, a major surface protein of influenza viruses and an important target of protective antibodies. Cells produce the protein temporarily, allowing the immune system to learn to recognize it.

The approved vaccine is trivalent. It encodes hemagglutinins from two influenza A strains, H1N1 and H3N2, and the B/Victoria lineage. The basic principle is similar to mRNA COVID-19 vaccines, although the encoded sequences and viral targets are different.

One potential advantage of the platform is manufacturing. mRNA vaccines do not require influenza viruses to be grown in chicken eggs. That can make strain updates faster and avoids egg-adaptive mutations, changes that sometimes occur when influenza viruses are propagated in eggs and that can alter how closely the vaccine antigen resembles circulating viruses.

But the trial did not establish that this mechanism explains why mRNA-1010 performed better. It demonstrated a clinical difference between the vaccine groups; it was not designed to identify the biological reason for that difference.

What the 26.6% figure leaves out

The mRNA vaccine was more reactogenic. Injection-site pain was reported by 65.8% of mRNA-1010 recipients versus 29.8% of standard-vaccine recipients. Fatigue occurred in 45.1% versus 20.3%. Most reactions were mild or moderate and transient. Serious adverse events were similar overall, occurring in 2.2% and 1.9% of participants, respectively.

There is also an important comparator issue. The pivotal efficacy trial compared mRNA-1010 with a standard-dose influenza vaccine. In the United States, adults 65 and older are generally preferentially offered more immunogenic options, such as high-dose, adjuvanted, or recombinant vaccines. For that reason, the FDA did not rely on the standard-dose comparison alone for traditional approval in the older age group.

For adults 65 and older, the agency instead considered separate immunogenicity data comparing mRNA-1010 with high-dose Fluzone and granted accelerated approval. A subsequent study is required to confirm clinical benefit in that age group.

Influenza vaccine performance also changes from season to season depending on which viruses circulate and how well vaccine strains match them. The 26.6% relative advantage was measured during a single influenza season and should not be assumed to recur every year.

The trial supports a specific conclusion: during the 2024–2025 season, adults 50 and older who received mRNA-1010 had fewer laboratory-confirmed influenza cases than those who received a standard-dose flu vaccine, at the cost of more short-lived post-vaccination reactions. FDA approval moves mRNA technology into routine seasonal influenza prevention, but the size and consistency of its advantage will become clearer only after additional seasons and real-world use.