An mRNA flu vaccine edges out the old standard shot

Seasonal influenza kills and hospitalizes hundreds of thousands of older adults every year, and the vaccines we give them are, by the standards of modern medicine, disappointingly mediocre. They work well against a well-matched strain and far less well against a drifted one, and even in good seasons the protection in older adults is only partial. A paper published online on 6 May in NEJM, from Isabel Leroux-Roels at Ghent University and colleagues on the Fluent trial, asks whether the mRNA technology that defined the last decade of vaccines can close that gap for flu. The answer, it turns out, is yes, by a little, and the details are more interesting than the headline.

The trial was large and conventional in its design: phase 3, double-blind, active-controlled, with 40,703 adults aged 50 or older randomly assigned either to receive Moderna’s mRNA-1010, a trivalent shot carrying 37.5 micrograms of messenger RNA encoding the surface proteins of the three flu strains the World Health Organization recommends for the season, or to get a licensed standard-dose comparator. The question was not simply whether the mRNA vaccine worked, but whether it worked better than the vaccine people already get.

The results are the heart of the paper. Across a median follow-up of 181 days, flu-like illness confirmed by PCR showed up in 411 of the 20,179 mRNA-1010 recipients, about 2.0 percent, and in 557 of the 20,124 comparator recipients, about 2.8 percent. That gap works out to a relative vaccine efficacy of 26.6 percent, with a confidence interval from 16.7 to 35.4. The number clears not just the threshold for superiority but the higher bar the team prespecified, which means the mRNA shot genuinely did a better job than the existing standard vaccine at stopping laboratory-confirmed flu illness.

Twenty-six percent is not the dramatic leap people remember from the early coronavirus vaccine trials, where efficacies landed in the nineties. It is important to put the number in its proper frame. The comparator here was not a placebo but a real, licensed vaccine, already in use, and beating an active vaccine by a quarter in relative terms is a meaningfully better outcome for a disease that infects so many people. On a population scale, even a modest incremental improvement over the existing baseline prevents a large number of hospital stays.

The trade-off is written plainly into the results. Solicited side effects were considerably more common with mRNA-1010: injection-site pain in 65.8 percent of recipients against 29.8 percent, fatigue in 45.1 against 20.3, headache in 37.8 against 18.0, muscle aches in 35.4 against 11.6. Most of these reactions were mild to moderate and passed quickly, and serious adverse events were essentially balanced between the two groups. But the experience of getting the shot is, for now, less pleasant than the old one.

That balance, a modestly better protection exchanged for a more reaction, is the whole argument the trial makes. It is not a revolution in how flu is prevented but an incremental upgrade, the kind of result that sits on a regulatory committee’s desk and gets weighed against cost and comfort. Messenger RNA has already demonstrated that it can be built and deployed quickly when a new pandemic strain appears. What the Fluent trial shows is that, for the ordinary seasonal flu people get vaccinated against every autumn, the technology can also beat the incumbent. The old shot is not obsolete. It has, finally, a competitor worth taking seriously.