After a rocky regulatory road, the August 5 approval of the first messenger RNA (mRNA) influenza vaccine in the US provides not only a more effective flu shot for older adults but also the ability to make last-minute changes in its composition should unanticipated strains begin circulating.
“This is a very good tool to have in your toolbox,” said Jesse Goodman, MD, MPH, professor of medicine and infectious diseases and attending physician at Georgetown University.
The US Food and Drug Administration (FDA) granted Moderna’s mRNA-1010 (mFLUSIVA) influenza vaccine traditional approval for use in adults 50 through 64 years of age and accelerated approval for those aged 65 years or older. Moderna says it expects the new flu shot will be available for the 2026-2027 flu season.
“Right now, every indication is the payors will cover it” for everyone 50 years or older, said Michael Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy at the University of Minnesota.
The US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP), which hasn’t yet met this year “due to ongoing litigation,” hasn’t weighed in on mRNA-1010, leaving official federal guidance on its use uncertain.
US Department of Health and Human Services (HHS) Secretary Robert F. Kennedy Jr completely revamped ACIP’s membership last year, spurring concerns that it is now driven by ideology instead of evidence. As a result, major medical organizations have been advising that members ignore ACIP and turn to independent sources of vaccine recommendations, such as the American Academy of Pediatrics and the Vaccine Integrity Project, which Osterholm founded.
Especially given Kennedy’s vaccine skepticism, Goodman, Osterholm, and other public health leaders applauded mRNA-1010’s approval, granted exactly 1 year after HHS announced that the Biomedical Advanced Research and Development Authority (BARDA) was terminating 22 mRNA vaccine development grants totaling nearly $500 million.
“[T]he data show these vaccines fail to protect effectively against upper respiratory infections like COVID and flu,” Kennedy stated in a press release about the BARDA move.
Just days before HHS issued that press release, though, a study in JAMA Health Forum estimated that COVID-19 vaccination, most of which involved Moderna’s or Pfizer-BioNTech’s mRNA shots, averted more than 2.5 million deaths worldwide, a figure that the authors acknowledged was conservative compared with previous estimates.
And in May of this year, researchers reported that the phase 3 trial of Moderna’s mRNA-1010 vaccine in volunteers 50 years or older found it to be 27% more effective than standard-dose flu shots containing inactivated viruses, which for more than 70 years have typically been grown in fertilized chicken eggs, a lengthier process than achievable with the mRNA platform.
A Matter of Time
Because the conventional methods of producing flu vaccines take so long, the decision about which 3 strains should be targeted must be made months in advance, usually in late February or March for the Northern Hemisphere, based on what’s circulating in the Southern Hemisphere.
However, the influenza virus is constantly evolving, so by the time immunization starts in the fall, new strains could be circulating, rendering the seasonal vaccine a poor match and increasing the risk of hospitalizations and deaths from the disease. “With flu, every day is a new day,” Osterholm explained.
The time it took to manufacture and deliver vaccines slowed the response to the 2009 H1N1 influenza pandemic, said Goodman, the FDA’s lead scientist at the time. “Although people died, we were fortunate that that pandemic was relatively mild,” he pointed out, noting that H1N1, which was not targeted by that season’s flu shots, had begun to recede by the time sufficient supplies of vaccines against it became available.
With an mRNA flu vaccine, “we’re going from a manufacturing process that takes about 6 months to one that takes about 6 weeks,” said Georges Benjamin, MD, MPH, chief executive officer of the American Public Health Association. The mRNA flu vaccine “is a game changer in terms of what you can do.”
The nimbleness the mRNA platform affords is especially valuable because “our surveillance systems, while they’re good, they’re still not real time,” Benjamin noted. “We’re still always looking retroactively at data.”
Ronald Nahass, MD, president of the Infectious Diseases Society of America, issued a statement along the same lines. “Unlike conventional manufacturing, the mRNA platform allows for streamlined development and rapid responses to emerging mutations in viruses,” said Nahass, a clinical professor of medicine at Rutgers Robert Wood Johnson Medical School.
A Change of Heart
The FDA based its approval of mRNA-1010 on results from a phase 3 trial that enrolled approximately 41 000 adults 50 years or older in 11 Northern Hemisphere countries, including the US. Half the participants were randomly assigned to receive the mRNA vaccine, half to a standard-dose licensed vaccine.
In the US but not all 10 other countries in the study, the standard of care for people 65 years or older is a high-dose influenza vaccine, which was not included in the phase 3 trial. For that stated reason, the FDA initially refused even to consider Moderna’s application.
Via a “refusal to file” letter dated February 3 of this year and signed by Vinay Prasad, MD, MPH, then director of the FDA’s Center for Biologics Evaluation and Research (CBER), the agency notified Moderna that it would not review the company’s application for mRNA-1010.
Prasad wrote that his center was refusing to consider the application because the “control arm does not reflect the best-available standard of care in the United States at the time of the study.”
However, according to Moderna, CBER had previously said that although it recommended using the high-dose flu vaccine as a comparator for the older participants, the trial could instead proceed with a standard-dose vaccine comparator for all age groups as long as the company carried out its plan to make note of that in the informed consent form.
A week after Moderna published the refusal-to-file letter on its website, FDA officials reversed course following a quickly scheduled formal meeting with Moderna representatives. A Politico report based on anonymous sources suggested that President Donald Trump had pressured then−FDA Commissioner Martin Makary, MD, MPH, to rescind the agency’s refusal to consider the mRNA flu vaccine because that decision would be unpopular with many voters, a claim that a White House official denied.
In a briefing document for a June meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC), agency scientists noted that the trial covered only 1 flu season and that it did not establish efficacy in immunocompromised or very frail older adults, who face the greatest risk of severe flu complications and may respond differently to mRNA vaccines. However, the FDA document said it had identified “no major deficiencies,” and VRBPAC voted unanimously to recommend that the agency approve the shot for adults ages 50 through 64 years and grant accelerated approval for those 65 or older.Still, Goodman noted, the FDA waited until the very last minute to approve the shot, given that Moderna had said that the deadline for the decision was August 5.
“I’m really gratified that FDA made and promulgated the decision that its senior scientists had recommended and that its advisory committee had supported,” Goodman, a former CBER director, said.
“I’ve been really concerned about protecting the scientific integrity of these federal agencies,” he continued. “It’s good that nobody seemed to interfere with this decision.”
A Choice for Those 65 or Older
In the pivotal phase 3 trial, the mRNA vaccine was as effective in participants 65 years or older as it was in trial participants overall, although whether its clinical efficacy is superior to that of the high-dose or other enhanced flu vaccines remains to be seen.
With a median follow-up of 181 days, the phase 3 trial found that the mRNA vaccine across all ages was approximately 27% more effective in preventing polymerase chain reaction–confirmed illness caused by any influenza A or B strain than the standard dose comparator vaccine, researchers reported in May. About 2% of participants who received the mRNA vaccine were diagnosed with the flu, compared with 2.8% who received a comparator vaccine.
Among the more than 19 000 trial participants who were at least 65 years of age, the mRNA vaccine’s relative efficacy was the same as that for all ages, which suggests benefits similar to those of high-dose and other enhanced influenza vaccines in the oldest adults, according to the authors. (Previous research has shown that the relative efficacy of high-dose flu vaccines vs standard-dose shots is about the same as that of the mRNA flu vaccine vs standard-dose shots, Goodman explained.)
Overall, those who received the mRNA vaccine were more likely to report experiencing the adverse events researchers asked about, including injection site pain, fatigue, headache, and muscle aches, which have also been seen after immunization with mRNA COVID-19 vaccines. Most adverse events were mild to moderate and transient, the scientists noted.
In another Moderna-sponsored phase 3 trial, researchers studied the immunogenicity of mRNA-1010 compared with a standard-dose comparator vaccine in adults ages 18 through 64 years or the high-dose flu vaccine in about 3000 people 65 years or older. The mRNA vaccine demonstrated an immune response superior to both the comparator vaccines, the scientists reported in February 2025.
“Based on immunogenicity data, this vaccine will perform in a superior manner” to the high-dose vaccine, Osterholm said. “Obviously, they’re going to be doing postmarketing evaluation.”
Accelerated approval is based on surrogate end points, in this case the immunogenicity data for people 65 years or older. Higher immunogenicity, such as increased neutralizing antibody titers, often correlates with better protection, but Moderna must confirm its vaccine’s clinical benefit in a postmarketing trial involving individuals who are at least 65 years old.
According to the FDA briefing document for the June VRBPAC meeting, the postmarket, or phase 4, confirmatory study will enroll approximately 400 000 adults 65 years or older in each of 2 flu seasons. Vaccine clinics that administer the shots will alternate weekly between mRNA-1010 and an agreed upon CDC-recommended vaccine throughout the flu seasons.
A Growing Family
The new flu shot is not the first approved mRNA vaccine besides those against COVID-19.
In 2024, the FDA greenlighted Moderna’s mRNA vaccine against respiratory syncytial virus (RSV) for adults 60 years or older (in June 2025, the FDA expanded the use of the RSV vaccine [mRESVIA] to include high-risk adults aged 18 through 59 years).
And in April of this year, the European Commission authorized Moderna’s mCOMBRIAX, the world’s first combination influenza and COVID-19 vaccine.
Whether the combination vaccine will eventually become available in the US isn’t clear. Moderna announced in May 2025 that, after consulting with the FDA, it had voluntarily withdrawn its application for the vaccine in the US, saying the company planned to resubmit it after phase 3 trial efficacy data for mRNA-1010 became available.
“Now that mFLUSIVA is approved, we plan to reengage with regulators for further guidance on refiling the submission for our flu plus COVID combination vaccine,” spokesperson Kelly Cunningham said in an email.
Moderna has not yet disclosed whether it plans to pursue approval of mRNA-1010 for younger adults or adolescents and children, Cunningham said.
“Those over 50 years of age face a disproportionate flu burden, so we focused our research on this more vulnerable population,” she wrote in her email. “While they make up less than 20% of the total US population, people 65 years and older account for an estimated 70% to 85% of flu-related deaths and 50% to 70% of flu-related hospitalizations in the 2024-2025 season.”
Despite the billions of doses of COVID-19 vaccines administered worldwide, though, “for some people, there’s still a lot of mistrust” in vaccines in general and mRNA vaccines in particular, acknowledged Goodman, who chairs the Expert Vaccine Analysis Team, a group of scientists, researchers, and former government officials that provides “facts and rapid analysis on emerging vaccine and outbreak issues.”
“We all still have a lot of work to do,” he said, “and no one knows all the answers for how we can do a better job in dealing with all the misinformation and rumors.”