Panel to Weigh ‘Favorable’ Data on Moderna's mRNA Flu Vaccine

An FDA briefing document released in advance of a 6/18 advisory committee meeting reviewing Moderna's investigational mRNA influenza vaccine, mFlusiva (mRNA-1010), reveals a more favorable outlook than many observers expected after a February Refusal-to-File letter was issued and then reversed shortly thereafter. That application setback was attributed to concerns that the company’s Phase 3 trial used an inadequate control group to demonstrate efficacy. The agency determined that Moderna should have compared its vaccine to a high-dose influenza shot in older adults rather than a standard-dose comparator used across all age groups in the trial.

That ruling landed in a politically charged environment surrounding mRNA-based vaccines, a technology that became widely known during the Covid-19 pandemic. While many scientists view mRNA as a platform with transformative potential, it has also become a lightning rod in partisan debates over vaccine mandates, pandemic policy and federal health authority, critics argue. FDA quickly reversed its filing rejection, agreeing to review Moderna’s vaccine following what media reports described as an unusual, high-level meeting between agency leadership and the vaccine maker (see earlier story).

According to the briefing document, FDA is asking advisors to consider separate regulatory approaches for two age groups: traditional approval for adults ages 50 to 64 based on demonstrated clinical efficacy, and accelerated approval for adults 65 and older based primarily on immunogenicity data, with a postmarketing confirmatory trial required to verify clinical benefit.

FDA reviewers highlighted findings from Moderna's Phase 3 P304 study, which enrolled adults aged 50 years and older and compared mFlusiva with a standard-dose influenza vaccine. Over a single influenza season, the mRNA vaccine demonstrated a relative vaccine efficacy (rVE) of 26.6%. The study also showed a 47.9% relative reduction in higher-level healthcare encounters, including influenza-related hospitalizations, emergency department visits, and urgent care visits, a finding FDA said supports the vaccine's clinical relevance.

The agency is asking VRBPAC members whether these efficacy data provide sufficient evidence of clinically meaningful protection to support traditional approval in adults ages 50 through 64.

For adults 65 years and older, FDA is considering a different regulatory pathway. The agency's review cites results from the Phase 3 P303 Part C trial, which compared mRNA-1010 with high-dose quadrivalent influenza vaccine, currently one of the influenza vaccines preferentially recommended by the Centers for Disease Control and Prevention for older adults.

According to FDA, mRNA-1010 met pre-specified noninferiority and superiority criteria for hemagglutination inhibition antibody responses across all four influenza strains evaluated in the study. Enhanced immune responses remained evident through six months of follow-up in a subset of participants, it says.

Because high-dose, recombinant, and adjuvanted influenza vaccines are considered the standard of care for older adults, FDA is asking advisors whether the immunogenicity findings can reasonably predict clinical benefit and support accelerated approval in this age group pending completion of a Phase 4 confirmatory efficacy trial.

Regarding safety, FDA's review found that local and systemic reactogenicity was more common among mRNA-1010 recipients than among comparator vaccine recipients. However, most adverse reactions were mild to moderate and resolved within about two days.

Across pooled Phase 3 studies involving nearly 72,000 participants age 50 and older, rates of serious adverse events, adverse events of special interest, and deaths were balanced between vaccine and comparator groups, according to the agency. Notably, FDA reported no vaccine-related cases of myocarditis or pericarditis and said no safety signals emerged from analyses across age, sex, race, or baseline risk categories.

Despite positive efficacy and immunogenicity findings, FDA identified several unresolved questions. Clinical efficacy data are currently limited to a single influenza season, leaving uncertainty about consistency across future seasons, it says. The agency also noted a lack of efficacy data in immunocompromised individuals and very frail older adults, populations at highest risk for severe influenza outcomes.

Additional evidence gaps include the absence of data on coadministration with other routinely administered adult vaccines, such as Covid-19, respiratory syncytial virus, and pneumococcal vaccines. FDA also noted that efficacy estimates against the B/Victoria influenza strain were less certain because relatively few cases occurred during the study period.

If approved, mFlusiva would become the first mRNA-based seasonal influenza vaccines available in the U.S. Moderna has argued that the platform could enable faster strain updates in response to emerging influenza variants.