FDA Staff Weighs In on Potential First mRNA Flu Shot

Ahead of an advisory committee meeting this week, FDA reviewers raised no serious efficacy or safety concerns about Moderna’s mRNA flu vaccine candidate for adults 50 and older, which has the potential to become the first such product approved by the agency.

The trivalent influenza vaccine (mRNA-1010) is the one FDA controversially refused to consider earlier this year amid questions about the pivotal study’s control arm.

In the Fluent randomized trial, the vaccine — which targets influenza A/H1N1, A/H3N2, and B/Victoria — outperformed standard flu shots among adults 50 and older, with a relative vaccine efficacy of 26.6%. Among Fluent’s more than 19,000 adults 65 and older, the mRNA shot’s relative vaccine efficacy was 27.4%.

In briefing documents released ahead of the Thursday meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC), FDA reviewers questioned whether comparing the mRNA vaccine against standard-dose flu shots is adequate and clinically meaningful in adults 65 or older, given that high-dose, recombinant, or adjuvanted vaccines are recommended in that age group.

Other concerns raised included a higher rate of solicited adverse events with the mRNA vaccine (76% vs 47% with the standard flu shot), that efficacy was not established in immunocompromised or frail patients, whether a single season of efficacy data was enough to support an approval, and uncertainty of effectiveness against influenza B/Victoria due to a limited number of cases.

On Thursday, VRBPAC will vote on whether the benefits of the mRNA flu vaccine outweigh its risks for preventing flu in two groups of adults: those 50 to 64 and those 65 or older.

Moderna is seeking accelerated approval for the older group, which would require a postmarketing study to confirm benefit.

Despite the concerns, the mRNA shot “demonstrated superior relative vaccine efficacy” versus a standard-dose comparator in adults 50 and older, the FDA scientists noted, adding the vaccine showed “superior immunogenicity” versus a CDC-preferred high-dose comparator vaccine in that older age group.

Three safety issues were also suggested for the panel’s review, including the greater rate of solicited adverse reactions with the mRNA shot. FDA scientists also highlighted the greater numbers of unspecified deaths (overall deaths were similar); serious adverse events related to anemia or urinary tract infections (UTIs) with the mRNA vaccine; and the potential for rare adverse events such as myocarditis, Guillain-Barré syndrome, and other neurologic events.

In their safety evaluation, the FDA scientists noted that they considered the mRNA vaccine’s reactogenicity profile “acceptable for the intended population.” The distribution of unspecified deaths, anemia, and UTIs doesn’t point to a causal relationship with the mRNA vaccine, they added, and is “unlikely to represent a vaccine safety signal.” Any risk of rare adverse events will require post-licensure monitoring, the scientists noted.

A Technology Advantage in Mismatch Years?

All of the current FDA-licensed flu vaccines are manufactured using egg-based, cell-culture based, or recombinant production technologies. Most of the vaccines use egg-based manufacturing, which can lead to egg-adaptive mutations and slow reformulation during vaccine-strain mismatch seasons.

Adding mRNA technology to the manufacturing lineup could improve response when vaccines don’t match circulating flu strains, the FDA staff explained.

“High-volume manufacturing capable of rapid strain reformulation is … needed to address antigenic drift and — more critically — antigenic shift, the latter posing pandemic risk,” the FDA document noted. The mRNA vaccine’s technology “supports rapid strain reformulation in response to antigenic drift or shift, a meaningful operational advantage over egg-based production,” FDA scientists said.

Administration Skeptics Slowed Path to Review

In February, the agency denied Moderna’s application, with former FDA vaccine chief Vinay Prasad, MD, MPH, asserting that Moderna’s application didn’t have an “adequate and well-controlled trial” and failed to compare the mRNA vaccine to “the best-available standard of care in the United States at the time of the study.”

After Moderna shared additional comparison data from a separate trial that used a high-dose shot for older people, former FDA commissioner Marty Makary, MD, MPH, reversed Prasad’s decision and paved the way for Thursday’s advisory committee review.