FDA poised to approve Moderna's mRNA flu vaccine despite earlier rejection

Four months after refusing to review Moderna's application, FDA advisers appear ready to endorse the same vaccine based on largely the same evidence.

Earlier this year, the FDA issued Moderna a Refusal-to-File letter, effectively rejecting the company’s application before a full scientific review could begin.

At the centre of the decision was Vinay Prasad, then director of the FDA’s Center for Biologics Evaluation and Research (CBER), who argued that Moderna had tested its vaccine against the wrong benchmark.

Because the vaccine was intended for older adults, the FDA said Moderna should have compared it against one of the influenza vaccines routinely recommended for people aged 65 and older, rather than a standard-dose flu shot.

The decision immediately sparked controversy.

Critics accused the FDA of moving the goalposts after the trial had already been completed. Others argued that the study design should never have been accepted in the first place.

But lost in the dispute was a simpler question — how well did the vaccine actually work?

Moderna’s phase 3 trial enrolled more than 40,000 adults aged 50 years and older across 11 countries. Participants received either the company’s mRNA influenza vaccine, mRNA-1010, or a licensed standard-dose influenza vaccine.

The results, published in the New England Journal of Medicine in May, showed that Moderna’s vaccine reduced laboratory-confirmed influenza-like illness by 26.6% relative to the comparator vaccine.

But the absolute difference was far less impressive.

Influenza-like illness occurred in 2.8% of participants who received the standard flu vaccine, compared with 2.0% of those who received mRNA-1010 — an absolute difference of just 0.8%.

Importantly, the trial was not designed to show that the vaccine prevented hospitalisations or deaths from influenza.

Given that modest benefit, the harms of the vaccine come into sharper focus.

Among recipients of Moderna’s vaccine, fatigue was reported in 45%, headache in 38%, muscle aches in 35%, and chills in 23%.

Those are strikingly high rates for a vaccine intended to be given every year.

Most notably, reactions severe enough to interfere with normal daily activities occurred in 6.4% of vaccine recipients, compared with just 1.0% among those who received the licensed flu vaccine — a 6-fold difference.

In other words, for every additional case of influenza-like illness prevented, several people experienced reactions serious enough to disrupt their normal activities.

Whether that trade-off is worthwhile is ultimately a value judgement.

Some people may question a vaccine that leaves them feeling as though they have come down with the very illness it is designed to prevent.

The controversy deepened when documents showed that the FDA had told Moderna early on that its chosen comparator was “acceptable.”

In written feedback provided in April 2024, before enrolment began and well before Prasad arrived at CBER, the agency stated:

While we agree it would be acceptable to use a licensed standard dose influenza vaccine as the comparator in your Phase 3 study, we recommend you use a vaccine preferentially recommended for use in older adults. [emphasis added]

That distinction between “acceptable” and “recommended” would prove consequential.

Moderna proceeded with a study design that the agency had explicitly deemed acceptable. Yet only after the trial was completed did the comparator become the primary reason for refusing to review the application.

The decision was not widely supported among Prasad’s colleagues and reportedly caught some senior officials by surprise, including then-Commissioner Dr Marty Makary.

But the rejection was short-lived.

According to people familiar with the matter, Makary was summoned to the White House shortly afterwards and urged to find a path forward for Moderna’s application.

Moderna subsequently met with FDA officials and revised its regulatory strategy.

The company agreed to seek traditional approval for adults aged 50 to 64 years and accelerated approval for those aged 65 years and older. It also committed to conducting a post-marketing study in older adults — the population at the centre of the FDA’s concerns.

That was enough for the agency to reverse course and accept the application for review.

This week, on 18 June, FDA advisers will meet to discuss the vaccine.

The comparator controversy that derailed Moderna’s application earlier this year now appears largely resolved.

The briefing documents just released ahead of the meeting read less like an examination of whether Moderna’s vaccine deserves approval, and more like a roadmap to approval.

That leaves a much simpler question.

Does a reduction in influenza-like illness from 2.8% to 2.0% justify a 6-fold increase in vaccine reactions severe enough to interfere with daily activities?

My guess is that the FDA’s rubber-stamping advisory committee will conclude that it does — and that Moderna’s new vaccine will sail through the review process and secure approval.

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