The regulatory environment in the United States encountered by Moderna during the development of its COVID-19 vaccine bears little resemblance to what the company experienced earlier this week when the FDA refused to review its application for approval of its flu shot mRNA-1010.
The rejection came despite the success of a phase 3 trial, which included more than 40,000 participants age 50 and older and showed that mRNA-1010 was 27% more effective than an FDA-approved shot. In its Refusal-to-File (RTF) letter, the FDA cited Moderna’s trial design in which it used a standard-dose flu vaccine in older adults enrolled in the comparator arm instead of a higher-dose, “best-available standard of care” shot.
According to Moderna, the FDA cleared the company’s use of the standard-dose vaccine for the trial in 2024. But that was before the entrance of a new administration and the appointment of HHS Secretary Robert F. Kennedy Jr., who has stacked the FDA with many like-minded vaccine skeptics.
Mani Foroohar, M.D., an analyst with Leerink Partners, says that the RTF decision reflects “how sharp the departure has been between the prior administration and this administration.”
“I think companies have found the pivot jarring, having developed drugs and clinical trials based on prior feedback,” Foroohar said in an interview with Fierce. “It feels like a bait and switch.”
The Moderna rejection is another example of the rapidly shifting vaccine landscape in the U.S., which has forced manufacturers of the shots to rethink their strategy. Four months ago, Moderna told Fierce that it was favoring its oncology portfolio and downplaying its efforts in infectious disease vaccines.
Last month, in an interview with Bloomberg, Moderna CEO Stephane Bancel said the company would not invest in new phase 3 infectious disease vaccine trials due to growing opposition from U.S. officials to immunizations.
“You cannot make a return on investment if you don’t have access to the U.S. market,” Bancel added.
Foroohar said that the FDA’s decision on Moderna’s application introduces uncertainty that could “reduce or deter” further investment in some vaccine indications and technologies in the U.S.
“As a developer, you have to know the rules of the road and the standards by which your data is being judged before plowing hundreds of millions, if not potentially billions, in building out a vaccine infrastructure and developing the vaccine,” he said. “I’m not sure it puts vaccines on hold, but it makes development of any particular vaccine—where you have this sort of uncertainty—potentially more expensive and just changes the risk-reward calculation on what investments are worth making.”
Adding to the companies' uncertainty is an unpredictable, apparently agenda-driven regulatory process. Vinay Prasad, M.D., who heads up the FDA’s Center for Biologics Evaluation and Research (CBER), overruled reviewers in signing off on the RTF for Moderna, according to a report earlier this week from STAT.
Additionally, two months ago, when RFK Jr. overhauled U.S. vaccine recommendations for children, the CDC was “blindsided” by the move, The Washington Post reported, as it contradicted guidance from experts in the agency.
The Alliance for mRNA Medicines called the decision “unprecedented,” said the FDA was in “disarray,” and warned of a “threat to public health.”
“Abrupt shifts in vaccine policy—introduced without transparent, evidence-based deliberation—risk undermining the rigorous framework that has long guided vaccine development and approval,” Executive Director Clay Alspach said in a statement. “Changes of this magnitude should be shaped through an open and public process. Circumventing this process will weaken public confidence and impair the ability to develop lifesaving vaccines in a timely manner.”
Along with the uncertain regulatory environment, plummeting sales in the U.S. are another reason for companies to think twice about investing in the development of vaccines. Each of the four top vaccine sellers in biopharma—Sanofi, GSK, Pfizer and Merck—has felt the pinch with declining sales in U.S.
Sanofi, for example, saw a 28% decline in U.S. sales of its RSV shot Beyfortus last year, while its sales were up 36% in Europe and 168% in the rest of the world, though some of the disparity can be explained by the timing of the launches in the different geographies. Another example is GSK’s top-selling vaccine, Shingrix. While the shingles shot’s sales declined (PDF) by 20% in the U.S. in 2025, they increased by 44% in Europe.
Foroohar doesn’t believe these large drugmakers will make significant investment adjustments based on the suddenly changing vaccine landscape in the U.S. He said that companies of this size view their vaccine businesses in a “multi-decade time horizon,” while vaccine planning for Sanofi occurs over a “multi-generation” timeline.
“The speed and volatility of these changes is perhaps new to the FDA’s recent history, but over the course of the life of companies the size of Merck or Sanofi, for example, it’s still an uncomfortable, painful blip, but still a blip,” Foroohar said. “I think we’re going to see companies making changes around the edges. And the greater the uncertainty becomes, the more conservative they become in their investments on the margin.”