The U.S. drug regulator has declined to review Moderna’s application for its first seasonal influenza vaccine based on mRNA technology, marking a significant hurdle for a platform once celebrated for its rapid pandemic response. The decision, disclosed by the company, centers on questions about the structure of its clinical trial rather than concerns over safety or effectiveness.
According to Moderna, the U.S. Food and Drug Administration determined that the submission lacked what it described as an “adequate and well-controlled” study. Specifically, regulators argued that the comparator used in the late-stage trial did not reflect the most appropriate standard of care in the United States at the time the research was conducted. The agency did not raise objections related to adverse effects or the vaccine’s performance outcomes.
The refusal-to-file letter represents an uncommon regulatory step. Academic research examining thousands of agency submissions in recent years suggests that only a small fraction—roughly 4%—receive such determinations. Moderna executives have expressed surprise, noting that earlier discussions with regulators had not indicated that the trial design would prevent formal review.
Dispute Over Trial Design and Comparator
At the center of the disagreement is the choice of comparator vaccine in a 40,700-person Phase 3 clinical trial. Moderna evaluated its experimental mRNA shot against Fluarix, a widely used standard-dose influenza vaccine. The company maintains that regulators had previously agreed with this approach and later suggested including comparative data involving a high-dose influenza vaccine for adults over 65, which Moderna says it provided.
The oversight of vaccine approvals falls under the FDA’s Center for Biologics Evaluation and Research, which signed the recent letter declining review. While the agency typically addresses methodological concerns during the formal evaluation process, Moderna said it had been led to believe that any outstanding questions about the comparator could be resolved during that stage rather than blocking the filing outright.
Company leadership has requested a meeting with regulators to clarify next steps. Executives argue that they aligned their trial structure with prior regulatory feedback and incorporated additional data comparing immune responses in older adults, a group at higher risk for severe influenza complications.
Broader Debate Over mRNA Technology
The setback arrives amid heightened political and scientific scrutiny of mRNA-based vaccines. During the COVID-19 pandemic, the technology enabled rapid development and distribution of vaccines credited with saving millions of lives. Data tracked by the Centers for Disease Control and Prevention show the substantial public health impact of vaccination campaigns in reducing hospitalizations and deaths.
However, policy shifts have influenced the research landscape. The Department of Health and Human Services recently canceled multiple mRNA-focused research projects valued at approximately $500 million, citing strategic reassessments. Critics argue that the decision reflects skepticism toward a platform that has otherwise demonstrated adaptability and speed in responding to emerging infectious threats.
Moderna is one of three manufacturers in the United States with authorized COVID-19 vaccines, alongside Pfizer and Novavax. Both Moderna and Pfizer rely on mRNA technology and have pursued expansion of the platform into seasonal influenza and combination vaccines targeting both flu and COVID-19 in a single shot.
Implications for Flu Vaccine Development
The promise of mRNA flu vaccines lies in their manufacturing agility. Traditional influenza vaccines require strain selection months in advance of flu season, typically in February, to allow time for production. mRNA platforms can significantly shorten that timeline, potentially enabling strain decisions closer to the start of peak transmission and improving the match between vaccines and circulating viruses.
In clinical results released earlier, Moderna reported that its mRNA flu candidate demonstrated approximately 27% higher efficacy compared with Fluarix among adults aged 50 and older. Additional data in participants 65 and older indicated superior immune responses compared with a high-dose flu vaccine. While immune response measurements are laboratory-based indicators derived from blood samples, efficacy figures reflect real-world protection against symptomatic disease.
The company had planned to advance its combined flu and COVID-19 vaccine candidate into regulatory review in parallel with the standalone flu shot. That strategy is now paused pending further guidance from U.S. regulators. Meanwhile, Moderna has indicated that regulatory processes are continuing in other regions, with potential approvals anticipated outside the United States before year’s end.
