Pfizer's experimental mRNA influenza vaccine outperformed standard flu shots by 34.5% in a large-scale Phase 3 clinical trial, marking a significant advancement in flu prevention technology. The results, published in the New England Journal of Medicine, involved more than 18,000 adults aged 18 to 64 across multiple countries during the 2022-2023 flu season.
Trial Design and Results
The randomized controlled trial compared Pfizer's mRNA flu vaccine to Fluzone, one of the most widely used seasonal flu vaccines in the United States. Participants were recruited primarily from the U.S., with additional trial sites in South Africa and the Philippines. Half received the standard vaccine while the other half received Pfizer's mRNA-based alternative.
The study demonstrated that only 0.63% of people who received the mRNA vaccine developed flu, compared to 0.95% of those who received the conventional vaccine. This translated to 57 cases in the mRNA group versus 87 cases in the Fluzone group. Nearly all infections were caused by two common influenza A strains: H3N2 and H1N1.
"The mRNA vaccine performed better than conventional flu vaccines," said Professor Archa Fox from the University of Western Australia, who was not involved in the study.
Safety Profile and Side Effects
While the mRNA vaccine showed superior efficacy, it was associated with a higher rate of mild to moderate side effects compared to traditional flu shots. Both vaccines caused side effects including arm pain and fatigue, but these were more common in the mRNA group.
Notably, 5.6% of people who received the mRNA vaccine reported fevers, compared to 1.7% in the traditional flu shot group. However, most side effects were mild to moderate and resolved within 1 to 2 days. The level of severe side effects remained similarly low for both vaccines.
"The mRNA vaccine was safe, but an elevated rate of side effects, such as headache and injection site pain, was detected compared to traditional vaccines," said Associate Professor Seth Cheetham from the University of Queensland.
Limitations and Challenges
The study revealed several important limitations. Most significantly, the vaccine showed no significant benefit for adults over 65, the population most vulnerable to severe influenza complications.
"Most crucially, it showed no significant benefit for adults over 65, the group most at risk from severe flu, highlighting that this is a promising step forward but not a complete solution for all," said molecular virologist Vinod Balasubramaniam.
Additionally, there weren't enough cases of influenza B in the study to determine the vaccine's effectiveness against that virus type. Laboratory tests suggested the new vaccine may not be as effective against B strains, according to Cheetham.
Manufacturing Advantages and Future Implications
The mRNA technology offers significant manufacturing advantages over traditional flu vaccine production methods. Dr. Emma Grant from La Trobe University explained that manufacturing mRNA vaccines is significantly faster than traditional methods, which rely on growing viruses in eggs or cells—a process that can take six months or more.
"Faster production means vaccine strains can be selected closer to the flu season, reducing the risk of mismatch with circulating viruses," Grant said. This timing advantage could address one of the primary reasons flu shots aren't as effective as they could be: the mismatch between vaccine strains and circulating viruses.
Dr. Buddy Creech, a pediatric infectious disease physician at Vanderbilt University Medical Center, described the vaccine as potentially "a game-changer." Because traditional flu shot development requires scientists to choose strains six to eight months before flu season begins, the faster mRNA development could allow for later decision-making and greater flexibility if circulating strains change.
Regulatory Pathway and Industry Context
Dr. Kelly Lindert, Pfizer's vice president of clinical research and development, confirmed that the company is "in discussion with health authorities on the path to licensure of mRNA influenza vaccines," though she declined to comment on submission or approval timelines.
The development comes as Moderna also advances its own mRNA flu vaccine program. In June, Moderna reported that its mRNA flu shot was about 27% more effective than an approved flu shot made by GSK in a late-stage trial involving older adults. The company plans to file for approval for its stand-alone flu vaccine by January 2026.
However, the regulatory environment for mRNA vaccines faces potential challenges, with some states introducing legislation to ban mRNA vaccines and recent cuts to federal funding for mRNA vaccine research.
Broader Impact on Influenza Prevention
The results represent progress toward what experts have long sought: a universal influenza vaccine providing broader and longer-lasting protection. As Grant noted, mRNA technology can activate multiple arms of the immune system, including long-lived killer T cells that recognize multiple different influenza strains.
"This capability moves us closer to the long-sought goal of a 'universal' influenza vaccine, one that provides broader and longer-lasting protection," Grant said.
The development is particularly relevant given declining flu vaccination rates in recent years, despite surges in influenza cases. The superior efficacy demonstrated in this trial could potentially improve public health outcomes, though the limitations in elderly populations and against influenza B strains indicate that further development may be needed for comprehensive protection.
