Phase 3 Trial Shows mRNA Flu Vaccines Outperform Standard Quadrivalent Shots

A large phase 3 randomized trial has shown that an investigational mRNA influenza vaccine was approximately 35% more effective than an inactivated quadrivalent flu vaccine at protecting against two circulating influenza strains. The findings, published in The New England Journal of Medicine, mark one of the strongest indications yet that mRNA technology may significantly advance seasonal flu prevention.

Although current flu vaccines prevent millions of illnesses each year, their overall effectiveness remains dependent on how closely the vaccine strains match circulating viruses. During the 2022–2023 influenza season alone, vaccination prevented an estimated 2.8 million illnesses, 22,000 hospitalizations, and more than 1000 deaths in adults aged 18–64. But as lead investigator David Fitz-Patrick, MD, and colleagues noted, the challenge of accurately predicting seasonal strains leaves substantial room for improvement.

Why mRNA May Offer an Advantage

“From COVID-19, we learned that mRNA vaccines can be a powerful tool against rapidly evolving viruses like influenza,” said corresponding author Kelly Lindert, MD, of Pfizer. The phase 3 study was designed specifically to measure how well an mRNA flu vaccine performs when directly compared with a licensed quadrivalent inactivated vaccine.

Earlier phase 1 and 2 trials established the safety, immunogenicity, and preliminary effectiveness of nucleoside-modified mRNA (modRNA) influenza vaccines. The new phase 3 trial expands on those results with large-scale, real-world data.

Study Design and Participants

The clinical trial enrolled 18,476 healthy adults aged 18–64 across sites in the United States, South Africa, and the Philippines during the 2022–2023 flu season. Participants were randomized to receive either the modRNA quadrivalent vaccine (n = 9225) or a licensed inactivated quadrivalent vaccine (n = 9251).

The primary endpoint was relative vaccine efficacy, defined as the reduction in laboratory-confirmed influenza associated with influenza-like illness occurring at least 14 days after vaccination.

Efficacy Results: mRNA Demonstrates Clear Superiority

Over a one-year follow-up period, the mRNA vaccine demonstrated a 34.5% relative efficacy advantage compared with the standard vaccine. Influenza was confirmed in 57 individuals in the modRNA group versus 87 individuals in the control group — meeting criteria for both noninferiority and superiority.

Most cases involved influenza A, and hemagglutination inhibition (HAI) responses were notably stronger for the mRNA vaccine against two influenza A strains. For influenza B, although cell-mediated responses were robust, antibody responses did not significantly exceed those seen with standard vaccines. The small number of influenza B cases prevented further conclusions.

Safety and Reactogenicity Profile

As expected with mRNA technology, the modRNA vaccine produced higher rates of mild to moderate reactogenicity:

• Local reactions: 70.1% (modRNA) vs. 43.1% (control)

• Systemic events: 65.8% (modRNA) vs. 48.7% (control)

No new safety concerns emerged, and reactions were generally short-lived. However, editorialists Hana M. El Sahly, MD, and Robert L. Atmar, MD, noted that increased reactogenicity may affect public willingness to adopt an annual mRNA-based flu shot.

A Shift in Flu Vaccine Technology

According to infectious diseases specialist Shirin Mazumder, MD, who was not involved in the study, the results are consistent with expectations based on prior mRNA vaccine performance. She emphasized that mRNA technology allows faster, large-scale production and could make it easier to match vaccines to emerging influenza strains more precisely.

“Given the potential for rapid manufacturing and higher efficacy, mRNA flu vaccines will likely play a major role in the future,” Mazumder said. She also noted the need for future trials involving high-risk groups, as only 25% of participants in this study met criteria for increased risk of severe flu complications.

Looking Ahead

Lindert emphasized that Pfizer is already refining next-generation mRNA flu candidates. The long-term goal is a broadly protective flu vaccine that covers multiple influenza A and B strains and provides strong protection across all age groups — from children to older adults.

For now, the phase 3 results offer compelling evidence that mRNA technology could change the landscape of seasonal and potentially pandemic influenza prevention.