An mRNA influenza vaccine was approximately 35% more effective than an inactivated quadrivalent flu vaccine against two different strains, based on new data from a phase 3 randomized trial.

Although the annual influenza vaccine prevented an estimated 2.8 million influenza-related illnesses, 22,000 hospitalizations, and at least 1000 deaths among adults aged 18-64 years during the 2022-2023 flu season, the effectiveness of the vaccine is perpetually hamstrung by misalignment with the dominant strain of any given year, wrote David Fitz-Patrick, MD, of East-West Medical Research Institute, Honolulu, Hawaii, and colleagues.

Despite the availability of effective vaccines for influenza, efficacy varies on a year-to-year basis and depends on matching circulating strains; therefore, opportunities remain both to improve vaccines to prevent influenza and mitigate its complications, said corresponding author Kelly Lindert, MD, in an interview.

“We learned from COVID-19 that mRNA vaccines could be a tool to prevent rapidly spreading and frequently changing viruses such as influenza,” said Lindert, employee of vaccine manufacturer, Pfizer. “This large, randomized efficacy and safety study was designed as a direct evaluation of how well mRNA influenza vaccines work when compared with currently licensed influenza vaccines,” she said.

The safety, effectiveness, and immunogenicity of the nucleoside-modified messenger RNA (modRNA) influenza vaccines against influenza was established in a phase 2a study.

In the new study, published in The New England Journal of Medicine, the researchers randomized healthy adults aged 18-64 years to either a quadrivalent modRNA flu vaccine or a licensed inactivated quadrivalent flu vaccine. The study took place during the 2022-2023 flu season in US, South Africa, and Philippines. The study population included 18,476 individuals (9225 assigned to modRNA and 9251 to control treatment). The primary endpoint was relative efficacy, defined as the reduction in the percentage of participants with laboratory-confirmed influenza associated with influenza-like illness at least 14 days after vaccination with the modRNA vaccine compared with control treatment.

The relative efficacy of the mRNA vaccine compared with the control treatment was 34.5% over a 1-year period, based on 57 modRNA patients and 87 control individuals, which met criteria for noninferiority and superiority.

In terms of safety, individuals in the modRNA group reported more mild or moderate reactogenicity than those in the control group. Overall local reactions in the modRNA and control groups were 70.1% and 43.1%, respectively; overall systemic events were 65.8% and 48.7%, respectively.

The immunogenicity results seen with this influenza vaccine were predicted by patterns we had seen in earlier phase 1 and 2 studies, and therefore were not unexpected, said Lindert. “The vaccine candidate we explored continues to show strong antibody and cell mediated immune responses to influenza A strains, and the candidate also showed strong cell mediated immune responses to influenza B, but the antibody responses to this strain did not show improvement over standard influenza vaccines,” she said.

The new data provide compelling evidence that the mRNA platform may protect against influenza, which could be meaningful for future use for both seasonal and pandemic influenza, if warranted, Lindert said.

The investigators have identified areas to refine the mRNA influenza vaccine, and they are working to evaluate these candidates in ongoing studies, Lindert told Medscape Medical News. “Our long-term goal is to develop an influenza vaccine that is broadly protective against influenza A and B strains, including protection against severe influenza in children through elderly adults,” she said.

Early Results Reassure, but Reactogenicity May Put Patients Off

Most of the cases reported in the study involved influenza A viruses, and the mRNA vaccine showed a stronger response than the control on hemagglutination inhibition (HAI) assays against two influenza A strains, wrote Hana M. El Sahly, MD, and Robert L. Atmar, MD, both of Baylor College of Medicine, Houston, in an accompanying editorial. Although HAI responses were lower against influenza B, the number of cases was too small for assessment, they said.

No new safety concerns regarding the mRNA vaccine appeared compared to control treatment, the authors said. However, the between-group differences in reactogenicity, while consistent with other studies of mRNA vaccines, may impact public acceptance, given that this is a vaccine intended for annual use, they noted.

Evolution in Flu Management

“Modified mRNA vaccines offer a new approach in regards to flu vaccines by increasing the likelihood of a more direct match to targeted influenza strains and can be produced on a large scale in a shorter period of time, allowing for a more practical approach,” said Shirin Mazumder, MD, infectious diseases specialist and associate professor at the University of Tennessee Health Science Center, Memphis, in an interview.

The overall efficacy of the mRNA vaccine compared to control treatment was not unexpected, given the established advantages of mRNA vaccines observed in the development of COVID vaccines, and the results supported clinical experience with mRNA vaccines to date, said Mazumder, who was not involved in the study.

“Reactogenicity, including local reaction and systemic events occurred more often with the mRNA influenza vaccine compared to the control vaccine; however, these reactions were mild or moderate and transient,” said Mazumder. “The overall safety profile was similar for both the mRNA and control vaccine in this study,” she noted. “Given the potential for rapid vaccine production and the increased efficacy, mRNA flu vaccines will most likely have a significant role in the future,” she said.

Next steps for research include evaluating how well mRNA flu vaccines perform in different flu seasons and against different influenza strains, including influenza B, Mazumder said. “Only 25% of the population included in this study were at high risk for severe flu-related complications; therefore, further study of the effectiveness of mRNA vaccines in immunocompromised persons and other high-risk groups is needed,” she said.

The study was supported by Pfizer, and Lindert is employed by Pfizer. Mazumder disclosed having no financial conflicts of interest.