A Phase 2 Trial Evaluating the Immunogenicity and Safety of an mRNA-Based Seasonal Influenza Vaccine Candidate Encoding Hemagglutinin and Neuraminidase

Influenza vaccines targeting both hemagglutinin (HA) and neuraminidase (NA) might offer broader protection than current vaccines, which primarily target HA. This randomized phase 2 study evaluated the immunogenicity and safety of an investigational mRNA-based trivalent seasonal influenza vaccine encoding HA and NA from A/H1N1, A/H3N2, and B/Victoria (FLUm3HA-3NA). Participants aged 18–64 years (younger adults) or 65–85 years (older adults) received one of several mRNA vaccine formulations—each containing different influenza A and B HA mRNA doses—or an age-appropriate licensed seasonal influenza vaccine as a comparator. Four formulations per age cohort were tested in part 1 of the study, and one formulation per age cohort in part 2. Day-29 hemagglutination inhibition (HI) and NA inhibition (NI) responses were assessed as primary and secondary endpoints, respectively, safety/reactogenicity as the secondary, and virus neutralization as the tertiary endpoint. A total of 250 younger and 260 older adults were vaccinated in part 1; 161 and 162, respectively, in part 2. All FLUm3HA-3NA formulations induced HI, NI, and neutralizing responses above baseline. In part 1, HI responses against A/H1N1 and A/H3N2 were similar or higher after FLUm3HA-3NA than after comparator vaccination in both age groups. For B/Victoria, HI responses were lower or similar versus comparator vaccination in younger adults and similar or higher in older adults. In part 2, HI responses were similar or higher with FLUm3HA-3NA versus comparators for A/H1N1 and A/H3N2, and lower for B/Victoria in both age groups. In both study parts and both age groups, NI titers were higher for all three strains with FLUm3HA-3NA versus comparators, and neutralizing titers were similar or higher for A/H1N1 and A/H3N2 and similar for B/Victoria. No safety concerns were identified. FLUm3HA-3NA induced HI, NI, and neutralizing responses, with an acceptable safety profile. The results support further development, including optimization of the influenza B HI response. ClinicalTrials.gov: NCT06431607. Each year, seasonal flu A and flu B viruses infect about 1 billion people worldwide, causing up to 650,000 deaths. Yearly vaccination helps protect against flu. Because flu viruses change over time, vaccines are not always fully effective. New vaccine technologies, including mRNA-based vaccines, are being explored to broaden protection. The available flu vaccines primarily target one key virus protein, called hemagglutinin (HA). Targeting a second virus protein, neuraminidase (NA), could improve protection. We therefore tested an mRNA vaccine candidate designed to target HA and NA from flu A and B viruses. The study evaluated formulations with different flu A and B HA mRNA amounts. The study analyzed 411 adults aged 18–64 years and 422 aged 65–85 years. Participants received either an mRNA vaccine formulation or a licensed flu vaccine as the comparator. The mRNA vaccine induced immune responses to both NA and HA. The NA response was higher with the mRNA vaccine than with the licensed vaccines for the flu A and B viruses. The HA response to the flu A viruses was similar or higher with the mRNA vaccine than with the licensed vaccines. The HA response to the flu B virus was lower or similar with the mRNA vaccine. No safety issues were identified. These results encourage further clinical evaluation of this mRNA HA/NA vaccine, focusing on strengthening the immune response to the flu B virus.