A Phase 1/2 Trial Evaluating the Safety and Immunogenicity of an mRNA-based Seasonal Influenza Vaccine Candidate Encoding Hemagglutinin and Neuraminidase

Hemagglutinin (HA) is the principal immunologic target of most licensed seasonal influenza vaccines. Targeting both HA and neuraminidase (NA) might improve vaccine effectiveness. This randomized phase 1/2 study evaluated an investigational mRNA-based quadrivalent seasonal influenza vaccine, encoding HA and NA of A/H1N1, A/H3N2, B/Victoria, and B/Yamagata (FLUm4HA-4NA). In phase 1, adults aged 18–50 years received either one of twelve mRNA vaccine formulations of varying HA-only or HA and NA mRNA doses, or a licensed quadrivalent seasonal influenza comparator. In phase 2, participants aged 18–64 years (younger adults) and 65–85 years (older adults) received FLUm4HA-4NA (three groups per age category, with different HA/NA mRNA doses) or age-appropriate licensed quadrivalent comparator. Primary endpoints were safety/reactogenicity, and hemagglutination inhibition [HI] and NA inhibition [NI] responses against the four seasonal strains at day 29. Cross-reactive HI/NI responses against drifted strains, virus neutralization, and HA-/NA-specific cell-mediated immunity were evaluated in phase 2 as tertiary objectives. A total of 293 participants (21–25 per group) were vaccinated in phase 1, 480 younger (108–137 per group) and 483 older adults (117–125 per group) in phase 2. Solicited events were more frequent with FLUm4HA-4NA than comparators and were mostly short-lived and mild or moderate. No deaths or vaccine-related serious adverse events were reported. Post-vaccination HI and neutralizing titers in the FLUm4HA-4NA groups were similar or higher for the A strains and lower for the B strains versus comparators. NI responses exceeded those of comparators for all four strains. HI and NI titers against evaluated drifted A strains were similar or higher after FLUm4HA-4NA than after comparator vaccination. HA-specific CD4+ and CD8+ T-cell responses were generally higher after FLUm4HA-4NA than comparator vaccination. FLUm4HA-4NA showed an acceptable safety profile and humoral and cellular immunogenicity in the study population, supporting further development and formulation optimization to improve influenza B HI responses. ClinicalTrials.gov: NCT05823974; euclinicaltrials.eu: 2022-502308-66-00. Seasonal flu causes serious illness and death each year. Vaccination can help prevent flu, but currently available flu vaccines are not always fully effective. This is because flu viruses change often, so the strains in the vaccine may not closely match the strains spreading each season. Current flu vaccines mainly target one viral protein called hemagglutinin (HA). Adding another viral protein, neuraminidase (NA), may improve vaccine effectiveness. Our study tested a new mRNA-based seasonal flu vaccine designed to target both HA and NA from the four major circulating flu strains. The study had a phase 1 part, analyzing 293 adults aged 18–50 years, and a phase 2 part, analyzing 480 younger adults (18–64 years) and 483 older adults (65–85 years). In each part, participants received one of several mRNA vaccine formulations (with various HA and NA mRNA doses) or an age-appropriate licensed flu vaccine. More people who received the mRNA vaccine had side effects than those who received the licensed vaccines. These side effects were usually short-lived and were mostly mild or moderate. The mRNA flu vaccine induced an immune response to both the HA and NA target proteins. For HA, the immune response was similar or higher than that of the licensed vaccines for two of the flu strains (A strains), and lower for the other two strains (B strains). For NA, responses were higher for all strains. These results support continued development of this mRNA HA/NA vaccine, including improvement of the response to the flu B strains.