Phase 2 mRNA-1010 trial observes improved influenza B immune responses with optimized formulations
Background
In a phase 2 trial of mRNA-1010, a seasonal influenza vaccine candidate, optimized formulations showed higher influenza B immune responses on day 29 after vaccination than the original formulation. The study did not compare protection against actual infection.
Influenza A and B viruses account for most influenza-related hospitalizations and deaths. The effectiveness of existing vaccines can vary because of differences in immune responses, waning immunity over time, and mismatches between vaccine and circulating strains.
Messenger RNA (mRNA) platforms are being studied as an alternative. Their potential advantages include rapid design changes, shorter manufacturing timelines, and optimized antigen expression. They can also avoid egg-adaptive mutations that arise when viruses change during growth in eggs. However, these platform characteristics must be distinguished from the actual protective efficacy of individual vaccine candidates.
Key findings
The researchers conducted a randomized, assessor-blinded phase 2 trial to evaluate the safety, reactogenicity, and immunogenicity of mRNA-1010 in 270 healthy adults aged 18–49 years. The trial (NCT05868382) was conducted at 10 sites in the United States, beginning in May 2023 and ending in December 2023. The final post-vaccination visit was on day 181.
Participants received a single dose of one of three formulations designed to express the hemagglutinins (HAs) of two influenza A strains and two influenza B strains recommended by the World Health Organization (WHO) for cell-based and recombinant vaccines for the 2022–2023 Northern Hemisphere season. The original formulation was tested at 50 µg; optimized formulation 1 at 25 and 50 µg; and optimized formulation 2 at 12.5, 25, and 50 µg. Both optimized formulations incorporated amino acid substitutions in regions of influenza B HA that are not exposed on its surface, aiming to increase expression while preserving antigenic sites. Formulation 1 also incorporated a change to the mRNA manufacturing process.
All formulations induced HA-specific humoral and cellular immune responses to the evaluated virus strains. At the same 50 µg dose, antibody responses to influenza B on day 29 were observed to be higher with both optimized formulations than with the original formulation. By contrast, no clear differences were observed in humoral responses to influenza A. The comparisons were descriptive and exploratory, without formal hypothesis testing; they do not establish statistical superiority. On day 181, humoral responses were similar across the three 50 µg groups for all virus strains. Multifunctional HA-specific CD4-positive T-cell responses peaked on day 29 and then declined, but remained above pre-vaccination levels on day 181.
Most local and systemic reactions recorded during the seven days after vaccination were mild or moderate. Injection-site pain was reported by 53.3–84.7% of participants across groups; headache, fatigue, and muscle pain were also reported. Five serious adverse events occurred in five participants during the study, and investigators assessed all as unrelated to vaccination. No vaccine-related serious adverse events or deaths were reported, although a small trial cannot rule out rare risks.
Meaning and outlook
The study suggests that optimized formulations may improve early influenza B immune responses compared with the original formulation. The researchers interpreted this as potentially related to increased antigen expression, but the trial did not test the mechanism itself. The candidate was not directly compared with licensed vaccines, and the study did not assess prevention of infection or hospitalization. The findings therefore do not support concluding that it overcomes limitations in the protection provided by traditional vaccines.
Only healthy adults in the United States participated, and the sample size and demographic composition were limited, making it difficult to generalize the results to older adults, children, or other regions. The six-month follow-up results also need to be read with a distinction between improved early responses and whether those improvements translate into a sustained advantage. The paper describes separate phase 3 studies, but their results are not efficacy data from this phase 2 trial. Moderna funded the study; many authors disclosed that they were company employees and might hold stock or stock options. The study design and results are available in the full paper.
Seasonal influenza causes considerable morbidity and mortality, with influenza A and B viruses driving most influenza-associated hospitalizations and deaths. Vaccination remains a key influenza prevention strategy; however, current seasonal influenza vaccines based on traditional platforms provide inconsistent protection. Messenger RNA - based vaccines may offer several key advantages over other vaccines, including the flexibility to optimize antigen expression to enhance immunogenicity without the need for adjuvants. mRNA-1010 is an investigational seasonal influenza vaccine candidate that encodes hemagglutinins (HAs) from WHO-recommended influenza strains. In this randomized, phase 2 study, safety, reactogenicity, and immunogenicity of 3 mRNA-1010 vaccine candidate compositions were evaluated in healthy adults aged 18-49 y in the United States (NCT05868382). Eligible participants were randomly assigned to receive a single dose of one of the mRNA-1010 compositions at several dose levels. The primary objective was the safety and reactogenicity of mRNA-1010 vaccine candidate compositions against vaccine-matched strains; secondary and exploratory objectives included humoral and cellular immunogenicity at evaluable timepoints, respectively. Two hundred and seventy participants received study vaccination between May and December 2023. All mRNA-1010 vaccine compositions were well tolerated, with no safety concerns identified; all compositions induced HA-specific humoral and cellular immune responses against all influenza strains evaluated, with the optimized compositions exhibiting higher immune responses against influenza B strains compared with the original mRNA-1010 composition. These results, together with findings from other mRNA-1010 clinical studies, support continued evaluation of mRNA-1010 for enhanced protection against seasonal influenza.
These findings provide direct comparative data that vaccine developers can consult when selecting formulations and doses intended to improve influenza B immune responses. For example, when selecting candidates for subsequent trials, developers can consider both the day-29 influenza B responses observed at the same 50 µg dose and adverse reactions after vaccination. However, humoral responses were similar across formulations on day 181, so an early improvement should not be interpreted as superior long-term protection. Further evaluation should establish how the magnitude and persistence of immune responses relate to actual prevention of infection. The results can inform research and development decisions; they do not recommend vaccination choices for patients or replacement of licensed vaccines.