A global phase 3 study found that Moderna’s investigational mRNA-1010 influenza vaccine reduced RT-PCR–confirmed influenza-like illness more effectively than standard-dose vaccines in adults aged 50 years and older.
A phase 3 trial evaluating Moderna’s investigational seasonal influenza vaccine,
The findings, published in The New England Journal of Medicine (NEJM), may have implications for future influenza vaccine development, particularly in older adults who remain at elevated risk for influenza-related complications despite routine vaccination.2
The Fluent trial enrolled more than 40,000 participants across 11 countries during the 2024-2025 Northern Hemisphere influenza season. According to Grace Huang, MD, senior vice president and head of infectious diseases at Moderna, the results suggest that the company’s mRNA platform may offer advantages over conventional influenza vaccine manufacturing approaches.
“The superior efficacy observed with mRNA-1010 compared with standard-dose influenza vaccines highlights the potential of mRNA technology to improve seasonal influenza prevention,” Huang said in a company statement.1
The randomized, double-blind, active-controlled study included adults aged 50 years and older who were randomly assigned in a 1:1 ratio to receive either a single dose of trivalent mRNA-1010 or a licensed standard-dose comparator vaccine. Comparators included Fluarix, Fluarix Tetra, Influsplit Tetra, or Alpharix Tetra, depending on regional availability.
The primary endpoint was relative vaccine efficacy against RT-PCR–confirmed, protocol-defined influenza-like illness caused by influenza A or B strains beginning at least 14 days after vaccination through the end of the influenza season. Active surveillance included twice-weekly electronic diary prompts and nasopharyngeal swab collection within 72 hours of symptom onset.
Among 20,179 participants in the mRNA-1010 group and 20,124 in the comparator arm included in the per-protocol efficacy analysis, influenza-like illness occurred in 2.0% and 2.8% of participants, respectively. Investigators reported a relative vaccine efficacy of 26.6% (95% CI, 16.7%-35.4%), meeting prespecified criteria for noninferiority and superiority.
Exploratory analyses suggested potential reductions in medically attended influenza-related healthcare encounters. Higher-level care visits, including emergency department utilization and hospitalization, were numerically lower among mRNA-1010 recipients, although the study was not powered for these outcomes.
Solicited local and systemic adverse events (AEs) occurred more frequently in the mRNA-1010 arm. Injection-site pain was reported in 65.8% of recipients compared with 29.8% in the comparator group, while fatigue, headache, and myalgia were also more common among mRNA-1010 recipients. Most AEs were transient and mild to moderate in severity.
Serious AEs occurred in 2.2% of participants receiving mRNA-1010 and 1.9% receiving comparator vaccines. Investigators identified no cases of myocarditis or pericarditis associated with mRNA-1010 within the predefined 42-day risk window.
Seasonal influenza continues to contribute substantially to morbidity and mortality worldwide, particularly among older adults and individuals with comorbid conditions.3 Current influenza vaccines demonstrate variable efficacy across seasons because of strain mismatch and limitations associated with egg-based manufacturing methods.4
Enhanced influenza vaccines, including high-dose and adjuvanted formulations, have shown improved protection in older populations, although effectiveness remains inconsistent.5
“A need remains for influenza vaccines that can be rapidly updated to evolving strains and elicit robust protection,” the NEJM authors wrote. “The investigational seasonal influenza vaccine mRNA-1010 encodes surface hemagglutinin (HA) antigens from the three WHO-recommended 2024-2025 strains for cell- or recombinant-based vaccines: A/H1N1, A/H3N2, and B/Victoria. By avoiding egg-based production and enabling rapid strain updates, the (mRNA) platform addresses key limitations of current influenza vaccines and may improve protection in older adults.”2
Unlike traditional egg-based influenza vaccines, mRNA-1010 encodes hemagglutinin antigens corresponding to World Health Organization-recommended strains using an mRNA platform. Investigators noted that this approach may allow faster strain updates and avoid egg-adaptive mutations that can reduce vaccine match with circulating viruses.1
Although the results demonstrated improved efficacy compared with standard-dose vaccines, the trial did not compare mRNA-1010 with enhanced influenza vaccines currently recommended for some older adult populations. Investigators acknowledged that the multinational design required the use of regionally available standard-dose comparators. Additionally, efficacy data reflected a single influenza season, and influenza B case numbers were limited.
Further evaluation may be needed to determine whether mRNA-1010 offers clinically meaningful advantages over currently available high-dose or adjuvanted vaccines and whether the findings remain consistent across multiple influenza seasons.
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