MRNA Influenza Vaccine Reduces Infection Risk in Adults Over 50

The Evolution of Seasonal Influenza Immunization Strategies

Seasonal influenza remains a significant cause of morbidity and mortality in older adults, particularly as immunosenescence (the age-related decline in immune function) reduces the efficacy of traditional inactivated vaccines [1, 2]. Current egg-based manufacturing platforms often struggle with antigenic drift (minor genetic changes in the virus that lead to a mismatch between the vaccine and circulating strains), which can significantly lower seasonal effectiveness [3, 4]. To address these limitations, researchers have utilized lipid-nanoparticle delivery systems (microscopic fatty capsules that protect and transport genetic material into cells) to develop messenger RNA vaccines against influenza [5, 6]. Previous clinical data have evaluated whether these platforms elicit hemagglutination inhibition titers (a laboratory measure of the ability of antibodies to prevent the virus from entering cells) that are comparable to traditional egg-based comparators [7, 3]. Recent phase 3 trial data now offer direct clinical evidence regarding the efficacy and safety of these mRNA vaccines in older adults, providing physicians with new comparative metrics for seasonal immunization planning.

Trial Design and mRNA-1010 Composition

Seasonal influenza continues to cause substantial illness and death in adults 50 years of age or older, even with the administration of current vaccines. Seeking to improve protection in this vulnerable demographic, researchers evaluated mRNA-1010, an investigational messenger RNA (mRNA) vaccine. This platform utilizes genetic sequences to encode hemagglutinin glycoproteins (the primary surface proteins that the influenza virus uses to attach to and enter human cells) from World Health Organization-recommended influenza strains. In this study, the trivalent mRNA-1010 vaccine was administered at a dose of 37.5 μg, which included 12.5 μg of mRNA for each of the three targeted strains.

To compare this candidate against established immunization standards, the researchers conducted a phase 3, double-blind, active-controlled trial (a study design that tests a new intervention against a proven standard of care rather than a placebo). The study enrolled a total of 40,703 participants, all adults 50 years of age or older. Through random assignment, 20,350 participants received mRNA-1010 and 20,353 participants received a licensed standard-dose comparator. This large-scale recruitment provided sufficient statistical power to evaluate relative vaccine efficacy in a population frequently affected by age-related immune decline.

Funded by Blackstone Life Sciences and Moderna, the trial tracked participants through the duration of the influenza season. The median follow-up was 181 days, with a range of 1 to 227 days, ensuring the data captured the period of peak viral circulation. By utilizing a double-blind design, the investigators ensured that neither the participants nor the clinical staff knew which vaccine was administered, maintaining the integrity of the efficacy and safety assessments throughout the study period.

Efficacy Benchmarks and Clinical Outcomes

The primary efficacy end point was relative vaccine efficacy against influenza-like illness caused by influenza A or B. To ensure diagnostic precision, every case required confirmation via reverse-transcriptase-polymerase-chain-reaction (RT-PCR), a highly sensitive molecular testing method that detects viral genetic material to definitively distinguish influenza from other circulating respiratory pathogens. Efficacy was measured starting at least 14 days after vaccination, allowing sufficient time for the immune system to mount a response, and continued through the conclusion of the influenza season.

To evaluate the performance of mRNA-1010 against the standard-dose comparator, the study utilized a hierarchical statistical framework with three distinct thresholds. The first level was noninferiority, defined as the lower boundary of the 95% confidence interval (CI) being greater than -10%. The second level was superiority, requiring the lower boundary of the 95% CI to be greater than 0%. Finally, the researchers tested for a higher level of superiority, defined as the lower boundary of the 95% CI exceeding 9.1%.

Clinical data demonstrated that RT-PCR-confirmed, protocol-defined influenza-like illness occurred in 411 of 20,179 recipients of mRNA-1010 (2.0%), compared to 557 of 20,124 recipients of the standard-dose comparator (2.8%). These results yielded a relative vaccine efficacy of 26.6% (95% CI, 16.7 to 35.4) for mRNA-1010. Because the lower bound of the confidence interval (16.7%) remained well above the predefined thresholds, the findings met the criteria for noninferiority, superiority, and higher-level superiority. For practicing physicians, this translates to a statistically significant reduction in laboratory-confirmed seasonal influenza among older adults when compared to standard immunization options.

Safety Profile and Reactogenicity

While the mRNA-1010 vaccine demonstrated higher efficacy, the study found that solicited adverse reactions (systemic or local symptoms specifically monitored and recorded by participants in a diary) were more frequent with mRNA-1010 than with the standard-dose comparator. Local reactogenicity was notably higher in the mRNA group, where injection-site pain occurred in 65.8% of mRNA-1010 recipients compared to 29.8% of those who received the standard-dose comparator. Systemic reactions followed a similar pattern of increased frequency. Specifically, fatigue was reported by 45.1% of mRNA-1010 recipients versus 20.3% of comparator recipients, while headache occurred in 37.8% of the mRNA group compared to 18.0% of the control group. Additionally, myalgia (muscle aches and pain) was reported by 35.4% of mRNA-1010 recipients versus 11.6% of those in the standard-dose group.

Despite the higher incidence of these symptoms, the researchers noted that most solicited reactions were mild to moderate in severity and transient, resolving shortly after vaccination. The profile for serious adverse events (untoward medical occurrences that result in death, are life-threatening, or require hospitalization) remained comparable between the two cohorts. Serious adverse events were reported in 2.2% of mRNA-1010 recipients, with three of these events considered by the investigator to be vaccine-related. In the standard-dose comparator group, serious adverse events occurred in 1.9% of recipients, with two events deemed vaccine-related by the investigator. Clinicians should be prepared to counsel patients that while the mRNA influenza vaccine offers enhanced protection, it is also more likely to cause temporary post-vaccination discomfort, though the overall risk of severe clinical complications remains low and similar to established immunization options.

References

1. Ananworanich J, Lee IT, Ensz DJ, et al. Safety and Immunogenicity of mRNA-1010, an Investigational Seasonal Influenza Vaccine, in Healthy Adults: Final Results From a Phase 1/2 Randomized Trial. Journal of Infectious Diseases. 2024. doi:10.1093/infdis/jiae329

2. Zhang G, Tang T, Chen Y, Huang X, Liang T. mRNA vaccines in disease prevention and treatment. Signal Transduction and Targeted Therapy. 2023. doi:10.1038/s41392-023-01579-1

3. Soens M, Ananworanich J, Hicks B, et al. A phase 3 randomized safety and immunogenicity trial of mRNA-1010 seasonal influenza vaccine in adults.. Vaccine. 2025. doi:10.1016/j.vaccine.2025.126847

4. Sevilla J, Knee J, Burnes D, et al. The full value of mRNA seasonal influenza and endemic-stage COVID-19 combination vaccines: a taxonomy.. Journal of Medical Economics. 2026. doi:10.1080/13696998.2026.2638676

5. Sharif N, Alzahrani KJ, Ahmed SN, Dey SK. Efficacy, Immunogenicity and Safety of COVID-19 Vaccines: A Systematic Review and Meta-Analysis. Frontiers in Immunology. 2021. doi:10.3389/fimmu.2021.714170

6. Thi TTH, Suys EJA, Lee JS, Nguyen DH, Park KD, Truong NP. Lipid-Based Nanoparticles in the Clinic and Clinical Trials: From Cancer Nanomedicine to COVID-19 Vaccines. Vaccines. 2021. doi:10.3390/vaccines9040359

7. Lee IT, Nachbagauer R, Ensz DJ, et al. Safety and immunogenicity of a phase 1/2 randomized clinical trial of a quadrivalent, mRNA-based seasonal influenza vaccine (mRNA-1010) in healthy adults: interim analysis. Nature Communications. 2023. doi:10.1038/s41467-023-39376-7