Efficacy and Safety of an mRNA Seasonal Influenza Vaccine in Adults
In adults aged 50 years or older, a messenger RNA seasonal influenza vaccine prevented more lab-confirmed influenza-like illness than a standard-dose licensed vaccine, but caused more short-term side effects.
*Randomized double-blind trial; Level 1b (OCEBM).
*Randomized double-blind trial; Level 1b (OCEBM).
Citation
Leroux‑Roels I, Huang G, Ferguson M, et al.; Fluent Trial Investigators. Efficacy and Safety of an mRNA Seasonal Influenza Vaccine in Adults. N Engl J Med. 2026;394:1803-1813. doi:10.1056/NEJMoa2516491. ClinicalTrials.gov: NCT06602024.
Background
Adults aged 50 years or older still experience substantial seasonal influenza illness despite current vaccines. A messenger RNA platform may better match vaccine strains and be updated faster than traditional production methods.
Patients
Adults aged ≥50 years (40,703 vaccinated) at 301 sites in 11 countries; participants were medically stable. The main efficacy analysis excluded participants with major protocol deviations affecting efficacy.
Intervention
Single intramuscular dose of trivalent messenger RNA-1010 (37.5 micrograms total).
Control
Single dose of a licensed standard-dose seasonal influenza vaccine (trivalent preferred; otherwise quadrivalent).
Outcome
Lab-confirmed, protocol-defined influenza-like illness due to influenza A or B starting ≥14 days after vaccination (primary).
Follow-up Period
Median 181 days.
Results
| Outcome | Messenger RNA vaccine | Standard-dose vaccine | Relative vaccine efficacy (95% CI) | NNT |
|---|---|---|---|---|
| Lab-confirmed, protocol-defined influenza-like illness (primary) | 411/20,179 (2.0%) | 557/20,124 (2.8%) | 26.6% (16.7 to 35.4) | 125 |
| Lab-confirmed influenza-like illness using a simpler symptom definition | 223/20,179 (1.1%) | 290/20,124 (1.4%) | 23.5% (9.0 to 35.8) | ≈303 |
Common short-term reactions were more frequent with the messenger RNA vaccine (in a subset): injection-site pain 65.8% vs 29.8%, fatigue 45.1% vs 20.3%, headache 37.8% vs 18.0%, muscle aches 35.4% vs 11.6% (mostly mild to moderate, lasting 1–2 days). Serious adverse events: 2.2% vs 1.9%.
Limitations
Only one influenza season was studied. The comparator was standard-dose (not higher-dose or enhanced vaccines often recommended for some older adults). Influenza B case numbers were small, and vaccine-strain matching data were not available at season-end. Higher reactogenicity may matter to patients even when illness reduction is modest (NNT 125).
Funding
Blackstone Life Sciences and Moderna; sponsor led design and analysis.
Clinical Application
For adults ≥50, consider messenger RNA flu vaccine as a more effective alternative to standard-dose vaccines, while counseling about more frequent short-lived side effects.
Discussion
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In this phase 3 double-blind randomized active-controlled trial, mRNA-1010 reduced RT-PCR–confirmed protocol-defined influenza-like illness from 2.8% to 2.0% (relative vaccine efficacy 26.6%, 95% CI 16.7–35.4). Is this benefit large enough to change practice given higher reactogenicity and a standard-dose (not high-dose/adjuvanted) comparator? The primary efficacy result was reported in a per-protocol population (2.0% vs 2.8%; relative vaccine efficacy 26.6%). In randomized trials, why is an intention-to-treat (ITT) analysis generally preferred when estimating real-world effectiveness?