Moderna says its experimental mRNA influenza vaccine, mRNA-1010, showed more than 30% greater relative vaccine efficacy against influenza A than a licensed egg-based flu shot in a large Phase 3 trial enrolling 40,817 adults ages 50 and older. The trial is registered on ClinicalTrials.gov and lists enrollment beginning in September 2024 with primary completion in August 2025; detailed efficacy results have not yet been published in a peer-reviewed journal. If the reported advantage holds up under independent review, the findings could reshape how seasonal flu shots are manufactured and distributed.
A 40,000-Person Trial Built to Measure Real Protection
Most earlier mRNA flu vaccine studies measured immune markers in the blood, not whether people actually got sick less often. The Phase 3 efficacy trial registered as NCT06602024 was designed differently. Titled “A Study of mRNA-1010 Compared With a Licensed Influenza Vaccine in Adults 50 Years of Age and older,” the trial’s primary objective was to measure relative vaccine efficacy against RT-PCR-confirmed influenza-like illness caused by influenza A or B. That means researchers did not simply count antibody levels; they tracked whether vaccinated participants developed symptomatic, lab-confirmed flu at lower rates than those who received a standard shot, providing a direct measure of real-world protection.
The trial enrolled 40,817 participants starting September 16, 2024, with a primary completion date of August 21, 2025. That scale matters because seasonal flu vaccine trials often struggle to enroll enough participants to detect statistically meaningful differences between two active vaccines, since both arms receive some protection. By recruiting more than 40,000 adults during a single flu season, the study was powered to identify even moderate advantages in clinical efficacy. Moderna has said it plans to present the full dataset at a scientific meeting and submit it for peer-reviewed publication, steps that will allow independent experts to scrutinize the case definitions, statistical methods and subgroup outcomes underlying the reported 30%-plus relative efficacy advantage against influenza A.
Immune Responses That Beat Both Standard and High-Dose Shots
The efficacy signal did not emerge in a vacuum. A separate Phase 3 randomized safety and immunogenicity trial, registered as NCT05827978, had already shown that mRNA-1010 produced hemagglutination inhibition (HAI) titers that were statistically noninferior and superior to both licensed standard-dose and high-dose egg-based quadrivalent vaccines. HAI titers are the standard laboratory measure regulators use to gauge whether a flu vaccine is likely to protect against infection. Beating a high-dose comparator is especially notable because high-dose flu shots are already recommended for older adults precisely because standard shots often fall short in that age group.
Earlier dose-ranging work in a Phase 1/2 randomized trial, NCT04956575, filled in the biological picture. Final results published in The Journal of Infectious Diseases showed that mRNA-1010 generated persistent HAI titers through six months, along with breadth against heterologous A/H3N2 strains and measurable T-cell responses. Those three features address specific weaknesses of egg-based vaccines: antibody levels from conventional shots tend to wane before flu season ends, egg adaptation can introduce antigenic mismatches that reduce effectiveness against circulating H3N2 variants, and traditional inactivated vaccines generally produce weaker cellular immunity. An interim analysis of the same Phase 1/2 trial, published in Nature Communications, had previously confirmed that mRNA-1010 elicited higher HAI titers than a standard-dose inactivated vaccine for influenza A strains with no major safety concerns, reinforcing the biological plausibility of the later efficacy advantage.
Why Egg-Based Manufacturing Creates a Built-In Weakness
To understand why a 30%-plus advantage against influenza A is significant, it helps to know how conventional flu vaccines are made. Each year, the World Health Organization selects target strains months before flu season based on global surveillance. Manufacturers then grow those viruses in chicken eggs, a process that can take weeks and sometimes forces the virus to mutate slightly to replicate efficiently in egg cells. Those egg-adapted mutations, particularly common with H3N2 strains, can shift the vaccine’s antigenic profile away from the virus actually circulating in humans. In mismatched years, vaccine effectiveness against H3N2 has historically dropped well below levels seen for influenza B, leaving older adults with limited protection during the seasons most likely to drive severe illness and hospitalization.
mRNA vaccines avoid the egg-adaptation step that can contribute to that problem. Because the vaccine delivers a synthetic genetic template rather than a whole virus grown in eggs, there is no opportunity for egg adaptation to distort the antigen. The broader cross-reactivity against heterologous A/H3N2 strains observed in the Phase 1/2 analysis suggests that mRNA-1010 may hold its edge precisely in the seasons when egg-based vaccines perform worst. That could be meaningful. For adults over 50, even a modest improvement in vaccine match during an H3N2-dominant year could reduce severe outcomes, though the size of any population-level impact would depend on uptake, season severity and how well the effect holds up outside the trial. If the relative efficacy advantage seen in the Phase 3 trial persists across multiple seasons and viral lineages, health systems could see downstream reductions in wintertime strain on hospitals.
Reactogenicity Tradeoffs and What Remains Unknown
The mRNA platform is not without drawbacks. Data from a large randomized study of 18,476 participants found that the mRNA influenza vaccine was associated with more frequent local and systemic reactions such as injection-site pain, fatigue and headache than a licensed inactivated comparator, a pattern broadly similar to what has been seen with mRNA COVID-19 vaccines. In that analysis, detailed in a peer-reviewed vaccine safety report, most adverse events were mild to moderate and transient, and serious adverse events were rare in both groups. However, higher reactogenicity could still influence uptake among older adults and clinicians, particularly in populations that already express fatigue with annual vaccination campaigns.
Important questions also remain about durability, breadth and real-world performance outside controlled trials. The Phase 1/2 data showing sustained antibody levels through six months are encouraging, but many older adults receive their flu shots early in the season, and circulation can extend well into late spring. It is not yet clear whether mRNA-1010 will maintain its relative advantage if the dominant strains shift late in the season or if substantial antigenic drift occurs after strain selection. Similarly, while early trials have not flagged major safety signals, longer-term pharmacovigilance will be needed to detect extremely rare events, especially as mRNA flu vaccines scale to tens of millions of doses per year. Regulators will also have to decide how to handle annual updates to the mRNA construct, balancing the need for rapid adaptation against the desire for robust clinical data on each new formulation.
What a Successful mRNA Flu Shot Would Mean for Public Health
If mRNA-1010 or a similar product ultimately secures regulatory approval on the strength of large efficacy trials and supportive immunogenicity data, the implications would extend well beyond influenza. Seasonal flu vaccination is one of the largest and most logistically complex immunization programs in the world, with hundreds of millions of doses administered each year. Demonstrating that an mRNA vaccine can not only match but surpass high-dose egg-based shots in older adults would validate the platform for other respiratory viruses that mutate rapidly, such as respiratory syncytial virus and emerging coronavirus variants. It could also accelerate investment in combination vaccines that package influenza, COVID-19 and RSV antigens into a single annual shot, simplifying campaigns for health systems and patients alike.
On the manufacturing side, mRNA technology offers a faster and more flexible response to unexpected viral shifts. Once a genetic sequence is selected, mRNA constructs can be designed and produced in weeks rather than the months required for egg-based production, potentially allowing later strain selection or mid-season updates in the face of a major mismatch. That agility could prove critical in pandemic scenarios where a novel influenza strain emerges outside the usual calendar. For now, though, the central question is whether the more than 30% relative efficacy advantage against influenza A seen in a rigorously conducted Phase 3 trial will be reproduced across multiple seasons, geographies and age bands. As full data sets are published and regulatory reviews proceed, clinicians and policymakers will be watching closely to see whether mRNA-1010 marks the beginning of a new era for flu prevention or a more incremental step in a long, ongoing effort to outpace a constantly evolving virus.
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*This article was researched with the help of AI, with human editors creating the final content.
