Investigational mRNA Flu Vaccine Broadens Antibody Defenses, Sustains Immune "Training Hub" Longer Than Standard Shot

An investigational mRNA-based influenza vaccine from Moderna, mRNA-1010, generated broader and more durable antibody responses than a licensed split-virion vaccine (Fluarix; GlaxoSmithKline Biologicals) over 2 consecutive influenza seasons, according to study findings published in Nature Immunology.¹ The results offer a mechanistic explanation for the vaccine’s performance in prior clinical trials and raise questions about whether the field’s traditional protection benchmark tells the whole story.^1,2

Study Design

Investigators at Washington University in St Louis, Missouri, followed 75 healthy adults (aged 20-50 years) across the 2022-2023 and 2023-2024 Northern Hemisphere flu seasons. Thirty-eight participants received mRNA-1010, which encodes the hemagglutinin glycoproteins from 4 recommended influenza strains, and 37 received Fluarix, a licensed egg-based, split-virion quadrivalent vaccine targeting the same strains. Both platforms are injected into the deltoid muscle, allowing researchers to track the immune response not only in blood but also directly at its source. A subset of participants (mRNA-1010, n = 13; Fluarix, n = 15) underwent ultrasound-guided fine needle aspiration (FNA) of axillary lymph nodes, enabling investigators to sample germinal centers (GCs)—the microanatomical structures where B cells are trained through repeated rounds of mutation and selection to recognize an expanding range of viral targets.¹

Key Findings

Across both seasons, mRNA-1010 recipients showed significantly higher peak antibody titers and greater frequencies of flu-specific memory B cells than Fluarix recipients. Proteomic analysis of the serum antibody repertoire also revealed that mRNA-1010 elicited a greater number of distinct antibody-producing clonotypes and promoted expansion within preexisting clonotypes, indicating that the vaccine was diversifying the antibody pool rather than simply amplifying an existing response.¹

Perhaps the most striking finding involved GC persistence within the FNA subset. At 26 weeks post vaccination, 5 of 13 mRNA-1010 recipients (about 38%) still had detectable flu-specific GC activity in their lymph nodes, whereas none of the 15 Fluarix recipients maintained a detectable GC response at that time point.¹

“We are seeing that the mRNA flu vaccine is driving strong, persistent germinal center responses,” Ali Ellebedy, PhD, the Leo Loeb Endowed Professor in the Department of Pathology and Immunology at Washington University School of Medicine in St Louis, Missouri, and senior study author, said in a news release.² “This can broaden the antibody response and better arm the immune system against an ever-changing virus.”

That broadening was measurable at the antibody level: Plasma from mRNA-1010 recipients bound significantly more strains of H1N1 and H3N2 spanning more than 5 decades of viral evolution than plasma from Fluarix recipients, and sequencing-based neutralization assays showed significantly greater increases in titers against 11 of 13 H1N1 viruses tested.¹ Ellebedy noted that this expansion appeared to go beyond a simple boost to preexisting immunity. “We are seeing that the mRNA flu vaccine doesn’t just boost the immune system’s response to what it has already seen; it can help expand and diversify the antibody response, covering a broader range of flu strains,” he said.²

A Disconnect With the Traditional Correlate of Protection

Despite these broader responses, hemagglutination-inhibition (HAI) titers—the assay traditionally used to gauge flu vaccine protection—did not differ significantly between the 2 vaccine groups in the subset of participants tested. Because HAI testing against a wide range of divergent viruses is technically difficult, investigators instead relied on a sequencing-based neutralization assay capable of screening many strains in parallel, which is where mRNA-1010’s advantage became apparent. The discrepancy suggests HAI titers, although still clinically useful, may not fully capture the protective potential of vaccines engineered to broaden—rather than simply boost—the antibody repertoire.¹

Regulatory Status

mRNA-1010 remains under FDA review, with a Prescription Drug User Fee Act decision date of August 5, 2026. In June 2026, the FDA’s Vaccines and Related Biological Products Advisory Committee voted unanimously that the vaccine’s benefits outweigh its risks in adults 50 years and older.³ If approved, it would become the first mRNA-based seasonal influenza vaccine on the market, arriving after a 2024-2025 season that the CDC classified as high severity, with an estimated 710,000 hospitalizations and 45,000 deaths nationwide.⁴

Expert Q&A With Hanover Matz, PhD

To better understand what these findings mean for the future of flu vaccination, Pharmacy Times spoke with study’s first author Hanover Matz, PhD, a postdoctoral research associate in the Ellebedy Lab in the Department of Pathology and Immunology at Washington University in St Louis, Missouri. Matz discussed the unexpected disconnect between HAI titers and the broader protection signals observed in the study, the biological mechanisms that may explain mRNA-1010’s persistent GC responses, and what pharmacists should keep telling patients at the vaccine counter in the meantime.

Pharmacy Times: Your data show mRNA-1010 drove broader, more durable antibody responses without a significant bump in HAI titers¹—the traditional correlate of protection. What do you think explains that disconnect, and does it suggest HAI titers alone may be an incomplete measure of a flu vaccine’s protective potential?

Hanover Matz, PhD: In the study, we tested [HAI] titers against the same strains of influenza virus used in both vaccines. Our results showed mRNA-1010 performed as well as the conventional inactivated split-virus vaccine at generating [HAI] titers, which in some ways is not surprising; the currently available seasonal vaccine works if the circulating strains are well matched to the vaccine strains. It is technically challenging to test a wide range of divergent viruses by [HAI] assay, so we utilized a different assay that relies on genetic sequencing to screen neutralization by antibodies of many viruses in parallel. In this assay, we did observe higher neutralization titers from mRNA-1010 against divergent influenza viruses. Although this is not exactly the same as [HAI] titers, it demonstrates a similar mechanism of protection against an infectious virus. It is possible [that HAI] may not be the only assay that should be used to evaluate the protective effectiveness of a vaccine. Additionally, it should be noted that we only assessed [HAI] titers in a subset of our cohort and that Moderna, Inc observed higher [HAI] titers from mRNA-1010 in a much larger cohort study.⁵

Pharmacy Times: One of the more striking findings is that mRNA-1010 induced persistent GC responses in about 38% of participants at 6 months, and Fluarix induced none.¹ What do you think is driving that difference—antigen persistence, the lipid nanoparticle’s self-adjuvanting effect, or something else?

Matz: We think both mechanisms may be driving the persistence of germinal centers. There is data from animal model studies to suggest mRNA-lipid nanoparticle vaccines have a self-adjuvanting effect that stimulates more robust immune responses. This could contribute to early signaling that activates immune cells and drives longer germinal centers. Antigen persistence remains an interesting idea for how long a germinal center lasts. Although it is unclear how long the antigen remains in these germinal centers, we do think mRNA-1010 delivers greater amounts of antigen to draining lymph nodes compared with Fluarix in the early stages of the immune response. This would likely activate a wider range of immune cells to produce antibodies, as we see in our data, and may cause the sustained germinal centers we observed.

Pharmacy Times: For pharmacists counseling patients at the vaccine counter today, is there anything in these findings that should change how they talk about the value of getting a flu shot every year, even before mRNA-1010 is available?

Matz: Even before mRNA-1010 is widely available, it is important that patients consider getting a flu shot every year. Even for individuals who feel that they rarely get sick or are relatively healthy, flu shots help reduce the chances of transmitting the virus to vulnerable members of the population, such as the elderly or immunocompromised. This helps cut down on the likelihood that these individuals will end up in the hospital with severe infections. Our study shows that mRNA-1010 generates a broad antibody response,¹ and hopefully this can be utilized to develop even more effective flu vaccines to handle seasons where circulating viral strains become mismatched to vaccine strains.

REFERENCES

1. Matz HC, Yu TG, Dixit K, et al. mRNA-based influenza vaccine expands the B cell response breadth in humans. Nat Immunol  Published online June 15, 2026. doi.org/10.1038/s41590-026-02569-5

2. mRNA flu vaccine offers immune protection against wide array of influenza virus strains. News release. WashU Medicine. June 15, 2026. Accessed July 17, 2026. https://www.eurekalert.org/news-releases/1132061

3. Antrim A. FDA panel unanimously backs Moderna’s breakthrough mRNA flu vaccine amid political turbulence. Pharmacy Times. June 19, 2026. Accessed July 17, 2026. https://www.pharmacytimes.com/view/fda-panel-unanimously-backs-moderna-s-breakthrough-mrna-flu-vaccine-amid-political-turbulence

4. 2024-2025 influenza season summary: severity, disease burden, and burden prevented. CDC. March 12, 2026. Accessed July 17, 2026. https://www.cdc.gov/flu-burden/php/data-vis-vac/2024-2025-prevented.html

5. 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;50:126847. doi:10.1016/j.vaccine.2025.126847