Unmodified quadrivalent influenza mRNA vaccine triggers strong innate immunity in primates, but neutralization varies by strain
Background: Comparing antibody quantity and function
An unmodified quadrivalent influenza mRNA vaccine induced a stronger early innate immune response in rhesus macaques than licensed inactivated vaccines. Antigen-binding antibody responses and memory B-cell responses in the draining lymph nodes, which receive lymph from the vaccination site, were also prominent. However, its ability to neutralize virus did not consistently exceed that of the comparators. Published in NPJ Vaccines, this study assessed preclinical immunogenicity; it should not be interpreted as a clinical trial demonstrating protection against infection in people.
Seasonal influenza vaccines use antigens selected to match expected circulating viruses, but difficulties in predicting strains and the time required for egg-based production can limit responses. The mRNA platform is being studied as an alternative because antigen sequences can be changed readily and it avoids adaptive mutations that arise during egg propagation. This comparison focused on platform differences not only in blood antibodies but also in early immune activation and lymph-node memory cells.
Key findings: Strong early responses, with strain-dependent neutralization
The researchers divided 18 rhesus macaques into groups of six. The candidate vaccine combined four nucleoside-unmodified mRNAs encoding hemagglutinin (HA) from influenza A H1N1 and H3N2 and influenza B Phuket and Colorado strains, packaged in lipid nanoparticles (LNPs). The total mRNA dose was 160 µg. Comparator groups received a full human dose of Vaxigrip or Fluad. Vaxigrip contained the same four strains, whereas Fluad, which contains the MF59 adjuvant, was a trivalent formulation without B/Phuket.
Animals were vaccinated at weeks 0 and 4. Subsequently, four animals per group received booster doses at weeks 35 and 39 and were evaluated through week 41. One day after the first dose, the mRNA group showed stronger changes in gene expression related to antiviral responses, antigen processing and presentation, and cell migration. The mean fold increase in the relative frequency of intermediate monocytes among all monocytes was 10.1-fold in the mRNA group, compared with 1.5-fold in the Vaxigrip group and 2.7-fold in the Fluad group. These figures describe changes in relative frequency, not absolute cell counts.
HA-binding antibody levels induced by the mRNA vaccine were generally similar to or higher than those induced by the comparator vaccines. However, neutralizing antibody titers against H3N2 and B/Colorado were lower than with Fluad, showing that higher levels of binding antibodies alone do not establish functional superiority. The absence of B/Phuket antigen from Fluad must also be considered when comparing responses to that strain.
At week 41, tissue analyses showed that the mRNA group had the strongest HA-specific memory B-cell responses in draining lymph nodes for all four strains. By contrast, between-group differences in tissue memory T cells were not statistically significant, and lymph-node T-cell responses with Fluad were similar to or greater than those with the mRNA vaccine. The memory B-cell and T-cell findings do not support describing the mRNA vaccine as uniformly superior.
Implications and outlook: Dose and reactogenicity are key for human use
These findings reveal differences in tissue immunity that are not apparent from blood antibody titers alone. They do not directly demonstrate greater antibody diversity or improved affinity. The possibility that sustained antigen expression supported the immune response is also an interpretation by the researchers.
Observational measures in the animals, including body temperature, weight, and blood tests, were generally similar to those with the comparator vaccines. However, the authors noted that the high 160 µg dose of unmodified mRNA could cause excessive early immune activation and post-vaccination reactions in people, making tolerability difficult to achieve. No infection challenge study was conducted, so actual protective efficacy remains unknown. Human use will require formulation and dose optimization and further evaluation of protective efficacy and durability of immunity.
Source: NPJ Vaccines article.
Oncology & Infectious Disease Core, Published May 2026. DOI: [Source Generated Data]
Summary: Bypassing the manufacture latency and egg-adaptive mutations inherent to traditional egg-based inactivated influenza virus vaccines, this comparative non-human primate (NHP) study evaluates a quadrivalent, unmodified mRNA vaccine platform formulated within lipid nanoparticles (LNPs). Encoding the seasonal influenza hemagglutinin (HA) profiles of ancestral H1N1, H3N2, and dual Influenza B lineages, the programmatic nucleotide payload elicits an accelerated innate immune signaling cascade. Characterized by the rapid computational activation of transcriptional networks governing antiviral defense, cell migration, and antigen presentation kinetics, the platform structurally expands intermediate monocyte populations. Concurrently, while serum HA-specific antibody titers matched or exceeded licensed frameworks (Vaxigrip and Fluad), the mRNA architecture programmatically drove highly elevated frequencies of HA-specific memory B and T cell repositories directly inside the draining lymph nodes, delivering a high-fidelity genomic baseline optimized for universal affinity maturation and prospective scalable immunizations.
This study illustrates why influenza mRNA vaccine candidates should be assessed by both the amount of antigen-binding antibody and the ability to neutralize virus. Future development could compare neutralization across strains while using memory B-cell responses in draining lymph nodes as a complementary measure. However, the study did not establish that more tissue memory cells predict better protection in people. Differences in the antigen composition and doses of the comparator vaccines also need to be considered when interpreting the results. In particular, the strong innate response to this high-dose, unmodified formulation highlights both a development advantage and a tolerability concern. Selecting a candidate for human use will require assessing the balance between stronger immune responses and post-vaccination reactogenicity.