Seasonal influenza mRNA vaccine induces stronger innate and comparable or better adaptive responses than licensed inactivated vaccines.

Seasonal vaccination is the most important strategy for mitigating the large disease burden caused by influenza virus. Licensed inactivated influenza virus vaccines rely on slow, egg-based production, underscoring the need for faster, more effective platforms that elicit robust immune responses. Here, we compare the immunogenicity of an unmodified mRNA-lipid nanoparticle vaccine encoding influenza hemagglutinin (HA) from A/Michigan/45/2015 (H1N1)pdm09, A/Singapore/INFIMH-16-0019/2016 (H3N2), B/Phuket/3073/2013 and B/Colorado/06/2017 with two approved, strain-matched, inactivated vaccines (Vaxigrip and Fluad) in non-human primates. The mRNA vaccine induced substantially stronger innate immune activation than Vaxigrip and Fluad, evidenced by rapid upregulation of genes involved in antiviral, antigen presentation and cell migration pathways, expansion of intermediate monocytes and increased secretion of pro-inflammatory cytokines. The mRNA vaccine elicited HA-specific antibodies against all four strains, with levels generally comparable to or exceeding those induced by Vaxigrip and Fluad, although this did not consistently translate to greater neutralizing capacity. Both the mRNA vaccine and Fluad generated higher frequencies of HA-specific memory B and T cell responses compared to Vaxigrip, with the mRNA vaccine inducing a particularly stronger response in the draining lymph nodes, potentially increasing antibody diversity and affinity. Altogether, these findings support the advancement of influenza mRNA vaccines as promising clinical candidates.