Intranasal vaccination with multi-neuraminidase and M2e virus-like particle vaccine results in greater mucosal immunity and protection against influenza than intramuscular injection

Intramuscular injection of seasonal influenza vaccines provides strain-specific neutralizing antibodies, but not against variants, and no effective mucosal immunity. Here, we report that multi-subtype neuraminidase (NA) and M2 ectodomain repeat (5xM2e) virus-like particle vaccine (NA-M2e) conferred higher efficacy of broad cross-protection after two doses of intranasal delivery than intramuscular injection. The intranasally vaccinated mice displayed high levels of IgA antibodies, IFN-γ⁺ CD4 and CD8 T cells, germinal center B cells, plasma cells, and early innate immune cells locally in the lungs. In contrast, intramuscular vaccination systemically induced innate and adaptive immune responses in the spleen. Our findings demonstrate that the intranasal delivery of NA-M2e vaccine induces enhanced mucosal immunity and comparable serum IgG antibodies, offering improved efficacy of cross-protection against diverse influenza virus strains compared to the intramuscular injection in a mouse model.