Abstract
Current influenza vaccine is not effective in providing cross-protection against variants. We evaluated the immunogenicity and efficacy of multi-subtype neuraminidase (NA) and M2 ectodomain virus-like particle (m-cNA-M2e VLP) and chimeric M2e-H3 stalk protein vaccines (M2e-H3 stalk) in ferrets. Our results showed that ferrets with recombinant m-cNA-M2e VLP or M2e-H3 stalk vaccination induced multi-vaccine antigen specific IgG antibodies (M2e, H3 stalk, NA), NA inhibition, antibody-secreting cells, and IFN-γ secreting cell responses. Ferrets immunized with either m-cNA-M2e VLP or M2e-H3 stalk vaccine were protected from H1N1 and H3N2 influenza viruses by lowering viral titers in nasal washes, trachea, and lungs after challenge. Vaccinated ferret antisera conferred broad humoral immunity in naïve mice. Our findings provide evidence that immunity to M2e and HA-stalk or M2e plus multi-subtype NA proteins induces cross-protection in ferrets.