Non-neutralizing immune-mediated cross-protection against influenza viruses by chimeric M2e-H3 stalk protein or multi-subtype neuraminidase plus M2e virus-like particle vaccine in ferrets

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Abstract Current influenza vaccine based on hemagglutinin (HA) immunity is not effective in providing cross protection against circulating variants and new pandemic viruses. In prior studies, we developed universal influenza vaccine candidates of multi-subtype neuraminidase and M2 ectodomain virus-like particles (m-cNA-M2e VLP) and chimeric M2e-H3 stalk protein vaccine (M2e-H3stalk), which were effective in inducing cross-protective immunity in mice. Here, we evaluated the immunogenicity and efficacy of these recombinant universal influenza vaccines in ferrets. Our results showed that immunization of ferrets with recombinant universal vaccines induced high levels of IgG antibody responses (M2e, H3stalk, multi-subtype NA), NA inhibition (NAI), antibody-secreting plasma cells in spleens, and IFN-γ secreting blood mononucleate cells. Ferrets with either m-cNA-M2e VLP or M2e-H3stalk vaccine were moderately protected from H1N1 and H3N2 influenza viruses as evidenced by lower viral titers in nasal washes, trachea and lung after challenge. Tests of passive immunity of vaccinated ferret antisera indicate that multi-NA plus M2e vaccine conferred more effective and broader humoral immunity in naïve mice than M2e-H3stalk vaccine. Our findings support that immunity to M2e, HA-stalk, and multi subtypes NA will induce broader cross protection in ferrets, which is likely translational to humans.

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