LAIV Inducing Cross Protection

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 DESCRIPTION (provided by applicant): Live attenuated influenza vaccine (LAIV) is a safe and effective platform for human use, and shown to have higher efficacy in children than inactivated vaccine. Nonetheless, current influenza vaccines including LAIV do not provide cross-protection against antigenically distinct epidemic strains or the unanticipated emergence of new pandemic strains. It is of a high priority to improve the breadth of cross protective efficacy of strain-specific vaccines based on hemagglutinin (HA) immunity. Our preliminary studies demonstrated that immune responses to highly conserved influenza M2 protein (M2e) provided a broader range of cross-protection (H1, H3, and H5 subtypes). In addition, we recently generated novel influenza mutants that express a chimeric conserved M2e-HA, which showed attenuated phenotypes as well as provided significantly broad and enhanced cross-protection. These findings strongly suggest that it should be possible to produce highly cross protective and safe LAIV. Thus, it is highly expected that incorporating conserved-protective M2e into HA will overcome the strain-specific protection of HA as well as poor immunogenicity of M2. The central hypothesis is that recombinant LAIV containing M2e-HA will be safer and more effective in inducing a broader range of cross-protection. The first goal (aim 1) is to generate recombinant LAIV containing M2e-HA and to determine the safety and cross-protective efficacy of recombinant LAIV. The aim 2 will test recombinant LAIV-M2e vaccines in ferrets, which is a more relevant animal model for testing influenza vaccines.