Development of broadly-protective vaccines for influenza B viruses

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PROJECT SUMMARY Influenza B viruses (IBV) cause annual epidemics with appreciable morbidity and mortality, but have been understudied compared to influenza A viruses (IAV). Currently available vaccines for IBV and IAV are sub- optimal and must be updated frequently due to the emergence of novel antigenic variants. To date, efforts to develop broadly protective, potentially ‘universal’ vaccines have almost exclusively focused on IAV. RFA-AI-20- 003 therefore calls for the “development and/or characterization of IBV vaccine components that complement existing lead IAV vaccine candidates”. In Aim 1 (R21 phase), we plan to develop broadly reactive influenza B candidate vaccine viruses. Using mutagenesis approaches, we have already generated mutant IBV hemagglutinins (HA, the major viral antigen) whose antigenic properties are in-between those of the two major lineages of IBV. Thus, these antigens may elicit immune responses that confer protection against viruses of both IBV lineages. Here, we plan to develop additional IBV HA mutants with potentially higher cross-reactivity than that of our current candidates. In addition, we will establish an antigenic map for IBV HA to analyze the antigenic properties of IBV HAs (antigenic maps are now widely used for IAV HAs, but have not been developed for IBV HA). In Aim 2 (R33 phase), we will assess the immunogenicity of influenza B candidate vaccine viruses. Briefly, the top 5 candidates from Aim 1 will be used to immunize ferrets. Immunization will be carried out with adjuvanted, secreted IBV HA (sHA) mutants (thus eliminating the contribution of other IBV proteins to immune responses), or with adjuvanted IBV HA presented on nanoparticles composed of a self-assembling phage protein (generated by Dr. R. Kane, Georgia Tech). The sera from vaccinated ferrets will be tested for reactivity with IBV HA antigens, and these data will be integrated into the antigenic map. Using an established phage display approach, Dr. S. Khurana (Federal Drug Administration) will identify the epitopes targeted by the antibodies elicited by our HA mutants. This analysis will allow us to identify antigens that elicit broadly reactive antibodies that target conserved epitopes. Immunology studies will be carried out by Dr. P. Thomas, St. Jude Children’s Research Hospital. On the basis of the data obtained in Aim 2, the top 2 IBV HA immunogens will be used to assess the protective efficacy of influenza B candidate vaccine viruses (Aim 3, R33 phase). Ferrets will be immunized as established in Aim 2 and challenged with IBVs representing both current lineages and an ancestral virus (isolated before the separation of the lineages). Virus titers and immune responses will be compared with those of control animals. We expect that a single immunization with the IBV HA mutants will elicit more broadly protective immunity than a single immunization with wild-type IBV HA. In summary, upon completion of both phases, we expect to have developed a novel strategy for the design of broadly protective IBV vaccines, and to have demonstrated their broadly protective efficacy in ferrets.