Influenza is responsible for significant morbidity and mortality worldwide every year and causes severe pandemics when new strains evolve that have not previously circulated in humans. The high viral mutation rate necessitates that new vaccines be generated based on the prevalence of circulating strains every year. These reformulated versions of influenza vaccines are not always protective; vaccine effectiveness (VE) has varied from 10 to 60% over the past 10 years based on how well vaccine strains are matched with circulating strains. There is an urgent unmet need for influenza vaccines that induce greater cross-protective immunity. We propose to harness the immunogenic potential of broadly reactive influenza-specific T cell epitopes to produce vaccines with universal significance. Our previous R21 funded work has provided proof-of-principle that advanced immunoinformatic tools can be used to efficiently identify highly conserved influenza A epitopes, including promiscuous CD4+ T cell epitopes and HLA-A2-restricted CD8+ T cell epitopes, that are immunogenic and can induce protective immunity. Furthermore, we have convincingly demonstrated that T cell-based vaccines designed to stimulate human T cell responses can induce heterotypic protective immunity. We now propose to extend our R21 studies to more fully evaluate promiscuous CD4+ T cell epitopes to confirm that these epitopes can elicit potent CD4+ T cell responses in >95% of all humans expressing diverse HLA class II alleles. We also will identify relevant CD8+ T cell epitopes restricted by additional non-HLA-A2 class I supertypes, to obtain sufficient epitopes for broad population coverage (>95% of humans). We then will develop and compare immunogenicity and protective efficacy of multi-epitope vaccines using several state-of-the art vaccine delivery platforms including: recombinant ?naked? DNA, purified proteins mixed with novel adjuvants, novel adenovirus (Ad) vaccines designed to evade preexisting human Ad immunity, and virus-like particle (VLP) encapsidated RNA vaccines. Vaccines will be tested in vitro using human PBMC and in vivo using humanized mice expressing transgenic HLA. Heterotypic efficacy will be evaluated upon challenge with 3 distinct influenza A strains (H1N1, H3N2, and H5N1). The proposed work can provide transformational new products and direction for influenza vaccine development, focusing on a paradigm-shifting concept of inducing broadly protective T cell responses.
We will identify and evaluate vaccine targets relevant for human infection with highly diverse strains of influenza A virus which cause seasonal epidemics or more serious pandemics. We will prepare several novel vaccines focused on inducing relevant immune cell types, and test these vaccines in humanized mice with the ultimate goal of developing a ?universally relevant? influenza vaccine.