Cure Lab has discovered a novel approach to vaccine design that provides broad spectrum immunity against influenza infection, influenza regularly affects the world population and imposes a considerable health care and economic burden. Annually, 5-15% of the world's population contracts influenza, resulting in 3-5 million cases of severe illness, and an estimated 250,000 to 500,000 deaths from influenza-associated complications. The purpose of this grant is to develop and bring to market a new generation influenza vaccine. In this phase I grant, we will establish proof of principle for our approach in an animal model and develop a product prototype. We will modify conserved internal NP and M1 proteins of influenza virus in such a way that they will generate enhanced T-cell response upon immunization. This will be accomplished by changing the conformation of said proteins in such a way that the ubiquitin-proteasome system degrades them more efficiently and thus produces more MHC class l-presented peptides, inducing a more effective and long-term T-cell response. First, we will construct both a plasmid and a recombinant vaccinia virus expressing a modified NP gene of influenza A and test protective efficacy and immunogenicity in the mouse model. Second, we will test proteasome-dependent degradation of additional conserved internal proteins of influenza viruses A and B, modify identified target proteins according to Cure Lab algorithm and analyze their intracellular degradation, thus preparing them for use as a part of our vaccine regimen. Third, we will construct multiple vaccine vectors expressing destabilized conserved influenza proteins and test their immunogenicity and protective efficacy in vivo, establishing along the way the immune correlates of protection, as well as the best immunization routes and schedules. The overall aim of this project is to demonstrate better protective effect or/and enhanced immune response using modified influenza proteins as immunogens compared to wild-type viral proteins.
