This program project is designed to explore novel approaches for producing safe, effective and economical vaccines against Rift Valley Fever virus (RVFV), and ultimately to produce an effective vaccine in large scale. The approach will emphasize the incorporation of RVFV glycoproteins into virus-like particles (VLPs) which should be well-suited for eliciting protective neutralizing antibody responses by systemic or mucosal immunization. Project 1 will design modified RVFV membrane glycoproteins for targeting to the plasma membrane; produce VLPs containing appropriate viral core proteins and RVFV glycoproteins; improve immunogenicity of RVFV VLP immunogens by incorporation of ligands designed to target the VLPs to antigen-presenting cells; and enhance mucosal immune responses elicited by chimeric VLPs by incorporating viral glycoproteins that exhibit high affinity to mucosal surfaces. Project 2 will evaluate immunogenicity of VLP antigens in a mouse model; develop and evaluate, in collaboration with investigators in Projects 1, and 3, potential mucosal adjuvants without any obvious toxicity; and evaluate the protective efficacy of the alternative VLPs designed in Project 1 and the preclinical VLP vaccine lots prepared by Novavax (Project 3) in a mouse model. Project 3 will optimize methods for scaleable upstream production of RVFV VLPs using vaccinia virus and baculovirus expression systems; develop robust downstream production methods for purification of RVFV VLP vaccines; develop standardized assays for RVFV VLP characterization; and manufacture bulk and final container lots of RVFV VLP vaccines for pre-clinical studies. Core A will serve as a coordinating unit for all projects.
