Sunday, May 11, 2025
5/11/2025
Epitope-Based CSP Vaccines Optimized to Achieve Long-Term Sterile Immunity - Abstract Given the very high burden malaria imposes on many developing countries and the continued need for an effective vaccine, the objective of this proposal is to develop a Plasmodium falciparum (Pf) vaccine by taking advantage of the knowledge gained in the last few years isolating and characterizing protective human monoclonal antibodies specific for major coat protein of the parasite, circumsporozoite (CS) protein. The malaria vaccine candidates currently most advanced in the clinic, RTS,S and R21, target only the major NANP repeat of the PfCS protein plus T cell epitopes in the C-terminal domain. Current limitations of the RTS,S vaccine have been the 30-50% efficacy and transient protection. A further potential complication is pre-existing immunity/tolerance to the HBsAg carrier, which is derived from a human pathogen. To circumvent these problems we have developed a non-human pathogen-derived carrier platform, specifically the core protein from the woodchuck hepadnavirus (WHcAg). Modified WHcAg VLPs are used as the vaccine platform for several reasons: WHc-CS hybrid VLPs elicit extremely high levels of anti-CS protective antibodies; new protective epitopes can be added simply; and since WHc-CS hybrid VLPs can be made in bacteria, the vaccine will have a low cost-of-goods. In preliminary studies we developed a WHc-CS hybrid VLP that contains two neutralizing Pf-CS repeat B cell epitopes and three “universal” malaria-specific T cell domains. This WHc-CS hybrid VLP (designated VLP-162) is very immunogenic in mice and rabbits and elicits neutralizing anti-CS repeat antibodies that prevent P. berghei/Pf hybrid sporozoite liver infection in vivo and produces sterile immunity to blood stage infection in 90-100% of mice. Our approach is to expand the scope and protective efficacy of VLP-162 by adding B cell epitopes defined by the protective human Mabs CIS43, 313/317, L9 and 5D5, plus expand the CS-specific T cell epitopes delivered by the VLP. The strategy for developing an optimal next-generation malaria vaccine is divided into 3 aims: Aim 1) build on VLP-162 by incorporation of the newly defined CS-derived protective B cell epitopes and broadening the number of CS-specific T cell epitopes; Aim 2) optimize immunogenicity by assessing adjuvant formulations in multiple mouse strains; and Aim 3) conduct in vivo protective efficacy tests in Pf mouse challenge models using PbPf hybrid sporozoites that contain the entire Pf CS or engineered Pf CS proteins that allow us to measure the contribution of each epitope to protective efficacy. Combination of these two technologies, the WHcAg platform and the PbPf hybrid sporozoite challenge models, will allow in vivo protective efficacy to be determined in infectious model systems.
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