The major challenges facing Pvs230D1-based TBV development are the following: 1) cGMP manufacturing of a Pvs230D1-EPA conjugated nanoparticle, 2) preparation and successful filing of an Investigational New Drug application with the FDA, and 3) demonstrating in a first-in-human study that Pvs230D1 is a suitable antigenic target to generate transmission-blocking antibodies, using a safe formulation that induces sustained high antibody responses. To date, LMIV has developed scalable bench-scale processes (fermentation and purification) for producing a Pichia pastoris expressed Pvs230D1 protein that shows the quality and quantity attributes required for human clinical studies. The purified recombinant Pvs230D1 induced antibodies (i.e., IgG) in rabbits that reduced parasite transmission to mosquitoes by greater than 80% in mosquito membrane feeding assays. These assays were conducted in Rockville MD using P. vivax infected primates as a source of P. vivax gametocytes, and in Thailand using infected humans as a source of P. vivax gametocytes. Furthermore, Pvs230D1 has been chemically conjugated to EPA and the conjugated nanoparticle has enhanced immunogenicity compared to the monomer in mice. The antibodies raised against the conjugate reduced transmission of P. vivax to mosquitoes in the ex vivo membrane feeding assay. Due to the importance of strong durable antibody titers, adjuvant selection will be important. LMIV is collaborating with multiple adjuvant partners to assess the best and most appropriate adjuvant for clinical studies.
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