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. In FY17, LMIV developed scalable bench-scale processes (fermentation and purification) for producing a P. pastoris expressed Pvs230D1 protein that showed 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 human volunteers as a source of P. vivax gametocytes. In FY18, the rabbit Pvs230D1 specific IgG was shown to reduce transmission of P. vivax to mosquitoes using the membrane feeding assay that used parasites from patient volunteers in Colombia, South America. Using our chemical conjugation platform, Pvs230D1 was chemically conjugated to EPA and the conjugated nanoparticle 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. In FY18, a campaign was initiated for the cGMP manufacturing of a Pvs230D1-EPA chemically conjugated vaccine for phase 1 human trials. The technical transfer process has proceeded according to project timelines. Due to the importance of strong durable antibody titers, adjuvant selection will be important. In FY18, LMIV in collaboration with other adjuvant partners is assessing the best and most appropriate adjuvant for clinical studies and it is anticipated that an IND will be filed in 2020 or 2021.
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| Scaria, Puthupparampil V; Chen, Beth; Rowe, Christopher G et al. (2017) Protein-protein conjugate nanoparticles for malaria antigen delivery and enhanced immunogenicity. PLoS One 12:e0190312 |
| Coulibaly, Mamadou B; Gabriel, Erin E; Sinaba, Youssouf et al. (2017) Optimizing Direct Membrane and Direct Skin Feeding Assays for Plasmodium falciparum Transmission-Blocking Vaccine Trials in Bancoumana, Mali. Am J Trop Med Hyg : |
