Manufacture of Aseptic, Purified, Cryopreserved PvSPZ Challenge for Controlled Human Malaria Infection (CHMI)
Abstract
Malaria caused by Plasmodium vivax (Pv) parasites is ranked second with respect to the incidence and severity of disease while Plasmodium falciparum (Pf) malaria is ranked first. However, unlike Pf, chemo-prophylactic measures against Pv do not prevent relapses, unique to Pv, that occur due to re-activation of persistent liver-stage sleeping forms of the parasites called hypnozoites. Primaquine is the only licensed drug that targets Pv hypnozoites, but it causes life-threatening acute hemolytic anemia in patients with G6PD deficiency, the most prevalent human genetic disorder, affecting 8% of people in malaria-endemic nations. Efforts to develop better drugs or produce a much needed vaccine are further hampered by the inability to propagate blood stages of Pv parasites in vitro, unlike Pf. Therefore, generating infected mosquitoes for controlled human malaria infection (CHMI) as a means to assess anti-Pv drugs and vaccines is entirely reliant on feeding of mosquitoes on fresh, Pv-infected blood from patients with Pv malaria. Together, these bottlenecks make the task of developing and testing robust interventions against Pv malaria more challenging compared to Pf. At Sanaria, we have applied the unique technology initially developed for manufacturing Pf sporozoites (SPZ)-based infectious and attenuated products towards vialing purified, cryopreserved PvSPZ. We have overcome the limitation of in vitro Pv blood stage cultures by using Saimiri boliviensis non-human primates (NHPs) or squirrel monkeys that are the most efficient available non-human hosts for Pv parasites to grow gametocytes in vivo. By feeding mosquitoes with Pv-infected blood from these NHPs, we have now produced non-aseptic and aseptic purified cryopreserved PvSPZ in vials. We have proven that these PvSPZ can infect liver hepatocyte cultures in vitro, they exhibit drug susceptibilities similar to what is observed in humans, and can infect S. boliviensis NHPs in vivo. Our immediate goal is to produce infectious PvSPZ that meet regulatory standards and can be used to infect humans, similar to Sanaria s PfSPZ Challenge. PfSPZ Challenge has enabled the successful infection of volunteers by intradermal, intramuscular, and intravenous injection in three countries in Africa and two countries in Europe that had never conducted CHMI before. In order to make manufacturing PvSPZ compliant with current Good Manufacturing Practices, we propose using specific pathogen-free (SPF) S. boliviensis that will be bred and reared at the only source in the US (MD Anderson Primate Center in Texas) for captive-bred squirrel monkeys. In addition, we will use extensively characterized and highly pedigreed Pv-infected blood drawn from humans or clonal Pv lines as the starting seed material to infect S. boliviensis. The product of this exercise will be called Sanaria® PvSPZ Challenge, and similar to PfSPZ Challenge will provide the larger malaria community with a tool to assess the efficacy of drugs and vaccines against Pv malaria with a safer quality-controlled reagent that exhibits minimal variability in potency between different lots, is logistically more feasible to administer, and is not subject to geographical limitations for application, compared to traditional CHMI using mosquito bites. Most importantly, it will form the basis of a powerful vaccine approach to preventing Pv malaria when administered with anti-malarial chemoprophylaxis, the PvSPZ chemoprophylaxis vaccine (PvSPZ-CVac). In a groundbreaking clinical trial in Tübingen, Germany, the corresponding Pf vaccine, PfSPZ-CVac, comprised of infectious PfSPZ administered with the anti-malarial drug chloroqine, protected 100% (9/9) volunteers who underwent CHMI 9 weeks after the last dose of vaccine. PfSPZ-CVac will soon be evaluated again in clinical trials in Germany, and also in Ghana, and two sites in the United States. A major advantage of this method of vaccination over irradiated SPZ is that the CVac app
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610383
Entities
People
- Stephen L. Hoffman
Organizations
- Sanaria
- United States Army