The annual estimated burden of malaria has increased to 216M clinical episodes and 445,000 deaths, and annual losses of >$12B of GDP to malaria in Africa alone. The world needs a malaria vaccine. Sanaria's Plasmodium falciparum sporozoite (PfSPZ) vaccines have protected 100% of subjects against controlled human malaria infection (CHMI) in five clinical trials in the U.S., Germany, Tanzania, and Mali; protected adults at least for 6 months against intense, heterogeneous transmission of Pf in two clinical trials in Mali, and are now being assessed in clinical trials in 5 months to 65-year old's in 5 African countries and in adults in 2 European countries as well as 3 sites in the US. The plan is to initiate the first Phase 3 clinical trials to support submission of a Biologics License Application to the FDA in the US in the second half of 2018, and in Africa in the first half of 2019. Sanaria's PfSPZ-based vaccines contain aseptic, purified, cryopreserved, live Plasmodium falciparum (Pf) sporozoites (SPZ) that are manufactured in aseptically reared Anopheles stephensi mosquitoes. The current method of aseptic mosquito production, while robust and reproducible, relies heavily upon manpower and large quantities of expensive consumables, and requires significant space. Semi-automation of mosquito dissection to remove salivary glands developed under another SBIR grant is expected to increase the efficiency of the process to 750-1,000 mosquitoes per hour per operator in the first half of 2018. Thus, production of mosquitoes is now the bottleneck and most expensive step in the GMP manufacture of PfSPZ vaccines. The overarching aim of this project is therefore to develop methods to reduce manpower and consumable costs and overall space requirements by developing a semi- automated system for culturing (manufacturing) aseptic mosquitoes. In specific aim 1, we will design, build and test a bioreactor for hands-free, aseptic culturing from eggs to larvae to adult mosquitoes. This bioreactor will be developed to 1) meet all GMP requirements, 2) remove the need for expensive consumables to increase output, 3) reduce human costs, 4) eliminate the need for many of the biological safety cabinets used in mosquito production, and 5) be adaptable for eventual removal of incubators from mosquito production. We will demonstrate that the new bioreactor is capable of maintaining the critical aseptic environment for the larval cultures, and that the mosquitoes raised in the larval bioreactor show equivalence with those produced by current methods. In specific aim 2 we will develop apparatus for automated harvesting of adult mosquitoes. Our aim is to be able to transfer newly emerged adult mosquitoes directly and hands free from the larval bioreactors into big aseptic mosquito containers in which the mosquitoes will be fed upon gametocytes and maintained until the day of extraction of PfSPZ from mosquitoes. Developing the larval bioreactor will lead to a sea change in Sanaria's capacity to manufacture its PfSPZ products, putting Sanaria on track for mass-scale manufacturing at phase 3 GMP compliance at a significantly reduced cost.
Public Health Relevance Statement: Project narrative: Malaria afflicts over two billion people, killing over 600,000 individuals each year mostly children in Africa. A powerful tool is needed for eliminating Plasmodium falciparum malaria from defined geographical areas. The ideal tool would be a highly effective, long-acting vaccine that prevents infection, disease and parasite transmission. Both Plasmodium falciparum (Pf) sporozoite (SPZ) Vaccine (PfSPZ Vaccine) and PfSPZ chemoprophylaxis vaccine (PfSPZ-CVac) provide durable 100% protective immunity against controlled human malaria infection (CHMI). As manufacture of PfSPZ Vaccine moves into phase 3 and launch, the manufacturing must be scaled up. Both PfSPZ Vaccine and PfSPZ-CVac are manufactured in aseptically reared mosquitoes. This proposal aims to develop a unique bioreactor system that will support the aseptic rearing of mosquitoes in a hands-free, semi-automated unit. Success in this project will allow massive scale up of mosquito production in support of the manufacture of PfSPZ vaccines, and simultaneously greatly reduce cost of goods.
Project Terms: Adult; adulthood; Adult Human; 21+ years old; Africa; Air; Anopheles Genus; Anopheles; Automation; Biological Assay; Biologic Assays; Bioassay; Assay; Child; youngster; childrens'; children; Children (0-21); Child Youth; 0-11 years old; Clinical Trials; Cessation of life; Death; Disease; Disorder; Dissection; Ebola virus; ebolavirus; Ebola; EBOV; Environment; Epidemic; Geographic Locations; geographic site; Geographical Location; Geographic Region; Geographic Area; Germany; Grant; Growth; ontogeny; Tissue Growth; Generalized Growth; Cyclic GMP; cGMP; Guanosine Cyclic Monophosphate; Hand; Heating; Human; Modern Man; Immunity; Incubators; Infection; Institutes; Larva; Licensure; Malaria; Plasmodium Infections; Paludism; Falciparum Malaria; Plasmodium falciparum Malaria; Mali; Manuals; Methods; Culicidae; Mosquitoes; Parasites; Plasmodium falciparum; P.falciparum; P. falciparum; P falciparum; Production; Pupa; Risk; Safety; Salivary Glands; Salivary Glands Head and Neck; seal; Sea; Tanzania; Testing; Vaccines; Waste Products; Price; pricing; Custom; Tube; base; improved; Site; Clinical; Phase; Biological; Medical; Malarial Vaccines; Malaria Vaccines; Ensure; Individual; African; European; Licensing; phase III protocol; phase 3 trial; Phase 3 Clinical Trials; Phase III Clinical Trials; Attenuated; Shapes; tool; Bioreactors; Hour; Stream; System; Country; Infection prevention; Prevent infection; Sporozoites; human old age (65+); aged â¥65; aged 65 and greater; age 65 and older; age 65 and greater; Aged 65 and Over; 65+ years old; success; Nutrient; Prevention; Human Resources; personnel; Manpower; Reporting; Excision; resection; Surgical Removal; Removal; Extirpation; Abscission; Radiation; flasks; Mass Vaccinations; fitness; Harvest; Reproducibility; Small Business Innovation Research; SBIR; Small Business Innovation Research Grant; Transmission; transmission process; Characteristics; Process; Output; cost; designing; design; PfSPZ Vaccine; Plasmodium falciparum vaccine; Sporozoite vaccine; manufacturing process; scale up; egg; Chemoprophylaxis; commercialization; protective efficacy; malaria-infected; malaria infection
