The WHO estimates that in 2017, malaria caused 219M clinical episodes and 435,000 deaths worldwide. 2017 was the 3rd consecutive year in which there was no decrease, instead an increase in malaria morbidity and mortality worldwide. A vaccine would the most efficient, cost-effective way to control malaria, yet despite billions of dollars of investment, there is no malaria vaccine with market authorization (licensure) by any regulatory body in the world. Sanaria?s platform technology, aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (SPZ), has enabled the development of the world?s most protective malaria vaccines. These PfSPZ-based vaccines have been assessed in 9 countries, 6 in Africa. PfSPZ Vaccine (radiation-attenuated) is extremely safe and well-tolerated and has induced >90% vaccine efficacy (VE) against homologous (same strains of Pf in vaccine and challenge) controlled human malaria (CHMI) at 3-11 weeks after immunization in the US, Germany, Mali and Tanzania; 80% and 54% VE against heterologous (different strains of Pf in vaccine and challenge) CHMI at 2.5 and 8 months; and ~50% VE for 6 months against intense naturally transmitted Pf malaria in 3 field trials in Africa. It is now advancing to Phase 3 clinical trials and licensure. Sanaria?s second generation vaccine, PfSPZ-CVac (chemo-attenuated) is more protective than PfSPZ Vaccine, and genetically-attenuated PfSPZ will follow. Long-term success will require improved products and more efficient, less costly manufacturing to decrease cost-of-goods (COGs). This Phase II SBIR competitive renewal supports the latter by eliminating aseptic mosquitoes from the manufacturing process through in vitro production of PfSPZ (iPfSPZ). In and subsequent to our successful Phase II SBIR, we 1) introduced a hollow fiber bioreactor (HFB) for producing iPfSPZ at scale, producing ?billions? of motile, PfSPZ- expressing PfCSP, with a conversion from gametocytes to Pf sporozoites ~30-times higher in vitro compared to in mosquitoes. GMP compliant materials were used throughout and we partially purified iPfSPZ; 2) demonstrated that the iPfSPZ were infectious to hepatocytes in vitro and to mice with human livers and human erythrocytes in vivo (a first in the history of malaria biology), and that despite being able to fully develop in human livers to infect human erythrocytes, the iPfSPZ may be intrinsically, partially attenuated at the late liver stage. In this Phase II project, we will demonstrate immunogenicity and protective efficacy of iPfSPZ in Aotus monkeys; further refine, optimize, and scale-up production and purification of potent iPfSPZ; optimize the cryopreservation process of iPfSPZs; develop, establish and conduct a quality control (QC) purity assay for product release; and manufacture a lot of aseptic, purified, cryopreserved iPfSPZ that meets QC release assay specifications for use in IND-directed studies. Switching to in vitro production of iPfSPZ, thereby eliminating mosquitoes from PfSPZ manufacture, will reduce COGs by a conservatively estimated 80%, and be an enabling technology for production of PfSPZ vaccines to meet the demands of Africa and the rest of the world.

Public Health Relevance

A highly effective malaria vaccine would have an enormous public health benefit. Sanaria?s attenuated malaria sporozoite (PfSPZ Vaccine) and PfSPZ-CVac (Chemoprophylaxis Vaccine)) vaccines have been highly safe, well tolerated, and efficacious in a series of clinical trials. Currently, PfSPZ vaccines are manufactured using aseptic mosquitoes. This project aims to scale up manufacturing and release of PfSPZ produced in vitro, demonstrating the infectiousness and protective efficacy in comparison to PfSPZ produced in mosquitoes. By eliminating the need for mosquitoes at any stage in the manufacturing process, the cost of goods can be reduced conservatively by 80%.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1)
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MO, Annie X Y
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Sanaria, Inc.
United States
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