In-Vitro Culture of Plasmodium falciparum Sporozoites for Malaria Vaccine

用于疟疾疫苗的恶性疟原虫子孢子的体外培养

• 批准号: 10011199
• 负责人: STEPHEN Lev HOFFMAN
• 金额: $ 100万
• 依托单位: SANARIA, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011199
• 关键词: Achievement; Africa; Africa South of the Sahara; African; Antibodies; Aotus primate; Area; Attenuated; Authorization documentation; Biological Assay; Biology; Bioreactors; Carrier Proteins; Cell Line; Cells; Cessation of life; Chemoprophylaxis; Child; Clinical; Clinical Trials; Country; Cryopreservation; Culicidae; Cyclic GMP; Data; Development; Dose; Drops; Erythrocytes; Europe; European; Extracellular Matrix; Falciparum Malaria; Female of child bearing age; Fiber; Generations; Geography; Germany; Goals; Health Benefit; Hepatocyte; Human; Human Resources; Immunization; Immunize; In Vitro; Insecta; Investments; Legal patent; Licensure; Liver; Malaria; Malaria Vaccines; Mali; Marketing; Medicine; Methodology; Methods; Monkeys; Morbidity - disease rate; Mus; Parasites; Phase; Phase III Clinical Trials; Plasmodium falciparum; Pregnancy Complications; Process; Production; Public Health; Quality Control; Radiation; Recording of previous events; Residual state; Rest; Risk; Salivary Glands; Series; Serum; Site; Small Business Innovation Research Grant; Sporozoite vaccine; Sporozoites; T cell response; Tanzania; Technology; Testing; Time; Vaccines; Vial device; Work; base; cGMP production; cell bank; cell motility; cost; cost effective; genetically modified cells; immunogenicity; improved; in vitro Assay; in vivo; innovation; lead candidate; lipid transport; manufacturing process; manufacturing scale-up; mortality; next generation; nonhuman primate; prevent; protective efficacy; scale up; success; vaccine efficacy

Abstract 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.

摘要