A Unique Automated Bioreactor for Rearing Aseptic Mosquitoes from Larvae to Adults to Support Manufacture of Sanaria PfSPZ Products

独特的自动化生物反应器，用于培养从幼虫到成虫的无菌蚊子，以支持 Sanaria PfSPZ 产品的生产

• 批准号: 10155927
• 负责人: Peter F. Billingsley
• 金额: $ 100万
• 依托单位: SANARIA, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-18 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155927
• 关键词: Adult; Africa; African; Air; Anopheles Genus; Behavior; Biology; Bioreactors; Burkina Faso; Cessation of life; Chemoprophylaxis; Child; Clinical Trials; Country; Cryopreservation; Culicidae; Cyclic GMP; Disease; Dissection; Elements; Engineering; Equipment; European; Falciparum Malaria; Female; Frequencies; Geographic Locations; Germany; Goals; Growth; Hand; Harvest; Human; Immunity; Individual; Infection prevention; Institutes; Larva; Left; Licensure; Light; Maintenance; Malaria; Malaria Vaccines; Mali; Manuals; Methods; Modification; Movement; Parasites; Phase; Plasmodium falciparum; Plasmodium falciparum vaccine; Population; Positioning Attribute; Price; Process; Production; Property; Pupa; Risk; Running; Sea; Site; Small Business Innovation Research Grant; Sporozoite vaccine; Sporozoites; System; Tanzania; Testing; Vaccines; Vial device; World Health Organization; base; commercialization; cost; density; design; egg; emerging adult; feeding; flasks; human old age (65+); improved; irradiation; malaria infection; manufacturing process; meetings; next generation; novel; operation; phase 1 study; prototype; scale up; success; tool; transmission process

PROJECT ABSTRACT: According to the World Health Organization, the 228 million cases of malaria in 2018 were an increase of ~16 million cases over 2015 while the number of deaths was 405,000, not substantially less than in 2015. 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 for at least 18 months against intense, heterogeneous transmission of Pf in clinical trials in Burkina Faso, and have been assessed in clinical trials in 6 African and 2 European countries, and 5 sites in the US in 5 month to 65 year olds. Sanaria has moved to Phase 3 GMP compliant manufacturing, and is moving toward licensure and commercialization of Sanaria® PfSPZ Vaccine. To manufacture enough PfSPZ Vaccine to meet the needs of the extensive world markets, particularly those in Africa, at affordable prices, the scale of manufacturing must be greatly increased and cost of goods (COGs) reduced. Sanaria’s PfSPZ-based vaccines contain aseptic, purified, cryopreserved, live PfSPZ that are manufactured in aseptically reared Anopheles stephensi mosquitoes. The current method of infected, aseptic, mosquito production relies heavily upon human power and large quantities of expensive consumables, and requires significant space. The overarching aim of this application is to design, build, test and refine a semi- automated mosquito bioreactor, which will enable hands-free harvesting of aseptic, PfSPZ-infected, adult A. stephensi and transfer of PfSPZ-infected mosquitoes to an Infected Mosquito Transfer Container (IMTC) ready for irradiation and dissection, significantly reducing upstream manufacturing costs of PfSPZ products. During this Phase II SBIR we will finalize a system for semi-automated, closed-system production of aseptic mosquitoes from eggs through to infected adults ready for irradiation. The specific aims are: 1) Redesign the larval bioreactor for hands-free, aseptic culturing from eggs to larvae to adult mosquitoes; 2) Redesign adult mosquito container part 1: direct transfer of adults from the larval bioreactor; 3) Redesign adult mosquito container part 2: semi-automated transfer of infected mosquitoes to the Infected Mosquito Transfer Container; 4) Redesign the Infected Mosquito Transfer Container for hands free transfer and re-use; and 5) Integrate all steps and demonstrate their utility for manufacturing in an engineering run of PfSPZ Challenge. Developing this bioreactor will lead to a sea change in Sanaria’s capacity to manufacture its PfSPZ products, putting Sanaria on track for robust, mass-scale manufacturing at phase 3 GMP compliance at a significantly reduced cost.

项目摘要： 据世界卫生组织称，2018 年疟疾病例为 2.28 亿例，同比增加约 16 例。 2015年确诊病例数为40.5万例，死亡人数为40.5万人，与2015年相比没有大幅减少。 世界需要一种疟疾疫苗，Sanaria 的恶性疟原虫子孢子 (PfSPZ) 疫苗可以提供保护。 在美国、德国、美国的五项临床试验中，受试者 100% 抵抗受控人类疟疾感染 (CHMI) 坦桑尼亚和马里；保护成年人至少 18 个月免受 Pf 的强烈、异质传播 在布基纳法索进行临床试验，并在 6 个非洲和 2 个欧洲的临床试验中进行了评估 国家和美国的 5 个工厂在 5 个月内已进入 65 岁人群的 GMP 合规阶段 3。 制造，并正在迈向 Sanaria® PfSPZ 疫苗的许可和商业化。 生产足够的 PfSPZ 疫苗以满足广泛的世界市场的需求，特别是 非洲，以可承受的价格，必须大幅提高制造规模和商品成本（COGs） Sanaria 的基于 PfSPZ 的疫苗含有无菌、纯化、冷冻保存的活 PfSPZ。 在无菌饲养的史氏按蚊中制造的，目前的感染方法，无菌， 蚊子的生产严重依赖人力和大量昂贵的消耗品， 该应用程序的总体目标是设计、构建、测试和改进半成品。 自动化蚊子生物反应器，将能够实现无菌、感染 PfSPZ 的成年蚊子的免提收获。 stephensi 并将受 PfSPZ 感染的蚊子转移到准备好的受感染蚊子转移容器 (IMTC) 用于辐照和解剖，显着降低 PfSPZ 产品的上游制造成本。 在第二阶段 SBIR 中，我们将最终确定一个用于无菌的半自动化、封闭系统生产的系统 蚊子从卵到受感染的成虫，准备接受照射。具体目标是： 1) 重新设计蚊子。 幼虫生物反应器，用于免手动、无菌培养从卵到幼虫再到成蚊 2) 重新设计成蚊； 蚊子容器第 1 部分：直接从幼虫生物反应器转移成蚊 3) 重新设计成蚊； 容器第 2 部分：将受感染的蚊子半自动转移到受感染的蚊子转移容器； 4) 重新设计受感染的蚊子转移容器，以便免提转移和重复使用；5) 整合所有内容； 步骤并在 PfSPZ 开发挑战赛的工程运行中展示其在制造中的实用性。 该生物反应器将导致 Sanaria 生产 PfSPZ 产品的能力发生翻天覆地的变化， Sanaria 有望在 GMP 合规性第 3 阶段实现稳健、大规模生产，并大幅降低成本 成本。