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: 10597642
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597642
• 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; Larva; Left; Licensure; Maintenance; Malaria; Malaria Vaccines; Mali; Manuals; Marketing; Methods; Modification; Movement; Parasites; Persons; Phase; Plasmodium falciparum; Plasmodium falciparum vaccine; Population; Positioning Attribute; Price; Process; Production; Property; Pupa; Risk; Running; Sea; Site; Small Business Innovation Research Grant; Specific qualifier value; Sporozoite vaccine; Sporozoites; System; Tanzania; Vaccines; Vial device; World Health Organization; commercialization; cost; density; design; design,build,test; egg; emerging adult; feeding; flasks; hatching; human old age (65+); improved; irradiation; light transmission; malaria infection; manufacture; manufacturing capabilities; manufacturing cost; 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： 根据世界卫生组织的数据，2018年的2.28亿例疟疾病例增加了约16例 2015年的百万个案件，虽然死亡人数为405,000，但并不比2015年少得多。 世界需要一种疟疾疫苗。 Sanaria的恶性疟原虫Sporozoite（PFSPZ）疫苗已保护 在美国，德国的五项临床试验中，100％针对受控人类疟疾感染（CHMI）的受试者中有100％ 坦桑尼亚和马里；保护成年人至少18个月，以防止PF的强烈，异质传播 在布基纳法索的临床试验中，已在6个非洲和2个欧洲的临床试验中进行了评估 在5个月到65岁的美国，国家和5个地点。 Sanaria已移至第三阶段GMP符合条件 制造业，正在朝着Sanaria®PFSPZ疫苗的许可和商业化迈进。到 生产足够的PFSPZ疫苗以满足广泛的世界市场的需求，尤其是那些 非洲以负担得起的价格，制造规模必须大大提高和商品成本（COGS） 减少。 Sanaria的基于PFSPZ的疫苗包含无菌，纯化，冷冻保存，现场PFSPZ 在训练有素饲养的围绕蚊子蚊子中生产。当前感染，无菌性的方法 蚊子生产严重依赖人类的力量和大量昂贵的消耗品，以及 需要大量空间。该应用程序的总体目的是设计，构建，测试和完善半 自动化的蚊子生物反应器，该蚊子将无助，PFSPZ感染，成人A。 Stephensi和PFSPZ感染的蚊子转移到准备好的蚊子转移容器（IMTC） 对于辐照和解剖，大大降低了PFSPZ产品的上游制造成本。期间 这二阶段SBIR我们将最终确定一种用于无菌的半自动化，封闭系统生产的系统 从卵到感染的成年人准备辐射的蚊子。具体目的是：1）重新设计 幼虫生物反应器，用于免提，无菌聚类，从卵到幼虫再到成年蚊子； 2）重新设计成人 蚊子容器第1部分：成年人从幼体生物反应器中直接转移； 3）重新设计成人蚊子 容器第2部分：被感染蚊子向被感染的蚊子转移容器的半自动转移； 4）重新设计受感染的蚊子转移容器，以免费转移和重复使用；和5）整合 步骤并展示其在PFSPZ挑战的工程运行中制造的实用性。发展 这种生物反应器将导致Sanaria生产其PFSPZ产品的能力，并放置 SANARIA在3阶段GMP合规性的稳健，大规模制造的正轨，大幅降低 成本。