Manufacture of aseptic, purified, cryopreserved Plasmodium vivax sporozoites

无菌、纯化、冷冻保存的间日疟原虫子孢子的制造

• 批准号: 10408759
• 负责人: Sumana Chakravarty
• 金额: $ 96.13万
• 依托单位: SANARIA, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-21 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408759
• 关键词: 3-Dimensional; Acute; Affect; Antigens; Antimalarials; Biological Assay; Bite; Blood; Chemoprophylaxis; Clinical; Clinical Protocols; Clinical trial protocol document; Communities; Cryopreservation; Culicidae; Development; Dose; Drug Targeting; Engineering; Event; Exhibits; Falciparum Malaria; Genetic Diseases; Glucosephosphate Dehydrogenase Deficiency; Goals; Grant; Hemolytic Anemia; Human; Human Genetics; In Vitro; Incidence; Intervention; Investigational Drugs; Investigational New Drug Application; Legal patent; Life; Life Cycle Stages; Liver; Logistics; Malaria; Measures; Methods; Modeling; Mus; Outcome; Parasitemia; Parasites; Patients; Persons; Pharmaceutical Preparations; Phase; Plasmodium falciparum; Plasmodium vivax; Primaquine; Primates; Process; Production; Quality Control; Reagent; Relapse; Reticulocytes; Running; Saimiri; Severity of illness; Sleep Stages; Source; Sporozoites; Standardization; Technology; Testing; Texas; Transgenic Organisms; University of Texas M D Anderson Cancer Center; Vaccines; Vial device; Vivax Malaria; base; cell bank; clinical lot; drug efficacy; efficacy study; feeding; follow-up; geographic barrier; germ free condition; human subject; immunogenicity; malaria infection; manufacturing process; meetings; mouse model; pathogen; pre-clinical assessment; preclinical study; prevent; prophylactic; protective efficacy; tool; vaccinology; 3-Dimensional; Acute; Affect; Antigens; Antimalarials; Biological Assay; Bite; Blood; Chemoprophylaxis; Clinical; Clinical Protocols; Clinical trial protocol document; Communities; Cryopreservation; Culicidae; Development; Dose; Drug Targeting; Engineering; Event; Exhibits; Falciparum Malaria; Genetic Diseases; Glucosephosphate Dehydrogenase Deficiency; Goals; Grant; Hemolytic Anemia; Human; Human Genetics; In Vitro; Incidence; Intervention; Investigational Drugs; Investigational New Drug Application; Legal patent; Life; Life Cycle Stages; Liver; Logistics; Malaria; Measures; Methods; Modeling; Mus; Outcome; Parasitemia; Parasites; Patients; Persons; Pharmaceutical Preparations; Phase; Plasmodium falciparum; Plasmodium vivax; Primaquine; Primates; Process; Production; Quality Control; Reagent; Relapse; Reticulocytes; Running; Saimiri; Severity of illness; Sleep Stages; Source; Sporozoites; Standardization; Technology; Testing; Texas; Transgenic Organisms; University of Texas M D Anderson Cancer Center; Vaccines; Vial device; Vivax Malaria; base; cell bank; clinical lot; drug efficacy; efficacy study; feeding; follow-up; geographic barrier; germ free condition; human subject; immunogenicity; malaria infection; manufacturing process; meetings; mouse model; pathogen; pre-clinical assessment; preclinical study; prevent; prophylactic; protective efficacy; tool; vaccinology

ABSTRACT Malaria caused by Plasmodium vivax (Pv) parasites is ranked second with respect to the incidence and severity of disease while Plasmodium falciparum (Pf) malaria is ranked first. However unlike Pf, chemo prophylactic measures against Pv do not prevent relapses, unique to Pv, that occur due to re-activation of persistent liver-stage sleeping forms of the parasites called hypnozoites. Primaquine is the only licensed drug that targets Pv hypnozoites, but it causes life threatening acute hemolytic anemia in patients with G6PD deficiency, the most prevalent human genetic disorder, affecting 8% of people in malaria-endemic nations. Efforts to develop better drugs or produce a much needed vaccine are further hampered by the inability to propagate blood stages of Pv parasites in vitro, unlike Pf. Therefore generating infected mosquitoes for controlled human malaria infection (CHMI) as a means to assess anti-Pv drugs and vaccines, is entirely reliant on feeding of mosquitoes on fresh, Pv-infected blood from patients with Pv malaria. Together, these bottlenecks make the task of developing and testing robust interventions against Pv malaria more challenging compared to Pf. We have made significant progress under a phase I grant toward establishing and maintaining a colony of specific pathogen free (SPF) Saimiri boliviensis (Sb). and vialing aseptic, purified Plasmodium vivax (Pv) sporozoites (SPZ) that were generated in aseptic mosquitoes using infected blood from SPF Sb and met asepticity and release criteria in all in process and for release. We now outline phase 2 follow-up plans to manufacture a lot of PvSPZ Challenge in compliance with cGMPs, conduct quality control release and stability studies, prepare a clinical trial protocol, and prepare and submit an Investigational New Drug (IND) application to the FDA along with an infectivity study in humanized FRG KO huHEP mice, and an immunogenicity and protective efficacy study in a mouse model with patent parasitemia as the protection outcome. The product resulting from studies outlined in this proposal will be called Sanaria® PvSPZ Challenge, and similar to PfSPZ Challenge will provide the larger malaria community with a tool to assess the efficacy of drugs and vaccines against Pv malaria with a safer quality-controlled reagent that exhibits minimal variability in potency between different lots, is logistically more feasible to administer, and is not subject to geographical limitations for application, compared to traditional CHMI using mosquito bites. It will represent an unprecedented milestone in the field of vaccinology, and vaccine manufacturing and most importantly it will form the basis of a powerful vaccine approach to preventing Pv malaria when administered with anti-malarial chemoprophylaxis, the PvSPZ chemoprophylaxis vaccine (PvSPZ-CVac).

抽象的 由疟原虫（PV）寄生虫引起的疟疾在此事件方面排名第二， 疾病的严重程度，而恶性疟原虫（PF）疟疾排名第一。但是与PF不同，化学疗法 针对PV采取的预防性测量并不能阻止PV的复发，这是由于重新激活而发生的。 寄生虫的持续性肝阶段睡眠形式称为催眠症。 Primaquine是唯一获得许可的药物 这是针对PV催眠症的，但会导致G6PD患者的生命威胁急性溶血性贫血 缺乏症，是最普遍的人类遗传疾病，影响了疟疾 - 内向国家中8％的人。 开发更好的药物或生产急需的疫苗的努力进一步阻碍了 与PF不同，体外PV寄生虫的血液阶段传播。因此，生成感染的蚊子 受控人类疟疾感染（CHMI）是评估抗PV药物和疫苗的一种手段，完全可靠 从PV疟疾患者的新鲜PV感染血液中喂食蚊子。在一起，这些 瓶颈使得针对PV Malaria的强大干预措施使瓶颈更加挑战 与PF相比。我们已经在I阶段授予建立和维护的I阶段取得了重大进展 特定病原体（SPF）saimiri boliviensis（SB）的菌落。和小葡萄染色的纯化疟原虫 在无菌蚊子中使用SPF SB的感染血液和 在整个过程中和释放中，元的无菌性和释放标准。我们现在概述了第2阶段的后续计划 根据CGMP制造许多PVSPZ挑战，进行质量控制释放和稳定性 研究，准备临床试验方案，准备并提交研究新药（IND）应用 在人源化的FRG KO Huhep小鼠中进行FDA以及感染研究，免疫原性和 具有专利寄生虫血症的小鼠模型中的保护效率研究作为保护结果。产品 该提案中概述的研究产生的将被称为Sanaria®PVSPZ挑战，类似于PFSPZ 挑战将为较大的疟疾社区提供评估药物和疫苗效率的工具 针对PV疟疾，具有更安全的质量控制的试剂，该试剂的效力最小 不同的地段在逻辑上更可行，并且不受地理上的限制 与传统的CHMI相比，使用蚊子的应用。它将代表一个前所未有的里程碑 疫苗学和疫苗制造领域，最重要的是，它将构成强大的基础 用抗疟疾化学预防剂施用PVSPZ，预防PV疟疾的疫苗方法 化学预防疫苗（PVSPZ-CVAC）。