PfSPZ Challenge with Chemoprophylaxis: Phase 1 Trial to Assess Liver Stage Drug

描述（由申请人提供）：Sanaria率先生产无菌，纯化，冷冻保存的I孢子虫（PfSPZ），适用于控制人类感染和免疫。迄今为止的人体研究已经证明，经静脉注射的减毒PfSPZ （PfSPZ疫苗）具有诱导保护性免疫反应的效力，而非减毒PfSPZ （PfSPZ挑战）具有传染性。进一步的开发将侧重于优化使用PfSPZ诱导对多种恶性疟原虫持久免疫的方案。Sanaria和LMIV在这里提出的试验将评估在肝脏发育阶段接受消除寄生虫的抗疟疾治疗的个体中使用PfSPZ Challenge的免疫接种，作为一种称为PfSPZ- cvac（化学预防疫苗）的潜在免疫策略，以减少保护性免疫所需的PfSPZ剂量，并最大限度地提高对异源寄生虫的活性。拟议的临床试验设计将分为两个阶段：1)试点试验阶段将确定PfSPZ接种后施用经FDA批准用于预防和治疗易感恶性疟原虫疟疾的药物乙胺嘧啶的最佳时机；2)主要试验阶段将评估PfSPZ和乙胺嘧啶处理免疫对同源寄生虫的保护程度。在第一年，研究团队将完成所有的生产、质量控制释放和稳定性分析，以及成功向FDA提交新药研究申请（IND）的监管要求，并提交该新产品的IND，该新产品结合了已经在人体中测试过的元素（PfSPZ）或批准用于人的元素（氯喹，乙胺嘧啶）；在第一年，我们还将启动筛选和招生

DESCRIPTION (provided by applicant): Sanaria has pioneered the manufacture of aseptic, purified, cryopreserved I sporozoites (PfSPZ) suitable for controlled infection and immunization of humans. Human studies to date have demonstrated the potency of attenuated PfSPZ (PfSPZ Vaccine) for inducing protective immune responses and the infectivity of non-attenuated PfSPZ (PfSPZ Challenge) when administered intravenously to humans. Further development will focus on optimization of regimens that use PfSPZ to induce durable immunity against multiple strains of P. falciparum. The trials proposed here by Sanaria and LMIV will assess immunization with PfSPZ Challenge in individuals who receive antimalarial treatments that eliminate parasites during their liver stage of development, as a potential strategy for immunization called PfSPZ-CVac (chemoprophylaxis vaccine) to reduce the PfSPZ dose required for protective immunity, and to maximize activity against heterologous parasites. The design of the proposed clinical trial will entail 2 phases: 1) the pilot trial phase will determine the optimal timing after PfSPZ inoculation to administer the drug pyrimethamine that is approved by FDA for prophylaxis and treatment of susceptible P. falciparum malaria; 2) the main trial phase will assess the degree of protection against homologous parasites induced by immunization with PfSPZ and pyrimethamine treatment. During Year 1, the study team will complete all manufacturing, quality control release and stability assays, and regulatory requirements for successful submission of Investigational New Drug Application (IND) to the FDA and submit the IND for this new product, which combines elements that have already tested in humans (PfSPZ) or approved for human use (chloroquine, pyrimethamine); in the first year, we will also initiate screening and enrollment of study participants. During Year 2, we will conduct the pilot phase trial to finalize the optimal regimen, submit the main trial for IRB review, and initiate the main trial, and during Year 3 we will conduct the main trial controlled human malaria infection to demonstrate efficacy against homologous parasites. These trials will establish a new modality for immunization with PfSPZ, which can subsequently be assessed for protection against heterologous and naturally occurring P. falciparum infections.