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

描述（由申请人提供）：Sanaria率先生产了适用于人类受控感染和免疫的无菌、纯化、冷冻保存的I型子孢子（PfSPZ）。迄今为止的人类研究已经证明了减毒PfSPZ（PfSPZ疫苗）诱导保护性免疫应答的效力和非减毒PfSPZ（PfSPZ攻击）在静脉内施用于人类时的感染性。进一步的开发将集中在优化使用PfSPZ诱导针对多种恶性疟原虫菌株的持久免疫的方案上。Sanaria和LMIV在此提出的试验将评估PfSPZ挑战免疫接种在接受抗疟治疗的个体中，这些治疗在肝脏发育阶段消除寄生虫，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。拟定临床试验的设计将包括2个阶段：1）中试试验阶段将确定PfSPZ接种后给予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间; 2）主要试验阶段将评估PfSPZ免疫接种和乙胺嘧啶治疗诱导的对同源寄生虫的保护程度。在第1年期间，研究团队将完成所有生产、质量控制放行和稳定性试验，以及成功向FDA提交研究性新药申请（IND）的法规要求，并提交该新产品的IND，该产品结合了已在人体（PfSPZ）中测试或批准用于人用的元素（氯喹、乙胺嘧啶）;第一年，我们还将启动筛查和入组 的研究参与者。在第二年，我们将进行试点阶段的试验，以确定最佳的 方案，提交主试验供IRB审查，并启动主试验，在第3年期间，我们将进行控制人类疟疾感染的主试验，以证明对同源寄生虫的疗效。这些试验将建立PfSPZ免疫的新模式，随后可以评估其对异源和天然恶性疟原虫感染的保护作用。

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.