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

描述（由申请人提供）：Sanaria 率先生产了适合人类控制感染和免疫的无菌、纯化、冷冻保存的 I 子孢子 (PfSPZ)。迄今为止的人体研究已经证明了减毒 PfSPZ（PfSPZ 疫苗）在静脉注射给人类时诱导保护性免疫反应的效力以及非减毒 PfSPZ（PfSPZ 挑战）的感染性。进一步的开发将集中于优化使用 PfSPZ 诱导针对多种恶性疟原虫菌株的持久免疫力的方案。 Sanaria 和 LMIV 在此提出的试验将评估接受抗疟治疗的个体的 PfSPZ Challenge 免疫情况，这些治疗可在肝脏发育阶段消除寄生虫，作为称为 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，并最大限度地提高针对异源寄生虫的活性。拟议临床试验的设计将分为两个阶段：1）预试验阶段将确定接种 PfSPZ 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对 PfSPZ 和乙胺嘧啶治疗免疫诱导的同源寄生虫的保护程度。在第一年，研究团队将完成所有制造、质量控制释放和稳定性测定，以及成功向 FDA 提交研究性新药申请 (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 (PfSPZ) 或批准用于人类使用的元素 (氯喹、乙胺嘧啶)；第一年，我们也会启动筛选和招生 研究参与者。在第二年，我们将进行试点阶段试验，以最终确定最佳方案 方案，提交主要试验进行IRB审查，并启动主要试验，在第3年我们将进行控制人类疟疾感染的主要试验，以证明对同源寄生虫的功效。这些试验将建立一种新的 PfSPZ 免疫方式，随后可以评估其对异源和自然发生的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.