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

描述(由申请人提供)：Sanaria率先制造了无菌、纯化、冷冻保存的I型子孢子(PfSPZ)，适用于控制人类感染和免疫。到目前为止，人体研究已经证明了减毒PfSPZ疫苗(PfSPZ疫苗)在诱导保护性免疫反应方面的效力，以及非减毒PfSPZ挑战疫苗(PfSPZ Challenger)静脉注射时的传染性。进一步的发展将集中在使用PfSPZ诱导针对多种恶性疟原虫株的持久免疫的方案的优化上。Sanaria和LMIV在这里提出的试验将评估PfSPZ Challenger在接受抗疟疾治疗的个体中的免疫效果，这些治疗在他们的肝脏发育阶段消除寄生虫，作为一种潜在的免疫策略，称为PfSPZ-CVac(化学预防疫苗)，以减少保护性免疫所需的PfSPZ剂量，并最大限度地对抗异源寄生虫。拟议临床试验的设计将包括两个阶段：1)试点试验阶段将确定接种PfSPZ后使用FDA批准的用于预防和治疗易感恶性疟原虫的药物乙胺嘧啶的最佳时机；2)主要试验阶段将评估PfSPZ和乙胺嘧啶治疗免疫诱导的同源寄生虫的保护程度。在第一年，研究小组将完成所有生产、质量控制释放和稳定性分析，以及成功向FDA提交研究新药申请(IND)的法规要求，并提交这种新产品的IND，该新药结合了已在人体上试验(PfSPZ)或批准用于人类使用的成分(氯喹、乙胺嘧啶)；在第一年，我们还将启动筛选和登记 研究参与者的数量。在第二年，我们将进行试验阶段的试验，以最终确定最佳方案 方案，提交主要试验供IRB审查，并启动主要试验，在第三年，我们将进行控制人类疟疾感染的主要试验，以展示对同源寄生虫的疗效。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.