Development of Non-Human Primate Models to Assess Immunological Mechanisms and Antigenic Targets of Protective Sporozoite (SPZ) Vaccines and Establish Superior Efficacy of Next Generation SPZ vaccines

摘要 基于恶性疟原虫（Pf）子孢子（SPZ）的疫苗已经显示出优异的安全性和疫苗安全性。 在非洲、欧洲和美国进行的超过25项临床试验中进行了有效性（VE）评估; 3期评估将于2015年开始。 2020年中期。我们在未来十年的目标是开发、许可和部署下一代SPZ疫苗 具有增加的VE的宽度、量级和/或耐久性以及降低的商品成本。目前的检测方法和 动物模型不能提供临床试验的替代方案来证明候选疫苗是否 表现出上级目前SPZ疫苗的性能。在这个项目中，我们的目标是开发体外测定和/或 非人灵长类动物（NHP）模型表明，疫苗接种者将受到保护，免受Pf疟疾的影响， SPZ疫苗，并利用它们来展示新型SPZ疫苗的优越性。成功可能来自于 了解1）保护性免疫（PI）的免疫效应机制，2） PI，和/或3）参与PI诱导的器官和细胞。尽管有许多研究，我们对这些的理解 在过去的20年里，3个领域只略有改善。在2000年，假设抗原特异性， 肝脏中的组织驻留CD 8 + T细胞，其识别结合到组织上的I类HLA分子的Pf肽。 Pf感染的肝细胞表面是介导PI的关键细胞。这一假设导致了一项开创性的研究， 证实PfSPZ疫苗的皮下给药不会诱导PfSPZ特异性， CD 8 + T细胞在免疫的NHP的肝脏中，但静脉内（IV）给药。大部分基于 根据这些结果，开始IV给药的临床试验，试验显示100%VE。随后，委员会注意到， PfSPZ疫苗的>25项临床试验表明，PfSPZ/剂量、剂量数 剂量之间的间隔和减毒方法可以改善PfSPZ疫苗的性能。但我们 对PI的作用机制、作用靶点以及参与PI诱导的组织了解甚少。我们认为 这是因为效应物活性发生在肝脏，PI的诱导也发生在中枢。 隔室，这是人类无法接近的。自从我们上一次的重大进展来自于研究 免疫NHP，我们认为可以从这种方法中收集更多的信息，包括阐明 免疫效应物和靶标，以及候选疫苗的比较和向下选择。因此在 本项目将在远交NHP中建立3个模型来研究SPZ疫苗诱导的免疫，并使用 在模型和系统生物学测定中生成的数据，以建立生物标志物和测定组 （签名）一致地预测NHP是否会受到保护，并建立组织的血液替代物 标记。最佳测定/生物标志物/特征将使用来自以下的血清、血浆和PBMC进行评估： PfSPZ疫苗临床试验中评估的保护/未保护受试者。最后，我们将使用 检测/生物标志物/签名和模型系统，以筛选新开发的SPZ疫苗，特别是 转基因疫苗，向下选择哪些应该转移到过程开发和临床测试。

ABSTRACT Plasmodium falciparum (Pf) sporozoite (SPZ)-based vaccines have shown excellent safety and vaccine efficacy (VE) in more than 25 clinical trials in Africa, Europe, and the US; Phase 3 assessment will begin in mid-2020. Our goal during the next decade is to develop, license, and deploy next generation SPZ vaccines with increased breadth, magnitude, and/or durability of VE and decreased cost of goods. Current assays and animal models do not offer an alternative to clinical trials for demonstrating whether a vaccine candidate exhibits superior performance to current SPZ vaccines. In this project we aim to develop in vitro assays and/or non-human primate (NHP) models that indicate a vaccine recipient will be protected against Pf malaria by a SPZ vaccine, and use them to show superiority of new SPZ vaccines. Success could come from increased understanding of the 1) immunological effector mechanisms of protective immunity (PI), 2) antigenic targets of PI, and/or 3) organs and cells involved in induction of the PI. Despite many studies, our understanding of these 3 areas has only modestly improved in the last 2 decades. In 2000 it was hypothesized that antigen-specific, tissue resident CD8+ T cells in the liver that recognized Pf peptides bound to class I HLA molecules on the surface of Pf-infected hepatocytes were the key cells mediating PI. This hypothesis led to a seminal study that demonstrated subcutaneous administration of PfSPZ Vaccine did not lead to induction of PfSPZ-specific, CD8+ T cells in the livers of immunized NHPs, but intravenous (IV) administration did. Based in large part on these results, a clinical trial of IV administration was initiated, and the trial showed 100% VE. Subsequently, >25 clinical trials of PfSPZ vaccines have shown that empirical alteration of PfSPZ/dose, number of doses, interval between doses, and method of attenuation can improve performance of PfSPZ vaccines. However, we have learned little about mechanisms and targets of PI, or the tissues involved in induction of PI. We believe this is because the effector activity takes place in the liver, and induction of PI also takes place in the central compartment, which is inaccessible in humans. Since our last major advance came from studying the livers of immunized NHPs, we think much more information can be gleaned from this approach, including elucidation of immunological effectors and targets, and comparison and down-selection of vaccine candidates. Therefore, in this project we will develop 3 models in outbred NHPs to study SPZ vaccine-induced immunity, and use the data generated in the models and systems biology assays to establish biomarkers and groups of assays (signature) that consistently predict whether a NHP will be protected, and establish blood surrogates of tissue markers. The best assays/ biomarkers/signatures will be assessed using serum, plasma, and PBMCs from protected/unprotected subjects assessed in clinical trials of PfSPZ vaccines. Finally, we will use the assays/biomarkers/signatures and model systems to screen newly developed SPZ vaccines, especially genetically altered vaccines, to down-select which should move to process development and clinical testing.