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 以恶性疟原虫(PF)子孢子(SPZ)为基础的疫苗表现出极好的安全性和疫苗 在非洲、欧洲和美国进行了超过25项临床试验的有效性(VE)；第三阶段评估将于#年开始 2020年年中。我们在下一个十年的目标是开发、许可和部署下一代SPZ疫苗 随着VE的广度、规模和/或耐用性的增加，以及商品成本的降低。目前的检测方法和 动物模型不能替代临床试验来证明候选疫苗 表现出优于目前SPZ疫苗的性能。在这个项目中，我们的目标是开发体外分析和/或 非人灵长类(NHP)模型，表明疫苗接受者将通过一种 SPZ疫苗，并用它们来展示新型SPZ疫苗的优越性。成功可能来自于增加 了解1)保护性免疫(PI)的免疫效应机制，2)抗原靶标 和/或3)参与诱导PI的器官和细胞。尽管有许多研究，但我们对这些问题的理解 在过去的20年里，有3个领域只有轻微的改善。2000年，有人假设抗原特异性的， 肝组织中驻留的CD8+T细胞识别与HLAI类分子结合的PF多肽 感染PF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 皮下接种PfSPZ疫苗不会导致PfSPZ特异性的诱导， CD8+T细胞在免疫的NHP的肝脏中，但静脉注射(IV)有。在很大程度上基于 这些结果，启动了静脉给药的临床试验，试验显示100%的VE。后来， PfSPZ疫苗的25项临床试验表明，PfSPZ/剂量、剂量和剂量的经验变化， 剂量间隔和减毒方法可以改善PfSPZ疫苗的性能。然而，我们 对PI的机制和靶点，或参与PI诱导的组织知之甚少。我们相信 这是因为效应器的活动发生在肝脏，PI的诱导也发生在中央 隔间，这是人类无法接触到的。因为我们上一次的重大进展来自于对 我们认为从这种方法中可以收集到更多的信息，包括阐明 免疫效应物和靶点，以及候选疫苗的比较和下选。因此，在 在本项目中，我们将在近交系中建立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分析中产生的数据，以建立生物标志物和化验组 (签名)持续预测NHP是否会受到保护，并建立组织的血液替代品 记号笔。最好的检测/生物标志物/标志物将使用血清、血浆和PBMC进行评估 在PfSPZ疫苗的临床试验中评估的保护/非保护受试者。最后，我们将使用 用于筛选新开发的SPZ疫苗的分析/生物标志物/签名和模型系统，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.