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

开发非人灵长类动物模型来评估保护性子孢子 (SPZ) 疫苗的免疫机制和抗原靶点并确定下一代 SPZ 疫苗的卓越功效

• 批准号: 10598147
• 负责人: STEPHEN Lev HOFFMAN
• 金额: $ 94.29万
• 依托单位: SANARIA, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598147
• 关键词: Affect; Africa; Amino Acids; Animal Model; Animals; Antibodies; Antigens; Aotus primate; Area; Attenuated; Binding; Biological Assay; Biological Markers; Biological Models; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Separation; Cells; Child; Clinical Trials; Cytoprotection; Data; Development; Disease; Dose; Erythrocytes; Europe; Exhibits; Falciparum Malaria; Geographic Locations; Germany; Glean; Goals; Hepatocyte; Human; Immune response; Immunity; Immunization; Immunize; Immunologics; Individual; Infection; Infection prevention; Interferons; Interleukin-12; Learning; Licensing; Liver; Macaca mulatta; Machine Learning; Malaria; Measures; Mediating; Methods; Modeling; Mus; Nitric Oxide; Organ; Parasites; Peptides; Performance; Peripheral Blood Mononuclear Cell; Persons; Phase; Plasma; Plasmodium falciparum; Plasmodium falciparum vaccine; Process; Production; Proteins; Radiation; Regimen; Safety; Seminal; Serum; Spleen; Sporozoite vaccine; Sporozoites; Statistical Models; Surface; Systems Biology; T cell response; T-Lymphocyte; Testing; Tissues; Transcript; Vaccines; Work; asexual; attenuation; cost; improved; in vitro Assay; in vivo; intravenous administration; lymph nodes; next generation; nonhuman primate; predictive test; prospective; protective efficacy; research clinical testing; response; subcutaneous; success; tissue biomarkers; tool; transmission process; vaccine candidate; vaccine efficacy; vaccine-induced immunity; volunteer

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.

抽象的 基于恶性疟原虫 (Pf) 子孢子 (SPZ) 的疫苗已显示出出色的安全性和疫苗效果 非洲、欧洲和美国超过 25 项临床试验的疗效 (VE)；第三阶段评估将于 2020 年中。我们未来十年的目标是开发、许可和部署下一代 SPZ 疫苗 增加 VE 的广度、规模和/或耐用性并降低商品成本。目前的检测和 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有效 表现出优于现有 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 非人类灵长类动物 (NHP) 模型表明，疫苗接种者将通过以下方式免受 Pf 疟疾的侵害： 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) 抗原靶点 PI，和/或3)参与PI诱导的器官和细胞。尽管进行了许多研究，但我们对这些的理解 过去 20 年来，3 个领域仅略有改善。 2000 年，有人假设抗原特异性， 肝脏中的组织驻留 CD8+ T 细胞识别与 I 类 HLA 分子结合的 Pf 肽 Pf感染的肝细胞表面是介导PI的关键细胞。这一假设引发了一项开创性的研究： 证明皮下注射 PfSPZ 疫苗不会导致 PfSPZ 特异性的诱导， 免疫 NHP 的肝脏中存在 CD8+ T 细胞，但静脉 (IV) 给药却如此。很大程度上基于 根据这些结果，启动了静脉注射临床试验，试验显示 VE 为 100%。随后， > 25 项 PfSPZ 疫苗临床试验表明，PfSPZ/剂量、剂量次数的经验性改变， 剂量间隔和减毒方法可以提高 PfSPZ 疫苗的性能。然而，我们 对 PI 的机制和靶点，或参与 PI 诱导的组织了解甚少。我们相信 这是因为效应器活性发生在肝脏中，PI 的诱导也发生在中枢 隔室，这是人类无法进入的。自从我们最后的重大进展来自于对肝脏的研究以来 免疫 NHP，我们认为可以从这种方法中收集更多信息，包括阐明 免疫效应物和靶标，以及候选疫苗的比较和下调选择。因此，在 在这个项目中，我们将开发 3 个近交 NHP 模型来研究 SPZ 疫苗诱导的免疫，并使用 模型和系统生物学测定中生成的数据，用于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品 标记。将使用来自以下组织的血清、血浆和 PBMC 来评估最佳检测/生物标志物/特征： 在 PfSPZ 疫苗临床试验中评估的受保护/未受保护受试者。最后，我们将使用 用于筛选新开发的 SPZ 疫苗的测定/生物标志物/特征和模型系统，特别是 转基因疫苗，以减少选择哪些应进入工艺开发和临床测试。