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; 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 恶性疟原虫（PF）Sporozoite（SPZ）的疫苗已显示出极好的安全性和疫苗 在非洲，欧洲和美国进行的25多次临床试验中的功效（VE）；第三阶段评估将开始 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 VE的宽度，大小和/或耐用性以及商品成本降低。当前的测定法和 动物模型没有提供临床试验的替代方法，以证明疫苗是否候选 与当前的SPZ疫苗相比表现出卓越的性能。在这个项目中，我们旨在开发体外测定和/或 表明疫苗接收者的非人类灵长类动物（NHP）模型将通过A保护PF疟疾 SPZ疫苗，并用它们来显示新的SPZ疫苗的优势。成功可能来自增加 了解1）保护性免疫的免疫效应器机制（PI），2） PI和/或3）器官和细胞参与PI的诱导。尽管进行了许多研究，但我们对这些 在过去的20年中，有3个领域仅适度改善。在2000年，假设抗原特异性 肝脏中的组织驻留CD8+ T细胞识别出与I类HLA分子结合的PF肽 PF感染的肝细胞的表面是介导PI的关键细胞。这一假设导致了一项开创性的研究 表现出皮下给药的PFSPZ疫苗并没有导致PFSPZ特异性诱导， 免疫NHP的肝脏中的CD8+ T细胞，但静脉内（IV）给药。主要基于 这些结果，启动了IV次给药的临床试验，该试验显示100％VE。随后， > 25 PFSPZ疫苗的临床试验表明，PFSPZ/剂量的经验改变，剂量的数量，数量 剂量和衰减方法之间的间隔可以改善PFSPZ疫苗的性能。但是，我们 对PI的机制和靶标或参与PI诱导的组织了解了很少的了解。我们相信 这是因为效应子活动发生在肝脏中，并且PI的诱导也发生在中央 隔间，在人类中无法访问。自从我们上次的重大进展以来，是从研究的 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 免疫效应子和靶标，以及候选疫苗的比较和下调。因此，在 该项目我们将在NHP中开发3种模型，以研究SPZ疫苗诱导的免疫力，并使用该模型 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）始终预测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/签名将使用血清，等离子体和PBMC进行评估 在PFSPZ疫苗的临床试验中评估的受保护/未受保护的受试者。最后，我们将使用 测定/生物标志物/签名和模型系统，以筛选新开发的SPZ疫苗，尤其是 遗传上改变的疫苗，以降低选择，该疫苗应转化为处理开发和临床测试。