A Cytomegalovirus-based Vaccine Targeting the Pre-erythrocytic Stage of Malaria

一种针对疟疾红细胞前阶段的巨细胞病毒疫苗

• 批准号: 9238234
• 负责人: Klaus J Fruh
• 金额: $ 81.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238234
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adenoviruses; Antigens; Appearance; Biology; Blood; CD8-Positive T-Lymphocytes; Cause of Death; Cellular Immunity; Characteristics; Child; Clinical Trials; Cytomegalovirus; Cytomegalovirus Vaccines; Cytoprotection; Cytotoxic T-Lymphocytes; Data; Development; Epitopes; Erythrocytes; Evaluation; Frequencies; Goals; HIV vaccine; Heterophile Antigens; Human; Immune; Immune response; Immunity; Immunization; Immunologics; Immunology; Life; Liver; Macaca mulatta; Malaria; Malaria Vaccines; Merozoite Surface Protein 1; Methods; Modeling; Modified Vaccinia Virus Ankara; Mus; Mycobacterium tuberculosis; Pan Genus; Parasites; Parasitic Diseases; Phase; Phenotype; Plasmodium falciparum; Plasmodium knowlesi; Population; Recruitment Activity; Research; Role; SIV; Safety; Site; Specificity; Sporozoites; Sterility; T cell response; T memory cell; T-Lymphocyte; Testing; Time; Tissues; Vaccinated; Vaccination; Vaccine Design; Vaccine Research; Vaccines; Validation; Vertebral column; Viral Vector; Virulent; Virus; Work; base; clinical development; global health; immunogenicity; improved; novel vaccines; pathogen; pre-clinical; programs; protective effect; prototype; research clinical testing; response; tool; vaccine candidate; vaccine development; vector

SUMMARY The development of a sterilizing vaccine against malaria remains one of the highest priorities for global health research. While experimental vaccines targeting the malaria parasite prior to entering the blood stage have shown great promise, it has so far not been possible to elicit the longterm immunity required to maintain protection over time. We propose to apply a fundamentally new vaccine tool to malaria vaccine research: persistent effector memory T cell-eliciting vaccines based on cytomegalovirus (CMV). By taking advantage of the natural ability of CMV to elicit and maintain high frequency, non-exhausted, life-long cellular immunity we demonstrated that CMV-based vaccines protect against highly virulent pathogens such as simian immune- deficiency virus and mycobacterium tuberculosis. Our work has renewed hope for AIDS eradication and we are now in clinical development of CMV/HIV vaccines. In preliminary work we now also show that CMV-based malaria vaccines containing a limited set of malaria antigens reduce the parasite burden prior to blood stage development. The central goal of this proposal is to further improve this protection in order to generate sterilizing immunity. We will apply the unique immunological characteristics of CMV-based vaccines by designing CMV-vaccines that recruit different types of cytotoxic T cells to eliminate the parasite liver stage. Specifically, we will address the role of conventional, MHC-I restricted CD8+ T cells versus unconventional MHC-II and MHC-E-restricted CD8+ T cells in protection. We will additionally broaden the spectrum of parasite antigens by including a new set of vaccine targets for the pre-erythrocytic stage of malaria. These new vaccine targets were selected based on systematic evaluation of T cell immunity in humans and validation in murine malaria models. Finally we will extend the immune responses and protective effects elicited by heterologous prime/boost immunization by boosting with CMV-vectors eliciting MHC-I restricted CD8+ T cells recognizing both immunodominant and subdominant epitopes. We anticipate that this project will validate CMV as new method to vaccinate against malaria.

概括 开发针对疟疾的灭菌疫苗仍然是全球健康的最高优先事项之一 研究。虽然在进入血液阶段之前针对疟疾寄生虫的实验性疫苗已经 显示出巨大的希望，但迄今为止还不可能获得维持所需的长期免疫力 随着时间的推移提供保护。我们建议将一种全新的疫苗工具应用于疟疾疫苗研究： 基于巨细胞病毒 (CMV) 的持久效应记忆 T 细胞诱导疫苗。通过利用 CMV 具有引发和维持高频、不间断、终生细胞免疫的天然能力 证明基于 CMV 的疫苗可以预防高毒力病原体，例如猿猴免疫- 缺乏病毒和结核分枝杆菌。我们的工作给根除艾滋病带来了新的希望，我们正在 目前正在进行 CMV/HIV 疫苗的临床开发。在初步工作中，我们现在还表明基于 CMV 含有一组有限疟疾抗原的疟疾疫苗可减少血液阶段之前的寄生虫负担 发展。该提案的中心目标是进一步改进这种保护，以产生 杀菌免疫力。我们将通过以下方式应用基于 CMV 的疫苗的独特免疫学特性： 设计 CMV 疫苗，招募不同类型​​的细胞毒性 T 细胞以消除寄生虫肝脏阶段。 具体来说，我们将讨论传统的 MHC-I 限制性 CD8+ T 细胞与非常规 T 细胞的作用 MHC-II 和 MHC-E 限制性 CD8+ T 细胞处于保护状态。我们还将进一步拓宽寄生虫谱 抗原，包括针对疟疾红细胞前阶段的一组新疫苗靶标。这些新疫苗 根据对人类 T 细胞免疫的系统评估和小鼠验证来选择靶点 疟疾模型。最后，我们将扩展异源引起的免疫反应和保护作用 通过 CMV 载体加强免疫，引发 MHC-I 限制性 CD8+ T 细胞识别 免疫显性和次显性表位。我们预计该项目将验证 CMV 为新的 接种疟疾疫苗的方法。