A universal malaria T cell vaccine based on HLA-E presentation

基于 HLA-E 表达的通用疟疾 T 细胞疫苗

• 批准号: 10625464
• 负责人: Caroline Junqueira
• 金额: $ 77.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-20 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625464
• 关键词: Animal Model; Animals; Antibodies; Antigen Presentation; Antigen Targeting; Antigens; Bacteria; Binding; Biological Assay; Blood; CD8-Positive T-Lymphocytes; CD94 Antigen; Cells; Cellular Structures; Complex; Cytomegalovirus; Data; Development; Disease; Epitopes; Erythrocytes; Genetic; Genetic Polymorphism; Goals; HLA-A gene; Haplotypes; Histones; Housekeeping; Human; Immune; Immune system; Immunity; Immunization; Immunize; In Vitro; Individual; Infection; Knowledge; Ligands; Liver; Macaca mulatta; Major Histocompatibility Complex; Malaria; Malaria Vaccines; Mediating; Modeling; Monitor; Parasites; Peptides; Peripheral Blood Mononuclear Cell; Phenotype; Plasmodium; Plasmodium falciparum; Plasmodium vaccine; Plasmodium vivax; Plasmodium vivax vaccine; Play; Population Heterogeneity; Primary Infection; Primates; Proteins; Public Health; Reagent; Relapse; Reticulocytes; Rhesus; Ribosomal Proteins; Role; SIV; Sampling; Source; Sporozoites; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Thinking; Transfection; Vaccination; Vaccine Design; Vaccine Research; Vaccines; Validation; Virulent; Virus; antigen processing; cell killing; cell type; experimental study; immunogenicity; innovation; nonhuman primate; novel; novel vaccines; programs; rational design; response; vaccine candidate; vaccine development; vaccine efficacy; vaccine platform; vaccine strategy; vector

ABSTRACT Malaria-specific CD8+ T cells have long been known to control the liver stages of malaria. We recently showed that they can also kill reticulocytes infected with Plasmodium vivax. However, the T cell targeted antigens presented by major histocompatibility complex (MHC) class I molecules on parasite-infected cells at any stage are largely unknown; a lack of knowledge that has hampered the development of rationally designed, T cell- based vaccines for malaria. In preliminary experiments we determined the MHC-I peptidome presented on P. vivax-infected reticulocytes. This analysis revealed that many MHC-I-bound peptides are derived from abundant house-keeping proteins such as histones and ribosomal proteins that are highly conserved among Plasmodium species—targets not represented in current vaccine strategies. This discovery thus creates the unique opportunity to develop pan-Plasmodium vaccines eliciting T cells to validated targets. Unexpectedly, several peptides were identified in multiple donors regardless of their MHC-haplotype and our preliminary data show this is in part due to peptide presentation on MHC-E, a non-polymorphic MHC-Ib molecule. We therefore hypothesize that MHC-E-restricted CD8+ T cells contribute to T cell-mediated protection against malaria and that this can be exploited for vaccine design using cytomegalovirus (CMV)-based vectors, the only platform that can be programmed to elicit MHC-E-restricted CD8+ T cell responses to inserted antigens. This hypothesis will be tested in three specific aims using the P. cynomolgi non-human primate model of P. vivax with validation in human P. vivax-infected samples: In Aim 1 we will determine the relative contribution of MHC-E to presentation of P.vivax peptides to CD8+ T cells and investigate a possible role of MHC-E-targeting in CD8+ T cell killing of infected reticulocytes (iRetics). In Aim 2 we will characterize the role of individual P. vivax antigens in MHC-E-restricted CD8+ T cell targeting of iRetics. This will be accomplished by identifying MHC- E/peptide-specific T cell receptors and examining the ability of TCR-transfected T cells to target iRetics . In addition, we will similarly characterize MHC-E-restricted CD8+ T cells elicited to selected antigens in rhesus macaques immunized with genetically modified rhesus cytomegalovirus vectors (RhCMV) that elicit exclusively MHC-E-restricted CD8+ T cells. In Aim 3, we will compare RhCMV-based P. vivax vaccines eliciting MHC-E or MHC-Ia-restricted responses to selected, conserved antigens with respect to their ability to protect against P. cynomolgi challenge in rhesus macaques. Specifically, we will monitor protection against the liver stage, primary blood stage and relapsing blood stage resulting from dormant liver stages. This collaborative program brings together diverse expertise and, if successful, will provide a highly innovative approach to malaria vaccine development that is expected to have a lasting impact on vaccine research.

抽象的 长期以来，已知疟疾特异性的CD8+ T细胞可以控制疟疾的肝脏阶段。我们最近显示 它们还可以杀死被疟原虫体内感染的网状细胞。但是，T细胞靶向抗原 由主要的组织相容性复合物（MHC）I类分子在寄生虫感染的细胞上提出 在很大程度上未知；缺乏知识阻碍了理性设计的T细胞的发展 基于疟疾的疫苗。在初步实验中，我们确定了P. Vivax感染的网状细胞。该分析表明，许多MHC-I结合的肽都是从 丰富的家具蛋白质（例如组蛋白和核糖体蛋白）在高度保守的 疟原虫物种 - 目前未在疫苗策略中表示的靶标。因此，这个发现创造了 开发泛质疫苗的独特机会，从而引发T细胞到经过验证的靶标。不料， 在多个捐赠者中发现了几个宠物，无论其MHC-Haplotype和我们的初步数据如何 表明这部分是由于在非甲状腺型MHC-IB分子MHC-E上的剥离呈现。因此，我们 假设MHC-E限制的CD8+ T细胞有助于T细胞介导的对疟疾和 可以使用巨细胞病毒（CMV）的矢量来探索疫苗设计，这是唯一的平台 可以对此进行编程以引起对插入抗原的MHC-E限制的CD8+ T细胞反应。这个假设 将使用P. cynomolgi非人类私有模型的Vivax的cynomolgi非人类私有模型在三个特定目标中进行测试 在人类疟原虫感染的样品中验证：在AIM 1中，我们将确定MHC-E对 在CD8+ T细胞中呈现斑vax肽，并研究MHC-E靶向在CD8+ T中的可能作用 受感染的网状细胞（IRETICS）的细胞杀死。在AIM 2中，我们将表征个体P. vivax的作用 MHC-E限制的CD8+ T细胞靶标的抗原。这将通过识别MHC-来实现 E/肽特异性T细胞受体，并检查了TCR转染T细胞靶向IRETICS的能力。在 此外，我们将同样地表征MHC-E限制的CD8+ T细胞，这些CD8+ T细胞引起了恒河的选定抗原 用普遍修饰的恒河虫巨细胞病毒载体（RHCMV）免疫的猕猴，仅引起 MHC-E限制的CD8+ T细胞。在AIM 3中，我们将比较基于RHCMV的P. vivax疫苗引起MHC-E或 MHC-IA对选定的反应构成了抗原的抗原，以保护P。 恒河猕猴中的cynomolgi挑战。具体来说，我们将监视针对肝脏阶段的保护 一级血液阶段和因休眠肝脏阶段引起的血液阶段。这个协作计划 汇集了潜水员的专业知识，如果成功，将为疟疾提供一种高度创新的方法 预计对疫苗研究产生持久影响的疫苗开发。