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

基本信息

批准号：
9982274
负责人：
Klaus J Fruh
金额：
$ 74.78万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982274
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 Research Rhesus 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 preclinical evaluation programs protective effect prototype recruit research clinical testing response tool vaccine candidate vaccine development vector

项目摘要

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.

概括针对疟疾的灭菌疫苗的开发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疫苗已经表现出巨大的前景，到目前为止不可能引起维持所需的长期免疫力随着时间的推移保护。我们建议将一种从根本上使用新的疫苗工具应用于疟疾疫苗研究： persistent effector memory T cell-eliciting vaccines based on cytomegalovirus (CMV).通过利用 CMV引起和维持高频，无需竭尽全力的终身细胞免疫的自然能力证明基于CMV的疫苗可以预防高毒性病原体，例如猿猴免疫 - 缺乏病毒和结核分枝杆菌。我们的工作对消除艾滋病的希望更新了，我们是现在在CMV/HIV疫苗的临床开发中。在初步工作中，我们现在还表明了基于CMV的含有有限疟疾抗原的疟疾疫苗减轻了血液阶段之前的寄生虫负担发展。该提案的核心目标是进一步改善此保护，以生成消毒免疫力。我们将采用基于CMV的疫苗的独特免疫学特征设计CMV-VACCINE，募集不同类型的细胞毒性T细胞以消除寄生虫阶段。具体而言，我们将解决常规的MHC-I限制CD8+ T细胞与非常规的作用在保护中，MHC-II和MHC-E限制的CD8+ T细胞。我们还将扩大寄生虫的光谱抗原通过在疟疾前肉毒杆菌前的疫苗靶标包括一组新的疫苗靶标。这些新的疫苗根据对人类T细胞免疫的系统评估和鼠的验证选择目标疟疾模型。 Finally we will extend the immune responses and protective effects elicited by heterologous 通过加强CMV向量引发MHC-I限制CD8+ T细胞识别识别的CMV-VECTOR来提高质量/增强免疫免疫主导和亚辅助表位。我们预计该项目将验证CMV为新疫苗接种疟疾的方法。