An Effector Memory T Cell-Inducing Subunit Vaccine against Malaria

一种针对疟疾的效应记忆 T 细胞诱导亚单位疫苗

基本信息

批准号：
8423271
负责人：
Klaus J Fruh
金额：
$ 21.88万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8423271
关键词：
AIDS Vaccines Adhesions Alveolar Animals Anopheles Genus Antibodies Antigen Presentation Antigens Antimalarials Apical Appearance Bacterial Artificial Chromosomes Blood CD8B1 gene Chloroquine Codon Nucleotides Control Groups Culicidae Cytomegalovirus Data Development Disease Drug resistance Generations Genes Genome Genomics Goals Herpesviridae Human Immune Immune response Immunity Immunization Individual Infection Infection prevention Intravenous Irrigation Life Liver Lung Lymphocyte Macaca mulatta Malaria Malaria Vaccines Mediating Membrane Proteins Memory Merozoite Surface Protein 1 Modeling Monitor Mus Parasite resistance Parasitemia Parasites Parasitic Diseases Peptides Plasmodium Plasmodium knowlesi Play Proteins Recombinants Role SELL gene SIV Salivary Glands Sporozoites Staging Sterility Subunit Vaccines T cell response T memory cell T-Lymphocyte Technology Testing Tissues Vaccinated Vaccination Vaccines Virus Virus Inhibitors apical membrane artesunate base circumsporozoite protein cohort exhaustion immunogenicity improved liver biopsy nonhuman primate novel prevent public health relevance response tool vector vector vaccine vector-based vaccine

AIDS Vaccines Adhesions Alveolar Animals Anopheles Genus Antibodies Antigen Presentation Antigens Antimalarials Apical Appearance Bacterial Artificial Chromosomes Blood CD8B1 gene Chloroquine Codon Nucleotides Control Groups Culicidae Cytomegalovirus Data Development Disease Drug resistance Generations Genes Genome Genomics Goals Herpesviridae Human Immune Immune response Immunity Immunization Individual Infection Infection prevention Intravenous Irrigation Life Liver Lung Lymphocyte Macaca mulatta Malaria Malaria Vaccines Mediating Membrane Proteins Memory Merozoite Surface Protein 1 Modeling Monitor Mus Parasite resistance Parasitemia Parasites Parasitic Diseases Peptides Plasmodium Plasmodium knowlesi Play Proteins Recombinants Role SELL gene SIV Salivary Glands Sporozoites Staging Sterility Subunit Vaccines T cell response T memory cell T-Lymphocyte Technology Testing Tissues Vaccinated Vaccination Vaccines Virus Virus Inhibitors apical membrane artesunate base circumsporozoite protein cohort exhaustion immunogenicity improved liver biopsy nonhuman primate novel prevent public health relevance response tool vector vector vaccine vector-based vaccine

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项目摘要

DESCRIPTION (provided by applicant): The ultimate goal of this project is to develop a sterilizing vaccine against malaria. The specific hypothesis tested in this proposal is that sterilizing immunity against malaria can be achieved by induction of a lasting effector memory T cell (TEM) response targeting the liver stage of Plasmodium parasites. Repeated immunizations with live or irradiated sporozoites are known to protect vaccinated individuals against malaria challenge. Recent evidence suggests that this protection correlated with the presence of frequent pluripotent TEM, suggesting that permanent sterilizing immunity against malaria requires the induction of high levels of long-lived TEM by vaccination. To test this hypothesis, we propose to use recombinant cytomegalovirus (CMV) as a vaccine vector because CMV is the prototypical virus inducing long-lived TEM that do not show signs of T cell exhaustion. This unique capability of CMV-vectors was recently applied to induce long-lived TEM against simian immunodeficiency virus, resulting in protection against SIV-challenge that was by far superior to conventional heterologous prime/boost vaccines with respect to efficacy and duration. Since sterilizing protection against Plasmodium knowlesi parasites was only partial and shortlived when heterologous prime/boost vaccines were used, we will examine whether CMV-derived vaccine vectors will similarly confer lasting and efficacious immunity against challenge with Plasmodium knowlesi (Pk) sporozoites. We propose to generate recombinant RhCMV expressing four Pk antigens previously used for heterologous prime boost vaccination: the circumsporozoite protein (CSP), the sporozoite surface protein 2 or thrombospondin-related adhesion protein (SSP2 or TRAP), the apical merozoite antigen-1 (AMA1) and the C-terminus of the merozoite surface protein 1 (MSP1c). We will inoculate animals with this panel of four recombinant RhCMV/Pk vectors and monitor the development of TEM in blood, lung and liver. To determine whether the RhCMV/Pk4 vaccine is protective we will challenge with P. knowlesi sporozoites. Upon completion of this exploratory project, we will thus know whether a TEM-inducing vaccine can improve the level and duration of sterilizing immunity induced by subunit vaccines against malaria parasites.

描述（由申请人提供）：该项目的最终目标是开发针对疟疾的疫苗。该提案中检验的特定假设是，可以通过诱导靶向疟原虫寄生虫肝脏阶段的持久效应记忆T细胞（TEM）反应来实现对疟疾的灭菌性。已知用活或辐照的子孢子反复进行免疫接种，可以保护接种疫苗的个体免受疟疾的挑战。最近的证据表明，这种保护与频繁多能TEM的存在相关，这表明对疟疾的永久性消毒免疫需要通过疫苗接种诱导高水平的长寿命TEM。为了检验这一假设，我们建议将重组巨细胞病毒（CMV）用作疫苗载体，因为CMV是诱导不显示T细胞衰竭迹象的长寿命TEM的原型病毒。最近，采用了CMV向量的这种独特能力，以诱导长寿的TEM抵抗SIMIAN免疫缺陷病毒，从而防止SIV-挑战，该siv-challenge的保护范围远优于传统的异源质量/增强疫苗，相对于效率和持续时间。由于使用异源质子/增强疫苗时，对疟原虫寄生虫的灭菌保护仅是部分和短暂的，因此我们将检查CMV衍生的疫苗载体是否同样会类似地赋予持久有效的免疫力，以防止质量植入率（PK）Sporozoites质量挑战。我们建议生成先前用于异源质量增强疫苗接种的四种PK抗原的重组RHCMV：绕过孢子菌蛋白（CSP），Sporozoite表面蛋白2或与蛋白相关的蛋白相关粘附蛋白（SSP2或TRAP），Apical Merozoite抗元素抗元素1（AMA1）（Ama11（Ama11）（Ama11）（Ama11（Ama11））（MSP1C）。我们将使用四个重组RHCMV/PK载体的该面板接种动物，并监测血液，肺和肝脏中TEM的发展。为了确定RHCMV/PK4疫苗是否具有保护性，我们将使用P. knowlesi sporozoites进行挑战。因此，在完成此探索项目后，我们将知道诱导温度的疫苗是否可以改善亚基疫苗对疟疾寄生虫诱导的灭菌免疫的水平和持续时间。