Virus-like Particle based malaria vaccines targeting vulnerable epitopes in the circumsporozoite protein

针对环子孢子蛋白中脆弱表位的基于病毒样颗粒的疟疾疫苗

基本信息

批准号：
10606388
负责人：
Bryce C Chackerian
金额：
$ 63.78万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-09 至 2027-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606388
关键词：
5 year old Adjuvant Animal Model Antibodies Antibody Response Antigens Antiparasitic Agents Area Avidity B-Cell Antigen Receptor B-Lymphocytes Bacteriophages Blood Cause of Death Cessation of life Child Clinical Trials Data Development Disease Engineering Epitopes Erythrocytes Event Falciparum Malaria Goals Hepatocyte Hour Immune Immune Targeting Immune response Immunity Immunize Immunology Infection Invaded Life Cycle Stages Liver Malaria Malaria Vaccines Measures Mediating Minor Modeling Monitor Monoclonal Antibodies Morbidity - disease rate Mus N-terminal Parasites Passive Immunization Persons Phenotype Plasmodium Plasmodium falciparum Proteins Public Health Publishing Research Personnel Site Source Sporozoites Surface Techniques Testing Time Transgenic Organisms Vaccines Virus-like particle Work cell motility circumsporozoite protein design effectiveness measure experience fighting immunogenic immunogenicity liver infection malaria infection mortality mouse model nanoparticle novel pathogen prevent prophylactic protective efficacy response technology platform tool transmission process vaccine candidate vaccine effectiveness vaccine platform vaccine-induced antibodies

5 year old Adjuvant Animal Model Antibodies Antibody Response Antigens Antiparasitic Agents Area Avidity B-Cell Antigen Receptor B-Lymphocytes Bacteriophages Blood Cause of Death Cessation of life Child Clinical Trials Data Development Disease Engineering Epitopes Erythrocytes Event Falciparum Malaria Goals Hepatocyte Hour Immune Immune Targeting Immune response Immunity Immunize Immunology Infection Invaded Life Cycle Stages Liver Malaria Malaria Vaccines Measures Mediating Minor Modeling Monitor Monoclonal Antibodies Morbidity - disease rate Mus N-terminal Parasites Passive Immunization Persons Phenotype Plasmodium Plasmodium falciparum Proteins Public Health Publishing Research Personnel Site Source Sporozoites Surface Techniques Testing Time Transgenic Organisms Vaccines Virus-like particle Work cell motility circumsporozoite protein design effectiveness measure experience fighting immunogenic immunogenicity liver infection malaria infection mortality mouse model nanoparticle novel pathogen prevent prophylactic protective efficacy response technology platform tool transmission process vaccine candidate vaccine effectiveness vaccine platform vaccine-induced antibodies

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项目摘要

PROJECT SUMMARY The Plasmodium falciparum circumsporozoite protein (CSP) is an attractive malaria vaccine candidate because anti-CSP antibodies can block liver invasion and potentially provide sterilizing immunity against the parasite. However, current vaccines that target CSP, including RTS,S, the most advanced malaria vaccine, elicit suboptimal protective immunity that wanes dramatically over time. In this proposal, our goal is to engineer new and more effective vaccines targeting CSP. We will take advantage of the recent identification of potently protective monoclonal antibodies that target epitopes within novel sites of vulnerability in CSP. We will specifically target these epitopes using a highly immunogenic bacteriophage virus-like particle (VLP) vaccine platform technology. In preliminary data, we have shown that VLP-based immunogens targeting short epitopes within CSP can elicit high-titer and long-lasting antibody responses that inhibit Plasmodium infection of the liver and can prevent blood-stage infection in mice. In this proposal, we will utilize an arsenal of approaches to maximize the immunogenicity of VLP-based vaccines (Aim 1), we will use sensitive techniques to carefully monitor the B cell responses to our vaccines (Aim 2), and we will measure the effectiveness of vaccines in a state-of-the-art mouse infection model (Aim 3). Our team, which has expertise in vaccine engineering and design, B cell immunology, and malaria challenge models, will carry out these Aims with the ultimate goal of identifying a pre-erythrocytic malaria vaccine candidate suitable of advancing to clinical trials.

项目摘要恶性疟原虫外孢菌岩蛋白（CSP）是一种吸引人的疟疾疫苗，因为抗CSP抗体可以阻止肝脏侵袭并可能对寄生虫提供灭菌性。但是，当前针对CSP的疫苗，包括RTS，S，最先进的疟疾疫苗，引起随着时间的流逝，次优的保护免疫会大大减轻。在此提案中，我们的目标是设计新的以及针对CSP的更有效的疫苗。我们将利用最近对靶向CSP脆弱性的新部位的保护性单克隆抗体。我们将使用高度免疫原性的噬菌体病毒样颗粒（VLP）疫苗专门针对这些表位平台技术。在初步数据中，我们已经表明，基于VLP的免疫原靶向短期表位在CSP内部可以引起抑制肝脏感染的高素质和持久抗体反应并可以防止小鼠的血液阶段感染。在此提案中，我们将利用一种方法最大化基于VLP的疫苗的免疫原性（AIM 1），我们将使用敏感技术仔细监视B细胞对我们疫苗的反应（AIM 2），我们将测量A中疫苗的有效性最新的小鼠感染模型（AIM 3）。我们的团队在疫苗工程和设计方面具有专业知识， B细胞免疫学和疟疾挑战模型将执行这些目标，其最终目标是确定肉毒杆菌前疟疾疫苗候选者适合前进到临床试验。