Infection-blocking antibody targets for malaria

疟疾感染阻断抗体靶点

基本信息

批准号：
9247922
负责人：
Stefan HI Kappe
金额：
$ 85.05万
依托单位：
SEATTLE BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247922
关键词：
ART protein Active Immunization Animal Model Anopheles Genus Antibodies Antibody Repertoire Antibody Response Antibody-mediated protection Antigen Targeting Antigens Antimalarials B-Lymphocytes Bite Blocking Antibodies Blood Cessation of life Clinical Clinical Trials Clone Cells Culicidae Dermis Development Disease Economics Ensure Erythrocytes Evaluation Exhibits Falciparum Malaria Goals Hepatocyte Human Humoral Immunities Immune response Immunity Immunization In Vitro Infection Infection prevention Injectable Life Cycle Stages Liver Malaria Malaria Vaccines Mediating Modeling Mus Outcome Parasites Pathway interactions Phase Plasmodium Plasmodium falciparum Plasmodium yoelii Population Production Protein Subunits Proteins Proteome Proteomics Recombinant Proteins Rodent Rodent Model Scheme Serological Skin Sporozoites Sterility Stream Subunit Vaccines Surface System T-Lymphocyte Techniques Technology Testing Transgenic Organisms Vaccination Vaccine Design Vaccines base circumsporozoite protein cost effective data modeling design disorder prevention evidence base falls gene replacement global health humanized antibody humanized monoclonal antibodies humanized mouse immunogenicity improved innovation liver infection malaria infection malaria transmission mouse model neutralizing antibody next generation novel novel vaccines pathogen polyclonal antibody prevent protective efficacy protein expression public health relevance response vaccine candidate vaccine development vaccine efficacy vaccine evaluation vaccine trial

项目摘要

DESCRIPTION (provided by applicant): A vaccine capable of targeting and neutralizing sporozoites, the infectious stage of the malaria parasites injected by mosquito bite, remains a promising target for preventing malaria infection and transmission. Analysis of malaria vaccine trials has shown that antibodies can neutralize the sporozoite and prevent infection of the liver. However, the most clinically advanced pre-erythrocytic vaccine candidate based on the circumsporozoite protein (CSP) confers only partial protection, indicating that it is necessary to add new antigen targets to increase vaccine efficacy. The overall goal of this proposal is to evaluate novel Plasmodium falciparum pre-erythrocytic antigen candidates that can elicit protective immunity from infection. Building on our recent unprecedented characterization of the P. falciparum sporozoite surface/secreted proteome, we have identified a number of promising surface/secreted antigens that warrant interrogation as new vaccine candidates. Based on this evidence, we will develop 15 P. falciparum sporozoite surface/secreted antigens in a state-of-the-art recombinant protein expression platform and evaluate whether they can elicit protective immunity against mosquito bite sporozoite infection. We will employ an innovative combination of transgenic Plasmodium parasite technology, B cell cloning techniques and humanized rodent models to develop a comprehensive pre-erythrocytic antigen development pipeline for analysis of antibody-mediated protection. In addition, we will evaluate the mechanisms of vaccine-elicited protective humoral immunity against the parasite and deepen our understanding of B cell-mediated protective immunity. Our experimental systems to study the human pathogen P. falciparum in a fully humanized humoral immunogenicity mouse model and a liver- humanized mouse challenge model will ensure our results provide the closest possible approximation of vaccination-elicited responses in humans. The outcomes of our aims will provide an evidence-based selection of novel vaccine candidates and will accelerate their pathway toward human clinical trials using the P. falciparum challenge model. If successful, novel non-CSP vaccine immunogens identified can be considered for inclusion into next generation multi-antigen subunit malaria vaccines.

描述（由申请人提供）：能够靶向和中和子孢子（蚊虫叮咬所注入的疟疾寄生虫的传染阶段）的疫苗仍然是预防疟疾感染和传播的有希望的目标。疟疾疫苗试验的分析表明，抗体可以中和子孢子。然而，基于环子孢子蛋白（CSP）的临床最先进的前红细胞候选疫苗只能提供部分保护，这表明有必要添加新的抗原靶点以提高疫苗功效，该提案的总体目标是在我们最近对恶性疟原虫子孢子进行前所未有的表征的基础上，对恶性疟原虫前红细胞抗原候选物进行新的评估。通过表面/分泌蛋白质组，我们已经确定了许多有前景的表面/分泌抗原，值得将其作为新的候选疫苗。基于这一证据，我们将开发 15 种恶性疟原虫。我们将采用转基因疟原虫寄生虫技术、B细胞克隆技术和人源化技术的创新组合，在最先进的重组蛋白表达平台中检测子孢子表面/分泌的抗原，并评估它们是否能够引发针对蚊子叮咬子孢子感染的保护性免疫。啮齿动物模型，开发全面的红细胞前抗原发育管道，用于分析抗体介导的保护。此外，我们将评估疫苗引发的针对寄生虫的体液保护性免疫的机制，并加深我们的理解。我们在完全人源化体液免疫原性小鼠模型和肝脏人源化小鼠攻击模型中研究人类病原体恶性疟原虫的实验系统将确保我们的结果提供最接近的疫苗接种引起的反应。我们的目标结果将提供基于证据的新型候选疫苗选择，并将加速其使用恶性疟原虫攻击模型进行人体临床试验的进程，如果成功，可以鉴定出新型非 CSP 疫苗免疫原。考虑纳入下一代多抗原亚单位疟疾疫苗。