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Optimization and preclinical development of a TB Multiple Antigen Presenting System (MAPS) vaccine

结核病多抗原呈递系统 (MAPS) 疫苗的优化和临床前开发

基本信息

批准号：
10316230
负责人：
RICHARD MALLEY
金额：
$ 114.45万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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：
2017-12-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10316230
关键词：
Affinity Animal Model Antibodies Antibody Response Antigen Presentation Antigens Autopsy B-Lymphocytes BCG Live BCG Vaccine Bacteria Bacterial Proteins Bacterial Vaccines Binding Biological Assay Biotin Boston Bronchoalveolar Lavage CD4 Positive T Lymphocytes Carrier Proteins Cells Chemicals Chemistry Chimeric Proteins Collaborations Complex Conjugate Vaccines Data Development Development Plans Evaluation Glucans Goals Histopathology Human Immunity Immunization Immunologics Infection Institutes Institution International Investigation Korea Laboratories Lead Link Lung Macaca mulatta Mediating Memory Microbiology Modeling Mucous Membrane Mus Mycobacterium tuberculosis Organism PET/CT scan Pediatric Hospitals Polysaccharides Prevention Prevention strategy Process Proteins Public Health Public Health Schools Pulmonary Tuberculosis Recombinants Research Research Personnel Role Scaffolding Protein Scientist Serotyping Site Streptococcus pneumoniae System T cell response T-Lymphocyte Technology Time Tuberculosis Tuberculosis Vaccines Universities Vaccines Work base booster vaccine experience experimental study immunogenicity industry partner invention link protein lipoarabinomannan mouse model mycobacterial new technology non-tuberculosis mycobacteria nonhuman primate novel novel vaccines preclinical development product development response vaccine candidate vaccine development vaccine efficacy vaccine platform vaccine strategy

项目摘要

Project Summary/Abstract The overall objective of the proposed research is to optimize and further the development of a vaccine directed against Mycobacterium tuberculosis (Mtb) using a novel platform, the Multiple Antigen Presentation System (MAPS) developed by the Malley laboratory at Boston Children’s Hospital (BCH). Most current bacterial vaccines are based on enhancing the immunogenicity of polysaccharide (PS) capsular antigens (which determine serotype in many bacteria) by chemical conjugation to proteins. These vaccines suffer from limitations including an inability to elicit CD4+ Th1 or Th17 responses to antigens and high complexity of manufacture. For several organisms, T cell responses (either alone or in conjunction with antibody responses) are deemed necessary for mucosal or systemic protection. To overcome these limitations, we have developed MAPS, a vaccine platform that confers comprehensive immunity by eliciting antibodies to the PS and proteins, and CD4+ Th1 and Th17 responses to proteins. The technology is based on our discovery that proteins and PS linked via the affinity interaction between biotin and rhizavidin behave like a conjugate protein-PS vaccine, with the added benefit of generating robust CD4+ Th1 and Th17 responses to proteins. In preliminary studies, we have developed a TB MAPS vaccine composed of several Mtb proteins scaffolded onto a non-Mtb PS (pneumococcus type 1) which shows significant protection against pulmonary tuberculosis (TB) in a mouse model, particularly when combined with the live BCG vaccine; protection elicited by the combination of TB MAPS and BCG given concurrently at separate sites followed by 2 TB MAPS boosters is significantly greater compared to BCG or TB MAPS alone. Here, we will examine if protection by this TB MAPS construct can be augmented by the inclusion of one of three Mtb-specific PS. Our preliminary data strongly support the feasibility of this approach. To meet our goals, we have assembled a group of investigators that are experts in vaccine development (Dr. Malley from BCH and Dr. Pavliak from the International Vaccine Institute (IVI) in Korea, our industry partner) and tuberculosis research and animal models (Dr. Rubin from Harvard School of Public Health and Dr. Kaushal from Tulane University). The project will thus be a collaborative effort between investigators from academic institutions and a nonprofit agency with extensive experience in vaccine development (IVI). In the proposed experiments, we will evaluate whether the addition of Mtb PS to our current TB MAPS vaccine enhances protection in the mouse model, select the optimal TB MAPS vaccine (i.e. with or without Mtb PS, the proteins having been already selected) and then evaluate whether the combination of BCG given concurrently (at separate sites) with TB MAPS then followed by two booster doses of TB MAPS is superior to BCG alone in a nonhuman primate model of tuberculosis. A Product Development Plan has been prepared, which IVI will lead. These experiments, if successful, will pave the way for further development of this vaccine strategy for the prevention of TB.

项目总结/摘要拟议研究的总体目标是优化和进一步开发疫苗利用一种新的平台，多抗原呈递，系统（MAPS）开发的马利实验室在波士顿儿童医院（BCH）。最新细菌疫苗基于增强多糖（PS）荚膜抗原的免疫原性（在许多细菌中决定血清型）通过化学结合蛋白质。这些疫苗会导致局限性包括不能引起对抗原的CD 4 + Th 1或Th 17应答和免疫调节的高度复杂性。制造。对于几种生物体，T细胞反应（单独或与抗体反应结合）被认为是粘膜或全身保护所必需的。为了克服这些限制，我们开发了 MAPS是一种疫苗平台，通过引发针对PS和蛋白质的抗体来赋予全面的免疫力，以及CD 4 + Th 1和Th 17对蛋白质的应答。这项技术是基于我们发现蛋白质和通过生物素和rhizavidin之间的亲和相互作用连接的PS表现得像缀合蛋白-PS疫苗，并具有产生对蛋白质的稳健的CD 4 + Th 1和Th 17应答的额外益处。在初步研究中，我们已经开发了由几种Mtb蛋白组成的TB MAPS疫苗支架上的非结核分枝杆菌PS（肺炎球菌1型），显示出显着的保护，结核病（TB）在小鼠模型中，特别是当与活BCG疫苗组合时; 在不同的部位同时给予TB MAPS和BCG，然后给予2 TB MAPS 与单独的BCG或TB MAPS相比，加强剂显著更大。在这里，我们将研究是否保护该TB MAPS构建体可以通过包括三种Mtb特异性PS之一来增强。我们的初步数据有力地支持了这一方法的可行性。为了实现我们的目标，我们召集了一组研究人员是疫苗开发专家（来自BCH的Malley博士和来自韩国国际疫苗研究所（IVI），我们的行业合作伙伴）和结核病研究和动物模型（来自哈佛公共卫生学院的鲁宾博士和杜兰大学的考沙尔博士）。项目因此，这将是学术机构和非营利机构的调查人员之间的合作努力，在疫苗开发（IVI）方面的丰富经验。在拟议的实验中，我们将评估是否在我们目前的TB MAPS疫苗中添加Mtb PS增强了小鼠模型中的保护作用，最佳TB MAPS疫苗（即有或没有Mtb PS，蛋白质已经选择），然后评估BCG与TB MAPS同时给药（在不同的研究中心）之后是否在非人灵长类动物结核病模型中，通过两次加强剂量的TB MAPS上级单独的BCG。一产品开发计划已经制定，IVI将领导该计划。这些实验如果成功，进一步发展这种预防结核病的疫苗战略的途径。