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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.

项目概要/摘要拟议研究的总体目标是优化和进一步开发疫苗使用新型平台“多抗原呈递”针对结核分枝杆菌 (Mtb) 系统 (MAPS) 由波士顿儿童医院 (BCH) 的 Malley 实验室开发。最新细菌疫苗基于增强多糖 (PS) 荚膜抗原的免疫原性（确定许多细菌的血清型）通过与蛋白质的化学结合。这些疫苗患有其局限性包括无法引发 CD4+ Th1 或 Th17 对抗原的反应以及抗原的高度复杂性生产。对于多种生物体，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，可通过引发针对 PS 和蛋白质的抗体来提供全面的免疫力， CD4+ Th1 和 Th17 对蛋白质的反应。该技术基于我们的发现，即蛋白质和通过生物素和根抗生物素蛋白之间的亲和力相互作用连接的 PS 表现得像结合蛋白-PS 疫苗，具有对蛋白质产生强大的 CD4+ Th1 和 Th17 反应的额外好处。在初步研究中，我们开发了一种由多种 Mtb 蛋白组成的 TB MAPS 疫苗支架上的非 Mtb PS（肺炎球菌 1 型），显示出对肺部的显着保护小鼠模型中的结核病 (TB)，特别是与活卡介苗疫苗联合使用时；引起的保护通过在不同地点同时给予 TB MAPS 和 BCG 组合，然后给予 2 TB MAPS 与单独使用 BCG 或 TB MAPS 相比，加强剂的效果显着增强。在这里，我们将检查是否通过该 TB MAPS 构建体可以通过包含三种 Mtb 特异性 PS 之一来增强。我们的初步数据有力地支持了这种方法的可行性。为了实现我们的目标，我们聚集了一群研究人员是疫苗开发方面的专家（BCH 的 Malley 博士和来自 BCH 的 Pavliak 博士）韩国国际疫苗研究所 (IVI)，我们的行业合作伙伴）以及结核病研究和动物模型（哈佛大学公共卫生学院的 Rubin 博士和杜兰大学的 Kaushal 博士）。项目因此，这将是学术机构和非营利机构研究人员之间的合作努力在疫苗开发（IVI）方面拥有丰富的经验。在建议的实验中，我们将评估是否在我们当前的 TB MAPS 疫苗中添加 Mtb PS 可增强小鼠模型的保护，选择最佳 TB MAPS 疫苗（即有或没有 Mtb PS，已选择蛋白质），然后评估是否同时（在不同地点）同时给予卡介苗和结核病地图（TB MAPS）在非人灵长类结核病模型中，两次加强剂量的 TB MAPS 优于单独使用 BCG。一个产品开发计划已经制定，由 IVI 牵头。这些实验如果成功，将为进一步开发这种预防结核病的疫苗策略的途径。