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

项目摘要/摘要 拟议研究的总体目标是优化和进一步开发疫苗。 针对结核分枝杆菌(Mtb)的一种新平台--多抗原呈递 系统(MAP)由波士顿儿童医院(BCH)的马利实验室开发。最新版本 细菌疫苗的基础是增强多糖(PS)囊膜抗原的免疫原性 (它决定了许多细菌的血清型)通过与蛋白质的化学结合。这些疫苗会受到 限制包括不能诱导CD4+Th1或Th17对抗原的反应以及高度复杂性 制造。对于几种生物，T细胞反应(单独或与抗体反应联合) 被认为是粘膜或系统保护所必需的。为了克服这些限制，我们开发了 MAPS是一个疫苗平台，通过诱导针对PS和蛋白质的抗体来提供全面的免疫力， 以及CD4+Th1和Th17对蛋白质的反应。这项技术是基于我们的发现，蛋白质和 通过生物素和根抗生物素之间的亲和作用连接起来的PS类似于结合蛋白-PS疫苗， 还有一个额外的好处，就是对蛋白质产生强大的CD4+Th1和Th17反应。 在初步研究中，我们开发了一种由几种结核分枝杆菌蛋白组成的结核分枝杆菌MAP疫苗。 脚手架固定在非结核分枝杆菌PS(1型肺炎球菌)上，对肺炎具有显著的保护作用 小鼠模型中的结核病(TB)，特别是与卡介苗活疫苗结合时；产生保护作用 通过在不同地点同时给予结核病地图和卡介苗，然后是2 TB地图的组合 与单独的卡介苗或结核病地图相比，Booster的作用要大得多。在这里，我们将检查是否通过 可以通过包括三个结核分枝杆菌特定的PS之一来扩大该结核分枝杆菌图谱的构建。我们的预赛 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，我们召集了一批 是疫苗开发专家的研究人员(BCH的Malley博士和BCH的Pavliak博士 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 模特(哈佛大学公共卫生学院的鲁宾博士和杜兰大学的考沙尔博士)。该项目 因此将是学术机构的研究人员和一个非营利性机构之间的合作努力 在疫苗开发(IVI)方面有丰富的经验。在建议的实验中，我们会评估 在我们目前的结核分枝杆菌MAP疫苗中添加结核分枝杆菌PS可增强对小鼠模型的保护，请选择 最佳结核病地图疫苗(即，有或没有结核分枝杆菌PS，蛋白质已经被选择)，然后 评估同时(在不同的地点)给予卡介苗与结核病地图的组合是否随后进行 在非人类灵长类结核病模型中，通过两次加强剂量的结核病，MAP优于单独使用卡介苗。一个 已经制定了产品开发计划，IVI将牵头制定该计划。这些实验如果成功，将为 进一步发展这一预防结核病的疫苗战略的方法。

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.