High-Throughput TB Vaccine Antigen Discovery

项目摘要/摘要： 世界上大约三分之一的人口感染了潜伏性结核病(LTBI)。而卡介苗 接种疫苗可以保护一些儿童免受儿童结核性脑膜炎的侵袭，但它并不能最大限度地预防 流行的疾病形式是成人肺结核病。到目前为止，每一种新的结核病疫苗 候选人在大规模临床试验中失败，没有已知的结核病疫苗保护的免疫相关性 都经过了验证。新的结核病疫苗如MVA-85A失败，尽管产生了高强度的Th1 对免疫优势抗原Ag85A的免疫反应可能与独占使用 这些疫苗中的免疫显性抗原，尽管免疫显性反应与 疫苗的效力。这些事实突显了发现新的亚优势结核抗原用于治疗的迫切需要 可以增强功能免疫和细菌杀灭的结核病疫苗。在这里，我们提出了一种新的结核抗原 发现平台，使系统和公正的结核病全基因组DNA疫苗探测成为可能 图书馆，总体目标是识别新的结核病抗原。我们的具体目标是产生免疫力 小鼠对亚群抗原的反应及鉴定新的亚群免疫原 具有诱导保护性免疫的能力。我们的目标是通过活体讯问结核病来做到这一点 使用小鼠挑战模型的蛋白质组。我们的长期目标是向结核病疫苗设计提供信息，并 发现结核病疫苗保护的新免疫关联。实现这些目标有能力 改变结核病疫苗领域，为开发有效的结核病疫苗做出贡献。巴鲁奇 贝丝以色列女执事医疗中心的实验室在疫苗设计和发现方面处于领先地位， 艾滋病毒和寨卡病毒感染。我的目标是将我在结核病细菌学和动物模型方面的专业知识与 在病毒学和疫苗研究中心加强免疫学和疫苗学培训，以获得 将自己定位为结核病疫苗发现领域的领导者所需的技能，作为主要研究人员和 我自己的研究小组的负责人。

Project Summary/Abstract: Approximately one third of the world's population is infected with latent tuberculosis (LTBI). While BCG vaccination protects some children against pediatric tuberculous meningitis, it does not prevent the most prevalent form of disease, pulmonary TB disease in adults. To date, every new tuberculosis (TB) vaccine candidate has failed in large-scale clinical trials and no known immune correlates of vaccine protection for TB have been validated. Failure of new TB vaccines such as MVA-85A, despite generating high-magnitude Th1 immune responses against the immunodominant antigen, Ag85A, is likely related to the exclusive use of immunodominant antigens in these vaccines, despite poor correlation of immunodominant responses with vaccine efficacy. These facts highlight a critical need for discovery of novel subdominant TB antigens for use in TB vaccines that can enhance functional immunity and bacterial killing. Here we propose a novel TB antigen discovery platform that enables systematic and unbiased probing of a TB genome-wide DNA vaccine library with the overall objective to identify new TB antigens. Our specific aims are to generate immune responses to pooled subdominant antigens in mice and to identify novel subdominant immunogens with capacity to induce protective immunity. We aim to do this by in vivo interrogation of the TB proteome using the mouse challenge model. Our long-term goal is to inform TB vaccine design and to uncover novel immune correlates of vaccine protection for TB. Achieving these aims has the capacity to transform the TB vaccine field and contribute to the development of an efficacious TB vaccine. The Barouch laboratory at Beth Israel Deaconess Medical Center leads in vaccine design and discovery for diseases such as HIV and Zika virus infection. I aim to synergize my expertise in TB bacteriology and animal models with enhanced training in immunology and vaccinology at the Center for Virology and Vaccine Research to gain the skills necessary to position myself to become a leader in TB vaccine discovery as a principle investigator and head of my own research group.