High-Throughput TB Vaccine Antigen Discovery

高通量结核疫苗抗原发现

基本信息

批准号：
9767017
负责人：
Amanda Martinot
金额：
$ 15.85万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767017
关键词：
Adenovirus Vector Adult Animal Model Animals Antigens Antitubercular Agents BCG Live BCG Vaccine Bacteriology CD8-Positive T-Lymphocytes Cells Child Childhood Clinical Trials Communicable Diseases Coupled DNA Vaccines Data Development Disease Expression Library Failure Gene Library Genes Genome Goals Growth HIV HIV vaccine Head Immune Immune response Immunity Immunodominant Antigens Immunology Infection Interferon Type II Israel Knowledge Laboratories Libraries Lymphocyte antigen Medical center Meningeal Tuberculosis Mentorship Microbiology Modeling Mucous Membrane Mus Open Reading Frames Population Positioning Attribute Proteins Proteome Pulmonary Tuberculosis Research Research Personnel Surface T cell response T memory cell T-Lymphocyte Testing Training Tuberculosis Tuberculosis Vaccines Vaccine Antigen Vaccine Design Vaccine Research Vaccines Whole Cell Vaccine Work ZIKV infection deep sequencing design genome-wide immunogenic immunogenicity immunopathology in vivo innovation mouse model mycobacterial new technology novel novel vaccines prevent primary endpoint protective efficacy response skills translational medicine vaccination against tuberculosis vaccine candidate vaccine development vaccine discovery vaccine efficacy vaccinology virology

项目摘要

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.

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）。而卡介苗疫苗接种可以保护一些儿童免受小儿结核性脑膜炎的侵害，但它并不能预防大多数儿童成人肺结核病的流行形式。迄今为止，每种新的结核病 (TB) 疫苗候选者在大规模临床试验中失败，并且没有已知的结核病疫苗保护免疫相关性已被验证。尽管产生了高强度的 Th1，但 MVA-85A 等新型结核病疫苗仍失败针对免疫显性抗原 Ag85A 的免疫反应可能与单独使用尽管免疫显性反应与这些疫苗中的免疫显性抗原的相关性较差疫苗功效。这些事实突出表明迫切需要发现新的亚显性结核抗原以用于结核疫苗可以增强功能性免疫力和杀灭细菌的作用。在这里，我们提出了一种新型结核病抗原能够系统、公正地探索结核病全基因组 DNA 疫苗的发现平台库的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对小鼠中混合的亚优势抗原的反应并鉴定新的亚优势免疫原具有诱导保护性免疫的能力。我们的目标是通过体内检测结核病来做到这一点使用小鼠挑战模型的蛋白质组。我们的长期目标是为结核病疫苗设计提供信息并揭示结核病疫苗保护的新免疫相关性。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。巴鲁克酒店贝斯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，例如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加强病毒学和疫苗研究中心的免疫学和疫苗学培训，以获得使自己成为结核病疫苗研发领域的主要研究者和领导者所需的技能我自己的研究小组的负责人。