High-Throughput TB Vaccine Antigen Discovery

高通量结核疫苗抗原发现

• 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
• 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

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.

项目概要/摘要： 世界上大约三分之一的人口感染了潜伏性结核病（LTBI）。虽然BCG 接种疫苗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结核性脑膜炎。 一种流行的疾病，成年人的肺结核病。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，并且没有已知的结核病疫苗保护的免疫相关性 已经得到验证。MVA-85 A等新型结核病疫苗的失败，尽管产生了高强度的Th 1 针对免疫显性抗原Ag 85 A的免疫应答可能与单独使用 这些疫苗中的免疫显性抗原，尽管免疫显性应答与 疫苗功效。这些事实突出了发现用于治疗结核病的新型亚显性TB抗原的迫切需要。 结核病疫苗可以增强功能性免疫和杀灭细菌。在这里，我们提出了一种新的结核抗原 一个发现平台，能够系统和公正地探测结核病全基因组DNA疫苗 总的目标是鉴定新的TB抗原。我们的具体目标是产生免疫 对小鼠中合并的亚显性抗原的应答和鉴定新的亚显性免疫原 具有诱导保护性免疫的能力我们的目标是通过体内结核病的审讯来做到这一点 蛋白质组使用小鼠攻击模型。我们的长期目标是为结核病疫苗设计提供信息， 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，并为开发有效的结核病疫苗做出贡献。巴鲁什 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， 艾滋病毒和寨卡病毒感染。我的目标是将我在结核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， 使自己成为结核病疫苗发现领域的主要研究者所需的技能， 我自己研究小组的负责人