A STINGing vaccine for TB

结核病疫苗

• 批准号: 10171783
• 负责人: WILLIAM Ramses BISHAI
• 金额: $ 80.89万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10171783
• 关键词: ATAC-seq; Address; Adult; Aerosols; Alveolar; Animal Model; Anti-Infective Agents; Antibacterial Response; Antitumor Response; Attenuated; Autophagocytosis; Autopsy; BCG Live; BCG Vaccine; Blood; Cause of Death; Cavia; Cell Line; Cells; Cellular Immunity; ChIP-seq; Chromatin; Clinical; Communicable Diseases; Confocal Microscopy; Dendritic Cells; Development; Disease; Engineering; Epigenetic Process; Evaluation; Flow Cytometry; Glycolysis; Histologic; Histones; Human; IRF3 gene; Immune; Immunity; Immunotherapy; Infant; Inflammatory; Inflammatory Response Pathway; Interferons; Intervention; Intravenous; Knockout Mice; Lymphoid Cell; Malignant neoplasm of urinary bladder; Measures; Medicine; Modeling; Mononuclear; Morbidity - disease rate; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Myeloid Cells; Nature; Phagocytosis; Phenotype; Population; Publishing; Pulmonary Tuberculosis; Rattus; Recombinants; Recording of previous events; Route; STING agonists; Safety; Sampling; Sting Injury; Testing; Tissues; Training; Translating; Tuberculosis; Tuberculosis Vaccines; Vaccinated; Vaccination; Vaccines; Virulent; base; cancer cell; cancer immunotherapy; cost effective; cytokine; disorder prevention; effector T cell; efficacy evaluation; epigenetic profiling; improved; in vitro Model; in vivo Model; intravesical; macrophage; metabolomics; monocyte; mortality; mouse model; non-muscle invasive bladder cancer; nonhuman primate; nonhuman tissue; novel; overexpression; peripheral blood; polarized cell; porcine model; prevent; protective efficacy; reactivation from latency; recruit; response; single-cell RNA sequencing; tool; transcriptional reprogramming; transcriptome sequencing; tuberculosis granuloma

PROJECT SUMMARY Tuberculosis (TB) is the leading cause of death from a single infectious disease agent worldwide. Vaccination is the most cost-effective control intervention for any infectious disease. Bacille Calmette–Guérin (BCG) remains the most widely used vaccine in human history, but as currently used it has failed to control TB. Thus, the development of improved vaccines against TB therefore remains a high global priority. Recent studies indicate that BCG, when modified, administered through alternate routes, or used in revaccination, offers improved protection, suggesting that it is well poised to make comeback. We have generated a novel recombinant BCG known as BCG-disA-OE which is engineered to overexpress c-di-AMP, a potent STING agonist Our preliminary studies show that BCG-disA-OE is more effective than BCG-WT (wild type BCG) in prevention of disease (POD) following TB challenge and also as an immunotherapy for non-muscle invasive bladder cancer (NMIBC) where intravesical BCG is currently the first-line therapy. Guinea pigs vaccinated with BCG-disA-OE were significantly better protected against aerosol challenge with virulent M.tb than with BCG-WT, and we found that BCG-disA-OE also showed superior efficacy BCG-WT in rat and mouse models of NMIBC. Compared with BCG-WT, BCG-disA-OE leads to more potent pro-inflammatory cytokine responses in macrophage and bladder cancer cells, a higher degree of proinflammatory epigenetic marks, and greater myeloid cell polarization towards the M1 phenotype—changes that are all consistent with enhanced “trained immunity”, a newly discovered phenomenon characterized by epigenetic and functional reprogramming of innate immune cells. In this application, our central scientific premise is that the addition of STING agonist overexpression to BCG will augment trained immunity changes in macrophages and provide more effective protection against TB. To test these hypotheses, in Aim 1 we will determine the protective efficacy of BCG-disA-OE versus BCG-WT against TB disease in non-human primates (NHPs) and against reactivation of latent tuberculosis in mice. In Aim 2 we will evaluate trained immunity changes induced by the two BCG strains in macrophage cell lines, as well as primary murine, NHP, and human (leukopacs from healthy donors) macrophages. We will include serial sampling of NHP mononuclear cells from blood and BAL of NHPs as well as their post-mortem tissues obtained under Aim 1. In Aim 3, we will characterize polarization of myeloid and lymphoid cell populations in the TB granuloma induced by prior vaccination with BCG-WT versus BCG-disA-OE in mouse and NHP models of TB.

项目摘要 结核病（TB）是全球单一传染病剂死亡的主要原因。疫苗接种 是任何传染病的最具成本效益的控制干预措施。巴奇·塞莱特 - 圭恩（BCG）仍然存在 人类历史上使用最广泛的疫苗，但目前使用的疫苗未能控制结核病。那， 因此，针对结核病的改进疫苗的开发仍然是高度的全球优先事项。最近的研究表明 该BCG修改后，通过替代路线进行管理或在重新接种中使用的BCG提供了改进 保护，表明它有毒品卷土重来。 我们已经产生了一种新型的重组BCG，称为BCG-DISA-OE，该BCG被设计为过表达 C-Di-Amp，潜在的刺痛激动剂我们的初步研究表明，BCG-DISA-OE比 在结核病挑战之后，BCG-WT（野生型BCG）预防疾病（POD），也作为免疫疗法 对于非肌肉浸润性膀胱癌（NMIBC），插入性BCG目前是一线治疗。 通过BCG-DISA-OE接种疫苗的豚鼠可以更好地保护与气溶胶挑战的保护 强度的M.TB比BCG-WT，我们发现BCG-DISA-OE在大鼠中也显示出较高的效率BCG-WT 和NMIBC的鼠标模型。与BCG-WT相比，BCG-DISA-OE会导致更多潜在的促炎性 巨噬细胞和膀胱癌细胞中的细胞因子反应，促炎的表观遗传较高 标记，较大的髓样细胞对M1表型的极化 - 改变与 增强的“受过训练的免疫学”，这是一种以表观遗传和功能为特征的新发现的现象 重新编程先天免疫细胞。 在此应用中，我们的中心科学前提是将刺痛激动剂过表达添加到 BCG将增加巨噬细胞中受过训练的免疫学变化，并为结核病提供更有效的保护。 为了检验这些假设，在AIM 1中，我们将确定BCG-DISA-OE与BCG-WT的受保护效率 反对非人类素数（NHP）中的结核病疾病，并反对小鼠潜在结核的重新激活。在 AIM 2我们将评估由巨噬细胞系中两个BCG菌株诱导的训练的免疫学变化，如 以及主要的鼠，NHP和人类（来自健康供体的白细胞）巨噬细胞。我们将包括串行 从NHP和BAL的NHP单核细胞以及获得的验尸组织取样 在AIM 1。在AIM 3中，我们将表征结核病中髓样和淋巴样细胞种群的极化 在小鼠和NHP模型中，用BCG-WT与BCG-DISA-OE诱导的肉芽肿是由TB的BCG-WT与BCG-DISA-OE诱导的。