SigH based attenuated, efficacious Mtb vaccines to protect against lethal TB

基于 SigH 的减毒、有效 Mtb 疫苗可预防致命结核病

• 批准号: 10398248
• 负责人: Chinnaswamy Jagannath
• 金额: $ 86.73万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-17 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398248
• 关键词: Address; Adult; Aerosols; Alleles; Antigens; Attenuated; BCG Vaccine; Biology; Bronchus-Associated Lymphoid Tissue; CD4 Positive T Lymphocytes; Cessation of life; Clinical; Communicable Diseases; Consensus; Disease; Dose; Ensure; Equilibrium; Failure; Fortune; Genes; Granuloma; Growth; Human; Immune; Immunocompetent; In Vitro; Infection; Interruption; Life Cycle Stages; Lung; Macaca; Memory; Microdissection; Modeling; Mus; Mutation; Mycobacterium tuberculosis; Nature; Phenotype; Physiological; Pulmonary Tuberculosis; Recombinants; Recommendation; SCID Mice; SIV; Safety; Signal Transduction; Stress; Testing; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccines; Virulence; Virulence Factors; Work; attenuation; auxotrophy; base; clinical development; co-infection; comparative; confocal imaging; efficacy evaluation; efficacy study; experience; experimental study; immunogenic; immunogenicity; in silico; macrophage; mortality; mutant; novel; novel vaccines; preclinical safety; product development; response; safety testing; stem; vaccine candidate

Abstract Infection with M. tuberculosis (Mtb) can cause TB, which is now the leading global cause of mortality due to a single infectious disease agent. The failure to control TB stems from the lack of an effective vaccine. BCG, the vaccine currently in use, is unable to generate long-lived memory responses and protect against pulmonary TB in adults. New vaccines against TB are therefore, urgently needed. Our work has shown that the ΔsigH mutant of Mtb is attenuated for replication and disease in macaques). Aerosol vaccination with this mutant induces strong lung immune signatures that protect against lethal TB. Nonpathogenic ΔsigH infection in macaques is not reactivated by SIV co-infection. Additional unrelated mutation(s) are however needed in ΔsigH to ensure its complete attenuation. This project aims to develop a ΔsigH -based human TB vaccine candidate that could eventually advance to clinical development. ΔsigH deletion will be added to 10 recombinant Mtb strains. Some of these mutants generate immune enhancement- or auxotrophy-based attenuation phenotypes, while others render Mtb avirulent in macaque lungs. We will assess the safety of these ten strains in SCID mice and progressively smaller numbers in immunocompetent and SIV co-infected macaques by multiplexing. Two strains that consistently provide the best results in terms of safety/immunogenicity will be evaluated in detail for immunogenicity and efficacy via aerosol (AER) vaccination relative to BCG- and ΔsigH - vaccination, in a physiologically relevant macaque model.

抽象的 结核分枝杆菌（MTB）感染可能引起结核病，这是现在的主要原因 由于单个传染病药物而导致的死亡率。无法控制结核病是由于缺乏 有效的疫苗。 BCG是当前正在使用的疫苗，无法生成长寿的内存 反应并预防成年人的肺结核。因此，针对结核病的新疫苗是 迫切需要。我们的工作表明，MTB的ΔSigh突变体已衰减进行复制 和猕猴中的疾病）。使用该突变体的气溶胶疫苗接种可诱导强肺免疫 防止致命结核的签名。猕猴中的非致病性ΔSigh感染不是 通过SIV共感染重新激活。但是，在ΔSigh中需要其他无关突变 确保其完全衰减。该项目旨在开发基于ΔSigh的人类结核疫苗 最终可以发展临床发展的候选人。 Δsigh缺失将添加到 10个重组MTB菌株。这些突变体中的一些产生免疫增强 - 或 基于辅助营养的衰减表型，而其他则在猕猴肺中呈MTB Aviruity。 我们将评估SCID小鼠中这十种菌株的安全性，并逐渐较少数字 免疫能力和SIV通过多重猕猴共同感染的猕猴。两种一贯的菌株 根据安全性/免疫原性提供最佳结果，将详细评估 通过气溶胶（AER）疫苗接种的免疫原性和效率相对于BCG-和ΔSigh-- 在物理相关的猕猴模型中疫苗接种。

项目成果

Sirtuin-dependent metabolic and epigenetic regulation of macrophages during tuberculosis.

• DOI: 10.3389/fimmu.2023.1121495
• 发表时间: 2023
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Multi-OMICs analysis reveals metabolic and epigenetic changes associated with macrophage polarization.

• DOI: 10.1016/j.jbc.2022.102418
• 发表时间: 2022-10
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Sowers, Mark L.;Tang, Hui;Singh, Vipul K.;Khan, Arshad;Mishra, Abhishek;Restrepo, Blanca I.;Jagannath, Chinnaswamy;Zhang, Kangling
• 通讯作者: Zhang, Kangling

Human monocyte-derived macrophage responses to M. tuberculosis differ by the host's tuberculosis, diabetes or obesity status, and are enhanced by rapamycin.

• DOI: 10.1016/j.tube.2020.102047
• 发表时间: 2021-01
• 期刊: Tuberculosis (Edinburgh, Scotland)
• 作者: Restrepo BI;Khan A;Singh VK;Erica de-Leon;Aguillón-Durán GP;Ledezma-Campos E;Canaday DH;Jagannath C
• 通讯作者: Jagannath C