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: 10162489
• 负责人: Chinnaswamy Jagannath
• 金额: $ 87.77万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162489
• 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.

摘要 杆菌感染结核病（Mtb）可以导致结核病，结核病现在是全球主要的结核病病因。 单一传染病病原体导致的死亡率。控制结核病的失败源于缺乏 有效的疫苗。目前使用的卡介苗不能产生长期记忆 预防和预防成人肺结核。因此，新的结核病疫苗， 迫切需要。我们的工作表明，Mtb的ΔsigH突变体的复制减弱， 和猕猴的疾病）。用这种突变体进行气溶胶疫苗接种诱导强的肺免疫 可以防止致命结核病的特征。猕猴中的非致病性ΔsigH感染不是 被SIV共同感染重新激活。然而，ΔsigH中需要额外的不相关突变 以确保其完全衰减。本项目旨在开发基于ΔsigH的人结核疫苗 候选人，最终可以推进到临床开发。ΔsigH缺失将被添加至 10株重组结核分枝杆菌。这些突变体中的一些产生免疫增强-或 基于营养缺陷型的减毒表型，而其他使Mtb在猕猴肺中无毒。 我们将评估这10个菌株在SCID小鼠中的安全性，并在SCID小鼠中逐渐减少数量。 免疫活性和SIV共感染的猕猴。两种菌株 提供安全性/免疫原性方面的最佳结果，将详细评价 相对于BCG-和ΔsigH -，通过气雾剂（AER）接种的免疫原性和效力 疫苗接种，在生理学相关的猕猴模型。