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

摘要 感染结核分枝杆菌(Mtb)可导致结核病，它现在是全球主要的 因单一传染病病原体造成的死亡率。结核病控制的失败源于缺乏 一种有效的疫苗。目前正在使用的卡介苗不能产生长寿记忆 成人对肺结核的反应和预防。因此，针对结核病的新疫苗是， 急需之物。我们的工作表明，结核分枝杆菌的ΔSIGH突变体在复制时是弱化的 和猕猴的疾病)。该突变株气雾剂免疫可诱导较强的肺部免疫 防止致命结核病的签名。猕猴的非致病性ΔSIGH感染并不是 被SIV混合感染重新激活。然而，Δ叹息中需要额外的无关突变(S) 以确保其完全衰减。该项目旨在开发一种基于ΔSIGH的人类结核病疫苗 最终可能进入临床开发的候选人。ΔSIGH删除将添加到 10株重组结核分枝杆菌。这些突变体中的一些会产生免疫增强-或者 以营养缺乏症为基础的衰减表型，而其他使Mtb在猕猴肺中无毒。 我们将评估这10种菌株在SCID小鼠中的安全性，并在 免疫活性和SIV通过多路复合感染猕猴。两个菌株一致地 提供安全性/免疫原性方面的最佳结果将详细评估 与卡介苗和Δ相比，气雾剂疫苗的免疫原性和有效性 接种疫苗，在生理上相关的猕猴模型中。

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.