Immuno-Chemotherapy to Shorten TB Treatment

描述(申请人提供)：结核病(TB)是一种由结核分枝杆菌(Mtb)引起的疾病，是对公共健康的持续威胁。全球约有20亿人感染结核病，每年有900万新确诊的活动性结核病病例导致150万人死亡。此外，对结核病感染的管理不善或治疗不当可能会导致耐药结核病病例的发展，治疗难度大、费用高。耐药的结核分枝杆菌菌株不能用一线疗法治疗 并需要12-24个月的复合二线和三线抗生素。此外，存在不能用任何可用的抗生素治疗的TDR(完全抗药性)菌株。目前的提案旨在开发一种新的协同联合化疗-免疫治疗方案，用于治疗结核分枝杆菌引起的感染，包括多重、极端和完全耐药菌株。一种有效的治疗方法可以减少细菌负荷，并将治疗时间缩短到六个月以下，这将在显着减少这种病原体的影响方面发挥重要作用。这项应用是我们开发结核病疫苗的系统和方法的延伸。在过去的二十年里，我们将这一策略应用于将M72/AS01E(目前处于第二阶段临床试验)和ID93/GLA-SE开发为可行的候选疫苗。目前，据我们所知，ID93/GLA-SE是唯一已在多种结核病动物模型中进行预防和治疗测试的候选结核病疫苗。我们的候选疫苗有三种保护作用：显著减少肺部细菌负荷，减少气雾剂攻击后播散性结核分枝杆菌感染，以及暴露后免疫治疗保护。为这项申请提供资金将有助于我们继续努力开发一种带佐剂的ID93疫苗，用于未来的人类临床试验，最终导致获得批准的暴露后结核病疫苗。

DESCRIPTION (provided by applicant): Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), is an ongoing threat to public health. Globally, approximately two billion people are infected with TB, with nine million newly diagnosed cases of active TB each year causing 1.5 million deaths. Furthermore, mismanagement or inappropriate treatments for TB infections can result in the development of drug resistant TB cases, for which treatments are difficult and expensive. Drug-resistant strains of Mtb are not treatable with frontline therapy and require 12-24 months of complex second and third line antibiotics. In addition, TDR (totally drug resistant) strains exist which cannot be treated with any available antibiotics. The current proposal is designed to develop a novel synergistic combination chemo-immunotherapeutic regimen for the treatment of infections caused by Mtb, including multi-, extremely- and totally- drug resistant strains. An effective treatment that reduces bacterial loads and shortens therapy to less than six months would play an important role in dramatically reducing the impact of this pathogen. This application is an extension of our systematic and methodical approach towards developing vaccines for TB. Over the last twenty years, we have applied this strategy towards developing M72/AS01E (currently in Phase II clinical trials) and ID93/GLA-SE into viable vaccine candidates. At present, to our knowledge, ID93/GLA-SE is the sole TB vaccine candidate that has been tested for prevention and therapy in multiple animal models of TB. Our candidate vaccine has three protective effects: significantly reduces pulmonary bacterial loads, reduces disseminated Mtb infection after aerosol challenge, and post-exposure immunotherapeutic protection. Funding this application will help our continuing efforts to develop an adjuvanted ID93 vaccine towards for future human clinical trials, ultimately resulting in an approved post- exposure TB vaccine.