Vaccine-based immunotherapy as an adjunct to drug treatment against NTM

项目总结/摘要 治疗由非结核分枝杆菌（NTM）引起的慢性肺部感染，如 鸟-胞内分枝杆菌复合体（MAC）既长又复杂，并且反复感染， 新的分枝杆菌菌株或由原来的生物体经常出现。免疫功能低下的人是 最易受NTM感染，在开发新的治疗方法时必须首先考虑到这一点。 在这里，我们提出了一种新的小鼠模型的发展，模仿人类疾病和病理， 免疫功能低下的宿主和免疫缺陷疫苗，以打击全球的NTM负担。我们 假设由免疫调节疫苗方案诱导宿主定向免疫应答 当作为药物的辅助治疗时， 治疗我们已经开发了一种亚单位疫苗（ID 91蛋白抗原）与合成的toll样 受体4（TLR 4）激动剂佐剂（GLA-SE），其显示针对以下气雾剂感染的保护功效： M.在小鼠模型中进行。除了ID 91亚单位疫苗，我们还开发了第二代 ID 91疫苗，并将测试该疫苗平台对M. avium我们相信， 战略，从事几个武器的免疫将提供更有效和持久的免疫M。 avium重要的是，我们的ID 91疫苗设计使用与BCG共享共有序列的细菌抗原 和不同的NTM菌株，我们认为这可能会促进免疫受损患者减弱的免疫反应。 个体此外，我们将利用我们从开发我们的第一个 第二代候选疫苗ID 93 +GLA-SE，目前处于2a期临床试验中，以优化和表征 基于ID 91的候选疫苗，包括新型ID 91疫苗平台。在目标1中，我们将测试 第一代和第二代疫苗平台在针对M. avium目的 2将致力于使用免疫缺陷Beige小鼠开发NTM治疗小鼠模型。 在这个目标中，我们将首先确定三种不同药物方案的体内细菌清除动力学。基于 在疗效方面，其中一种药物方案将在不同的治疗时间后， 抗M.在同一个小鼠模型中。最后，我们将测试最佳疫苗策略（下 目标1中选择的）作为新开发的最佳药物治疗方案（目标2中选择的）的辅助治疗。 NTM小鼠治疗模型。完成本提案中的目标将导致建立一个新的 用于进一步评估新药和实验性免疫治疗方案的NTM治疗小鼠模型 抗肺部感染M. avium

PROJECT SUMMARY / ABSTRACT Treatments for chronic pulmonary infections caused by nontuberculous mycobacteria (NTM), such as Mycobacterium avium-intracellulare complex (MAC) are both lengthy and complex, and recurrent infection with new strains of mycobacteria or by the original organism often occur. Immunocompromised individuals are the most susceptible to NTM infections and must be primarily considered with the development of new treatments. Here, we propose the development of a novel mouse model that mimics human disease and pathology in immunocompromised hosts and an immunotherapeutic vaccine to combat the global burden of NTM. We hypothesize that host-directed immune responses induced by an immunotherapeutic vaccine regimen may enable clearance of clinically important pulmonary infections, when given as an adjunct to drug treatment. We have developed a subunit vaccine (ID91 protein antigen) combined with a synthetic toll-like receptor 4 (TLR4) agonist adjuvant (GLA-SE), that shows protective efficacy against an aerosol infection with M. avium in a mouse model. In addition to the ID91 subunit vaccine, we have developed a second generation ID91 vaccine and will test this vaccine platform for efficacy against M. avium. We believe that a prime-boost strategy, engaging several arms of immunity will provide more effective and long-lasting immunity against M. avium. Importantly, our ID91 vaccine design uses bacterial antigens that share consensus sequences with BCG and different NTM strains, which we believe may boost waning immune responses in immune-compromised individuals. Furthermore, we will leverage our extensive expertise derived from the development of our first generation candidate vaccine ID93+GLA-SE, currently in Phase 2a clinical testing, to optimize and characterize the candidate ID91-based vaccines, including the novel ID91 vaccine platform. In Aim 1, we will test the efficacy of the first generation and second generation vaccine platforms in a prime-boost strategy against M. avium. Aim 2 will be devoted to the development of an NTM therapeutic mouse model, using immunodeficient Beige mice. In this Aim, we will first determine the in vivo bacterial clearance kinetics of three different drug regimens. Based on efficacy, one of the drug regimens will be further characterized for relapse rates, following different lengths of treatment against M. avium, in the same mouse model. Finally, we will test the optimal vaccine strategy (down selected in Aim 1) as an adjunct to the optimal drug therapy regimen (selected in Aim 2) in the newly developed NTM mouse therapy model. Completion of the Aims in this proposal will lead to the establishment of a novel NTM therapeutic mouse model for further evaluation of new drugs and experimental immunotherapy regimens against pulmonary infection with M. avium.