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

项目摘要/摘要 治疗由非结核分支杆菌(NTM)引起的慢性肺部感染，如 禽分枝杆菌-细胞内复合体(MAC)既长又复杂，反复感染 新的分枝杆菌菌株或由原生物体产生的情况时有发生。免疫功能低下的人是 最容易感染非传染性支气管炎，必须随着新治疗方法的开发而主要考虑。 在这里，我们建议开发一种新的小鼠模型，模拟人类疾病和病理 免疫受损的宿主和免疫治疗性疫苗，以对抗全球非传染性疾病的负担。我们 假设免疫治疗性疫苗方案诱导的宿主定向免疫反应 作为药物的辅助用药，可清除临床上重要的肺部感染 治疗。我们已经开发出一种亚单位疫苗(ID91蛋白抗原)，它与合成的Toll样蛋白相结合 受体4(TLR4)激动剂佐剂(GLA-SE)，显示出对气溶胶感染的保护效果 在小鼠模型中发现。除了ID91亚单位疫苗外，我们还开发了第二代疫苗 ID91疫苗，并将测试该疫苗平台对禽类分枝杆菌的效力。我们认为，主要的提振措施 战略，使用多个免疫武器将提供更有效和更持久的免疫力。 阿维姆。重要的是，我们的ID91疫苗设计使用的细菌抗原与卡介苗有相同的序列 和不同的NTM菌株，我们认为这可能会增强免疫受损的人的免疫反应 个人。此外，我们将利用我们从开发第一个 新一代候选疫苗ID93+GLA-SE，目前处于2a期临床测试，以优化和表征 候选的ID91疫苗，包括新型ID91疫苗平台。在目标1中，我们将测试其疗效 第一代和第二代疫苗平台在针对禽类分枝杆菌的主要增强战略中。目标 2将致力于开发一种NTM治疗性小鼠模型，使用免疫缺陷的米色小鼠。 为此，我们将首先测定三种不同药物方案的体内细菌清除动力学。基座 在疗效方面，其中一种药物方案将进一步表征复发率，遵循不同的时长 在相同的小鼠模型中，对鸟型支原体进行治疗。最后，我们将测试最佳疫苗策略(向下 在目标1中选择)作为新开发的(在目标2中选择的)最佳药物治疗方案的辅助方案 NTM小鼠治疗模型。完成这项提案中的目标将导致建立一部小说 用于进一步评价新药和实验性免疫治疗方案的NTM治疗性小鼠模型 抗肺炎支原体肺部感染。

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.