Identification of ID93+GLA-SE biomarkers for prevention of recurrent TB

鉴定用于预防结核病复发的 ID93 GLA-SE 生物标志物

• 批准号: 9236150
• 负责人: Rhea N Coler
• 金额: $ 13.4万
• 依托单位: ACCESS TO ADVANCED HEALTH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236150
• 关键词: Adjuvant; Adult; Adverse event; Aftercare; Animal Model; Animals; Antibodies; Antibody Response; Antibody titer measurement; Antigens; BCG Vaccine; Bacteriology; Binding; Biological Assay; Biological Markers; Blood specimen; Cavia; Cessation of life; Clinical Trials; Communities; Complex; Data; Disease; Dose; Drug resistance; Drug-sensitive; Enzyme-Linked Immunosorbent Assay; Evaluation; Event; Exhibits; Frequencies; Funding; Future; Genus Mycobacterium; Goals; Growth; HIV; Immune; Immune response; Immunization; Immunoglobulin G; Immunoglobulins; Immunologics; Immunology procedure; In Vitro; Incidence; Infection; Interferons; Interleukin-2; Macaca; Measures; Methods; Modeling; Mus; Mycobacterium tuberculosis; Patients; Performance; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Placebo Control; Population; Preparation; Prevention; Protein Subunits; Pulmonary Tuberculosis; Recurrence; Regimen; Risk; Safety; South Africa; Specimen; Staining method; Stains; Subunit Vaccines; T cell response; T-Lymphocyte; TNF gene; Target Populations; Testing; Treatment Efficacy; Treatment Protocols; Trust; Tuberculosis; Tuberculosis Vaccines; Vaccinated; Vaccines; adaptive immune response; base; chemokine; chemotherapy; clinical development; cost; cytokine; design; disorder control; disorder later incidence prevention; efficacy trial; immunogenicity; improved; in vivo; killings; mycobacterial; novel; novel vaccines; peripheral blood; phase 1 study; potential biomarker; pre-clinical; preclinical study; prevent; profiles in patients; programs; prophylactic; public health relevance; response; standard of care; therapeutic vaccine; tool; tuberculosis drugs; tuberculosis treatment; vaccination against tuberculosis; vaccine candidate; vaccine efficacy; vaccine evaluation; volunteer

 DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB) in more than 8 million people worldwide and kills more than 1 million people annually. The Bacille Calmette-Guérin (BCG) vaccine is the most commonly used vaccine in the world, yet it does not effectively prevent Mtb infection or pulmonary TB in adults. New vaccines to supplement or replace BCG are urgently needed. The current standard of care for drug-sensitive TB consists of a 6-9-month drug treatment regimen. This long course of treatment is designed to prevent TB recurrence. Nonetheless, the incidence of recurrent TB is 2%-8%. A therapeutic vaccine administered as an adjunct to drug treatment could advance global efforts to improve and shorten TB treatment. IDRI has developed a novel vaccine candidate, ID93+GLA-SE, which has shown prophylactic and therapeutic efficacy in preclinical animal models of TB. Phase 1 studies yielded promising safety and immunogenicity results in uninfected adults in the US and in Mtb-infected and uninfected adults in South Africa. IDRI 203 is an ongoing Phase 2a trial funded by the Wellcome Trust that will evaluate ID93+GLA-SE for safety, dose selection, and immunogenicity in cured TB patients following a standard course of chemotherapy in South Africa. This is in preparation for a planned Phase 2b trial, IDRI 204, which will evaluate the selected dose for efficacy in the prevention of recurrence (PoR) of TB disease in cured TB patients. The immune responses that correlate with reduced risk of TB disease and/or protection against TB recurrence are not yet known. The IDRI 204 Phase 2b trial will be the first trial to evaluate vaccine efficacy for PoR, an important test of concept for TB vaccine strategy and provides a unique opportunity to identify immune correlates of risk for recurrent TB. However, conducting a broad range of immunological assays is cost-prohibitive. We therefore propose to evaluate and rank assays for their performance as potential biomarkers of recurrent TB in IDRI 203, a smaller, dose-finding study (n=60). Several innate and adaptive immunological responses are already being evaluated in IDRI 203. The evaluation of additional vaccine-induced immune responses would provide a broader characterization of ID93+GLA-SE immunogenicity in a post-treatment setting. We propose a longitudinal assessment of 23 cytokine and chemokine profiles from patient specimens using a multiplex assay. Humoral responses will also be characterized to determine titers of specific immunoglobulin subtypes. Additionally, we will develop a novel functional assay to measure the capacity of cellular specimens to inhibit mycobacterial growth and evaluate this assay as a potential in vitro correlate of in vivo vaccine efficacy. This project will result in important immunogenicity data to inform the next steps in clinical development of the ID93+GLA-SE vaccine and to further the post-treatment immunization concept as a strategy against TB. Identification of immune correlates of risk for recurrent TB would be a transformative event for the TB vaccine field, enabling hypotheses for surrogates of protection to be tested in future trial of candidate TB vaccines.

 描述（由申请人提供）：结核分枝杆菌（Mtb）在全世界引起超过800万人的结核病（TB），每年导致超过100万人死亡。卡介苗（BCG）是世界上最常用的疫苗，但它不能有效预防成人结核分枝杆菌感染或肺结核。迫切需要补充或取代卡介苗的新疫苗。目前药物敏感性结核病的标准治疗包括6 - 9个月的药物治疗方案。这种长期治疗旨在防止结核病复发。尽管如此，结核病复发率为2%-8%。作为药物治疗的辅助手段施用的治疗性疫苗可以促进全球改善和缩短结核病治疗的努力。 IDRI开发了一种新的候选疫苗ID93 + GLA-SE，它在结核病的临床前动物模型中显示出预防和治疗效果。I期研究在美国未感染成人和南非结核分枝杆菌感染和未感染成人中产生了有希望的安全性和免疫原性结果。IDRI 203是一项由Wellcome Trust资助的正在进行的2a期试验，该试验将评估ID93 + GLA-SE在南非标准化疗后治愈的结核病患者中的安全性，剂量选择和免疫原性。这是为计划中的2b期试验IDRI 204做准备，该试验将评估选定剂量在预防治愈的结核病患者结核病复发（PoR）方面的疗效。与降低结核病风险和/或防止结核病复发相关的免疫应答尚不清楚。IDRI 204 2b期试验将是第一个评估PoR疫苗有效性的试验，PoR是结核病疫苗策略概念的重要测试，并为确定复发性结核病风险的免疫相关性提供了独特的机会。然而，进行广泛的免疫测定是成本高昂的。因此，我们建议在IDRI 203（一项规模较小的剂量探索研究，n = 60）中评估和排名检测作为复发性TB潜在生物标志物的性能。在IDRI 203中已经评估了几种先天性和适应性免疫反应。对额外疫苗诱导的免疫应答的评价将在治疗后环境中提供ID93 + GLA-SE免疫原性的更广泛表征。我们提出了一个纵向评估的23个细胞因子和趋化因子配置文件从患者标本使用多重检测。还将表征体液应答以确定特定免疫球蛋白亚型的滴度。此外，我们将开发一种新的功能测定法来测量细胞标本抑制分枝杆菌生长的能力，并将该测定法作为体内疫苗效力的潜在体外相关性进行评价。该项目将产生重要的免疫原性数据，为ID93 + GLA-SE疫苗的后续临床开发提供信息，并促进治疗后免疫概念作为结核病的一种策略。确定复发性结核病风险的免疫相关性将是结核病疫苗领域的一个变革性事件，使保护替代物的假设能够在未来的候选结核病疫苗试验中得到检验。