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: 9112761
• 负责人: Rhea N Coler
• 金额: $ 35.72万
• 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 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112761
• 关键词: Adult; Adverse event; Aftercare; Animal Model; Animals; Antibodies; Antibody Response; Antigens; Binding; Biological Assay; Biological Markers; Blood specimen; Calmette-Guerin Bacillus; Cavia; Cessation of life; Clinical; Clinical Trials; Communities; Complex; Data; Development; 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; 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; Vaccine Adjuvant; Vaccines; base; chemokine; chemotherapy; 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; 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(申请人提供)：结核分枝杆菌(Mtb)在全球800多万人中引起结核病，每年导致100多万人死亡。卡介苗(BCG)是世界上最常用的疫苗，但它不能有效预防成人的结核杆菌感染或肺结核。迫切需要新的疫苗来补充或取代卡介苗。目前对药物敏感结核病的护理标准包括6-9个月的药物治疗方案。这种长疗程的治疗是为了防止结核病复发。尽管如此，结核病复发的发生率为2%-8%。作为药物治疗辅助手段的治疗性疫苗可以推动改善和缩短结核病治疗的全球努力。IDRI已开发出一种新的候选疫苗ID93+GLA-SE，该疫苗已在临床前结核病动物模型中显示出预防和治疗效果。第一阶段研究在美国未感染的成人和南非感染和未感染结核杆菌的成人中产生了良好的安全性和免疫原性结果。IDRI 203是由Wellcome Trust资助的正在进行的2a期试验，将评估ID93+GLA-SE在南非接受标准疗程化疗后治愈的结核病患者的安全性、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，该试验将评估选定的剂量对预防治愈的结核病患者的结核病复发(POR)的有效性。与降低结核病风险和/或预防结核病复发相关的免疫反应尚不清楚。IDRI 204阶段2b试验将是第一个评估POR疫苗效力的试验，这是对结核病疫苗战略的重要概念测试，并提供了一个独特的机会来确定复发结核病风险的免疫相关因素。然而，进行广泛的免疫学检测是成本高昂的。因此，我们建议在IDRI 203中对作为复发结核病潜在生物标记物的分析进行评估和排名，这是一项较小的剂量发现研究(n=60)。IDRI 203已经评估了几种先天和获得性免疫反应。对疫苗诱导的额外免疫反应的评估将提供治疗后环境中ID93+GLA-SE免疫原性的更广泛特征。我们建议使用多重分析方法对患者标本中的23种细胞因子和趋化因子图谱进行纵向评估。体液反应也将用于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试方法来测量细胞样本抑制分枝杆菌生长的能力，并评估该方法作为体内疫苗效力的潜在体外相关性。该项目将产生重要的免疫原性数据，为ID93+GLA-SE疫苗临床开发的下一步提供信息，并促进作为结核病战略的治疗后免疫概念。确定复发结核病风险的免疫相关因素将是结核病疫苗领域的一项变革性事件，使替代保护的假设能够在未来候选结核病疫苗的试验中得到测试。