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（由适用提供）：结核分枝杆菌（MTB）在全球超过800万人中引起结核病（TB），每年造成超过100万人丧生。 Bacille Calmette-guérin（BCG）疫苗是世界上最常用的疫苗，但它不能有效防止成人MTB感染或肺结核。迫切需要新的补充或替代BCG的疫苗。当前对药物敏感性结核病的护理标准包括6-9个月的药物治疗方案。这项漫长的治疗方法旨在防止结核病复发。但是，复发性结核病的发生率为2％-8％。作为药物治疗辅助的治疗疫苗可以改善和缩短结核病治疗。 IDRI开发了一种新型的疫苗ID93+GLA-SE，该疫苗在TB的临床前动物模型中显示出预防性和治疗有效性。第1阶段的研究产生了承诺的安全性和免疫原性，导致美国未感染的成年人以及南非的MTB感染和未感染的成年人。 IDRI 203是一项由惠康基金会（Wellcome Trust）资助的正在进行的2A期试验，该试验将在南非进行标准的化学疗法后，评估ID93+GLA-SE，以确保安全性，剂量选择和免疫原性。这是为计划的2B期试验IDRI 204做准备的，该试验将评估所选剂量以预防固化结核病患者的结核病疾病复发（POR）的效率。与TB疾病风险降低和/或针对结核病复发的保护相关的免疫调查尚不清楚。 IDRI 204阶段2B试验将是评估POR的疫苗效率的第一个试验，POR是TB疫苗策略的重要概念测试，并提供了一个独特的机会来识别复发性结核病风险的免疫相关性。但是，进行广泛的免疫学测定范围是成本良好的。因此，我们建议在IDRI 203（一项较小的剂量调查研究）（n = 60）中评估和对分析的性能，以作为复发性结核病的潜在生物标志物的性能。在IDRI 203中已经评估了几种先天和适应性免疫反应。对其他疫苗诱导的免疫复发的评估将在治疗后环境中更广泛地表征ID93+GLA-SE免疫原性。我们提出使用多重测定法对患者标本的23个细胞因子和趋化因子谱进行纵向评估。体液反应也将被表征以确定特定免疫球蛋白亚型的滴度。此外，我们将开发一种新型的功能测定，以测量细胞标本抑制分枝杆菌生长的能力，并评估该测定法作为体外疫苗效率的潜在体外相关。该项目将导致重要的免疫原性数据，以告知ID93+GLA-SE疫苗临床开发的下一步，并将治疗后免疫抑制概念作为反对结核病的策略。鉴定复发性结核病风险的免疫复合物将是TB疫苗场的变革性事件，从而在未来的候选结核病疫苗试验中可以测试保护替代物的假设。