A double-blind randomized controlled Phase IIb trial of safety and immunogenicity

描述（由申请人提供）：肺结核（TB）患者已接受治疗并治愈，在流行病学和/或免疫学上易患复发性TB。复发性结核病与发展耐多药结核病的风险有关，耐多药结核病带来了巨大的发病和死亡负担。南非将其结核病控制预算的一半用于耐药结核病。为结核病患者接种疫苗以预防结核病复发将是一种简单的预防性干预措施，这将对结核病控制的负担产生重大的全球卫生影响。这项R34计划补助金将支持一项新结核疫苗（MVA 85 A）临床试验的准备工作，该疫苗用于预防已成功完成治疗的未感染艾滋病毒的成年结核病患者的复发性结核病。MVA 85 A已在19项人体临床试验中进行了研究，在未感染HIV的成人中没有报告与MVA 85 A疫苗接种相关的严重并发症。对MVA 85 A的免疫应答被认为对于预防TB是重要的。一组经验丰富的结核病研究人员将在南非的3个地点进行试验，那里复发性结核病非常常见（2010年报告了18，000例病例）。本试验的主要目的是在该研究人群中检测MVA 85 A疫苗接种的安全性和免疫原性。850例经培养确诊的药物敏感性肺结核患者将从入组开始接受密切监测，直至完成6个月的一线标准结核治疗。治愈将通过阴性痰结核培养来确认。受试者将通过双盲皮内注射随机接受MVA 85 A或安慰剂。将在接种后测量局部和全身不良事件以及抗原特异性T细胞应答和基因表达特征。安全性监查委员会将审查来自初始安全性小组的安全性数据，然后继续为剩余试验受试者接种疫苗。该试验的次要目的是确定风险和保护的相关性，并测试MVA 85 A疫苗接种对复发性结核病的保护效力。我们的初步研究结果表明，炎症和干扰素反应的标志预测结核病的风险。在结核病治疗结束时收集的血液样本中，我们将通过RNA测序测量基因表达，并通过多参数流式细胞术测量抗原特异性T细胞反应，以描绘结核病风险的预测特征。受试者将在接种疫苗后随访1年，以识别和治疗复发性结核病。疫苗诱导的保护机制只能在有效疫苗的背景下进行研究，但此类试验的成本过高。因此，我们将利用非常高的结核病复发率来衡量所有受试者的潜在相关性，使用这种高效，成本效益高的新型研究设计。如果MVA 85 A显示出对复发性TB的保护作用，我们将从受保护（对照）或未受保护（病例）的受试者中检索疫苗接种后样品，以测量基因表达和抗原特异性T细胞应答，以鉴定MVA 85 A疫苗诱导的对TB的保护的相关性，其也可应用于其他候选疫苗。

DESCRIPTION (provided by applicant): Patients with pulmonary tuberculosis (TB), who have been treated and cured, are epidemiologically and/or immunologically susceptible to recurrent TB episodes. Recurrent TB is associated with risk of developing drug-resistant (MDR-TB) disease, which carries a massive burden of morbidity and mortality. South Africa spends half its TB control budget on drug-resistant TB. Vaccination of TB patients to prevent recurrent TB would be a simple preventive intervention, which would have major global health impact on the burden of TB control. This R34 planning grant will support preparation for a clinical trial of a ne TB vaccine (MVA85A), given for prevention of recurrent TB disease in HIV-uninfected adult TB patients, who have successfully completed treatment. MVA85A has been studied in 19 human clinical trials and no serious complications related to MVA85A vaccination have been reported in HIV uninfected adults. The immune response to MVA85A is thought to be important for protection against TB. A team of experienced TB researchers will conduct the trial at 3 sites in South Africa, where recurrent TB is very common (18,000 cases were reported in 2010). The primary aims of the trial are to test the safety and immunogenicity of MVA85A vaccination in this study population. 850 patients with culture-confirmed, drug-sensitive, pulmonary TB will be closely monitored from enrolment until completion of a 6-month course of first-line, standard-of-care TB treatment. Cure will be confirmed by negative sputum TB cultures. Subjects will be randomized to receive either MVA85A or placebo by double-blind intradermal injection. Local and systemic adverse events, and antigen-specific T cell responses and gene expression signatures, will be measured post vaccination. A Safety Monitoring Committee will review safety data from an initial Safety Group, before proceeding to vaccinate the remaining trial subjects. The secondary aims of the trial are to identify correlates of risk and protection, and to test the protective efficacy of MVA85A vaccination against recurrent TB. Our preliminary results suggest that signatures of inflammation and the interferon response predict risk of TB disease. In blood samples collected at the end of TB treatment, we will measure gene expression by RNA sequencing and antigen-specific T cell responses by multiparameter flow cytometry, to delineate predictive signatures of TB risk. Subjects will be followed up for 1 year after vaccination to identify and treat recurrent TB disease. Vaccine-induced mechanisms of protection can only be studied in the setting of an efficacious vaccine, but the cost of such trials is prohibitive. Therefore, we will leverage the very high rate of recurrent TB to measure potential correlates in all subjects, using this highly efficient, cost-effective, novel study design. If MVA85A is shown t protect against recurrent TB, we will retrieve post-vaccination samples from subjects who were protected (controls), or not protected (cases), to measure gene expression and antigen-specific T cell responses, in order to identify correlates of MVA85A vaccine-induced protection against TB that might also be applied to other vaccine candidates.