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

描述(申请人提供)：经治疗和治愈的肺结核患者，在流行病学和/或免疫学上容易复发结核病。复发性结核病与发展耐药(MDR-TB)疾病的风险有关，这种疾病带来巨大的发病率和死亡率负担。南非将其结核病控制预算的一半用于抗药性结核病。为结核病患者接种疫苗以防止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健康影响。这笔R34规划赠款将支持为新城疫疫苗(MVA85A)的临床试验准备工作，该疫苗用于预防成功完成治疗的未感染艾滋病毒的成年结核病患者的结核病复发。MVA85A已经在19个人类临床试验中进行了研究，没有报告在未感染艾滋病毒的成年人中出现与接种MVA85A疫苗有关的严重并发症。对MVA85A的免疫反应被认为对预防结核病很重要。一个由经验丰富的结核病研究人员组成的团队将在南非的3个地点进行试验，那里的结核病复发非常常见(2010年报告了1.8万例)。试验的主要目的是测试MVA85A疫苗在该研究人群中的安全性和免疫原性。将对850名培养确诊、对药物敏感的肺结核病患者进行密切监测，直到完成为期6个月的一线标准护理结核病治疗。治愈将通过痰培养阴性来确认。受试者将随机接受MVA85A或安慰剂双盲皮内注射。将在接种疫苗后测量局部和全身不良事件以及抗原特异性T细胞反应和基因表达特征。安全监测委员会将审查来自初始安全小组的安全数据，然后继续为其余试验受试者接种疫苗。试验的次要目标是确定风险和保护的相关性，并测试MVA85A疫苗对复发结核病的保护效果。我们的初步结果表明，炎症和干扰素反应的征兆可以预测结核病的风险。在结核病治疗结束时采集的血液样本中，我们将通过RNA测序来测量基因表达，并通过多参数流式细胞仪来测量抗原特异性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进行为期1年的随访，以识别和治疗复发的结核病。疫苗诱导的保护机制只能在有效疫苗的背景下进行研究，但这种试验的费用令人望而却步。因此，我们将利用极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、经济、新颖的研究设计。如果MVA85A被证明对结核病复发具有保护作用，我们将从受到保护的受试者(对照组)和未受保护的受试者(病例)中提取疫苗接种后的样本，以测量基因表达和抗原特异性T细胞反应，以确定MVA85A疫苗诱导的抗结核病保护的相关性，这可能也适用于其他候选疫苗。

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.