MTBVAC Phase 1b/2a Randomized, Double-blind, Active-controlled, Safety, Immunogenicity, and Dose-escalation Study in Adults with and without Latent Tuberculosis Infection in South Africa

项目摘要 2014年，估计有960万例结核病病例，其中150万例 结核病导致的死亡人数比任何其他单一传染病都多。巴西尔·卡尔梅特 卡介苗（BCG）是一种减毒活牛分枝杆菌（M. bovis），是唯一获得许可的疫苗 对抗结核病。虽然它对严重的儿童结核病有效， 对于新生儿，它对青少年/成人的肺结核几乎没有保护作用， 他们是结核分枝杆菌（Mtb）传播的主要来源。是肺结核 在这些年龄较大的群体中，这推动了全球流行病。对结核病的迫切需求 研究和开发新的、改进的工具，特别是新的和更有效的结核病 疫苗，以实现世界卫生组织（世卫组织）的目标， 到2035年实现类似的联合国可持续发展目标 到2030年终结结核病减毒活疫苗接种策略可能是最好的方法， 赋予持久的T细胞免疫应答，被认为是保护免受 TB. MTBVAC是一种新型的减毒活Mtb疫苗，基于缺失两个独立的Mtb基因。 编码主要毒力因子的基因，但保留BCG中不存在的Mtb基因。因为 MTBVAC基于活的减毒Mtb，因此呈现更广泛的Mtb- 对宿主免疫系统的特异性抗原比卡介苗，它可以提供更好的保护。我们 在一项1b/2a期、双盲、随机、BCG对照、剂量范围探索研究中， 评估既往有和无结核分枝杆菌感染（潜伏性结核感染; LTBI）的成人中的MTBVAC， 获得关键的安全性和免疫原性数据，以指导剂量选择， 将MTBVAC推进到结核病流行国家的疗效试验中。参加者将有 在婴儿期接受过卡介苗接种。主要终点是安全性比较 与BCG相比，在四个剂量水平中的每一个剂量水平下皮内注射MTBVAC的特征 再接种疫苗。拟议的试验将在南非进行，南非拥有第二个 世界上结核病年发病率最高（每10万人834例）。对MTBVAC的投资是 重要的是，它1）显示出有希望的结果2）是唯一的活减毒结核分枝杆菌疫苗 目前在临床开发中（同类中第一）和3）含有牛支原体的额外抗原， 目前疫苗BGC的祖先，因此可能提供增强的保护 对抗结核病。

Project Summary In 2014 there were an estimated 9.6 million cases of tuberculosis (TB) disease with 1.5 million deaths due to TB, more deaths than from any other single infectious agent. Bacille Calmette Guerin (BCG), a live attenuated Mycobacterium bovis (M.bovis), is the only licensed vaccine against TB. Although it is efficacious against severe forms of childhood TB when administered to newborn infants, it provides little or no protection against pulmonary TB in adolescents/adults, who are the major source of Mycobacterium tuberculosis (Mtb) transmission. It is pulmonary TB in these older age groups that drives the global epidemic. There is a critical need for TB research and development of new, improved tools, especially new and more effective TB vaccines, in order to reach the World Health Organization’s (WHO) goal of ending the TB epidemic by 2035 and achieving the similar United Nations (UN) Sustainable Development Goal of ending TB by 2030. Live-attenuated vaccination strategies may be the best approach for conferring durable T-cell immune responses, believed to be necessary for protecting against TB. MTBVAC is a novel, live-attenuated Mtb vaccine based on deletion of two independent genes encoding major virulence factors, but retaining Mtb genes not present in BCG. Because MTBVAC is based on live, attenuated Mtb, and therefore presents a wider collection of Mtb- specific antigens to the host immune system than BCG, it may provide better protection. We aim, in a Phase 1b/2a, double-blind, randomized, BCG-controlled, dose-ranging study, to evaluate MTBVAC in adults with and without prior Mtb infection (Latent TB Infection; LTBI) to obtain critical safety and immunogenicity data to guide dose selection and to facilitate the advancement of MTBVAC into efficacy trials in TB endemic countries. Participants will have received previous BCG vaccination in infancy. The primary endpoint is comparison of the safety profile of intradermal MTBVAC injection at each of four dose levels compared to BCG revaccination. The proposed trial will be conducted in South Africa which has the second highest annual TB incidence in the world (834 per 100,000). Investment in MTBVAC is important as it has 1) shown promising results 2) is the only live attenuated Mtb vaccine currently in clinical development (first in class) and 3) contains additional antigens to M.bovis, the progenitor of the current vaccine BGC, and therefore may provide enhanced protection against TB.