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960万结核病病例，其中150万 死于结核病，比任何其他单一感染源造成的死亡都要多。卡米特杆菌 盖林(BCG)是一种活的减毒牛分枝杆菌(M.bovis)，是唯一获得许可的疫苗 抗结核病。尽管它对严重形式的儿童结核病有效 对于新生儿，它对青少年/成人的肺结核病提供的保护很少或根本没有， 他们是结核分枝杆菌(Mtb)传播的主要来源。是肺结核病。 在这些年龄较大的人群中，这推动了全球流行。对结核病的需求非常迫切 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，以达到世界卫生组织(WHO)结束结核病的目标 到2035年流行，并实现类似的联合国可持续发展目标 到2030年消灭结核病的目标。减毒活疫苗接种策略可能是最好的方法 产生持久的T细胞免疫反应，被认为是预防疾病所必需的 结核病。MTBVAC是一种新型的减毒活疫苗，其基础是缺失两个独立的 编码主要毒力因子的基因，但保留卡介苗中不存在的结核分枝杆菌基因。因为 MTBVAC基于实况、衰减的MTB，因此提供了更广泛的MTB集合- 特异性抗原比卡介苗对宿主免疫系统有更好的保护作用。我们 目的：在1b/2a期双盲、随机、卡介苗对照剂量范围研究中， 评估既往有和没有结核分枝杆菌感染(潜伏结核感染；LTBI)的成年人的MTBVAC 获得关键的安全性和免疫原性数据，以指导剂量选择和促进 MTBVAC在结核病流行国家进入疗效试验的进展。参与者将拥有 在婴儿期接受过卡介苗接种。主要终点是安全性的比较 四种剂量水平MTBVAC皮内注射与卡介苗的比较 重新接种疫苗。拟议中的试验将在南非进行，南非有第二个 结核病年发病率世界最高(每10万人中有834人)。对MTBVAC的投资是 重要的是，它1)显示了有希望的结果2)是唯一活的结核分枝杆菌减毒疫苗 目前在临床开发中(第一类)和3)含有额外的牛分枝杆菌抗原， 目前的疫苗BGC的前身，因此可以提供增强的保护 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.