EFFICACY AND SAFETY OF LIVE ATTENUATED MYCOBACTERIUM TUBERCULOSIS VACCINES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 结核病（TB）仍然是全球健康负担，需要安全的疫苗。BCG作为结核病疫苗具有局限性，因此我们将重点放在减毒活结核分枝杆菌突变体作为候选疫苗上。 然而，在进行人体研究之前，有必要证明在非人灵长类动物（NHP）中的安全性。在这项研究中，我们评估了两种减毒活M。结核病双缺失疫苗株mc^2 6020（Δ lysA Δ panCD）和mc^2 6030（Δ RD 1 Δ panCD）。 在小鼠模型中，mc^2 6020被迅速清除，而mc^2 6030持续存在。mc^2 6020和mc^2 6030在食蟹猴中均安全且耐受性良好。在高剂量支气管内用强毒M.接种mc^2 6020疫苗的受试者获得的保护水平介于卡介苗接种和未接种之间。与生理盐水和mc^2 6030疫苗接种组相比，BCG疫苗接种组的结核病相关病理减少，临床评分改善，但各组间的存活率没有差异。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Tuberculosis (TB) remains a global health burden for which safe vaccines are needed. BCG has limitations as a TB vaccine so we have focused on live attenuated Mycobacterium tuberculosis mutants as vaccine candidates. Prior to human studies, however, it is necessary to demonstrate safety in non-human primates (NHP). In this study, we evaluate the safety and efficacy of two live attenuated M. tuberculosis double deletion vaccine strains mc^2 6020 (delta lysA delta panCD) and mc^2 6030 (delta RD1 delta panCD) in cynomolgus macaques. In murine models, mc^2 6020 is rapidly cleared while mc^2 6030 persists. Both mc^2 6020 and mc^2 6030 were safe and well tolerated in cynomolgus macaques. Following a high-dose intrabronchial challenge with virulent M. tuberculosis, mc^2 6020-vaccinates were afforded a level of protection intermediate between that elicited by BCG vaccination and no vaccination. BCG vaccinates had reduced tuberculosis-associated pathology and improved clinical scores as compared to saline and mc^2 6030 vaccinates, but survival did not differ among the groups.