Vaccines for Extensively Drug Resistant Tuberculosis

描述(由申请人提供)：结核病(TB)仍然是一个全球健康问题，尽管卡介苗作为结核病疫苗已经获得并被广泛使用，而且对这种药物敏感的疾病存在有效的绝育化疗。事实上，近年来，世界许多地区的结核病问题都在恶化。全球艾滋病毒疫情继续增长，对非洲和亚洲资源有限的国家造成了不成比例的影响。除了感染发病率增加外，耐多药结核病和广泛耐药结核病已经成为更难治疗的结核病形式。显然，迫切需要新的疫苗和新的化疗方法。我们已经发现，一种特定的III型分泌系统负责通过先天免疫来逃避杀戮。一种删除了这些基因的耻垢分枝杆菌菌株被命名为IKE，已被证明在至少八种不同的免疫缺陷小鼠模型中是安全的。免疫活性小鼠感染IKE可诱导出与亲本株完全不同的TH1免疫应答，使IKE成为一种有吸引力的疫苗载体。我们已经证明，将编码免疫显性结核抗原的基因引入IKE中，可以产生一种菌株(IKEPLUS)，该菌株可以在受到强毒MTB的攻击时诱导杀菌免疫。在这项应用中，我们计划改进IKEPLUS并开发一种制造工艺，以生产可重复的良好制造规范(GMP)批次的有效IKEPLUS疫苗供人类使用。我们将开发检测方法，为最有效的批次识别生物标记物。我们计划单独评估这一方法的效果，并 在卡介苗诱导的IKEPLUS-Boost方案中，以预防结核分枝杆菌和XDR-M的毒力挑战。肺结核。

DESCRIPTION (provided by applicant): Tuberculosis (TB) has remained a global health problem, despite the availability and widespread use of BCG as a TB vaccine and the existence of effective sterilizing chemotherapy for drug sensitive forms of the disease. In fact, the TB problem has worsened in recent years in many areas of the world. The global HIV epidemic has continued to grow, and it has disproportionately affected resource-limited countries in Africa and Asia. In addition to increased incidence of infection, MDR (Multi Drug Resistant)-TB and XDR (Extensively drug Resistant)-TB have emerged as forms of TB that are significantly more difficult, if not impossible, to treat. Clearly, novel vaccines and novel chemotherapies are urgently needed. We have discovered that a specific Type VII secretion system is responsible for evading killing by innate immunity. An M. smegmatis strain in which these genes have been deleted, designated IKE, has been demonstrated to be safe in at least eight different immunocompromised mouse models. Infection of immunocompetent mice with IKE induces a robust TH1 immune response, which is radically different than that induced by the parental strain, making IKE an attractive vaccine vector. We have shown that the introduction of genes encoding immunodominant TB antigens into IKE creates a strain (IKEPLUS) that can induce bacteriocidal immunity upon challenge with virulent MTB. In this application, we plan to improve IKEPLUS and develop a manufacturing process to make reproducible Good Manufacturing Practices (GMP) batches of a potent IKEPLUS vaccine for human use. We will develop assays to identify biomarkers for the most potent lots. We plan to evaluate the efficacy of this alone and in BCG-primed IKEPLUS-boost regimens to protect against virulent challenges of M. tuberculosis and XDR-M. tuberculosis.