Vaccines for Extensively Drug Resistant Tuberculosis

描述（由申请人提供）：结核病（TB）仍然是一个全球性的健康问题，尽管BCG作为TB疫苗的可用性和广泛使用，并且存在针对药物敏感形式的疾病的有效灭菌化疗。事实上，近年来结核病问题在世界许多地区都有所恶化。全球艾滋病毒流行病继续蔓延，对非洲和亚洲资源有限的国家造成了不成比例的影响。除了感染发生率增加外，MDR（多重耐药）-TB和XDR（广泛耐药）-TB已成为结核病的一种形式，即使不是不可能，也明显更难治疗。显然，迫切需要新的疫苗和新的化疗。我们已经发现，一种特殊的VII型分泌系统负责逃避先天免疫的杀伤。个核磁其中这些基因已被删除的命名为IKE的耻垢病菌株已被证明在至少八种不同的免疫受损小鼠模型中是安全的。免疫活性小鼠感染IKE诱导一个强大的TH 1免疫反应，这是根本不同的，由亲本菌株诱导，使IKE有吸引力的疫苗载体。我们已经表明，将编码免疫显性TB抗原的基因引入IKE中产生了一种菌株（IKEPLUS），该菌株在用毒性MTB攻击时可以诱导杀菌免疫。在此应用中，我们计划改进IKEPLUS并开发生产工艺，以生产可重现的良好生产规范（GMP）批次的人用强效IKEPLUS疫苗。我们将开发检测方法，以确定最有效批次的生物标志物。我们计划单独评估这种方法的有效性， 在BCG引发的IKEPLUS加强方案中，以保护免受M.结核病和广泛耐药-M。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.