Vaccines for Extensively Drug Resistant Tuberculosis

描述（由申请人提供）：尽管卡介苗作为结核病疫苗的可获得性和广泛使用，以及对药物敏感形式的结核病存在有效的灭菌化疗，但结核病（TB）仍然是一个全球性的健康问题。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，对资源有限的非洲和亚洲国家的影响尤为严重。除了感染发生率增加之外，MDR（耐多药）结核病和XDR（广泛耐药）结核病已成为更难以治疗的结核病形式，如果不是不可能治疗的话。显然，迫切需要新的疫苗和新的化疗方法。我们发现一种特殊的VII型分泌系统负责逃避先天免疫的杀伤。一种将这些基因删除的耻垢分枝杆菌被命名为IKE，已被证明在至少8种不同的免疫功能低下的小鼠模型中是安全的。感染具有免疫功能的小鼠后，可诱导强烈的TH1免疫应答，这与亲本菌株诱导的应答完全不同，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到IKE中可以产生一种菌株（IKEPLUS），该菌株可以在毒性MTB攻击时诱导杀菌免疫。在本申请中，我们计划改进IKEPLUS并开发生产工艺，以生产可重复的良好生产规范（GMP）批次的人用强效IKEPLUS疫苗。我们将开发检测方法来识别最有效批次的生物标志物。我们计划单独评估这种药物的疗效

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. PUBLIC HEALTH RELEVANCE: M. tuberculosis strains that are resistant to 2-10 drugs are emerging around the world, causing a worsening of the global TB problem. Novel therapies are urgently needed - particularly, a new and effective vaccine; to this end we have developed a genetically engineered M. smegmatis strain that elicits bacteriocidal immunity against M. tuberculosis. This application will develop the methodologies to optimize this vaccine for use in humans.