Generation and Evaluation of Pro-Apoptotic rBCG and Viral Vectors as TB Vaccine C

描述(申请人提供)：结核病每年导致近200万人死亡，是全球传染病死亡的主要原因之一。2007年，估计有927万例结核病病例。与艾滋病毒的混合感染和耐药结核病菌株的增加使这一流行病变得更加严重和复杂。目前的结核病疫苗卡介苗已有近90年的历史，在挽救每年死于结核病的数百万人方面效果不佳。AERS全球结核病疫苗基金会是一个非营利性的产品开发伙伴关系，与来自学术界、工业界、非营利组织和政府部门的顶尖研究人员和科学家合作，开发新的有效疫苗方案来遏制结核病。卡介苗的一个日益得到证实的缺陷在于它无法逃脱受感染的巨噬细胞和树突状细胞的吞噬溶酶体，与结核分枝杆菌或麻风杆菌不同，这些巨噬细胞和树突状细胞将免疫反应主要转移到MHC II类抗原递呈，这可能是疫苗接种后以CD4为主的T细胞反应的原因。利用结核分枝杆菌和相关无毒的堪萨斯分枝杆菌进行功能筛选的丧失和获得已经确定了存在于结核分枝杆菌复合体中的特定基因，包括卡介苗，其基因产物具有抑制受感染巨噬细胞凋亡的功能。AERS将创建完全符合cGxP的重组卡介苗，其中包括已知抑制细胞凋亡的基因的缺失，以通过交叉启动来增强免疫反应，并将构建编码和表达高价CD8+T细胞免疫原的cGxP增强疫苗，以创造最佳的结核病疫苗方案。加强疫苗将由重组腺病毒血清4型和重组人CMV载体组成，这两种载体都已被证明能激发强大的CD8+T细胞反应。我们将在小鼠和恒河猴身上评估这些方案，以及我们有丰富经验的结核疫苗免疫学模型和有效性，以便更方便地选择最佳方案。

DESCRIPTION (provided by applicant): Killing nearly 2 million people a year, TB is one of the leading causes of infectious disease deaths globally. In 2007, there were an estimated 9.27 million cases of TB. Co-infection with HIV and an increase in drug-resistant strains of TB are making the epidemic even more severe and complicated to address. The current TB vaccine, BCG, is almost 90 years old and has been ineffective in saving the millions of lives lost to TB each year. Aeras Global TB Vaccine Foundation is a non-profit Product Development Partnership working in collaboration with leading researchers and scientists from the academic, industry, non-profit and government sectors to develop new and effective vaccine regimens to stop TB. An increasingly well documented defect in the BCG vaccine lies in its inability to escape the phagolysosome of infected macrophages and dendritic cells, which, unlike M. tuberculosis or M. leprae, diverts the immune response to primarily MHC class II antigen presentation and is the likely reason for the CD4 dominant T cell response to vaccination. Loss and gain of function screens using M. tuberculosis and the related avirulent M. kansasii have identified specific genes present in Mtb complex organisms, including BCG, whose gene products function to inhibit apoptosis of infected macrophages. Aeras will create fully cGxP compliant recombinant BCG vaccines incorporating deletions in genes known to inhibit apoptosis to enhance immune responses by cross-priming and will also construct cGxP compliant booster vaccines encoding and expressing high valency CD8+ T cell immunogens to create an optimal tuberculosis vaccine regimen. The booster vaccines will consist of recombinant adenovirus serotype 4 and recombinant human CMV vectors, both of which have been shown to elicit potent CD8+ T cell responses. We will evaluate these regimens in mice and rhesus macaques, models of TB vaccine immunology and efficacy with which we have extensive experience, to expediently select an optimal regimen.