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

作为结核疫苗 C 的促凋亡 rBCG 和病毒载体的生成和评价

基本信息

批准号：
8317681
负责人：
Thomas G Evans
金额：
$ 61.9万
依托单位：
AERAS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8317681
关键词：
Accounting Address Adenovirus Vector Adenoviruses Antigen Presentation Antigens Apoptosis Apoptosis Inhibitor Apoptotic Attenuated BCG Vaccine CD8B1 gene Caring Cells Cessation of life Clinic Collaborations Communicable Diseases Complex Country Cross Presentation Cross-Priming Cytomegalovirus Defect Dendritic Cells Developing Countries Development Diagnostic Disease Drug Resistant Tuberculosis Drug resistance Economic Development Economics Endosomes Epidemic Evaluation Extreme drug resistant tuberculosis Family Foundations Gene Library Generations Genes Genus Mycobacterium Government Grant HIV HIV Seropositivity Health system Histocompatibility Antigens Class II Human Immune response Immunization Immunology Individual Industry Infection Inhibition of Apoptosis Libraries Macaca Macaca mulatta Mediator of activation protein Medical Modeling Multi-Drug Resistance Multidrug-Resistant Tuberculosis Mus Mycobacterium smegmatis Mycobacterium tuberculosis NADH dehydrogenase (ubiquinone)Oral Organism Oxidation-Reduction Oxidative Stress Phagocytosis Phagolysosome Pharmaceutical Preparations Process Proteins Pulmonary Tuberculosis Recombinants Regimen Reporting Research Infrastructure Research Personnel Role SIV Scientist Serotyping Signal Transduction T cell response T-Lymphocyte Techniques Tuberculosis Tuberculosis Vaccines Tumor Necrosis Factor Receptor Vaccination Vaccines Vertebral column Viral Vector Virulent Work age group base booster vaccine cost experience gain of function immunogenicity killings loss of function macrophage mutant mycobacterial nonhuman primate novel vaccines pre-clinical prevent pro-apoptotic protein product development receptor recombinant viral vector resistant strain response social success vaccine candidate vector young adult

项目摘要

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.

描述（由申请人提供）：结核病每年造成近 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 万结核病病例。艾滋病毒的合并感染和结核病耐药菌株的增加使这一流行病变得更加严重和难以应对。目前的结核病疫苗卡介苗已有近 90 年的历史，未能有效挽救每年因结核病而丧生的数百万人的生命。 Aeras 全球结核病疫苗基金会是一个非营利性产品开发合作伙伴，与学术界、工业界、非营利组织和政府部门的领先研究人员和科学家合作，开发新的有效疫苗方案来阻止结核病。 BCG 疫苗的一个越来越有据可查的缺陷在于它无法逃脱受感染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分枝杆菌不同，它会将免疫反应转向主要的 MHC II 类抗原呈递，并且可能是CD4 显性 T 细胞对疫苗接种产生反应的原因。使用结核分枝杆菌和相关的无毒力堪萨斯分枝杆菌进行的功能丧失和获得筛选已经鉴定出结核分枝杆菌复杂生物体中存在的特定基因，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。 Aeras 将创建完全符合 cGxP 要求的重组 BCG 疫苗，其中包含已知抑制细胞凋亡的基因缺失，以通过交叉引发增强免疫反应，还将构建编码和表达高价 CD8+ T 细胞免疫原的符合 cGxP 要求的加强疫苗，以创建最佳的结核病疫苗方案。加强疫苗将由重组腺病毒血清型 4 和重组人 CMV 载体组成，这两种载体均已被证明能够引发有效的 CD8+ T 细胞反应。我们将在小鼠和恒河猴中评估这些方案，这是我们拥有丰富经验的结核疫苗免疫学模型和疗效，以便方便地选择最佳方案。