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

• 批准号: 8113899
• 负责人: Donata Sizemore
• 金额: $ 13.14万
• 依托单位: AERAS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113899
• 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

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927万结核病例。同时感染艾滋病毒和结核病耐药菌株的增加使这一流行病更加严重和复杂。目前的结核病疫苗卡介苗（BCG）已有近90年的历史，但在挽救每年因结核病而丧生的数百万人的生命方面一直无效。Aeras全球结核病疫苗基金会是一个非营利产品开发伙伴关系，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，以阻止结核病。BCG疫苗越来越多的缺陷在于它不能逃脱受感染的巨噬细胞和树突细胞的吞噬溶酶体，这与M。结核或M.麻风病将免疫应答转移到主要的MHC II类抗原呈递，并且是CD4显性T细胞对疫苗接种应答的可能原因。使用M.结核分枝杆菌和相关的无毒分枝杆菌。Kansasii已经鉴定了存在于Mtb复合生物体（包括BCG）中的特异性基因，其基因产物具有抑制感染的巨噬细胞凋亡的功能。Aeras将创建完全符合cGxP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应答，还将构建编码和表达高效价CD8+ T细胞免疫原的符合cGxP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，这两种载体都已显示出引发有效的CD8+ T细胞应答。我们将在小鼠和恒河猴中评估这些方案，这些小鼠和恒河猴是我们具有丰富经验的结核疫苗免疫学和功效模型，以方便地选择最佳方案。