M Tuberculosis CTL Epitopes: Vaccine Design/Evaluation

结核分枝杆菌 CTL 表位：疫苗设计/评估

• 批准号: 7175398
• 负责人: Elizabeth D Mellins
• 金额: $ 37.93万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7175398
• 关键词: Adjuvant; Alleles; Antibiotics; Antibodies; Antigen Targeting; Antigens; Antitubercular Agents; Bacteria; Biological Products; Birth; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Categories; Cause of Death; Cells; Cessation of life; Condition; Contracts; Cytotoxic T-Lymphocytes; Defect; Development; Disease; Dose; Drug resistance; Epitopes; Evaluation; Future; Genes; Genus Mycobacterium; Goals; HIV vaccine; HLA-A2 Antigen; Hepatitis B; Human; Immune; Immune response; Immunity; Immunization; In Vitro; Individual; Infection; Infectious Agent; Leukocytes; Localized; Meningeal Tuberculosis; Mycobacterium bovis; Mycobacterium tuberculosis; Patients; Peptides; Peripheral Blood Lymphocyte; Population; Preparation; Proteins; Research; Schedule; Specific qualifier value; Streptococcus pneumoniae; T memory cell; T-Lymphocyte; Testing; Tuberculosis; Tuberculosis Vaccines; Vaccine Antigen; Vaccine Design; Vaccines; Virus; efficacy trial; extracellular; improved; in vivo; neonate; peripheral blood; research clinical testing; response; vaccine development; vaccine evaluation

Tuberculosis (TB) is the leading cause of death from a single infectious agent (Mycobacterium tuberculosis (Mtb)), causing -3,000,000 deaths each year. Although TB can be effectively treated with a combination of antibiotics, drug resistant Mtb strains have recently emerged which are classified as Category C biological agents. Thus, it is widely felt that the long term control of TB will require the development of a more effective vaccine. Mycobacterium boris Bacille Calmette-Guerin (BCG), the current anti-TB vaccine, is quite variable in its ability to protect against TB but is effective against tuberculosis meningitis, suggesting that for the foreseeable future, new TB vaccines will be given as an adjuvant or boost to BCG. Thus, understanding the immune response to both Mtb and BCG is critical for the development of an improved vaccine for TB. An increasing body of evidence indicates that both CD4+ and CD8+ T lymphocytes are critical to a protective immune response against Mtb. However, little is known about the antigens targeted by protective immune responses against Mtb in humans. Such information is required for the rational development and clinical evaluation of new, more effective TB vaccines. We propose here to characterize the human CD4+ and CD8+ T cell response to a panel of Mtb antigens in order to identify correlates with protective immunity. Antigens to be tested include proteins as well as peptide epitopes restricted by HLA-A2, an allele expressed by -50% of the population. Some of these proteins and epitopes were selected from a subset of Mtb genes that are highly expressed under specified conditions and whose products are predicted to localize to the extracellular milieu, while the remainder represent previously identified HLA-A2 restricted epitopes. The T cell response to these antigens will be evaluated in peripheral blood leukocytes from three different groups of BCG immune and/or Mtb infected individuals: i. Neonates immunized a birth with one of 4 strains of BCG; ii. Individuals infected with Mtb but who do not progress to disease (latent TB infected individuals); and iii. PPD+ TB patients and PPD- "anergic" TB patients. Some of these peptid.e epitopes will be used to develop epitope oligomers which will be used to analyze anti-Mtb responses In vitro and in vivo. Lastly, the localization and function of Mtb peptide specific memory T cells will be studied in vivo. Correlates of protective immunity can be used to identify or prioritize protective antigens and vaccine candidates, to optimize vaccine dosing, schedules, adjuvants, etc., and to provide early evidence of efficacy. For TB, which takes years to decades to develop after infection with Mtb, immune correlates with protection are an attractive, and perhaps essential, supplement to efficacy trials.

结核病（TB）是单一感染剂（分枝杆菌）死亡的主要原因 结核病（MTB）），每年造成-3,000,000人死亡。尽管可以用A有效治疗结核 最近出现了抗生素，耐药MTB菌株的组合，被归类为 C类生物剂。因此，人们普遍认为，TB的长期控制需要 开发更有效的疫苗。分枝杆菌Boris Bacille Calmette-Guerin（BCG）， 当前的抗结核病疫苗在防御结核病的能力方面有很大变化，但有效 结核病脑膜炎，表明在可预见的未来，新的结核病疫苗将作为一种 辅助或提升到BCG。因此，了解对MTB和BCG的免疫反应对 TB的改进疫苗的开发。越来越多的证据表明 CD4+和CD8+ T淋巴细胞对于针对MTB的保护性免疫反应至关重要。但是，很少 关于人类对MTB的保护性免疫反应靶向的抗原已知。这样的 新的，更有效的结核病的合理发展和临床评估需要信息 疫苗。我们在这里提出要表征人类CD4+和CD8+ T细胞对一个面板的响应 MTB抗原以识别与保护性免疫相关。要测试的抗原包括 蛋白质以及受HLA -A2限制的肽表位，该等位基因由-50％表示 人口。其中一些蛋白质和表位是从MTB基因的子集中选择的 高度表达在指定条件下，并预测其产品本地化 细胞外环境，其余代表先前确定的HLA-A2限制表位。 t 细胞对这些抗原的反应将在三种不同的外周血白细胞中评估 BCG免疫和/或MTB感染的个体组：i。新生儿以4之一的身份免疫出生 BCG菌株； ii。感染了MTB但没有发展为疾病的人（潜在结核病感染 个人）；和iii。 PPD+结核病患者和PPD-“厌食”结核病患者。其中一些肽。E表位 将用于开发表位寡聚物，该低聚物将用于在体外分析抗MTB反应和 体内。最后，将研究MTB肽特定记忆T细胞的定位和功能 体内。保护性免疫的相关性可用于识别或优先考虑保护性抗原和优先级 候选疫苗，以优化疫苗给药，时间表，佐剂等，并提早提供 功效的证据。对于结核病，在用MTB感染后需要数十年的时间才能发育 与保护相关的是有吸引力的，也许是对功效试验的必不可少的补充。