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: 6701338
• 负责人: Carol A. Clayberger
• 金额: $ 40万
• 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 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6701338
• 关键词: Tuberculosis; CTL; Epitopes; Vaccine; Design

DESCRIPTION (provided by applicant): Tuberculosis (TB) is the leading cause of death from a single infectious agent (Mycobacterium tuberculosis (Mtb)), causing approximately 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 bovis 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 approximately 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 peptide 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.

描述（由申请人提供）：结核病（TB）是单个传染病（结核分枝杆菌（MTB））死亡的主要原因，每年造成约3,000,000人死亡。尽管可以通过抗生素的组合有效地治疗结核病，但最近出现了抗药性MTB菌株，这些菌株被归类为C类生物学剂。因此，人们普遍认为，TB的长期控制需要开发更有效的疫苗。目前的抗TB疫苗的牛肉分枝杆菌巴基氏菌（BCG）的预防能力有很大的变化，但有效地防止结核病脑膜炎，这表明在可预见的未来，新的TB疫苗将作为辅助剂或增强BCG。因此，了解对MTB和BCG的免疫反应对于TB改善疫苗的开发至关重要。越来越多的证据表明，CD4+和CD8+ T淋巴细胞均对针对MTB的保护性免疫反应至关重要。然而，对于针对人类MTB的保护性免疫反应靶向的抗原知之甚少。这种信息是对新的，更有效的结核病疫苗的合理发展和临床评估所必需的。我们在这里提出，以表征人类CD4+和CD8+ T细胞对MTB抗原面板的反应，以鉴定与保护性免疫相关。要测试的抗原包括受HLA-A2限制的蛋白质以及肽表位，该等位基因约有50％的群体表达。其中一些蛋白质和表位是从MTB基因的一个子集中选择的，这些基因在指定条件下高度表达，并且预测其产物将其定位于细胞外环境，而其余的则代表先前鉴定的HLA-A2限制性eptope。 T细胞对这些抗原的反应将在三个不同组的BCG免疫和/或MTB感染个体的外​​周血白细胞中进行评估：i。新生儿用4种BCG菌株之一免疫了出生； ii。感染了MTB但不发展疾病的个体（潜在结核病感染的个体）；和iii。 PPD+结核病患者和PPD-“厌食”结核病患者。这些肽表位中的一些将用于开发表位低聚物，这些肽将用于分析体外和体内抗MTB反应。最后，将在体内研究MTB肽特定记忆T细胞的定位和功能。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候选疫苗，以优化疫苗给药，调度，佐剂等，并提供疗效的早期证据。对于结核病（TB），在感染MTB后需要数十年的时间才能与保护相关，这是一种有吸引力的，也许是对效力试验的必不可少的补充。