M Tuberculosis CTL Epitopes: Vaccine Design/Evaluation

结核病(TB)是单一感染源(分枝杆菌)导致死亡的主要原因 结核病)，每年造成300万人死亡。尽管结核病可以通过一种有效的 抗生素的组合，耐药的结核分枝杆菌最近出现，被归类为 C类生物制剂。因此，人们普遍认为，长期控制结核病将需要 开发一种更有效的疫苗。卡介苗(BCG)、卡介苗 目前的抗结核疫苗，在预防结核病的能力上有很大的差异，但对 结核病脑膜炎，这表明在可预见的未来，新的结核病疫苗将作为一种 卡介苗的佐剂或助剂。因此，了解结核分枝杆菌和卡介苗的免疫反应对于 一种改进的结核病疫苗的开发。越来越多的证据表明， CD4+和CD8+T淋巴细胞对结核分枝杆菌的保护性免疫反应至关重要。然而，几乎没有 已知人类对结核分枝杆菌的保护性免疫反应所针对的抗原。是这样的 合理开发和临床评估新的、更有效的结核病需要信息 疫苗。我们建议在这里描述人类CD4+和CD8+T细胞对一组 以确定结核分枝杆菌抗原与保护性免疫的相关性。待检测的抗原包括 受人类白细胞抗原A2限制的蛋白质和多肽表位，-50%的人表达的等位基因 人口。这些蛋白质和表位中的一些选自结核分枝杆菌基因的子集 在特定条件下高度表达，其产品预计将本地化到 细胞外环境，其余的代表先前发现的人类白细胞抗原A2限制性表位。《The T》 将评估来自三个不同来源的外周血白细胞对这些抗原的细胞反应 卡介苗免疫组和/或结核分枝杆菌感染者组：I.新生儿接种了以下4种中的一种 卡介苗菌株；感染结核分枝杆菌但没有进展为疾病(感染潜伏结核病)的个人 个人)；以及iii.PPD+结核病患者和PPD-“无能”结核病患者。其中一些肽.e表位 将用于开发表位低聚体，用于体外分析抗结核分枝杆菌反应和 在活体内。最后，我们将研究Mtb多肽特异性记忆T细胞的定位和功能。 活着。保护性免疫的相关因素可用于识别保护性抗原或确定保护性抗原的优先顺序 候选疫苗，优化疫苗剂量、计划、佐剂等，并及早提供 有效的证据。对于感染结核分枝杆菌后需要数年至数十年才能发展的结核病，免疫 与保护相关的是一种有吸引力的，也许是必要的，疗效试验的补充。

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.