IMMUNITY & VIRAL REPLICATION IN CHILDREN WITH VARICELLA

免疫

• 批准号: 2061227
• 负责人: Ann Arvin
• 金额: $ 22.49万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2061227
• 关键词: Herpesviridae vaccine; active immunization; adult human (21+); age difference; antigen presentation; cellular immunity; chickenpox; child (0-11); cytokine; cytotoxic T lymphocyte; dendritic cells; enzyme linked immunosorbent assay; epitope mapping; flow cytometry; helper T lymphocyte; host organism interaction; human subject; immunologic memory; live vaccine; lymphocyte proliferation; major histocompatibility complex; shingles; varicella zoster virus; virus antigen; virus protein

Varicella-zoster virus (VZV), a human herpesvirus, causes varicella (chickenpox) and herpes zoster (singles). VZV disease produces serious morbidity and can be life-threatening in otherwise healthy adults, the elderly, and in human immunodeficiency virus (HIV)-infected, cancer and transplant patients. Our objective is to define immunogenic proteins and host factors affecting cellular immune responses to VZV in experiments which will be relevant to VZV vaccine design and optimal use of live attenuated varicella vaccine. Helper and cytotoxic T-cell (CTL) recognition of structural/regulatory gene products (ORF4, ORF10, ORF61, and ORF63) will be evaluated using VZV-vaccinia recombinants. Since memory T-cells recognize gp I, gp IV and IE62 protein, immunodominant regions will be identified with recombinants that express truncated forms of each protein. T-cell epitopes will be mapped using peptides that fit proposed overlapping CD4+ and DC8+ T-cell motifs and expressing the sequences in vaccinia. The dendritic cell system will be developed as an in vitro method to determine whether the same VZV proteins or peptides that elicit T-cell recognition after natural infection in vivo are active primary immunogens when presented as purified proteins or related peptides to naive T-cells. Since the expression of viral proteins in infected cells does not predict their immunogenicity, this method has broad potential value for designing protein or peptide vaccines. Genetic factors affecting the host response will be determined by analyzing T- cell recognition of glycoproteins and IE62 protein in donors of known MHC phenotype. Age-related factors influencing the primary host response will be assessed by comparing VZV specific CD4+ and DC8+ responses in children and adults immunized with varicella vaccine. Cytokine production will be investigated to determine whether adults have a relative failure to prime Th1-like CD4+ T-cells or a relative predominance of the Th3-like subset which could downregulate essential Th1-like responses. Whether the increased susceptibility to VZV reactivation in elderly individuals correlates with a quantitative decrease in T-cells that recognize VZV proteins and/or in the relative predominance of Th1 or Th2-like CD4+ T-cell responses will be evaluated. Understanding cytokine responses to viral antigens could yield new insights about their potential value as vaccine components. Finally, because the widespread use of varicella vaccine will reduce opportunities to boost VZV immunity by re-exposure during the annual varicella epidemics, it is important to investigate whether there ar any age- related obstacles to using the vaccine to enhance T-cell immunity. Helper and CTL recall responses will be evaluated in children and adults with vaccine-induced immunity who ar re-vaccinated after 4-10 years. The comparative efficacy of immunization for enhancing natural immunity will be assessed in younger and elderly adults since VZV vaccines may have therapeutic value for preventing herpes zoster. Investigating VZV immunity is directly relevant to clinical practice because current evidence is that a single vaccine preparation will be effective optimally in all clinical circumstances.

水痘-带状疱疹病毒（VZV），一种人类疱疹病毒，可引起水痘 （水痘）和带状疱疹（单打）。 VZV疾病产生严重的 发病率，并可能危及生命，否则健康的成年人， 老年人、艾滋病毒感染者、癌症患者和 移植患者 我们的目标是定义免疫原性蛋白质， 影响VZV细胞免疫应答的宿主因素 这将与VZV疫苗设计和活疫苗的最佳使用有关。 水痘疫苗。 辅助和细胞毒性T细胞（CTL） 识别结构/调节基因产物（ORF 4，ORF 10，ORF 61， 和ORF 63）将使用VZV-牛痘重组体进行评估。 以来 记忆性T细胞识别gp I、gp IV和IE62蛋白，免疫显性 将用表达截短形式的重组体鉴定区域 每种蛋白质。 T细胞表位将使用符合以下条件的肽进行定位： 提出了重叠的CD 4+和DC 8 + T细胞基序，并表达 牛痘中的序列。 树突状细胞系统将被开发为 确定相同VZV蛋白或肽是否 在体内自然感染后引发T细胞识别的抗体是有活性的 当作为纯化蛋白质或相关蛋白质存在时， 肽与初始T细胞的结合。 由于病毒蛋白质的表达， 感染的细胞不能预测其免疫原性，该方法具有 对设计蛋白质或肽疫苗具有广泛的潜在价值。 遗传 影响宿主反应的因素将通过分析T- 已知MHC供体中糖蛋白和IE62蛋白的细胞识别 表型 影响主要宿主反应的病原体相关因素 将通过比较VZV特异性CD 4+和DC 8+应答进行评估， 接种水痘疫苗的儿童和成人。 细胞因子 生产将进行调查，以确定是否成年人有一个 相对未能引发Th 1样CD 4 + T细胞或相对 Th 3样亚群的优势，其可以下调必需的 Th 1类反应。 对VZV的易感性增加是否 老年人的再激活与定量的 识别VZV蛋白的T细胞和/或相对免疫应答的减少。 将评价Th 1或Th 2样CD 4 + T细胞应答的优势。 了解细胞因子对病毒抗原的反应可以产生新的 了解它们作为疫苗成分的潜在价值。 最后， 因为水痘疫苗的广泛使用会减少 在每年的水痘期间重新接触VZV， 流行病，重要的是要调查是否有任何年龄- 使用疫苗增强T细胞免疫力的相关障碍。 将在儿童和成人中评估助手和CTL回忆反应 接种疫苗后4-10年后重新接种疫苗的人。 的 免疫接种对增强自然免疫力的比较效果将 在年轻和老年人中进行评估，因为VZV疫苗可能 预防带状疱疹的治疗价值。 调查VZV 免疫力与临床实践直接相关， 有证据表明，单一的疫苗制剂将是有效的最佳 在所有临床情况下。