PERSISTENCE OF PROTECTION CONFERRED BY SHINGRIX AGAINST HERPES ZOSTER IN OLDER ADULTS

SHINGRIX 对老年人的带状疱疹提供持久保护

• 批准号: 9886187
• 负责人: MYRON J LEVIN
• 金额: $ 71.55万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-06 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886187
• 关键词: Adjuvant; Adult; Afferent Neurons; Age; Age-Years; Alleles; Antigen-Presenting Cells; Attenuated; Attenuated Vaccines; Binding Sites; Biopsy; Blood; CD8-Positive T-Lymphocytes; Cells; Cellular Immunity; Characteristics; Chickenpox; Childhood; Dose; ERG gene; Elderly; Epigenetic Process; Epitopes; Event; Ganglia; Glycoproteins; Herpes zoster disease; Herpesviridae; Herpesvirus Type 3; Herpesvirus Vaccines; Human; Human body; Immune; Immune response; Immunity; Immunization; Immunologics; Infection; Kinetics; Measures; Mediating; Memory; Modeling; Nature; Nucleic Acids; Outcome Measure; Pain; Participant; Pathogenesis; Patient Recruitments; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Play; Recombinants; Research; Risk Factors; Role; Sensory Ganglia; Site; Skin; T cell response; T memory cell; T-Lymphocyte; Time; Tissue imaging; Tissues; Tumor-infiltrating immune cells; VZV vaccine; Vaccination; Vaccines; Viremia; Virus; Virus Diseases; Virus Replication; Work; Zoster Vaccine; adaptive immune response; afferent nerve; cell type; chemokine; cytokine; experimental study; immunogenic; immunogenicity; improved; interest; prevent; response; success; tissue biomarkers; transcriptomics; vaccine candidate; vaccine efficacy; vaccinology

Summary Herpes zoster (HZ) is the consequence of the reactivation of varicella-zoster virus (VZV), latent in sensory neurons, that is not adequately controlled by ambient VZV-specific T cell immunity. These critical immune responses decline with age. Of the two available HZ vaccines, one (Zostavax; zoster vaccine live [ZVL]) is moderately efficacious (~50%), but efficacy is greatly influenced by the age of the vaccinee and efficacy wanes at 5-8 years; the other vaccine (Shingrix; adjuvanted recombinant glycoprotein E vaccine [SRX]) is ~90% effective, regardless of age at the time of administration, and to date has not waned. This proposal will define important differences in the immune response to each of the vaccines, and will investigate mechanisms that explain these differences. We are able to recruit participants who received each of these vaccines at least 5 years previously or in the past year, thus facilitating research on the difference in durability of the two vaccines. As a model of reactivation of VZV, we will challenge participants (note: humans are the only hosts in which VZV can be reliably studied) with intradermal VZV (the licensed vOka vaccine strain) and use as an outcome measure the presence of VZV nucleic acids in blood, which we previously showed occurred frequently after administration of this strain. This measure of viremia will be correlated with measures of VZV-specific immune responses that limit the replication of the live VZV challenge virus. These will include: 1) measures of local tissue (skin biopsy) responses using tissue imaging to detect VZV and the nature of the early infiltrating immune cell types; 2) early plasma and tissue biomarkers (cytokines and chemokines); 3) the phenotype of cell-mediated responses (T cells, NK, and antigen-presenting cell subsets); 4) transcriptomic analysis of early gene responses in skin and PBMC after the VZV challenge. This will be aided by our finding gE-specific epitopes for HLA class I and II alleles that will be used to prepare gE-specific tetramers. We will identify the components of the immune response to VZV challenge that are most likely to mediate the control of viral replication. We are interested in systemic markers, since blood is readily accessible and we seek immune correlates with control of viral replication that can be used in other studies. We are including local responses, because rapidity and success of immune control of viral replication at the site of inoculation (modelling the site of early replication of reactivated VZV) is crucial for HZ pathogenesis and vaccine-conferred protection. The last aim of this application is to analyze the relationship of the responses to SRX administration with the immune responses that reduce viremia after VZV challenge, especially the relationship between the magnitude of gE-memory T cell responses to SRX (which we previously showed was a marker of this superior HZ vaccine) and reduced viremia after VZV challenge.

概括 带状疱疹 (HZ) 是水痘带状疱疹病毒 (VZV) 重新激活的结果，潜伏在 感觉神经元，不受环境 VZV 特异性 T 细胞免疫的充分控制。这些关键的 免疫反应随着年龄的增长而下降。在两种可用的带状疱疹疫苗中，一种是（Zostavax；带状疱疹活疫苗） [ZVL]) 具有中等功效 (~50%)，但功效很大程度上受接种者年龄和 5-8年后疗效减弱；另一种疫苗（Shingrix；佐剂重组糖蛋白 E 疫苗 [SRX]）的有效性约为 90%，无论给药时的年龄如何，并且迄今为止尚未减弱。 该提案将定义每种疫苗的免疫反应的重要差异，并将 研究解释这些差异的机制。我们能够招募获得每个项目的参与者 至少 5 年前或过去一年接种过这些疫苗，从而促进对差异的研究 两种疫苗的持久性。作为VZV重新激活的模型，我们将挑战参与者（注：人类 是唯一可以可靠地研究 VZV 的宿主），皮内注射 VZV（获得许可的 vOka 疫苗） 毒株）并用作测量血液中 VZV 核酸存在的结果，我们之前 表明在施用该菌株后频繁发生。这种病毒血症的测量将与 限制活 VZV 攻击病毒复制的 VZV 特异性免疫反应的措施。这些 将包括： 1) 使用组织成像来检测 VZV 和局部组织（皮肤活检）反应的测量 早期浸润免疫细胞类型的性质； 2) 早期血浆和组织生物标志物（细胞因子和 趋化因子）； 3) 细胞介导反应的表型（T 细胞、NK 和抗原呈递细胞亚群）； 4) VZV攻击后皮肤和PBMC中早期基因反应的转录组分析。这将是 借助我们发现的 HLA I 类和 II 类等位基因的 gE 特异性表位，这些表位将用于制备 gE 特异性 四聚体。 我们将确定对水痘带状疱疹病毒攻击的免疫反应最有可能的组成部分 介导病毒复制的控制。我们对全身标记感兴趣，因为血液很容易获得 我们寻找可用于其他研究的免疫与病毒复制控制的相关性。我们是 包括局部反应，因为病毒复制位点的免疫控制快速且成功 接种（模拟重新激活的 VZV 早期复制位点）对于带状疱疹发病机制至关重要， 疫苗赋予的保护。 此应用程序的最后一个目标是分析 SRX 管理响应的关系 与水痘带状疱疹病毒攻击后减少病毒血症的免疫反应有关，尤其是 gE 记忆 T 细胞对 SRX 反应的强度（我们之前表明这是这种优越性的标志） 带状疱疹疫苗）并减少水痘带状疱疹病毒攻击后的病毒血症。