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.

摘要 带状疱疹(HZ)是水痘-带状疱疹病毒(VZV)重新激活的结果，潜伏于 感觉神经元，不能被周围的VZV特异性T细胞免疫充分控制。这些关键因素 免疫反应随着年龄的增长而下降。在两种可用的HZ疫苗中，一种(Zostavax；带状疱疹疫苗活疫苗 [ZVL])是中等有效的(~50%)，但疗效受受试者年龄的影响很大， 效力在5-8年后减弱；另一种疫苗(Shingrix；佐剂重组糖蛋白E疫苗 [SRX])有效率约为90%，与给药时的年龄无关，而且到目前为止还没有减弱。 这项提案将定义对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。我们能够招募每一位收到 这些疫苗至少在5年前或过去一年内接种，从而有助于研究 这两种疫苗的耐久性。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VZV(获得许可的Voka疫苗 菌株)，并将其用作测量血液中是否存在VZV核酸的结果，我们之前 在给药后频繁出现。病毒血症的这一指标将与 测量限制活体VZV挑战病毒复制的VZV特异性免疫反应。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 早期浸润性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)细胞介导的反应的表型(T细胞、NK和抗原提呈细胞亚群)； 4)VZV攻击后皮肤和PBMC中早期基因反应的转录转录分析。这将是 在我们为人类白细胞抗原I和II类等位基因发现的GE特异性表位的帮助下，这些表位将被用于制备GE特异性 四聚体。 我们将确定对VZV挑战的免疫反应中最有可能 调节病毒复制的控制。我们对系统标志物很感兴趣，因为血液很容易获得 我们还寻求与控制病毒复制相关的免疫学，可用于其他研究。我们是 包括局部反应，因为病毒复制的免疫控制的快速和成功 接种(模拟重新激活的VZV的早期复制部位)对HZ的发病和 疫苗--提供保护。 此应用程序的最后一个目标是分析响应与SRX管理的关系 与VZV攻击后减少病毒血症的免疫反应，特别是与 GE-Memory T细胞对SRX的反应幅度(我们之前展示的是这种优势的标志 HZ疫苗)，减少VZV攻击后的病毒血症。