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

总结 带状疱疹（HZ）是潜伏在皮肤中的水痘-带状疱疹病毒（VZV）再活化的结果。 感觉神经元，其不受周围VZV特异性T细胞免疫的充分控制。这些关键 免疫反应随年龄增长而下降。在两种可用的HZ疫苗中，一种（Zostavax;带状疱疹活疫苗 [ZVL]）是中等有效的（~50%），但效力受接种者年龄的影响很大， 效力在5-8年减弱;另一种疫苗（Shingrix;佐剂重组糖蛋白E疫苗 [SRX]）的有效性约为90%，与给药时的年龄无关，迄今为止尚未减弱。 该提案将确定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。我们能够招募获得每一个 这些疫苗至少在5年前或过去一年中，从而促进研究的差异， 两种疫苗的持久性。作为VZV再激活的模型，我们将挑战参与者（注：人类 是唯一可以可靠研究VZV的宿主）与皮内VZV（许可的vOka疫苗 菌株），并将其用作测量血液中VZV核酸的存在的结果，我们以前 显示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特异性免疫应答的测量。这些 将包括：1）使用组织成像来检测VZV的局部组织（皮肤活检）反应的测量，以及 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 3）细胞介导的应答的表型（T细胞、NK和抗原呈递细胞亚群）; 4)VZV攻击后皮肤和PBMC中早期基因应答的转录组学分析。这将是 通过我们发现的HLA I类和II类等位基因的gE特异性表位， 四聚体。 我们将确定对VZV攻击的免疫应答的组成部分，这些组成部分最有可能 介导病毒复制的控制。我们感兴趣的是全身标记物，因为血液是容易获得的 我们寻找免疫与控制病毒复制的相关性，这可以用于其他研究。我们 包括局部反应，因为免疫控制病毒复制的速度和成功， 接种（模拟再活化VZV的早期复制位点）对HZ发病至关重要， 疫苗保护。 本研究的最后一个目的是分析SRX管理的反应之间的关系 与VZV攻击后减少病毒血症的免疫应答有关，特别是与VZV攻击后减少病毒血症的免疫应答之间的关系。 GE-记忆T细胞对SRX的应答的幅度（我们先前表明这是这种优越的上级应答的标志） HZ疫苗）和VZV攻击后减少的病毒血症。

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.