MECHANISMS PROGRAMMING PROTECTIVE IMMUNITY FROM RhCMV-SIV VACCINE AND IL-15 ACTIONS

RhCMV-SIV 疫苗和 IL-15 作用的保护性免疫编程机制

• 批准号: 10723635
• 负责人: Michael Gale
• 金额: $ 164.55万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723635
• 关键词: Acute; Address; Animals; Autopsy; Bioinformatics; Biological Markers; Blood; CD8-Positive T-Lymphocytes; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Characteristics; Clinical Research; Coupled; Cytomegalovirus; Cytomegalovirus Vaccines; Disease; Epitopes; Exhibits; Extinction; Foundations; Frequencies; Future; Gene Expression; Gene Expression Profile; Genes; HIV; HIV Antigens; HIV vaccine; Human; Immune; Immune response; Immunity; Immunologics; In Vitro; Infection; Inflammatory; Intercept; Interleukin-15; Knowledge; Link; Macaca mulatta; Major Histocompatibility Complex; Mediating; Memory; Modality; Modeling; Molecular; Molecular Profiling; Monitor; Pathogenicity; Pathway interactions; Pattern; Phase I/II Trial; Program Research Project Grants; Research Design; Rhesus; Role; SIV; SIV Vaccines; Services; Signal Pathway; Signal Transduction; Statistical Models; System; Systems Biology; T cell differentiation; T cell response; T-Lymphocyte; Technology; Testing; Time; Tissues; Translating; Vaccinated; Vaccination; Vaccines; Viral; Viremia; Virulent; Virus; Virus Diseases; Virus Replication; Whole Blood; Work; biomarker signature; cancer immunotherapy; cell type; cohort; design; efficacy outcomes; gene network; genetic signature; immune activation; in vivo; monocyte; multiple omics; nano-string; nonhuman primate; outcome prediction; preclinical study; programs; response; response biomarker; transcriptome sequencing; transcriptomics; vaccine development; vaccine efficacy; vaccine evaluation; vaccine platform; vaccine response; vaccinology; vector; vector induced; vector-based vaccine

This Program-project (PPG) application is focused on conducting preclinical studies to understand the molecular basis of immune programming by the rhesus cytomegalovirus vaccine against SIV infection (RhCMV/SIV vaccine), and on defining the role and actions of IL-15 in eliciting vaccine protection against persistent SIV infection. These studies are highly relevant for HIV vaccine development. RhCMV/SIV elicits high frequency and persistent effector-differentiated T cell responses in diverse tissues. Using of this vaccine in the rhesus macaque (RM) model of Simian immunodeficiency Virus (SIV) infection has demonstrated superior efficacy against highly pathogenic SIV challenge over conventional SIV vaccines (overall 59% of RhCMV/SIV vaccinated RM with abrogation of progressive SIV infection). The RhCMV/SIV vaccine response mediates early SIV intercept and replication arrest followed by eventual viral clearance. Vaccine protection is mediated by an MHC-E-restricted immune response of effector memory-differentiated CD8+ T cells unique to CMV-vector vaccination. We have revealed also that interleukin (IL)-15 and the IL-15 response are correlates of protection by RhCMV/SIV vaccination. The IL-15 response is rapidly induced following vaccination, with low prevaccination baseline IL-15 expression/response in blood, followed by rapid induction of IL-15 response networks linked with vaccine protection. This IL-15 dynamic serves as RhCMV/SIV vaccine efficacy outcome predictor. We have defined an inclusive whole blood predictive protective signature (wbPPTS) biomarker of RhCMV/SIV vaccine efficacy, and we will monitor this wbPPTS across RM vaccina cohorts within vivo studies to define the molecular mechanisms of vaccine immune programming. We hypothesize that RhCMV/SIV vaccine and IL-15 together direct expression of specific gene networks across tissues and cells to program effective vaccine immunity and establish the wbPPTS biomarker signature of vaccine protection. To investigate this hypothesis we have designed our PPG with two projects and three service cores including: Project 1. Systemic analysis of the origin and tissue effects of the 68-1 RhCMV/SIV vaccine efficacy-predictive whole blood transcriptomic signature; Project 2: Systems vaccinology of RhCMV/SIV and IL-15 mechanisms of immune programming; Core A, Administration, Core B, Nonhuman primates, and Core C, Systems biology. We feature in vitro/ex vivo and in vivo studies within a Systems Vaccinology design using multiomics 4-platform RNAseq applications (bulk RNAseq, scRNAseq/CITEseq, GeoMx/CosMx, Nanostring) and bioinformatics and statistical modeling approaches to define the systems response across tissues and cell types revealing the molecular basis of immune programming by IL-15 and RhCMV/SIV vaccine.

该计划-项目(PPG)的应用重点是进行临床前研究，以了解分子 恒河猴巨细胞病毒疫苗(RhCMV/SIV)免疫规划的基础 疫苗)，以及确定IL-15在诱导针对持续SIV的疫苗保护方面的作用和行动 感染。这些研究与艾滋病毒疫苗的开发高度相关。重组人巨细胞病毒/SIV诱导高频率和 不同组织中持续的效应器分化T细胞反应。该疫苗在恒河猴中的应用 猴免疫缺陷病毒(SIV)感染(RM)模型已显示出对高度免疫缺陷病毒的优越疗效 致病性SIV疫苗对传统SIV疫苗的挑战(总体而言，59%的RhCMV/SIV疫苗接种了 废除进行性SIV感染)。重组人巨细胞病毒/SIV疫苗应答介导早期SIV拦截和 复制停止，然后最终清除病毒。疫苗保护是由MHC-E限制性病毒介导的 巨细胞病毒载体疫苗特有的效应记忆分化CD8+T细胞的免疫应答。我们有 还揭示了IL-15和IL-15应答与RhCMV/SIV的保护作用相关 接种疫苗。IL-15在接种后迅速诱导，预防接种基线IL-15较低 在血液中表达/应答，随后快速诱导与疫苗相关的IL-15应答网络 保护。这种IL-15的动态变化可作为RhCMV/SIV疫苗疗效结果的预测指标。我们已经定义了一个 RhCMV/SIV疫苗效力的包容性全血预测性保护性签名(WbPPTS)生物标志物，以及 我们将在活体研究中通过rm痘苗队列监测这种wbPPTS，以确定分子机制。 疫苗免疫规划。我们推测，RhCMV/SIV疫苗和IL-15共同直接表达 跨组织和细胞的特定基因网络，以编程有效的疫苗免疫并建立 疫苗保护的wbPPTS生物标志物签名。为了研究这一假设，我们设计了我们的PPG 有两个项目和三个服务核心，包括：项目1.系统分析来源和组织效应 68-1 RhCMV/SIV疫苗疗效预测全血转录特征；项目2：系统 免疫规划的RhCMV/SIV和IL-15机制的疫苗学；核心A、管理、核心B 非人灵长类和核心C，系统生物学。我们以体外/体外和体内研究为特色 使用多组学4平台RNAseq应用程序的系统疫苗设计(Bulk RNAseq， ScRNAseq/CITEseq，GeoMx/CosMx，NanoString)以及生物信息学和统计建模方法 定义跨组织和细胞类型的系统反应，揭示免疫编程的分子基础 用IL-15和RhCMV/SIV疫苗。