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）应用程序的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针对 SIV 感染的免疫编程基础（RhCMV/SIV 疫苗），以及定义 IL-15 在引发针对持续性 SIV 的疫苗保护中的作用和作用 感染。这些研究与艾滋病毒疫苗的开发高度相关。 RhCMV/SIV 引发高频率和 不同组织中持续的效应分化 T 细胞反应。该疫苗在恒河猴中的应用 猿猴免疫缺陷病毒（SIV）感染的（RM）模型已证明对高度 与传统 SIV 疫苗相比，致病性 SIV 的挑战（总共 59% 的 RhCMV/SIV 接种 RM 消除进行性 SIV 感染）。 RhCMV/SIV 疫苗反应介导早期 SIV 拦截和 复制停滞，然后最终病毒清除。疫苗保护是由 MHC-E 限制性介导的 CMV 载体疫苗接种所特有的效应记忆分化 CD8+ T 细胞的免疫反应。我们有 还揭示了白细胞介素 (IL)-15 和 IL-15 反应与 RhCMV/SIV 的保护相关 疫苗接种。疫苗接种后迅速诱导 IL-15 反应，疫苗接种前 IL-15 基线较低 血液中的表达/反应，然后快速诱导与疫苗相关的 IL-15 反应网络 保护。这种 IL-15 动态可作为 RhCMV/SIV 疫苗功效结果预测因子。我们定义了一个 RhCMV/SIV 疫苗功效的包容性全血预测保护特征 (wbPPTS) 生物标志物，以及 我们将在体内研究中监测 RM 疫苗队列中的 wbPPTS，以确定分子机制 疫苗免疫编程。我们假设 RhCMV/SIV 疫苗和 IL-15 一起直接表达 跨组织和细胞的特定基因网络，以规划有效的疫苗免疫并建立 wbPPTS 疫苗保护的生物标志物特征。为了研究这个假设，我们设计了 PPG 拥有两个项目和三个服务核心，包括： 项目1. 起源和组织效应的系统分析 68-1 RhCMV/SIV 疫苗功效预测全血转录组特征；项目2：系统 RhCMV/SIV 和 IL-15 免疫编程机制的疫苗学；核心 A、管理、核心 B、 非人类灵长类动物和核心 C，系统生物学。我们的特色是体外/离体和体内研究 使用多组学 4 平台 RNAseq 应用程序（批量 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 IL-15 和 RhCMV/SIV 疫苗。