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.

该程序项目（PPG）应用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的免疫程序基础针对SIV感染（RHCMV/SIV） 疫苗），并定义IL-15在引发疫苗保护抗持续SIV中的作用和行动时 感染。这些研究与HIV疫苗发育高度相关。 RHCMV/SIV引起高频和 持续的效应子分化的T细胞反应在不同组织中。在恒河猴中使用这种疫苗 （RM）邻苯二甲酸免疫缺陷病毒（SIV）感染的模型表现出对高度的效力 传统SIV疫苗对病原SIV挑战（总计59％的RHCMV/SIV接种RM的RM 消除进行性SIV感染）。 RHCMV/SIV疫苗反应介导SIV早期截距和 复制逮捕，最终进行病毒清除。疫苗保护是由MHC-E限制的 效应器记忆分化的CD8+ T细胞的免疫反应是CMV-vector疫苗接种。我们有 还揭示了白介素（IL）-15和IL-15响应是RHCMV/SIV保护的相关性 疫苗接种。疫苗接种后，IL-15响应迅速诱导，prevacination基线IL-15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。该IL-15动态充当RHCMV/SIV疫苗疗效预测因子。我们定义了一个 RHCMV/SIV疫苗功效的包含全血预测性保护签名（WBPPTS）生物标志物和 我们将在体内研究中跨RM Vaccina队列进行监测以定义分子机制的WBPPT 疫苗免疫编程。我们假设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 WBPPTS保护疫苗保护的生物标志物特征。为了研究这一假设，我们设计了PPG 有两个项目和三个服务核心，包括：项目1。对起源和组织效应的系统性分析 68-1 RHCMV/SIV疫苗疗效预测性全血记录组学特征；项目2：系统 RHCMV/SIV和IL-15免疫编程机制的疫苗接种学；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。我们在体外/Ex ex Vivo和体内研究中具有 使用多组合4平台RNASEQ应用程序的系统疫苗学设计（Bulk RNASEQ， scrnaseq/citeseq，Geomx/cosmx，纳米串）和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响应，揭示了免疫编程的分子基础 由IL-15和RHCMV/SIV疫苗。