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

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（RhCMV/SIV）免疫程序的基础 疫苗），以及确定IL-15在引发疫苗保护对抗持续性SIV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的出现频率高， 不同组织中持续的效应分化T细胞应答。该疫苗在恒河猴中的应用 (RM)猴免疫缺陷病毒（SIV）感染的模型已经证明上级对高度免疫缺陷病毒（HIV） 与常规SIV疫苗相比，致病性SIV攻击（总体上59%的RhCMV/SIV接种RM， 消除进行性SIV感染）。RhCMV/SIV疫苗应答介导早期SIV拦截， 复制停滞，随后最终病毒清除。疫苗保护是由MHC-E限制性 CMV载体疫苗接种特有的效应记忆分化的CD 8 + T细胞的免疫应答。我们有 IL-15和IL-15应答与RhCMV/SIV的保护作用相关 预防针IL-15应答在接种后迅速诱导，接种前基线IL-15较低 在血液中表达/应答，随后快速诱导与疫苗连接的IL-15应答网络 保护这种IL-15动态可作为RhCMV/SIV疫苗效力结果预测因子。我们定义了一个 包括RhCMV/SIV疫苗效力的全血预测保护特征（wbPPTS）生物标志物，以及 我们将在体内研究中监测RM疫苗队列的wbPPTS，以确定分子机制 疫苗免疫程序的一部分。我们假设RhCMV/SIV疫苗和IL-15一起直接表达 在组织和细胞中建立特定的基因网络，以编程有效的疫苗免疫， 疫苗保护的wbPPTS生物标志物特征。为了研究这一假设，我们设计了PPG 包括两个项目和三个服务核心，包括：项目1。系统地分析了起源和组织效应 68-1 RhCMV/SIV疫苗有效性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，给药，核心B， 非人类灵长类，以及核心C，系统生物学。我们的特点是在体外/离体和体内研究中， 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。

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.