Immunologic and virologic determinants of congenital Cytomegalovirus transmission and disease in rhesus monkeys

恒河猴先天性巨细胞病毒传播和疾病的免疫学和病毒学决定因素

基本信息

批准号：
10215778
负责人：
Peter A Barry
金额：
$ 1.25万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-24 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10215778
关键词：
Animal Model Animals Awareness Brain Injuries Cellular Immunity Clinical Trials Complex Congenital Abnormality Cytomegalovirus Cytomegalovirus Vaccines Decision Making Development Disease Fc Receptor Fetal Diseases Future Genetic Glycoproteins Goals Human Humoral Immunities Immune Immune Targeting Immune response Immunocompetent Immunoglobulin G Immunologics Impairment Infant Infection Infrastructure Institute of Medicine (U.S.)Knowledge Length Lymphocyte Depletion Macaca mulatta Modeling Neurologic Neurologic Deficit Newborn Infant Outcome Population Dynamics Population Genetics Preclinical Testing Prevention Prevention strategy Production Quality of life Research Resources Rhesus Role Statistical Data Interpretation Testing Vaccine Research Vaccines Variant Viral Viral Genome Virus Work base clinically relevant congenital cytomegalovirus congenital infection design effective intervention fetal fetal loss genetic selection genome sequencing improved in vivo evaluation infant morbidity mathematical model next generation nonhuman primate novel novel strategies pregnant pressure prevent programs protective efficacy research clinical testing response transmission process vaccine candidate vaccine development vaccine evaluation vaccine trial viral transmission virology virus genetics whole genome

项目摘要

ABSTRACT – Immunologic and virologic determinants of congenital cytomegalovirus transmission and disease in rhesus monkeys. Congenital cytomegalovirus (CMV) is the leading infectious cause of birth defects and infant neurologic deficits, yet gaps in our knowledge of the protective maternal immune responses has impeded the development of a successful CMV vaccine to eliminate this cause of infant morbidity. The overarching goal of this Program is to end the stalemate in congenital CMV vaccine research by defining the key immune responses and viral-host interactions that dictate primary fetal CMV transmission and disease. To accomplish this, the Program builds on our novel nonhuman primate (NHP) model of placental transmission of rhesus CMV (RhCMV). Specifically, the Program will employ this newly defined NHP model in RhCMV-seronegative pregnant dams to investigate the immune correlates of placental virus transmission and fetal disease (Project 1) and the viral determinants of placental RhCMV transmission (Project 2). An Administrative Core and four scientific Cores provide critical expertise and resources required to integrate Program activities, including administrative infrastructure and oversight (Administrative Core), NHP study implementation expertise (Core 1), virus production and quantitation (Core 2), whole viral genome sequencing and population genetics (Core 3) and statistical analyses and mathematical modeling (Core 4). Our overall hypothesis is that maternal humoral and cellular immunity provides partial protection against placental CMV transmission and disease, and viral-host immune interactions determine the emergence of both placentally transmitted and fetal CMV variants. Our overall specific aims are: 1) Demonstrate whether CMV-specific humoral and/or cellular responses confer protective efficacy against congenital infection and fetal disease; and 2) Define the key virologic determinants and viral selection pressures of placental CMV transmission and subsequent fetal disease. We expect the work of this Program will identify immune responses and virologic-host interactions that will guide the design of the next generation of congenital CMV vaccines and will also refine the NHP model to tailor it for future CMV vaccine candidate testing.

摘要 - 先天性巨细胞病毒传播的免疫学和病毒学确定和恒河猴的疾病。先天性巨细胞病毒（CMV）是先天缺陷和婴儿神经系统的主要感染原因缺陷，但是我们对受保护物质免疫反应的了解的差距阻碍了开发成功的CMV疫苗，以消除这种婴儿发病率的原因。总体目标该计划是通过定义关键免疫力来结束先天性CMV疫苗研究中的僵局反应和病毒宿主相互作用决定了原发性胎儿CMV的传播和疾病。完成这是基于我们新颖的非人类灵长类动物（NHP）恒河传播的模型 CMV（RHCMV）。具体而言，该程序将在RHCMV-SeroneNotative中采用这种新定义的NHP模型怀孕的大坝研究了斑点病毒传播和胎儿疾病的免疫复合物（项目 1）和PlacenAl RHCMV传播的病毒决定剂（项目2）。行政核心和四个科学核心提供了整合计划活动所需的重要专业知识和资源，包括行政基础设施和监督（行政核心），NHP研究实施专业知识（核心 1），病毒生产和定量（核心2），整个病毒基因组测序和种群遗传学（核心 3）和统计分析和数学建模（Core 4）。我们的总体假设是母亲体液和细胞免疫学提供了针对斑点CMV传播和疾病的部分保护，以及病毒宿主免疫相互作用决定了局部传播和胎儿CMV的出现变体。我们的总体具体目的是：1）证明CMV特异性的体液和/或细胞是否是否针对先天性感染和胎儿疾病的反应会议保护效率； 2）定义钥匙 lopenal CMV传播的病毒性决定剂和病毒选择压力和随后的胎儿疾病。我们预计该计划的工作将确定免疫反应和病毒式 - 宿主相互作用这将指导下一代先天性CMV疫苗的设计，还将完善NHP模型对其进行调整以进行将来的CMV疫苗候选测试。