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

• 批准号: 10455266
• 负责人: Sallie R. Permar
• 金额: $ 9.19万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-24 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455266
• 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

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.

先天性巨细胞病毒传播的免疫学和病毒学决定因素 和疾病之间的联系。 先天性巨细胞病毒（CMV）是导致出生缺陷和婴儿神经系统疾病的主要感染原因 缺陷，但我们对保护性母体免疫反应的知识差距阻碍了 因此，我们需要开发一种成功的CMV疫苗，以消除婴儿发病的这一原因。的首要目标 该计划旨在通过确定关键免疫指标， 反应和病毒-宿主相互作用决定了原发性胎儿CMV传播和疾病。完成 该计划建立在我们新的恒河猴胎盘传播的非人灵长类动物（NHP）模型基础上 CMV（RhCMV）。具体而言，该计划将在RhCMV-血清阴性中采用这种新定义的NHP模型 妊娠母鼠研究胎盘病毒传播和胎儿疾病的免疫相关性（项目 1)以及胎盘RhCMV传播的病毒决定因素（项目2）。一个行政核心和四个 科学核心提供整合计划活动所需的关键专业知识和资源，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），全病毒基因组测序和群体遗传学（核心 3)统计分析和数学建模（核心4）。我们的总体假设是 体液和细胞免疫提供了部分保护，以防止胎盘CMV传播和疾病， 病毒-宿主免疫相互作用决定了胎盘传播和胎儿CMV的出现 变体。我们的总体具体目标是：1）证明CMV特异性体液和/或细胞免疫抑制剂是否是CMV特异性的。 反应赋予对先天性感染和胎儿疾病的保护效力; 2）定义关键 胎盘巨细胞病毒传播和随后胎儿的病毒学决定因素和病毒选择压力 疾病我们希望这项计划的工作将确定免疫反应和病毒-宿主相互作用 这将指导下一代先天性巨细胞病毒疫苗的设计，并将完善NHP模型 为未来的CMV疫苗候选测试量身定制。