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: 10461200
• 负责人: Sallie R. Permar
• 金额: $ 290.28万
• 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/10461200
• 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; rational design; research clinical testing; response; transmission process; vaccine candidate; vaccine development; vaccine evaluation; vaccine strategy; vaccine trial; viral transmission; 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