Project-002

项目-002

基本信息

批准号：
10666746
负责人：
Sallie R. Permar
金额：
$ 1.41万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10666746
关键词：
Acquired Immunodeficiency Syndrome Acute Lymphocytic Leukemia Adult Affect Animals Antibodies Antibody Response B-Lymphocytes Binding CD4 Positive T Lymphocytes CMV glycoprotein B Cells Cessation of life Child Childhood Clinical Trials Complication Congenital Abnormality Cytomegalovirus Cytomegalovirus Vaccines Data Development Developmental Delay Disorders Disease Effector Cell Fc Receptor Fetal Diseases Fetus Health Human Humoral Immunities Immune Immune response Immune system Immunity Immunocompetent Immunocompromised Host Immunoglobulin G Immunologics Impairment Incidence Individual Infection Infusion procedures Knowledge Link Lymphocyte MF59 Macaca Macaca mulatta Maternal-Fetal Transmission Mediating Mediator of activation protein Modeling Natural Killer Cells Neurologic Neurologic Deficit Passive Immunity Patients Phagocytosis Phenotype Population Pregnancy Prevention Prevention strategy Primary Infection Receptor Cell Research Rhesus Risk Role Sampling Seizures Specificity T-Lymphocyte Subsets Testing Transplant Recipients Universities Vaccine Design Vaccines Vertical Disease Transmission Viral Load result Virion Virus Virus Diseases Virus Latency Work antibody-dependent cellular phagocytosis antigen binding cancer type career development cell type cohort congenital cytomegalovirus cytotoxicity expectation fetal hearing impairment improved macrophage monocyte neutralizing antibody nonhuman primate pre-doctoral pregnant prevent programs public health relevance receptor binding response transmission process treatment group vaccine development vaccine trial

项目摘要

ABSTRACT: Congenital cytomegalovirus (cCMV) infection is the most common placentally transmitted infection worldwide, causing long-lasting complications for affected children, including hearing loss, developmental delays, seizures, and even death. After 40+ years of research, there is no licensed vaccine against CMV, despite high prioritization in vaccine development. Little is currently known about the maternal immune responses that prevent transmission during pregnancy, which is vital information for developing effective vaccines and treatments for cCMV. Prior studies using our rhesus monkey model of placental CMV transmission have determined that the presence of pre-existing antibodies reduce peak maternal viral load and protect against placental transmission, yet the antibody functions that mediated this protection has not been defined. Moreover, our group has demonstrated that non-neutralizing antibody effector functions mediated the partial protection against CMV acquisition achieved in three CMV glycoprotein B vaccine trials. Thus, this study will assess antibody effector functions, including antibody dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC), as correlates of protection against in utero transmission of CMV in animals with and without pre-existing passive humoral immunity. Binding mediators of antibody effector functions, including Fc receptor binding and cell-associated antigen binding, will also be assessed. Additionally, we will characterize the maternal effector cell populations that mediate non-neutralizing effector functions to explore the role of these cell types in vertical CMV transmission. Considering the high global incidence of cCMV and associated neurologic impairment, developing an effective vaccine guided by established immune correlates to prevent cCMV is imperative to improving global pediatric health.

抽象的：先天性巨细胞病毒（CCMV）感染是全球最常见的胎盘传播感染，导致受影响儿童的持久并发症，包括听力损失，发育延迟，癫痫发作甚至死亡。经过40多年的研究，尽管疫苗开发方面的优先次序很高，但没有针对CMV的许可疫苗。目前，关于预防怀孕期间传播的母体免疫反应的了解知之甚少，这是开发有效的疫苗和CCMV处理的重要信息。先前使用我们的恒河猴胎盘CMV传播模型的研究确定，现有抗体的存在减少了母体病毒载量并防止胎盘传播，但是介导这种保护的抗体功能尚未定义。此外，我们的小组已经证明，非中和抗体效应子功能介导了针对三项CMV糖蛋白B疫苗试验中获得的CMV采集的部分保护。因此，这项研究将评估抗体效应功能，包括依赖性的细胞吞噬作用（ADCP）和细胞毒性（ADCC），因为在具有和没有预先存在的被动性体体免疫力的动物中，针对子宫内CMV的保护措施相关。还将评估抗体效应功能的结合介质，包括FC受体结合和与细胞相关的抗原结合。此外，我们将表征介导非中和效应子功能的母体效应细胞群，以探索这些细胞类型在垂直CMV传播中的作用。考虑到CCMV的全球发病率和相关的神经系统障碍的高发病率，开发了一种有效的疫苗，以确定的免疫相关性以防止CCMV，这对于改善全球儿科健康至关重要。