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，会给受影响的儿童带来长期的并发症，包括听力损失、发育迟缓、癫痫发作，甚至死亡。经过 40 多年的研究，尽管疫苗开发处于高度优先地位，但还没有针对 CMV 的疫苗获得许可。目前对预防怀孕期间传播的母体免疫反应知之甚少，而这对于开发有效的 cCMV 疫苗和治疗方法至关重要。之前使用我们的恒河猴胎盘巨细胞病毒传播模型进行的研究已经确定，预先存在的抗体的存在会降低母体病毒载量峰值并防止胎盘传播，但介导这种保护的抗体功能尚未确定。此外，我们的小组已经证明，在三项 CMV 糖蛋白 B 疫苗试验中，非中和抗体效应功能介导了针对 CMV 获得的部分保护。因此，本研究将评估抗体效应器功能，包括抗体依赖性细胞吞噬作用（ADCP）和细胞毒性（ADCC），作为在具有或不具有预先存在的被动体液免疫的动物中防止CMV在子宫内传播的相关性。还将评估抗体效应功能的结合介质，包括 Fc 受体结合和细胞相关抗原结合。此外，我们将表征介导非中和效应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 和相关神经系统损伤的全球高发病率，开发一种由已建立的免疫相关因素指导的有效疫苗来预防 cCMV 对于改善全球儿科健康至关重要。