Project 3: Hyperimmune globulin prophylaxis and treatment of ZIKV in pregnancy

项目3：妊娠期高免疫球蛋白预防和治疗寨卡病毒

基本信息

批准号：
10220704
负责人：
David H. O'Connor
金额：
$ 72.12万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220704
关键词：
Acute Americas Animals Antibodies Antibody Repertoire Antibody Response Antibody Therapy B cell repertoire B-Lymphocytes Biological Assay Blood Centers for Disease Control and Prevention (U.S.)Chronic Congenital Abnormality Dose Epitopes Evaluation Fetus First Pregnancy Trimester Frequencies Functional disorder Future Generations GlobulinN Globulins Goals Histopathology Immunity Individual Infection Macaca Macaca mulatta Medical Monkeys Monoclonal Antibodies Mothers Mus Neonatal Ocular Pathology Passive Immunotherapy Plasma Play Population Pregnancy Pregnant Women Preparation Prophylactic treatment Reporting Risk Role Severities Specificity Testing Therapeutic Therapeutic Intervention Tissues Vaccine Design Vaccines Vertical Disease Transmission Viremia Virus Replication Woman ZIKV infection Zika Virus congenital infection congenital zika syndrome efficacy evaluation experience experimental study fetal human monoclonal antibodies hyperimmunization in utero neonatal injury neutralizing antibody neutralizing monoclonal antibodies passive antibodies polyclonal antibody pregnant prevent response therapy design translational approach transmission process vaccine evaluation

项目摘要

Project 3 - Project Summary/Abstract Thousands of babies have been born with congenital Zika syndrome as a result of the emergence of Zika virus (ZIKV) that has spread across the Americas and will continue to reach new ZIKV naive populations in the future. There are currently no available treatments or medical prophylaxis options. Furthermore, some women and macaques infected with Zika virus during pregnancy experience extended virus rep- lication in the blood for a longer duration than nonpregnant individuals. This project seeks to test the hypothesis that hyperimmune globulin and monoclonal antibody treatment administered shortly after ZIKV infection can effectively control viral replication in both the mother and fetus and reduce the impact of congenital Zika syndrome. This hypothesis will be tested in the following three specific aims: Aim 1: Define highly potent ZIKV-specific second-generation monoclonal antibodies from macaques with and without prolonged plasma viremia. Aim 2: Evaluate the efficacy of post-exposure hyperimmune globulin (HIG) treatment to clear maternal viremia and limit fetal transmission and neonatal injury. Aim 3: Evaluate the efficacy of potently-neutralizing anti-ZIKV monoclonal antibodies to clear maternal viremia and limit fetal transmission and neonatal injury. Specifically, in Aim 1 antibodies will be isolated from pregnant and nonpregnant ZIKV infected macaques and will be characterized to determine what may make one antibody response better at controlling in- fection than another antibody response. Secondly, HIG purified from infected rhesus macaques (Aim 2) or potently neutralizing mAbs isolated in Aim 1 (Aim 3), will be administered 5 days after infection to pregnant macaques infected at ~6 weeks gestation. The impact of treatment on the duration of maternal viremia, fetal transmission, tissue damage and congenital birth defects will be compared to untreated pregnant animals. The results from these experiments will define effective ZIKV antibody responses important for treatment and vaccine design and test two viable and translatable treatment options for pregnant women.

项目 3 - 项目摘要/摘要由于寨卡病毒的出现，成千上万的婴儿出生时患有先天性寨卡综合症病毒 (ZIKV) 已在美洲传播，并将继续影响新的 ZIKV 幼稚人群将来。目前没有可用的治疗或医学预防方案。此外，一些在怀孕期间感染寨卡病毒的妇女和猕猴经历了长期的病毒传播与非怀孕个体相比，其在血液中的停留时间更长。该项目旨在测试假设超免疫球蛋白和单克隆抗体治疗后不久进行 ZIKV感染可有效控制病毒在母体和胎儿体内的复制，减少影响先天性寨卡综合症。该假设将在以下三个具体目标中得到检验：目标 1：从猕猴中定义高效的 ZIKV 特异性第二代单克隆抗体有或没有长期血浆病毒血症。目标 2：评估暴露后高免疫球蛋白 (HIG) 治疗清除母体感染的效果病毒血症并限制胎儿传播和新生儿损伤。目标 3：评估强效中和抗 ZIKV 单克隆抗体清除母体病毒的功效病毒血症并限制胎儿传播和新生儿损伤。具体来说，目标 1 将从怀孕和非怀孕的 ZIKV 感染猕猴中分离出抗体并将被表征以确定什么可以使一种抗体反应更好地控制in- 感染比另一种抗体反应。其次，从受感染的恒河猴中纯化出 HIG（Aim 2) 或在目标 1 (目标 3) 中分离的强效中和 mAb，将在感染后 5 天施用给怀孕猕猴在妊娠约 6 周时被感染。治疗对产妇持续时间的影响病毒血症、胎儿传播、组织损伤和先天性出生缺陷将与未经治疗的进行比较怀孕的动物。这些实验的结果将定义有效的 ZIKV 抗体反应对于治疗和疫苗设计很重要，并测试两种可行且可转化的治疗方案孕妇。