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

• 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
• 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

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 -项目概要/摘要 由于寨卡病毒的出现，已有数千名婴儿出生时患有先天性寨卡综合征 ZIKV病毒已经传播到整个美洲，并将继续感染新的ZIKV未感染人群 在未来目前没有可用的治疗或医疗预防方案。此外，委员会认为， 一些在怀孕期间感染寨卡病毒的妇女和猕猴经历了延长的病毒复制， 在血液中的作用时间比未怀孕的个体更长。该项目旨在测试 假设高免疫球蛋白和单克隆抗体治疗后不久， ZIKV感染可以有效控制病毒在母亲和胎儿中的复制， 先天性寨卡综合征将在以下三个具体目标中检验这一假设： 目的1：定义来自猕猴的高效ZIKV特异性第二代单克隆抗体 伴有或不伴有长期血浆病毒血症。 目的2：评价暴露后高免疫球蛋白（HIG）治疗对清除孕产妇 病毒血症和限制胎儿传播和新生儿损伤。 目的3：评估有效中和的抗ZIKV单克隆抗体清除母体ZIKV的功效。 病毒血症和限制胎儿传播和新生儿损伤。 具体地，在目标1中，将从妊娠和非妊娠ZIKV感染的猕猴中分离抗体。 并将被表征以确定什么可以使一种抗体应答在控制免疫应答方面更好。 感染比另一种抗体反应。其次，从感染的恒河猴中纯化HIG（目的 2)或在目标1（目标3）中分离的有效中和mAb，将在感染后5天施用， 妊娠猕猴在妊娠约6周时感染。治疗对孕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 怀孕的动物这些实验的结果将定义有效的ZIKV抗体应答 重要的治疗和疫苗设计和测试两个可行的和可翻译的治疗方案， 孕妇