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-项目摘要/摘要 由于Zika的出现，成千上万的婴儿出生于先天性寨卡综合症 散布在美洲的病毒（ZIKV），并将继续到达新的Zikv Naive人群 将来。目前没有可用的治疗方法或医疗预防选择。此外， 怀孕期间感染了寨卡病毒的一些妇女和猕猴经历了延长病毒的代表。 与非怀孕个体相比，血液中的作用更长。该项目旨在测试 假设过度免疫球蛋白和单克隆抗体治疗不久 ZIKV感染可以有效控制母亲和胎儿的病毒复制，并减少影响 先天性寨卡综合症。该假设将在以下三个特定目标中进行检验： AIM 1：定义猕猴的高效ZIKV特异性第二代单克隆抗体 有或没有长时间血浆病毒血症。 AIM 2：评估暴露后超免疫球蛋白（HIG）处理以清除母体的功效 病毒血症并限制胎儿传播和新生儿损伤。 AIM 3：评估有效中和抗ZIKV单克隆抗体的功效以清除母体 病毒血症并限制胎儿传播和新生儿损伤。 具体而言，在AIM 1中，将从怀孕和未怀孕的ZIKV感染猕猴中分离出1抗体 并将被表征以确定什么可能使一种抗体反应更好地控制In- 与另一种抗体反应相比。其次，从被感染的恒河猕猴中纯化的高格（AIM 2）或在AIM 1中孤立的MAB有效中和MAB（AIM 3），将在感染后5天给予 妊娠约6周感染了怀孕的猕猴。治疗对孕产妇持续时间的影响 将病毒血症，胎儿传播，组织损伤和先天性先天缺陷与未治疗 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和测试两个可行且可翻译的治疗方案的重要 孕妇。