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