Implications of Congenital Zika Virus Infection

先天性寨卡病毒感染的影响

• 批准号: 9901447
• 负责人: Sylvia Irene Becker-Dreps
• 金额: $ 14.89万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901447
• 关键词: Affect; Age-Months; American; Americas; Antibodies; Antibody-Dependent Enhancement; Arbovirus Infections; Birth; Blood specimen; Brain imaging; Brazil; Caribbean region; Central America; Child; Child Development; Childhood; Clinical Data; Collaborations; Congenital Abnormality; Country; Data; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Development; Diagnosis; Disease; Early Intervention; Enzyme-Linked Immunosorbent Assay; Epidemic; Epidemiology; Exposure to; Flavivirus; Flavivirus Infections; Future; Head circumference; Health; Hearing; Hearing Tests; Human; Immunity; Immunoglobulin G; Immunoglobulin M; Immunology; Incidence; Infant; Infection; Injury; Kinetics; Language; Learning; Life; Link; Maternal antibody; Maternally-Acquired Immunity; Measures; Mediating; Microcephaly; Mothers; Motor; Neurodevelopmental Deficit; Neurodevelopmental Impairment; Neurologic; Neutralization Tests; Newborn Infant; Nicaragua; North Carolina; Ophthalmology; Outcome; Phase; Population; Pregnancy; Pregnant Women; Prevalence; Research; Resources; Risk; Role; Sampling; Schedule; Serum; Severities; Site; South America; Structure; Teratogens; Time; Umbilical Cord Blood; Universities; Vaccines; Vector-transmitted infectious disease; Venous blood sampling; Vision; Visual; Woman; ZIKA; ZIKV infection; Zika Virus; Zika virus vaccine; brain abnormalities; cohort; congenital anomaly; cross reactivity; early childhood; experience; follow-up; hazard; in utero; multidisciplinary; neonatal infection; neutralizing antibody; placental transfer; population based; postnatal; pregnant; prenatal; prenatal exposure; prospective; public health intervention; seroconversion; tool; vaccine development; viral transmission

Zika virus (ZIKV) emerged in the Americas in early 2015, causing millions of infections and affecting more than 40 countries and territories. The American ZIKV epidemic was the first time that ZIKV's teratogenic potential was recognized after Brazil experienced a surge in the incidence of newborn microcephaly linked to congenital ZIKV infection. While the link between congenital ZIKV infection and structural brain abnormalities is well established, the spectrum of developmental sequelae of congenital ZIKV infection findings is still not well described. Additionally, no data exists about the role of maternally acquired antibodies against ZIKV in the protection against (or risk for) flavivirus infections in early childhood. Due to the cross-reactivity of ZIKV and dengue virus (DENV) antibodies, there is the concern that decaying ZIKV antibodies may contribute to antibody-dependent enhancement of DENV infections. Characterizing the kinetics of maternally acquired antibodies against ZIKV is also crucial to inform schedules for ZIKV and DENV vaccines under development. Here, we propose to leverage an existing cohort of 400 pregnant women and their infants in León, Nicaragua, where the ZIKV swept through the population in the second half of 2016. The women were pregnant during a period of intense ZIKV transmission, and we have collected prenatal maternal, cord blood, and quarterly postnatal serum samples, alongside longitudinal developmental data on the infants. We propose to extend follow up of children up to 36 months of age to better characterize the prevalence and spectrum of developmental abnormalities that occur after ZIKV exposure in utero and to measure duration of maternally derived neutralizing antibodies to ZIKV after birth. Neurodevelopmental outcomes will be evaluated with Mullen Scales of Early Learning at 3, 6, 12, 18, 24, 30, and 36 months. This tool assesses gross motor, fine motor, visual reception, expressive language, and receptive language domains. Vision and hearing will be formally assessed once during the study. ZIKV congenital exposure will be diagnosed using ZIKV and DENV IgM and IgG ELISA in maternal and cord blood samples; indeterminate results will be resolved using antibody depletion and focus reduction neutralizing tests for DENV and ZIKV. We hypothesize that infants with evidence of in utero exposure to ZIKV will display a range of developmental deficits and that the prevalence of deficits will be substantially higher in the ZIKV-exposed group than in unexposed infants. Additionally, we hypothesize that maternally acquired ZIKV immunity will wane over 2-9 months, similar to maternally acquired DENV antibodies. We will assess the effect of maternally acquired ZIKV antibodies on the incidence of DENV infections in the cohort. These findings will provide essential clinical data to characterize the types of developmental deficits resulting from congenital ZIKV infection, to direct early intervention efforts and will further our understanding of ZIKV immunity and its effect on DENV infection in early childhood, which are crucial to vaccine development and timing.

寨卡病毒（ZIKV）于2015年初在美洲出现，造成数百万人感染，影响40多个国家和地区。在巴西经历了与先天性ZIKV感染相关的新生儿小头畸形发病率激增之后，美国ZIKV疫情首次认识到ZIKV的致畸潜力。虽然先天性ZIKV感染和结构性脑异常之间的联系已得到很好的建立，但先天性ZIKV感染发现的发育后遗症的范围仍没有得到很好的描述。此外，没有关于母源获得的抗ZIKV抗体在儿童早期黄病毒感染保护（或风险）中的作用的数据。由于ZIKV和登革病毒（DENV）抗体的交叉反应性，人们担心衰减的ZIKV抗体可能有助于DENV感染的抗体依赖性增强。表征针对ZIKV的母体获得性抗体的动力学对于告知正在开发的ZIKV和DENV疫苗的时间表也是至关重要的。在这里，我们建议利用尼加拉瓜莱昂现有的400名孕妇及其婴儿的队列，ZIKV在2016年下半年席卷了那里的人口。这些妇女是在ZIKV病毒密集传播期间怀孕的，我们收集了产前母体、脐带血和每季度一次的产后血清样本，以及婴儿的纵向发育数据。我们建议将儿童的随访延长至36个月，以更好地表征子宫内ZIKV暴露后发生的发育异常的患病率和谱，并测量出生后母体来源的ZIKV中和抗体的持续时间。将在3、6、12、18、24、30和36个月时使用马伦早期学习量表评价神经发育结局。该工具评估粗大运动、精细运动、视觉接收、表达性语言和接受性语言领域。在研究期间，将对视力和听力进行一次正式评估。ZIKV先天性暴露将使用母体和脐带血样品中的ZIKV和DENV IgM和IgG ELISA来诊断;不确定的结果将使用DENV和ZIKV的抗体消耗和病灶减少中和试验来解决。我们假设，具有子宫内暴露于ZIKV的证据的婴儿将显示一系列发育缺陷，并且ZIKV暴露组中缺陷的患病率将显著高于未暴露的婴儿。此外，我们假设母体获得的ZIKV免疫力将在2-9个月内减弱，类似于母体获得的DENV抗体。我们将评估母体获得的ZIKV抗体对队列中DENV感染发生率的影响。这些发现将提供基本的临床数据来表征由先天性ZIKV感染引起的发育缺陷的类型，以指导早期干预工作，并将进一步了解ZIKV免疫及其对儿童早期DENV感染的影响，这对疫苗开发和时机至关重要。