Implications of Congenital Zika Virus Infection

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寨卡病毒感染有关的新生儿小头畸形发病率激增之后，美国寨卡病毒流行首次认识到寨卡病毒的致畸潜力。虽然先天性寨卡病毒感染与结构性脑异常之间的联系已得到充分证实，但先天性寨卡病毒感染的发育后遗症仍未得到很好的描述。此外，尚无关于母体获得的抗寨卡病毒抗体在儿童早期预防（或风险）黄病毒感染中的作用的数据。由于寨卡病毒和登革热病毒（DENV）抗体的交叉反应性，人们担心，腐烂的寨卡病毒抗体可能导致登革热病毒感染的抗体依赖性增强。描述母体获得的抗寨卡病毒抗体的动力学特征，对于为正在开发的寨卡病毒和DENV疫苗的时间表提供信息也至关重要。在这里，我们建议利用尼加拉瓜León现有的400名孕妇和她们的婴儿，那里的寨卡病毒在2016年下半年席卷了人口。这些妇女是在寨卡病毒强烈传播期间怀孕的，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。我们建议延长对36个月大的儿童的随访，以更好地描述在子宫内暴露于寨卡病毒后发生的发育异常的患病率和频谱，并测量出生后母源性寨卡病毒中和抗体的持续时间。神经发育结果将在3、6、12、18、24、30和36个月时用马伦早期学习量表评估。这个工具评估大运动，精细运动，视觉接收，表达语言和接受语言领域。视力和听力将在研究期间进行一次正式评估。将使用孕妇和脐带血样本中的ZIKV和DENV IgM和IgG ELISA进行诊断；不确定的结果将通过DENV和ZIKV的抗体消耗和焦点减少中和试验来解决。我们假设，有证据表明在子宫内暴露于寨卡病毒的婴儿将表现出一系列发育缺陷，并且寨卡病毒暴露组的缺陷发生率将大大高于未暴露组的婴儿。此外，我们假设母体获得的ZIKV免疫将在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。这些发现将提供必要的临床数据，以表征先天性寨卡病毒感染导致的发育缺陷类型，指导早期干预工作，并将进一步了解寨卡病毒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。

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.