Identifying and modeling immune correlates of protection against congenital CMV transmission after primary maternal infection

摘要 先天性巨细胞病毒(CCMV)感染是导致出生缺陷和脑损伤的主要感染原因 在世界范围内，仅在美国每年就有5000名婴儿患有永久性残疾， 在少数民族人口中比例不成比例。而一种预防CCMV的疫苗则被贴上了“一级”的标签 20多年来，我们一直没有获得许可的疫苗产品，部分原因是对 对胎盘CMV传播具有保护作用的免疫反应类型。原发感染 孕期传播CCMV的风险很高，但只有大约三分之一的母亲急性感染 在怀孕期间会将病毒传播给他们的婴儿，这表明病毒传播的速度和规模 母体免疫反应在预防胎盘病毒传播中起着重要作用。最重要的是 这项建议的目标是定义与CMV相关的特异性体液和细胞免疫反应 降低胎儿传播的风险，并模拟它们对胎盘传播的影响。为了实现这一目标，我们 有机会接触到399名急性感染CMV的传播和非传播孕妇的独特队列 参加NIH国家儿童健康与人类发展研究所(NICHD)母胎研究的妇女 医疗单位(MFMU)巨细胞病毒高免疫球蛋白试验(NCT01376778)。这项试验是双盲的。 对100,000名孕妇进行急性CMV感染筛查的随机试验 CMV高免疫球蛋白(HIG)或安慰剂，但因无效而被停用，创造了一个独特的机会 明确HIG以来与传播风险相关的急性细胞和体液免疫反应 血清转换后的输液不会改变传播风险。我们的假设是， 早期功能性巨细胞病毒特异性免疫球蛋白和CD4T细胞及特异性天然免疫细胞反应 孕期感染巨细胞病毒预示着胎儿传播和疾病的风险降低。这个 这个独特的庞大的急性感染CMV的孕妇队列的综合力量，我们在测量方面的专业知识 CMV特异性体液和细胞免疫反应，以及在新的数学和胎盘方面的专业知识 有机模型将为CMV疫苗开发的免疫靶点提供信息，预计将减少 CCMV传播的风险。我们的具体目标包括：1)确定CMV特异性的免疫球蛋白结合和功能 妊娠期间原发巨细胞病毒感染后传播和疾病减少相关的反应；2) 定义在原发CMV感染过程中引发的与减少相关的细胞免疫反应 孕期传播；3)开发一种计算机内模型，可以预测候选CMV疫苗对 基于CCMV母体免疫相关因素的胎盘传播预防研究 病毒在胎盘器官模型中的传播。定义免疫靶点，以减少胎儿传播和 初级母亲感染巨细胞病毒后的婴儿疾病将加快有效疫苗的设计 大大减少世界各地儿童的神经损伤和长期残疾。

ABSTRACT Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of birth defects and brain damage worldwide, leaving >5,000 infants with permanent disabilities each year in the U.S. alone, with a disproportionate proportion in minority populations. While a vaccine to prevent cCMV has been labeled “tier 1 priority” for over 20 years, we remain without a licensed vaccine product, in part due to limited understanding of the types of immune responses that are protective against placental CMV transmission. Primary infection during pregnancy is high risk for cCMV transmission, yet only approximately a third of mothers acutely-infected during pregnancy will transmit the virus to their infants, suggesting that the rapidity and magnitude of the maternal immune responses plays a role in protection against placental virus transmission. The overarching goal of this proposal is to define CMV-specific humoral and cellular immune responses associated with reduced risk of fetal transmission and model their impact on placental transmission. To address this goal, we have access to a unique cohort of 399 acutely CMV-infected transmitting and non-transmitting pregnant women enrolled in the NIH National Institute of Child Health and Human Development (NICHD) Maternal Fetal Medicine Unit (MFMU) CMV hyperimmunoglobulin trial (NCT01376778). This trial was a double-blind randomized trial that screened >100,000 pregnant women for acute CMV infection for enrollment to receive either CMV hyperimmunoglobulin (HIG) or placebo, yet was stopped for futility, creating a unique opportunity to define the acute cellular and humoral immune responses that are associated with transmission risk since HIG infusion after seroconversion did not change transmission risk. Our hypothesis is that the combination of early, functional CMV-specific IgG responses and CD4+ T cell and specialized innate immune cell responses to primary CMV infection during pregnancy will predict reduced risk of fetal transmission and disease. The combined strength of this uniquely large acutely CMV-infected pregnant cohort, our expertise in measuring CMV-specific humoral and cellular immune responses, and expertise in novel mathematical and placental organoid models will inform immune targets of CMV vaccine development that will be predicted to reduce the risk of cCMV transmission. Our Specific Aims include: 1) Define the CMV-specific IgG binding and functional responses associated with reduced transmission and disease following primary CMV infection in pregnancy; 2) Define the cellular immune responses elicited during primary CMV infection that associate with reduced transmission in pregnancy; 3) Develop an in silico model that can predict candidate CMV vaccine efficacy for prevention of placental transmission based on maternal immune correlates of cCMV transmission and the rate of viral spread in placental organoid models. Defining immune targets that will reduce fetal transmission and infant disease following primary maternal CMV infection will speed the design of effective vaccines to drastically decrease neurologic impairment and long-term disabilities in children worldwide.