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原因 在世界范围内，仅在美国每年就有超过5,000名婴儿患有永久性残疾， 在少数民族人口中比例过高。虽然预防cCMV的疫苗已被标记为“1级 20多年来，我们仍然没有获得许可的疫苗产品，部分原因是对 保护免受胎盘CMV传播的免疫反应类型。原发感染 怀孕期间是cCMV传播的高风险，但只有大约三分之一的母亲急性感染 在怀孕期间将病毒传播给婴儿，这表明， 母体免疫应答在防止胎盘病毒传播中起作用。总体 该提案的目标是定义CMV特异性体液和细胞免疫应答， 降低胎儿传播的风险，并模拟其对胎盘传播的影响。为了实现这一目标，我们 有机会获得一个独特的队列399急性CMV感染传播和非传播孕妇 美国国立卫生研究院国家儿童健康和人类发展研究所（NICHD）的女性 医学单位（MFMU）CMV高免疫球蛋白试验（NCT 01376778）。本试验为双盲试验 一项随机试验，筛选了> 100，000名孕妇的急性CMV感染， 无论是巨细胞病毒高免疫球蛋白（HIG）或安慰剂，但被停止无效，创造一个独特的机会， 定义急性细胞和体液免疫反应与自HIG以来的传播风险相关 血清转换后输注没有改变传播风险。我们的假设是 早期功能性CMV特异性IgG应答和CD 4 + T细胞及特化先天免疫细胞应答 妊娠期原发性CMV感染将预测胎儿传播和疾病的风险降低。的 这个独特的大型急性CMV感染妊娠队列的综合实力，我们在测量 CMV特异性体液和细胞免疫反应，以及新的数学和胎盘 类器官模型将告知CMV疫苗开发的免疫靶点，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IgG结合和功能 与妊娠期原发性CMV感染后传播和疾病减少相关的反应; 2） 定义原发性CMV感染期间引起的细胞免疫应答， 3）开发一种计算机模型，可以预测候选CMV疫苗的有效性， 基于cCMV传播的母体免疫相关性和发生率预防胎盘传播 病毒在胎盘类器官模型中的传播。确定免疫靶点，减少胎儿传播， 母亲CMV感染后的婴儿疾病将加速有效疫苗的设计， 大幅度减少全世界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.