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

原发性母体感染后预防先天性巨细胞病毒传播的免疫相关性的识别和建模

• 批准号: 10677439
• 负责人: Sallie R. Permar
• 金额: $ 84.84万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-17 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677439
• 关键词: Acute; Address; Antibodies; Binding; Biological Assay; Birth; Blood donor; Brain Injuries; CD4 Positive T Lymphocytes; Cells; Child; Chronic; Complex; Computer Simulation; Congenital Abnormality; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Dangerousness; Demographic Factors; Diagnosis; Disease; Double-Blind Method; Enrollment; Enzyme-Linked Immunosorbent Assay; Fetal Diseases; Fetal Reduction; Fetus; Futility; Glycoproteins; Goals; Human; Immune; Immune Targeting; Immune response; Immunity; Immunoglobulin G; Immunologic Factors; Immunological Models; Impairment; Infant; Infection; Infusion procedures; Knowledge; Label; Licensing; Maps; Maternal-Fetal Medicine Units Network; Maternal-Fetal Transmission; Maternally-Acquired Immunity; Mathematics; Measures; Mediating; Minority Groups; Modeling; Molecular Conformation; Monkeys; Mothers; National Institute of Child Health and Human Development; Natural Killer Cells; Neurologic; Neurologic Deficit; Organoids; Outcome; Placebos; Population; Predictive Factor; Pregnancy; Pregnant Women; Prevention; Primary Infection; Randomized, Controlled Trials; Risk; Risk Factors; Risk Reduction; Signal Transduction; Speed; T cell response; T-Lymphocyte Subsets; Time; Tissue Model; Transfection; Umbilical Cord Blood; United States National Institutes of Health; Vaccines; Viral; Virion; Virus; antibody-dependent cell cytotoxicity; cohort; congenital cytomegalovirus; design; disability; disease transmission; fetal; fetal infection; hearing impairment; high risk; immunogenicity; in silico; nonhuman primate; novel; predicting response; pregnant; prevent; randomized trial; response; risk prediction; seroconversion; transmission process; trial design; vaccine candidate; vaccine development; vaccine efficacy; vaccine trial; viral transmission; γδ T cells

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.

抽象的 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 全世界每年仅在美国就有超过 5,000 名婴儿患有永久性残疾， 而预防 cCMV 的疫苗被标记为“一级”。 20多年来，我们仍然没有获得许可的疫苗产品，部分原因是对疫苗产品的了解有限 预防胎盘 CMV 传播的免疫反应类型。 怀孕期间是 cCMV 传播的高风险，但只有大约三分之一的母亲受到急性感染 怀孕期间会将病毒传播给婴儿，这表明病毒传播的速度和程度 母体免疫反应在防止胎盘病毒传播方面发挥着重要作用。 该提案的目标是定义与 CMV 相关的体液和细胞免疫反应 降低胎儿传播的风险并模拟其对胎盘传播的影响。 可以接触到由 399 名急性 CMV 感染的传播性和非传播性孕妇组成的独特队列 就读于 NIH 国家儿童健康和人类发展研究所 (NICHD) 的女性 医学单位 (MFMU) CMV 超免疫球蛋白试验 (NCT01376778) 该试验是双盲试验。 对超过 100,000 名孕妇进行急性 CMV 感染筛查的随机试验，以便入组接受治疗 CMV 超免疫球蛋白 (HIG) 或安慰剂，但因徒劳而停止，创造了一个独特的机会 定义自 HIG 以来与传播风险相关的急性细胞和体液免疫反应 血清转化后的输注并没有改变传播风险。 早期、功能性 CMV 特异性 IgG 反应以及 CD4+ T 细胞和专门的先天免疫细胞反应 怀孕期间原发性 CMV 感染将预测胎儿传播和疾病的风险降低。 这个独特的大型急性巨细胞病毒感染孕妇群体的综合实力，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，以及新型数学和胎盘方面的专业知识 类器官模型将告知 CMV 疫苗开发的免疫目标，预计将减少 cCMV 传播的风险。我们的具体目标包括： 1) 定义 CMV 特异性 IgG 结合和功能。 与妊娠期原发性巨细胞病毒感染后传播和疾病减少相关的反应2) 定义原发性 CMV 感染期间引发的细胞免疫反应，该反应与减少相关 妊娠期传播；3) 开发可以预测候选 CMV 疫苗功效的计算机模型 基于 cCMV 传播的母体免疫相关性和比率来预防胎盘传播 确定胎盘类器官模型中病毒传播的免疫目标，以减少胎儿传播和传播。 原发性母体 CMV 感染后的婴儿疾病将加速有效疫苗的设计 大幅减少全世界儿童的神经损伤和长期残疾。