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）感染是先天缺陷和脑损伤的主要感染原因 全世界，仅在美国，每年就留下> 5,000名永久残疾婴儿 少数族裔人口中的比例不成比例。虽然预防CCMV的疫苗已被标记为“ Tier 1 优先事项”超过20年，我们没有许可的疫苗产品，部分原因是对 免受胎盘CMV传播的免疫反应的类型。原发性感染 怀孕期间是CCMV传播的高风险，但只有三分之一的母亲急性感染 在怀孕期间，病毒会将病毒传播给婴儿，这表明 母体免疫反应在防止斑点病毒传播中起作用。总体 该提案的目标是定义与与之相关的CMV特异性体液和细胞免疫调查。 降低了胎儿传播的风险，并建模其对胎盘传播的影响。为了解决这个目标，我们 有399个敏锐的CMV感染的传播和非传播怀孕的唯一队列 NIH国家儿童健康与人类发展研究所（NICHD）孕产妇胎儿的妇女 医学单位（MFMU）CMV高免疫球蛋白试验（NCT01376778）。该试验是双盲 随机试验筛查> 100,000名孕妇急性CMV感染以接受 CMV Hypermunoglobulin（HIG）或安慰剂要么被停止徒劳无功，创造了独特的机会 定义与传输风险相关的急性细胞和体液免疫反应，因为 血清转化后的输液不会改变传播风险。我们的假设是 早期，功能性CMV特异性IgG响应和CD4+ T细胞以及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 这个独特的急性CMV感染的怀孕人群的结合强度，我们的测量专业知识 CMV特异性的体液和细胞免疫回报，以及新颖的数学和位置方面的专业知识 类器官模型将告知CMV疫苗开发的免疫靶标，该靶标将预测 CCMV传输的风险。我们的具体目的包括：1）定义CMV特异性IgG结合和功能 妊娠期原发性CMV感染后的传播和疾病降低相关的反应； 2） 定义在初次CMV感染期间引起的细胞免疫反应，该反应与降低相关 怀孕的传播； 3）开发一个计算机模型，可以预测候选CMV疫苗的效率 预防基于母体免疫相关的CCMV传播和速率的胎盘传播 斑点器官模型中的病毒扩散。定义将减少胎儿传播和的免疫靶标 初次母体CMV感染后的婴儿疾病将加快有效疫苗的设计 全世界儿童的神经系统障碍和长期残疾大大减少。