Project 1: Immune correlates of cCMV

项目 1：cCMV 的免疫相关因素

基本信息

批准号：
10215784
负责人：
Sallie R. Permar
金额：
$ 0.19万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-24 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10215784
关键词：
Adaptive Immune System Adverse effects Antibodies Antibody Response Automobile Driving B-Lymphocytes Birth Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cytomegalovirus Cytomegalovirus Infections Cytomegalovirus Vaccines Cytotoxic T-Lymphocytes Development Disease Epilepsy Epithelial Epithelium Evaluation Face Female Fetal Diseases Fetus Future Globulins Human Immune Immune Targeting Immune response Immune system Immunity Immunocompetent Immunological Models Immunologics Impaired cognition Individual Infant Infusion procedures Kinetics Length Lymphocyte MS4A1 gene Macaca Macaca mulatta Measures Modeling Mothers Natural Immunity Neurologic Outcome Partner in relationship Pathology Placenta Plasma Population Pregnancy Pregnancy Outcome Primary Infection Rhesus Risk Role T cell response T memory cell T-Cell Depletion T-Lymphocyte Tacrolimus Binding Proteins Testing Vaccinated Vaccines Variant Viral Viremia Virus arm congenital cytomegalovirus congenital infection deep sequencing design disability exhaustion experimental study fetal fetal loss genetic analysis genetic manipulation hearing impairment in vivo insight motor impairment neutralizing antibody nonhuman primate novel pregnant pressure prevent programs response seropositive transmission process viral transmission virology virus genetics

项目摘要

Abstract – Project 1: Immune correlates of protection against congenital CMV Cytomegalovirus is the most common congenital infection, complicating 40,000 births in the U.S. annually. Up to 25% of infants born with CMV will have permanent neurologic disabilities, including hearing loss. Development of a maternal vaccine that induces effective preconception immunity offers the best hope of eliminating congenital CMV (cCMV), yet this strategy faces significant hurdles. Among these are the incomplete protection conferred by natural immunity and an incomplete understanding of what constitutes protective CMV immunity. While CMV-seropositive mothers have a reduced risk of vertical CMV transmission upon reinfection compared to CMV-naïve mothers with primary infection during pregnancy, they can still transmit virus. Because natural immunity is only partially protective, an effective vaccine will need to induce a more robust or modified preconception immune response. To investigate immune protection against cCMV, we established a novel nonhuman primate (NHP) model of placental cCMV transmission in rhesus monkeys, and showed that maternal CD4+ T cell responses are critical in protection. A lag in the development of CMV-neutralizing antibodies and cytotoxic T lymphocytes was associated with a more severe outcome; and passive infusion of CMV seronegative dams with hyperimmune globulin prior to rhesus CMV inoculation protected against fetal loss. Although these studies highlight the importance of maternal immunity, the contribution of individual arms of the immune system in preventing cCMV remains unclear. Project 1 will therefore test the hypothesis that both humoral and cellular maternal CMV-specific immune responses are required to prevent cCMV infection. Defining the precise contribution of individual components of anti-CMV immunity to (i) inhibition of placental transmission and (ii) modulation of fetal disease is necessary to determine whether CMV vaccines should target one or both arms of the adaptive immune system. In concert with Cores 1-4, Project 1 will use a combination of genetic analysis, in vivo depletion experiments, and exhaustive immune and virologic evaluation to characterize transmitted virus variants and determine the contribution of CMV-specific humoral and cellular immune responses in protecting against cCMV in the NHP model. Our specific aims are as follows: Aim 1: Characterize placental CMV transmission during primary infection in immunocompetent dams and define maternal and fetal immune correlates of protection against transmission; Aim 2: Determine the contribution of B and CD8+ T cell immunity to protection against placental CMV transmission; Aim 3: Determine whether vaccine-induced pre-conception T cell immunity is sufficient to lower plasma viremia and protect against placental CMV transmission or fetal loss in primary infection. These studies will provide insight in to the correlates of immune protection against placental CMV transmission in a highly relevant model of cCMV infection and inform the immunologic targets of an effective CMV vaccine.

摘要 – 项目 1：先天性 CMV 保护的免疫相关性巨细胞病毒是最常见的先天性感染，每年使美国 40,000 名新生儿出现并发症。 25% 的出生时患有 CMV 的婴儿将出现永久性神经残疾，包括听力损失。开发一种能诱导有效孕前免疫的母体疫苗为孕产妇提供了最大的希望消除先天性巨细胞病毒（cCMV），但该策略面临重大障碍：不完整的赋予自然免疫力的保护和对构成的不完整理解保护性巨细胞病毒免疫。巨细胞病毒血清阳性母亲的巨细胞病毒垂直传播风险较低。与怀孕期间初次感染 CMV 的母亲相比，在再次感染后，她们仍然可以由于自然免疫只能提供部分保护，因此需要有效的疫苗来诱导。更强大或改良的孕前免疫反应，以研究针对其的免疫保护。 cCMV，我们建立了一种新型的恒河猴胎盘 cCMV 传播非人类灵长类动物 (NHP) 模型猴子，并表明母体 CD4+ T 细胞反应对于发育滞后至关重要。 CMV 中和抗体和细胞毒性 T 淋巴细胞的减少与更严重的结果相关；在接种恒河猴 CMV 之前，对 CMV 血清阴性母鼠被动输注超免疫球蛋白尽管这些研究强调了母体免疫力的重要性，但项目 1 中免疫系统各个部分在预防 cCMV 中的作用仍不清楚。因此，检验以下假设：体液和细胞母体 CMV 特异性免疫反应都是定义抗 CMV 各个成分的精确贡献。确定对（i）抑制胎盘传播和（ii）调节胎儿疾病的免疫力是必要的 CMV 疫苗是否应针对适应性免疫系统的一侧或两侧？ 1-4，项目1将结合遗传分析、体内耗竭实验和详尽的免疫和病毒学评估，以表征传播的病毒变体并确定我们的 NHP 模型中 CMV 特异性体液和细胞免疫反应可预防 cCMV。具体目标如下：目标 1：表征原发感染期间胎盘 CMV 传播的特征具有免疫能力的母鼠，并确定母体和胎儿免疫相关的预防传播的方法；目标 2：确定 B 细胞和 CD8+ T 细胞免疫对预防胎盘 CMV 的贡献目标 3：确定疫苗诱导的孕前 T 细胞免疫是否足以降低血浆病毒血症并防止原发感染中的胎盘巨细胞病毒传播或胎儿流产。将深入了解针对胎盘 CMV 传播的免疫保护的相关性。 cCMV 感染的相关模型，并为有效的 CMV 疫苗的免疫目标提供信息。