Project 1: Immune correlates of cCMV

项目 1：cCMV 的免疫相关因素

• 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
• 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

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：免疫相关性针对先天性CMV 巨细胞病毒是最常见的先天性感染，每年在美国40,000例出生。向上 患有CMV的婴儿中有25％将患有永久性神经系统疾病，包括听力损失。 开发影响有效的先入疫苗免疫的产妇疫苗为您带来了最大的希望 消除先天性CMV（CCMV），但该策略面临重大障碍。其中包括 自然免疫提供的不完整的保护和对构成的不完全理解 保护性CMV免疫。虽然CMV阳性母亲的垂直CMV传播风险降低了 与怀孕期间原发性感染的CMV未经CMV的母亲相比，他们仍然可以 传播病毒。由于自然免疫力仅受到部分保护，因此有效的疫苗需要诱导 更健壮或改良的先选后的免疫反应。调查免疫保护 CCMV，我们建立了一种新型的非人类灵长类动物（NHP）模型 猴子，并表明材料CD4+ T细胞反应在保护中至关重要。发展的滞后 CMV中和抗体的抗体和细胞毒性T淋巴细胞与更严重的结果有关。和 在恒河猴接种之前，用超免疫球蛋白的CMV血清神经坝被动输注 防止胎儿损失。尽管这些研究强调了孕产妇免疫的重要性，但 免疫系统的个体臂在防止CCMV方面的贡献尚不清楚。项目1将 因此，检验了体液和细胞母体CMV特异性免疫反应的假设是 防止CCMV感染所需。定义抗CMV单个组件的精确贡献 对（i）抑制位置传播的免疫力和（ii）对胎儿疾病的调节是必要的 CMV疫苗是否应靶向自适应免疫系统的一个或两个臂。与核心 1-4，项目1将结合遗传分析，体内耗竭实验和详尽 免疫和病毒学评估以表征传播的病毒变体并确定 在NHP模型中预防CCMV时，CMV特异性的体液和细胞免疫激素。我们的 具体目的如下：AIM 1：特征在原发中心的placenal CMV传播中 免疫能力的大坝，并定义防止传播的材料和胎儿免疫复合物； AIM 2：确定B和CD8+ T细胞免疫对防止位置CMV的保护的贡献 传播; AIM 3：确定疫苗诱导的概念前T细胞免疫是否足以降低 血浆病毒血症并预防原发性感染中的胎盘CMV传播或胎儿丧失。这些研究 将提供有关免疫保护的相关性，以防止在高度 CCMV感染的相关模型并为有效CMV疫苗的免疫靶标提供了信息。