Project 1: Immune correlates of cCMV

项目1：预防先天性巨细胞病毒的免疫相关因素 巨细胞病毒是最常见的先天性感染，在美国每年导致4万名新生儿并发。向上 出生时患有巨细胞病毒的婴儿中有25%会有永久性的神经残疾，包括听力损失。 开发一种诱导有效先天免疫的母体疫苗提供了最大的希望 消除先天性巨细胞病毒(CCMV)，但这一战略面临重大障碍。其中包括 自然豁免权给予的不完全保护和对构成因素的不完全理解 保护性巨细胞病毒免疫。而CMV血清阳性的母亲垂直传播CMV的风险较低 在再次感染时，与初次感染巨细胞病毒的母亲相比，她们仍然可以 传播病毒。由于自然免疫只能起到部分保护作用，因此一种有效的疫苗需要诱导 一种更强健的或修改过的先入为主的免疫反应。研究针对病毒的免疫保护 CCMV，我们建立了一种新的恒河猴胎盘CCMV传播模型 并表明母体的CD4+T细胞反应在保护中是至关重要的。发展中的滞后 巨细胞病毒中和抗体和细胞毒性T淋巴细胞与更严重的结局相关； 在恒河猴接种巨细胞病毒前用高免球蛋白被动输注巨细胞病毒血清阴性鼠 保护胎儿不会丢失。尽管这些研究强调了母体免疫的重要性，但 免疫系统的各个分支在预防CCMV中的作用尚不清楚。项目1将 因此，验证体液和细胞性母体CMV特异性免疫反应都是 预防CCMV感染所需的。确定抗CMV单项成分的确切作用 免疫(I)抑制胎盘传播和(Ii)调节胎儿疾病是必要的，以确定 巨细胞病毒疫苗是否应该针对适应性免疫系统的一只或两只手臂。与岩心协调一致 1-4，项目1将结合使用遗传分析、体内耗尽实验和穷举法 免疫学和病毒学评估以确定传播的病毒变体的特征并确定 在NHP模型中，CMV特异性体液和细胞免疫反应在预防CCMV中的作用。我们的 具体目标如下：目标1：研究人胎盘巨细胞病毒在初次感染过程中的传播特征 建立具有免疫活性的母体，并确定预防传播的母婴免疫相关因素； 目的2：确定B和CD8+T细胞免疫在胎盘CMV免疫保护中的作用 传播；目标3：确定疫苗诱导的受孕前T细胞免疫是否足以降低 血浆病毒血症和预防原发感染时胎盘巨细胞病毒传播或胎儿丢失。这些研究 将提供对胎盘CMV传播的免疫保护的相关性的洞察 CCMV感染的相关模型，并为有效的CMV疫苗的免疫学指标提供信息。

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.