Project 1: Immune correlates of cCMV

摘要-项目1：保护先天性CMV的免疫相关性 巨细胞病毒是最常见的先天性感染，美国每年有40，000例新生儿出现并发症。起来 25%的巨细胞病毒婴儿会有永久性的神经功能障碍，包括听力损失。 开发一种能诱导有效孕前免疫的母体疫苗， 消除先天性CMV（cCMV），但这一战略面临重大障碍。这其中包括 不完全的自然免疫力所赋予的保护和不完全的理解是什么 保护性CMV免疫。虽然CMV血清阳性母亲的垂直CMV传播风险降低， 与妊娠期间初次感染CMV的未感染母亲相比， 传播病毒由于天然免疫只是部分保护，有效的疫苗将需要诱导 一个更强大或改良的孕前免疫反应。为了研究免疫保护， 本研究建立了一种新的恒河猴胎盘cCMV传播的非人灵长类动物模型 猴子，并表明母体CD 4 + T细胞反应在保护中至关重要。发展滞后 CMV中和抗体和细胞毒性T淋巴细胞与更严重的结果相关; 在恒河猴CMV接种前，用高免疫球蛋白被动输注CMV血清阴性母鼠 防止胎儿丢失。尽管这些研究强调了母体免疫的重要性， 免疫系统的各个分支在预防cCMV中的贡献仍然不清楚。项目1将 因此，检验体液和细胞母体CMV特异性免疫应答均 预防cCMV感染。确定抗CMV单个组分的精确贡献 对（i）胎盘传递抑制和（ii）胎儿疾病调节的免疫是确定 CMV疫苗是否应该靶向适应性免疫系统的一个或两个臂。与Cores合作 1-4，项目1将使用遗传分析，体内消耗实验和详尽的 免疫学和病毒学评价，以表征传播的病毒变体，并确定 CMV特异性体液和细胞免疫应答在NHP模型中针对cCMV的保护作用。我们 具体目的如下：目的1：表征在原发感染期间的胎盘CMV传播， 免疫活性母鼠和确定的母体和胎儿免疫相关的保护，以防止传播; 目的2：确定B和CD 8 + T细胞免疫对胎盘CMV保护的贡献 目的3：确定疫苗诱导的孕前T细胞免疫是否足以降低 血浆病毒血症和保护免受胎盘CMV传播或在原发感染中的胎儿损失。这些研究 将提供深入了解免疫保护对胎盘CMV传播的相关性， cCMV感染的相关模型，并告知有效CMV疫苗的免疫学靶点。

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.