CMV Vaccines: Reinfection and Antigenic Variation

描述（由申请人提供）：人巨细胞病毒（HCMV）感染是最常见的宫内传播病毒感染，是儿童神经发育障碍的重要原因。先天性HCMV感染率在美国占活产婴儿的0.2-1.0%，在世界许多地区超过1%。虽然怀孕期间的孕产妇感染（原发性孕产妇感染）是病毒传播给胎儿和疾病的重大风险，但对这种病毒具有免疫力的妇女（非原发性孕产妇感染）感染和传播给胎儿的情况很常见。非原发母亲感染后感染婴儿的疾病有充分的记录。在世界范围内，包括大多数美国人口，非原发感染妇女所生的受感染婴儿的疾病负担超过了原发母亲感染妇女的后代的疾病负担。在这个建议中，我们将探讨两种非原发母体感染的机制，新病毒株的再感染和持续感染的复发/再激活。我们的目标是确定非原发性感染的病毒学特征和高度血清免疫人群的HCMV特异性免疫参数，其中非原发性母体感染占绝大多数感染婴儿。我们还将确定最常见的先天性HCMV感染的长期后遗症，听力损失，在感染婴儿的发生率。我们预计这些研究将有助于确定与子宫内传播和非原发性感染妇女群体中破坏性胎儿感染相关的宿主反应，并有助于开发有效的预防性和可能的治疗性疫苗，以限制这种先天性感染的发病率。

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) infection represents the most common viral infection transmitted in-utero and is a significant cause of neurodevelopmental disorders in children. The rate of congenital HCMV infection ranges from 0.2-1.0% of live births in the US and exceeds 1% in many parts of the world. Although maternal infection during pregnancy (primary maternal infection) represents a significant risk for virus transmission to the fetus and disease, infection and transmission to the fetus in women with existing immunity to this virus (non-primary maternal infection) is frequent. Disease in babies infected following non-primary maternal infection is well documented. Worldwide, including most US populations, the disease burden in infected infants born to women with non-primary infections exceeds that of offspring of women with primary maternal infection. In this proposal we will explore two mechanisms of non-primary maternal infections, reinfection with new strain of viruses and recurrence/reactivation of a persistent infection. Our goals are to define virological characteristics of non-primary infections and parameters of HCMV specific immunity in a highly seroimmune population in which non-primary maternal infections account for the vast majority of infected babies. We will also determine the incidence of the most common long term sequelae of congenital HCMV infection, hearing loss, in infected babies. We anticipate these studies will help identify host responses associated with intrauterine transmission and damaging fetal infections in this population of women with non-primary infection and could aid in the rationale development of effective prophylactic and possibly therapeutic vaccines to limit the morbidity from this congenital infection. PUBLIC HEALTH RELEVANCE: This project will investigate the characteristics of human cytomegalovirus infection in a population of women in which over 98% have immunity to this virus. Even in the presence of immunity, these women still transmit virus to their developing offspring and about 10% of infected babies develop hearing loss, the most common sequelae of this congenital infection. Current vaccine strategies will not prevent this type of congenital infection and in almost every part of the world, including the US, infected infants born to immune mothers represent the largest contribution to the overall disease burden of this infection. Our goals are to elucidate the mechanisms responsible for transmission of virus in these immune women in order to more rationally design strategies that could prevent infection of the developing fetus with this virus.