CMV Vaccines: Reinfection and Antigenic Variation

描述(申请人提供)：人类巨细胞病毒(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。在美国，先天性巨细胞病毒感染率从活产儿的0.2-1.0%不等，在世界许多地区超过1%。虽然孕期母体感染(主要母体感染)是病毒传播给胎儿和疾病的重大风险，但对这种病毒具有现有免疫力的妇女(非主要母体感染)感染和传播给胎儿的情况很常见。非原发孕产妇感染后感染的婴儿的疾病有很好的记录。在世界范围内，包括大多数美国人口在内，患有非原发感染的妇女所生的受感染婴儿的疾病负担超过了患有原发母体感染的妇女的后代。在这项建议中，我们将探讨非原发母体感染的两种机制，即用新的病毒株再次感染和持续感染的复发/再激活。我们的目标是确定非原发感染的病毒学特征和高血清免疫力人群中HCMV特异性免疫的参数，在该人群中，非原发母体感染占感染婴儿的绝大多数。我们还将确定先天性HCMV感染最常见的长期后遗症--听力损失在感染婴儿中的发生率。我们预计这些研究将有助于确定与宫内传播和破坏性胎儿感染相关的宿主反应，并可能有助于开发有效的预防性疫苗和可能的治疗性疫苗，以限制这种先天性感染的发病率。 公共卫生相关性：该项目将调查人类巨细胞病毒在98%以上对该病毒具有免疫力的妇女人群中的感染特征。即使在有免疫力的情况下，这些妇女仍然会将病毒传播给她们发育中的后代，大约10%的受感染婴儿会出现听力损失，这是这种先天性感染最常见的后遗症。目前的疫苗策略无法预防这种类型的先天性感染，在世界几乎每个地方，包括美国，免疫母亲所生的受感染婴儿对这种感染的总体疾病负担贡献最大。我们的目标是阐明病毒在这些免疫女性中传播的机制，以便更合理地设计策略，防止发育中的胎儿感染这种病毒。

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.