Acquisition of HCMV from breast milk-correlates of protection

描述(申请人提供)：先天性人类巨细胞病毒(HCMV)感染是最常见的病毒感染，是导致感音神经性耳聋和其他神经后遗症的主要非遗传原因。尽管预防这种宫内感染仍然是疫苗开发的高度优先事项，但目前还没有疫苗可用，早期临床试验只取得了有限的成功。了解抗病毒抗体反应在限制病毒传播中的作用是成功设计有效疫苗的必要前提。由于限制HCMV感染的抗病毒免疫反应的特征尚不清楚，因此在正常宿主中识别潜在的保护性反应将继续依赖于经验主义疫苗试验，候选免疫原是通过善意和有限的临床观察和实验动物研究数据相结合的方式选择的。血清阳性母亲所生的婴儿被经胎盘和通过母乳获得的抗病毒抗体(包括中和抗体)被动免疫，然而，在上皮暴露于母乳中存在的病毒后，婴儿一直受到感染。尽管这些发现 可能会争辩说，HCMV免疫对病毒感染几乎没有保护作用，因为只有大约一半暴露于母乳中的HCMV的婴儿会被感染，这种自然获得HCMV的模型提供了一个独特的机会来确定防止感染HCMV的病毒学和免疫学相关性。通过研究人巨细胞病毒在母乳中的传播，我们希望能更好地了解针对粘膜感染巨细胞病毒的保护性抗病毒免疫反应。我们的假设是，当婴儿的口腔粘膜接触受HCMV感染的母乳后，当对病毒复制的免疫控制不足或出现新的病毒基因组类型超过防止传播所需的病毒宿主保护阈值时，就会发生HCMV感染。阐明导致这种保护性抗病毒免疫瓶颈的机制将导致更合理地设计能够诱导对HCMV的保护性免疫的免疫原。该项目的目标是确定人类巨细胞病毒特异性抗体的数量、特异性和功能。 孕妇母乳和婴儿唾液中的HCMV基因组变异模式与这些液体中较低的病毒载量和抗病毒抗体以及在分娩后前6个月防止HCMV母乳传播有关。

DESCRIPTION (provided by applicant): Congenital human cytomegalovirus (HCMV) infection is the most common viral infection a leading non- genetic cause of sensorineural hearing loss and other neurological sequelae. Although prevention of this intrauterine infection remains a high priority for vaccine development, currently no vaccine is available and early clinical trials have had only limited success. Understanding the role of antiviral antibody responses in limiting virus transmission is a necessary prerequisite for the successful design of an efficacious vaccine. Since the characteristics of antiviral immune responses that limit HCMV acquisition are unknown, identification of potentially protective responses in the normal host will continue to rel on the empiricism vaccine trials with candidate immunogens selected by a combination of good faith and limited data from clinical observations and studies in experimental animals. Infants born to seropositive mothers are passively immunized by antiviral antibodies acquired transplacentally and via breast milk including neutralizing antibodies, yet, are consistently infected following epithelial exposure to virus present within breast milk. Although these findings might argue that HCMV immunity offers little protection against virus acquisition, since only about half of the infants exposed to HCMV in breast milk will become infected, this model of natural HCMV acquisition provides an unique opportunity to define virologic and immunologic correlates of protection from acquisition of HCMV. By investigating the breast milk transmission of HCMV, we expect to develop a better understanding of the protective antiviral immune responses against mucosal acquisition of HCMV. It is our hypothesis that acquisition of HCMV following exposure of the infant's oral mucosa to HCMV-infected breast milk occurs when inadequate immune control of viral replication or emergence of new viral genome types overcoming the virus-host protective threshold required to prevent transmission. Delineation of the mechanisms leading to this breech of protective antiviral immunity will lead to a more rational design of immunogens capable of inducing protective immunity to HCMV. The goals of the project are to determine the quantity, specificity, and function of HCMV-specific antibodies in maternal breast milk and infant saliva, and the HCMV genome variability patterns associated with lower viral load and antiviral antibodies in these fluids and protection from HCMV breast milk transmission over the first 6 months after delivery.