The Effect of Aging on LAIV Replication in Human Nasal Epithelial Cells

描述(申请人提供)：美国人口增长最快的老年人对季节性流感的易感性增加，加上疫苗效力下降，构成了一种新的公共卫生危机。流行性感冒减毒活疫苗(LAIV)是一种鼻用疫苗，已被证明在儿科人群中比三价灭活疫苗(TIV)更有效，因为它能够在自然感染的部位-鼻上皮复制并引发粘膜免疫反应。我们的初步数据显示，与年轻受试者相比，LAIV在65岁以上成年人的鼻腔上皮细胞(HNEC)培养中的复制显著减少。鼻上皮不充分的感染限制了疫苗激活的免疫反应，我们假设老年人鼻上皮中LAIV感染和复制的减少是导致疫苗接种效果降低的原因之一。这项建议旨在通过比较65岁以上的成年人和5岁至17岁的年轻受试者之间的病毒复制和鼻腔上皮细胞免疫反应来表征LAIV感染老年人鼻腔上皮细胞的缺陷。将评估年轻和老年宿主之间上皮细胞来源的免疫反应的任何差异的功能意义，以确定在上皮水平上调节对LAIV的免疫反应的潜在机制。然后，我们将研究衰老对hNECs和树突状细胞之间相互作用的影响，以深入了解LAIV复制和鼻黏膜上皮免疫反应中这些年龄特异性变化如何影响树突状细胞启动的适应性免疫反应。该项目的最终目标是确定影响病毒复制的特定年龄的上皮细胞因素，然后将其用于开发具有扩大免疫保护的新型疫苗或免疫调节佐剂，这些佐剂可以通过增强疫苗复制来提高老年人的疫苗效力。

DESCRIPTION (provided by applicant): The increased susceptibility to seasonal influenza coupled with decreased vaccine efficacy among older adults, who make up the fastest growing population in the United States, constitutes an emerging public health crisis. The Live Attenuated Influenza Vaccine (LAIV) is a nasally administered vaccine that has been shown to be more effective than the trivalent inactivated vaccine (TIV) in pediatric populations due to its ability to replicate and elicit a mucosal immune response at the site of natural infection - the nasal epithelium. Our preliminary data demonstrate that the LAIV exhibits significantly less replication in human nasal epithelial cell (hNEC) cultures from adults over 65 compared with younger subjects. Inadequate infection of the nasal epithelium limits the vaccine-activated immune response and we hypothesize that decreased LAIV infection and replication in the nasal epithelium of older adults contributes to the reduced vaccination efficacy. This proposal aims to characterize the defect in LAIV infection of nasal epithelial cells from older adults by comparing virus replication and nasal epithelial cell immune responses between adults over 65 and younger subjects between the ages of 5 and 17. The functional significance of any differences in the epithelial cell-derived immune responses between younger and older hosts will be assessed in order to identify potential mechanisms at the level of the epithelium, which modulate immune responses to the LAIV. Then we will study the effect of aging on the interaction between hNECs and dendritic cells in order to gain insight into how these age-specific changes in LAIV replication and nasal epithelial immune responses affect the dendritic cell-initiated adaptive immune response. The ultimate goal of this project is to identify age-specific epithelial cell factors that affect virus replication, which can then be used in the development of either novel vaccines with expanded immunoprotection or immune-modulatory adjuvants that can improve vaccine efficacy in older adults by enhancing vaccine replication.