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

描述（由申请方提供）：老年人对季节性流感的易感性增加，加上疫苗效力降低，构成了美国增长最快的人口，构成了一场新的公共卫生危机。减毒流感活疫苗（LAIV）是一种经鼻接种的疫苗，由于其在自然感染部位（鼻上皮）复制和引发粘膜免疫应答的能力，已被证明在儿科人群中比三价灭活疫苗（TIV）更有效。我们的初步数据表明，LAIV在65岁以上成人的人鼻上皮细胞（hNEC）培养物中的复制显著低于年轻受试者。鼻上皮的感染不足限制了疫苗激活的免疫应答，我们假设老年人鼻上皮中LAIV感染和复制的减少有助于降低疫苗接种效果。该提案旨在通过比较65岁以上成年人和5至17岁年轻受试者之间的病毒复制和鼻上皮细胞免疫应答来表征老年人鼻上皮细胞LAIV感染的缺陷。将评估年轻和老年宿主之间上皮细胞源性免疫应答的任何差异的功能意义，以确定调节对LAIV的免疫应答的上皮水平的潜在机制。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复制和鼻上皮免疫应答中的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应答。该项目的最终目标是确定影响病毒复制的年龄特异性上皮细胞因子，然后可用于开发具有扩大免疫保护的新型疫苗或免疫调节佐剂，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.