The Cotton Rat: Translational Model of Influenza Vaccines for the Elderly

描述（由申请人提供）：仅在美国，季节性流感每年平均导致超过20万例住院治疗和36，000例死亡。在所有流感相关死亡中，90%发生在65岁以上的成年人中。目前对老年人进行季节性流感疫苗接种的方法是不够的。由于缺乏适当的老年人流感疾病动物模型，为老年人开发改进的流感干预措施的任务变得复杂。不适应的季节性流感病毒很容易感染棉鼠S.hispidus，这是一种对呼吸道病毒研究具有高转化价值的动物。棉鼠的衰老显著改变了呼吸道病毒感染的发病机制，季节性流感感染在老年棉鼠中引起更严重的疾病。使用三价灭活疫苗FluLaval，已在幼龄棉鼠中证明了人流感疫苗的有效性。在这项工作中，我们将通过证明三价灭活（FluLaval，GSK）和减毒活疫苗（FluMist，MedImmune）的免疫原性随年龄的下降来验证人类季节性流感疫苗的老年棉鼠模型。将根据报告用于表征人类衰老的免疫学参数评价疫苗效力，并扩展至定义老年人严重季节性流感疾病的生物标志物及其通过各种疫苗接种方案的修饰。该平台的验证将产生一个有价值的翻译模型，可用于改进现有的人类老年人季节性流感疫苗接种方法，并设计新的有效疫苗。 公共卫生相关性：季节性流感引起的疾病对老年人造成致命的伤害。目前老年人接种流感疫苗的方法并不有效，在缺乏适当动物模型的情况下无法改进。棉鼠S.hispidus易感染不适应的流感病毒，并显示出与年龄相关的流感发病机制的变化，导致更严重的疾病。在本提案中，我们将使用老年棉鼠来重现三价灭活和减毒活流感疫苗在老年人中报告的缺陷。建立老年人流感疫苗转化动物模型将有助于设计更有效的疫苗接种方法，并减少这一快速增长的人群的疾病负担。

DESCRIPTION (provided by applicant): Seasonal influenza leads to an annual average of over 200,000 cases of hospitalizations and 36,000 deaths in the United States alone. Of all influenza-associated deaths, 90% occur in adults over the age of 65 years. Current approaches to vaccination of human elderly against seasonal influenza are inadequate. The task of developing an improved influenza intervention for the elderly is complicated by the absence of an appropriate animal model of influenza disease in the aged. Infection with unadapted seasonal influenza viruses is easily achieved in the cotton rat S.hispidus, an animal with high translational value for research on respiratory viruses. Aging in cotton rats significantly alters pathogenesis of respiratory viral infections, with seasonal influenza infection causing a more severe disease in the aged cotton rats. Efficacy of human influenza vaccines has been demonstrated in younger cotton rats using trivalent inactivated vaccine FluLaval. In this work, we will validate the aged cotton rat model of human seasonal influenza vaccines by demonstrating age-related decline in immunogenicity of both trivalent inactivated (FluLaval, GSK) and live attenuated (FluMist, MedImmune) vaccines. Vaccine efficacy will be evaluated against immunologic parameters reported to characterize aging in humans and expanded to define biomarkers of severe seasonal influenza disease in human elderly and their modification by various vaccination regimes. Validation of this platform would yield a valuable translational model that can be used to improve existing methods of seasonal influenza vaccination of human elderly and to devise novel effective vaccines. PUBLIC HEALTH RELEVANCE: Disease caused by seasonal influenza carries a deadly toll on human elderly. Current approaches to vaccination of elderly against influenza are not effective and cannot be improved in the absence of an appropriate animal model. The cotton rat S.hispidus is susceptible to infection with unadapted influenza viruses and shows age-related alterations in influenza pathogenesis leading to a more severe disease. In this proposal we will use the aged cotton rats to recapitulate deficiencies of trivalent inactivated and live attenuated influenza vaccines as reported for human elderly. Creation of a translational animal model of influenza vaccines for elderly would facilitate design of a more effective vaccination approaches and reduce disease burden in this fast-growing population.