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

描述(申请人提供)：仅在美国，季节性流感每年平均导致超过20万例住院和3.6万人死亡。在所有与流感相关的死亡中，90%发生在65岁以上的成年人中。目前为人类老年人接种季节性流感疫苗的方法是不够的。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。棉鼠很容易感染未适应的季节性流感病毒，这是一种对呼吸道病毒研究具有很高翻译价值的动物。棉鼠的衰老显著改变了呼吸道病毒感染的发病机制，季节性流感感染导致了老年棉鼠更严重的疾病。在使用三价灭活疫苗FluLaval的年轻棉鼠身上，已经证明了人类流感疫苗的有效性。在这项工作中，我们将通过展示三价灭活疫苗(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龄棉鼠模型。疫苗效力将根据报告的表征人类衰老的免疫学参数进行评估，并扩大到确定人类老年人严重季节性流感疾病的生物标记物及其通过各种疫苗接种方案的修改。对这一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，并设计出新的有效疫苗。 公共卫生相关性：季节性流感引起的疾病对人类老年人造成致命损失。目前为老年人接种流感疫苗的方法并不有效，在没有适当的动物模型的情况下也无法改进。棉鼠容易感染未适应的流感病毒，并在流感发病机制中表现出与年龄相关的变化，导致更严重的疾病。在这项提案中，我们将使用老化的棉鼠来概括三价灭活和减毒活流感疫苗的不足之处，正如对人类老年人的报道一样。为老年人建立流感疫苗的翻译动物模型将有助于设计更有效的疫苗接种方法，并在这一快速增长的人口中减少疾病负担。

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.