Immune Response to High-Dose vs. Standard Dose Influenza Vaccine

描述(申请人提供)：临床医生目前还没有方法来预测老年人的流感疫苗反应，这些方法是可获得的，而且相对便宜。这项研究的长期目标是确定T细胞反应，这些T细胞反应是流感严重并发症的替代品(生物标记物)，可以用来预测疫苗的有效性。这种定义宽松的生物标志物将使临床医生能够决定谁可能从较新或更具反应性的疫苗中受益，例如更高抗原剂量的疫苗，或者谁可能由于对疫苗接种反应不足而在流感季节需要化学预防。这项为期5年的建议是在五个流感季节的每个季节对大剂量(HD)和标准剂量(SD)配方的裂解病毒流感疫苗(SVV)进行随机研究，以确定疫苗介导的流感保护的关键决定因素，以及在虚弱的老年人中接种新批准的大剂量流感疫苗如何增强这些免疫介质。这项研究将使我们能够解决以下目标：目标I：确定新上市的大剂量疫苗在实现干扰素γ：IL-10比率和GrzB水平的保护性增加方面是否比标准剂量表现得更好。我们的假设是，接种后干扰素γ：IL-10比率(&gt；10)和/或GrzB(&gt；990U/mg蛋白)超过阈值水平的受试者在接受高剂量SVV的人中将显著高于标准剂量SVV的受试者。目的II：评估脆弱程度与CMV状态和静息T细胞中GrzB水平的关系。脆弱性代表经过验证的 以及老年人脆弱性增强的可衡量状态。我们的假设是，越来越脆弱将与更高的bGrzB水平正相关。目的三：建立疫苗介导性保护的预测指标，可开发用于护理点测试。我们的假设是，虚弱程度、CMV血清阳性状态和bGrzB活性的增加与较低的细胞溶解活性、对流感挑战的Th1：Th2反应减弱以及流感疾病的风险增加有关。

DESCRIPTION (provided by applicant): Clinicians currently do not have methods to predict influenza vaccine responses in older adults that are accessible and relatively inexpensive. The long-term goal of this research is to identify the T-cell responses that are surrogates (biomarkers) of serious complications of influenza and can be used to predict vaccine effectiveness. Such loosely termed biomarkers would provide clinicians with the ability to decide who might benefit from newer or more reactogenic vaccines, such as a higher antigen dose vaccine, or who might require chemoprophylaxis during influenza season due to inadequate response to vaccination. This 5-year proposal is a randomized study of split-virus influenza vaccine (SVV) in a high-dose (HD) vs. standard dose (SD) formulation in each of five influenza seasons to define the key determinants of vaccine-mediated protection against influenza and how these immunologic mediators may be enhanced by vaccination with a newly approved high-dose influenza vaccine in frail older subjects. This study will allow us to address the following aims: AIM I: Determine whether a newly marketed high dose vaccine performs better than standard doses in achieving protective increases in IFNγ:IL-10 ratios and GrzB levels. Our hypothesis is that the proportion of subjects above the threshold level for the IFNγ:IL-10 ratio (>10) and/or GrzB (>990 U/mg protein) following vaccination will be significantly higher in those receiving the high-dose SVV vs. standard-dose SVV. AIM II: Evaluate the association of degree of frailty to CMV status and GrzB levels in resting T cells (bGrzB). Frailty represents a validated and measurable state of enhanced vulnerability in older individuals. Our hypothesis is that increasing frailty will be positively associated with higher bGrzB levels. AIM III: Establish predictors of vaccine-mediated protection that can be developed for point-of-care testing. Our hypothesis is that increased levels of frailty, CMV seropositive status, and bGrzB activity are associated with lower cytolytic activity, diminished Th1:Th2 responses to influenza challenge, and an enhanced risk of an influenza illness.