Predictors of Immunologic Failure in Older Adults

描述（由申请人提供）： 从历史上看，虚弱这个词已经与合并症、残疾和极端老年互换。在过去的十年中，老年医学研究人员已经发展，完善和验证了脆弱的概念。这是一种综合征，其核心涉及被认为是由于“多系统失调”引起的对压力源的脆弱性的临床状态。测量虚弱指数的标准包括：无意的体重减轻，疲惫，力量损失，缓慢的步行速度和低水平的活动。虚弱指数是一种经过验证的工具，将老年人分为三个定义的类别：健壮（健康），虚弱前和虚弱。在美国和欧洲的几个种族人群中，虚弱、死亡率增加和其他表现指标下降之间存在明显的关联。虚弱是社区居住老年人的常见病症，在65岁的人中患病率为7 - 10%，在80岁以上的人中患病率为25%，在长期护理机构中的人中患病率甚至更高。前虚弱是介于强健和虚弱之间的一个中间类别，它预示着虚弱的发展。虚弱前期的发病率甚至比虚弱更常见。 目前对老年人免疫系统的了解几乎完全基于年龄。很少有免疫学研究涉及免疫功能障碍和虚弱之间的任何关系。老年人，特别是那些身体虚弱的人，在很大程度上被排除在临床试验之外，而且研究得很不够。 已经确定，年龄的增加导致免疫功能障碍和对疫苗接种的不良反应。虚弱和年龄预测老年人免疫和疫苗接种失败的总体假设。然而，虚弱将是一个更强的预测比年龄的免疫和疫苗接种失败。这一假设将通过以下具体目标来解决：目标1。确定老年人虚弱和免疫功能障碍之间的关系。该假说认为，某些免疫缺陷与虚弱的关系比与年龄的关系更密切。为了检验这一假设，将使用一组已建立的免疫学试验来测量老年人中的T细胞、抗原呈递细胞（APC）和B细胞的功能，这些老年人是健壮（健康）、虚弱前和虚弱的，通过虚弱指数测量。受试者将入组65 - 74岁、75 - 84岁和85岁以上的年龄组，以直接比较虚弱和年龄之间免疫功能的特定方面。免疫学小组的研究将集中在T细胞、APC和B细胞表型和功能上，这些对成功的疫苗应答至关重要。我们预测，T细胞区室将表现出最大的功能障碍，与先进的脆弱性和年龄。目标2.确定老年人虚弱状态与流感疫苗应答差之间的关系。我们假设疫苗失败与虚弱和年龄密切相关。为了检验这一假设，我们将在目标1中对相同的虚弱和年龄匹配的受试者接种三价灭活流感疫苗，并在4 - 12周后测量抗体应答。目标3：确定哪些特异性免疫功能障碍介导了虚弱和流感疫苗应答不良之间的关系。将在虚弱组中确定观察到的介导接种疫苗（目的2）导致流感特异性抗体滴度降低的特异性免疫缺陷（目的1），年龄作为协变量。考虑到虚弱和年龄的影响，我们将确定哪些免疫功能最有可能是疫苗应答不良的机制。目标4。开发一种临床算法，根据虚弱和年龄类别预测流感疫苗接种的有效性。我们将使用3个虚弱类别和3个年龄组来开发一种临床上有用的算法来预测流感疫苗的成功和失败。该工具可以指导临床预防和替代保护策略的使用。 公共卫生相关性： 拟议的研究对退伍军人群体具有重要意义。超过900万退伍军人，包括VA系统中39%的患者，年龄在65岁或以上。在美国，约90%的流感相关死亡发生在65岁以上的成年人中。尽管开展了积极的疫苗接种运动，但老年人因流感死亡的风险仍在增加。在有和没有虚弱的老年人中识别和验证保护性疫苗接种的特定生物标志物以及估计保护效力的算法可以帮助确定在流感爆发的背景下谁可能需要额外的保护措施。需要开发新的疫苗和/或给药时间表，以适应衰老免疫系统的需求。为了实现这一目标，有必要增加对老年退伍军人免疫功能障碍的了解，以确定必须克服哪些特定缺陷。

DESCRIPTION (provided by applicant): Historically the term frailty has been interchanged with co-morbidity, disability, and extreme old age. In the last decade Geriatrics researchers have developed, refined, and validated a concept of frailty. It is a syndrome that at its core involves a clinical state of vulnerability to stressors thought to be due to "multisystem dysregulation". The criteria of measuring a Frailty Index include: unintentional weight loss, exhaustion, loss of strength, slow walking speed, and low level of activity. The Frailty Index is a validated instrument that classifies older adults into three defined categories: robust (healthy), pre-frail, and frail. There is a clear association between frailty, increased mortality, and declines in other performance measures in several ethnic populations in the U.S. and Europe. Frailty is a common condition in community dwelling elderly adults with a prevalence 7-10 % among those age 65, 25% in individuals over age 80, and even higher in individuals in long-term care facilities. Pre-frailty is an intermediate category between robust and frail, and predicts progress to frailty. The incidence of pre-frailty is even more common than frailty. The current level of understanding of the immune system in older individuals is based almost exclusively on age. There have been very few immunologic studies that have addressed any relationship between immunologic dysfunction and frailty. Older individuals, especially ones with greater debility and frailty, are largely excluded from clinical trials and are significantly understudied. It has been established that increasing age leads to both immunologic dysfunction and poor responses to vaccination. The overall hypothesis that frailty and age predict immunologic and vaccination failure in older adults. However, frailty will be a stronger predictor than age of immunologic and vaccination failure. This hypothesis will be addressed with the following specific Aims: Aim 1. To determine the relationship between frailty and immunologic dysfunction in older adults. The hypothesis is that certain immune defects will be more strongly associated with frailty than age. To test this hypothesis, a panel of established immunologic tests to measure the function of T cells, antigen presenting cells (APC), and B cells in older adults that are robust (healthy), pre-frail, and frail as measured by a Frailty Index will be used. Subjects will be enrolled in the age groups of 65-74, 75-84 and over 85 years to allow a direct comparison of specific aspects of immunologic function between frailty and age. The studies in the immunologic panel will focus on T cell, APC, and B cell phenotypes and functions that are critical for a successful vaccine response. We predict that the T cell compartment will demonstrate the greatest dysfunction with advancing frailty and age. Aim 2. To determine the relationship between frailty status and poor influenza vaccine response in older adults. We hypothesize that vaccine failure correlates closely with frailty as well as age. To test this hypothesis, we will vaccinate the same frailty and age matched subjects in Aim 1 with trivalent inactivated influenza vaccine and measure antibody responses after 4-12 weeks. Aim 3. To determine which specific immunologic dysfunction(s) mediate the relationship between frailty and poor influenza vaccine responses. The specific immune defects observed (Aim 1) that mediate the reduced influenza-specific antibody titers that result from vaccination (Aim 2) will be determined in the frailty groups with age as a covariable. Taking into account the influence of frailty and age, we will determine which immune functions most likely are the mechanism(s) of the poor vaccine response. Aim 4. To develop a clinical algorithm to predict the efficacy of influenza vaccination based on categories of frailty and age. We will use the 3 frailty categories and 3 age groups to develop a clinically useful algorithm to predict influenza vaccine success and failure. This tool could guide use of prophylaxis and alternative protective strategies clinically. PUBLIC HEALTH RELEVANCE: The proposed studies are highly significant to the Veteran population. Over 9 million veterans comprising of 39% of patients in the VA system are 65 or older. Around 90% of influenza-related deaths occurred among adults aged >65 years in the United Sates. The risk of mortality due to influenza is increased in older individuals in spite of an aggressive vaccination campaign. Identification and validation of specific biomarkers of protective vaccination in older adults with and without frailty and the algorithm of estimation of protective efficacy could help determine who might require additional protective measures in the setting of an influenza outbreak. New vaccines and/or administration schedules need to be developed to tailor to the needs of the aging immune system. In order to achieve this, it is necessary to have an increased understanding of the immune dysfunction in older veterans to identify what specific defects must be overcome.