Influenza vaccine failure in adults over age 75: role of chronic CMV infection

描述（由申请方提供）：季节性流感导致显著的发病率和死亡率。建议每年接种一次三价灭活疫苗（TIV）。然而，尽管随着时间的推移，老年人的疫苗接种覆盖率有所提高，但流感相关死亡率实际上有所增加。虽然许多TIV研究表明，它对老年人的好处是一种 总的来说，这些研究缺乏对老年人和体弱者的代表性，这些老年人的流感相关死亡率超过四分之三。由Beeson K23奖资助的我们的试点研究显示，TIV在对TIV的抗体应答和对体弱老年人的临床保护方面均显着失败。 根据抗CMV IgG血清学，慢性CMV感染在老年人中高度流行。大量文献表明，慢性CMV感染有助于T细胞免疫衰老和死亡。然而，抗CMV IgG血清学是一种粗略的测量方法，仅表明先前暴露于CMV，并不能区分慢性（持续性）和既往（已消退）感染。我们最近开发了一种高灵敏度和特异性的巢式PCR为基础的检测CMV DNA在外周血单个核细胞（PBMC）在老年人。我们的数据表明，CMV DNA存在于只有约60%的CMV血清阳性的老年人和CMV DNA阳性，而不是IgG滴度，与CMV特异性CD 8 + T细胞增加和慢性免疫激活增强。基于这些已发表的初步研究和本申请中描述的初步数据，我们的总体假设是，慢性CMV感染（定义为PBMC中存在CMV DNA）显著导致75岁以上成人TIV失败。我们提出了一项前瞻性的4年TIV免疫研究，在社区居住的成年人超过75以下3个目标：1）测试的假设，CMV DNA阳性导致接种后流感样疾病（ILI）和流感感染的发病率增加。ILI病例将通过疫苗接种后监测来识别，呼吸道标本将使用基于PCR的尖端IBIS检测试剂盒进行检测，该检测试剂盒可准确分型流感病毒和其他呼吸道病毒。作为次要目的，我们还将探讨慢性CMV感染对ILI和流感感染的影响是否因虚弱状态而异; 2）检验CMV DNA阳性导致对TIV的毒株特异性抗体应答受损的假设; 3）检验CMV DNA阳性导致在基线和TIV免疫后对流感病毒的同型和异型T细胞应答受限的假设。完成后，这项研究将有助于确定慢性CMV感染在TIV失败中的作用及其在老年人群脆弱亚群中的潜在体液和T细胞免疫机制，这在以前的疫苗研究中代表性不足。4年的研究设计是必要的，以解释流感流行的季节性变化和给定年份中抗原错配的可能性。这项研究的最终目标是通过预防和减轻慢性CMV感染来加强脆弱的美国老年人对流感的免疫保护。

DESCRIPTION (provided by applicant): Seasonal influenza causes significant morbidity and mortality. Annual immunization with a trivalent inactivated vaccine (TIV) is recommended. However, despite improved vaccination coverage in older adults over time, influenza-related mortality has actually increased. While many TIV studies indicate its benefit for older adults as a whole, these studies lacked representation of the older and frail subset of the elderly who suffer over three-quarters of influenza-related mortality. Our pilot study funded by a Beeson K23 award showed significant TIV failures in both antibody response to TIV and clinical protection in the frail elderly. Chronic CMV infection is highly prevalent in older adults based on anti-CMV IgG serology. A large body of literature suggests that chronic CMV infection contributes to T-cell immunosenescence and mortality. However, anti-CMV IgG serology is a crude measure that merely indicates prior exposure to CMV and does not distinguish chronic (persistent) from past (resolved) infections. We have recently developed a highly sensitive and specific nested PCR-based assay for the detection of CMV DNA in peripheral blood mononuclear cells (PBMCs) in older adults. Our data indicate that CMV DNA is present in only about 60% of CMV seropositive older adults and that CMV DNA positivity, rather than IgG titer, is associated with increased CMV-specific CD8+ T cells and heightened chronic immune activation. Based on these published pilot studies and preliminary data described in this application, our overall hypothesis is that chronic CMV infection as defined by the presence of CMV DNA in PBMCs contributes significantly to TIV failure in adults over 75. We propose a prospective 4-yr TIV immunization study in community-dwelling adults over 75 with the following 3 aims: 1) Test the hypothesis that CMV DNA positivity leads to increased rates of post-vaccination Influenza-like illness (ILI) and influenza infection. ILI cases will be identified by post-vaccination surveillance and respiratory specimens will be tested using the cutting edge PCR-based IBIS assay which can accurately subtype influenza and other respiratory viruses. As a secondary aim, we will also explore whether the effects of chronic CMV infection on ILI and influenza infection vary by frailty status; 2) Test the hypothesis that CMV DNA positivity leads to impaired strain-specific antibody responses to TIV; and 3) Test the hypothesis that CMV DNA positivity leads to restricting homotypic and heterotypic T-cell responses to influenza viruses at baseline and after TIV immunization. Upon completion, this study will help define the role of chronic CMV infection in TIV failure and its underlying humoral and T-cell immune mechanisms in the vulnerable subset of the elderly population, which has been underrepresented in previous vaccine studies. The 4-year study design is necessary to account for seasonal variations in influenza epidemics and the potential for antigenic mismatch in a given year. The ultimate goal of this research is to strengthen immune protection against influenza for vulnerable older Americans through prevention and mitigation of chronic CMV infection.