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

75 岁以上成年人流感疫苗失败：慢性 CMV 感染的作用

基本信息

批准号：
9191339
负责人：
Sean Xiao Leng
金额：
$ 62.4万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9191339
关键词：
Adult Age Aged, 80 and over American Antibody Response Antibody titer measurement Biological Assay CD8-Positive T-Lymphocytes Cause of Death Chronic Clinical Clinical Research Communities Cytomegalovirus Cytomegalovirus Infections DNA DNA Viruses Data Detection Elderly Evaluation Exposure to Failure Frail Elderly Funding Generations Goals Health Immune Immunity Immunization Immunoglobulin G Impairment Inactivated Vaccines Individual Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A virus Influenza vaccination Investigation Laboratories Lead Literature Measures Mentored Patient-Oriented Research Career Development Award Morbidity - disease rate Nested PCR Octogenarian Peripheral Blood Mononuclear Cell Pilot Projects Population Prevention Publishing Research Research Design Risk Risk Factors Role Seasonal Variations Serologic tests Specimen Staining method Stains Syndrome T cell response T-Lymphocyte Testing Time Vaccination Vaccines base cytokine frailty functional decline immune activation immunosenescence improved influenza epidemic influenza virus vaccine influenzavirus monocyte mortality peripheral blood prospective public health relevance respiratory respiratory virus response seasonal influenza seroconversion seropositive trend vaccine trial

项目摘要

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.

描述（由申请人提供）：季节性流感会引起明显的发病率和死亡率。建议使用三价灭活疫苗（TIV）的年度免疫接种。但是，尽管随着时间的流逝，老年人的疫苗接种覆盖率得到改善，但与流感相关的死亡率实际上增加了。尽管许多TIV研究表明它对老年人的好处总体而言，这些研究缺乏代表年龄较大和脆弱的老年人，他们在四分之三的与流感相关的死亡率中受苦。我们由Beeson K23奖资助的试点研究表明，在脆弱的老年人对TIV和临床保护的抗体反应中，TIV失败了。基于抗CMV IgG血清学的老年人，慢性CMV感染高度普遍。大量文献表明，慢性CMV感染有助于T细胞免疫衰老和死亡率。然而，抗CMV IgG血清学是一种粗略的措施，仅表示事先暴露于CMV，并且不会将慢性（持久性）与过去（解决）感染区分开。我们最近开发了一种高度敏感的基于PCR的基于PCR的测定方法，用于检测老年人外周血单核细胞（PBMC）中CMV DNA。我们的数据表明，CMV DNA仅存在于约60％的CMV血清阳性老年人中，并且CMV DNA阳性而不是IgG滴度与CMV特异性CD8+ T细胞的增加有关，并增加了慢性免疫激活。 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疫苗后流感样疾病（ILI）和流感感染率。 ILI病例将通过疫苗接种后的监测来鉴定，并将使用基于尖端PCR的IBIS测定法对呼吸标本进行测试，该测定法可以准确地亚型流感和其他呼吸道病毒。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脆弱状态而异。 2）检验了CMV DNA阳性导致菌株特异性抗体对TIV的阳性的假设； 3）检验了CMV DNA阳性导致限制在基线和TIV免疫后对流感病毒的同型和异型T细胞反应的假设。完成后，这项研究将有助于定义慢性CMV感染在TIV衰竭中的作用及其潜在的体液和T细胞免疫机制在老年人群的脆弱子集中，这在先前的疫苗研究中的代表性不足。为了说明流感流行病的季节性变化以及在给定年份中抗原不匹配的潜力，必不可少的4年研究设计。这项研究的最终目标是通过预防和缓解慢性CMV感染来增强对脆弱的美国人的免疫保护。