Seasonal influenza causes significant morbidity and mortality and is the fourth leading cause of death for older Americans. Annual immunization with a trivalent inactivated influenza vaccine (TIV) is recommended for all adults 50 years and older. 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 vaccine failures in both antibody response to TIV and clinical protection in the frail elderly. Our preliminary data also suggest that chronic cytomegalovirus (CMV) infection as defined by the presence of CMV viral DNA in peripheral monocytes using a highly sensitive and specific nested PCR-based assay developed in our laboratory, rather than anti-CMV IgG serology, is associated with poor antibody and T-cell responses to TIV immunization as well as poor clinical protection. This is likely because anti-CMV IgG serology, the conventional diagnostic measure for chronic CMV infection, is a crude measure that merely indicates prior exposure to CMV and does not distinguish chronic (persistent) from past (resolved) infections. Mechanistically, precipitous immune functional decline has been observed in those over 75 and chronic CMV infection may contribute significantly to age-related immune senescent remodeling, termed immunosenescence. In order to improve our assessment of the effectiveness of TIV immunization and understanding of risk factors and underlying immune mechanisms that determine vaccine failure in adults over age 75, the frail, oldest old adult subset, this study is designed to conduct prospective, 4-year TIV immunization and post-vaccination influenza surveillance in adults over 75 years. We will first assess chronic CMV infection defined by detectable CMV DNA in peripheral blood monocytes and frailty status of the study participants and administer the Fluzone High-Dose TIV vaccine. Influenza-like illness (ILI) cases will be identified through post-vaccination influenza surveillance as previously done in the Beeson project and respiratory specimens obtained from ILI cases will be tested using the cutting edge PCR-based IBIS assay which can accurately subtype influenza and other respiratory viruses in the laboratory of Dr. Charlotte Gaydos in Division of Infectious Disease, a co-investigator of this project. Strain-specific antibody responses to TIV immunization will be measured by the standard hemogglutination inhibition (HI) assay. We will also evaluate T-cell responses to influenza viruses at baseline and after TIV immunization. Taken together, these studies will provide more accurate assessment of the clinical effectiveness of TIV immunization in real world geriatric population over age 75 and its underlying humoral and cell-mediated immune mechanisms. Moreover, we investigate the role of chronic CMV infection as defined by the presence of CMV viral DNA in peripheral monocytes as a risk factor for vaccine failure in the elderly over age 75. Because this oldest old subset is growing most rapidly in numbers and is at greatest risk for influenza-related morbidity and mortality. The long-term goal of this research is to strengthen immune protection against influenza for vulnerable older Americans through more effective and targeted immunization strategies as well as possibly through prevention and mitigation of chronic CMV infection.