Sara van den Berg

54 Chapter 3 INTRODUCTION Age-related reduced function of the immune system, often referred to as “immunosenescence”, is suggested to be influenced by cytomegalovirus (CMV) infection [1]. Main features of CMV- seropositivity include low percentages of naïve T-cells and reduced diversity in the T-cell repertoire, which may impair the ability to respond to heterologous infection or vaccination [2] and result in lower B-cell functions by lack of T-cell help [3, 4]. CMV-seropositivity has also been identified as a factor of the Immune Risk Profile (IRP) for mortality in the Swedish longevity studies [5]. CMV prevalence increases with age in the general population from 30% in children to above 90% at the age of 80 and older [6, 7]. Primary CMV infection and reactivation from latency can cause significant problems when the immune system is compromised or immature, but is usually asymptomatic in healthy individuals [8]. However, CMV frequently reactivates during life [9, 10], and can lead to detectable CMV DNA levels, mainly in the elderly [8, 11]. Control of CMV requires continuous immune surveillance and leads to large numbers of CMV-specific T-cells, up to 10-30% of CD8+ T-cells in the periphery. The lifelong need to control CMV is by many thought to take its toll and to hamper immune responses to heterologous infections or vaccination [3]. Indeed, in several mouse models the immune responses to heterologous infections was shown to be negatively affected by CMV [12-14]. However, other studies suggested a positive effect of CMV on the response to heterologous infections [12, 15] In humans, the potential effect of CMV infection on a heterologous immune response are mainly studied in the context of influenza vaccination. Seasonal influenza vaccination is an effective means to prevent influenza infection [16-18]. However, effectiveness of influenza vaccination decreases with age, leaving older adults exposed to an increased risk of influenza infection [1]. In older adults, influenza infection more often leads to disease-related hospitalization, complications and mortality [17, 19-21]. Influenza vaccines are primarily focused on eliciting a strain-specific antibody response. Antibodies are important as they give rise to so-called sterilizing immunity; the immune status where the host immune response effectively blocks virus infection. The most widely used method to measure strain-specific influenza titers is the hemagglutination-inhibition (HI) assay, which reflects the ability of specific antibodies to bind influenza virus and inhibit viral agglutination of red blood cells [22, 23]. European medicine agency guidelines describe the analysis and presentation of influenza antibody data for development of influenza vaccines [24], stating as a minimum requirement that geometric mean titers (GMTs) (with 95% confidence intervals) and pre-/ post-vaccination ratios (GMR), and response rates should be reported. Clarification of the effect of CMV on influenza vaccine responses is of high importance. The current suboptimal immune response to influenza vaccination in elderly will become an increasingly large problem. By 2050, the population of older persons (defined by the United Nations as those aged 60 years and above) is expected to double in size compared to 2015. With an increasing life expectancy, the group of elderly at high-risk for influenza