Sara van den Berg

26 Chapter 2 INTRODUCTION Ageing of the population poses an important public health problem. With age, the function of the human immune system declines, a phenomenon also referred to as immunosenescence [1]. Profound changes of the immune system include the gradual loss of naïve cells, increase of memory cell numbers and decreased diversity of the T-cell and B cell repertoire [1-3]. These changes contribute to reduced protection against infectious diseases and reduced vaccine responses in older adults. Indeed, the incidence of influenza virus infections is increased and accompanied with more complications and higher mortality in older adults [4, 5]. Most developed countries recommend yearly influenza vaccination in individuals above 60 or 65 years of age [6], in order to prevent influenza virus infection by the induction of protective antibodies [4, 7]. However, the antibody response to influenza vaccination in older adults is impaired, causing a suboptimal protection in this vulnerable group [7-9]. Accumulating evidence indicates that latent cytomegalovirus (CMV) infection is associated with age-related changes of the immune system, and might enhance immunosenescence [2, 10, 11]. CMV is a common b-herpesvirus with a prevalence of 45-100% worldwide, which increases with advancing age [12]. CMV infection causes morbidity and mortality in severely immunocompromised patients, while the virus rarely causes clinical symptoms in healthy individuals. Despite the ability of the immune system to control primary infection, the virus establishes a latent infection, with episodes of viral reactivation during lifetime [13]. The frequent reactivation of CMV causes continuous antigenic stress for the immune system [3]. Anti-CMV IgG levels increase with age [14-16] and are thought to increase after viral reactivation episodes, thereby reflecting the amount of experienced CMV antigenic stress during lifetime [12, 14, 17]. The profound effect of CMV infection on the immune system is especially shown by the progressive large expansion of oligoclonal CMV-specific CD8 T-cells and, to a lesser extent, CD4 T-cells. Furthermore, CMV-seropositivity is strongly associated with an inverted CD4/8 ratio [18], bias of the TCR repertoire [19] and increase of highly differentiated T-cells [20]. It has been suggested that CMV-enhanced immunosenescence could impair the immune response to influenza vaccination [21, 22]. Indeed, in several studies CMV-seropositivity or a high anti-CMV IgG titer was associated with lower antibody responses to influenza vaccination in both adults [23-25] and older adults [25-28]. However, others did not find an effect of CMV infection [29, 30], or reported even an enhanced antibody response to influenza vaccination in both young [31, 32] and older CMV-seropositive individuals [33]. The overall impact of latent CMV infection on the antibody induction by influenza vaccines remains controversial and depends, among other factors, on pre-existing immunity to influenza virus [34]. Most studies investigated the antibody response to seasonal influenza vaccination; a yearly recommended trivalent influenza vaccine that often contains overlapping influenza vaccine strains in consecutive years. Natural exposure to influenza virus and previous vaccination causes preexisting immunity, which influences the consecutive vaccine