Sara van den Berg

36 Chapter 2 a negative effect on the influenza antibody fold increase in one strain of the trivalent vaccine in CMV-seropositive adults with high anti-CMV IgG levels compared to CMV-seronegative adults. Wald et al [23] also reported a negative effect of CMV-seropositivity in adults, by investigating the same pandemic H1N1pdm vaccine response in 2009 as we did. However, they did not adjust for confounders in the analysis [23]. These differences in findings of the effect of latent CMV infection on the influenza vaccine response without pre-existing immunity are unexplained. We speculate that the vaccine dose and adjuvant use may be a reason for these differences. In Turner et al half the recommended dose was used [24]. Likewise, an unadjuvanted monovalent vaccine [47] was used in Wald et al while in our study the vaccine was adjuvanted. The use of MF59 adjuvant is expected to activate the CD4+ T-cells and further enhance antibody production, thereby eliciting a stronger immune response compared to an unadjuvanted vaccine. Taken together, it may be possible that only with less potent influenza vaccines, a short term negative effect of latent CMV infection is present. The correlation of lower antibody response to the novel pandemic influenza vaccination with age points to an immunosenescence-driven weakened immune response. Typically, lower antibody responses to influenza vaccination are associated with high age (> 60 years old). Interestingly, we observed already an effect of age in this group of non-elderly (18-52 years of age), although small. This effect of age was due to a lower influenza antibody response from the age of 40 years onwards. It is suggested that differences between age groups to influenza vaccination responses might also explained by HA imprinting [48]. HA imprinting implicates that the immune response is skewed to the group of HA antigens of the influenza strain that is first encountered during childhood. However, this was not the case and HA imprinting could be excluded as an explanation for the age differences. Similar analyzes were performed for the effect of age and latent CMV on the seasonal influenza vaccine response in season 2010-2011. Seasonal vaccination in 2010-2011 contained the same H1N1pdm strain of the pandemic season and the antigen-drifted H3N2 strain that overlaps in serological response to great extent with previous H3N2 strains [49]. Thus both seasonal strains elicit an immunological memory response. Immunosenescence mainly affects the de novo immune responses [36, 37]. In line with this, effects of age on an influenza vaccine response diminish after further vaccination with the same strain [34], explaining the different findings for the effect of age between the pandemic season and season 2010-2011. It was surprising to find that individuals with high anti-CMV IgG levels showed a higher influenza titer and protection rate to seasonal vaccination. We cannot exclude that these individuals might be high-antibody producers in general, as previously shown for Respiratory Syncytial Virus (RSV) and the response to other respiratory viruses [50]. Also, the total group that continued to season 2010-2011 with the study was smaller (n=128) and had a higher number of previous vaccinations than the group of the pandemic season (n=263), complicating the asjusted analysis. Different results were obtained for using seroconversion rate instead of protection rate as definition of responder on the seasonal vaccination. A