Sara van den Berg

35 2 CMV on influenza vaccination Our study showed no negative association between latent CMV infection and the antibody response to influenza vaccination. Other studies did report negative effects in adults [23, 25, 32] and older adults [25, 26, 28, 43]. However, most of these studies investigated the effect of latent CMV infection on the influenza vaccine response in the presence of pre-existing immunity. In one study, all subjects were even seroprotected (influenza antibody titer > 40 HAU) before influenza vaccination [26]. It is known that individuals with high pre-titers show a lower increase in influenza antibody response after influenza vaccination [7, 19, 35, 44]. Therefore, high pre-titers are associated with lower seroconversion (antibody titer ≥ 40 HAU and ≥ 4-fold increase) and higher protection rate (> 40 HAU). Furthermore, in all but two studies [25, 43], vaccine history was not taken into account, while previous vaccination is associated with lower seroconversion independently of pre-titers [7]. Not accounting for pre- existing immunity in influenza vaccine responses therefore may obscure findings and lead to different findings on the effect of latent CMV infection. Here, we controlled for pre-existing immunity by investigating the effect of latent CMV infection on pandemic vaccination for which pre-existing immunity was low, and by performing analysis adjusted for pre-titers and vaccine history. By doing so, we found that influenza vaccine responses are not impaired by latent CMV infection. If anything, signs of enhanced persistence of protection after influenza vaccination was observed in CMV-seropositive individuals. We observed similar results when we analyzed the effect of latent CMV infection on the seroconversion rate. No impairment by CMV-latent infection on the vaccine response was found, but CMV-seropositive individuals showed a higher seroconversion rate six months and one year after vaccination (T4 p=0.044, T5 p=0.02) (data not shown). A beneficial effect of latent CMV infection on the immune system has been indicated [10] and is suggested to reflect higher activation status of innate cells after primary CMV infection or reactivation. Accordingly, an increased antibody titer short-term after influenza vaccination in young CMV-seropositive compared to young CMV-seronegative individuals was observed [31-33] and suggested to depend on boosting by low grade inflammation and high levels of circulating IFN γ in CMV-seropositive young individuals [31, 33]. A beneficial effect of latent CMV infection on the long-term persistence of protection after vaccination in adults has to our knowledge not been reported. Waning of protection is thought to be most significant in individuals above 65 years of age [45] and accelerated by latent CMV infection [46]. Our results might suggest a positive effect of CMV infection in adults on the protection rate. Thereby our data fit in a scenario in which latent CMV infection has a beneficial effect in adults and may become detrimental with ageing. Two studies that reported a short-term negative effect of latent CMV infection in adults, did take the factor pre-existing immunity into account by either correcting for antibody titers pre- vaccination [24] or by investigating the effect of latent CMV infection on the novel pandemic vaccine [23]. However, these studies differ from our study in terms of vaccine type and analysis of the antibody response. Turner et al studied the fold increase of influenza antibody titers to seasonal vaccination, corrected for pre-titers before vaccination [24]. They reported