Sara van den Berg

69 3 CMV on influenza vaccination: a systematic review All records reported a negative association between the CMV antibody level and the influenza antibody titer, and 8 out of 10 were reported to be significant. Reported correlation coefficients (8 outcomes) were on average r = -0,49 and varied from r = -0.16 to r = -0.77, showing mainly low to moderate negative correlations [57]. In addition, two models [42, 47] showed a significant negative association between CMV antibody levels and the influenza antibody titer to influenza vaccination. Overall, these correlation results indicate a small but significant negative association between CMV antibody levels and influenza antibody titers after vaccination. DISCUSSION This is the first systematic review investigating the association between latent CMV infection and the immune response to influenza vaccination. Almost two decades ago, CMV was associated with “immunosenescence” [58]. Since then, multiple studies on CMV-induced immunosenescence have been performed. The idea that CMV decreases the ability of the immune system to respond to other pathogens or vaccination [59, 60] is mainly based on studies investigating the influenza vaccine response [61]. Indeed, various studies reported a negative association between latent CMV infection and influenza vaccine responses, while other studies lacked to find an effect of CMV or even reported a positive effect of CMV. Thus, consensus on the effect of CMV is lacking. Nevertheless, an effect of CMV on the influenza vaccine response in the elderly is generally assumed [29, 61, 62]. By systematically reviewing and integrating the available studies, we here show that there is no unequivocal evidence for an impact of CMV on the influenza vaccine response. We systematically selected studies on CMV and influenza vaccine responses and extracted three standardized influenza antibody outcome variables. The geometric mean titer ratio (GMR) pre/post influenza vaccination with ( Figure 4A ) and without ( Figure 4B ) 95% CI revealed no difference between CMV-seropositive and CMV-seronegative individuals (outcome a). Of note, also when only the post-vaccination geometric mean titer (post- GMT) was summarized, no overall trend for an effect of CMV-serostatus was observed ( Supplementary Figure 5 ). We primarily assessed the GMR and not the post-GMT since the participants in the studies were not all influenza seronegative before vaccination. Pre- existing immunity is usually present in the case of seasonal influenza vaccination. Thus, post-vaccination titers as outcome will overestimate the vaccine antibody response and are therefore less meaningful. Linear regression analysis, as performed in some studies [42, 63], is the best method to correct for pre-vaccination titers [46], but this could not be analysed on the basis of the extracted data of the studies included for this review. Thus, with the GMR, the best outcome available, no effect of CMV-seropositivity on the influenza vaccine response is observed. The meta-analysis of response rate to influenza vaccination (outcome b) ( Figure 5 ) revealed a small (albeit non-significant) trend that CMV-seropositive participants respond less often