Sara van den Berg

55 3 CMV on influenza vaccination: a systematic review complications will increase quickly and contribute to the rising challenges of public health. As latent CMV infection is highly frequent in the population, it is critical to elucidate whether CMV infection influences influenza vaccination responses, in order to be able to optimize vaccine strategies in the population. Several studies investigated the effect of CMV infection on immune responses induced by influenza vaccination. The first study by Trzonkowski et al. reported a negative association between CMV infection and the response to influenza vaccination [25]. Some studies confirmed this result [26], but others did not find an effect of CMV infection on the influenza vaccine response [27]. In contrast, Furman et al. reported a positive effect of CMV infection on the immune response to influenza vaccination in adults [28]. To date, no consensus of the effect of latent CMV infection on the antibody response to influenza vaccination has been reached [4, 29, 30]. Here, we systematically reviewed studies on the effect of CMV infection on the antibody response to influenza vaccination in healthy individuals. The process of systematic reviewing the available evidence in literature was reported in line with the PRISMA criteria (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [31]. We extracted three standardized outcome variables of 17 studies, in line with European Medicine Agency (EMA) [24] and Food and Drug Administration (FDA) guidelines [32]. Summarizing all extracted data on GMR to influenza vaccination revealed no clear difference between CMV-seropositive and CMV-seronegative individuals. In a meta-analysis, a small (but non-significant) trend was observed that CMV-seropositive participants responded less often to influenza vaccination than CMV-seronegative individuals. We show that this effect is likely explained by publication bias. In addition, we summarized reports on a possible correlation between CMV antibody titers and influenza antibody titers, which showed weak negative correlations between the two. Together, these analyses provide no unequivocal evidence that latent CMV infection affects the influenza antibody response to vaccination. MATERIAL AND METHODS Search strategy and selection criteria The database EMBASE was systematically searched for articles on CMV and influenza vaccination, combined with a search on CMV and immune response to include articles that covered the subject but did not explicitly mention influenza vaccination. The full search strategy was performed on 27-06-2017 and is provided in Supplementary Table 1 . Two authors independently performed the selection process (SB and KW), in which all identified articles were first screened based on title and abstract and the remaining articles were reviewed in-depth. Discrepancies regarding the inclusion or exclusion of an article between the authors were resolved by discussion. English articles that reported an immunological response to influenza vaccination and had included at least a CMV-seronegative group or a CMV-seropositive group were considered for inclusion.