Sara van den Berg

71 3 CMV on influenza vaccination: a systematic review Merani et al (sept 2017) concluded that there is no difference in influenza GMR between CMV- seronegative and CMV-seropositive individuals, while CMV-seropositive individuals do show an impaired cellular granzyme B response to influenza virus challenge [64]. We published in Van den Berg et al (January 2018) that there is no negative effect of CMV infection on the antibody response to a novel influenza vaccine strain in adults [65]. Both studies will not change the conclusion of this systematic review that there is no unequivocal evidence for an effect of CMV infection on the antibody response to influenza vaccination. In this review the direct association between CMV infection and the influenza antibody vaccine response is investigated. Several mechanisms of a potential negative effect have been postulated, based on the known effects of CMV infection on the immune system and the subsequent potential impact on the influenza vaccine response [47, 58]. CMV infection leads to increased pro-inflammatory cytokine levels, which in turn are associated with decreased influenza vaccine responses [29]. Likewise, CMV infection leads to increased differentiation of T-cells, which has been associated with poor influenza vaccination responses [25, 53]. It has also been reported that CMV infection is associated with decreased switched B cell percentages before influenza vaccination, and subsequently lower influenza vaccine responses [32]. In contrast, De Bourcy et al (2017) suggested a potential mechanism for the positive effect of CMV on the antibody influenza vaccine response reported in Furman et al : based on B-cell repertoire analyses, CMV infection is associated with more activated B cells after influenza vaccination. This systematic review also has some limitations. Ideally, a systematic review is based on randomized controlled trials (RCT), but due to obvious ethical and practical reasons, no RCT’s have been conducted to study the relation between CMV infection and influenza vaccine responses. Consequently, only observational studies were included. We assumed that the reported sizes of the study populations were correct for the duration of the studies, even if no statement was made on the number of participants that were lost to follow up. Furthermore, this systematic review was limited by the number of studies that was found to be eligible for inclusion, which led to a meta-analysis of only 5 studies leading to 13 records. Another limitation is the incomplete correcting for confounders. We only adjusted for pre-vaccination antibody levels by investigating the GMR and partially adjusted for age by separating the results for young and old adults. However, age is associated with different influenza antibody responses, not only because of immunosenescence, but also due to immunologic imprinting and different influenza exposure during lifetime. Thus, merely assigning individuals to a young and old age group might not be sufficient to adjust for age as a confounder. Research on the effect of CMV on the influenza antibody vaccine response is further complicated by different study populations, and different influenza strains, as summarized previously [29]. There is no biological basis for a differential effect of CMV on different influenza strains, but influenza vaccine responses vary a lot per season and subtype [66]. Unfortunately, data from Reed et al could not be incorporated in this review. They reported a negative association between CMV-seropositivity and influenza antibody vaccine response in a study including different