Sara van den Berg

70 Chapter 3 to influenza vaccination than CMV-seronegative individuals. Funnel plot analysis suggested that publication bias most likely underlies this trend in the literature ( Figure 6 ). Unfortunately, it was not possible to extract a standardized outcome for an association between CMV antibody level and the influenza antibody response to vaccination (outcome c), since the methods of the studies varied and no raw data was available. Overall, the reported correlation results ( Table 4 ) of the studies indicated a small negative association between CMV antibody titers levels and influenza antibody levels after vaccination, suggesting that individuals who experienced multiple CMV reactivations during life may have impaired influenza vaccine responses. The tabulated correlations however should be interpreted with caution. CMV antibody levels increase with age and are thought to reflect experienced CMV reactivation or reinfection [7]. Therefore, high anti-CMV antibody levels may be related to enhanced CMV-induced immunosenescence and impaired influenza vaccine responses [42]. However, we noticed that in most studies CMV-seronegative individuals were included in the correlation of CMV antibody titers and influenza antibody titers, which may affect the correlation coefficient or the significance of the correlation. Of importance, in only one study CMV antibody levels were correlated with the fold increase in influenza antibody titers [47]; in all other studies it was correlated with the post-vaccination titer, thereby overestimating the vaccine response. Together, this questions the importance of the reported weak correlations between CMV antibody levels and influenza antibody titers to vaccination. To illustrate the controversy in the literature, we also summarized the reported conclusions of various studies on the influenza antibody response ( Figure 3) . Two previous reviews directly combined the various results in literature on the effect of latent CMV infection on the antibody response to influenza vaccination [4, 29]. Frasca et al (2015) and Merani et al (2017) refer to some of the studies included in our systematic review, and describe the effect of CMV on influenza antibody vaccine responses as controversial or ambiguous. Despite this, both reviews come to the conclusion that CMV does affect the immune response to influenza vaccination [4, 29]. In addition, Merani et al discuss possible methods to reduce the impact of immunosenescence on influenza vaccine responses by anti-CMV strategies [29]. The controversy in the literature and the difficulty to compare different influenza antibody outcomes in different studies highlights that a systematic approach is necessary. The strength of our review lies in its systematic approach. This allowed us to synthesize all the available evidence (until 27 th June 2017) on this particular question and to eliminate the effect of potential publication bias. Instead of merely summarizing the conclusions in literature, we extracted the published data in three standardized outcome variables of influenza antibody response, separated per age group. Furthermore, whenever possible, we assessed the data of each study per influenza strain. By this, we included multiple records per study and not only the record on which the authors’ conclusion was based. To the best of our knowledge, only two new articles came out that investigated the effect of latent CMV infection on the influenza antibody response since the systematic search of this review (27 th June 2017).