Sara van den Berg

72 Chapter 3 seasons and influenza strains. Their data could however not be extracted for analysis for one of the outcomes of this systematic review, since they were only reported as a result of a multi-factor model. Universality in reported influenza antibody data in the CMV-immunosenescence field is necessary to reveal the potential effect of CMV on the antibody influenza vaccine response. We recommend further studies investigating the effect of CMV infection on the influenza antibody vaccine response to follow the EMA guidelines [24] and as an absolute minimum, to always report the influenza pre-GMT and post-GMT (with 95% CI) and the number of participants per group. It is important to take influenza strain and season into account by measuring and reporting the titers separately per influenza strain. A response rate is also of interest, but should not be the only outcome reported. The response rate can be defined in several ways [24] and the correlate of protection of 40 is based on adults, making the use in elderly questionable [24, 67]. In addition, a regression analysis to correct for pre-existing immunity is necessary. Especially when the effect of CMV infection on the influenza antibody response is small, correcting for confounders, like age (as continuous variable), pre-existing immunity, vaccination history, medicine use or comorbidities is highly recommended. In conclusion, we show that based on the GMR, which in our perception is the best outcome available, there is no evidence for an effect of CMV-seropositivity on the influenza antibody vaccine response, and that publication bias probably explains the trend in the literature that CMV-seropositive individuals seem to respond less often to influenza vaccines than CMV-seronegative individuals. We suspect that in the past, several studies did not reach publication because they did not fit the prevailing idea that CMV induces immunosenescence. Our systematic review emphasizes that the effect of CMV infection on a clinically relevant immune function in humans, such as influenza vaccine responses, is not as black-and- white as previously suggested. Further large studies investigating the relation between CMV antibody levels and influenza vaccine responses with enough power to detect a potential small effect of CMV infection are needed, in which also confounding factors in addition to age are taken into account. Only if there is unequivocal evidence for CMV-associated impaired influenza vaccine responses, can we begin to address whether a CMV-impaired vaccine response in the elderly is merely a sign of immunosenescence, or whether CMV is causing immunosenescence. ACKNOWLEDGEMENT We thank Michiel van Boven for critically proofreading the article.