Sara van den Berg

64 Chapter 3 no meta-analysis was performed. Instead, we summarized the GMR with the 95% CI in an overview figure ( Figure 4A ). For the remaining 5 studies, we were unable to estimate a reliable 95% CI [26, 28, 49], either due to illegible charts [49] or due to lack of clarity surrounding reported measure of spread [26, 28] ( Figure 4B ). Overall, the influenza GMR differed greatly between studies: some records suggested a higher increase in the influenza-specific antibody titer in CMV-seropositive individuals compared to CMV-seronegative individuals, while other studies suggested the opposite ( Figure 4 ). Even analyses restricted to young or old individuals only revealed contradicting results on the effect of CMV-serostatus. Likewise, even restricting the analysis to studies of good quality revealed no overall effect of CMV-seropositivity on the influenza-specific GMR after vaccination. In conclusion, the primary outcome of our systematic analysis revealed neither evidence for a negative nor for a positive effect of CMV-seropositivity on the influenza vaccine response in young or old individuals. Meta-analysis: no significant differences in response to influenza vaccination between CMV-seropositive and CMV-seronegative individuals (outcome b) Next, we investigated by odds ratio (OR) analysis whether there is any evidence for a positive (OR>1) or negative (OR<1) association between CMV-seropositivity (exposure) and response to influenza vaccination (outcome b). From five studies a clear definition of responders and non-responders could be extracted [40, 51-54] for different influenza strains and age groups, leading to a total of 13 OR records ( Supplementary figure 3 ). Most studies defined a response to influenza vaccination as a ≥4 fold increase in antibody titer after vaccination; one study ( Strindhall et al , 2016) used the stricter definition of a ≥4 fold increase in antibody titer and a post-titer of ≥ 40 HAU. Meta-analysis of all 13 records revealed a pooled OR of 0.65 (95% CI 0.40-1.08; I 2  = 33%; p=0.11). Although this OR indicates a trend that CMV-seropositive participants respond less often to influenza vaccination than CMV-seronegative individuals, this is not statistically significant. ( Figure 5 ). Stratified meta-analyses for the separate young and old groups and for the data in Strindhall et al, which used the stricter definition of response, also did not reveal any significant effects of CMV-serostatus on the influenza antibody response. A sensitivity analysis was done to assess the role of the quality of the studies on the pooled OR; meta-analysis restricted to high quality studies revealed an OR of 0.60 (95% CI 0.35-1.03), which did not markedly differ from the pooled OR of all study records. In conclusion, the average OR of 0.65 (95% CI: 0.40-1.08) suggests a (non-significant) trend that CMV-seropositive participants respond less often to influenza vaccination than CMV-seronegative individuals.