Sara van den Berg

37 2 CMV on influenza vaccination positive effect of high anti-CMV levels group was not observed on the seroconversion rate (data not shown). This shows the importance for correcting in our statistical model for these factors and strongly implies caution with interpretations of CMV-induced effects in small study groups or non-adjusted studies as reported in literature. Important strengths of our study compared to others, are the use of a novel influenza vaccine strain, the relatively large groups of study subjects in the pandemic season and the adjusted analysis with the GEE model. Since aging and latent CMV infection are thought to affect the immune system both independently and by interacting with each other, separation of these factors in analysis is crucial [51]. A limitation of the study is that the study population consists of health care workers who received repeated previous influenza vaccinations. Individuals with repeated previous seasonal influenza vaccinations show in general higher pre-vaccination titers than first time vaccinated individuals [44]. Even in the pandemic season, cross reactivity was reported for the H1N1pdm strain [52, 53]. Together with potential natural exposure to the H1N1pdm strain just before the study, this may explain the detectable titers before pandemic vaccination in this study. The seasonal 2009 vaccination 3 weeks before the study in the pandemic season indeed increased the pandemic pre-titer (data not shown). However, vaccine history of the last years preceding the vaccine trial of the study subjects was reported and was adjusted for in the analysis. Importantly pre titers did not affect the study results, since individuals in our study without detectable pre-titers (n=203) for pandemic influenza vaccination, showed comparable results for the effect of CMV infection for the pandemic season (data not shown). The influenza response in humans is complex and raises the question if influenza vaccination is the best model to investigate the effect of latent CMV infection on vaccine responses. A less complicated model, in which a vaccine for people that are truly naïve is used, might be a better study design for this question. However, we consider influenza vaccination represents the most relevant because of its high societal importance. Therefore, knowledge on the effect of CMV infection on the influenza antibody response is of great importance. In conclusion, we used a novel influenza vaccine strain to investigate the effect of age and latent CMV infection on the de novo immune response to influenza. We found indeed already impaired antibody responses to vaccination in adults with increasing age, but latent CMV infection did not impair the influenza virus-specific antibody response. Thereby, we show that CMV infection does not per se enhance the age-related impaired immunity as assumed, but if anything might give opposite effects. A model in which CMV infection boosts the immune system during adulthood, while in older adults CMV infection enhances the ageing of the immune system, might be appropriate. These results are important in the decision to invest in preventing latent CMV infection in healthy individuals through strategies like CMV vaccination.