In order to develop predictive markers for a beneficial humoral immune response, we evaluated the in vivo and in vitro response to the pandemic (p)H1N1 vaccine in young and elderly individuals. We measured serum antibody response and associated this with the in vitro B-cell response to the vaccine, measured by activation-induced cytidine deaminase (AID). Both responses decrease with age and are significantly correlated. The percentage of switched memory B cells in blood, both before and after vaccination, is decreased with age. The percentage of switched memory B cells at t0 correlates with the hemagglutination inhibition response and therefore, we suggest that this may be used as a predictive marker for B-cell responsiveness. AID induced by CpG before vaccination also predicts the robustness of the vaccine response. Plasmablasts showed a trend to increase after vaccination in young individuals only. This report establishes molecular biomarkers of response, percentage of switched memory B cells and AID response to CpG, useful for identifying individuals at risk of poor response and also for measuring improvements in vaccines and monitoring optimal humoral responses.