Highlights d Longitudinal profiling of anti-H1N1 serum antibodies (Abs) reveals persisting Abs d The persistent Abs on average account for >70% of the serum responses over 5 years d Most persistent Abs bind and neutralize a highly divergent H5N1 viral strain d Cross-neutralizing anti-influenza Abs can persist in the circulation Authors

In the last decade, progress in the analysis of the human immune response and in the isolation of human monoclonal antibodies have provided an innovative approach to the identification of protective antigens which are the basis for the design of vaccines capable of eliciting effective B-cell immunity. In this review we illustrate, with relevant examples, the power of this approach that can rapidly lead to the identification of protective antigens in complex pathogens, such as human cytomegalovirus and Plasmodium falciparum, and of conserved sites in highly variable antigens, such as influenza hemagglutinin and HIV-1 Env. We will also discuss how the genealogical analysis of antigen-stimulated B cell clones provides the basis to delineate the best suitable prime-boost vaccination strategy for the induction of broadly neutralizing antibodies.