LAUSR

&NA; Although immune memory often lasts for life, this is not the case for certain vaccines in some individuals. We sought a mechanism for this phenomenon by studying B cell responses to phycoerythrin (PE). PE immunization of mouse strains with Ighb immunoglobulin (Ig) variable heavy chain (VH) genes elicited affinity‐matured switched Ig memory B cells that declined with time, while the comparable population from an Igha strain was numerically stable. Ighb strains had larger numbers of PE‐specific naive B cells and generated smaller germinal center responses and larger numbers of IgM memory cells than the Igha strain. The properties of PE‐specific B cells in Ighb mice correlated with usage of a single VH that afforded high‐affinity PE binding in its germline form. These results suggest that some individuals may be genetically predisposed to generate non‐canonical memory B cell responses to certain antigens because of avid antigen binding via germline‐encoded VH elements. Graphical Abstract Figure. No caption available. HighlightsA population of antigen‐specific naive B cells mainly expresses a single VH segmentThis VH confers high‐affinity antigen binding that depends on an un‐mutated CDR‐H2These cells made more plasmablasts and fewer germinal center cells than other B cellsB cells with this VH produced abundant stable IgM+ and transient IgG+ memory cells &NA; Immunity induced by certain vaccines declines over time. By studying B cell responses to phycoerythrin, Pape et al. find that memory B cells can be short‐lived when generated from precursors that experience unusually strong early signals through their un‐mutated antigen receptors.