Abstract Long-term humoral immunity elicited by pathogens and vaccines alike relies upon the generation of both memory B cells (B mem) and long-lived plasma cells (PCs). Virtually all vaccine formulations induce the concomitant emergence of both B mem and PCs, suggesting that the emergence of these two differentiated B cells subsets is commonly controlled. Evidence presented shows specific Toll-like receptor (TLR) agonists coupled with soluble protein antigen (sAg) can selectively induce the expansion of antigen specific B mem in the absence of PC generation. The co-administration of either TLR 3 or 9 agonists with sAg induced germinal centre (GC) formation, antigen-specific B mem, but failed to substantively induce the generation of long-lived bone marrow (BM) PCs. Upon re-challenge, high levels of PCs were induced with concomitant high titres of antigen-specific serum IgG. Hence, vaccines can be developed that can prime and protect the host to subsequent infectious agents without initial, high levels of antibody production. Furthermore, these studies suggest that the signals that govern the expansion and differentiation of B mem can be uncoupled from those that induce long-lived BM PCs.