The antibody response to natural infection, with a number of viruses, is life-long. Furthermore, neutralising antibody is by far the best correlate of long-term protective immunity conferred by effective vaccines. Indeed, humoral immunity to smallpox elicited by the live vaccinia virus vaccine is stable, lasts for decades, and is considered a valuable benchmark for the functional attributes of a good vaccine. We hypothesized that it is the escalating concentration of replicating virus (antigens) which provide important cues to key immune cell subsets, including CD4 T follicular helper (T_FH) cells and B cells in the germinal centre (GC) responses, and these are critical for induction and maintenance of robust, long-lived antibody responses. We used replication-competent or replication-poor poxviruses along with live or inactivated influenza A virus strains to infect mice. We found that replication-competent viruses, compared with poorly replicating or inactivated viruses, induced more robust T_FH and GC responses. These responses to replication-competent viruses persisted longer and correlated with significantly higher virus-neutralizing antibody titres. We next transferred antigen-specific B cell receptor (BCR) transgenic B cells into recipient animals and infected them with recombinant poxviruses that express a foreign antigen (recognised by the BCR) to study antigen-specific responses to infection. We found that, compared with poorly replicating viruses, replicating viruses induced increased frequency of somatic hypermutations in the variable region exon of the immunoglobulin heavy chain of transgenic B cells and this was associated with affinity maturation. Our data indicates that replicative capacity of virus directs the induction of durable, long-lived neutralizing antibody responses through generation of robust T_FH and GC responses.