Imprinted antibody lineages can persist for half a century and dominate cross-neutralizing recall responses to poliovirus

SUMMARY Humoral immunity depends on a dynamic interplay between circulating polyclonal IgG antibodies and long-lived memory B cells (MBC). To elucidate this relationship, we integrated B-cell receptor sequencing with plasma IgG immunoproteomics to identify and quantify the recall response (plasma IgG and MBC) to inactivated poliovirus vaccine (IPV) in eight adults, 24–55 years after their childhood immunization. IPV immunization elicited highly skewed plasma IgG recall repertoires, dominated by a small subset (∼8%) of total antibody lineages that were detectable prior to boosting (i.e., “pre-existing”). These IgG lineages spiked logarithmically in abundance (∼10 2 -10 4 fold-increase) and potently cross-neutralized multiple PV serotypes in vitro (titers ≥ 1:10 5 ). Notably, these dominant plasma IgG lineages were clonally linked to class-switched MBCs that circulated in blood 21 days post-boost and bore heavily mutated VH and VL variable region genes. Importantly, IPV-primed ex vivo B-cell cultures (MIMIC, Modular IMmune In vitro Construct) yielded clonal expansions that mirrored the dominant post-boost plasma IgG lineages in vivo , providing an in vitro mechanistic correlate of recall immunity. Together these findings demonstrate a decades-long interconnectivity between persistent MBC clones and the serological IgG repertoire. They further highlight the central role of immunological imprinting, whereby cross-reactive MBC clones—originally primed in childhood—can be reactivated to dominate the circulating IgG recall response more than 50 years after initial exposure.