Imprinted antibody lineages can persist for half a century and dominate cross-neutralizing recall responses to poliovirus 2310306

Abstract Introduction Humoral immunity depends on a dynamic interplay between durable, circulating polyclonal IgG antibodies and long-lived memory B cells (MBC). However, the clonal relationship between these long-lived compartments remains poorly defined, particularly decades after childhood vaccination. Methods To investigate the durability of immunological memory to poliovirus (PV), we analyzed the molecular features of the recall response to inactivated poliovirus vaccine (IPV) boosting in healthy adults who had received their primary immunizations 24—55 years earlier during childhood in the United States. Using IgG immunoproteomics (Ig-Seq) coupled with ex vivo activation of MBCs via the Modular Immune In vitro Construct (MIMIC) system, we distinguished the respective contributions of LLPCs (as proxied by secreted plasma IgG proteomics) and MBCs to the anti-PV antibody response. Results 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 (∼102-104 fold-increase) and potently cross-neutralized multiple PV serotypes in vitro (titers ≥ 1:105). 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 yielded clonal expansions that mirrored the dominant post-boost plasma IgG lineages in vivo, providing an in vitro mechanistic correlate of recall immunity. Conclusion 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. Funding Source DARPA Topic Categories Vaccines and Immunotherapy (VAC)