Phage-display immunoprecipitation sequencing reveals distinct antibody repertoire patterns across rural and urban populations

Environmental microbial exposures are hypothesized to shape immune profile differences across rural and urban populations, yet evidence linking exposures to immune phenotypes remains limited. We used phage-displayed immunoprecipitation sequencing (PhIP-seq) to profile antibody repertoires against 357,192 epitopes from >700 organisms in 62 age-matched healthy adults from rural Senegal ( n = 29), urban Senegal ( n = 20), and urban Netherlands ( n = 13). We identified two major patterns of variation: geographically restricted signatures distinguishing Senegal from the Netherlands and an ordered axis spanning rural Senegal, urban Senegal, and urban Netherlands. Rural populations were enriched for antibodies against Shigella species and human gammaherpesvirus 8, whereas urban populations showed higher responses against rhinovirus B and Neisseria meningitidis . Upon integration of PhIP-seq data with high-dimensional immunological profiling, the antibody repertoire trajectory correlated with a previously established rural-urban immune trajectory and ILC2 frequencies, IgG Fc galactosylation, and serum cytokines. These findings show that antibody repertoire profiling captures distinct microbial exposures across geographic regions.