Epitope-resolved Epstein-Barr virus antibody mapping identifies disease-stratifying signatures in nasopharyngeal carcinoma

Epstein-Barr virus (EBV) infects most adults worldwide and usually persists without symptoms, yet in some individuals it is associated with malignancies such as nasopharyngeal carcinoma (NPC). How antibody responses to specific regions of EBV proteins differ between healthy individuals and patients with NPC remains incompletely understood. Here we show that epitope-resolved profiling of EBV antibodies reveals serological patterns associated with NPC development and clinical outcomes. We developed EBVScan, a quantitative phage-display platform covering 42 EBV isolates, to map IgA and IgG responses across the viral proteome. Multi-centre validation identified an antibody response to the TK139-194 region that distinguished NPC from controls with an area under the receiver operating characteristic curve of 0.97. We also identified antibody-reactive regions enriched in healthy individuals that overlapped known viral receptor-interaction interfaces, and selected peptides from these regions reduced EBV infection in vitro. In patients with NPC, baseline antibody signatures were additionally associated with chemotherapy response and progression-free survival. Together, these findings provide an epitope-resolved view of EBV-host immune interactions and identify serological features with potential applications in NPC detection and patient stratification. Here, the authors map antibody responses to Epstein-Barr virus protein regions, identifying signatures associated with nasopharyngeal carcinoma detection, chemotherapy response and progression-free survival.