BK virus-neutralizing antibodies converge on a shared site of vulnerability on VP1

BK virus is a human polyomavirus that infects approximately 80% of adults and establishes lifelong latency. Although primary infection is typically asymptomatic, viral reactivation in kidney transplant recipients can cause BK virus-associated nephropathy, leading to graft dysfunction and rejection. Despite the clinical severity of viral reactivation, antiviral treatment options remain limited. Notably, high serum titers of BK virus-neutralizing antibodies are associated with reduced BK virus DNAemia in kidney transplant recipients, suggesting an important role for humoral immunity in controlling viral replication. Here, we curated a comprehensive database of human antibodies targeting the major capsid protein VP1 by integrating previously reported sequences with newly generated data. Sequence analysis revealed only limited convergence among these antibodies. Nevertheless, functional and biochemical characterization showed that most neutralizing antibodies compete for overlapping epitopes, indicating convergence on a common antigenic site within the receptor-binding cleft of VP1. Together, these findings define an immunodominant site of vulnerability on the BK virus capsid and provide a mechanistic basis for the rational design of vaccines and antibody-based therapies. IMPORTANCE: BK virus (BKV) reactivation is a common complication in kidney transplant recipients, yet no approved antivirals are currently available. The standard of care consists of reducing immunosuppressive therapy, which carries an inherent risk of graft rejection. Antibodies represent promising therapeutic agents for the prevention and treatment of viral infections, particularly when effective vaccines are unavailable. Elucidating the dominant mechanisms of antibody-mediated protection is crucial for guiding the design and optimization of antibody-based therapies. In this study, we identify novel potent neutralizing antibodies against BKV, compare them with previously reported monoclonal antibodies (mAbs), and demonstrate that they compete for binding. Our findings show that most neutralizing mAbs converge on the receptor-binding cleft of VP1, identifying this region as both a major site of vulnerability and a hotspot for immune-driven viral escape, with important implications for therapeutic design.