A Fully Human Derived Monoclonal Antibody Provides Potent Pre- and Postexposure Protection Against Rabies Virus.

Rabies remains a critical global health concern, particularly in endemic regions where timely access to postexposure prophylaxis (PEP) is often limited. The effectiveness of PEP relies heavily on rabies immune globulin (RIG), yet plasma-derived products continue to face persistent issues of limited supply, variable potency, and high cost. These constraints have intensified the demand for recombinant monoclonal antibodies (mAbs) that provide consistent quality and scalable production. Here, we describe the development of a fully human mAb, H81L90, directed against the rabies virus glycoprotein (RABV-G). The antibody was isolated from a phage-display library constructed using peripheral blood mononuclear cells (PBMCs) from vaccinated donors. H81L90 exhibited strong, specific binding to native RABV-G with nanomolar affinity as determined by surface plasmon resonance (SPR) analysis. In cell-based neutralization assays, H81L90 efficiently blocked infection by the ERA-enhanced green fluorescent protein (EGFP) strain, achieving complete viral inhibition at low microgram concentrations. Protective efficacy was subsequently evaluated in a murine challenge model, where a single intramuscular injection of H81L90 conferred full survival when administered before or at the time of viral exposure and retained measurable activity at reduced doses postexposure. Histopathological assessment revealed substantially lower viral antigen in hippocampal tissue from treated animals, indicating suppression of early neuroinvasion. Collectively, these data establish H81L90 as a potent, fully human antibody with both preventive and postexposure prophylactic potential, supporting its continued development as a next-generation biologic to complement or replace current RIG formulations in rabies PEP.