A pan-serotype human monoclonal antibody protects against pneumococcal infection by targeting multiple choline binding domain proteins.

Streptococcus pneumoniae remains a global health threat, particularly to young children, the elderly, and immunocompromised individuals. Pneumococcal vaccines targeting the bacterial capsule polysaccharide do not protect against all 100+ pneumococcal serotypes, contributing to non-vaccine serotype infections and antibiotic resistance. To address these limitations, we isolated human monoclonal antibodies (mAbs) targeting pneumococcal surface proteins and identified a first-in-class mAb, derived from a patient with prior pneumococcal infection, namely mAb 5995-40. mAb 5995-40 bound multiple pneumococcal proteins, including PcpA and PspA, through a conserved choline-binding domain shared across serotypes. Functionally, mAb 5995-40 provided complete protection in lethal pneumococcal challenge models and improved survival in influenza A, influenza B, and respiratory syncytial virus-associated bacterial coinfection models. Mechanistic studies showed enhanced opsonophagocytic killing, reduced bacterial dissemination, and blocked epithelial translocation. Cryo-electron microscopy identified a repeating motif within the choline-binding domain targeted by mAb 5995-40, highlighting its potential as a broadly protective pneumococcal therapeutic.