Protein A-specific monoclonal antibodies and prevention of staphylococcus aureus disease in mice

Staphylococcus aureus is a leading cause of human soft tissue infections and bacterial sepsis. The emergence of antibiotic-resistant strains (methicillin-resistant S. aureus [MRSA]) has prompted research into staphylococcal vaccines and preventive measures. The envelope of S. aureus is decorated with staphylococcal protein A (SpA), which captures the Fcγ portion of immunoglobulins to prevent opsonophagocytosis and associates with the Fab portion of V_H3-type B cell receptors to trigger B cell superantigen activity. Nontoxigenic protein A (SpA_KKAA), when used as an immunogen in mice, stimulates humoral immune responses that neutralize the Fcγ and the V_H3⁺ Fab binding activities of SpA and provide protection from staphylococcal abscess formation in mice. Here, we isolated monoclonal antibodies (MAbs) against SpA_KKAA that, by binding to the triple-helical bundle fold of its immunoglobulin binding domains (IgBDs), neutralize the Fcγ and Fab binding activities of SpA. SpA_KKAA MAbs promoted opsonophagocytic killing of MRSA in mouse and human blood, provided protection from abscess formation, and stimulated pathogen-specific immune responses in a mouse model of staphylococcal disease. Thus, SpA_KKAA MAbs may be useful for the prevention and therapy of staphylococcal disease in humans.