Nontoxigenic protein A vaccine for methicillin-resistant staphylococcus aureus infections in mice

The current epidemic of hospital- and community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections has caused significant human morbidity, but a protective vaccine is not yet available. Prior infection with S. aureus is not associated with protective immunity. This phenomenon involves staphylococcal protein A (SpA), an S. aureus surface molecule that binds to Fcγ of immunoglobulin (Ig) and to the Fab portion of V_H3-type B cell receptors, thereby interfering with opsonophagocytic clearance of the pathogen and ablating adaptive immune responses. We show that mutation of each of the five Ig-binding domains of SpA with amino acid substitutions abolished the ability of the resulting variant SpA_KKAA to bind Fcγ or Fab V_H3 and promote B cell apoptosis. Immunization of mice with SpA_KKAA raised antibodies that blocked the virulence of staphylococci, promoted opsonophagocytic clearance, and protected mice against challenge with highly virulent MRSA strains. Furthermore, SpA_KKAA immunization enabled MRSA-challenged mice to mount antibody responses to many different staphylococcal antigens.