A Protein A basedStaphylococcus aureusvaccine with improved safety

Exposure to Staphylococcus aureus does not lead to immunity as evidenced by the persistent colonization of one third of the human population. S. aureus immune escape is mediated by factors that preempt complement activation, destroy phagocytes, and modify B and T cell responses. One such factor, Staphylococcal protein A (SpA) encompasses five Immunoglobulin binding domains (IgBDs) that associate with the Fcγ domain to block phagocytosis. IgBDs also associate with the Fab domain of V H 3-idiotypic IgM which activates B cells with the resulting secretion of antibodies that cannot bind determinants of S. aureus . SpA crosslinking of V H 3-idiotypic IgG and IgE receptors of mast cells and basophils promotes histamine release and anaphylaxis. Previous work demonstrated the safety, immunogenicity, and protective efficacy of SpA KKAA, a variant partially defective for V H 3-idiotypic Ig cross-linking, in murine models of S. aureus . Compared to mice (10%), humans produce significantly more V H 3-idiotypic B cells (50%), prompting a search for safer SpA variants that may be suitably developed as clinical-grade vaccines for efficacy testing in humans. Here, we report the identification of such variants.