A protein A based Staphylococcus aureus vaccine 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 com-plement activation, destroy phagocytes, and modify B and T cell responses. One such factor, Staphylococcal protein A (SpA) encompasses five Immunoglobulin binding domains (IgBDs) that associ-ate with the Fcc domain to block phagocytosis. IgBDs also associate with Fab encoded by V(H)3 clan related genes. SpA binding to V(H)3-IgM that serves as a B cell receptor results in B cell expansion and secretion of antibodies with no specificity for S. aureus. SpA crosslinking of V(H)3-IgG and V(H)3-IgE bound to cognate receptors of mast cells and basophils promotes histamine release and anaphylaxis. Earlier work devel-oped a prototype variant SpA(KKAA) with four amino acid substitutions in each IgBD. When tested in animal models, SpA(KKAA) elicited neutralizing antibodies and protection against infection. We show here that SpA(KKAA) retains crosslinking activity for V(H)3-IgG and V(H)3-IgE. We use a rational approach to design and test 67 new SpA variants for loss of V(H)3 binding and anaphylactic activities. We identify two detox-ified candidates that elicit SpA-neutralizing antibodies and protect animals from S. aureus colonization and bloodstream infection. The new detoxified SpA candidates bear three instead of four amino acid sub-stitutions thus increasing the development of SpA-specific antibodies. We propose that detoxified SpA variants unable to crosslink V(H)3-idiotypic immunoglobulin may be suitably developed as clinical-grade vaccines for safety and efficacy testing in humans. (C) 2021 Elsevier Ltd. All rights reserved.

Automated summary

Exposure to Staphylococcus aureus does not lead to immunity due to immune escape mechanisms including factors like Staphylococcal protein A (SpA). Developing a prototype variant SpA eliciting neutralizing antibodies provides protection against infection in animal models. Detoxified SpA variants devoid of crosslinking V(H)3-idiotype immunoglobulin may be suitable for developing clinical-grade vaccines for safety and efficacy testing in humans.