Utilization of Staphylococcal Immune Evasion Protein Sbi as a Novel Vaccine Adjuvant

• Published in: Frontiers in immunology Vol. 9; p. 3139
• Main Authors: Yang, Yi, Back, Catherine R, Gräwert, Melissa A, Wahid, Ayla A, Denton, Harriet, Kildani, Rebecca, Paulin, Joshua, Wörner, Kristin, Kaiser, Wolgang, Svergun, Dmitri I, Sartbaeva, Asel, Watts, Andrew G, Marchbank, Kevin J, van den Elsen, Jean M H
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 11-01-2019
• Subjects: Acyltransferases - genetics; Acyltransferases - immunology; adjuvant; Adjuvants, Immunologic - chemistry; Adjuvants, Immunologic - genetics; Animals; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - immunology; Carrier Proteins - chemistry; Carrier Proteins - genetics; Carrier Proteins - immunology; complement; Disease Models, Animal; Immune Evasion; Immunization; Immunology; Mice; Mice, Knockout; Models, Molecular; Protein Conformation; Recombinant Fusion Proteins - immunology; Staphycoccus aureus; Staphylococcal Infections - immunology; Staphylococcal Infections - prevention & control; Staphylococcal Vaccines - immunology; Staphylococcus - immunology; Structure-Activity Relationship; vaccine; vaccine; Staphycoccus aureus; immune evasion; complement; adjuvant
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2018.03139

Co-ligation of the B cell antigen receptor with complement receptor 2 on B-cells via a C3d-opsonised antigen complex significantly lowers the threshold required for B cell activation. Consequently, fusions of antigens with C3d polymers have shown great potential in vaccine design. However, these linear arrays of C3d multimers do not mimic the natural opsonisation of antigens with C3d. Here we investigate the potential of using the unique complement activating characteristics of Staphylococcal immune-evasion protein Sbi to develop a pro-vaccine approach that spontaneously coats antigens with C3 degradation products in a natural way. We show that Sbi rapidly triggers the alternative complement pathway through recruitment of complement regulators, forming tripartite complexes that act as competitive antagonists of factor H, resulting in enhanced complement consumption. These functional results are corroborated by the structure of the complement activating Sbi-III-IV:C3d:FHR-1 complex. Finally, we demonstrate that Sbi, fused with
antigen Ag85b, causes efficient opsonisation with C3 fragments, thereby enhancing the immune response significantly beyond that of Ag85b alone, providing proof of concept for our pro-vaccine approach.