Staphylococcus aureus vaccines: Deviating from the carol

Abstract

Staphylococcus aureus, a commensal of the human nasopharynx and skin, also causes invasive disease, most frequently skin and soft tissue infections. Invasive disease caused by drug-resistant strains, designated MRSA (methicillin-resistant S. aureus), is associated with failure of antibiotic therapy and elevated mortality. Here we review polysaccharide-conjugate and subunit vaccines that were designed to prevent S. aureus infection in patients at risk of bacteremia or surgical wound infection but failed to reach their clinical endpoints. We also discuss vaccines with ongoing trials for combinations of polysaccharide-conjugates and subunits. S. aureus colonization and invasive disease are not associated with the development of protective immune responses, which is attributable to a large spectrum of immune evasion factors. Two evasive strategies, assembly of protective fibrin shields via coagulases and protein A-mediated B cell superantigen activity, are discussed as possible vaccine targets. Although correlates for protective immunity are not yet known, opsonophagocytic killing of staphylococci by phagocytic cells offers opportunities to establish such criteria.

Figure 1.

S. aureus CPs. (A) CP5 and CP8 have similar trisaccharide repeating structures that differ in glycosidic linkages and O-acetylation sites. (B) Genetic cap loci of S. aureus strains producing CP5 and CP8. Genes printed in color are responsible for the synthesis of serotype-specific modifications of CP. The diagram reveals the position of mutations in CP⁻ strains of the S. aureus USA300 and USA500 lineages (Boyle-Vavra et al., 2015). (C) Diagram illustrating the hypothesis that capsule-specific antibody may induce OPA, inducing uptake of S. aureus by neutrophils via FcγR or complement receptors.

Figure 2.

IsdB surface protein and heme-iron scavenging of S. aureus. Diagram illustrating the physiological role of IsdB in scavenging heme-iron from host hemoglobin and transferring this nutrient across the bacterial envelope, followed by iron release from heme in the bacterial cytoplasm. Antibodies against IsdB are thought to block heme-iron scavenging during infection (Kim et al., 2010b).

Figure 3.

S. aureus agglutination with fibrin as a defense against phagocytosis. Diagram illustrating the agglutination pathway. Staphylococcal Coa, a secreted protein, associates with factor II (FII, prothrombin). The resulting staphylothrombin complex removes fibrinopeptides A and B off fibrinogen to generate fibrin cables. ClfA, a staphylococcal surface protein, binds to fibrinogen and fibrin, thereby coating S. aureus with a fibrin shield for protection against host neutrophils. Antibodies against Coa or ClfA may prevent the association with FII and fibrin, respectively, thereby blocking staphylococcal agglutination and/or inducing OPA.

Figure 4.

Immune evasive attributes of SpA. SpA coats the surface of S. aureus and binds the Fcγ domain of antibodies to block their effector functions and inhibit opsonophagocytosis. Cell wall–anchored SpA is released from the bacterial surface by murein hydrolases and cross-links B cell receptors of V_H3 clonal B lymphocytes. SpA induces B cell proliferation and maturation into antibody-secreting cells (ASC) via a pathway requiring CD4 T cells, MHC class II activation, activation-induced cytidine deamination (AID), and somatic hypermutation (SHM) for the secretion of mature antibodies. SpA induces the secretion V_H3 clonal antibodies that are nonreactive to staphylococcal antigens. The B cell superantigen activity is dependent on the peptidoglycan modification of SpA and on RIPK2 signaling by immune cells.