Staphylococcus aureus represents a serious infectious threat to global public health and a vaccine against S. aureus represents an unmet medical need. We here characterise two S. aureus vaccine candidates, coproporphyrinogen III oxidase (CgoX) and triose phosphate isomerase (TPI), which fulfil essential housekeeping functions in heme synthesis and glycolysis, respectively. Immunisation with rCgoX and rTPI elicited protective immunity against S. aureus bacteremia. Two monoclonal antibodies (mAb), CgoX-D3 and TPI-H8, raised against CgoX and TPI, efficiently provided protection against S. aureus infection. MAb-CgoX-D3 recognised a linear epitope spanning 12 amino acids (aa), whereas TPI-H8 recognised a larger discontinuous epitope. The CgoX-D3 epitope conjugated to BSA elicited a strong, protective immune response against S. aureus infection. The CgoX-D3 epitope is highly conserved in clinical S. aureus isolates, indicating its potential wide usability against S. aureus infection. These data suggest that immunofocusing through epitope-based immunisation constitutes a strategy for the development of a S. aureus vaccine with greater efficacy and better safety profile.

Staphylococcus aureus (S. aureus) is associated with a significant disease burden causing life-threatening diseases, such as deep wound infections, bacteremia, endocarditis, pneumonia, osteomyelitis, and enterotoxin-mediated shock. Antibiotic resistance, specifically methicillin-resistant Staphylococcus aureus (MRSA), is widespread and of aggravating concern. Although vaccination strategies against S. aureus have attracted much attention in basic and clinical research, no S. aureus vaccine is currently available. Specific challenges to development of a S. aureus vaccine include low immunogenicity of pathogen-derived antigens, a lack of natural immunity to S. aureus, multiple virulence and immune evasion factors as well as redundant nutrition acquisition pathways. All of these challenges compromise a straightforward strategy to delineate a correlate of protection.

In general, neutralising antibodies inhibiting pathogen interaction with or entry into host cells or detoxifying virulence factors represent a dominant principle of protection provided by vaccines. For instance, due to nasal colonization most adult humans have high levels of circulating antibodies against many staphylococcal antigens which seem to provide some protection against invasive infection with S. aureus Classical vaccine approaches, targeting S. aureus toxins for neutralisation or surface antigens for production of opsonising antibodies, have not worked against S. aureus in clinical trials. Similarly, the targeting of S. aureus proteins serving important roles in host-pathogen interactions, including adhesion to host cells, binding to and degradation of extracellular matrix proteins, iron-uptake or intervention with the host fibrinolytic system remained unsuccessful. Preclinical and clinical data repetitively indicate that although immunisation with S. aureus antigens usually results in high antibody titers, this does not confer protection against S. aureus infections.

Induction of a high-titered antibody response by a vaccine is not tantamount to protection and may even be detrimental by causing immune enhancement of disease, which is well known for vaccines against viral pathogens. For example, Song and coworkers recently identified a linear B-cell epitope on the prM protein of dengue virus as a major immunodominant B-cell epitope involved in antibody-dependent enhancement of dengue virus infection8. Although vaccine-mediated immune enhancement has not been an obvious safety concern for S. aureus vaccine development, the knowledge of protective, non-protective and disease enhancing B-cell epitopes represents a strategy for refined vaccine development. In this respect, the use of monoclonal antibodies (mAbs) to design new vaccines has been previously proposed by Burton9. Monoclonal Abs are now an integral part of the ‘reverse vaccinology 2.0’ concept, where mAbs are used to distinguish protective from non-protective epitopes and to support immunofocused antigen design. An epitope-focused vaccine is anticipated to improve its immunogenic precision level, resulting in a vaccine with a greater efficacy and safety profile. Indeed, an epitope-focused strategy has been successfully employed for the development of a vaccine against RSV that has resisted traditional vaccine development in the past.

Conclusion

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