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Expert Commentary & Five-year View
Vaccine development to combat S. epidermidis infections is still in its infancy. Hitherto, most efforts were aimed at reducing S. epidermidis infections in low-birthweight neonates resulting in antibody preparations, Veronate® (INH-A21, Inhibitex Inc.) and pagibaximab (BSYX-A110, Biosynexus Inc.), which were both assessed in clinical studies. A relatively small number of studies, however, have been published about immunologic approaches to control S. epidermidis implant-related infections. As a ubiquitous, protective skin colonizer and, at the same time, an extremely versatile, opportunistic pathogen, S. epidermidis confronts researchers with enormous challenges. Infection-linked targets that are not involved in the commensal lifestyle and that will evoke an immune response different from the antibodies already present in healthy individuals have to be identified.
The growing insight into S. epidermidis virulence, including the multifactorial biofilm formation process and its regulation, together with the application of new technologies such as reverse vaccinology, epitope mapping, antigenome and immunome analyses, constantly enlarges the pool of possible vaccine targets. In-depth in vitro and in vivo research on S. epidermidis virulence factors and immune evasion is irrefutably required to further unravel virulence mechanisms and to identify 'Achilles heel' factors in S. epidermidis infections.
Variability in the prevalence and expression of infection-related S. epidermidis factors definitely necessitates the development of multivalent vaccines, comprising highly conserved antigens expressed at some stage of infection. An ideal S. epidermidis vaccine should prevent cell–biomaterial interaction and eliminate cells shed by a formed biofilm. A conjugated recombinant vaccine combining MSCRAMM, proteinaceous intercellular adhesin and PSM epitopes with PIA, preferably deacetylated, would probably provide broader efficacy than the respective univalent vaccines. Inclusion of PIA, PGA or other factors common among staphylococci might provide cross-protection against other infection-causing staphylococci. However, combining epitopes does not necessarily result in synergistic immunoprotective effects as reported for the mix of anticapsular polysaccharide and anti-PIA antibodies targeting S. aureus infections. Hence, the finding of an effective multivalent S. epidermidis vaccine will depend on defining the best epitope combination resulting in a vaccine with high protective capacity against many staphylococcal strains.
As concerns passive immunization, dual antibody conjugates (or heteropolymers) resembling ETI-211 from Elusys Therapeutics Inc. (NJ, USA) against blood-borne S. aureus infections might be an option. This heteropolymer consists of an anti-protein A mAb linked to a mAb directed against the human complement receptor CR1. It evoked a superior protection against S. aureus challenge compared with anti-protein A mAb alone, probably due to the rapid, complement-independent clearance of the bacterium. Recent progresses made in the field of humanized antibodies minimize safety concerns.
Combination therapies of antibiofilm antibodies and antibiotics could be an opportunity to hinder biofilm development and to keep cells in suspension, rendering them more susceptible to antibiotic activity and immune responses.
In addition to immunoprophylaxis, preventive measures to control the spread of drug-resistant S. epidermidis clones comparable to those preventing spread of methicillin-resistant S. aureus should be considered. Surveillance of biofilm-forming, drug-resistant S. epidermidis in healthcare personnel and high-risk patients will definitely help to further reduce S. epidermidis hospital-acquired infections.
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