Immunoprophylaxis and Immunotherapy of Staphylococcus Epidermidis Infections

Table 1.  Explored and proposed Staphylococcus epidermidis vaccine targets.

Target	Function	Immunological tool	Observations/effects	R&D stage	Ref.
MSCRAMMs
SdrG (Fbe)	Fibrinogen binding Platelet adhesion and aggregation	Recombinant SdrG-N2N3 and His-SdrG-N1N2N3 Veronate® (INH-A21, Inhibitex Inc.): human polyclonal Igs against Staphylococcus aureus ClfA and S. epidermidis SdrG	Vaccination with both derivatives led to different protection against bacteremia Protection of late-onset sepsis by S. aureus and candidemia in very-low-birthweight neonates, however, without effect on CoNS infections Infection-related immune reaction to SdrG	Animal model Animal model Phase I–II Phase III (failed)	[79] [80] [81] [82] [73]
SdrF	Collagen binding	Anti-SdrF pAbs	Prevention of ventricular assist device driveline-related infections and other biomaterial-related S. epidermidis infections	Animal model	[84]
GehD	Collagen binding? Role in persistence to fatty acid skin secretions		Infection-related increase of anti-GehD IgG titer		[71]
Embp	Fibronectin binding Proteinaceous intercellular adhesin Evasion of macrophage phagocytosis	Anti-Embp pAbs	Abs show insufficiently opsonic activity in vitro		[37,75]
AtlE	Vitronectin binding Autolysin setting free DNA that contributes to the initial biofilm phase Involved in host cell internalization	Anti-AtlE pAbs	Infection-related increase of anti-Aae IgG titer Antibodies have opsonic capacity in vitro		[71]
Aae (ScaA)	Binding to vitronectin, fibrinogen and fibronectin Autolysin		Infection-related increase of anti-Aae IgG titer		[71]
Cell wall-associated proteins
SesC	Potential fibrinogen binding	Anti-SesC pAbs	Prevention of catheter-related infections	Animal model	[85,89]
SesI	Presence correlated with invasive capacity				[91]
Acetyl-CoA-acetyltransferase, Na+/H+antiporter, lipoate ligase, cysteine synthase, alanine dehydrogenase	Immunogenic and/or serum-binding cell wall-associated proteins	Recombinantly produced proteins used for active immunization	Prevention of bacteremia	Animal model	[69]
Intercellular adhesins
PIA (= PNAG)	Important compound of EPS Role in immune evasion	PIA-DT and dPIA-DT conjugates human mAbs against PIA and dPIA	Antibodies directed against deacetylated PIA are more effective than anti-PIA antibodies in bacterial killing		[93]
Aap	Corneocyte binding (role in commensal lifestyle) Proteinaceous intercellular adhesin (role in sessile lifestyle)	Anti-Aap pAb Anti-Aap mAbs mAbs 18B6, 20B9 and 25C11 (directed against AapBrpt1.5)	Inhibition of biofilm formation of PIA-negative strains in vitro Reduction of biofilm accumulation in vitro, however, no protection against catheter infection by ica-positive strain Inhibition of in vitro biofilm accumulation by 18B6, but enhanced biofilm formation in the presence of 20B9 and 25C11	Animal model	[33,34] [96] [97]
Bhp	Putative proteinaceous intercellular adhesin
Teichoic acids
LTAs	Role in biofilm initiation PAMP recognized by TLRs Role in immune evasion	Pagibaximab® (BSYX-A11): anti-LTA humanized mouse chimeric mAb (Biosynexus Inc.)	Prevention of neonatal bacteremia	Phase IIb/III	[99–102]
Cell wall teichoic acids	Fibronectin binding Role in initial biofilm phase				[27]
Others
PGA	Key factor for both skin colonization as it contributes to salt resistance, and for survival during biofilm-related infections by means of protection against antimicrobial peptides and neutrophil phagocytosis				[48]
PSMs	Modulins with versatile functions in biofilm formation and virulence. PSMγ: equal to δ-toxin PSMβs: important for biofilm dispersion	Anti-PSMβ pAb	Prevention of bacterial systemic dissemination from biofilm-related infection	Animal model	[40]

Ab: Antibody; CoNS: Coagulase-negative staphylococci; dPIA: Deacetylated PIA; DT: Diphtheria toxin; Embp: Extracellular matrix-binding protein; EPS: Extracellular polymeric substance; Ig: Immunoglobulin; LTA: Lipoteichoic acid; mAb: Monoclonal antibody; MSCRAMM: Microbial surface components recognizing adhesive matrix molecule; pAb: Polyclonal antibody; PAMP: Pathogen-associated molecular pattern; PGA: Poly-γ-dl-glutamic acid; PIA: Polysaccharide intercellular adhesin; PNAG: Poly-N-acetylglucosamine; PSM: Phenol-soluble modulin; TLR: Toll-like receptor.

Authors and Disclosures

Lieve Van Mellaert^*1; Mohammad Shahrooei²; Dorien Hofmans¹ and Johan Van Eldere<sup>2

1</sup>Laboratory of Bacteriology, Rega Institute for Medical Research, K.U.Leuven, Leuven, Belgium.
²Laboratory for Experimental and Clinical Microbiology, K.U.Leuven, Leuven, Belgium

Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

*Author for correspondence
Tel.: +32 16 337 375 Fax: +32 16 337 340 Lieve.VanMellaert@rega.kuleuven.be

Sidebar

Key Issues

• Staphylococcus epidermidisis an extremely versatile commensal species, which has become an opportunistic pathogen, occasionally causing infections in high-risk patients such as low-birthweight neonates, elderly and immunocompromised patients and emerging as the most frequent nosocomial agent related to chronic, persistent infections on indwelling biomaterials.

• Despite the paucity of obvious virulence factors, the amazingly adaptive capacity enables this opportunistic pathogen to deal with changing and possibly hostile environments. The success of this pathogen is further sustained by the presence of multidrug-resistant strains.

• Although biofilm formation is regarded as the most important virulence factor protecting the sessile bacteria against antibacterial compounds and host immune responses, S. epidermidisalso possesses alternative virulence factors, allowing it to invade host tissues and to evade host immune responses.

• The number of potential vaccine targets is constantly growing. One group of compounds envisaged are the microbial surface components recognizing adhesive matrix molecules that play a role in bacterial adhesion to the biomaterial. Other potential targets are factors that establish cell–cell interactions, including polysaccharide intercellular adhesin and proteinaceous intercellular adhesins. The list of explored or putative vaccine candidates also includes lipoteichoic acids, protective poly-γ-DL-glutamic acid and phenol-soluble modulins. Further research on virulence mechanisms and distinct biofilm formation processes will surely reveal still unknown infection-related factors, which might serve as good vaccine targets.

• A successful vaccine will most likely be multivalent. Ideally, it will interfere with different steps in biofilm formation, block specifically infection-related factors and enhance immune control. In addition, the use of conserved antigens common among staphylococci will guarantee a broad coverage of disease-causing staphylococci. Vaccines, together with preventive surveillance of multidrug-resistant S. epidermidisstrains in healthcare personnel and high-risk patients, will hopefully succeed in reducing S. epidermidisinfections and the costs involved.