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Sadowska, B. S. aureus Infections as a Challenge to Vaccinology. Encyclopedia. Available online: https://encyclopedia.pub/entry/19395 (accessed on 06 December 2025).
Sadowska B. S. aureus Infections as a Challenge to Vaccinology. Encyclopedia. Available at: https://encyclopedia.pub/entry/19395. Accessed December 06, 2025.
Sadowska, Beata. "S. aureus Infections as a Challenge to Vaccinology" Encyclopedia, https://encyclopedia.pub/entry/19395 (accessed December 06, 2025).
Sadowska, B. (2022, February 13). S. aureus Infections as a Challenge to Vaccinology. In Encyclopedia. https://encyclopedia.pub/entry/19395
Sadowska, Beata. "S. aureus Infections as a Challenge to Vaccinology." Encyclopedia. Web. 13 February, 2022.
S. aureus Infections as a Challenge to Vaccinology
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This entry is adapted from the peer-reviewed paper 10.3390/ijms23020948

Staphylococcus aureus is a Gram-positive pathogenic bacterium that may be found on the skin and mucous membranes of humans and several animal species. S. aureus colonizes the nares or nasopharynx of about 30% of a population in an asymptomatic manner and becomes pathogenic after breaching epithelial barriers, making colonization an important risk factor. Typical staphylococcal infections range from minor skin and soft tissue infections, such as abscesses, furuncles and impetigo, to life threatening diseases, such as bacteremia, infective endocarditis, sepsis and toxic shock syndrome. S. aureus is also a leading causative agent in surgical site infections, biomaterial-associated infections (e.g., catheters, artificial heart valves, bone and joint prostheses) and food poisoning. Epidemiological data show that S. aureus bacteremia leads to approximately 20,000 deaths a year in the USA, which accounts for more deaths than those from AIDS, tuberculosis and viral hepatitis combined together. Furthermore, patients with risk factors (e.g., diabetics, immunocompromised, transplant recipients, oncological patients) are prone to developing severe staphylococcal infections.

Staphylococcus aureus staphylococcal virulence factors vaccines antimicrobial resistance

1. Introduction

Over many decades it has been established that, thanks to vaccines, efficient hygiene procedures and antibiotics, successful treatment and limitation of infectious diseases spread can be easily achieved. Indeed, the discovery and use of antibiotics, considered one of the greatest advances in medicine, was, in the beginning, a very promising direction. Unfortunately, their widespread and not always proper use in medicine, veterinary, livestock breeding and agriculture contributes to a growing phenomenon of antimicrobial resistance (AMR). As a result, treatment options for the most severe infections have gradually decreased over the years. Considering the above, it is strongly justified return greater attention once again to the improvement of specific (immune) prevention, i.e., protective vaccinations, and immunotherapy[1].
Ten years ago, the World Health Assembly endorsed the Global Vaccine Action Plan (GVAP) for 2011–2020. It assumed to reduce the number of global deaths due to infectious diseases by ten times (25 million people). However, the analysis by the Strategic Advisory Group of Experts on Immunization (SAGE) of the World Health Organization (WHO) showed this goal was not met because of many reasons. In addition, the COVID-19 pandemic situation has contributed significantly to the slowing down of the ability to achieve the GVAP targets. According to the experts, in order to extend the beneficial impact of vaccines and vaccination on global health, new vaccines for other diseases, as well as improved supply and delivery mechanisms, need to be developed [2].
Based on the information provided by the WHO, the list of infectious diseases/etiological agents targeted for vaccination and globally available comprises 16 items with the prevalence of viruses. Novel cell targets pending the urgent modification of the composition of current antibacterial vaccines or the development of an entirely new framework and formulations are needed. The list of such vaccines includes those against the bacteria: Bordetella pertussis, Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae [3][4][5][6]. Furthermore, the inventory of new “neglected” species of bacteria or those for which no vaccine has been developed, despite attempts, is also long and includes: Group A, B Streptococcus (S. pyogenes, S. agalactiae), invasive non-typhoid Salmonella (iNTS), Shigella sp., Pseudomonas aeruginosa, Acinetobacter sp., Clostridioides difficile, and Staphylococcus aureus. Although many different vaccine formulations have been proposed to prevent infections caused by these pathogens, no successful phase III clinical trial data have been published yet. The multiple virulence mechanisms that a vaccine should target are among the numerous other possible reasons for the failure to develop such vaccines [1][2][7][8].

2. S. aureus Infections as a Challenge to Vaccinology: Why Is It Important?

Staphylococcus aureus is the most common human pathogen, causing a wide variety of nosocomial and community-acquired infections: from mild, usually self-limiting skin and soft tissues infections to severe,  systemic infections [9][10][11][12]. In healthcare settings, S. aureus spreads rapidly, not only due to transmission from patients or medical staff, but also due to the ability of these microorganisms to survive on abiotic surfaces, including hospital equipment and medical biomaterials [13]. Treatment of staphylococcal infections is particularly problematic due to the constantly increasing acquisition of resistance genes and selection of antibiotic resistant S. aureus strains. Both community- and hospital-acquired methicillin-resistant S. aureus (CA-MRSA, HA-MRSA), representing multidrug-resistant strains (MDR), spread very quickly [12][14][15]. Finally, during the infection process, the staphylococci frequently form biofilms on both the inserted/implanted biomaterials and host tissues, which once established are difficult to eradicate and tend to recur. This is due to the multifactorial tolerance/resistance of biofilms, which results in a weakened effect of antimicrobial drugs and impaired function of the host defense mechanisms [16].
The success of S. aureus as a pathogen depends on its ability to produce multiple virulence factors simultaneously and to regulate their expression quickly in response to environmental changes. As shown in Table 1, these factors allow staphylococci adhesion to the cell membranes or extracellular matrix proteins/glycoproteins as well as invasion of the host tissues. Then, they make them capable of avoiding immune response (both innate and adaptive), which consequently leads to the spread of infection and serious damage throughout the body [17][18][19][20][21]. These multiple S. aureus virulence factors and the strategies of avoiding host immune response contribute to huge difficulties in both treating staphylococcal infections and developing preventive options such as vaccines or immune therapy.
Table 1. The most important virulence factors of S. aureus and their targets during infection [17][18][19].
Type of Virulence Factor Name Target Effect
Cell wall-associated factors Cell wall components—peptidoglycan, teichoic acid, lipoteichoic acid Immune cells, other tissues Stimulate immune cell activation and inflammatory response; participate in adhesion and biofilm formation
Staphylococcal protein A (SpA) IgG, IgM, complement Binds Fc region of IgG and IgM, thus inhibiting opsonization and phagocytosis; activates B cells
Fibronectin-binding proteins (FnBPA, FnBPB) Fibronectin, fibrinogen, elastin, plasminogen, keratin, complement Binding to extracellular matrix proteins (ECM), enable adhesion to host tissues and biomaterials; limit phagocytosis and complement activation
Collagen-binding protein (Cna) Cartilage and collagen-rich tissues, complement Binding cartilage and collagen, enables adhesion to host tissues; inhibits complement activation
Clumping factors (ClfA, ClfB) Fibrinogen, blood platelets, complement (ClfA), cytokeratin 10 (ClfB) Binding to fibrinogen, enables adhesion to host tissues; inhibit complement preventing opsonization and phagocytosis; activate platelets
Serine-aspartate repeat protein E (SdrE) Complement Inhibits complement preventing opsonization and phagocytosis
Iron-regulated
surface determinant proteins
(IsdA, IsdB)		 Heme-iron Heme uptake and iron acquisition contribute
to increased pathogenesis, tissue invasion and abscess formation
Polysaccharide intercellular adhesion/polymeric N-acetyl-glucosamine (PIA/PNAG) Staphylococcal cells, mucous membranes, other tissues, abiotic surfaces Participates in bacterial aggregation, adhesion and biofilm formation (major component of biofilm matrix); reduces phagocytosis
Capsular polysaccharides Mucous membranes, other tissues, abiotic surfaces Reduce phagocytosis; increase the efficiency of colonization and durability on the surface of mucous membranes or biomaterials
Enzymes Catalase Hydrogen peroxide Catalyzes breakdown of hydrogen peroxide into water and oxygen, preventing oxidative stress
Coagulase Prothrombin Reacts with prothrombin, allowing fibrinogen polymerization and clot formation, thus reducing phagocytosis
Staphylokinase (SAK) Plasminogen Converts plasminogen to active serine protease plasmin, which promotes degradation of ECM, complement and IgG
Lipases Lipids of cell membranes and components of sebum Decompose lipids, which allows spreading of staphylococci
Nucleases Nucleic acids Degrade nucleic acids, thereby releasing them from extracellular traps (ETs)
Proteases, e.g., serine protease V8 (SspA), staphopain A (Scp A) and B (SspB), aureolysin (Aur) ECM proteins, complement, mucins, pulmonary surfactant Degrade ECM proteins, mucins and pulmonary surfactant, which allow staphylococcal spread in the host tissues; inhibit chemotaxis and phagocytosis by proteolysis of immune cell receptors; degrade complement preventing opsonization and lysis of bacteria; degrade antimicrobial peptides
Superoxide dismutases Superoxide Convert superoxide to hydrogen peroxide and oxygen, thereby preventing oxidative stress
Toxins Hemolysins (alpha, beta, gamma, delta) Erythrocytes, platelets, leukocytes Cause lysis of red blood cells, platelets, leukocytes—evading of host immune response; bacterial spreading
Enterotoxins Enterocytes, lymphocytes T Cause diarrhea; after translocation into blood, activate lymphocytes T leading to cytokine storm
Exfoliative toxins Desmosomes between keratinocytes Cleave the granular layer of the epidermis by damaging desmosomes (staphylococcal scalded skin syndrome)
Panton-–Valentine leukocidin (PVL) Neutrophils, monocytes, macrophages Causes lysis of neutrophils, monocytes, macrophages—avoiding innate immune response; development of necrotic changes
Toxic shock syndrome toxin 1 (TSST-1) Lymphocytes T Activates lymphocytes T, which causes massive production of cytokines and leads to toxic shock syndrome
Other secreted proteins Chemotaxis inhibitory protein of Staphylococcus (CHIPS) Neutrophils Binds to cell receptors (FPR1 and C5aR) inhibiting neutrophils chemotaxis, thereby preventing phagocytosis
Staphylococcal complement inhibitor (SCIN) Complement (C4, C3b) Inhibits complement activation, thus preventing bacterial lysis, opsonization and phagocytosis
SSL-5 Neutrophils, platelets Binds to cell receptors (PSGL-1 and GPCRs) inhibiting neutrophil diapedesis and activation; activates platelets (aggregate formation)
SSL-7 IgA, complement (C5) Binds Fc region of IgA and complement protein C5, thus blocking antibodies and inhibiting complement activation
Extracellular fibrinogen-binding protein (Efb) Fibrinogen, blood platelets, complement Binds fibrinogen enabling adhesion and aggregation: interferes with platelet aggregation; inhibits complement activation
Extracellular adherence protein (Eap) ICAM-1 Binds ICAM-1 inhibiting neutrophil rolling and migration (diapedesis)

3. Past and Present in Active Immunization against  Staphylococcal Infections

A wide repertoire of S. aureus adhesive molecules, toxins and enzymes seems to be an excellent starting point to choose proper antigens for vaccine development. Conversely, such diversity allows these bacteria to avoid the activity of specific antibodies by replacing one virulence factor with another during a regular life
cycle or by using toxins and enzymes to dampen the immune response. The first vaccine programs targeting single S. aureus virulence factors ended in failure. The vaccine containing iron surface determinant B (IsdB), necessary for iron acquisition, did not pass the safety tests [22]. The StaphVax vaccine, comprising two predominant staphylococcal capsular polysaccharide (CP) serotypes (CP5 and CP8) conjugated to the recombinant Pseudomonas aeruginosa exoprotein A, was one of the first bivalent preparations developed; it achieved phase III efficacy studies and failed [7][23]. Therefore, multivalent anti-staphylococcal vaccines containing a few different antigens targeting multiple virulence mechanisms started to be developed. The CP5 and CP8 (each conjugated to CRM197), a recombinant clumping factor A (rClfA) and, additionally, a recombinant lipoprotein rP305A obtained from a manganese transporter C (MntC) were used as the target antigens in the 3-antigen (SA3Ag) and 4-antigen S. aureus vaccine (SA4Ag), respectively. Both vaccines offered acceptable safety and tolerability, and induced a rapid and robust immune response leading to a generation of functional specific antibodies against all antigens used [24][25][26].

The current paradigm for vaccine development is targeting multiple staphylococcal virulence factors, considering both the surface antigens and secreted biologically active substances. An example of such a complex preparation is the S. aureus toxoid vaccine, containing modified bi-component pore-forming toxins: the S and F subunits of PVL and alpha hemolysin (Hla), as well as the fusion toxoid TBA225 of superantigens (SEA, SEB and TSST-1). The toxoid vaccine was tested in the non-human primate model (rhesus macaques) and described as safe, well tolerated and immunogenic [27]. A new trend in vaccine development is also “epitope-focused immunization”. Klimka et al. [28] suggested narrowing the composition of antistaphylococcal vaccine to small epitopes of coproporphyrinogen III oxidase (CgoX) and triose phosphate isomerase (TPI), which are highly conserved among S. aureus clinical strains. The new approaches, such as reverse vaccinology, novel adjuvants, structural vaccinology, bioconjugates and rationally designed bacterial outer membrane vesicles (OMVs), seem also promising. 

References

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