Bacterial Infections
Staphylococcal infection
Disease burden
Staphylococcus aureus is an opportunistic bacterial pathogen associated with asymptomatic colonization of the skin and mucosal surfaces of normal humans. However, it also is the cause of wound infections and has the potential to induce osteomyelitis, endocarditis and bacteremia, leading to infections in any of the major organs of the body. It also is responsible for many serious community- and nosocomially- acquired infections, being the most frequently isolated bacterial pathogen from patients with hospital-acquired infections, especially patients with implants or prosthetic devices
[78]
. Although there are considerable knowledge gaps in staphylococcal disease burden in the tropics, recent data from Thailand show similar clinical manifestations and endocarditis prevalence, with higher mortality than industrialized countries
[79]
.
Asymptomatic S. aureus colonization occurs intermittently in children and adults, most commonly in the anterior nasal vestibule, and occasionally on the skin, hair, nails, axillae, perineum, and vagina. Invasive infections of the skin occur in previously healthy individuals, ranging from impetigo to abcess formation, cellulitis and lymphadenitis. Ocular infections include conjunctivitis and endophtalmitis. S. aureus is a frequent cause of endocarditis with possible complications of pericarditis, respiratory tract infections, osteomyelitis and septic arthritis. According to a current estimate, S aureus is responsible for 25% to 35% of endocarditis cases
[80]
. Most often, S. aureus infections are associated with medical insertion of foreign metal, plastic or Gore-Tex devices such as those used for hemodialysis, venous catheterization, or artificial prostheses. Postoperation staphylococcal disease is a constant threat to the convalescence of hospitalized surgical patients, especially in view of the increased use of prosthetic devices and indwelling catheters.
S. aureus also is the cause of a number of toxinoses, including toxic shock syndrome (TSS), food poisoning, scalded skin syndrome and necrotizing pneumonia. Staphylococcal food intoxication is the result of the presence and multiplication of S aureus in food, most often transmitted by the hands of food-handlers. Several enterotoxins are involved including the heat-stable staphylococcal enterotoxin. TSS is caused by strains of S aureus which produce the toxic shock syndrome toxin 1. It frequently is associated with menses, most of the times with the use of vaginal tampons, vaginal contraception sponges or diaphragms.
Before the introduction of antimicrobials in the 1940s, the mortality rate of S. aureus invasive infection was about 90%. The initial success of antibiotherapy was rapidly countered by the successive emergence of penicillin-resistant, then methicillin-resistant S. aureus (MRSA) strains
[81]
[82]
, and since 2002 by that of vancomycin-resistant strains
[83]
. MRSA isolates most often are multidrug resistant. In view of its importance as a cause of community-acquired infections
[84]
, the development of antibiotic resistance in S. aureus is a strong incentive that spurs vaccine development. The same is true in veterinary medicine, where S aureus is an important cause of infections in animals, especially of mastitis in dairy cattle
[85].
Bacteriology
The virulence of S. aureus is due to a combination of numerous virulence factors, which include surface-associated proteins that allow the bacterium to adhere to eukaryotic cell membranes, a capsular polysaccharide (CP) that protects it from opsonophagocytosis, and several exotoxins among which ?-hemolysin, which lyses erythrocytes, necroses skin, and causes the release of cytokines that may produce shock; toxins A and B, which cause the sloughing of skin that characterizes the scalded skin syndrome; the toxic shock syndrome toxin-1 (TSST-1) which is responsible for most TSS cases, especially those associated with menses; and enterotoxins that cause vomiting and diarrhoeas when ingested and are responsible for food poisoning. Enterotoxins and TSST-1 have superantigen activity, which results in a massive release of cytokines that is responsible for the clinical picture of TSS. Case fatality rates in some S. aureus infections today still can reach 30%.
Serotyping studies of staphylococcal isolates helped reveal at least eight putative capsular serotypes, with types 5 and 8 (CP5 and CP8) accounting for ~25% and 50% of isolates recovered from humans, respectively
[86]
[87]
.
The same isolates also were recovered from poultry, cows, horses and pigs
[88]
[89]
. Expression of CP is highly sensitive to environmental factors, such as bacterial growth conditions. Thus, staphylococci harvested in the log phase of growth express little or no CP
[90]
. Paradoxically, CP production attenuated staphylococcal virulence in a rat model of catheter-induced endocarditis
[91]
, suggesting that the S aureus binding domain for endothelial cells may be masked by the presence of CP
[87]
.
Numerous staphylococcal virulence factors have been described, including hemolysins alpha
[92]
beta, gamma and delta, which hemolyse erythrocytes, necrose skin and cause the release of cytokines that can produce a shock syndrome, coagulase, which binds to host prothrombin, activates thrombin and results in the formation of fibrin from fibrinogen
[93]
, and clumping factors ClfA and ClfB, which bind fibrinogen
[94].
Vaccines
Substantial controversy exists as to whether S. aureus infections may be prevented by a vaccination approach, and, if so, which antigens should be selected and which patients should be targeted for vaccination. An early attempt at using a killed whole-cell vaccine combined with an ?-hemolysin toxoid was a failure, as no protection could be observed against peritonitis, catheter-associated infection or asymptomatic carriage in patients undergoing continuous ambulatory peritoneal dialysis.
Attention then shifted to the S. aureus capsular polysaccharide (CP). Type 5 and 8 CP conjugated to a detoxified recombinant Pseudomonas aeruginosa exotoxin A carrier were shown to be highly immunogenic and protective in a mouse model
[95]
[96]
and passive transfer of the CP5-specific antibodies from the immunized animals induced protection against systemic infection in mice
[97]
and against endocarditis in rats challenged with a serotype 5 S aureus
[98]
. A bivalent CP5 and CP8 conjugate vaccine (StaphVAX, Nabi Biopharmaceutical) was developed that provided 75% protection in mice against S. aureus challenge. The vaccine was tested on humans in a double blind, Phase III clinical trial on 1850 end-stage renal disease (ESRD) patients in hemodialysis: a 60% efficacy was observed for up to 10 months following vaccination but the figure dropped to 26% at 1 year, mirroring the decline in antibody levels
[99]
[100]
[101]
. A second Phase III trial was started on end-stage ESRD patients on hemodialysis who were vaccinated twice 8 months apart, but the vaccine was found not to be effective in that confirmatory trial
[102]
.
Immunization with poly-N-acetylglucosamine
[103]
or poly-N-succinyl glucosamine (PNSG)
[104]
, both S aureus surface carbohydrates, or with staphylococcal surface proteins such as clumping factor A (ClfA)
[105]
[106]
, clumping factor B (ClfB)
[107]
, iron-regulated surface determinant B (IsdB)
[108]
or fibronectin-binding protein (FnBP) together with ClfA
[109]
was shown to generate at least partial protection against S aureus challenge in experimental animal models. An IsdB-based vaccine is now in Phase II clinical trials.
The reverse vaccinology approach
[110]
[111]
which led to the identification of multiple conserved surface proteins in group B meningococci
[75]
(see above) and their eventual combination into a broad-spectrum vaccine candidate, was also used to identify surface proteins of S aureus and test their capacity to generate protective immune responses against invasive staphylococcal disease
[112]. Surface proteins ClfA, IsdA, IsdB, SdrD and SdrE were identified as generating the highest levels of protection against staphylococcal renal infection in mice. IsdA, IsdB, SdrD and SdrE were combined together into a candidate vaccine that induced high level opsonophagocytic antibodies in rabbits and generated protective immunity against lethal challenge infections with a variety of S aureus clinical isolates in mice
[112]
. This hopefully will pave the way to the development of a successful, multi-antigen vaccine that can protect humans at high risk for invasive S aureus infection.
Attempts were also made at developing immunotherapy products for passive anti-staphylococcal immunization (Nabi, Inhibitex and Biosynexus).