Anti-Staphylococcus aureus immunotherapy: current status and prospects

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Immunological prophylaxis and therapy for Staphylococcus aureus are attractive goals. However, there is nothing currently available in the clinic. Several approaches have failed and more are being undertaken. Here we assess current progress and the potential for success.

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Introduction: Staphylococcus aureus, a ‘superbug’

S. aureus colonizes the nares and skin of approximately one-third of the human population [1] and causes a wide variety of diseases ranging from superficial skin lesions to life-threatening septicaemia. In healthcare settings it is the main pathogen responsible for infections of the skin and soft tissues, as well as for those associated with medical procedures and indwelling devices [2, 3]. S. aureus has developed resistance to multiple antibiotics, and its methicillin-resistant variant (MRSA)

Can staphylococci join the great medical success story of vaccination?

No immunological therapy and/or prophylaxis for S. aureus infections is available, but it might be possible as (i) previous infective exposure to the pathogen results in subsequent less severe infections; (ii) patients with higher anti-staphylococcal antibody levels are less likely to contract staphylococcal infections and (iii) a combined killed-whole bacteria plus toxoid vaccine showed 50–70% protection against bovine mastitis (see commentary [5]).

Historically, a variety of whole bacteria

If vaccine or immunotherapy becomes available, who should get it first?

High-risk groups for invasive S. aureus infections are those with dialysis dependence, organ transplantation, HIV infection, cancer or diabetes [6]. Within the community the risk is extended to collectives like long-term care patients, healthcare providers, military personnel and contact sport participants. In hospital, invasive infections are most common in patients undergoing surgery or those with indwelling medical devices [7, 8]. Additional risk groups are low birth weight (LBW) neonates

CP5 and CP8 polysaccharides [Nabi Biopharmaceuticals—StaphVax]

CP5 and CP8 capsular polysaccharides (CPs) of S. aureus have been conjugated to recombinant Pseudomonas aeruginosa exoprotein A (ETA). The conjugates are immunogenic in mice and rabbits, leading to sera opsonic for S. aureus [9]. Human immune IgGs obtained from CP5-ETA-immunized donors increased the survival of lethally challenged mice and prevented bacteraemia with a sublethal S. aureus challenge [10]. Purified anti-CP5-ETA rabbit antibodies were protective in a rat endocarditis model [11].

CP5 and CP8 polysaccharides [Nabi Biopharmaceuticals—Altastaph]

Altastaph is a hyperimmune polyclonal immunoglobulin preparation targeting CP5 and CP8 obtained from volunteers given Staphvax. In two Phase II clinical trials, one with LBW neonates and another with adults with persisting S. aureus bacteraemia and fever, no significant efficacy was observed [15, 16].

Lipoteichoic acid [Biosynexus—Pagimaximab]

Lipoteichoic acid (LTA) is a Gram-positive membrane-bound glycolipid that extends into the cell wall. Biosynexus (http://www.biosynexus.com) has developed a humanized mouse chimeric IgG1 monoclonal

Alpha-toxin

Alpha-toxin (or alpha-haemolysin, Hla) is a secreted pore-forming protein with cytotoxic and other properties. Mice, passively immunized with alpha-toxin (H35L mutant form) cross-reactive rabbit antiserum, were protected against alpha-toxin and alpha-toxin-producing S. aureus [26]. Vaccination with H35L or with the first 50 aminoacids of Hla has shown to reduce lethality in a murine model of pneumonia [27, 28]. Similar, results have been obtained following passive immunization with anti-H35L

Are we heading to multicomponent vaccines?

Variability in the prevalence and expression of virulence determinants by S. aureus suggests the use of highly conserved antigens and development of a multivalent vaccine. A single most prevalent serotype with significant disease-causing potential might, however, suffice for immunotherapeutic development, that is, the Hib vaccine against Haemophilus influenzae type b [45]. Whether such could be the case for S. aureus remains to be proven. Several authors have proposed multivalent vaccines as

Any more candidates or clever ideas?

Various screenings have revealed conserved proteins and peptides, expressed during infection and immunogenic, that can be added to the previous list of components amenable to an immunological approach [5•, 41•, 47]. Perhaps it is just the sheer amount of antibodies that might defeat S. aureus. However, caution must be applied as immunogenicity may not equate to protective efficacy. Importantly, S. aureus is quite ubiquitous in the human environment and has evolved to cope with immunological

Concluding remarks

The Phase III clinical trials completed thus far have failed to deliver a vaccine against S. aureus. Several of the clinical and pre-clinical trials have unveiled promising candidates based primarily on animal models. There are a plethora of animal models varying in physiopathology analyzed, staphylococcal and animal model species/strain used and so on. However, our knowledge of S. aureus pathogenesis in humans is rather preliminary and so it is difficult to predict how animal data will equate

References and recommended reading

Paper of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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