Prospects for Active and Passive Immunization Against Staphylococcus aureus

Abstract

Transient asymptomatic colonization with Staphylococcus aureus, a hardy, Grampositive bacterium, is common, but S. aureus infection is also a frequent cause of community-acquired and nosocomial disease, and in a minority of cases it is associated with severe disease, including bacteremia, osteomyelitis, endocarditis, meningitis and abscess formation. S. aureus infections are relatively difficult to treat, and invasive disease and relapse may occur after antibiotic treatment. Treatment is made more difficult by the increasing number of strains that are resistant to multiple antibiotics. The problem of staphylococcal infections can be further complicated when the disease occurs in young infants, who have immature immunologic systems. S. aureus virulence is determined by a wide variety of factors that influence bacterial attachment to host cells, penetration into tissue and escape from host defenses. Some of these virulence factors have been investigated in vitro and in animals as products that might be suitable candidates for an S. aureus vaccine; a small number have been tested in humans. A vaccine that contains type 5 and type 8 polysaccharides each bound to recombinant (nontoxic) Pseudomonas aeruginosa exotoxin A (StaphVAX; Nabi Biopharmaceuticals) is the only staphylococcal vaccine to date that has been tested in a phase 3 clinical trial. Capsular polysaccharides act as virulence factors by reducing the ability of host polymorphonuclear neutrophils to opsonize the bacteria. Although 12 S. aureus capsular polysaccharides have been identified, types 5 and 8 have historically accounted for the majority of S. aureus disease; type 336, a newly identified capsular polysaccharide, is also appearing more frequently. Protein conjugation improves the poor immunologic response that follows immunization with polysaccharide alone. The randomized double blind phase 3 trial of StaphVAX enrolled adult patients with end stage renal disease who were receiving hemodialysis, a population that is at particular risk of developing severe S. aureus disease. Between April 1998 and August 1999, 1804 adult patients at 73 hemodialysis centers were randomly assigned to receive a single intramuscular injection of either vaccine or saline. IgG antibodies to S. aureus type 5 and 8 capsular polysaccharides were measured for up to 2 years, and episodes of S. aureus bacteremia were recorded. At 54 weeks, the study end point, the number of subjects developing bacteremia was not significantly different between vaccine (27 of 892) and control groups (37 of 906), subjects who received vaccine did have a significantly lower rate of bacteremia through week 40, when antibody levels were estimated to be 80 g/mL. This antibody level thus represents a crude correlate of protection. Seventy-nine subjects who received StaphVAX in this study were enrolled in a follow-on trial that investigated use of a booster dose 2–3 years after original vaccination. Although peak levels were lower after the booster dose than after initial vaccination, antibody levels declined more slowly than after initial vaccination and were maintained above the estimated protective level for 6 months after the booster dose. Thus antibodies to S. aureus capsular polysaccharides induced with a conjugate vaccine may provide partial protection against S. aureus bacteremia, and the duration of protection may be extended with an appropriately timed booster dose. Because patients receiving hemodialysis are among the least likely to have a response to immunoprophylaxis, both in terms of maintaining antibody levels and gaining protection from a given antibody level, the efficacy of the vaccine may be greater in other patient populations. A vaccine that includes capsular polysaccharide type 336 as well as types 5 and 8 is under development and might provide broader protection. Another approach to targeting S. aureus capsular polysaccharides is an immunoglobulin containing high levels of opsonizing antibodies against types 5 and 8 (Altastaph; Nabi Biopharmaceuticals). In a recently reported phase 2 trial, very low birth weight infants, a group at high risk of staphylococcal infections, achieved high geometric mean titers ( 400 g/mL) of both antitype 5 and antitype 8 antibodies; however, efficacy has not yet been evaluated. Toxic shock syndrome toxin 1 (TSST-1), an exotoxin, is another factor involved in S. aureus evasion of host immune response. Vaccination with a nontoxic form, mutant TSST-1 (mTSST-1), protects against S. aureus infection in mice and rabbits. Because TSST-1 is common among invasive S. aureus isolates, including methicillin-resistant strains, mTSST-1 may be useful as an antistaphylococcal vaccine in humans. A number of molecules involved in staphylococcal attachment to host cells have been identified, including some produced by S. aureus, such as teichoic acid and clumping factor, From the *University of California, San Francisco, CA; and the †Kaiser Permanente Vaccine Study Center, Oakland, CA Copyright © 2006 by Lippincott Williams & Wilkins ISSN: 0891-3668/06/2502-0167 DOI: 10.1097/01.inf.0000199887.18267.9a