VAIL, COLO. – Don’t hold your breath waiting for a working Staphylococcus aureus vaccine.
Development of a successful S. aureus vaccine is a high research priority. After all, it’s estimated that more people in the United States now die annually of methicillin-resistant S. aureus than of AIDS, according to data from the Centers for Disease Control and Prevention. Pharmaceutical giants including Merck, Pfizer, and Novartis, as well as smallish biotech companies, are in the hunt for an S. aureus vaccine. But S. aureus is proving to be an elusive target.
Dr. James K. Todd
"When you think about the bugs that we’ve been successful in developing vaccines to, they generally have a single main virulence factor that you can target: either a capsule, like Haemophilus influenzae, Streptococcus pneumoniae, or Neisseria meningitis, or a toxin, as in tetanus or diphtheria. But S. aureus has many strains with multiple virulence factors," Dr. James K. Todd explained at a conference on pediatric infectious diseases, which was sponsored by Children’s Hospital Colorado, Aurora.
What this means is that conventional active immunization strategies that zero in on a single target are unlikely to be successful in the case of S. aureus. Following the failure in a phase III trial of Nabi Biopharmaceutical’s StaphVax vaccine targeting capsular polysaccharides types 5 and 8 (Curr. Opin. Investig. Drugs 2002;3:48-50), the research thrust has shifted from the single-target approach to the development of vaccines that address composite targets encompassing multiple virulence factors.
"You’re going to have to come up with a polyvalent vaccine with a large combination of antigens if you want to successfully deal with Staphylococcus aureus infections. It’s a very time-consuming and expensive process," cautioned Dr. Todd, professor of pediatrics, microbiology, and epidemiology at the University of Colorado at Denver.
At least five such vaccines addressing composite targets in an active immunization strategy are in early stages of the developmental pipeline.
Also being aggressively pursued is a strategy involving passive immunization using therapeutic antibodies that are specifically targeted against toxins with an established role in S. aureus virulence. Again, candidate passive immunization vaccines targeting a single virulence factor have not panned out to date. Two such products have flopped in phase II trials, although roughly another half-dozen, single-target, passive immunization vaccines are in preclinical development.
Here again, the latest thinking is that passive immunization against a cocktail of virulence determinants, not just one, is likely to be necessary. The tough decision for vaccine developers is which virulence factors to include.
The appeal of passive immunization is that it’s designed to directly bottle up virulence factors and render them powerless. In contrast, active immunization aims to enhance uptake of S. aureus by white blood cells through the process of opsonization. This may be a losing proposition, in light of the nimble microorganism’s numerous means of avoiding death via phagocytosis.
For example, the highly problematic PVL (Panton-Valentine leukocidin) virulence factor, which is associated with severe invasive S. aureus disease, including pneumonia and necrotizing fasciitis, enables PVL-containing strains of S. aureus to lyse and kill WBCs that have successfully surrounded the pathogen.
"We’re going to have to deal with what goes on once the bug is inside the white blood cell, and that’s much more difficult to do with a vaccine," according to Dr. Todd.
Assuming an effective S. aureus vaccine can be developed, how might it be used? Depending upon the vaccine’s properties, it might be employed in patients who are at high risk of infection, such as those on dialysis, or patients undergoing surgery, or those with chronic diseases, or patients with a lengthy hospital stay. Health care workers might be immunized to prevent nosocomial spread. In community practice, a vaccine might be utilized to decolonize chronic carriers of S. aureus or to curb outbreaks in athletic teams.
Dr. Todd is credited with being first to describe S. aureus toxic shock syndrome. He noted that other S. aureus experts share his view that a S. aureus vaccine development faces a rocky road. For example, in a recent review, Michael Otto, Ph.D., senior investigator at the National Institute of Allergy and Infectious Diseases, observed that attempts to create an effective S. aureus vaccine have been going on for nearly a century, without success.
"The many mechanisms by which S. aureus can evade elimination by phagocytes after ingestion may help to explain why S. aureus vaccines have failed and antistaphylococcal antibodies present in many people are not protective," observed Dr. Otto (Expert Opin. Biol. Ther. 2010;10:1049-59).
Dr. Mary P. Glodé declared that a successful S. aureus vaccine is near the top of her wish list for the next 5-10 years. "There’s a true need for a S. aureus vaccine to prevent serious disease. If we look at the positive blood cultures at our hospital, it’s S. aureus leading the list, certainly for bone and joint infections, but also for bacteremia and pneumonia," according to Dr. Glodé, professor of pediatrics and head of the section of infectious disease at the University of Colorado at Denver.