By David N. Leff

Unless treated promptly and properly, infective endocarditis is 100 percent fatal. And there's the rub.

The infection often targets an artificial heart valve because plastic is a preferred site of colonization for Staphylococcus aureus, the bacterium most guilty of endocarditis. By the same sinister token, S. aureus infects catheters, artificial joints and other indwelling devices of modern surgery.

One-half million Americans a year end up in hospital with Staph infections. The bug is everywhere: In the nostrils and on the skin of physicians, nurses and other medical personnel, not to mention well-wishers who are visiting patients. Out in the real world it perpetrates everything from boils and carbuncles to ear infection in babies to septic arthritis and pneumonia in adults to epizootics in farm animals. (See BioWorld Today, Sept. 14, 1998, p. 1.)

One salient source of endocarditis is infected blood from the contaminated needles of intravenous drug abusers; another is dental surgery.

Confronted with a case of the valvular infection, a cardiologist's first thought is to prescribe an antibiotic against Staphylococcus bacterial strains. Increasingly, he or she has to think again. The usual penicillin-based drugs are largely ineffective against Staph's ever-widening antibiotic resistance.

The answer of last resort to this tightening crisis is vancomycin, an antibiotic that is still partially potent in killing Staphylococci. But the bacterium's drug resistance is catching up fast with vancomycin.

"That's why it's so important to develop a vaccine against Staphylococcus aureus," observed microbiologist and immunologist David McKenney, a postdoctoral research fellow at Harvard-affiliated Brigham and Women's Hospital in Boston. "They inherently become resistant to antibiotics," he said. "Until recently, vancomycin was the last one to go. Now there are vancomycin-resistant strains of the bacterium in the U.S. and Japan. So, there's a real serious need to come up with a vaccine that would avoid this resistance problem."

McKenney is lead author of a paper in today's Science, dated May 28, 1999, which reports just such a prototype immune defense. Its title is "Broadly protective vaccine for Staphylococcus aureus based on an in vivo-expressed antigen." Its senior author is microbiologist and immunologist Gerald Pier, who led the research reported in Science. He has been trying since the early 1980s to trap the artfully dodging bacterial antigen.

McKenney told BioWorld Today how Pier and his team finally captured it:

"It was first discovered in a different pathogenic Staph species, Staphylococcus epidermides," he began. "Pier had real problems purifying that one in the early-'80s. Last year, we published an article reporting that we had been able to purify that bacterial surface molecule, and found it to be a large polysaccharide that we called PNSG. We hadn't found it on the surface of Staphylococcus aureus, however. What we had found was that the ica gene complex encoding PNSG within S. epidermides was also present in Staphylococcus aureus. So, then, we went into some experimentation to see if we could actually induce PNSG, and found out that passage in vivo caused the bacteria to turn on this antigen."

They determined that it was identical in both Staph species, and looked like a likely vaccine candidate. Whereupon the team injected their antigenic PSNG into rabbits. The animals duly produced large amounts of anti-Staph. antibodies, and this output persisted for eight months.

"We vaccinated mice with that rabbit antibody against the polysaccharide," McKenney said, "and then challenged them with eight strains of S. aureus, including two resistant to methicillin antibiotic, and two partially resistant to vancomycin. All of the animals survived the infection."

Co-authors of Pier's Science paper, at the University of T|bingen, Germany, McKenney said, "took some small [2-mm-square] lung biopsies and sputum samples, colonized with Staph aureus, from two young cystic fibrosis patients. These infected specimens bound to our PSNG antibodies. This showed that our antigen is produced in human infection, something not normally seen in bacterial infections."

Elusive Antigen Is A 'First'

"This new vaccine," Pier said in a press statement, "is the first to be made from a bacterial molecule produced primarily during infection, rather than in laboratory culture. Our findings suggest that this vaccine has the potential to provide immunity to the multidrug-resistant S. aureus 'superbug' that we have heard alarming reports of in the last year or so."

Anthony Fauci, director of the National Institutes of Health's National Institute of Allergy and Infectious Diseases, (NIAID), which funds Pier's work, seconded his statement: "This is an intriguing finding and a hopeful step against a very worrisome pathogen," Fauci said. "Within the last two years, S. aureus has become increasingly resistant to antibiotics. Most troubling is the emergence of strains that are partially resistant to vancomycin, the last line of defense against S. aureus. New treatments and, ideally, an effective vaccine, are urgently needed."

Company Sought To License Vaccine, Run Phase I Trial

To meet this need, McKenney said, Pier and his co-authors aim at putting their vaccine into Phase I human trials within the next 18 months. "The vaccine would first be given to healthy individuals to see if they mount an immune response," McKenney said. "And then the antibodies produced in these individuals will probably be tested in various animal models to see if we can get protection against Staphylococcus aureus. That would be the first thing we'd be looking at."

At present, the hospital is negotiating with companies for one that would conduct this clinical trial and license the vaccine. Meanwhile, McKinney said, "We are trying to get scale-up procedures, and continuing with different animal models to see if we get protection for different types of infection - testing wound infections in mice, endocarditis in rats."

He sees the vaccine as targeti+ng "prevention first, treatment eventually. To start with, I think we'd be looking at passive therapy in neonates. But there doesn't seem to be any reason why we couldn't incorporate this in the existing multi-vaccine cocktail for kids." As for nosocomial infection, he said, "One might envisage an active therapy for people who go in to hospital for a heart valve operation, or suchlike."