Staph vaccine the answer to vancomycin resistance?
Animal studies hopeful; human trials to come
Researchers have developed a vaccine that protects mice against multiple strains of Staphylo coc cus aureus, the most common cause of nosocomial infections and a much-feared "superbug" in strains that show emerging resistance to vancomycin. While current research is based solely on animal studies, the findings are encouraging because the vaccine protected the mice from infection with both methicillin-resistant S. aureus (MRSA) and strains with intermediate resistance to vancomycin.1-4
"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," says Gerald B. Pier, PhD, who directed the research team at the Channing Laboratory at Brigham and Women’s Hospital in Boston. Pier and colleagues at Harvard University Medical School developed the vaccine with research support from the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, MD. NIAID has made development of a staph vaccine a priority since the appearance of the first strains with emerging vancomycin resistance in Japan and the United States.2-4 (See Hospital Infection Control, October 1997, pp. 145-152.)
"This is an intriguing finding and a hopeful step against a very worrisome pathogen," says Anthony Fauci, MD, director of NIAID. "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, our last line of defense against S. aureus. New treatments — and, ideally, an effective vaccine — are urgently needed."
The new vaccine is the first to be made from a bacterial molecule produced primarily during infection rather than in laboratory culture. The researchers used animal and human clinical isolates, including lung tissue from two cystic fibrosis patients infected with S. aureus. The researchers found that although tissue from humans and mice infected with S. aureus contained a staph polysaccharide molecule known as PNSG, few S. aureus strains produced PNSG when cultivated in the laboratory.
"Presumably, these products are critical for infection and disease progression, and would therefore be logical targets for new therapeutics or vaccines," Pier says.
Researchers injected the molecule into rabbits, who produced large amounts of PNSG antibodies. The researchers then injected the PNSG antibodies into mice and exposed them to eight different strains of S. aureus, including strains resistant to methicillin and partially resistant to vancomycin. None of the animals developed an infection.
"It looks like a great vaccine candidate for staphylococci in general, both S. aureus and S. epidermidis," says Stephen Heyse, MD, medical bacteriology and antibacterial resistance program officer at NIAID. Indeed, the researchers note that the PNSG molecule is also produced by another common nosocomial pathogen, coagulase-negative staphylococci (CNS).
"Together, S. aureus and CNS account for 40% to 60% of bacterial blood isolates from hospitalized patients," Pier says. "An additional potential advantage of a PNSG vaccine might be protection against the spectrum of clinically important CNS [infections]."
The team hopes to move the PNSG vaccine into human trials within the next year or two, and they currently are negotiating licensing rights for the vaccine. If borne out in human trials, the vaccine eventually could have an impact in reducing the estimated 500,000 nosocomial staph infections acquired annually by patients in U.S. hospitals. S. aureus also is a common source of community-acquired infections, ranging from minor skin infections and abscesses to life-threatening diseases such as severe pneumonia, meningitis, and bloodstream infections.
Even as the vaccine initiative continues, researchers are aggressively pursuing ways to preserve antibiotic efficacy against S. aureus. NIAID recently awarded a seven-year contract to MRL Pharmaceutical Services in Herndon, VA, to establish a network for tracking antibiotic resistance in the pathogen. The Network on Antimicrobial Resistance in S. aureus is designed to enhance communication and collaboration among investigators and clinicians. Plans call for establishment of an Internet Web site so researchers can evaluate and compare methods for testing antibiotic susceptibility. The network also will establish a repository of antibiotic-resistant S. aureus isolates for distribution to researchers. Meanwhile, efforts continue to sequence the genomes of two S. aureus strains in order to pinpoint the specific genes that select for resistance to antibiotics. Researchers at the Institute for Genomic Research in Rockville, MD, are sequencing an MRSA strain, while a research team at the Oklahoma (City) University Health Science Center is sequencing a strain that remains sensitive to antibiotics.
References
1. McKenney D, Pouliot KL, Wang Y. Broadly protective vaccine for Staphylococcus aureus based on in vivo-expressed antigen. Science 1999; 284:1,523-1,527.
2. Centers for Disease Control and Prevention. Reduced susceptibility of Staphylococcus aureus to vancomycin — Japan, 1996. MMWR 1997; 46:624-626.
3. Centers for Disease Control and Prevention. Staphylo coccus aureus with reduced susceptibility to vancomycin — United States, 1997. MMWR 1997; 46:765-766.
4. Centers for Disease Control and Prevention. Update: Staphylococcus aureus with reduced susceptibility to vanco mycin — United States, 1997. MMWR 1997; 46:813-814. n
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