Feb. 15, 2002 Scientists at the National Institute of Child Health and Human Development (NICHD) and the biologics firm Nabi have developed the first vaccine against Staphylococcus aureus, a major cause of infection and death among hospital patients. The study appears in the February 14 New England Journal of Medicine.
"Staphylococcus aureus bacteria can be life-threatening and are rapidly growing resistant to the antibiotics used to treat them," said Duane Alexander, M.D., director of the NICHD. "This new vaccine may provide a powerful new way to prevent the thousands of serious S. aureus infections that occur each year."
S. aureus is an opportunistic bacteria — infecting people whose immune systems have been weakened, explained an author of the study, John Robbins, M.D., chief of the NICHD's Laboratory of Developmental and Molecular Immunity. S. aureus is a common cause of bacteremia-bacterial infection of the bloodstream. Patients undergoing hemodialysis for end stage kidney disease are particularly susceptible to S. aureus blood infection, with nearly 3 percent developing the infection each year.
S. aureus infection causes illness ranging from minor skin infections to life-threatening diseases such as severe pneumonia, meningitis, bone and joint infections, and infections of the heart and bloodstream. Many strains of S. aureus are resistant to methicillin, the antibiotic used to treat it. Similarly, researchers have also discovered strains of the bacteria that are resistant to the antibiotic vancomycin, the only antibiotic known to kill methicillin-resistant S. aureus.
Dr. Robbins explained that the late Walter Karakawa, of Pennsylvania State University, first made the critical discovery that S. aureus has capsular polysaccharides — complex sugar molecules — in its outer covering, or capsule. Dr. Karakawa, working with scientists at the NICHD; Willie Van of the U.S. Food and Drug Administration; Jean-Michel Fournier of the Institute Pasteur, in Paris; and Ali Fattom, then with NICHD, and now with Nabi, conducted additional research on the organism.
In a series of experiments over the past 15 years, these researchers showed that S. aureus had 13 capsular polysaccharides, only two of which, types 5 and 8, accounted for about 85 percent of polysaccharides isolated from the blood of patients infected with the bacteria. These two polysaccharides shielded S. aureus, preventing the white blood cells of the immune system from recognizing it and targeting it for destruction.
The researchers knew that antibodies to these polysaccharides were capable of killing the bacteria, but were confronted with a technical problem. Without assistance, the immune system could not recognize the polysaccharides, and so could not make antibodies against them. Antibodies are immune system proteins that recognize a particular substance. Together with another protein called complement, antibodies begin the first steps in the complex sequences of events by which the immune system destroys disease-causing organisms.
The researchers then chemically coupled the polysaccharides to a medically useful protein to form a "conjugate." Tests in mice showed that this conjugate approach allowed the immune system to produce antibodies that could then inactivate the bacteria. Later testing showed that this approach produced antibodies in healthy adults. Similarly, hemodialysis patients produced low levels of the antibodies. The project was then transferred to Nabi, under the direction of Dr. Fattom, another author of the paper. Dr. Fattom showed that increasing the amount of the new vaccine given to hemodialysis patients would allow them to produce higher levels of antibodies.
Soon after, the NABI researchers conducted a double-blinded, randomized, saline controlled trial of the vaccine. In this kind of trial, neither the patients nor their physicians know who receives the vaccine or who receives the placebo, in this case, a harmless salt solution.
From three to 40 weeks after the start of the trial, the vaccine reduced the occurrence of bacteremia by 57 percent, with 11 bacteremias in the vaccinated group (892 patients) and 26 in the control group (906 patients). After the 40th week, this figure fell to 26 percent. In general, the authors noted, antibody levels tend to decline rapidly in dialysis patients.
Dr. Robbins said that efforts to increase the efficacy of the vaccines will include studies on the effectiveness of a booster dose of the vaccine given one year later. In addition, researchers will target the vaccine to a newly discovered polysaccharide type 336. This resulting new vaccine should allow the immune systems of vaccinated patients to be able to recognize nearly 100 percent of S. aureus types found in blood infections.
"The conjugate vaccines were effective in hemodialysis patients who had severely depressed immunity," Dr. Robbins said. "It is likely that the vaccine will be more effective in individuals with less depressed immune systems who are at risk for S. aureus infections, such as patients with chest and cardiac surgery and with joint replacements."
Dr. Robbins and another author of the paper, Rachel Schneerson, M.D., had earlier received the Pasteur and Lasker Awards for using the conjugate approach to develop a vaccine that virtually eliminated disease caused by the deadly and debilitating bacteria, Haemophilus influenzae type B (Hib), from the developed world. (http://www.nichd.nih.gov/new/releases/cviawar2.htm).
The NICHD is part of the National Institutes of Health, the biomedical research arm of the federal government. The Institute sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. NICHD publications, as well as information about the Institute, are available from the NICHD Web site, http://www.nichd.nih.gov, or from the NICHD Clearinghouse, 1-800-370-2943; e-mail NICHDClearinghouse@mail.nih.gov.
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