By combining the four bacterial surface proteins that generate the strongest immune response in mice, researchers at the University of Chicago have created a vaccine that significantly protects immunized animals from multiple disease-causing, drug-resistant strains of Staphylococcus aureus, the most common cause of hospital-acquired infections and a rapidly spreading source of community-associated illness.
The vaccine protected mice against potentially lethal infections with five virulent S. aureus strains, the researchers report in the Nov. 7, 2006, issue of the Proceedings of the National Academy of Sciences, available early online. These strains include USA100, a common cause of hospital-acquired infections, and USA400, a virulent community-associated strain that carries lung-damaging toxins. All five strains were resistant to most of the drugs used to treat S. aureus infections.
"This microbe's ability to acquire the tools it needs to protect itself from the drugs we use to treat it is legendary," said study director Olaf Schneewind, M.D., Ph.D., professor and chairman of microbiology at the University of Chicago, "which is why a vaccine has become such a high priority. One by one, this organism has learned how to evade nearly all of our current antibiotics. So, generating protective immunity against invasive S. aureus has become an important goal."
Previous vaccine attempts using killed or live attenuated bacteria, or selected bacterial subunits, produced, at best, only partial immunity. "For S. aureus vaccines to succeed," said Schneewind, "we need to stimulate an immune response that can recognize the specific cell-surface proteins responsible for virulence and can recognize them from multiple strains."
The researchers turned to a newer technique, known as "reverse vaccinology," recently used to develop candidate vaccines against group A and group B streptococci and group B meningococci. Access to the S. aureus genome enabled the team to compile a list of cell-surface antigens from diverse strains of the bacteria, many of them new targets. From that list, Schneewind and colleagues selected 19 potential vaccine targets taken from eight different strains of S. aureus.
By injecting each of the 19 target proteins into mice and measuring the immune response, they identified the four proteins that generated the strongest immune response. Two of those proteins, IsdA and IsdB, help the microbe acquire needed iron from the host's red blood cells. The other two, SdrD and SdrE, are thought to be involved in bacterial adhesion to host tissues.
When tested alone as a vaccine, each of the four proteins provided only partial or no protection. Fifty to 70 percent of mice vaccinated with one of these proteins and injected with a dose of a laboratory strain of the bacteria calculated to kill 50 percent of the mice, were still alive one week later.
When they vaccinated the mice using the combined vaccine, however, all of the mice survived. Although unvaccinated mice had clear evidence of kidney infections, the "bacterial load" in vaccinated mice was reduced "to a level below detection."
The next step was to test the vaccine's ability to protect mice from multiple bacterial strains isolated from humans. The researchers vaccinated 50 mice. Three weeks later, they injected groups of 10 with potentially lethal doses of one of five different clinical isolates.
The vaccine completely protected mice against two strains--including the virulent community-associated strain--and offered significant protection, resulting in 60- to 90-percent survival, against three other strains. All unprotected mice injected with the USA100 strain died within 36 hours, for example, but 60 percent of vaccinated mice survived injection with that strain.
"Further testing," said first author of the study Yukiko K. Stranger-Jones, a graduate student in the Schneewind Lab, "may yield a molecular appreciation of immunity against S. aureus and permit rational development of a vaccine." Schneewind and colleagues are now exploring the relationship between antibodies that fight S. aureus infection and surface proteins of the bacterium that facilitate the spread of the infection.
S. aureus, often referred to simply as "Staph," is common, found on the skin and in the noses of an estimated 30 percent of people worldwide. It is a frequent source of skin infections, which can usually be treated without antibiotics, but it can also cause serious surgical wound infections, bloodstream and bone infections, or pneumonia. The burden of such infections, according to one recent study, is "staggering: almost 12,000 inpatient deaths annually," an estimated 2.7 million days in excess hospital length of stay, and $9.5 billion in excess charges.
Physicians are particularly concerned about S. aureus because of its ability to survive in the presence of antibiotics designed to kill it. In 1972, according to the Centers for Disease Control, only two percent of S. aureus infections were drug-resistant. By 2004, 63 percent had learned to resist the antibiotics commonly used to treat them.
While such methicillin-resistant Staphylococcus aureus (MRSA) infections have long been a problem in hospitals, nursing homes and dialysis centers, more and more healthy people with no apparent risk factors have been turning up in emergency rooms with virulent S. aureus infections acquired from community rather than health care related sources.
Taeok Bae, from the department of microbiology at the University of Chicago, also contributed to the study.
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