An estimated 10 million Americans a year are at risk of nosocomial infection from Staphylococcus aureus. Any break in the skin, from major surgery to a needle prick, invites entry by S. aureus. It strikes people in nursing homes, patients on kidney dialysis and those with Type 1 diabetes. The bacterium lurks especially on nasal mucosa and hair follicles.

"S. aureus is among the most common causes of hospital-acquired infections," said Robert Naso, vice president of research at Nabi (Boca Raton, Florida), a biopharmaceutical firm. "The pathogen is reportedly associated with a death rate of 10% to 25%, owing to its serious complications. It can spread from bacteremia in the blood stream to osteomyelitis in the bones to endocarditis on the inner lining of the heart and its valves, or cause abscesses in internal organs, such as the lungs and kidneys."

A Phase III, placebo-controlled, clinical trial tested the efficacy of Nabi's experimental StaphVax vaccine against infection by S. aureus. It enrolled 1,804 adult patients with end-stage kidney disease in 73 dialysis centers between April 1998 and April 2000. "These patients are generally immune-compromised owing to their age and underlying disease," Naso said. "So they are at high risk for bacterial infections and are among the least likely at-risk patients to respond successfully to a vaccine."

He described the StaphVax target bacterial antigen as "two surface polysaccharides in the two most frequent types of Staph aureus that infect people — types 5 and 8. These account for about 85% of all S. aureus clinical isolates." It's a conjugate vaccine, he added, "so those polysaccharides are linked to a nontoxic carrier protein. This is a recombinant form of Pseudomonas endotoxin A, which we expressed in Escherichia coli."

Once given a single intramuscular injection of this first Staph vaccine, Naso said, "the patients' immune systems produced antibodies, which bind to S. aureus on subsequent exposure to the bacteria. "These antibodies helped the immune system identify the infectious agent while it was still in the blood — and kill it." He said the vaccine elicited a significant antibody response in 86% of the patients in the trial, Naso noted. "Between three and 40 weeks after vaccination, bacteremia developed in 11 of 892 vaccinated patients, compared to 26 of 906 placebo-controlled subjects, a reduction of 57% in the incidence of that infection."

That protection persisted for an average of 10 months, Naso said. He noted that "most of us are already primed by our immune system to react when we see staph. So when we get a shot of StaphVax, we quickly raise high levels of antibodies to the vaccine." Naso said that has allowed Nabi to go into plasma donors with this vaccine — to volunteer to donate the liquid part of their blood. "We vaccinate the plasma donors; they raise high levels of antibodies to the StaphVax. We collect their plasma, pool it from a number of different donors, purify the antibodies in our FDA-licensed fractionation facility, then put those high-titer antibodies in bottles."

The result, he said, "is Altastaph — a second experimental vaccine product that we believe can be administered to anyone who is at risk of infection, but who can't respond to the vaccine because of being immune-compromised, for example." The most likely candidates, Naso said, would be premature babies, who lack mature immune defenses. "We also can use Altastaph for people who don't have time to respond to the StaphVax vaccine, if they're at immediate risk — such as a patient coming into the hospital after an automobile accident. They're at risk within two or three days of incurring a staph infection, so this product could be used to protect them."

Altastaph was in Phase I/II studies in low-birth-weight babies at Baylor College of Medicine (Houston, Texas), Naso said. "That study looked at safety, and at the trough level of antibody that could be maintained in those kids. In other words, if we gave two injections of Altastaph 14 days apart, what was the lowest level of antibody that we saw in the newborn preemies." He added, "We're trying to maintain a protective level over, let's say, a 30-day period, which is their primary risk. This year we expect to have a second study in low-birth-weight babies, and we'll also begin looking at the Altastaph antibody in adults who already have Staph infection. It will be used therapeutically to help them get over it."

Naso added that, "S. aureus in general is among the most antibiotic-resistant pathogens. That's one reason why there's such a huge problem with it today. For example, in this Phase III patient population, we saw a 4% infection rate in the placebo cohort. That's a very high incidence of infection. And it occurred in spite of the potential use of prophylactic antibiotics."

The problem, he noted, "is that antibiotics are having less and less effect on Staph. It is more difficult for the physician to try to figure out which antibiotic to use in his specific clinical setting." Antibiotic resistance plays no role here, he said, "but this vaccine appears to reduce the incidence of infection of both antibiotic-resistant and non-resistant Staph."

Nabi is planning a second, confirmatory, Phase III trial in this same kidney-dialysis population, to begin some time in 2003. "It will better define the duration of protection," Naso noted.