“Nosocomial” is a smooth-sounding word with a grim meaning. It defines a disease acquired in the hospital. One of its most rapacious perpetrators is a pathogen called Staphylococcus aureus.
An estimated 10 million Americans a year are at risk of nosocomial Staph infection. Any break in the skin, from major surgery to the prick of a needle, invites entry by S. aureus. It strikes people in nursing homes, patients on kidney dialysis and those with Type I diabetes. The bacterium lurks especially on nasal mucosa and hair follicles.
“S. aureus is among the most common causes of hospital-acquired infections,” observed vaccinologist Robert Naso, vice president of research at Nabi, a biopharmaceutical firm in Boca Raton, Fla. “The pathogen is reportedly associated with a death rate of 10 [percent] to 25 percent, 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.”
Naso is co-author of a paper in today’s New England Journal of Medicine (NEJM), dated Feb. 14, 2002, and titled: “Use of a Staphylococcus aureus conjugate vaccine in patients receiving chemodialysis.” Its senior author is Henry Scheinfeld of the Kaiser-Permanente Vaccine Center in San Francisco.
The 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 told BioWorld Today. “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 percent of all S. aureus clinical isolates. It’s a conjugate vaccine,” he continued, “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. That carrier is what makes the antigens immunogenic.”
Antibody Response To Vaccine Is 86 Percent
“Once given a single intramuscular injection of this first Staph vaccine,” Naso went on, “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. The vaccine elicited a significant antibody response in 86 percent 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 percent in the incidence of that infection.
“This protection persisted for an average of 10 months,” Naso observed, “Clearly, we will have to do booster studies to look at prolonging or extending protection, as one would with any vaccine at some point.”
Naso pointed out 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. 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,” Naso said, “is Altastaph a second experimental vaccine product, which 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 would be premature babies, who lack mature immune defenses.
“We can also 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, in Houston,” Naso recounted. “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? 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.”
Vaccine Ignores Bacterial Antibody Resistance
Naso made the added point 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 percent 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 pointed out, “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, but this vaccine appears to reduce the incidence of infection of both antibiotic-resistant and nonresistant Staph. It works by a completely different mechanism than antibacterials, so it’s irrelevant to the antibodies we generate with this vaccine whether the bacteria is antibiotic-resistant or not.”
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 concluded.