Phase 3 study results published in the New England Journal of Medicine
Patients with compromised immune systems benefit significantly
Rockville, MD, Feb. 13, 2002 – A single injection of a first-of-its-kind experimental vaccine, Nabi(tm) StaphVAX(tm)(S. aureus polysaccharide conjugate vaccine), reduced bloodstream infections caused by the often drug-resistant and potentially deadly bacteria, Staphylococcus aureus, in end-stage kidney disease patients by nearly 60 percent, according to a phase 3 study that appears in the February 14th issue of The New England Journal of Medicine. The study was conducted by investigators from Kaiser Permanente in collaboration with scientists at the National Institutes of Health (NIH) and at Nabi (Nasdaq: NABI).
Staphylococcus aureus is a major cause of hospital-acquired infections, including bloodstream infections, or bacteremias. Community-acquired Staph infections are also of growing concern. “Staph is one of the most frequent and potentially deadly bacterial infections in hospitals today. Now, for the first time, an experimental vaccine has been shown to reduce the incidence of bloodstream infections caused by this bacteria,” says co-author Robert Naso, Ph.D., senior vice president of quality, regulatory and product development at Nabi, the biopharmaceutical company that is developing the vaccine and supported the study.
After just one injection, StaphVAX reduced the incidence of systemic S. aureus infection in the blood by 57 percent, through 40 weeks of the 54-week study. By the end of the study, 86 percent of the patients had responded to the candidate vaccine with high levels of specific antibody.
“Kidney disease patients on hemodialysis are among the least likely to respond to a vaccine because their immune systems are generally compromised. Based upon previous clinical studies in normal, healthy volunteers, we believe that other patient populations at risk for Staph infections will respond to the vaccine with even higher levels of antibodies than was achievable in kidney disease patients,” Naso says.
Hospitals and other health care settings worldwide face unprecedented crises from the rapid emergence and dissemination of antibiotic-resistant bacteria, according to the NIH. Strains of drug-resistant S. aureus are found in most hospitals, often leaving vancomycin as the antibiotic of last resort for treating patients with these infections. With vancomycin-resistant strains of staph now appearing, many experts believe that a vaccine to prevent these infections may offer the best long-term solution.
According to the U.S. Centers for Disease Control and Prevention (CDC), more than two million patients in the U.S. each year contract an infection as a result of exposure while receiving health care in a hospital. S. aureus is among the most common causes of these hospital-acquired infections and is reportedly associated with a death rate of 10 percent to 25 percent because of its capacity to cause serious complications. S. aureus can spread from the blood (bacteremia), to the bones (osteomyelitis), or the inner lining of the heart and its valves (endocarditis), or cause abscesses in internal organs such as the lungs and kidneys. Most at risk for these infections are surgical patients, trauma or burn victims, newborns whose immune systems are not yet developed and people with such chronic illnesses as diabetes, cancer or lung or kidney diseases. People whose immune systems are suppressed due to disease, drugs or radiation therapy also are more susceptible to these bacterial infections.
For the study, the investigators examined StaphVAX’s safety, its immune system-stimulating abilities, or immunogenicity, and its effectiveness in preventing S. aureus bacteremia compared to a placebo of saline solution in 1804 adult patients with end-stage kidney disease in 73 dialysis centers between April 1998 and April 2000. In each group, 76 percent of the patients completed the study for at least 54 weeks.
All of the patients received routine hemodialysis, a process that cleans waste from the blood system and that requires repeated exposure to invasive dialysis procedures through a surgically implanted fistula or graft. These patients are generally immune compromised as a result of their age and underlying disease. As a result, they are at high risk for bacterial infections and are among the least likely at-risk patients to respond successfully to a vaccine. The annual incidence of S. aureus bacteremia among hemodialysis patients is typically three to five percent per year, according to previous studies.
StaphVAX contains molecules found in the polysaccharide outer coating of two strains of S. aureus, types 5 and 8, which account for about 85 percent of all S. aureus types. The polysaccharide molecules were joined, or conjugated, in the vaccine with a non-toxic, carrier protein derived from the bacteria Pseudomonas aeruginosa. Once given the vaccine, the patients’ immune systems produce proteins, called antibodies, which bind to S. aureus on subsequent exposure to the bacteria. These antibodies help the immune system to identify the staph bacteria while it is still in the blood and kill it.
Patients in the trial were randomly given a single intramuscular injection of either StaphVAX or a saline solution. Antibodies were measured for up to two years. Investigators estimated vaccine efficacy by comparing the incidence of S. aureus bacteremia in vaccinated patients to that in control patients.
The vaccine elicited a significant antibody response in 86% of the patients. Between weeks 3 and 40 after vaccination, S. aureus bacteremia developed in 11 of 892 vaccinated patients compared to 26 of 906 control patients. This was a reduction of 57% in the incidence in bacteremia in vaccinated patients (p value = 0.02), but by 54 weeks efficacy had fallen to 23% and was no longer statistically significant. In the New England Journal of Medicine article, the authors explain that a decrease in vaccine efficacy after 10 months appeared to parallel a decrease in levels of specific antibodies in the vaccinated patient population. Reactions to StaphVAX were similar to other vaccines. They were generally mild to moderate and included induration, erythema, pain and heat at the injection site and malaise and myalgia. These reactions typically resolved within one or two days.
“Because the data showed the ability to reduce S. aureus bacteremia for up to 40 weeks, we now are examining the potential for booster doses to re-stimulate antibody levels in this chronically at-risk patient population,” says Dr. Naso. Nabi expects that immunogenicity results from a preliminary booster study in the vaccinated patient group from the phase 3 study will be available during the first half of 2002.
In the published study, the vaccine and placebo groups had a similar distribution of types of S. aureus in patients who developed bacteremia. “The distribution of the different types of S. aureus isolates from patients with bacteremia in this study was consistent with that previously reported and there was no shift among the different types in the two study groups,” said Dr. Naso. “We also saw a similar distribution of methicillin resistance among isolates from both the vaccine and placebo groups, which is consistent with laboratory data showing that both antibiotic-resistant and antibiotic-sensitive strains of S. aureus are killed by antibody-mediated immune system responses.”
Nabi plans to conduct a confirmatory phase 3 study of the vaccine in end-stage kidney disease patients to support eventual product registration. In addition, Nabi is developing a second-generation version of the vaccine that is intended to address the third most common type of S. aureus, type 336, which has been identified and patented by Nabi researchers.
Nabi estimates that approximately 10 million people are at risk for hospital staph infections each year in the US, including people having surgery or invasive outpatient procedures, people in long-term care facilities, individuals on kidney dialysis and those with type 1 diabetes. The CDC estimates that treatment costs for S. aureus and other hospital-acquired infections totals $4.5 billion a year.
To complement StaphVAX, Nabi is also developing Altastaph™, an investigational product that contains high levels of human antibodies against S. aureus. Altastaph is being developed to provide immediate protection from staph infections for people who can’t develop their own antibodies or don’t have time for a vaccine to take effect, such as neonates and trauma patients. To date, Altastaph has been evaluated for safety and pharmacokinetics in low-birth weight babies in a phase 1/2 clinical trial. Additional clinical studies of Altastaph, expected to begin in 2002, are currently in the planning stages.
According to David J. Gury, Nabi’s chairman, president and chief executive officer, “The success of StaphVAX reported in this week’s New England Journal of Medicine has very positive implications for Nabi’s entire Gram-positive program of vaccine and antibody products.”
For the study reported in The New England Journal of Medicine, the co-authors include Henry Shinefield, M.D., Steven Black, M.D., Juan Ordonez, M.D. and Gregory Law, M.D., from the Kaiser Vaccine Center; Scott Rasgon, M.D. and Hock Yeoh, M.D. from Southern California Kaiser; John Robbins, M.D. and Rachel Schneerson, M.D. from the National Institute of Child Health and Human Development at NIH; and Robert Naso, Ph.D., Ali Fattom, Ph.D., Gary Horwith, M.D., and Steve Fuller, Ph.D. from Nabi.