Staphylococcus aureus Polysaccharide Conjugate Vaccine - StaphVax; Staphlyococcus aureus types 5 and 8 capsular polysaccharides--Pseudomonas aeruginosa exotoxin A, recombinant, conjugates
Status: recently failed in Phase III trial; undergoing further development
Organizations involved:
Nabi Biopharmaceuticals, Inc. – Manuf.; R&D; Tech.; World mark.
Univax, Inc. – R&D; Tech.; Former
Cambrex Bio Science, Inc. – Manuf.
Lonza Biologics plc – Parent
Dow Chemical Co. – Manuf.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH – R&D; Tech.
National Cancer Institute (NCI) – Tech.
National Institutes of Health (NIH) – Parent
Description: StaphVax is a bivalent polysaccharide, protein-conjugated vaccine formulation containing nonrecombinant purified Staphyloccus aureus (S. aureus) types 5 and 8 capsular polysaccharides each chemically conjugated to a protein carrier composed of a recombinant detoxified form of Pseudomonas aeruginosa exotoxin A (rEPA) expressed by a transformed Escherichia coli (E. coli) bacterium. The recombinant Pseudomonas exotoxin A mutein (mutant form) used is analogous to the native bacterial exotoxin, but has deletions at glutamate 553 and adjacent residues. After purification, rEPA has no detectable ADP-ribosyl activity, i.e., is substantially detoxified/nontoxic. Each dose of StaphVax contains ~100 µg of capsular polysaccharides conjugated to rEPA formulated in phosphate-buffered saline.
StaphVax is being developed initially for prevention of S. aureus infections in patients receiving kidney dialaysis, i.e., patients with end-stage renal disease, a group particularly prone to serious Staphylococcal infections.
Nomenclature: Staphylococcus vaccine (rDNA) [BIO]; StaphVax [TR]; Staphlyococcus aureus Polysaccharide Con-jugate Vaccine [SY]; Staphlyococcus aureus types 5 and 8 capsular polysaccharides—Pseudomonas aeruginosa exotoxin A, recombinant, conjugates [SY]
Biological.: Staphylococci are Gram-positive opportunistic bacteria that cause a variety of diseases, including dermal pustules, impetigo, food poisoning, toxic shock syndrome, and potentially fatal septicemia. Staphylococci cause different diseases and manifestations, depending on a number of factors, e.g., route and location of infection and age. Food poisoning attributed to Staphylococci is primarily due to toxicity from accumulated Staphylococcal enterotoxin, not active infection. Toxic shock syndrome, often associated with catamenial products (e.g., tampons), is associated with Staphylococcal infection which produces exotoxin superantigen.
Healthy, i.e., non-immune compromised, individuals are at negligible risk for serious S. aureus infection, and S. aureus may be considered an opportunistic infection. S. aureus is ubiquitous, e.g., it is carried in the nasal tissue of about 25% of the general population, and it is ease to transmit through breaches in the dermal barrier. S. aureus has developed widespread antibiotic resistance. Related to these factors, the bacterium is one of the most common causes of hospital infections. An estimated 2.5-5 million nosocomial (hospitalization-associated) infections each year are attributed to S. aureus, with this resulting in doubling of the cost and length of infected patients’ hospital stays. Individuals with implants, such as the implanted catheters in kidney disease patients used for dialysis, are particularly prone to S. aureus infections.
Due to many strains already being antibiotic-resistant and concerns about inducing antibiotic resistance, treatment of S. aureus infections is becoming increasingly complex and difficult. In some areas, over 95% of S. aureus infection isolates are now resistant to penicillin or ampicillin, and over 50% are resistant to newer methicillin. Most reports of methicillin-resistant S. aureus (MRSA) originate from hospitals, but an increasing number come from the general community. Vancomycin, the antibiotic of last resort against MRSA, multi-antibiotic resistant S. aureus, is increasingly unable to clear many infections as resistance develops to this antibiotic. A prophylactic vaccine, such as StaphVax, is expected to reduce the incidence of S. aureus infections in those receiving it, preventing considerable morbidity.
Of the 13 known variation of capsular polysaccharide that characterize the different strains of S. aureus, type 5 accounts for ~33% of infections and type 8 for ~60%, with the two combined accounting for 93%. An individual vaccinated with these antigens (StaphVax) would, theoretically, be protected from infection by 85-90% of clinically-significant S. aureus strains, although a significant risk of initial infection still would exist. A vaccine containing antigens from the other six serotypes theoretically could provide 100% protection, but would require production and purification of additional components. S. aureus capsular polysaccharides type 5 and 8 are smaller in size than other bacterial capsular polysaccharides. By themselves, these polysaccharides are not immunogenic. However, they are immunogenic after conjugation to a protein carrier, such as Pseudomonas auruginosa exotoxin. From its clinical trials, Nabi has reported that nearly all persons tested had low baseline levels of antibodies to S. aureus capsular polysaccharides from prior exposure, potentially priming the immune system for subsequent vaccination with StaphVax.
StaphVax contains the same polysaccharides as found on the outer coating of the most dangerous strains of S. aureus, types 5 and 8. The outer polysaccharide-rich coating allows the bacteria to evade the body’s immune system. StaphVax, however, contains the purified S. aureus polysaccharides linked to a large carrier protein. This combination is readily recognizable as foreign to the immune system, triggering the body to produce antibodies to the S. aureus polysaccharides in response to vaccination. A 10-20 fold increase in S. aureus antibody titers, both types humoral IgG and mucosal IgM, results after StaphVax vaccination.
Conjugation of the modified Pseudomonas exotoxin to the S. aureus capsular polysaccharides enables induction of potent T-cell dependent immunity against the capsular polysaccharides. The use of a bacterial toxin-based protein as a carrier for a bacterial antigen (though chemical conjugation) to increase immune responses to the bacterial antigen has already been successfully used in Haemophilus influenzae vaccines (see related entries). Conjugate vaccine technology enables induction of antibodies to the most common forms of S. aureus infections without the development of resistance.
The primary mechanism of action of StaphVax, like other bacterial polysaccharide-protein conjugate vaccines, involves opsonization and phagocytosis. Upon infection, when S. aureus invades the blood , these antibodies attach to the surface of the bacteria, resulting in phagocytosis (their engulfment) by white blood cells that kill the bacteria and clear it from the blood. Circulating humoral antibodies induced by StaphVax selectively bind to and opsonize S. aureus bacteria cells. Complement is deposited on the opsonized cells and further binds circulating polymorphonuclear cells (PMNs) through complement receptors. This induces phagocytosis (engulfment and enzymatic destruction) of the opsonized cells by the PMNs.
Multiple animal species vaccinated with StaphVax have shown induction of high affinity, type-specific S. aureus antibody responses. Altastaph or immune globulin (also being developed by Nabi) isolated from individual vaccinated with StaphVax contains S. aureus type-specific antibodies, and passive immunization of multiple animal species with Altastaph has protected them from lethal challenge with homologous live S. aureus. The detoxification of Pseudomonas exotoxin A by genetic modification has been confirmed by animal and clinical studies.
Nabi Biopharmaceuticals has been developing StaphVax for patients who are at high risk of S. aureus infections due to compromised immune systems, but who are still able to respond to a vaccine by producing their own antibodies, and at high risk of S. aureus infection, e.g., from implanted catheters in dialysis patients. StaphVAX is intended to stimulate a patient’s immune system to produce antibodies to S. aureus that provide active, long-term protection from the bacteria. S. aureus humoral (IgG) antibodies induced by StaphVax in hemodialysis patients have been shown to have affinity for S. aureus equivalent to that of antibodies induced in healthy individuals, and the antibodies exhibit comparable effectiveness in in vitro opsonization-phagocytosis assays.
Companies.: Univax Biologics, Inc., which later became, Nabi, now Nabi Biopharmaceuticals, Inc. (Nabi), is the developer and will market StaphVax in major markets. Much of the vaccines development and technology has came from collaborations (and licensing) with federal labs., particularly the National Institutes of Health (NIH).
Nabi has contracted with Cambrex Bio Science, Inc. for commercial manufacture of StaphVax. Cambrex was aquired by and merged into Lonza Biologics plc in mid-2006. Nabi had previously contracted (June 2000) with Collaborative BioAlliance (later acquired by Dow Chemical), which presumably supplied product for the earlier clinical trials. Nabi is also developing facilities for StaphVax manufacture at new facilities in Florida.
StaphVax is based largely on National Institute of Digestive Diseases and Kidney Disorders (NIDDK), NIH, research and inventions, and NIH collaborated in early StaphVax research and development. Formal StaphVax-related Collaborative R&D Agreements (CRADA) between federal labs and Univax, included:
a) “Development of Conjugated Vaccine for Staphylococcus Type 5 and Type 8,” NIH ref. #91/486, 1991, between Dr. J. Shiloach, NIDDK, and Univax Biologics, Inc. NIH-sponsored Phase I and other trials in end-stage renal disease (ESRD) kidney dialysis patients and healthy volunteers using monovalent conjugate vaccines against S. aureus types 5 and 8.
b) “Development of Adaptive Control System for Fermentation Control,” NIH Ref. #90/436, between Dr. J. Shiloach, NIDDK and M. Ahluwali, Flour Daniel, Inc. (Greenville, SC), initiated June 11, 1990; active in 1992, ended by10/93. Apparently, involved scale-up of StaphVax manufacture and facilities design.
c) “NMR Structure Analysis of Bacterial Polysaccharides,” initiated in fiscal year 1994 between Univax and the National Institute of Standards and Technology (NIST), Department of Commerce.
Manufacture: S. aureus strains 5 and 8 are separately cultured. After bulk growth has occurred, cultures are inactivated with a phenol and ethanol mixture, and cell pastes are harvested. S. aureus capsular polysaccharides are obtained and purified by enzyme treatment, anion-exchange chromatography, and gel filtration. The size of S. aureus type 8 polysaccharide is reduced by sonication.
Purified polysaccharides are chemically conjugated to the carrier protein – recombinant E. coli expressed Pseudomonas auruginosa exoprotein A (rEPA) that has been purified by repeated ion-exchange chromatography. A thiol derivative of each polysaccharide is formed, and the thiol derivative is then bonded to rEPA protein which has been reacted with a hetereobifunctional crosslinking agent — N-succinimidyl 3-(-2-pyridyldithio)propionate (SPDP) . Conjugates are formed using the carboxyl function of the bacterial polysaccharide to form a thiol derivative. The rEPA protein is first reacted (derivatized) with SPDP. rEPA-SPDP is then thiolated by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)-mediated derivatization with cystamine, then reduced and mixed/reacted with the thiolated polysaccharides to form the final polysaccharide-rEPA conjugates.
In Sept. 2003, Nabi completed a clinical trial to evaluate the immunogenicity of a lot of StaphVax manufactured by Cambrex. The study demonstrated that Nabi could successfully transfer and scaleup commercial production of StaphVAX. Based on this result, Nabi initiated its confirmatory Phase III clinical trial for StaphVax in the U.S. using vaccine manufactured by Cambrex (now Lonza).
Status: In 2000, NABI’s first Phase III study failed to meet its primary endpoint – a significant reduction in blood stream infections at 12 months. However, the result was significant at 10 months, and Nabi continued development.
StaphVax encountered delays with its original BLA filing with FDA. Nabi had filed for approval of StaphVax in 1999 based on a single Phase III study in end-stage renal disease (ESRD) patients. As discussed in the Trials section below, Nabi completed a pivotal Phase III U.S. trial in 1,800 end-stage renal disease patients on hemodialysis. A significant decrease in S. aureus bacteremia (systemic infection) was observed in the first 10 months after vaccination, but response decreased after month 10, and the decrease in infections at 12 months, the primary endpoint of the study, failed to reach statistical significance. In Dec. 2002, FDA indicated that a second randomized Phase III trial in which the primary endpoint is reached would be required for approval.
Nabi is currently conducting the FDA-required confirmatory Phase III trial, and intends to request either accelerated approval or fast-track review by the FDA, on the basis that the vaccine prevents a fatal disease for which no other prophylactics are available, but first has filed for European approval.
On Jan. 26, 2005, Nabi reported that its MAA filed in Dec. 2004 for European Union (EU) approval had been accepted for filing. The application is seeking StaphVax approval for prevention of S. aureus bacteremia in patients with end-stage renal disease (ESRD) on hemodialysis for up to 40 weeks. This MAA is based on data from the previously completed U.S. Phase III clinical trial of StaphVAX in ESRD patients, not the ongoing confirmatory trial. Nabi planned to later file a supplemental MAA in the EU for the prevention of S. aureus bacteremia in at-risk adults including data from its second U.S. Phase III trial, along with data from its U.S. and EU immunogenicity studies conducted in other at- risk patient populations.
On Nov. 1, 2005, Nabi announced that the StaphVAX confirmatory Phase III clinical study in 3,600 end-stage renal disease (ESRD) patients on hemodialysis had failed to meet its primary endpoint. Nabi withdrew its MAA in the European Union and has indefinitely delayed its BLA filing. Because the trial results were not consistent with previous positive clinical data for StaphVAX, the company conducted an assessment to determine the factors that led to these unexpected results. This panel was tasked with three main objectives: review and revise the plan; analyze the data; and provide direction for the future development of the company’s Gram-positive infections.
The first Phase III clinical study used vaccine produced at small scale in Nabi’s own research and development pilot manufacturing facility. The confirmatory Phase III study used vaccine produced at large scale by a contract manufacturer, Dow Chemical Co. Subsequent bridging and immunogenicity clinical studies completed in 2005 used vaccine lots produced by a second contract manufacturer, Cambrex Bio Science Baltimore, Inc. Nabi has now moved production to Cambrex, because their facility is configured to be licensable for the Europe Union.
In March 2006, Nabi announced it would continue development of StaphVAX [and also Altastaph or Staphylococcus aureus Immune Globulin Intravenous (Human)]. This was based on conclusions from the outside advisory panel’s review. The assessment revealed marked differences in the effectiveness of the lot of vaccine used in the confirmatory Phase III study compared to the lot used in the prior Phase III clinical study. The quality or functional characteristics of the antibodies generated by the vaccine used in the confirmatory clinical study were inferior to the antibodies generated by vaccine lots used in previous clinical studies. As an example, healthy animals dosed with the vaccines or with human antibodies generated from vaccines manufactured by Nabi Biopharmaceuticals were 100% protected from challenge against Type 8 S. aureus bacteria. In contrast, only 30-50% of the animals dosed with the vaccine or human antibodies from the lot used in the confirmatory Phase III study manufactured by Dow Chemical were protected against subsequent challenge with Type 8 S. aureus bacteria. Also, medical factors associated with kidney disease in dialysis patients impaired immune response to the vaccine. When considered in combination with an increase in the virulence of the bacteria, these factors also contributed to the observed lack of protection in this study population.
The company’s review has defined subtle but significant changes in the manufacturing process for the lot used in the confirmatory Phase III study. These resulted in differences in the capsular polysaccharide structure that are believed to be important for inducing high-quality and high-affinity antibodies. Nabi is already seeking patents concerning improvements in the manufacturing process. Nabi has also developed a new assay for antibody quality. This will be used to ensure that future vaccine and antibody product lots generate antibodies of optimal quality prior to initiating additional clinical studies.
Regarding future StaphVAX development, Nabi plans to incorporate additional S. aureus antigens and toxins released by the bacteria to broaden immune responses protection. Future clinical studies of the vaccine will be focused on larger at-risk patient populations who are healthier and more immune competent than dialysis patients; and development will focus initially on treating patients with active infections and preventing infection in high-risk, but healthier groups, in the hospital. A study will be initiated in first half of 2007 for StaphVAX incorporating S. aureus Types 5, 8 and 336 and S. epidermidis PS-1 antigens. The would cover the strains responsible for essentially 100% of healthcare-associated S. aureus infections, as well as the cause of an estimated 70% of healthcare-associated S. epidermidis infections.
Nabi now plans to seek a corporate partner for further development of StaphVAX (and Altastaph).
Tech. transfer: Univax/Nabi exclusively licensed StaphVax-related technology from the National Institutes of Health (NIH). This includes U.S. 5,204,098, “Polysaccharide-Protein Conjugates,” Apr. 20, 1993. This patent concerns bacterial capsular polysaccharides, e.g., S. aureus capsular polysaccharide, and chemical conjugation to a bacterial toxin protein, e.g., detoxified Pseudomonas exotoxin, to increase immune response to the polysaccharide component. The broadest claim reads, “A composition for enhancing the antibody response of a host comprising a capsular polysaccharide having carboxyl groups conjugated through a thio derivative of said carboxyl groups to a protein in a physiologically acceptable carrier.” A heterobifunctional cross-linking agent, such as N-succinimidyl 3-(-2-pyridyldithio)propionate, is used to bind thiol derivatives of polysaccharides to derivatized toxin proteins.
Nabi also received a nonexclusive license from the National Cancer Institute (NCI), NIH, for recombinant Pseudomonas aeruginosa exotoxin A mutein (mutant form) used in StaphVax. NCI researchers have received a number of related patents. However, these primarily involve exotoxins with increased toxicity (useful for immunotoxins), rather than detoxified versions; and Nabi licensed an unpatented toxin mutein..
Trials: Results from the first pivotal multicenter placebo-controlled Phase III trial of StaphVax in 1,804 ESRD patients were published in the New England Journal of Medicine in Feb. 2002. This study began in April 1998, and data collection was completed in May 2000. Study participants were evaluated at intervals for up to a year to evaluate safety and S. aureus infection rates. A single injection was shown to be safe and immunogenic, with no significant side effects attributable to the vaccine. At 10 months post-vaccination, a statistically significant reduction of almost 60% in S. aureus infections (bacteremia) was observed. However, only a 26% reduction was observed at one year post-vaccination, the study’s primary endpoint. The reduction in effectiveness between months 10 and 12 and failure to attain the primary endpoint was attributable to reduction in S. aureus polysaccharide antibody levels. StaphVAX was well tolerated, with ~38% of vaccinees and 20% of placebo recipients reporting mild to moderate reactogenicity, which resolved without intervention within 2 days.
StaphVax injection of ESRD patients induced high levels of S. aureus polysaccharide-specific antibodies, with levels peaking after 14 days, maintaining a plateau through 40 weeks, and then rapidly declining to baseline. At their peak, capsular polysaccharide antibody levels reached 230 µg/mL for type 5 and 206 µg/mL for type 8. However, at 54 weeks levels declined to 74 and 65.5 µg/mL, respectively. Efficacy is substantially reduced when geometric mean antibody levels fall below ~80 µg/mL. These results in end-stage renal disease patients were considered particularly promising, since patients are severely immune compromised and generally respond poorly to vaccines, i.e., less immune compromised patients would be expected to respond more favorably with higher antibody levels.
In May 2001, Nabi initiated a boosting study of Staph-VAX , administering a second dose of Nabi-StaphVAX to 100 patients enrolled in the original Phase III trial, with patients receiving this booster 2-3 years after their initial injection. Results were reported in 2002 from 79 patients. S. aureus capsular polysaccharide-specific antibody levels increased to about 60% of the peak levels achieved after the initial vaccination, with over 80% having ≥80 µg/mL antibody levels calculated as providing protection from infection, and a slower decline in levels than after the initial vaccination. Most booster recipients developed slight tenderness and erythema at the injection site that resolved itself within 48 hours. This supports repeated use, which will like be required for ESRD and other long-term immunocompromised patients.
In Sept. 2003, Nabi completed a bridging study of the immunogenicity of a lot of StaphVAX manufactured by Cambrex, its contract manufacturer. The study demonstrated comparability between Cambrex- and Nabi-Manufactured batches of StaphVax, including that used in the first Phase III trial. This allowed the confirmatory Phase III study to begin immediately using Cambrex-Manufactured StaphVax. In Oct. 2005, Nabi reported positive results from its consistency lots study, an open-labeled study in 354 healthy adults testing the safety and immune response of three commercial scale lots of StaphVAX produced by Cambrex Bio Science Baltimore, Inc.
A confirmatory, double-blind, placebo-controlled, randomized Phase III study was conducted in cooperation with major leading dialysis providers, and included 3,600 ESRD patients on hemodialysis at more than 400 main sites and sub sites across the U.S. Patient enrollment was completed in August 2004. This trial was designed to demonstrate statistical significance with a clinical reduction of 50% or more in types 5 and 8 S. aureus infections through 8 months post-vaccination, the peak efficacy point in the first Phase III trial. This trial included a booster vaccination at 8 months, after which vaccinees were followed up for up to 6 months to evaluate the vaccine’s ability to generate antibodies, efficacy and safety. Results had been expected to support filing of a BLA at the end of 2005.
In Jan. 2005, Nabi began a U.S. trial of StaphVax in 120 patients undergoing orthopedic surgery that involves the implantation of synthetic material (such as hip or knee replacement). Patients undergoing orthopedic surgery are at high risk of developing S. aureus bacteremia and subsequent infections because of the invasive nature of this surgery. The objective was to evaluate safety and antibody levels in these patients over a six-month period. Nabi expected this study will demonstrate that after vaccination with StaphVAX, this large at-risk patient group can achieve antibody levels equal to or greater than the levels proven to be protective in immune-compromised ESRD patients. In Sept. 2005, Nabi reported that StaphVax met the co-primary endpoints of safety and immune response. Results from the double-blind, 6-week portion of the trial showed that StaphVax caused 94% of the patients to have antibody levels above estimated protective levels.
In July 2005, Nabi initiated a Phase I study with a StaphVAX-like S. aureus type 336 vaccine.
In Sept. 2005, Nabi initiated a repeated dosing study to evaluate the ability of StaphVAX to provide continuous protection in end-stage renal disease (ESRD) patients on dialysis who are at high risk of contracting a S. aureus infection during their invasive and long-term treatment.
In Nov. 2005, Nabi reported that the confirmatory Phase III trial in dialysis patients failed to meet its primary endpoint. See the Status section for further discussion.
Disease: S. aureus is a major cause of hospital-acquired infections, particularly in kidney dialysis patients. Over 90% of these infections are due to S. aureus types 5 and 8. Surveys reported in 2001 and 2002 of clinical sites in the U.S., Canada and Europe by the SENTRY Antimicrobial Surveillance Program reported that S. aureus is the cause of 22% of all blood infections (septicemia), 23.2% of all lower respiratory tract infections, and 39.2% of all skin and soft tissue infections.
StaphVAX is intended for the estimated 12 million patients in the U.S. at risk for developing serious S. aureus infections. Those at greatest risk include: surgical patients, particularly those undergoing lengthy cardiac and orthopedic procedures; trauma and burn patients; those undergoing invasive outpatient procedures; patients receiving an implanted medical device or prosthetic; newborns whose immune systems are not yet developed; individuals in long-term care; kidney disease patients on dialysis; type 1 diabetics; and immune compromised patients, such as those with cancer, AIDS, or receiving immune suppressive treatment.
S. aureus community and hospital-acquired infections are among the most drug-resistant and most deadly bacterial infections. Current therapies include a variety of antibiotics whose efficacy is decreasing at an alarming rate due the rapid emergence of antibiotic-resistant bacteria. It is currently estimated that in intensive care units of U.S. hospitals, up to 55% of S. aureus infections are resistant to methicillin, the current antibiotic of last resort against antibiotic-resistant bacteria.
Normally, mucosal (mucous membrane) and epidermal (skin) barriers protect against S. aureus infections. When those barriers are broken as a result of injuries or as a consequence of medical treatment, particularly treatments requiring indwelling catheters like the ones used in dialysis, there is a significantly greater risk of infection. Once introduced into the bloodstream, S. aureus is largely undetected by the immune system and can spread to the bones (osteomyelitis) and to the inner lining of the heart and its valves (endocarditis) or cause abscesses in internal organs such as the lungs, liver and kidneys. Many of the factors that contribute to developing ESRD also compromise the immune system (e.g., diabetes, hypertension), further increasing the risk of infection and making these infections more difficult to treat. As a result, among patients receiving hemodialysis, S. aureus bacteremia is a prominent cause of illness, complications and death.
The end-stage renal disease (ESRD) patient population in the U.S. has grown dramatically in recent year. n 2002, an additional 100,359 dialysis and transplant patients initiated treatment for ESRD with the total number of patients receiving ESRD therapy was 431,284. ESRD is a condition that occurs when a person’s kidney function is not adequate to support life. With the kidneys no longer able to excrete wastes and urine or to regulate hormones, patients suffer severe complications and/or death without dialysis or a kidney transplant. Hemodialysis cleans a patient’s blood by filtering it through a machine, and patient receiving dialysis typically have a catheter inserted into a vein to facilitate blood exchange.
The number of new patients starting dialysis has increased 139% since 1988. The increases in incidence and prevalent rates of ESRD in the U.S. can be attributed to the aging baby boomer population; increased rates of diabetes, hypertension and obesity; and longer survival rates of ESRD patients. Due to the invasive nature of ESRD treatments (dialysis), infectious complications are the second leading cause of mortality in ESRD patients, accounting for nearly 20% of all deaths in 2001. Projections indicate the number of ESRD patients in the U.S. will reach 2 million by 2030 The growing resistance of S. aureus to antibiotics makes a prophylactic vaccines more needed.
In Sept. 2003, results of two pharmacoeconomic studies by Duke University Medical Center of the substantial costs and illness suffered by ESRD patients who develop S. aureus bacteremia were reported. These studies concluded that charges for treating serious S. aureus bacteremia total ~$33,000 per patient, and that mortality associated with these infections ranges from 10-45%. ESRD treatment costs are a major issue for Medicare/Medicaid programs and private insurers. ESRD patients account for 1% of the Medicare beneficiaries, but their treatment consumes 6.7% of the Medicare budget. The mean cost associated with treating S. aureus bacteremia among hemodialysis-dependent patients, including readmissions and outpatient costs, has been estimated to be $24,000 per patient per episode. These costs are significantly greater for ESRD patients with complicated versus uncomplicated S. aureus bacteremia, resulting in mean hospitalization costs of approximately $32,500. For those patients with infection from the methicillin-resistant S. aureus strain, there were even higher inpatient costs, longer hospitalizations and higher risk of death.
Medical: StaphVax is administered one time by intramuscular injection. Patients need to be immunized two or more weeks prior to catheter implantation or other procedure involving potential exposure to S. aureus infection.
R&D: In July 2003, Nabi Biopharmaceuticals began a Phase II clinical trial of Altastaph [Staphlyococcus aureus Immune Globulin Intravenous (Human)] in very low birth weight neonates (newborn infants weighing between 500 and 1,500 grams). Altastaph is S. aureus antibody-rich immune globulin from healthy persons having received vaccination with StaphVax.
Other companies are developing S. aureus vaccines or related products. For example Intercell AG and Merck & Co., Inc. are collaborating to develop S. aureus human monoclonal antibodies. Promising results from Phase I studies were reported in Dec. 2006.
Index Terms:
Companies involvement:
Full monograph
542 Staphylococcus vaccine (rDNA)
Nomenclature:
Staphylococcus vaccine (rDNA) [BIO]
StaphVax [TR]
Staphylococcus aureus Polysaccharide Conjugate Vaccine [SY]
Staphylococcus aureus types 5 and 8 capsular polysaccharides--Pseudomonas aeruginosa exotoxin A, recombinant, conjugates [SY]
FDA Class: Biologic BLA
biopharmaceutical products
conjugates
exempt from CBER lot release requirements
recombinant DNA
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
prothrombin, human
prothrombin, human
stannous gluconate
1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide
Bacillus anthracis prophylaxis
cyclosporine
ethanol
ethyl mercury
N-acetyl-O-acetyl mannosamine phosphate
phenol
phosphate buffered saline (PBS)
polysaccharides
prothrombin, human
stannous gluconate
stannous gluconate
North American coral snake
North American coral snake
EU000 Not yet/Never filed with EU
UM999 Not Available/Not Marketed in US
US000 never filed/no plans
EM999 Not Available/Not Marketed in EU
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