Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/02—Bacterial antigens
  • A61K39/085—Staphylococcus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/02—Bacterial antigens
  • A61K39/116—Polyvalent bacterial antigens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
  • A61K2039/6031—Proteins
  • A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]

Definitions

• the invention relates generally to the use of staphylococcal and enterococcal glycoconjugate vaccines in preventing or treating bacterial infection in an immune-compromised individual.
• Staphylococci and Enterococci rarely cause systemic infections in otherwise healthy individuals, and therefore are considered opportunistic pathogens.
• normal adult humans and animals with competent immune system attain an innate natural resistance to these bacterial infections.
• These include mucosal and epidermal barriers, in addition to possible immunological mechanisms. Interruption of these natural barriers as a result of injuries such as burns, traumas, or surgical procedures involving indwelling medical devices, increases the risk for staphylococcal and enterococcal infections.
• individuals with a compromised immune response such as cancer patients undergoing chemotherapy and radiation therapy, diabetes, AIDS, alcoholics, drug abuse patients, post organ transplantation patients and infants are at an increased risk for staphylococcal and enterococcal infections.
• Staphylococci are commensal bacteria of the anterior nares, skin, and the gastrointestinal tract of humans. It is estimated that staphylococcal infections account for >50% of all hospital acquired infections. S. aureus alone is responsible for 15-25% of such infections and is surpassed only by S. epidermidis which accounts for 35% of these infections. Staphylococcal infections, especially those caused by S. aureus are associated with high morbidity and mortality.
• Staphylococcus and enterococcus are a major cause of nosocomial and community-acquired infections, including bacteremia, metastatic abscesses, septic arthritis, endocarditis, osteomyelitis, and wound infections.
• bacteremia associated overall mortality for S. aureus is approximately 25 percent.
• a study of hospitalized patients in 1995 found that death rate, length of stay, and medical costs were twice as high for S. aureus -associated hospitalizations compared with other hospitalizations.
• S. aureus bacteremia is a prominent cause of morbidity and mortality in hemodialysis patients with an annual incidence of three to four percent. Contributing to the seriousness of S. aureus infections is the increasing percentage of isolates resistant to methicillin, and early reports of resistance to vancomycin. Hence, immunoprophylaxis against S. aureus is highly desired.
• S. aureus CPS capsular polysaccharides
• PMN polymorphonuclear neutrophils
• S. aureus CPS confer invasiveness by inhibiting opsonphagocytic killing by polymorphonuclear neutrophils (PMN), similar to other encapsulated bacteria, such as Streptococcus pneumoniae . This enables the bacteria to persist in the blood, where they elaborate several different virulence factors, including toxins and extracellular enzymes.
• PMN polymorphonuclear neutrophils
• Types 5 and 8 account for approximately 85 percent of all clinical isolates. Most of the remaining isolates carry a more-recently identified antigen known as Type 336.
• Antibodies to Types 5, 8 and 336 CPS induce type-specific opsonophagocytic killing by human PMNs in vitro, and confer protection in animal infection models.
• Staphylococci have developed very sophisticated mechanisms for inducing diseases in humans, including both intracellular and extracellular factors.
• S. aureus possesses other surface antigens that facilitate its survival in the blood stream by helping the bacteria to evade phagocytic killing by the host leukocytes.
• These surface antigens include cell wall components such as teichoic acid, protein A, and capsular polysaccharides (CPS). Due in part to the versatility of these bacteria and their ability to produce extracellular products that enhance infectivity and pathogenesis, staphylococcal bacteremia and its complications such as endocarditis, septic arthritis, and osteomyelitis continue to be serious and frequently observed nosocomial infections.
• Antibiotics such as penicillin have been used successfully against both staphylococcal and enterococcal infections in humans, but more recently the effectiveness of such antibiotics has been thwarted by the ability of bacteria to develop resistance.
• methicillin a newer synthetic antibiotic
• strains of methicillin-resistant S. aureus were isolated. Antibiotic resistance among staphylococcal isolates from nosocomial infections continues to increase in frequency, and resistant S. aureus strains continue to cause epidemics in hospitals in spite of developed preventive procedures and extensive research into bacterial epidemiology and antibiotic development.
• Enterococci resistant to vancomycin are now emerging, and methicillin-resistant S. aureus organisms with intermediate resistance to vancomycin have been identified in some centers. Cross transfer of resistance will eventually lead to the widespread development of organisms that are more difficult to eradicate.
• Vaccines that are immunogenic in healthy vaccinees are often found to be less or nonimmunogenic in immunocompromised patients, and thus to provide an insufficient level of protection.
• the immune response of hemodialysis patients to hepatitis B vaccine was shown to be reduced to 50-80% of that seen in healthy vaccinees.
• the immune response of elderly patients to this vaccine was reduced to 46%. Pirofski and Casadevall, Clin. Microbiol. Rev. 11:1-26 (1998).
• Bacterial capsular polysaccharides are generally poor immunogens. Their immunogenicity in humans is known to be related to their molecular size and the age of the vaccinee. Infants below the age of two years, the elderly, and other immune-compromised patients are typically poor responders to CPS vaccines. While polysaccharide vaccines have been developed for some primary bacterial pathogens that induce acute diseases in normal individuals, namely, Streptococcus pneumoniae, Neisseria meningitidis and Hemophilus influenzae, none have been described specifically for treatment of opportunistic bacteria. Furthermore, when these vaccines were tested in immune-compromised individuals, a rapid decline in the immune response was observed, resulting in a lack of effective protection.
• Live vaccines generally are more immunogenic, but present a concern when vaccinating immune-compromised patients. Although the viral and bacterial strains used in such vaccines are attenuated, some of the strains can revert back and cause disease. Immunization with a bacterial component vaccine especially is preferred for immune-compromised patients, such as chemotherapy patients, hemodialysis patients, infants, shock trauma patients, surgical patients, and others with reduced resistance or partially compromised immune systems.
• Polysaccharide antigens normally generate a T-cell independent immune response and they induce humoral antibodies with no boost of the immune response observed upon reinjection.
• conjugation of polysaccharide to protein carriers can alter bacterial CPS antigens to make them T-cell dependent immunogens, thus increasing their immunogenicity and potentiating their use in infants and immune-compromised patients.
• Immune-compromised individuals often are at high risk for bacterial infections, for example, from procedures such as catheterization. Given their poor immune response, exposure to an infectious strain of bacteria is likely to lead to a high level of infection. The fact that many bacterial strains have developed resistance to many or all current antibiotics increases the likelihood of a negative outcome when an immune-compromised individual does develop a bacterial infection. Therefore, it would be highly desirable to vaccinate immune-compromised against common clinically-significant bacterial strains. However, bacterial antigens such as the staphylococcal and enterococcal polysaccharide antigens are known to be poor immunogens.
• conjugates of certain staphylococcal and enterrococcal polysaccharide and glycopeptide bacterial surface antigens are effective in protecting against bacterial infection in immune-compromised individuals.
• bivalent vaccines containing S. aureus Types 5 or 8 CPS bound to recombinant exoprotein A (rEPA), a nontoxic variant of Pseudomonas aeruginosa exotoxin A expressed in Escherichia coli were immunogenic and well-tolerated in healthy adults and in patients with end-stage renal disease (ESRD), and, more importantly, were able to prevent bacteremia in ESRD hemodialysis patients.
• rEPA recombinant exoprotein A
• ESRD end-stage renal disease
• ESRD patients on hemodialysis are the patients with the most severe conditions among at-risk adult populations. They are mostly elderly, many are diabetic ( ⁇ 50%), and they routinely suffer from uremia. Uremia and hyperglycemia have a major debilitating impact on host defense mechanisms, especially opsonophagocytosis. These conditions cause major impairment of immune function via impaired complement or phagocyte functionality. ESRD patients typically have depressed neutrophil function and impaired phagocytosis, leukopenia secondary to complement activation, reduced natural killer cell activity, decreased T and B lymphocyte function, and decreased T lymphocyte response to standard antigens. The ability of vaccines according to the invention to protect such a highly immune-compromised target population could not have been predicted.
• the present invention comprehends the protecting of an immune-compromised human from at least one of Staphylococcal and Enterococcal bacterial infection.
• the vaccine comprises a glyconjugate of a polysaccharide or glycopeptide bacterial surface antigen and an immunocarrier.
• the inventive approach entails administering the vaccine to immune-compromised individuals in a dose that produces a serotype-specific antibody level in the immune-compromised individual that is comparable to that achievable in normal healthy subjects in response to the vaccine.
• the vaccine comprises:
• the vaccine produces in immune-compromised individuals a level of serotype-specific antibody to the antigens contained in the vaccines that is the same, within the limits of expected experimental variation, to the level that is achieved in normal healthy subjects when they are immunized with a vaccine that contains glyconjugates.
• immune-compromised individuals can be protected effectively against bacterial infection by administering a vaccine that contains, with an immunocarrier, a conjugate of a polysaccharide or glycopeptide surface antigen from a clinically-significant staphylococcal or enterococcal bacterial strain.
• a “clinically-significant” bacterial strain is one that is pathogenic in humans.
• the vaccine can be used for active protection in immune-compromised individuals that are about to be subjected to conditions which place them at immediate risk of developing a bacterial infection. These conditions would include, for example, catheterization or a surgical procedure.
• the present inventors found that immune-compromised individuals mounted an effective immune response when vaccinated with a vaccine according to the present invention.
• Immune-compromised individuals may suffer a deficiency with respect to either or both of the cellular and the humoral arm of the immune system. Both of these arms combat infectious diseases.
• Bacterial infections in particular, are cleared mainly by two mechanismsa: bactericidal activity, which requires both antibodies and complement, and opsonophagocytosis, which requires phagocytes in addition to complement and antibodies.
• bactericidal activity which requires both antibodies and complement
• opsonophagocytosis which requires phagocytes in addition to complement and antibodies.
• Each of the steps in these processes may suffer from a defect that will impact to a different extent the functionality of the whole process, any such defect results in a host that is “immune-compromised.”
• ESRD patients provide an excellent model for predicting the ability of a vaccine to protect an immune-compromised, because so many aspects of the immune response are compromised in such patients. For example, many of these patients have diabetes, or hyperglycemia, which interferes with complement fixation. The inability to fix complement limits the usefulness of antibodies in these patients. Moreover, phagocytes may, as a result of diabetes, have weakened chemotactic movement which, in turn, may result in their inability to reach the location of an infection. Hemodialysis patients also suffer from uremia which impacts the functionality of granulocytes and complement fixation, resulting in inefficient opsonophagocytosis. Diabetes and uremia also impact the functionality of B cells that results in lower than optimal immune response to vaccination.
• a polysaccharide or glycopeptide surface antigen is one that contains a major proportion of carbohydrate residues. Antigens that comprise only carbohydrate residues are referred to as polysaccharide antigens. Some bacterial surface antigens additionally contain a smaller proportion of amino acid residues, typically less than 40% by weight of the antigen, in which case they are referred to as glycopeptide antigens. Bacterial surface antigens according to the present invention may be capsular polysaccharides, or they may comprise teichoic acid.
• a variety of staphylococcal and enterococcal bacterial surface antigens have been identified as suitable for preparation of a conjugate vaccine according to the present invention.
• these include polysaccharide and glycopeptide antigens found on various strains of S. aureus, S. epidermidis, S. haemolyticus or S. hominis, E. faecium and E. faecalis.
• Antigens for the preparation of a conjugate vaccines according to the present invention include the Type 5 and Type 8 antigens of S. aureus .
• Surveys have shown that approximately 85-90% of isolates are capsular polysaccharide Type 5 or Type 8.
• Normal individuals vaccinated with a vaccine containing Type 5 and Type 8 capsular polysaccharide antigens are protected from infection by 85-90% of S. aureus strains.
• the structures of Types 5 and 8 polysaccharide antigens have been elucidated by Moreau et al., Carbohydr. Res. 201:285 (1990); and Fournier et al., Infect. Imm. 45:87 (1984). Both have FucNAcp in their repeat unit as well as ManNAcA which can be used to introduce a sulfhydryl group.
• the structures are as follows:
• a preferred vaccine according to the present invention includes conjugates of both the Type 5 and Type 8 antigens. It is particularly surprising that this bivalent vaccine provides an excellent level of protection in immune-compromised individuals. Welch et al (1996), supra, discloses that a monovalent Type 5 vaccine produces a very limited immune response in ESRD patients. The protection achieved with a bivalent Type 5/Type 8 S. aureus vaccine according to the present invention could not have been forseen based on the poor result reported in Welch et al., particularly when coupled with a teaching in the art that the addition of a second component antigen to a vaccine actually decreases the efficacy of each component individually. Fattom et al. 17:126-133 (1999).
• Staphylococcus antigen that can be used in the preparation of conjugates according to the invention is described in U.S. Pat. No. 5,770,208 and No. 6,194,161.
• This negatively-charged antigen comprises ⁇ -linked hexosamine as a major carbohydrate component, and contains no O-acetyl groups detectable by nuclear magnetic resonance spectroscopy.
• the antigen specifically binds with antibodies to S. aureus Type 336 deposited under ATCC 55804.
• S. aureus strains that carry this antigen account for nearly all of the clinically significant strains of S. aureus that are not Type 5 or Type 8 strains.
• a conjugate vaccine prepared with a so-called Type 1 antigen as disclosed in U.S. Pat. Nos. 5,961,975 and 5,866,140 is preferred.
• This antigen is an acidic polysaccharide antigen that is obtained by a process that comprises growing cells of an isolate of S.
• epidermidis that agglutinates antisera to ATCC 55254 (a Type I isolate); extracting polysaccharide antigen from the cells to produce a crude extract of polysaccharide antigen; purifying this crude extract to produce purified antigen that contains less than 1% protein; loading the purified antigen on a separatory column and eluting it with a NaCl gradient; and identifying fractions containing the polysaccharide antigen using antibodies specific to a Type I isolate.
• Staphylococcus antigen for the preparation of conjugate vaccines according to the present invention is described in WO 00/56357.
• This antigen comprises amino acids and a N-acetylated hexosamine in an a configuration, contains no O-acetyl groups detectable by nuclear magnetic resonance spectroscopy, and contains no hexose. It specifically binds with antibodies to a Staphylococcus strain deposited under ATCC 202176.
• Amino acid analysis of the antigen shows the presence of serine, alanine, aspartic acid/asparagine, valine, and threonine in molar ratios of approximately 39:25:16:10:7. Amino acids constitute about 32% by weight of the antigen molecule.
• conjugate vaccines with Enterococcus antigens as described in WO 99/18996 are preferred according to the invention.
• This application discloses five different antigens, two of which are isolated from E. faecalis strains and three of which are isolated from E. faecium strains. Representatives of each of the two E. faecalis and three E. faecium strains have been deposited under the Budapest Treaty with the American Type Culture Collection, and have been given Accession Nos. 202013 ( E. faecalis EFS1), 202014 ( E. faecalis EFS2), 202015 ( E.
• Antigen for use in the present invention can be isolated from the deposited strains, or the deposited strains can be used to identify other strains which express antigen according to the invention, from which antigen may be extracted and purified.
• One of the E. faecalis antigens, EFS1 comprises 2-acetamido-2-deoxy-glucose, rhamnose, glucose and 2-acetamido-2-deoxy-galactose in an approximate calculated molar ratio of 1:2:2:2, another E.
• EFS2 comprises a trisaccharide repeat which comprises a 6-deoxy sugar
• EFM3 comprises 2-acetamido-2-deoxy-galactose and galactose.
• each of the foregoing antigens can be obtained in recoverable amount, from certain Staphylococcus and Enterococcus isolates cultured pursuant to the protocols described in the cited documents, in substantially pure form.
• the purified antigens contain less than 1% nucleic acids.
• a “recoverable” amount in this regard means that the isolated amount of the antigen is detectable by a methodology less sensitive than radiolabeling, such as immunoassay, and can be subjected to further manipulations involving transfer of the antigen per se into solution.
• an antigen is conjugated to an immunocarrier.
• An immunocarrier is a substance, usually a polypeptide or protein, which improves the interaction between T and B cells for the induction of an immune response against the antigen and thus enhances immunogenicity both for active immunization and for preparing high-titered antisera in volunteers for use in subsequent passive immunization.
• Suitable immunocarriers include tetanus toxoid and diphtheria toxoid and recombinantly produced, genetically detoxified variants thereof, Staphylococcal exotoxin or toxoid, Pseudomonas aeruginosa Exotoxin A or its derivatives, including particularly recombinantly-produced non-toxic mutant strains of Pseudomonas aeruginosa Exotoxin A, as described, for example, in Fattom et al., Inf and Imm. 61: 1023-1032 (1993), as well as other proteins commonly used as immunocarriers.
• the antigen is first derivatized.
• Various methods can be used to derivatize antigen and covalently link it to an immunocarrier.
• Activated carboxylate groups of the antigen can be derivatized with ADH, cystamine or PDPH, and then the antigen can be coupled to a carrier protein either by a carbodiimide-mediated reaction of the partially-amidated antigen to a carboxylate group on the carrier protein or by disulfide interchange of thiolated antigen with an SPDP-derivatized carrier protein.
• Hydroxyl groups on the antigen can be activated using cyanogen bromide or 1-cyano-4-dimethylamino-pyridinium tetrafluoroborate, and then the antigen can be derivatized with the six carbon bifunctional spacer adipic acid dihydrazide (ADH), according to techniques known in the art, according to the method of Kohn et al. FEBS Lett. 154: 209:210 (1993).
• ADH six carbon bifunctional spacer adipic acid dihydrazide
• This material then is linked to diphtheria toxoid (Dtd), recombinant exoprotein A from Pseudomonas aeruginosa (rEPA), tetanus toxoid (TTd) or another suitable carrier protein by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC).
• Dtd diphtheria toxoid
• rEPA Pseudomonas aeruginosa
• TTd tetanus toxoid
• EDAC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
• the antigen-immunocarrier conjugate according to the present invention is the active ingredient in a composition, further comprising a pharmaceutically acceptable carrier for the active ingredient, and is used as a vaccine to induce a cellular immune response and/or production in vivo of antibodies which combat bacterial infections in immune-compromised populations, particularly Staphylococcus and/or Enterococcus infections.
• a pharmaceutically acceptable carrier is a material that can be used as a vehicle for administering a medicament because the material is inert or otherwise medically acceptable, as well as compatible with the active agent, in the context of vaccine administration.
• a pharmaceutically acceptable carrier can contain conventional vaccine additives like diluents, adjuvants and other immunostimulants, antioxidants, preservatives and solubilizing agents.
• the vaccine according to the invention can be administered with or without an adjuvant. If an adjuvant is used, it is selected so as to avoid adjuvant-induced toxicity.
• a vaccine according the invention additionally may comprise a ⁇ -glucan or granulocyte colony stimulating factor, in particular, a ⁇ -glucan as described in U.S. application serial No. 09/395,360, filed Sep. 14, 1999.
• a composition of the antigen/immunocarrier conjugate according to the present invention “consists essentially of” the conjugate.
• the phrase “consists essentially of” means that the composition does not contain any material that interferes with elicitation of an immune response to the antigen (and to other antigens, if present) when the composition is administered to a subject as a vaccine.
• ESRD end stage renal disease
• cancer patients on immunosuppressive therapy cancer patients on immunosuppressive therapy
• AIDS patients diabetic patients, the elderly in extended care facilities
• patients with autoimmune disease on immunosuppressive therapy transplant patients, and burn patients.
• the immune system is composed of two arms, the cellular and the humoral arm. Both of these arms combat infectious diseases.
• Bacterial infections in particular are cleared mainly by two mechanisms. Bactericidal activity which includes antibodies and complement, and opsonophagocytosis which in addition to complement and antibodies, phagocytes are essential. Each of these steps in these processes may suffer from a defect that will impact to a different extent the functionality of the whole process.
• Any such defect make the host an immunocompromised person.
• Examples for such unfunctional or compromised mechanisms can occur as a result of diabetes.
• Diabetes or hyperglycemia interferes with the complement fixation. So even if a person have enough antibodies, the inability to fix complement render these antibodies of limited use.
• phagocytes may, as a result of diabetes, have weakened chemotactic movement which, in turn, may result in their inability to reach the location of an infection.
• Hemodialysis patients suffer from uremia which impacts the functionality of granulocytes and complement fixation, resulting in inefficient opsonophagocytosis.
• diabetes and uremia impact the functionality of B cells that results in lower than optimal immune response to vaccination.
• ESRD end stage renal disease
• rEPA Pseudomonas exoprotein
• Inclusion criteria were: age 18 years or older, ESRD on hemodialysis using a native vessel fistula or a synthetic/heterologous graft access for at least 8 weeks prior to enrollment, Karnofsky score of at least 50 at entry, and expected to complete the required follow-up visits.
• Exclusion criteria were: symptoms or signs consistent with an infection within the 2 weeks prior to vaccination, history of HIV infection, hypersensitivity or previous anaphylaxis caused by polysaccharide or polysaccharide-conjugate vaccines, drug abuse in the past year, use of immunosuppressive or immunomodulatory drugs, and malignancy or treatment for malignancy within 6 months prior to vaccination.
• Eligible subjects were assigned randomly to receive a single injection of vaccine or placebo. Randomization was stratified by (1) vascular access (native-vessel fistula or synthetic/heterologous graft) and (2) presence or absence of persistent S. aureus nasal carriage.
• the vaccine (StaphVAX®, supplied by Nabi, Rockville, Md.) was composed of S. aureus Type 5 and Type 8 CPS (100 ⁇ g/type/mL) conjugated to an equal weight of recombinant Pseudomonas aeruginosa non-toxic exotoxin A (rEPA), in 0.01 percent polysorbate 80 and sodium phosphate-buffered saline, pH 7.4. This dose was selected on the basis of studies in patients with ESRD (Nabi, unpublished data). Vaccine and placebo (sodium phosphate-buffered saline) were supplied as 1 mL of clear liquid in identical vials, each bearing a unique code.
• Subjects were evaluated 30 minutes after the injection and instructed to record local (redness, swelling, aching, burning, tenderness, heat) and systemic (fever, general discomfort, muscle ache, headache, nausea, vomiting) reactions each day for 1 week.
• local redness, swelling, aching, burning, tenderness, heat
• systemic fever, general discomfort, muscle ache, headache, nausea, vomiting
• Subjects were evaluated for adverse events up to 6 weeks after the injection. Deaths and all bacteremias were recorded until the study ended or the subject withdrew.
• the primary outcome measure was a subject's first occurrence of S. aureus bacteremia. Blood cultures were obtained before beginning antibiotic therapy.
• Sera were obtained prior to and 6, 26, 54, and 67 weeks after vaccination.
• Antibodies to the S. aureus Type 5 and Type 8 CPS were measured by ELISA, as described in Fattom et al., Infect Immun 1990;58:67-74 and Fattom et al., Infect Immun 1993;61:1023-32.
• a vaccine response was defined as a concentration of antibody of at least 25 ⁇ g/mL and at least two-fold greater than the prevaccination level.
• SAS PROC GENMOD logistic regression models
• the vaccinees and controls contributed a median time on study of 75 weeks and 74 weeks, respectively, with 76 percent of the subjects in each group on study for at least 54 weeks.
• the two groups were similar in pretreatment demographics and clinical characteristics, and were representative of the diversity of California.
• the subjects were 33 percent Caucasian, 31 percent Hispanic, 23 percent Black, and 13 percent Asian.
• 894 vaccinees and 910 controls there were 46 and 44 percent female subjects, and 52 and 51 percent diabetics, respectively.
• At vaccination 69 percent of subjects in both groups had graft access, and 22 percent were nasal carriers in both groups.
• the mean age in both groups was 58.3 years.
• the vaccine and control groups had a similar distribution of S. aureus types among bacteremic patients. It was not possible to retrieve 13 of 37 isolates in the vaccine group and 12 of 49 in the placebo group for typing. In the vaccine group, 8 (33 percent) were Type 5, and 11 (46 percent) were Type 8. Five (21 percent) were Type 336. In the placebo group, 10 (27 percent) were type 5, 20 (54 percent) were type 8, and 7 (19 percent) were Type 336. Type distribution of S. aureus isolates from bacteremic patients in this study was consistent with results reported by others. Methicillin resistance was found in 7 of 37 S. aureus isolates in the vaccine group and 12 of 48 in the placebo group (one isolate from a control was not tested). The similar distribution of methicillin resistance among isolates from both the vaccine and placebo groups is consistent with in vitro data showing that both antibiotic-resistant and -sensitive S. aureus are killed by antibody-mediated opsonophagocytosis.
• Type 8 Evaluation Time N ( ⁇ g/mL) ( ⁇ g/mL) N ( ⁇ g/mL) ( ⁇ g/mL) Pretreatment 892 5.9 8.6 910 5.7 8.6 Week 6 884 230 206 900 5.6 8.6 Week 26 838 120 100 859 5.8 8.9 Week 54 763 74.2 64.5 776 5.7 8.9 Week 67 507 78.1 65.8 512 6.2 9.4
• the minimal protective level of antibodies in patients with ESRD was calculated to be approximately 80 ⁇ g/mL, which is 2-3 logs higher than the protective levels of CPS antibodies of Haemophilus influenzae type b and Streptococcus pneumoniae , (0.15 and 1 ⁇ g/mL, respectively).
• the difference in protective antibody level may be attributable to impaired phagocyte function and underlying disease in patients with ESRD.
• identification of a protective antibody level for this patient population provides a surrogate for clinical efficacy of this vaccine in other at-risk patients.
• Nasal carriage has been associated with an increased risk of S. aureus bacteremia among hemodialysis patients.
• S. aureus is the most common pathogen of vascular access site infection, and it is the most frequent cause of access-related bacteremias. Although the numbers are small, it appears that nasal carriage put controls, but not vaccinee, at higher risk of bacteremia. This suggests that vaccination protected against an increased risk of S. aureus infection associated with nasal carriage.
• the bivalent vaccine induced statistically significant protection against all S. aureus bacteremias. Efficacy is increased following addition of other antigens, particularly Type 336 antigen.
• S. aureus Type 5 and Type 8 CPS-recombinant Pseudomonas aeruginosa non-toxic exotoxin A (rEPA) conjugate vaccine (StaphVAX®) was evaluated for its safety, immunogenicity, and efficacy in a double-blinded, randomized, placebo-controlled study of end-stage renal disease (ESRD) patients maintained on hemodialysis.
• ESRD end-stage renal disease
• IgG antibodies to Types 5 and 8 CPS were measured at intervals for up to 2 years, and episodes of S. aureus bacteremia were recorded. Efficacy was determined by comparing the attack rate of S. aureus bacteremia in the vaccine group to that of the controls.

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