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Infect Immun. 1993 Mar; 61(3): 1023–1032.
PMCID: PMC302834

Laboratory and clinical evaluation of conjugate vaccines composed of Staphylococcus aureus type 5 and type 8 capsular polysaccharides bound to Pseudomonas aeruginosa recombinant exoprotein A.

Abstract

The synthesis, standardization, and immunogenicity in young outbred mice and clinical evaluation in adult volunteers of investigational vaccines designed to induce serum antibodies to the type 5 and type 8 capsular polysaccharides (CPs) of Staphylococcus aureus are described. Conjugates composed of the type 5 CP and a sonicated preparation of a high-molecular-weight type 8 CP bound to a nontoxic recombinant protein derived from Pseudomonas aeruginosa exotoxin A (rEPA) were synthesized. The conjugates were nontoxic and elicited serum CP antibodies after two subcutaneous injections into young outbred mice; a third injection elicited a booster response. The lower-molecular-weight type 8 CP was not immunogenic in the mice, and the high-molecular-weight type 8 CP elicited low levels of antibodies without a booster effect. In the volunteers, neither the conjugates nor the type 8 CP alone caused significant local reactions or fever. The conjugates elicited type-specific antibodies of both the immunoglobulin M (IgM) and IgG classes after the first injection; a second injection 6 weeks later did not stimulate a booster effect. The high-molecular-weight type 8 CP alone, injected once only, elicited levels of IgG and IgM type-specific antibodies similar to those of the conjugate. The vaccine-induced CP antibodies were mostly of the IgG1 and IgG2 subclasses and had opsonophagocytic activity. The conjugates elicited IgG antibodies to the native exotoxin A with neutralizing activity. In summary, the type 5 and type 8 conjugates were safe and elicited biologically active antibodies to both the CP and rEPA components.

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  • Arbeit RD, Karakawa WW, Vann WF, Robbins JB. Predominance of two newly described capsular polysaccharide types among clinical isolates of Staphylococcus aureus. Diagn Microbiol Infect Dis. 1984 Apr;2(2):85–91. [PubMed]
  • Boutonnier A, Nato F, Bouvet A, Lebrun L, Audurier A, Mazie JC, Fournier JM. Direct testing of blood culture for detection of the serotype 5 and 8 capsular polysaccharides of Staphylococcus aureus. J Clin Microbiol. 1989 May;27(5):989–993. [PMC free article] [PubMed]
  • Douglas CM, Collier RJ. Exotoxin A of Pseudomonas aeruginosa: substitution of glutamic acid 553 with aspartic acid drastically reduces toxicity and enzymatic activity. J Bacteriol. 1987 Nov;169(11):4967–4971. [PMC free article] [PubMed]
  • Carlsson J, Drevin H, Axén R. Protein thiolation and reversible protein-protein conjugation. N-Succinimidyl 3-(2-pyridyldithio)propionate, a new heterobifunctional reagent. Biochem J. 1978 Sep 1;173(3):723–737. [PMC free article] [PubMed]
  • Mortality patterns--United States, 1988. MMWR Morb Mortal Wkly Rep. 1991 Jul 26;40(29):493–502. [PubMed]
  • Chaudhary VK, Jinno Y, FitzGerald D, Pastan I. Pseudomonas exotoxin contains a specific sequence at the carboxyl terminus that is required for cytotoxicity. Proc Natl Acad Sci U S A. 1990 Jan;87(1):308–312. [PMC free article] [PubMed]
  • Cisse MF, Ba M, Sow AI, Samb A. Infections néonatales bacteriennes en zone tropicale. Med Trop (Mars) 1991 Oct-Dec;51(4):429–433. [PubMed]
  • Claesson BA, Trollfors B, Lagergard T, Taranger J, Bryla D, Otterman G, Cramton T, Yang Y, Reimer CB, Robbins JB, et al. Clinical and immunologic responses to the capsular polysaccharide of Haemophilus influenzae type b alone or conjugated to tetanus toxoid in 18- to 23-month-old children. J Pediatr. 1988 May;112(5):695–702. [PubMed]
  • Cryz SJ, Jr, Sadoff JC, Fürer E. Immunization with a Pseudomonas aeruginosa immunotype 5 O polysaccharide-toxin A conjugate vaccine: effect of a booster dose on antibody levels in humans. Infect Immun. 1988 Jul;56(7):1829–1830. [PMC free article] [PubMed]
  • Dobkin JF, Miller MH, Steigbigel NH. Septicemia in patients on chronic hemodialysis. Ann Intern Med. 1978 Jan;88(1):28–33. [PubMed]
  • Douglas CM, Guidi-Rontani C, Collier RJ. Exotoxin A of Pseudomonas aeruginosa: active, cloned toxin is secreted into the periplasmic space of Escherichia coli. J Bacteriol. 1987 Nov;169(11):4962–4966. [PMC free article] [PubMed]
  • Fass R, van de Walle M, Shiloach A, Joslyn A, Kaufman J, Shiloach J. Use of high density cultures of Escherichia coli for high level production of recombinant Pseudomonas aeruginosa exotoxin A. Appl Microbiol Biotechnol. 1991 Oct;36(1):65–69. [PubMed]
  • Fattom A, Lue C, Szu SC, Mestecky J, Schiffman G, Bryla D, Vann WF, Watson D, Kimzey LM, Robbins JB, et al. Serum antibody response in adult volunteers elicited by injection of Streptococcus pneumoniae type 12F polysaccharide alone or conjugated to diphtheria toxoid. Infect Immun. 1990 Jul;58(7):2309–2312. [PMC free article] [PubMed]
  • Fattom A, Schneerson R, Szu SC, Vann WF, Shiloach J, Karakawa WW, Robbins JB. Synthesis and immunologic properties in mice of vaccines composed of Staphylococcus aureus type 5 and type 8 capsular polysaccharides conjugated to Pseudomonas aeruginosa exotoxin A. Infect Immun. 1990 Jul;58(7):2367–2374. [PMC free article] [PubMed]
  • Fattom A, Shiloach J, Bryla D, Fitzgerald D, Pastan I, Karakawa WW, Robbins JB, Schneerson R. Comparative immunogenicity of conjugates composed of the Staphylococcus aureus type 8 capsular polysaccharide bound to carrier proteins by adipic acid dihydrazide or N-succinimidyl-3-(2-pyridyldithio)propionate. Infect Immun. 1992 Feb;60(2):584–589. [PMC free article] [PubMed]
  • Foster TJ. Potential for vaccination against infections caused by Staphylococcus aureus. Vaccine. 1991 Apr;9(4):221–227. [PubMed]
  • Fournier JM, Bouvet A, Boutonnier A, Audurier A, Goldstein F, Pierre J, Bure A, Lebrun L, Hochkeppel HK. Predominance of capsular polysaccharide type 5 among oxacillin-resistant Staphylococcus aureus. J Clin Microbiol. 1987 Oct;25(10):1932–1933. [PMC free article] [PubMed]
  • Fournier JM, Vann WF, Karakawa WW. Purification and characterization of Staphylococcus aureus type 8 capsular polysaccharide. Infect Immun. 1984 Jul;45(1):87–93. [PMC free article] [PubMed]
  • Heidelberger M, Macpherson CF. QUANTITATIVE MICRO-ESTIMATION OF ANTIBODIES IN THE SERA OF MAN AND OTHER ANIMALS. Science. 1943 Apr 30;97(2522):405–406. [PubMed]
  • Hochkeppel HK, Braun DG, Vischer W, Imm A, Sutter S, Staeubli U, Guggenheim R, Kaplan EL, Boutonnier A, Fournier JM. Serotyping and electron microscopy studies of Staphylococcus aureus clinical isolates with monoclonal antibodies to capsular polysaccharide types 5 and 8. J Clin Microbiol. 1987 Mar;25(3):526–530. [PMC free article] [PubMed]
  • Iglewski BH, Sadoff JC. Toxin inhibitors of protein synthesis: production, purification, and assay of Pseudomonas aeruginosa toxin A. Methods Enzymol. 1979;60:780–793. [PubMed]
  • Jinno Y, Ogata M, Chaudhary VK, Willingham MC, Adhya S, FitzGerald D, Pastan I. Domain II mutants of Pseudomonas exotoxin deficient in translocation. J Biol Chem. 1989 Sep 25;264(27):15953–15959. [PubMed]
  • Karakawa WW, Fournier JM, Vann WF, Arbeit R, Schneerson RS, Robbins JB. Method for the serological typing of the capsular polysaccharides of Staphylococcus aureus. J Clin Microbiol. 1985 Sep;22(3):445–447. [PMC free article] [PubMed]
  • Karakawa WW, Sutton A, Schneerson R, Karpas A, Vann WF. Capsular antibodies induce type-specific phagocytosis of capsulated Staphylococcus aureus by human polymorphonuclear leukocytes. Infect Immun. 1988 May;56(5):1090–1095. [PMC free article] [PubMed]
  • Legaard PK, LeGrand RD, Misfeldt ML. Lymphoproliferative activity of Pseudomonas exotoxin A is dependent on intracellular processing and is associated with the carboxyl-terminal portion. Infect Immun. 1992 Apr;60(4):1273–1278. [PMC free article] [PubMed]
  • Liau DF, Hash JH. Structural analysis of the surface polysaccharide of Staphylococcus aureus M. J Bacteriol. 1977 Jul;131(1):194–200. [PMC free article] [PubMed]
  • LOURIA DB, BLUMENFELD HL, ELLIS JT, KILBOURNE ED, ROGERS DE. Studies on influenza in the pandemic of 1957-1958. II. Pulmonary complications of influenza. J Clin Invest. 1959 Jan;38(1 Pt 2):213–265. [PMC free article] [PubMed]
  • Ludlam HA, Young AE, Berry AJ, Phillips I. The prevention of infection with Staphylococcus aureus in continuous ambulatory peritoneal dialysis. J Hosp Infect. 1989 Nov;14(4):293–301. [PubMed]
  • Lukac M, Pier GB, Collier RJ. Toxoid of Pseudomonas aeruginosa exotoxin A generated by deletion of an active-site residue. Infect Immun. 1988 Dec;56(12):3095–3098. [PMC free article] [PubMed]
  • McGowan JE, Jr, Barnes MW, Finland M. Bacteremia at Boston City Hospital: Occurrence and mortality during 12 selected years (1935-1972), with special reference to hospital-acquired cases. J Infect Dis. 1975 Sep;132(3):316–335. [PubMed]
  • Moreau M, Richards JC, Fournier JM, Byrd RA, Karakawa WW, Vann WF. Structure of the type 5 capsular polysaccharide of Staphylococcus aureus. Carbohydr Res. 1990 Jul 1;201(2):285–297. [PubMed]
  • Neville LO, Billington OJ, Kibbler CC, Gillespie SH. Methicillin resistant Staphylococcus aureus without clumping factor, protein A, and DNAse. Lancet. 1991 Aug 24;338(8765):518–518. [PubMed]
  • Nolan CM, Beaty HN. Staphylococcus aureus bacteremia. Current clinical patterns. Am J Med. 1976 Apr;60(4):495–500. [PubMed]
  • Pollack M, Callahan LT, 3rd, Taylor NS. Neutralizing antibody to Pseudomonas aeruginosa exotoxin in human sera: evidence for in vivo toxin production during infection. Infect Immun. 1976 Oct;14(4):942–947. [PMC free article] [PubMed]
  • Pollack M, Young LS. Protective activity of antibodies to exotoxin A and lipopolysaccharide at the onset of Pseudomonas aeruginosa septicemia in man. J Clin Invest. 1979 Feb;63(2):276–286. [PMC free article] [PubMed]
  • Poutrel B, Boutonnier A, Sutra L, Fournier JM. Prevalence of capsular polysaccharide types 5 and 8 among Staphylococcus aureus isolates from cow, goat, and ewe milk. J Clin Microbiol. 1988 Jan;26(1):38–40. [PMC free article] [PubMed]
  • Raad II, Sabbagh MF. Optimal duration of therapy for catheter-related Staphylococcus aureus bacteremia: a study of 55 cases and review. Clin Infect Dis. 1992 Jan;14(1):75–82. [PubMed]
  • Robbins JB, Schneerson R. Polysaccharide-protein conjugates: a new generation of vaccines. J Infect Dis. 1990 May;161(5):821–832. [PubMed]
  • Schneerson R, Barrera O, Sutton A, Robbins JB. Preparation, characterization, and immunogenicity of Haemophilus influenzae type b polysaccharide-protein conjugates. J Exp Med. 1980 Aug 1;152(2):361–376. [PMC free article] [PubMed]
  • Schneerson R, Robbins JB, Parke JC, Jr, Bell C, Schlesselman JJ, Sutton A, Wang Z, Schiffman G, Karpas A, Shiloach J. Quantitative and qualitative analyses of serum antibodies elicited in adults by Haemophilus influenzae type b and pneumococcus type 6A capsular polysaccharide-tetanus toxoid conjugates. Infect Immun. 1986 May;52(2):519–528. [PMC free article] [PubMed]
  • Sheagren JN. Staphylococcus aureus. The persistent pathogen (first of two parts). N Engl J Med. 1984 May 24;310(21):1368–1373. [PubMed]
  • Siber GR, Weitzman SA, Aisenberg AC, Weinstein HJ, Schiffman G. Impaired antibody response to pneumococcal vaccine after treatment for Hodgkin's disease. N Engl J Med. 1978 Aug 31;299(9):442–448. [PubMed]
  • Sompolinsky D, Samra Z, Karakawa WW, Vann WF, Schneerson R, Malik Z. Encapsulation and capsular types in isolates of Staphylococcus aureus from different sources and relationship to phage types. J Clin Microbiol. 1985 Nov;22(5):828–834. [PMC free article] [PubMed]
  • Steinhoff MC, Auerbach BS, Nelson KE, Vlahov D, Becker RL, Graham NM, Schwartz DH, Lucas AH, Chaisson RE. Antibody responses to Haemophilus influenzae type B vaccines in men with human immunodeficiency virus infection. N Engl J Med. 1991 Dec 26;325(26):1837–1842. [PubMed]
  • Sutra L, Mendolia C, Rainard P, Poutrel B. Encapsulation of Staphylococcus aureus isolates from mastitic milk: relationship between capsular polysaccharide types 5 and 8 and colony morphology in serum-soft agar, clumping factor, teichoic acid, and protein A. J Clin Microbiol. 1990 Mar;28(3):447–451. [PMC free article] [PubMed]
  • Sutra L, Rainard P, Poutrel B. Phagocytosis of mastitis isolates of Staphylococcus aureus and expression of type 5 capsular polysaccharide are influenced by growth in the presence of milk. J Clin Microbiol. 1990 Oct;28(10):2253–2258. [PMC free article] [PubMed]
  • Sutton A, Vann WF, Karpas AB, Stein KE, Schneerson R. An avidin-biotin based ELISA for quantitation of antibody to bacterial polysaccharides. J Immunol Methods. 1985 Oct 10;82(2):215–224. [PubMed]
  • Szu SC, Li XR, Schneerson R, Vickers JH, Bryla D, Robbins JB. Comparative immunogenicities of Vi polysaccharide-protein conjugates composed of cholera toxin or its B subunit as a carrier bound to high- or lower-molecular-weight Vi. Infect Immun. 1989 Dec;57(12):3823–3827. [PMC free article] [PubMed]
  • Szu SC, Zon G, Schneerson R, Robbins JB. Ultrasonic irradiation of bacterial polysaccharides. Characterization of the depolymerized products and some applications of the process. Carbohydr Res. 1986 Sep 1;152:7–20. [PubMed]
  • Tam AY, Yeung CY. The changing pattern of severe neonatal staphylococcal infection: a 10-year study. Aust Paediatr J. 1988 Oct;24(5):275–279. [PubMed]
  • Xu S, Arbeit RD, Lee JC. Phagocytic killing of encapsulated and microencapsulated Staphylococcus aureus by human polymorphonuclear leukocytes. Infect Immun. 1992 Apr;60(4):1358–1362. [PMC free article] [PubMed]
  • Yu VL, Goetz A, Wagener M, Smith PB, Rihs JD, Hanchett J, Zuravleff JJ. Staphylococcus aureus nasal carriage and infection in patients on hemodialysis. Efficacy of antibiotic prophylaxis. N Engl J Med. 1986 Jul 10;315(2):91–96. [PubMed]

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