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BioDrugs

, Volume 10, Issue 3, pp 173–181 | Cite as

Prospects for a Vaccine for Clostridium difficile

  • Lorraine Kyne
  • Ciarán P. Kelly
Leading Article

Abstract

Clostridium difficile diarrhoea and colitis is a new disease that is attributable to broad spectrum antibiotic therapy. During the past 2 decades C. difficile has become one of the most common nosocomial pathogens in the developed world. As changing demographics create an increasingly elderly population and the use of broad spectrum antimicrobials continues to expand, C. difficile is likely to become increasingly problematic.

Disease caused by this organism is caused by the inflammatory actions of its 2 toxins, A and B, on the intestinal mucosa. Human antibody responses to these toxins are common in the general population and in patients with C. difficile-associated disease. There is substantial, albeit inconclusive, evidence to indicate that antitoxin antibodies provide protection against severe, prolonged or recurrent C. difficile diarrhoea.

Immunity induced by oral or parenteral passive administration of antibody is protective in animal models of C. difficile infection. In humans, intravenous passive immunisation with pooled human immunoglobulin has been successful in the treatment of recurrent and severe C. difficile colitis. Human trials of oral passive immunotherapy with bovine immunoglobulin therapy are in progress. Formalin—inactivated culture filtrate from toxigenic C. difficile, as well as purified and inactivated toxins, have been used to successfully immunise animals. Similar preparations are under investigation as possible human vaccines.

Antibiotic therapy is effective in treating most individual patients with C. difficile diarrhoea, but has proven ineffective in reducing the overall incidence of nosocomial infection. Active immunisation is probably the most promising approach to long term control of this difficult iatrogenic disease.

Keywords

Adis International Limited Clostridium Difficile Infection Clostridium Difficile Pseudomembranous Colitis Beth Israel Deaconess Medical 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Guerrant RL, Hughes JM, Lima NL, et al. Diarrhea in developed and developing countries: magnitude, special settings, and etiologies. Rev Infect Dis 1990; 12: S41–50PubMedCrossRefGoogle Scholar
  2. 2.
    Samore MH, DeGirolami PC, Tlucko A, et al. Clostridium difficile colonization and diarrhea at a tertriary care hospital. Clin Infect Dis 1994; 18: 181–7PubMedCrossRefGoogle Scholar
  3. 3.
    McFarland LV, Mulligan ME, Kwok RY, et al. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 1989; 320: 204–10PubMedCrossRefGoogle Scholar
  4. 4.
    Bentley D. Clostridium difficile-associated disease in long-term care facilities. Infect Control Hosp Epidemiol 1990; 11(8): 434–8PubMedCrossRefGoogle Scholar
  5. 5.
    Hirschhorn LR, Trnka Y, Onderdonk A, et al. Epidemiology of community-acquired Clostridium difficile-associated diarrhoea. J Infect Dis 1994; 169: 127–33PubMedCrossRefGoogle Scholar
  6. 6.
    Riley TV, Cooper M, Bell B, et al. Community-acquired Clostridium difficile-associated diarrhea. Clin Infect Dis 1995; 20(S2): S263–5PubMedCrossRefGoogle Scholar
  7. 7.
    Anand A, Bashey B, Mir T, et al. Epidemiology, clinical manifestations and outcome of Clostridium difficile-associated diarrhea. Am J Gastroenterol 1994; 89: 519–23PubMedGoogle Scholar
  8. 8.
    Rubin M, Bodenstein L, Kent K. Severe Clostridium difficile colitis. Dis Colon Rectum 1995; 38: 350–4Google Scholar
  9. 9.
    Umashanker R, Nicholls PJ, Landau SB. Clostridium difficile disease (CDID) has identifiable high risk subjects, prolongs stay and is very costly. Gastroenterology 1997; 112(4): A46Google Scholar
  10. 10.
    Wilcox MH, Cunniffe JG, Trundle C, et al. Financial burden of hospital-acquired Clostridium difficile infection. J Hosp Infect 1996; 34: 23–30PubMedCrossRefGoogle Scholar
  11. 11.
    Riley TV, Codde JP, Rouse IL. Increased length of stay due to Clostridium difficile associated diarrhoea. Lancet 1995; 345: 455–6PubMedCrossRefGoogle Scholar
  12. 12.
    Cartmill TDI, Pinigrahi H, Worsley MA, et al. Management and control of a large outbreak of diarrhoea due to Clostridium difficile. J Hosp Infect 1994; 27: 1–15PubMedCrossRefGoogle Scholar
  13. 13.
    Nolan NPM, Kelly CP, Humphreys JFH, et al. An epidemic of pseudomembranous colitis: importance of person to person spread. Gut 1987; 28: 1467–73PubMedCrossRefGoogle Scholar
  14. 14.
    Nath SK, Thornley JH, Kelly M, et al. A sustained outbreak of Clostridium difficile in a general hospital: persistence of a toxigenic clone in four units. Infect Control Hosp Epidemiol 1994; 15: 382–9PubMedCrossRefGoogle Scholar
  15. 15.
    Fekety R. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. Am J Gastroenterol 1997; 92(5): 739–50PubMedGoogle Scholar
  16. 16.
    Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med 1994; 330: 257–62PubMedCrossRefGoogle Scholar
  17. 17.
    Teasley DG, Gerding DN, Olson MM, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet 1983; II: 1043–6CrossRefGoogle Scholar
  18. 18.
    Fekety R, Shah A. Diagnosis and treatment of Clostridium difficile colitis. JAMA 1993; 269(1): 71–5PubMedCrossRefGoogle Scholar
  19. 19.
    Kelly CP, LaMont JT. Treatment of Clostridium difficile diarrhea and colitis. In: Wolfe MM, editor. Gastrointestinal pharmacotherapy. Philadelphia (PA): WB Saunders, 1993; 199–212Google Scholar
  20. 20.
    Hospital Infection Control Practices Advisory Committee (HICPAC). Recommendations for preventing the spread of vancomycin resistance. Infect Control Hosp Epidemiol 1995; 16: 105–13CrossRefGoogle Scholar
  21. 21.
    Sung JJY, Chung SCS, Ling TKW, et al. Dual therapy versus triple therapy for Helicobacter pylori-associated duodenal ulcers. Dig Dis Sci 1996; 41: 453–7PubMedCrossRefGoogle Scholar
  22. 22.
    Linevsky JK, Kelly CP. Clostridium difficile colitis. In: LaMont JT, editor. Gastrointestinal infections: diagnosis and management. New York (NY): Marcel Dekker,Inc. 1997: 293–325Google Scholar
  23. 23.
    Pothoulakis C. Pathogenesis of Clostridium difficile-associated diarrhoea. Eur J Gastroenterol Hepatol 1996; 8: 1041–7PubMedCrossRefGoogle Scholar
  24. 24.
    Dove CH, Wang SZ, Proce SB, et al. Molecular characterization of the Clostridium difficile toxin Agene. Infect Immun 1990; 58: 480–8PubMedGoogle Scholar
  25. 25.
    von Eichel-Streiber C, Laufenberg-Feldman R, Sartinger S, et al. Cloning of Clostridium difficile toxin B gene and demonstration of high N-terminal homology between toxin A and toxin B. Med Microbiol Immunol 1990; 179: 271–9CrossRefGoogle Scholar
  26. 26.
    Barroso LA, Wang SZ, Phelps CJ, et al. Nucleotide sequence of Clostridium difficile toxin B gene. Nucleic Acids Res 1990; 18: 4004PubMedCrossRefGoogle Scholar
  27. 27.
    Just I, Selzer J, Wilm M, et al. Glcosylation of Rho proteins by Clostridium difficile toxin B. Nature 1995; 375: 500–3PubMedCrossRefGoogle Scholar
  28. 28.
    Just I, Wilm M, Selzer J, et al. The enterotoxin from Clostridium difficile (Tox A) monoglucosylates the Rho proteins. J Biol Chem 1995; 270: 13932–63PubMedCrossRefGoogle Scholar
  29. 29.
    Flegal WA, Muller F, Daubener W, et al. Cytokine response by human monocytes to Clostridium difficile toxin A and B. Infect Immun 1991; 59: 3659–66Google Scholar
  30. 30.
    Linevsky JK, Keates S, Pothoulakis C, et al. IL-8 release and neutrophil activation by Clostridium difficile toxin-exposed monocytes [abstract]. Gastroenterology 1995; 108: A863Google Scholar
  31. 31.
    Castagliuolo I, LaMont JT, Letourneau R, et al. Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Vibrio cholerae enterotoxin in rat ileum. Gastroenterology 1994; 107: 657–65PubMedCrossRefGoogle Scholar
  32. 32.
    Kelly CP, Becker S, Linevsky JK, et al. Neutrophil recruitment in Clostridium difficile toxin A enteritis in the rabbit. J Clin Invest 1994; 93: 1257–65PubMedCrossRefGoogle Scholar
  33. 33.
    Kelly CP. Immune response to Clostridium difficile infection. Eur J Gastroenterol Hepatol 1996; 8: 1048–53PubMedCrossRefGoogle Scholar
  34. 34.
    Viscidi R, Laughon BE, Yolken R, et al. Serum antibody response to toxins A and B of Clostridium difficile. J Infect Dis 1983; 148: 93–100PubMedCrossRefGoogle Scholar
  35. 35.
    Kelly CP, Pothoulakis C, Orellana J, et al. Human colonic aspirates containing immunoglobulin A antibody to Clostridium difficile toxin A inhibit toxin A-receptor binding. Gastroenterology 1992; 102: 35–40PubMedGoogle Scholar
  36. 36.
    Warny M, Vaerman JP, Avesani V, et al. Human antibody response to Clostridium difficile toxin A in relation to clinical course of infection. Infect Immun 1994; 62: 384–9PubMedGoogle Scholar
  37. 37.
    Johnson S, Gerding DN, Janoff EN. Systemic and mucosal antibody responses to toxin A in patients infected with Clostridium difficile. J Infect Dis 1992; 166: 1287–94PubMedCrossRefGoogle Scholar
  38. 38.
    Nakamura S, Mikawa M, Nakashio S, et al. Isolation of Clostridium difficile from the feces and the antibody in sera of young and elderly adults. Microbiol Immunol 1981; 25: 345–51PubMedGoogle Scholar
  39. 39.
    Bacon AE, Fekety R. Immunoglobulin G directed against toxins A and B of Clostridium difficile in the general population and patients with antibiotic-associated diarrhea. Diagn Microbiol Infect Dis 1994; 18: 205–9PubMedCrossRefGoogle Scholar
  40. 40.
    Wada N, Nisheda N, Iwaki S, et al. Neutralizing activity against Clostridium difficile toxin in the supernatants of cultured colostral cells. Infect Immun 1980; 29: 545–50PubMedGoogle Scholar
  41. 41.
    Kim K, Pickering LK, DuPont HL, et al. In vitro and in vivo neutralizing activity of human colostrum against purified toxins A and B of Clostridium difficile. J Infect Dis 194; 150: 57–62Google Scholar
  42. 42.
    Mulligan ME, Miller SD, McFarland LV, et al. Elevated levels of serum immunoglobulins in asymptomatic carriers of Clostridium difficile. Clin Infect Dis 1993; 16Suppl. 4: S239–44PubMedCrossRefGoogle Scholar
  43. 43.
    Aronsson B, Granstrom M, Mollby R, et al. Enzyme-linked immunosorbent assay (ELISA) for antibodies to Clostridium difficile toxins in patients with pseudomembranous colitis and antibiotic-associated diarrhoea. J Immunol Methods 1983; 60: 341–50PubMedCrossRefGoogle Scholar
  44. 44.
    Aronsson B, Granstrom M, Mollby R, et al. Serum antibody response to Clostridium difficile toxins in patients with Clostridium difficile diarrhoea. Infection 1985; 13: 97–101PubMedCrossRefGoogle Scholar
  45. 45.
    Leung DY, Kelly CP, Boguniewicz M, et al. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin. J Pediatr 1991; 118: 633–7PubMedCrossRefGoogle Scholar
  46. 46.
    Kim PH, Iaconis JP, Rolfe RD. Immunization of adult hamsters against Clostridium difficile-associated ileocecitis and transfer of protection to infant hamsters. Infect Immun 1987; 55: 2984–92PubMedGoogle Scholar
  47. 47.
    Allo M, Silva J, Fekety R, et al. Prevention of clindamycin-induced colitis in hamsters by Clostridium sordellii antitoxin. Gastroenterology 1979; 76: 351–5PubMedGoogle Scholar
  48. 48.
    Corthier G, Muller MC, Wilkins TD, et al. Protection against experimental pseudomembranous colitis in gnotobiotic mice by use of monoclonal antibodies against Clostridium difficile toxin A. Infect Immun 1991; 59: 1192–5PubMedGoogle Scholar
  49. 49.
    Lyerly DM, Saum KE, MacDonald D, et al. Effects of Clostridium difficile toxins A and B given intragastrically to animals. Infect Immun 1985; 47: 349–52PubMedGoogle Scholar
  50. 50.
    Mitchell TJ, Ketley JM, Haslam SC, et al. Effect of toxins A and B of Clostridium difficile on rabbit ileum and colon. Gut 1986; 27: 78–85PubMedCrossRefGoogle Scholar
  51. 51.
    Salcedo J, Keates S, Pothoulakis C, et al. Intravenous immunoglobulin therapy for severe Clostridium difficile colitis. Gut 1997; 41: 366–70PubMedCrossRefGoogle Scholar
  52. 52.
    Kelly CP, Pothoulakis C, Vavva F, et al. Anti-Clostridium difficile bovine immunoglobulin concentrate inhibits cytotoxicity and enterotoxicity of C. difficile toxins. Antimicrob Agents Chemother 1996; 40: 373–9PubMedGoogle Scholar
  53. 53.
    Kelly CP, Chetham S, Keates S, et al. Survival of anti-Clostridium difficile bovine immunoglobulin concentrate in the human gastrointestinal tract. Antimicrob Agents Chemother 1997; 41: 236–41PubMedGoogle Scholar
  54. 54.
    Warny M, Fatima A, Bostwick EF, et al. Bovine immunoglobulin concentrate C.difficile retains C. difficile toxin neutralising activity after passage through the human stomach and small intestine. GUT. In pressGoogle Scholar
  55. 55.
    Lyerly DM, Bostwick EF, Binion SB, et al. Passive immunization of hamsters against disease caused by Clostridium difficile by use of bovine immunoglobulin G concentrate. Infect Immun 1991; 59: 2215–8PubMedGoogle Scholar
  56. 56.
    Ketley JM, Mitchell TJ, Candy DC, et al. The effects of Clostridium difficile crude toxins and toxin A on ileal loops in immune and non-immune rabbits. J Med Microbiol 1987; 24(1): 41–52PubMedCrossRefGoogle Scholar
  57. 57.
    Libby JM, Jortner BS, Wilkins TD. Effects of the two toxins of Clostridium difficile in antibiotic-associated cecitis in hamsters. Infect Immun 1982; 36: 822–9PubMedGoogle Scholar
  58. 58.
    Fernie DS, Thomson RO, Batty I, et al. Active and passive immunization against antibiotic associated caecitis in hamsters. Devel Biol Standard 1983; 53: 325–32Google Scholar
  59. 59.
    Riegler M, Sedivy R, Pothoulakis C, et al. Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro. J Clin Invest 1995; 95: 2004–11PubMedCrossRefGoogle Scholar
  60. 60.
    Torres JF, Lyerly DM, Hill JE, et al. Evaluation of formalin-inactivated Clostridium difficile vaccines administered by parenteral and mucosal routes of immunization in hamsters. Infect Immun 1995; 63: 4619–27PubMedGoogle Scholar
  61. 61.
    Ryan ET, Butterton JR, Smith RN, et al. Protective immunity against Clostridium difficile induced by oral immunization with a live, attentuated Vibrio cholera vector strain. Infect Immun 1997; 65: 2941–9PubMedGoogle Scholar
  62. 62.
    Holmgren J, Svennerholm AM. Bacterial enteric infections and vaccine development. Gastroenterol Clin North Am 1992; 21(2): 283–301PubMedGoogle Scholar
  63. 63.
    Clemens JD, Sack DA, Harris JR, et al. Field trials of oral cholera vaccines in Bangladesh; results from three-year follow-up. Lancet 1990; 335: 270–3PubMedCrossRefGoogle Scholar
  64. 64.
    Centers for Disease Control. Prevention and control of influenza: recommendations of the Immunization Practices Advisory Committee. Ann Intern Med 1986; 105: 399-404Google Scholar
  65. 65.
    Sims RV, Steinmann WC, McConville JH, et al. The clinical effectiveness of Pneumococcal vaccine in the elderly. Ann Intern Med 1988; 108: 653–7PubMedGoogle Scholar
  66. 66.
    American College of Physicians Task Force on Adult Immunization, Infectious Diseases Society of America. Guide for adult immunization. 3rd ed. Philadelphia (PA): American College of Physicians, 1994Google Scholar
  67. 67.
    Schmucker D, Heyworth MH, Owen RL, et al. Impact of aging on gastrointestinal mucosal immunity. Dig Dis Sci 1996; 41(6): 1183–93PubMedCrossRefGoogle Scholar
  68. 68.
    Saltzman RL, Peterson PK. Immunodeficiency of the elderly. Rev Infect Dis 1987; 9(6): 1127–39PubMedCrossRefGoogle Scholar
  69. 69.
    Olive KE, Berk SL. Infections in the nursing home. Clin Geriatr Med 1992; 8(4): 821–34PubMedGoogle Scholar
  70. 70.
    Samore M, Venkataraman L, DeGirolami PC, et al. Clinical and molecular epidemiology of sporadic and clustered cases of nosocomial Clostridium difficile diarrhea. Am J Med 1996; 100: 32–40PubMedCrossRefGoogle Scholar
  71. 71.
    Starr JM, Rogers TR, Impallomeni M. Hospital-acquired Clostridium difficile diarrhoea and herd immunity. Lancet 1997; 349: 426–28PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  1. 1.Division of GerontologyBeth Israel Deaconess Medical CenterBostonUSA
  2. 2.Division of GastroenterologyBeth Israel Deaconess Medical CenterBostonUSA

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