Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhea.

BACKGROUND & AIMS: Recurrent C difficile -associated diarrhea (CDAD) is associated with a lack of protective immunity to C difficile toxins. A parenteral C difficile vaccine containing toxoid A and toxoid B was reported previously to be safe and immunogenic in healthy volunteers. Our aim was to examine whether the vaccine is also well tolerated and immunogenic in patients with recurrent CDAD. METHODS: Subjects received 4, 50-microg intramuscular inoculations of the C difficile vaccine over an 8-week period. Serum antitoxin antibodies were measured by ELISA, and toxin neutralizing activity was evaluated using the tissue culture cytotoxin assay. RESULTS: Three patients with multiple episodes of recurrent CDAD were vaccinated. Two of the 3 showed an increase in serum IgG antitoxin A antibodies (3-fold and 4-fold increases, respectively) and in serum IgG antitoxin B antibodies (52-fold and 20-fold, respectively). Both also developed cytotoxin neutralizing activity against toxin A and toxin B. Prior to vaccination, the subjects had required nearly continuous treatment with oral vancomycin for 7, 9, and 22 months, respectively, to treat recurrent episodes of CDAD. After vaccination, all 3 subjects discontinued treatment with oral vancomycin without any further recurrence. CONCLUSIONS: A C difficile toxoid vaccine induced immune responses to toxins A and B in patients with CDAD and was associated with resolution of recurrent diarrhea. The results of this study support the feasibility of active vaccination against C difficile and its toxins in high-risk individuals but must be validated in larger, randomized, controlled trials.

Active and passive immunization against Clostridium difficile diarrhea and colitis.

Clostridium difficile, a gram-positive bacterium, is the major cause of hospital-acquired infectious diarrhea and colitis in industrialized nations. C. difficile colonization results from antibiotic administration and subsequent loss of protection provided by intestinal flora. C. difficile induced-colitis is caused by the release of two exotoxins, toxin A and B. Host factors including advanced age, pre-existing severe illness and weakened immune defenses predispose individuals to symptomatic infection. The generation of antibody responses to toxin A through natural exposure is associated with protection from disease. In addition, an inability to acquire immunity to toxin A puts individuals at risk for recurrent and/or severe disease. Immunological approaches for the management of this disease are being developed which could reduce the reliance on antibiotics for treatment and allow for re-establishment of the natural barrier provided by an intact commensal flora. An active vaccine and various immunotherapeutic strategies under evaluation may prove to be effective against severe or relapsing C. difficile infection.

Clostridium difficile vaccine and serum immunoglobulin G antibody response to toxin A.

There is a strong association between serum antibody responses to toxin A and protection against Clostridium difficile diarrhea. A parenteral C. difficile toxoid vaccine induced very-high-level responses to anti-toxin A immunoglobulin G (IgG) in the sera of healthy volunteers. After vaccination, the concentrations of anti-toxin A IgG in the sera of all 30 recipients exceeded the concentrations that were associated with protection in previous clinical studies. Furthermore, the median concentration of serum anti-toxin A IgG in the test group was 50-fold higher than the previous threshold. These findings support the feasibility of using a vaccine to protect high-risk individuals against C. difficile-associated diarrhea and colitis.