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

Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, 02215,USA.
Gastroenterology (Impact Factor: 16.72). 03/2005; 128(3):764-70. DOI: 10.1053/j.gastro.2004.11.004
Source: PubMed

ABSTRACT 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.
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.
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.
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.

Download full-text


Available from: Michael Warny, Sep 25, 2015
100 Reads
  • Source
    • "One of the approaches to prevention of C. difficile infection is the development of an effective vaccine. Toxoids A and B are the best candidates for C. difficile vaccine and they are able to exert excellent serum antibody responses in healthy adults [54]. As a first report of a DNA vaccine targeting C. difficile toxins, Gardiner et al. explained the receptor-binding domain of C. difficile toxin A that is able to induce well immune responses in mice and protect them from death. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The incidence and mortality rate of Clostridium difficile infection have increased remarkably in both hospital and community settings during the last two decades. The growth of infection may be caused by multiple factors including inappropriate antibiotic usage, poor standards of environmental cleanliness, changes in infection control practices, large outbreaks of C. difficile infection in hospitals, alteration of circulating strains of C. difficile, and spread of hypervirulent strains. Detection of high-risk populations could be helpful for prompt diagnosis and consequent treatment of patients suffering from C. difficile infection. Metronidazole and oral vancomycin are recommended antibiotics for the treatment of initial infection. Current treatments for C. difficile infection consist of supportive care, discontinuing the unnecessary antibiotic, and specific antimicrobial therapy. Moreover, novel approaches include fidaxomicin therapy, monoclonal antibodies, and fecal microbiota transplantation mediated therapy. Fecal microbiota transplantation has shown relevant efficacy to overcome C. difficile infection and reduce its recurrence.
    06/2014; 2014:916826. DOI:10.1155/2014/916826
  • Source
    • "A vaccine based on formaldehyde-inactivated TcdA and TcdB has been developed and used in healthy volunteers, and induced high levels of specific neutralizing IgG. Initial studies have been conducted with promising results in a few patients with recurrent CDI [6]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Clostridium difficile is a pathogen which is responsible for diarrhea and colitis, particularly after treatment with antibiotics. Clinical signs are mainly due to two toxins, TcdA and TcdB. However, the first step of pathogenesis is the colonization process. We evaluated C. difficile surface proteins as vaccine antigens in the hamster model to prevent intestinal colonization. This vaccination induced a partial protection of hamsters against death after a C. difficile challenge. A proteomic analysis of animal sera allowed us to identify proteins which could be responsible for the protection observed. Among these proteins, we identified the GroEL heat shock protein. To confirm the role of the specific GroEL antibodies in the delayed C. difficile colonization of hamsters, we performed an immunization assay in a mouse model. After intranasal immunization with the recombinant protein GroEL, we observed a lower C. difficile intestinal colonization in the immunized group as compared to the control group.
    PLoS ONE 11/2013; 8(11):e81112. DOI:10.1371/journal.pone.0081112 · 3.23 Impact Factor
  • Source
    • "Furthermore, reduction in recurrence of CDAD was achieved in a Phase I clinical trial with A and B toxin monoclonal antibodies in combination with standard antibiotic therapy (Lowy et al., 2010). In addition, in a small study with three patients with chronic relapsing CDAD, an investigational vaccine using formalininactivated A and B toxoid antigens prevented CDAD recurrence (Sougioultzis et al., 2005). Collectively, these observations provide validation for, and encourage further development of C. difficile toxin A-and B-based vaccines to prevent CDAD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Clostridium difficile toxins A and B are primarily responsible for symptoms of C. difficile associated disease and are prime targets for vaccine development. We describe a plasmid-based system for the production of genetically modified toxins in a non-sporulating strain of C. difficile that lacks the toxin genes tcdA and tcdB. TcdA and TcdB mutations targeting established glucosyltransferase cytotoxicity determinants were introduced into recombinant plasmids and episomally expressed toxin mutants purified from C. difficile transformants. TcdA and TcdB mutants lacking glucosyltransferase and autoproteolytic processing activities were ~10,000-fold less toxic to cultured human IMR-90 cells than corresponding recombinant or native toxins. However, both mutants retained residual cytotoxicity that could be prevented by preincubating the antigens with specific antibodies or by formalin treatment. Such non-toxic formalin-treated mutant antigens were immunogenic and protective in a hamster model of infection. The remaining toxicity of untreated TcdA and TcdB mutant antigens was associated with cellular swelling, a phenotype consistent with pore-induced membrane leakage. TcdB substitution mutations previously shown to block vesicular pore formation and toxin translocation substantially reduced residual toxicity. We discuss the implications of these results for the development of a C. difficile toxoid vaccine.
    Microbiology 04/2013; 159(Pt 7). DOI:10.1099/mic.0.066712-0 · 2.56 Impact Factor
Show more