Vaccination against Clostridium difficile using toxin fragments

Clostridium difficile is a major cause of antibiotic associated diarrhea. Recently, we have shown that effective protection can be mediated in hamsters through the inclusion of specific recombinant fragments from toxin A and B in a systemically delivered vaccine. Interestingly while neutralizing antibodies to the binding domains of both toxin A and B are moderately protective, enhanced survival is observed when fragments from the glucosyltransferase region of toxin B replace those from the binding domain of this toxin. In this addendum, we discuss additional information that has been derived from such vaccination studies. This includes observations on efficacy and cross-protection against different ribotypes mediated by these vaccines and the challenges that remain for a vaccine which prevents clinical symptoms but not colonization. The use and value of vaccination both in the prevention of infection and for treatment of disease relapse will be discussed.

[1]  H. Kleanthous,et al.  Systemic antibody responses induced by a two-component Clostridium difficile toxoid vaccine protect against C. difficile-associated disease in hamsters. , 2013, Journal of medical microbiology.

[2]  P. H. Arruda,et al.  Effect of age, dose and antibiotic therapy on the development of Clostridium difficile infection in neonatal piglets. , 2013, Anaerobe.

[3]  J. James,et al.  Clostridium difficile 027/BI/NAP1 Encodes a Hypertoxic and Antigenically Variable Form of TcdB , 2013, PLoS pathogens.

[4]  K. Jansen,et al.  A novel approach to generate a recombinant toxoid vaccine against Clostridium difficile , 2013, Microbiology.

[5]  R. Rappuoli,et al.  Protective Efficacy Induced by Recombinant Clostridium difficile Toxin Fragments , 2013, Infection and Immunity.

[6]  S. Tzipori,et al.  Antibody against TcdB, but not TcdA, prevents development of gastrointestinal and systemic Clostridium difficile disease. , 2013, The Journal of infectious diseases.

[7]  B. Wren,et al.  Characterisation of Clostridium difficile Biofilm Formation, a Role for Spo0A , 2012, PloS one.

[8]  D. Serruto,et al.  Multiple Factors Modulate Biofilm Formation by the Anaerobic Pathogen Clostridium difficile , 2012, Journal of bacteriology.

[9]  M. Pirmohamed,et al.  Emergence and global spread of epidemic healthcare-associated Clostridium difficile , 2012, Nature Genetics.

[10]  Jane W. Marsh,et al.  Association of Relapse of Clostridium difficile Disease with BI/NAP1/027 , 2012, Journal of Clinical Microbiology.

[11]  Taane G. Clark,et al.  Targeted Restoration of the Intestinal Microbiota with a Simple, Defined Bacteriotherapy Resolves Relapsing Clostridium difficile Disease in Mice , 2012, PLoS pathogens.

[12]  D. Gerding,et al.  Relapse Versus Reinfection: Recurrent Clostridium difficile Infection Following Treatment With Fidaxomicin or Vancomycin , 2012, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[13]  R. Carman,et al.  A novel fusion protein containing the receptor binding domains of C. difficile toxin A and toxin B elicits protective immunity against lethal toxin and spore challenge in preclinical efficacy models. , 2012, Vaccine.

[14]  S. Tzipori,et al.  A Chimeric Toxin Vaccine Protects against Primary and Recurrent Clostridium difficile Infection , 2012, Infection and Immunity.

[15]  T. Marbury,et al.  Phase I dose finding studies of an adjuvanted Clostridium difficile toxoid vaccine. , 2012, Vaccine.

[16]  A. Amalfitano,et al.  Adenovirus-based vaccination against Clostridium difficile toxin A allows for rapid humoral immunity and complete protection from toxin A lethal challenge in mice. , 2012, Vaccine.

[17]  E. Fattal,et al.  Encapsulation of Cwp84 into pectin beads for oral vaccination against Clostridium difficile. , 2011, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[18]  A. Le Monnier,et al.  Immunization of hamsters against Clostridium difficile infection using the Cwp84 protease as an antigen. , 2011, FEMS immunology and medical microbiology.

[19]  I. Poxton,et al.  Comparison of toxin and spore production in clinically relevant strains of Clostridium difficile. , 2011, Microbiology.

[20]  N. Fairweather,et al.  Immunization with Bacillus Spores Expressing Toxin A Peptide Repeats Protects against Infection with Clostridium difficile Strains Producing Toxins A and B , 2011, Infection and Immunity.

[21]  Yan Li,et al.  Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome. , 2010, Gastroenterology.

[22]  Marcus J. Claesson,et al.  Composition, variability, and temporal stability of the intestinal microbiota of the elderly , 2010, Proceedings of the National Academy of Sciences.

[23]  M. Wilcox,et al.  The potential for airborne dispersal of Clostridium difficile from symptomatic patients. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[24]  Roger Baxter,et al.  Treatment with monoclonal antibodies against Clostridium difficile toxins. , 2010, The New England journal of medicine.

[25]  Roger Baxter,et al.  Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). , 2010, Vaccine.

[26]  M. Quail,et al.  Comparative genome and phenotypic analysis of Clostridium difficile 027 strains provides insight into the evolution of a hypervirulent bacterium , 2009, Genome Biology.

[27]  D. Ho,et al.  A DNA vaccine targeting the receptor-binding domain of Clostridium difficile toxin A. , 2009, Vaccine.

[28]  E. Dubberke,et al.  Review of Current Literature on the Economic Burden of Clostridium difficile Infection , 2009, Infection Control & Hospital Epidemiology.

[29]  Jeffrey D Goldsmith,et al.  A mouse model of Clostridium difficile-associated disease. , 2008, Gastroenterology.

[30]  D. Kelleher,et al.  Active immunization of hamsters against Clostridium difficile infection using surface-layer protein. , 2008, FEMS immunology and medical microbiology.

[31]  E. Fattal,et al.  Diminished intestinal colonization by Clostridium difficile and immune response in mice after mucosal immunization with surface proteins of Clostridium difficile. , 2007, Vaccine.

[32]  J. Ballard,et al.  Identification of Clostridium difficile toxin B cardiotoxicity using a zebrafish embryo model of intoxication , 2006, Proceedings of the National Academy of Sciences.

[33]  Julian Parkhill,et al.  The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome , 2006, Nature Genetics.

[34]  M. Palcic,et al.  Carbohydrate recognition by Clostridium difficile toxin A , 2006, Nature Structural &Molecular Biology.

[35]  T. Monath,et al.  Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhea. , 2005, Gastroenterology.

[36]  T. Monath,et al.  Clostridium difficile Vaccine and Serum Immunoglobulin G Antibody Response to Toxin A , 2003, Infection and Immunity.

[37]  T. Monath,et al.  Safety and Immunogenicity of Increasing Doses of aClostridium difficile Toxoid Vaccine Administered to Healthy Adults , 2001, Infection and Immunity.

[38]  C. Kelly,et al.  Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. , 2000, The New England journal of medicine.

[39]  G. Dougan,et al.  Local and Systemic Neutralizing Antibody Responses Induced by Intranasal Immunization with the Nontoxic Binding Domain of Toxin A from Clostridium difficile , 1999, Infection and Immunity.

[40]  S. Meyers Clostridium difficile Colitis , 1999, American Journal of Gastroenterology.

[41]  T. Monath,et al.  Serum Antitoxin Antibodies Mediate Systemic and Mucosal Protection from Clostridium difficileDisease in Hamsters , 1999, Infection and Immunity.

[42]  M. Weidmann,et al.  Toxins A and B from Clostridium difficile differ with respect to enzymatic potencies, cellular substrate specificities, and surface binding to cultured cells. , 1997, The Journal of clinical investigation.

[43]  S. Calderwood,et al.  Protective immunity against Clostridium difficile toxin A induced by oral immunization with a live, attenuated Vibrio cholerae vector strain , 1997, Infection and immunity.

[44]  A. Dunn,et al.  Effect of Homologous lnterleukin-1, lnterleukin-6 and Tumor Necrosis Factor-α on the Core Body Temperature of Mice , 1997 .

[45]  T. Monath,et al.  Evaluation of formalin-inactivated Clostridium difficile vaccines administered by parenteral and mucosal routes of immunization in hamsters , 1995, Infection and immunity.

[46]  John L. Johnson,et al.  Vaccination against lethalClostridium difficile enterocolitis with a nontoxic recombinant peptide of toxin A , 1990, Current Microbiology.

[47]  D. Gerding,et al.  Vaccination with parenteral toxoid B protects hamsters against lethal challenge with toxin A-negative, toxin B-positive clostridium difficile but does not prevent colonization. , 2012, The Journal of infectious diseases.

[48]  A. Dunn,et al.  Effect of homologous interleukin-1, interleukin-6 and tumor necrosis factor-alpha on the core body temperature of mice. , 1997, Neuroimmunomodulation.