A chimeric protein comprising the glucosyltransferase and cysteine proteinase domains of toxin B and the receptor binding domain of toxin A induces protective immunity against Clostridium difficile infection in mice and hamsters

References

• Rebeaud F, MF Bachmann. Immunization strategies for Clostridium difficile infections. Expert Rev Vaccines. 11(4): p. 469-79; PMID:22551032; http://dx.doi.org/10.1586/erv.12.18
   PubMed Web of Science ®Google Scholar
• O'Brien JA, Lahue BJ, Caro JJ, Davidson DM. The emerging infectious challenge of clostridium difficile-associated disease in Massachusetts hospitals: clinical and economic consequences. Infect Control Hosp Epidemiol, 2007. 28(11): p. 1219-27; http://dx.doi.org/10.1086/522676
   PubMed Web of Science ®Google Scholar
• Dubberke ER, AI Wertheimer. Review of current literature on the economic burden of Clostridium difficile infection. Infect Control Hosp Epidemiol, 2009. 30(1): p. 57-66; http://dx.doi.org/10.1086/592981
   PubMed Web of Science ®Google Scholar
• Bauer MP, Notermans DW, van Benthem BH, Brazier JS, Wilcox MH, Rupnik M, Monnet DL, van Dissel JT, Kuijper EJ; ECDIS Study Group. Clostridium difficile infection in Europe: a hospital-based survey. Lancet. 377(9759): p. 63-73; PMID:21084111; http://dx.doi.org/10.1016/S0140-6736(10)61266-4
   PubMed Web of Science ®Google Scholar
• Jank T, K Aktories. Structure and mode of action of clostridial glucosylating toxins: the ABCD model. Trends Microbiol, 2008. 16(5): p. 222-9; http://dx.doi.org/10.1016/j.tim.2008.01.011
   PubMed Web of Science ®Google Scholar
• Pruitt RN, DB Lacy. Toward a structural understanding of Clostridium difficile toxins A and B. Front Cell Infect Microbiol. 2: p. 28; PMID:22919620
   PubMed Web of Science ®Google Scholar
• McDonald LC, Coignard B, Dubberke E, Song X, Horan T, Kutty PK; Ad Hoc Clostridium difficile Surveillance Working Group. Recommendations for surveillance of Clostridium difficile-associated disease. Infect Control Hosp Epidemiol, 2007. 28(2): p. 140-5; http://dx.doi.org/10.1086/511798
   PubMed Web of Science ®Google Scholar
• Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepin J, Wilcox MH; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America, Clinical practice guidelines for Clostridium difficile infection in adults: update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010; 31(5): p. 431-55; PMID:20307191; http://dx.doi.org/10.1086/651706
   PubMed Web of Science ®Google Scholar
• Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, Weiss K, Sears P, Gorbach S; OPT-80-004 Clinical Study Group. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 12(4): p. 281-9; PMID:22321770
   PubMed Web of Science ®Google Scholar
• Tonna I, PD Welsby. Pathogenesis and treatment of Clostridium difficile infection. Postgrad Med J, 2005. 81(956): p. 367-9; http://dx.doi.org/10.1136/pgmj.2004.028480
   PubMed Web of Science ®Google Scholar
• Barbut F, Richard A, Hamadi K, Chomette V, Burghoffer B, Petit JC. Epidemiology of recurrences or reinfections of Clostridium difficile-associated diarrhea. J Clin Microbiol, 2000. 38(6): p. 2386-8.
   PubMed Web of Science ®Google Scholar
• Lee BY, Popovich MJ, Tian Y, Bailey RR, Ufberg PJ, Wiringa AE, Muder RR. The potential value of Clostridium difficile vaccine: an economic computer simulation model. Vaccine, 2010. 28(32): p. 5245-53; http://dx.doi.org/10.1016/j.vaccine.2010.05.062
   PubMed Web of Science ®Google Scholar
• Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med, 2000. 342(6): p. 390-7; http://dx.doi.org/10.1056/NEJM200002103420604
   PubMed Web of Science ®Google Scholar
• Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet, 2001. 357(9251): p. 189-93; http://dx.doi.org/10.1016/S0140-6736(00)03592-3
   PubMed Web of Science ®Google Scholar
• Johnson S, Kent SA, O'Leary KJ, Merrigan MM, Sambol SP, Peterson LR, Gerding DN. Fatal pseudomembranous colitis associated with a variant clostridium difficile strain not detected by toxin A immunoassay. Ann Intern Med, 2001. 135(6): p. 434-8; http://dx.doi.org/10.7326/0003-4819-135-6-200109180-00012
   PubMed Web of Science ®Google Scholar
• Drudy D, S Fanning, L Kyne. Toxin A-negative, toxin B-positive Clostridium difficile. Int J Infect Dis, 2007. 11(1): p. 5-10; http://dx.doi.org/10.1016/j.ijid.2006.04.003
   PubMed Web of Science ®Google Scholar
• Kuijper EJ, de Weerdt J, Kato H, Kato N, van Dam AP, van der Vorm ER, Weel J, van Rheenen C, Dankert J. Nosocomial outbreak of Clostridium difficile-associated diarrhoea due to a clindamycin-resistant enterotoxin A-negative strain. Eur J Clin Microbiol Infect Dis, 2001. 20(8): p. 528-34; http://dx.doi.org/10.1007/s100960100550
   PubMed Web of Science ®Google Scholar
• van den Berg RJ, Claas EC, Oyib DH, Klaassen CH, Dijkshoorn L, Brazier JS, Kuijper EJ. Characterization of toxin A-negative, toxin B-positive Clostridium difficile isolates from outbreaks in different countries by amplified fragment length polymorphism and PCR ribotyping. J Clin Microbiol, 2004. 42(3): p. 1035-41; http://dx.doi.org/10.1128/JCM.42.3.1035-1041.2004
   PubMed Web of Science ®Google Scholar
• Aboudola S, Kotloff KL, Kyne L, Warny M, Kelly EC, Sougioultzis S, Giannasca PJ, Monath TP, Kelly CP. Clostridium difficile vaccine and serum immunoglobulin G antibody response to toxin A. Infect Immun, 2003. 71(3): p. 1608-10; http://dx.doi.org/10.1128/IAI.71.3.1608-1610.2003
   PubMed Web of Science ®Google Scholar
• Giannasca PJ, Zhang ZX, Lei WD, Boden JA, Giel MA, Monath TP, Thomas WD Jr. Serum antitoxin antibodies mediate systemic and mucosal protection from Clostridium difficile disease in hamsters. Infect Immun, 1999. 67(2): p. 527-38
   PubMed Web of Science ®Google Scholar
• Siddiqui F, O'Connor JR, Nagaro K, Cheknis A, Sambol SP, Vedantam G, Gerding DN, Johnson S. Vaccination with parenteral toxoid B protects hamsters against lethal challenge with toxin A-negative, toxin B-positive clostridium difficile but does not prevent colonization. J Infect Dis. 205(1): p. 128-33; PMID:22124129; http://dx.doi.org/10.1093/infdis/jir688
   PubMed Web of Science ®Google Scholar
• Sougioultzis S, Kyne L, Drudy D, Keates S, Maroo S, Pothoulakis C, Giannasca PJ, Lee CK, Warny M, Monath TP, et al. Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhea. Gastroenterology, 2005. 128(3): p. 764-70; http://dx.doi.org/10.1053/j.gastro.2004.11.004
   PubMed Web of Science ®Google Scholar
• Anosova NG, Brown AM, Li L, Liu N, Cole LE, Zhang J, Mehta H, Kleanthous H. Systemic antibody responses induced by a two-component Clostridium difficile toxoid vaccine protect against C. difficile-associated disease in hamsters. J Med Microbiol. 62(Pt 9): p. 1394-404; PMID:23518659
   PubMed Web of Science ®Google Scholar
• Belyi IF, NA Varfolomeeva. Construction of a fusion protein carrying antigenic determinants of enteric clostridial toxins. FEMS Microbiol Lett, 2003. 225(2): p. 325-9; http://dx.doi.org/10.1016/S0378-1097(03)00560-3
   PubMed Web of Science ®Google Scholar
• Permpoonpattana P, Hong HA, Phetcharaburanin J, Huang JM, Cook J, Fairweather NF, Cutting SM. Immunization with Bacillus spores expressing toxin A peptide repeats protects against infection with Clostridium difficile strains producing toxins A and B. Infect Immun. 79(6): p. 2295-302; PMID:21482682; http://dx.doi.org/10.1128/IAI.00130-11
   PubMed Web of Science ®Google Scholar
• Ryan ET, Butterton JR, Smith RN, Carroll PA, Crean TI, Calderwood SB. Protective immunity against Clostridium difficile toxin A induced by oral immunization with a live, attenuated Vibrio cholerae vector strain. Infect Immun, 1997. 65(7): p. 2941-9
   PubMed Web of Science ®Google Scholar
• Seregin SS, Aldhamen YA, Rastall DP, Godbehere S, Amalfitano A. Adenovirus-based vaccination against Clostridium difficile toxin A allows for rapid humoral immunity and complete protection from toxin A lethal challenge in mice. Vaccine. 30(8): p. 1492-501; PMID:22200503; http://dx.doi.org/10.1016/j.vaccine.2011.12.064
   PubMed Web of Science ®Google Scholar
• Ward SJ, Douce G, Dougan G, Wren BW. Local and systemic neutralizing antibody responses induced by intranasal immunization with the nontoxic binding domain of toxin A from Clostridium difficile. Infect Immun, 1999. 67(10): p. 5124-32
   PubMed Web of Science ®Google Scholar
• Ward SJ, Douce G, Figueiredo D, Dougan G, Wren BW. Immunogenicity of a Salmonella typhimurium aroA aroD vaccine expressing a nontoxic domain of Clostridium difficile toxin A. Infect Immun, 1999. 67(5): p. 2145-52
   PubMed Web of Science ®Google Scholar
• Greenberg RN, Marbury TC, Foglia G, Warny M. Phase I dose finding studies of an adjuvanted Clostridium difficile toxoid vaccine. Vaccine. 30(13): p. 2245-9; PMID:22306375; http://dx.doi.org/10.1016/j.vaccine.2012.01.065
   PubMed Web of Science ®Google Scholar
• Kotloff KL, Wasserman SS, Losonsky GA, Thomas W Jr, Nichols R, Edelman R, Bridwell M, Monath TP. Safety and immunogenicity of increasing doses of a Clostridium difficile toxoid vaccine administered to healthy adults. Infect Immun, 2001. 69(2): p. 988-95; http://dx.doi.org/10.1128/IAI.69.2.988-995.2001
   PubMed Web of Science ®Google Scholar
• Tian JH, Fuhrmann SR, Kluepfel-Stahl S, Carman RJ, Ellingsworth L, Flyer DC. 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. Vaccine. 30(28): p. 4249-58; PMID:22537987; http://dx.doi.org/10.1016/j.vaccine.2012.04.045
   PubMed Web of Science ®Google Scholar
• Ghose C, Verhagen JM, Chen X, Yu J, Huang Y, Chenesseau O, Kelly CP, Ho DD. Toll-like receptor 5-dependent immunogenicity and protective efficacy of a recombinant fusion protein vaccine containing the nontoxic domains of Clostridium difficile toxins A and B and Salmonella enterica serovar typhimurium flagellin in a mouse model of Clostridium difficile disease. Infect Immun. 81(6): p. 2190-6; PMID:23545305; http://dx.doi.org/10.1128/IAI.01074-12
   PubMed Web of Science ®Google Scholar
• Gardiner DF, Rosenberg T, Zaharatos J, Franco D, Ho DD. A DNA vaccine targeting the receptor-binding domain of Clostridium difficile toxin A. Vaccine, 2009. 27(27): p. 3598-604; http://dx.doi.org/10.1016/j.vaccine.2009.03.058
   PubMed Web of Science ®Google Scholar
• Jin K, Wang S, Zhang C, Xiao Y, Lu S, Huang Z. Protective antibody responses against Clostridium difficile elicited by a DNA vaccine expressing the enzymatic domain of toxin B. Hum Vaccin Immunother. 9(1): p. 63-73; PMID:23143772; http://dx.doi.org/10.4161/hv.22434
   PubMed Web of Science ®Google Scholar
• Leuzzi R, Spencer J, Buckley A, Brettoni C, Martinelli M, Tulli L, Marchi S, Luzzi E, Irvine J, Candlish D, et al. Protective efficacy induced by recombinant Clostridium difficile toxin fragments. Infect Immun. 81(8): p. 2851-60; PMID:23716610; http://dx.doi.org/10.1128/IAI.01341-12
   PubMed Web of Science ®Google Scholar
• Wang H, Sun X, Zhang Y, Li S, Chen K, Shi L, Nie W, Kumar R, Tzipori S, Wang J, et al. A chimeric toxin vaccine protects against primary and recurrent Clostridium difficile infection. Infect Immun. 80(8): p. 2678-88; PMID:22615245; http://dx.doi.org/10.1128/IAI.00215-12
   PubMed Web of Science ®Google Scholar
• Lanis JM, S Barua, JD Ballard. Variations in TcdB activity and the hypervirulence of emerging strains of Clostridium difficile. PLoS Pathog. 6(8): p. e1001061; PMID:20808849; http://dx.doi.org/10.1371/journal.ppat.1001061
   PubMedGoogle Scholar
• Stabler RA, He M, Dawson L, Martin M, Valiente E, Corton C, Lawley TD, Sebaihia M, Quail MA, Rose G, et al. Comparative genome and phenotypic analysis of Clostridium difficile 027 strains provides insight into the evolution of a hypervirulent bacterium. Genome Biol, 2009. 10(9): p. R102; http://dx.doi.org/10.1186/gb-2009-10-9-r102
   PubMed Web of Science ®Google Scholar
• Brun P, Scarpa M, Grillo A, Palù G, Mengoli C, Zecconi A, Spigaglia P, Mastrantonio P, Castagliuolo I. Clostridium difficile TxAC314 and SLP-36kDa enhance the immune response toward a co-administered antigen. J Med Microbiol, 2008. 57(Pt 6): p. 725-31; http://dx.doi.org/10.1099/jmm.0.47736-0
   PubMed Web of Science ®Google Scholar
• Zemljic M, Rupnik M, Scarpa M, Anderluh G, Palù G, Castagliuolo I. Repetitive domain of Clostridium difficile toxin B exhibits cytotoxic effects on human intestinal epithelial cells and decreases epithelial barrier function. Anaerobe, 2010. 16(5): p. 527-32; http://dx.doi.org/10.1016/j.anaerobe.2010.06.010
   PubMed Web of Science ®Google Scholar
• Donald RG, Flint M, Kalyan N, Johnson E, Witko SE, Kotash C, Zhao P, Megati S, Yurgelonis I, Lee PK, et al. A novel approach to generate a recombinant toxoid vaccine against Clostridium difficile. Microbiology, 2013. 159(Pt 7): p. 1254-66; http://dx.doi.org/10.1099/mic.0.066712-0
   PubMed Web of Science ®Google Scholar
• Teichert M, Tatge H, Schoentaube J, Just I, Gerhard R. Application of mutated Clostridium difficile toxin A for determination of glucosyltransferase-dependent effects. Infect Immun, 2006. 74(10): p. 6006-10; http://dx.doi.org/10.1128/IAI.00545-06
   PubMed Web of Science ®Google Scholar
• Busch C, Hofmann F, Selzer J, Munro S, Jeckel D, Aktories K. A common motif of eukaryotic glycosyltransferases is essential for the enzyme activity of large clostridial cytotoxins. J Biol Chem, 1998. 273(31): p. 19566-72; http://dx.doi.org/10.1074/jbc.273.31.19566
   PubMed Web of Science ®Google Scholar
• Maynard-Smith M, Ahern H, McGlashan J, Nugent P, Ling R, Denton H, Coxon R, Landon J, Roberts A, Shone C. Recombinant antigens based on toxins A and B of Clostridium difficile that evoke a potent toxin-neutralising immune response. Vaccine. 32(6): p. 700-5; PMID:24342251; http://dx.doi.org/10.1016/j.vaccine.2013.11.099
   PubMed Web of Science ®Google Scholar
• Killgore G, Thompson A, Johnson S, Brazier J, Kuijper E, Pepin J, Frost EH, Savelkoul P, Nicholson B, van den Berg RJ, et al. Comparison of seven techniques for typing international epidemic strains of Clostridium difficile: restriction endonuclease analysis, pulsed-field gel electrophoresis, PCR-ribotyping, multilocus sequence typing, multilocus variable-number tandem-repeat analysis, amplified fragment length polymorphism, and surface layer protein A gene sequence typing. J Clin Microbiol, 2008. 46(2): p. 431-7; http://dx.doi.org/10.1128/JCM.01484-07
   PubMed Web of Science ®Google Scholar
• Perez J, VS Springthorpe, SA Sattar. Clospore: a liquid medium for producing high titers of semi-purified spores of Clostridium difficile. J AOAC Int, 2011. 94(2): p. 618-26.
   PubMed Web of Science ®Google Scholar
• Sorg JA, AL Sonenshein. Inhibiting the initiation of Clostridium difficile spore germination using analogs of chenodeoxycholic acid, a bile acid. J Bacteriol, 2010. 192(19): p. 4983-90; http://dx.doi.org/10.1128/JB.00610-10
   PubMed Web of Science ®Google Scholar
• Yang G, Zhou B, Wang J, He X, Sun X, Nie W, Tzipori S, Feng H. Expression of recombinant Clostridium difficile toxin A and B in Bacillus megaterium. BMC Microbiol, 2008. 8: p. 192; http://dx.doi.org/10.1186/1471-2180-8-192
   PubMed Web of Science ®Google Scholar
• Lee S, WL Picking, S Tzipori. The immune response of two microbial antigens delivered intradermally, sublingually, or the combination thereof. Microbes Infect 2014; 16(9):796-803; PMID:25111827; http://dx.doi.org/10.1016/j.micinf.2014.07.013
   PubMed Web of Science ®Google Scholar
• Chen X, Katchar K, Goldsmith JD, Nanthakumar N, Cheknis A, Gerding DN, Kelly CP. A mouse model of Clostridium difficile-associated disease. Gastroenterology, 2008. 135(6): p. 1984-92; http://dx.doi.org/10.1053/j.gastro.2008.09.002
   PubMed Web of Science ®Google Scholar
• Sun X, Wang H, Zhang Y, Chen K, Davis B, Feng H. Mouse relapse model of Clostridium difficile infection. Infect Immun, 2011. 79(7): p. 2856-64; http://dx.doi.org/10.1128/IAI.01336-10
   PubMed Web of Science ®Google Scholar