Vaccination With Parenteral Toxoid B Protects Hamsters Against Lethal Challenge With Toxin A–Negative, Toxin B–Positive Clostridium difficile but Does Not Prevent Colonization

Siddiqui, Farida; O'Connor, Jennifer Ruth; Nagaro, Kristin; Cheknis, Adam; Sambol, Susan P.; Vedantam, Gayatri; Gerding, Dale N.; Johnson, Stuart

doi:10.1093/infdis/jir688

Cited by 32 publications

(26 citation statements)

References 24 publications

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“…Toxoids TcdA and TcdB, generated by formalin inactivation of holotoxins, represent the major focus of vaccine development and have been tested in patients (1,19,29,50,51). Recent studies in patients (36) and in animal models (30,41) have highlighted the relative importance of TcdB as one of the primary virulence factors in CDI.…”

Section: Resultsmentioning

confidence: 99%

“…In support of this notion, antibodies against both toxins are protective in hamsters (13,28,34), and serum anti-Tcd antibodies in patients correlate with protection against symptomatic disease and recurrence (31,33). Vaccine candidates that target the C. difficile toxins include toxoids (1,16,18,50,51,56) and recombinant TcdA RBD fragments (4, 15, 43, 46-48, 59, 60). Toxoids, generated by formalin inactivation of holotoxins, represent the major focus of vaccine development and have been tested in patients (1,19,29,51).…”

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confidence: 98%

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A Chimeric Toxin Vaccine Protects against Primary and Recurrent Clostridium difficile Infection

et al. 2012

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fThe global emergence of Clostridium difficile infection (CDI) has contributed to the recent surge in severe antibiotic-associated diarrhea and colonic inflammation. C. difficile produces two homologous glucosylating exotoxins, TcdA and TcdB, both of which are pathogenic and require neutralization to prevent disease occurrence. However, because of their large size and complex multifunctional domain structures, it has been a challenge to produce native recombinant toxins that may serve as vaccine candidates. Here, we describe a novel chimeric toxin vaccine that retains major neutralizing epitopes from both toxins and confers complete protection against primary and recurrent CDI in mice. Using a nonpathogenic Bacillus megaterium expression system, we generated glucosyltransferase-deficient holotoxins and demonstrated their loss of toxicity. The atoxic holotoxins induced potent antitoxin neutralizing antibodies showing little cross-immunogenicity or protection between TcdA and TcdB. To facilitate simultaneous protection against both toxins, we generated an active clostridial toxin chimera by switching the receptor binding domain of TcdB with that of TcdA. The toxin chimera was fully cytotoxic and showed potent proinflammatory activities. This toxicity was essentially abolished in a glucosyltransferase-deficient toxin chimera, cTxAB. Parenteral immunization of mice or hamsters with cTxAB induced rapid and potent neutralizing antibodies against both toxins. Complete and long-lasting disease protection was conferred by cTxAB vaccinations against both laboratory and hypervirulent C. difficile strains. Finally, prophylactic cTxAB vaccination prevented spore-induced disease relapse, which constitutes one of the most significant clinical issues in CDI. Thus, the rational design of recombinant chimeric toxins provides a novel approach for protecting individuals at high risk of developing CDI.

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Section: Resultsmentioning

confidence: 99%

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confidence: 98%

A Chimeric Toxin Vaccine Protects against Primary and Recurrent Clostridium difficile Infection

et al. 2012

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“…Vaccines targeting the C. difficile toxins include toxoids [19][20][21][22][23] and toxin fragments. [24][25][26][27][28][29] Formaldehyde-inactivated native C. difficile toxins have been reported to be well tolerated and able to induce protective immunity in CDI in humans.…”

Section: Introductionmentioning

confidence: 99%

A chimeric protein comprising the glucosyltransferase and cysteine proteinase domains of toxin B and the receptor binding domain of toxin A induces protective immunity againstClostridium difficileinfection in mice and hamsters

Wang

Yan

Kim

et al. 2015

Human Vaccines & Immunotherapeutics

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“…Torres et al found that a combination of parenteral and mucosal toxoid immunization protected hamsters from CDI (11), and in humans, toxoid immunization induced an anti-toxin Ab response that correlated with decreased recurrent CDI (12,13). However, toxoid vaccination does not affect colonization (14). Because no vaccine for CDI is available, we think that an important step in developing a vaccine is to fully understand the nature of protective immune responses to C. difficile.…”

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Protection from Clostridium difficile Infection in CD4 T Cell- and Polymeric Immunoglobulin Receptor-Deficient Mice

2014

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Clostridium difficile rivals methicillin-resistant Staphylococcus aureus as the primary hospital-acquired infection. C. difficile infection (CDI) caused by toxins A and/or B can manifest as mild diarrhea to life-threatening pseudomembranous colitis. Although most patients recover fully from CDI, ϳ20% undergo recurrent disease. Several studies have demonstrated a correlation between anti-toxin antibody (Ab) and decreased recurrence; however, the contributions of the systemic and mucosal Ab responses remain unclear. Our goal was to use the CDI mouse model to characterize the protective immune response to C. difficile. C57BL/6 mice infected with epidemic C. difficile strain BI17 developed protective immunity against CDI and did not develop CDI upon rechallenge; they generated systemic IgG and IgA as well as mucosal IgA Ab to toxin. To determine if protective immunity to C. difficile could be generated in immunodeficient individuals, we infected CD4 ؊/؊ mice and found that they generated both mucosal and serum IgA anti-toxin Abs and were protected from CDI upon rechallenge, with protection dependent on major histocompatibility complex class II (MHCII) expression; no IgG anti-toxin Ab was found. We found that protection was likely due to neutralizing mucosal IgA Ab. In contrast, pIgR ؊/؊ mice, which lack the receptor to transcytose polymeric Ab across the epithelium, were also protected from CDI, suggesting that although mucosal anti-toxin Ab may contribute to protection, it is not required. We conclude that protection from CDI can occur by several mechanisms and that the mechanism of protection is determined by the state of immunocompetence of the host.

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Vaccination With Parenteral Toxoid B Protects Hamsters Against Lethal Challenge With Toxin A–Negative, Toxin B–Positive Clostridium difficile but Does Not Prevent Colonization

Cited by 32 publications

References 24 publications

A Chimeric Toxin Vaccine Protects against Primary and Recurrent Clostridium difficile Infection

A Chimeric Toxin Vaccine Protects against Primary and Recurrent Clostridium difficile Infection

A chimeric protein comprising the glucosyltransferase and cysteine proteinase domains of toxin B and the receptor binding domain of toxin A induces protective immunity againstClostridium difficileinfection in mice and hamsters

Protection from Clostridium difficile Infection in CD4 T Cell- and Polymeric Immunoglobulin Receptor-Deficient Mice

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