An Optimized, Synthetic DNA Vaccine Encoding the Toxin A and Toxin B Receptor Binding Domains of Clostridium difficile Induces Protective Antibody Responses<i>In Vivo</i>

Baliban, Scott M.; Michael, Amanda; Shammassian, Berje; Mudakha, Shikata; Khan, Amir S.; Simon, Chantal; Zentner, Isaac; Latimer, Brian; Bouillaut, Laurent; Hunter, Meredith; Marx, Preston A.; Sardesai, Niranjan Y.; Welles, Seth L.; Jacobson, Jeffrey M.; Weiner, David B.; Kutzler, Michele A.

doi:10.1128/iai.01950-14

Cited by 32 publications

(25 citation statements)

References 72 publications

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“…Emerging data indicate that sporulation rates may vary based on ribotype, with a heightened rate of sporulation for C. difficile ribotype 027 (24), which is associated with the higher disease recurrence rate for this particular ribotype (25). Enhancing the therapeutic options to address such disease recurrence is clearly an unmet need that is currently being evaluated with strategies such as fecal microbiota transplantation (FMT) and C. difficile vaccines (26)(27)(28)(29)(30). Should the activity observed in these in vitro experiments mirror activity in the human gut, then the use of ramoplanin as an agent for secondary prophylaxis may be a therapeutic option for clinicians.…”

Section: Discussionmentioning

confidence: 99%

Ambush of Clostridium difficile Spores by Ramoplanin: Activity in an In Vitro Model

Kraus

Lyerly

Carman

2015

Antimicrob Agents Chemother

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bClostridium difficile infection (CDI) is a gastrointestinal disease caused by C. difficile, a spore-forming bacterium that in its spore form is tolerant to standard antimicrobials. Ramoplanin is a glycolipodepsipeptide antibiotic that is active against C. difficile with MICs ranging from 0.25 to 0.50 g/ml. The activity of ramoplanin against the spores of C. difficile has not been well characterized; such activity, however, may hold promise, since posttreatment residual intraluminal spores are likely elements of disease relapse, which can impact more than 20% of patients who are successfully treated. C. difficile spores were found to be stable in deionized water for 6 days. In vitro spore counts were consistently below the level of detection for 28 days after even brief (30-min) exposure to ramoplanin at concentrations found in feces (300 g/ml). In contrast, suppression of spore counts was not observed for metronidazole or vancomycin at human fecal concentrations during treatment (10 g/ml and 500 g/ml, respectively). Removal of the C. difficile exosporium resulted in an increase in spore counts after exposure to 300 g/ml of ramoplanin. Therefore, we propose that rather than being directly sporicidal, ramoplanin adheres to the exosporium for a prolonged period, during which time it is available to attack germinating cells. This action, in conjunction with its already established bactericidal activity against vegetative C. difficile forms, supports further evaluation of ramoplanin for the prevention of relapse after C. difficile infection in patients. Clostridium difficile infection (CDI) remains a clinically important disease, with increasing incidence and mortality rates in the United States; it now surpasses methicillin-resistant Staphylococcus aureus as the most common health care-associated infection (HAI) and results in an annual cost burden to the health care system of $4.8 billion (1-3). A prolonged cure for treated patients remains elusive, as evidenced by the high rates of relapse (same ribotype within 30 days) and reinfection (different ribotype within 30 days). Recurrence rates have ranged from 15% to 40% (4-6) and are most commonly associated with the ribotype 027 epidemic strain (7). One contributing factor for high relapse rates is the presence of spores that persist within the intestinal lumen and evade elimination by standard anti-CDI treatments (8, 9). C. difficile spores are tolerant to standard antimicrobial therapy; hence, antimicrobial interventions targeting vegetative cells alone are unlikely to eradicate this disease reservoir (10).Ramoplanin is a glycolipodepsipeptide antibiotic produced from Actinoplanes, which inhibits peptidoglycan biosynthesis by limiting lipid II availability (11); it is bactericidal to many Grampositive aerobic and anaerobic bacteria, including C. difficile and vancomycin-resistant Enterococcus (11). Ramoplanin has known bactericidal activities against wild-type C. difficile and strains with reduced susceptibilities to vancomycin and has been studied in an open-labe...

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Section: Discussionmentioning

confidence: 99%

Ambush of Clostridium difficile Spores by Ramoplanin: Activity in an In Vitro Model

Kraus

Lyerly

Carman

2015

Antimicrob Agents Chemother

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“…Delivery of crude toxins intraperitoneally is lethal in mice. However, systemic toxin is not indicative of a normal infection scenario [37]. Entry of the toxin into circulation is thought to be a possible cause [38].…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity and Protection from Receptor-Binding Domains of Toxins as Potential Vaccine Candidates for Clostridium difficile

et al. 2019

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The receptor-binding domains (RBDs) located in toxin A and toxin B of Clostridium difficile are known to be nontoxic and immunogenic. We need to develop a new type vaccine based on RBDs. In this study, we expressed and purified recombinant proteins (named RBD-TcdA and RBD-TcdB) as vaccine candidates containing the RBDs of toxin A and toxin B, respectively, from the C. difficile reference strain VPI10463. The immunogenicity and protection of the vaccine candidates RBD-TcdA, RBD-TcdB, and RBD-TcdA/B was evaluated by ELISA and survival assays. The data indicated that mice immunized with all vaccine candidates displayed potent levels of RBD-specific serum IgG. Following intramuscular immunization of mice with RBD-TcdA and/or RBD-TcdB, these vaccine candidates triggered immune responses that protected mice compared to mice immunized with aluminum hydroxide alone. Taken together, the results of this study reveal that recombinant proteins containing RBDs of C. difficile toxins can be used for vaccine development. Additionally, we found that an RBD-TcdA/B vaccine can elicit a stronger humoral immune response and provide better immunoprotection than the univalent vaccines. This RBD vaccine candidate conferred significant protection against disease symptoms and death caused by toxins from a wild-type C. difficile strain.

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“…Finally, vaccination against C. difficile is a promising option, as demonstrated by two recent publications, one based on utilization of anatoxin [39], the other proposing a DNA vaccine [40].…”

Section: What Alternatives Are There To Faecal Microbiota Administratmentioning

confidence: 98%

Faecal microbiota transplantation: Key points to consider

Bourlioux

2015

Annales Pharmaceutiques Françaises

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An Optimized, Synthetic DNA Vaccine Encoding the Toxin A and Toxin B Receptor Binding Domains of Clostridium difficile Induces Protective Antibody ResponsesIn Vivo

Cited by 32 publications

References 72 publications

Ambush of Clostridium difficile Spores by Ramoplanin: Activity in an In Vitro Model

Ambush of Clostridium difficile Spores by Ramoplanin: Activity in an In Vitro Model

Immunogenicity and Protection from Receptor-Binding Domains of Toxins as Potential Vaccine Candidates for Clostridium difficile

Faecal microbiota transplantation: Key points to consider

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