Abstract
Clostridium difficile disease is mediated primarily by toxins A and B (TcdA and TcdB, respectively). The receptor binding domains (RBD) of TcdA and TcdB are immunogenic, and anti-RBD antibodies are protective. Since these toxins act locally, an optimal C. difficile vaccine would generate both systemic and mucosal responses. We have repurposed an attenuated Salmonella enterica serovar Typhimurium strain (YS1646) to produce such a vaccine. Plasmid-based candidates expressing either the TcdA or TcdB RBD were screened. Different vaccine routes and schedules were tested to achieve detectable serum and mucosal antibody titers in C57BL/6J mice. When given in a multimodality schedule over 1 week (intramuscularly and orally [p.o.] on day 0 and p.o. on days 2 and 4), several candidates provided 100% protection against lethal challenge. Substantial protection (82%) was achieved with combined p.o. TcdA and TcdB vaccination alone (days 0, 2, and 4). These data demonstrate the potential of the YS1646-based vaccines for C. difficile and strongly support their further development.
Highlights
Clostridium difficile disease is mediated primarily by toxins A and B (TcdA and TcdB, respectively)
The pathology associated with C. difficile infection (CDI) is thought to be toxin mediated [3], and there are strong precedents for the efficacy of vaccine-induced antitoxin antibodies in the prevention or modification of toxin-mediated diseases [29, 30]
In addition to passive immunotherapy, the generation of antitoxin antibodies is secretion signals, produced in E. coli), and the film was exposed for 2 min
Summary
Clostridium difficile disease is mediated primarily by toxins A and B (TcdA and TcdB, respectively). Live attenuated Salmonella strains have other potential advantages as vaccine vectors, including targeting of the intestinal M cells that overlie the gut-associated lymphoid tissues (GALT) [19] and invasion of macrophages, leading to the induction of both humoral and cellular responses to their foreign protein cargo [20]. They have a large carrying capacity and are easy to manipulate both in the laboratory and at an industrial scale
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