Non-toxigenic Clostridium difficile spores for use in oral vaccination
Inventors
Sun, Xingmin • Sonenshein, Abraham
Assignees
University of South Florida • Tufts University • University of South Florida St Petersburg
Publication Number
US-10668140-B2
Publication Date
2020-06-02
Expiration Date
2038-02-26
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Abstract
Described are non-toxigenic Clostridium difficile strains and spores. Also described are vaccines comprising the Clostridium difficile spores. Further described are methods of preventing or treating a Clostridium difficile infection in a subject in need thereof.
Core Innovation
The invention pertains to genetically modified non-toxigenic Clostridium difficile strains that express specific immunogenic proteins comprising domains from Clostridium difficile toxins. These immunogenic proteins include the glucosyltransferase domain and cysteine proteinase domain of toxin TcdB (with specific mutations such as W102A and D288N that eliminate toxicity), and one or more receptor binding domains from toxins TcdA and/or TcdB. The engineered strains, including NTCD_Tcd138 and NTCD_Tcd169, form spores capable of being incorporated into vaccines.
The core problem addressed is the high incidence and difficulty in treating Clostridium difficile infections, which are resistant to conventional antibiotics due to factors like spore formation and toxin production. There is a significant need for new therapies and preventative approaches, especially for recurrent or antibiotic-resistant cases of Clostridium difficile infection.
This invention introduces both the creation of non-toxigenic, genetically engineered C. difficile strains carrying immunogenic but non-toxic protein domains and the use of their spores in vaccines. The compositions can be administered (including orally) to prevent or treat infections by inducing systemic and mucosal antibodies against C. difficile toxins (TcdA and TcdB), thereby providing protective immunity against both standard and hyper-virulent strains.
Claims Coverage
The patent contains multiple independent claims that encompass the core inventive features related to genetically modified non-toxigenic Clostridium difficile strains, their immunogenic proteins, and vaccines/methods of use.
Non-toxigenic Clostridium difficile strain expressing chimeric immunogenic protein with mutated TcdB and TcdA domains
A non-toxigenic Clostridium difficile strain comprising an immunogenic protein that contains: - A glucosyltransferase domain of Clostridium difficile toxin TcdB with W102A and D288N amino acid substitutions, - A cysteine proteinase domain of Clostridium difficile toxin TcdB, - A receptor binding domain of Clostridium difficile toxin TcdA. The mutated domains render the protein non-toxic while retaining immunogenicity.
Non-toxigenic Clostridium difficile strain with additional TcdB receptor binding domain and specific mutations
A non-toxigenic Clostridium difficile strain comprising a chimeric immunogenic protein that includes: - A glucosyltransferase domain of Clostridium difficile toxin TcdB with W102A and D288N substitutions, - A cysteine proteinase domain of TcdB with a C698A substitution, - A receptor binding domain of TcdA, - A receptor binding domain of TcdB. This structure further broadens the immunogenic profile and includes additional mutation for safety.
Vaccine composition comprising C. difficile spores and carrier/excipient
A vaccine comprising spores from the above non-toxigenic genetically modified Clostridium difficile strains (such as those expressing the immunogenic proteins described) formulated with a pharmaceutically acceptable excipient or carrier. The vaccine can utilize spores from strains that form spores and deliver the immunogenic proteins.
Method for treating or preventing Clostridium difficile infection using the vaccine
A method involving the administration of the aforementioned vaccine to a subject in need thereof to treat or prevent Clostridium difficile bacterial infection. The vaccine can be administered orally and is capable of increasing anti-TcdA and anti-TcdB IgG antibodies. The method is effective against infection by hyper-virulent strains.
The independent claims collectively protect the genetically modified non-toxigenic C. difficile strains expressing engineered immunogenic proteins, the use of their spores in vaccine formulations, and the therapeutic or prophylactic method of treating Clostridium difficile infection by administering these vaccines.
Stated Advantages
Oral vaccination with the non-toxigenic C. difficile spores induces both mucosal and systemic antibody responses, providing protective immunity against C. difficile infection.
The engineered strains express immunogenic but non-toxic versions of C. difficile toxin domains, eliminating toxicity while retaining immunogenicity.
The vaccines can increase anti-TcdA and anti-TcdB IgG antibodies, enhancing protection against infection by both standard and hyper-virulent C. difficile strains.
The spores are resilient and suitable for oral administration, which is highlighted as the most effective method for protecting the gut against C. difficile infection.
Documented Applications
Prevention or treatment of Clostridium difficile infection in a subject in need thereof.
Use as an oral vaccine to induce anti-toxin antibody responses against C. difficile toxins.
Protection against infection by hyper-virulent strains of Clostridium difficile.
Potential use in both human and veterinary contexts, as the subject may include humans, mammals, and animals susceptible to bacterial infection.
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