CLOSTRIDIUM DIFFICILE VACCINE
The present invention relates to a lipidated immunogenic Clostridium difficile toxin A and toxin B polypeptide, a pharmaceutical composition comprising the immunogenic Clostridium difficile toxin A and/or toxin B polypeptide for use as a medicament, particularly a vaccine and/or for use in a method for the prevention or treatment of C. difficile infection and/or C. difficile -associated disease.
1 . An immunogenic composition comprising a lipidated C. difficile toxin B polypeptide for use in the prevention or treatment of C. difficile infection and/or C. difficile -associated disease in a subject, wherein the lipidated polypeptide comprises (i) a C. difficile toxin B cell-binding domain or fragment thereof and (ii) lacks a C. difficile toxin A cell-binding domain sequence, and wherein the composition (iii) optionally comprises a further C. difficile antigen.
2 . An immunogenic composition for use according to claim 1 , wherein the immunogenic composition does not comprise a C. difficile toxin A C-terminal repeat domain-containing polypeptide.
3 . An immunogenic composition for use according to claim 1 or claim 2 , wherein the lipidated polypeptide is the sole active agent in the immunogenic composition.
4 . An immunogenic composition for use according to any preceding claim , wherein the composition is administered to the subject without administration of a C. difficile toxin A immunogenic polypeptide, preferably wherein the composition is administered to the subject as a sole immunogenic composition for the prevention or treatment of C. difficile infection and/or C. difficile -associated disease.
5 . An immunogenic composition for use according to claim 1 , wherein the immunogenic composition further comprises a lipidated C. difficile toxin A polypeptide comprising a toxin A cell-binding domain or fragment thereof.
6 . An immunogenic composition for use according to claim 1 , wherein the immunogenic composition is administered to the subject in combination with a further immunogenic composition comprising a lipidated C. difficile toxin A polypeptide comprising a toxin A cell-binding domain or fragment thereof, preferably wherein the lipidated C. difficile toxin A polypeptide lacks C. difficile toxin B cell-binding domain or C-terminal repeat domain sequence.
7 . An immunogenic composition for use according to any preceding claim , wherein the lipidated C. difficile toxin B polypeptide comprises or consists of a lipidated form of SEQ ID NO: 6, or a lipidated form of the full length C. difficile toxin B C-terminal repeat domain sequence of SEQ ID NO: 4, or a variant thereof with a sequence identity to SEQ ID Nos 4 or 6 of at least about 80%, preferably about 90%, more preferably about 95%.
8 . An immunogenic composition for use according to any of claims 5 to 7 , wherein the lipidated C. difficile toxin A polypeptide comprises or consists of a lipidated form of SEQ ID NO: 5, or a lipidated form of the full length C. difficile toxin A C-terminal repeat domain sequence of SEQ ID NO: 3, or a variant thereof with a sequence identity to SEQ ID Nos 3 or 5 of at least about 80%, preferably about 90%, more preferably about 95%.
9 . An immunogenic composition for use according to any preceding claim , wherein the composition further comprises a C. difficile antigen selected from the group consisting of Acd protein (WP_009892971.1), C40 family peptidase (WP_009890599.1), Cwp66, Cwp84, FliC, FliD, CDTa, CDTb, Bc1A3 glycoprotein, PSII antigen and rlipoA-RBD.
10 . An immunogenic composition for use according to any preceding claim , wherein the composition further comprises a pharmaceutically acceptable carrier and/or excipient, and optionally one or more adjuvant(s).
11 . An immunogenic composition for use according to claim 10 , wherein the composition comprises a CpG-containing oligodeoxynucleotide (CpG-ODN) and/or an alum adjuvant.
12 . An immunogenic composition for use according to claim 11 , wherein the CpG-ODN is CpG1018 as defined by SEQ ID NO: 10.
13 . An immunogenic composition for use according to claim 11 , wherein the alum adjuvant is aluminium hydroxide comprising less than 1.25 ppb copper based on the weight of the composition.
14 . A method for the prevention or treatment of C. difficile infection and/or C. difficile -associated disease in a subject in need thereof, comprising administering to the subject an immunogenic composition comprising a lipidated C. difficile toxin B polypeptide, wherein the lipidated polypeptide comprises a C. difficile cell-binding domain or fragment thereof and wherein the lipidated polypeptide lacks the C. difficile toxin A cell-binding domain sequence.
15 . The method according to claim 14 , wherein the immunogenic composition is administered to the subject without administration of a C. difficile toxin A immunogenic polypeptide.
16 . The method according to claim 14 , wherein the immunogenic composition is administered to the subject without administration of a C. difficile toxin A immunogenic polypeptide, preferably wherein the composition is administered to the subject as a sole immunogenic composition for the prevention or treatment of C. difficile infection and/or C. difficile -associated disease, wherein no further immunogenic composition for the prevention or treatment of C. difficile infection and/or C. difficile -associated disease is administered to the subject.