Immunogenic composition
The present invention relates to immunogenic compositions comprising a Clostridium difficile ( C. difficile ) polypeptide and an aluminum-free adjuvant.
1. An immunogenic composition comprising:
a) a fusion polypeptide comprising a Clostridium difficile toxin A fragment and a C. difficile toxin B fragment; and
b) an adjuvant comprising an immunologically active saponin fraction presented in the form of a liposome.
2. An immunogenic composition according to claim 1 in which said adjuvant further comprises any one or more of a sterol, a lipopolysaccharide and 1, 2-Dioleoyl-sn-Glycero-3-phosphocholine (DOPC).
3. An immunogenic composition according to claim 2 wherein said sterol is cholesterol.
4. An immunogenic composition according to claim 1 wherein said immunologically active saponin fraction is QS21.
5. An immunogenic composition according to claim 2 wherein said lipopolysaccharide is a lipid A derivative.
6. The immunogenic composition according to claim 1 wherein said adjuvant comprises cholesterol, DOPC, 3D-MPL and QS21.
7. The immunogenic composition of claim 1 , wherein the adjuvant is formulated in a dose comprising:
from about 0.1 to about 0.5 mg cholesterol,
from about 0.25 to about 2 mg DOPC,
from about 10 μg to about 70 μg 3D-MPL, and
from about 10 μg to about 70 μg QS21.
8. The immunogenic composition of claim 7 , wherein the adjuvant is formulated in a dose comprising:
about 0.25 mg cholesterol,
about 1.0 mg DOPC,
about 50 μg 3D-MPL, and
about 50 μg QS21.
9. An immunogenic composition according to claim 1 wherein the polypeptide is a fusion polypeptide comprising a first fragment and a second fragment, wherein
(i) the first fragment is a toxin A repeating domain fragment;
(ii) the second fragment is a toxin B repeating domain fragment;
(iii) the first fragment has a first proximal end;
(iv) the second fragment has a second proximal end; and
wherein the first fragment and the second fragment are adjacent to one another.
10. An immunogenic composition according to claim 9 wherein the first proximal end is within a short repeat and/or the second proximal end is within a short repeat.
11. An immunogenic composition according to claim 9 wherein the first proximal end and the second proximal end do not disrupt short repeat-long repeat-short repeat (SR-LR-SR) portions.
12. An immunogenic composition according to claim 9 wherein the polypeptide comprises an immunogenic fragment of SEQ ID NO:4.
13. An immunogenic composition according to claim 1 wherein the polypeptide is a polypeptide comprising a first fragment and a second fragment, wherein
(i) the first fragment is a toxin A repeating domain fragment;
(ii) the second fragment is a toxin B repeating domain fragment;
(iii) the first fragment comprises a first proximal end within a first repeat portion;
(iv) the second fragment comprises a second proximal end within a second repeat portion; and
wherein the first fragment and the second fragment are adjacent to one another and wherein the first repeat portion and the second repeat portion have high structural similarity to one another.
14. An immunogenic composition according to claim 13 wherein the first proximal end is within repeat portion VII of toxin A and the second proximal end is within repeat portion II of toxin B.
15. An immunogenic composition according to claim 13 wherein the first proximal end is within a long repeat and/or the second proximal end is within a long repeat.
16. A vaccine comprising the immunogenic composition of claim 1 and a pharmaceutically acceptable excipient.
17. A method of preventing or treating C. difficile disease comprising administering the immunogenic composition of claim 1 to a patient.
18. An immunogenic composition according to claim 1 wherein the polypeptide is a polypeptide comprising a first fragment and a second fragment, wherein
i. the first fragment is a toxin A repeating domain fragment as set forth in SEQ ID NO:11;
ii. the second fragment is a toxin B repeating domain fragment as set forth in SEQ ID NO:16;
iii. the first fragment has a first proximal end; and
iv. the second fragment has a second proximal end; and
wherein the first fragment and the second fragment are adjacent to one another.
19. An immunogenic composition according to claim 2 wherein said lipopolysaccharide is 3D-MPL.