Immunogenic compositions and methods for eliciting an immune response against clostridioides (clostridium) difficile

Patent metadata

Field	Value
Publication number	US-2024189410-A1
Application number	US-202318535116-A
Country	US
Kind code	A1
Filing date	Dec 11, 2023
Priority date	Dec 13, 2022
Publication date	Jun 13, 2024
Grant date	—

Abstract

The present invention relates to immunogenic compositions that comprise a Clostridioides difficile toxoid A and/or a C. difficile toxoid B, and an adjuvant, and methods of use thereof. The present invention further relate to a methods for eliciting an enhanced immune response in a human against a C. difficile infection. The methods include administering to the human an effective dose of an immunogenic composition, which includes a C. difficile toxoid and an adjuvant, wherein the composition is administered two times.

First claim

1 . A immunogenic composition comprising a Clostridioides difficile ( C. difficile ) toxoid A and/or toxoid B, and a CpG adjuvant comprising at least one CpG or a saponin containing liposomal adjuvant.

2 . (canceled)

3 . The immunogenic composition of claim 1 , wherein the CpG adjuvant comprises a B class CpG.

4 . The immunogenic composition of claim 1 , wherein the CpG adjuvant comprises CpG 24555 (SEQ ID NO: 48).

5 . The immunogenic composition of claim 1 , comprising about 0.1 to 5 mg/mL or higher, about 0.1 to about 1.0 mg/mL, about 0.5 to about 1.5 mg/mL, about 0.8 to about 1.8 mg/mL, or about 3.0 to about 4.0 mg/mL CpG.

6 . The immunogenic composition of claim 1 , comprising about 0.5 mg/mL, about 1.0 mg/mL, about 1.2 mg/mL, or about 3.6 mg/mL CpG.

7 . The immunogenic composition of claim 1 , comprising about 3.6 mg/mL CpG.

8 . The immunogenic composition of claim 1 , wherein the CpG adjuvant further comprises an additional adjuvant.

9 . The immunogenic composition of claim 1 , wherein the CpG adjuvant further comprises an aluminum salt selected from aluminum phosphate, aluminum sulfate and aluminum hydroxide (Al(OH) 3 ).

10 . (canceled)

11 . The immunogenic composition of claim 1 , comprising a CpG and about 0.1 to 5 mg/mL, about 0.5 to about 1.5 mg/mL, or about 1.0 to about 2.5 mg/mL Al(OH) 3 .

12 . The immunogenic composition of claim 1 , comprising a CpG and about 1.0, about 1.5, about 1.7, about 1.8, about 2.0, or about 2.5 Al(OH) 3 .

13 . The immunogenic composition of claim 1 , comprising about 0.5 to about 3.6 mg/mL CpG and about 0.1 to 5 mg/mL Al(OH) 3 .

14 . The immunogenic composition of claim 1 , comprising:
about 1.0 mg/mL CpG and about 1.5 mg/mL Al(OH) 3 ; about 1.2, 1.3, 1.4, 1.5, or 1.6 mg/mL CpG and about 1.7 mg/mL Al(OH) 3 ; about 1.5, 1.6, 1.7, 1.8, or 1.9 mg/mL CpG and about 2.0 mg/mL Al(OH) 3 ; about 1.8, 1.9, 2.0, 2.1, 2.2, or 2.4 mg/mL CpG and about 2.5 mg/mL Al(OH) 3 ; about 3.6 mg/mL CpG and about 1.8 mg/mL Al(OH) 3 ; about 1.4 mg/mL CpG and about 1.7 mg/mL or higher Al(OH) 3 ; about 1.6 mg/mL CpG and about 2.0 mg/mL or higher Al(OH) 3 ; or about 2.0 mg/mL CpG and about 2.5 mg/mL or higher Al(OH) 3 .

15 . The immunogenic composition of claim 1 ,
comprising a mass ratio of CpG/Al(OH) 3 of about 1.21 or higher.

16 . The immunogenic composition of claim 1 , wherein the CpG adjuvant comprises a histidine or phosphate buffer.

17 . The immunogenic composition of claim 16 , wherein the histidine or phosphate buffer is at a concentration of about 5 mM to 15 mM, or preferably about 10 mM.

18 . The immunogenic composition of claim 1 , wherein the CpG adjuvant comprises sodium chloride.

19 . The immunogenic composition of claim 18 , wherein the sodium chloride is at a concentration of about 20 mM to 100 mM, or preferably about 50 mM or about 60 mM.

20 . The immunogenic composition of claim 1 , wherein the CpG adjuvant has a pH of about 6.0 to 7.0, or preferably about 6.5.

21 . The immunogenic composition of claim 1 , wherein the CpG adjuvant comprises about 3.6 mg/mL CpG 24555.

22 . The immunogenic composition of claim 1 , wherein the CpG adjuvant comprises about 1.0 mg/mL CpG 24555 and about 1.5 mg/mL of Al(OH) 3 .

23 . The immunogenic composition of claim 1 , wherein the saponin containing liposomal adjuvant comprises a saponin and a monophosphoryl lipid A (MPLA)-containing liposome composition, wherein the liposome composition comprises i) a lipid bilayer comprising phospholipids and ii) cholesterol.

24 . The immunogenic composition of claim 23 , wherein the saponin is selected from QS-7, QS-18, QS-21, or a mixture thereof.

25 . (canceled)

26 . The immunogenic composition of claim 23 , wherein the phospholipid is selected from dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearyl phosphatidylcholine (DSPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylglycerol (DPPG), and distearyl phosphatidylglycerol (DSPG).

27 . (canceled)

28 . The immunogenic composition of claim 1 , wherein the saponin containing liposomal adjuvant comprises QS-21, Monophosphoryl Lipid A (MPLA), DMPC, DMPG and cholesterol.

29 . (canceled)

30 . The immunogenic composition of claim 1 , comprising:
about 0.1 to about 0.4 mg/mL of QS-21, preferably about 0.2 mg/mL of QS-21; about 0.2 to about 0.6 mg/mL of MPLA, preferably about 0.4 mg/mL of MPLA; about 5 to about 15 mg/mL of cholesterol, preferably about 11 mg/mL of cholesterol; about 5 to about 20 mg/mL of DMPC, preferably about 14 mg/mL of DMPC; and/or about 1.0 to about 2.0 mg/mL of DMPG, preferably about 1.6 mg/mL of DMPG.

31 . The immunogenic composition of claim 1 , wherein the saponin containing liposomal adjuvant comprises a histidine or phosphate buffer.

32 . The immunogenic composition of claim 31 , wherein the phosphate buffer is at a concentration of about 5 mM to 15 mM, or preferably about 10 mM, and optionally, further comprises sodium chloride at a concentration of about 100 mM to 200 mM, or preferably about 150 mM.

33 . (canceled)

34 . The immunogenic composition of claim 1 , wherein the saponin containing liposomal adjuvant has a pH of about 5.5 to 7.0, preferably about 6.2.

35 . The immunogenic composition of claim 1 , wherein the C. difficile toxoid A comprises the amino acid sequence of SEQ ID NO: 4, wherein the initial methionine is absent, and C. difficile toxoid B comprises the amino acid sequence of SEQ ID NO: 6, wherein the initial methionine is absent.

36 . The immunogenic composition of claim 1 , wherein the C. difficile toxoid A comprises the amino acid sequence of SEQ ID NO: 84, and C. difficile toxoid B comprises the amino acid sequence of SEQ ID NO: 86.

37 . The immunogenic composition of claim 1 , wherein the composition comprises the C. difficile toxoid A and the C. difficile toxoid B in a ratio of about 3:1 to about 1:1 and/or the composition comprises 200 ρq of toxoid per dose.

38 . (canceled)

39 . The immunogenic composition of claim 1 , wherein the C. difficile toxoid A and toxoid B are lyophilized and reconstituted with a CpG adjuvant or a saponin containing liposomal adjuvant.

40 . The immunogenic composition of claim 39 , wherein the lyophilized C. difficile toxoid A and toxoid B are reconstituted with:
a CpG adjuvant comprising about 3.6 mg/mL CpG 24555, a CpG adjuvant comprising about 1.0 mg/mL CpG 24555 and about 1.5 mq/mL Al(OH) 3 ; and/or a saponin containing liposomal adjuvant comprising about 0.2 mq/mL QS-21, about 0.4 mg/mL Monophosphoryl 3-Deacyl Lipid A, about 14 mq/mL DMPC, about 1.6 mq/mL DMPG and about 11 mq/mL cholesterol.

41 . (canceled)

42 . (canceled)

43 . The immunogenic composition of claim 1 , wherein the composition is administered at a dose volume of 0.5 mL.

44 . (canceled)

45 . (canceled)

46 . A method of eliciting an immune response in a human subject against C. difficile , the method comprising administering to the human subject

Assignees

• Pfizer

Inventors

• Anderson Annaliesa Sybil
• Gonzalez-Garis Marina A
• Hu Lei
• Kanevsky Isis
• Liberator Paul Arthur
• Moran Justin Keith
• Phelan Lynn Marie
• Pride Michael William
• Shi Shuai
• Surendran Naveen

Classifications

• A61K2039/575

  humoral response · CPC title

• A61K2039/55505

  Inorganic adjuvants · CPC title

• A61K2039/55555

  Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers · CPC title

• A61K2039/55577

  Saponins; Quil A; QS21; ISCOMS · CPC title

• A61K2039/55561

  CpG containing adjuvants; Oligonucleotide containing adjuvants · CPC title