IMMUNOGENIC COMPOSITIONS AND METHODS FOR ELICITING AN IMMUNE RESPONSE AGAINST CLOSTRIDIOIDES (CLOSTRIDIUM) DIFFICILE
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.
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 an immunogenic composition of claim 1 .
47 . A method of preventing, treating or ameliorating an infection, disease or condition associated with C. difficile in a human subject, the method comprising administering to the human subject an immunogenic composition of claim 1 .
48 . A method of preventing, treating or ameliorating a medically attended C. difficile infection in a human subject, the method comprising administering to the human subject an immunogenic composition of claim 1 .
49 . The method of claim 46 , wherein the immunogenic composition is administered in a first and second dose.
50 . The method of claim 49 , wherein the second dose is administered about 2 months after the first dose (e.g. M 0, 2) or about 6 months after the first dose (M 0, 6).
51 . The method of claim 46 , wherein the human subject is 18 years of age or older, 50 years of age or older, 55 years of age or older, 60 years of age or older, 65 years of age or older, or 70 years of age or older.
52 . The method of claim 46 , wherein
the immune response elicits neutralizing antibodies against C. difficile toxin A and/or neutralizing antibodies against C. difficile toxin B; and/or
the immune response elicits greater neutralizing antibodies against C. difficile toxin A and/or B after administration of 2 doses of the immunogenic composition compared to administration of 3 doses of the investigational C. difficile vaccine.
53 . (canceled)