Norovirus Vaccine Formulations

• US 20080299152A1
• Filed: 09/28/2007
• Published: 12/04/2008
• Est. Priority Date: 09/29/2006
• Status: Active Grant

• Current Assignee: Montana Inc.
• Original Assignee: LigoCyte Pharmaceuticals, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Vedvick, Thomas S., Richardson, Charles, Tino, William T., Foubert, Thomas R.
• Granted Patent: US 7,955,603 B2
• Time in Patent Office: Days
• US Class Current: 424/216.1
• CPC Class Codes: A61K 2039/5258 Virus-like particles
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/543 intranasal
• CPC Class Codes: A61K 2039/55572 Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
• CPC Class Codes: A61K 2039/70 Multivalent vaccine
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 39/125 Picornaviridae, e.g. calicivirus
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 16/10 from RNA viruses
• CPC Class Codes: C12N 2770/16023 Virus like particles [VLP]
• CPC Class Codes: C12N 2770/16034 Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 7/00 Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00

Abstract

The present invention relates to antigenic and vaccine compositions comprising Norovirus antigens and adjuvants, in particular, mixtures of monovalent VLPs and mixtures of multivalent VLPs, and to a process for the production of both monovalent and multivalent VLPs, the VLPs comprising capsid proteins from one or more Norovirus genogroups.

Claims

1. A composition comprising at least one Norovirus antigen and at least one adjuvant.

2. The composition of claim 1, wherein said Norovirus antigen comprises peptides, proteins Norovirus virus-like particles (VLPs), denatured VLPs, capsid monomers, capsid multimers, aggregates, or mixtures thereof.

3. The composition of claim 2, wherein said Norovirus antigen is selected from the group consisting of Norovirus genogroup I and genogroup II viral strains.

4. The composition of claim 2, wherein said Norovirus VLPs are recombinant VLPs produced in an expression system using a Norovirus nucleic acid sequence.

5. The composition of claim 4, wherein said nucleic acid sequence encodes a capsid protein.

6. The composition of claim 5, wherein said capsid protein is selected from the group consisting of VP1 and VP2.

7. The composition of claim 4, wherein the VLPs are monovalent VLPs.

8. The composition of claim 4, wherein the VLPs are multivalent VLPs.

9. The composition of claim 8, wherein the multivalent VLPs are selected from the group consisting of genogroup I and genogroup II Noroviruses.

10. The composition of claim 4, wherein the expression system is a recombinant cellular expression system or a baculovirus-infected cellular expression system.

11. The composition of claim 10, wherein the cellular expression system is selected from the group consisting of yeast, bacterial, insect, and mammalian expression system.

12. The composition of claim 1, further comprising a second Norovirus antigen.

13. The composition of claim 12, wherein said first and second Norovirus antigens are monovalent VLPs from different genogroups.

14. The composition of claim 1, further comprising a delivery agent.

15. The composition of claim 14, wherein the delivery agent functions to enhance antigen uptake, provide a depot effect, or increase antigen retention time at the site of delivery.

16. The composition of claim 14, wherein the delivery agent is a bioadhesive.

17. The composition of claim 16, wherein said bioadhesive is a mucoadhesive.

18. The composition of claim 17, wherein said mucoadhesive is selected from the group consisting of glycosaminoglycans (e.g., chondroitin sulfate, dermatan sulfate chondroitin, keratan sulfate, heparin, heparan sulfate, hyaluronan), carbohydrate polymers (e.g., pectin, alginate, glycogen, amylase, amylopectin, cellulose, chitin, stachyose, unulin, dextrin, dextran), cross-linked derivatives of poly(acrylic acid), polyvinyl alcohol, polyvinyl pyrollidone, polysaccharides (including mucin and other mucopolysaccharides), polyions, cellulose derivatives (e.g., hydroxypropyl methylcellulose, carboxymethylcellulose), proteins (e.g. lectins, fimbrial proteins), and deoxyribonucleic acid.

19. The composition of claim 18 wherein said mucoadhesive is a polysaccharide.

20. The composition of claim 19 wherein said polysaccharide is chitosan, chitosan salt, or chitosan base.

21. The composition of claim 14, wherein said Norovirus antigen is a Norovirus VLP, said adjuvant is MPL, and said delivery agent is chitosan, chitosan salt or chitosan base.

22. The composition of claim 1, wherein the adjuvant is selected from the group consisting of toll-like receptor (TLR) agonists, monophosphoryl lipid A (MPL), synthetic lipid A, lipid A mimetics or analogs, aluminum salts, cytokines, saponins, muramyl dipeptide (MDP) derivatives, CpG oligos, lipopolysaccharide (LPS) of gram-negative bacteria, polyphosphazenes, emulsions, virosomes, cochleates, poly(lactide-co-glycolides) (PLG) microparticles, poloxamer particles, microparticles, and liposomes.

23. The composition of claim 22, wherein the adjuvant is a toll-like receptor (TLR) agonist.

24. The composition of claim 22, wherein the adjuvant is MPL.

25. The composition of claim 1, wherein the adjuvant is not a toxin adjuvant.

26. The composition of claim 1, wherein the composition is in a liquid formulation.

27. The composition of claim 1, wherein the composition is in a powder formulation.

28. The composition of claim 27, wherein the composition has an average particle size from about 10 to 500 micrometers in diameter.

29. The dry powder composition of claim 27 in combination with one or more devices for administering one or more doses of said composition.

30. The dry powder composition of claim 29, wherein said one or more doses are unit doses.

31. The dry powder composition of claim 29, wherein the device is a single-use nasal administration device.

32. The dry powder composition of claim 29, wherein said composition is stored in said device.

33. An antigenic formulation comprising the composition of claim 1.

34. A vaccine formulation comprising the composition of claim 1.

35. The formulation of claim 33 or 34, wherein said formulation is administered to a subject by a route selected from the group consisting of mucosal, intramuscular, intravenous, subcutaneous, intradermal, subdermal, and transdermal routes of administration.

36. The formulation of claim 35, wherein the route of administration is intramuscular.

37. The formulation of claim 35, wherein the mucosal route of administration is intranasal, oral, or vaginal.

38. The formulation of claim 37, wherein the formulation is in the form of a nasal spray, nasal drops or dry powder.

39. The formulation of claim 38, wherein the formulation is administered to the nasal mucosa by rapid deposition within the nasal passage from a device of the formulation held close or inserted into the nasal passageway.

40. The formulation of claim 39, wherein formulation is administrated to one or both nostrils.

41. The composition of claim 33 or 34, wherein the Norovirus antigen is present in a concentration of from about 0.01% (w/w) to about 80% (w/w).

42. The composition of claim 33 or 34, wherein the dosage of the Norovirus antigen is present in an amount of from about 1 μ

g to about 100 mg per dose.

43. The composition of claim 42, wherein the dosage of the Norovirus antigen is from about 1 μ

g to about 1 mg per dose.

44. The composition of claim 42, wherein the dosage of the Norovirus antigen is from about 1 μ

g to about 500 μ

g per dose.

45. The composition of claim 42, wherein the dosage of the Norovirus antigen is from about 1 μ

g to about 100 μ

g per dose.

46. A method of generating antibodies to Norovirus antigens, comprising administering to a subject the antigenic formulation of claim 33.

47. A method of inducing an immune response in a subject experiencing a Norovirus infection, comprising administering to the subject the vaccine formulation of claim 34, wherein said immune response is therapeutic.

48. A method of making Norovirus antigen formulations, comprising the steps of:

(a) preparing a pre-lyophilization solution comprising Norovirus antigen, sucrose, and chitosan, wherein the mass ratio of sucrose to chitosan is from about 0;

1 to about 10;

1;

(b) freezing said solution; and

(c) lyophilizing the frozen solution for 30-72 hours, wherein the final lyophilized product contains a percentage of said Norovirus antigen in aggregated form.

49. The method of claim 48, wherein the pre-lyophilization solution further comprises a bulking agent.

50. The method of claim 49, wherein said bulking agent is mannitol.

51. The method of claim 50, wherein said pre-lyophilization solution consists of mannitol and Norovirus antigen and wherein said percentage of aggregated Norovirus antigen is greater than 90%.

52. The method of claim 48, wherein said mass ratio of sucrose to chitosan is from about 2:

1 to about 10;

1 and wherein said percentage of aggregated Norovirus antigen is from about 0% to about 50%.

53. The method of claim 48, wherein said weight ratio of sucrose to chitosan is about 0:

1 and wherein said percentage of aggregated Norovirus antigen is greater than 70%.