CA2461380A1 - Hepatitis c virus vaccine - Google Patents

Hepatitis c virus vaccine Download PDF

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CA2461380A1
CA2461380A1 CA002461380A CA2461380A CA2461380A1 CA 2461380 A1 CA2461380 A1 CA 2461380A1 CA 002461380 A CA002461380 A CA 002461380A CA 2461380 A CA2461380 A CA 2461380A CA 2461380 A1 CA2461380 A1 CA 2461380A1
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base pair
region
nucleic acid
seq
adenovirus
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CA2461380C (en
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Emilio A. Emini
David C. Kaslow
Andrew J. Bett
John W. Shiver
Alfredo Nicosia
Armin Lahm
Alessandra Luzzago
Riccardo Cortese
Stefano Colloca
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MSD Italia SRL
Merck Sharp and Dohme LLC
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    • C12N2770/24211—Hepacivirus, e.g. hepatitis C virus, hepatitis G virus
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Abstract

The present invention features Ad6 vectors and a nucleic acid encoding a Met-NS3-NS4A-NS4B-NS5A-NS5B polypeptide containing an inactive NS5B RNA-dependent RNA polymerase region. The nucleic acid is particularly useful as a component of an adenovector or DNA plasmid vaccine providing a broad range of antigens for generating an HCV specific cell mediated immune (CMI) response against HCV.

Claims (59)

1. A nucleic acid comprising a nucleotide sequence encoding a Met-NS3-NS4A-NS4B-NS5A-NS5B polypeptide substantially similar to SEQ ID
NO: 1, provided that said polypeptide has sufficient protease activity to process itself to produce an NS5B protein and said NS5B protein is enzymatically inactive.
2. The nucleic acid of claim 1, wherein said nucleotide sequence is substantially similar to the coding sequence of SEQ ID NO: 2.
3. The nucleic acid of claim 1, wherein said nucleotide sequence encodes for the polypeptide of SEQ ID NO: 1.
4. The nucleic acid of claim 3, wherein said nucleotide sequence is the coding sequence of either SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 10, or SEQ ID NO: 11.
5. The nucleic acid of claim 3, wherein said nucleotide sequence is the coding sequence of either SEQ ID NO: 2 or SEQ ID NO: 3.
6. The nucleic acid of any one of claims 1-5, wherein said nucleic acid is an expression vector capable of expressing said polypeptide from said nucleotide sequence in a human cell.
7. A nucleic acid comprising a gene expression cassette able to express a Met-NS3-NS4A-NS4B-NS5A-NS5B polypeptide substantially similar to SEQ ID NO: 1 in a human cell, provided that said polypeptide can process itself to produce an NS5B protein and said NS5B protein is enzymatically inactive, said expression cassette comprising:
a) a promoter transcriptionally coupled to a nucleotide sequence encoding said polypeptide;
b) a 5' ribosome binding site functionally coupled to said nucleotide sequence, c) a terminator joined to the 3' end of said nucleotide sequence, and d) a 3' polyadenylation signal functionally coupled to said nucleotide sequence.
8. The nucleic acid of claim 7, wherein said nucleotide sequence is substantially similar to either SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 10, or SEQ ID NO: 11.
9. The nucleic acid of claim 8, wherein said nucleic acid is a shuttle vector further comprising a selectable marker, an origin of replication, a first adenovirus homology region and a second adenovirus homology region flanking said expression cassette, wherein said first homology region has at least about 100 base pairs substantially homologous to at least right end of a wild-type adenovirus region from about base pairs 1-425, and said second homology region has at least about 100 base pairs substantially homologous to at least the left end of a wild-type adenovirus region from about base pairs 3511-5792 of Ad5 or corresponding region of another adenovirus.
10. The nucleic acid of claim 9, wherein said nucleotide sequence encodes for a polypeptide of SEQ ID NO: 1.
11. The nucleic acid of claim 9, wherein said nucleotide sequence is SEQ ID NO: 2.
12. The nucleic acid of claim 9, wherein said nucleotide sequence is either SEQ ID NO: 3, SEQ ID NO: 10, or SEQ ID NO: 11.
13. The nucleic acid of claim 8, wherein said nucleic acid is a plasmid suitable for administration into a human and further comprises a prokaryotic origin of replication and a gene coding for a selectable marker.
14. The nucleic acid of claim 13, wherein said nucleotide sequence encodes for a polypeptide of SEQ ID NO: 1.
15. The nucleic acid of claim 14, wherein said nucleotide sequence is the coding sequence of either SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 10, or SEQ ID NO: 11.
16. The nucleic acid of claim 14, wherein said nucleotide sequence is the coding sequence of SEQ ID NO: 2 or SEQ ID NO: 3.
17. The nucleic acid of claim 14, wherein said promoter is the human intermediate early cytomegalovirus promoter (intron A), said 5' ribosome binding site consists of SEQ ID NO: 12, and said 3' polyadenylation is the bovine growth hormone (BGH) polyadenylation signal.
18. The nucleic acid of claim 8, wherein said nucleic acid is a adenovirus genome plasmid comprising a selectable marker, an origin of replication, and a recombinant adenovector genome containing an E1 deletion, an E3 deletion, and said expression cassette.
19. The nucleic acid of claim 8, wherein said nucleic acid is a adenovirus genome plasmid comprising a selectable marker, an origin of replication, and a) a first adenovirus region from about base pair 1 to about base pair 450 corresponding to either Ad5 or Ad6;
b) said gene expression cassette in a E1 parallel or El anti-parallel orientation joined to said first region;
c) a second adenovirus region from about base pair 3511 to about base pair 5548 corresponding to Ad5 or from about base pair 3508 to about base pair 5541 corresponding to Ad6, joined to said expression cassette;
d) a third adenovirus region from about base pair 5549 to about base pair 28133 corresponding to Ad5 or from about base pair 5542 to about base pair 28156 corresponding to Ad6, joined to said second region;
e) a fourth adenovirus region from about base pair 30818 to about base pair 33966 corresponding to Ad5 or from about base pair 30789 to about base pair 33784 corresponding to Ad6, joined to said third region; and f) a fifth adenovirus region from about base pair 33967 to about base pair 35935 corresponding to Ad5 or from about base pair 33785 to about base pair 35759 corresponding to Ad6, joined to said fourth region.
20. The nucleic acid of claim 19, wherein said first region corresponds to Ad5, said second region corresponds to Ad5, said third region corresponds to Ad5, said fourth region corresponds to Ad5, and said fifth region corresponds to Ad5.
21. The nucleic acid of claim 20, wherein said promoter is the human intermediate early cytomegalovirus promoter, said 5' ribosome binding site consists of SEQ ID NO: 12, and said 3' polyadenylation is the BGH
polyadenylation signal.
22. The nucleic acid of claim 21, wherein said expression cassette is in an E1 anti parallel orientation and said nucleotide sequence is either SEQ ID NO:
2, SEQ ID NO: 3, SEQ ID NO: 10, or SEQ ID NO: 11.
23. The nucleic acid of claim 19, wherein said first region corresponds to Ad5 or Ad6, said second region corresponds to Ad5 or Ad6, said third region corresponds to Ad6, said fourth region corresponds to Ad6, and said fifth region corresponds to Ad5 or Ad6.
24. The nucleic acid of claim 23, wherein said promoter is the human intermediate early cytomegalovirus promoter, said 5' ribosome binding site consists of SEQ ID NO: 12, and said 3' polyadenylation is the BGH
polyadenylation signal.
25. The nucleic acid of claim 24, wherein said expression cassette is in an E1 anti parallel orientation and said nucleotide sequence is either SEQ ID NO:
2, SEQ ID NO: 3, SEQ ID NO: 10, or SEQ ID NO: 11.
26. The nucleic acid of claim 24, wherein said expression cassette is in an E1 anti parallel orientation and said nucleotide sequence is either SEQ ID NO:
2 or SEQ ID NO: 3.
27. The nucleic acid of claim 8, wherein said nucleic acid is a adenovirus genome plasmid comprising an origin of replication, a selectable marker, and:
a) a first adenovirus region from about base pair 1 to about base pair 450 corresponding to either Ad5 or Ad6;
b) a second adenovirus region from about base pair 3511 to about base pair 5548 corresponding to Ad5 or from about base pair 3508 to about base pair 5541 corresponding to Ad6, joined to said first region;
c) a third adenovirus region from about base pair 5549 to about base pair 28133 corresponding to Ad5 or from about base pair 5542 to about base pair 28156 corresponding to Ad6, joined to said second region;
d) said gene expression cassette in a E3 parallel or E3 anti-parallel orientation joined to said third region;
e) a fourth adenovirus region from about base pair 30818 to about base pair 33966 corresponding to Ad5 or from about base pair 30789 to about base pair 33784 corresponding to Ad6, joined to said gene expression cassette; and f) a fifth adenovirus region from about base pair 33967 to about base pair 35935 corresponding to Ad5 or from about base pair 33785 to about base pair 35759 corresponding to Ad6, joined to said fourth region.
28. The nucleic acid of claim 27, wherein said first region corresponds to Ad5, said second region corresponds to Ad5, said third region corresponds to Ad5, said fourth region corresponds to Ad5, and said fifth region corresponds to Ad5.
29. The nucleic acid of claim 28, wherein said promoter is the human intermediate early cytomegalovirus promoter, said 5' ribosome binding site consists of SEQ ID NO: 12, and said 3' polyadenylation is the BGH
polyadenylation signal.
30. The nucleic acid of claim 27, wherein said first region corresponds to Ad5 or Ad6, said second region corresponds to Ad5 of Ad6, said third region corresponds to Ad6, said fourth region corresponds to Ad6, and said fifth region corresponds to Ad5 or Ad6.
31. The nucleic acid of claim 30, wherein said promoter is the human intermediate early cytomegalovirus promoter, said 5' ribosome binding site consists of SEQ ID NO: 12, and said 3' polyadenylation is the BGH
polyadenylation signal.
32. The nucleic acid of claim 8, wherein said nucleic acid is a adenovector consisting of a nucleotide sequence substantially similar to of SEQ ID
NO. 4 or a derivative thereof, wherein said derivative thereof has the HCV
polyprotein encoding sequence present in SEQ ID NO: 4 replaced with the HCV
polyprotein encoding sequence of either SEQ ID NO: 3, SEQ ID NO: 10 or SEQ ID
NO: 11.
33. The nucleic acid of claim 8, wherein said nucleic acid is an adenovector having an adenovector genome containing an E1 deletion, an E3 deletion, and said expression cassette
34. The nucleic acid of claim 8, wherein said nucleic acid is an adenovector consisting of:
a) a first adenovirus region from about base pair 1 to about base pair 450 corresponding to either Ad5 or Ad6;
b) said gene expression cassette in a E1 parallel or E1 anti-parallel orientation joined to said first region;
c) a second adenovirus region from about base pair 3511 to about base pair 5548 corresponding to Ad5 or from about base pair 3508 to about base pair 5541 corresponding to Ad6, joined to said expression cassette;
d) a third adenovirus region from about base pair 5549 to about base pair 28133 corresponding to Ad5 or from about base pair 5542 to about base pair 28156 corresponding to Ad6, joined to said second region;
e) a fourth adenovirus region from about base pair 30818 to about base pair 33966 corresponding to Ad5 or from about base pair 30789 to about base pair 33784 corresponding to Ad6, joined to said third region; and f) a fifth adenovirus region from about base pair 33967 to about base pair 35935 corresponding to Ad5 or from about base pair 33785 to about base pair 35759 corresponding to Ad6, joined to said fourth region.
35. The nucleic acid of claim 34, wherein said first region corresponds to Ad5, said second region corresponds to Ad5, said third region corresponds to Ad5, said fourth region corresponds to Ad5, and said fifth region corresponds to Ad5.
36. The nucleic acid of claim 35, wherein said promoter is the human intermediate early cytomegalovirus promoter, said 5' ribosome binding site consists of SEQ ID NO: 12, and said 3' polyadenylation is the BGH
polyadenylation signal.
37. The nucleic acid of claim 36, wherein said expression cassette is in an E1 anti parallel orientation and said nucleotide sequence is either SEQ ID NO:
2, SEQ ID NO: 3, SEQ ID NO: 10, or SEQ ID NO: 11.
38. The nucleic acid of claim 34, wherein said first region corresponds to Ad5 or Ad6, said second region corresponds to Ad5 or Ad6, said third region corresponds to Ad6, said fourth region corresponds to Ad6, and said fifth region corresponds to Ad5 or Ad6.
39. The nucleic acid of claim 37, where said promoter is the human intermediate early cytomegalovirus promoter, said 5' ribosome binding site consists of SEQ ID NO: 12, and said 3' polyadenylation is the BGH polyadenylation signal.
40. The nucleic acid of claim 39, wherein said expression cassette is in an E1 anti parallel orientation and said nucleotide sequence is SEQ ID
NO: 2, SEQ ID NO: 3, SEQ ID NO: 10, or SEQ ID NO: 11.
41. The nucleic acid of claim 39, wherein said expression cassette is in an E1 anti parallel orientation and said nucleotide sequence is SEQ ID
NO: 2 or SEQ ID NO: 3.
42. The nucleic acid of claim 8, wherein said nucleic acid is an adenovector consisting of:

a) a first adenovirus region from about base pair 1 to about base pair 450 corresponding to either Ad5 or Ad6;
b) a second adenovirus region from about base pair 3511 to about base pair 5548 corresponding to Ad5 or from about base pair 3508 to about base pair 5541 corresponding to Ad6, joined to said first region;
c) a third adenovirus region from about base pair 5549 to about base pair 28133 corresponding to Ad5 or from about base pair 5542 to about base pair 28156 corresponding to Ad6, joined to said second region;
d) said gene expression cassette in a E3 parallel or E3 anti-parallel orientation joined to said third region;
e) a fourth adenovirus region from about base pair 30818 to about base pair 33966 corresponding to Ad5 or from about base pair 30789 to about base pair 33784 corresponding to Ad6, joined to said gene expression cassette; and f) a fifth adenovirus region from about base pair 33967 to about base pair 35935 corresponding to Ad5 or from about base pair 33785 to about base pair 35759 corresponding to Ad6, joined to said fourth region.
43. The nucleic acid of claim 42, wherein said first region corresponds to Ad5, said second region corresponds to Ad5, said third region corresponds to Ad5, said fourth region corresponds to Ad5, and said fifth region corresponds to Ad5.
44. The nucleic acid of claim 42, wherein said first region corresponds to Ad5 or Ad6, said second region corresponds to Ad5 or Ad6, said third region corresponds to Ad6, said fourth region corresponds to Ad6, and said fifth region corresponds to Ad5 or Ad6.
45. An adenovector consisting of the nucleic acid sequence of SEQ
1D NO. 4 or a derivative thereof, wherein said derivative thereof has the HCV
polyprotein encoding sequence present in SEQ ID NO: 4 replaced with the HCV
polyprotein encoding sequence of either SEQ ID NO: 3, SEQ ID NO: 10 or SEQ ID
NO: 11.
46. An adenovector produced by a process comprising the steps of:

a) producing an adenovirus genome plasmid by homologous recombination between the shuttle vector of claim 9 and a nucleic acid comprising;
a first adenovirus region from about base pair 1 to about base pair 450 corresponding to either Ad5 or Ad6;

a second adenovirus region from about base pair 3511 to about base pair 5548 corresponding to Ad5 or from about base pair 3508 to about base pair 5541 corresponding to Ad6, joined to said first region;

a third adenovirus region from about base pair 5549 to about base pair 28133 corresponding to Ad5 or from about base pair 5542 to about base pair 28156 corresponding to Ad6, joined to said second region;

a fourth adenovirus region from about base pair 30818 to about base pair 33966 corresponding to Ad5 or from about base pair 30789 to about base pair 33784 corresponding to Ad6, joined to said third region; and a fifth adenovirus region from about base pair 33967 to about base pair 35935 corresponding to Ad5 or from about base pair 33785 to about base pair 35759 corresponding to Ad6, joined to said fourth region; and b) rescuing said adenovector from said adenovirus plasmid.
47. A cultured recombinant cell comprising the nucleic acid of claim 6.
48. A cultured recombinant cell comprising the nucleic acid of any one of claims 9-46.
49. A method of making an adenovector comprising the steps of:

a) producing an adenovirus genome plasmid comprising a gene expression cassette by homologous recombination between the nucleic acid of claim 9 and a nucleic acid comprising;

a first adenovirus region from about base pair 1 to about base pair 450 corresponding to either Ad5 or Ad6;

a second adenovirus region from about base pair 3511 to about base pair 5548 corresponding to Ad5 or from about base pair 3508 to about base pair 5541 corresponding to Ad6, joined to said first region;

a third adenovirus region from about base pair 5549 to about base pair 28133 corresponding to Ad5 or from about base pair 5542 to about base pair 28156 corresponding to Ad6, joined to said second region;
a fourth adenovirus region from about base pair 30818 to about base pair 33966 corresponding to Ad5 or from about base pair 30789 to about base pair 33784 corresponding to Ad6, joined to said third region; and a fifth adenovirus region from about base pair 33967 to about base pair 35935 corresponding to Ad5 or from about base pair 33785 to about base pair 35759 corresponding to Ad6, joined to the fourth region; and b) rescuing said recombinant adenovirus from said recombinant adenovirus plasmid.
50. A pharmaceutical composition comprising the nucleic acid of any one of claims 13-17 and 32-46 and pharmaceutically acceptable carrier.
51. A method of treating a patient comprising the step of administering to said patient an effective amount of the nucleic acid of any one of claims 13-17 and 32-46.
52. The method of claim 51, wherein said patient is a human.
53. The method of claim 52, wherein said patient is not infected with HCV.
54. The method of claim 52, wherein said patient is infected with HCV.
55. A recombinant nucleic acid comprising one or more Ad6 regions and a region not present in Ad6, wherein at least one Ad6 region is selected from the group consisting of: E1A, E1B, E2B, E2A, E4, L1, L2, L4, and L5.
56. The recombinant nucleic acid of claim 55, wherein said region not present in Ad6, is an expression cassette coding for a polypeptide not found in Ad6.
57. The recombinant nucleic acid of claim 56, wherein said recombinant nucleic acid is an adenovirus vector defective in at least E1 that is able to replicate when E1 is supplied in trans.
58. The recombinant nucleic acid of claim 57, wherein said vector consists of:

a) a first adenovirus region from about base pair 1 to about base pair 450 corresponding to either Ad5 or Ad6;

b) said gene expression cassette in an E1 parallel or E1 anti-parallel orientation joined to said first region;

c) a second adenovirus region from about base pair 3511 to about base pair 5548 corresponding to Ad5 or from about base pair 3508 to about base pair 5541 corresponding to Ad6, joined to said gene expression cassette;

d) a third adenovirus region from about base pair 5549 to about base pair 28133 corresponding to Ad5 or from about base pair 5542 to about base pair 28156 corresponding to Ad6, joined to said second region;

e) an optionally present fourth region from about base pair 28134 to about base pair 30817 corresponding to Ad5, or from about base pair 28157 to about 30789 corresponding to Ad6, joined to said third region;

f) a fifth adenovirus region from about base pair 30818 to about base pair 33966 corresponding to Ad5 or from about base pair 30789 to about base pair 33784 corresponding to Ad6, wherein said fifth region is joined to said fourth region if said fourth region is present, or said fifth is joined to said third region if said fourth region is not present; and g) a sixth adenovirus region from about base pair 33967 to about base pair 35935 corresponding to Ad5 or from about base pair 33785 to about base pair 35759 corresponding to Ad6, joined to said fourth region;
provided that at least one of said second, third, and fifth regions is from Ad6.
59. The recombinant nucleic acid of claim 57, wherein said vector consists of:

a) a first adenovirus region from about base pair 1 to about base pair 450 corresponding to either Ad5 or Ad6;

b) a second adenovirus region from about base pair 3511 to about base pair 5548 corresponding to Ad5 or from about base pair 3508 to about base pair 5541 corresponding to Ad6, joined to said first region;

c) a third adenovirus region from about base pair 5549 to about base pair 28133 corresponding to Ad5 or from about base pair 5542 to about base pair 28156 corresponding to Ad6, joined to said second region;

d) said gene expression cassette in a E3 parallel or E3 anti-parallel orientation joined to said third region;

e) a fourth adenovirus region from about base pair 30818 to about base pair 33966 corresponding to Ad5 or from about base pair 30789 to about base pair 33784 corresponding to Ad6, joined to said gene expression cassette; and f) a fifth adenovirus region from about base pair 33967 to about base pair 35935 corresponding to Ad5 or from about base pair 33785 to about base pair 35759 corresponding to Ad6, joined to said fourth region;

provided that at least one of said second, third, and fourth regions is from Ad6.
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