US4859587A
Expired / Lapsed
US
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Recombinant herpes simplex viruses, vaccines and methods
Assignee: Institut Merieux SA
•
Filing: 1986-04-25
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Granted: 1989-08-22
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Expires: 2006-04-25
Abstract
Abstract Recombinant herpes viruses useful as effective ingredients in vaccines against both virulent HSV-1 and HSV-2 are disclosed. Methods of preparing the recombinant viruses, vaccines incorporating the viruses, and methods of immunizing a human host by inoculation with the vaccines are also disclosed. The genomes of the recombinant viruses each comprise a mutant of the HSV-1 genome from which a portion thereof responsible for neurovirulence yet nonessential for growth is deleted. A gene from the HSV-2 genome responsible for coding an immunity-inducing glycoprotein is inserted in the mutant genome between the end points of deletion therein.
Inventors
- 👤 Bernard Roizman
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 08:31
CPC Classifications
C; C12; C12N; C12N15/00; C12N15/09; C12N15/63; C12N15/79; C12N15/85; C12N15/86; A; A61; A61P; A61P31/00; A61P31/12; A61P31/20; A61P31/22; C07; C07K; C07K14/00; C07K14/005; A61K; A61K39/00; C12N2710/00; C12N2710/00011; C12N2710/16011; C12N2710/16611; C12N2710/16622; C12N2710/16641; C12N2710/16643; C12N2730/00; C12N2730/00011; C12N2730/10011; C12N2730/10111; C12N2730/10122
Claims Analysis
Total Claims: 64
Claim 1
Independent Claim
90 words
A recombinant herpes simplex virus (HSV), the genome of which comprises a mutant of the genome of HSV-1 wherein the portion of said HSV-1 genome which is responsible for neurovirulence yet non-essential for growth and which is located at or near the internal inverted repeated sequences of said HSV-1 genome is deleted, and wherein a portion of the genome of HSV-2 which is responsible for coding one or more immunity inducing portions of glycoproteins of said HSV-2 is inserted in said mutant genome between the end points of said deletion.
Claim 2
Dependent Claim
90 words
A recombinant herpes simplex virus (HSV), the genome of which comprises a mutant of the genome of HSV-1 wherein the portion of said HSV-1 genome which is responsible for neurovirulence yet non-essential for growth and which is located at or near the internal inverted repeated sequences of said HSV-1 genome is deleted, and wherein a portion of the genome of HSV-2 which is responsible for coding one or more immunity inducing portions of glycoproteins of said HSV-2 is inserted in said mutant genome between the end points of said deletion.
Claim 3
Dependent Claim
26 words
The recombinant virus of claim 1 wherein said deleted portion includes DNA sequences necessary for the function of the thymidine kinase gene of said HSV-1 genome.
Claim 4
Dependent Claim
26 words
The recombinant virus of claim 2 wherein about 500 base pairs between and including the BglII and SacI sites of said thymidine kinase gene are deleted.
Claim 5
Dependent Claim
31 words
The recombinant virus of claim 1 wherein all sequences of said HSV-1 genome between the 3' terminus of the α27 gene and the promoter region of the α4 gene are deleted.
Claim 6
Dependent Claim
28 words
The recombinant virus of claim 1 wherein said immunity inducing portion of glycoprotein is selected from the group consisting of glycoproteins B, C, and D of said HSV-2.
Claim 7
Dependent Claim
28 words
The recombinant virus of claim 5 wherein the portion responsible for coding for HSV-2 glycoprotein D is inserted in said mutant genome between said end points of deletion.
Claim 8
Dependent Claim
36 words
The recombinant virus of claim 6 wherein said portion coding for HSV-2 glycoprotein D is inserted as part of a DNA sequence containing all or part of the genes coding for HSV-2 glycoproteins G and E.
Claim 9
Dependent Claim
30 words
The recombinant virus of claim 1 wherein an HSV thymidine kinase gene is inserted into said mutant genome at other than its natural location under the regulation of a promoter.
Claim 10
Dependent Claim
18 words
The recombinant virus of claim 8 wherein said inserted HSV thymidine kinase gene is from an HSV-1 genome.
Claim 11
Dependent Claim
20 words
The recombinant virus of claim 8 wherein said promoter is the promoter of the α4 gene of said HSV-1 genome.
Claim 12
Dependent Claim
83 words
A recombinant herpes simplex virus (HSV), the genome of which comprises a mutant of the genome of HSV-1 wherein all sequences of said HSV-1 genome between the 3' terminus of the α27 gene and the promoter region of the α4 gene thereof are deleted, and wherein a portion of the genome of HSV-2 which is responsible for coding one or more of glycoproteins B, C and D of said HSV-2 is inserted in said mutant genome between the end points of said deletion.
Claim 13
Dependent Claim
83 words
A recombinant herpes simplex virus (HSV), the genome of which comprises a mutant of the genome of HSV-1 wherein all sequences of said HSV-1 genome between the 3' terminus of the α27 gene and the promoter region of the α4 gene thereof are deleted, and wherein a portion of the genome of HSV-2 which is responsible for coding one or more of glycoproteins B, C and D of said HSV-2 is inserted in said mutant genome between the end points of said deletion.
Claim 14
Dependent Claim
26 words
The recombinant virus of claim 11 wherein said deleted portion includes DNA sequences necessary for the function of the thymidine kinase gene of said HSV-1 genome.
Claim 15
Dependent Claim
26 words
The recombinant virus of claim 12 wherein about 500 base pairs between and including the BglII and SacI sites of said thymidine kinase gene are deleted.
Claim 16
Dependent Claim
28 words
The recombinant virus of claim 11 wherein the portion responsible for coding for HSV-2 glycoprotein D is inserted in said mutant genome between said end points of deletion.
Claim 17
Dependent Claim
36 words
The recombinant virus of claim 14 wherein said portion coding for HSV-2 glycoprotein D is inserted as part of a DNA sequence containing all or part of the genes coding for HSV-2 glycoproteins G and E.
Claim 18
Dependent Claim
30 words
The recombinant virus of claim 11 wherein an HSV thymidine kinase gene is inserted into said mutant genome at other than its natural location under the regulation of a promoter.
Claim 19
Dependent Claim
17 words
The recombinant virus of claim 16 wherein said HSV thymidine kinase gene is from an HSV-1 genome.
Claim 20
Dependent Claim
20 words
The recombinant virus of claim 16 wherein said promoter is the promoter of the α4 gene of said HSV-1 genome.
Claim 21
Dependent Claim
5 words
Recombinant virus R7017 (ATCC VR2121)
Claim 22
Dependent Claim
5 words
Recombinant virus R7017 (ATCC VR2121)
Claim 23
Dependent Claim
5 words
Recombinant virus R7020 (ATCC VR2123).
Claim 24
Dependent Claim
5 words
Recombinant virus R7020 (ATCC VR2123).
Claim 25
Dependent Claim
19 words
A vaccine effective against both virulent HSV-1 and HSV-2 incorporating as an effective ingredient recombinant virus R7017 (ATCC VR2121).
Claim 26
Dependent Claim
19 words
A vaccine effective against both virulent HSV-1 and HSV-2 incorporating as an effective ingredient recombinant virus R7017 (ATCC VR2121).
Claim 27
Dependent Claim
20 words
A vaccine effective against both virulent HSV-1 and virulent HSV-2 incorporating as an effective ingredient recombinant virus R7020 (ATCC VR2123).
Claim 28
Dependent Claim
20 words
A vaccine effective against both virulent HSV-1 and virulent HSV-2 incorporating as an effective ingredient recombinant virus R7020 (ATCC VR2123).
Claim 29
Dependent Claim
32 words
A method of immunizing a human host against virulent HSV-1 and virulent HSV-2, said method comprising the step of inoculating said host with an immunity-inducing dose of the vaccine of claim 21.
Claim 30
Dependent Claim
32 words
A method of immunizing a human host against virulent HSV-1 and virulent HSV-2, said method comprising the step of inoculating said host with an immunity-inducing dose of the vaccine of claim 22.
Claim 31
Independent Claim
179 words
A method of preparing a recombinant herpes simplex virus (HSV) useful as an effective ingredient in a vaccine against both virulent HSV-1 and virulent HSV-2, said method comprising the steps of: (a) deleting from the genome of parental HSV-1 the portion of said genome which is responsible for neurovirulence yet non-essential for growth and which is located at or near the internal inverted repeated sequences of said HSV-1 genome to provide a first mutant genome; (b) inserting into said first mutant genome between the end points of said deletion of step (a) a portion of the genome of HSV-2 which is responsible for coding at least one immunity-inducing portion of glycoproteins of said HSV-2 to provide a second mutant genome; (c) contransfecting said second mutant genome with the genome of said parental HSV-1 of (a) under conditions permitting recombination at sites of DNA sequence homology to produce recombinant progeny; (d) selecting for a recombinant genome lacking the deleted portion of (a); and, (e) screening said selected genome of (d) for the presence of said glycoprotein coding gene of (b).
Claim 32
Independent Claim
179 words
A method of preparing a recombinant herpes simplex virus (HSV) useful as an effective ingredient in a vaccine against both virulent HSV-1 and virulent HSV-2, said method comprising the steps of: (a) deleting from the genome of parental HSV-1 the portion of said genome which is responsible for neurovirulence yet non-essential for growth and which is located at or near the internal inverted repeated sequences of said HSV-1 genome to provide a first mutant genome; (b) inserting into said first mutant genome between the end points of said deletion of step (a) a portion of the genome of HSV-2 which is responsible for coding at least one immunity-inducing portion of glycoproteins of said HSV-2 to provide a second mutant genome; (c) contransfecting said second mutant genome with the genome of said parental HSV-1 of (a) under conditions permitting recombination at sites of DNA sequence homology to produce recombinant progeny; (d) selecting for a recombinant genome lacking the deleted portion of (a); and, (e) screening said selected genome of (d) for the presence of said glycoprotein coding gene of (b).
Claim 33
Dependent Claim
26 words
The method of claim 25 wherein said deleted portion includes DNA sequences necessary for the function of the thymidine kinase gene of said parental HSV-1 genome.
Claim 34
Dependent Claim
25 words
The method of claim 26 wherein about 500 base pairs between and including the BglII and SacI sites of said thymidine kinase gene are deleted.
Claim 35
Dependent Claim
30 words
The method of claim 25 wherein all sequences of said HSV-1 genome between the 3' terminus of the α27 gene and the promoter region of the α4 gene are deleted.
Claim 36
Dependent Claim
24 words
The method of claim 25 wherein said immunity-inducing glycoprotein is selected from the group consisting of glycoproteins B, C and D of said HSV-2.
Claim 37
Dependent Claim
28 words
The method of claim 25 wherein the portion responsible for coding for HSV-2 glycoprotein D is inserted into said first mutant genome between said end points of deletion.
Claim 38
Dependent Claim
36 words
The method of claim 30 wherein said portion coding for HSV-2 glycoprotein D is inserted as a part of a DNA sequence comprising all or part of the genes coding for HSV-2 glycoproteins G and E.
Claim 39
Dependent Claim
32 words
The method of claim 29 wherein an HSV thymidine kinase gene is inserted into said first or second mutant genome at other than its natural location under the regulation of a promoter.
Claim 40
Dependent Claim
16 words
The method of claim 32 wherein said HSV thymidine kinase gene is from an HSV-1 genome.
Claim 41
Dependent Claim
20 words
The method of claim 32 wherein said promoter is the promoter of the α4 gene of said parental HSV-1 genome.
Claim 42
Independent Claim
177 words
A method of preparing a recombinant herpes simplex virus (HSV) useful as an effective ingredient in a vaccine against both virulent HSV-1 and virulent HSV-2, said method comprising the steps of: (a) deleting from the genome of parental HSV-1 all sequences of said HSV-1 genome between the 3' terminus of the α27 gene and the promoter region of the α4 gene thereof to provide a first mutant genome; (b) inserting into said first mutant genome between the end points of said deletion of step (a) a portion of the genome of HSV-2 which is responsible for coding at least one immunity inducing portion of glycoproteins B, C and D of said HSV-2 to provide a second mutant genome; (c) cotransfecting said second mutant genome with the genome of said parental HSV-1 of (a) under conditions permitting recombination at sites of DNA sequence homology to produce recombinant progeny; (d) selecting for a recombinant genome lacking the deleted portion of (a); and, (e) screening said selected genome of (d) for the presence of said glycoprotein coding gene of (b).
Claim 43
Independent Claim
177 words
A method of preparing a recombinant herpes simplex virus (HSV) useful as an effective ingredient in a vaccine against both virulent HSV-1 and virulent HSV-2, said method comprising the steps of: (a) deleting from the genome of parental HSV-1 all sequences of said HSV-1 genome between the 3' terminus of the α27 gene and the promoter region of the α4 gene thereof to provide a first mutant genome; (b) inserting into said first mutant genome between the end points of said deletion of step (a) a portion of the genome of HSV-2 which is responsible for coding at least one immunity inducing portion of glycoproteins B, C and D of said HSV-2 to provide a second mutant genome; (c) cotransfecting said second mutant genome with the genome of said parental HSV-1 of (a) under conditions permitting recombination at sites of DNA sequence homology to produce recombinant progeny; (d) selecting for a recombinant genome lacking the deleted portion of (a); and, (e) screening said selected genome of (d) for the presence of said glycoprotein coding gene of (b).
Claim 44
Dependent Claim
26 words
The method of claim 35, wherein said deleted portion includes DNA sequences necessary for the function of the thymidine kinase gene of said parental HSV-1 genome.
Claim 45
Dependent Claim
25 words
The method of claim 36 wherein about 500 base pairs between and including the BglII and SacI sites of said thymidine kinase gene are deleted.
Claim 46
Dependent Claim
28 words
The method of claim 35 wherein the portion responsible for coding for HSV-2 glycoprotein D is inserted into said first mutant genome between said end points of deletion.
Claim 47
Dependent Claim
35 words
The method of claim 38 wherein said portion coding for HSV-2 glycoprotein D is inserted as part of a DNA sequence comprising all or part of the genes coding for HSV-2 glycoproteins G and E.
Claim 48
Dependent Claim
32 words
The method of claim 35 wherein an HSV thymidine kinase gene is inserted into said first or second mutant genome at other than its natural location under the regulation of a promoter.
Claim 49
Dependent Claim
16 words
The method of claim 40 wherein said HSV thymidine kinase gene is from an HSV-1 genome.
Claim 50
Dependent Claim
20 words
The method of claim 35 wherein said promoter is the promoter of the α4 gene of said parenteral HSV-1 genome.
Claim 51
Dependent Claim
4 words
Plasmid pRB3410 (ATCC 53350).
Claim 52
Dependent Claim
4 words
Plasmid pRB3410 (ATCC 53350).
Claim 53
Dependent Claim
92 words
A recombinant herpes simplex virus (HSV), the genome of which comprises a mutant of the genome of HSV-1 wherein the portion of said HSV-1 genome which is responsible for neurovirulence yet non-essential for growth and which is located at or near the internal inverted repeated sequences of said HSV-1 genome is deleted, and wherein a portion of the HindIII L fragment of HSV-2 which is responsible for coding one or more immunity inducing portions of glycoproteins of said HSV-2 is inserted in said mutant genome between the end points of said deletion.
Claim 54
Dependent Claim
92 words
A recombinant herpes simplex virus (HSV), the genome of which comprises a mutant of the genome of HSV-1 wherein the portion of said HSV-1 genome which is responsible for neurovirulence yet non-essential for growth and which is located at or near the internal inverted repeated sequences of said HSV-1 genome is deleted, and wherein a portion of the HindIII L fragment of HSV-2 which is responsible for coding one or more immunity inducing portions of glycoproteins of said HSV-2 is inserted in said mutant genome between the end points of said deletion.
Claim 55
Dependent Claim
29 words
A vaccine effective against both virulent HSV-1 and virulent HSV-2 incorporating as an effective ingredient a recombinant herpes simplex virus according to any one of claims 1-10 and 44.
Claim 56
Dependent Claim
32 words
A method of immunizing a human host against virulent HSV-1 and virulent HSV-2, said method comprising the step of inoculating said host with an immunity-inducing dose of the vaccine of claim 45.
Claim 57
Dependent Claim
82 words
A recombinant herpes simplex virus (HSV), the genome of which comprises a mutant of the genome of HSV-1 wherein all sequences of said HSV-1 genome between the 3' terminus of the α27 gene and the promoter region of the α4 gene thereof are deleted, and wherein a portion of the HindIII L fragment of HSV-2 which is responsible for coding one or more of the glycoproteins of said HSV-2 is inserted in said mutant genome between the end points of said deletion.
Claim 58
Dependent Claim
82 words
A recombinant herpes simplex virus (HSV), the genome of which comprises a mutant of the genome of HSV-1 wherein all sequences of said HSV-1 genome between the 3' terminus of the α27 gene and the promoter region of the α4 gene thereof are deleted, and wherein a portion of the HindIII L fragment of HSV-2 which is responsible for coding one or more of the glycoproteins of said HSV-2 is inserted in said mutant genome between the end points of said deletion.
Claim 59
Dependent Claim
31 words
A vaccine effective against both virulent HSV-1 and virulent HSV-2 incorporating as an effective ingredient an immunity inducing recombinant herpes simplex virus according to any one of claims 11-18 and 26.
Claim 60
Dependent Claim
32 words
A method of immunizing a human host against virulent HSV-1 and virulent HSV-2, said method comprising the step of inoculating said host with an immunity-inducing dose of the vaccine of claim 48.
Claim 61
Independent Claim
183 words
A method of preparing a recombinant herpes simplex virus (HSV) useful as an effective ingredient in a vaccine against both virulent HSV-1 and virulent HSV-2, said method comprising the steps of: (a) deleting from the genome of parental HSV-1 the portion of said genome which is responsible for neurovirulence yet non-essential for growth and which is located at or near the internal inverted repeated sequences of said HSV-1 genome to provide a first mutant genome; (b) inserting into said first mutant genome between the end points of said deletion of step (a) a portion of the HindIII L fragment of HSV-2 which is responsible for coding at least one or more immunity-inducing portions of glycoproteins of said HSV-2 to provide a second mutant genome; (c) cotransfecting said second mutant genome with the genome of said parental HSV-1 of (a) under conditions permitting recombination at sites of DNA sequence homology to produce recombinant progeny; (d) selecting for a recombinant genome lacking the deleted portion of (a); and, (e) screening said selected genome of (d) for the presence of said glycoprotein coding gene of (b).
Claim 62
Independent Claim
183 words
A method of preparing a recombinant herpes simplex virus (HSV) useful as an effective ingredient in a vaccine against both virulent HSV-1 and virulent HSV-2, said method comprising the steps of: (a) deleting from the genome of parental HSV-1 the portion of said genome which is responsible for neurovirulence yet non-essential for growth and which is located at or near the internal inverted repeated sequences of said HSV-1 genome to provide a first mutant genome; (b) inserting into said first mutant genome between the end points of said deletion of step (a) a portion of the HindIII L fragment of HSV-2 which is responsible for coding at least one or more immunity-inducing portions of glycoproteins of said HSV-2 to provide a second mutant genome; (c) cotransfecting said second mutant genome with the genome of said parental HSV-1 of (a) under conditions permitting recombination at sites of DNA sequence homology to produce recombinant progeny; (d) selecting for a recombinant genome lacking the deleted portion of (a); and, (e) screening said selected genome of (d) for the presence of said glycoprotein coding gene of (b).
Claim 63
Independent Claim
173 words
A method of preparing a recombinant herpes simplex virus (HSV) useful as an effective ingredient in a vaccine against both virulent HSV-1 and virulent HSV-2, said method comprising the steps of: (a) deleting from the genome of parental HSV-1 all sequences of said HSV-1 genome between the 3' terminus of the α27 gene and the promoter region of the α4 gene thereof to provide a first mutant genome; (b) inserting into said first mutant genome between the end points of said deletion of step (a) a portion of the HindIII L fragment of HSV-2 which is responsible for coding one or more of the glycoproteins of said HSV-2 to provide a second mutant genome; (c) cotransfecting said second mutant genome with the genome of said parental HSV-1 of (a) under conditions permitting recombination at sites of DNA sequence homology to produce recombinant progeny; (d) selecting for a recombinant genome lacking the deleted portion of (a); and, (e) screening said selected genome of (d) for the presence of said glycoprotein coding gene of (b).
Claim 64
Independent Claim
173 words
A method of preparing a recombinant herpes simplex virus (HSV) useful as an effective ingredient in a vaccine against both virulent HSV-1 and virulent HSV-2, said method comprising the steps of: (a) deleting from the genome of parental HSV-1 all sequences of said HSV-1 genome between the 3' terminus of the α27 gene and the promoter region of the α4 gene thereof to provide a first mutant genome; (b) inserting into said first mutant genome between the end points of said deletion of step (a) a portion of the HindIII L fragment of HSV-2 which is responsible for coding one or more of the glycoproteins of said HSV-2 to provide a second mutant genome; (c) cotransfecting said second mutant genome with the genome of said parental HSV-1 of (a) under conditions permitting recombination at sites of DNA sequence homology to produce recombinant progeny; (d) selecting for a recombinant genome lacking the deleted portion of (a); and, (e) screening said selected genome of (d) for the presence of said glycoprotein coding gene of (b).
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