USRE37381EExpiredUtility

Vaccine against hepatitis A virus

28
Assignee: US HEALTHPriority: Apr 7, 1982Filed: Sep 6, 1995Granted: Sep 18, 2001
Est. expiryApr 7, 2002(expired)· nominal 20-yr term from priority
Inventors:Robert H. PurcellJohn R. TicehurstJeffrey I. CohenSuzanne U. EmersonStephen M. FeinstoneRichard J. DaemerIan D. Gust
A61P 31/12C12N 2770/32422C12N 2770/32464C12N 2770/32434C12N 7/00A61K 2039/5254A61K 39/12A61K 39/29C12N 2770/32421C07K 14/005C12N 2770/32451A61K 39/00Y02A50/30
28
PatentIndex Score
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Cited by
11
References
24
Claims

Abstract

The present invention provides an attenuated hepatitis A virus useful as a vaccine.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
       1. An attenuated hepatitis A virus comprising a  whose genome has a cDNA sequence according to FIG. 1characterized by the following nucleotides: cytosine atexcept for nucleotide positions 3919, 4043, 4222 and 4810; which have cytosines as bases; guanine atnucleotide positions 964 and 3196 which have guanines as bases; adenine atnucleotide positions 1742, 2864, 4185, 4563, 5204, 6147 and 6522 which have adenines as bases; and thymine atnucleotide positions 3025, 3889, 4087 and 5232 which have thymines as bases. 
     
     
       2. The attenuated hepatitis A virus of claim  1  wherein said genome encodes the following amino acids: an arginine is encoded at nucleotide  the base change at position 964 results in a codon which encodes arginine; valine at nucleotide  the base changes at positions  3025  and  3889  result in codons which encode valine; the base changes at positions 3196, 4222 and 4810 result in codons which encode serine; alanine at  the base change at position 3919 results in a codon which encodes an alanine; methionine at  the base change at position 4087 results in a codon which encodes a methionine; lysine at  the base change at position 4185 results in a codon which encodes a lysine; isoleucine at  the base change at position 4563 results in a codon which encodes an isoleucine; tyrosine at  the base change at position 5232 results in a codon which encodes a tyrosine; asparagine at  the nucleotide change at position 6147 results in a codon which encodes an asparagine; and threonine at  the nucleotide change at position 6522 results in a codon which encodes a threonine. 
     
     
       3. A tissue culture adapted hepatitis A virus comprising a  whose genome has a cDNA sequence according to FIG. 1characterized by a cytosine atexcept for nucleotide position 3191 which has cytosine as a base and a thymine at  nucleotide position 3889 which has thymine as a base. 
     
     
       4. The tissue culture adapted hepatitis A virus of claim  3  wherein said genome encodes the following amino acids: an alanine at nucleotide  the base change at position 3919 results in a codon which encodes an alanine and a valine at nucleotide  the base change at position 3889 results in a codon which encodes a valine. 
     
     
       5. A pharmaceutical composition, comprising an immunogenic amount of the virus of claim  4  and pharmaceutically acceptable carrier. 
     
     
       6. A method for inducing protective immunity against HAV, comprising administering to a host susceptible to HAV infection, immunogenic amount of hepatitis A virus comprising a genome coding for alanine at nucleotide position 3919 and valine at nucleotide position 3889, to render said host immune to HAV infection. 
     
     
       7. An isolated nucleic acid molecule comprising sequence according to FIG. 1 where said sequence encodes HAV HM-   175  wild - type hepatitis A virus.   
     
     
       8. A nucleic acid molecule encoding an attenuated hepatitis A virus, said molecule having a nucleotide sequence according to FIG. 1 except for nucleotide positions  3919 ,  4043 ,  4222  and  4810  which have cytosines as bases; nucleotide positions  964  and  3196  which have guanines as bases; nucleotide positions  1742 ,  2864 ,  4185 ,  4563 ,  5204 ,  6147  and  6522  which have adenines as bases; and nucleotide positions  3025 ,  3889 ,  4087  and  5232  which have thymines as bases. 
     
     
       9. A nucleic acid molecule encoding an attenuated hepatitis A virus, said molecule having a nucleotide sequence according to FIG. 1 except for nucleotide positions  3919 ,  4043  and  4222  which have cytosines as bases, nucleotide positions  4185 ,  4563 ,  5204 ,  6147  and  6522  which have adenines as bases; and nucleotide positions  3889 ,  4087  and  5232  which have thymines as bases. 
     
     
       10. A nucleic acid molecule encoding an attenuated hepatitis A virus, said molecule having a nucleotide sequence according to FIG. 1 except for nucleotide positions  3919 ,  4043  and  4222  which have cytosines as bases; nucleotide positions  1742 ,  2864 ,  4185 ,  4563 ,  5204 ,  6147  and  6522  which have adenines as bases; nucleotide positions  3025 ,  3889 ,  4087  and  5232  which have thymines as bases, and nucleotide positions  964  and  3196  which have guanines as bases. 
     
     
       11. An attenuated hepatitis A virus whose genome has a cDNA sequence according to FIG. 1 except for nucleotide positions  3919 ,  4043  and  4222  which have cytosines as bases, nucleotide positions  4185 ,  4563 ,  5204 ,  6147  and  6522  which have adenines as bases, and nucleotide positions  3889 ,  4087  and  5232  which have thymines as bases. 
     
     
       12. A vaccine comprising an immunologically effective amount of the virus according to claim  11  in a pharmaceutically acceptable carrier or diluent. 
     
     
       13. An attenuated hepatitis A virus whose genome as a cDNA sequence according to FIG. 1 except for nucleotide positions  3919 ,  4043  and  4222  which have cytosines as bases; nucleotide positions  1742 ,  2864 ,  4185 ,  4563 ,  5204 ,  6147  and  6522  which have adenines as bases; nucleotide positions  3025 ,  3889 ,  4087  and  5232  which have thymines as bases; and nucleotide positions  964  and  3196  which have guanines as bases. 
     
     
       14. A vaccine comprising an immunologically effective amount of the virus according to claim  13  in a pharmaceutically acceptable carrier or diluent. 
     
     
       15. A nucleic acid molecule encoding a tissue culture adapted hepatitis A virus, said molecule having a nucleotide sequence according to FIG. 1 except for nucleotide position  3919  which has cytosine as a base and nucleotide position  3889  which has thymine as a base. 
     
     
       16. A nucleic acid molecule encoding an attenuated hepatitis A virus, said molecule having a nucleotide sequence according to FIG. 1 except for nucleotide positions  131 - 134  which are deleted, and nucleotide positions  203 - 207  from which a single thymine is deleted; nucleotide positions  124 ,  3919 ,  4043  and  4222  which have cytosines as bases, nucleotide positions  4185 ,  4563 ,  5204 ,  6147  and  6522  which have adenines as bases; nucleotide positions  3889 ,  4087  and  5232  which have thymines as bases; and nucleotide position  152  which has a guanine as a base. 
     
     
       17. An attenuated hepatitis A virus whose genome has a cDNA sequence according to FIG. 1 except for nucleotide positions  131 - 134  which are deleted, nucleotide positions  203 - 207  from which a single thymine is deleted; nucleotide positions  124 ,  3919 ,  4043  and  4222  which have cytosines as bases, nucleotide positions  4185 ,  4563 ,  5204 ,  6147  and  6522  which have adenines as bases; nucleotide positions  3889 ,  4087  and  5232  which have thymines as bases; and nucleotide position  142  which has a guanine as a base. 
     
     
       18. A vaccine comprising an immunologically effective amount of a virus according to claim  17  in a pharmaceutically acceptable carrier or diluent. 
     
     
       19. A nucleic acid molecule encoding an attenuated hepatitis A virus, said molecule having a nucleotide sequence according to FIG. 1 except for nucleotide positions  131 - 134  which are deleted, at nucleotide positions  203 - 207  from which a single thymine is deleted; nucleotide positions  124 ,  3919 ,  4043  and  4222  which have cytosines as bases; nucleotide positions  1742 ,  2864 ,  4185 ,  4563 ,  5204 ,  6147  and  6522  which have adenines as bases; and nucleotide positions  3889 ,  4087  and  5232  which have thymines as bases, nucleotide positions  152 ,  964  and  3196  which have guanines as bases. 
     
     
       20. An attenuated hepatitis A virus whose genome has a cDNA sequence according to FIG. 1 except for nucleotide positions  131 - 134  which are deleted, nucleotide positions  203 - 207  from which a single thymine is deleted; nucleotide positions  124 ,  3919 ,  4043  and  4222  which have cytosines as bases; nucleotide positions  1742 ,  2864 ,  4185 ,  4563 ,  5204 ,  6147  and  6522  which have adenines as bases; nucleotide positions  3889 ,  4087  and  5232  which have thymines as bases; nucleotide positions  152 ,  964  and  3196  which have guanine as bases. 
     
     
       21. A vaccine comprising an immunologically effective amount of a virus according to claim  20  in a pharmaceutically acceptable carrier or diluent. 
     
     
       22. An attenuated hepatitis A virus whose genome has a cDNA sequence according to FIG. 1 except for nucleotide positions  3919 ,  4043  and  4222  which have cytosines as bases; nucleotide positions  964  and  3196  which have guanines as bases; nucleotide positions  1742 ,  2864 ,  4185 ,  4563 ,  5204 ,  6147  and  6522  which have adenines as bases; nucleotide positions  3025 ,  3889 ,  4087  and  5232  which have thymines as bases. 
     
     
       23. The attenuated hepatitis A virus of claim  22  wherein the base change at position  964  results in a codon which encodes arginine; the base changes at positions  3025  and  3889  result in codons which encode valine; the base changes at positions  3196  and  4222  result in codons which encode serine; the base change at position  3919  results in a codon which encodes an alanine; the base change at position  4087  results in a codon which encodes a methionine; the base change at position  4185  results in a codon which encodes a lysine; the base change at position  4563  results in a codon which encodes an isoleucine; the base change at position  5232  results in a codon which encodes a tyrosine; the base change at position  6147  results in a codon which encodes an asparagine; and the base change at position  6522  results in a codon which encodes a threonine. 
     
     
       24. A nucleic acid molecule encoding an attenuated hepatitis A virus, said molecule having a nucleotide sequence according to FIG. 1 except for nucleotide positions  3919 ,  4043  and  4222  which have cytosines as bases; nucleotide positions  964  and  3196  which have guanines as bases; nucleotide positions  1742 ,  2864 ,  4185 ,  4563 ,  5204 ,  6147  and  6522  which have adenines as bases; nucleotide positions  3025 ,  3889 ,  4087  and  5232  which have thymines as bases.

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