# US 6,136,322 A · Hepatitis A virus deletion mutants and vaccine formulations containing the same

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- Number: US 6,136,322 A
- Document ID: US6136322A
- Status: Granted
- Kind: A
- Application number: 09/094,919
- Filed: 1998-06-15
- Granted: 2000-10-24
- Earliest claimed: 1994-07-11
- Assignees: The University of North Carolina at Chapel Hill
- Inventors: Stanley M. Lemon; David R. Shaffer
- Web page: https://patentgrep.com/patent/US6136322A

## CPC

- C07K 14/005: from viruses
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- C12N 2770/32421: Viruses as such, e.g. new isolates, mutants or their genomic sequences
- C12N 2770/32422: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2770/32461: Methods of inactivation or attenuation
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Disclosed are live hepatitis A virus deletion mutants having a deletion mutation in the 5' nontranslated region of the viral genome. The deletion mutation may be selected from the group consisting of (a) pY1 deletion mutations that cause the virus to retain the ability to replicate in monkey kidney cells; and (b) deletion mutations between nucleotides 140 and 144 that render the virus temperature sensitive. Advantageously, the deletion mutation may be an attenuating mutation. Pharmaceutical formulations containing such viruses are disclosed, along with the use thereof to produce antibodies useful for diagnostic purposes and for imparting protective immunity against hepatitis A virus.

## Claims

### Claim 1

A live hepatitis A virus deletion mutant having a deletion mutation in the 5' nontranslated region of the viral genome, wherein said deletion mutation is selected from the group consisting of:
(a) .DELTA.99-115 deletion mutants;
(b) .DELTA.99-130 deletion mutants:
(c) .DELTA.142 deletion mutants;
(d) .DELTA.143 deletion mutants;
(e) .DELTA.144 deletion mutants;
(f) .DELTA.141-142 deletion mutants;
(g) .DELTA.142-143 deletion mutants;
(h) .DELTA.143-144 deletion mutants;
(i) .DELTA.141-143 deletion mutants;
(j) .DELTA.143-144 deletion mutants;
(k) .DELTA.140-144 deletion mutants;
(l) .DELTA.96-141 deletion mutants;
(m) .DELTA.99-144 deletion mutants;
(n) .DELTA.116-144 deletion mutants; and
(o) .DELTA.131-144 deletion mutants.

### Claim 2 (depends on 1)

A cDNA encoding a virus according to claim 1.

### Claim 3

A method for inducing protective immunity against hepatitis A virus in a subject, comprising:
administering to said subject an infectious, immunogenic, hepatitis A virus carrying an attenuating mutation, said virus being administered in an amount effective to induce protective immunity against hepatitis A virus, and said attenuating mutation being a deletion mutation in the 5' nontranslated region of the viral genome, wherein said deletion mutation is selected from the group consisting of:
(a) .DELTA.99-115 deletion mutants;
(b) .DELTA.99-130 deletion mutants;
(c) .DELTA.142 deletion mutants;
(d) .DELTA.143 deletion mutants;
(e) .DELTA.144 deletion mutants;
(f) .DELTA.141-142 deletion mutants;
(g) .DELTA.142-143 deletion mutants;
(h) .DELTA.143-144 deletion mutants;
(i) .DELTA.141-143 deletion mutants;
(j) .DELTA.143-144 deletion mutants;
(k) .DELTA.140-144 deletion mutants;
(l) .DELTA.96-141 deletion mutants;
(m) .DELTA.99-144 deletion mutants;
(n) .DELTA.116-144 deletion mutants; and
(o) .DELTA.131-144 deletion mutants.

### Claim 4 (depends on 3)

A method according to claim 3, wherein said administering step is carried out by orally administering said virus to said subject.

### Claim 5 (depends on 3)

A method according to claim 3, wherein said administering step is carried out by parenterally injecting said virus into said subject.

### Claim 6

A vaccine formulation useful for inducing protective immunity against hepatitis A virus, comprising, in a pharmaceutically acceptable carrier, an infectious, immunogenic, hepatitis A virus carrying an attenuating mutation in an amount effective to induce protective immunity against hepatitis A virus, said attenuating mutation being a deletion mutation in the 5' nontranslated region of the viral genome that is selected from the group consisting of:
(a) .DELTA.99-115 deletion mutants;
(b) .DELTA.99-130 deletion mutants;
(c) .DELTA.142 deletion mutants;
(d) .DELTA.143 deletion mutants;
(e) .DELTA.144 deletion mutants;
(f) .DELTA.141-142 deletion mutants;
(g) .DELTA.142-143 deletion mutants;
(h) .DELTA.143-144 deletion mutants;
(i) .DELTA.141-143 deletion mutants;
(j) .DELTA.143-144 deletion mutants;
(k) .DELTA.140-144 deletion mutants;
(l) .DELTA.96-141 deletion mutants;
(m) .DELTA.99-144 deletion mutants;
(n) .DELTA.116-144 deletion mutants; and
(o) .DELTA.131-144 deletion mutants.

### Claim 7 (depends on 6)

A vaccine formulation according to claim 6, wherein said vaccine formulation is an oral vaccine formulation.

### Claim 8 (depends on 6)

A vaccine formulation according to claim 6, wherein said vaccine formulation is a parenterally injectable vaccine formulation.

### Claim 9 (depends on 6)

A vaccine formulation according to claim 6, wherein said vaccine formulation is an inhalation vaccine formulation.