Development of mutations useful for attenuating dengue viruses and chimeric dengue viruses

Patent metadata

Field	Value
Publication number	US-10500264-B2
Application number	US-201715650482-A
Country	US
Kind code	B2
Filing date	Jul 14, 2017
Priority date	May 22, 2001
Publication date	Dec 10, 2019
Grant date	Dec 10, 2019

Abstract

A menu of mutations was developed that is useful in fine-tuning the attenuation and growth characteristics of dengue virus vaccines.

First claim

What is claimed is:

1. A dengue virus comprising a U to C mutation at nucleotide 10634 of the 3′ untranslated region, wherein the numbering is based upon the prototypic isolate DEN4 Dominica 1981 and wherein the virus has a phenotype comprising temperature sensitivity in Vero cells or human liver cell line HuH-7 and/or attenuation in mice.

2. The dengue virus of claim 1 , further comprising the 430 mutation.

3. The dengue virus of claim 1 , wherein the dengue virus is a dengue virus type 1, a dengue virus type 2, a dengue virus type 3, or a dengue virus type 4.

4. The dengue virus of claim 1 , wherein the dengue virus is a chimeric virus.

5. The chimeric virus of claim 4 having a dengue 1 backbone, a dengue 2 backbone, a dengue 3 backbone, or a dengue 4 backbone.

6. A pharmaceutical composition comprising a pharmacologically acceptable vehicle and a dengue virus according to claim 1 .

7. A kit comprising a pharmaceutical composition according to claim 6 in a pack or dispenser device and instructions for administration.

8. A method of producing neutralizing antibodies against dengue virus in a subject comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmacologically acceptable vehicle and the dengue virus according to claim 1 to the subject.

9. The method of claim 8 , wherein administration is by subcutaneous, intradermal, or intramuscular injection.

10. An immunogenic composition comprising a pharmacologically acceptable vehicle and a dengue virus according to claim 1 .

11. The immunogenic composition of claim 10 in unit dosage form having from about 10 2 -10 9 plaque forming units (PFU)/ml.

12. The immunogenic composition of claim 10 in unit dosage form having from about 0.1 to 50 μg of E protein/ml.

13. A method of making a pharmaceutical composition comprising:
isolating the dengue virus according to claim 1 ; and
combining the isolated dengue virus with a pharmacologically acceptable vehicle.

Assignees

• Us Health

Inventors

• Whitehead Stephen S
• Murphy Brian R
• Hanley Kathryn A
• Blaney Joseph E
• Lai Ching-Juh

Classifications

• A61P37/04

  Immunostimulants · CPC title

• A61P31/14

  for RNA viruses · CPC title

• C12N7/00 Primary

  Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00) · CPC title

• A61K39/12 Primary

  Viral antigens · CPC title

• C12N2770/24121

  Viruses as such, e.g. new isolates, mutants or their genomic sequences · CPC title