IP Library › Granted Patent US 8,999,352

Granted Patent B2

US 8,999,352 · App. 13/304,175 · Granted Apr 7, 2015

Genetically engineered swine influenza virus and uses thereof

Inventors: Peter Palese (Leonia, NJ); Adolfo Garcia-Sastre (New York, NY); Richard J. Webby (Memphis, TN); Juergen A. Richt (Ames, IA); Robert G. Webster (Memphis, TN); Kelly M. Lager (Colo, IA)

Assignees: Icahn School of Medicine at Mount Sinai; St. Jude Children's Research Hospital; The United States of America, as represented by the Secretary of Agriculture

C12N7/00 A61K39/145 A61K2039/5254 C12N2760/16034 C12N2760/16061

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Quick Facts

Patent No.: US 8,999,352
App. No.: 13/304,175
Granted: Apr 7, 2015
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention relates, in general, to attenuated swine influenza viruses having an impaired ability to antagonize the cellular interferon (IFN) response, and the use of such attenuated viruses in vaccine and pharmaceutical formulations. In particular, the invention relates to attenuated swine influenza viruses having modifications to a swine NS1 gene that diminish or eliminate the ability of the NS1 gene product to antagonize the cellular IFN response. These viruses replicate in vivo, but demonstrate decreased replication, virulence and increased attenuation, and therefore are well suited for use in live virus vaccines, and pharmaceutical formulations.

Claims (40)

1. A genetically engineered attenuated swine influenza virus having an impaired interferon antagonist phenotype, wherein said virus comprises a swine influenza virus A/Swine/Texas/4199-2/98 NS1 gene with a mutation resulting in an NS1 protein with a deletion of all of the amino acid residues of NS1 protein except amino acid residues 1-126, wherein the amino terminal amino acid is number 1 and the mutation in the NS 1 gene confers an impaired interferon antagonist phenotype.

2. The genetically engineered attenuated swine influenza virus of claim 1 , wherein the genetically engineered attenuated swine influenza virus is a reassortant.

3. The genetically engineered attenuated swine influenza virus of claim 1 , wherein the genetically engineered attenuated swine influenza virus is a chimeric virus that expresses a heterologous sequence.

4. The genetically engineered attenuated swine influenza virus of claim 1 , wherein the genetically engineered attenuated swine influenza virus is a chimeric virus that expresses an epitope of a foreign pathogen.

5. The genetically engineered attenuated swine influenza virus of claim 1 , wherein the genetically engineered attenuated swine influenza virus is a engineered to encode an epitope from another virus or at least one genomic segment derived from a different influenza virus.

6. The genetically engineered attenuated swine influenza virus of claim 5 , wherein the at least one genomic segment is a segment from swine influenza virus selected from the group consisting of: A/Swine/Colorado/1/77, A/Swine/Colorado/23619/99, A/Swine/Cote d'Armor/3633/84, A/Swine/England/195852/92, A/Swine/Finistere/2899/82, A/Swine/Hong Kong/10/98, A/Swine/Hong Kong/9/98, A/Swine/Hong Kong/81/78, A/Swine/Illinois/100084/01, A/Swine/Illinois/100085A/01, A/Swine/Illinois/21587/99, A/Swine/Indiana/1726/88, A/Swine/Indiana/9K035/99, A/Swine/Indiana/P12439/00, A/Swine/Iowa/15/30, A/Swine/Iowa/533/99, A/Swine/Iowa/569/99, A/Swine/Iowa/3421/90, A/Swine/Iowa/8548-1/98, A/Swine/Iowa/930/01, A/Swine/Iowa/17672/88, A/Swine/Italy/1513-1/98, A/Swine/Italy/1523/98, A/Swine/Korea/CY02/02, A/Swine/Minnesota/55551/00, A/Swine/Minnesota/593/99, A/Swine/Minnesota/9088-2/98, A/Swine/Nebraska/1/92, A/Swine/Nebraska/209/98, A/Swine/Netherlands/12/85, A/Swine/North Carolina/16497/99, A/Swine/North Carolina/35922/98, A/Swine/North Carolina/93523/01, A/Swine/North Carolina/98225/01, A/Swine/Oedenrode/7C/96, A/Swine/Ohio/891/01, A/Swine/Oklahoma/18717/99, A/Swine/Oklahoma/18089/99, A/Swine/Ontario/01911-1/99, A/Swine/Ontario/01911-2/99, A/Swine/Ontario/41848/97, A/Swine/Quebec/192/81, A/Swine/Quebec/5393/91, A/Swine/Taiwan/7310/70, A/Swine/Tennessee/24/77, A/Swine/Texas/4199-2/98, A/Swine/Wisconsin/125/97, A/Swine/Wisconsin/136/97, A/Swine/Wisconsin/163/97, A/Swine/Wisconsin/164/97, A/Swine/Wisconsin/166/97, A/Swine/Wisconsin/168/97, A/Swine/Wisconsin/235/97, A/Swine/Wisconsin/238/97, A/Swine/Wisconsin/457/98, A/Swine/Wisconsin/458/98, A/Swine/Wisconsin/464/98 and A/Swine/Wisconsin/14094/99.

7. The genetically engineered attenuated swine influenza virus of claim 1 , wherein the genetically engineered attenuated swine influenza virus is a chimeric virus that expresses a tumor antigen.

8. An immunogenic formulation comprising the genetically engineered attenuated swine influenza virus of claim 1 , and a physiologically acceptable excipient.

9. An immunogenic formulation comprising the genetically engineered attenuated swine influenza virus of claim 3 , and a physiologically acceptable excipient.

10. An immunogenic formulation comprising the genetically engineered attenuated swine influenza virus of claim 5 , and a physiologically acceptable excipient.

11. The immunogenic formulation of claim 8 , wherein the genetically engineered attenuated swine influenza virus concentration in the immunogenic formulation is about 10 4 to about 10 7 pfu/ml.

12. The immunogenic formulation of claim 9 , wherein the genetically engineered attenuated swine influenza virus concentration in the immunogenic formulation is about 10 4 to about 10 7 pfu/ml.

13. The immunogenic formulation of claim 10 , wherein the genetically engineered attenuated swine influenza virus concentration in the immunogenic formulation is about 10 4 to about 10 7 pfu/ml.

14. A pharmaceutical formulation comprising the genetically engineered attenuated swine influenza virus of claim 1 , and a pharmaceutically acceptable carrier.

15. A pharmaceutical formulation comprising the genetically engineered attenuated swine influenza virus of claim 3 , and a pharmaceutically acceptable carrier.

16. A pharmaceutical formulation comprising the genetically engineered attenuated swine influenza virus of claim 5 and a pharmaceutically acceptable carrier.

17. An isolated cell containing the genetically engineered attenuated swine influenza virus of claim 1 .

18. An isolated cell containing the genetically engineered attenuated swine influenza virus of claim 3 .

19. An isolated cell containing the genetically engineered attenuated swine influenza virus of claim 5 .

20. The isolated cell of claim 17 , wherein the isolated cell is a pig cell or a pig cell line.

21. The isolated cell of claim 18 , wherein the isolated cell is a pig cell or a pig cell line.

22. The isolated cell of claim 19 , wherein the isolated cell is a pig cell or a pig cell line.

23. The isolated cell of claim 20 , wherein the pig cell line is PK(D1) cells, PK(15) cells, PK13 cells, SJPL cells, NSK cells, LLC-PK1 cells, LLC-PK1A cells, ESK-4 cells, ST cells, PT-K75 cells or PK-2a/CL 13 cells.

24. The isolated cell of claim 21 , wherein the pig cell line is PK(D1) cells, PK(15) cells, PK13 cells, SJPL cells, NSK cells, LLC-PK1 cells, LLC-PK1A cells, ESK-4 cells, ST cells, PT-K75 cells or PK-2a/CL 13 cells.

25. The isolated cell of claim 22 , wherein the pig cell line is PK(D1) cells, PK(15) cells, PK13 cells, SJPL cells, NSK cells, LLC-PK1 cells, LLC-PK1A cells, ESK-4 cells, ST cells, PT-K75 cells or PK-2a/CL 13 cells.

26. The isolated cell of claim 17 , wherein the cell is interferon deficient.

27. The isolated cell of claim 18 , wherein the cell is interferon deficient.

28. The isolated cell of claim 19 , wherein the cell is interferon deficient.

29. An isolated embryonated chicken egg containing the genetically engineered attenuated swine influenza virus of claim 1 .

30. An isolated embryonated chicken egg containing the genetically engineered attenuated swine influenza virus of claim 3 .

31. An isolated embryonated chicken egg containing the genetically engineered attenuated swine influenza virus of claim 5 .

32. The isolated embryonated chicken egg of claim 29 , wherein the embryonated chicken egg is interferon deficient.

33. The isolated embryonated chicken egg of claim 30 , wherein the embryonated chicken egg is interferon deficient.

34. The isolated embryonated chicken egg of claim 31 , wherein the embryonated chicken egg is interferon deficient.

35. A method for inducing an immune response in a pig to a swine influenza virus, comprising administering the genetically engineered attenuated swine influenza virus of claim 1 to a pig in an amount sufficient to induce an immune response.

36. A method for production of a pharmaceutical formulation comprising:

(a) propagating in a substrate the genetically engineered attenuated swine influenza virus of claim 1 ,

(b) collecting progeny virus from the substrate, and

Wherein the substrate is an isolated cell, cell line or embryonated chicken egg.

Assignments (7)

CHANGE OF NAME Recorded Dec 4, 2014

From: MOUNT SINAI SCHOOL OF MEDICINE OF NEW YORK UNIVERSITY

To: MOUNT SINAI SCHOOL OF MEDICINE

Reel/Frame 034378/0153 →

CHANGE OF NAME Recorded Dec 4, 2014

From: MOUNT SINAI SCHOOL OF MEDCINE

To: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI