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

A61K39/145 A61K39/12 C12N7/00 A61K2039/5254 A61K2039/544 A61K2039/552 A61K2039/58 C12N2760/16034 C12N2760/16061 C12N2760/16121 C12N2760/16134 C12N2760/16151 C12N2760/16171

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Quick Facts

Patent No.: US 9,549,975
App. No.: 14/636,651
Granted: Jan 24, 2017
Kind: B2

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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 (26)

1. A genetically engineered attenuated swine influenza virus having an impaired interferon antagonist phenotype, wherein the virus comprises a swine influenza virus NS1 gene with a mutation resulting in a swine influenza virus NS1 protein having a deletion of between 90 and 94 amino acid residues from the carboxy-terminus of NS1, wherein the swine influenza virus NS1 gene is from A/Swine/Texas/4199-2/98.

2. The genetically engineered attenuated swine influenza virus of claim 1 , wherein the swine influenza virus is H1N1, H1N2, H3N2, H3N1, H9N2, or H5N1.

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

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

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

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

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

8. The genetically engineered attenuated swine influenza virus of claim 7 , 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/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/30, 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/Ontario/97, A/Swine/Quebec/192/81, A/Swine/Quebec/192/91, 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 or A/Swine/Wisconsin/14094/99.

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

10. A pharmaceutical formulation comprising the genetically engineered attenuated swine influenza virus of claim 1 , and a physiologically acceptable excipient.

11. A cultured cell containing the genetically engineered attenuated swine influenza virus of claim 1 .

12. The cultured cell of claim 11 , wherein the cell is a pig cell or pig cell line.

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

14. A genetically engineered attenuated swine influenza virus having an impaired interferon antagonist phenotype, wherein the virus comprises a swine influenza virus NS1 gene with a mutation resulting in a swine influenza virus NS1 protein having a deletion of 90 amino acid residues from the carboxy-terminus of NS1, wherein the swine influenza virus NS1 gene is from A/Swine/Texas/4199-2/98.

15. The genetically engineered attenuated swine influenza virus of claim 14 , wherein the swine influenza virus is H1N1, H1N2, H3N2, H3N1, H9N2, or H5N1.

16. The genetically engineered attenuated swine influenza virus of claim 14 , wherein the attenuated virus is a reassortant.

17. The genetically engineered attenuated swine influenza virus of claim 14 , wherein the attenuated virus is a chimeric virus that expresses a heterologous sequence.

18. The genetically engineered attenuated swine influenza virus of claim 14 , wherein the attenuated virus is a chimeric virus that expresses an epitope of a foreign pathogen.

19. The genetically engineered attenuated swine influenza virus of claim 14 , wherein the attenuated virus is a chimeric virus that expresses a tumor antigen.

20. The genetically engineered attenuated swine influenza virus of claim 14 , wherein the attenuated virus is engineered to express an epitope from a different virus or at least one segment derived from a different virus.

21. The genetically engineered attenuated swine influenza virus of claim 20 , 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/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/30, 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/Ontario/97, A/Swine/Quebec/192/81, A/Swine/Quebec/192/91, 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 or A/Swine/Wisconsin/14094/99.

22. An immunogenic formulation comprising the genetically engineered attenuated swine influenza virus of claim 14 , and a physiologically acceptable excipient.

23. A pharmaceutical formulation comprising the genetically engineered attenuated swine influenza virus of claim 14 , and a physiologically acceptable excipient.

24. A cultured cell containing the genetically engineered attenuated swine influenza virus of claim 14 .

25. The cultured cell of claim 24 , wherein the cell is a pig cell or pig cell line.

26. An embryonated chicken egg containing the genetically engineered attenuated swine influenza virus of claim 14 .

Assignments (5)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 30, 2015

From: RICHT, JUERGEN A.; LAGER, KELLY M.

To: THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY OF AGRICULTURE

Reel/Frame 036919/0385 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 30, 2015

From: PALESE, PETER; GARCIA-SASTRE, ADOLFO

To: MOUNT SINAI SCHOOL OF MEDICINE OF NEW YORK UNIVERSITY

Reel/Frame 036919/0415 →