CMV glycoproteins and recombinant vectors

Patent metadata

Field	Value
Publication number	US-9862972-B2
Application number	US-201314086602-A
Country	US
Kind code	B2
Filing date	Nov 21, 2013
Priority date	Jun 10, 2011
Publication date	Jan 9, 2018
Grant date	Jan 9, 2018

Abstract

Disclosed herein are recombinant CMV vectors which may comprise a heterologous antigen that can repeatedly infect an organism while inducing a CD8+ T cell response to immunodominant epitopes of the heterologous antigen. The CMV vector may comprise a deleterious mutation in the US11 glycoprotein or a homolog thereof.

First claim

What is claimed is:

1. A method of eliciting an immune response to at least one immunodominant epitope of at least one heterologous antigen in a cytomegalovirus (CMV)-seropositive subject in need thereof, the method comprising administering a recombinant CMV vector encoding the at least one heterologous antigen to the CMV-seropositive subject in an amount effective to elicit a long-term CD8+ T cell response to the at least one immunodominant epitope,
wherein the recombinant CMV vector does not express an active US11 protein or a functional homologue thereof, and
wherein the recombinant CMV vector encodes functional US2, US3, and US6 proteins, or functional homologues thereof.

2. The method of claim 1 , wherein the at least one heterologous antigen comprises an infectious disease antigen or a tumor antigen.

3. The method of claim 1 , wherein the CMV-seropositive subject is a human or a rhesus macaque.

4. The method of claim 1 , wherein the recombinant CMV vector comprises one or more of: (1) a point mutation in a nucleic acid sequence encoding US11 or a functional homologue thereof, (2) a frameshift mutation in the nucleic acid sequence encoding US11 or a functional homologue thereof, or (3) a deletion of all or part of the nucleic acid sequence encoding US11 or a functional homologue thereof.

5. The method of claim 1 , wherein administering comprises intravenous, intramuscular, intraperitoneal, or oral administration of the recombinant CMV vector.

6. The method of claim 1 , wherein the at least one heterologous antigen is selected from the group consisting of: a Hepatitis B virus antigen; a Hepatitis C virus antigen; a human immunodeficiency virus (HIV) antigen; a simian immunodeficiency virus (SIV) antigen; a Clostridium tetani antigen; a Mycobacterium tuberculosis antigen; and a Plasmodium antigen.

7. The method of claim 1 , wherein expression of the at least one heterologous antigen is driven by a heterologous antigen-encoding sequence operably linked to a promoter.

8. The method of claim 7 , wherein the promoter is selected from the group consisting of: a constitutive promoter, an inducible promoter, a non-viral promoter, and a viral promoter.

9. The method of claim 4 , wherein the recombinant CMV vector comprises a deletion of all of the nucleic acid sequence encoding US11 or a functional homologue thereof.

10. The method of claim 1 , wherein the recombinant CMV vector encodes the US2 of SEQ ID NO:1, the US3 of SEQ ID NO:2, and the US6 of SEQ ID NO:3.

11. The method of claim 1 , wherein the at least one heterologous antigen comprises an infectious disease antigen or a tumor antigen,
wherein the CMV-seropositive subject is a human cytomegalovirus (HCMV)-seropositive human subject, and
wherein the recombinant CMV vector is a recombinant HCMV vector.

12. The method of claim 8 , wherein the promoter is an EF1-alpha promoter or a CMV-IE promoter.

13. The method of claim 1 , wherein the at least one heterologous antigen comprises an infectious disease antigen or tumor antigen,
wherein the CMV-seropositive subject is a HCMV-seropositive human subject,
wherein the recombinant CMV vector is a recombinant HCMV vector, and
wherein the recombinant HCMV vector does not express an active US8 or US10 protein.

14. The method of claim 13 , wherein the recombinant HCMV vector does not express active US8 and US10 proteins.

15. The method of claim 14 , wherein the recombinant HCMV vector comprises a deletion of all of the nucleic acid sequence encoding US8-US11.

16. The method of claim 1 , wherein the recombinant CMV vector does not express an active US8 or US10 protein, or a functional homologue thereof.

17. The method of claim 16 , wherein the recombinant CMV vector does not express active US8 and US10 proteins, or functional homologues thereof.

18. The method of claim 17 , wherein the recombinant CMV vector comprises a deletion of all of the nucleic acid sequence encoding US8-US11 or functional homologues thereof.

19. The method of claim 1 , wherein the recombinant CMV vector is a recombinant rhesus CMV (RhCMV) vector.

20. The method of claim 13 , wherein the at least one heterologous antigen is selected from the group consisting of: an HIV antigen, an SIV antigen, a hepatitis B virus antigen, a hepatitis C virus antigen, a Clostridium tetani antigen, Mycobacterium tuberculosis antigen, and a plasmodium antigen.

21. The method of claim 11 , wherein the at least one heterologous antigen is selected from the group consisting of: an HIV antigen, an SIV antigen, a hepatitis B virus antigen, a hepatitis C virus antigen, a Clostridium tetani antigen, a Mycobacterium tuberculosis antigen, and a plasmodium antigen.

22. A method of eliciting an immune response to at least one immunodominant epitope of at least one heterologous antigen in a CMV-seropositive subject in need thereof, the method comprising administering a recombinant CMV vector to the CMV-seropositive subject in an amount effective to elicit a long-term CD8+ T cell response to the at least one immunodominant epitope;
wherein the recombinant CMV vector does not express an active US11 protein or a functional homologue thereof;
wherein the recombinant CMV vector comprises: a nucleic acid sequence encoding functional US2, US3, and US6 proteins, or functional homologues thereof; a nucleic acid sequence encoding US12 or a functional homologue thereof; and a nucleic acid sequence encoding the at least one heterologous antigen; and
wherein the nucleic acid sequence encoding the at least one heterologous antigen is located between the nucleic acid sequence encoding US6 or a functional homologue thereof and the nucleic acid sequence encoding US12 or a functional homologue thereof.

23. The method of claim 22 , wherein the CMV-seropositive subject is a human or a rhesus macaque.

24. The method of claim 22 , wherein the recombinant CMV vector is a recombinant HCMV vector or a recombinant RhCMV vector.

25. The method of claim 22 , wherein the recombinant CMV vector comprises a deletion of all of the nucleic acid sequence encoding US8, US10, and US11, or functional homologues thereof.

26. The method of claim 22 , wherein the nucleic acid sequence encoding the at least one heterologous antigen is located between the nucleic acid sequence encoding US8 or a functional homologue thereof and the nucleic acid sequence encoding US12 or a functional homologue thereof.

27. The method of claim 26 , wherein the recombinant CMV vector comprises a deletion of all of the nucleic acid sequence encoding US10 and US11, or functional homologues thereof.

28. The method of claim 22 , wherein the nucleic acid sequence encoding the at least one heterologous antigen is located between the nucleic acid sequence encoding US10 or a functional homologue thereof and the nucleic acid sequence encoding US12 or a functional homologue thereof.

29. The method of claim 22 , wherein the at least one heterologous antigen comprises an infectious disease antigen or a tumor antigen.

30. The method of claim 22 , wherein the at least one heterologous antigen is selected from the group consisting of: an HIV antigen, an SIV antigen, a hepatitis B virus antigen, a hepatitis C virus antigen, a Clostridium tetani antigen, a Mycobacterium tuberculosis antigen, and a plasmodium antigen.

31.

Assignees

• Univ Oregon Health & Science

Inventors

• Picker Louis
• Früh Klaus
• Hansen Scott

Classifications

• C12N2710/16143

  viral genome or elements thereof as genetic vector · CPC title

• C12N2740/15034

  Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein · CPC title

• C12N2740/15071

  Demonstrated in vivo effect · CPC title

• C12N2800/204

  of bacterial origin, e.g. BAC · CPC title

• A61K2039/5256

  expressing foreign proteins · CPC title