Recombinant HCMV and RHCMV vectors and uses thereof

Patent metadata

Field	Value
Publication number	US-9982241-B2
Application number	US-201514872756-A
Country	US
Kind code	B2
Filing date	Oct 1, 2015
Priority date	May 14, 2010
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

The recombinant rhesus cytomegalovirus (RhCMV) and human cytomegalovirus (HCMV) vectors of this invention encode heterologous antigens, such as pathogen-specific antigens or tumor antigens, which may be used, for example, for the treatment or prevention of infectious disease or cancer. The recombinant RhCMV or HCMV vectors elicit and maintain high level cellular immune responses specific for the heterologous antigen while including deletions in one or more genes essential or augmenting for CMV replication, dissemination or spread.

First claim

What is claimed is:

1. A method of treating a subject with an infectious disease or cancer comprising administering to the subject in need thereof a recombinant viral vector comprising a nucleic acid sequence encoding a human cytomegalovirus (HCMV) or rhesus cytomegalovirus (RhCMV) backbone vector and at least one heterologous antigen,
wherein the at least one heterologous antigen is a pathogen-specific antigen or a tumor antigen, and
wherein the recombinant viral vector: (a) comprises a deletion in the HCMV UL82 or RhCMV Rh110 gene that eliminates expression of a functional pp71 protein, (b) is deficient in host to host spread, (c) infects a HCMV or RhCMV seropositive host upon administration of said recombinant viral vector, and (d) induces and maintains a long-term effector memory T cell response to the at least one heterologous antigen in the seropositive host.

2. The method of claim 1 , wherein the recombinant viral vector further comprises a deletion in a HCMV or RhCMV gene or gene region non-essential for growth in vivo.

3. The method of claim 2 , wherein the non-essential HCMV or RhCMV gene region is selected from the group consisting of: the RL11 family, the pp65 family, the US12 family, and the US28 family.

4. The method of claim 1 , wherein the recombinant viral vector further comprises at least one deletion in a HCMV or RhCMV gene required for optimal growth in certain cell types.

5. The method of claim 4 , wherein the at least one deletion in a HCMV gene required for optimal growth in certain cell types comprises a deletion in UL64 or US29, or a combination thereof.

6. The method of claim 4 , wherein the recombinant viral vector has a deficient tropism for epithelial cells, the central nervous system (CNS), macrophages, or a combination thereof.

7. The method of claim 1 , wherein the recombinant viral vector further comprises a deletion in at least one immune modulatory HCMV gene selected from the group consisting of: US2, US3, US4, US5, US6, US7, US8, US9, US10, US11, UL118, UL119, UL36, UL37, UL111a, UL146, and UL147.

8. The method of claim 1 , wherein the recombinant viral vector further comprises a deletion in at least one immune modulatory RhCMV gene selected from the group consisting of: Rh158, Rh159, Rh160, Rh161, Rh162, Rh163, Rh164, Rh165, Rh166, Rh182, Rh183, Rh184, Rh185, Rh186, Rh187, Rh188, and Rh189.

9. The method of claim 1 , wherein the subject is a human.

10. The method of claim 1 , wherein the subject is a non-human primate.

11. A method of treating a subject infected with human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) comprising administering to the subject in need thereof a recombinant viral vector comprising a nucleic acid sequence encoding a HCMV or RhCMV backbone vector and at least one HIV-derived or SIV-derived antigen,
wherein the recombinant viral vector: (a) comprises a deletion in the HCMV UL82 or RhCMV Rh110 gene that eliminates expression of a functional pp71 protein, (b) is deficient in host to host spread, (c) infects a HCMV or RhCMV seropositive host upon administration of said recombinant viral vector, and (d) induces and maintains a long-term effector memory T cell response to the at least one HIV-derived or SIV-derived antigen in the seropositive host.

12. The method of claim 11 , wherein the HIV-derived or SIV-derived antigen is selected from the group consisting of: Gag, Pol, Env, Rev, Tat, and Nef, or an epitope or antigenic fragment thereof.

13. The method of claim 11 , wherein the subject is a human.

14. The method of claim 11 , wherein the subject is a non-human primate.

15. A method of inducing a tumor-specific or pathogen-specific immune response in a subject at risk of developing cancer or becoming infected with an infectious disease comprising administering to the subject in need thereof a recombinant viral vector comprising a nucleic acid sequence encoding a HCMV or RhCMV backbone vector and at least one heterologous antigen,
wherein the at least one heterologous antigen is a tumor antigen or a pathogen-specific antigen, and
wherein the recombinant viral vector: (a) comprises a deletion in the HCMV UL82 or RhCMV Rh110 gene that eliminates expression of a functional pp71 protein, (b) is deficient in host to host spread, (c) infects a HCMV or RhCMV seropositive host upon administration of said recombinant viral vector, and (d) induces and maintains a long-term effector memory T cell response to the at least one heterologous antigen in the seropositive host.

16. The method of claim 15 , wherein the recombinant viral vector further comprises a deletion in a HCMV or RhCMV gene or gene region non-essential for growth in vivo.

17. The method of claim 16 , wherein the non-essential HCMV or RhCMV gene region is selected from the group consisting of: the RL11 family, the pp65 family, the US12 family, and the US28 family.

18. The method of claim 15 , wherein the recombinant viral vector further comprises at least one deletion in a HCMV or RhCMV gene required for optimal growth in certain cell types.

19. The method of claim 18 , wherein the at least one deletion in a HCMV gene required for optimal growth in certain cell types comprises a deletion in UL64 or US29, or a combination thereof.

20. The method of claim 18 , wherein the recombinant viral vector has a deficient tropism for epithelial cells, the CNS, macrophages, or a combination thereof.

21. The method of claim 15 , wherein the recombinant viral vector further comprises a deletion in at least one immune modulatory HCMV gene selected from the group consisting of: US2, US3, US4, US5, US6, US7, US8, US9, US10, US11, UL118, UL119, UL36, UL37, UL111a, UL146, and UL147.

22. The method of claim 15 , wherein the recombinant viral vector further comprises a deletion in at least one immune modulatory RhCMV gene selected from the group consisting of: Rh158, Rh159, Rh160, Rh161, Rh162, Rh163, Rh164, Rh165, Rh166, Rh182, Rh183, Rh184, Rh185, Rh186, Rh187, Rh188, and Rh189.

23. The method of claim 15 , wherein the subject is a human.

24. The method of claim 15 , wherein the subject is a non-human primate.

25. A method of inducing an HIV-specific or SIV-specific immune response in a subject at risk of becoming infected with HIV or SIV comprising administering to the subject in need thereof a recombinant viral vector comprising a nucleic acid sequence encoding a HCMV or RhCMV backbone vector and at least one HIV-derived or SIV-derived antigen,
wherein the recombinant viral vector: (a) comprises a deletion in the HCMV UL82 or RhCMV Rh110 gene that eliminates expression of a functional pp71 protein, (b) is deficient in host to host spread, (c) infects a HCMV or RhCMV seropositive host upon administration of the recombinant viral vector, and (d) induces and maintains a long-term effector memory T cell response to the at least one HIV-derived or SIV-derived antigen in the seropositive host.

26. The method of claim 25 , wherein the HIV-derived or SIV-derived antigen is selected from the group consisting of: Gag, Pol, Env, Rev, Tat, and Nef, or an epitope or antigenic fragment thereof.

27. The method of claim 25 , wherein the subject is a human.

28. The method of claim 25 , wherein the subject is a non-human primate.

29. The method of claim 1 , wherein the nucleic acid sequence of the recombinant viral vector further encodes at least

Assignees

• Univ Oregon Health & Science

Inventors

• Picker Louis
• Nelson Jay A
• Frueh Klaus
• Jarvis Michael A
• Hansen Scott G

Classifications

• A61P31/18

  for HIV · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P31/12

  Antivirals · CPC title