Recombinant adenoviruses and use thereof
The present invention relates to recombinant adenoviruses and vectors thereof. In particular, the adenoviruses are novel simian adenoviruses having a low seroprevalence and high immunogenicity relative to other adenoviruses and vectors thereof. The invention also provides methods for production of the adenoviruses and for the treatment of diseases by administering the adenoviral vector(s) to a subject (e.g., a human).
1. A recombinant adenovirus comprising a nucleotide sequence having
90% or greater sequence identity over the entire sequence of SEQ ID NO: 11, or a complementary sequence to a nucleotide sequence having at least 90% sequence identity to SEQ ID NO: 11 over the entire sequence of SEQ ID NO: 11;
wherein said recombinant adenovirus comprises a deletion in or of an E1 region, said deletion rendering said recombinant adenovirus a replication-defective virus.
2. The recombinant adenovirus of claim 1 , wherein said nucleotide sequence further comprises all or a portion of any one of SEQ ID NOs: 5, 8, 14, and 17, or a complementary sequence thereto.
3. The recombinant adenovirus of claim 1 , wherein
said nucleotide sequence comprises the nucleic acid sequence of any one of SEQ ID NOs: 40-45.
4. The recombinant adenovirus of claim 1 , further comprising a deletion in or of an E3 region and/or an E4 region.
5. The recombinant adenovirus of claim 1 , further comprising a heterologous nucleotide sequence encoding an antigenic or therapeutic gene product of interest, or fragment thereof.
6. The recombinant adenovirus of claim 5 , wherein said antigenic gene product, or fragment thereof, comprises a viral protein, or fragment thereof.
7. The recombinant adenovirus of claim 6 , wherein said viral protein, or fragment thereof, is from a viral family selected from the group consisting of Retroviridae, Flaviviridae, Arenaviridae, Bunyaviridae, Filoviridae, Togaviridae, Poxviridae, Herpesviridae, Orthomyxoviridae, Coronaviridae, Rhabdoviridae, Paramyxoviridae, Picornaviridae, Hepadnaviridae, Papillomaviridae, Parvoviridae, Astroviridae, Polyomaviridae, Calciviridae, or Reoviridae, or
said viral protein, or fragment thereof, is from human immunodeficiency virus (HIV), human papillomavirus (HPV), hepatitis A virus (Hep A), hepatitis B virus (HBV), hepatitis C virus (HCV), Variola major, Variola minor, monkeypox virus, measles virus, rubella virus, mumps virus, varicella zoster virus (VZV), poliovirus, rabies virus, Japanese encephalitis virus, herpes simplex virus (HSV), cytomegalovirus (CMV), rotavirus, influenza, Ebola virus, yellow fever virus, Zika virus, or Marburg virus.
8. The recombinant adenovirus of claim 6 , wherein
said viral protein, or fragment thereof, is from HIV and is Gag, Pol, Env, Nef, Tat, Rev, Vif, Vpr, or Vpu.
9. A method of treating a subject having a disease, said method comprising administering the recombinant adenovirus of claim 5 to said subject.
10. The method of claim 9 , wherein said recombinant adenovirus comprises an antigenic gene product, or fragment thereof, that promotes an immune response in said subject against a virus.
11. A method of inducing an immune response against a flavivirus in a subject comprising administering the recombinant adenovirus of claim 5 to said subject, wherein the antigenic gene product, or fragment thereof is a viral gene product from the flavivirus.
12. The method of claim 11 , wherein said flavivirus is Zika virus.
13. The method of claim 9 , wherein said subject is a human.
14. The method of claim 9 , wherein said adenovirus is administered intramuscularly.
15. The method of claim 9 , wherein said adenovirus is administered as a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
16. The method of claim 15 , wherein said subject is administered at least one or two doses of said pharmaceutical composition, optionally wherein said pharmaceutical composition is administered to said subject as a prime boost.
17. A method of producing a recombinant adenovirus comprising transfecting a cell with a) an isolated polynucleotide comprising a nucleotide sequence having at least 90% or greater sequence identity to SEQ ID NO: 11 over the entire sequence of SEQ ID NO: 11, or a complementary sequence to a nucleotide sequence having at least 90% or greater sequence identity to SEQ ID NO: 11 over the entire sequence of SEQ ID NO: 11, or identical to, or the complementary sequence to, SEQ ID NO: 2, or b) a recombinant vector comprising said polynucleotide; culturing said cell in a suitable medium to allow replication of said polynucleotide or said vector in said cell; and harvesting said recombinant adenovirus from said cell and/or from said medium.
18. The recombinant adenovirus of claim 6 , wherein the viral gene product is an envelope glycoprotein or fragment thereof.
19. The recombinant adenovirus of claim 6 , wherein the viral gene product is a protein or fragment thereof from a Zika virus.
20. The recombinant adenovirus of claim 18 , wherein the envelope glycoprotein or fragment thereof is from a Zika virus.
21. The recombinant adenovirus of claim 20 , wherein the recombinant adenovirus further comprises a deletion in or of an E3 region and/or an E4 region.
22. The method of claim 11 , wherein the viral gene product is an envelope glycoprotein or fragment thereof.
23. The method of claim 11 , wherein the flavivirus is a Zika virus.
24. The method of claim 22 , wherein the envelope glycoprotein or fragment thereof is from a Zika virus.
25. The method of claim 24 , wherein the recombinant adenovirus comprises a deletion in or of an E3 region and/or an E4 region.
26. The method of claim 11 , wherein the recombinant adenovirus comprises a deletion in or of an E3 region and/or an E4 region.
27. The method of claim 11 , wherein said subject is a human.
28. The method of claim 11 , wherein said adenovirus is administered intramuscularly.
29. The method of claim 11 , wherein said adenovirus is administered as a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
30. The method of claim 29 , wherein said subject is administered at least one or two doses of said pharmaceutical composition, optionally wherein said pharmaceutical composition is administered to said subject as a prime boost.
31. A method of inducing an immune response against a retrovirus in a subject comprising administering the recombinant adenovirus of claim 5 to said subject, wherein the antigenic gene product, or fragment thereof is a viral gene product from the retrovirus.
32. The method of claim 31 , wherein the retrovirus is human immunodeficiency virus (HIV).
33. The method of claim 31 , wherein said subject is a human.
34. The method of claim 31 , wherein the viral gene product is an envelope glycoprotein or fragment thereof.
35. The method of claim 34 , wherein the viral gene product is a protein or fragment thereof from HIV.
36. The method of claim 34 , wherein the recombinant adenovirus further comprises a deletion in or of an E3 region and/or an E4 region.
37. The method of claim 31 , wherein said recombinant adenovirus is administered intramuscularly.
38. The method of claim 31 , wherein said recombinant adenovirus is administered as a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
39. The method of claim 38 , wherein said subject is administered at least one or two doses of said pharmaceutical composition, optionally wherein said pharmaceutical composition is administered to said subject as a prime boost.
40. The recombinant adenovirus of claim 1 , wherein the recombinant adenovirus comprises a nucleotide sequence having at least 90% sequence identity to SEQ ID NO: 2 over the entire sequence of SEQ ID NO: 2, or a complementary sequence to a nucleotide sequence having at least 90% sequence identity to SEQ ID NO: 2 over the entire sequence of SEQ ID NO: 2.
41. The recombinant adenovirus of claim 1 , wherein the nucleotide sequence of the recombinant adenovirus further comprises all or a portion of the nucleic acid sequence of SEQ ID NO: 5, or a complementary sequence thereto.
42. The recombinant adenovirus of claim 1 , wherein the nucleotide sequence of the recombinant adenovirus further comprises all or a portion of the nucleic acid sequence of SEQ ID NO: 8, or a complementary sequence thereto.
43. The method of claim 17 , wherein said cell is a bacterial, plant, or mammalian cell.
44. The method of claim 43 , wherein the mammalian cell is a Chinese hamster ovary (CHO) cell.