CMV vaccines
Provided herein are genetically modified arenaviral vectors suitable as vaccines for prevention and treatment of cytomegalovirus infections and reactivation. Also provided herein are pharmaceutical compositions and methods for the treatment of cytomegalovirus infections and reactivation. Specifically, provided herein are pharmaceutical compositions, vaccines, and methods of treating cytomegalovirus infections and reactivation.
1. A method of inducing an immune response against cytomegalovirus (CMV) infection in a patient, wherein said method comprises administering to the patient a first infectious, replication-deficient arenavirus viral vector engineered to contain a genome with the ability to amplify and express its genetic information in infected cells but unable to produce further infectious progeny particles in normal, not genetically engineered cells,
wherein the arenavirus open reading frame encoding the glycoprotein (GP) is removed and replaced by a first nucleotide sequence encoding a cytomegalovirus glycoprotein B (gB) with a truncation of the cytoplasmic domain and/or transmembrane domain or an antigenic fragment thereof,
wherein the first arenavirus viral vector is based on lymphocytic choriomeningitis virus.
2. The method of claim 1 , further comprising administering to the patient a second infectious, replication-deficient arenavirus viral vector engineered to contain a genome with the ability to amplify and express its genetic information in infected cells but unable to produce further infectious progeny particles in normal, not genetically engineered cells,
wherein the arenavirus open reading frame encoding the glycoprotein (GP) of the second arenavirus viral vector is removed and replaced by a second nucleotide sequence encoding a cytomegalovirus tegument protein pp65 or an antigenic fragment thereof,
wherein the second arenavirus viral vector is based on lymphocytic choriomeningitis virus.
3. The method of claim 1 , wherein the first nucleotide sequence encodes a cytomegalovirus gB with a truncation of the cytoplasmic domain and/or transmembrane domain comprising an amino acid sequence that is: (a) at least 80% identical to amino acids 1 to 771 of SEQ ID NO: 3 or amino acids 1 to 772 of SEQ ID NO: 60, and comprises a deletion of the cytoplasmic domain between amino acids 772 to 906 of SEQ ID NO: 3 or between amino acids 773 to 907 of SEQ ID NO: 60, respectively; or (b) at least 80% identical to SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 12, SEQ ID NO: 15, SEQ ID NO: 18, or SEQ ID NO: 63.
4. The method of claim 1 , wherein the truncation of the cytoplasmic domain is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, or 134 amino acids long.
5. The method of claim 2 , wherein the administration of the first arenavirus viral vector or the second arenavirus viral vector, or both, is intramuscular.
6. The method of claim 3 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain comprises an amino acid sequence that is 100% identical to SEQ ID NO: 18.
7. The method of claim 2 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is 100% identical to SEQ ID NO: 36.
8. The method of claim 3 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 18.
9. The method of claim 3 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 18.
10. The method of claim 3 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 18.
11. The method of claim 3 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 18.
12. The method of claim 3 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 18.
13. The method of claim 3 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain consists of an amino acid sequence that is 100% identical to SEQ ID NO: 18.
14. The method of claim 1 , wherein the first nucleotide sequence encodes a cytomegalovirus gB wherein: (i) the cytoplasmic domain of the cytomegalovirus gB has been deleted; (ii) the transmembrane domain of the cytomegalovirus gB has been deleted; or (iii) the cytoplasmic domain and transmembrane domain of the cytomegalovirus gB have been deleted.
15. The method of claim 2 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 36.
16. The method of claim 2 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 36.
17. The method of claim 2 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 36.
18. The method of claim 2 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 36.
19. The method of claim 2 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 36.
20. The method of claim 2 , wherein the cytomegalovirus tegument protein pp65 consists of an amino acid sequence that is 100% identical to SEQ ID NO: 36.
21. The method of claim 1 , wherein the first arenavirus viral vector is based on lymphocytic choriomeningitis virus Clone 13 strain.
22. The method of claim 2 , wherein the second arenavirus viral vector is based on lymphocytic choriomeningitis virus Clone 13 strain.
23. The method of claim 2 , wherein the first arenavirus viral vector and the second arenavirus viral vector are administered separately.
24. The method of claim 2 , wherein the first arenavirus viral vector and the second arenavirus viral vector are administered simultaneously.
25. A method of inducing an immune response against CMV infection in a patient, wherein said method comprises administering to the patient:
a) a first infectious, replication-deficient arenavirus viral vector engineered to contain a genome with the ability to amplify and express its genetic information in infected cells but unable to produce further infectious progeny particles in normal, not genetically engineered cells, wherein the arenavirus open reading frame encoding the glycoprotein (GP) is removed and replaced by a nucleotide sequence encoding a cytomegalovirus glycoprotein B (gB), wherein the cytomegalovirus gB has a truncation of the cytoplasmic domain; and
b) a second infectious, replication-deficient arenavirus viral vector engineered to contain a genome with the ability to amplify and express its genetic information in infected cells but unable to produce further infectious progeny particles in normal, not genetically engineered cells, wherein the arenavirus open reading frame encoding the glycoprotein (GP) is removed and replaced by a nucleotide sequence encoding a cytomegalovirus tegument protein pp65,
wherein the first arenavirus viral vector, or the second arenavirus viral vector, or both are based on lymphocytic choriomeningitis virus.
26. The method of claim 25 , wherein the administration is intramuscular.
27. The method of claim 25 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 18.
28. The method of claim 25 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 18.
29. The method of claim 25 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 18.
30. The method of claim 25 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 18.
31. The method of claim 25 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 18.
32. The method of claim 25 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain consists of an amino acid sequence that is 100% identical to SEQ ID NO: 18.
33. The method of claim 25 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 36.
34. The method of claim 25 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 36.
35. The method of claim 25 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 36.
36. The method of claim 25 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 36.
37. The method of claim 25 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 36.
38. The method of claim 25 , wherein the cytomegalovirus tegument protein pp65 consists of an amino acid sequence that is 100% identical to SEQ ID NO: 36.
39. The method of claim 25 , wherein the first arenavirus viral vector, or the second arenavirus viral vector, or both are based on lymphocytic choriomeningitis virus Clone 13 strain.
40. The method of claim 25 , wherein the first arenavirus viral vector and the second arenavirus viral vector are administered separately.
41. The method of claim 25 , wherein the first arenavirus viral vector and the second arenavirus viral vector are administered simultaneously.
42. A method of inducing an immune response against CMV infection in a patient, wherein said method comprises administering to the patient:
a) a first infectious, replication-deficient arenavirus viral vector engineered to contain a genome with the ability to amplify and express its genetic information in infected cells but unable to produce further infectious progeny particles in normal, not genetically engineered cells, wherein the arenavirus open reading frame encoding the glycoprotein (GP) is removed and replaced by a nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 18; and
b) a second infectious, replication-deficient arenavirus viral vector engineered to contain a genome with the ability to amplify and express its genetic information in infected cells but unable to produce further infectious progeny particles in normal, not genetically engineered cells, wherein the arenavirus open reading frame encoding the glycoprotein (GP) is removed and replaced by a nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 36,
wherein the first arenavirus viral vector and the second arenavirus viral vector are administered simultaneously and the administration is intramuscular,
wherein the first arenavirus viral vector, or the second arenavirus viral vector, or both are based on lymphocytic choriomeningitis virus.
43. The method of claim 42 , wherein the first arenavirus viral vector, or the second arenavirus viral vector, or both are based on lymphocytic choriomeningitis virus Clone 13 strain.
44. The method of claim 1 , wherein the administration is intramuscular.
45. The method of claim 3 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain comprises a deletion of the cytoplasmic domain between amino acids 772 to 906 of SEQ ID NO: 3.
46. The method of claim 3 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain comprises a deletion of the cytoplasmic domain between amino acids 773 to 907 of SEQ ID NO: 60.
47. The method of claim 3 , wherein the cytomegalovirus gB with a truncation of the cytoplasmic domain comprises an amino acid sequence consisting of the amino acid sequence of SEQ ID NO: 18.
48. The method of claim 2 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence consisting of the amino acid sequence of SEQ ID NO: 36.
49. The method of claim 1 , wherein the method is treating a cytomegalovirus infection in the patient.
50. The method of claim 1 , wherein the method is preventing a disease associated with a cytomegalovirus infection in the patient.
51. The method of claim 25 , wherein the method is treating a cytomegalovirus infection in the patient.
52. The method of claim 25 , wherein the method is preventing a disease associated with a cytomegalovirus infection in the patient.
53. The method of claim 42 , wherein the method is treating a cytomegalovirus infection in the patient.
54. The method of claim 42 , wherein the method is preventing a disease associated with a cytomegalovirus infection in the patient.
55. The method of claim 42 , wherein the normal, not genetically engineered cells do not express the glycoprotein (GP) of the first and second arenavirus viral vector.