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 pharmaceutical composition comprising 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 one arenavirus open reading frame is removed and replaced by a first nucleotide sequence selected from the group consisting of:
a) a nucleotide sequence encoding a cytomegalovirus glycoprotein B (gB) or an antigenic fragment thereof;
b) a nucleotide sequence encoding a cytomegalovirus tegument protein pp65 or an antigenic fragment thereof;
c) a nucleotide sequence encoding a cytomegalovirus glycoprotein H (gH) or an antigenic fragment thereof;
d) a nucleotide sequence encoding a cytomegalovirus glycoprotein L (gL) or an antigenic fragment thereof;
e) a nucleotide sequence encoding a cytomegalovirus UL128 protein or an antigenic fragment thereof;
f) a nucleotide sequence encoding a cytomegalovirus UL130 protein or an antigenic fragment thereof; and
g) a nucleotide sequence encoding a cytomegalovirus UL131A protein or an antigenic fragment thereof,
and 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 one arenavirus open reading frame is removed and replaced by a second nucleotide sequence selected from the group consisting of:
a) a nucleotide sequence encoding a cytomegalovirus glycoprotein B (gB) or an antigenic fragment thereof;
b) a nucleotide sequence encoding a cytomegalovirus tegument protein pp65 or an antigenic fragment thereof;
c) a nucleotide sequence encoding a cytomegalovirus glycoprotein H (gH) or an antigenic fragment thereof;
d) a nucleotide sequence encoding a cytomegalovirus glycoprotein L (gL) or an antigenic fragment thereof;
e) a nucleotide sequence encoding a cytomegalovirus UL128 protein or an antigenic fragment thereof;
f) a nucleotide sequence encoding a cytomegalovirus UL130 protein or an antigenic fragment thereof; and
g) a nucleotide sequence encoding a cytomegalovirus UL131A protein or an antigenic fragment thereof wherein the first and second nucleotide sequences are different.
2. The pharmaceutical composition of claim 1 , wherein the first nucleotide sequence encodes the cytomegalovirus gB or fragment thereof, and wherein the second nucleotide sequence encodes the cytomegalovirus tegument protein pp65 or a fragment thereof.
3. The pharmaceutical composition of claim 1 , wherein the first nucleotide sequence encodes the cytomegalovirus gB with a truncation of the carboxy-terminus, and wherein the second nucleotide sequence encodes the cytomegalovirus tegument protein pp65 or a fragment thereof.
4. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus gB with a truncation of the carboxy-terminus is at least 80%, 85%, 90%, 95%, 98%, 99% or at least 100% identical to the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 60 over the entire length of the truncated gB, wherein the truncation is in the region of amino acids 772-906 of SEQ ID NO: 3 or SEQ ID NO: 60, respectively.
5. The pharmaceutical composition of claim 4 , wherein the truncation 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, 29, 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.
6. The pharmaceutical composition of claim 1 , wherein the composition is suitable for intramuscular administration.
7. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus gB with a truncation of the carboxy-terminus comprises an amino acid sequence that is 100% identical to SEQ ID NO: 18.
8. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is 100% identical to SEQ ID NO: 36.
9. The pharmaceutical composition of claim 1 , wherein the arenavirus open reading frame encoding the glycoprotein (GP) within the S segment of the first arenavirus viral vector is removed and replaced by the first nucleotide sequence.
10. The pharmaceutical composition of claim 1 , wherein the arenavirus open reading frame encoding the glycoprotein (GP) within the S segment of the second arenavirus viral vector is removed and replaced by the second nucleotide sequence.
11. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus gB with a truncation of the carboxy-terminus comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 18.
12. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus gB with a truncation of the carboxy-terminus comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 18.
13. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus gB with a truncation of the carboxy-terminus comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 18.
14. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus gB with a truncation of the carboxy-terminus comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 18.
15. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus gB with a truncation of the carboxy-terminus comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 18.
16. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus gB with a truncation of the carboxy-terminus consists of an amino acid sequence that is 100% identical to SEQ ID NO: 18.
17. The pharmaceutical composition of claim 3 , 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.
18. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 36.
19. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 36.
20. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 36.
21. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 36.
22. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus tegument protein pp65 comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 36.
23. The pharmaceutical composition of claim 3 , wherein the cytomegalovirus tegument protein pp65 consists of an amino acid sequence that is 100% identical to SEQ ID NO: 36.
24. The pharmaceutical composition of claim 1 , wherein the first arenavirus viral vector, the second arenavirus viral vector, or both are lymphocytic choriomeningitis viruses.
25. The pharmaceutical composition of claim 1 , wherein the first arenavirus viral vector, the second arenavirus viral vector, or both are lymphocytic choriomeningitis virus Clone 13 strains.
26. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is suitable to protect against a cytomegalovirus infection.
27. A pharmaceutical composition comprising:
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 within the S segment is removed and replaced by a nucleotide sequence encoding a cytomegalovirus glycoprotein B (gB), wherein the cytoplasmic domain of the cytomegalovirus gB has been deleted; and
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 within the S segment is removed and replaced by a nucleotide sequence encoding a cytomegalovirus tegument protein pp65.
28. The pharmaceutical composition of claim 27 , wherein the cytomegalovirus gB consists of an amino acid sequence that is 100% identical to SEQ ID NO: 18, and the cytomegalovirus tegument protein pp65 consists of an amino acid sequence that is 100% identical to SEQ ID NO: 36.
29. The pharmaceutical composition of claim 27 , wherein both the first arenavirus viral vector and the second arenavirus viral vector are lymphocytic choriomeningitis viruses.