Epstein-Barr virus antigen construct

Abstract

To provide Epstein-Barr virus vaccines for use in prevention of Epstein-Barr virus infection, and in treatment of malignant tumor and diseases such as multiple sclerosis associated with Epstein-Barr virus.SOLUTION: The invention provides Epstein-Barr virus antigen polypeptides, polynucleotide and vectors comprising specific sequences, and immunogenic compositions comprising the same. The invention includes the use of Epstein-Barr virus antigen constructs to produce vaccines for treating and preventing Epstein-Barr virus infections and Epstein-Barr virus-associated diseases such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus.SELECTED DRAWING: None

Description

Technical Field

[0001] Statement Regarding Government Interests This invention was made in the performance of a joint research and development agreement between the National Institutes of Health, an agency of the Department of Health and Human Services, and the United States Government has certain rights in this invention.

[0002] Sequence Listing This application is electronically filed in ASCII format and includes a sequence listing which is hereby incorporated by reference in its entirety. The ASCII copy created on December 5, 2018, is named VU66487_WO_SL.txt and is 419,960 bytes in size.

[0003] Field of the Invention The present invention belongs to the field of treating and preventing viral infections. In particular, the present invention relates to Epstein-Barr virus antigen constructs. The present invention includes the use of Epstein-Barr virus antigen constructs for treating and preventing Epstein-Barr virus infections and Epstein-Barr virus-related diseases.

Background Art

[0004] Epstein-Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is one of the most common viruses in humans and infects at least 90% of adults. EBV causes asymptomatic latent infection in most infected individuals but is also known as the major pathogen of infectious mononucleosis.

[0005] More importantly, EBV infection is associated with an increased risk of certain malignancies (e.g., gastric cancer, nasopharyngeal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma), as well as multiple sclerosis (MS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome.

[0006] Similar to other members of the herpesvirus family, EBV contains a double-stranded DNA genome of approximately 192 kilobases that encodes approximately 85 genes. The EBV genome is encapsulated within a protein nucleocapsid that is surrounded by the viral envelope. The outer envelope layer contains lipids and surface glycoproteins that are thought to be involved in targeting the virus to its major host cells, B lymphocytes and epithelial cells.

[0007] The replication cycle of the EBV virus is well-characterized. After initial infection of the host cell, EBV enters a stage of active production of infectious virions called the lytic replication stage (or lytic stage). During the lytic stage, EBV gene expression is characterized by the expression of one or more lytic gene products, including ZEBRA, BRLF1, BNLF2, BCRF1, and viral capsid antigen (VCA), as well as envelope glycoproteins, such as gp350 and gp110.

[0008] After the lytic replication period, EBV enters a state of persistent viral infection called latency (or the latent phase), during which there is no active virus production. Latent EBV infection is associated with a characteristic gene expression program that includes the expression of one or more latent gene products, such as EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA3C, EBNA leader protein (EBNA-LP), LMP1, and / or LMP2. Latently infected cells can be reactivated to produce lytic virus by triggers that are not yet understood.

[0009] In animal models and human trials, several EBV vaccine candidates have been evaluated. Most prophylactic vaccine candidates have focused on the major EBV envelope glycoprotein gp350 as an immunogen. Gu et al. reported that a recombinant live vaccinia virus expressing gp350 of EBV induced EBV-neutralizing antibodies and moderate protection in children, but not in adults. Gu et al., Dev. Biol. Stand. 1995;84:171-177. The recombinant gp350 vaccine was found not to protect against EBV infection, but reduced the incidence of infectious mononucleosis. Sokal et al., J. Infect. Dis. 2007;196(12):1749-1753.

[0010] Therapeutic EBV vaccine candidates have mainly targeted T cell epitopes of EBV nuclear antigen-1 (EBNA1) and LMP2. For example, Taylor et al. described a modified vaccinia virus Ankara (MVA) vector expressing a peptide fragment of EBNA1 fused to the full-length LMP2 protein. The so-called MVA-EL vaccine was reported to induce antigen-specific CD4+ and CD8+ T cell responses in early clinical trials. Taylor et al., J. Virol. Jan. 2004, 768-778. Similarly, a recombinant human adenovirus vector expressing the full-length LMP2 protein was reported to induce antigen-specific T cell responses in vitro and in mice. Pan et al., Biochem Biophys Res Commun. Sep. 1, 2006;347(3):551-7. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0011] Despite the clear needs in the art, an EBV vaccine approved for use in humans is still not available. Thus, there remains a need for an EBV vaccine for use in preventing EBV infection and in treating EBV-related malignancies and EBV-related diseases such as multiple sclerosis.

Means for Solving the Problems

[0012] The present inventors provide an EBV antigen polypeptide, polynucleotide and vector useful as a component of an immunogenic composition for inducing an immune response in a subject against Epstein-Barr virus (EBV) infection; methods for using them in the prevention and treatment of EBV infection and EBV-related diseases; and methods for their production.

[0013] (a) at least one fragment of at least 8 amino acids of SEQ ID NO: 1, (b) at least one fragment of at least 8 amino acids of SEQ ID NO: 6, (c) at least one fragment of at least 8 amino acids of SEQ ID NO: 11, and (d) at least one fragment of at least 8 amino acids of SEQ ID NO: 13 A polynucleotide encoding an EBV antigen polypeptide comprising: A polynucleotide is provided that is operably linked to one or more sequences that direct the expression of the polypeptide in a host cell. In some embodiments, the polypeptide further comprises at least one fragment of at least 8 amino acids of SEQ ID NO: 21.

[0014] (a) at least two LMP1 fragments of at least 8 amino acids of SEQ ID NO: 1 that are not adjacent to each other, (b) at least two LMP2 fragments of at least 8 amino acids of SEQ ID NO: 6 that are not adjacent to each other, (c) at least two EBNA1 fragments of at least 8 amino acids of SEQ ID NO: 11 that are not adjacent to each other, (d) at least two EBNA3A fragments of at least 8 amino acids of SEQ ID NO: 13 that are not adjacent to each other, and / or (e) at least two ZEBRA fragments of at least 8 amino acids of SEQ ID NO: 21 that are not adjacent to each other A polynucleotide encoding an EBV antigen polypeptide, comprising: There is also provided a polynucleotide operably linked to one or more sequences that direct the expression of said polypeptide in a host cell.

[0015] The EBV antigen polypeptide is (a) a first fragment of LMP1 consisting of SEQ ID NO: 2, (b) a second fragment of LMP1 consisting of SEQ ID NO: 3, (c) a third fragment of LMP1 consisting of SEQ ID NO: 4, (d) a fourth fragment of LMP1 consisting of SEQ ID NO: 5, (e) a first fragment of LMP2 consisting of SEQ ID NO: 7, (f) a second fragment of LMP2 consisting of SEQ ID NO: 8, (g) a third fragment of LMP2 consisting of SEQ ID NO: 9, (h) a fourth fragment of LMP2 consisting of SEQ ID NO: 10, (i) a first fragment of EBNA1 consisting of SEQ ID NO: 12, (j) a first fragment of EBNA3A consisting of SEQ ID NO: 14, (k) a second fragment of EBNA3A consisting of SEQ ID NO: 15, (l) a third fragment of EBNA3A consisting of SEQ ID NO: 16, (m) a fourth fragment of EBNA3A consisting of SEQ ID NO: 17, (n) a fifth fragment of EBNA3A consisting of SEQ ID NO: 18, (o) a sixth fragment of EBNA3A consisting of SEQ ID NO: 19, and (p) a seventh fragment of EBNA3A consisting of SEQ ID NO: 20 and The first, second, third, and fourth LMP1 fragments are not adjacent to each other; the first, second, third, and fourth LMP2 fragments are not adjacent to each other; and the first, second, third, fourth, fifth, sixth, and seventh EBNA3A fragments are not adjacent to each other, and the above polynucleotides are also provided. Optionally, the polypeptide further comprises (a) a first fragment of ZEBRA consisting of SEQ ID NO: 22, and (b) a second fragment of ZEBRA consisting of SEQ ID NO: 23, and the first and second ZEBRA fragments are not adjacent to each other.

[0016] Also provided are the above polynucleotides wherein the EBV antigen polypeptide is at least 80% identical to SEQ ID NO: 24 or SEQ ID NO: 26.

[0017] Also provided are vectors comprising the polynucleotides described herein, including, for example, adenoviral vectors (e.g., non-human simian adenoviral vectors) and vaccinia viral vectors (e.g., modified vaccinia Ankara (MVA) vectors).

[0018] Also provided are EBV antigen polypeptides encoded by the polynucleotides and vectors described herein, for example, polypeptides that are at least 80% identical to SEQ ID NO: 24 or SEQ ID NO: 26.

[0019] Also provided are compositions comprising the polynucleotides, vectors, and polypeptides described herein, and a pharmaceutically acceptable excipient. Such compositions optionally include one or more adjuvants.

[0020] Also provided is the use of the polynucleotides, vectors, polypeptides, and compositions described herein in the manufacture of a medicament for the treatment or prevention of a disease caused by Epstein-Barr virus infection.

[0021] A method of inducing an immune response in a subject, the method comprising administering to the subject a polynucleotide, vector, polypeptide and composition described herein is also described.

[0022] A method of treating or preventing an EBV-related disease in a subject, the method comprising administering to the subject a polynucleotide, vector, polypeptide and composition described herein is also provided. Examples of EBV-related diseases include, for example, EBV-related diseases (e.g., multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus).

[0023] Also provided are polynucleotides, vectors, polypeptides and compositions described herein for use in the treatment or prevention of diseases caused by Epstein-Barr virus infection.

[0024] A method of inducing an immune response in a subject, (a) administering an adenovirus comprising a polynucleotide encoding an EBV antigen polypeptide described herein, and (b) administering a vaccinia virus comprising a polynucleotide encoding an EBV antigen polypeptide described herein comprising, A method is also provided, wherein steps (a) and (b) are performed in either order.

[0025] A method of treating or preventing an EBV-related disease in a subject, (a) administering an adenovirus comprising a polynucleotide encoding an EBV antigen polypeptide described herein, and (b) administering a vaccinia virus comprising a polynucleotide encoding an EBV antigen polypeptide described herein comprising, A method is also provided, wherein steps (a) and (b) are performed in either order. The present invention also relates to the following. [Item 1] (a) At least one fragment of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 1, (b) At least one fragment of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 6, (c) At least one fragment of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 11, and (d) At least one fragment of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 13 A polynucleotide encoding a polypeptide comprising operatively linked to one or more sequences that direct the expression of the polypeptide in a host cell. [Item 2] The polynucleotide according to item 1, wherein the polypeptide further comprises at least one fragment of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 21. [Item 3] The polypeptide is (a) at least two fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 1, (b) at least two fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 6, (c) at least two fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 11, (d) at least two fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 13, or (e) At least 2 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 21 The polynucleotide according to item 1 or 2, comprising [Item 4] Said polypeptide is (a) At least 3 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 1, (b) At least 3 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 6, (c) At least 3 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 11, (d) At least 3 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 13, or (e) At least 3 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids among SEQ ID NO: 21 The polynucleotide according to any one of items 1 to 3, comprising . [Item 5] The polypeptide is (a) At least 4 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids among SEQ ID NO: 1 (b) At least 4 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids among SEQ ID NO: 6 (c) At least 4 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids among SEQ ID NO: 11 (d) At least 4 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids among SEQ ID NO: 13, or (e) At least 4 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 21 The polynucleotide according to any one of items 1 to 4, comprising . [Item 6] Wherein the polypeptide is (a) At least 5 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 1, (b) At least 5 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 6, (c) At least 5 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 11, (d) At least 5 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 13, or (e) At least 5 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids in SEQ ID NO: 21 The polynucleotide according to any one of items 1 to 5, comprising . [Item 7] The polypeptide is (a) At least 6 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids in SEQ ID NO: 1 (b) At least 6 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids in SEQ ID NO: 6 (c) At least 6 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids in SEQ ID NO: 11 (d) At least 6 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids in SEQ ID NO: 13, or (e) At least 6 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 21 The polynucleotide according to any one of items 1 to 6, comprising [Item 8] wherein the polypeptide is (a) At least 7 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 1, (b) At least 7 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 6, (c) At least 7 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 11, (d) At least 7 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 13, or (e) At least 7 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids in SEQ ID NO: 21 The polynucleotide according to any one of items 1 to 7, comprising [Item 9] wherein the polypeptide is (a) At least 8 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids in SEQ ID NO: 1, (b) At least 8 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids in SEQ ID NO: 6, (c) At least 8 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids in SEQ ID NO: 11, (d) At least 8 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids in SEQ ID NO: 13, or (e) At least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of at least 8 fragments of SEQ ID NO: 21 The polynucleotide according to any one of items 1 to 8, comprising [Item 10] The polypeptide is (a) At least 9 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 1 (b) At least 9 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 6 (c) At least 9 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 11 (d) At least 9 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 13, or (e) At least 9 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 21 The polynucleotide according to any one of items 1 to 9, comprising . [Item 11] The polypeptide is (a) At least 10 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 1 (b) At least 10 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 6 (c) At least 10 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 11 (d) At least 10 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids in SEQ ID NO: 13, or (e) At least 10 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 21 The polynucleotide according to any one of items 1 to 10, comprising [Item 12] The polynucleotide according to any one of items 3 to 11, wherein the fragments of SEQ ID NO: 1 are not adjacent to each other. [Item 13] The polynucleotide according to any one of items 3 to 12, wherein the fragments of SEQ ID NO: 6 are not adjacent to each other. [Item 14] The polynucleotide according to any one of items 3 to 13, wherein the fragments of SEQ ID NO: 11 are not adjacent to each other. [Item 15] The polynucleotide according to any one of items 3 to 14, wherein the fragments of SEQ ID NO: 13 are not adjacent to each other. [Item 16] The polynucleotide according to any one of items 3 to 15, wherein the fragments of SEQ ID NO: 21 are not adjacent to each other. [Item 17] The polypeptide is (a) The first and second fragments of LMP1, wherein the first and second fragments of LMP1 are selected from the group consisting of SEQ ID NOs: 2 to 5, and the first and second fragments of LMP1 are not adjacent to each other in the polypeptide, the first and second fragments of LMP1 (b) The first and second fragments of LMP2, wherein the first and second fragments of LMP2 are selected from the group consisting of SEQ ID NOs: 7 to 10, and the first and second fragments of LMP2 are not adjacent to each other in the polypeptide, the first and second fragments of LMP2 (c) The fragment of EBNA1 consisting of SEQ ID NO: 12, and (d) The first and second fragments of EBNA3A, wherein the first and second fragments of EBNA3A are selected from the group consisting of SEQ ID NOs: 14 to 20, and the first and second fragments of EBNA3A are not adjacent to each other in the polypeptide, the first and second fragments of EBNA3A The polynucleotide according to any one of items 1 to 16, comprising the same. [Item 18] Wherein the polypeptide (a) The first fragment of LMP1 consisting of SEQ ID NO: 2, (b) The second fragment of LMP1 consisting of SEQ ID NO: 3, (c) The third fragment of LMP1 consisting of SEQ ID NO: 4, (d) The fourth fragment of LMP1 consisting of SEQ ID NO: 5, (e) The first fragment of LMP2 consisting of SEQ ID NO: 7, (f) The second fragment of LMP2 consisting of SEQ ID NO: 8, (g) The third fragment of LMP2 consisting of SEQ ID NO: 9, (h) The fourth fragment of LMP2 consisting of SEQ ID NO: 10, (i) The first fragment of EBNA1 consisting of SEQ ID NO: 12, (j) The first fragment of EBNA3A consisting of SEQ ID NO: 14, (k) The second fragment of EBNA3A consisting of SEQ ID NO: 15, (l) The third fragment of EBNA3A consisting of SEQ ID NO: 16, (m) The fourth fragment of EBNA3A consisting of SEQ ID NO: 17, (n) The fifth fragment of EBNA3A consisting of SEQ ID NO: 18, (o) The sixth fragment of EBNA3A consisting of SEQ ID NO: 19, and (p) The seventh fragment of EBNA3A consisting of SEQ ID NO: 20 comprising, The first, second, third, and fourth LMP1 fragments are not adjacent to each other, the first, second, third, and fourth LMP2 fragments are not adjacent to each other, and the first, second, third, fourth, fifth, sixth, and seventh EBNA3A fragments are not adjacent to each other. The polynucleotide according to any one of items 1 to 17. [Item 19] wherein the polypeptide further comprises (a) a first fragment of ZEBRA consisting of SEQ ID NO: 22, and (b) a second fragment of ZEBRA consisting of SEQ ID NO: 23 and the first and second ZEBRA fragments are not adjacent to each other, the polynucleotide according to item 17 or 18. [Item 20] wherein the polypeptide is at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 24 or SEQ ID NO: 26, the polynucleotide according to any one of items 1 to 19. [Item 21] wherein the fragment is an immunogenic fragment, the polynucleotide according to any one of items 1 to 20. [Item 22] A vector comprising the polynucleotide according to any one of items 1 to 21. [Item 23] The vector according to item 22, which is an adenovirus vector or a vaccinia virus vector. [Item 24] The vector according to item 22 or 23, which is a non-human simian adenovirus vector. [Item 25] The vector according to item 24, wherein the non-human simian adenovirus vector is a chimpanzee adenovirus vector. [Item 26] The vector according to item 22 or 23, which is a modified vaccinia Ankara vector. [Item 27] The vector according to any one of items 22 to 25, which is a ChAd155-EBV-L expression vector comprising a nucleic acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO: 50. [Item 28] The vector according to item 22 or 23, which is a modified vaccinia Ankara vector. [Item 29]The vector according to any one of items 22 to 25, which is a ChAd155-EBV-LLy expression vector comprising a nucleic acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO: 51. [Item 29] A polypeptide encoded by the polynucleotide according to any one of items 1 to 21 or the vector according to any one of items 22 to 28. [Item 30] The polypeptide according to item 29, which is at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 24 or SEQ ID NO: 26. [Item 31] An immunogenic composition comprising the polynucleotide according to any one of items 1 to 21, the vector according to any one of items 22 to 28, or the polypeptide according to item 29 or 30, and a pharmaceutically acceptable excipient. [Item 32] The immunogenic composition according to item 31, further comprising an adjuvant. [Item 33] Use of the polynucleotide according to any one of items 1 to 21, the vector according to any one of items 22 to 28, the polypeptide according to item 29 or 30, or the immunogenic composition according to item 31 or 32 in the manufacture of a medicament for the treatment or prevention of a disease caused by Epstein-Barr virus infection. [Item 34] The polynucleotide according to any one of items 1 to 21, the vector according to any one of items 22 to 28, the polypeptide according to item 29 or 30, or the immunogenic composition according to item 31 or 32 for use in the treatment or prevention of a disease caused by Epstein-Barr virus infection. [Item 35] A method for generating recombinant virus particles capable of expressing EBV antigens, the method comprising expressing the vector according to any one of items 22 to 28 in a host cell. [Item 36] A method for inducing an immune response in a subject, comprising administering to the subject a polynucleotide according to any one of Items 1 to 21, a vector according to any one of Items 22 to 28, a polypeptide according to Item 29 or 30, or an immunogenic composition according to Item 31 or 32. [Item 37] The method according to Item 36, wherein the subject is Epstein - Barr virus seronegative. [Item 38] The method according to Item 36, wherein the subject is Epstein - Barr virus seropositive. [Item 39] A method for treating or preventing an EBV - related disease in a subject, comprising administering to the subject a polynucleotide according to any one of Items 1 to 21, a vector according to any one of Items 22 to 28, a polypeptide according to Item 29 or 30, or an immunogenic composition according to Item 31 or 32. [Item 40] The method according to Item 39, wherein the EBV - related disease is an EBV - related autoimmune disease or an EBV - related malignancy. [Item 41] The method according to Item 39, wherein the EBV - related disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. [Item 42] A method for inducing an immune response in a subject, comprising (a) administering an adenovirus vector comprising a polynucleotide according to any one of Items 1 to 21, and (b) administering a vaccinia virus vector comprising a polynucleotide according to any one of Items 1 to 21 wherein steps (a) and (b) are performed in either order. [Item 43] A method for treating or preventing an EBV - related disease in a subject, comprising (a) Administering an adenovirus vector comprising the polynucleotide according to any one of items 1 to 21, and (b) Administering a vaccinia virus vector comprising the polynucleotide according to any one of items 1 to 21 comprising, a method in which steps (a) and (b) are performed in either order. [Item 44] The method according to item 42 or 43, wherein step (b) is performed 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks or more weeks after step (a).

Brief Description of the Drawings

[0026]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Mode for Carrying Out the Invention

[0027] Sequence Description SEQ ID NO: 1 EBV LMP1 protein (Genbank number P03230) SEQ ID NO: 2 Immunogenic fragment of EBV LMP1 protein SEQ ID NO: 3 Immunogenic fragment of EBV LMP1 protein SEQ ID NO: 4 Immunogenic fragment of EBV LMP1 protein SEQ ID NO: 5 Immunogenic fragment of EBV LMP1 protein SEQ ID NO: 6 EBV LMP2 protein (Genbank number P13285) SEQ ID NO: 7 Immunogenic fragment of EBV LMP2 protein SEQ ID NO: 8 Immunogenic fragment of EBV LMP2 protein SEQ ID NO: 9 Immunogenic fragment of EBV LMP2 protein Immunogenic fragment of EBV LMP2 protein with accession number 10 EBV EBNA1 protein with accession number 11 (Genbank number P03211) Immunogenic fragment of EBV EBNA1 protein with accession number 12 EBV EBNA3A protein with accession number 13 (Genbank number YP401669) Immunogenic fragment of EBV EBNA3A protein with accession number 14 Immunogenic fragment of EBV EBNA3A protein with accession number 15 Immunogenic fragment of EBV EBNA3A protein with accession number 16 Immunogenic fragment of EBV EBNA3A protein with accession number 17 Immunogenic fragment of EBV EBNA3A protein with accession number 18 Immunogenic fragment of EBV EBNA3A protein with accession number 19 Immunogenic fragment of EBV EBNA3A protein with accession number 20 EBV ZEBRA protein with accession number 21 (Genbank number P03206) Immunogenic fragment of EBV ZEBRA protein with accession number 22 Immunogenic fragment of EBV ZEBRA protein with accession number 23 EBV-L antigen polypeptide with accession number 24 DNA encoding EBV-L antigen polypeptide with accession number 25 EBV-LLy antigen polypeptide with accession number 26 DNA encoding EBV-LLy antigen polypeptide with accession number 27 CalHV3 C1 protein with accession number 28 (Genbank number NP_733852) Immunogenic fragment of CalHV3 C1 protein with accession number 29 Immunogenic fragment of CalHV3 C1 protein with accession number 30 Immunogenic fragment of CalHV3 C1 protein with accession number 31 CalHV3 C7 protein with accession number 32 (Genbank number NP_733851) Immunogenic fragment of the array number 33 CalHV3 C7 protein Immunogenic fragment of the array number 34 CalHV3 C7 protein Immunogenic fragment of the array number 35 CalHV3 C7 protein Array number 36 CalHV3 ORF39 (Genbank number NP_733892) Immunogenic fragment of the array number 37 CalHV3 ORF39 Immunogenic fragment of the array number 38 CalHV3 ORF39 Immunogenic fragment of the array number 39 CalHV3 ORF39 Array number 40 CalHv3 ORF43 protein (Genbank number NP_733896) Immunogenic fragment of the array number 41 CalHv3 ORF43 protein Immunogenic fragment of the array number 42 CalHv3 ORF43 protein Array number 43 Marmoset invariant chain polypeptide Array number 44 CalHv3_L antigen polypeptide DNA encoding the array number 45 CalHV3_L antigen polypeptide Array number 46 CalHV3_LLy antigen polypeptide DNA encoding the array number 47 CalHV3_LLy antigen polypeptide Array number 48 Ii_CalHV3_LLy antigen polypeptide DNA encoding the array number 49 Ii_CalHV3_LLy antigen polypeptide Array number 50 pChAd155 (ΔE1, ΔE4_Ad5E4 orf6) TetO hCMV-EBV-L expression vector Array number 51 pChAd155 (ΔE1, ΔE3, ΔE4_Ad5E4 orf6) TetO hCMV-EBV-LLy expression vector Array number 52 pChAd155 (ΔE1, ΔE4_Ad5E4 orf6) TetO hCMV-CalHV3-L expression vector Array number 53 pChAd155(ΔE1, ΔE3, ΔE4_Ad5E4 orf6) TetO hCMV-CalHV3-LLy expression vector Array number 54 pChAd155(ΔE1, ΔE3, ΔE4_Ad5E4 orf6) TetO hCMV-mli-CalHV3-LLy expression vector

[0028] Detailed description of the invention Epstein-Barr virus antigen polypeptide The EBV antigen polypeptide of the present invention includes a polypeptide containing one or more immunogenic fragments of EBV latent and / or lytic proteins. Examples of EBV latent proteins include Latent Membrane Proteins (LMP1 and LMP2); and EBV Nuclear Antigens (EBNA1, EBNA2, EBNA3A, EBNA3B, and EBNA3C). Examples of EBV lytic proteins include, for example, ZEBRA (encoded by the BZLF1 gene).

[0029] An "immunogenic fragment" of an EBV protein, as used herein, means a fragment that is smaller than the full-length EBV protein and is capable of inducing an immune response, e.g., a humoral (e.g., antibody) and / or cell-mediated (e.g., cytotoxic T cell) response. Immunogenic fragments include fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, and at least 100 amino acids of the full-length protein. In some embodiments, the immunogenic fragment consists of about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, and about 100 amino acids of the full-length protein. One aspect of the invention is to provide an EBV antigen polypeptide capable of inducing a T cell response against B cells having latent EBV infection. Thus, in some embodiments, an immunogenic fragment of an EBV protein contains one or more T cell epitopes capable of inducing an antigen-specific T cell response.

[0030] The immunogenic fragment may have one or more substitutions, deletions, or insertions relative to the full-length protein from which the fragment is derived. Thus, immunogenic fragments include fragments that are at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the corresponding region of the full-length protein.

[0031] In one embodiment, the EBV antigen polypeptide of the present invention includes the Latent Membrane Protein 1 (LMP1) antigen. LMP1 is a 386 - amino acid protein that is expressed during the latent stage of the viral life cycle of EBV. Immunogenic fragments of LMP1 suitable for use in the EBV antigen polypeptide of the present invention include fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, and at least 100 amino acids of SEQ ID NO: 1. In some embodiments, the immunogenic fragment of LMP1 consists of about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, and about 100 amino acids of SEQ ID NO: 1. In some embodiments, the immunogenic fragment of LMP1 includes fragments that are at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the corresponding region of SEQ ID NO: 1.

[0032] In some embodiments, the immunogenic fragment of LMP1 includes one or more T - cell epitopes. In a preferred embodiment, the immunogenic epitopes of LMP1 include, but are not limited to, fragments that are at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NOs: 2 - 5.

[0033] In some embodiments, the EBV antigen polypeptide of the present invention comprises a Latent Membrane Protein 2 (LMP2) antigen. LMP2 is a 497 - amino acid protein that is expressed during the latent stage of the viral life cycle of EBV. Immunogenic fragments of LMP2 suitable for use in the EBV antigen polypeptides of the present invention include fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 and at least 100 amino acids of SEQ ID NO: 6. In some embodiments, the immunogenic fragment of LMP2 consists of about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90 and about 100 amino acids of SEQ ID NO: 6. In some embodiments, the immunogenic fragment of LMP2 includes fragments that are at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to the corresponding region of SEQ ID NO: 6.

[0034] In some embodiments, the immunogenic fragment of LMP2 comprises one or more T - cell epitopes. In a preferred embodiment, the immunogenic epitopes of LMP2 include, but are not limited to, SEQ ID NOs: 7 - 10, and fragments that are at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to SEQ ID NOs: 7 - 10.

[0035] In one embodiment, the EBV antigen polypeptide of the present invention comprises Epstein-Barr Nuclear Antigen 1 (EBNA1) antigen. EBNA1 is a 641-amino acid protein that is expressed during the latent stage of the viral life cycle of EBV. Immunogenic fragments of EBNA1 suitable for use in the EBV antigen polypeptide of the present invention include fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, and at least 100 amino acids of SEQ ID NO: 11. In some embodiments, the immunogenic fragment of EBNA1 consists of about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, and about 100 amino acids of SEQ ID NO: 11. In some embodiments, the immunogenic fragment of EBNA1 includes a fragment that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the corresponding region of SEQ ID NO: 11.

[0036] In some embodiments, the immunogenic fragment of EBNA1 includes one or more T cell epitopes. In a preferred embodiment, the immunogenic epitopes of EBNA1 include, but are not limited to, SEQ ID NO: 12, and fragments that are at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 12.

[0037] In one embodiment, the EBV antigen polypeptide of the present invention comprises Epstein-Barr Nuclear Antigen 3A (EBNA3A) antigen. EBNA3A is a 944-amino acid protein expressed during the latent stage of the viral life cycle of EBV. Immunogenic fragments of EBNA3A suitable for use in the EBV antigen polypeptide of the present invention include fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 and at least 100 amino acids of SEQ ID NO: 13. In some embodiments, the immunogenic fragment of EBNA3A consists of about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90 and about 100 amino acids of SEQ ID NO: 13. In some embodiments, the immunogenic fragment of EBNA3A includes fragments that are at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to the corresponding region of SEQ ID NO: 13.

[0038] In some embodiments, the immunogenic fragment of EBNA3A comprises one or more T cell epitopes. In preferred embodiments, the immunogenic epitopes of EBNA3A include, but are not limited to, SEQ ID NOs: 14-20, and fragments that are at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to SEQ ID NOs: 14-20.

[0039] In one embodiment, the EBV antigen polypeptide of the present invention comprises the ZEBRA antigen. ZEBRA is a 245 - amino acid protein that is expressed during the lytic phase of the EBV viral life cycle. Immunogenic fragments of ZEBRA suitable for use in the EBV antigen polypeptides of the present invention include fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, and at least 100 amino acids of SEQ ID NO: 21. In some embodiments, the immunogenic fragment of ZEBRA consists of about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, and about 100 amino acids of SEQ ID NO: 21. In some embodiments, the immunogenic fragment of ZEBRA includes fragments that are at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the corresponding region of SEQ ID NO: 21.

[0040] In some embodiments, the immunogenic fragment of ZEBRA includes one or more T - cell epitopes. In preferred embodiments, the immunogenic epitopes of ZEBRA include, but are not limited to, SEQ ID NOs: 22 - 23, and fragments that are at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NOs: 22 - 23.

[0041] In some embodiments, the EBV antigen polypeptide is a multivalent EBV antigen polypeptide. By "multivalent", polypeptides containing immunogenic fragments of 2, 3, 4, 5, or more EBV proteins are intended. By "fragment", fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of the full - length protein are intended.

[0042] Thus, in one embodiment, (a) at least one fragment of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 1, (b) at least one fragment of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 6, (c) at least one fragment of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 11, and (d) at least one fragment of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 13 A polypeptide is provided that comprises

[0043] Optionally, the polypeptide further comprises at least one fragment of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 21.

[0044] In some embodiments, the multivalent EBV antigen polypeptide comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 fragments of one or more EBV proteins. Thus, in one embodiment, the multivalent EBV antigen is (a) at least 2 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 1, (b) at least 2 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 6, (c) at least 2 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 11, (d) at least 2 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 13, or (e) at least 2 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 21 and is a polypeptide comprising the same.

[0045] In one embodiment, the multivalent EBV antigen is (a) at least 3 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 1, (b) at least 3 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 6, (c) at least 3 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 11, (d) At least 3 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 13, or (e) At least 3 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 21 is a polypeptide comprising

[0046] In one embodiment, the multivalent EBV antigen is (a) At least 4 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 1, (b) At least 4 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 6, (c) At least 4 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids of SEQ ID NO: 11, (d) at least 4 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 13, or (e) at least 4 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 21 is a polypeptide comprising the same.

[0047] In one embodiment, the multivalent EBV antigen is (a) at least 5 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 1, (b) at least 5 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 6, (c) at least 5 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 11, (d) at least 5 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 13, or (e) at least 5 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 21 is a polypeptide comprising

[0048] In one embodiment, the multivalent EBV antigen is (a) at least 6 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 1, (b) at least 6 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 6, (c) at least 6 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 11, (d) at least 6 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 13, or (e) at least 6 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 21 which is a polypeptide comprising

[0049] In one embodiment, the multivalent EBV antigen is (a) at least 7 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 1, (b) at least 7 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 6, (c) at least 7 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 11, (d) at least 7 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 13, or (e) at least 7 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 21 which is a polypeptide comprising:

[0050] In one embodiment, the multivalent EBV antigen is (a) at least 8 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 1, (b) at least 8 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 6, (c) at least 8 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 11, (d) at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of at least 8 fragments, or (e) at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of at least 8 fragments of SEQ ID NO: 21 a polypeptide comprising

[0051] In one embodiment, the multivalent EBV antigen is (a) at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of at least 9 fragments of SEQ ID NO: 1, (b) at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of at least 9 fragments of SEQ ID NO: 6, (c) at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of at least 9 fragments of SEQ ID NO: 11, (d) at least 9 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 13, or (e) at least 9 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 21 and is a polypeptide comprising the same.

[0052] In one embodiment, the multivalent EBV antigen is (a) at least 10 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 1, (b) at least 10 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 6, (c) at least 10 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 11, (d) at least 10 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 13, or (e) at least 10 fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids of SEQ ID NO: 21 A polypeptide comprising the same.

[0053] In some embodiments, the multivalent EBV antigen polypeptide comprises at least two immunogenic fragments derived from the same EBV protein, and the at least two immunogenic fragments are not adjacent to each other in the multivalent EBV antigen polypeptide. By "not adjacent" it is intended to mean that the at least two immunogenic fragments do not form a contiguous amino acid sequence in the EBV antigen polypeptide. The non - adjacent immunogenic fragments are separated from each other by at least 1, 2, 3, 4, 5, 10 or more amino acids that are not derived from the same EBV protein as the immunogenic fragments.

[0054] For example, in one embodiment, the multivalent EBV antigen polypeptide comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 fragments of LMP1 (SEQ ID NO: 1), and the fragments of LMP1 are not adjacent to each other.

[0055] In another embodiment, the multivalent EBV antigen polypeptide comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 fragments of LMP2 (SEQ ID NO: 6), and the fragments of LMP2 are not adjacent to each other.

[0056] In another embodiment, the multivalent EBV antigen polypeptide comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 fragments of EBNA1 (SEQ ID NO: 11), and the fragments of EBNA1 are not adjacent to each other.

[0057] In another embodiment, the multivalent EBV antigen polypeptide comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 fragments of EBNA3A (SEQ ID NO: 13), and the fragments of EBNA3A are not adjacent to each other.

[0058] In another embodiment, the multivalent EBV antigen polypeptide comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 fragments of ZEBRA (SEQ ID NO: 21), and the fragments of ZEBRA are not adjacent to each other.

[0059] In one embodiment, the multivalent EBV antigen polypeptide is (a) the first and second fragments of LMP1, wherein the first and second fragments of LMP1 are selected from the group consisting of SEQ ID NOs: 2-5, and the first and second fragments of LMP1 are not adjacent to each other in the polypeptide, the first and second fragments of LMP1, (b) the first and second fragments of LMP2, wherein the first and second fragments of LMP1 are selected from the group consisting of SEQ ID NOs: 7-10, and the first and second fragments of LMP2 are not adjacent to each other in the polypeptide, the first and second fragments of LMP2, (c) the fragment of EBNA1 consisting of SEQ ID NO: 12, and (d) The first and second fragments of EBNA3A, wherein the first and second fragments of EBNA3A are selected from the group consisting of SEQ ID NOs: 14 to 20, and the first and second fragments of EBNA3A are not adjacent to each other in the polypeptide, the first and second fragments of EBNA3A comprises.

[0060] Optionally, the multivalent EBV antigen (a) The first fragment of ZEBRA consisting of SEQ ID NO: 22, and (b) The second fragment of ZEBRA consisting of SEQ ID NO: 23 further comprises, The first and second ZEBRA fragments are not adjacent to each other.

[0061] In one embodiment, the multivalent EBV antigen polypeptide (a) The first fragment of LMP1 consisting of SEQ ID NO: 2, (b) The second fragment of LMP1 consisting of SEQ ID NO: 3, (c) The third fragment of LMP1 consisting of SEQ ID NO: 4, (d) The fourth fragment of LMP1 consisting of SEQ ID NO: 5, (e) The first fragment of LMP2 consisting of SEQ ID NO: 7, (f) The second fragment of LMP2 consisting of SEQ ID NO: 8, (g) The third fragment of LMP2 consisting of SEQ ID NO: 9, (h) The fourth fragment of LMP2 consisting of SEQ ID NO: 10, (i) The first fragment of EBNA1 consisting of SEQ ID NO: 12, (j) The first fragment of EBNA3A consisting of SEQ ID NO: 14, (k) The second fragment of EBNA3A consisting of SEQ ID NO: 15, (l) The third fragment of EBNA3A consisting of SEQ ID NO: 16, (m) The fourth fragment of EBNA3A consisting of SEQ ID NO: 17, (n) The fifth fragment of EBNA3A consisting of SEQ ID NO: 18, (o) The sixth fragment of EBNA3A consisting of SEQ ID NO: 19, and (p) The 7th fragment of EBNA3A consisting of SEQ ID NO: 20 comprising the 1st, 2nd, 3rd, and 4th LMP1 fragments are not adjacent to each other, the 1st, 2nd, 3rd, and 4th LMP2 fragments are not adjacent to each other, and the 1st, 2nd, 3rd, 4th, 5th, 6th, and 7th EBNA3A fragments are not adjacent to each other. Optionally, the multivalent EBV antigen (a) the 1st fragment of ZEBRA consisting of SEQ ID NO: 22, and (b) the 2nd fragment of ZEBRA consisting of SEQ ID NO: 23 further comprises the 1st and 2nd ZEBRA fragments are not adjacent to each other.

[0062] To facilitate a clear description of the polypeptides and polynucleotides described herein, certain sequence components are referred to as the "1st" polypeptide or polynucleotide sequence, the "2nd" polypeptide or polynucleotide sequence, etc. It should be understood that the 1st, 2nd, etc. sequences can occur in any desired order or orientation, and no particular order or orientation is intended by the terms "1st", "2nd", etc.

[0063] In some embodiments, the multivalent EBV antigen does not contain junction neoepitopes that map to human (i.e., self) proteins. An immunogenic junction neoepitope is an epitope that elicits an immune response against the junction of two heterologous protein sequences, and the epitope is not present in any of the heterologous protein sequences themselves. The T cell response to the junction neoepitope can be identified using methods known in the art, such as an immunological assay using a peptide pool that covers all the junctions used, as described in Example 4.

[0064] In one embodiment, the multivalent EBV antigen is the "EBV-L" construct shown in FIG. 2A. In another embodiment, the multivalent EBV antigen polypeptide is a polypeptide that is at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 24.

[0065] In another embodiment, the multivalent EBV antigen is the "EBV-LLy" construct shown in FIG. 2B. In another embodiment, the multivalent EBV antigen polypeptide is a polypeptide that is at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 26.

[0066] In a preferred embodiment, the EBV antigen polypeptide of the present invention contains at least one amino acid insertion, deletion and / or substitution as compared to the wild-type EBV protein.

[0067] In another embodiment, the EBV antigen polypeptide is a polypeptide encoded by the polynucleotide described herein.

[0068] Polynucleotide Also provided are polynucleotides and expression cassettes encoding the EBV antigen polypeptides of the present invention. By "expression cassette" is meant a combination of a selected heterologous gene (the "transgene" encoding the EBV antigen polypeptide) and other regulatory elements necessary to drive the translation, transcription and / or expression of the gene product in a host cell.

[0069] The present invention provides a polynucleotide encoding the EBV antigen polypeptide of the present invention.

[0070] In one embodiment, a polynucleotide encoding a polypeptide that is at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 24 is provided. In one embodiment, the polynucleotide is at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 25.

[0071] In one embodiment, a polynucleotide encoding a polypeptide that is at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 26 is provided. In one embodiment, the polynucleotide is at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 27.

[0072] Preferably, the polynucleotide of the present invention is a recombinant. A recombinant means that the polynucleotide is a product of at least one of cloning, restriction, recombination or ligation steps, or other procedures that result in a polynucleotide different from the polynucleotide found in nature. A recombinant virus is a virus containing a recombinant polynucleotide. A recombinant vector is a vector containing a recombinant polynucleotide. A recombinant virus includes the progeny of the original recombinant virus. "Recombinant vector" includes replicas of the original recombinant vector. "Recombinant polynucleotide" includes replicas of the original recombinant polynucleotide. The recombinant polynucleotide of the present invention contains at least one nucleic acid substitution as compared to the wild-type EBV genome.

[0073] In some embodiments, the polynucleotide encoding the EBV antigen of the present invention is operably linked to one or more regulatory elements in a manner that enables its transcription, translation, and / or expression in cells transfected with or infected by the polynucleotide. As used herein, an "operably linked" sequence includes both an expression control sequence contiguous with the gene of interest and an expression control sequence that acts in trans or at a distance to control the gene of interest. Thus, in one embodiment, the polynucleotide is operably linked to one or more sequences that direct the expression of the polypeptide in a host cell. In some embodiments, the expression control sequence is heterologous to the polynucleotide encoding the EBV antigen.

[0074] Expression control sequences include appropriate transcription start, termination, promoter, and enhancer sequences; efficient RNA processing signals, such as splicing and polyadenylation (poly A) signals including rabbit beta-globin polyA; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (e.g., Kozak consensus sequences); sequences that enhance protein stability; and, if desired, sequences that enhance the secretion of the encoded product. Among other sequences, chimeric introns may be used.

[0075] A "promoter" is a nucleotide sequence that enables the binding of RNA polymerase and directs the transcription of a gene. Typically, a promoter is located in the 5' non-coding region of a gene, proximal to the transcription start site of the gene. The sequence elements within a promoter that function in transcription initiation often feature consensus nucleotide sequences. Examples of promoters include, but are not limited to, promoters from bacteria, yeast, plants, viruses, and mammals (including humans). A wide variety of expression control sequences, including internal promoters, heterologous promoters, natural promoters, constitutive promoters, inducible and / or tissue-specific promoters, are known in the art and can be utilized.

[0076] In some embodiments, the polynucleotide is operably linked to a heterologous expression control sequence, such as a promoter. Typically, "heterologous" means derived from an entity that has a different genotype from that of the remainder of the entity being compared. A heterologous nucleic acid sequence refers to any nucleic acid sequence that is not isolated from, not derived from, or not based on the naturally occurring nucleic acid sequences of an adenoviral vector.

[0077] Examples of constitutive promoters include, but are not limited to, the TBG promoter, the Rous sarcoma virus LTR promoter of retroviruses (optionally including an enhancer), the cytomegalovirus (CMV) promoter (optionally including the CMV enhancer, see, for example, Boshart et al., Cell, 41: 521-530 (1985)), the CASI promoter (WO2012 / 115980), the SV40 promoter, the dihydrofolate reductase promoter, the β-actin promoter, the phosphoglycerol kinase (PGK) promoter, and the EF1a promoter (Invitrogen).

[0078] Inducible promoters enable the regulation of gene expression and can be regulated by exogenously supplied compounds, environmental factors such as temperature, or the presence of a specific physiological state (e.g., acute phase, a specific differentiation state of cells, or only in replicating cells). Inducible promoters and induction systems are available from a variety of commercial sources including, but not limited to, Invitrogen, Clontech, and Ariad. Many other systems have been described and can be readily selected by those skilled in the art. For example, inducible promoters include the zinc-inducible sheep metallothionein (MT) promoter and the dexamethasone (Dex)-inducible mouse mammary tumor virus (MMTV) promoter. Other induction systems include the T7 polymerase promoter system; the ecdysone insect promoter, the tetracycline repression system, and the tetracycline induction system. Other systems include the FK506 dimer, VP16 or p65 using castradiol, diphenol murislerone, the RU486 induction system, and the rapamycin induction system. The effectiveness of some inducible promoters increases over time. In such cases, the effectiveness of such systems can be improved by inserting multiple repressors in tandem (e.g., TetR linked to TetR by an IRES).

[0079] In another embodiment, a native EBV promoter may be used. A native promoter may be preferred if it is desirable for the expression of the transgene to mimic native expression. A native promoter can be used when the expression of the transgene must be regulated temporally (transiently) or developmentally (ontogenetically), or tissue-specifically, or in response to a specific transcriptional stimulus. In a further embodiment, other native expression control elements such as enhancer elements, polyadenylation sites, or Kozak consensus sequences can also be used to mimic native expression.

[0080] The introduced gene may be operably linked to a tissue-specific promoter. For example, if expression in skeletal muscle is desired, a promoter active in muscle should be used. These include promoters derived from genes encoding skeletal β-actin, myosin light chain 2A, dystrophin, muscle creatine kinase, and synthetic (artificial) muscle promoters having higher activity than naturally occurring promoters. Examples of tissue-specific promoters include, among others, liver; hepatitis B virus core; alpha-fetoprotein, bone osteocalcin; bone sialoprotein, lymphocytes, immunoglobulin heavy chain; T cell receptor chain), neuron promoters, for example, the neuron-specific enolase (NSE) promoter, the neurofilament light chain gene, and the neuron-specific vgf gene are known.

[0081] Vector Also provided are vectors containing polynucleotides encoding the EBV antigen constructs described herein. Such vectors are suitable for delivery to host cells and expression in host cells. The vector can be in the form of a replicating vector or a replication-deficient vector, for example, a viral vector. Numerous viral vectors are known in the art that are suitable for introducing immunogenic nucleic acids into a subject, including both DNA viruses and RNA viruses. Examples of vectors suitable for encoding the EBV antigens described herein include the following: adenoviral vectors (replicating or replication-deficient), poxviral vectors (including vaccinia virus vectors, for example, modified vaccinia Ankara virus (MVA), NYVAC, avipox vectors, canarypox (ALVAC), and fowlpox virus (FPV)), alphavirus vectors (e.g., Sindbis virus, Semliki Forest virus (SFV), Ross River virus, and Venezuelan equine encephalitis (VEE) virus) and their chimeras and replicons, herpesvirus vectors (e.g., vectors derived from cytomegalovirus (CMV)), arenavirus vectors, e.g., lymphocytic choriomeningitis virus (LCMV) vectors, measles virus vectors, vesicular stomatitis virus vectors, pseudorabies virus, adeno-associated virus, retroviruses, lentiviruses, virus-like particles, and many others.

[0082] In one embodiment, the vector is an adenovirus. The generation and use of adenoviral vectors are well known to those skilled in the art. In the context of the immunogenic combinations disclosed herein, exemplary disclosures of the design, generation, and use of adenoviral vectors expressing vaccine antigens can be found, for example, in U.S. Patent Application Publication No. US2014 / 0141042 (WO2012 / 089833), U.S. Patent No. 8,216,834 (WO2005 / 071093), U.S. Patent Application Publication No. US2012 / 0027788 (WO2010 / 086189), and U.S. Patent Application Publication No. US2005 / 0214323.

[0083] Typically, an adenovirus vector is designed such that the expression cassette is located in a nucleic acid molecule that contains other adenovirus sequences within a region native to the selected adenovirus gene. The expression cassette can be inserted, if desired, into an existing gene region so as to disrupt the function of that region. Alternatively, the expression cassette can be inserted into a site of an adenovirus gene that is partially or completely deleted. For example, the expression cassette may be located at a site of a mutation, insertion, or deletion that inactivates at least one gene of a genomic region selected from the group consisting of E1A, E1B, E2A, E2B, E3, and E4. The term "inactivate" means that a sufficient amount of the gene region is removed or otherwise disrupted such that the gene region can no longer produce a functional product of gene expression. If desired, the entire gene region can be removed (preferably replaced with the expression cassette). Preferably, the E1 gene of the adenovirus is deleted and replaced with an expression cassette consisting of a selected promoter, the cDNA sequence of the gene of interest, and a polyA signal, resulting in a replication-deficient recombinant virus.

[0084] The adenovirus vectors used in the present invention may be derived from a range of mammalian hosts. Over 100 different serotypes of adenoviruses that infect various mammalian species have been isolated, 51 of which are of human origin. Thus, one or more of the adenovirus vectors can be derived from human adenoviruses. Examples of such human-derived adenoviruses are Ad1, Ad2, Ad4, Ad5, Ad6, Ad11, Ad24, Ad26, Ad34, Ad35, Ad48, particularly Ad5, Ad11, and Ad35. Human and non-human adenovirus serotypes are classified into six subfamilies (A - F) based on several biological, chemical, immunological, and structural criteria.

[0085] Ad5-based vectors are widely used in several gene therapy trials, but the use of Ad5 and other human group C adenoviral vectors may be limited because the general population already has immunity from natural infection. Ad5 and other human group C members tend to be included in the most seroprevalent serotypes. Immunity to the existing vectors can occur as a result of exposure to the vectors during treatment. These types of existing or developed immunity to seroprevalent vectors can limit the effectiveness of gene therapy or vaccination efforts. Thus, alternative adenoviral serotypes constitute extremely important targets in the pursuit of gene delivery systems that can avoid the host immune response.

[0086] One area of such alternative serotypes is adenoviruses isolated from non-human primates, particularly chimpanzees, bonobos, and gorillas. See U.S. Patent No. 6,083,716, which describes the genomes of two chimpanzee adenoviruses.

[0087] Non-human simian adenoviral vectors have been shown to induce a strong immune response to transgene products as efficiently as human adenoviral vectors (Fitzgerald et al. (2003) J. Immunol. 170:1416; Colloca et al. (2012) Science Translational Medicine 4:1-9; Roy et al. (2004) Virology 324:361-372; Roy et al. (2010) J. of Gene Medicine 13:17-25).

[0088] Non-human simian adenoviruses can be isolated from the mesenteric lymph nodes or feces of animals and can replicate in vitro in HEK 293 cells. Despite these similarities, non-human simian adenoviruses are phylogenetically and immunologically distinct from the more common human serotypes (Ad2 and Ad5).

[0089] Thus, in one embodiment, one or more of the adenovirus vectors may be derived from a non-human primate adenovirus, such as a chimpanzee adenovirus, such as serotypes ChAd3, ChAd63, ChAd83, ChAd155, Pan5, Pan6, Pan7 (also designated C7), and Pan9. Specifically, the virus may be a non-human adenovirus, such as a simian adenovirus, particularly a chimpanzee adenovirus, such as ChAd155, Pan 5, 6, 7, or 9. Examples of such strains are described in US20040241181 (WO03 / 000283) and are available from the American Type Culture Collection (10801 University Boulevard, Manassas, Va. 20110 - 2209) and other sources. Desirable chimpanzee adenovirus strains include Pan 5 [ATCC VR-591], Pan 6 [ATCC VR-592], and Pan 7 [ATCC VR-593]. Alternatively, the adenovirus vector may be derived from a non-human simian adenovirus, bonobo-derived, such as PanAd1, PanAd2, or PanAd3. Examples of such vectors described herein can be found, for example, in US20110217332 (WO2005 / 071093), US2012 / 0027788 (WO2010 / 086189), and WO2016 / 198621.

[0090] The use of non-human simian adenoviruses is considered more advantageous than the use of human adenovirus serotypes because the existing immunity to adenoviruses in the target population is low and infrequent, particularly the lack of cross-neutralizing antibodies. The cross-reaction between chimpanzee adenoviruses and the existing neutralizing antibody response is present in only 2% of the target population compared to 35% in the case of certain candidate human adenovirus vectors. Pan 6 has a lower relatedness to Pan 5, 7, and 9.

[0091] The adenovirus of the present invention can be replication - defective. This means that it has a reduced ability to replicate in non - complementing cells compared to the wild - type virus. This can be brought about by mutating the virus, for example, by deleting genes involved in replication, such as by deleting the E1a, E1b, E3, or E4 genes.

[0092] The adenovirus vector according to the present invention can be derived from a replication - defective adenovirus containing a functional E1 deletion. Thus, the adenovirus vector according to the present invention can be replication - defective because it lacks the ability to express adenovirus E1a and E1b, that is, because E1a and E1b are functionally deleted. Recombinant adenoviruses may also have functional deletions in other genes [see, for example, US20040241181 (WO03 / 000283)], for example, they may have deletions in the E3 or E4 genes. The adenovirus delayed - early gene E3 can be excluded from the adenovirus sequence that forms part of the recombinant virus. The function of E3 is not necessary for the production of recombinant adenovirus particles. Thus, there is no need to replace the function of this gene product to package the recombinant adenovirus useful in the present invention. In a particular embodiment, the recombinant adenovirus has functionally deleted E1 and E3 genes. The construction of such vectors is described in Roy et al., (2004) Human Gene Therapy 15: 519 - 530.

[0093] Recombinant adenoviruses may also desirably retain the E4 ORF6 function, but can be constructed to have a functional deletion of the E4 gene. The adenovirus vector according to the present invention may also contain a deletion in the delayed - early gene E2a. The deletion can also be made in any of the late genes L1 - L5 of the adenovirus genome. Similarly, deletions in the intermediate genes IX and IVa may also be useful.

[0094] Other deletions may be made in other structural or non-structural genes of the adenovirus. The above deletions can be used individually, i.e., the adenovirus sequence for use in the present invention may contain only the E1 deletion. Alternatively, deletions of all or part of a gene effective to disrupt biological activity may be used in any combination. For example, in one exemplary vector, the adenovirus sequence may have a deletion of the E1 gene and the E4 gene, or a deletion of the E1, E2a and E3 genes, or a deletion of the E1 and E3 genes (e.g., a functional deletion of E1a and E1b, and at least a partial deletion of E3), or a deletion of the E1, E2a and E4 genes with or without a deletion of E3, etc. Such deletions may be partial or complete deletions of these genes and may be used in combination with other mutations, such as temperature-sensitive mutations, to achieve the desired result. Examples of adenovirus vectors for use in the present invention include PanAd3 (WO2010 / 086189) and ChAd155 (WO2016 / 198621).

[0095] In another embodiment, the viral vector is a poxvirus vector. In a specific embodiment, the poxvirus vector is a vaccinia virus vector, e.g., a modified vaccinia Ankara virus (MVA) vector. The (MVA) vector is replication-deficient in humans and other mammals. It was first developed to improve the safety of smallpox vaccination by more than 570 passages of vaccinia virus in chicken embryo fibroblast (CEF) cells, resulting in multiple, fully characterized deletions, after which the virus was highly attenuated and replication-deficient in humans and other mammals. Replication deficiency occurs late in virion assembly, such that virus and recombinant gene expression are not impaired and MVA becomes an effective single-round expression vector that cannot cause infection in mammals.

[0096] Subsequently, MVA has been widely used as a viral vector that induces antigen-specific immunity against transgenes in both animal models and humans. Descriptions of MVA can be found in Mayr A et al., "The smallpox vaccination strain MVA: marker, genetic structure, experience gained with the parenteral vaccination and behavior in organisms with a debilitated defense mechanism.", "Abstammung, Eigenschaften und Verwendung des attenuierten Vaccinia-Stammes MVA.", Zentralbl Bakteriol B. 1978 Dec;167(5-6):375-90 and Mayr, A., Hochstein-Mintzel, V. & Stickl, H. (1975). Infection 3, 6-14.

[0097] In one embodiment, MVA is derived from the viral seed batch 460MG obtained from the 571st passage of vaccinia virus in CEF cells. In a further embodiment, MVA is derived or produced prior to December 31, 1978 and is free of prion contamination.

[0098] MVA vectors and methods for generating such vectors are described, for example, in U.S. Patent No. 6,761,893 (WO02 / 042480); U.S. Patent No. 7,964,395; U.S. Patent No. 7,964,396; U.S. Patent Application Publication No. US2013 / 0183335 (WO2012 / 048817); and U.S. Patent Application Publication No. 2015 / 0209421 (WO2014 / 019718). Each of the foregoing is incorporated herein by reference to teach suitable MVA vectors and methods.

[0099] In another embodiment, the viral vector is an alphavirus vector, e.g., an alphavirus replicon or other self-replicating RNA vector. Exemplary alphavirus vectors and methods for their production and delivery suitable for use in the context of the immunogenic combinations disclosed herein are described, for example, in US20090104226 (WO2006078294); US20110300205 (WO2011005799); US20130195968 (WO2012 / 006376); US20130177639 (WO2012006377); WO2013006838; and WO2013006842, each of which is incorporated herein by reference for the disclosure of exemplary self-replicating RNA vectors suitable in the context of the disclosed immunogenic combinations.

[0100] Also provided is a method of generating recombinant virus particles expressing the EBV antigens of the invention, the method comprising expressing the vectors described herein in a host cell. The virus particles can be generated in any suitable cell line in which the viral vector is capable of replicating.

[0101] Adenoviral vectors can be produced in any suitable cell line in which the virus is capable of replicating. In particular, complementing cell lines that supply factors (e.g., E1 and / or E4) that are missing from the viral vector and that result in a loss of replication properties can be used. Without limitation, such cell lines can be, inter alia, HeLa [ATCC accession number CCL 2], A549 [ATCC accession number CCL 185], HEK 293, KB [CCL 17], Detroit [e.g., Detroit 510, CCL 72] and WI-38 [CCL 75] cells. These cell lines are all available from the American Type Culture Collection, 10801 University Boulevard, Manassas, Va. 20110 - pages 2209. Other suitable parental cell lines can be obtained from other sources, e.g., PER.C6 cells represented by cells deposited with the European Collection of Animal Cell Cultures (ECACC) of the Centre for Applied Microbiology and Research (CAMR, UK) with ECACC number 96022940, or from Her 96 cells (Crucell).

[0102] Particularly suitable complementing cell lines are the Procell92 cell lines. The Procell92 cell line is based on HEK293 cells transfected with a Tet repressor under the control of the human phosphoglycerate kinase-1 (PGK) promoter and a G418 resistance gene and expressing the adenoviral E1 gene (Vitelli et al. PLOS One (2013) 8(e55435): 1 - 9). Procell92.S is also adapted for growth under suspension conditions and is useful for generating adenoviral vectors expressing toxic proteins (www.okairos.com / e / inners.php?m = 00084, last access date April 13, 2015).

[0103] Vaccinia vectors can be generated according to methods described in the art. For example, the preparation and use of MVA vectors are described in Ourmanov et al., J. Virol. (2009) 83:5388 - 5400; and Martinon et al. Vaccine (2008) 26:532 - 545.

[0104] Composition The EBV antigen polypeptides, polynucleotides and vectors described herein can be administered in an immunogenic composition. The immunogenic compositions described herein are compositions that include one or more recombinant polypeptides, polynucleotides and / or vectors that are capable of inducing an immune response, such as a humoral (e.g., antibody) and / or cell-mediated (e.g., cytotoxic T cell) response, after delivery to a mammal, preferably a human.

[0105] The immunogenic compositions disclosed herein typically contain one or more pharmaceutically acceptable carriers and / or excipients. Pharmaceutically acceptable carriers and excipients are well known and can be selected by those skilled in the art. The adjective "pharmaceutically acceptable" indicates that the indicated subject is suitable for administration to a subject (e.g., a human or animal subject). Remington's Pharmaceutical Sciences by E.W. Martin, Mack Publishing Co., Easton, Pa., 15th Edition (1975) describes compositions and formulations (including diluents) suitable for the pharmaceutical delivery of therapeutic and / or prophylactic compositions, including immunogenic compositions.

[0106] For example, the carrier or excipient can preferably contain a buffer. Optionally, the carrier or excipient can also contain at least one component that stabilizes solubility and / or stability. Examples of solubilizers / stabilizers include surfactants such as lauroyl sarcosine and / or Tween. Alternative solubilizers / stabilizers include arginine and glass-forming polyols (such as sucrose, trehalose, etc.). Numerous pharmaceutically acceptable carriers and / or pharmaceutically acceptable excipients are known in the art and are described, for example, in Remington's Pharmaceutical Sciences by E. W. Martin, Mack Publishing Co., Easton, Pa, 5th Edition (1975).

[0107] Accordingly, suitable excipients and carriers can be selected by those skilled in the art to manufacture a formulation suitable for delivery to a subject by the selected route of administration.

[0108] Suitable excipients include, but are not limited to, the following: glycerol, polyethylene glycol (PEG), sorbitol, trehalose, sodium lauroyl sarcosinate, L-proline, nonionic sulfobetaine, guanidine hydrochloride, urea, trimethylamine oxide, KCl, Ca2+, Mg2+, Mn2+, Zn2+ and other divalent cation-related salts, dithiothreitol, dithioerythritol, and 13-mercaptoethanol. Other excipients can be surfactants (including Tween80, Tween20, Triton X-00, NP-40, Empigen BB, octyl glucoside, lauroyl maltoside, Zwittergent 3-08, Zwittergent 3-0, Zwittergent 3-2, Zwittergent 3-4, Zwittergent 3-6, CHAPS, sodium deoxycholate, sodium dodecyl sulfate, cetyltrimethylammonium bromide).

[0109] Optionally, the immunogenic composition of the present invention may be formulated to contain other components such as, for example, adjuvants, stabilizers, pH adjusters, preservatives, etc. Examples of suitable adjuvants are provided in "Adjuvants" below.

[0110] Method of Use The EBV antigen polypeptides, polynucleotides, and vectors described herein can be used, for example, as vaccines for inducing an immune response in the prevention and / or treatment of EBV infection and EBV-related diseases. As used herein, the induction of an immune response refers to the ability of a protein to induce a T cell and / or humoral immune response against that protein.

[0111] As used herein, the induction of an immune response refers to the ability of a protein, also known as an "antigen" or "immunogen," to induce a T cell and / or humoral immune response against that protein. For example, the immunogenic composition can, particularly in embodiments where the composition contains a nucleic acid comprising a sequence encoding an EBV antigen polypeptide, induce a memory T cell and / or B cell population after immunization with the composition, as compared to an untreated subject. In some embodiments, the subject is a vertebrate, such as a mammal, such as a human or a veterinary mammal.

[0112] The immune response can be measured by methods known in the art, including assays for the proliferation or induction of effector functions of specific lymphocyte populations of interest, such as B cells, T cells, T cell lines, and T cell clones.

[0113] Thus, in one embodiment, there is provided a method of inducing an immune response in a subject, the method comprising administering to the subject the polynucleotide, polypeptide, vector or immunogenic composition of the present invention. In one embodiment, the subject is Epstein-Barr virus seronegative. A subject is "seronegative" if they have no serological evidence of past or current EBV infection. In another embodiment, the subject is Epstein-Barr virus seropositive. A subject is "seropositive" if they have serological evidence of past or current EBV infection.

[0114] Also provided is a method of treating or preventing an EBV-related disease in a subject, the method comprising administering to the subject the polynucleotide, polypeptide, vector or immunogenic composition of the present invention. In one embodiment, the EBV-related disease is an EBV-related malignancy or an EBV-related autoimmune disease. Examples of EBV-related diseases include, for example, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus.

[0115] Also provided is a dosing regimen designed to maximize the immunogenicity of the polynucleotide, polypeptide, vector or immunogenic composition of the present invention. Thus, in one embodiment, there is provided a method of inducing an immune response in a subject, the method comprising administering to the subject two or more doses of the polynucleotide, polypeptide, vector and / or immunogenic composition of the present invention. In certain embodiments, the administrations are separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks or more weeks. In another embodiment, the administrations are separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more months. Alternatively, the administrations can be separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 years or more years.

[0116] In one embodiment, there is provided a method of inducing an immune response in a subject, (a) administering an adenovirus vector comprising the polynucleotide of the present invention, and (b) administering a vaccinia virus vector comprising the polynucleotide of the present invention, A method is provided, wherein steps (a) and (b) are carried out in either order. In one embodiment, the adenovirus vector is ChAd155. In another embodiment, the vaccinia virus vector is MVA. In one embodiment, step (b) is carried out 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks or more weeks after step (a). In one embodiment, step (b) is carried out 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more months after step (a).

[0117] In one embodiment, a method for treating or preventing an EBV-related disease in a subject, (a) administering an adenovirus vector comprising the polynucleotide of the present invention, and (b) administering a vaccinia virus vector comprising the polynucleotide of the present invention, A method is provided, wherein steps (a) and (b) are carried out in either order. In one embodiment, the adenovirus vector is ChAd155. In another embodiment, the vaccinia virus vector is MVA. In one embodiment, step (b) is carried out 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks or more weeks after step (a). In one embodiment, step (b) is carried out 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more months after step (a).

[0118] Also provided is the use of the polynucleotide, vector, polypeptide, or immunogenic composition of the present invention in the manufacture of a medicament for the treatment or prevention of a disease caused by Epstein-Barr virus infection.

[0119] Adjuvant "Adjuvant", as used herein, refers to a composition that enhances the immune response to an immunogen. The compositions according to the invention comprising an adjuvant can be used, for example, as a vaccine for a human subject. An adjuvant accelerates, prolongs and / or enhances the quality and / or intensity of the immune response to an antigen / immunogen as compared to administration of the antigen alone, thus reducing the amount of antigen / immunogen required for any given vaccine and / or the frequency of injections required to elicit an appropriate immune response to the antigen / immunogen of interest.

[0120] Examples of adjuvants that can be used in connection with the compositions of the present invention include inorganic adjuvants (e.g., inorganic metal salts such as aluminum phosphate or aluminum hydroxide), gel-like precipitates of aluminum hydroxide (alum); AlPO4; alhydrogels; bacterial products derived from the outer membrane of Gram-negative bacteria, in particular monophosphoryl lipid A (MPLA), lipopolysaccharides (LPS), muramyl dipeptide and its derivatives; Freund's incomplete adjuvant; liposomes, in particular neutral liposomes, liposome compositions and liposomes containing cytokines in some cases; AS01B, AS01E, AS02; non-ionic block copolymers; ISCOMATRIX adjuvant; CpG dinucleotides (CpG motifs), in particular non-methylated DNA containing CpG ODN having a phosphorothioate (PTO) backbone (CpG PTO ODN) or a phosphodiester (PO) backbone (CpG PO ODN); synthetic lipopeptide derivatives, in particular Pam3Cys; lipoarabinomannan; peptidoglycan; zymosan; heat shock proteins (HSP), in particular HSP 70; dsRNA and its synthetic derivatives, in particular Poly I:poly C; polycationic peptides, in particular poly-L-arginine; taxol; fibronectin; flagellin; imidazoquinoline; cytokines having adjuvant activity, in particular GM-CSF, interleukin- (IL-2, IL-6, IL-7, IL-18, type I and type II interferons, in particular interferon-gamma, TNF-alpha; 25-dihydroxyvitamin D3 (calcitriol); and synthetic oligopeptides, in particular MHCII-presenting peptides. Non-ionic block polymers containing polyoxyethylene (POE) and polyoxypropylene (POP), such as POE-POP-POE block copolymers, can be used as adjuvants.

[0121] Further examples of adjuvants include inorganic adjuvants (e.g., inorganic metal salts such as aluminum phosphate or aluminum hydroxide), organic adjuvants (e.g., saponins such as QS21 or squalene), oil-based adjuvants (e.g., Freund's complete adjuvant and Freund's incomplete adjuvant), cytokines (e.g., IL-1β, IL-2, IL-7, IL-12, IL-18, GM-CFS, and INF-γ), particulate adjuvants (e.g., immunostimulating complexes (ISCOMs), liposomes, biodegradable microspheres), virosomes, bacterial adjuvants (e.g., monophosphoryl lipid A such as 3-de-O-acylated monophosphoryl lipid A (3D-MPL) or muramyl peptides), synthetic adjuvants (e.g., monophosphoryl lipid A (MPL), particularly 3-de-O-acylated monophosphoryl lipid A (3D-MPL) and muramyl peptide analogs, or synthetic lipid A, and synthetic polynucleotide adjuvants such as polyarginine or polylysine).

[0122] Saponins are also suitable adjuvants, for example, saponin Quil A (derived from the bark of the South American tree Quillaja Saponaria Molina) and its fractions. The purified fractions of Quil A are also known as immunostimulants such as squalene, QS21, QS17, and QS7 (the non-hemolytic fraction of Quil-A). The combination of QS21 and polysorbate or cyclodextrin is also suitable.

[0123] Another example of an adjuvant is an immunostimulatory oligonucleotide containing an unmethylated cytosine-guanosine dinucleotide motif present in DNA ("CpG"). CpG is known as an adjuvant when administered by either the systemic or mucosal route. When formulated in a vaccine, CpG may be administered in free solution together with the free antigen, covalently conjugated to the antigen, or formulated together with a carrier such as aluminum hydroxide.

[0124] Activation of specific receptors can stimulate an immune response. Such receptors are known to those skilled in the art and include, for example, cytokine receptors, in particular, type I cytokine receptors, type II cytokine receptors, TNF receptors; and vitamin D receptors that act as transcription factors; and Toll-like receptors 1 (TLR1), TLR-2, TLR3, TLR4, TLR5, TLR-6, TLR7, and TLR9. Agonists for such receptors have adjuvant activity, i.e., are immunostimulatory. Other suitable adjuvants include alkylglucosaminide phosphate (AGP) or a pharmaceutically acceptable salt of AGP. Some AGPs are TLR4 agonists and some are TLR4 antagonists. The adjuvant of the composition of the present invention may be one or more Toll-like receptor agonists. In a more preferred embodiment, the adjuvant is a Toll-like receptor 4 agonist. In a particularly preferred embodiment, the adjuvant is a Toll-like receptor 9 agonist.

[0125] Adjuvants, such as those described above, may be formulated together with a carrier, such as liposomes, oil-in-water emulsions, and / or metal salts (including aluminum salts, such as aluminum hydroxide). For example, 3D-MPL may be formulated with aluminum hydroxide or an oil-in-water emulsion, QS21 may be formulated with cholesterol-containing liposomes, an oil-in-water emulsion or alum, and CpG may be formulated with alum or another cationic carrier.

[0126] Combinations of adjuvants, in particular combinations of monophosphoryl lipid A and saponin derivatives, more particularly combinations of QS21 and 3D-MPL or compositions (DQ) in which QS21 is quenched in cholesterol-containing liposomes, can be utilized in the present invention. Alternatively, combinations of saponins, such as CpG with added QS21, are adjuvants suitable for use in the present invention, similar to a potent adjuvant formulation containing QS21, 3D-MPL and tocopherol in an oil-in-water emulsion. Saponin adjuvants can be formulated in liposomes and combined with immunostimulatory oligonucleotides. Thus, suitable adjuvant systems include, for example, combinations of monophosphoryl lipid A, preferably 3D-MPL, with aluminum salts. Further exemplary adjuvants include QS21 and / or MPL and / or CpG. QS21 can be quenched in cholesterol-containing liposomes.

[0127] Fusion of the MHC class II invariant chain (also known as CD74) to an antigen contained in an expression system used for vaccination increases the immune response against said antigen when administered using a viral vector, such as an adenovirus. Thus, in one embodiment of the present invention, the immunogenic transgene can be co-expressed with the invariant chain in a recombinant ChAd155 viral vector.

[0128] In another embodiment, the present invention provides the use of the ChAd155 capsid for inducing an immunomodulatory response or for enhancing a cytotoxic T cell response against or acting as an adjuvant to another active agent by delivering the ChAd155 capsid to a subject (optionally, intact or recombinant virus particles or empty capsids are used). The ChAd155 capsid can be delivered, alone or in a combination regimen with an active agent, to enhance the immune response against it. Advantageously, the desired effect can be achieved without infecting the host with an adenovirus.

[0129] Sequence identity Identity with respect to a sequence is defined herein as the percentage of amino acid residues in a candidate sequence that is identical to a reference amino acid sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity.

[0130] Sequence identity can be determined by standard methods commonly used to compare the similarity at the amino acid positions of two polypeptides. Using a computer program, such as BLAST or FASTA, the two polypeptides are aligned for optimal matching of their respective amino acids (along the entire length of one or both sequences or along a predetermined portion of one or both sequences). These programs provide a default open penalty and a default gap penalty, and a scoring matrix, such as PAM250 (a standard scoring matrix), can be used with the computer program. For example, percent identity can be calculated by multiplying the total number of identical matches by 100 and then dividing by the sum of the length of the longer sequence within the aligned range and the number of gaps introduced into the shorter sequence to align the two sequences.

[0131] When the present disclosure refers to a sequence by reference to a UniProt or Genbank accession code, the sequence referred to is the current version as of the filing date of the present application.

[0132] One of ordinary skill in the art will recognize that an individual substitution, deletion, or addition to a protein that changes, adds, or deletes a single amino acid or a small percentage of amino acids is an "immunogenic derivative" if the change(s) result in an amino acid substitution by a functionally similar amino acid or a substitution / deletion / addition of a residue that does not substantially affect the immunogenic function.

[0133] Conservative substitution tables that provide functionally similar amino acids are well known in the art. In general, such conservative substitutions will correspond to one of the amino acid groups specified below, but in some cases other substitutions may be possible without substantially affecting the immunogenic properties of the antigen. Each of the following eight groups contains amino acids that are generally conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M).

[0134] Preferably, such substitutions do not occur in the epitope region and thus do not have a major effect on the immunogenic properties of the antigen.

[0135] Immunogenic derivatives may also include those in which additional amino acids are inserted compared to the reference sequence. Preferably, such insertions do not occur in the epitope region and thus do not have a major effect on the immunogenic properties of the antigen. One example of an insertion includes a short stretch of histidine residues (e.g., 2 - 6 residues) that assist in the expression and / or purification of the antigen in question.

[0136] Immunogenic derivatives include those in which amino acids are deleted compared to the reference sequence. Preferably, such deletions do not occur in the epitope region and thus do not have a major effect on the immunogenic properties of the antigen.

[0137] One of ordinary skill in the art will recognize that a particular immunogenic derivative may contain substitutions, deletions, and additions (or any combination thereof).

[0138] Generally Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular terms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the term "or" is intended to include "and" unless the context clearly dictates otherwise. The term "plural" refers to two or more. Further, numerical limitations given with respect to the concentration or level of a substance, e.g., the concentration of a solution component or its ratio, and reaction conditions, e.g., temperature, pressure, and number of cycles, are intended to be approximate. The term "about" as used herein is intended to mean ±10% of the quantity.

[0139] The term "comprises" means "includes". Thus, unless the context otherwise requires, the word "comprises", and variations thereof, such as "comprise" and "comprising", are to be understood to mean the inclusion of the stated compound or composition (e.g., nucleic acid, polypeptide, antigen) or step, or group of compounds or steps, but not the exclusion of any other compound, composition, step, or group thereof. The abbreviation "e.g." is derived from the Latin exempli gratia and is used herein to indicate non-limiting examples. Thus, the abbreviation "e.g." is synonymous with the term "for example".

[0140] The present invention is further illustrated by the following non-limiting examples and reference to the drawings.

Examples

[0141] [Example 1] Design of Antigen a. Design of EBV Antigen A multivalent Epstein-Barr virus antigen construct was rationally designed with the following design goals in mind: 1) In the design, by including a plurality of latent-stage antigens and optionally a lytic-stage antigen, broadly targeting EBV antigens expressed in Epstein-Barr virus (EBV)-associated multiple sclerosis (EBV-MS); 2) By excluding regions known to be problematic, fragmenting and shuffling EBV protein antigens in the multivalent antigen construct, reducing the risk of carcinogenesis and immune interference; 3) By including T cell epitopes in the multivalent antigen construct, focusing the induced immune response on EBV-specific T cell activation; and 4) In the final antigen sequence, excluding the presence of unwanted anti-self neoepitopes.

[0142] Two multivalent EBV antigen constructs that meet these criteria were designed. The first multivalent antigen construct (EBV-L; Figure 2A) contains immunogenic fragments of the latent-stage EBV proteins LMP1, LMP2, EBNA1, and EBNA3A. The second construct (EBV-LLy; Figure 2B) contains the same latent antigen fragments as EBV-L and also includes an immunogenic fragment of the EBV lytic protein ZEBRA. The EBV latent proteins selected for inclusion in the antigen constructs have been reported to be expressed by B cells in postmortem brain tissue of multiple sclerosis patients (Serafini et al., J. Exp. Medicine (2007) 204(12):2899; Serafini et al., J. Neuropathol. Exp. Neurol. (2010) 69(7):677). Inclusion of the lytic antigen ZEBRA, an important regulator of the switch from latency to the lytic phase of EBV, is aimed at controlling viral reactivation and limiting further amplification and spread of EBV.

[0143] Full-length EBV proteins have the ability to transform immune cells. Therefore, to improve the safety of the antigen construct, problematic regions were excluded and only the remaining fragments of the EBV protein were selected for construct design. Figure 1 shows the positions of the selected immunogenic fragments in each of the EBV proteins. As shown in Figures 2A - B, the selected fragments were shuffled and assembled to yield a polyprotein containing 16 (EBV-L) or 18 (EBV-LLy) immunogenic fragments such that fragments derived from the same EBV protein are not adjacent to each other.

[0144] Finally, to reduce the risk of unwanted junction epitopes formed by joining two immunogenic fragments together, bioinformatics screening was performed to identify potential anti-self neoepitopes in the junction regions of the candidate antigen constructs. Briefly, 16-amino acid-long peptides spanning the boundary (junction) region between each pair of two consecutive antigen fragments were extracted from the vaccine polypeptide sequence (8 amino acids from each antigen fragment). The 16-amino acid length of the junction region ensures that each 9mer sequence within the junction region contains amino acids from both antigens. For each 16mer junction peptide, then all 9mer peptides were compared to a collection of 9mer peptides representing the complete human proteome (obtained from the NCBI RefSeq peptide database). In all cases, 9mer peptides derived from the junction regions of the vaccine polypeptide sequences were not found to be present in human proteins.

[0145] b. Design of CalHV3 Antigen CalHV3 is a gammaherpesvirus isolated from the common marmoset (Callithrix jacchus). Based on sequence and structural, viral replication cycle, and pathogenicity similarities, CalHV3 is considered the marmoset equivalent of human EBV. See, for example, Cho et al., PNAS 98(3):1224-1229 (2001). CalHV3 is acquired early in life and has been reported to be highly prevalent in natural and captive marmoset colonies.

[0146] To evaluate the ability of a similar vaccine to re-expand functional T cell responses against latent and lytic viral antigens in individuals latently infected with a gamma-herpesvirus in a marmoset model, orthologous CalHV3 antigen constructs were developed. Briefly, the CalHV3 latent antigen construct (CalHV3-L; shown in Figure 4A) was constructed from immunogenic fragments of proteins C1 (SEQ ID NO: 28), C7 (SEQ ID NO: 32), and ORF39 (SEQ ID NO: 36), which are the CalHV3 orthologs of EBV LMP1, LMP2, and EBNA1, respectively. As in the EBV-L antigen construct, the antigen regions contained in the CalHV3-L construct were fragmented and shuffled so that fragments from the same CalHV3 protein were not adjacent to each other. The amino acid sequence of the final CalHV3-L antigen construct is shown in SEQ ID NO: 44 (encoded by the polynucleotide shown in SEQ ID NO: 45).

[0147] The CalHV3 latent / lytic antigen construct (CalHV3-LLy; shown in Figure 4B) was also constructed. In addition to containing fragments of the latent proteins C1, C7, and ORF39, CalHV3-LLy also contains a fragment of ORF43, which is the CalHV3 ortholog of the EBV ZEBRA protein. The amino acid sequence of the final CalHV3-LLy antigen construct is shown in SEQ ID NO: 46 (encoded by the polynucleotide shown in SEQ ID NO: 47).

[0148] Finally, a genetically adjuvanted version of CalHV3-LLy (li-CalHV3-LLy) was constructed by fusing the MHC class II-associated invariant chain polypeptide of marmoset (SEQ ID NO: 43) to the N-terminus of CalHV3-LLy. The amino acid sequence of the final li-CalHV3-LLy antigen construct is shown in SEQ ID NO: 48 (encoded by the polynucleotide shown in SEQ ID NO: 49).

[0149] [Example 2] Construction of vectors Polynucleotides encoding EBV-L (SEQ ID NO: 25) and EBV-LLy (SEQ ID NO: 27) were cloned into plasmid pvjTetOhCMV-bghpolyA containing the tetOhCMV promoter and the bovine growth hormone polyadenylation signal (BGH pA) according to the method described in WO2016 / 198621. Subsequently, the EBV-L and EBV-LLy expression cassettes were transferred into the ChAd155 vector backbone by homologous recombination in competent cells of Escherichia coli (E. coli) BJ5183 to generate the pChAd155(ΔE1, ΔE4_Ad5E4 orf6) TetO hCMV-EBV-L (and EBV-LLy) vector. The nucleic acid sequence of the vector pChAd155(ΔE1, ΔE4_Ad5E4 orf6) TetO hCMV-EBV-L is shown in SEQ ID NO: 50. The antigen-encoding region is at nucleotides 1348 to 4806 of SEQ ID NO: 50. The nucleic acid sequence of the vector pChAd155(ΔE1, ΔE3, ΔE4_Ad5E4 orf6) TetO hCMV-EBV-LLy expression vector is shown in SEQ ID NO: 51. The antigen-encoding region is at nucleotides 1348 to 5157 of SEQ ID NO: 51. The construction of the ChAd155-EBV vector was confirmed by sequencing of the transgene and restriction analysis. Using the same method, EBV adenovirus vectors can be prepared based on alternative modified ChAd155 backbones, as described, for example, in WO2016 / 198621.

[0150] ​Continuing in the same manner, vectors ChAd155-CalHV3-L, ChAd155-CalHV3-LLy, and ChAd155-li-CalHV3-LLy (encoding CalHV3 antigens CalHV3-L, CalHV3-LLy, and li-CalHV3-LLy, respectively) were prepared. The nucleic acid sequence of vector pChAd155(ΔE1, ΔE4_Ad5E4 orf6) TetO hCMV-CalHV3-L is shown in SEQ ID NO: 52 (the antigen-encoding region nucleotides 1348 to 4482). The nucleic acid sequence of vector pChAd155(ΔE1, ΔE3, ΔE4_Ad5E4 orf6) TetO hCMV-CalHV3-LLy is shown in SEQ ID NO: 53 (the antigen-encoding region nucleotides 1348 to 5238). The nucleic acid sequence of vector pChAd155(ΔE1, ΔE3, ΔE4_Ad5E4 orf6) TetO hCMV-li-CalHV3-LLy is shown in SEQ ID NO: 54 (the antigen-encoding region nucleotides 1348 to 5883).

[0151] MVA vectors encoding EBV-LLy and CalHV3-LLy antigen constructs were also prepared according to methods known in the art. See, for example, Ourmanov et al., J. Virol. (2009) 83:5388-5400; and Martinon et al. Vaccine (2008) 26:532-545.

[0152] [Example 3] Generation of Virus Particles The ChAd155_EBV-L and ChAd155_EBV-LLy vectors were linearized with the restriction endonuclease Pmel and transfected into a HEK293-derived cell line (Procell 92.S) as described by Vitelli et al., PLOS One (2013) 8(e55435):1-9. These cells were genetically modified to constitutively express the TetO repressor to suppress transgene expression during virus production. Virus amplification was carried out on a small scale (shaking flasks), and ChAd155-EBV virus particles were purified from 1 liter of suspension culture by a two-fold CsCl gradient. The titer of the ChAd155-EBV virus particles was determined by QPCR targeting the tetOhCMV promoter. Continuing with the same method, virus particles were prepared from ChAd155-CalHV3-L, ChAd155-CalHV3-LLy, and ChAd155-li-CalHV3-LLy.

[0153] Recombinant MVA expressing the EBV-LLy and CalHV3-LLy antigen constructs was obtained using standard methods. Briefly, primary cell cultures of chicken embryo fibroblasts (CEF) at a defined cell density were infected with MVA-EBV and MVA-CalHV3 virus seeds at a defined multiplicity of infection. The harvests of MVA-EBV and MVA-CalHV3 viruses were purified by fractionation gradient centrifugation.

[0154] [Example 4] Immunogenicity of ChAd155-EBV and ChAd155-CalHV3 Antigens in Mice a. ChAd155-EBV The immunogenicity of ChAd155-EBV virus particles generated from vectors expressing latent or latent + lytic antigens was evaluated in mice using the experimental design shown in Table 1. Briefly, CB6F1 mice (6 per group) were given a single dose (10 6 、10 7 or 10 8 virus particles, intramuscularly) of the vectors ChAd155-EBV-L or ChAd155-EBV-LLy.

[0155] Three weeks after immunization, splenocytes were isolated and assayed for T cell responses to EBV antigens according to the standard IFNγ ELISpot assay. Briefly, splenocytes from immunized animals were stimulated with overlapping 15mer peptides arrayed in five pools, each covering an immunogenic fragment derived from each of the EBV proteins included in the vaccine (LMP1, LMP2, EBNA1, EBNA3A, ZEBRA; n = 19 to 84 single peptides / pool). A sixth pool of 16mer peptides covering each single junction between fragments (E J , n = 18 peptides), and DMSO (peptide diluent) were also used as stimulants to monitor responses to junctional epitopes and as negative controls, respectively. T cell activation was detected by counting IFNγ-secreting T cells induced by the vaccine in enzyme-linked immunospot (ELISPOT).

[0156]

Table 1

[0157] The results are shown in Figure 5A. Both ChAd155-EBV-L and ChAd155-EBV-LLy induced IFNγ secretion by T cells in vaccinated mice in a dose-dependent manner. T cell responses were detected against each of the EBV latent antigens (LMP1, LMP2, EBNA1 and EBNA3A) in both EBV-L and EBV-LLy immunized mice. However, T cell responses to the EBV lytic protein ZEBRA were detected only in EBV-LLy immunized mice. No responses were detected against the EBV junction peptide (Ej) or the DMSO negative control.

[0158] The results show that virus particles generated from the ChAd155-EBV-L and ChAd155-EBV-LLy vectors are capable of inducing antigen-specific T cell responses against immunogenic fragments contained within the antigen constructs. Furthermore, the primary immune responses against the EBV-L and EBV-LLy antigen constructs do not target junctional epitopes.

[0159] b.ChAd155-CalHV3 The immunogenicity of ChAd155-CalHV3 virus particles was evaluated according to the same method as described above for ChAd155-EBV virus particles. Antigen stimulation of splenocytes 3 weeks after vaccination was performed with overlapping 15mer peptides arrayed in 4 pools (each covering the immunogenic fragments contained in the vaccine) (C1, C7, ORF39, ORF43, n = 58 to 96 single peptides / pool). A fifth pool of 16mer peptides covering each single junction between the fragments (C J , n = 12 peptides), and DMSO (peptide diluent) were also used as stimulants to monitor responses against junctional epitopes and as negative controls, respectively. The experimental design is summarized in Table 2.

[0160]

Table 2

[0161] The results are shown in Figure 5B. Both ChAd155-CalHV3-L and ChAd155-CalHV3-LLy induced T cell IFNγ secretion in vaccinated mice in a dose-dependent manner. T cell responses against peptide pools covering the CalHV3 latency antigens C1, C7, and ORF39 were detected in both CalHV3-L and CalHV3-LLy immunized mice. However, T cell responses against ORF43, a CalHV3 soluble protein, were detected only in CalHV3-LLy immunized mice. Responses against the CalHV3 junction peptide (Cj) or the negative control DMSO were not detected.

[0162] The results indicate that virus particles generated from the ChAd155-EBV-L and ChAd155-EBV-LLy vectors are capable of inducing antigen-specific T cell responses against immunogenic fragments contained within the antigen constructs. Furthermore, the primary immune responses against the CalHV3-L and CalHV3-LLy antigen constructs do not target junctional epitopes.

[0163] [Example 5] Effect of prime-boost in mice a. EBV-LLy prime-boost The ability of the second administration of the EBV-LLy antigen to boost the immune response to the first administration of the EBV-LLy antigen was evaluated using the experimental design summarized in Table 3. Briefly, groups of CB6F1 mice (n = 5 / group) were immunized intramuscularly on day 0 with 5 × 10 7 virus particles of Chad155-EBV-LLy. On day 21 (3 weeks), group 2 received a second immunization with 10 7 plaque-forming units (PFU) of MVA-EBV-LLy. Control mice either did not receive a further immunization (group 3: "no boost") or received a boost (booster immunization) with an MVA vector encoding an EBV-unrelated antigen (group 1: MVA-unrelated).

[0164]

Table 3

[0165] Four weeks after the first immunization, splenocytes were isolated from the mice and the antigen-specific T cell responses were evaluated using the method described in Example 4.

[0166] As shown in Figure 6, boosting (booster immunization) with MVA-EBV-LLy following immunization with ChAd155-EBV-LLy resulted in a significant increase in EBV-specific interferon gamma release compared to mice without boosting or mice receiving a "boost" injection of an unrelated antigen. Figure 6A represents the cumulative T cell responses to all antigens (LMP1, LMP2, EBNA1, EBNA3A, and ZEBRA), and Figure 6B shows the responses to individual antigens.

[0167] b. CalHV3-LLy prime-boost The ability to boost the immune response to the CalHV3 antigen was evaluated using the experimental design summarized in Table 4. Briefly, groups of CB6F1 mice (n = 6 / group) were immunized intramuscularly with 5 × 10 7 viral particles of Chad155-CalHV3-LLy on day 0. On day 42 (6 weeks), group 4 received a second immunization with the same ChAd155-CalHV3-LLy antigen construct, while group 3 received a boost (booster immunization) with MVA-CalHV3-LLy. Control mice received either no boost (group 1) or a boost with MVA encoding a CalHV3-unrelated antigen (MVA-unrelated).

[0168]

Table 4

[0169] Seven weeks after the first immunization, splenocytes were isolated from the mice and the antigen-specific T cell response was evaluated using the method described in Example 4.

[0170] As shown in Figure 7, boosting (booster immunization) with the same antigen construct (ChAd155-CalHV3) or MVA-CalHV3-LLy following immunization with ChAd155-CalHV3-LLy resulted in a significant increase in CalHV3-specific interferon gamma release at week 7 compared to mice without boosting or mice receiving a "boost" injection of an unrelated antigen.

[0171] These results demonstrate the ability to enhance the immune response to EBV and CalHV3 antigen constructs using a prime-boost regimen.

[0172] [Example 6] Invariant chain-CalHV3-LLy fusion protein It has been reported that antigen-specific T cell responses are enhanced by fusing an antigen to the major histocompatibility complex (MHC) class II-associated invariant chain (li). See, for example, Capone et al., Mol Ther. May 2014;22(5):1039-1047. Therefore, the immunogenicity of virus particles expressing marmoset invariant chain (li) fused to the N-terminus of the CalHV3-LLy antigen polypeptide was evaluated in CB6F1 mice according to the study design described in Table 5. Antigen-specific T cell responses were evaluated using the IFNγ assay described in Example 4.

[0173]

Table 5

[0174] Figure 8 summarizes the cumulative T cell responses to all CalHV3-LLy antigens (C1, C7, ORF39, and ORF43) observed 2 weeks after immunization. With a lower dose of antigen (5×10 6 virus particles), ChAd155-li-CalHV3-LLy induced significantly greater IFNγ release in immunized mice than ChAd155-CalHV3-LLy. At higher doses of antigen (5×10 7 virus particles) tested, no difference was observed.

[0175] These results indicate that fusion of the CalHV3-LLy antigen polypeptide to the MHC class II-associated invariant chain polypeptide enhances the T cell immune response to CalHV3 latent and lytic antigens.

[0176] [Example 7] Immunogenicity of CalHV3 Antigens in Non-Human Primates The immunogenicity of the CalHV3 antigen construct was evaluated in CalHV3-seropositive marmosets (common marmosets (Callithrix jacchus)), a genus of New World primates. CalHV3 infection is known to be endemic in marmosets. See, e.g., Cho et al., PNAS 98(3):1224-1229 (2001). Due to the structural and pathological similarities between CalHV3 and EBV, CalHV3-positive marmosets can serve as a valuable model for human EBV infection and pathology. Id.

[0177] Animals were immunized using a ChAd155 prime / MVA boost vaccination schedule. Briefly, a group consisting of four adult animals (three males and one female) received an initial immunization with ChAd155-CalHV3-LLy (5x10 10 vp) on day 0 and a boost (booster immunization) with MVA-CalHV3-LLy (2x10 8 ) on day 56 (8 weeks). Blood samples were taken 2 weeks before the prime injection, 3 weeks after the prime injection, and 1, 4, and 7 weeks after the boost injection. Antigen-specific T cell responses in peripheral blood mononuclear cells (PBMCs) were evaluated using the method described in Example 4.

[0178] Figure 9 shows the cumulative T cell responses in individual animals against all CalHV3-LLy antigens (C1, C7, ORF39, and ORF43) observed at baseline (w0), 3 weeks post-prime (w3 pp), and 1, 4, and 7 weeks post-boost (w1, w4, w7 pb). Prior to immunization, the animals showed a baseline CalHV3-specific T cell response, which was consistent with the fact that the animals were virus carriers. Three weeks after ChAd155-CalHV3-LLy immunization, the animals showed a significant expansion of the existing CalHV3-specific T cell response. The T cell response continued to increase even 1 week after boosting with MVA-CalHV3-LLy and converged over the following 2 months but remained above baseline levels in most animals. As shown in Figure 10, the enhancement of the T cell response against CalHV3-LLy was maintained and was poly-specific (i.e., against C1, C7, ORF39, and ORF43).

[0179] These results indicate that the ChAd155 and MVA vectors encoding the CalHV3-LLy antigen can efficiently re-expand and maintain the existing antigen-specific T cell response in CalHV3-positive marmosets and that the circulating T cells induced by the gammaherpesvirus are not functionally impaired or depleted.

[0180] [Example 8] Recognition of EBV fragments encoded by ChAd155 and MVA latent + lytic EBV vaccines by human PBMCs To evaluate the selection of EBV latent (EBNA1, EBNA3A, LMP1, and LMP2) and lytic (ZEBRA) antigenic fragments included in the vaccine, T cell responses against the corresponding peptide pools were measured in otherwise healthy human EBV carriers.

[0181] Briefly, cryopreserved peripheral blood mononuclear cells (PBMCs) from 8 healthy human donors were thawed and assayed for T cell responses against EBV antigens according to a standard IFNγ ELISpot assay. The PBMCs were adjusted to 2×10 5Plated in triplicate in cells / wells and stimulated overnight with overlapping 15-mer peptides arrayed in 5 pools (each covering an immunogenic fragment derived from each of the EBV proteins included in the vaccine) (LMP1, LMP2, EBNA1, EBNA3A, ZEBRA; n = 19 to 84 single peptides / pool). Stimulation with DMSO (peptide diluent) was used as a negative control. T cell activation was detected by counting IFNγ-secreting T cells by enzyme-linked immunospot (ELISPOT).

[0182] As shown in Figure 11, the results indicate that antigen-specific T cell responses to immunogenic fragments contained within the EBV Lly antigen constructs can be readily detected in healthy EBV carriers, and that EBNA3A and ZEBRA are recognized with the highest frequency and can induce the highest responses, which is consistent with previous reports (e.g., Taylor et al. Ann. Rev. Immunol. 33:787-821, 2015).

[0183] This disclosure includes the following sequence information. SEQUENCE LISTING <110> GLAXOSMITHKLINE BIOLOGICALS S.A. <120> EPSTEIN-BARR VIRUS ANTIGEN CONSTRUCTS <130> PA23-352 <140> <141> 2018-12-14 <150> US 62 / 608,038 <151> 2017-12-20 <160> 54 <170> PatentIn version 3.5 <210> 1 <211> 386 <212> PRT <213> Human herpesvirus 4 <400> 1 Met Glu His Asp Leu Glu Arg Gly Pro Pro Gly Pro Arg Arg Pro Pro 1 5 10 15 Arg Gly Pro Pro Leu Ser Ser Ser Leu Gly Leu Ala Leu Leu Leu Leu 20 25 30 Leu Leu Ala Leu Leu Phe Trp Leu Tyr Ile Val Met Ser Asp Trp Thr 35 40 45 Gly Gly Ala Leu Leu Val Leu Tyr Ser Phe Ala Leu Met Leu Ile Ile 50 55 60 Ile Ile Leu Ile Ile Phe Ile Phe Arg Arg Asp Leu Leu Cys Pro Leu 65 70 75 80 Gly Ala Leu Cys Ile Leu Leu Leu Met Ile Thr Leu Leu Leu Ile Ala 85 90 95 Leu Trp Asn Leu His Gly Gln Ala Leu Phe Leu Gly Ile Val Leu Phe 100 105 110 Ile Phe Gly Cys Leu Leu Val Leu Gly Ile Trp Ile Tyr Leu Leu Glu 115 120 125 Met Leu Trp Arg Leu Gly Ala Thr Ile Trp Gln Leu Leu Ala Phe Phe 130 135 140 Leu Ala Phe Phe Leu Asp Leu Ile Leu Leu Ile Ile Ala Leu Tyr Leu 145 150 155 160 Gln Gln Asn Trp Trp Thr Leu Leu Val Asp Leu Leu Trp Leu Leu Leu 165 170 175 Phe Leu Ala Ile Leu Ile Trp Met Tyr Tyr His Gly Gln Arg His Ser 180 185 190 Asp Glu His His His Asp Asp Ser Leu Pro His Pro Gln Gln Ala Thr 195 200 205 Asp Asp Ser Gly His Glu Ser Asp Ser Asn Ser Asn Glu Gly Arg His 210 215 220 His Leu Leu Val Ser Gly Ala Gly Asp Gly Pro Pro Leu Cys Ser Gln 225 230 235 240 Asn Leu Gly Ala Pro Gly Gly Gly Pro Asp Asn Gly Pro Gln Asp Pro 245 250 255 Asp Asn Thr Asp Asp Asn Gly Pro Gln Asp Pro Asp Asn Thr Asp Asp 260 265 270 Asn Gly Pro His Asp Pro Leu Pro Gln Asp Pro Asp Asn Thr Asp Asp 275 280 285 Asn Gly Pro Gln Asp Pro Asp Asn Thr Asp Asp Asn Gly Pro His Asp 290 295 300 Pro Leu Pro His Ser Pro Ser Asp Ser Ala Gly Asn Asp Gly Gly Pro 305 310 315 320 Pro Gln Leu Thr Glu Glu Val Glu Asn Lys Gly Gly Asp Gln Gly Pro 325 330 335 Pro Leu Met Thr Asp Gly Gly Gly Gly His Ser His Asp Ser Gly His 340 345 350 Gly Gly Gly Asp Pro His Leu Pro Thr Leu Leu Leu Gly Ser Ser Gly 355 360 365 Ser Gly Gly Asp Asp Asp Asp Pro His Gly Pro Val Gln Leu Ser Tyr 370 375 380 Tyr Asp 385 <210> 2 <211> 62 <212> PRT <213> Human herpesvirus 4 <400> 2 Met Ser Asp Trp Thr Gly Gly Ala Leu Leu Val Leu Tyr Ser Phe Ala 1 5 10 15 Leu Met Leu Ile Ile Ile Ile Leu Ile Ile Phe Ile Phe Arg Arg Asp 20 25 30 Leu Leu Cys Pro Leu Gly Ala Leu Cys Ile Leu Leu Leu Met Ile Thr 35 40 45 Leu Leu Leu Ile Ala Leu Trp Asn Leu His Gly Gln Ala Leu 50 55 60 <210> 3 <211> 85 <212> PRT <213> Human herpesvirus 4 <400> 3 Phe Leu Gly Ile Val Leu Phe Ile Phe Gly Cys Leu Leu Val Leu Gly 1 5 10 15 Ile Trp Ile Tyr Leu Leu Glu Met Leu Trp Arg Leu Gly Ala Thr Ile 20 25 30 Trp Gln Leu Leu Ala Phe Phe Leu Ala Phe Phe Leu Asp Leu Ile Leu 35 40 45 Leu Ile Ile Ala Leu Tyr Leu Gln Gln Asn Trp Trp Thr Leu Leu Val 50 55 60 Asp Leu Leu Trp Leu Leu Leu Phe Leu Ala Ile Leu Ile Trp Met Tyr 65 70 75 80 Tyr His Gly Gln Arg 85 <210> 4 <211> 40 <212> PRT <213> Human herpesvirus 4 <400> 4 His Ser Asp Glu His His His Asp Asp Ser Leu Pro His Pro Gln Gln 1 5 10 15 Ala Thr Asp Asp Ser Gly His Glu Ser Asp Ser Asn Ser Asn Glu Gly 20 25 30 Arg His His Leu Leu Val Ser Gly 35 40 <210> 5 <211> 114 <212> PRT <213> Human herpesvirus 4 <400> 5 Asn Gly Pro His Asp Pro Leu Pro Gln Asp Pro Asp Asn Thr Asp Asp 1 5 10 15 Asn Gly Pro Gln Asp Pro Asp Asn Thr Asp Asp Asn Gly Pro His Asp 20 25 30 Pro Leu Pro His Ser Pro Ser Asp Ser Ala Gly Asn Asp Gly Gly Pro 35 40 45 Pro Gln Leu Thr Glu Glu Val Glu Asn Lys Gly Gly Asp Gln Gly Pro 50 55 60 Pro Leu Met Thr Asp Gly Gly Gly Gly His Ser His Asp Ser Gly His 65 70 75 80 Gly Gly Gly Asp Pro His Leu Pro Thr Leu Leu Leu Gly Ser Ser Gly 85 90 95 Ser Gly Gly Asp Asp Asp Asp Pro His Gly Pro Val Gln Leu Ser Tyr 100 105 110 Tyr Asp <210> 6 <211> 497 <212> PRT <213> Human herpesvirus 4 <400> 6 Met Gly Ser Leu Glu Met Val Pro Met Gly Ala Gly Pro Pro Ser Pro 1 5 10 15 Gly Gly Asp Pro Asp Gly Tyr Asp Gly Gly Asn Asn Ser Gln Tyr Pro 20 25 30 Ser Ala Ser Gly Ser Ser Gly Asn Thr Pro Thr Pro Pro Asn Asp Glu 35 40 45 Glu Arg Glu Ser Asn Glu Glu Pro Pro Pro Pro Tyr Glu Asp Pro Tyr 50 55 60 Trp Gly Asn Gly Asp Arg His Ser Asp Tyr Gln Pro Leu Gly Thr Gln 65 70 75 80 Asp Gln Ser Leu Tyr Leu Gly Leu Gln His Asp Gly Asn Asp Gly Leu 85 90 95 Pro Pro Pro Pro Tyr Ser Pro Arg Asp Asp Ser Ser Gln His Ile Tyr 100 105 110 Glu Glu Ala Gly Arg Gly Ser Met Asn Pro Val Cys Leu Pro Val Ile 115 120 125 Val Ala Pro Tyr Leu Phe Trp Leu Ala Ala Ile Ala Ala Ser Cys Phe 130 135 140 Thr Ala Ser Val Ser Thr Val Val Thr Ala Thr Gly Leu Ala Leu Ser 145 150 155 160 Leu Leu Leu Leu Ala Ala Val Ala Ser Ser Tyr Ala Ala Ala Gln Arg 165 170 175 Lys Leu Leu Thr Pro Val Thr Val Leu Thr Ala Val Val Thr Phe Phe 180 185 190 Ala Ile Cys Leu Thr Trp Arg Ile Glu Asp Pro Pro Phe Asn Ser Leu 195 200 205 Leu Phe Ala Leu Leu Ala Ala Ala Gly Gly Leu Gln Gly Ile Tyr Val 210 215 220 Leu Val Met Leu Val Leu Leu Ile Leu Ala Tyr Arg Arg Arg Trp Arg 225 230 235 240 Arg Leu Thr Val Cys Gly Gly Ile Met Phe Leu Ala Cys Val Leu Val 245 250 255 Leu Ile Val Asp Ala Val Leu Gln Leu Ser Pro Leu Leu Gly Ala Val 260 265 270 Thr Val Val Ser Met Thr Leu Leu Leu Leu Ala Phe Val Leu Trp Leu 275 280 285 Ser Ser Pro Gly Gly Leu Gly Thr Leu Gly Ala Ala Leu Leu Thr Leu 290 295 300 Ala Ala Ala Leu Ala Leu Leu Ala Ser Leu Ile Leu Gly Thr Leu Asn 305 310 315 320 Leu Thr Thr Met Phe Leu Leu Met Leu Leu Trp Thr Leu Val Val Leu 325 330 335 Leu Ile Cys Ser Ser Cys Ser Ser Cys Pro Leu Ser Lys Ile Leu Leu 340 345 350 Ala Arg Leu Phe Leu Tyr Ala Leu Ala Leu Leu Leu Leu Ala Ser Ala 355 360 365 Leu Ile Ala Gly Gly Ser Ile Leu Gln Thr Asn Phe Lys Ser Leu Ser 370 375 380 Ser Thr Glu Phe Ile Pro Asn Leu Phe Cys Met Leu Leu Leu Ile Val 385 390 395 400 Ala Gly Ile Leu Phe Ile Leu Ala Ile Leu Thr Glu Trp Gly Ser Gly 405 410 415 Asn Arg Thr Tyr Gly Pro Val Phe Met Cys Leu Gly Gly Leu Leu Thr 420 425 430 Met Val Ala Gly Ala Val Trp Leu Thr Val Met Ser Asn Thr Leu Leu 435 440 445 Ser Ala Trp Ile Leu Thr Ala Gly Phe Leu Ile Phe Leu Ile Gly Phe 450 455 460 Ala Leu Phe Gly Val Ile Arg Cys Cys Arg Tyr Cys Cys Tyr Tyr Cys 465 470 475 480 Leu Thr Leu Glu Ser Glu Glu Arg Pro Pro Thr Pro Tyr Arg Asn Thr 485 490 495 Val <210> 7 <211> 71 <212> PRT <213> Human herpesvirus 4 <400> 7 Met Asn Pro Val Cys Leu Pro Val Ile Val Ala Pro Tyr Leu Phe Trp 1 5 10 15 Leu Ala Ala Ile Ala Ala Ser Cys Phe Thr Ala Ser Val Ser Thr Val 20 25 30 Val Thr Ala Thr Gly Leu Ala Leu Ser Leu Leu Leu Leu Ala Ala Val 35 40 45 Ala Ser Ser Tyr Ala Ala Ala Gln Arg Lys Leu Leu Thr Pro Val Thr 50 55 60 Val Leu Thr Ala Val Val Thr 65 70 <210> 8 <211> 94 <212> PRT <213> Human herpesvirus 4 <400> 8 Phe Phe Ala Ile Cys Leu Thr Trp Arg Ile Glu Asp Pro Pro Phe Asn 1 5 10 15 Ser Leu Leu Phe Ala Leu Leu Ala Ala Ala Gly Gly Leu Gln Gly Ile 20 25 30 Tyr Val Leu Val Met Leu Val Leu Leu Ile Leu Ala Tyr Arg Arg Arg 35 40 45 Trp Arg Arg Leu Thr Val Cys Gly Gly Ile Met Phe Leu Ala Cys Val 50 55 60 Leu Val Leu Ile Val Asp Ala Val Leu Gln Leu Ser Pro Leu Leu Gly 65 70 75 80 Ala Val Thr Val Val Ser Met Thr Leu Leu Leu Leu Ala Phe 85 90 <210> 9 <211> 115 <212> PRT <213> Human herpesvirus 4 <400> 9 Val Leu Trp Leu Ser Ser Pro Gly Gly Leu Gly Thr Leu Gly Ala Ala 1 5 10 15 Leu Leu Thr Leu Ala Ala Ala Leu Ala Leu Leu Ala Ser Leu Ile Leu 20 25 30 Gly Thr Leu Asn Leu Thr Thr Met Phe Leu Leu Met Leu Leu Trp Thr 35 40 45 Leu Val Val Leu Leu Ile Cys Ser Ser Cys Ser Ser Cys Pro Leu Ser 50 55 60 Lys Ile Leu Leu Ala Arg Leu Phe Leu Tyr Ala Leu Ala Leu Leu Leu 65 70 75 80 Leu Ala Ser Ala Leu Ile Ala Gly Gly Ser Ile Leu Gln Thr Asn Phe 85 90 95 Lys Ser Leu Ser Ser Thr Glu Phe Ile Pro Asn Leu Phe Cys Met Leu 100 105 110 Leu Leu Ile 115 <210> 10 <211> 98 <212> PRT <213> Human herpesvirus 4 <400> 10 Val Ala Gly Ile Leu Phe Ile Leu Ala Ile Leu Thr Glu Trp Gly Ser 1 5 10 15 Gly Asn Arg Thr Tyr Gly Pro Val Phe Met Cys Leu Gly Gly Leu Leu 20 25 30 Thr Met Val Ala Gly Ala Val Trp Leu Thr Val Met Ser Asn Thr Leu 35 40 45 Leu Ser Ala Trp Ile Leu Thr Ala Gly Phe Leu Ile Phe Leu Ile Gly 50 55 60 Phe Ala Leu Phe Gly Val Ile Arg Cys Cys Arg Tyr Cys Cys Tyr Tyr 65 70 75 80 Cys Leu Thr Leu Glu Ser Glu Glu Arg Pro Pro Thr Pro Tyr Arg Asn 85 90 95 Thr Val <210> 11 <211> 641 <212> PRT <213> Human herpesvirus 4 <400> 11 Met Ser Asp Glu Gly Pro Gly Thr Gly Pro Gly Asn Gly Leu Gly Glu 1 5 10 15 Lys Gly Asp Thr Ser Gly Pro Glu Gly Ser Gly Gly Ser Gly Pro Gln 20 25 30 Arg Arg Gly Gly Asp Asn His Gly Arg Gly Arg Gly Arg Gly Arg Gly 35 40 45 Arg Gly Gly Gly Arg Pro Gly Ala Pro Gly Gly Ser Gly Ser Gly Pro 50 55 60 Arg His Arg Asp Gly Val Arg Arg Pro Gln Lys Arg Pro Ser Cys Ile 65 70 75 80 Gly Cys Lys Gly Thr His Gly Gly Thr Gly Ala Gly Ala Gly Ala Gly 85 90 95 Gly Ala Gly Ala Gly Gly Ala Gly Ala Gly Gly Gly Ala Gly Ala Gly 100 105 110 Gly Gly Ala Gly Gly Ala Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly 115 120 125 Gly Ala Gly Ala Gly Gly Gly Ala Gly Gly Ala Gly Gly Ala Gly Ala 130 135 140 Gly Gly Gly Ala Gly Ala Gly Gly Gly Ala Gly Gly Ala Gly Ala Gly 145 150 155 160 Gly Gly Ala Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly Gly Ala Gly 165 170 175 Ala Gly Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly Gly Ala Gly Gly 180 185 190 Ala Gly Gly Ala Gly Ala Gly Gly Gly Ala Gly Ala Gly Gly Ala Gly 195 200 205 Gly Ala Gly Gly Ala Gly Ala Gly Gly Ala Gly Ala Gly Gly Gly Ala 210 215 220 Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly Ala Gly Ala Gly Gly Ala 225 230 235 240 Gly Ala Gly Gly Ala Gly Ala Gly Gly Ala Gly Gly Ala Gly Ala Gly 245 250 255 Gly Ala Gly Gly Ala Gly Ala Gly Gly Ala Gly Gly Ala Gly Ala Gly 260 265 270 Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly Gly Ala Gly Gly Ala Gly 275 280 285 Ala Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly Ala Gly Gly Ala Gly 290 295 300 Ala Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly Gly Ala Gly Ala Gly 305 310 315 320 Gly Ala Gly Ala Gly Gly Gly Gly Arg Gly Arg Gly Gly Ser Gly Gly 325 330 335 Arg Gly Arg Gly Gly Ser Gly Gly Arg Gly Arg Gly Gly Ser Gly Gly 340 345 350 Arg Arg Gly Arg Gly Arg Glu Arg Ala Arg Gly Gly Ser Arg Glu Arg 355 360 365 Ala Arg Gly Arg Gly Arg Gly Arg Gly Glu Lys Arg Pro Arg Ser Pro 370 375 380 Ser Ser Gln Ser Ser Ser Ser Gly Ser Pro Pro Arg Arg Pro Pro Pro 385 390 395 400 Gly Arg Arg Pro Phe Phe His Pro Val Gly Glu Ala Asp Tyr Phe Glu 405 410 415 Tyr His Gln Glu Gly Gly Pro Asp Gly Glu Pro Asp Val Pro Pro Gly 420 425 430 Ala Ile Glu Gln Gly Pro Ala Asp Asp Pro Gly Glu Gly Pro Ser Thr 435 440 445 Gly Pro Arg Gly Gln Gly Asp Gly Gly Arg Arg Lys Lys Gly Gly Trp 450 455 460 Phe Gly Lys His Arg Gly Gln Gly Gly Ser Asn Pro Lys Phe Glu Asn 465 470 475 480 Ile Ala Glu Gly Leu Arg Ala Leu Leu Ala Arg Ser His Val Glu Arg 485 490 495 Thr Thr Asp Glu Gly Thr Trp Val Ala Gly Val Phe Val Tyr Gly Gly 500 505 510 Ser Lys Thr Ser Leu Tyr Asn Leu Arg Arg Gly Thr Ala Leu Ala Ile 515 520 525 Pro Gln Cys Arg Leu Thr Pro Leu Ser Arg Leu Pro Phe Gly Met Ala 530 535 540 Pro Gly Pro Gly Pro Gln Pro Gly Pro Leu Arg Glu Ser Ile Val Cys 545 550 555 560 Tyr Phe Met Val Phe Leu Gln Thr His Ile Phe Ala Glu Val Leu Lys 565 570 575 Asp Ala Ile Lys Asp Leu Val Met Thr Lys Pro Ala Pro Thr Cys Asn 580 585 590 Ile Arg Val Thr Val Cys Ser Phe Asp Asp Gly Val Asp Leu Pro Pro 595 600 605 Trp Phe Pro Pro Met Val Glu Gly Ala Ala Ala Glu Gly Asp Asp Gly 610 615 620 Asp Asp Gly Asp Glu Gly Gly Asp Gly Asp Glu Gly Glu Glu Gly Gln 625 630 635 640 Glu <210> 12 <211> 86 <212> PRT <213> Human herpesvirus 4 <400> 12 Met Ser Asp Glu Gly Pro Gly Thr Gly Pro Gly Asn Gly Leu Gly Glu 1 5 10 15 Lys Gly Asp Thr Ser Gly Pro Glu Gly Ser Gly Gly Ser Gly Pro Gln 20 25 30 Arg Arg Gly Gly Asp Asn His Gly Arg Gly Arg Gly Arg Gly Arg Gly 35 40 45 Arg Gly Gly Gly Arg Pro Gly Ala Pro Gly Gly Ser Gly Ser Gly Pro 50 55 60 Arg His Arg Asp Gly Val Arg Arg Pro Gln Lys Arg Pro Ser Cys Ile 65 70 75 80 Gly Cys Lys Gly Thr His 85 <210> 13 <211> 944 <212> PRT <213> Human herpesvirus 4 <400> 13 Met Asp Lys Asp Arg Pro Gly Pro Pro Ala Leu Asp Asp Asn Met Glu 1 5 10 15 Glu Glu Val Pro Ser Thr Ser Val Val Gln Glu Gln Val Ser Ala Gly 20 25 30 Asp Trp Glu Asn Val Leu Ile Glu Leu Ser Asp Ser Ser Ser Glu Lys 35 40 45 Glu Ala Glu Asp Ala His Leu Glu Pro Ala Gln Lys Gly Thr Lys Arg 50 55 60 Lys Arg Val Asp His Asp Ala Gly Gly Ser Ala Pro Ala Arg Pro Met 65 70 75 80 Leu Pro Pro Gln Pro Asp Leu Pro Gly Arg Glu Ala Ile Leu Arg Arg 85 90 95 Phe Pro Leu Asp Leu Arg Thr Leu Leu Gln Ala Ile Gly Ala Ala Ala 100 105 110 Thr Arg Ile Asp Thr Arg Ala Ile Asp Gln Phe Phe Gly Ser Gln Ile 115 120 125 Ser Asn Thr Glu Met Tyr Ile Met Tyr Ala Met Ala Ile Arg Gln Ala 130 135 140 Ile Arg Asp Arg Arg Arg Asn Pro Ala Ser Arg Arg Asp Gln Ala Lys 145 150 155 160 Trp Arg Leu Gln Thr Leu Ala Ala Gly Trp Pro Met Gly Tyr Gln Ala 165 170 175 Tyr Ser Ser Trp Met Tyr Ser Tyr Thr Asp His Gln Thr Thr Pro Thr 180 185 190 Phe Val His Leu Gln Ala Thr Leu Gly Cys Thr Gly Gly Arg Arg Cys 195 200 205 His Val Thr Phe Ser Ala Gly Thr Phe Lys Leu Pro Arg Cys Thr Pro 210 215 220 Gly Asp Arg Gln Trp Leu Tyr Val Gln Ser Ser Val Gly Asn Ile Val 225 230 235 240 Gln Ser Cys Asn Pro Arg Tyr Ser Ile Phe Phe Asp Tyr Met Ala Ile 245 250 255 His Arg Ser Leu Thr Lys Ile Trp Glu Glu Val Leu Thr Pro Asp Gln 260 265 270 Arg Val Ser Phe Met Glu Phe Leu Gly Phe Leu Gln Arg Thr Asp Leu 275 280 285 Ser Tyr Ile Lys Ser Phe Val Ser Asp Ala Leu Gly Thr Thr Ser Ile 290 295 300 Gln Thr Pro Trp Ile Asp Asp Asn Pro Ser Thr Glu Thr Ala Gln Ala 305 310 315 320 Trp Asn Ala Gly Phe Leu Arg Gly Arg Ala Tyr Gly Ile Asp Leu Leu 325 330 335 Arg Thr Glu Gly Glu His Val Glu Gly Ala Thr Gly Glu Thr Arg Glu 340 345 350 Glu Ser Glu Asp Thr Glu Ser Asp Gly Asp Asp Glu Asp Leu Pro Cys 355 360 365 Ile Val Ser Arg Gly Gly Pro Lys Val Lys Arg Pro Pro Ile Phe Ile 370 375 380 Arg Arg Leu His Arg Leu Leu Leu Met Arg Ala Gly Lys Arg Thr Glu 385 390 395 400 Gln Gly Lys Glu Val Leu Glu Lys Ala Arg Gly Ser Thr Tyr Gly Thr 405 410 415 Pro Arg Pro Pro Val Pro Lys Pro Arg Pro Glu Val Pro Gln Ser Asp 420 425 430 Glu Thr Ala Thr Ser His Gly Ser Ala Gln Val Pro Glu Pro Pro Thr 435 440 445 Ile His Leu Ala Ala Gln Gly Met Ala Tyr Pro Leu His Glu Gln His 450 455 460 Gly Met Ala Pro Cys Pro Val Ala Gln Ala Pro Pro Thr Pro Leu Pro 465 470 475 480 Pro Val Ser Pro Gly Asp Gln Leu Pro Gly Val Phe Ser Asp Gly Arg 485 490 495 Val Ala Cys Ala Pro Val Pro Ala Pro Ala Gly Pro Ile Val Arg Pro 500 505 510 Trp Glu Pro Ser Leu Thr Gln Ala Ala Gly Gln Ala Phe Ala Pro Val 515 520 525 Arg Pro Gln His Met Pro Val Glu Pro Val Pro Val Pro Thr Val Ala 530 535 540 Leu Glu Arg Pro Val Tyr Pro Lys Pro Val Arg Pro Ala Pro Pro Lys 545 550 555 560 Ile Ala Met Gln Gly Pro Gly Glu Thr Ser Gly Ile Arg Arg Ala Arg 565 570 575 Glu Arg Trp Arg Pro Ala Pro Trp Thr Pro Asn Pro Pro Arg Ser Pro 580 585 590 Ser Gln Met Ser Val Arg Asp Arg Leu Ala Arg Leu Arg Ala Glu Ala 595 600 605 Gln Val Lys Gln Ala Ser Val Glu Val Gln Pro Pro Gln Leu Thr Gln 610 615 620 Val Ser Pro Gln Gln Pro Met Glu Gly Pro Leu Val Pro Glu Gln Gln 625 630 635 640 Met Phe Pro Gly Ala Pro Phe Ser Gln Val Ala Asp Val Val Arg Ala 645 650 655 Pro Gly Val Pro Ala Met Gln Pro Gln Tyr Phe Asp Leu Pro Leu Ile 660 665 670 Gln Pro Ile Ser Gln Gly Ala Pro Val Ala Pro Leu Arg Ala Ser Met 675 680 685 Gly Pro Val Pro Pro Val Pro Ala Thr Gln Pro Gln Tyr Phe Asp Ile 690 695 700 Pro Leu Thr Glu Pro Ile Asn Gln Gly Ala Ser Ala Ala His Phe Leu 705 710 715 720 Pro Gln Gln Pro Met Glu Gly Pro Leu Val Pro Glu Gln Trp Met Phe 725 730 735 Pro Gly Ala Ala Leu Ser Gln Ser Val Arg Pro Gly Val Ala Gln Ser 740 745 750 Gln Tyr Phe Asp Leu Pro Leu Thr Gln Pro Ile Asn His Gly Ala Pro 755 760 765 Ala Ala His Phe Leu His Gln Pro Pro Met Glu Gly Pro Trp Val Pro 770 775 780 Glu Gln Trp Met Phe Gln Gly Ala Pro Pro Ser Gln Gly Thr Asp Val 785 790 795 800 Val Gln His Gln Leu Asp Ala Leu Gly Tyr Thr Leu His Gly Leu Asn 805 810 815 His Pro Gly Val Pro Val Ser Pro Ala Val Asn Gln Tyr His Leu Ser 820 825 830 Gln Ala Ala Phe Gly Leu Pro Ile Asp Glu Asp Glu Ser Gly Glu Gly 835 840 845 Ser Asp Thr Ser Glu Pro Cys Glu Ala Leu Asp Leu Ser Ile His Gly 850 855 860 Arg Pro Cys Pro Gln Ala Pro Glu Trp Pro Val Gln Glu Glu Gly Gly 865 870 875 880 Gln Asp Ala Thr Glu Val Leu Asp Leu Ser Ile His Gly Arg Pro Arg 885 890 895 Pro Arg Thr Pro Glu Trp Pro Val Gln Gly Glu Gly Gly Gln Asn Val 900 905 910 Thr Gly Pro Glu Thr Arg Arg Val Val Val Ser Ala Val Val His Met 915 920 925 Cys Gln Asp Asp Glu Phe Pro Asp Leu Gln Asp Pro Pro Asp Glu Ala 930 935 940 <210> 14 <211> 66 <212> PRT <213> Human herpesvirus 4 <400> 14 Ile Arg Asp Arg Arg Arg Asn Pro Ala Ser Arg Arg Asp Gln Ala Lys 1 5 10 15 Trp Arg Leu Gln Thr Leu Ala Ala Gly Trp Pro Met Gly Tyr Gln Ala 20 25 30 Tyr Ser Ser Trp Met Tyr Ser Tyr Thr Asp His Gln Thr Thr Pro Thr 35 40 45 Phe Val His Leu Gln Ala Thr Leu Gly Cys Thr Gly Gly Arg Arg Cys 50 55 60 His Val 65 <210> 15 <211> 55 <212> PRT <213> Human herpesvirus 4 <400> 15 Thr Phe Ser Ala Gly Thr Phe Lys Leu Pro Arg Cys Thr Pro Gly Asp 1 5 10 15 Arg Gln Trp Leu Tyr Val Gln Ser Ser Val Gly Asn Ile Val Gln Ser 20 25 30 Cys Asn Pro Arg Tyr Ser Ile Phe Phe Asp Tyr Met Ala Ile His Arg 35 40 45 Ser Leu Thr Lys Ile Trp Glu 50 55 <210> 16 <211> 88 <212> PRT <213> Human herpesvirus 4 <400> 16 Trp Ile Asp Asp Asn Pro Ser Thr Glu Thr Ala Gln Ala Trp Asn Ala 1 5 10 15 Gly Phe Leu Arg Gly Arg Ala Tyr Gly Ile Asp Leu Leu Arg Thr Glu 20 25 30 Gly Glu His Val Glu Gly Ala Thr Gly Glu Thr Arg Glu Glu Ser Glu 35 40 45 Asp Thr Glu Ser Asp Gly Asp Asp Glu Asp Leu Pro Cys Ile Val Ser 50 55 60 Arg Gly Gly Pro Lys Val Lys Arg Pro Pro Ile Phe Ile Arg Arg Leu 65 70 75 80 His Arg Leu Leu Leu Met Arg Ala 85 <210> 17 <211> 25 <212> PRT <213> Human herpesvirus 4 <400> 17 Gly Lys Arg Thr Glu Gln Gly Lys Glu Val Leu Glu Lys Ala Arg Gly 1 5 10 15 Ser Thr Tyr Gly Thr Pro Arg Pro Pro 20 25 <210> 18 <211> 40 <212> PRT <213> Human herpesvirus 4 <400> 18 Ala Gln Val Pro Glu Pro Pro Thr Ile His Leu Ala Ala Gln Gly Met 1 5 10 15 Ala Tyr Pro Leu His Glu Gln His Gly Met Ala Pro Cys Pro Val Ala 20 25 30 Gln Ala Pro Pro Thr Pro Leu Pro 35 40 <210> 19 <211> 62 <212> PRT <213> Human herpesvirus 4 <400> 19 Gly Arg Val Ala Cys Ala Pro Val Pro Ala Pro Ala Gly Pro Ile Val 1 5 10 15 Arg Pro Trp Glu Pro Ser Leu Thr Gln Ala Ala Gly Gln Ala Phe Ala 20 25 30 Pro Val Arg Pro Gln His Met Pro Val Glu Pro Val Pro Val Pro Thr 35 40 45 Val Ala Leu Glu Arg Pro Val Tyr Pro Lys Pro Val Arg Pro 50 55 60 <210> 20 <211> 51 <212> PRT <213> Human herpesvirus 4 <400> 20 Arg Pro Ala Pro Trp Thr Pro Asn Pro Pro Arg Ser Pro Ser Gln Met 1 5 10 15 Ser Val Arg Asp Arg Leu Ala Arg Leu Arg Ala Glu Ala Gln Val Lys 20 25 30 Gln Ala Ser Val Glu Val Gln Pro Pro Gln Leu Thr Gln Val Ser Pro 35 40 45 Gln Gln Pro 50 <210> 21 <211> 245 <212> PRT <213> Human herpesvirus 4 <400> 21 Met Met Asp Pro Asn Ser Thr Ser Glu Asp Val Lys Phe Thr Pro Asp 1 5 10 15 Pro Tyr Gln Val Pro Phe Val Gln Ala Phe Asp Gln Ala Thr Arg Val 20 25 30 Tyr Gln Asp Leu Gly Gly Pro Ser Gln Ala Pro Leu Pro Cys Val Leu 35 40 45 Trp Pro Val Leu Pro Glu Pro Leu Pro Gln Gly Gln Leu Thr Ala Tyr 50 55 60 His Val Ser Thr Ala Pro Thr Gly Ser Trp Phe Ser Ala Pro Gln Pro 65 70 75 80 Ala Pro Glu Asn Ala Tyr Gln Ala Tyr Ala Ala Pro Gln Leu Phe Pro 85 90 95 Val Ser Asp Ile Thr Gln Asn Gln Gln Thr Asn Gln Ala Gly Gly Glu 100 105 110 Ala Pro Gln Pro Gly Asp Asn Ser Thr Val Gln Thr Ala Ala Ala Val 115 120 125 Val Phe Ala Cys Pro Gly Ala Asn Gln Gly Gln Gln Leu Ala Asp Ile 130 135 140 Gly Val Pro Gln Pro Ala Pro Val Ala Ala Pro Ala Arg Arg Thr Arg 145 150 155 160 Lys Pro Gln Gln Pro Glu Ser Leu Glu Glu Cys Asp Ser Glu Leu Glu 165 170 175 Ile Lys Arg Tyr Lys Asn Arg Val Ala Ser Arg Lys Cys Arg Ala Lys 180 185 190 Phe Lys Gln Leu Leu Gln His Tyr Arg Glu Val Ala Ala Ala Lys Ser 195 200 205 Ser Glu Asn Asp Arg Leu Arg Leu Leu Leu Lys Gln Met Cys Pro Ser 210 215 220 Leu Asp Val Asp Ser Ile Ile Pro Arg Thr Pro Asp Val Leu His Glu 225 230 235 240 Asp Leu Leu Asn Phe 245 <210> 22 <211> 66 <212> PRT <213> Human herpesvirus 4 <400> 22 Asp Leu Gly Gly Pro Ser Gln Ala Pro Leu Pro Cys Val Leu Trp Pro 1 5 10 15 Val Leu Pro Glu Pro Leu Pro Gln Gly Gln Leu Thr Ala Tyr His Val 20 25 30 Ser Thr Ala Pro Thr Gly Ser Trp Phe Ser Ala Pro Gln Pro Ala Pro 35 40 45 Glu Asn Ala Tyr Gln Ala Tyr Ala Ala Pro Gln Leu Phe Pro Val Ser 50 55 60 Asp Ile 65 <210> 23 <211> 51 <212> PRT <213> Human herpesvirus 4 <400> 23 Arg Lys Pro Gln Gln Pro Glu Ser Leu Glu Glu Cys Asp Ser Glu Leu 1 5 10 15 Glu Ile Lys Arg Tyr Lys Asn Arg Val Ala Ser Arg Lys Cys Arg Ala 20 25 30 Lys Phe Lys Gln Leu Leu Gln His Tyr Arg Glu Val Ala Ala Ala Lys 35 40 45 Ser Ser Glu 50 <210> 24 <211> 1153 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 24 Met Arg Pro Ala Pro Trp Thr Pro Asn Pro Pro Arg Ser Pro Ser Gln 1 5 10 15 Methionine, Serine, Valine, Arginine, Aspartic acid, Arginine, Leucine, Alanine, Arginine, Leucine, Arginine, Alanine, Glutamic acid, Alanine, Glutamine, Valine 20 25 30 Lysine, Glutamine, Alanine, Serine, Valine, Glutamic acid, Valine, Glutamine, Proline, Proline, Glutamine, Leucine, Threonine, Glutamine, Valine, Serine 35 40 45 Proline, Glutamine, Glutamine, Proline, Valine, Alanine, Glycine, Isoleucine, Leucine, Phenylalanine, Isoleucine, Leucine, Alanine, Isoleucine, Leucine, Threonine 50 55 60 Glutamic acid, Tryptophan, Glycine, Serine, Glycine, Asparagine, Arginine, Threonine, Tyrosine, Glycine, Proline, Valine, Phenylalanine, Methionine, Cysteine, Leucine 65 70 75 80 Glycine, Glycine, Leucine, Leucine, Threonine, Methionine, Valine, Alanine, Glycine, Alanine, Valine, Tryptophan, Leucine, Threonine, Valine, Methionine 85 90 95 Serine, Asparagine, Threonine, Leucine, Leucine, Serine, Alanine, Tryptophan, Isoleucine, Leucine, Threonine, Alanine, Glycine, Phenylalanine, Leucine, Isoleucine 100 105 110 Phenylalanine, Leucine, Isoleucine, Glycine, Phenylalanine, Alanine, Leucine, Phenylalanine, Glycine, Valine, Isoleucine, Arginine, Cysteine, Cysteine, Arginine, Tyrosine 115 120 125 Cysteine, Cysteine, Tyrosine, Tyrosine, Cysteine, Leucine, Threonine, Leucine, Glutamic acid, Serine, Glutamic acid, Glutamic acid, Arginine, Proline, Proline, Threonine 130 135 140 Pro Tyr Arg Asn Thr Val Ile Arg Asp Arg Arg Arg Asn Pro Ala Ser 145 150 155 160 Arg Arg Asp Gln Ala Lys Trp Arg Leu Gln Thr Leu Ala Ala Gly Trp 165 170 175 Pro Met Gly Tyr Gln Ala Tyr Ser Ser Trp Met Tyr Ser Tyr Thr Asp 180 185 190 His Gln Thr Thr Pro Thr Phe Val His Leu Gln Ala Thr Leu Gly Cys 195 200 205 Thr Gly Gly Arg Arg Cys His Val Phe Leu Gly Ile Val Leu Phe Ile 210 215 220 Phe Gly Cys Leu Leu Val Leu Gly Ile Trp Ile Tyr Leu Leu Glu Met 225 230 235 240 Leu Trp Arg Leu Gly Ala Thr Ile Trp Gln Leu Leu Ala Phe Phe Leu 245 250 255 Ala Phe Phe Leu Asp Leu Ile Leu Leu Ile Ile Ala Leu Tyr Leu Gln 260 265 270 Gln Asn Trp Trp Thr Leu Leu Val Asp Leu Leu Trp Leu Leu Leu Phe 275 280 285 Leu Ala Ile Leu Ile Trp Met Tyr Tyr His Gly Gln Arg Gly Arg Val 290 295 300 Ala Cys Ala Pro Val Pro Ala Pro Ala Gly Pro Ile Val Arg Pro Trp 305 310 315 320 Glu Pro Ser Leu Thr Gln Ala Ala Gly Gln Ala Phe Ala Pro Val Arg 325 330 335 Pro Gln His Met Pro Val Glu Pro Val Pro Val Pro Thr Val Ala Leu 340 345 350 Glu Arg Pro Val Tyr Pro Lys Pro Val Arg Pro Val Leu Trp Leu Ser 355 360 365 Ser Pro Gly Gly Leu Gly Thr Leu Gly Ala Ala Leu Leu Thr Leu Ala 370 375 380 Ala Ala Leu Ala Leu Leu Ala Ser Leu Ile Leu Gly Thr Leu Asn Leu 385 390 395 400 Thr Thr Met Phe Leu Leu Met Leu Leu Trp Thr Leu Val Val Leu Leu 405 410 415 Ile Cys Ser Ser Cys Ser Ser Cys Pro Leu Ser Lys Ile Leu Leu Ala 420 425 430 Arg Leu Phe Leu Tyr Ala Leu Ala Leu Leu Leu Leu Ala Ser Ala Leu 435 440 445 Ile Ala Gly Gly Ser Ile Leu Gln Thr Asn Phe Lys Ser Leu Ser Ser 450 455 460 Thr Glu Phe Ile Pro Asn Leu Phe Cys Met Leu Leu Leu Ile His Ser 465 470 475 480 Asp Glu His His His Asp Asp Ser Leu Pro His Pro Gln Gln Ala Thr 485 490 495 Asp Asp Ser Gly His Glu Ser Asp Ser Asn Ser Asn Glu Gly Arg His 500 505 510 His Leu Leu Val Ser Gly Ala Gln Val Pro Glu Pro Pro Thr Ile His 515 520 525 Leu Ala Ala Gln Gly Met Ala Tyr Pro Leu His Glu Gln His Gly Met 530 535 540 Ala Pro Cys Pro Val Ala Gln Ala Pro Pro Thr Pro Leu Pro Phe Phe 545 550 555 560 Ala Ile Cys Leu Thr Trp Arg Ile Glu Asp Pro Pro Phe Asn Ser Leu 565 570 575 Leu Phe Ala Leu Leu Ala Ala Ala Gly Gly Leu Gln Gly Ile Tyr Val 580 585 590 Leu Val Met Leu Val Leu Leu Ile Leu Ala Tyr Arg Arg Arg Trp Arg 595 600 605 Arg Leu Thr Val Cys Gly Gly Ile Met Phe Leu Ala Cys Val Leu Val 610 615 620 Leu Ile Val Asp Ala Val Leu Gln Leu Ser Pro Leu Leu Gly Ala Val 625 630 635 640 Thr Val Val Ser Met Thr Leu Leu Leu Leu Ala Phe Asn Gly Pro His 645 650 655 Asp Pro Leu Pro Gln Asp Pro Asp Asn Thr Asp Asp Asn Gly Pro Gln 660 665 670 Asp Pro Asp Asn Thr Asp Asp Asn Gly Pro His Asp Pro Leu Pro His 675 680 685 Ser Pro Ser Asp Ser Ala Gly Asn Asp Gly Gly Pro Pro Gln Leu Thr 690 695 700 Glu Glu Val Glu Asn Lys Gly Gly Asp Gln Gly Pro Pro Leu Met Thr 705 710 715 720 Asp Gly Gly Gly Gly His Ser His Asp Ser Gly His Gly Gly Gly Asp 725 730 735 Pro His Leu Pro Thr Leu Leu Leu Gly Ser Ser Gly Ser Gly Gly Asp 740 745 750 Asp Asp Asp Pro His Gly Pro Val Gln Leu Ser Tyr Tyr Asp Gly Lys 755 760 765 Arg Thr Glu Gln Gly Lys Glu Val Leu Glu Lys Ala Arg Gly Ser Thr 770 775 780 Tyr Gly Thr Pro Arg Pro Pro Met Ser Asp Trp Thr Gly Gly Ala Leu 785 790 795 800 Leu Val Leu Tyr Ser Phe Ala Leu Met Leu Ile Ile Ile Ile Leu Ile 805 810 815 Ile Phe Ile Phe Arg Arg Asp Leu Leu Cys Pro Leu Gly Ala Leu Cys 820 825 830 Ile Leu Leu Leu Met Ile Thr Leu Leu Leu Ile Ala Leu Trp Asn Leu 835 840 845 His Gly Gln Ala Leu Met Ser Asp Glu Gly Pro Gly Thr Gly Pro Gly 850 855 860 Asn Gly Leu Gly Glu Lys Gly Asp Thr Ser Gly Pro Glu Gly Ser Gly 865 870 875 880 Gly Ser Gly Pro Gln Arg Arg Gly Gly Asp Asn His Gly Arg Gly Arg 885 890 895 Gly Arg Gly Arg Gly Arg Gly Gly Gly Arg Pro Gly Ala Pro Gly Gly 900 905 910 Ser Gly Ser Gly Pro Arg His Arg Asp Gly Val Arg Arg Pro Gln Lys 915 920 925 Arg Pro Ser Cys Ile Gly Cys Lys Gly Thr His Trp Ile Asp Asp Asn 930 935 940 Pro Ser Thr Glu Thr Ala Gln Ala Trp Asn Ala Gly Phe Leu Arg Gly 945 950 955 960 Arg Ala Tyr Gly Ile Asp Leu Leu Arg Thr Glu Gly Glu His Val Glu 965 970 975 Gly Ala Thr Gly Glu Thr Arg Glu Glu Ser Glu Asp Thr Glu Ser Asp 980 985 990 Gly Asp Asp Glu Asp Leu Pro Cys Ile Val Ser Arg Gly Gly Pro Lys 995 1000 1005 Val Lys Arg Pro Pro Ile Phe Ile Arg Arg Leu His Arg Leu Leu 1010 1015 1020 Leu Met Arg Ala Met Asn Pro Val Cys Leu Pro Val Ile Val Ala 1025 1030 1035 Pro Tyr Leu Phe Trp Leu Ala Ala Ile Ala Ala Ser Cys Phe Thr 1040 1045 1050 Ala Ser Val Ser Thr Val Val Thr Ala Thr Gly Leu Ala Leu Ser 1055 1060 1065 Leu Leu Leu Leu Ala Ala Val Ala Ser Ser Tyr Ala Ala Ala Gln 1070 1075 1080 Arg Lys Leu Leu Thr Pro Val Thr Val Leu Thr Ala Val Val Thr 1085 1090 1095 Thr Phe Ser Ala Gly Thr Phe Lys Leu Pro Arg Cys Thr Pro Gly 1100 1105 1110 Asp Arg Gln Trp Leu Tyr Val Gln Ser Ser Val Gly Asn Ile Val 1115 1120 1125 Gln Ser Cys Asn Pro Arg Tyr Ser Ile Phe Phe Asp Tyr Met Ala 1130 1135 1140 Ile His Arg Ser Leu Thr Lys Ile Trp Glu 1145 1150 <210> 25 <211> 3459 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 25 atgagacctg ctccctggac acctaatcct cccaggtccc ccagccagat gagcgtgaga 60 gacagactgg ctaggctgag agccgaggct caggtcaagc aggccagcgt cgaggtgcaa 120 ccccctcagc tcacccaggt gtccccccag cagcctgtgg ccggcattct gttcattctg 180 gccattctga ccgagtgggg aagcggcaac agaacctacg gccctgtctt catgtgcctc 240 ggaggactgc tgacaatggt ggctggcgcc gtgtggctca ccgtcatgtc caacaccctg 300 ctcagcgcct ggattctgac cgccggattc ctgatctttc tgatcggatt cgctctcttt 360 ggcgtcatca ggtgttgcag gtactgttgc tactactgcc tgaccctcga gagcgaggaa 420 agacccccca ccccctacag gaatacagtg attagggaca gaaggaggaa tcctgcctcc 480 aggagagacc aggccaaatg gagactccaa acactcgccg ctggatggcc catgggctac 540 caggcctata gctcctggat gtacagctac accgaccatc agacaacacc caccttcgtg 600 catctgcagg ctacactggg ctgcaccgga ggcagaaggt gtcacgtgtt tctgggaatc 660 gtgctgttca tctttggatg cctgctcgtg ctgggcatct ggatttatct cctggagatg 720 ctctggagac tcggcgctac aatttggcag ctgctcgcct tttttctggc cttctttctg 780 gacctgatcc tcctgatcat cgccctgtac ctccaacaga actggtggac cctcctggtg 840 gatctgctgt ggctcctcct cttcctggcc atcctgatct ggatgtacta ccatggccag 900 agaggaaggg tcgcttgcgc tcctgtccct gctcctgctg gccccatcgt gaggccttgg 960 gagccttccc tcacacaggc cgccggccag gcctttgctc ccgtgaggcc ccagcacatg 1020 cctgtggaac ccgtgcccgt ccccacagtg gctctggaaa ggcctgtgta ccccaagccc 1080 gtgagacctg tcctctggct cagcagccct ggaggactcg gaacactcgg agccgctctc 1140 ctgacactgg ccgctgctct ggctctgctg gctagcctga tcctgggaac cctcaacctc 1200 accaccatgt ttctcctcat gctcctgtgg accctcgtgg tgctgctcat ctgttccagc 1260 tgctccagct gccccctgag caagatcctg ctggccaggc tgttcctgta cgccctcgcc 1320 ctcctgctgc tggctagcgc cctgatcgct ggcggaagca tcctccagac caatttcaag 1380 agcctctcct ccaccgagtt catccccaac ctgttctgta tgttactgct gatccatagc 1440 gacgagcacc atcatgacga ctccctgccc catcctcagc aggccacaga cgactccggc 1500 cacgagagcg acagcaatag caatgagggc aggcaccatc tgctcgtgtc cggagctcaa 1560 gtccccgagc ctcccaccat ccatctcgcc gcccagggaa tggcttaccc cctccacgag 1620 cagcacggca tggccccttg tcccgtcgct caagcccccc ctacacctct gccctttttc 1680 gccatttgtc tgacctggag aatcgaggac ccccccttca acagcctgct gttcgccctg 1740 ctcgccgccg ctggcggcct ccagggcatt tacgtcctcg tgatgctggt gctgctgatc 1800 ctcgcttaca ggagaagatg gaggagactg acagtgtgcg gcggcatcat gtttctcgcc 1860 tgcgtcctgg tcctgatcgt ggacgccgtc ctgcaactca gccccctcct gggagctgtg 1920 acagtggtct ccatgaccct gctgctgctg gccttcaacg gaccccacga tcctctgccc 1980 caagatcctg acaataccga cgataacggc ccccaagacc ccgataacac cgacgacaat 2040 ggccctcacg accctctgcc ccatagccct tccgatagcg ctggcaacga tggcggccct 2100 cctcagctga cagaggaggt ggaaaataag ggcggcgatc agggaccccc cctgatgaca 2160 gatggcggag gaggacacag ccatgatagc ggacatggcg gaggcgatcc ccatctgcct 2220 accctcctcc tgggcagctc cggttctgga ggcgacgatg atgaccctca cggccctgtg 2280 cagctctcct actacgacgg caaaaggacc gaacaaggaa aagaggtcct ggagaaggcc 2340 aggggcagca catacggaac ccccaggcct cccatgtccg attggaccgg aggagccctg 2400 ctggtcctct acagcttcgc cctgatgctg atcattatca tcctgatcat ctttatcttc 2460 agaagggacc tgctgtgccc tctcggcgcc ctgtgcatcc tgctgctcat gatcacactc 2520 ctcctgatcg ccctctggaa cctgcacgga caagccctga tgtccgatga gggacctgga 2580 acaggacccg gaaacggact gggcgagaag ggagatacaa gcggccccga aggcagcggc 2640 ggaagcggac cccaaagaag gggcggcgac aaccacggaa gaggaagagg caggggcaga 2700 ggcagaggag gaggaagacc tggagcccct ggcggttctg gaagcggacc caggcacagg 2760 gacggagtga ggaggcctca aaaaagaccc agctgcatcg gctgcaaggg aacccactgg 2820 attgatgata acccctccac agagaccgct caggcctgga acgccggctt cctgagggga 2880 agagcctatg gcatcgatct gctgaggacc gagggcgaac acgtggaggg agccaccgga 2940 gagacaaggg aggaaagcga agacacagaa agcgatggcg acgacgaaga cctgccctgc 3000 attgtgtcca ggggcggacc caaggtgaag aggcccccta tctttatcag aaggctccat 3060 agactgctcc tgatgagggc catgaaccct gtgtgcctgc ccgtgatcgt ggccccctac 3120 ctcttttggc tggccgccat tgccgctagc tgcttcaccg cctccgtgtc cacagtggtg 3180 acagccaccg gcctcgccct gagcctgctg ctcctcgctg ccgtggcctc cagctacgcc 3240 gctgctcaaa gaaagctcct gacccctgtc accgtcctga cagccgtcgt gaccaccttt 3300 tccgctggca ccttcaagct gcctaggtgc acacctggcg acaggcagtg gctctacgtg 3360 cagagctccg tgggcaatat tgtgcagagc tgcaatccca ggtacagcat ttttttcgac 3420 tacatggcca tccataggtc cctcaccaag atctgggag 3459 <210> 26 <211> 1270 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 26 Met Arg Pro Ala Pro Trp Thr Pro Asn Pro Pro Arg Ser Pro Ser Gln 1 5 10 15 Met Ser Val Arg Asp Arg Leu Ala Arg Leu Arg Ala Glu Ala Gln Val 20 25 30 Lys Gln Ala Ser Val Glu Val Gln Pro Pro Gln Leu Thr Gln Val Ser 35 40 45 Pro Gln Gln Pro Val Ala Gly Ile Leu Phe Ile Leu Ala Ile Leu Thr 50 55 60 Glu Trp Gly Ser Gly Asn Arg Thr Tyr Gly Pro Val Phe Met Cys Leu 65 70 75 80 Gly Gly Leu Leu Thr Met Val Ala Gly Ala Val Trp Leu Thr Val Met 85 90 95 Ser Asn Thr Leu Leu Ser Ala Trp Ile Leu Thr Ala Gly Phe Leu Ile 100 105 110 Phe Leu Ile Gly Phe Ala Leu Phe Gly Val Ile Arg Cys Cys Arg Tyr 115 120 125 Cys Cys Tyr Tyr Cys Leu Thr Leu Glu Ser Glu Glu Arg Pro Pro Thr 130 135 140 Pro Tyr Arg Asn Thr Val Arg Lys Pro Gln Gln Pro Glu Ser Leu Glu 145 150 155 160 Glu Cys Asp Ser Glu Leu Glu Ile Lys Arg Tyr Lys Asn Arg Val Ala 165 170 175 Ser Arg Lys Cys Arg Ala Lys Phe Lys Gln Leu Leu Gln His Tyr Arg 180 185 190 Glu Val Ala Ala Ala Lys Ser Ser Glu Ile Arg Asp Arg Arg Arg Asn 195 200 205 Pro Ala Ser Arg Arg Asp Gln Ala Lys Trp Arg Leu Gln Thr Leu Ala 210 215 220 Ala Gly Trp Pro Met Gly Tyr Gln Ala Tyr Ser Ser Trp Met Tyr Ser 225 230 235 240 Tyr Thr Asp His Gln Thr Thr Pro Thr Phe Val His Leu Gln Ala Thr 245 250 255 Leu Gly Cys Thr Gly Gly Arg Arg Cys His Val Phe Leu Gly Ile Val 260 265 270 Leu Phe Ile Phe Gly Cys Leu Leu Val Leu Gly Ile Trp Ile Tyr Leu 275 280 285 Leu Glu Met Leu Trp Arg Leu Gly Ala Thr Ile Trp Gln Leu Leu Ala 290 295 300 Phe Phe Leu Ala Phe Phe Leu Asp Leu Ile Leu Leu Ile Ile Ala Leu 305 310 315 320 Tyr Leu Gln Gln Asn Trp Trp Thr Leu Leu Val Asp Leu Leu Trp Leu 325 330 335 Leu Leu Phe Leu Ala Ile Leu Ile Trp Met Tyr Tyr His Gly Gln Arg 340 345 350 Gly Arg Val Ala Cys Ala Pro Val Pro Ala Pro Ala Gly Pro Ile Val 355 360 365 Arg Pro Trp Glu Pro Ser Leu Thr Gln Ala Ala Gly Gln Ala Phe Ala 370 375 380 Pro Val Arg Pro Gln His Met Pro Val Glu Pro Val Pro Val Pro Thr 385 390 395 400 Val Ala Leu Glu Arg Pro Val Tyr Pro Lys Pro Val Arg Pro Val Leu 405 410 415 Trp Leu Ser Ser Pro Gly Gly Leu Gly Thr Leu Gly Ala Ala Leu Leu 420 425 430 Thr Leu Ala Ala Ala Leu Ala Leu Leu Ala Ser Leu Ile Leu Gly Thr 435 440 445 Leu Asn Leu Thr Thr Met Phe Leu Leu Met Leu Leu Trp Thr Leu Val 450 455 460 Val Leu Leu Ile Cys Ser Ser Cys Ser Ser Cys Pro Leu Ser Lys Ile 465 470 475 480 Leu Leu Ala Arg Leu Phe Leu Tyr Ala Leu Ala Leu Leu Leu Leu Ala 485 490 495 Ser Ala Leu Ile Ala Gly Gly Ser Ile Leu Gln Thr Asn Phe Lys Ser 500 505 510 Leu Ser Ser Thr Glu Phe Ile Pro Asn Leu Phe Cys Met Leu Leu Leu 515 520 525 Ile His Ser Asp Glu His His His Asp Asp Ser Leu Pro His Pro Gln 530 535 540 Gln Ala Thr Asp Asp Ser Gly His Glu Ser Asp Ser Asn Ser Asn Glu 545 550 555 560 Gly Arg His His Leu Leu Val Ser Gly Ala Gln Val Pro Glu Pro Pro 565 570 575 Thr Ile His Leu Ala Ala Gln Gly Met Ala Tyr Pro Leu His Glu Gln 580 585 590 His Gly Met Ala Pro Cys Pro Val Ala Gln Ala Pro Pro Thr Pro Leu 595 600 605 Pro Phe Phe Ala Ile Cys Leu Thr Trp Arg Ile Glu Asp Pro Pro Phe 610 615 620 Asn Ser Leu Leu Phe Ala Leu Leu Ala Ala Ala Gly Gly Leu Gln Gly 625 630 635 640 Ile Tyr Val Leu Val Met Leu Val Leu Leu Ile Leu Ala Tyr Arg Arg 645 650 655 Arg Trp Arg Arg Leu Thr Val Cys Gly Gly Ile Met Phe Leu Ala Cys 660 665 670 Val Leu Val Leu Ile Val Asp Ala Val Leu Gln Leu Ser Pro Leu Leu 675 680 685 Gly Ala Val Thr Val Val Ser Met Thr Leu Leu Leu Leu Ala Phe Asn 690 695 700 Gly Pro His Asp Pro Leu Pro Gln Asp Pro Asp Asn Thr Asp Asp Asn 705 710 715 720 Gly Pro Gln Asp Pro Asp Asn Thr Asp Asp Asn Gly Pro His Asp Pro 725 730 735 Leu Pro His Ser Pro Ser Asp Ser Ala Gly Asn Asp Gly Gly Pro Pro 740 745 750 Gln Leu Thr Glu Glu Val Glu Asn Lys Gly Gly Asp Gln Gly Pro Pro 755 760 765 Leu Met Thr Asp Gly Gly Gly Gly His Ser His Asp Ser Gly His Gly 770 775 780 Gly Gly Asp Pro His Leu Pro Thr Leu Leu Leu Gly Ser Ser Gly Ser 785 790 795 800 Gly Gly Asp Asp Asp Asp Pro His Gly Pro Val Gln Leu Ser Tyr Tyr 805 810 815 Asp Gly Lys Arg Thr Glu Gln Gly Lys Glu Val Leu Glu Lys Ala Arg 820 825 830 Gly Ser Thr Tyr Gly Thr Pro Arg Pro Pro Met Ser Asp Trp Thr Gly 835 840 845 Gly Ala Leu Leu Val Leu Tyr Ser Phe Ala Leu Met Leu Ile Ile Ile 850 855 860 Ile Leu Ile Ile Phe Ile Phe Arg Arg Asp Leu Leu Cys Pro Leu Gly 865 870 875 880 Ala Leu Cys Ile Leu Leu Leu Met Ile Thr Leu Leu Leu Ile Ala Leu 885 890 895 Trp Asn Leu His Gly Gln Ala Leu Met Ser Asp Glu Gly Pro Gly Thr 900 905 910 Gly Pro Gly Asn Gly Leu Gly Glu Lys Gly Asp Thr Ser Gly Pro Glu 915 920 925 Gly Ser Gly Gly Ser Gly Pro Gln Arg Arg Gly Gly Asp Asn His Gly 930 935 940 Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Gly Gly Arg Pro Gly Ala 945 950 955 960 Pro Gly Gly Ser Gly Ser Gly Pro Arg His Arg Asp Gly Val Arg Arg 965 970 975 Pro Gln Lys Arg Pro Ser Cys Ile Gly Cys Lys Gly Thr His Trp Ile 980 985 990 Asp Asp Asn Pro Ser Thr Glu Thr Ala Gln Ala Trp Asn Ala Gly Phe 995 1000 1005 Leu Arg Gly Arg Ala Tyr Gly Ile Asp Leu Leu Arg Thr Glu Gly 1010 1015 1020 Glu His Val Glu Gly Ala Thr Gly Glu Thr Arg Glu Glu Ser Glu 1025 1030 1035 Asp Thr Glu Ser Asp Gly Asp Asp Glu Asp Leu Pro Cys Ile Val 1040 1045 1050 Ser Arg Gly Gly Pro Lys Val Lys Arg Pro Pro Ile Phe Ile Arg 1055 1060 1065 Arg Leu His Arg Leu Leu Leu Met Arg Ala Met Asn Pro Val Cys 1070 1075 1080 Leu Pro Val Ile Val Ala Pro Tyr Leu Phe Trp Leu Ala Ala Ile 1085 1090 1095 Ala Ala Ser Cys Phe Thr Ala Ser Val Ser Thr Val Val Thr Ala 1100 1105 1110 Thr Gly Leu Ala Leu Ser Leu Leu Leu Leu Ala Ala Val Ala Ser 1115 1120 1125 Ser Tyr Ala Ala Ala Gln Arg Lys Leu Leu Thr Pro Val Thr Val 1130 1135 1140 Leu Thr Ala Val Val Thr Thr Phe Ser Ala Gly Thr Phe Lys Leu 1145 1150 1155 Pro Arg Cys Thr Pro Gly Asp Arg Gln Trp Leu Tyr Val Gln Ser 1160 1165 1170 Ser Val Gly Asn Ile Val Gln Ser Cys Asn Pro Arg Tyr Ser Ile 1175 1180 1185 Phe Phe Asp Tyr Met Ala Ile His Arg Ser Leu Thr Lys Ile Trp 1190 1195 1200 Glu Asp Leu Gly Gly Pro Ser Gln Ala Pro Leu Pro Cys Val Leu 1205 1210 1215 Trp Pro Val Leu Pro Glu Pro Leu Pro Gln Gly Gln Leu Thr Ala 1220 1225 1230 Tyr His Val Ser Thr Ala Pro Thr Gly Ser Trp Phe Ser Ala Pro 1235 1240 1245 Gln Pro Ala Pro Glu Asn Ala Tyr Gln Ala Tyr Ala Ala Pro Gln 1250 1255 1260 Leu Phe Pro Val Ser Asp Ile 1265 1270 <210> 27 <211> 3810 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 27 atgagacctg ctccctggac acctaatcct cccaggtccc ccagccagat gagcgtgaga 60 gacagactgg ctaggctgag agccgaggct caggtcaagc aggccagcgt cgaggtgcaa 120 ccccctcagc tcacccaggt gtccccccag cagcctgtgg ccggcattct gttcattctg 180 gccattctga ccgagtgggg aagcggcaac agaacctacg gccctgtctt catgtgcctc 240 ggaggactgc tgacaatggt ggctggcgcc gtgtggctca ccgtcatgtc caacaccctg 300 ctcagcgcct ggattctgac cgccggattc ctgatctttc tgatcggatt cgctctcttt 360 ggcgtcatca ggtgttgcag gtactgttgc tactactgcc tgaccctcga gagcgaggaa 420 agacccccca ccccctacag gaatacagtg aggaaacctc agcagcccga gagcctcgag 480 gagtgcgata gcgagctgga gattaaaagg tataagaata gggtggcctc caggaagtgt 540 agggctaaat tcaaacagct cctgcaacac tatagggaag tggccgccgc caagtccagc 600 gagattaggg acagaaggag gaatcctgcc tccaggagag accaggccaa atggagactc 660 caaacactcg ccgctggatg gcccatgggc taccaggcct atagctcctg gatgtacagc 720 tacaccgacc atcagacaac acccaccttc gtgcatctgc aggctacact gggctgcacc 780 ggaggcagaa ggtgtcacgt gtttctggga atcgtgctgt tcatctttgg atgcctgctc 840 gtgctgggca tctggattta tctcctggag atgctctgga gactcggcgc tacaatttgg 900 cagctgctcg ccttttttct ggccttcttt ctggacctga tcctcctgat catcgccctg 960 tacctccaac agaactggtg gaccctcctg gtggatctgc tgtggctcct cctcttcctg 1020 gccatcctga tctggatgta ctaccatggc cagagaggaa gggtcgcttg cgctcctgtc 1080 cctgctcctg ctggccccat cgtgaggcct tgggagcctt ccctcacaca ggccgccggc 1140 caggcctttg ctcccgtgag gccccagcac atgcctgtgg aacccgtgcc cgtccccaca 1200 gtggctctgg aaaggcctgt gtaccccaag cccgtgagac ctgtcctctg gctcagcagc 1260 cctggaggac tcggaacact cggagccgct ctcctgacac tggccgctgc tctggctctg 1320 ctggctagcc tgatcctggg aaccctcaac ctcaccacca tgtttctcct catgctcctg 1380 tggaccctcg tggtgctgct catctgttcc agctgctcca gctgccccct gagcaagatc 1440 ctgctggcca ggctgttcct gtacgccctc gccctcctgc tgctggctag cgccctgatc 1500 gctggcggaa gcatcctcca gaccaatttc aagagcctct cctccaccga gttcatcccc 1560 aacctgttct gtatgttact gctgatccat agcgacgagc accatcatga cgactccctg 1620 ccccatcctc agcaggccac agacgactcc ggccacgaga gcgacagcaa tagcaatgag 1680 ggcaggcacc atctgctcgt gtccggagct caagtccccg agcctcccac catccatctc 1740 gccgcccagg gaatggctta ccccctccac gagcagcacg gcatggcccc ttgtcccgtc 1800 gctcaagccc cccctacacc tctgcccttt ttcgccattt gtctgacctg gagaatcgag 1860 gaccccccct tcaacagcct gctgttcgcc ctgctcgccg ccgctggcgg cctccagggc 1920 atttacgtcc tcgtgatgct ggtgctgctg atcctcgctt acaggagaag atggaggaga 1980 ctgacagtgt gcggcggcat catgtttctc gcctgcgtcc tggtcctgat cgtggacgcc 2040 gtcctgcaac tcagccccct cctgggagct gtgacagtgg tctccatgac cctgctgctg 2100 ctggccttca acggacccca cgatcctctg ccccaagatc ctgacaatac cgacgataac 2160 ggcccccaag accccgataa caccgacgac aatggccctc acgaccctct gccccatagc 2220 ccttccgata gcgctggcaa cgatggcggc cctcctcagc tgacagagga ggtggaaaat 2280 aagggcggcg atcagggacc ccccctgatg acagatggcg gaggaggaca cagccatgat 2340 agcggacatg gcggaggcga tccccatctg cctaccctcc tcctgggcag ctccggttct 2400 ggaggcgacg atgatgaccc tcacggccct gtgcagctct cctactacga cggcaaaagg 2460 accgaacaag gaaaagaggt cctggagaag gccaggggca gcacatacgg aacccccagg 2520 cctcccatgt ccgattggac cggaggagcc ctgctggtcc tctacagctt cgccctgatg 2580 ctgatcatta tcatcctgat catctttatc ttcagaaggg acctgctgtg ccctctcggc 2640 gccctgtgca tcctgctgct catgatcaca ctcctcctga tcgccctctg gaacctgcac 2700 ggacaagccc tgatgtccga tgagggacct ggaacaggac ccggaaacgg actgggcgag 2760 aagggagata caagcggccc cgaaggcagc ggcggaagcg gaccccaaag aaggggcggc 2820 gacaaccacg gaagaggaag aggcaggggc agaggcagag gaggaggaag acctggagcc 2880 cctggcggtt ctggaagcgg acccaggcac agggacggag tgaggaggcc tcaaaaaaga 2940 cccagctgca tcggctgcaa gggaacccac tggattgatg ataacccctc cacagagacc 3000 gctcaggcct ggaacgccgg cttcctgagg ggaagagcct atggcatcga tctgctgagg 3060 accgagggcg aacacgtgga gggagccacc ggagagacaa gggaggaaag cgaagacaca 3120 gaaagcgatg gcgacgacga agacctgccc tgcattgtgt ccaggggcgg acccaaggtg 3180 aagaggcccc ctatctttat cagaaggctc catagactgc tcctgatgag ggccatgaac 3240 cctgtgtgcc tgcccgtgat cgtggccccc tacctctttt ggctggccgc cattgccgct 3300 agctgcttca ccgcctccgt gtccacagtg gtgacagcca ccggcctcgc cctgagcctg 3360 ctgctcctcg ctgccgtggc ctccagctac gccgctgctc aaagaaagct cctgacccct 3420 gtcaccgtcc tgacagccgt cgtgaccacc ttttccgctg gcaccttcaa gctgcctagg 3480 tgcacacctg gcgacaggca gtggctctac gtgcagagct ccgtgggcaa tattgtgcag 3540 agctgcaatc ccaggtacag catttttttc gactacatgg ccatccatag gtccctcacc 3600 aagatctggg aggatctggg aggcccttcc caggctcctc tgccctgcgt gctgtggcct 3660 gtgctgcctg agcctctgcc ccaaggccag ctgacagcct atcacgtgtc caccgctcct 3720 acaggttctt ggttcagcgc tccccagccc gctcccgaaa acgcttacca ggcttacgcc 3780 gccccccagc tgttccccgt ctccgacatc 3810 <210> 28 <211> 355 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 28 Met Ala Pro Arg Arg Arg Leu Ser Gly Pro Pro Trp Leu Thr Val Leu 1 5 10 15 Leu Leu Leu Ser Thr Leu Ser Val Ala Ala Leu Leu Ile Leu Phe Leu 20 25 30 Ile Phe Ser Ala Gly Ala Thr Ile Ser Thr Glu Ala Ser Leu Leu Val 35 40 45 Leu Leu Leu Leu Phe Val Thr Leu Leu Leu Pro Leu Leu Ser Ser Asn 50 55 60 Gly Leu Gln Leu Pro Ala Ala Leu Ile Leu Ile Gln Cys Phe Leu Leu 65 70 75 80 Ala Ala Asp Tyr Leu Ala Tyr Leu Ile Leu Pro Thr Ile Ser Glu Asp 85 90 95 Phe Leu Ile Leu Ile Ala Ile Leu Val Ile Val Ile Leu Val Gly Thr 100 105 110 Ile Thr Thr Leu Val Gly Ala Ile Gly Gly Ile Arg Ala Arg Arg Ser 115 120 125 Phe Leu Phe Ile Cys Ile Phe Phe Leu Phe Leu Ser Leu Phe Leu Thr 130 135 140 Ile Leu Ala Leu Leu Leu Gly Phe Ser Trp Leu Leu Leu Val Ala Ile 145 150 155 160 Leu Phe Trp Val Leu Trp Leu Val Ile Leu Ile Leu Leu Leu Leu Val 165 170 175 Tyr Pro Ile Pro His His Pro Leu Pro Thr Ser Leu Arg Phe Arg Met 180 185 190 Lys Gln Arg Val Ser Ser Asp Pro Thr Gly Ser Asp Arg Ser Pro Gln 195 200 205 Gly Ser His Asn Ser Leu Asn Ser Pro Asp Glu Glu Asp Pro Lys Asp 210 215 220 Asp Thr Lys Gln Pro Leu Cys Asn Met Thr Gln Gly Gly Pro Pro Val 225 230 235 240 Asn Gly Gln Leu Leu Gly Gln His Ala Gln Cys Pro Pro His Tyr Pro 245 250 255 Cys Cys His Ile Gln His Pro Asp Gly Glu Asp Ser Asp Gly Asp Asp 260 265 270 Gly Lys Ser Trp Gly Asp Ala Gly Glu Glu Asp Asn Gly Pro Asn Asp 275 280 285 Pro Asn Thr Asn Asn Gly Asn Glu Gly Gly Glu Gly Asp Asp Tyr Lys 290 295 300 Ser Trp Arg Lys Pro Glu Glu Glu Asp Asn Gly Pro Asn Asp Pro Asn 305 310 315 320 Thr Asn Asn Arg Ile Glu Asp Gly Asp Gly Asp Asp Gly Lys Ser Trp 325 330 335 Arg Asn Pro Glu Glu Glu Asp Asn Arg Lys Gln Asp Arg Leu Gly Thr 340 345 350 Lys Pro Phe 355 <210> 29 <211> 93 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 29 Met Ala Pro Arg Arg Arg Leu Ser Gly Pro Pro Trp Leu Thr Val Leu 1 5 10 15 Leu Leu Leu Ser Thr Leu Ser Val Ala Ala Leu Leu Ile Leu Phe Leu 20 25 30 Ile Phe Ser Ala Gly Ala Thr Ile Ser Thr Glu Ala Ser Leu Leu Val 35 40 45 Leu Leu Leu Leu Phe Val Thr Leu Leu Leu Pro Leu Leu Ser Ser Asn 50 55 60 Gly Leu Gln Leu Pro Ala Ala Leu Ile Leu Ile Gln Cys Phe Leu Leu 65 70 75 80 Ala Ala Asp Tyr Leu Ala Tyr Leu Ile Leu Pro Thr Ile 85 90 <210> 30 <211> 198 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 30 Ser Glu Asp Phe Leu Ile Leu Ile Ala Ile Leu Val Ile Val Ile Leu 1 5 10 15 Val Gly Thr Ile Thr Thr Leu Val Gly Ala Ile Gly Gly Ile Arg Ala 20 25 30 Arg Arg Ser Phe Leu Phe Ile Cys Ile Phe Phe Leu Phe Leu Ser Leu 35 40 45 Phe Leu Thr Ile Leu Ala Leu Leu Leu Gly Phe Ser Trp Leu Leu Leu 50 55 60 Val Ala Ile Leu Phe Trp Val Leu Trp Leu Val Ile Leu Ile Leu Leu 65 70 75 80 Leu Leu Val Tyr Pro Ile Pro His His Pro Leu Pro Thr Ser Leu Arg 85 90 95 Phe Arg Met Lys Gln Arg Val Ser Ser Asp Pro Thr Gly Ser Asp Arg 100 105 110 Ser Pro Gln Gly Ser His Asn Ser Leu Asn Ser Pro Asp Glu Glu Asp 115 120 125 Pro Lys Asp Asp Thr Lys Gln Pro Leu Cys Asn Met Thr Gln Gly Gly 130 135 140 Pro Pro Val Asn Gly Gln Leu Leu Gly Gln His Ala Gln Cys Pro Pro 145 150 155 160 His Tyr Pro Cys Cys His Ile Gln His Pro Asp Gly Glu Asp Ser Asp 165 170 175 Gly Asp Asp Gly Lys Ser Trp Gly Asp Ala Gly Glu Glu Asp Asn Gly 180 185 190 Pro Asn Asp Pro Asn Thr 195 <210> 31 <211> 64 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 31 Asn Asn Gly Asn Glu Gly Gly Glu Gly Asp Asp Tyr Lys Ser Trp Arg 1 5 10 15 Lys Pro Glu Glu Glu Asp Asn Gly Pro Asn Asp Pro Asn Thr Asn Asn 20 25 30 Arg Ile Glu Asp Gly Asp Gly Asp Asp Gly Lys Ser Trp Arg Asn Pro 35 40 45 Glu Glu Glu Asp Asn Arg Lys Gln Asp Arg Leu Gly Thr Lys Pro Phe 50 55 60 <210> 32 <211> 413 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 32 Met Ala Gly His Trp Tyr Glu Ser Val Ile Pro Gly Leu Phe Leu Cys 1 5 10 15 Pro Leu Ile Leu Pro Ser Leu Phe Trp Ile Cys Ser Leu Leu Thr Phe 20 25 30 Leu Val Gly His Gly Ala Asn Ile Val Ser Ala Val Leu Phe Leu Val 35 40 45 Leu Ala Trp Cys Leu Leu Ile Ala Asn Trp Asn Val Thr Arg Glu Asp 50 55 60 Phe Val Ser Gly Arg Arg Ser Ser Met Ser Ser Leu Ser Val Ala Ala 65 70 75 80 Ser Thr Ala Thr Ala Met Phe Ala Ser Phe Leu Thr Leu Ser Phe Asp 85 90 95 Gly Leu Gly Leu Leu Leu Phe Gly Thr Ala Leu Val Ile Gln Thr Ile 100 105 110 Tyr Val Leu Tyr Leu Val Val Met Glu Ile Thr Val Trp Ile Met Met 115 120 125 Phe Arg Tyr Leu His Phe Trp Ile Thr Leu Leu Phe Leu Leu Ser Pro 130 135 140 Ile Ile Leu Ser Val Ala Cys Leu Ile Ile Gln Ser Ser Ala Leu Leu 145 150 155 160 Ile Glu Ala Val Val Val Thr Thr Ile Thr Val Leu Ala Ile Phe Leu 165 170 175 Trp Leu Pro Pro Gln Gly Ala Glu Ala Asp Leu Gly Thr Ala Leu Leu 180 185 190 Ile Leu Asn Thr Ala Leu Cys Leu Val Val Leu Ile Leu Thr Ala Ile 195 200 205 Pro Thr Asp Ala Gln Ile Leu Thr Val Phe Cys Leu Phe Cys Gln Trp 210 215 220 Thr Leu Phe Ile Cys Leu Gly Ile Arg Met Ile Cys Asn Trp Arg Gly 225 230 235 240 Lys Leu Thr Arg Ile Ile Cys Leu Lys Phe Cys Leu Tyr Gly Leu Ile 245 250 255 Ser Ala Ser Leu Ser Phe Gly Trp Tyr Ala Phe Leu Lys Glu Val Thr 260 265 270 Leu Pro Thr Thr Ala Thr Val Asp Pro Arg Gln Leu Pro Leu Phe Leu 275 280 285 Phe Ile Leu Ser Ser Val Leu Val Ile Leu Ala Ile Met Met Glu Phe 290 295 300 Gln Thr Ser Ser Ser Leu Phe Ala Ala Leu Phe Val Ile Ile Ala Gly 305 310 315 320 Met Leu Cys Val Thr Val Gly Val Ile Phe Leu Leu Ala Gly Val Lys 325 330 335 Pro Leu Leu Ser Gly Met Ile Cys Ala Ser Gly Ile Thr Met Leu Val 340 345 350 Leu Gly Val Val Leu Leu Val Val Cys Thr Arg Ala Ser Thr Arg Glu 355 360 365 Ser Ile Tyr Glu Asp Leu Arg Tyr Pro Thr Arg Asp Ala Asn Gly Glu 370 375 380 Tyr Glu Asn Val Gly Tyr Pro Pro Arg Asp Gly Asp Ala Pro His Arg 385 390 395 400 Leu Gly Glu Pro Val Tyr Asp Asp Val Glu Gln Ala Thr 405 410 <210> 33 <211> 210 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 33 Met Ala Gly His Trp Tyr Glu Ser Val Ile Pro Gly Leu Phe Leu Cys 1 5 10 15 Pro Leu Ile Leu Pro Ser Leu Phe Trp Ile Cys Ser Leu Leu Thr Phe 20 25 30 Leu Val Gly His Gly Ala Asn Ile Val Ser Ala Val Leu Phe Leu Val 35 40 45 Leu Ala Trp Cys Leu Leu Ile Ala Asn Trp Asn Val Thr Arg Glu Asp 50 55 60 Phe Val Ser Gly Arg Arg Ser Ser Met Ser Ser Leu Ser Val Ala Ala 65 70 75 80 Ser Thr Ala Thr Ala Met Phe Ala Ser Phe Leu Thr Leu Ser Phe Asp 85 90 95 Gly Leu Gly Leu Leu Leu Phe Gly Thr Ala Leu Val Ile Gln Thr Ile 100 105 110 Tyr Val Leu Tyr Leu Val Val Met Glu Ile Thr Val Trp Ile Met Met 115 120 125 Phe Arg Tyr Leu His Phe Trp Ile Thr Leu Leu Phe Leu Leu Ser Pro 130 135 140 Ile Ile Leu Ser Val Ala Cys Leu Ile Ile Gln Ser Ser Ala Leu Leu 145 150 155 160 Ile Glu Ala Val Val Val Thr Thr Ile Thr Val Leu Ala Ile Phe Leu 165 170 175 Trp Leu Pro Pro Gln Gly Ala Glu Ala Asp Leu Gly Thr Ala Leu Leu 180 185 190 Ile Leu Asn Thr Ala Leu Cys Leu Val Val Leu Ile Leu Thr Ala Ile 195 200 205 Pro Thr 210 <210> 34 <211> 153 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 34 Asp Ala Gln Ile Leu Thr Val Phe Cys Leu Phe Cys Gln Trp Thr Leu 1 5 10 15 Phe Ile Cys Leu Gly Ile Arg Met Ile Cys Asn Trp Arg Gly Lys Leu 20 25 30 Thr Arg Ile Ile Cys Leu Lys Phe Cys Leu Tyr Gly Leu Ile Ser Ala 35 40 45 Ser Leu Ser Phe Gly Trp Tyr Ala Phe Leu Lys Glu Val Thr Leu Pro 50 55 60 Thr Thr Ala Thr Val Asp Pro Arg Gln Leu Pro Leu Phe Leu Phe Ile 65 70 75 80 Leu Ser Ser Val Leu Val Ile Leu Ala Ile Met Met Glu Phe Gln Thr 85 90 95 Ser Ser Ser Leu Phe Ala Ala Leu Phe Val Ile Ile Ala Gly Met Leu 100 105 110 Cys Val Thr Val Gly Val Ile Phe Leu Leu Ala Gly Val Lys Pro Leu 115 120 125 Leu Ser Gly Met Ile Cys Ala Ser Gly Ile Thr Met Leu Val Leu Gly 130 135 140 Val Val Leu Leu Val Val Cys Thr Arg 145 150 <210> 35 <211> 50 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 35 Ala Ser Thr Arg Glu Ser Ile Tyr Glu Asp Leu Arg Tyr Pro Thr Arg 1 5 10 15 Asp Ala Asn Gly Glu Tyr Glu Asn Val Gly Tyr Pro Pro Arg Asp Gly 20 25 30 Asp Ala Pro His Arg Leu Gly Glu Pro Val Tyr Asp Asp Val Glu Gln 35 40 45 Ala Thr 50 <210> 36 <211> 327 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 36 Met Pro Arg Gly Arg Ser Thr Gly Arg Lys Gly Arg Asp Thr Glu Lys 1 5 10 15 Glu Arg Ser Arg Ser Pro Leu Arg Ala Pro Gly Gly Ser Asp Gly Pro 20 25 30 Ser Thr Arg Ala Gly Cys Gly Ala Gly Pro Cys Gln Leu Ser Ser Pro 35 40 45 Ile Ala Gly Gly Ser Arg Gly Gly Arg Gly Gly Arg Gly Gly Arg Gly 50 55 60 Gly Ser Arg Gly Arg Gly Ala Ser Arg Gly Arg Gly Gly Arg Gly Gly 65 70 75 80 Arg Gly Gly Arg Gly Gly Arg Gly Gly Arg Gly Gly Arg Gly Gly Arg 85 90 95 Gly Ser Pro Gly Asp Asp Ser Pro Ser Pro Cys His His Arg Asp Glu 100 105 110 Pro Pro Ser Arg Ser Pro Ser Pro Gln Pro Thr Val Ser Glu Gln Ser 115 120 125 Gln Gln Ser Pro Arg Gln Gln Ser Pro Gln Gly Thr Ser Gln Gly Ser 130 135 140 Thr Arg Pro Gln Val Pro Gly Gly Ala Thr Thr Arg Lys Arg Gly Gly 145 150 155 160 Val Arg Gly Gln Pro Ala Lys Cys His Gly Lys Tyr Thr Thr Thr Ala 165 170 175 Glu Gly Leu Thr Ala Leu Leu Asn Arg Arg His Ser Pro Arg Thr Ser 180 185 190 Asn Glu Gly Arg Trp Met Asn Gly Val Met Ala Val Asn Leu Ser Lys 195 200 205 Trp Pro Leu Tyr Ser Leu Arg Arg Ala Leu Ala Leu Ala Ala Asn Glu 210 215 220 Val Arg Ile Ser Pro Leu Phe Arg Leu Pro Tyr Gly Ser Ala Phe Gly 225 230 235 240 Pro Gly Pro Gln Pro Gly Pro Ile Leu Glu Ser Ser Thr Trp Gly Phe 245 250 255 Leu Val Phe Thr Gln Thr Ser Leu Phe Ala Asp Asp Ile Ala Asp Ala 260 265 270 Ile Arg Asp Tyr Cys Thr Thr His Pro Gly Pro Thr Arg Asn Thr Gln 275 280 285 Val Val Leu Met Asn Phe Glu Gly Ser Gly Val Pro Leu Pro Met Phe 290 295 300 Phe Pro Pro Gly Glu Glu Thr Glu Glu Gln Arg Glu Gly Asp Arg Ala 305 310 315 320 Ser Asp Ser Asp Glu Ser Glu 325 <210> 37 <211> 51 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 37 Met Pro Arg Gly Arg Ser Thr Gly Arg Lys Gly Arg Asp Thr Glu Lys 1 5 10 15 Glu Arg Ser Arg Ser Pro Leu Arg Ala Pro Gly Gly Ser Asp Gly Pro 20 25 30 Ser Thr Arg Ala Gly Cys Gly Ala Gly Pro Cys Gln Leu Ser Ser Pro 35 40 45 Ile Ala Gly 50 <210> 38 <211> 119 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 38 Ser Pro Ser Pro Cys His His Arg Asp Glu Pro Pro Ser Arg Ser Pro 1 5 10 15 Ser Pro Gln Pro Thr Val Ser Glu Gln Ser Gln Gln Ser Pro Arg Gln 20 25 30 Gln Ser Pro Gln Gly Thr Ser Gln Gly Ser Thr Arg Pro Gln Val Pro 35 40 45 Gly Gly Ala Thr Thr Arg Lys Arg Gly Gly Val Arg Gly Gln Pro Ala 50 55 60 Lys Cys His Gly Lys Tyr Thr Thr Thr Ala Glu Gly Leu Thr Ala Leu 65 70 75 80 Leu Asn Arg Arg His Ser Pro Arg Thr Ser Asn Glu Gly Arg Trp Met 85 90 95 Asn Gly Val Met Ala Val Asn Leu Ser Lys Trp Pro Leu Tyr Ser Leu 100 105 110 Arg Arg Ala Leu Ala Leu Ala 115 <210> 39 <211> 106 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 39 Ala Asn Glu Val Arg Ile Ser Pro Leu Phe Arg Leu Pro Tyr Gly Ser 1 5 10 15 Ala Phe Gly Pro Gly Pro Gln Pro Gly Pro Ile Leu Glu Ser Ser Thr 20 25 30 Trp Gly Phe Leu Val Phe Thr Gln Thr Ser Leu Phe Ala Asp Asp Ile 35 40 45 Ala Asp Ala Ile Arg Asp Tyr Cys Thr Thr His Pro Gly Pro Thr Arg 50 55 60 Asn Thr Gln Val Val Leu Met Asn Phe Glu Gly Ser Gly Val Pro Leu 65 70 75 80 Pro Met Phe Phe Pro Pro Gly Glu Glu Thr Glu Glu Gln Arg Glu Gly 85 90 95 Asp Arg Ala Ser Asp Ser Asp Glu Ser Glu 100 105 <210> 40 <211> 252 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 40 Met Asp Leu Asp Gly Thr Gly Gly Gly Glu Gly Tyr Ser Gln Met Val 1 5 10 15 Pro Ile Ala Thr Ala Pro Gly Ser Gly His Ala Ala Thr Tyr Gln Asp 20 25 30 Leu Gln Ala Ala Pro Tyr Ile Ile Trp Pro Leu Gln Thr Asp Cys Gln 35 40 45 Pro Val Ala Thr Thr Phe Ala Ser Pro Gly Gln Ile Gln Trp Tyr Thr 50 55 60 Ser Ala Val Pro Gln Pro Thr Glu His Cys Ser Gln Phe Thr Asn Ala 65 70 75 80 Pro Thr Val Asn Gln Gln Gln Pro Ile Ser Gln Pro Gln Pro Glu Asn 85 90 95 Pro Pro Ala Phe Thr Phe Thr Gln Pro Ala Ser Ile Ile Pro Gly Val 100 105 110 Ile Ser Ala Ser Asn Leu Asn Val Ser Ala Ser Pro Ile Ile Pro Ser 115 120 125 Asp His Val Leu Pro Ile Ile Thr Ser Val Thr Ser Leu Ala Gln Pro 130 135 140 Asn Asn Asp Glu His Ala Ile Ser Ala Ser His His Ala Ser Asp Gly 145 150 155 160 Ser Val Asn Gln Gln Lys Glu Asn Gln Pro Gln Thr Leu Glu Glu Cys 165 170 175 Lys Thr Asp Gln Glu Arg Lys Arg Tyr Arg Asn Arg Leu Ala Ser Arg 180 185 190 Arg Cys Arg Ala Lys Phe Arg Asn Gln Leu Glu His Phe Arg Thr Val 195 200 205 Ala Ala Ala Lys Thr Glu Glu Asn Asn Arg Leu Arg Val Leu Ile Arg 210 215 220 Gln Met Cys Pro Thr Leu Asp Val Glu Ser Ile Val Pro Ser Thr Ser 225 230 235 240 Ala Gly Tyr His Glu Pro Leu Asn His Leu Thr His 245 250 <210> 41 <211> 146 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 41 Met Asp Leu Asp Gly Thr Gly Gly Gly Glu Gly Tyr Ser Gln Met Val 1 5 10 15 Pro Ile Ala Thr Ala Pro Gly Ser Gly His Ala Ala Thr Tyr Gln Asp 20 25 30 Leu Gln Ala Ala Pro Tyr Ile Ile Trp Pro Leu Gln Thr Asp Cys Gln 35 40 45 Pro Val Ala Thr Thr Phe Ala Ser Pro Gly Gln Ile Gln Trp Tyr Thr 50 55 60 Ser Ala Val Pro Gln Pro Thr Glu His Cys Ser Gln Phe Thr Asn Ala 65 70 75 80 Pro Thr Val Asn Gln Gln Gln Pro Ile Ser Gln Pro Gln Pro Glu Asn 85 90 95 Pro Pro Ala Phe Thr Phe Thr Gln Pro Ala Ser Ile Ile Pro Gly Val 100 105 110 Ile Ser Ala Ser Asn Leu Asn Val Ser Ala Ser Pro Ile Ile Pro Ser 115 120 125 Asp His Val Leu Pro Ile Ile Thr Ser Val Thr Ser Leu Ala Gln Pro 130 135 140 Asn Asn 145 <210> 42 <211> 106 <212> PRT <213> Callitrichine gammaherpesvirus 3 <400> 42 Asp Glu His Ala Ile Ser Ala Ser His His Ala Ser Asp Gly Ser Val 1 5 10 15 Asn Gln Gln Lys Glu Asn Gln Pro Gln Thr Leu Glu Glu Cys Lys Thr 20 25 30 Asp Gln Glu Arg Lys Arg Tyr Arg Asn Arg Leu Ala Ser Arg Arg Cys 35 40 45 Arg Ala Lys Phe Arg Asn Gln Leu Glu His Phe Arg Thr Val Ala Ala 50 55 60 Ala Lys Thr Glu Glu Asn Asn Arg Leu Arg Val Leu Ile Arg Gln Met 65 70 75 80 Cys Pro Thr Leu Asp Val Glu Ser Ile Val Pro Ser Thr Ser Ala Gly 85 90 95 Tyr His Glu Pro Leu Asn His Leu Thr His 100 105 <210> 43 <211> 216 <212> PRT <213> Callithrix jacchus <400> 43 Met Asp Asp Gln Arg Asp Leu Ile Ser Asn Asn Glu Gln Leu Pro Met 1 5 10 15 Leu Gly Gln Arg Pro Gly Ala Pro Glu Ser Lys Cys Ser Arg Gly Ala 20 25 30 Val Tyr Thr Val Phe Ser Ile Leu Val Ala Leu Leu Leu Ala Gly Gln 35 40 45 Ala Thr Thr Ala Tyr Phe Leu Tyr Gln Gln Gln Gly Arg Leu Asp Lys 50 55 60 Leu Thr Val Thr Ser Gln Asn Leu Gln Leu Glu Asn Leu Arg Met Lys 65 70 75 80 Leu Pro Lys Pro Ala Lys Pro Leu Ser Gln Met Arg Met Ala Thr Pro 85 90 95 Leu Leu Met Gln Ala Leu Pro Met Ala Gly Leu Pro Gln Lys Pro Met 100 105 110 Gln Asn Ala Thr Lys His Gly Asn Met Thr Glu Asp His Val Met His 115 120 125 Leu Leu Leu Asn Ala Asp Pro Leu Lys Val Tyr Pro Pro Leu Lys Gly 130 135 140 Ser Leu Ser Glu Asn Leu Lys His Leu Lys Asn Thr Met Glu Thr Met 145 150 155 160 Asp Trp Lys Val Phe Glu Ser Trp Leu His His Trp Leu Leu Phe Glu 165 170 175 Met Ser Lys His Ser Leu Glu Gln Lys Pro Thr Glu Ala Pro Pro Lys 180 185 190 Glu Ser Leu Glu Leu Glu Asp Pro Ser Ser Gly Leu Gly Val Thr Lys 195 200 205 Gln Asp Leu Gly Pro Val Ala Met 210 215 <210> 44 <211> 1045 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 44 Met Ser Glu Asp Phe Leu Ile Leu Ile Ala Ile Leu Val Ile Val Ile 1 5 10 15 Leu Val Gly Thr Ile Thr Thr Leu Val Gly Ala Ile Gly Gly Ile Arg 20 25 30 Ala Arg Arg Ser Phe Leu Phe Ile Cys Ile Phe Phe Leu Phe Leu Ser 35 40 45 Leu Phe Leu Thr Ile Leu Ala Leu Leu Leu Gly Phe Ser Trp Leu Leu 50 55 60 Leu Val Ala Ile Leu Phe Trp Val Leu Trp Leu Val Ile Leu Ile Leu 65 70 75 80 Leu Leu Leu Val Tyr Pro Ile Pro His His Pro Leu Pro Thr Ser Leu 85 90 95 Arg Phe Arg Met Lys Gln Arg Val Ser Ser Asp Pro Thr Gly Ser Asp 100 105 110 Arg Ser Pro Gln Gly Ser His Asn Ser Leu Asn Ser Pro Asp Glu Glu 115 120 125 Asp Pro Lys Asp Asp Thr Lys Gln Pro Leu Cys Asn Met Thr Gln Gly 130 135 140 Gly Pro Pro Val Asn Gly Gln Leu Leu Gly Gln His Ala Gln Cys Pro 145 150 155 160 Pro His Tyr Pro Cys Cys His Ile Gln His Pro Asp Gly Glu Asp Ser 165 170 175 Asp Gly Asp Asp Gly Lys Ser Trp Gly Asp Ala Gly Glu Glu Asp Asn 180 185 190 Gly Pro Asn Asp Pro Asn Thr Ala Ser Thr Arg Glu Ser Ile Tyr Glu 195 200 205 Asp Leu Arg Tyr Pro Thr Arg Asp Ala Asn Gly Glu Tyr Glu Asn Val 210 215 220 Gly Tyr Pro Pro Arg Asp Gly Asp Ala Pro His Arg Leu Gly Glu Pro 225 230 235 240 Val Tyr Asp Asp Val Glu Gln Ala Thr Ala Asn Glu Val Arg Ile Ser 245 250 255 Pro Leu Phe Arg Leu Pro Tyr Gly Ser Ala Phe Gly Pro Gly Pro Gln 260 265 270 Pro Gly Pro Ile Leu Glu Ser Ser Thr Trp Gly Phe Leu Val Phe Thr 275 280 285 Gln Thr Ser Leu Phe Ala Asp Asp Ile Ala Asp Ala Ile Arg Asp Tyr 290 295 300 Cys Thr Thr His Pro Gly Pro Thr Arg Asn Thr Gln Val Val Leu Met 305 310 315 320 Asn Phe Glu Gly Ser Gly Val Pro Leu Pro Met Phe Phe Pro Pro Gly 325 330 335 Glu Glu Thr Glu Glu Gln Arg Glu Gly Asp Arg Ala Ser Asp Ser Asp 340 345 350 Glu Ser Glu Asp Ala Gln Ile Leu Thr Val Phe Cys Leu Phe Cys Gln 355 360 365 Trp Thr Leu Phe Ile Cys Leu Gly Ile Arg Met Ile Cys Asn Trp Arg 370 375 380 Gly Lys Leu Thr Arg Ile Ile Cys Leu Lys Phe Cys Leu Tyr Gly Leu 385 390 395 400 Ile Ser Ala Ser Leu Ser Phe Gly Trp Tyr Ala Phe Leu Lys Glu Val 405 410 415 Thr Leu Pro Thr Thr Ala Thr Val Asp Pro Arg Gln Leu Pro Leu Phe 420 425 430 Leu Phe Ile Leu Ser Ser Val Leu Val Ile Leu Ala Ile Met Met Glu 435 440 445 Phe Gln Thr Ser Ser Ser Leu Phe Ala Ala Leu Phe Val Ile Ile Ala 450 455 460 Gly Met Leu Cys Val Thr Val Gly Val Ile Phe Leu Leu Ala Gly Val 465 470 475 480 Lys Pro Leu Leu Ser Gly Met Ile Cys Ala Ser Gly Ile Thr Met Leu 485 490 495 Val Leu Gly Val Val Leu Leu Val Val Cys Thr Arg Ser Pro Ser Pro 500 505 510 Cys His His Arg Asp Glu Pro Pro Ser Arg Ser Pro Ser Pro Gln Pro 515 520 525 Thr Val Ser Glu Gln Ser Gln Gln Ser Pro Arg Gln Gln Ser Pro Gln 530 535 540 Gly Thr Ser Gln Gly Ser Thr Arg Pro Gln Val Pro Gly Gly Ala Thr 545 550 555 560 Thr Arg Lys Arg Gly Gly Val Arg Gly Gln Pro Ala Lys Cys His Gly 565 570 575 Lys Tyr Thr Thr Thr Ala Glu Gly Leu Thr Ala Leu Leu Asn Arg Arg 580 585 590 His Ser Pro Arg Thr Ser Asn Glu Gly Arg Trp Met Asn Gly Val Met 595 600 605 Ala Val Asn Leu Ser Lys Trp Pro Leu Tyr Ser Leu Arg Arg Ala Leu 610 615 620 Ala Leu Ala Met Ala Pro Arg Arg Arg Leu Ser Gly Pro Pro Trp Leu 625 630 635 640 Thr Val Leu Leu Leu Leu Ser Thr Leu Ser Val Ala Ala Leu Leu Ile 645 650 655 Leu Phe Leu Ile Phe Ser Ala Gly Ala Thr Ile Ser Thr Glu Ala Ser 660 665 670 Leu Leu Val Leu Leu Leu Leu Phe Val Thr Leu Leu Leu Pro Leu Leu 675 680 685 Ser Ser Asn Gly Leu Gln Leu Pro Ala Ala Leu Ile Leu Ile Gln Cys 690 695 700 Phe Leu Leu Ala Ala Asp Tyr Leu Ala Tyr Leu Ile Leu Pro Thr Ile 705 710 715 720 Met Pro Arg Gly Arg Ser Thr Gly Arg Lys Gly Arg Asp Thr Glu Lys 725 730 735 Glu Arg Ser Arg Ser Pro Leu Arg Ala Pro Gly Gly Ser Asp Gly Pro 740 745 750 Ser Thr Arg Ala Gly Cys Gly Ala Gly Pro Cys Gln Leu Ser Ser Pro 755 760 765 Ile Ala Gly Asn Asn Gly Asn Glu Gly Gly Glu Gly Asp Asp Tyr Lys 770 775 780 Ser Trp Arg Lys Pro Glu Glu Glu Asp Asn Gly Pro Asn Asp Pro Asn 785 790 795 800 Thr Asn Asn Arg Ile Glu Asp Gly Asp Gly Asp Asp Gly Lys Ser Trp 805 810 815 Arg Asn Pro Glu Glu Glu Asp Asn Arg Lys Gln Asp Arg Leu Gly Thr 820 825 830 Lys Pro Phe Met Ala Gly His Trp Tyr Glu Ser Val Ile Pro Gly Leu 835 840 845 Phe Leu Cys Pro Leu Ile Leu Pro Ser Leu Phe Trp Ile Cys Ser Leu 850 855 860 Leu Thr Phe Leu Val Gly His Gly Ala Asn Ile Val Ser Ala Val Leu 865 870 875 880 Phe Leu Val Leu Ala Trp Cys Leu Leu Ile Ala Asn Trp Asn Val Thr 885 890 895 Arg Glu Asp Phe Val Ser Gly Arg Arg Ser Ser Met Ser Ser Leu Ser 900 905 910 Val Ala Ala Ser Thr Ala Thr Ala Met Phe Ala Ser Phe Leu Thr Leu 915 920 925 Ser Phe Asp Gly Leu Gly Leu Leu Leu Phe Gly Thr Ala Leu Val Ile 930 935 940 Gln Thr Ile Tyr Val Leu Tyr Leu Val Val Met Glu Ile Thr Val Trp 945 950 955 960 Ile Met Met Phe Arg Tyr Leu His Phe Trp Ile Thr Leu Leu Phe Leu 965 970 975 Leu Ser Pro Ile Ile Leu Ser Val Ala Cys Leu Ile Ile Gln Ser Ser 980 985 990 Ala Leu Leu Ile Glu Ala Val Val Val Thr Thr Ile Thr Val Leu Ala 995 1000 1005 Ile Phe Leu Trp Leu Pro Pro Gln Gly Ala Glu Ala Asp Leu Gly 1010 1015 1020 Thr Ala Leu Leu Ile Leu Asn Thr Ala Leu Cys Leu Val Val Leu 1025 1030 1035 Ile Leu Thr Ala Ile Pro Thr 1040 1045 <210> 45 <211> 3135 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 45 atgtccgagg actttctgat tctgatcgcc atcctggtga tcgtgattct cgtgggcaca 60 atcacaaccc tggtgggcgc catcggcggc attagggcca ggaggagctt cctcttcatt 120 tgcatcttct tcctgttcct ctccctcttc ctgacaatcc tcgccctgct gctgggcttc 180 agctggctcc tgctggtggc catcctgttc tgggtgctct ggctggtcat cctcattctg 240 ctgctgctgg tgtaccctat tcctcaccac cccctgccca cctccctcag gtttagaatg 300 aagcagaggg tgagcagcga ccccacaggt tctgacagaa gccctcaggg cagccataat 360 agcctgaact cccccgatga ggaggacccc aaggatgaca ccaagcaacc tctgtgcaac 420 atgacccagg gcggacctcc cgtcaatgga cagctcctcg gacaacatgc tcaatgcccc 480 cctcactatc cctgctgcca tattcagcat cccgacggag aggattccga tggagacgat 540 ggcaagtcct ggggcgatgc cggagaggaa gacaatggcc ctaacgaccc taacaccgcc 600 agcaccagag agtccattta cgaggacctc agatacccca caagggacgc caatggcgag 660 tatgagaacg tgggataccc ccctagggac ggagatgccc ctcataggct cggagagcct 720 gtgtatgacg atgtggagca agccaccgct aacgaggtga gaatctcccc tctgttcaga 780 ctgccctacg gaagcgcttt cggacctggc ccccagcctg gacccattct ggagagctcc 840 acatggggct ttctggtctt cacacagacc tccctgttcg ccgacgacat tgccgacgct 900 attagggact actgcacaac ccaccctggc cccacaagga acacccaggt ggtcctcatg 960 aacttcgagg gcagcggagt gcccctgcct atgttttttc cccctggaga ggagacagaa 1020 gagcagagag agggcgatag agctagcgac tccgacgagt ccgaagacgc tcagatcctg 1080 accgtgttct gcctgttttg ccagtggaca ctctttatct gcctgggaat caggatgatc 1140 tgtaactgga ggggcaaact caccaggatc atctgcctga agttctgcct ctacggactg 1200 atttccgcct ccctgtcctt cggctggtac gcttttctga aggaagtgac cctccccacc 1260 acagccaccg ttgatcctag gcaactcccc ctgttcctct tcatcctgag ctccgtgctg 1320 gtgattctcg ccatcatgat ggagtttcaa acatcctcca gcctcttcgc tgctctgttc 1380 gtgattatcg ccggaatgct gtgcgtcaca gtgggcgtga tttttctgct ggctggcgtc 1440 gtgattatcg ccggaatgct gtgcgtcaca gtgggcgtga tttttctgct ggctggcgtc 1440 aagcctctcc tgagcggcat gatctgcgcc tccggcatca caatgctcgt gctcggcgtc 1500 aagcctctcc tgagcggcat gatctgcgcc tccggcatca caatgctcgt gctcggcgtc 1500 gtgctgctgg tggtgtgcac cagaagcccc agcccttgtc atcacaggga tgaacccccc 1560 gtgctgctgg tggtgtgcac cagaagcccc agcccttgtc atcacaggga tgaacccccc 1560 tccagaagcc ccagccctca acccaccgtc tccgagcagt cccagcagtc ccccaggcag 1620 tccagaagcc ccagccctca acccaccgtc tccgagcagt cccagcagtc ccccaggcag 1620 cagagccctc aaggcacatc ccagggttct acaagacctc aggtgcctgg aggcgccacc 1680 cagagccctc aaggcacatc ccagggttct acaagacctc aggtgcctgg aggcgccacc 1680 accagaaaaa gaggcggcgt gagaggccaa cctgccaagt gtcacggcaa gtacaccaca 1740 accagaaaaa gaggcggcgt gagaggccaa cctgccaagt gtcacggcaa gtacaccaca 1740 accgccgagg gactgaccgc tctcctgaat aggaggcaca gccccaggac atccaacgag 1800 accgccgagg gactgaccgc tctcctgaat aggaggcaca gccccaggac atccaacgag 1800 ggcaggtgga tgaatggagt catggctgtg aacctctcca aatggcccct gtacagcctg 1860 ggcaggtgga tgaatggagt catggctgtg aacctctcca aatggcccct gtacagcctg 1860 aggagagccc tggccctcgc catggctcct agaaggaggc tctccggccc tccctggctg 1920 aggagagccc tggccctcgc catggctcct agaaggaggc tctccggccc tccctggctg 1920 acagtgctgc tgctgctgtc cacactgagc gtggccgccc tgctgattct cttcctgatt 1980 acagtgctgc tgctgctgtc cacactgagc gtggccgccc tgctgattct cttcctgatt 1980 ttcagcgccg gcgccaccat tagcacagaa gccagcctgc tggtcctgct cctgctgttt 2040 gtgaccctgc tgctgcctct cctgtcctcc aacggactcc agctccctgc cgccctgatt 2100 ctgatccagt gtttcctcct ggccgctgat tatctcgcct acctgattct gcctaccatt 2160 atgcccaggg gcagaagcac aggaaggaag ggcagggaca cagagaaaga gaggagcaga 2220 tcccctctca gagctcctgg cggttctgat ggacccagca caagggctgg ctgtggagcc 2280 ggaccctgtc agctgagcag ccccatcgcc ggaaacaacg gcaatgaagg cggcgagggc 2340 gacgactaca agagctggag gaagcccgag gaagaggaca acggccccaa tgaccccaat 2400 accaacaaca ggattgagga tggagacggc gacgacggaa aatcctggag gaatcctgag 2460 gaggaggata acagaaagca ggacaggctg ggcaccaagc ctttcatggc cggccactgg 2520 tatgagagcg tgattcccgg cctgttcctc tgccccctga tcctcccttc cctgttctgg 2580 atttgctccc tgctgacctt cctggtgggc cacggagcca atattgtgag cgccgtcctg 2640 ttcctcgtgc tggcttggtg tctcctcatt gccaactgga acgtgacaag agaggacttc 2700 gtgtccggca ggagaagctc catgagcagc ctgtccgtgg ccgcttccac cgccacagcc 2760 atgttcgcca gcttcctcac cctgagcttt gatggcctgg gcctgctgct gtttggcacc 2820 gccctggtga tccagacaat ttacgtgctg tatctggtgg tcatggagat caccgtgtgg 2880 atcatgatgt ttaggtatct ccacttttgg atcaccctgc tgttcctgct gagccccatt 2940 attctctccg tcgcctgtct catcatccaa tcctccgccc tgctgatcga ggctgtggtc 3000 gtcaccacca tcacagtcct ggccattttt ctgtggctcc ctcctcaagg cgctgaggcc 3060 gatctcggca ccgccctgct gattctgaat accgccctgt gcctggtcgt gctgatcctg 3120 accgctatcc ctaca 3135 <210> 46 <211> 1270 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 46 Met Arg Pro Ala Pro Trp Thr Pro Asn Pro Pro Arg Ser Pro Ser Gln 1 5 10 15 Met Ser Val Arg Asp Arg Leu Ala Arg Leu Arg Ala Glu Ala Gln Val 20 25 30 Lys Gln Ala Ser Val Glu Val Gln Pro Pro Gln Leu Thr Gln Val Ser 35 40 45 Pro Gln Gln Pro Val Ala Gly Ile Leu Phe Ile Leu Ala Ile Leu Thr 50 55 60 Glu Trp Gly Ser Gly Asn Arg Thr Tyr Gly Pro Val Phe Met Cys Leu 65 70 75 80 Gly Gly Leu Leu Thr Met Val Ala Gly Ala Val Trp Leu Thr Val Met 85 90 95 Ser Asn Thr Leu Leu Ser Ala Trp Ile Leu Thr Ala Gly Phe Leu Ile 100 105 110 Phe Leu Ile Gly Phe Ala Leu Phe Gly Val Ile Arg Cys Cys Arg Tyr 115 120 125 Cys Cys Tyr Tyr Cys Leu Thr Leu Glu Ser Glu Glu Arg Pro Pro Thr 130 135 140 Pro Tyr Arg Asn Thr Val Arg Lys Pro Gln Gln Pro Glu Ser Leu Glu 145 150 155 160 Glu Cys Asp Ser Glu Leu Glu Ile Lys Arg Tyr Lys Asn Arg Val Ala 165 170 175 Ser Arg Lys Cys Arg Ala Lys Phe Lys Gln Leu Leu Gln His Tyr Arg 180 185 190 Glu Val Ala Ala Ala Lys Ser Ser Glu Ile Arg Asp Arg Arg Arg Asn 195 200 205 Pro Ala Ser Arg Arg Asp Gln Ala Lys Trp Arg Leu Gln Thr Leu Ala 210 215 220 Ala Gly Trp Pro Met Gly Tyr Gln Ala Tyr Ser Ser Trp Met Tyr Ser 225 230 235 240 Tyr Thr Asp His Gln Thr Thr Pro Thr Phe Val His Leu Gln Ala Thr 245 250 255 Leu Gly Cys Thr Gly Gly Arg Arg Cys His Val Phe Leu Gly Ile Val 260 265 270 Leu Phe Ile Phe Gly Cys Leu Leu Val Leu Gly Ile Trp Ile Tyr Leu 275 280 285 Leu Glu Met Leu Trp Arg Leu Gly Ala Thr Ile Trp Gln Leu Leu Ala 290 295 300 Phe Phe Leu Ala Phe Phe Leu Asp Leu Ile Leu Leu Ile Ile Ala Leu 305 310 315 320 Tyr Leu Gln Gln Asn Trp Trp Thr Leu Leu Val Asp Leu Leu Trp Leu 325 330 335 Leu Leu Phe Leu Ala Ile Leu Ile Trp Met Tyr Tyr His Gly Gln Arg 340 345 350 Gly Arg Val Ala Cys Ala Pro Val Pro Ala Pro Ala Gly Pro Ile Val 355 360 365 Arg Pro Trp Glu Pro Ser Leu Thr Gln Ala Ala Gly Gln Ala Phe Ala 370 375 380 Pro Val Arg Pro Gln His Met Pro Val Glu Pro Val Pro Val Pro Thr 385 390 395 400 Val Ala Leu Glu Arg Pro Val Tyr Pro Lys Pro Val Arg Pro Val Leu 405 410 415 Trp Leu Ser Ser Pro Gly Gly Leu Gly Thr Leu Gly Ala Ala Leu Leu 420 425 430 Thr Leu Ala Ala Ala Leu Ala Leu Leu Ala Ser Leu Ile Leu Gly Thr 435 440 445 Leu Asn Leu Thr Thr Met Phe Leu Leu Met Leu Leu Trp Thr Leu Val 450 455 460 Val Leu Leu Ile Cys Ser Ser Cys Ser Ser Cys Pro Leu Ser Lys Ile 465 470 475 480 Leu Leu Ala Arg Leu Phe Leu Tyr Ala Leu Ala Leu Leu Leu Leu Ala 485 490 495 Ser Ala Leu Ile Ala Gly Gly Ser Ile Leu Gln Thr Asn Phe Lys Ser 500 505 510 Leu Ser Ser Thr Glu Phe Ile Pro Asn Leu Phe Cys Met Leu Leu Leu 515 520 525 Ile His Ser Asp Glu His His His Asp Asp Ser Leu Pro His Pro Gln 530 535 540 Gln Ala Thr Asp Asp Ser Gly His Glu Ser Asp Ser Asn Ser Asn Glu 545 550 555 560 Gly Arg His His Leu Leu Val Ser Gly Ala Gln Val Pro Glu Pro Pro 565 570 575 Thr Ile His Leu Ala Ala Gln Gly Met Ala Tyr Pro Leu His Glu Gln 580 585 590 His Gly Met Ala Pro Cys Pro Val Ala Gln Ala Pro Pro Thr Pro Leu 595 600 605 Pro Phe Phe Ala Ile Cys Leu Thr Trp Arg Ile Glu Asp Pro Pro Phe 610 615 620 Asn Ser Leu Leu Phe Ala Leu Leu Ala Ala Ala Gly Gly Leu Gln Gly 625 630 635 640 Ile Tyr Val Leu Val Met Leu Val Leu Leu Ile Leu Ala Tyr Arg Arg 645 650 655 Arg Trp Arg Arg Leu Thr Val Cys Gly Gly Ile Met Phe Leu Ala Cys 660 665 670 Val Leu Val Leu Ile Val Asp Ala Val Leu Gln Leu Ser Pro Leu Leu 675 680 685 Gly Ala Val Thr Val Val Ser Met Thr Leu Leu Leu Leu Ala Phe Asn 690 695 700 Gly Pro His Asp Pro Leu Pro Gln Asp Pro Asp Asn Thr Asp Asp Asn 705 710 715 720 Gly Pro Gln Asp Pro Asp Asn Thr Asp Asp Asn Gly Pro His Asp Pro 725 730 735 Leu Pro His Ser Pro Ser Asp Ser Ala Gly Asn Asp Gly Gly Pro Pro 740 745 750 Gln Leu Thr Glu Glu Val Glu Asn Lys Gly Gly Asp Gln Gly Pro Pro 755 760 765 Leu Met Thr Asp Gly Gly Gly Gly His Ser His Asp Ser Gly His Gly 770 775 780 Gly Gly Asp Pro His Leu Pro Thr Leu Leu Leu Gly Ser Ser Gly Ser 785 790 795 800 Gly Gly Asp Asp Asp Asp Pro His Gly Pro Val Gln Leu Ser Tyr Tyr 805 810 815 Asp Gly Lys Arg Thr Glu Gln Gly Lys Glu Val Leu Glu Lys Ala Arg 820 825 830 Gly Ser Thr Tyr Gly Thr Pro Arg Pro Pro Met Ser Asp Trp Thr Gly 835 840 845 Gly Ala Leu Leu Val Leu Tyr Ser Phe Ala Leu Met Leu Ile Ile Ile 850 855 860 Ile Leu Ile Ile Phe Ile Phe Arg Arg Asp Leu Leu Cys Pro Leu Gly 865 870 875 880 Ala Leu Cys Ile Leu Leu Leu Met Ile Thr Leu Leu Leu Ile Ala Leu 885 890 895 Trp Asn Leu His Gly Gln Ala Leu Met Ser Asp Glu Gly Pro Gly Thr 900 905 910 Gly Pro Gly Asn Gly Leu Gly Glu Lys Gly Asp Thr Ser Gly Pro Glu 915 920 925 Gly Ser Gly Gly Ser Gly Pro Gln Arg Arg Gly Gly Asp Asn His Gly 930 935 940 Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Gly Gly Arg Pro Gly Ala 945 950 955 960 Pro Gly Gly Ser Gly Ser Gly Pro Arg His Arg Asp Gly Val Arg Arg 965 970 975 Pro Gln Lys Arg Pro Ser Cys Ile Gly Cys Lys Gly Thr His Trp Ile 980 985 990 Asp Asp Asn Pro Ser Thr Glu Thr Ala Gln Ala Trp Asn Ala Gly Phe 995 1000 1005 Leu Arg Gly Arg Ala Tyr Gly Ile Asp Leu Leu Arg Thr Glu Gly 1010 1015 1020 Glu His Val Glu Gly Ala Thr Gly Glu Thr Arg Glu Glu Ser Glu 1025 1030 1035 Asp Thr Glu Ser Asp Gly Asp Asp Glu Asp Leu Pro Cys Ile Val 1040 1045 1050 Ser Arg Gly Gly Pro Lys Val Lys Arg Pro Pro Ile Phe Ile Arg 1055 1060 1065 Arg Leu His Arg Leu Leu Leu Met Arg Ala Met Asn Pro Val Cys 1070 1075 1080 Leu Pro Val Ile Val Ala Pro Tyr Leu Phe Trp Leu Ala Ala Ile 1085 1090 1095 Ala Ala Ser Cys Phe Thr Ala Ser Val Ser Thr Val Val Thr Ala 1100 1105 1110 Thr Gly Leu Ala Leu Ser Leu Leu Leu Leu Ala Ala Val Ala Ser 1115 1120 1125 Ser Tyr Ala Ala Ala Gln Arg Lys Leu Leu Thr Pro Val Thr Val 1130 1135 1140 Leu Thr Ala Val Val Thr Thr Phe Ser Ala Gly Thr Phe Lys Leu 1145 1150 1155 Pro Arg Cys Thr Pro Gly Asp Arg Gln Trp Leu Tyr Val Gln Ser 1160 1165 1170 Ser Val Gly Asn Ile Val Gln Ser Cys Asn Pro Arg Tyr Ser Ile 1175 1180 1185 Phe Phe Asp Tyr Met Ala Ile His Arg Ser Leu Thr Lys Ile Trp 1190 1195 1200 Glu Asp Leu Gly Gly Pro Ser Gln Ala Pro Leu Pro Cys Val Leu 1205 1210 1215 Tryptophan Proline Valine Leucine Proline Glutamic acid Proline Leucine Proline Glutamine Glycine Glutamine Leucine Threonine Alanine 1220 1225 1230 Tyrosine Histidine Valine Serine Threonine Alanine Proline Threonine Glycine Serine Tryptophan Phenylalanine Serine Alanine Proline 1235 1240 1245 Glutamine Proline Alanine Proline Glutamic acid Asparagine Alanine Tyrosine Glutamine Alanine Tyrosine Alanine Alanine Proline Glutamine 1250 1255 1260 Leucine Phenylalanine Proline Valine Serine Aspartic acid Isoleucine 1265 1270 <210> 47 <211> 3810 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 47 atgagacctg ctccctggac acctaatcct cccaggtccc ccagccagat gagcgtgaga 60 gacagactgg ctaggctgag agccgaggct caggtcaagc aggccagcgt cgaggtgcaa 120 ccccctcagc tcacccaggt gtccccccag cagcctgtgg ccggcattct gttcattctg 180 gccattctga ccgagtgggg aagcggcaac agaacctacg gccctgtctt catgtgcctc 240 ggaggactgc tgacaatggt ggctggcgcc gtgtggctca ccgtcatgtc caacaccctg 300 ctcagcgcct ggattctgac cgccggattc ctgatctttc tgatcggatt cgctctcttt 360 ggcgtcatca ggtgttgcag gtactgttgc tactactgcc tgaccctcga gagcgaggaa 420 agacccccca ccccctacag gaatacagtg aggaaacctc agcagcccga gagcctcgag 480 gagtgcgata gcgagctgga gattaaaagg tataagaata gggtggcctc caggaagtgt 540 agggctaaat tcaaacagct cctgcaacac tatagggaag tggccgccgc caagtccagc 600 gagattaggg acagaaggag gaatcctgcc tccaggagag accaggccaa atggagactc 660 caaacactcg ccgctggatg gcccatgggc taccaggcct atagctcctg gatgtacagc 720 tacaccgacc atcagacaac acccaccttc gtgcatctgc aggctacact gggctgcacc 780 ggaggcagaa ggtgtcacgt gtttctggga atcgtgctgt tcatctttgg atgcctgctc 840 gtgctgggca tctggattta tctcctggag atgctctgga gactcggcgc tacaatttgg 900 cagctgctcg ccttttttct ggccttcttt ctggacctga tcctcctgat catcgccctg 960 tacctccaac agaactggtg gaccctcctg gtggatctgc tgtggctcct cctcttcctg 1020 gccatcctga tctggatgta ctaccatggc cagagaggaa gggtcgcttg cgctcctgtc 1080 cctgctcctg ctggccccat cgtgaggcct tgggagcctt ccctcacaca ggccgccggc 1140 caggcctttg ctcccgtgag gccccagcac atgcctgtgg aacccgtgcc cgtccccaca 1200 gtggctctgg aaaggcctgt gtaccccaag cccgtgagac ctgtcctctg gctcagcagc 1260 cctggaggac tcggaacact cggagccgct ctcctgacac tggccgctgc tctggctctg 1320 ctggctagcc tgatcctggg aaccctcaac ctcaccacca tgtttctcct catgctcctg 1380 tggaccctcg tggtgctgct catctgttcc agctgctcca gctgccccct gagcaagatc 1440 ctgctggcca ggctgttcct gtacgccctc gccctcctgc tgctggctag cgccctgatc 1500 gctggcggaa gcatcctcca gaccaatttc aagagcctct cctccaccga gttcatcccc 1560 aacctgttct gtatgttact gctgatccat agcgacgagc accatcatga cgactccctg 1620 ccccatcctc agcaggccac agacgactcc ggccacgaga gcgacagcaa tagcaatgag 1680 ggcaggcacc atctgctcgt gtccggagct caagtccccg agcctcccac catccatctc 1740 gccgcccagg gaatggctta ccccctccac gagcagcacg gcatggcccc ttgtcccgtc 1800 gctcaagccc cccctacacc tctgcccttt ttcgccattt gtctgacctg gagaatcgag 1860 gaccccccct tcaacagcct gctgttcgcc ctgctcgccg ccgctggcgg cctccagggc 1920 atttacgtcc tcgtgatgct ggtgctgctg atcctcgctt acaggagaag atggaggaga 1980 ctgacagtgt gcggcggcat catgtttctc gcctgcgtcc tggtcctgat cgtggacgcc 2040 gtcctgcaac tcagccccct cctgggagct gtgacagtgg tctccatgac cctgctgctg 2100 ctggccttca acggacccca cgatcctctg ccccaagatc ctgacaatac cgacgataac 2160 ggcccccaag accccgataa caccgacgac aatggccctc acgaccctct gccccatagc 2220 ccttccgata gcgctggcaa cgatggcggc cctcctcagc tgacagagga ggtggaaaat 2280 aagggcggcg atcagggacc ccccctgatg acagatggcg gaggaggaca cagccatgat 2340 agcggacatg gcggaggcga tccccatctg cctaccctcc tcctgggcag ctccggttct 2400 ggaggcgacg atgatgaccc tcacggccct gtgcagctct cctactacga cggcaaaagg 2460 accgaacaag gaaaagaggt cctggagaag gccaggggca gcacatacgg aacccccagg 2520 cctcccatgt ccgattggac cggaggagcc ctgctggtcc tctacagctt cgccctgatg 2580 ctgatcatta tcatcctgat catctttatc ttcagaaggg acctgctgtg ccctctcggc 2640 gccctgtgca tcctgctgct catgatcaca ctcctcctga tcgccctctg gaacctgcac 2700 ggacaagccc tgatgtccga tgagggacct ggaacaggac ccggaaacgg actgggcgag 2760 aagggagata caagcggccc cgaaggcagc ggcggaagcg gaccccaaag aaggggcggc 2820 gacaaccacg gaagaggaag aggcaggggc agaggcagag gaggaggaag acctggagcc 2880 cctggcggtt ctggaagcgg acccaggcac agggacggag tgaggaggcc tcaaaaaaga 2940 cccagctgca tcggctgcaa gggaacccac tggattgatg ataacccctc cacagagacc 3000 gctcaggcct ggaacgccgg cttcctgagg ggaagagcct atggcatcga tctgctgagg 3060 accgagggcg aacacgtgga gggagccacc ggagagacaa gggaggaaag cgaagacaca 3120 gaaagcgatg gcgacgacga agacctgccc tgcattgtgt ccaggggcgg acccaaggtg 3180 aagaggcccc ctatctttat cagaaggctc catagactgc tcctgatgag ggccatgaac 3240 cctgtgtgcc tgcccgtgat cgtggccccc tacctctttt ggctggccgc cattgccgct 3300 agctgcttca ccgcctccgt gtccacagtg gtgacagcca ccggcctcgc cctgagcctg 3360 ctgctcctcg ctgccgtggc ctccagctac gccgctgctc aaagaaagct cctgacccct 3420 gtcaccgtcc tgacagccgt cgtgaccacc ttttccgctg gcaccttcaa gctgcctagg 3480 tgcacacctg gcgacaggca gtggctctac gtgcagagct ccgtgggcaa tattgtgcag 3540 agctgcaatc ccaggtacag catttttttc gactacatgg ccatccatag gtccctcacc 3600 aagatctggg aggatctggg aggcccttcc caggctcctc tgccctgcgt gctgtggcct 3660 gtgctgcctg agcctctgcc ccaaggccag ctgacagcct atcacgtgtc caccgctcct 3720 acaggttctt ggttcagcgc tccccagccc gctcccgaaa acgcttacca ggcttacgcc 3780 gccccccagc tgttccccgt ctccgacatc 3810 <210> 48 <211> 1512 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 48 Met Asp Asp Gln Arg Asp Leu Ile Ser Asn Asn Glu Gln Leu Pro Met 1 5 10 15 Leu Gly Gln Arg Pro Gly Ala Pro Glu Ser Lys Cys Ser Arg Gly Ala 20 25 30 Val Tyr Thr Val Phe Ser Ile Leu Val Ala Leu Leu Leu Ala Gly Gln 35 40 45 Ala Thr Thr Ala Tyr Phe Leu Tyr Gln Gln Gln Gly Arg Leu Asp Lys 50 55 60 Leu Thr Val Thr Ser Gln Asn Leu Gln Leu Glu Asn Leu Arg Met Lys 65 70 75 80 Leu Pro Lys Pro Ala Lys Pro Leu Ser Gln Met Arg Met Ala Thr Pro 85 90 95 Leu Leu Met Gln Ala Leu Pro Met Ala Gly Leu Pro Gln Lys Pro Met 100 105 110 Gln Asn Ala Thr Lys His Gly Asn Met Thr Glu Asp His Val Met His 115 120 125 Leu Leu Leu Asn Ala Asp Pro Leu Lys Val Tyr Pro Pro Leu Lys Gly 130 135 140 Ser Leu Ser Glu Asn Leu Lys His Leu Lys Asn Thr Met Glu Thr Met 145 150 155 160 Asp Trp Lys Val Phe Glu Ser Trp Leu His His Trp Leu Leu Phe Glu 165 170 175 Met Ser Lys His Ser Leu Glu Gln Lys Pro Thr Glu Ala Pro Pro Lys 180 185 190 Glu Ser Leu Glu Leu Glu Asp Pro Ser Ser Gly Leu Gly Val Thr Lys 195 200 205 Gln Asp Leu Gly Pro Val Ala Met Ser Glu Asp Phe Leu Ile Leu Ile 210 215 220 Ala Ile Leu Val Ile Val Ile Leu Val Gly Thr Ile Thr Thr Leu Val 225 230 235 240 Gly Ala Ile Gly Gly Ile Arg Ala Arg Arg Ser Phe Leu Phe Ile Cys 245 250 255 Ile Phe Phe Leu Phe Leu Ser Leu Phe Leu Thr Ile Leu Ala Leu Leu 260 265 270 Leu Gly Phe Ser Trp Leu Leu Leu Val Ala Ile Leu Phe Trp Val Leu 275 280 285 Trp Leu Val Ile Leu Ile Leu Leu Leu Leu Val Tyr Pro Ile Pro His 290 295 300 His Pro Leu Pro Thr Ser Leu Arg Phe Arg Met Lys Gln Arg Val Ser 305 310 315 320 Ser Asp Pro Thr Gly Ser Asp Arg Ser Pro Gln Gly Ser His Asn Ser 325 330 335 Leu Asn Ser Pro Asp Glu Glu Asp Pro Lys Asp Asp Thr Lys Gln Pro 340 345 350 Leu Cys Asn Met Thr Gln Gly Gly Pro Pro Val Asn Gly Gln Leu Leu 355 360 365 Gly Gln His Ala Gln Cys Pro Pro His Tyr Pro Cys Cys His Ile Gln 370 375 380 His Pro Asp Gly Glu Asp Ser Asp Gly Asp Asp Gly Lys Ser Trp Gly 385 390 395 400 Asp Ala Gly Glu Glu Asp Asn Gly Pro Asn Asp Pro Asn Thr Ala Ser 405 410 415 Thr Arg Glu Ser Ile Tyr Glu Asp Leu Arg Tyr Pro Thr Arg Asp Ala 420 425 430 Asn Gly Glu Tyr Glu Asn Val Gly Tyr Pro Pro Arg Asp Gly Asp Ala 435 440 445 Pro His Arg Leu Gly Glu Pro Val Tyr Asp Asp Val Glu Gln Ala Thr 450 455 460 Ala Asn Glu Val Arg Ile Ser Pro Leu Phe Arg Leu Pro Tyr Gly Ser 465 470 475 480 Ala Phe Gly Pro Gly Pro Gln Pro Gly Pro Ile Leu Glu Ser Ser Thr 485 490 495 Trp Gly Phe Leu Val Phe Thr Gln Thr Ser Leu Phe Ala Asp Asp Ile 500 505 510 Ala Asp Ala Ile Arg Asp Tyr Cys Thr Thr His Pro Gly Pro Thr Arg 515 520 525 Asn Thr Gln Val Val Leu Met Asn Phe Glu Gly Ser Gly Val Pro Leu 530 535 540 Pro Met Phe Phe Pro Pro Gly Glu Glu Thr Glu Glu Gln Arg Glu Gly 545 550 555 560 Asp Arg Ala Ser Asp Ser Asp Glu Ser Glu Asp Ala Gln Ile Leu Thr 565 570 575 Val Phe Cys Leu Phe Cys Gln Trp Thr Leu Phe Ile Cys Leu Gly Ile 580 585 590 Arg Met Ile Cys Asn Trp Arg Gly Lys Leu Thr Arg Ile Ile Cys Leu 595 600 605 Lys Phe Cys Leu Tyr Gly Leu Ile Ser Ala Ser Leu Ser Phe Gly Trp 610 615 620 Tyr Ala Phe Leu Lys Glu Val Thr Leu Pro Thr Thr Ala Thr Val Asp 625 630 635 640 Pro Arg Gln Leu Pro Leu Phe Leu Phe Ile Leu Ser Ser Val Leu Val 645 650 655 Ile Leu Ala Ile Met Met Glu Phe Gln Thr Ser Ser Ser Leu Phe Ala 660 665 670 Ala Leu Phe Val Ile Ile Ala Gly Met Leu Cys Val Thr Val Gly Val 675 680 685 Ile Phe Leu Leu Ala Gly Val Lys Pro Leu Leu Ser Gly Met Ile Cys 690 695 700 Ala Ser Gly Ile Thr Met Leu Val Leu Gly Val Val Leu Leu Val Val 705 710 715 720 Cys Thr Arg Asp Glu His Ala Ile Ser Ala Ser His His Ala Ser Asp 725 730 735 Gly Ser Val Asn Gln Gln Lys Glu Asn Gln Pro Gln Thr Leu Glu Glu 740 745 750 Cys Lys Thr Asp Gln Glu Arg Lys Arg Tyr Arg Asn Arg Leu Ala Ser 755 760 765 Arg Arg Cys Arg Ala Lys Phe Arg Asn Gln Leu Glu His Phe Arg Thr 770 775 780 Val Ala Ala Ala Lys Thr Glu Glu Asn Asn Arg Leu Arg Val Leu Ile 785 790 795 800 Arg Gln Met Cys Pro Thr Leu Asp Val Glu Ser Ile Val Pro Ser Thr 805 810 815 Ser Ala Gly Tyr His Glu Pro Leu Asn His Leu Thr His Ser Pro Ser 820 825 830 Pro Cys His His Arg Asp Glu Pro Pro Ser Arg Ser Pro Ser Pro Gln 835 840 845 Pro Thr Val Ser Glu Gln Ser Gln Gln Ser Pro Arg Gln Gln Ser Pro 850 855 860 Gln Gly Thr Ser Gln Gly Ser Thr Arg Pro Gln Val Pro Gly Gly Ala 865 870 875 880 Thr Thr Arg Lys Arg Gly Gly Val Arg Gly Gln Pro Ala Lys Cys His 885 890 895 Gly Lys Tyr Thr Thr Thr Ala Glu Gly Leu Thr Ala Leu Leu Asn Arg 900 905 910 Arg His Ser Pro Arg Thr Ser Asn Glu Gly Arg Trp Met Asn Gly Val 915 920 925 Met Ala Val Asn Leu Ser Lys Trp Pro Leu Tyr Ser Leu Arg Arg Ala 930 935 940 Leu Ala Leu Ala Met Ala Pro Arg Arg Arg Leu Ser Gly Pro Pro Trp 945 950 955 960 Leu Thr Val Leu Leu Leu Leu Ser Thr Leu Ser Val Ala Ala Leu Leu 965 970 975 Ile Leu Phe Leu Ile Phe Ser Ala Gly Ala Thr Ile Ser Thr Glu Ala 980 985 990 Ser Leu Leu Val Leu Leu Leu Leu Phe Val Thr Leu Leu Leu Pro Leu 995 1000 1005 Leu Ser Ser Asn Gly Leu Gln Leu Pro Ala Ala Leu Ile Leu Ile 1010 1015 1020 Gln Cys Phe Leu Leu Ala Ala Asp Tyr Leu Ala Tyr Leu Ile Leu 1025 1030 1035 Pro Thr Ile Met Pro Arg Gly Arg Ser Thr Gly Arg Lys Gly Arg 1040 1045 1050 Asp Thr Glu Lys Glu Arg Ser Arg Ser Pro Leu Arg Ala Pro Gly 1055 1060 1065 Gly Ser Asp Gly Pro Ser Thr Arg Ala Gly Cys Gly Ala Gly Pro 1070 1075 1080 Cys Gln Leu Ser Ser Pro Ile Ala Gly Asn Asn Gly Asn Glu Gly 1085 1090 1095 Gly Glu Gly Asp Asp Tyr Lys Ser Trp Arg Lys Pro Glu Glu Glu 1100 1105 1110 Asp Asn Gly Pro Asn Asp Pro Asn Thr Asn Asn Arg Ile Glu Asp 1115 1120 1125 Gly Asp Gly Asp Asp Gly Lys Ser Trp Arg Asn Pro Glu Glu Glu 1130 1135 1140 Asp Asn Arg Lys Gln Asp Arg Leu Gly Thr Lys Pro Phe Met Asp 1145 1150 1155 Leu Asp Gly Thr Gly Gly Gly Glu Gly Tyr Ser Gln Met Val Pro 1160 1165 1170 Ile Ala Thr Ala Pro Gly Ser Gly His Ala Ala Thr Tyr Gln Asp 1175 1180 1185 Leu Gln Ala Ala Pro Tyr Ile Ile Trp Pro Leu Gln Thr Asp Cys 1190 1195 1200 Gln Pro Val Ala Thr Thr Phe Ala Ser Pro Gly Gln Ile Gln Trp 1205 1210 1215 Tyr Thr Ser Ala Val Pro Gln Pro Thr Glu His Cys Ser Gln Phe 1220 1225 1230 Thr Asn Ala Pro Thr Val Asn Gln Gln Gln Pro Ile Ser Gln Pro 1235 1240 1245 Gln Pro Glu Asn Pro Pro Ala Phe Thr Phe Thr Gln Pro Ala Ser 1250 1255 1260 Ile Ile Pro Gly Val Ile Ser Ala Ser Asn Leu Asn Val Ser Ala 1265 1270 1275 Ser Pro Ile Ile Pro Ser Asp His Val Leu Pro Ile Ile Thr Ser 1280 1285 1290 Val Thr Ser Leu Ala Gln Pro Asn Asn Met Ala Gly His Trp Tyr 1295 1300 1305 Glu Ser Val Ile Pro Gly Leu Phe Leu Cys Pro Leu Ile Leu Pro 1310 1315 1320 Ser Leu Phe Trp Ile Cys Ser Leu Leu Thr Phe Leu Val Gly His 1325 1330 1335 Gly Ala Asn Ile Val Ser Ala Val Leu Phe Leu Val Leu Ala Trp 1340 1345 1350 Cys Leu Leu Ile Ala Asn Trp Asn Val Thr Arg Glu Asp Phe Val 1355 1360 1365 Ser Gly Arg Arg Ser Ser Met Ser Ser Leu Ser Val Ala Ala Ser 1370 1375 1380 Thr Ala Thr Ala Met Phe Ala Ser Phe Leu Thr Leu Ser Phe Asp 1385 1390 1395 Gly Leu Gly Leu Leu Leu Phe Gly Thr Ala Leu Val Ile Gln Thr 1400 1405 1410 Ile Tyr Val Leu Tyr Leu Val Val Met Glu Ile Thr Val Trp Ile 1415 1420 1425 Methionine Methionine Phenylalanine Arginine Tyrosine Leucine Histidine Phenylalanine Tryptophan Isoleucine Threonine Leucine Leucine Phenylalanine Leucine 1430 1435 1440 Leucine Serine Proline Isoleucine Isoleucine Leucine Serine Valine Alanine Cysteine Leucine Isoleucine Isoleucine Glutamine Serine 1445 1450 1455 Serine Alanine Leucine Leucine Isoleucine Glutamic Acid Alanine Valine Valine Valine Threonine Threonine Isoleucine Threonine Valine 1460 1465 1470 Leucine Alanine Isoleucine Phenylalanine Leucine Tryptophan Leucine Proline Proline Glutamine Glycine Alanine Glutamic Acid Alanine Aspartic Acid 1475 1480 1485 Leucine Glycine Threonine Alanine Leucine Leucine Isoleucine Leucine Asparagine Threonine Alanine Leucine Cysteine Leucine Valine 1490 1495 1500 Valine Leucine Isoleucine Leucine Threonine Alanine Isoleucine Proline Threonine 1505 1510 <210> 49 <211> 4536 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 49 atggacgacc agcgggacct gatcagcaac aacgagcagc tgcccatgct gggccagagg 60 cctggcgccc ctgagagcaa gtgtagcaga ggcgccgtgt acaccgtgtt cagcatcctg 120 gtggccctgc tgctggccgg acaggccacc accgcctact ttctgtatca gcagcaggga 180 cggctggaca agctgaccgt gaccagccag aacctgcagc tggaaaacct gcggatgaag 240 ctgcccaagc ccgccaagcc cctgagccag atgagaatgg ccacccccct gctgatgcag 300 gccctgccta tggccggcct gccccagaaa cccatgcaga acgccaccaa gcacggcaac 360 atgaccgagg accacgtgat gcatctgctg ctgaacgccg accccctgaa ggtgtacccc 420 ccactgaagg gcagcctgag cgagaacctg aagcacctga agaacaccat ggaaaccatg 480 gactggaagg tgttcgagag ctggctgcac cactggctgc tgttcgagat gagcaagcac 540 agcctggaac agaagcccac cgaggcccct cccaaagaga gcctggaact ggaagatccc 600 agcagcggcc tgggcgtgac caagcaggat ctgggccccg tggctatgtc cgaggacttt 660 agcagcggcc tgggcgtgac caagcaggat ctgggccccg tggctatgtc cgaggacttt 660 ctgattctga tcgccatcct ggtgatcgtg attctcgtgg gcacaatcac aaccctggtg 720 ctgattctga tcgccatcct ggtgatcgtg attctcgtgg gcacaatcac aaccctggtg 720 ggcgccatcg gcggcattag ggccaggagg agcttcctct tcatttgcat cttcttcctg 780 ggcgccatcg gcggcattag ggccaggagg agcttcctct tcatttgcat cttcttcctg 780 ttcctctccc tcttcctgac aatcctcgcc ctgctgctgg gcttcagctg gctcctgctg 840 ttcctctccc tcttcctgac aatcctcgcc ctgctgctgg gcttcagctg gctcctgctg 840 gtggccatcc tgttctgggt gctctggctg gtcatcctca ttctgctgct gctggtgtac 900 gtggccatcc tgttctgggt gctctggctg gtcatcctca ttctgctgct gctggtgtac 900 cctattcctc accaccccct gcccacctcc ctcaggttta gaatgaagca gagggtgagc 960 cctattcctc accaccccct gcccacctcc ctcaggttta gaatgaagca gagggtgagc 960 agcgacccca caggttctga cagaagccct cagggcagcc ataatagcct gaactccccc 1020 agcgacccca caggttctga cagaagccct cagggcagcc ataatagcct gaactccccc 1020 gatgaggagg accccaagga tgacaccaag caacctctgt gcaacatgac ccagggcgga 1080 gatgaggagg accccaagga tgacaccaag caacctctgt gcaacatgac ccagggcgga 1080 cctcccgtca atggacagct cctcggacaa catgctcaat gcccccctca ctatccctgc 1140 cctcccgtca atggacagct cctcggacaa catgctcaat gcccccctca ctatccctgc 1140 tgccatattc agcatcccga cggagaggat tccgatggag acgatggcaa gtcctggggc 1200 tgccatattc agcatcccga cggagaggat tccgatggag acgatggcaa gtcctggggc 1200 gatgccggag aggaagacaa tggccctaac gaccctaaca ccgccagcac cagagagtcc 1260 atttacgagg acctcagata ccccacaagg gacgccaatg gcgagtatga gaacgtggga 1320 taccccccta gggacggaga tgcccctcat aggctcggag agcctgtgta tgacgatgtg 1380 gagcaagcca ccgctaacga ggtgagaatc tcccctctgt tcagactgcc ctacggaagc 1440 gctttcggac ctggccccca gcctggaccc attctggaga gctccacatg gggctttctg 1500 gtcttcacac agacctccct gttcgccgac gacattgccg acgctattag ggactactgc 1560 acaacccacc ctggccccac aaggaacacc caggtggtcc tcatgaactt cgagggcagc 1620 ggagtgcccc tgcctatgtt ttttccccct ggagaggaga cagaagagca gagagagggc 1680 gatagagcta gcgactccga cgagtccgaa gacgctcaga tcctgaccgt gttctgcctg 1740 ttttgccagt ggacactctt tatctgcctg ggaatcagga tgatctgtaa ctggaggggc 1800 aaactcacca ggatcatctg cctgaagttc tgcctctacg gactgatttc cgcctccctg 1860 tccttcggct ggtacgcttt tctgaaggaa gtgaccctcc ccaccacagc caccgttgat 1920 cctaggcaac tccccctgtt cctcttcatc ctgagctccg tgctggtgat tctcgccatc 1980 atgatggagt ttcaaacatc ctccagcctc ttcgctgctc tgttcgtgat tatcgccgga 2040 atgctgtgcg tcacagtggg cgtgattttt ctgctggctg gcgtcaagcc tctcctgagc 2100 ggcatgatct gcgcctccgg catcacaatg ctcgtgctcg gcgtcgtgct gctggtggtg 2160 tgcaccagag atgagcacgc tatttccgcc agccaccatg ctagcgatgg ctccgtgaat 2220 cagcagaagg aaaatcagcc ccagaccctg gaggaatgca agacagatca ggagaggaag 2280 aggtacagga acaggctggc ctccaggagg tgtagagcta agttcaggaa ccagctggaa 2340 cattttagga cagtcgccgc tgctaagaca gaggagaaca acaggctcag ggtgctcatc 2400 aggcagatgt gtcctacact ggacgtggaa tccatcgtcc cctccacctc cgccggctac 2460 cacgagcctc tgaatcacct gacccacagc cccagccctt gtcatcacag ggatgaaccc 2520 ccctccagaa gccccagccc tcaacccacc gtctccgagc agtcccagca gtcccccagg 2580 cagcagagcc ctcaaggcac atcccagggt tctacaagac ctcaggtgcc tggaggcgcc 2640 accaccagaa aaagaggcgg cgtgagaggc caacctgcca agtgtcacgg caagtacacc 2700 acaaccgccg agggactgac cgctctcctg aataggaggc acagccccag gacatccaac 2760 gagggcaggt ggatgaatgg agtcatggct gtgaacctct ccaaatggcc cctgtacagc 2820 ctgaggagag ccctggccct cgccatggct cctagaagga ggctctccgg ccctccctgg 2880 ctgacagtgc tgctgctgct gtccacactg agcgtggccg ccctgctgat tctcttcctg 2940 attttcagcg ccggcgccac cattagcaca gaagccagcc tgctggtcct gctcctgctg 3000 tttgtgaccc tgctgctgcc tctcctgtcc tccaacggac tccagctccc tgccgccctg 3060 attctgatcc agtgtttcct cctggccgct gattatctcg cctacctgat tctgcctacc 3120 attatgccca ggggcagaag cacaggaagg aagggcaggg acacagagaa agagaggagc 3180 agatcccctc tcagagctcc tggcggttct gatggaccca gcacaagggc tggctgtgga 3240 gccggaccct gtcagctgag cagccccatc gccggaaaca acggcaatga aggcggcgag 3300 ggcgacgact acaagagctg gaggaagccc gaggaagagg acaacggccc caatgacccc 3360 aataccaaca acaggattga ggatggagac ggcgacgacg gaaaatcctg gaggaatcct 3420 gaggaggagg ataacagaaa gcaggacagg ctgggcacca agcctttcat ggacctcgac 3480 ggaaccggcg gaggcgaggg ctacagccag atggtcccta tcgccaccgc ccccggaagc 3540 ggccacgccg ctacctatca ggatctccag gccgcccctt acatcatctg gcctctccag 3600 accgattgcc agcctgtggc taccaccttc gcctcccccg gacagatcca gtggtataca 3660 agcgccgtcc cccagcccac agagcattgc tcccagttta caaacgctcc caccgtcaac 3720 cagcagcagc ctattagcca accccagccc gaaaatcccc ctgctttcac ctttacccag 3780 cccgcttcca tcattcccgg cgtcattagc gcctccaacc tgaacgtgag cgcttcccct 3840 atcatcccta gcgaccatgt cctccccatc attacctccg tgaccagcct cgcccaacct 3900 aataacatgg ccggccactg gtatgagagc gtgattcccg gcctgttcct ctgccccctg 3960 atcctccctt ccctgttctg gatttgctcc ctgctgacct tcctggtggg ccacggagcc 4020 aatattgtga gcgccgtcct gttcctcgtg ctggcttggt gtctcctcat tgccaactgg 4080 aacgtgacaa gagaggactt cgtgtccggc aggagaagct ccatgagcag cctgtccgtg 4140 gccgcttcca ccgccacagc catgttcgcc agcttcctca ccctgagctt tgatggcctg 4200 ggcctgctgc tgtttggcac cgccctggtg atccagacaa tttacgtgct gtatctggtg 4260 gtcatggaga tcaccgtgtg gatcatgatg tttaggtatc tccacttttg gatcaccctg 4320 ctgttcctgc tgagccccat tattctctcc gtcgcctgtc tcatcatcca atcctccgcc 4380 ctgctgatcg aggctgtggt cgtcaccacc atcacagtcc tggccatttt tctgtggctc 4440 cctcctcaag gcgctgaggc cgatctcggc accgccctgc tgattctgaa taccgccctg 4500 tgcctggtcg tgctgatcct gaccgctatc cctaca 4536 <210> 50 <211> 44035 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polynucleotide" <220> <221> modified_base <222> (15712)..(15712) <223> a, c, t, g, unknown or other <400> 50 catcatcaat aatatacctt attttggatt gaagccaata tgataatgag atgggcggcg 60 cggggcgggg cgcggggcgg gaggcgggtt tgggggcggg ccggcgggcg gggcggtgtg 120 gcggaagtgg actttgtaag tgtggcggat gtgacttgct agtgccgggc gcggtaaaag 180 tgacgttttc cgtgcgcgac aacgcccccg ggaagtgaca tttttcccgc ggtttttacc 240 ggatgttgta gtgaatttgg gcgtaaccaa gtaagatttg gccattttcg cgggaaaact 300 gaaacgggga agtgaaatct gattaatttt gcgttagtca taccgcgtaa tatttgtcta 360 gggccgaggg actttggccg attacgtgga ggactcgccc aggtgttttt tgaggtgaat 420 ttccgcgttc cgggtcaaag tctgcgtttt attattatag gatatcccat tgcatacgtt 480 gtatccatat cataatatgt acatttatat tggctcatgt ccaacattac cgccatgttg 540 acattgatta ttgactagtt attaatagta atcaattacg gggtcattag ttcatagccc 600 atatatggag ttccgcgtta cataacttac ggtaaatggc ccgcctggct gaccgcccaa 660 cgacccccgc ccattgacgt caataatgac gtatgttccc atagtaacgc caatagggac 720 tttccattga cgtcaatggg tggagtattt acggtaaact gcccacttgg cagtacatca 780 agtgtatcat atgccaagta cgccccctat tgacgtcaat gacggtaaat ggcccgcctg 840 gcattatgcc cagtacatga ccttatggga ctttcctact tggcagtaca tctacgtatt 900 agtcatcgct attaccatgg tgatgcggtt ttggcagtac atcaatgggc gtggatagcg 960 gtttgactca cggggatttc caagtctcca ccccattgac gtcaatggga gtttgttttg 1020 gcaccaaaat caacgggact ttccaaaatg tcgtaacaac tccgccccat tgacgcaaat 1080 gggcggtagg cgtgtacggt gggaggtcta tataagcaga gctctcccta tcagtgatag 1140 agatctccct atcagtgata gagatcgtcg acgagctcgt ttagtgaacc gtcagatcgc 1200 ctggagacgc catccacgct gttttgacct ccatagaaga caccgggacc gatccagcct 1260 ccgcggccgg gaacggtgca ttggaacgcg gattccccgt gccaagagtg agatcttccg 1320 tttatctagg taccagatat cgccaccatg agacctgctc cctggacacc taatcctccc 1380 aggtccccca gccagatgag cgtgagagac agactggcta ggctgagagc cgaggctcag 1440 gtcaagcagg ccagcgtcga ggtgcaaccc cctcagctca cccaggtgtc cccccagcag 1500 cctgtggccg gcattctgtt cattctggcc attctgaccg agtggggaag cggcaacaga 1560 acctacggcc ctgtcttcat gtgcctcgga ggactgctga caatggtggc tggcgccgtg 1620 tggctcaccg tcatgtccaa caccctgctc agcgcctgga ttctgaccgc cggattcctg 1680 atctttctga tcggattcgc tctctttggc gtcatcaggt gttgcaggta ctgttgctac 1740 tactgcctga ccctcgagag cgaggaaaga ccccccaccc cctacaggaa tacagtgatt 1800 agggacagaa ggaggaatcc tgcctccagg agagaccagg ccaaatggag actccaaaca 1860 ctcgccgctg gatggcccat gggctaccag gcctatagct cctggatgta cagctacacc 1920 gaccatcaga caacacccac cttcgtgcat ctgcaggcta cactgggctg caccggaggc 1980 agaaggtgtc acgtgtttct gggaatcgtg ctgttcatct ttggatgcct gctcgtgctg 2040 ggcatctgga tttatctcct ggagatgctc tggagactcg gcgctacaat ttggcagctg 2100 ctcgcctttt ttctggcctt ctttctggac ctgatcctcc tgatcatcgc cctgtacctc 2160 caacagaact ggtggaccct cctggtggat ctgctgtggc tcctcctctt cctggccatc 2220 ctgatctgga tgtactacca tggccagaga ggaagggtcg cttgcgctcc tgtccctgct 2280 cctgctggcc ccatcgtgag gccttgggag ccttccctca cacaggccgc cggccaggcc 2340 tttgctcccg tgaggcccca gcacatgcct gtggaacccg tgcccgtccc cacagtggct 2400 ctggaaaggc ctgtgtaccc caagcccgtg agacctgtcc tctggctcag cagccctgga 2460 ggactcggaa cactcggagc cgctctcctg acactggccg ctgctctggc tctgctggct 2520 agcctgatcc tgggaaccct caacctcacc accatgtttc tcctcatgct cctgtggacc 2580 ctcgtggtgc tgctcatctg ttccagctgc tccagctgcc ccctgagcaa gatcctgctg 2640 gccaggctgt tcctgtacgc cctcgccctc ctgctgctgg ctagcgccct gatcgctggc 2700 ggaagcatcc tccagaccaa tttcaagagc ctctcctcca ccgagttcat ccccaacctg 2760 ttctgtatgt tactgctgat ccatagcgac gagcaccatc atgacgactc cctgccccat 2820 cctcagcagg ccacagacga ctccggccac gagagcgaca gcaatagcaa tgagggcagg 2880 caccatctgc tcgtgtccgg agctcaagtc cccgagcctc ccaccatcca tctcgccgcc 2940 cagggaatgg cttaccccct ccacgagcag cacggcatgg ccccttgtcc cgtcgctcaa 3000 gcccccccta cacctctgcc ctttttcgcc atttgtctga cctggagaat cgaggacccc 3060 cccttcaaca gcctgctgtt cgccctgctc gccgccgctg gcggcctcca gggcatttac 3120 gtcctcgtga tgctggtgct gctgatcctc gcttacagga gaagatggag gagactgaca 3180 gtgtgcggcg gcatcatgtt tctcgcctgc gtcctggtcc tgatcgtgga cgccgtcctg 3240 caactcagcc ccctcctggg agctgtgaca gtggtctcca tgaccctgct gctgctggcc 3300 ttcaacggac cccacgatcc tctgccccaa gatcctgaca ataccgacga taacggcccc 3360 caagaccccg ataacaccga cgacaatggc cctcacgacc ctctgcccca tagcccttcc 3420 gatagcgctg gcaacgatgg cggccctcct cagctgacag aggaggtgga aaataagggc 3480 ggcgatcagg gaccccccct gatgacagat ggcggaggag gacacagcca tgatagcgga 3540 catggcggag gcgatcccca tctgcctacc ctcctcctgg gcagctccgg ttctggaggc 3600 gacgatgatg accctcacgg ccctgtgcag ctctcctact acgacggcaa aaggaccgaa 3660 caaggaaaag aggtcctgga gaaggccagg ggcagcacat acggaacccc caggcctccc 3720 atgtccgatt ggaccggagg agccctgctg gtcctctaca gcttcgccct gatgctgatc 3780 attatcatcc tgatcatctt tatcttcaga agggacctgc tgtgccctct cggcgccctg 3840 tgcatcctgc tgctcatgat cacactcctc ctgatcgccc tctggaacct gcacggacaa 3900 gccctgatgt ccgatgaggg acctggaaca ggacccggaa acggactggg cgagaaggga 3960 gatacaagcg gccccgaagg cagcggcgga agcggacccc aaagaagggg cggcgacaac 4020 cacggaagag gaagaggcag gggcagaggc agaggaggag gaagacctgg agcccctggc 4080 ggttctggaa gcggacccag gcacagggac ggagtgagga ggcctcaaaa aagacccagc 4140 tgcatcggct gcaagggaac ccactggatt gatgataacc cctccacaga gaccgctcag 4200 gcctggaacg ccggcttcct gaggggaaga gcctatggca tcgatctgct gaggaccgag 4260 ggcgaacacg tggagggagc caccggagag acaagggagg aaagcgaaga cacagaaagc 4320 gatggcgacg acgaagacct gccctgcatt gtgtccaggg gcggacccaa ggtgaagagg 4380 ccccctatct ttatcagaag gctccataga ctgctcctga tgagggccat gaaccctgtg 4440 tgcctgcccg tgatcgtggc cccctacctc ttttggctgg ccgccattgc cgctagctgc 4500 ttcaccgcct ccgtgtccac agtggtgaca gccaccggcc tcgccctgag cctgctgctc 4560 ctcgctgccg tggcctccag ctacgccgct gctcaaagaa agctcctgac ccctgtcacc 4620 gtcctgacag ccgtcgtgac caccttttcc gctggcacct tcaagctgcc taggtgcaca 4680 cctggcgaca ggcagtggct ctacgtgcag agctccgtgg gcaatattgt gcagagctgc 4740 aatcccaggt acagcatttt tttcgactac atggccatcc ataggtccct caccaagatc 4800 tgggagtgat gatgagcggc cgcgatctgc tgtgccttct agttgccagc catctgttgt 4860 ttgcccctcc cccgtgcctt ccttgaccct ggaaggtgcc actcccactg tcctttccta 4920 ataaaatgag gaaattgcat cgcattgtct gagtaggtgt cattctattc tggggggtgg 4980 ggtggggcag gacagcaagg gggaggattg ggaagacaat agcaggcatg ctggggatgc 5040 ggtgggctct atggccgatc agcgatcgct gaggtgggtg agtgggcgtg gcctggggtg 5100 gtcatgaaaa tatataagtt gggggtctta gggtctcttt atttgtgttg cagagaccgc 5160 cggagccatg agcgggagca gcagcagcag cagtagcagc agcgccttgg atggcagcat 5220 cgtgagccct tatttgacga cgcggatgcc ccactgggcc ggggtgcgtc agaatgtgat 5280 gggctccagc atcgacggcc gacccgtcct gcccgcaaat tccgccacgc tgacctatgc 5340 gaccgtcgcg gggacgccgt tggacgccac cgccgccgcc gccgccaccg cagccgcctc 5400 ggccgtgcgc agcctggcca cggactttgc attcctggga ccactggcga caggggctac 5460 ttctcgggcc gctgctgccg ccgttcgcga tgacaagctg accgccctgc tggcgcagtt 5520 ggatgcgctt actcgggaac tgggtgacct ttctcagcag gtcatggccc tgcgccagca 5580 ggtctcctcc ctgcaagctg gcgggaatgc ttctcccaca aatgccgttt aagataaata 5640 aaaccagact ctgtttggat taaagaaaag tagcaagtgc attgctctct ttatttcata 5700 attttccgcg cgcgataggc cctagaccag cgttctcggt cgttgagggt gcggtgtatc 5760 ttctccagga cgtggtagag gtggctctgg acgttgagat acatgggcat gagcccgtcc 5820 cgggggtgga ggtagcacca ctgcagagct tcatgctccg gggtggtgtt gtagatgatc 5880 cagtcgtagc aggagcgctg ggcatggtgc ctaaaaatgt ccttcagcag caggccgatg 5940 gccaggggga ggcccttggt gtaagtgttt acaaaacggt taagttggga agggtgcatt 6000 cggggagaga tgatgtgcat cttggactgt atttttagat tggcgatgtt tccgcccaga 6060 tcccttctgg gattcatgtt gtgcaggacc accagtacag tgtatccggt gcacttgggg 6120 aatttgtcat gcagcttaga gggaaaagcg tggaagaact tggagacgcc tttgtggcct 6180 cccagatttt ccatgcattc gtccatgatg atggcaatgg gcccgcggga ggcagcttgg 6240 gcaaagatat ttctggggtc gctgacgtcg tagttgtgtt ccagggtgag gtcgtcatag 6300 gccattttta caaagcgcgg gcggagggtg cccgactggg ggatgatggt cccctctggc 6360 cctggggcgt agttgccctc gcagatctgc atttcccagg ccttaatctc ggagggggga 6420 atcatatcca cctgcggggc gatgaagaaa acggtttccg gagccgggga gattaactgg 6480 gatgagagca ggtttctaag cagctgtgat tttccacaac cggtgggccc ataaataaca 6540 cctataaccg gttgcagctg gtagtttaga gagctgcagc tgccgtcgtc ccggaggagg 6600 ggggccacct cgttgagcat gtccctgacg cgcatgttct ccccgaccag atccgccaga 6660 aggcgctcgc cgcccaggga cagcagctct tgcaaggaag caaagttttt cagcggcttg 6720 aggccgtccg ccgtgggcat gtttttcagg gtctggctca gcagctccag gcggtcccag 6780 agctcggtga cgtgctctac ggcatctcta tccagcatat ctcctcgttt cgcgggttgg 6840 ggcgactttc gctgtagggc accaagcggt ggtcgtccag cggggccaga gtcatgtcct 6900 tccatgggcg cagggtcctc gtcagggtgg tctgggtcac ggtgaagggg tgcgctccgg 6960 gctgagcgct tgccaaggtg cgcttgaggc tggttctgct ggtgctgaag cgctgccggt 7020 cttcgccctg cgcgtcggcc aggtagcatt tgaccatggt gtcatagtcc agcccctccg 7080 cggcgtgtcc cttggcgcgc agcttgccct tggaggtggc gccgcacgag gggcagagca 7140 ggctcttgag cgcgtagagc ttgggggcga ggaagaccga ttcgggggag taggcgtccg 7200 cgccgcagac cccgcacacg gtctcgcact ccaccagcca ggtgagctcg gggcgcgccg 7260 ggtcaaaaac caggtttccc ccatgctttt tgatgcgttt cttacctcgg gtctccatga 7320 ggtggtgtcc ccgctcggtg acgaagaggc tgtccgtgtc tccgtagacc gacttgaggg 7380 gtcttttctc caggggggtc cctcggtctt cctcgtagag gaactcggac cactctgaga 7440 cgaaggcccg cgtccaggcc aggacgaagg aggctatgtg ggaggggtag cggtcgttgt 7500 ccactagggg gtccaccttc tccaaggtgt gaagacacat gtcgccttcc tcggcgtcca 7560 ggaaggtgat tggcttgtag gtgtaggcca cgtgaccggg ggttcctgac gggggggtat 7620 aaaagggggt gggggcgcgc tcgtcgtcac tctcttccgc atcgctgtct gcgagggcca 7680 gctgctgggg tgagtattcc ctctcgaagg cgggcatgac ctccgcgctg aggttgtcag 7740 tttccaaaaa cgaggaggat ttgatgttca cctgtcccga ggtgatacct ttgagggtac 7800 ccgcgtccat ctggtcagaa aacacgatct ttttattgtc cagcttggtg gcgaacgacc 7860 cgtagagggc gttggagagc agcttggcga tggagcgcag ggtctggttc ttgtccctgt 7920 cggcgcgctc cttggccgcg atgttgagct gcacgtactc gcgcgcgacg cagcgccact 7980 cggggaagac ggtggtgcgc tcgtcgggca ccaggcgcac gcgccagccg cggttgtgca 8040 gggtgaccag gtccacgctg gtggcgacct cgccgcgcag gcgctcgttg gtccagcaga 8100 gacggccgcc cttgcgcgag cagaaggggg gcagggggtc gagctgggtc tcgtccgggg 8160 ggtccgcgtc cacggtgaaa accccggggc gcaggcgcgc gtcgaagtag tctatcttgc 8220 aaccttgcat gtccagcgcc tgctgccagt cgcgggcggc gagcgcgcgc tcgtaggggt 8280 tgagcggcgg gccccagggc atggggtggg tgagtgcgga ggcgtacatg ccgcagatgt 8340 catagacgta gaggggctcc cgcaggaccc cgatgtaggt ggggtagcag cggccgccgc 8400 ggatgctggc gcgcacgtag tcatacagct cgtgcgaggg ggcgaggagg tcggggccca 8460 ggttggtgcg ggcggggcgc tccgcgcgga agacgatctg cctgaagatg gcatgcgagt 8520 tggaagagat ggtggggcgc tggaagacgt tgaagctggc gtcctgcagg ccgacggcgt 8580 cgcgcacgaa ggaggcgtag gagtcgcgca gcttgtgtac cagctcggcg gtgacctgca 8640 cgtcgagcgc gcagtagtcg agggtctcgc ggatgatgtc atatttagcc tgccccttct 8700 ttttccacag ctcgcggttg aggacaaact cttcgcggtc tttccagtac tcttggatcg 8760 ggaaaccgtc cggttccgaa cggtaagagc ctagcatgta gaactggttg acggcctggt 8820 aggcgcagca gcccttctcc acggggaggg cgtaggcctg cgcggccttg cggagcgagg 8880 tgtgggtcag ggcgaaggtg tccctgacca tgactttgag gtactggtgc ttgaagtcgg 8940 agtcgtcgca gccgccccgc tcccagagcg agaagtcggt gcgcttcttg gagcgggggt 9000 tgggcagagc gaaggtgaca tcgttgaaga ggattttgcc cgcgcggggc atgaagttgc 9060 gggtgatgcg gaagggcccc ggcacttcag agcggttgtt gatgacctgg gcggcgagca 9120 cgatctcgtc gaagccgttg atgttgtggc ccacgatgta gagttccagg aagcggggcc 9180 ggccctttac ggtgggcagc ttctttagct cttcgtaggt gagctcctcg ggcgaggcga 9240 ggccgtgctc ggccagggcc cagtccgcga ggtgcgggtt gtctctgagg aaggacttcc 9300 agaggtcgcg ggccaggagg gtctgcaggc ggtctctgaa ggtcctgaac tggcggccca 9360 cggccatttt ttcgggggtg atgcagtaga aggtgagggg gtcttgctgc cagcggtccc 9420 agtcgagctg cagggcgagg tcgcgcgcgg cggtgaccag gcgctcgtcg cccccgaatt 9480 tcatgaccag catgaagggc acgagctgct ttccgaaggc ccccatccaa gtgtaggtct 9540 ctacatcgta ggtgacaaag aggcgctccg tgcgaggatg cgagccgatc gggaagaact 9600 ggatctcccg ccaccagttg gaggagtggc tgttgatgtg gtggaagtag aagtcccgtc 9660 gccgggccga acactcgtgc tggcttttgt aaaagcgagc gcagtactgg cagcgctgca 9720 cgggctgtac ctcatgcacg agatgcacct ttcgcccgcg cacgaggaag ccgaggggaa 9780 atctgagccc cccgcctggc tcgcggcatg gctggttctc ttctactttg gatgcgtgtc 9840 cgtctccgtc tggctcctcg aggggtgtta cggtggagcg gaccaccacg ccgcgcgagc 9900 cgcaggtcca gatatcggcg cgcggcggtc ggagtttgat gacgacatcg cgcagctggg 9960 agctgtccat ggtctggagc tcccgcggcg gcggcaggtc agccgggagt tcttgcaggt 10020 tcacctcgca gagtcgggcc agggcgcggg gcaggtctag gtggtacctg atctctaggg 10080 gcgtgttggt ggcggcgtcg atggcttgca ggagcccgca gccccggggg gcgacgacgg 10140 tgccccgcgg ggtggtggtg gtggtggcgg tgcagctcag aagcggtgcc gcgggcgggc 10200 ccccggaggt agggggggct ccggtcccgc gggcaggggc ggcagcggca cgtcggcgtg 10260 gagcgcgggc aggagttggt gctgtgcccg gaggttgctg gcgaaggcga cgacgcggcg 10320 gttgatctcc tggatctggc gcctctgcgt gaagacgacg ggcccggtga gcttgaacct 10380 gaaagagagt tcgacagaat caatctcggt gtcattgacc gcggcctggc gcaggatctc 10440 ctgcacgtct cccgagttgt cttggtaggc gatctcggcc atgaactgct cgatctcttc 10500 ctcctggagg tctccgcgtc cggcgcgttc cacggtggcc gccaggtcgt tggagatgcg 10560 ccccatgagc tgcgagaagg cgttgagtcc gccctcgttc cagactcggc tgtagaccac 10620 gcccccctgg tcatcgcggg cgcgcatgac cacctgcgcg aggttgagct ccacgtgccg 10680 cgcgaagacg gcgtagttgc gcagacgctg gaagaggtag ttgagggtgg tggcggtgtg 10740 ctcggccacg aagaagttca tgacccagcg gcgcaacgtg gattcgttga tgtcccccaa 10800 ggcctccagc cgttccatgg cctcgtagaa gtccacggcg aagttgaaaa actgggagtt 10860 gcgcgccgac acggtcaact cctcctccag aagacggatg agctcggcga cggtgtcgcg 10920 cacctcgcgc tcgaaggcta tggggatctc ttcctccgct agcatcacca cctcctcctc 10980 ttcctcctct tctggcactt ccatgatggc ttcctcctct tcggggggtg gcggcggcgg 11040 cggtggggga gggggcgctc tgcgccggcg gcggcgcacc gggaggcggt ccacgaagcg 11100 cgcgatcatc tccccgcggc ggcggcgcat ggtctcggtg acggcgcggc cgttctcccg 11160 ggggcgcagt tggaagacgc cgccggacat ctggtgctgg ggcgggtggc cgtgaggcag 11220 cgagacggcg ctgacgatgc atctcaacaa ttgctgcgta ggtacgccgc cgagggacct 11280 gagggagtcc atatccaccg gatccgaaaa cctttcgagg aaggcgtcta accagtcgca 11340 gtcgcaaggt aggctgagca ccgtggcggg cggcgggggg tggggggagt gtctggcgga 11400 ggtgctgctg atgatgtaat tgaagtaggc ggacttgaca cggcggatgg tcgacaggag 11460 ggtgctgctg atgatgtaat tgaagtaggc ggacttgaca cggcggatgg tcgacaggag 11460 caccatgtcc ttgggtccgg cctgctggat gcggaggcgg tcggctatgc cccaggcttc 11520 caccatgtcc ttgggtccgg cctgctggat gcggaggcgg tcggctatgc cccaggcttc 11520 gttctggcat cggcgcaggt ccttgtagta gtcttgcatg agcctttcca ccggcacctc 11580 gttctggcat cggcgcaggt ccttgtagta gtcttgcatg agcctttcca ccggcacctc 11580 ttctccttcc tcttctgctt cttccatgtc tgcttcggcc ctggggcggc gccgcgcccc 11640 ttctccttcc tcttctgctt cttccatgtc tgcttcggcc ctggggcggc gccgcgcccc 11640 cctgcccccc atgcgcgtga ccccgaaccc cctgagcggt tggagcaggg ccaggtcggc 11700 cctgcccccc atgcgcgtga ccccgaaccc cctgagcggt tggagcaggg ccaggtcggc 11700 gacgacgcgc tcggccagga tggcctgctg cacctgcgtg agggtggttt ggaagtcatc 11760 gacgacgcgc tcggccagga tggcctgctg cacctgcgtg agggtggttt ggaagtcatc 11760 caagtccacg aagcggtggt aggcgcccgt gttgatggtg taggtgcagt tggccatgac 11820 caagtccacg aagcggtggt aggcgcccgt gttgatggtg taggtgcagt tggccatgac 11820 ggaccagttg acggtctggt ggcccggttg cgacatctcg gtgtacctga gtcgcgagta 11880 ggaccagttg acggtctggt ggcccggttg cgacatctcg gtgtacctga gtcgcgagta 11880 ggcgcgggag tcgaagacgt agtcgttgca agtccgcacc aggtactggt agcccaccag 11940 ggcgcgggag tcgaagacgt agtcgttgca agtccgcacc aggtactggt agcccaccag 11940 gaagtgcggc ggcggctggc ggtagagggg ccagcgcagg gtggcggggg ctccgggggc 12000 gaagtgcggc ggcggctggc ggtagagggg ccagcgcagg gtggcggggg ctccgggggc 12000 caggtcttcc agcatgaggc ggtggtaggc gtagatgtac ctggacatcc aggtgatacc 12060 cgcggcggtg gtggaggcgc gcgggaagtc gcgcacccgg ttccagatgt tgcgcagggg 12120 cagaaagtgc tccatggtag gcgtgctctg tccagtcaga cgcgcgcagt cgttgatact 12180 ctagaccagg gaaaacgaaa gccggtcagc gggcactctt ccgtggtctg gtgaatagat 12240 cgcaagggta tcatggcgga gggcctcggt tcgagccccg ggtccgggcc ggacggtccg 12300 ccatgatcca cgcggttacc gcccgcgtgt cgaacccagg tgtgcgacgt cagacaacgg 12360 tggagtgttc cttttggcgt ttttctggcc gggcgccggc gccgcgtaag agactaagcc 12420 gcgaaagcga aagcagtaag tggctcgctc cccgtagccg gagggatcct tgctaagggt 12480 tgcgttgcgg cgaaccccgg ttcgaatccc gtactcgggc cggccggacc cgcggctaag 12540 gtgttggatt ggcctccccc tcgtataaag accccgcttg cggattgact ccggacacgg 12600 ggacgagccc cttttatttt tgctttcccc agatgcatcc ggtgctgcgg cagatgcgcc 12660 ccccgcccca gcagcagcaa caacaccagc aagagcggca gcaacagcag cgggagtcat 12720 gcagggcccc ctcacccacc ctcggcgggc cggccacctc ggcgtccgcg gccgtgtctg 12780 gcgcctgcgg cggcggcggg gggccggctg acgaccccga ggagcccccg cggcgcaggg 12840 ccagacacta cctggacctg gaggagggcg agggcctggc gcggctgggg gcgccgtctc 12900 ccgagcgcca cccgcgggtg cagctgaagc gcgactcgcg cgaggcgtac gtgcctcggc 12960 agaacctgtt cagggaccgc gcgggcgagg agcccgagga gatgcgggac aggaggttca 13020 gcgcagggcg ggagctgcgg caggggctga accgcgagcg gctgctgcgc gaggaggact 13080 ttgagcccga cgcgcggacg gggatcagcc ccgcgcgcgc gcacgtggcg gccgccgacc 13140 tggtgacggc gtacgagcag acggtgaacc aggagatcaa cttccaaaag agtttcaaca 13200 accacgtgcg cacgctggtg gcgcgcgagg aggtgaccat cgggctgatg cacctgtggg 13260 actttgtaag cgcgctggtg cagaacccca acagcaagcc tctgacggcg cagctgttcc 13320 tgatagtgca gcacagcagg gacaacgagg cgtttaggga cgcgctgctg aacatcaccg 13380 agcccgaggg tcggtggctg ctggacctga ttaacatcct gcagagcata gtggtgcagg 13440 agcgcagcct gagcctggcc gacaaggtgg cggccatcaa ctactcgatg ctgagcctgg 13500 gcaagtttta cgcgcgcaag atctaccaga cgccgtacgt gcccatagac aaggaggtga 13560 agatcgacgg tttttacatg cgcatggcgc tgaaggtgct caccctgagc gacgacctgg 13620 gcgtgtaccg caacgagcgc atccacaagg ccgtgagcgt gagccggcgg cgcgagctga 13680 gcgaccgcga gctgatgcac agcctgcagc gggcgctggc gggcgccggc agcggcgaca 13740 gggaggcgga gtcctacttc gatgcggggg cggacctgcg ctgggcgccc agccggcggg 13800 ccctggaggc cgcgggggtc cgcgaggact atgacgagga cggcgaggag gatgaggagt 13860 ccctggaggc cgcgggggtc cgcgaggact atgacgagga cggcgaggag gatgaggagt 13860 acgagctaga ggagggcgag tacctggact aaaccgcggg tggtgtttcc ggtagatgca 13920 acgagctaga ggagggcgag tacctggact aaaccgcggg tggtgtttcc ggtagatgca 13920 agacccgaac gtggtggacc cggcgctgcg ggcggctctg cagagccagc cgtccggcct 13980 agacccgaac gtggtggacc cggcgctgcg ggcggctctg cagagccagc cgtccggcct 13980 taactcctca gacgactggc gacaggtcat ggaccgcatc atgtcgctga cggcgcgtaa 14040 taactcctca gacgactggc gacaggtcat ggaccgcatc atgtcgctga cggcgcgtaa 14040 cccggacgcg ttccggcagc agccgcaggc caacaggctc tccgccatcc tggaggcggt 14100 cccggacgcg ttccggcagc agccgcaggc caacaggctc tccgccatcc tggaggcggt 14100 ggtgcctgcg cgctcgaacc ccacgcacga gaaggtgctg gccatagtga acgcgctggc 14160 ggtgcctgcg cgctcgaacc ccacgcacga gaaggtgctg gccatagtga acgcgctggc 14160 cgagaacagg gccatccgcc cggacgaggc cgggctggtg tacgacgcgc tgctgcagcg 14220 cgagaacagg gccatccgcc cggacgaggc cgggctggtg tacgacgcgc tgctgcagcg 14220 cgtggcccgc tacaacagcg gcaacgtgca gaccaacctg gaccggctgg tgggggacgt 14280 cgtggcccgc tacaacagcg gcaacgtgca gaccaacctg gaccggctgg tgggggacgt 14280 gcgcgaggcg gtggcgcagc gcgagcgcgc ggatcggcag ggcaacctgg gctccatggt 14340 gcgcgaggcg gtggcgcagc gcgagcgcgc ggatcggcag ggcaacctgg gctccatggt 14340 ggcgctgaat gccttcctga gcacgcagcc ggccaacgtg ccgcgggggc aggaagacta 14400 ggcgctgaat gccttcctga gcacgcagcc ggccaacgtg ccgcgggggc aggaagacta 14400 caccaacttt gtgagcgcgc tgcggctgat ggtgaccgag accccccaga gcgaggtgta 14460 ccagtcgggc ccggactact tcttccagac cagcagacag ggcctgcaga cggtgaacct 14520 gagccaggct ttcaagaacc tgcgggggct gtggggcgtg aaggcgccca ccggcgaccg 14580 ggcgacggtg tccagcctgc tgacgcccaa ctcgcgcctg ctgctgctgc tgatcgcgcc 14640 gttcacggac agcggcagcg tgtcccggga cacctacctg gggcacctgc tgaccctgta 14700 ccgcgaggcc atcgggcagg cgcaggtgga cgagcacacc ttccaggaga tcaccagcgt 14760 gagccgcgcg ctggggcagg aggacacgag cagcctggag gcgactctga actacctgct 14820 gaccaaccgg cggcagaaga ttccctcgct gcacagcctg acctccgagg aggagcgcat 14880 cttgcgctac gtgcagcaga gcgtgagcct gaacctgatg cgcgacgggg tgacgcccag 14940 cgtggcgctg gacatgaccg cgcgcaacat ggaaccgggc atgtacgccg cgcaccggcc 15000 ttacatcaac cgcctgatgg actacctgca tcgcgcggcg gccgtgaacc ccgagtactt 15060 taccaacgcc atcctgaacc cgcactggct cccgccgccc gggttctaca gcgggggctt 15120 cgaggtcccg gagaccaacg atggcttcct gtgggacgac atggacgaca gcgtgttctc 15180 cccgcggccg caggcgctgg cggaagcgtc cctgctgcgt cccaagaagg aggaggagga 15240 ggaggcgagt cgccgccgcg gcagcagcgg cgtggcttct ctgtccgagc tgggggcggc 15300 agccgccgcg cgccccgggt ccctgggcgg cagccccttt ccgagcctgg tggggtctct 15360 gcacagcgag cgcaccaccc gccctcggct gctgggcgag gacgagtacc tgaataactc 15420 cctgctgcag ccggtgcggg agaaaaacct gcctcccgcc ttccccaaca acgggataga 15480 gagcctggtg gacaagatga gcagatggaa gacctatgcg caggagcaca gggacgcgcc 15540 tgcgctccgg ccgcccacgc ggcgccagcg ccacgaccgg cagcgggggc tggtgtggga 15600 tgacgaggac tccgcggacg atagcagcgt gctggacctg ggagggagcg gcaacccgtt 15660 cgcgcacctg cgcccccgcc tggggaggat gttttaaaaa aaaaaaaaaa angcaagaag 15720 catgatgcaa aaattaaata aaactcacca aggccatggc gaccgagcgt tggtttcttg 15780 tgttcccttc agtatgcggc gcgcggcgat gtaccaggag ggacctcctc cctcttacga 15840 gagcgtggtg ggcgcggcgg cggcggcgcc ctcttctccc tttgcgtcgc agctgctgga 15900 gccgccgtac gtgcctccgc gctacctgcg gcctacgggg gggagaaaca gcatccgtta 15960 ctcggagctg gcgcccctgt tcgacaccac ccgggtgtac ctggtggaca acaagtcggc 16020 ggacgtggcc tccctgaact accagaacga ccacagcaat tttttgacca cggtcatcca 16080 gaacaatgac tacagcccga gcgaggccag cacccagacc atcaatctgg atgaccggtc 16140 gcactggggc ggcgacctga aaaccatcct gcacaccaac atgcccaacg tgaacgagtt 16200 catgttcacc aataagttca aggcgcgggt gatggtgtcg cgctcgcaca ccaaggaaga 16260 ccgggtggag ctgaagtacg agtgggtgga gttcgagctg ccagagggca actactccga 16320 gaccatgacc attgacctga tgaacaacgc gatcgtggag cactatctga aagtgggcag 16380 gcagaacggg gtcctggaga gcgacatcgg ggtcaagttc gacaccagga acttccgcct 16440 ggggctggac cccgtgaccg ggctggttat gcccggggtg tacaccaacg aggccttcca 16500 tcccgacatc atcctgctgc ccggctgcgg ggtggacttc acttacagcc gcctgagcaa 16560 cctcctgggc atccgcaagc ggcagccctt ccaggagggc ttcaggatca cctacgagga 16620 cctggagggg ggcaacatcc ccgcgctcct cgatgtggag gcctaccagg atagcttgaa 16680 ggaaaatgag gcgggacagg aggataccgc ccccgccgcc tccgccgccg ccgagcaggg 16740 cgaggatgct gctgacaccg cggccgcgga cggggcagag gccgaccccg ctatggtggt 16800 ggaggctccc gagcaggagg aggacatgaa tgacagtgcg gtgcgcggag acaccttcgt 16860 cacccggggg gaggaaaagc aagcggaggc cgaggccgcg gccgaggaaa agcaactggc 16920 ggcagcagcg gcggcggcgg cgttggccgc ggcggaggct gagtctgagg ggaccaagcc 16980 cgccaaggag cccgtgatta agcccctgac cgaagatagc aagaagcgca gttacaacct 17040 gctcaaggac agcaccaaca ccgcgtaccg cagctggtac ctggcctaca actacggcga 17100 cccgtcgacg ggggtgcgct cctggaccct gctgtgcacg ccggacgtga cctgcggctc 17160 ggagcaggtg tactggtcgc tgcccgacat gatgcaagac cccgtgacct tccgctccac 17220 gcggcaggtc agcaacttcc cggtggtggg cgccgagctg ctgcccgtgc actccaagag 17280 cttctacaac gaccaggccg tctactccca gctcatccgc cagttcacct ctctgaccca 17340 cgtgttcaat cgctttcctg agaaccagat tctggcgcgc ccgcccgccc ccaccatcac 17400 caccgtcagt gaaaacgttc ctgctctcac agatcacggg acgctaccgc tgcgcaacag 17460 catcggagga gtccagcgag tgaccgttac tgacgccaga cgccgcacct gcccctacgt 17520 ttacaaggcc ttgggcatag tctcgccgcg cgtcctttcc agccgcactt tttgagcaac 17580 accaccatca tgtccatcct gatctcaccc agcaataact ccggctgggg actgctgcgc 17640 gcgcccagca agatgttcgg aggggcgagg aagcgttccg agcagcaccc cgtgcgcgtg 17700 cgcgggcact tccgcgcccc ctggggagcg cacaaacgcg gccgcgcggg gcgcaccacc 17760 gtggacgacg ccatcgactc ggtggtggag caggcgcgca actacaggcc cgcggtctct 17820 accgtggacg cggccatcca gaccgtggtg cggggcgcgc ggcggtacgc caagctgaag 17880 agccgccgga agcgcgtggc ccgccgccac cgccgccgac ccggggccgc cgccaaacgc 17940 gccgccgcgg ccctgcttcg ccgggccaag cgcacgggcc gccgcgccgc catgagggcc 18000 gcgcgccgct tggccgccgg catcaccgcc gccaccatgg ccccccgtac ccgaagacgc 18060 gcggccgccg ccgccgccgc cgccatcagt gacatggcca gcaggcgccg gggcaacgtg 18120 tactgggtgc gcgactcggt gaccggcacg cgcgtgcccg tgcgcttccg ccccccgcgg 18180 acttgagatg atgtgaaaaa acaacactga gtctcctgct gttgtgtgta tcccagcggc 18240 ggcggcgcgc gcagcgtcat gtccaagcgc aaaatcaaag aagagatgct ccaggtcgtc 18300 gcgccggaga tctatgggcc cccgaagaag gaagagcagg attcgaagcc ccgcaagata 18360 aagcgggtca aaaagaaaaa gaaagatgat gacgatgccg atggggaggt ggagttcctg 18420 cgcgccacgg cgcccaggcg cccggtgcag tggaagggcc ggcgcgtaaa gcgcgtcctg 18480 cgccccggca ccgcggtggt cttcacgccc ggcgagcgct ccacccggac tttcaagcgc 18540 gtctatgacg aggtgtacgg cgacgaagac ctgctggagc aggccaacga gcgcttcgga 18600 gagtttgctt acgggaagcg tcagcgggcg ctggggaagg aggacctgct ggcgctgccg 18660 ctggaccagg gcaaccccac ccccagtctg aagcccgtga ccctgcagca ggtgctgccg 18720 agcagcgcac cctccgaggc gaagcggggt ctgaagcgcg agggcggcga cctggcgccc 18780 accgtgcagc tcatggtgcc caagcggcag aggctggagg atgtgctgga gaaaatgaaa 18840 gtagaccccg gtctgcagcc ggacatcagg gtccgcccca tcaagcaggt ggcgccgggc 18900 ctcggcgtgc agaccgtgga cgtggtcatc cccaccggca actcccccgc cgccgccacc 18960 actaccgctg cctccacgga catggagaca cagaccgatc ccgccgcagc cgcagccgca 19020 gccgccgccg cgacctcctc ggcggaggtg cagacggacc cctggctgcc gccggcgatg 19080 tcagctcccc gcgcgcgtcg cgggcgcagg aagtacggcg ccgccaacgc gctcctgccc 19140 gagtacgcct tgcatccttc catcgcgccc acccccggct accgaggcta tacctaccgc 19200 ccgcgaagag ccaagggttc cacccgccgt ccccgccgac gcgccgccgc caccacccgc 19260 cgccgccgcc gcagacgcca gcccgcactg gctccagtct ccgtgaggaa agtggcgcgc 19320 gacggacaca ccctggtgct gcccagggcg cgctaccacc ccagcatcgt ttaaaagcct 19380 gttgtggttc ttgcagatat ggccctcact tgccgcctcc gtttcccggt gccgggatac 19440 cgaggaggaa gatcgcgccg caggaggggt ctggccggcc gcggcctgag cggaggcagc 19500 cgccgcgcgc accggcggcg acgcgccacc agccgacgca tgcgcggcgg ggtgctgccc 19560 ctgttaatcc ccctgatcgc cgcggcgatc ggcgccgtgc ccgggatcgc ctccgtggcc 19620 ttgcaagcgt cccagaggca ttgacagact tgcaaacttg caaatatgga aaaaaaaacc 19680 ccaataaaaa agtctagact ctcacgctcg cttggtcctg tgactatttt gtagaatgga 19740 agacatcaac tttgcgtcgc tggccccgcg tcacggctcg cgcccgttcc tgggacactg 19800 gaacgatatc ggcaccagca acatgagcgg tggcgccttc agttggggct ctctgtggag 19860 cggcattaaa agtatcgggt ctgccgttaa aaattacggc tcccgggcct ggaacagcag 19920 cacgggccag atgttgagag acaagttgaa agagcagaac ttccagcaga aggtggtgga 19980 gggcctggcc tccggcatca acggggtggt ggacctggcc aaccaggccg tgcagaataa 20040 gatcaacagc agactggacc cccggccgcc ggtggaggag gtgccgccgg cgctggagac 20100 ggtgtccccc gatgggcgtg gcgagaagcg cccgcggccc gatagggaag agaccactct 20160 ggtcacgcag accgatgagc cgcccccgta tgaggaggcc ctgaagcaag gtctgcccac 20220 cacgcggccc atcgcgccca tggccaccgg ggtggtgggc cgccacaccc ccgccacgct 20280 ggacttgcct ccgcccgccg atgtgccgca gcagcagaag gcggcacagc cgggcccgcc 20340 cgcgaccgcc tcccgttcct ccgccggtcc tctgcgccgc gcggccagcg gcccccgcgg 20400 gggggtcgcg aggcacggca actggcagag cacgctgaac agcatcgtgg gtctgggggt 20460 gcggtccgtg aagcgccgcc gatgctactg aatagcttag ctaacgtgtt gtatgtgtgt 20520 atgcgcccta tgtcgccgcc agaggagctg ctgagtcgcc gccgttcgcg cgcccaccac 20580 caccgccact ccgcccctca agatggcgac cccatcgatg atgccgcagt ggtcgtacat 20640 gcacatctcg ggccaggacg cctcggagta cctgagcccc gggctggtgc agttcgcccg 20700 cgccaccgag agctacttca gcctgagtaa caagtttagg aaccccacgg tggcgcccac 20760 gcacgatgtg accaccgacc ggtctcagcg cctgacgctg cggttcattc ccgtggaccg 20820 cgaggacacc gcgtactcgt acaaggcgcg gttcaccctg gccgtgggcg acaaccgcgt 20880 gctggacatg gcctccacct actttgacat ccgcggggtg ctggaccggg gtcccacttt 20940 caagccctac tctggcaccg cctacaactc cctggccccc aagggcgctc ccaactcctg 21000 cgagtgggag caagaggaaa ctcaggcagt tgaagaagca gcagaagagg aagaagaaga 21060 tgctgacggt caagctgagg aagagcaagc agctaccaaa aagactcatg tatatgctca 21120 ggctcccctt tctggcgaaa aaattagtaa agatggtctg caaataggaa cggacgctac 21180 agctacagaa caaaaaccta tttatgcaga ccctacattc cagcccgaac cccaaatcgg 21240 ggagtcccag tggaatgagg cagatgctac agtcgccggc ggtagagtgc taaagaaatc 21300 tactcccatg aaaccatgct atggttccta tgcaagaccc acaaatgcta atggaggtca 21360 gggtgtacta acggcaaatg cccagggaca gctagaatct caggttgaaa tgcaattctt 21420 ttcaacttct gaaaacgccc gtaacgaggc taacaacatt cagcccaaat tggtgctgta 21480 tagtgaggat gtgcacatgg agaccccgga tacgcacctt tcttacaagc ccgcaaaaag 21540 cgatgacaat tcaaaaatca tgctgggtca gcagtccatg cccaacagac ctaattacat 21600 cggcttcaga gacaacttta tcggcctcat gtattacaat agcactggca acatgggagt 21660 gcttgcaggt caggcctctc agttgaatgc agtggtggac ttgcaagaca gaaacacaga 21720 actgtcctac cagctcttgc ttgattccat gggtgacaga accagatact tttccatgtg 21780 gaatcaggca gtggacagtt atgacccaga tgttagaatt attgaaaatc atggaactga 21840 agacgagctc cccaactatt gtttccctct gggtggcata ggggtaactg acacttacca 21900 ggctgttaaa accaacaatg gcaataacgg gggccaggtg acttggacaa aagatgaaac 21960 ttttgcagat cgcaatgaaa taggggtggg aaacaatttc gctatggaga tcaacctcag 22020 tgccaacctg tggagaaact tcctgtactc caacgtggcg ctgtacctac cagacaagct 22080 taagtacaac ccctccaatg tggacatctc tgacaacccc aacacctacg attacatgaa 22140 caagcgagtg gtggccccgg ggctggtgga ctgctacatc aacctgggcg cgcgctggtc 22200 gctggactac atggacaacg tcaacccctt caaccaccac cgcaatgcgg gcctgcgcta 22260 ccgctccatg ctcctgggca acgggcgcta cgtgcccttc cacatccagg tgccccagaa 22320 gttctttgcc atcaagaacc tcctcctcct gccgggctcc tacacctacg agtggaactt 22380 caggaaggat gtcaacatgg tcctccagag ctctctgggt aacgatctca gggtggacgg 22440 ggccagcatc aagttcgaga gcatctgcct ctacgccacc ttcttcccca tggcccacaa 22500 cacggcctcc acgctcgagg ccatgctcag gaacgacacc aacgaccagt ccttcaatga 22560 ctacctctcc gccgccaaca tgctctaccc catacccgcc aacgccacca acgtccccat 22620 ctccatcccc tcgcgcaact gggcggcctt ccgcggctgg gccttcaccc gcctcaagac 22680 caaggagacc ccctccctgg gctcgggatt cgacccctac tacacctact cgggctccat 22740 tccctacctg gacggcacct tctacctcaa ccacactttc aagaaggtct cggtcacctt 22800 cgactcctcg gtcagctggc cgggcaacga ccgtctgctc acccccaacg agttcgagat 22860 cgactcctcg gtcagctggc cgggcaacga ccgtctgctc acccccaacg agttcgagat 22860 caagcgctcg gtcgacgggg agggctacaa cgtggcccag tgcaacatga ccaaggactg 22920 caagcgctcg gtcgacgggg agggctacaa cgtggcccag tgcaacatga ccaaggactg 22920 gttcctggtc cagatgctgg ccaactacaa catcggctac cagggcttct acatcccaga 22980 gttcctggtc cagatgctgg ccaactacaa catcggctac cagggcttct acatcccaga 22980 gagctacaag gacaggatgt actccttctt caggaacttc cagcccatga gccggcaggt 23040 gagctacaag gacaggatgt actccttctt caggaacttc cagcccatga gccggcaggt 23040 ggtggaccag accaagtaca aggactacca ggaggtgggc atcatccacc agcacaacaa 23100 ggtggaccag accaagtaca aggactacca ggaggtgggc atcatccacc agcacaacaa 23100 ctcgggcttc gtgggctacc tcgcccccac catgcgcgag ggacaggcct accccgccaa 23160 ctcgggcttc gtgggctacc tcgcccccac catgcgcgag ggacaggcct accccgccaa 23160 cttcccctat ccgctcatag gcaagaccgc ggtcgacagc atcacccaga aaaagttcct 23220 cttcccctat ccgctcatag gcaagaccgc ggtcgacagc atcacccaga aaaagttcct 23220 ctgcgaccgc accctctggc gcatcccctt ctccagcaac ttcatgtcca tgggtgcgct 23280 ctgcgaccgc accctctggc gcatcccctt ctccagcaac ttcatgtcca tgggtgcgct 23280 ctcggacctg ggccagaact tgctctacgc caactccgcc cacgccctcg acatgacctt 23340 ctcggacctg ggccagaact tgctctacgc caactccgcc cacgccctcg acatgacctt 23340 cgaggtcgac cccatggacg agcccaccct tctctatgtt ctgttcgaag tctttgacgt 23400 cgaggtcgac cccatggacg agcccaccct tctctatgtt ctgttcgaag tctttgacgt 23400 ggtccgggtc caccagccgc accgcggcgt catcgagacc gtgtacctgc gtacgccctt 23460 ctcggccggc aacgccacca cctaaagaag caagccgcag tcatcgccgc ctgcatgccg 23520 tcgggttcca ccgagcaaga gctcagggcc atcgtcagag acctgggatg cgggccctat 23580 tttttgggca ccttcgacaa gcgcttccct ggctttgtct ccccacacaa gctggcctgc 23640 gccatcgtca acacggccgg ccgcgagacc gggggcgtgc actggctggc cttcgcctgg 23700 aacccgcgct ccaaaacatg cttcctcttt gaccccttcg gcttttcgga ccagcggctc 23760 aagcaaatct acgagttcga gtacgagggc ttgctgcgtc gcagcgccat cgcctcctcg 23820 cccgaccgct gcgtcaccct cgaaaagtcc acccagaccg tgcaggggcc cgactcggcc 23880 gcctgcggtc tcttctgctg catgtttctg cacgcctttg tgcactggcc tcagagtccc 23940 atggaccgca accccaccat gaacttgctg acgggggtgc ccaactccat gctccagagc 24000 ccccaggtcg agcccaccct gcgccgcaac caggagcagc tctacagctt cctggagcgc 24060 cactcgcctt acttccgccg ccacagcgca cagatcagga gggccacctc cttctgccac 24120 ttgcaagaga tgcaagaagg gtaataacga tgtacacact ttttttctca ataaatggca 24180 tctttttatt tatacaagct ctctggggta ttcatttccc accaccaccc gccgttgtcg 24240 ccatctggct ctatttagaa atcgaaaggg ttctgccggg agtcgccgtg cgccacgggc 24300 agggacacgt tgcgatactg gtagcgggtg ccccacttga actcgggcac caccaggcga 24360 ggcagctcgg ggaagttttc gctccacagg ctgcgggtca gcaccagcgc gttcatcagg 24420 tcgggcgccg agatcttgaa gtcgcagttg gggccgccgc cctgcgcgcg cgagttgcgg 24480 tacaccgggt tgcagcactg gaacaccaac agcgccgggt gcttcacgct ggccagcacg 24540 ctgcggtcgg agatcagctc ggcgtccagg tcctccgcgt tgctcagcgc gaacggggtc 24600 atcttgggca cttgccgccc caggaagggc gcgtgccccg gtttcgagtt gcagtcgcag 24660 cgcagcggga tcagcaggtg cccgtgcccg gactcggcgt tggggtacag cgcgcgcatg 24720 aaggcctgca tctggcggaa ggccatctgg gccttggcgc cctccgagaa gaacatgccg 24780 caggacttgc ccgagaactg gtttgcgggg cagctggcgt cgtgcaggca gcagcgcgcg 24840 tcggtgttgg cgatctgcac cacgttgcgc ccccaccggt tcttcacgat cttggccttg 24900 gacgattgct ccttcagcgc gcgctgcccg ttctcgctgg tcacatccat ctcgatcaca 24960 tgttccttgt tcaccatgct gctgccgtgc agacacttca gctcgccctc cgtctcggtg 25020 cagcggtgct gccacagcgc gcagcccgtg ggctcgaaag acttgtaggt cacctccgcg 25080 aaggactgca ggtacccctg caaaaagcgg cccatcatgg tcacgaaggt cttgttgctg 25140 ctgaaggtca gctgcagccc gcggtgctcc tcgttcagcc aggtcttgca cacggccgcc 25200 agcgcctcca cctggtcggg cagcatcttg aagttcacct tcagctcatt ctccacgtgg 25260 tacttgtcca tcagcgtgcg cgccgcctcc atgcccttct cccaggccga caccagcggc 25320 aggctcacgg ggttcttcac catcaccgtg gccgccgcct ccgccgcgct ttcgctttcc 25380 gccccgctgt tctcttcctc ttcctcctct tcctcgccgc cgcccactcg cagcccccgc 25440 accacggggt cgtcttcctg caggcgctgc accttgcgct tgccgttgcg cccctgcttg 25500 atgcgcacgg gcgggttgct gaagcccacc atcaccagcg cggcctcttc ttgctcgtcc 25560 tcgctgtcca gaatgacctc cggggagggg gggttggtca tcctcagtac cgaggcacgc 25620 ttctttttct tcctgggggc gttcgccagc tccgcggctg cggccgctgc cgaggtcgaa 25680 ggccgagggc tgggcgtgcg cggcaccagc gcgtcctgcg agccgtcctc gtcctcctcg 25740 gactcgagac ggaggcgggc ccgcttcttc gggggcgcgc ggggcggcgg aggcggcggc 25800 ggcgacggag acggggacga gacatcgtcc agggtgggtg gacggcgggc cgcgccgcgt 25860 ccgcgctcgg gggtggtctc gcgctggtcc tcttcccgac tggccatctc ccactgctcc 25920 ttctcctata ggcagaaaga gatcatggag tctctcatgc gagtcgagaa ggaggaggac 25980 agcctaaccg ccccctctga gccctccacc accgccgcca ccaccgccaa tgccgccgcg 26040 gacgacgcgc ccaccgagac caccgccagt accaccctcc ccagcgacgc acccccgctc 26100 gagaatgaag tgctgatcga gcaggacccg ggttttgtga gcggagagga ggatgaggtg 26160 gatgagaagg agaaggagga ggtcgccgcc tcagtgccaa aagaggataa aaagcaagac 26220 caggacgacg cagataagga tgagacagca gtcgggcggg ggaacggaag ccatgatgct 26280 gatgacggct acctagacgt gggagacgac gtgctgctta agcacctgca ccgccagtgc 26340 gtcatcgtct gcgacgcgct gcaggagcgc tgcgaagtgc ccctggacgt ggcggaggtc 26400 agccgcgcct acgagcggca cctcttcgcg ccgcacgtgc cccccaagcg ccgggagaac 26460 ggcacctgcg agcccaaccc gcgtctcaac ttctacccgg tcttcgcggt acccgaggtg 26520 ctggccacct accacatctt tttccaaaac tgcaagatcc ccctctcctg ccgcgccaac 26580 cgcacccgcg ccgacaaaac cctgaccctg cggcagggcg cccacatacc tgatatcgcc 26640 tctctggagg aagtgcccaa gatcttcgag ggtctcggtc gcgacgagaa acgggcggcg 26700 aacgctctgc acggagacag cgaaaacgag agtcactcgg gggtgctggt ggagctcgag 26760 ggcgacaacg cgcgcctggc cgtactcaag cgcagcatag aggtcaccca ctttgcctac 26820 ccggcgctca acctgccccc caaggtcatg agtgtggtca tgggcgagct catcatgcgc 26880 cgcgcccagc ccctggccgc ggatgcaaac ttgcaagagt cctccgagga aggcctgccc 26940 gcggtcagcg acgagcagct ggcgcgctgg ctggagaccc gcgaccccgc gcagctggag 27000 gagcggcgca agctcatgat ggccgcggtg ctggtcaccg tggagctcga gtgtctgcag 27060 cgcttcttcg cggaccccga gatgcagcgc aagctcgagg agaccctgca ctacaccttc 27120 cgccagggct acgtgcgcca ggcctgcaag atctccaacg tggagctctg caacctggtc 27180 tcctacctgg gcatcctgca cgagaaccgc ctcgggcaga acgtcctgca ctccaccctc 27240 aaaggggagg cgcgccgcga ctacatccgc gactgcgcct acctcttcct ctgctacacc 27300 tggcagacgg ccatgggggt ctggcagcag tgcctggagg agcgcaacct caaggagctg 27360 gaaaagctcc tcaagcgcac cctcagggac ctctggacgg gcttcaacga gcgctcggtg 27420 gccgccgcgc tggcggacat catctttccc gagcgcctgc tcaagaccct gcagcagggc 27480 ctgcccgact tcaccagcca gagcatgctg cagaacttca ggactttcat cctggagcgc 27540 tcgggcatcc tgccggccac ttgctgcgcg ctgcccagcg acttcgtgcc catcaagtac 27600 agggagtgcc cgccgccgct ctggggccac tgctacctct tccagctggc caactacctc 27660 gcctaccact cggacctcat ggaagacgtg agcggcgagg gcctgctcga gtgccactgc 27720 cgctgcaacc tctgcacgcc ccaccgctct ctagtctgca acccgcagct gctcagcgag 27780 agtcagatta tcggtacctt cgagctgcag ggtccctcgc ctgacgagaa gtccgcggct 27840 ccagggctga aactcactcc ggggctgtgg acttccgcct acctacgcaa atttgtacct 27900 gaggactacc acgcccacga gatcaggttc tacgaagacc aatcccgccc gcccaaggcg 27960 gagctcaccg cctgcgtcat cacccagggg cacatcctgg gccaattgca agccatcaac 28020 aaagcccgcc gagagttctt gctgaaaaag ggtcgggggg tgtacctgga cccccagtcc 28080 ggcgaggagc taaacccgct acccccgccg ccgccccagc agcgggacct tgcttcccag 28140 gatggcaccc agaaagaagc agcagccgcc gccgccgccg cagccataca tgcttctgga 28200 ggaagaggag gaggactggg acagtcaggc agaggaggtt tcggacgagg agcaggagga 28260 gatgatggaa gactgggagg aggacagcag cctagacgag gaagcttcag aggccgaaga 28320 ggtggcagac gcaacaccat cgccctcggt cgcagccccc tcgccggggc ccctgaaatc 28380 ctccgaaccc agcaccagcg ctataacctc cgctcctccg gcgccggcgc cacccgcccg 28440 cagacccaac cgtagatggg acaccacagg aaccggggtc ggtaagtcca agtgcccgcc 28500 gccgccaccg cagcagcagc agcagcagcg ccagggctac cgctcgtggc gcgggcacaa 28560 gaacgccata gtcgcctgct tgcaagactg cgggggcaac atctctttcg cccgccgctt 28620 cctgctattc caccacgggg tcgcctttcc ccgcaatgtc ctgcattact accgtcatct 28680 ctacagcccc tactgcagcg gcgacccaga ggcggcagcg gcagccacag cggcgaccac 28740 cacctaggaa gatatcctcc gcgggcaaga cagcggcagc agcggccagg agacccgcgg 28800 cagcagcggc gggagcggtg ggcgcactgc gcctctcgcc caacgaaccc ctctcgaccc 28860 gggagctcag acacaggatc ttccccactt tgtatgccat cttccaacag agcagaggcc 28920 aggagcagga gctgaaaata aaaaacagat ctctgcgctc cctcacccgc agctgtctgt 28980 atcacaaaag cgaagatcag cttcggcgca cgctggagga cgcggaggca ctcttcagca 29040 aatactgcgc gctcactctt aaagactagc tccgcgccct tctcgaattt aggcgggaga 29100 aaactacgtc atcgccggcc gccgcccagc ccgcccagcc gagatgagca aagagattcc 29160 cacgccatac atgtggagct accagccgca gatgggactc gcggcgggag cggcccagga 29220 ctactccacc cgcatgaact acatgagcgc gggaccccac atgatctcac aggtcaacgg 29280 gatccgcgcc cagcgaaacc aaatactgct ggaacaggcg gccatcaccg ccacgccccg 29340 ccataatctc aacccccgaa attggcccgc cgccctcgtg taccaggaaa ccccctccgc 29400 caccaccgta ctacttccgc gtgacgccca ggccgaagtc cagatgacta actcaggggc 29460 gcagctcgcg ggcggctttc gtcacggggc gcggccgctc cgaccaggta taagacacct 29520 gatgatcaga ggccgaggta tccagctcaa cgacgagtcg gtgagctctt cgctcggtct 29580 ccgtccggac ggaactttcc agctcgccgg atccggccgc tcttcgttca cgccccgcca 29640 ggcgtacctg actctgcaga cctcgtcctc ggagccccgc tccggcggca tcggaaccct 29700 ccagttcgtg gaggagttcg tgccctcggt ctacttcaac cccttctcgg gacctcccgg 29760 acgctacccc gaccagttca ttccgaactt tgacgcggtg aaggactcgg cggacggcta 29820 cgactgaatg tcaggtgtcg aggcagagca gcttcgcctg agacacctcg agcactgccg 29880 ccgccacaag tgcttcgccc gcggttctgg tgagttctgc tactttcagc tacccgagga 29940 gcataccgag gggccggcgc acggcgtccg cctgaccacc cagggcgagg ttacctgttc 30000 cctcatccgg gagtttaccc tccgtcccct gctagtggag cgggagcggg gtccctgtgt 30060 cctaactatc gcctgcaact gccctaaccc tggattacat caagatcttt gctgtcatct 30120 ctgtgctgag tttaataaac gctgagatca gaatctactg gggctcctgt cgccatcctg 30180 tgaacgccac cgtcttcacc caccccgacc aggcccaggc gaacctcacc tgcggtctgc 30240 atcggagggc caagaagtac ctcacctggt acttcaacgg cacccccttt gtggtttaca 30300 acagcttcga cggggacgga gtctccctga aagaccagct ctccggtctc agctactcca 30360 tccacaagaa caccaccctc caactcttcc ctccctacct gccgggaacc tacgagtgcg 30420 tcaccggccg ctgcacccac ctcacccgcc tgatcgtaaa ccagagcttt ccgggaacag 30480 ataactccct cttccccaga acaggaggtg agctcaggaa actccccggg gaccagggcg 30540 gagacgtacc ttcgaccctt gtggggttag gattttttat taccgggttg ctggctcttt 30600 taatcaaagt ttccttgaga tttgttcttt ccttctacgt gtatgaacac ctcaacctcc 30660 aataactcta ccctttcttc ggaatcaggt gacttctctg aaatcgggct tggtgtgctg 30720 cttactctgt tgattttttt ccttatcata ctcagccttc tgtgcctcag gctcgccgcc 30780 tgctgcgcac acatctatat ctactgctgg ttgctcaagt gcaggggtcg ccacccaaga 30840 tgaacaggta catggtccta tcgatcctag gcctgctggc cctggcggcc tgcagcgccg 30900 ccaaaaaaga gattaccttt gaggagcccg cttgcaatgt aactttcaag cccgagggtg 30960 accaatgcac caccctcgtc aaatgcgtta ccaatcatga gaggctgcgc atcgactaca 31020 aaaacaaaac tggccagttt gcggtctata gtgtgtttac gcccggagac ccctctaact 31080 actctgtcac cgtcttccag ggcggacagt ctaagatatt caattacact ttcccttttt 31140 atgagttatg cgatgcggtc atgtacatgt caaaacagta caacctgtgg cctccctctc 31200 cccaggcgtg tgtggaaaat actgggtctt actgctgtat ggctttcgca atcactacgc 31260 tcgctctaat ctgcacggtg ctatacataa aattcaggca gaggcgaatc tttatcgatg 31320 aaaagaaaat gccttgatcg ctaacaccgg ctttctatct gcagaatgaa tgcaatcacc 31380 tccctactaa tcaccaccac cctccttgcg attgcccatg ggttgacacg aatcgaagtg 31440 ccagtggggt ccaatgtcac catggtgggc cccgccggca attccaccct catgtgggaa 31500 aaatttgtcc gcaatcaatg ggttcatttc tgctctaacc gaatcagtat caagcccaga 31560 gccatctgcg atgggcaaaa tctaactctg atcaatgtgc aaatgatgga tgctgggtac 31620 tattacgggc agcggggaga aatcattaat tactggcgac cccacaagga ctacatgctg 31680 catgtagtcg aggcacttcc cactaccacc cccactacca cctctcccac caccaccacc 31740 actactacta ctactactac tactactact actaccacta ccgctgcccg ccatacccgc 31800 aaaagcacca tgattagcac aaagccccct cgtgctcact cccacgccgg cgggcccatc 31860 ggtgcgacct cagaaaccac cgagctttgc ttctgccaat gcactaacgc cagcgctcat 31920 gaactgttcg acctggagaa tgaggatgtc cagcagagct ccgcttgcct gacccaggag 31980 gctgtggagc ccgttgccct gaagcagatc ggtgattcaa taattgactc ttcttctttt 32040 gccactcccg aataccctcc cgattctact ttccacatca cgggtaccaa agaccctaac 32100 ctctctttct acctgatgct gctgctctgt atctctgtgg tctcttccgc gctgatgtta 32160 ctggggatgt tctgctgcct gatctgccgc agaaagagaa aagctcgctc tcagggccaa 32220 ccactgatgc ccttccccta ccccccggat tttgcagata acaagatatg agctcgctgc 32280 tgacactaac cgctttacta gcctgcgctc taacccttgt cgcttgcgac tcgagattcc 32340 acaatgtcac agctgtggca ggagaaaatg ttactttcaa ctccacggcc gatacccagt 32400 ggtcgtggag tggctcaggt agctacttaa ctatctgcaa tagctccact tcccccggca 32460 tatccccaac caagtaccaa tgcaatgcca gcctgttcac cctcatcaac gcttccaccc 32520 tggacaatgg actctatgta ggctatgtac cctttggtgg gcaaggaaag acccacgctt 32580 acaacctgga agttcgccag cccagaacca ctacccaagc ttctcccacc accaccacca 32640 ccaccaccat caccagcagc agcagcagca gcagccacag cagcagcagc agattattga 32700 ctttggtttt ggccagctca tctgccgcta cccaggccat ctacagctct gtgcccgaaa 32760 ccactcagat ccaccgccca gaaacgacca ccgccaccac cctacacacc tccagcgatc 32820 agatgccgac caacatcacc cccttggctc ttcaaatggg acttacaagc cccactccaa 32880 aaccagtgga tgcggccgag gtctccgccc tcgtcaatga ctgggcgggg ctgggaatgt 32940 ggtggttcgc cataggcatg atggcgctct gcctgcttct gctctggctc atctgctgcc 33000 tccaccgcag gcgagccaga ccccccatct atagacccat cattgtcctg aaccccgata 33060 atgatgggat ccatagattg gatggcctga aaaacctact tttttctttt acagtatgat 33120 aaattgagac atgcctcgca ttttcttgta catgttcctt ctcccacctt ttctggggtg 33180 ttctacgctg gccgctgtgt ctcacctgga ggtagactgc ctctcaccct tcactgtcta 33240 cctgctttac ggattggtca ccctcactct catctgcagc ctaatcacag taatcatcgc 33300 cttcatccag tgcattgatt acatctgtgt gcgcctcgca tacttcagac accacccgca 33360 gtaccgagac aggaacattg cccaacttct aagactgctc taatcatgca taagactgtg 33420 atctgccttc tgatcctctg catcctgccc accctcacct cctgccagta caccacaaaa 33480 tctccgcgca aaagacatgc ctcctgccgc ttcacccaac tgtggaatat acccaaatgc 33540 tacaacgaaa agagcgagct ctccgaagct tggctgtatg gggtcatctg tgtcttagtt 33600 ttctgcagca ctgtctttgc cctcataatc tacccctact ttgatttggg atggaacgcg 33660 atcgatgcca tgaattaccc cacctttccc gcacccgaga taattccact gcgacaagtt 33720 gtacccgttg tcgttaatca acgcccccca tcccctacgc ccactgaaat cagctacttt 33780 aacctaacag gcggagatga ctgacgccct agatctagaa atggacggca tcagtaccga 33840 gcagcgtctc ctagagaggc gcaggcaggc ggctgagcaa gagcgcctca atcaggagct 33900 ccgagatctc gttaacctgc accagtgcaa aagaggcatc ttttgtctgg taaagcaggc 33960 caaagtcacc tacgagaaga ccggcaacag ccaccgcctc agttacaaat tgcccaccca 34020 gcgccagaag ctggtgctca tggtgggtga gaatcccatc accgtcaccc agcactcggt 34080 agagaccgag gggtgtctgc actccccctg tcggggtcca gaagacctct gcaccctggt 34140 aaagaccctg tgcggtctca gagatttagt cccctttaac taatcaaaca ctggaatcaa 34200 taaaaagaat cacttactta aaatcagaca gcaggtctct gtccagttta ttcagcagca 34260 cctccttccc ctcctcccaa ctctggtact ccaaacgcct tctggcggca aacttcctcc 34320 acaccctgaa gggaatgtca gattcttgct cctgtccctc cgcacccact atcttcatgt 34380 tgttgcagat gaagcgcacc aaaacgtctg acgagagctt caaccccgtg tacccctatg 34440 acacggaaag cggccctccc tccgtccctt tcctcacccc tcccttcgtg tctcccgatg 34500 gattccaaga aagtcccccc ggggtcctgt ctctgaacct ggccgagccc ctggtcactt 34560 cccacggcat gctcgccctg aaaatgggaa gtggcctctc cctggacgac gctggcaacc 34620 tcacctctca agatatcacc accgctagcc ctcccctcaa aaaaaccaag accaacctca 34680 gcctagaaac ctcatccccc ctaactgtga gcacctcagg cgccctcacc gtagcagccg 34740 ccgctcccct ggcggtggcc ggcacctccc tcaccatgca atcagaggcc cccctgacag 34800 tacaggatgc aaaactcacc ctggccacca aaggccccct gaccgtgtct gaaggcaaac 34860 tggccttgca aacatcggcc ccgctgacgg ccgctgacag cagcaccctc acagtcagtg 34920 ccacaccacc ccttagcaca agcaatggca gcttgggtat tgacatgcaa gcccccattt 34980 acaccaccaa tggaaaacta ggacttaact ttggcgctcc cctgcatgtg gtagacagcc 35040 taaatgcact gactgtagtt actggccaag gtcttacgat aaacggaaca gccctacaaa 35100 ctagagtctc aggtgccctc aactatgaca catcaggaaa cctagaattg agagctgcag 35160 ggggtatgcg agttgatgca aatggtcaac ttatccttga tgtagcttac ccatttgatg 35220 cacaaaacaa tctcagcctt aggcttggac agggacccct gtttgttaac tctgcccaca 35280 acttggatgt taactacaac agaggcctct acctgttcac atctggaaat accaaaaagc 35340 tagaagttaa tatcaaaaca gccaagggtc tcatttatga tgacactgct atagcaatca 35400 atgcgggtga tgggctacag tttgactcag gctcagatac aaatccatta aaaactaaac 35460 ttggattagg actggattat gactccagca gagccataat tgctaaactg ggaactggcc 35520 taagctttga caacacaggt gccatcacag taggcaacaa aaatgatgac aagcttacct 35580 tgtggaccac accagaccca tcccctaact gtagaatcta ttcagagaaa gatgctaaat 35640 tcacacttgt tttgactaaa tgcggcagtc aggtgttggc cagcgtttct gttttatctg 35700 taaaaggtag ccttgcgccc atcagtggca cagtaactag tgctcagatt gtcctcagat 35760 ttgatgaaaa tggagttcta ctaagcaatt cttcccttga ccctcaatac tggaactaca 35820 gaaaaggtga ccttacagag ggcactgcat ataccaacgc agtgggattt atgcccaacc 35880 tcacagcata cccaaaaaca cagagccaaa ctgctaaaag caacattgta agtcaggttt 35940 acttgaatgg ggacaaatcc aaacccatga ccctcaccat taccctcaat ggaactaatg 36000 aaacaggaga tgccacagta agcacttact ccatgtcatt ctcatggaac tggaatggaa 36060 gtaattacat taatgaaacg ttccaaacca actccttcac cttctcctac atcgcccaag 36120 aataaaaagc atgacgctgt tgatttgatt caatgtgttt ctgttttatt ttcaagcaca 36180 acaaaatcat tcaagtcatt cttccatctt agcttaatag acacagtagc ttaatagacc 36240 cagtagtgca aagccccatt ctagcttata actagtggag aagtactcgc ctacatgggg 36300 gtagagtcat aatcgtgcat caggataggg cggtggtgct gcagcagcgc gcgaataaac 36360 tgctgccgcc gccgctccgt cctgcaggaa tacaacatgg cagtggtctc ctcagcgatg 36420 attcgcaccg cccgcagcat aaggcgcctt gtcctccggg cacagcagcg caccctgatc 36480 tcacttaaat cagcacagta actgcagcac agcaccacaa tattgttcaa aatcccacag 36540 tgcaaggcgc tgtatccaaa gctcatggcg gggaccacag aacccacgtg gccatcatac 36600 cacaagcgca ggtagattaa gtggcgaccc ctcataaaca cgctggacat aaacattacc 36660 tcttttggca tgttgtaatt caccacctcc cggtaccata taaacctctg attaaacatg 36720 gcgccatcca ccaccatcct aaaccagctg gccaaaacct gcccgccggc tatacactgc 36780 agggaaccgg gactggaaca atgacagtgg agagcccagg actcgtaacc atggatcatc 36840 atgctcgtca tgatatcaat gttggcacaa cacaggcaca cgtgcataca cttcctcagg 36900 attacaagct cctcccgcgt tagaaccata tcccagggaa caacccattc ctgaatcagc 36960 gtaaatccca cactgcaggg aagacctcgc acgtaactca cgttgtgcat tgtcaaagtg 37020 ttacattcgg gcagcagcgg atgatcctcc agtatggtag cgcgggtttc tgtctcaaaa 37080 ggaggtagac gatccctact gtacggagtg cgccgagaca accgagatcg tgttggtcgt 37140 agtgtcatgc caaatggaac gccggacgta gtcatatttc ctgaagtctt agatctctca 37200 acgcagcacc agcaccaaca cttcgcagtg taaaaggcca agtgccgaga gagtatatat 37260 aggaataaaa agtgacgtaa acgggcaaag tccaaaaaac gcccagaaaa accgcacgcg 37320 aacctacgcc ccgaaacgaa agccaaaaaa cactagacac tcccttccgg cgtcaacttc 37380 cgctttccca cgctacgtca cttgccccag tcaaacaaac tacatatccc gaacttccaa 37440 gtcgccacgc ccaaaacacc gcctacacct ccccgcccgc cggcccgccc ccaaacccgc 37500 ctcccgcccc gcgccccgcc ccgcgccgcc catctcatta tcatattggc ttcaatccaa 37560 aataaggtat attattgatg atggtttaaa cggatcctct agagtcgacc tgcaggcatg 37620 caagcttgag tataaccccc ttgcggccgc ccgggccgtc gaccaattct catgtttgac 37680 agcttatcat cgaatttctg ccattcatcc gcttattatc acttattcag gcgtagcaac 37740 caggcgttta agggcaccaa taactgcctt aaaaaaatta cgccccgccc tgccactcat 37800 cgcagtactg ttgtaattca ttaagcattc tgccgacatg gaagccatca caaacggcat 37860 gatgaacctg aatcgccagc ggcatcagca ccttgtcgcc ttgcgtataa tatttgccca 37920 tggtgaaaac gggggcgaag aagttgtcca tattggccac gtttaaatca aaactggtga 37980 aactcaccca gggattggct gagacgaaaa acatattctc aataaaccct ttagggaaat 38040 aggccaggtt ttcaccgtaa cacgccacat cttgcgaata tatgtgtaga aactgccgga 38100 aatcgtcgtg gtattcactc cagagcgatg aaaacgtttc agtttgctca tggaaaacgg 38160 tgtaacaagg gtgaacacta tcccatatca ccagctcacc gtctttcatt gccatacgga 38220 attccggatg agcattcatc aggcgggcaa gaatgtgaat aaaggccgga taaaacttgt 38280 gcttattttt ctttacggtc tttaaaaagg ccgtaatatc cagctgaacg gtctggttat 38340 aggtacattg agcaactgac tgaaatgcct caaaatgttc tttacgatgc cattgggata 38400 tatcaacggt ggtatatcca gtgatttttt tctccatttt agcttcctta gctcctgaaa 38460 atctcgataa ctcaaaaaat acgcccggta gtgatcttat ttcattatgg tgaaagttgg 38520 aacctcttac gtgccgatca acgtctcatt ttcgccaaaa gttggcccag ggcttcccgg 38580 tatcaacagg gacaccagga tttatttatt ctgcgaagtg atcttccgtc acaggtattt 38640 attcgcgata agctcatgga gcggcgtaac cgtcgcacag gaaggacaga gaaagcgcgg 38700 atctgggaag tgacggacag aacggtcagg acctggattg gggaggcggt tgccgccgct 38760 gctgctgacg gtgtgacgtt ctctgttccg gtcacaccac atacgttccg ccattcctat 38820 gcgatgcaca tgctgtatgc cggtataccg ctgaaagttc tgcaaagcct gatgggacat 38880 aagtccatca gttcaacgga agtctacacg aaggtttttg cgctggatgt ggctgcccgg 38940 caccgggtgc agtttgcgat gccggagtct gatgcggttg cgatgctgaa acaattatcc 39000 tgagaataaa tgccttggcc tttatatgga aatgtggaac tgagtggata tgctgttttt 39060 gtctgttaaa cagagaagct ggctgttatc cactgagaag cgaacgaaac agtcgggaaa 39120 atctcccatt atcgtagaga tccgcattat taatctcagg agcctgtgta gcgtttatag 39180 gaagtagtgt tctgtcatga tgcctgcaag cggtaacgaa aacgatttga atatgccttc 39240 aggaacaata gaaatcttcg tgcggtgtta cgttgaagtg gagcggatta tgtcagcaat 39300 ggacagaaca acctaatgaa cacagaacca tgatgtggtc tgtcctttta cagccagtag 39360 tgctcgccgc agtcgagcga cagggcgaag ccctcgagtg agcgaggaag caccagggaa 39420 cagcacttat atattctgct tacacacgat gcctgaaaaa acttcccttg gggttatcca 39480 cttatccacg gggatatttt tataattatt ttttttatag tttttagatc ttctttttta 39540 gagcgccttg taggccttta tccatgctgg ttctagagaa ggtgttgtga caaattgccc 39600 tttcagtgtg acaaatcacc ctcaaatgac agtcctgtct gtgacaaatt gcccttaacc 39660 ctgtgacaaa ttgccctcag aagaagctgt tttttcacaa agttatccct gcttattgac 39720 tcttttttat ttagtgtgac aatctaaaaa cttgtcacac ttcacatgga tctgtcatgg 39780 cggaaacagc ggttatcaat cacaagaaac gtaaaaatag cccgcgaatc gtccagtcaa 39840 acgacctcac tgaggcggca tatagtctct cccgggatca aaaacgtatg ctgtatctgt 39900 tcgttgacca gatcagaaaa tctgatggca ccctacagga acatgacggt atctgcgaga 39960 tccatgttgc taaatatgct gaaatattcg gattgacctc tgcggaagcc agtaaggata 40020 tacggcaggc attgaagagt ttcgcgggga aggaagtggt tttttatcgc cctgaagagg 40080 atgccggcga tgaaaaaggc tatgaatctt ttccttggtt tatcaaacgt gcgcacagtc 40140 catccagagg gctttacagt gtacatatca acccatatct cattcccttc tttatcgggt 40200 tacagaaccg gtttacgcag tttcggctta gtgaaacaaa agaaatcacc aatccgtatg 40260 ccatgcgttt atacgaatcc ctgtgtcagt atcgtaagcc ggatggctca ggcatcgtct 40320 ctctgaaaat cgactggatc atagagcgtt accagctgcc tcaaagttac cagcgtatgc 40380 ctgacttccg ccgccgcttc ctgcaggtct gtgttaatga gatcaacagc agaactccaa 40440 tgcgcctctc atacattgag aaaaagaaag gccgccagac gactcatatc gtattttcct 40500 tccgcgatat cacttccatg acgacaggat agtctgaggg ttatctgtca cagatttgag 40560 ggtggttcgt cacatttgtt ctgacctact gagggtaatt tgtcacagtt ttgctgtttc 40620 cttcagcctg catggatttt ctcatacttt ttgaactgta atttttaagg aagccaaatt 40680 tgagggcagt ttgtcacagt tgatttcctt ctctttccct tcgtcatgtg acctgatatc 40740 gggggttagt tcgtcatcat tgatgagggt tgattatcac agtttattac tctgaattgg 40800 ctatccgcgt gtgtacctct acctggagtt tttcccacgg tggatatttc ttcttgcgct 40860 gagcgtaaga gctatctgac agaacagttc ttctttgctt cctcgccagt tcgctcgcta 40920 tgctcggtta cacggctgcg gcgagcgcta gtgataataa gtgactgagg tatgtgctct 40980 tcttatctcc ttttgtagtg ttgctcttat tttaaacaac tttgcggttt tttgatgact 41040 ttgcgatttt gttgttgctt tgcagtaaat tgcaagattt aataaaaaaa cgcaaagcaa 41100 tgattaaagg atgttcagaa tgaaactcat ggaaacactt aaccagtgca taaacgctgg 41160 tcatgaaatg acgaaggcta tcgccattgc acagtttaat gatgacagcc cggaagcgag 41220 gaaaataacc cggcgctgga gaataggtga agcagcggat ttagttgggg tttcttctca 41280 ggctatcaga gatgccgaga aagcagggcg actaccgcac ccggatatgg aaattcgagg 41340 acgggttgag caacgtgttg gttatacaat tgaacaaatt aatcatatgc gtgatgtgtt 41400 tggtacgcga ttgcgacgtg ctgaagacgt atttccaccg gtgatcgggg ttgctgccca 41460 taaaggtggc gtttacaaaa cctcagtttc tgttcatctt gctcaggatc tggctctgaa 41520 ggggctacgt gttttgctcg tggaaggtaa cgacccccag ggaacagcct caatgtatca 41580 cggatgggta ccagatcttc atattcatgc agaagacact ctcctgcctt tctatcttgg 41640 ggaaaaggac gatgtcactt atgcaataaa gcccacttgc tggccggggc ttgacattat 41700 tccttcctgt ctggctctgc accgtattga aactgagtta atgggcaaat ttgatgaagg 41760 taaactgccc accgatccac acctgatgct ccgactggcc attgaaactg ttgctcatga 41820 ctatgatgtc atagttattg acagcgcgcc taacctgggt atcggcacga ttaatgtcgt 41880 atgtgctgct gatgtgctga ttgttcccac gcctgctgag ttgtttgact acacctccgc 41940 actgcagttt ttcgatatgc ttcgtgatct gctcaagaac gttgatctta aagggttcga 42000 gcctgatgta cgtattttgc ttaccaaata cagcaatagt aatggctctc agtccccgtg 42060 gatggaggag caaattcggg atgcctgggg aagcatggtt ctaaaaaatg ttgtacgtga 42120 aacggatgaa gttggtaaag gtcagatccg gatgagaact gtttttgaac aggccattga 42180 tcaacgctct tcaactggtg cctggagaaa tgctctttct atttgggaac ctgtctgcaa 42240 tgaaattttc gatcgtctga ttaaaccacg ctgggagatt agataatgaa gcgtgcgcct 42300 gttattccaa aacatacgct caatactcaa ccggttgaag atacttcgtt atcgacacca 42360 gctgccccga tggtggattc gttaattgcg cgcgtaggag taatggctcg cggtaatgcc 42420 attactttgc ctgtatgtgg tcgggatgtg aagtttactc ttgaagtgct ccggggtgat 42480 agtgttgaga agacctctcg ggtatggtca ggtaatgaac gtgaccagga gctgcttact 42540 gaggacgcac tggatgatct catcccttct tttctactga ctggtcaaca gacaccggcg 42600 ttcggtcgaa gagtatctgg tgtcatagaa attgccgatg ggagtcgccg tcgtaaagct 42660 gctgcactta ccgaaagtga ttatcgtgtt ctggttggcg agctggatga tgagcagatg 42720 gctgcattat ccagattggg taacgattat cgcccaacaa gtgcttatga acgtggtcag 42780 cgttatgcaa gccgattgca gaatgaattt gctggaaata tttctgcgct ggctgatgcg 42840 gaaaatattt cacgtaagat tattacccgc tgtatcaaca ccgccaaatt gcctaaatca 42900 gttgttgctc ttttttctca ccccggtgaa ctatctgccc ggtcaggtga tgcacttcaa 42960 aaagccttta cagataaaga ggaattactt aagcagcagg catctaacct tcatgagcag 43020 aaaaaagctg gggtgatatt tgaagctgaa gaagttatca ctcttttaac ttctgtgctt 43080 aaaacgtcat ctgcatcaag aactagttta agctcacgac atcagtttgc tcctggagcg 43140 acagtattgt ataagggcga taaaatggtg cttaacctgg acaggtctcg tgttccaact 43200 gagtgtatag agaaaattga ggccattctt aaggaacttg aaaagccagc accctgatgc 43260 gaccacgttt tagtctacgt ttatctgtct ttacttaatg tcctttgtta caggccagaa 43320 agcataactg gcctgaatat tctctctggg cccactgttc cacttgtatc gtcggtctga 43380 taatcagact gggaccacgg tcccactcgt atcgtcggtc tgattattag tctgggacca 43440 cggtcccact cgtatcgtcg gtctgattat tagtctggga ccacggtccc actcgtatcg 43500 tcggtctgat aatcagactg ggaccacggt cccactcgta tcgtcggtct gattattagt 43560 ctgggaccat ggtcccactc gtatcgtcgg tctgattatt agtctgggac cacggtccca 43620 ctcgtatcgt cggtctgatt attagtctgg aaccacggtc ccactcgtat cgtcggtctg 43680 attattagtc tgggaccacg gtcccactcg tatcgtcggt ctgattatta gtctgggacc 43740 acgatcccac tcgtgttgtc ggtctgatta tcggtctggg accacggtcc cacttgtatt 43800 gtcgatcaga ctatcagcgt gagactacga ttccatcaat gcctgtcaag ggcaagtatt 43860 gacatgtcgt cgtaacctgt agaacggagt aacctcggtg tgcggttgta tgcctgctgt 43920 ggattgctgc tgtgtcctgc ttatccacaa cattttgcgc acggttatgt ggacaaaata 43980 cctggttacc caggccgtgc cggcacgctc ggtacccggg gatcctcgtt taaac 44035 <210> 51 <211> 41464 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polynucleotide" <220> <221> modified_base <222> (16063)..(16063) <223> a, c, t, g, unknown or other <400> 51 catcatcaat aatatacctt attttggatt gaagccaata tgataatgag atgggcggcg 60 cggggcgggg cgcggggcgg gaggcgggtt tgggggcggg ccggcgggcg gggcggtgtg 120 gcggaagtgg actttgtaag tgtggcggat gtgacttgct agtgccgggc gcggtaaaag 180 tgacgttttc cgtgcgcgac aacgcccccg ggaagtgaca tttttcccgc ggtttttacc 240 ggatgttgta gtgaatttgg gcgtaaccaa gtaagatttg gccattttcg cgggaaaact 300 gaaacgggga agtgaaatct gattaatttt gcgttagtca taccgcgtaa tatttgtcta 360 gggccgaggg actttggccg attacgtgga ggactcgccc aggtgttttt tgaggtgaat 420 ttccgcgttc cgggtcaaag tctgcgtttt attattatag gatatcccat tgcatacgtt 480 gtatccatat cataatatgt acatttatat tggctcatgt ccaacattac cgccatgttg 540 acattgatta ttgactagtt attaatagta atcaattacg gggtcattag ttcatagccc 600 atatatggag ttccgcgtta cataacttac ggtaaatggc ccgcctggct gaccgcccaa 660 cgacccccgc ccattgacgt caataatgac gtatgttccc atagtaacgc caatagggac 720 tttccattga cgtcaatggg tggagtattt acggtaaact gcccacttgg cagtacatca 780 agtgtatcat atgccaagta cgccccctat tgacgtcaat gacggtaaat ggcccgcctg 840 gcattatgcc cagtacatga ccttatggga ctttcctact tggcagtaca tctacgtatt 900 agtcatcgct attaccatgg tgatgcggtt ttggcagtac atcaatgggc gtggatagcg 960 gtttgactca cggggatttc caagtctcca ccccattgac gtcaatggga gtttgttttg 1020 gcaccaaaat caacgggact ttccaaaatg tcgtaacaac tccgccccat tgacgcaaat 1080 gggcggtagg cgtgtacggt gggaggtcta tataagcaga gctctcccta tcagtgatag 1140 agatctccct atcagtgata gagatcgtcg acgagctcgt ttagtgaacc gtcagatcgc 1200 ctggagacgc catccacgct gttttgacct ccatagaaga caccgggacc gatccagcct 1260 ccgcggccgg gaacggtgca ttggaacgcg gattccccgt gccaagagtg agatcttccg 1320 tttatctagg taccagatat cgccaccatg agacctgctc cctggacacc taatcctccc 1380 aggtccccca gccagatgag cgtgagagac agactggcta ggctgagagc cgaggctcag 1440 gtcaagcagg ccagcgtcga ggtgcaaccc cctcagctca cccaggtgtc cccccagcag 1500 cctgtggccg gcattctgtt cattctggcc attctgaccg agtggggaag cggcaacaga 1560 acctacggcc ctgtcttcat gtgcctcgga ggactgctga caatggtggc tggcgccgtg 1620 tggctcaccg tcatgtccaa caccctgctc agcgcctgga ttctgaccgc cggattcctg 1680 atctttctga tcggattc...

Claims

1. (i) A polynucleotide encoding a polypeptide, and (ii) a nucleic acid comprising one or more sequences that direct the expression of said polypeptide in a host cell, wherein the polypeptide is (a) a first fragment and a second fragment of LMP1, wherein the first fragment and the second fragment of LMP1 are selected from the group consisting of SEQ ID NOs: 2-5, and the first fragment and the second fragment of LMP1 are not adjacent to each other in the polypeptide, (b) a first fragment and a second fragment of LMP2, wherein the first fragment and the second fragment of LMP2 are selected from the group consisting of SEQ ID NOs: 7-10, and the first fragment and the second fragment of LMP2 are not adjacent to each other in the polypeptide, (c) a fragment of EBNA1 consisting of SEQ ID NO: 12, and (d) a first fragment and a second fragment of EBNA3A, wherein the first fragment and the second fragment of EBNA3A are selected from the group consisting of SEQ ID NOs: 14-20, and the first fragment and the second fragment of EBNA3A are not adjacent to each other in the polypeptide, comprises, and the polynucleotide is operably linked to the one or more sequences that direct the expression of the polypeptide in the host cell, the nucleic acid.

2. The nucleic acid according to claim 1, wherein the polypeptide further comprises (e) one or more sequences (ZEBRA fragments) among SEQ ID NOs: 22-23.

3. The polypeptide is (a) the first fragment of LMP1 consisting of SEQ ID NO: 2, (b) the second fragment of LMP1 consisting of SEQ ID NO: 3, (c) the third fragment of LMP1 consisting of SEQ ID NO: 4, (d) the fourth fragment of LMP1 consisting of SEQ ID NO: 5, (e) the first fragment of LMP2 consisting of SEQ ID NO: 7, (f) the second fragment of LMP2 consisting of SEQ ID NO: 8, (g) the third fragment of LMP2 consisting of SEQ ID NO: 9, (h) the fourth fragment of LMP2 consisting of SEQ ID NO: 10, (i) the first fragment of EBNA1 consisting of SEQ ID NO: 12, (j) the first fragment of EBNA3A consisting of SEQ ID NO: 14, (k) the second fragment of EBNA3A consisting of SEQ ID NO: 15, (l) the third fragment of EBNA3A consisting of SEQ ID NO: 16, (m) the fourth fragment of EBNA3A consisting of SEQ ID NO: 17, (n) the fifth fragment of EBNA3A consisting of SEQ ID NO: 18, (o) the sixth fragment of EBNA3A consisting of SEQ ID NO: 19, and (p) the seventh fragment of EBNA3A consisting of SEQ ID NO: 20, comprises, The first, second, third, and fourth LMP1 fragments are not adjacent to each other, the first, second, third, and fourth LMP2 fragments are not adjacent to each other, and the first, second, third, fourth, fifth, sixth, and seventh EBNA3A fragments are not adjacent to each other. The nucleic acid according to claim 1 or 2.

4. The polypeptide is (q) a first fragment of ZEBRA consisting of SEQ ID NO: 22, and (r) a second fragment of ZEBRA consisting of SEQ ID NO: 23, The nucleic acid according to claim 3, further comprising, wherein in the polypeptide, the first and second ZEBRA fragments are not adjacent to each other.

5. The nucleic acid according to claim 1, wherein the polypeptide has at least 90%, at least 95%, or at least 99% sequence identity with SEQ ID NO: 24 or SEQ ID NO:

26.

6. A vector comprising the nucleic acid according to any one of claims 1 to 5.

7. A polypeptide encoded by the nucleic acid according to claim 1 or 5, having at least 90%, at least 95%, or at least 99% sequence identity with SEQ ID NO: 24 or SEQ ID NO:

26.

8. A composition comprising a pharmaceutically acceptable excipient and the nucleic acid according to any one of claims 1 to 5, the vector according to claim 6, or the polypeptide according to claim 7.

9. The nucleic acid according to any one of claims 1 to 5, the vector according to claim 6, the polypeptide according to claim 7, or the composition according to claim 8 for use in the treatment or prevention of a disease caused by Epstein-Barr virus infection.

Images