HCV vaccines

Abstract

The invention concerns a fusion polypeptide comprising a plurality of conserved peptide sequences, or variants thereof, wherein at least one of the conserved sequences is conserved across: i) HCV genotypes 1a and 1b; ii) HCV genotypes 1 and 3; or iii) HCV genotypes 1 to 6; and wherein at least one of the conserved peptide sequences comprises at least part of a sequence of a non-structural protein of the HCV genotypes; including associated nucleic acid and vector sequences, and use in methods of treatment or prophylaxis, such as vaccination.

Claims

1. A nucleic acid encoding a fusion polypeptide comprising a plurality of conserved peptide sequences, wherein at least one of the conserved sequences is conserved across: i) HCV genotypes 1a and 1b; ii) HCV genotypes 1 and 3; or iii) HCV genotypes 1 to 6; and wherein at least one of the conserved peptide sequences comprises at least part of a sequence of a non-structural protein of the HCV genotypes, and wherein at least one of the conserved sequences is selected from SEQ ID NO: 118-125.

2. The nucleic acid according to claim 1, wherein the plurality of conserved peptide sequences comprise 5 or more conserved peptide sequences.

3. The nucleic acid according to claim 1, wherein the conserved peptide sequences are not distanced apart by more than 10 residues in the polypeptide sequence.

4. The nucleic acid according to claim 1, wherein two or more, or all, of the plurality of conserved peptide sequences are directly joined together in the polypeptide.

5. The nucleic acid according to claim 1, wherein some or all of the conserved peptide sequences are derived from non-structural HCV proteins.

6. The nucleic acid according to claim 1, wherein the polypeptide comprises or consists of the sequence of any one of SEQ ID NOs: 118 to 125 without the TPA peptide adjuvant, or with an alternative peptide adjuvant.

7. The nucleic acid according to claim 1, wherein the nucleic acid further encodes a peptide adjuvant.

8. The nucleic acid according to claim 1, wherein the nucleic acid is a viral vector.

9. A composition comprising the nucleic acid according to claim 1.

10. A method of treatment of HCV infection comprising the administration of: the nucleic acid according to claim 1; or a composition comprising the nucleic acid according to claim 1.

Description

(1) Embodiments of the invention will now be described in more detail, by way of example only, with reference to the accompanying drawings.

(2) FIG. 1: Identification of conserved HCV peptide segments. Sequence diversity plot of the full HCV genome with defined conserved HCV segments. (A) The calculated sequence diversity for an example sequence dataset is shown for the full HCV genome (sequence dataset HCV gt1/3a, containing 72 sequences) using a window size of k=20. For conserved vaccine design, segments with a variability <25% (lowest quartile, marked blue) were defined as conserved and selected for conserved immunogen design. (B) Consensus sequences for selected conserved segments for three different immunogen analyses HCV genotype 1 (a, blue) (SEQ ID NO: 1-7, 9, 10. 12, 13, 15, 17, 18. 20, 21, 23-27, 29-35, 37 and 38), HCV genotype 1/3 (b, green) (SEQ ID NO: 39, 41, 43-48, 50, 52, 54, 56, 58, 60, 61, 63-65, 67, 69, 71-73, 75, 76, 78 and 80) and HCV genotype 1-6 (c, orange) (SEQ ID NO: 81, 83, 84, 44, 85, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 106, 108, 109, 110, 112-114 and 116) are depicted. Conserved segments are numbered after position on the HCV genome, with viral regions specified.

(3) FIG. 2: Patient sequence selection for final immunogen design. (A) Similarity of subtype consensus sequences (depicted as coloured spots) to overall consensus sequences at each conserved segment, shown for analyses HCV gt1 (a, left), HCV gt1/3 (b, middle) and HCV gt1-6 (c, right) immunogens. (B) Number of patient sequences selected of each genotype for the final conserved immunogens HCV gt1 (left), HCV gt1/3 (middle) and HCV gt1-6 (right).

(4) FIG. 3: The Total magnitude of HCV specific T cell responses to conserved segment vaccines in mouse models. BALB/c mice (4/group) are vaccinated with each vaccine at 10.sup.8IU intramuscularly. Splenocytes are harvested 2 weeks later. The total magnitude of HCV specific T cell responses using pools of HCV genotype 1b peptides in ex vivo IFN-γ ELISpot assays. Bars represent the mean.

(5) FIG. 4: The breadth of HCV specific T cell responses to conserved segment vaccines. BALB/c mice receive 10.sup.8IU vaccine intramuscularly. Splenocytes are harvested 2 weeks later. The magnitude of HCV specific T cell responses to individual pools (A-M) of HCV genotype 1b peptides spanning the viral genome and concavalin A (positive control) are assessed in ex vivo IFN-γ ELISpot assays. Bars represent the mean+/−SD. (A) Individual data in four mice receiving Gt1-6D-TPA vaccine is shown. (B) HCV specific T cell responses to gt1-6D, GT1/3D and ChAdOx1 GFP control vaccines are shown.

(6) FIG. 5: Inter-genotypic T cell cross-reactivity of total HCV specific T cell responses to conserved segment vaccines. C57BL/6 mice receive 10.sup.8 IU Gt1-6D-TPA vaccine intramuscularly. Splenocytes are harvested 2 weeks later. The total magnitude of HCV specific T cell responses to HCV genotype 1a, ab and 3a peptides spanning the entire immunogen are shown. Bars represent the mean.

(7) FIG. 6: Inter-genotypic T cell cross-reactivity in peptide pools to conserved segment vaccines. C57BL/6 mice receive 10.sup.8 IU of gt1-6D-TPA vaccine intramuscularly. Splenocytes are harvested 2 weeks later. The magnitude of HCV specific T cell responses to individual pools of HCV genotype 1a, 1b and 3b peptides spanning the viral genome are assessed in ex vivo IFN-γ ELISpot assays. Bars represent the mean+/−SD.

(8) FIG. 7: Breadth, magnitude and T cell cross-reactivity of conserved segment compared to an NS genotype 1b immunogen. BALB/c mice receive 10.sup.8IU of gt1-6D-TPA, Gt1/3D ChAdOx1 or NS1b ChAdOx1 vaccine intramuscularly. Splenocytes are harvested 2 weeks later and stimulated with HCV peptides or the positive control concavalin A in in ex vivo IFN-γ ELISpot assays. (A) The magnitude of HCV specific T cell responses to individual peptide pools (genotype 1b; A-M) is shown for each vaccine. (B) and (C) total T cell cross-reactivity to HCV 1a, 1b and 3b peptides spanning the viral genome are assessed. Bars represent the mean+/−SD.

(9) FIG. 8: A2-restricted HCV-specific T cell responses in C57BL/6-Tg (HLA-A2.1) transgenic mice. Ex vivo IFNg ELISpot responses from transgenic C57BL/6-Tg (HLA A2.1) mice when vaccinated, intramuscularly, with conserved segment HCV vaccines, Gt1/3D-TPA and Gt1-6D-TPA, and a Gt1b NS-TPA control. At 14 days post-vaccination, splenocytes were harvest and stimulated with 15-18mer peptides matching known HCV A2 epitopes. Of the 10-15 A2-specific epitopes present in the conserved segment vaccines, only the statistically significant responses are shown (unpaired T-test). Note, the significant A2-specific T cell response in Gt1-6D was stimulated by the Gt-3 variant of E2614, despite the recalled T cell population initially primed with a Gt-1a sequence during vaccination. Bars represent the geometric mean.

(10) FIG. 9: Effect of shark invariant chain (sIi) on the immunogenicity of conserved segment vaccine, Gt1-6D. T cell magnitude of conserved segment vaccine, Gt1-6L, is shown with different genetic adjuvants tethered to the immunogen cassette. Outbred CD-1 mice (8/group) received various dosages (IU) of gt1-6D-TPA vaccine, in a ChAdOx1 vector, intramuscularly. Splenocytes were harvested 3-weeks post-vaccination and stimulated with HCV 1b peptides. Bars represent the mean.

(11) 1. We developed a computer algorithm to identify HCV genomic segments from open resource databases and in-house sequences that were conserved between viral subtypes. Conserved segments below a pre-defined threshold spanning the entire HCV coding genome were selected (FIG. 1A) and combined to create novel immunogens of either approximately 1000 amino acids (denoted in vaccine name by letter A), or 1500 AA (denoted in vaccine name by letter D) for each of HCV genotypes 1a and 1b, genotypes 1 and 3, and genotypes 1 to 6. In the vaccine constructs following homology was observed—Genotype 1: 94.8%, Genotypes 1-3:95.5%, genotypes 1-6: 90.3%.

(12) We note 1141 amino-acids are 100% conserved between the GT1, GT1/3 and GT1-6 vaccines, which equates to 74% for GT1 (1141/1544), 79% for GT1/3 (1141/1444) and 83% for GT1-6 (1141/1377).

(13) 2. The exact sequence to be included in each conserved segment was identified in 2 steps-(i) assessing the HCV subtype or genotype consensus sequence that was most homologous with a consensus of all HCV sequences in the algorithm, and (ii) identifying a real patient sequence that was most homologous with the HCV subtype consensus sequence (FIG. 2).

(14) 3. Putative artificial epitopes restricted by common HLA super-types in junction regions were abrogated through the insertion of amino-acid linkers and analysed using BLAST to exclude potential cross-reactivity with human self-peptides.

(15) 4. Plasmid DNA, encoding HCV conserved genomic segments with linkers, tissue plasminogen activator (TPA) leader sequence and Kozak sequence were chemically synthesised using ThermoFisher Scientific GeneArt™ Gene Synthesis service. Gene constructs were cloned into a pENTR4 vector downsteam to the human cytomegalovirus immediate early promoter and tetracycline operator sequences. The entire coding cassette was then moved into the ChAdOx1 destination vector using Thermo Fisher Scientific LR gateway cloning procedure. Simian adenoviral vaccines (ChAdOx1) encoding the new HCV immunogens were derived by transfecting ChAdOx1-HCV.sub.cons plasmids into T-REx™-293 cells (Thermo Fisher Scientific). All the ChAdOx1-HCV.sub.cons vaccines were generated at the viral vector core facility at the Jenner Institute, University of Oxford, Oxford, UK.

(16) 5. We show that conserved immunogens administered using the adenoviral vector ChAdOx1 prime potent T-cell response in mice. In BALB/c mice, total responses for Gt1/3D ChAdOx1 and Gt1-6D ChAdOx1 had an average SFU/10.sup.6 splenocytes of 594 and 2514 (FIG. 3). These immunogens gave significant responses to most individual HCV peptides pools when compared to the DMSO control (FIG. 4a; gt1-6D-TPA shown and to the control eGFP ChAdOx1 vaccine (FIG. 4b).

(17) 6. Vaccination with conserved immunogen vaccines induced T cell responses that were highly cross-reactive with different HCV genotypes. C57BL6 mice were vaccinated with Gt1-6D ChAdOx1. Splenocytes were harvested 2 weeks later and stimulated with peptides from HCV genotypes 1a, 1b and 3a giving mean total magnitude responses of 935, 1474 and 1112 SFU/10.sup.6 splenocytes respectively that were significantly higher than the negative DMSO control (FIG. 5). T cell responses that were cross-reactive were also observed at the level of the individual HCV peptide pools (FIG. 6). The novel conserved immunogen vaccines were equally immunogenic and more cross-reactive with multiple HCV genotypes than a vaccine encoding a single HCV genotype-1b genome (NS1b ChAdOx1) encoded by the same ChAdOx1 vector (FIG. 7).

(18) Conclusions: Novel pan-genotypic HCV simian adenoviral vectored vaccines encoding conserved segments from all major HCV genotypes are highly immunogenic target multiple areas of the HCV genome and are cross-reactive between HCV genotypes, in mouse models. These studies pave the way for the assessment of pan-genotypic HCV T cell vaccines in humans.

(19) Overview on Immunogens Designed, Generated and Tested in Mice

(20) TABLE-US-00001 TABLE 1 Experimental stages of designed HCV conserved vaccine constructs. Constructs are marked in an “X” if they have moved forward to the next experimental stage. pENTR4/plasmid Inserted into Tested in Immunogen ID Designed cloning ChAdOx1 mice GT1_short_A_TPA_linkers X X X GT1_long_D_TPA_linkers X GT1/3_short_A_TPA_linkers X X X X GT1/3_long_D_TPA_linkers X X X X GT1-6_short_A_TPA_linkers X X X X GT1-6_long_D_TPA_linkers X X X X GT1-6_long_D_TPA_nolinkers X X X X GT1-6_long_D_noTPA_linkers X

(21) Key for sequences below:

(22) TPA leader sequence (underlined bold):

(23) TABLE-US-00002 (SEQ ID NO: 194) MDAMKRGLCCVLLLCGAVFVSPSQEIHARFRR

(24) Linkers=in lower case and marked in bold.

(25) TABLE-US-00003 >GT1_short_A_TPA (SEQ ID NO: 118) MDAMKRGLCCVLLLCGAVFVSPSQEIHARFRRkgggpgggkSTNPKPQRKTKRNTNRRP QDVKFPGGGQIVGGVYLLPRRGPRLGVRATRKTSERSQPRGRRQPIPKARRPEGRTWAQ PGYPWPLYGNEGCGWAGWLLSPRGSRPSWGPTDPRRRSRNLGKVIDTLTCGFADLMGYI PLVGAPLGGAARALAHGVRVLEDGVNYATGNLPGCSFSIFLLALLSCLTVPASAggsgD RDRSELSPLLLSTTQWQVLPCSFTTLPALSTGLIHLHQNIVDVQYLYGVGSSVgpPCTC GSSDLYLVTRHADVIPVRRRGDSRGSLLSPRPISYLKGSSGGPLLCPSGHAVGIFRAAV CTRGVAKAVDFIPVESMETTMRSPVFTDNSSPPAVPQTFQVAHLHAPTGSGKSTKVPAA YAAQGYKVLVLNPSVAATLGFGAYMSKAHGVsgTGVRTITTGSPITYSTYGKFLADGGC SGGAYDIIICDECHSTDATSILGIGTVLDQAETAGARLVVLATATPPGSVTVPHPNIEE VgpgNAVAYYRGLDVSVIPTSGDVVVVATDALMTGFTGDFDSVIDCNTCVTQTVDFSLD PTFTIETTTLPQDAVSRTQRRGRTGRGRpgggsgggYRFVTPGERPSGMFDSSVLCECY DAGCAWYELTPAETTVRLRAYLNTPGLPVCQDHLEFWEGVFTGLTHIDAHFLSQTKQAG DNFPYLVAYQATVCARAQAPPPSWDQMWKCLIRLKPggkgpggKYIMTCMSADLEVVTS TWVLVGGVLAALAAYCLSTGCVVIVGRIVLSGgsgGSIGLGKVLVDILAGYGAGVAGAL VAFKIMSGEVPSTEDLVNLLPAILSPGALVVGVVCAAILRRHVGPGEGAVQWMNRLIAF ASRGNHVSPTHYVPESDAAARVTQILSgpSLTERLYVGGPLTNSKGQNCGYRRCRASGV LTTSCGNTLTCYLKASAACRAAKLggpgSLRAFTEAMTRYSAPPGDPPQPEYDLELITS CSSNVSVAHDASGKRVYYLTRDPTTPLARAAWETARHTPVNSWLGNIIMYAPTLWARMI LggsggEPLDLPQIIQRLHGLSAFSLHSYSPGEINRVAACLRKLGVPPLRAWRHRARSV RA >GT1_long_D_TPA (SEQ ID NO: 119) MDAMKRGLCCVLLLCGAVFVSPSQEIHARFRRkgggpgggkSTNPKPQRKTKRNTNRRP QDVKFPGGGQIVGGVYLLPRRGPRLGVRATRKTSERSQPRGRRQPIPKARRPEGRTWAQ PGYPWPLYGNEGCGWAGWLLSPRGSRPSWGPTDPRRRSRNLGKVIDTLTCGFADLMGYI PLVGAPLGGAARALAHGVRVLEDGVNYATGNLPGCSFSIFLLALLSCLTVPASAggsgY VGDLCGSVFLVSQLFTFSPRpYPGHITGHRMAWDMMMNWSPVCGPVYCFTPSPVVVGTT DRTDVFLLNNTRPPLGNWFGCTWMCPTDCFRKHPEATYSRCGSGPWLTPRCLVDYPYRL WgDRDRSELSPLLLSTTQWQVLPCSFTTLPALSTGLIHLHQNIVDVQYLYGVGSSVARV CACLWMMLLIAQAEAALENLVKGWRLLAPITAYAQQTRGLLGCIITSLTGRDKNQVEGE VQIVSTQSFLATCINGVCWTVYHGAGPCTCGSSDLYLVTRHADVIPVRRRGDSRGSLLS PRPISYLKGSSGGPLLCPSGHAVGIFRAAVCTRGVAKAVDFIPVESMETTMRSPVFTDN SSPPAVPQTFQVAHLHAPTGSGKSTKVPAAYAAQGYKVLVLNPSVAATLGFGAYMSKAH GVsgTGVRTITTGSPITYSTYGKFLADGGCSGGAYDIIICDECHSTDATSILGIGTVLD QAETAGARLVVLATATPPGSVTVPHPNIEEVgpgNAVAYYRGLDVSVIPTSGDVVVVAT DALMTGFTGDFDSVIDCNTCVTQTVDFSLDPTFTIETTTLPQDAVSRTQRRGRTGRGRp gggsgggYRFVTPGERPSGMFDSSVLCECYDAGCAWYELTPAETTVRLRAYLNTPGLPV CQDHLEFWEGVFTGLTHIDAHFLSQTKQAGDNFPYLVAYQATVCARAQAPPPSWDQMWK CLIRLKPggkgpggKYIMTCMSADLEVVTSTWVLVGGVLAALAAYCLSTGCVVIVGRIV LSGgpgFWAKHMWNFISGIQYLAGLSTLPGNPAIASLMAFTASVTSPLTTQpGSIGLGK VLVDILAGYGAGVAGALVAFKIMSGEVPSTEDLVNLLPAILSPGALVVGVVCAAILRRH VGPGEGAVQWMNRLIAFASRGNHVSPTHYVPESDAAARVTQILSSWLRDIWDWICEVLS DFKTWLKCPCQVPSPEFFTELDGVRLHRkkgpgsgpgpRRLARGSPPSLASSSASQLSAPSLKA TCTTNHSDAESYSSMPPLEGEPGDPDLSDGSWSTVSSEAgsgsLSNSLLRHHNMVYATTS RSAgpLTPPHSAKSKFGYGAKDVRCHsgsgggsKPARLIVFPDLGVRVCEKMALYDVVg gPMGFSYDTRCFDSTVTESDIRTEggsgggSLTERLYVGGPLTNSKGQNCGYRRCRASG VLTTSCGNTLTCYLKASAACRAAKLggsggCTMLVCGDDLVVICESAGTQEDASLRAFT EAMTRYSAPPGDPPQPEYDLELITSCSSNVSVAHDASGKRVYYLTRDPTTPLARAAWET ARHTPVNSWLGNIIMYAPTLWARMILggsggEPLDLPQIIQRLHGLSAFSLHSYSPGEI NRVAACLRKLGVPPLRAWRHRARSVRAsGGRAAICGKYLFNWAVRTKLKLTPIPAA >GT1 & 3_short_A_TPA (SEQ ID NO: 120) MDAMKRGLCCVLLLCGAVFVSPSQEIHARFRRkgggpgggkSTNPKPQRKTKRNTNRRP QDVKFPGGGQIVGGVYLLPRRGPRLGVRATRKTSERSQPRGRRQPIPKARRPEGRSWAQ PGYPWPLYGNEGCGWAGWLLSPRGSRPSWGPTDPRRRSRNLGKVIDTLTCGFADLMGYI PLVGAPLGGAARALAHGVRVLEDGVNYATGNLPGCSFSIFLLALLSCLTVPASgkggTT ELAILPCSFTPLPALSTGLIHLHQNIVDVQYLYGVGSGMMGWRLLAPITAYAQQTRGLL GTIVTSLTGRDKNVVTGEVQVLSTAgsgPCTCGSADLYLVTRDADVIPARRRGDSTASL LSPRPLACLKGSSGGPVMCPSGHVAGIFRAAVCTRGVAKALQFIPVETLRSPVFSDNSS PPAVPQSYQVAHLHAPTGSGKSTKVPAAYAAQGYKVLVLNPSVAATLGFGAYMSKATGN RTITTGAKLTYSTYGKFLADGGCSGGAYDVIICDECHAQDATSILGIGTVLDQAETAGV RLTVLATATPPGSITVPHSNIEEVALSVIPTAGDVVVCATDALMTGFTGDFDSVIDCNV AVEQYVDFSLDPTFSIETRTAPQDAVSRSQRRGRTGRGRLGTYRYVGPGERPSGMFDSV VLCECYDAGCAWYELQPAETTVRLRAYLSTPGLPVCQDHLDFWESVFTGLTHIDAHFLS QTKQQGLNFPYLTAYQATVCARAQAPPPSWDEMWKCLVRLKPTLHGPTPLLYRLGPVQN ggsgkggIGSVGLGKVLVDILAGYGAGVAGALVAFKIMSGEIPSTEDLVNLLPAILSPG ALVVGVVCAAILRRHVGPGEGAVQWMNRLIAFASRGNHVSPTHYVPESDAAARVTAILS SLTsgQSVVCCSMSYSWTGALITPCSAEEEKLPINPLSNSLLRHHNLVYSTSSRSASQR QKKVTFDRLQVLDDHYKKGKRYYYLTRDPTTPLARAAWETARHTPVNSWLGNIIMYAPT IWVRMVMgkgpgsYGATYSVTPLDLPAIIERLHGLSAFTLHSYSPVELNRVAGTLRKLG CPPLRAWRHR >GT1 & 3_long_D_TPA (SEQ ID NO: 121) MDAMKRGLCCVLLLCGAVFVSPSQEIHARFRRkgggpgggkSTNPKPQRKTKRNTNRRP QDVKFPGGGQIVGGVYLLPRRGPRLGVRATRKTSERSQPRGRRQPIPKARRPEGRSWAQ PGYPWPLYGNEGCGWAGWLLSPRGSRPSWGPTDPRRRSRNLGKVIDTLTCGFADLMGYI PLVGAPLGGAARALAHGVRVLEDGVNYATGNLPGCSFSIFLLALLSCLTVPASgggsgg gVDLLVGAATMCSALYVGDMCGpHWGVLAGLAYYSMQGNWAKVSVCGPVYCFTPSPVVV GTTDRgpgsgkgpggRCGSGPWLTPRCLVDYPYRLWHYPCTAACNWTRGERCDIEDRDR SELggsgTTELAILPCSFTPLPALSTGLIHLHQNIVDVQYLYGVGSGMMGWRLLAPITA YAQQTRGLLGTIVTSLTGRDKNVVTGEVQVLSTAgsgPCTCGSADLYLVTRDADVIPAR RRGDSTASLLSPRPLACLKGSSGGPVMCPSGHVAGIFRAAVCTRGVAKALQFIPVETLR SPVFSDNSSPPAVPQSYQVAHLHAPTGSGKSTKVPAAYAAQGYKVLVLNPSVAATLGFG AYMSKATGNRTITTGAKLTYSTYGKFLADGGCSGGAYDVIICDECHAQDATSILGIGTV LDQAETAGVRLTVLATATPPGSITVPHSNIEEVALSVIPTAGDVVVCATDALMTGFTGD FDSVIDCNVAVEQYVDFSLDPTFSIETRTAPQDAVSRSQRRGRTGRGRLGTYRYVGPGE RPSGMFDSVVLCECYDAGCAWYELQPAETTVRLRAYLSTPGLPVCQDHLDFWESVFTGL THIDAHFLSQTKQQGLNFPYLTAYQATVCARAQAPPPSWDEMWKCLVRLKPTLHGPTPL LYRLGPVQNgppMACMSADLEVTTSTWVLLGGVLAALAAYCLSVGCVVIVGHFWAKHMW NFISGIQYLAGLSTLPGNPAIASLMAFTAgpIGSVGLGKVLVDILAGYGAGVAGALVAF KIMSGEIPSTEDLVNLLPAILSPGALVVGVVCAAILRRHVGPGEGAVQWMNRLIAFASR GNHVSPTHYVPESDAAARVTAILSSLTCPCQVPAPEFFTEVDGVRLHRgggppgggIGS QLPCEPEPDVSVLTSMLpTAARRLARGSPPSEASSSASQLSAPSLKATCQTHRESDSES CSSMPPLEGEPGDPDLSCDSWSTVSDQSVVCCSMSYSWTGALITPCSAEEEKLPINPLS NSLLRHHNLVYSTSSRSASQRQKKVTFDRLQVLDDHYKgpgPEKGGRKPARLIVYPDLG VRVCEKMALYDVpgpgggWTSKKTPMGFSYDTRCFDSTVTEQDIRVEEEgpCGYRRCRA SGVLTTSCGNTLTCYIKARAACggsggALRAFTEAMTRYSAPPGDAPQPggKGKRYYYL TRDPTTPLARAAWETARHTPVNSWLGNIIMYAPTIWVRMVMgkgpgsYGATYSVTPLDL PAIIERLHGLSAFTLHSYSPVELNRVAGTLRKLGCPPLRAWRHRggpggpggVRAKLLS QGGRAAICGKYLFNWAVRTK >GT1-6_short_A_TPA (SEQ ID NO: 122) MDAMKRGLCCVLLLCGAVFVSPSQEIHARFRRkgggpgggTKRNTNRRPMDVKFPGGGQ IVGGVYLLPRRGPRLGVRATRKTSERSQPRGRRQPIPKARRPEGRSWAQPGYPWPLYGN EGCGWAGWLLSPRGSRPSWGPNDPRRRSRNLGKVIDTLTCGFADLMGYIPLVGAPVGGV ARALAHGVRALEDGINYATGNLPGCSFSIFLLALLSCLTVPASCPTDCFRKHPEATYTK CGSGPWLTPRCLVDYPYRLWHYPCTVNFgsgLLLSTTEWQILPCSFTTLPALSTGLIHL HQNIVDVQYLYGVGSgpPCTCGSSDLYLVTRHADVIPVRRRGDSRGSLLSPRPISYLKG SSGGPVLCPSGHAVGIFRAAVCTRGVAKAVDFIPVESLEMRSPVFTDNSTPPAVPQTYQ VAHLHAPTGSGKSTKVPAAYAAQGYKVLVLNPSVAATLGFGAYMSKAYGIggsRSGVRT ITTGAPITYSTYGKFLADGGCSGGAYDIIICDECHSTDSTTILGIGTVLDQAETAGVRL VVLATATPPGgNAVAYYRGLDVSVIPTSGDVVVVATDALMTGFTGDFDSVIDCNTCVTQ TVDFSLDPTFTIETTTVPQDAVSRSQRRGRTGRGRRGIYRFVTPGERPSGMFDSSVLCE CYDAGCAWYELTPAETSVRLRAYLNTPGLPVCQDHLEFWEGVFTGLTHIDAHFLSQTKQ AGDNFPYLVAYQATVCARAQAPPPSWDQMWTHPITKYIMACMSADLEVVTSTWVLVGGV LAALAAYCLSVGSVVIVGgpgFWAKHMWNFISGIQYLAGLSTLPGNPAIASLMAFTAAV TSPLGAAVGSVGLGKVLVDILAGYGAGVAGALVAFKIMSGEVPSTEDLVNLLPAILSPG ALVVGVVCAAILRRHVGPGEGAVQWMNRLIAFASRGNHVSPTHYVPESDAAARVgggsg ggVCCSMSYSWTGALITPCAAEEEKLPINPLSNSLIRHHNMVYSTTSRSASLRQKKVTF DRgggkgggpTPLARAAWETARHTPVNSWLGNIIMYAPTIWVRMVLMTHFFSILQgggs ggpELNRVGACLRKLGVPPLRAWRHRARAVRAKLIAQGGKAAICGKYLFNWAV >GT1-6_long_D_TPA (SEQ ID NO: 123) MDAMKRGLCCVLLLCGAVFVSPSQEIHARFRRkgggpgggTKRNTNRRPMDVKFPGGGQ IVGGVYLLPRRGPRLGVRATRKTSERSQPRGRRQPIPKARRPEGRSWAQPGYPWPLYGN EGCGWAGWLLSPRGSRPSWGPNDPRRRSRNLGKVIDTLTCGFADLMGYIPLVGAPVGGV ARALAHGVRALEDGINYATGNLPGCSFSIFLLALLSCLTVPASpgCNCSIYPGHITGHR MAWDMMMNWSPTTkkNGSWHINRTALNCNDSLNTGFIgpggSVCGPVYCFTPSPVVVGT TDRgpgCPTDCFRKHPEATYTKCGSGPWLTPRCLVDYPYRLWHYPCTVNFgsgLLLSTT EWQILPCSFTTLPALSTGLIHLHQNIVDVQYLYGVGSMGWRLLAPITAYAQQTRGLLGT IVTSLTGRDKNPCTCGSSDLYLVTRHADVIPVRRRGDSRGSLLSPRPISYLKGSSGGPV LCPSGHAVGIFRAAVCTRGVAKAVDFIPVESLEMRSPVFTDNSTPPAVPQTYQVAHLHA PTGSGKSTKVPAAYAAQGYKVLVLNPSVAATLGFGAYMSKAYGIggsRSGVRTITTGAP ITYSTYGKFLADGGCSGGAYDIIICDECHSTDSTTILGIGTVLDQAETAGVRLVVLATA TPPGgkggkgIKGGRHLIFCHSKKKCDELAgpgNAVAYYRGLDVSVIPTSGDVVVVATD ALMTGFTGDFDSVIDCNTCVTQTVDFSLDPTFTIETTTVPQDAVSRSQRRGRTGRGRRG IYRFVTPGERPSGMFDSSVLCECYDAGCAWYELTPAETSVRLRAYLNTPGLPVCQDHLE FWEGVFTGLTHIDAHFLSQTKQAGDNFPYLVAYQATVCARAQAPPPSWDQMWTHPITKY IMACMSADLEVVTSTWVLVGGVLAALAAYCLSVGSVVIVGgpgFWAKHMWNFISGIQYL AGLSTLPGNPAIASLMAFTAAVTSPLGAAVGSVGLGKVLVDILAGYGAGVAGALVAFKI MSGEVPSTEDLVNLLPAILSPGALVVGVVCAAILRRHVGPGEGAVQWMNRLIAFASRGN HVSPTHYVPESDAAARVgpTAETAARRLARGSPPSLASSSASQLSAPSLKATCTVCCSM SYSWTGALITPCAAEEEKLPINPLSNSLIRHHNMVYSTTSRSASLRQKKVTFDRggsgg pgPSKGGRKPARLIVYPDLGVRVCEKRALYDVpggpKKTPMGFSYDTRCFDSTVTERDI RTEgggpggCGYRRCRASGVLTTSMGNTITCYIKALAAEAMTRYSAPPGDPPQPEYDLE LITSCSSNVSVAHDggsggTPLARAAWETARHTPVNSWLGNIIMYAPTIWVRMVLMTHF FSILQggpgYGATYSVTPLDLPAIIERLHGLSAFTLHSYSggpggpELNRVGACLRKLG VPPLRAWRHRARAVRAKLIAQGGKAAICGKYLFNWAV >GT1-6_long_D_Nolinkers (SEQ ID NO: 124) MDAMKRGLCCVLLLCGAVFVSPSQEIHARFRRkgggpgggTKRNTNRRPMDVKFPGGGQ IVGGVYLLPRRGPRLGVRATRKTSERSQPRGRRQPIPKARRPEGRSWAQPGYPWPLYGN EGCGWAGWLLSPRGSRPSWGPNDPRRRSRNLGKVIDTLTCGFADLMGYIPLVGAPVGGV ARALAHGVRALEDGINYATGNLPGCSFSIFLLALLSCLTVPASCNCSIYPGHITGHRMA WDMMMNWSPTTNGSWHINRTALNCNDSLNTGFISVCGPVYCFTPSPVVVGTTDRCPTDC FRKHPEATYTKCGSGPWLTPRCLVDYPYRLWHYPCTVNFLLLSTTEWQILPCSFTTLPA LSTGLIHLHQNIVDVQYLYGVGSMGWRLLAPITAYAQQTRGLLGTIVTSLTGRDKNPCT CGSSDLYLVTRHADVIPVRRRGDSRGSLLSPRPISYLKGSSGGPVLCPSGHAVGIFRAA VCTRGVAKAVDFIPVESLEMRSPVFTDNSTPPAVPQTYQVAHLHAPTGSGKSTKVPAAY AAQGYKVLVLNPSVAATLGFGAYMSKAYGIRSGVRTITTGAPITYSTYGKFLADGGCSG GAYDIIICDECHSTDSTTILGIGTVLDQAETAGVRLVVLATATPPGIKGGRHLIFCHSK KKCDELANAVAYYRGLDVSVIPTSGDVVVVATDALMTGFTGDFDSVIDCNTCVTQTVDF SLDPTFTIETTTVPQDAVSRSQRRGRTGRGRRGIYRFVTPGERPSGMFDSSVLCECYDA GCAWYELTPAETSVRLRAYLNTPGLPVCQDHLEFWEGVFTGLTHIDAHFLSQTKQAGDN FPYLVAYQATVCARAQAPPPSWDQMWTHPITKYIMACMSADLEVVTSTWVLVGGVLAAL AAYCLSVGSVVIVGFWAKHMWNFISGIQYLAGLSTLPGNPAIASLMAFTAAVTSPLGAA VGSVGLGKVLVDILAGYGAGVAGALVAFKIMSGEVPSTEDLVNLLPAILSPGALVVGVV CAAILRRHVGPGEGAVQWMNRLIAFASRGNHVSPTHYVPESDAAARVTAETAARRLARG SPPSLASSSASQLSAPSLKATCTVCCSMSYSWTGALITPCAAEEEKLPINPLSNSLIRH HNMVYSTTSRSASLRQKKVTFDRPSKGGRKPARLIVYPDLGVRVCEKRALYDVKKTPMG FSYDTRCFDSTVTERDIRTECGYRRCRASGVLTTSMGNTITCYIKALAAEAMTRYSAPP GDPPQPEYDLELITSCSSNVSVAHDTPLARAAWETARHTPVNSWLGNIIMYAPTIWVRM VLMTHFFSILQYGATYSVTPLDLPAIIERLHGLSAFTLHSYSELNRVGACLRKLGVPPL RAWRHRARAVRAKLIAQGGKAAICGKYLFNWAV >GT1-6_long_D_Non-TPA_linkers (SEQ ID NO: 125) MTKRNTNRRPMDVKFPGGGQIVGGVYLLPRRGPRLGVRATRKTSERSQPRGRRQPIPKA RRPEGRSWAQPGYPWPLYGNEGCGWAGWLLSPRGSRPSWGPNDPRRRSRNLGKVIDTLT CGFADLMGYIPLVGAPVGGVARALAHGVRALEDGINYATGNLPGCSFSIFLLALLSCLT VPASpgCNCSIYPGHITGHRMAWDMMMNWSPTTkkNGSWHINRTALNCNDSLNTGFIgp ggSVCGPVYCFTPSPVVVGTTDRgpgCPTDCFRKHPEATYTKCGSGPWLTPRCLVDYPY RLWHYPCTVNFgsgLLLSTTEWQILPCSFTTLPALSTGLIHLHQNIVDVQYLYGVGSMG WRLLAPITAYAQQTRGLLGTIVTSLTGRDKNPCTCGSSDLYLVTRHADVIPVRRRGDSR GSLLSPRPISYLKGSSGGPVLCPSGHAVGIFRAAVCTRGVAKAVDFIPVESLEMRSPVF TDNSTPPAVPQTYQVAHLHAPTGSGKSTKVPAAYAAQGYKVLVLNPSVAATLGFGAYMS KAYGIggsRSGVRTITTGAPITYSTYGKFLADGGCSGGAYDIIICDECHSTDSTTILGI GTVLDQAETAGVRLVVLATATPPGgkggkgIKGGRHLIFCHSKKKCDELAgpgNAVAYY RGLDVSVIPTSGDVVVVATDALMTGFTGDFDSVIDCNTCVTQTVDFSLDPTFTIETTTV PQDAVSRSQRRGRTGRGRRGIYRFVTPGERPSGMFDSSVLCECYDAGCAWYELTPAETS VRLRAYLNTPGLPVCQDHLEFWEGVFTGLTHIDAHFLSQTKQAGDNFPYLVAYQATVCA RAQAPPPSWDQMWTHPITKYIMACMSADLEVVTSTWVLVGGVLAALAAYCLSVGSVVIV GgpgFWAKHMWNFISGIQYLAGLSTLPGNPAIASLMAFTAAVTSPLGAAVGSVGLGKVL VDILAGYGAGVAGALVAFKIMSGEVPSTEDLVNLLPAILSPGALVVGVVCAAILRRHVG PGEGAVQWMNRLIAFASRGNHVSPTHYVPESDAAARVgpTAETAARRLARGSPPSLASS SASQLSAPSLKATCTVCCSMSYSWTGALITPCAAEEEKLPINPLSNSLIRHHNMVYSTT SRSASLRQKKVTFDRggsggpgPSKGGRKPARLIVYPDLGVRVCEKRALYDVpggpKKT PMGFSYDTRCFDSTVTERDIRTEgggpggCGYRRCRASGVLTTSMGNTITCYIKALAAE AMTRYSAPPGDPPQPEYDLELITSCSSNVSVAHDggsggTPLARAAWETARHTPVNSWL GNIIMYAPTIWVRMVLMTHFFSILQggpgYGATYSVTPLDLPAIIERLHGLSAFTLHSY SggpggpELNRVGACLRKLGVPPLRAWRHRARAVRAKLIAQGGKAAICGKYLFNWAV

(26) Summary of Conserved Sequences in Each Example Embodiment

(27) TABLE-US-00004 GT1 long  1-192 SEQ ID NO: 1 276-297 SEQ ID NO: 2 309-329 SEQ ID NO: 3 502-522 SEQ ID NO: 4 534-556 SEQ ID NO: 5 581-617 SEQ ID NO: 6 656-710 SEQ ID NO: 7/8 729-753 SEQ ID NO: 9 1021-1065 SEQ ID NO: 10/11 1067-1087 SEQ ID NO: 12 1122-1275 SEQ ID NO: 13/14 1280-1366 SEQ ID NO: 15/16 1413-1496 SEQ ID NO: 17 1499-1617 SEQ ID NO: 18/19 1643-1691 SEQ ID NO: 20 1760-1805 SEQ ID NO: 21/22 1840-1950 SEQ ID NO: 23 1975-1997 SEQ ID NO: 24 2112-2133 SEQ ID NO: 25 2188-2220 SEQ ID NO: 26 2380-2413 SEQ ID NO: 27/28 2445-2465 SEQ ID NO: 29 2511-2532 SEQ ID NO: 30 2575-2600 SEQ ID NO: 31 2634-2657 SEQ ID NO: 32 2675-2729 SEQ ID NO: 33 2731-2754 SEQ ID NO: 34 2755-2846 SEQ ID NO: 35/36 2875-2930 SEQ ID NO: 37 2935-2963 SEQ ID NO: 38 GT1 short  1-192 SEQ ID NO: 1 656-710 SEQ ID NO: 7/8 1122-1275 SEQ ID NO: 13/14 1280-1366 SEQ ID NO: 15/16 1413-1496 SEQ ID NO: 17 1499-1617 SEQ ID NO: 18/19 1643-1691 SEQ ID NO: 20 1840-1950 SEQ ID NO: 23 2675-2729 SEQ ID NO: 33 2755-2846 SEQ ID NO: 35/36 2875-2930 SEQ ID NO: 37 GT1/3 long  1-191 SEQ ID NO: 39/40 262-283 SEQ ID NO: 41/42 352-372 SEQ ID NO: 43 503-524 SEQ ID NO: 44 603-629 SEQ ID NO: 45 649-670 SEQ ID NO: 46 676-717 SEQ ID NO: 47 1028-1073 SEQ ID NO: 48/49 1129-1209 SEQ ID NO: 50/51 1213-1379 SEQ ID NO: 52/53 1287-1375 SEQ ID NO: 54/55 1431-1641 SEQ ID NO: 56/57 1653-1693 SEQ ID NO: 58/59 1767-1803 SEQ ID NO: 60 1846-1960 SEQ ID NO: 61/62 2119-2140 SEQ ID NO: 63 2163-2183 SEQ ID NO: 64 2192-2227 SEQ ID NO: 65/66 2391-2423 SEQ ID NO: 67/68 2427-2498 SEQ ID NO: 69/70 2581-2611 SEQ ID NO: 71 2640-2671 SEQ ID NO: 72 2706-2736 SEQ ID NO: 73/74 2767-2789 SEQ ID NO: 75 2809-2858 SEQ ID NO: 76/77 2880-2936 SEQ ID NO: 78/79 2939-2966 SEQ ID NO: 80 GT1/3 short  1-191 SEQ ID NO: 39/40 676-717 SEQ ID NO: 47 1028-1073 SEQ ID NO: 48/49 1129-1209 SEQ ID NO: 50/51 1213-1379 SEQ ID NO: 52/53 1287-1375 SEQ ID NO: 54/55 1431-1641 SEQ ID NO: 56/57 1846-1960 SEQ ID NO: 61/62 2427-2498 SEQ ID NO: 69/70 2809-2858 SEQ ID NO: 76/77 2880-2936 SEQ ID NO: 78/79 .sup. GT1-6 long  11-191 SEQ ID NO: 81/82 304-331 SEQ ID NO: 83 417-439 SEQ ID NO: 84 503-524 SEQ ID NO: 44 588-632 SEQ ID NO: 85 672-715 SEQ ID NO: 86/87 1028-1061 SEQ ID NO: 88/89 1129-1210 SEQ ID NO: 90/91 1212-1282 SEQ ID NO: 92/93 1286-1361 SEQ ID NO: 94/95 1392-1412 SEQ ID NO: 96 1420-1616 SEQ ID NO: 97/98 1645-1692 SEQ ID NO: 99/100 1767-1809 SEQ ID NO: 101/102 1843-1952 SEQ ID NO: 103/104 2189-2224 SEQ ID NO: 105 2453-2512 SEQ ID NO: 106/107 2604-2634 SEQ ID NO: 108 2666-2692 SEQ ID NO: 109 2729-2758 SEQ ID NO: 110/111 2796-2831 SEQ ID NO: 112 2845-2890 SEQ ID NO: 113 2903-2934 SEQ ID NO: 114/115 2936-2986 SEQ ID NO: 116/117  GT1-6 short  11-191 SEQ ID NO: 81/82 588-632 SEQ ID NO: 85 672-715 SEQ ID NO: 86/87 1129-1210 SEQ ID NO: 90/91 1212-1282 SEQ ID NO: 92/93 1286-1361 SEQ ID NO: 94/95 1420-1616 SEQ ID NO: 97/98 1645-1692 SEQ ID NO: 99/100 1767-1809 SEQ ID NO: 101/102 1843-1952 SEQ ID NO: 103/104 2453-2512 SEQ ID NO: 106/107 2936-2986 SEQ ID NO: 116/117

(28) Conserved Peptide Sequences Produced from Alignments of GT1/GT1 and 3/GT1-6:

(29) TABLE-US-00005 SEQ ID NO: 126 TKRNTNRRPQDVKFPGGGQIVGGVYLLPRRGPRLGVRATRKTSERSQPR GRRQPIPKARRPEGR(T/S)WAQPGYPWPLYGNEGCGWAGWLLSPRGSR PSWGP(T/N)DPRRRSRNLGKVIDTLTCGFADLMGYIPLVGAP(L/V)G G(A/V)ARALAHGVR(V/A)LEDG(V/I)N(Y/F)ATGNLPGCSFSIFL LALLSCLT(V/H)PAS SEQ ID NO: 127 VCGPVYCFTPSPVVVGTTDR SEQ ID NO: 128 (R/K)CGSGPWLTPRCLVDYPYRLW SEQ ID NO: 129 TTE(W/L)(Q/A)(V/I)LPCSFT(T/P)LPALSTGLIHLHQNIVDVQY LYGVGS SEQ ID NO: 130 (Q/M/K)GWRLLAPITAYAQQTRGLLG(C/T)I(I/V)TSLTGRDKN SEQ ID NO: 131 PCTCGSSDLYLVTRHADVIP(V/A)RRRGDSR(G/A)SLLSPRP(I/L) (S/A)(Y/T)LKGSSGGP(L/V)LCPSGH(A/V)(A/V)GIFRAAVCTR GVAKA(V/L)(D/Q)FIPVE(S/T)L SEQ ID NO: 132 RSP(V/S)F(T/S)DNS(S/T)PPAVPQ(T/S)(F/Y)QV(A/G)HLHA PTGSGKSTKVPAAYAAQGYKVLVLNPSVAATLGFGAYMSKA SEQ ID NO: 133 TG(V/N)RT(I/V)TTGA(P/K)ITYSTYGKFLADGGCSGGAYDIIICD ECHS(T/Q)DAT(S/T)ILGIGTVLDQAETAG(A/V)RL(V/T)VLATA TPPG SEQ ID NO: 134 SVIPTSGDVVV(V/C)ATDALMTGFTGDFDSVIDCN(T/V)(C/A)V (T/E)QTVDFSLDPTF(T/S)IETTT(L/A)PQDAVSR(T/S)QRRG RTGRGR SEQ ID NO: 135 YR(F/Y)V(T/S)PGERPSGMFDS(S/V)VLCECYDAGCAWYEL(T/Q) PAETTVRLRAYLNTPGLPVCQDHLEFWE(G/S)VFTGLTHIDAHFLSQ TKQ(A/Q/G)G(E/L)NFPYLVAYQATVCARA(Q/K)APPPSWD(Q/ E/T)MW SEQ ID NO: 136 M(T/A)CMSADLEV(V/T)TSTWVL(V/L)GGVLAALAAYCLS(T/V)G CVVIVG SEQ ID NO: 137 FWAKHMWNFISGIQYLAGLSTLPGNPA(I/V)ASLMAFTA SEQ ID NO: 138 GSIGLGKVLVDILAGYGAGVAGALVAFKIM(S/G)GE(V/L/K)PSTED (L/M)VNLLPAILSPGALVVGVVCAAILRRHVGPGEGAVQWMNRLIAFA SRGNHVSPTHYVPESDAAARV SEQ ID NO: 139 RRLARGSPPS(L/E)ASSSASQLSAPSLKATC(T/Q) SEQ ID NO: 140 ES(Y/C)SSMPPLEGEPGDPDL(S/E)(D/F)(G/E)(S/Q)(W/V) (S/E)(T/S)(V/Q) SEQ ID NO: 141 LSNSLLRHHN(M/L)VY(A/S)T(T/S)SRSA SEQ ID NO: 142 KPARLIV(F/Y)PDLGVRVCEK(M/R)ALYDV SEQ ID NO: 143 PMGFSYDTRCFDSTVTE(S/Q/R)DIR(T/V)E SEQ ID NO: 144 CGYRRCRASGVL(T/P)TS(C/M)GNTLTCY(L/I)KA(S/T/L)AA SEQ ID NO: 145 EAMTRYSAPPGD(P/A)PQP SEQ ID NO: 146 TPLARAAWETARHTPVNSWLGNIIM(F/Y)APT(L/I)W(A/V)RM (I/V)L SEQ ID NO: 147 (E/T)PLDLP(Q/A)II(Q/E)RLHGLSAFSLHSYS SEQ ID NO: 148 E(I/L)NRVA(A/G)CLRKLG(V/C)PPLRAWRHR SEQ ID NO: 149 GGRAAICGKYLFNWAV

(30) With reference to SEQ ID NOs: 126-149, the residues placed in parentheses are intended to be provided as options, such that one residue within the parentheses is selected. In one embodiment where the option is between two residues, the first option is selected in any given sequence. In another embodiment where the option is between two residues the second option is selected in any given sequence.

(31) 44 Conserved Peptide Sequences that are 100% Conserved Across HCV1-6 and Useful as an Epitope:

(32) TABLE-US-00006 (SEQ ID NO: 150) TKRNTNRRPQDVKFPGGGQIVGGVYLLPRRGPRLGVRATRKTSERSQPRG RRQPIPKARRPEGR (SEQ ID NO: 151) WAQPGYPWPLYGNEGCGWAGWLLSPRGSRPSWGP (SEQ ID NO: 152) DPRRRSRNLGKVIDTLTCGFADLMGYIPLVGAP (SEQ ID NO: 153) ARALAHGVR (SEQ ID NO: 154) ATGNLPGCSFSIFLLALLSCLT (SEQ ID NO: 155) VCGPVYCFTPSPVVVGTTDR (SEQ ID NO: 156) CGSGPWLTPRCLVDYPYRLW (SEQ ID NO: 157) LPALSTGLIHLHQNIVDVQYLYGVGS (SEQ ID NO: 158) GWRLLAPITAYAQQTRGLLG (SEQ ID NO: 159) TSLTGRDKN (SEQ ID NO: 160) PCTCGSSDLYLVTRHADVIP (SEQ ID NO: 161) LKGSSGGP (SEQ ID NO: 162) GIFRAAVCTRGVAKA (SEQ ID NO: 163) HLHAPTGSGKSTKVPAAYAAQGYKVLVLNPSVAATLGFGAYMSKA (SEQ ID NO: 164) ITYSTYGKFLADGGCSGGAYDIIICDECHS (SEQ ID NO: 165) ILGIGTVLDQAETAG (SEQ ID NO: 166) VLATATPPG (SEQ ID NO: 167) SVIPTSGDVVV (SEQ ID NO: 168) ATDALMTGFTGDFDSVIDCN (SEQ ID NO: 169) QTVDFSLDPTF (SEQ ID NO: 170) QRRGRTGRGR (SEQ ID NO: 171) PGERPSGMFDS (SEQ ID NO: 172) VLCECYDAGCAWYEL (SEQ ID NO: 173) PAETTVRLRAYLNTPGLPVCQDHLEFWE (SEQ ID NO: 174) VFTGLTHIDAHFLSQTKQ (SEQ ID NO: 175) NFPYLVAYQATVCARA (SEQ ID NO: 176) CMSADLEV (SEQ ID NO: 177) GGVLAALAAYCLS (SEQ ID NO: 178) FWAKHMWNFISGIQYLAGLSTLPGNPA (SEQ ID NO: 179) ASLMAFTA (SEQ ID NO: 180) GSIGLGKVLVDILAGYGAGVAGALVAFKIM (SEQ ID NO: 181) VNLLPAILSPGALVVGVVCAAILRRHVGPGEGAVQWMNRLIAFASRGNHV SPTHYVPESDAAARV (SEQ ID NO: 182) RRLARGSPPS (SEQ ID NO: 183) ASSSASQLSAPSLKATC (SEQ ID NO: 184) SSMPPLEGEPGDPDL (SEQ ID NO: 185) LSNSLLRHH (SEQ ID NO: 186) PDLGVRVCEK (SEQ ID NO: 187) PMGFSYDTRCFDSTVTE (SEQ ID NO: 188) CGYRRCRASGVL (SEQ ID NO: 189) EAMTRYSAPPGD (SEQ ID NO: 190) TPLARAAWETARHTPVNSWLGNIIM (SEQ ID NO: 191) RLHGLSAFSLHSYS (SEQ ID NO: 192) PPLRAWRHR (SEQ ID NO: 193) GGRAAICGKYLFNWAV