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Vibrio cholerae

Table of Contents
  1. General Information
    1. NCBI Taxonomy ID
    2. Disease
    3. Introduction
    4. Microbial Pathogenesis
    5. Host Ranges and Animal Models
    6. Host Protective Immunity
  2. Vaccine Related Pathogen Genes
    1. CtxB (Protective antigen)
    2. TcpA (Protective antigen)
    3. TcpF (Protective antigen)
    4. hemA (Virmugen)
  3. Vaccine Related Host Genes
    1. IgA
    2. IgG Fc fragment
  4. Vaccine Information
    1. Dukoral
    2. Mutacol
    3. V. cholerae CTB DNA Vaccine
    4. Vaxchora
    5. Vibrio cholerae hemA mutant vaccine
  5. References
I. General Information
1. NCBI Taxonomy ID:
666
2. Disease:
Cholera
3. Introduction
Cholera is an acute intestinal infection caused by ingestion of food or water contaminated with the bacterium Vibrio cholerae. It has a short incubation period and produces an enterotoxin that causes a copious, painless, watery diarrhoea that can quickly lead to severe dehydration and death if treatment is not promptly given. Vomiting also occurs in most patients. Most persons infected with V. cholerae do not become ill, although the bacterium is present in their faeces for 7-14 days. When illness does occur, about 80-90% of episodes are of mild or moderate severity and are difficult to distinguish clinically from other types of acute diarrhoea. Less than 20% of ill persons develop typical cholera with signs of moderate or severe dehydration. Cholera remains a global threat and is one of the key indicators of social development. While the disease no longer poses a threat to countries with minimum standards of hygiene, it remains a challenge to countries where access to safe drinking water and adequate sanitation cannot be guaranteed. Almost every developing country faces cholera outbreaks or the threat of a cholera epidemic (WHO: Cholera).
4. Microbial Pathogenesis
Cholera is transmitted via the fecal–oral route through contaminated food or water. Soon after oral ingestion, V. cholerae colonizes in the small intestine and produces virulence factors, including cholera toxin (CT). Acute secretory diarrhea mediated primarily by CT causes massive dehydration and a mortality rate of 20–50% if left untreated (Xu et al., 2009).
5. Host Ranges and Animal Models
Cholera can be modeled in an infant mouse model (Kirn and Taylor, 2005).
6. Host Protective Immunity
The adapted protective immunity against cholera is thought to be essentially humoral and predominantly based on intestinal mucosal antibodies, especially secretory IgA (sIgA), which is generally considered a correlation of protection for cholera (Xu et al., 2009).
1. CtxB
  • Gene Name : CtxB
  • VO ID : VO_0011270
  • NCBI Protein GI : 110264635
  • Other Database IDs : CDD:144824
  • Taxonomy ID : 127906
  • Gene Strand (Orientation) : ?
  • Protein Name : cholera toxin B
  • Protein Length : 104
  • Protein Note : Heat-labile enterotoxin beta chain; pfam01376
  • Protein Sequence : Show Sequence
    >gi|110264635|gb|ABG56901.1| cholera toxin B [Vibrio cholerae O1]
    MIKLKFGVFFTVLLSSAYAHGTPQNITDLCAEYHNTQIHTLNDKIFSYTESLAGKREMAIITFKNGATFQ
    VEVPGSQHIDSQKKAIERMKDTLRIAYLTEAKVE
  • Molecule Role : Protective antigen
  • Molecule Role Annotation : The immune sera elicited by CTB DNA vaccine were functional and protective against V. cholerae O1 infection in mice (Xu et al., 2009).
  • Related Vaccine(s): V. cholerae CTB DNA Vaccine
2. hemA
  • Gene Name : hemA
  • NCBI Protein GI : 12656010
  • Other Database IDs : CDD:178819
    CDD:133452
    CDD:144372
  • Taxonomy ID : 666
  • Gene Strand (Orientation) : ?
  • Protein Name : glutamyl-tRNA reductase
  • Protein Length : 419
  • Protein Note : glutamyl-tRNA reductase; Reviewed; PRK00045
  • Protein Sequence : Show Sequence
    >gi|12656010|gb|AAK00701.1|AF227752_2 glutamyl-tRNA reductase [Vibrio cholerae]
    MSLLAIGINHNTASVELREKVAFGPEKLSLALNQLSTSSHVKGGVILSTCNRTEIYCDVRSASKNKVIEW
    LSQFHQVSLDELKPSLYVHEEQAAIRHLMRVACGLDSLVLGEPQILGQVKQAYAEARENHAVNPATEKLF
    QKAFSVAKRVRTETEIGGSAVSVAYAACTLAKHIFESLADATVLLVGAGETIELVAKHLAGHHCKRMIVA
    NRTRERALSLAQQFGADVIALNEIPDYLAQADIVISSTASPLPIIGKGMVESALKARRHQPMLLVDIAVP
    RDIEPQVGKLNDAYLYSVDDLQSIVDSNIEQRKVEAIQAEAIVSEESATFMSWMRSLQAVDSIRDYRKQA
    NEAREELLNKSLQALAAGGDPEKLLIELSNKLTNKLIHTPTRALQTAAEQGEPAKLAVIRQSLGLDDLN
  • Molecule Role : Virmugen
  • Molecule Role Annotation : A hemA mutant is highly attenuated in mice and rabbits and induces protection from challenge with wild type V. cholerae in rabbits (Ravichandran et al., 2006).
  • Related Vaccine(s): Vibrio cholerae hemA mutant vaccine
3. TcpA
  • Gene Name : TcpA
  • Sequence Strain (Species/Organism) : Vibrio cholerae O1
  • VO ID : VO_0011271
  • NCBI Protein GI : 21616882
  • 3D structure: PDB ID : 1OQV
  • Other Database IDs : CDD:147867
  • Taxonomy ID : 127906
  • Gene Strand (Orientation) : +
  • Protein Name : TcpA
  • Protein Length : 188
  • Protein Note : non-toxic serogroup: O1; biotype: EVC
  • Protein Sequence : Show Sequence
    >gi|21616882|gb|AAM66403.1|AF512425_1 TcpA [Vibrio cholerae O1]
    IMGVVSAGVVTLAQRAIDSQNMTKAAQSLNSIQVAMTQTYRALGNYPATADAAAAAKLTTGLISLGKISA
    DEAKNPFTGGNMNIFSFSRNAAQNKAFAITVDGLTQAQCKTLITSVGDMFPYVAIKAGAAIAFGDLTDFE
    TTQADAAAGAGVIKSIAPASKNLDLTNIIHVEELCKGAAPFGVAFGNS
  • Molecule Role : Protective antigen
  • Molecule Role Annotation : Antibodies against TCP were able to protect baby mice against challenge with V. cholerae O1 of the classical but not of the El Tor biotype (Osek et al., 1994).
4. TcpF
  • Gene Name : TcpF
  • Sequence Strain (Species/Organism) : Vibrio cholerae O1 biovar El Tor str. N16961
  • VO ID : VO_0011272
  • NCBI Gene ID : 2614504
  • NCBI Protein GI : 15640854
  • Locus Tag : VC0837
  • Genbank Accession : AE003852
  • Protein Accession : NP_230485
  • Other Database IDs : GDB:5363132
  • Taxonomy ID : 243277
  • Chromosome No : I
  • Gene Starting Position : 898672
  • Gene Ending Position : 899688
  • Gene Strand (Orientation) : +
  • Protein Name : toxin co-regulated pilus biosynthesis protein F
  • Protein pI : 6.37
  • Protein Weight : 35844.42
  • Protein Length : 338
  • Protein Note : similar to SP:P29488 GB:L01623 PID:155281 PID:155284 PID:48417; identified by sequence similarity; putative
  • DNA Sequence : Show Sequence
    >gi|15640032:898672-899688 Vibrio cholerae O1 biovar El Tor str. N16961 chromosome I, complete genome
    TATGAGATATAAAAAAACCTTAATGTTATCAATCATGATTACATCATTTAACTCATTTGCATTTAATGAT
    AATTATAGTTCAACCAGTACGGTTTATGCTACGTCTAATGAAGCTACGGATTCAAGGGGGAGTGAGCACC
    TTAGATACCCTTATTTAGAGTGTATCAAAATCGGTATGAGTAGAGATTATCTTGAAAACTGTGTGAAAGT
    ATCTTTTCCAACCTCTCAAGATATGTTTTATGACGCATACCCATCGACAGAATCTGACGGTGCTAAGACA
    AGAACAAAAGAAGATTTCTCTGCTCGGCTTTTAGCTGGTGATTATGATAGTTTACAGAAATTGTATATAG
    ATTTTTATCTTGCTCAAACGACTTTCGATTGGGAAATACCGACAAGGGATCAAATTGAGACACTAGTTAA
    TTATGCTAATGAAGGTAAATTGTCTACGGCACTTAATCAAGAGTATATTACAGGTCGATTTCTTACAAAA
    GAAAATGGTCGATATGATATTGTGAATGTTGGTGGTGTTCCAGATAATACTCCAGTTAAACTACCAGCTA
    TTGTTTCTAAACGCGGACTAATGGGTACAACTTCTGTAGTTAATGCAATTCCCAATGAAATTTATCCTCA
    TATCAAAGTTTATGAAGGGACTCTTAGTCGTTTAAAACCTGGTGGTGCAATGATCGCAGTATTAGAATAT
    GACGTAAGTGAATTAAGTAAGCACGGGTATACCAATCTGTGGGATGTGCAGTTTAAGGTTCTTGTTGGAG
    TTCCACATGCAGAAACAGGAGTTATCTATGACCCTGTTTATGAAGAAACTGTCAAACCATATCAGCCTAG
    TGGCAACTTAACGGGTAAGAAGTTGTATAATGTATCTACAAATGACATGCATAATGGTTACAAGTGGTCA
    AATACTATGTTCTCAAATTCTAATTATAAAACGCAAATATTATTAACTAAAGGAGATGGAAGTGGTGTGA
    AACTGTATAGCAAAGCATATTCAGAGAACTTTAAATA
  • Protein Sequence : Show Sequence
    >gi|15640854|ref|NP_230485.1| toxin co-regulated pilus biosynthesis protein F [Vibrio cholerae O1 biovar El Tor str. N16961]
    MRYKKTLMLSIMITSFNSFAFNDNYSSTSTVYATSNEATDSRGSEHLRYPYLECIKIGMSRDYLENCVKV
    SFPTSQDMFYDAYPSTESDGAKTRTKEDFSARLLAGDYDSLQKLYIDFYLAQTTFDWEIPTRDQIETLVN
    YANEGKLSTALNQEYITGRFLTKENGRYDIVNVGGVPDNTPVKLPAIVSKRGLMGTTSVVNAIPNEIYPH
    IKVYEGTLSRLKPGGAMIAVLEYDVSELSKHGYTNLWDVQFKVLVGVPHAETGVIYDPVYEETVKPYQPS
    GNLTGKKLYNVSTNDMHNGYKWSNTMFSNSNYKTQILLTKGDGSGVKLYSKAYSENFK
  • Molecule Role : Protective antigen
  • Molecule Role Annotation : Antibodies generated against TcpF are protective against experimental V. cholerae infection in the infant mouse cholera model (Kirn and Taylor, 2005).
1. IgA
  • Gene Name : IgA
  • Sequence Strain (Species/Organism) : Oryctolagus cuniculus
  • NCBI Protein GI : 4063655
  • Other Database IDs : CDD:143182
    CDD:197704
    CDD:209398
  • Taxonomy ID : 9986
  • Gene Strand (Orientation) : ?
  • Protein Name : immunoglobulin heavy chain VDJC-alpha transrecombinant region
  • Protein Length : 306
  • Protein Note : Immunoglobulin (Ig) heavy chain (H), variable (V) domain; cd04981
  • Protein Sequence : Show Sequence
    >gi|4063655|gb|AAC98362.1| immunoglobulin heavy chain VDJC-alpha transrecombinant region [Oryctolagus cuniculus]
    METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGGSLTLTCTVSGFSLNTYPMQWVRQAPGKGLEWIGWMN
    NNGNIYYASWAKSRSTITRNTNENTVTLKMTSLTTEDTATYFCARYLSSHGYDIWGPGTLVTVSSDPVNT
    RPILIPLPCPILGPGEPVVIGCLIRGFFPLGPLSVTWNTSGENLTFPPVQSATSSLYTTCSLLRLPAEQC
    PEENSVACHVEHNYDKGQDVTVPSPPECQPPTPGPSDTTTCPCPCPSPSCGEPSLSLQRPDLRDLLLNSN
    ASLTCTLRGLKNPEGAVFTWEPTNGN
  • Molecule Role : Vaximmutor
  • Related Vaccine(s): Vibrio cholerae hemA mutant vaccine
2. IgG Fc fragment
  • Gene Name : IgG Fc fragment
  • Sequence Strain (Species/Organism) : Oryctolagus cuniculus
  • NCBI Gene ID : 100343867
  • Taxonomy ID : 9986
  • Chromosome No : Un
  • Gene Starting Position : 315920
  • Gene Ending Position : 352013
  • Gene Strand (Orientation) : +
  • Protein Name : Fc fragment of IgG binding protein
  • DNA Sequence : Show Sequence
    >gi|283557656:315920-352013 Oryctolagus cuniculus breed Thorbecke inbred unplaced genomic scaffold, OryCun2.0 chrUn0214, whole genome shotgun sequence
    CATGGGTTCCCTGAGAAGCTGGTGGACGCTGTGGGCCGGAGCCACCCTCCTGTGGGGTAAGTCAGACCCA
    GTCCCCATCTGTGTCTTTCTCCCACTCTGCCTGGGTGGCCCATGCCCAACTTGTGCCCCTCCAGGCACTC
    GCCTTCCGAGGCCTCCCCATGCCAGCTGGGATGGGAGAGAGGCCCCCAGTTCCTGCAGAGGGGCACGGCG
    GGCTCTGCCCAGGCTCACTCTTCTGGAGGGAAGCCACAGAGCCCTCGGCCCCCAAAGCCGAGGGCGCAAC
    AGAAACCACTGTCTTGGTTCTCTGCAACTCAGCTAAGCCATGGCTCTGAGTCTCCTTCTGCCAAGGTGAT
    GGGAACCGTCACCAAGGACATTCCTGGAGAGCTCTGGTGCCCAGTTCTCCTGGGGGAACCGCCAAGAGTC
    TTAGGTGAACCCGGAGGTCCCTTGACTCTTGACCCCCTGGGCCTGGGGCACACTGGGATGTCCTCCAAGT
    CTCCCTGAACTTGGCAAGTTGTCACTCCAGCGCCCCCAACTCTCTCTCTATCTCTCTCAGCACTGGGCAC
    TCTCTTCCTGGTAGGGGCTGTTGAGACATCCACCTTTCCCACAACCCCCTTCTTTCCTTTACCTTCTTCA
    CACAAACCCTCCGGGTCGTATCAAGACAAAAGTCACCCGCCGGCCGCGGAGTGCTGCCGGTTGGGACCCC
    CGAGGTGCCTCAAAACAATTTTGGGTTGAAGAGTTCACATACACATTCAGAGAGCCAGTTTCTCTTGAAC
    ATGGTAAGATCTAGCACTGAAGATAAAAATAAAAATAAAAAAAGGCCGCAATCCCTCCTGTCAGCCCCCT
    GCAACAGCAGGCAGCGAGCGCCCACTCTGCCTTCCACGTCGCCGCGGGACTGCGCGTCTGTGTGTCTCAC
    CGGCCCCCTCAGCACCTGAGAGCCCTGTCCAAAGAGTTTGGGCTTGTAGAAAAATGAAAGCCAGAATGGC
    TTGTAGGCAGGTGAGCGGTGCAGGAATAAGAACAAAGGCAAGAGAAGAGGAAAAAAAAAAAAGTTCCTGG
    CACAGGGCAAAGGGTTGGCCGACTGACCAGGCGGATTAGGTAAGTGGACCAACGACTGCATTTTCTCAAG
    GGTGGACCCAGGAGGCAGCTGTGGAGCCCAGGAATCCTGGGGGGCAGGAATTCCTCATGGCCTTCCTGCA
    GAATTACCAGCCCGAGTACAGCGCCGCCTCCCTCTACCTGCTCGTGTCCAGCCTATCGGAGAGCCCGGCC
    TTGGTCTCCGTGCTCAGCCAGGCCGACAAAGCCTCGCAGACGGTCACAGTGAAGCCAGGGGAGTCAGTCG
    TGGTCAATATCAGTGCTGCGGCTGAGATGACCGGCAGCAACATCTTCCAGCACGCGGTTGTGGTCCGCTC
    CGACCACCGCATCACTGTGCAGGCCCTCAGTGCCAAGCCCAGCACGGCGGAGCTGACCCTGTTGCGACCG
    GTCAGCGCTCTGGGCACCGAATACTTCGTGCTCACACCCCCGGGTACCTCAGCCAACAGCCTCAGGGAGT
    TTGCTGTGGTGGCCGGGGCGTCAGGTGCCTCGGTCAGTATCACCCTGAAGGGGGCAGTGACGTTCCAGGA
    CAAGATCTACCCAGCAGGCGATGTGCTGAGCGTGACCCTGCAGCCCTACGAGGTGGCTCAGGTACAGGGC
    GAAGTTGATCTCTCGGGATCGAAGGTCACAGCCAGTAACCCTGTGGCTGTCCTCTCGGGCCACAGCTGTG
    CCCAGAAACACACAAACTGCAACCACGTGGTAGAGCAGCTGCTGCCCACGTCTGCGTGGGGCACCCAGTA
    TGTGGTGCCCCCACTGGCCTCCCAGAGCCGCTATGATCTGGCCTACGTAGTGGCCAGCCAGGCCACGAAA
    CTGACCTACAACCACGGAGGTACCACAGGCTCCCGTTCACTCCAGATGGGAGGCGTGGTAGAGTTTGAGG
    TGCGGCCGTCCCGGCCACTCTACCTGTCCGCAGATGTGGGCATCCAGGTCCTGCTCTTCGGCACGGGGGC
    TATAAAGAATGACATGACCTATGACCCCTACCTGGTGCTGATCCCGGATGTGGCAGCCTACTGCCCCACC
    TATGTGGTCCAGAGCGCACCAGGCTCTATGGGTGTGGCTGTGCTGGTGGCACAGACAAAGGCTGTCAACG
    GGCTGACCATGGATGGAGACACGCTGAAGGCCACGCTCCCCTGGGTGGCTGTGCCAGGCAGTGAATTCTC
    ATATACTGAAGTGGACCTTGGCACAGCTAACAGGATTCACACAGTCAACGCCAACACCAACATCGGGCTG
    CTCACGTTCGGGCTGGGCCAGGCTATGGGCTACGGGACAGCAGCTTCCTGCGGCCAAAGTGAGTGATGGG
    AAATGGCCCCTGGCCCCCACCCACCTGCTCCTCCATGGCTTTCTGGTTCAATGGGGCTGTCCACCCTCAC
    CTCCATCCTCCCCGCCATCCTTTCTTGAGTCCAGGACATGGATGCCACTCAACTTCAAGGGATCACTTTG
    GGGCTTGGATAATCAAAGAGAGGAGGAATCGATGATCCATCTCCGTAGCTAACACTCACTGTGACACCTG
    GGTTCACTTCCAAATCTTACTTCTGTTTTAGCTTCTTCAGGGGCGGGCATTGTGGTGCAGTGTGCTGAGC
    TGCAGCTTGGAATGCCCACGTCCCAAATCGGAGTGCCAGTCTGAGTCCCCCCACCTCTGCTTCTACCCAG
    CTTCCTGCCAATGCATCCAGTGGGGGGAGGGGGAGGCAGCAGATGGTGGCTCAAGTACTTGGGTCCCTGA
    TGCCTATTTGGGAAACCCTGTTGAAGTTCTGGGCCCCTGGCTTAAGACTGGTCCTGTGCTGGCTGTTACA
    GGCACTTGGAGATTAAGCCAGCGGATGGAGTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTC
    TCTCTCTCTCTCTCCCTCTCCCTCTCCCTCTCCCTCTCTCCATCTCCCCCACTCACTCTCCTCTCTCCCT
    CTCTCCCTCCTCCTCTGCCTTTTAAGTAGATGAAAACAACTAAACATCTTTTAAAAATAAGCAAAACCAT
    CTCCACACCTCTGCCAGATTCCCCTATGGAGATGGGATTGCTATCCTATTCCCCTCATCCTACGAATGAG
    GCAACTGGGGCACTAAGAGTTTAAAAATAAGTTGCCCGGTGTCTCCGAGCTGCATGATGCAGCCCGGATT
    CCTAGCTAGACAACGTGACTCCACAGTCATTGCCACTGTGCTGAGCGGCCTCTGCCTTCTACTTTCTGCT
    CTTCAAAAGATCCCTCAGCCTTTAGAGCCTGGTGGGATGGCAGGGGTGAGGGGGAAAAGGGAGGGAATAC
    AATGAAGATGTCAATAACAGTTCCTGTCACTCCATCTGCACTGCCTTCCCTTCTGCTCAGCTGCTCTGTG
    TTAAACAGGGGGATCAGAAAGCCCAGGCCTGAGCAGCTCTGTCTCTGTGTGATGCCAGCCCTCAGTCTCC
    CCATCTCTAAAATGGGCAGCTATGAATGCACTCCTTGTGGTGAGAGAGACCCAGGACTCCTGCCCCTGTG
    GGCATTTCTTTTTATTTTTTCTGAGGCAGTGAGAGAGAGAGATTTCATCAGTTGGTTCATTCCCTTTGCA
    AAGGGCCAACACAGTGGGAGCCAGGAGGCAGACCTCAATGCAGGCCTCCCACATGGGTAGGGGAACCCAG
    CCCCACTGCCTGCCAGGGTCTCCAGCCAGCAGGAAGCTGTAGCCAGGAGCCAGAGGTGGGAACTGGCCCC
    AGGCACTCTGATGTGGCACGTAGGTTTCTGGACCATTGGGCTAATGGCCCCCGCTGGCCCTGGGTGTGGC
    TGACTCTGCTCCCACCCTCTTCCCCCCAGGCCTGGTGTCCTCGGAGGAGCCCTCCTGTGAAGGCGTGACG
    TGCGCGGCAGGGCAGCAATGCCAGGTGGTGGACGGGAAGGCCGTGTGCGTGGCAGAGTCCACGGCCGTGT
    GCCGCGCCCAGGGCGACCCCCACTACACCACCTTCGACGGCCGGCGCTATGACATGATGGGCACTTGCTC
    CTACACGATGGCCGAGCTGTGTGGCTTGGACGAAACCCTGCCTGCCTTCAGCGTGGAGGCCAAGAACGAG
    CACCGGGGCAGCCTCCTGGTCTCCTACGTGGGCTTGGTCACCGTGCGTGCCTACAACCACGACGTGACAC
    TGGCCCGCGGGGAGGTCGGCTTTGTTCGGGTGAGTGTCCGGGGGCTTGGGGGCTTGGCCCCCTGGGAGCC
    GTGAGTCTGAAGGCAGAGGCAAAGGCCTTTCTGTGGGCTGGGGAGTGGGAGACGGGGAGCGGGGGTTAGA
    AAACAATAGCTGAGCCTTAAAACCTTTCAATGCCACGTCTAGAAATTCCAAAGATGCTCAGAAAGACAAT
    TAGAAAAACAAATATGCCAACATGGTGTACAAATGAGGAATTTCTTTCTTTCTTTCTTTCTTTTTTTTTT
    GCTTTAAAGATTTATTTTATTAATTTTAAAGAGAGTTACAGAGAGAGGTAGACAGAGAGAAGAGAAAGGT
    CTTCCATCCGCTGGTTCACTCCCCAGGTGGCCACAACAGATCGGAGCTGTGTTGATCCAAAGCCAGGAGC
    CAGGAGTCTCCTCCAGGTCTCCCACATGGGCGCAGGGGCCCAAAGACTTGGGCCATCTTCTACTGCTATC
    CCAGGCCATAGCAGAGAGCTGGATCAGAAGAGGAGCAGCTGGTACTAGAACTGGCGCCCATATGGGATGC
    CAGCACTTCAGGCCAGGGTGTTAACCCACTGCGCCACAGCGCTGGCCCCATGAATGAGGAATTTCTTGGG
    ACCAAATCACTGACCTATTTAAGTGCCCCAGTTGGTTCTTAGCTCTTAATGCTCACAGCAACTCTGGGAG
    TAGGCCTTGTTATTACGGACATGCACAGAGGAGGGTACAGGGTGGGAAAGGTGAGTGATGCCCCAAGCAC
    TGGGAGCTGTAAGAGCTGGCGCTGGGAACGCAGGCAGACTGGCTCCCAAGTCCCCGTTCCTCGTCCCGAG
    TCTCTCTCTTCCACTGCTTGTCCGTGCTGTGCCGTTCCGCCAGTACCAGCAGCATCTGGAGCAATGACTT
    CCTTTTTTTTTTTTTTTTTTATTTTGACAGGCAGAGTGGACAGTGAGAGAGAGAGACAGAGAGAAAGGTC
    TTCCTTTGCCGTTGGTTCACCCTCCAATGGCCGCCGCGGCCGGCGCGCTGCGGCCGGCGCACCGCGCTGA
    TCCGATGGCAGGAGCCAGGAGCCAGGTGCTTTTCCTGGTCTCCCATGGGGTGCAGGGCCCAAGCACCTGG
    GCCATCCTCCACTGCACTCCCTGGCCACAGCAGAGAGCTGGCCTGGAAGAGGGGCAACCGGGACAGAATC
    CGGCGCCCCGACCGGGACTAGAACCCGGTGTGCCGGCGCCGCTAGGCGGAGGATTAGCCTAGTGAGCCGC
    GGCGCTGGCCTGATTTCCTTTTTTGTCACGTTATTATGAAAATGTTAGAGCATCCAAAGCAGGTGAAATC
    ACCAGACAGTGAACCTCGTGGGCCCAGCGCCTCAGTTCCAAGCTTTTTGCTATTCTTGGCTGATTAGACC
    TCTGTCCACACAGTCTGCCCTCCCTCCAACAGCCGCTCTTGTCTATGTGCCTGGAAGTAAGCTCTGCACA
    CCAGCTCCACTTTCTGTAAGGTCTCCTCATGCAGATCACCCAGAAGGGTGCACTATTGTAAAACTCCCCC
    GTTTTGTTAATTTTAAGATTTTTAAGAAAACATTTAGTTTGTAACAGATTCAATATAGCTTTTAGATATG
    ATTCTAAGGATATAATGACATTCCCTTCCTCCTTTTTCCATGTTTTCAAGATTAAACTTACATATCACAA
    AATTCACAAATTGCAAATGAGCAGTTTGCTGTTTTGGCAAATGTGTAACCCAGAGTCCCATTAAGATACA
    GAATATTCCCATCAACTCAGAAAGTTCCCTCCCGAACAACCCCCAGCCCACTGCACAAGGCACAGTTCTA
    ATTTTTTTTCCCCACCATGATCTACCGTGGATCAGTTTTGCTTGCTTAAGAATGTCCAATAAAAGCAGGC
    ACACAGCTTAGCAGGCAAAGAATTCACATAGCACAAAATAAAAGGGGTAAGATACAAAAGATCTTGTTTC
    TATTCCAGTCTTCATCTACTCCCCTCCTCCGCCCTCCCCCCCACCCTCCCCCCACTCCTTACAGATAACT
    TCTCCTATTGGTTTCTGGAGAATTCATCTAGAGTTTCTTCCTGCCAATAGAAGCAAATACAAGCGGATGA
    CTTACCTTTCCCCTTTCTTAACAAAATGTACCCTACATGCTCCATTCTGCACTTGACCGTACCTTCTGGG
    CCCCTTTCCCTATCAGCACGTAGGGAGCCTCCTCTCTTCTTTTGGGTGCGGGGATGGGGGAGCTGCACAG
    TTCTGCATGGGATGAATGTCCCAGAGTTCACTGAAGCAGCGTGGGAGGGATGGATACTGTTCCATCTTGC
    AAACAGTGCTACAATGTATATTCTTACACCTGCTCAGCCTGTGAGTGTGCAGGTGGATCTGGGAGACCAA
    CAACCGGGTGTGTTACAGCAGGTGTTCTAGCGGGATAGGGCACAAGCTCAGGGGACTCCCGAGCCGCTGC
    AGTTGTGTGCAGCTTCTCATGGATCTTCTGTCAGCTCCTCACAGAGGTCACTGACTTTCTCAAGAGTTGG
    CGCTCCTGGTAGAATCGTGGTAGGATGTGCACAAAACATCGTGAGAAGGAGAGAGAGATCATGAAACTGT
    GACTTCTGCATGGTGGCATTATCTTTTTTCATTAAAGTATAAAAGCATTGAAAAGTAGTTGGAATAACAA
    NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN
    NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN
    NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN
    NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN
    NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN
    NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN
    NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN
    NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN
    NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN
    NNNNNNNNNNNNNNNNCCCCTGGACTGAGAAGCTGTGAGCAGGGGTCCCTAGCACTGGCTGGCGTGTTAC
    ATGGATGCATAGTAGGACTCCTGGTGGCTTTGCTGCAGGCCTGGGTGCGTGCATTCTGTCTTCTCCTCCT
    GCCATTGCTGAGGCTGTCCCCTCTGCCTGCTGCTCCTGTTTTTGGAGCTCTGGCACTTGGCTAAGACGTT
    CTCATCCCTCAAGTCTCAGCTCTAACATAGCCCCGGACATGTGTGAGGAGTGAGAAAGAAGTGTCTGCGG
    ACACACCGAGATGCTCCTGGCTCCTGGTATCTCAGGCAGCCCTGGCTGCCACAGCAGGGGTGGCTTCTCA
    ACAGCACAAGCTTCTAGCTCTGCTCTACAAGCTGGGAGCCTGAGGTCAGGGTGCCGGCATGGTTGGGTTC
    TGGTGAGGGCCTGCCTGCAGCCTGCAGACTGCAGGGTTCTCACTGTGTCCTGACCAGAGAGCGCTCTGCG
    GTGACATCATTCACCCATTGTGCACCTGCTGTTTTTACCAGACACAGTTTCTGCCTCTGTGGATAAAGCA
    GCAAAGTGCCTGGGTAGCGCAGATGTCTGGTGGACTCAGACTGACAATAAACAGGATGAATTTGCAAGTT
    ACTTTTTAGAAGGCAAGAAGCTATTCTTAACAAATGAAACATGTCAGGGGAAAGACATAGGGAATGGAGA
    GGGCTCGCCATGTGAAACAGGGCTGGGATGGGCATTTAGCCTGGCAGTCAGGATGCTGGTTCAGACGCTT
    GCAGCCCACACTGGAGTGCCTGGGTTCAAGTCCCAGCTTGGGATCCTGCTCACAGCTTTCTGTTCATGAA
    GACCCTGGGAGGCAACGTGGGTCCCTGCCACCCATGAGAGAGACCTGGATTGAGTTCCTGGCTTCCAGCT
    TTGCCCCAGCCCAGCCCCAGCTGTTGCAGACAGTTGGAGAGTAAACCAACAGATGGGAGTTCTCTCTCTT
    TCTCTCAAATAAATAAAAATGTAAATAATTAAAATAATAAAAAGAGAGAGTGGCCTCACAAATATGGGAA
    CAGCTGAGCAAGTGTTTTTTATTTATTTGAAAATAAATAGGAGAGAGAGAGAGGGAGAGAGAGATAGAAA
    GAGATCTTCCATCTGCTGATTCATTCCCCAGATGTCCACGACAGCTGGAGCTGGGCCAGGCAGAAGCCAG
    GAGCACCTTGAGGCAGGAAGCCCAGGGACATCCTCCACTGCTTTCCCAGACACATGAGCAGGGAGCTGGA
    TTAGAAGTGGAGTAGCCACGACTTGAACCCGTGCTCGTATGGGATGCCAGTGTTGCAGGCGGCAGCTTAG
    CCCCTTATGCCACAACACCAGCCCTCCCTGAGCAGATATTTTCTGTGAGCCAAGGAAGTGAGCCACATGC
    TCATCTTGGGCAAGATCACTCCTGGCCACAGGAAGTGGGAGAGCAGAACTGTGGAGGCACAGAGGGTGGC
    AGTAACAAGGAGGGATCCCAGGACAGTGAGACCCGGGCCAGGGAGCAGCCAGCCCACCCTGGGCTCTGAC
    CACCCCACCTCACCCCACCTGCAGATCAACAACCAGCGTTCAGGCCTGCCAGTCTCCCTGAGCAAGGACC
    GCCTGCGCGTGTATCAGCGCGGGACCCGGGCCGTGGTGGAGCTGGACTTCGGGCTGGTGGTCACCTACGA
    CTGGGACGCTCAGCTGACCGTGAGCCTGCCTGCCAAATTCCAAGACCAGGTGTGCGGGCTGTGTGGCAAC
    TACAATGGCAACCCCGCCGACGACTTCCTCACACCCGACTGGGTACAGGCCTCGGATGCCCTGGAGTTTG
    CCAACAGCTGGAAACTGGACGATGGGGATCCCCTGTGTGATGATGGTTGCCAGGGCAACTGTCCCTCCTG
    CACCGCAGCCCAGACCGAGCAGTACAAGGGCGACCATCTGTGCGGCATGCTGACCCTGGCTGAGGGCCCC
    TTTGCCCCCTGCCATGAGGTCCTGGAACCCCAGTCCTTCCTAGATGATTGTGTGTACGACCTGTGTGTGA
    CGGGCGGGGAGCGGCTCAGCCTGTGCCGCCTCCTCAGCACGTACGCCCAGGCCTGCCAGGAGCTCGGTGT
    CTCTGTCACGGACTGGAGATCGTCAGCCAGCTGCCGTGAGTGATGCCACTAGGGGCGCCCGGGGCACATG
    GGGATAGACAGGCGGGCCTCTTGGGTCTGCTTAGAATCTGAGCCCTTAGTTTGCTTGAGACTAATGCCGA
    GCCTATCTGGGGCACAAGGATGGCCAAGACAGCCAGGGTCACGGCAGGCATAGCAGTATACGGCGACACC
    CTGGAGCCGTCAGGCTGGGGGTGGCAGAGAGGTTGAGGCTGGGTTGGGGAAGTTCAATGGCATTGCAGGA
    GACACACAGTTCTTGATCTAGATGAGGGGTGTCAGGAAGTGTTTCCTAAAAAAAGGGGTGCCCAAGTTCA
    AAGCCACAGGAAGAAGTAGGAAAAAAGGAGGAGAAACTGGGTTCCTGGGGGACAGCACGTAGAGGCTTGG
    CAGGAGAGGAGATCTGCAGGATCCCAACAGAGAATTGTGCAGCCTCTTCCCACTCACCACCCTTGTGTGA
    CTCGCTTCTCCTCCCTGGATCAGGTCCAAGCCTTTTGGCCAGGTGTCATGCACTTCAGTCACTCACTCAT
    TCAGTAAATGAGCCTTCCTTGGGCCCCCTGCCTGGCCCTGCATCACCAGTGGGTTCGTCCATCTCCCTTC
    CCCCTTTCATTTCCACATCTGCCTCATTTCTGAGCACCTGCTGGGTGCCGGGCCCCTGTCCATGGTGCTG
    AAGACTCAGCAGTGACTGAGGCAGACCAGGTCCCCACTGCCACAAAACTTACGTGCCAGGGAGAGAAGGG
    GGAGACAGACAGCACGCAGGTAAAGTGTGAAATAGCTTCAGAGAGCAATAGGAGGAAAGTTTGCACGGTG
    GAAGTGGCTGCGAGACTCCTAGAGCAGGGATGGCCTTTGTGAGCAGGTGGCATTGGAGCTGAGATGGGGC
    GGGGGGCAGGCAAGGCAGGCAGCAGTGATGTTTGTGGAGCACTTCCACATCAATAACCCATTTAATCCTC
    ACAACAGCTCTGTGAGGCCGGTGCTATAGCATCCTATTTACCAACAGGGAAACCAGACAAGGGGAGATGG
    GAGTCATTTGCTCACCGTCACACAGCTAAGAAGGAGCAGAGCTGAGATCTGAACCCAGGCTGTCTGGGCT
    CCAGTTGGCATGCTCTGTGGATGCCGTGCTGAGGGAAGGGTACACCAGGCAGAGGGAACAGCCAGTGCAA
    AGGTCCTGAGGACGGAGGCCACTGTGACTGGGGCAGAGAGAGAGGGAGAGGAGATGAGAGCAAGGGAGAG
    GAGATGAGAGCAAGGGAGAGGAGATGAGAGCAAGGGAGAGGAGATGAGAGCAAGGGAGTGGTGGAACAGA
    TGGTGCAGGGCCTTGGGGTGACTGATGGAACCTCAGGAGGGCCCTAAGAGGGGACAAACCTGATCTGATT
    CAGGTGTCCCTGGCTGCTCAGGGCAGGCAGGTGGGAGTCCAGGCAGCAGGCAACATGCTGGATAGGTTTT
    GAATATGGAGTTCCCAGGACACACTGGCAGGTTGGTTGTCCAGTGGATGGCAGTGGAGTGGGAAGGGAGC
    TGCTCAAGGCAGAGCTGGGGGTTCGGGCCTGGGCCGTTGTCATTGACTGAGAGGATAGTGCTGAGTTTGC
    AGCCAGCAGAGGGGGGTTGCTGGGGGAGCCTGGACACTTGGCCTGACCCACCCTCATGTCTCCCCTGCAG
    CCTTGTCCTGCCCCGCCAACAGCAGCTATGAGCTCTGTGGCCCCGCCTGCCCCGCCACCTGCAACTCCGT
    CGCAGCACCGTCTAACTGCTCTGAGCGCCCGTGCGTGGAGGGCTGCGTGTGCCTTTCGGGTTTCGTGGCC
    AGCGGCGGCGCCTGCATCCCTGAGTCATCGTGCGGGTGCACCTTCGAGGGCCTCCTACTGGCACCTGGCC
    AGCAGGTATGGGCTGACACCCTGTGCAAACAGAGCTGCACCTGCGATGGCACCACCCACCAGGTGAGCTG
    CCAAGACACGCAGGGCTGCCCGGAAGGCGAGCGCTGCCGCGTGGAGAACAACCTCCTGGGATGCTACCCT
    GAAAGCTTTGGTAGCTGCCAGGCCTCTGGGGACCCGCACTATGTGAGCTTTGATGGCCGGCGCTTCGACT
    TCATGGGCACCTGCACCTACCTGCTGGCGGGCTCCTGTGGCCAGAACACAGCACTGCCCAGCTTCAGCGT
    GCTGGTGGAGAATGAGCACCGGGGCAGCCAGACCGTGAGCTACACAAGTGCCGTACAGCTGAAGGTCTAT
    GGGGTGGAAGTGGCCGTGAACCGGAAGTACCCTGGGCAAGTGCTGGTGAGTGACATGGGCCCAGAGCTGG
    GCAGAGGGGAGGGAGACCCCCGGGATGGGAGTTGGGGCCTGCTCCTCCTGGCCTGTGTGCCTTAGTCTTT
    CACTGCCTGAGTTTTGTCCCCTGTTGAGAAGCATGAGTGGGGGCAGTTCCCGGGCTGGTTGTGGGGACTT
    GGGGAGTTGGTCGTTGAGTGGTCTTTGAAAGAAGCCTGGGGGCCTGGCAGGAGCTCAGCAAATGTTGGCT
    ACTGCTTATTGTTGTTGTTGTTATGCACACTCGGAACTGTAGACCCGTGCGTTTTCTGTAGGATGCTGGT
    TTTTCAGGGTGCAGGTTGACATGTCGGGTGACAGGTGAGATGCCGGGAGCTGGAGGGGAGTGGATCACAG
    AGGTCCTTACCCGATGTCTCCAGGGATGCTGGTGGGGAAGGCCTCCCAGGGGCCCCAATGGTCCCGGGTT
    TCTGTCCAGAGGATCCTAGAGGGACTACTGCCCAGTGGGAGCCAAGGGCTACTGGCTTTGTGTTAGAAGG
    TAGACATGGAGACGTGGGACTGTTGTGGCTGGTATTTGGTACTGAGCAGTGGCCTGTAGCCTGGGGAGAG
    GGGTGGATGATGTGTCCAACACCACTCTAAACCCTTCATACATCTTAACTCATCACCCTCACGACAACCT
    CGGAATAAAGGAAATGCTGCCCCCAGAGAACACTCTAGAGAAACGGGACAGAATTTTGACTGTATTTCTA
    GTCACTGCTCTGAGATGACACTTGGGCTGAGGCTTGGAGAATACCAACCAACACATACTGGGTTAATTTA
    ATGTGCTGTATCCATATGCATCAACCTGTTTAATCTGTACCACAACCCTGTGAAGTAGCTGGTCTTCAGT
    GAGACTGGGCGGGGCTTCAGTGAGGATGGGCGGAGTTCGGCGAGACTGGGCGGGGATTCAGTGAGGCTGG
    GCGGAGTTCAGTGAGGCTGGGCGGAGTTCAGTGAGGCTGGGCAGGGCTTCAGTGAGGCTGGGTGGGGCTT
    TGGTAGAGTTGGGTGGGGCTTCGTGTGCTCAAGATGCCCGCCTGCCTGGAGTGGCAGGAGTTGGGGGTGG
    GCCATACTGGGGGGTTAAACTGGGGTTCTTTCAGGCCATTGTAAAGGGTTTGGATCAAAGCTGAACCTAA
    CAGGTGAGGTGGATGGAAGTGGTCCCGGGAAGAGCGATGAGGGCATAGCAAGTGCAGAGGTCCTGAGGTT
    GGGGATGGGAATGCATTTGATGTGCCCAGAGACACAACAAGAGGCCAGAGCGGCTGGGGCTGAGTGAGTG
    GTGTGGACACAGGAGTGGACAGGGCAGGGGTCAATCAGGACTTTATAGGGAAGGGGCCTGGATTGAAGGC
    AAATCCCAAAGGCGGGGAGGAGGGGGTAAGTGTGATGATCCTGAGGCCAGGCTGAGCTGGGGCAGCTGAG
    GGCTCCTGAGCAAGCCCACAGGGCTGGAGCAGAGGGAGGGGCAGAGTGGGAGGAGGGAAGCTCAGGGGGT
    GGCAGGGAGACAGAGCAGGCAGGCTTTGAGGGCCCTGAGTCAGAGGTTTGCATTTAAGCTGATGCCTGAA
    GAACCAGGTCAGTGGACGGCGTTCCAGGCAGAAGGAAACAGCAGGTGCCAAGGCCCTGAGGCAGAACTGA
    GCATGTTACCTTCCAGAGAGTAGCAAGGAGGCCAGGGAAGCTGGAGCCAAGTGGGAGGGGGGTGAGCCAT
    GGGGCCAGGAATGCCTGGCCTCTGCACCCTCCTGCCTCTCCCCCCAGGTGGATGGCGTCCTGAAGAACCT
    GCCCTTCCAAGCAGCCGATGGGCGGGTGCAGCTGTTCCGCCAGGGCAACAATGCTGTCGTGCGCACGGAC
    TTTGGCCTGACTGTCACCTACGACTGGGACGCCCTGGTGACCGTCAAGGTGCCCAGCAGCTACGCGAAGG
    CCCTGTGTGGACTCTGTGGGAACTTCAACGGGGACCCCAGCGATGACCTGGCTCTGCGCGATGGGAACCA
    GGCTGCCAATGCTCTGGACTTCGGGAACAGCTGGCAGGAGGGGACGAGACCTGGCTGTGGGGCGAGTGAC
    GCCGGGGACTGTCCCACGCTGGACTCGCAGGTGACCCAGCAGCTGCAGAGCAAGAAGGAGTGTGGGATCC
    TTGCTGACCCTGAAGGACCCTTCCGGGACTGTCACAAGAAGCTGGACCCCCAGGGTGCCTTGCGCGACTG
    TGTGTATGACCTCTGCCTGCTGCCTGGCCAGTCTGAGCTACTGTGTGATGCTTTGGCTACATACGCTGCT
    GAATGCCAGGCTGCCGGGGCCACCGTGGAGCCCTGGAGGAGCGAGGAGCTTTGCCGTGAGTACCAGAGTG
    GCGAGGATGTATGTATGCGTGAGCATGTCAATATCATTCATTCACTGAATCTTTAGAACAGCGCTGTGAT
    GCAGGGGCTGTGGTTCTACTCACTTAGGAGATGAGGAAAGTGAGGTTCAGCAAGGCAGGGCTGCAGGGTC
    ACCACAACCAGCAAGTCACAGATGGTAGGCGTGGCCGCCAATGTTTGTGAAATGACAGGTGACATCCAGC
    GGCCGCACGTCTGAAGCCCACGTGGCAGCTGTCACTCAGAGGGCATCAGCGGTGCTGCCTTAGAAGAGGC
    ACGGCCCCCATCCAGGTCCTCCTGGTCCCCAGCTGGCCTGCTCCACTCACCCCACCTGCCAGGCCCCTTG
    GGCAGCGCGTCTGAGAGCCTGGCTGTGGATGCGGGTGCAGGGATGACCTGCAAACGTTTTTGCTCACCTG
    TGCATTTGGAAAACCACGCTTCCCCTCACCTGATTTTTTTAAAAGTTTATTTGAGAGGTAGAGTTACAGA
    CTATGAGAAGGAGAGACAGAGAGAGAGGTCTTCCATCCATTGGTTCACTCCCCAAACGGCCACAACAGCT
    GGAGCTGAGCCCATCCGAAGCCAGGAGCCAGGATCCTTTTCTGTGTCTCCCACACAGGCGCAGGGGTCCA
    AACACTTGGGCCATCTTCCACTGCTTTCCCAGGCATAGCAGAGAGCTAGATTGGAAGAGGAGCAGCCAGG
    ACCAGAATCGGTGCCCATATGGGATGCCGGTGCCTCTGGCAGAGGATTAGCCTACTATGCCACAGTTCAG
    GCCTCACCCTCACCTGATTTTTAAAAATCTTGGGATACAATGTACATATTCAAAAAGACCTGGGTAAGGG
    AACCACTTGATCAGTTTTTCAGTAAGAGAGCGTATCTGAGTAGACAGCCCACGTTCAGAGAAAGAACAGG
    GGCGGGCGTTTGGCACAGTGGTTAAGATGTCACTTGGGATTCCTGTATCCCATATCATAGTGCCTGGGTT
    CAAGTCCTGACTCTGCTTCCGACACACCTTCCTGCTAATGTGCACCCTGGGAGGCAGCAGTGACAGCTCA
    AGTGCTTAGGTCGCTGCCAACCACATGAGAAACCCTGATGGAGTTCCTGGTTCCTGGTTTTGACCTGGTC
    CATCCCTGGCTGTTTCAGGATTTGGAGAGTGAGCCAGCAGATGGAAGATGTCTCTGTCTCTTTGTCTCAC
    TGTCTCTCAAATAAAAATGAAAATAAATAAATGTACAAAAATTTCAAATGAGCATACCAAGACCCCCATC
    CCAAGAGGTAACCAATATTTTGACTTCTAAAATTGTTGAACTTCATATAAATGGAAACATACATCATTAG
    CTTTCTTCTTTGGTGTAAATAATCACAAAAGATATAATTCCCAACAAATAGTAACTTTTTACTTTTAAAA
    TACATTTTATTATGGAAAAATTCCAACATACCCAAAAGTAGACCAGGATGATGAACCTGCATATATCCAC
    CAGAAAATTGCTACCATTATTAATATAATGTTGACATCTTAGCAGGCAACTGTTACTGATGTAACTCTCT
    TCAATGTATTCAACAGAGACACAGTACACAGTAGAGCCCACCACTGCCCCCTGCAGATTCCATGAGAAAT
    GGGTGGATGCCTTCAACCGTCCATCCACCCGTCCGTTCACTGATCAAATGCACTCGTGTACCATATAATG
    GTGTCTCAGTCAGCAGTGGGCTGCATATACGATAGTGTTTCTGTGAGACTGGCGGGGCCTTCACTGTGTT
    AGTTTGTGTTAGGGCACTTCATGGTGTTCACACAACTAAACTGCTCAATAATGCACCTCACAGAACATGT
    GCCTGTCATAATGTATTTGTTGGCCCTGTGCCACATCCCAGGCAGTAGGGGTATGACAGTCCTTTTTTAA
    AAGATTTATTAGAAAGAGTACAGAGAGAGAGAGAAAGAGACACTGGTTCACTCCCCAAACAGCTGCAACA
    GTCAGGTCTCGTCTAGGCCAAAGCCAGGAACCAGAAACTCCATCCAGATCTCCCATGTGAGTAGCAGAGG
    CCCAAACACTTGGGCCATGCTCTGCTCTTTCCCAGGCACCCAGCAGGGAGCTGGATCCGCAATGGGACAG
    CCAGGATTTGCACTGGCGCTCCAATATGGGGTCCGGTGTCGCAGATGGTGGCTTAACACCCTGCACCACA
    GTGCTGGCCCAGCAGTGAAAGCCTCTGTCTTCCTAAACAATGATTATTTGTTCTAAAAGAATTTTTAAGT
    GATTTTTTACCATTTGCTTATTCTTTATTTGAGGGAGGGAGGGAGGGAGGGAGAGAGAGAGAGAGAGATC
    TCCACTGATTTACTCCTCAAATGCCTGCAAAAGCCAGGGCTGGGACAGGCTAAAAGCTAGAAGCCTGGAA
    CCCGGTCCAGGTCTCCCACATATGTGGTAGGAACCCAACCGCTTTAGCCATCACCACTGCCTCCTAAGGT
    GCAAAGCTAGGATTTGAACCCGGGCACTCCCATGCGGGGTGCAGGCGTCCAAAACAGGAGCTTCATCATG
    GGACCAAGTGCCTAACCTAAAAGAGATCTTTCTTTTTTAAAAATGATTTATTTATTTGAAAGAGAGTTAC
    AGAGAGAGAAGGAGAGACAGAGAGATCTTCCTTCTGCTGATCCACTCCTCAAATGGCTACAACAGCCAGA
    GCTGCACCAGGCCAAAGCCAGGAGCTAGGAGCCAGGAGCCAGGAGCCAGGAGCTTCTTTGAGGTCTCCCG
    TGTGGGTAGCAGAGACCCAAGCACTTGGGTCATCCTCCGCTGTTTTCCAGGCACATTATCAGGGAGTGGG
    ATCTGAAGTGGAGTGACGGGGACTCAAACCGGTGCCCATATGGGATGCCAGTGTCAAAGGAGGTGGCTTA
    ACCCACTGCGCCACCTGCTGGCCCCAAAGATATCTTTCCATGAGACGAATGGGACTCTGCTTCACCAGTG
    TTTCACACACATTGTTAAAATGAGGCCGGGGCCCCCATCCAGGCTGTCCCAGGGCGCACTTTCGCAGGAA
    CAGGATTTTAAGCGGGTGGGGGTGGCCGGAATCCTGGCGAGACCTCTGTCCACTAGTTGAATCGCTTCTG
    AGTCACAGGGAAGGAGCACAGGACACTAGAAAATCCATGGGTGTTTTTGGTGTGCATGTGATTTTTGAGC
    GGCCGATTCTATCAGGCCCTTATTCCATCTTTTTGGGAGCAGAGAACTGGAAGGAATTTTTTGCCCATAA
    TGATGCATCACCCTTTGTCCTCACAACCTTAGTGACGTTTGCAACCATGTCCCTTTCTGTCCCTGCGAGT
    TCTCTCACCCCAGGGCGGCACTCCGGGGTGAGATTTGGGAGGAGAGGAGGCTGCACTGTTCTCCCCTGTC
    AAGTGGGAGCACGTGCTTGGGAAAGGACACTGGGATGCTGAGAAGCGGGGATGCCCCCTGTGCCGGCACA
    TCTCAGGCCGCCATTTAAGGAAGGGCCCGCATGGCGCTAGCTGGCGCTGGTGTAACCAGGCTCTGTTCTG
    GGGGCTTCATGTCGTCTTTGACTCCTCACTGTCACCCTGTGGGGCTGACTCTGTCCTGTTTCCATTGTAT
    AAGATGAAGAAGTGCCCAGAGATGGTGAGTAACTTGCCTGAGGTCACCCAGCATAGCACAGAGACTTGAG
    CCCAGCAAGTGTGTCCTGTGTCCTGTGAATTGCCACACTCGGTGATGCCTGTGCAAATGGACACTCTCTT
    ATTTCCTTTAACAGCTCTTGGCCCTTGCACCTTCAGAAGTTCTAGAAGGAGCAGGGCAGGGCCTGACCCT
    ACGCCCCCCAGCCTGAGCTTCTGTGGTCATTAGAACTATCTTCTGCCTCCTGTCACTCTTCATTTTTTCT
    GAAATATTCTAAAGCAAATTCTAGACATATGAGCTTTTCTATAAATACTTCAGCAAGTGCTTGCTATTCA
    GTGACAGAAAGGGGCTTTTTTTTTTTTTTTAAAGAAACTTCATTTATTTGAAAGGCAGAGTTACAGAGAG
    GTAGAGGCAGAGAGAGAGGTCTTCCATCTGCTGGTTCACTCATCAGATGGCCACAATGGCCAGAGCTGCG
    CCGATCCAAAGCTAGGATCCAGGAGCTTCTTCCGGGTCTCCCACATGGGTGCAGGGGCTTAAGGACTTGG
    GCCATCTTCCACTGCCTTCCCGGGCCACAGCAGAGAGCTGGACTAGAAGAGGAGCAACCGGGACTAGAAC
    CCGGCGCCCATATGGGATGCCGGTGCTGCAGGTGGAGGATTAACCTAGTGTGCCACTGTGCTGGCCCCTT
    TTAAGTCATTTTTATTCTGTAAAAACTTCCTTCCTTTCCCCCCAACACATGTGGGACTGCAAAAAAAGTT
    CATGGGAAATATGTATTATGAAAATAAAAACTGCACTCAAATAAGCTTTTCTTTTAATTCCACCTTCCAC
    GACCCTTCTGAAATGCCCTTATATCATTATGAAGTTTTTTAGATGTAAAGAAAAGTTGAAAGAATTTTAC
    AGTGATTGTCAATACCCCCCCAGCCCATGCTCCACAACCTATTTGCCCTCTACCTGCTGGCTCATTAGCT
    ACCACTGTCTACCCCCTTGCATCAGCCAGATTTTCGTCGCTATAGTGAAACACCTGGGGTAGGCATCTTT
    ATAAAGAGAGGAGGGTTATGTGGGGCCGCTGTTCTTGAGGTGCAAGGTGTAGGGGCTGCATCTGGTGAGG
    GCTGAAAGTAGCATGGGACATCACATGACAGGAGCCGGCCAGCATACTGGCAGCAGCATTTCCCACTTCC
    CCTCTGCTCTTTGGTTCTGCTCTGAACTGGCTGTTGGATCTAGAACCGTGCTGTGGGGCTGGCATTGAGG
    TGTAACGGGTGAAGCTGCCGTCTGCAATGCCAGTGTCCCATGTGGGTGCTGGTTCAAGTTCTGGCTGCTC
    TACTTCCAGTCCAGCTTTGTGACATGGCCTGGGAAAGCAGTAGAAGATGGCGCATGTGCTTGGGCCCTTG
    CACCTAGGTGGGAGGCCTGGAAGAAGCTCCTGGCATCCAGCTTTGGCCTGGCCCAGCTCTGGCCATTACA
    GCCATCTGGGGAGTGAACCAGCAGGTGGAAGTACTGTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTC
    CTAGTCTCCCTTTCAAATAAATAAATGTCTTTTAAAAATACACAAATAAATAAATAAATAAATAAAATTT
    GTAACTTATCACCAACCTACAGCCAAGTTAAACAGGACTGTTAAAGACATCACAGGCTGGCGCCGCGGCT
    CACTGGGCTAATCCTCCGCCTGCGGCACCGACACCCCAGGTTCTAGTCCCGGTTGGGGTGCTGGATTCTG
    TCCTGGCTGCTCCTCTTCCAGTCCAGCTCTCTGCTGTGGCCCGGGAGTGCAGTGGAGGATGGCCCAGGTC
    CTTGGGCCCTGCACCTGCATGGGAGACCGGGAGGGGGCACCTGGCTCCTGGCTTCGGATCTGCGCAGCAT
    GCTGGCCGCAATGCACTGGCCGTGACGGCCACTTGGCGGGGTGAACCAACAGAAAATGGAGGACCTTTCT
    CTCTGTCTTCTCTCTCACTGTCTGACTCTGCCTGTCCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
    AAAAGAAAGAAAGAAAGAAAGAAAAGACATCACAGATGATCCCAAACTGTGGTCAGACTGGAACAGAACT
    GCAGTGATCACAATCAGATAATCAGATTCACAATGGTCAAGTGTGTTCCCCAGGCCTCACTGGACCCAGG
    GGCTTCTAGTGTGTGTGTGTGTGCGTGTGCGTGTGTGTTCACGTTATGCACATGTATGTGTGTGAGTACA
    TGTTACACACATGTATATGTTGAGGGTCAGCCATGTCAGGCTGGGAGCAGGAAGTTTGACTGACGGCCTC
    TCTCTCTGCAGCACGGAGCTGTCCAGAGCACAGCCACTATGAGTCCTGTGCCCGCGGCTGCCCGCTGAGC
    TGCGGGGACCTCCCGGTGTCCGGGGGCTGTGGCTCAGAATGCTACGAGAGCTGCGTGTGCGATGAAGGCT
    TTGTGCTCAGCGGCGAGTCCTGCGTGCCCCTGGCCTCCTGTGGCTGTGTATACCAGGGCTCCTACTACCA
    GCCAGGCCAGACCTTCCACCCTGGCCCCGGGTGCGACTCCCTGTGCCACTGCCAGGAGGGTGGCCTGGTG
    TCCTGTGAGGACTCCTCCTGCGGCCCGCAAGAGGAGTGCCAGCTGTCTGGTGGCGTCCTGGGCTGCGTGG
    TTGTGGGCTCTGCCACGTGTCAGGCATCCGGAGACCCCCATTACGTCACATTCGATGGCAGCCGCTTTGA
    CTTCATGGGCACCTGTGTGTACGTGCTGGCTCAGACCTGCGGGACCCCGCCCGGCCGGCCCCAGTTCACC
    GTCCTGCAGGAGAACGAGGCCTGGGGCAACGGACAGGTCAGCGTGACCAAAGCAATCACGGTCCTCGTGG
    GCAACCACACCATACGTCTGGAGCAGAGTCAGCAGAAGGTCACGGTGAGAACCACGGCTTGCATGGGAGG
    GGCGGTGCTGGAGTGGGGGTGCGGCCTGATCTCCCCTGTCTGTGCCCCTCCACCTCTCCGCCTTCGGCCC
    CTCGGCCTACGCTGCACTGTCCTGTCTGAAGGCCTCTTCCACCCCCTCCTCCCTCCTTCTCCATCCTCTC
    GCCACCCCTCCCCTAACCCGTCCCAGCCCCCTCCTTCATCTCCCACCCTATCAGAGGTTGGGAAAGATCA
    GAGAGTGGGCAGGGTCCAAGGACAGAAGATGGGGTGTGGGGGTGACCCTGTCCCCGACTCGACAACCACA
    GTAGCTACAGACTTTGCAGGCTGAGCCCGGACCCTGCGTCGAGCCCACAGGTCACTCTGTCTTCCCTGTG
    GCAGCTGGAGGCACCACGATTAACTCTCTTTTTGTAGATGAGGAGGTCCGGCTGTTGGCCTAAGAAACTG
    GCATTTCGGCTGCACTGGAGGGGAGGGGACTTTCTCAGAGACCCCACTCCCACACAGCCACTGCTCTGGT
    CCTGTCCTGGATCAGTAGATGACTTCATCACACATGACATAGCTTAATACAGCCCCCAACCCAGCCCAGC
    TCTTAGAGCAGCGCCCCGACTGTGGTTTGCTCTAAGCTTCTTGTAATTGACATCTCACTACATCCCACCC
    CACCCCCGCTTCCCTGAGAAGTAGGAAGTATCATCCCCACTATGCAGAGGAGCAAGGCGAGGCACAGGTG
    AAGTCAGTTCTCTGCTTGGGAAGTCCAGCAGTTGGTTATGCTCTGTGGGGACAGACACAGCCAGGAACCC
    GCCTTTCTCCTGCCTCCTCCCCTGATTCCTCACACTCCAAAAGACTCCAGCGTGCACCACATCTGCCCCC
    ACGGAACGAGGAGCAAGTGGGTTAATCGGGGTGGGTTTGCACAGCTTTGCCAGTGGCCAGCAGCCATTGG
    CTGAAACCACGGGTCCACAGCTCTCGGGGCTGAAGGTCATTTGCCCAGGAATGTAGCTTGGCCTTCCAGC
    CTTCAGTGTTTAAAGCAAAAACCTTCAGTGGCCGCTCACCCGTTAAAATGAAGCCTTCCAGTCAGGGCTG
    GTGATCACCTGGATGCACGGCAGCCCCCCCCCCCCCACGCCTCCCCGCTCCTTCACGTTCACACGGCCCT
    CTGCTCTGTGTCTTCCGGCTTGTCACTGGATACAGGGCCCGCCCTAATCTCCTCTCCAGGTCATTCCCCT
    AATTATGTCCATGAAGATTCTTATTCCAAAGTCACATTCTGCTGTTGAAAAAACAATATTTATTTATTTG
    AAATAATTGCAGAGATAGAGAAAGAGAAAGAGAGAGAGAGAGAGAGAGAGAGAGATCTTCCATCCGCTGG
    GTCATGCCCCCAAATACCCACAACAGCCAGAGCTGGGCCAGGCTGAAGCCAGGAGCCTGGAACTCCATCC
    GGATCCTCCCACTTGGGTACAGGGGCCCAAGTACTTGGGCCATCCTCTGTTGCTTTCCCAGGCACTTAGC
    AGGAAGCTGGATCAGAAGCAGAACAGCTGGGACTCAAACCAGTGCTCACAGGGGATGCCGGCGCATCACA
    GGCAGTGGCTTAACATGCTGTGCCATGAGACGAGCCCCTAAAGTCACAGTCTGTGATTCTAAGTAGACAT
    ATATTTTGGAGACCAGCATCCAACCCCCTATAAGACTCTATTATTATACCCATTTCACAAATACAGAAAC
    CACAACTCAGGGAGGTGAGGCACCACAGACCCTCACTGTCGGGCAGGGGCTGTAGCGGGTGTGGCTGGGC
    CGAACCCACCCTCTGAGACCCTGCTCCTCCCGCCTCCCAGGTGGACGGCGTGGACCTCAAGCCGCCGGTG
    GAGCTGGACAAGGGCGAGATCCGCATCAACCAGCACGGCTCGGACGTGGTGATCGAGACCGACTTCGGCC
    TGCGCGTGGTCTACGACCTCATGTACTACGTGCGGGTCACTGTCCCGGGCAACTACTACCAGCAGATGTG
    TGGCCTCTGTGGTGATTACAACGGCAAGGCCGAGGACGACTTCCAGAAGCGCAACGGCTCACAGGCGGCC
    AACCCCAACGACTTCGGCAACTCCTGGGAGGAGGCCGTGCCGGGCTCGCCCTGCCTGCCGCCCCCTGAGT
    GCGACTCGGATGCAGATTGCAAGTGCACCCCCGAGCTGGAGGAGCAGTACAAGAAGGAGGAGTTCTGTGG
    GCTGCTCACCAGCTCCACGGGCCCGCTGTCCTCCTGCCACAAGCTGCTGGATCCTCAGAACTCCTTGCAA
    GACTGTGTCTTCGACCTCTGCCTGGGCGGCGGGAACGAGAGCATCTTGTGCGGCCACATCCACGCCTACG
    TGAGCGCCTGCCAGGCAGCTGGAGGCCAGGTTCAGCCCTGGAGGAATGAAAAGTTCTGTCGTGAGTGAGG
    GGGACCCCGCAGGGCAGGGGCAGGGACATTGAGACCCAGACGGTGGGGCTCGTGCCGTGCTGCCCTTGCA
    GGGCTCTGACGGGTGCCCCCTCCTTGCAGCGATGGAGTGCCCCCCTCACAGCCACTACGAGCTGTGCGCA
    GACACCTGCTCCCTGGGCTGCTCGGCTCTCAGCGGCTCCGTGCAGTGCCCGGATGGCTGTGCTGAGGGCT
    GCCAGTGTGACCCTGACTTCTACTACAACGGTGAAGCCTGCGTGCCCATCCAGCAGTGTGGCTGCTACCA
    CAACGGTGTCTACTACGAGGTAGGATCGCGGACACCCCCCCTCCCTGGAGGGCCGCTCCTGGGACCTCGT
    CCTGAGCCCCCTCCCACCACCGCTCTTCCCCCAGTCTGTCCACTCCTGCCCACGCCTCTCGCTTGCCCAG
    CTCCTTTTCCCCACCTGGATCTCTCCTACCCCCATTTTCCGGCCTCTGGATGACCATCCATTTGCCAGTG
    GGGGAGCTCTTTCTAAATATGACTGTGGGCCCTGGGATACCCTTGCTGCCCACATCAAGTTGGGGCTTTG
    GGGCTCAGGCGTGGACAAAGGTGGCTCTTAGGACCACAAGGATGAGATTTGGTCTTTATCCCACCTGGCC
    AACTCCGCGTCCCTCGTCCACTCTCTCACTGTCGGTCCTTTTTAAAAAATGTTTTTATATATTTATTTTC
    ATTTTATATGAAAGGCAGAAAGAGAAACAGAGAGAAATCATCCATCCCCCTCCCCCTCCCCCTCTCCCTC
    TCTGTCTCCCTCTCCCTCTTCCTCTCTCTCTCCCTCTTCCTCTCTCTCTCCGTCTCTCTCCCTCTCTCTC
    TCTCTCTTTCTCTCTTTCTCATCCATCCACTGGTTCACTTCCCAAATGTCCACAACAGCCGCCAGAGCCA
    GGAGCCCAGAACTCCATCCAGGTCTCCTGAGTACTGGAGCCGGCACCTGTGGCCTCCCAGGGTGCACATT
    AGCAGGGAGCCAGACTGGAAGCGGAGGAGCCGGGACTTGAAGCAGGCAACTCTGATACGGGATGCAGGCG
    CCCCCGGCAGCCGCATAGACCCCGCTGGGCAAACACCCAGCCCTGTGTTAGTCCTCATTTCAGCTGAGTA
    GAGTTTGTCCGACGTGCATCTCCCTCACAGGGCTGTGAGCTCTACGAGGGCAGGGGCCTCTCTGTTCTCC
    TCCCATGCATAAGAGCAGTAACTCGTCCACAGTAAGCAGGAAACACGCGGATGGTGCTTCCTGGGTGCCC
    TTGCTGTGTGTATGTTTTACACGCACTGCCTATGGACGTAAGCTTTTTATTATGACGATGTTCAAACTTG
    CGAAAGTTCAGAGAACAATAGAACGAACCTCCACGTGTCTGAGCATCCCTGGGGCTGCCAAAGTTGACGT
    CTTCCCCAGTCGTGTTCTCTAGCCTCCTTCCATCTCCTACTGGGATGATTGGCCGGAAGCCTCTTTTCAT
    CCGACGTATACTTTCTATGTGCTGCTAACTCAGGCTTGCACGGGTAGGTGCTGTTGTTATCTGCAGATTG
    CAGGTGAGGAGACTGAGGCAGAACAAGGCTAAGTAATTTGCCCAGAGTATCATAGTCTGGAGACAGCAGA
    GACGGACTTCAGATGGCCCGCTCCGAATTCCCGCCACACTCTTTCTCCCACACTGCAGAGCTGAATGAAT
    GAGTGGAAGTGAATGTATGCATTGGGTCCCAAGGCCATGCTGTCCACAGGGTCCCTGATGGCCATGCCTT
    ATGTCCCTGCAGCCGGAGCAGACGGTACTGACTGACAACTGCCAGCAGCAGTGCGTGTGCCACTCAGGCA
    CAGGCGTGACGTGTCAGGAACACAGCTGCAAGCCGGGGCAGGTGTGCGAGCCCTCGGGAGGCGTCCTGAG
    CTGCGTCTCCAAAGGTACTGGGCTGGGGCTGGGGCTGGGACTGGCGAGGCACAGGGGACACGGGGCCAGG
    AGCCAAGAGGGGCGTGGCAGCGGTGTACATGGTGGGAGGTGCAGAAGACTGAGGATGAGGTCTCAGGCCC
    TGCATTGATCTTTCAGGGCCAGCAGCAGAGACTCCCTTGTCTTGGGGACCTTCCAGGCCAGGTTTCCCAG
    AGCACATGTCAGAGACCCTCAGTGAAAGGCAAATCTGGAGGCGCCTCCAAGGCCATGAGGCTGAAACACA
    GGGGCCCCAGGAAGCATGTTGGGACCCCTGCCACTGGTTCTTCCCAGGAAGTCCTCTAGGACCTTGGTGT
    TGGGCACAGAGAGCCCTAAGACGTGGGTCTCAGATGCAGAGAAGCCCACAGGGCTAGGACCTCAGCTATG
    GAGGAAGCTAGGGCCCAGGTCCCATATGGACACCCTGAGGCCGGCATCGCAGACACAGGCGCCCTCAGGG
    CTGGCATCGCAAACCCAAGGACTCCTGAGGTTCAGGTCTCAACCTAGGTCCCCTGCAAAGAAAACCCTGG
    GGACCCCGGGAGCTGGGTCTCAGATGTGGCAACTCTGGATGCTCATGTCTTAGACACAGCCTGGCCCAGG
    GCCTGAGTGCCAGACCTGGAGGACTCCCTGGGCCTGGTCTTAGAAACAGCATCTGAGCCAGCGCCATGGC
    TCACTAGGCTAATCCTCCGCCTAGCGGCGCCGGCACACCGGGTTCTAGTCCTGGTTGGGGTGCCGGATTC
    TGTCCCGGTTGCCCCTCTTCCAGCCCAGCTCTCTGCTGTGGCCAGGGAGTGCAGTGGAGGATGGCGCAGG
    TGCTTGGGCTCTGCACCCCATGGGAGACCAGGAAAAGCACCTGGCTCCTGGCTTCTGCCATCGGATCAGC
    GCGGTGCGCCGGCCGCAGCGCGCTGGCTGCGGCGGCCATTGGAGGGTGAACCAACGGCAAAGGAAGACCT
    TTCTCTCTGTCTCTCTCTCACTGTCCACTCTGCCTGTCAAAAAAAAAAAAAAAAAAAATATAAAGAAAGA
    AAGAACAGCATCTGTGGGATCTTAGAAGTAAACCTTGGATCTGCTCTCTCCTGTGGTAGTCCTCGGGGCC
    GGTGTCCCTGGCACAGCCTGAGGTCTTCTCTCCTCTGCCCCCAGACCCATGCCAGGGTGTCACGTGCCGG
    CCCCAGGAGACCTGCAAGGAGCAGGACGGCCAGGGTGTGTGTGTGCCCAACTACAACGCCACGTGCTGGC
    TGTGGGGCGACCCACACTACAACACCTTCGACGGCCGGGCCTTTGACTTCCAAGGCACCTGCAACTACAT
    TCTGGTGCAAGTTGGCTGCCCGGGGGTGGACGCCGAGGGCCTGACACCCTTTACCATCACCACCAAGAAT
    GAGAACCGGGGCAACCCCACCGTGTCCTATGTGAAGGAGGTCACCGTGTCTGTCCTGGGCACCAACATCT
    CCATCCACAAGGGCGAGACGGGCAAAGTCAGGGTATGTGTGGCAAGGTGGTCCCCTGAACCCCCAGGAGG
    GCTGGGGGAGCCCTGACAGCCCCAGTGAGGAGCCGAGGTTCTCTGTATTCCCCTAGGCCTGAACCAAATC
    AGCCACCGAACAAACAGGCTTAGCTCTGTGCTGAGCACTTCGGCATCTGCCTCTCAGTAGACTTGGGTTT
    GAATCCAAGCTCTGCTTCCCAGGTGCTGGTGGGTGGGCCATGTGCCCAGCTCAGAGTCTGGCCCAGATGA
    GCTCCAGAGAGCAGATTAAGAGGCCTGGAGACTCGGACCCAGAGGGAAATCCAGGGAGGTGAGGGCAGAG
    AGGTGGGCCTCTGCTTCTGCCCAGGGAAGAGCCATGTGGGTCCACTCAGCAGACACTAAGATGGGCATGC
    GCACAGGAGTGCACAGAGAGTGTGTACGGCCAGTGGGGAGAGCCAGAGACAGAGAGGACAGTGACGGGAG
    GGAGTGCAGAGACCCAAAGAAAGAGGGAGAAGCGGAGGTCCAGCAAGAGAGCTAGACCCAGGTGAAGCAA
    CAGAGAGGGAGGAGAGAGCAATCCAGAGGAAGAAGCAGACACAAAGACGGGAACAGATGTTCATGACATT
    GTCAAACGGCTATACAACTTTCAGGCGGGGGGAAAGCCATGGCAGCTCCCAACCCCCGTCAGGACAAGGT
    GGGGAGTCGAGAGCTGGGGCCTCCCACCCTGAGTGACCCAGGCACCTGCTTCCCCCTCCGCCAGGTGAAC
    GGCGTGCTGACGACGCTGCCTGTCTCCGCGGCCGGCGGGCGGATTTACGTGTCCCATGGAGTGTGGAAGG
    CTGTGCTGGTGACAGACTTTGGGCTGCAGGTCACCTATGACTGGGACAATCGCGTGGAGGTGATCCTGCC
    CAGCAGCTATCACGGCGCCGTGTGCGGGCTCTGTGGAAACCTGGATGGCGACCCCAACAATGACCAAGTC
    TTTCCCAACGGCACAGCCGCTCCCTCCATACCCGCCTGGGGTGGCAGCTGGCGGGCCCCAGGCTGGGACC
    CACTGTGCTGGGACGAGTGCCAGGGCTCCTGCCCGACGTGTTCTGAGGACCTGCTGGAGAAGTACCAGGG
    CCCTGGCTTCTGCGGCCCCCTGGTCCCCGGGACCGAGAGCCCCTTCGCCGACTGCCTCGCCCACGTGTCG
    CCCGACAGCTACTTCCAGGGCTGTGTCCTGGACGTGTGCCTGAGTGGTGGGGCTCAGGACATACTTTGCC
    AGGCGCTGGCTAGCTATGCGGCTGCCTGCCAGGCCGCTGGCGTCGCCATCCAGGAATGGAGGGAGCAGGC
    CGGCTGTGGTGAGTGCCGGGGAGGGGGCAGAGGCTGGGGGTGGGGTCCTGTCTGCCAGGCGGGCTTGACT
    GCTCTCCAGCCCTTCTGGGTTCTTCTTGTATTTCTGTTCCCGAGCGCCTGTCTCTCGGCGCTTCTCTGTG
    TGTCTCCCTTTGGGTCTCTCTGTATCCCTCTCTGTGCCTCTTGCTCTCTCTCCTTCGGTCTCTGTCTCTC
    TTCCTCTCTCTGTCAGCCCCTTGGTTTCTGTATTTTGCCACCGTGTCCTTGGACCCCACCCCTAACATCC
    TTCCCTCTTTCTCCCTCTCCCACCCGCCCGCAGGGGTCTCCTGCCCTGAAAACAGCCACTACGAGCTCTG
    TGGCTCACCCTGCCCAGCCAGCTGCCCGGCTCCTGAGTCCACCAAGACCTCAGCCCTCTGTGAAGGTTCC
    TGCGTGGAGGGCTGCCAGTGCGACACGGGCTTCGTGTTGAGCGCTGGGCGCTGCGTGCCCCTGGAGGGCG
    GCTGCGGCTGCTGGGCCAACAGCACCTACTATGAGACCGGCAGCGAGTTCTGGACGGACGCCACATGCTC
    CCAGCGGTGCCGCTGTGGGGCTGAGGGCGGCTCGCTGGTCTGCACACCTGCCAGCTGCGCCAAGGGCGAG
    GCATGTGCCCTGCTGTCCTCGGGCCAGTACGGCTGCCAACCAGTGAGCACTGCGGAGTGCCAGGCCTGGG
    GTGACCCCCATTACGTCACCCTGGACGGGCACCGATTCGACTTCCAAGGCACCTGCGAGTACCTGCTGAG
    TGCACCCTGCTCTGAGCCGCCGGCCGGGACTGAGAATTTCACCGTCACCGTTGTCAACGAGCACCGGGGC
    AGCCAGGCTGTCAGCTACACCCGCAGTGTCACCCTGTATATCTACGACCACCGCCTGACCCTCAGCGCCC
    GCTGGCCTCGGCAGCTACAGGTGAGGAGGGCATGGGCCGCACAGGAGCAGGTGCCGGCCCTGGGGTTGCC
    TGGGACGGTAAGAGGTCCGCCAGGTCCCTGAACACCTTACAGCTTAGCTGGGACTTGATGGACGGGGTCT
    GGAGCATAGGCCTGGGAGCTGGATGGTGTGAGGCAGTGGCTCCCCCTCCCCCTGCGCTGAGCCTTAGTTT
    ATTCCTACGAGAAATGGGCCCAAGAAGTCATGTGCTGCAGGGTGGCGTCAAGAGCCTGTTGTTTTTACTA
    CAAGAAGCCCTGGACTCAGAGTCCCACAGCTCCTAGGTGGTGGAGACGGGCTTCGAACCTGACTGGCCCG
    CCCCGCCCTGCCCCACGCCCGCAGGTGGACGGCGAGTTCGTGACGCTGCCCTTCCAGCTGGACTCGCGCC
    TGAACGCGTATGTGAGCAGCGCCGACGTGGTGGTGACCACGGCCGCCGGGATCTCGCTCAGTTTCGACGG
    GGACAGCTTCGTGCGCCTCCGCGTGCCGGCGGCCTACGCGGGCGCCCTCTGCGGCCTGTGCGGGGACTAC
    AACGAGAACTCGGCCGACGACCTGGCAGCGGTGAACGGGAAGCCCGAGGGCTGGCAGGTGGGCGGTGAGC
    CGGGCTGCGAAAAGTGCGAGCCCGAGCCGTGCCCGGAGCCGTGCACGCCCGAGGAGCAGGAGCCCTTCGG
    CGGCCCCGACGCCTGCGGGGTGATCATGTCCCGCAAAGGCCCGCTGGGGCCCTGCCACTGCATCGTGCCG
    CCGGAGCAGTACTTCCAGGCCTGCCTGCTGGACGCCTGCCAGGCCCAGGGCCATCCGGGAGGCTTCTGCC
    CTGCGGTGGCCGCCTATGTGGCTGCCTGTCAGGCCGCCGGGGCCGAGATCGGCGAATGGAGGCTGCCGGA
    CTTCTGTTGTGAGTACTGGCCCTTGCACGTTCACAAAGCAGGCGCCTCCTCCTCTCCCCAGCTTCTTCCC
    TCTTCCTGGGCTCAGGGACCAGCGAGGTGTCTGTTAGACTATGCGCGGCGACAGACTGGTCAGGTACACC
    TACGGTCAGGGCTCTGAGGACCCCAAACAGCTGCCTAAGACAGGGTCCGGGAGTCCCTGCAGTTCCTTTT
    GGACAGATAGATCTCCTCGGTCAGGTGCATCCTGGCAGCTTCAACAACCAGACCTAGTTGTAGTCCCCGC
    ACAGGCCGCAGAGGGCGCCCGCGTAGGCCGCCGGCACGCGGAGGCGCACGAAGCTGTCCCCGTCGAAACT
    CTGTGGGTCAGAGTCACACCCTAAAACAAACGGAGTCGGGGAGACTCCAGCAGGTGCTCGGACACCCACG
    CCAGGCACAGCCCCACAGGCGCACGCCCCGGGATACCTGTGGCTGATCCTAACCCTTGTATCCTGGTCAC
    ACATCCATGACCAGACACTCACTGGACACTTAGAAGTTTTAGGGTGTGACACACACCTGGTCAGAGGGTG
    TTGCCCCCACCCCGTGGGAGGTGCTGGGTCCGATCCTGGTACCTGGGTGTGTTGTCCCAGGGGAAGCCTC
    ACCCTCGTCCCGTCTCACCCCCGCAGCCATCCAGTGTCCAGCCAACAGCCACTACGAGCTCTGCGGCAAC
    TCCTGCCCCGTGAGCTGCCCCAGCCTCTCGGCGCCCGAAGGCTGCGAGCCAACCTGCCGCGAAGGTTGCT
    ACTGCGACGCCGGCTACGTGCTCAGCGGTGACACATGCGTCCCCCTGGGCCAGTGCGGCTGCCTCCACGA
    GGGCCGCTACTACCCACTGGGCGCAGCCTTCTACCCAGGGCCCGAGTGCGAGAGACGCTGTGAGTGCGGC
    CCAGGGGGCCAAGTCAGCTGCAAGGAGGGTGCGGCCTGCGGGCCTTACGAGGAGTGCCGGCTGGAGGACG
    GCGTCCAGGCCTGTCACCCCAAAGGCTGCGGCCGCTGCCTGGCCGACGGAGGCATCCACTACCTCACCCT
    GGACGGACGCGTCTACGACCTGCACGGCTCCTGCTCCTACATCTTGGCCCAGGTCTGTGACCCGCAGCCC
    GGGGATGAGGACTTCACCATCGTCCTGGAGAAGAACGCGGCTGGAGAACCGCAGCGCGTGCTGGTTACCG
    TGGCTGGCCAGGTCGTGGGCCTGGCCCGGGGACCGGAGGTGAGTGGCCCGCCCAGGGACCCAGGGAGACA
    CAGCCAAGTCCTGGGCTTCTGGAGGTTCTGTGAGCCACTCACCCGCCCCTTCCTCCCGTGCAGGTCACCA
    TCGACGGCGAGGTGGTGGACCTGCCCGTGGCCGTGGGCCATGTGCGGGTGACCTCCGAGGGCCGAAACCT
    GATCCTGCAGACAACCGAGGGGCTGCGGCTTCTCTTTGACGGCGACGCCCACGTCCTCATCTCCATCCCC
    AGCCCCTTCCACGGTCGGCTCTGCGGCCTGTGCGGCAACTTCAACGGCAACTGGAGCGACGACTTCGAGC
    TACCCGACGGCTCGGTGGCCCCCAGCGTGGAGGACTTCGGGGCGGCGTGGCGGGCACCCGGCTCCCCCCA
    GGACTGCACCGAGGGCTGTGGGGCCCAAGGCTGCCCCGTGTGCCGGGCGGAGGAGACGGCACCCTACGAG
    AGCAGCGAGCTCTGTGGGCGGCTGCTCGACCCCAGCGGCCCCTGGGCCGCCTGCCACGAGGTGCTGAGTC
    CTTCCGAGTACTTCCGCCAGTGCGTGTACGACCTGTGCGCCCAGAAGGGCGACCAGGCCTTCCTCTGCCG
    CAGCCTGGCCGCCTACACAGCCGACTGTCAGGCGGCCGGCGTGGCCGTGAAGCCCTGGAGGACAGACAGC
    TTCTGCCGTGAGTGTCGGGGGCGGGGGTGGGGTGGGGTGGTGCCTGGGAGGTCTCCCGCCCGCCACGCCC
    CGCCCTCCTCCGTCTGCATCTCAGGAGCAGCCCAGCCCCCTCCTGCGAAAGCTCCTCCCACGCCCGCTGC
    TCGCCTGGCGGCTCCCCTCTGCCCCCTCTGACCGCCCCCTTTCTCCTCAAAGCGCTTCACATCTTCCCTG
    GGCCTCCATCCTGGGCACTTTCTCACCTTGCAGCCTGAGTCTGTGGCTTGCCAGCCCCCTGGGGGCAACA
    CCGGCTCCCCTCAGAGCACCCAGGACAAAGCTGCAGGCCGTTGGGCCCCCAAACCAGGGCTGTCCCTCTC
    CCCCAAATCTCCTGCTGCAAGGACATGCCCCTCCCCAACCTAGGCTCTGCAGGAAAAGGCCATGGCCGAG
    TTTGCTTCGGTCTCCTCAGAGCAGGACCCCTACCCAGGGCCTTATAGGCTTCACAGCCTTGGCCTTGTCC
    TCAGCGGGGACAGTGGAGCCTGTCTCCTGCTCCGAGCTCTCTCCTGACTGCCAGCCCCAGGGGTCCAGTG
    TGAGCGCGTTCCCTCCAGCATCCTCACAATGTCTTGCACCTGCTGTGTTCCCAGACGACATCAGCGCCTC
    ACCCCAAGCCAGTCCTCCTTCCCCTGGCCCCCCCGTGTCCCGGCACTGGGCAGCCACAGCAGCCACCAGT
    TCTCAGCCAGAGCCCAGGACCTCACCCCGAATGCTTCCCCTGGGTCCTCCCAGCCCCCTGTGTTTCACTT
    GCCCCGGCCCTGAGCCCCAAGCCTGACCTTGCCCAATGCAGCACAGCCACATGGGCCCCTCATGGCCTGT
    CCCTCCGGTTTGAGCTCTGCAGGGCAGAGTTTGGGGCTGTCTGCGTCATTTGGGTCATCAGCGCAGCCCA
    CGCCCGGGCTGGCTGTATAGAAGCTCTTGTGGCCGTCCATGGAGGCGTGACCCCAGCCCGCCATGTCTCT
    CTCCACAGCGCTGCAGTGCCCAGCTAACAGCCACTACTCCGTCTGCACCTACTCCTGCCAGGGCTCCTGC
    ACAGCGCTCTCTGGCCTCACGGGCTGCACCAGCCACTGCTTCGAGGGCTGTGAGTGTGACGACCGCTTCC
    TGCTCGCCCAGGGCGTCTGCGTCCCCTCCCAGGAGTGTGGCTGCACCTACAATGGCCGGTACTTGCCTGT
    GAGTAGGGGCTCGAGGTGGGCAGGGAGGGCGGGAGGGAGTCTAACCTCCCCGAGGACTGGGACAGGGGTG
    CCGCTGCCATCTCCCAGCTGGGACACTTGCTGTGTGTGATGCTGCTGACCTCCAACCTGGTAGTCTAACA
    CGGAAGCAATGTGTTCTCCCACCATTCCGGAAATCAGTACCCCCACGCTGGAGGCAGGCTGCCCCCAGCC
    CCCCCCCCCCCCGCAGTCTAACTGCTCCCTGCAGCTTCTGGGGGCTGCCAGCATCCCGTGCCTTGGGGCT
    GCATCCCTGCAGTATCGGCCTGTGTGTGTCAGGAACGCTCCCTCCAGCTTCCTCTTGGGAGGACACCCGG
    ATAATCCAGCATGAATTCTCCACTTCCAAGTCCTCGGTTTAACACCGCTGCAAACACCTTTTTCCCACAG
    AAGGGGATGTTTACTTGGTCCCAGGGATTGGGATCTGATGTCTGTGAGGGACCACACTTGGCCTGCCATG
    GTCCCCACCCTGAACCTCATTTTCTCCACCTGTAAGATGGGGGTAGTCATTGTCCTTGCACCACAGGTGT
    GTAAGGGAAGGTGTGATTGTGTGGAAGACGCCAGCTGTGCCCTGGGCCTGGCACTCCCTGCGCATCCCAC
    TCAGGGAAAGGAATAGGAACTTAGACGGTGCTCTAGGCAGCCCCCAACCATCACTTACTCTGCAAACTGA
    AATGCAATCCTTGATTTATTCGTGTTAACAGTATTTTTTTGGGCTCTTGCTCTGCACTGGTTGTTATGGG
    TGTTTAAAGATTTAGTTATTTATTCGAAGAGGAGAGAGAGAGAGAGATTTTTCATCTGCTGGTTCACTCC
    CCAAAGGACCACAAGACTGGGACTGGTCCAGCTCAAAACCAAGAGCCTGGAGCTCCATCCTGGTCTCCCA
    CATGGGAGGCAGGGCCCCAACTACCTGGGCCGTCCTCTGCTGCCTTCCCAGGTGCATTTAGGGAGCTGGA
    TCAGAAGTGGAGCTGCTGGGACTTATTGGCGCTATTGCTGTTTCCCCCTGTTACAGAGCCATCCCTGTAA
    CCCCCCAACCTCTTACCTGCCCCCTTCTGCACACAGGTGAACTCCTCCCTCCTGTCCTCAGACTGCAACG
    AGCTCTGCTACTGCTCCCCAGACGCAGACCTGCAGTGCTATGAGGCCAGCTGCAAGGCGGGCAGCGTCTG
    CGAGGTCCAGAACGGGGTTCGGGTCTGCCAGGCCTCCGGCGCCCAGTGTACCCTCTCCGCAGGCTCCAAC
    CTCACCACCTTTGATGGGGCCCTCAGTGCCTTCAACTCCTCTGGTGTCTATGAGCTCTCCTTCCGCTGCC
    CAGGACTACAGACCCCCTGGTATCGTGTGGTGGCAGCCATCCAGCCCTGCGCTGGCACAGCTGAGACGGT
    GGGCCAGCTCCACGTCTTCTTCGAGGACGGGATAGTCACCGTGACCCGAGACGGGGGCGTGTGGGTAAGC
    CTGGGCGTGGCGGCGGGCGGGCGGGGGTCGGGGTGATGTGCAGTGTCCTTGCATTGTTGCCTGCCTGTCT
    TGCTGTCTCTTTCCTCTGCAATTTGATCTCTGGATTGGTATTTGCCTCAGTATTTCAGCTGAGTTCGTGG
    GAGGCAGAACGCATTCAAGGAACGTCATAGTTTTGATATTAGCGTCAATCAGGACTCCATTGGTTGCAGG
    TGACAGAAAAACCGAGCTCAAACTTCCTGAGAAGCAGAAGTGAATTGATTGGCCCACGGAACTAGAAAAC
    TCAGGGTCAGGACTATAGGCCTCTATGTTTTAGATGTGCTGGTCACCAAGTCGGCTTGATTCTCCGGCTT
    TCCTCTCGCAGACCCACACCGCACTGGTTTAGCTACGCTGGACCAGTTTGGGCCCTTGCCTATCCCTGGA
    ACCAGTCACCATGGCCTTGGGGATGGAATGCTGTGATTGGTCAGGTGGTTTTTATTGGAGGGGGTAGGGC
    TGGTCACCCAGGCAGCTCTGCCTAGCACATGCCAAACGTCAGGCTCCCGGAAGGAAGCTGCGGAAGCTGC
    ACCTTGCATCAGCTCCGGAACCTGAGCCCTGGGTGCGCAGGGATCCTGTCTGTCCCCGTCACCCCTTTAT
    TCCCAGTCCCCAGATCCAGGCCTGGCACCTGGACCCCGGAAAAGTCGGGTTTGGTGACTCAGCTCAGCCC
    CGCCCCTCTGAGTCAGGCTGGGAGCCGACTCCCACTCCAGGGCCGACTCGAACCCAGTTCTCATACTCAG
    GAAGCAGCCGGGAGAGGCTTCCCCTGCCCCGCCCCGCCCCTCCTGGCTGTCTCCATCCTCCCTCCCTTTC
    TCCCTCCTCCCTTCTTTCCTCCCTCCCCCCCATCTCAGCTCCACACCTACTTTTCCCATCAGTCTGCCTG
    TCTCTCCAGTCACCCGACAGAGGCAGACTCAGATACAAAAGCATTTCGGGAAAAAAAGAGAACTTCTGTT
    TAAAAGCAATTTTTGCTAGAGAGACTAACTTTAGAAGGATGAACTTACCAACAAAAACAAACAACACTTG
    TTTCAAGGGAAAAAAAACTCCCGACGTCGCTGAGTCTGCAACCCAGGACGAGGAAGCAGGCATCTCCTCA
    CAGGCCTATTATATTTGCTATGCTCACTACTTATCTTTAGACACCAGCATTACAATGATAAGGGATAAAC
    TCTCCTCTTGGGGAAGCAGTAACAGAGAACATGCTCCTCAGAGGCCTTTTGTTTTGAAAAGTAGACCCCA
    ACAGGGTGGCCCTGAGGTTGGTTGGTTGGGATGGGCCTCTGGTACAAAGTCCCTCCCACCCCCGACCCTG
    GGACACTGCGTGGGTCCCCCAATCCCTTTCTCCATCCGCCCAGTCTCCAGCTATCTCCCCGAGTCTGTCT
    GGCCACACGCAGCCTCCATCCGGGTCTTCATGGCTTTCAGAACCTGCTCCTTGCTTTAGTTCCTGAACTC
    ATGACCTCGCTCGGGGTCTCCGTCCTGGTAACTCGCCGGCTGCGCTGCGGCTCCGGCCTCACCTGTGTCT
    GCCCGCCTCCATCGCCAGGTGAATGGTCGCCAGGTGGACCTCCCAGCTGAAGTGTTGACATCGGTGTCCG
    TGACGCGCAACAGCGACAACTCCATACTTGTCCACCAAAAGGATGGGCTTTGGGTGTGGCTGGGCGCCGA
    TGGGCAGCTGACCGTGACGGTGGACAGTGGCCGCGCTGGCCAGCTGTGTGGGGCCTGCGGAAACTTTGAC
    GGAGACCCGACCAACGACAAGTCGGTCACGGAGAGCTGGACAGCACCGGACCTTTCCCCATGGTGAGGAT
    GTGGCGGGGAAGCCGGGCTTCTCGGGCGCGAGGGCGTTGGATGCTCACGGGAACGGGCAGTGGACGCGTG
    GGCAAGAGGAGGTGCTGAGTGTCTGTCTCTTGCAGTGAGGACTG
  • Molecule Role : Vaximmutor
  • Related Vaccine(s): Vibrio cholerae hemA mutant vaccine
IV. Vaccine Information
1. Dukoral
a. Product Name:
Oral Inactivated Cholera vaccine
b. Tradename:
Dukoral
c. Manufacturer:
SBL Vaccine, Sanofi Pasteur Ltd
d. Vaccine Ontology ID:
VO_0010710
e. Type:
Subunit vaccine + Inactivated or "killed" vaccine
f. Status:
Licensed
g. Location Licensed:
Canada
h. Host Species for Licensed Use:
Human
i. Immunization Route
Oral
j. Storage
Store in a refrigerator (2°C – 8°C)
k . Approved Age for Licensed Use
2 months and older.
l. Description
Products: Proteins + killed bacteria. Other components: Saccharin.
2. Mutacol
a. Tradename:
Mutacol
b. Manufacturer:
Berna Biotech
c. Vaccine Ontology ID:
VO_0010728
d. Type:
Live, attenuated vaccine
e. Status:
Licensed
f. Location Licensed:
Canada
g. Host Species for Licensed Use:
Human
h. Immunization Route
oral
i . Approved Age for Licensed Use
Ages 2 and older
j. Description
Products: Live bacteria. It uses the V. Cholera live attenuated strain CVD 103-HGR. Other components: Yeast extract, Lactose, Aspartame.
3. V. cholerae CTB DNA Vaccine
a. Vaccine Ontology ID:
VO_0011360
b. Type:
DNA vaccine
c. Status:
Research
d. Antigen
cholera toxin B subunit (CTB) (Xu et al., 2009).
e. Gene Engineering of CtxB
  • Type: DNA vaccine construction
  • Description:
  • Detailed Gene Information: Click here.
f. Vector:
pJW4303 (Xu et al., 2009)
g. Immunization Route
Intramuscular injection (i.m.)
h. Mouse Response
  • Host Strain: BALB/c mice
  • Vaccination Protocol: Mice were immunized intramuscularly with 100 μg of the CTB DNA vaccine or vector control. The DNA immunizations for mice were given at Weeks 0 and 2 in DNA alone prime boost groups, or Week 0 only for those receiving DNA prime followed by KWC-B vaccine boost at Week 2 (Xu et al., 2009).
  • Challenge Protocol: Naïve suckling BALB/C mice at 5- to 6-day-old were separated from their mothers for 4 h, then inoculated by oral gavage with 50 μl of the appropriate serial dilution of the inoculum. To prepare the inoculum, V. cholerae O1 El Tor biotype Ogawa strain V48-65 growing overnight on an LB plate, were re-suspended in PBS and adjusted to 5 LD50 in 25 μl, then incubated with 25 of properly diluted immune or normal rabbit serum samples for 1 h at 37 °C. The suckling mice were kept in a 25 °C environment and observed every 4 h for 48 h post-inoculation. The survival rates were documented at each time point (Xu et al., 2009).
  • Efficacy: The immune sera elicited by CTB DNA vaccine were functional and protective against V. cholerae O1 infection in mice (Xu et al., 2009).
4. Vaxchora
a. Tradename:
Vaxchora
b. Manufacturer:
PaxVax, Inc.
c. CDC CVX code:
174
d. Type:
Live, attenuated vaccine
e. Status:
Licensed
f. Location Licensed:
USA
g. Host Species for Licensed Use:
Human
h. Immunization Route
Oral
i. Storage
Store at −25°C to −15°C (−13°F to 5°F), and protect from light and moisture.
j . Approved Age for Licensed Use
18 to 64 years of age.
k. Description
VAXCHORA (Cholera Vaccine, Live, Oral) is a live, attenuated bacterial vaccine suspension for oral administration containing the V. cholerae strain CVD 103-HgR. CVD 103-HgR was constructed from the serogroup O1 classical Inaba strain 569B by deleting the catalytic domain sequence of both copies of the ctxA gene, which prevents the synthesis of active cholera toxin (CT). (FDA: Vaxchora)
5. Vibrio cholerae hemA mutant vaccine
a. Vaccine Ontology ID:
VO_0002934
b. Type:
Live, attenuated vaccine
c. Status:
Research
d. Host Species as Laboratory Animal Model:
Rabbit
e. Gene Engineering of hemA
f. Immunization Route
Oral immunization
g. Rabbit Response
  • Persistence: A hemA mutant is highly attenuated in rabbits (Ravichandran et al., 2006).
  • Efficacy: A hemA mutant induces protection in rabbits from challenge with wild type V. cholerae (Ravichandran et al., 2006).
  • Host Gene Response of IgA
    • Gene Response: VCUSM2 elicited high titer of anti-LPS IgG/IgA antibodies on the fourth week post-vaccination. These titers were comparable to those elicited by the wild type strain and were significantly higher than titers pre-vaccination (Ravichandran et al., 2006).
    • Detailed Gene Information: Click here.
  • Host Gene Response of IgG Fc fragment
    • Gene Response: VCUSM2 elicited high titer of anti-LPS IgG/IgA antibodies on the fourth week post-vaccination. These titers were comparable to those elicited by the wild type strain and were significantly higher than titers pre-vaccination (Ravichandran et al., 2006).
    • Detailed Gene Information: Click here.
V. References
1. FDA: Vaxchora: FDA: Vaxchora vaccine information [https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM506235.pdf]
2. Kirn and Taylor, 2005: Kirn TJ, Taylor RK. TcpF is a soluble colonization factor and protective antigen secreted by El Tor and classical O1 and O139 Vibrio cholerae serogroups. Infection and immunity. 2005; 73(8); 4461-4470. [PubMed: 16040956].
3. Osek et al., 1994: Osek J, Jonson G, Svennerholm AM, Holmgren J. Role of antibodies against biotype-specific Vibrio cholerae pili in protection against experimental classical and El Tor cholera. Infection and immunity. 1994; 62(7); 2901-2907. [PubMed: 7911787].
4. Product Monograph: Dukoral: Product Monograph: Dukoral vaccine information [http://healthsensetravelclinic.ca/wp-content/uploads/dukoral.pdf]
5. Ravichandran et al., 2006: Ravichandran M, Ali SA, Rashid NH, Kurunathan S, Yean CY, Ting LC, Bakar AS, Lalitha P, Zainuddin ZF. Construction and evaluation of a O139 Vibrio cholerae vaccine candidate based on a hemA gene mutation. Vaccine. 2006; 24(18); 3750-3761. [PubMed: 16102875].
6. WHO: Cholera: WHO: Cholera [http://www.who.int/topics/cholera/about/en/index.html]
7. Xu et al., 2009: Xu G, Wang S, Zhuang L, Hackett A, Gu L, Zhang L, Zhang C, Wang H, Huang Z, Lu S. Intramuscular delivery of a cholera DNA vaccine primes both systemic and mucosal protective antibody responses against cholera. Vaccine. 2009; 27(29); 3821-3830. [PubMed: 19443090].
8. Yu et al., 2005: Yu F, Qi G, Liu Y, Gao S, Kan B. Construction and characterization of a thyA mutant derived from cholera vaccine candidate IEM101. Molecular biotechnology. 2005; 29(3); 191-196. [PubMed: 15767696].