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Tick-borne Encephalitis Virus (TBEV)

Table of Contents
  1. General Information
    1. NCBI Taxonomy ID
    2. Disease
    3. Introduction
  2. Vaccine Related Pathogen Genes
    1. E (Protective antigen)
    2. NS1 (Protective antigen)
    3. NS3 (Protective antigen)
    4. TBEVgp1 polyprotein (Protective antigen)
    5. C protein (Virmugen)
  3. Vaccine Information
    1. Encepur
    2. FSME-IMMUN
    3. TBEV DNA vaccine encoding E protein
    4. TBEV Virus Like Particle Vaccine
    5. Tick-borne Encephalitis Virus C protein mutant vaccine
  4. References
I. General Information
1. NCBI Taxonomy ID:
11084
2. Disease:
Tick-borne Encephalitis
3. Introduction
Tick-borne encephalitis virus (TBEV) is a virus of the family Flaviviridae and has three subtypes: European or Western tick-borne encephalitis virus, Siberian tick-borne encephalitis virus and Far eastern tick-borne encephalitis virus (formerly known as Russian Spring Summer encephalitis virus). TBEV causes tick-borne encephalitis, a human viral disease of the central nervous system, typically presenting in meningitis, encephalitis or meningoencephilitis. Ixodid Ticks are the vector and reservoir for TBEV, with the main hosts being rodents, with humans being accidental hosts. The disease is endemic to Europe, Russia and Asia.
1. C protein
  • Gene Name : C protein
  • Sequence Strain (Species/Organism) : Tick-borne encephalitis virus
  • NCBI Protein GI : 206570298
  • Other Database IDs : CDD:110034
  • Taxonomy ID : 11084
  • Gene Strand (Orientation) : ?
  • Protein Name : capsid protein
  • Protein Length : 35
  • Protein Note : Flavivirus capsid protein C; pfam01003
  • Protein Sequence : Show Sequence
    >gi|206570298|gb|ACI12930.1| capsid protein [Tick-borne encephalitis virus]
    MARKAILKGKGGGPPRRVSKETAKKTRQSRVQMPN
  • Molecule Role : Virmugen
  • Molecule Role Annotation : A virus with a mutation in protein C is attenuated in mice and induced protection from challenge with wild type TBE virus (Kofler et al., 2002).
  • Related Vaccine(s): Tick-borne Encephalitis Virus C protein mutant vaccine
2. E
  • Gene Name : E
  • Sequence Strain (Species/Organism) : Tick-borne Encephalitis Virus (TBEV)
  • NCBI Protein GI : CAC94472
  • Other Database IDs : CDD:279241
    CDD:213392
    CDD:213897
    GOA:Q8UYS5
    HSSP: 1SVB
    InterPro: IPR000336
    InterPro: IPR011998
    InterPro: IPR011999
    InterPro: IPR013755
    InterPro: IPR013756
    InterPro: IPR014756
    UniProtKB/TrEMBL: Q8UYS5
  • Taxonomy ID : 11084
  • Protein Name : E protein
  • Protein pI : 7.56
  • Protein Weight : 42769
  • Protein Length : 494
  • Protein Note : Flavivirus glycoprotein, central and dimerization domains; pfam00869
  • Protein Sequence : Show Sequence
    >CAC94472.1 E protein, partial [Tick-borne encephalitis virus]
    TQGTTRVTLVLELGGCVTITAEGKPSMDVWLDSIYQENPAKTREYCLHAKLSDTKVAARCPTMGPAVLAE
    EHQSGTVCKRDQSDRGWGNHCGLFGKGSIVTCVKAACEAKKKATGHVYDANKIVYTVKVEPHTGDYVAAN
    ETHSGRKTASFTVSSEKTILNMGDYGDVSLLCRVASGVDLAQTVILELDKTLEHLPTAWQVHRDWFNDLA
    LPWKHEGAQHWNNAERLVEFGAPHAVKMDVYNLGDQTGVLLKSLAGVPVAHIDGTKYHLKSGHVTCEVGL
    EKLKMKGLTYTMCDKTKFTWKRTPTDSGHDTVVMEVTFSGTKPCRIPVRAVAHGSPDVNVAMLITPNPTI
    ENNGGGFIEMQLPPGDNIIYVGELSHQWFQKGSSIGRVFQKTRKGIERLTVIGEHAWDFGSTGGFLTSVG
    KAL
    
    
  • Molecule Role : Protective antigen
  • Molecule Role Annotation : (Stenkova et al., 2017)
  • Related Vaccine(s): Encepur
3. NS1
  • Gene Name : NS1
  • Sequence Strain (Species/Organism) : Tick-borne Encephalitis Virus (TBEV)
  • NCBI Protein GI : CAA44678
  • Other Database IDs : CDD:213897
    CDD:279316
    InterPro: IPR001157
    UniProtKB/TrEMBL: Q88482
  • Taxonomy ID : 11084
  • Protein Name : unnamed
  • Protein pI : 6.07
  • Protein Weight : 38586.51
  • Protein Length : 441
  • Protein Note : flavivirus envelope glycoprotein E, stem/anchor domain; TIGR04240
  • Protein Sequence : Show Sequence
    >CAA44678.1 NS1, partial [Tick-borne encephalitis virus]
    RNPTMSMSFLLAGGLVLAMTLGVGADVGCAVDTERMELRCGEGLVVWREVSEWYDNYAYYPETPGALASA
    IKETFEEGSCGVVPQNRLEMAMWRSSVTVLNLALAEGEANLTVVVDKFDPTDYRGGVSGLLRKGKDIKAS
    WKSWGHSIIWSTPEAPRRFMVGTEGQSECPLERRKTGVFTVAEFGVGLRTKVFLDFRQEPTHECDTGVMG
    AAVKNGMAIHTDQSLWMRSMKNDTGTYIVELLVTDLRNCSWPASHTIDNADVVDSELLLPASLAGPRSWY
    NRIPGYSEQVKGPWKYTPIRVIREECPGTTVTINAKCDKRGASVRSTTESGKVIPEWCCRACTMPPVTFR
    TGADCWYAMEIRPVHDQGGLVRSMVVA
    
    
  • Molecule Role : Protective antigen
  • Molecule Role Annotation : (Dmitriev et al., 1996)
  • Related Vaccine(s): Encepur
4. NS3
  • Gene Name : NS3
  • Sequence Strain (Species/Organism) : Tick-borne Encephalitis Virus (TBEV)
  • NCBI Protein GI : AGL40608
  • Other Database IDs : CDD:214692
    CDD:284962
    CDD:238005
  • Taxonomy ID : 11084
  • Protein Name : NS3
  • Protein pI : 9.85
  • Protein Weight : 22543.99
  • Protein Length : 271
  • Protein Note : genotype: European
  • Protein Sequence : Show Sequence
    >AGL40608.1 NS3, partial [Tick-borne encephalitis virus]
    GTGWTSKGQITVLDMHPGSGKTHRVLPELIRQCIDRRLRTLVLAPTRVVLKEMERALNGKRVRFHSPAVS
    DQQAGGAIVDVMCHATYVNRRLLPQGRQNWEVAIMDEAHWTDPHSIAARGHLYTLAKENKCALVLMTATP
    PGKSEPFPESNGAITSEERQIPDGEWRDGFDWITEYEGRTAWFVPSIAKGGAIARTLRQKGKSVICLNSK
    
    
  • Molecule Role : Protective antigen
  • Molecule Role Annotation : (Dmitriev et al., 1996)
5. TBEVgp1 polyprotein
  • Gene Name : TBEVgp1 polyprotein
  • Sequence Strain (Species/Organism) : Tick-borne encephalitis virus
  • VO ID : VO_0011245
  • NCBI Gene ID : 1489719
  • NCBI Protein GI : 9628432
  • Locus Tag : TBEVgp1
  • Genbank Accession : U27495
  • Protein Accession : NP_043135
  • Taxonomy ID : 11084
  • Gene Starting Position : 132
  • Gene Ending Position : 10376
  • Gene Strand (Orientation) : +
  • Protein Name : polyprotein
  • Protein pI : 8.16
  • Protein Weight : 347270.05
  • Protein Length : 3414
  • DNA Sequence : Show Sequence
    >NC_001672.1:132-10376 Tick-borne encephalitis virus, complete genome
    GATGGTCAAGAAGGCCATCCTGAAAGGTAAGGGGGGCGGTCCCCCTCGACGAGTGTCGAAAGAGACCGCA
    ACGAAGACGCGTCAACCCAGAGTCCAAATGCCAAATGGGCTTGTGTTGATGCGCATGATGGGGATCTTGT
    GGCATGCCGTAGCCGGCACCGCGAGAAACCCCGTATTGAAGGCGTTCTGGAACTCAGTCCCTCTGAAACA
    GGCAACAGCAGCACTGCGGAAGATCAAAAGGACGGTGAGTGCCCTAATGGTTGGCTTGCAAAAACGTGGG
    AAAAGGAGGTCAGCGACGGACTGGATGAGCTGGTTGCTGGTCATCACTCTGTTGGGGATGACGCTTGCTG
    CAACGGTGAGGAAAGAAAGGGATGGCTCAACTGTGATCAGAGCTGAAGGAAAGGATGCAGCAACTCAGGT
    GCGTGTGGAGAATGGCACCTGTGTGATCCTGGCTACTGACATGGGGTCATGGTGTGATGATTCACTGTCC
    TATGAGTGTGTGACCATAGATCAAGGAGAAGAGCCTGTTGACGTGGATTGTTTTTGCCGGAACGTTGATG
    GAGTCTATCTGGAGTACGGACGCTGTGGGAAACAGGAAGGCTCACGGACAAGGCGCTCAGTGCTGATCCC
    ATCCCATGCTCAGGGAGAGCTGACGGGAAGGGGACACAAATGGCTAGAAGGAGACTCGCTGCGAACACAC
    CTTACTAGAGTTGAGGGATGGGTCTGGAAGAACAAGCTACTTGCCTTGGCAATGGTTACCGTTGTGTGGT
    TGACCCTGGAGAGTGTGGTGACCAGGGTTGCCGTTCTTGTTGTGCTCCTGTGTTTGGCACCGGTTTACGC
    TTCGCGTTGCACACACTTGGAAAACAGGGACTTTGTGACTGGTACTCAGGGGACTACGAGGGTCACCTTG
    GTGCTGGAACTGGGTGGATGTGTTACTATAACAGCTGAGGGGAAGCCTTCAATGGATGTGTGGCTTGACG
    CCATTTACCAGGAGAACCCTGCTAAGACACGTGAGTACTGTTTACACGCCAAGTTGTCGGACACTAAGGT
    TGCAGCCAGATGCCCAACAATGGGACCAGCCACTTTGGCTGAAGAACACCAGGGTGGCACAGTGTGTAAG
    AGAGATCAGAGTGATCGAGGCTGGGGCAACCACTGTGGACTGTTTGGAAAGGGTAGCATTGTGGCCTGTG
    TCAAGGCGGCTTGTGAGGCAAAAAAGAAAGCCACAGGACATGTGTACGACGCCAACAAAATAGTGTACAC
    GGTCAAAGTCGAACCACACACGGGAGACTATGTTGCCGCAAACGAGACACATAGTGGGAGGAAGACGGCA
    TCCTTCACAATTTCTTCAGAGAAAACCATTTTGACTATGGGTGAGTATGGAGATGTGTCTTTGTTGTGCA
    GGGTCGCTAGTGGCGTTGACTTGGCCCAGACCGTCATCCTTGAGCTTGACAAGACAGTGGAACACCTTCC
    AACGGCTTGGCAGGTCCATAGGGACTGGTTCAATGATCTGGCTCTGCCATGGAAACATGAGGGAGCGCAA
    AACTGGAACAACGCAGAAAGACTGGTTGAATTTGGGGCTCCTCACGCTGTCAAGATGGACGTGTACAACC
    TCGGAGACCAGACTGGAGTGTTACTGAAGGCTCTCGCTGGGGTTCCTGTGGCACACATTGAGGGAACCAA
    GTACCACCTGAAGAGTGGCCACGTGACCTGCGAAGTGGGACTGGAAAAACTGAAGATGAAAGGTCTTACG
    TACACAATGTGTGACAAAACAAAGTTCACATGGAAGAGAGCTCCAACAGACAGTGGGCATGATACAGTGG
    TCATGGAAGTCACATTCTCTGGAACAAAGCCCTGTAGGATCCCAGTCAGGGCAGTGGCACATGGATCTCC
    AGATGTGAACGTGGCCATGCTGATAACGCCAAACCCAACAATTGAAAACAATGGAGGTGGCTTCATAGAG
    ATGCAGCTGCCCCCAGGGGATAACATCATCTATGTTGGGGAACTGAGTCATCAATGGTTCCAAAAAGGGA
    GCAGCATCGGAAGGGTTTTCCAAAAGACCAAGAAAGGCATAGAAAGACTGACAGTGATAGGAGAGCACGC
    CTGGGACTTCGGTTCTGCTGGAGGCTTTCTGAGTTCAATTGGGAAGGCGGTACATACGGTCCTTGGTGGC
    GCTTTCAACAGCATCTTCGGGGGAGTGGGGTTTCTACCAAAACTTTTATTAGGAGTGGCATTGGCTTGGT
    TGGGCCTGAACATGAGAAACCCTACAATGTCCATGAGCTTTCTCTTGGCTGGAGGTCTGGTCTTGGCCAT
    GACCCTTGGAGTGGGGGCGGATGTTGGTTGCGCTGTGGACACGGAACGAATGGAGCTCCGCTGTGGCGAG
    GGCCTGGTCGTGTGGAGAGAGGTCTCAGAATGGTATGACAATTATGCCTACTACCCGGAGACACCGGGGG
    CCCTTGCATCAGCCATAAAGGAGACATTTGAGGAGGGAAGCTGTGGTGTAGTCCCCCAGAACAGGCTCGA
    GATGGCCATGTGGAGAAGCTCGGTCACAGAGCTGAATTTGGCTCTGGCGGAAGGGGAGGCAAATCTCACA
    GTGGTGGTGGACAAGTTTGACCCCACTGACTACCGAGGTGGTGTCCCTGGTTTACTGAAAAAAGGAAAGG
    ACATAAAAGTCTCCTGGAAAAGCTGGGGCCATTCAATGATCTGGAGCATTCCTGAGGCCCCCCGTCGCTT
    CATGGTGGGCACGGAAGGACAAAGTGAGTGTCCCCTAGAGAGACGGAAGACAGGTGTTTTCACGGTGGCA
    GAATTCGGGGTTGGCCTGAGAACAAAGGTCTTCTTGGATTTCAGACAGGAACCAACACATGAGTGTGACA
    CAGGAGTGATGGGAGCTGCAGTCAAGAACGGCATGGCAATCCACACAGATCAAAGTCTCTGGATGAGATC
    AATGAAAAATGACACAGGCACTTACATAGTTGAACTTTTGGTCACTGACCTGAGGAACTGCTCATGGCCT
    GCTAGCCACACTATCGATAATGCTGACGTGGTGGACTCAGAGTTATTCCTTCCGGCGAGCCTGGCAGGAC
    CCAGATCCTGGTACAACAGGATACCTGGCTATTCAGAACAGGTGAAAGGGCCATGGAAGTACACGCCTAT
    CCGAGTTATCAGAGAGGAGTGTCCCGGCACGACCGTTACCATCAACGCCAAGTGTGACAAAAGAGGAGCA
    TCTGTGAGGAGTACCACAGAGAGTGGCAAGGTTATCCCAGAATGGTGCTGCCGAGCGTGCACAATGCCAC
    CAGTGACGTTCCGGACTGGAACTGATTGCTGGTATGCCATGGAAATACGGCCAGTCCATGACCAGGGGGG
    GCTTGTTCGCTCAATGGTGGTTGCGGACAACGGTGAATTACTTAGTGAGGGAGGAGTCCCCGGAATAGTG
    GCATTGTTTGTGGTCCTTGAATACATCATCCGTAGGAGGCCCTCCACGGGAACGACGGTTGTGTGGGGGG
    GTATCGTCGTTCTCGCTCTGCTTGTCACCGGGATGGTCAGGATAGAGAGCCTGGTGCGCTATGTGGTGGC
    AGTGGGGATCACATTCCACCTTGAGCTGGGGCCAGAGATCGTGGCCTTGATGCTACTCCAGGCTGTGTTT
    GAGCTGAGGGTGGGTTTGCTCAGCGCATTTGCATTGCGCAGAAGCCTCACCGTCCGAGAGATGGTGACCA
    CCTACTTTCTTTTGCTGGTCCTGGAATTGGGGCTGCCGGGTGCGAGCCTTGAGGAGTTCTGGAAATGGGG
    TGATGCACTGGCCATGGGGGCGCTGATATTCAGGGCTTGCACGGCAGAAGGAAAGACTGGAGCGGGGCTT
    TTGCTCATGGCTCTCATGACACAGCAGGATGTGGTGACTGTGCACCATGGACTGGTGTGCTTCCTAAGTG
    TAGCTTCGGCATGCTCGGTCTGGAGGCTGCTCAAGGGACACAGAGAGCAGAAGGGATTGACCTGGGTTGT
    CCCCCTGGCTGGGTTGCTTGGGGGAGAGGGCTCTGGAATCAGACTGCTGGCGTTTTGGGAGTTGTCAGCG
    CACAGAGGAAGACGATCTTTCAGTGAACCACTAACTGTGGTAGGAGTCATGCTAACACTGGCCAGCGGCA
    TGATGCGACACACTTCCCAGGAGGCTCTCTGTGCACTCGCAGTGGCCTCGTTTCTCTTGCTGATGCTGGT
    GCTGGGGACAAGAAAGATGCAGCTGGTTGCCGAATGGAGTGGCTGCGTTGAATGGTATCCGGAACTAGTG
    AATGAGGGTGGAGAGGTTAGCCTGCGGGTCCGGCAGGACGCGATGGGTAACTTTCACTTGACTGAGCTCG
    AGAAAGAAGAGAGAATGATGGCTTTTTGGCTGATTGCCGGCTTGGCAGCTTCGGCCATTCACTGGTCAGG
    CATTCTTGGTGTGATGGGACTGTGGACGCTCACGGAAATGCTGAGGTCATCCCGAAGGTCTGACCTGGTT
    TTCTCTGGACAGGGGGGTCGAGAGCGTGGTGACAGACCTTTCGAGGTTAAGGACGGTGTCTACAGGATTT
    TTAGCCCCGGCTTGTTCTGGGGTCAGAACCAGGTGGGAGTTGGCTACGGTTCCAAGGGTGTCTTGCACAC
    GATGTGGCACGTGACGAGAGGAGCGGCGCTGTCTATTGATGACGCTGTGGCCGGTCCCTACTGGGCTGAT
    GTGAGGGAAGATGTCGTGTGTTACGGAGGAGCCTGGAGCCTGGAGGAAAAATGGAAAGGTGAAACAGTAC
    AGGTCCATGCCTTCCCACCGGGGAGGGCGCATGAGGTGCATCAGTGCCAGCCTGGGGAGTTGATCCTTGA
    CACCGGAAGAAAGCTTGGGGCAATACCAATTGATTTGGTGAAAGGAACATCAGGCAGCCCCATTCTCAAC
    GCCCAGGGAGTGGTTGTGGGGCTATACGGAAATGGCCTAAAAACTAATGAGACCTACGTCAGCAGCATTG
    CTCAAGGGGAAGCGGAGAAGAGTCGCCCCAACCTCCCACAGGCTGTTGTGGGTACGGGCTGGACATCAAA
    GGGTCAGATCACAGTGCTGGACATGCACCCAGGCTCGGGGAAGACCCACAGAGTCCTCCCGGAGCTCATT
    CGCCAATGCATTGACAGGCGCCTGAGAACGTTGGTGTTGGCTCCAACTCGTGTGGTACTCAAAGAAATGG
    AGCGTGCTTTGAATGGGAAACGGGTCAGGTTCCACTCACCAGCAGTCAGTGACCAACAGGCTGGAGGGGC
    AATTGTCGATGTGATGTGTCACGCAACCTATGTCAACAGAAGGCTACTCCCACAGGGAAGACAAAATTGG
    GAGGTGGCAATCATGGATGAGGCCCACTGGACGGACCCCCACAGCATAGCTGCCAGAGGTCATTTGTATA
    CTCTGGCAAAAGAAAACAAGTGTGCACTGGTCTTGATGACAGCGACACCTCCTGGTAAGAGTGAACCCTT
    TCCGGAGTCCAATGGAGCCATTACTAGTGAGGAAAGACAGATTCCTGATGGGGAGTGGCGTGACGGGTTT
    GACTGGATCACTGAGTATGAAGGGCGCACCGCCTGGTTTGTCCCTTCGATTGCAAAAGGTGGTGCTATAG
    CTCGCACCTTGAGACAGAAGGGGAAAAGTGTGATTTGTTTGAACAGCAAAACCTTTGAAAAGGACTACTC
    CAGAGTGAGGGATGAGAAGCCTGACTTTGTGGTGACGACTGATATCTCGGAGATGGGAGCTAACCTTGAC
    GTGAGCCGCGTCATAGATGGGAGGACAAACATCAAGCCCGAGGAGGTTGATGGGAAAGTCGAGCTCACCG
    GGACCAGGCGAGTGACCACGGCTTCCGCTGCCCAACGGCGCGGAAGAGTTGGTCGGCAAGACGGACGAAC
    AGATGAATACATATACTCTGGACAGTGTGATGATGATGACAGTGGATTAGTGCAATGGAAAGAGGCGCAA
    ATACTTCTTGACAACATAACAACCTTGCGGGGGCCCGTGGCCACCTTCTATGGACCAGAACAGGACAAGA
    TGCCGGAGGTGGCCGGTCACTTTCGACTCACTGAAGAGAAAAGAAAGCACTTCCGACATCTTCTCACCCA
    TTGTGACTTCACACCGTGGCTGGCATGGCACGTCGCAGCGAATGTATCCAGCGTCACGGATCGAAGCTGG
    ACATGGGAAGGGCCGGAGGCAAATGCCGTGGATGAGGCCAGTGGTGACTTGGTCACCTTTAGGAGCCCGA
    ATGGGGCGGAGAGAACTCTCAGGCCGGTGTGGAAGGACGCACGTATGTTCAAAGAGGGACGTGACATCAA
    AGAGTTCGTGGCGTACGCGTCTGGGCGTCGCAGCTTCGGAGATGTTCTGACAGGAATGTCGGGAGTTCCT
    GAGCTCCTGCGGCACAGATGCGTCAGTGCCCTGGATGTCTTCTACACGCTTATGCATGAGGAACCTGGCA
    GCAGGGCAATGAGAATGGCGGAGAGAGATGCCCCAGAGGCCTTTCTGACTATGGTTGAGATGATGGTGCT
    GGGTTTGGCAACCCTGGGTGTCATCTGGTGCTTCGTCGTCCGGACTTCAATCAGCCGCATGATGCTGGGC
    ACGCTGGTCCTGCTGGCCTCCTTGCTACTCTTGTGGGCAGGTGGCGTCGGCTATGGGAACATGGCTGGAG
    TGGCTCTCATCTTTTACACGTTGCTGACGGTGCTGCAGCCTGAGGCGGGAAAACAGAGAAGCAGTGACGA
    CAACAAACTGGCATATTTCTTGCTGACGCTCTGCAGCCTTGCTGGACTGGTTGCAGCCAATGAGATGGGC
    TTTCTGGAGAAGACCAAGGCAGACTTGTCCACGGCGCTGTGGAGTGAACGGGAGGAACCCCGGCCATGGA
    GTGAATGGACGAATGTGGACATCCAGCCAGCGAGGTCCTGGGGGACCTATGTGCTGGTGGTGTCTCTGTT
    CACACCTTACATCATCCACCAACTGCAGACCAAAATCCAACAACTTGTCAACAGTGCCGTGGCATCTGGT
    GCACAGGCCATGAGAGACCTTGGGGGAGGTGCCCCCTTCTTTGGTGTGGCGGGACATGTCATGACCCTCG
    GGGTGGTGTCACTGATTGGGGCTACTCCCACCTCACTGATGGTGGGCGTTGGCTTGGCGGCACTCCATCT
    GGCCATTGTGGTGTCTGGTCTGGAGGCTGAATTAACACAGAGAGCTCATAAGGTCTTTTTCTCTGCAATG
    GTGCGCAACCCCATGGTGGATGGGGATGTCATCAACCCATTCGGGGAGGGGGAGGCAAAACCTGCTCTAT
    ATGAAAGGAAAATGAGTCTGGTGTTGGCCACAGTGTTGTGCCTCATGTCGGTGGTCATGAACCGAACGGT
    GGCCTCCATAACAGAGGCTTCAGCAGTGGGACTGGCAGCAGCGGGACAGCTGCTTAGACCGGAGGCTGAC
    ACGTTGTGGACGATGCCGGTTGCTTGTGGCATGAGTGGTGTGGTCAGGGGTAGCCTGTGGGGGTTTTTGC
    CTCTTGGGCATAGACTCTGGCTTCGAGCCTCTGGGGGTAGGCGTGGTGGTTCTGAGGGAGACACGCTTGG
    AGATCTCTGGAAGCGGAGGCTGAACAACTGCACGAGGGAGGAATTCTTTGTGTACAGGCGCACCGGCATC
    CTGGAGACGGAACGTGACAAGGCTAGAGAGTTGCTCAGAAGAGGAGAGACCAATGTGGGATTGGCTGTCT
    CTCGGGGCACGGCAAAGCTTGCCTGGCTTGAGGAACGCGGATATGCCACCCTCAAGGGAGAGGTGGTAGA
    TCTTGGATGTGGAAGGGGCGGCTGGTCCTATTATGCGGCATCCCGACCGGCAGTCATGAGTGTCAGGGCA
    TATACCATTGGTGGAAAAGGGCACGAGGCTCCAAAGATGGTAACAAGCCTGGGTTGGAACTTGATTAAAT
    TCAGATCAGGAATGGACGTGTTCAGCATGCAGCCACACCGGGCTGACACTGTCATGTGTGACATCGGAGA
    GAGCAGCCCAGATGCCGCTGTGGAGGGTGAGAGGACAAGGAAAGTGATACTGCTCATGGAGCAATGGAAA
    AACAGGAACCCCACGGCTGCCTGTGTGTTCAAGGTGCTGGCCCCATATCGCCCAGAAGTGATAGAGGCAC
    TGCACAGATTCCAACTGCAATGGGGGGGGGGTCTGGTGAGGACCCCTTTTTCAAGGAACTCCACCCATGA
    GATGTATTACTCAACAGCCGTCACTGGGAACATAGTGAACTCCGTCAATGTACAGTCGAGGAAACTTTTG
    GCTCGGTTTGGAGACCAGAGAGGGCCAACCAAGGTGCCTGAACTCGACCTGGGAGTTGGAACGAGGTGTG
    TGGTCTTAGCTGAGGACAAGGTGAAAGAACAAGACGTACAAGAGAGGATCAGAGCGTTGCGGGAGCAATA
    CAGCGAAACCTGGCATATGGACGAGGAACACCCGTACCGGACATGGCAGTACTGGGGCAGCTACCGCACG
    GCACCAACCGGCTCGGCGGCGTCACTGATCAATGGGGTTGTGAAACTTCTCAGCTGGCCATGGAACGCAC
    GGGAAGATGTGGTGCGCATGGCTATGACTGACACAACGGCTTTCGGACAGCAGAGAGTGTTCAAAGATAA
    AGTTGACACAAAGGCACAGGAGCCTCAGCCCGGTACAAGAGTCATCATGAGAGCTGTAAATGATTGGATT
    TTGGAACGACTGGCGCAGAAAAGCAAACCGCGCATGTGCAGCAGGGAAGAATTCATAGCAAAAGTGAAAT
    CAAATGCAGCCTTGGGAGCTTGGTCAGATGAGCAAAACAGATGGGCAAGTGCAAGAGAGGCTGTAGAGGA
    TCCTGCATTCTGGCGCCTCGTGGATGAAGAGAGAGAAAGGCACCTCATGGGGAGATGTGCGCACTGCGTG
    TACAACATGATGGGCAAGAGAGAAAAGAAACTGGGAGAGTTCGGAGTGGCGAAAGGAAGTCGGGCCATTT
    GGTACATGTGGCTGGGGAGTCGCTTTTTGGAGTTCGAGGCTCTTGGATTCTTGAATGAAGACCATTGGGC
    CTCTAGAGAGTCCAGTGGAGCTGGAGTTGAGGGAATAAGCTTGAACTACCTGGGCTGGCACCTCAAGAAG
    TTGTCAACCCTGAATGGAGGACTCTTCTATGCAGATGACACAGCTGGCTGGGACACGAAAGTTACCAATG
    CAGACTTAGAGGATGAAGAACAGATCCTACGGTACATGGAGGGTGAGCACAAACAATTGGCAACCACAAT
    AATGCAAAAAGCATACCATGCCAAAGTCGTGAAGGTCGCGAGGCCTTCCCGTGATGGAGGCTGCATCATG
    GATGTCATCACAAGAAGAGACCAAAGAGGTTCGGGTCAGGTTGTGACCTATGCCCTTAACACCCTCACCA
    ACATAAAGGTGCAATTAATCCGAATGATGGAAGGGGAAGGGGTCATAGAGGCAGCGGATGCACACAACCC
    GAGACTGCTTCGAGTGGAGCGCTGGCTGAAAGAACACGGAGAAGAGCGTCTTGGAAGAATGCTCGTCAGT
    GGTGACGATTGTGTGGTGAGGCCCTTGGATGACAGATTTGGCAAAGCACTTTACTTTCTGAATGACATGG
    CCAAGACCAGGAAGGACATTGGGGAATGGGAGCACTCAGCCGGCTTTTCAAGCTGGGAGGAGGTACCCTT
    TTGTTCACACCATTTCCACGAGCTAGTGATGAAGGATGGACGCACCCTGGTGGTGCCGTGCCGAGACCAA
    GATGAACTCGTTGGGAGGGCGCGCATCTCACCGGGGTGCGGCTGGAGTGTCCGCGAGACGGCCTGCCTTT
    CAAAAGCCTACGGGCAGATGTGGCTGCTGAGCTACTTCCACCGACGAGACCTGAGGACGCTCGGGCTTGC
    CATTAACTCAGCAGTGCCTGCCGATTGGGTTCCTACCGGCCGCACGACGTGGAGCATTCATGCCAGTGGG
    GCCTGGATGACCACAGAAGACATGCTGGACGTTTGGAACCGGGTGTGGATTCTGGACAACCCTTTCATGC
    AGAACAAGGAAAGGGTCATGGAGTGGAGGGATGTTCCGTACCTCCCTAAAGCTCAGGACATGTTATGTTC
    CTCCCTTGTTGGGAGGAGAGAAAGAGCAGAATGGGCCAAGAACATCTGGGGAGCGGTGGAAAAGGTGAGG
    AAGATGATAGGTCCTGAAAAGTTCAAGGACTATCTCTCCTGTATGGACCGCCATGACCTGCACTGGGAGC
    TCAGACTGGAGAGCTCAATAATCTA
    
    
  • Protein Sequence : Show Sequence
    >NP_043135.1 polyprotein [Tick-borne encephalitis virus]
    MVKKAILKGKGGGPPRRVSKETATKTRQPRVQMPNGLVLMRMMGILWHAVAGTARNPVLKAFWNSVPLKQ
    ATAALRKIKRTVSALMVGLQKRGKRRSATDWMSWLLVITLLGMTLAATVRKERDGSTVIRAEGKDAATQV
    RVENGTCVILATDMGSWCDDSLSYECVTIDQGEEPVDVDCFCRNVDGVYLEYGRCGKQEGSRTRRSVLIP
    SHAQGELTGRGHKWLEGDSLRTHLTRVEGWVWKNKLLALAMVTVVWLTLESVVTRVAVLVVLLCLAPVYA
    SRCTHLENRDFVTGTQGTTRVTLVLELGGCVTITAEGKPSMDVWLDAIYQENPAKTREYCLHAKLSDTKV
    AARCPTMGPATLAEEHQGGTVCKRDQSDRGWGNHCGLFGKGSIVACVKAACEAKKKATGHVYDANKIVYT
    VKVEPHTGDYVAANETHSGRKTASFTISSEKTILTMGEYGDVSLLCRVASGVDLAQTVILELDKTVEHLP
    TAWQVHRDWFNDLALPWKHEGAQNWNNAERLVEFGAPHAVKMDVYNLGDQTGVLLKALAGVPVAHIEGTK
    YHLKSGHVTCEVGLEKLKMKGLTYTMCDKTKFTWKRAPTDSGHDTVVMEVTFSGTKPCRIPVRAVAHGSP
    DVNVAMLITPNPTIENNGGGFIEMQLPPGDNIIYVGELSHQWFQKGSSIGRVFQKTKKGIERLTVIGEHA
    WDFGSAGGFLSSIGKAVHTVLGGAFNSIFGGVGFLPKLLLGVALAWLGLNMRNPTMSMSFLLAGGLVLAM
    TLGVGADVGCAVDTERMELRCGEGLVVWREVSEWYDNYAYYPETPGALASAIKETFEEGSCGVVPQNRLE
    MAMWRSSVTELNLALAEGEANLTVVVDKFDPTDYRGGVPGLLKKGKDIKVSWKSWGHSMIWSIPEAPRRF
    MVGTEGQSECPLERRKTGVFTVAEFGVGLRTKVFLDFRQEPTHECDTGVMGAAVKNGMAIHTDQSLWMRS
    MKNDTGTYIVELLVTDLRNCSWPASHTIDNADVVDSELFLPASLAGPRSWYNRIPGYSEQVKGPWKYTPI
    RVIREECPGTTVTINAKCDKRGASVRSTTESGKVIPEWCCRACTMPPVTFRTGTDCWYAMEIRPVHDQGG
    LVRSMVVADNGELLSEGGVPGIVALFVVLEYIIRRRPSTGTTVVWGGIVVLALLVTGMVRIESLVRYVVA
    VGITFHLELGPEIVALMLLQAVFELRVGLLSAFALRRSLTVREMVTTYFLLLVLELGLPGASLEEFWKWG
    DALAMGALIFRACTAEGKTGAGLLLMALMTQQDVVTVHHGLVCFLSVASACSVWRLLKGHREQKGLTWVV
    PLAGLLGGEGSGIRLLAFWELSAHRGRRSFSEPLTVVGVMLTLASGMMRHTSQEALCALAVASFLLLMLV
    LGTRKMQLVAEWSGCVEWYPELVNEGGEVSLRVRQDAMGNFHLTELEKEERMMAFWLIAGLAASAIHWSG
    ILGVMGLWTLTEMLRSSRRSDLVFSGQGGRERGDRPFEVKDGVYRIFSPGLFWGQNQVGVGYGSKGVLHT
    MWHVTRGAALSIDDAVAGPYWADVREDVVCYGGAWSLEEKWKGETVQVHAFPPGRAHEVHQCQPGELILD
    TGRKLGAIPIDLVKGTSGSPILNAQGVVVGLYGNGLKTNETYVSSIAQGEAEKSRPNLPQAVVGTGWTSK
    GQITVLDMHPGSGKTHRVLPELIRQCIDRRLRTLVLAPTRVVLKEMERALNGKRVRFHSPAVSDQQAGGA
    IVDVMCHATYVNRRLLPQGRQNWEVAIMDEAHWTDPHSIAARGHLYTLAKENKCALVLMTATPPGKSEPF
    PESNGAITSEERQIPDGEWRDGFDWITEYEGRTAWFVPSIAKGGAIARTLRQKGKSVICLNSKTFEKDYS
    RVRDEKPDFVVTTDISEMGANLDVSRVIDGRTNIKPEEVDGKVELTGTRRVTTASAAQRRGRVGRQDGRT
    DEYIYSGQCDDDDSGLVQWKEAQILLDNITTLRGPVATFYGPEQDKMPEVAGHFRLTEEKRKHFRHLLTH
    CDFTPWLAWHVAANVSSVTDRSWTWEGPEANAVDEASGDLVTFRSPNGAERTLRPVWKDARMFKEGRDIK
    EFVAYASGRRSFGDVLTGMSGVPELLRHRCVSALDVFYTLMHEEPGSRAMRMAERDAPEAFLTMVEMMVL
    GLATLGVIWCFVVRTSISRMMLGTLVLLASLLLLWAGGVGYGNMAGVALIFYTLLTVLQPEAGKQRSSDD
    NKLAYFLLTLCSLAGLVAANEMGFLEKTKADLSTALWSEREEPRPWSEWTNVDIQPARSWGTYVLVVSLF
    TPYIIHQLQTKIQQLVNSAVASGAQAMRDLGGGAPFFGVAGHVMTLGVVSLIGATPTSLMVGVGLAALHL
    AIVVSGLEAELTQRAHKVFFSAMVRNPMVDGDVINPFGEGEAKPALYERKMSLVLATVLCLMSVVMNRTV
    ASITEASAVGLAAAGQLLRPEADTLWTMPVACGMSGVVRGSLWGFLPLGHRLWLRASGGRRGGSEGDTLG
    DLWKRRLNNCTREEFFVYRRTGILETERDKARELLRRGETNVGLAVSRGTAKLAWLEERGYATLKGEVVD
    LGCGRGGWSYYAASRPAVMSVRAYTIGGKGHEAPKMVTSLGWNLIKFRSGMDVFSMQPHRADTVMCDIGE
    SSPDAAVEGERTRKVILLMEQWKNRNPTAACVFKVLAPYRPEVIEALHRFQLQWGGGLVRTPFSRNSTHE
    MYYSTAVTGNIVNSVNVQSRKLLARFGDQRGPTKVPELDLGVGTRCVVLAEDKVKEQDVQERIRALREQY
    SETWHMDEEHPYRTWQYWGSYRTAPTGSAASLINGVVKLLSWPWNAREDVVRMAMTDTTAFGQQRVFKDK
    VDTKAQEPQPGTRVIMRAVNDWILERLAQKSKPRMCSREEFIAKVKSNAALGAWSDEQNRWASAREAVED
    PAFWRLVDEERERHLMGRCAHCVYNMMGKREKKLGEFGVAKGSRAIWYMWLGSRFLEFEALGFLNEDHWA
    SRESSGAGVEGISLNYLGWHLKKLSTLNGGLFYADDTAGWDTKVTNADLEDEEQILRYMEGEHKQLATTI
    MQKAYHAKVVKVARPSRDGGCIMDVITRRDQRGSGQVVTYALNTLTNIKVQLIRMMEGEGVIEAADAHNP
    RLLRVERWLKEHGEERLGRMLVSGDDCVVRPLDDRFGKALYFLNDMAKTRKDIGEWEHSAGFSSWEEVPF
    CSHHFHELVMKDGRTLVVPCRDQDELVGRARISPGCGWSVRETACLSKAYGQMWLLSYFHRRDLRTLGLA
    INSAVPADWVPTGRTTWSIHASGAWMTTEDMLDVWNRVWILDNPFMQNKERVMEWRDVPYLPKAQDMLCS
    SLVGRRERAEWAKNIWGAVEKVRKMIGPEKFKDYLSCMDRHDLHWELRLESSII
    
    
  • Molecule Role : Protective antigen
  • Molecule Role Annotation : Series of plasmid constructs encoding different forms of the envelope glycoprotein E of the flavivirus tick-borne encephalitis virus were constructed. These included a secreted recombinant subviral particle, a secreted carboxyl-terminally truncated soluble homodimer, a nonsecreted full-length form, and an inefficiently secreted truncated form. Mice were immunized using both i.m. injection and Gene Gun-mediated application of plasmids. The functional immune response was evaluated by determining specific neutralizing and hemagglutination-inhibiting Ab activities and by challenging the mice with a lethal dose of the virus.The plasmid construct encoding a secreted subviral particle, which carries multiple copies of the protective Ag on its surface, was superior to the other constructs in terms of extent and functionality of the Ab response as well as protection against virus challenge (Aberle et al., 1999).
  • Related Vaccine(s): TBEV DNA vaccine encoding E protein
III. Vaccine Information
1. Encepur
a. Product Name:
GlaxoSmithKline
b. Manufacturer:
Pfizer
c. Type:
Inactivated or "killed" vaccine
d. Status:
Licensed
e. Host Species for Licensed Use:
Human
f. Antigen
Proteins of whole virus particle and viral non structural protein 1 (NS1) and E protein.(Salat et al., 2020)
g. Gene Engineering of NS1
  • Type: Recombinant protein preparation
  • Description: Inactivated
  • Detailed Gene Information: Click here.
h. Gene Engineering of E
  • Type: Recombinant protein preparation
  • Description: Inactivated
  • Detailed Gene Information: Click here.
i. Preparation
ncepur Adults vaccines were processed using filter-aided sample preparation (FASP). , protein cysteine disulfide bonds were reduced in 0.1M dithiothreitol (DTT) in 8 M urea/0.1 M Tris/HCl (pH 8.5), and 50 mM iodoacetamide was used to alkylate cysteine residues (Salat et al., 2020).
j. Immunization Route
Intramuscular injection (i.m.)
k. Description
Encepur is a -virus formalin-inactivated TBEV vaccines avaliable in the European Union and European Economic Area. Vaccination induces neutralizing antibodies directed against the main antigenic determinant of the viral particle, the E protein.(Salat et al., 2020)
2. FSME-IMMUN
a. Product Name:
Tick-borne encephalitis vaccine, inactivated
b. Tradename:
FSME-IMMUN
c. Manufacturer:
Baxter
d. Vaccine Ontology ID:
VO_0010714
e. Type:
Inactivated or "killed" vaccine
f. Status:
Licensed
g. Location Licensed:
Canada
h. Host Species for Licensed Use:
Human
i. Adjuvant:
j. Allergen:
eggs, gentamicin, neomycin, protamine sulfate
k. Immunization Route
Intramuscular injection (i.m.)
l. Storage
FSME-IMMUN should be stored between +2°C to +8°C.
m . Approved Age for Licensed Use
Adults (18 years of age and older)
3. TBEV DNA vaccine encoding E protein
a. Vaccine Ontology ID:
VO_0004154
b. Type:
DNA vaccine
c. Status:
Research
d. Gene Engineering of TBEVgp1 polyprotein
  • Type: DNA vaccine construction
  • Description:
  • Detailed Gene Information: Click here.
e. Vector:
pCMV-β (Aberle et al., 1999)
f. Immunization Route
Intramuscular injection (i.m.)
g. Mouse Response
  • Host Strain: BALB/c
  • Vaccination Protocol: Groups of 16 BALB/c mice each received primary and booster immunizations spaced 4 wk apart. Plasmids were purified and administered i.m. (100 µg/dose) or by particle bombardment with DNA-coated gold beads (2 µg/dose) using the helium-powered Helios Gene Gun delivery system. Intramuscular inoculation of DNA in saline was done as a 100-µl injection in the right quadriceps. For Gene Gun inoculation, 1.0 µg of the same DNA was coupled to 0.5 mg of 1.0-µm-diameter gold particles, as recommended by the manufacturer (Bio-Rad). DNA-coated microcarriers were delivered into the abdominal epidermis of mice using the Gene Gun at a helium pressure setting of 400 psi. Mice immunized with the commercial TBE vaccine received 0.2 ml s.c. inoculations containing 1 µg formalin-inactivated virus (FSME Immun Inject, Baxter-Immuno, Vienna, Austria) (Aberle et al., 1999).
  • Challenge Protocol: Mice were subsequently challenged by i.p. inoculation with 1000 LD50 of the highly mouse-pathogenic TBE virus strain Hypr. (Aberle et al., 1999).
  • Efficacy: The plasmid construct encoding a secreted subviral particle, which carries multiple copies of the protective Ag on its surface, was superior to the other constructs in terms of extent and functionality of the Ab response as well as protection against virus challenge (Aberle et al., 1999).
4. TBEV Virus Like Particle Vaccine
a. Type:
Virus Particle Vaccine
b. Status:
Research
c. Host Species for Licensed Use:
None
d. Host Species as Laboratory Animal Model:
Mouse
e. Antigen
Atructural (Core/prM/E) and non-structural (NS2B/NS3Pro) proteins of TBEV (Tang et al., 2023)
f. Preparation
Expi293 cells were diluted to a density of 1.5 × 106 cells/mL before transfection with pcDNA3.1-NS2B/NS3Pro and pcDNA3.1-C/prM/E at a ratio of 1:2, then the cells were cultivated at 37°C in an atmosphere of 5% CO2, with agitation at 150 rpm. For the production of VLPs, the plasmids (480 μg) were added to polyethylenimine hydrochloride (1,350 μg; Polysciences) in 10 mL of Expi293 medium and incubated for 10 min, the mixture was then added to 470 mL of cell solution. The transfected cells were harvested at 4 days post-transfection and the supernatant was collected by two successive centrifugation steps at 400 ×g for 10 min at 4°C, then 10,000 ×g for 10 min at 4°C. The proteins in the supernatant were precipitated using 8% (wt/vol) polyethylene glycol 8000 and incubated overnight at 4°C. (Tang et al., 2023)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
Virus-like particle-based vaccine co-expressing the structural (Core/prM/E) and non-structural (NS2B/NS3Pro) proteins of TBEV confers complete protection against TBEV in mice. (Tang et al., 2023)
i. Mouse Response
  • Vaccination Protocol: Eight-week-old male C57BL/6 mice were used for the immunization and viral neutralization experiments. The mice (n=5 per group) were immunized by twice intramuscular injections with PBS or 10 μg of VLPs.Six to eight-week-old male IFNAR-/- mice were used for immunization and challenge experiments. The mice (n=10 per group) were immunized with PBS or 10 μg of VLPs. (Tang et al., 2023)
  • Immune Response: The results of ELISA demonstrated that vaccination with the VLPs stimulated a high total serum IgG response, and the prime antibody response increased by 2.5-fold following boost immunization (Fig. 2C). Additionally, the antibodies elicited by the VLPs significantly neutralized both TBEV-FE and TBEV-Eu infections in BHK-21 cells, with inhibition rates reaching up to 90%. Altogether, these findings suggested that the VLPs exhibited superior immunogenicity and induced high levels of humoral immunity (IgG and NAb) against different subtypes of TBEV. (Tang et al., 2023)
  • Challenge Protocol: VLP-immunized IFNAR−/− mice were challenged with a lethal dose (3.2×106 PFU) of the WH2012 strain of TBEV by intramuscular injection after two weeks post-boost immunization with 10 μg VLPs. (Tang et al., 2023)
  • Efficacy: The infected mice displayed some abnormal behaviors, such as listlessness, circling and freezing, and all the infected mice died within 8 dpi. In contrast, immunized mice survived the challenge, and their weights did not decrease significantly. The viremia of the control group was notably high (7.9×104 TCID50/mL), with average values in the brain and intestinal tissues reaching 1.0×10^7 and 5.0×10^5 TCID50/mL, respectively. In contrast, the mice that had been immunized with the VLPs did not exhibit any neurological symptoms and the viral loads in the serum samples, brain, and intestinal tissues were negligible or undetectable. (Tang et al., 2023)
5. Tick-borne Encephalitis Virus C protein mutant vaccine
a. Vaccine Ontology ID:
VO_0004278
b. Type:
Live, attenuated vaccine
c. Status:
Research
d. Host Species as Laboratory Animal Model:
Mouse
e. Gene Engineering of C protein
  • Type: Gene mutation
  • Description: This C protein mutant is from Tick-borne encephalitis virus (Kofler et al., 2002).
  • Detailed Gene Information: Click here.
f. Immunization Route
subcutaneous injection
g. Mouse Response
  • Persistence: A C protein mutant is attenuated in mice (Kofler et al., 2002).
  • Efficacy: A C protein mutant induced protection in mice from challenge with wild type TBEV (Kofler et al., 2002).
IV. References
1. Aberle et al., 1999: Aberle JH, Aberle SW, Allison SL, Stiasny K, Ecker M, Mandl CW, Berger R, Heinz FX. A DNA immunization model study with constructs expressing the tick-borne encephalitis virus envelope protein E in different physical forms. Journal of immunology (Baltimore, Md. : 1950). 1999; 163(12); 6756-6761. [PubMed: 10586074].
2. CDC: TBE: CDC: Tick-borne Encephalitis [http://www.cdc.gov/ncidod/dvrd/Spb/mnpages/dispages/TBE.htm]
3. Dmitriev et al., 1996: Dmitriev IP, Khromykh AA, Ignatyev GM, Gainullina MN, Ageenko VA, Dryga SA, Vorobyeva MS, Sandakhchiev LS. Immunization with recombinant vaccinia viruses expressing structural and part of the nonstructural region of tick-borne encephalitis virus cDNA protect mice against lethal encephalitis. Journal of biotechnology. 1996; 44(1-3); 97-103. [PubMed: 8717392].
4. Kofler et al., 2002: Kofler RM, Heinz FX, Mandl CW. Capsid protein C of tick-borne encephalitis virus tolerates large internal deletions and is a favorable target for attenuation of virulence. Journal of virology. 2002; 76(7); 3534-3543. [PubMed: 11884577].
5. Stenkova et al., 2017: Stenkova AM, Chopenko NS, Davydova LA, Mazeika AN, Bystritskaya EP, Portnyagina OY, Anastyuk SD, Kulbatskii DS, Lyukmanova EN, Dolgikh DA, Kostetsky EY, Sanina NM. Engineering of Chimeric Protein Based on E Protein Domain III of Tick- Borne Encephalitis Virus and OmpF Porin of Yersinia pseudotuberculosis. Protein and peptide letters. 2017; 24(10); 974-981. [PubMed: 28741465].