WO2011004263A2 - Conserved escherichia coli immunogens - Google Patents

Conserved escherichia coli immunogens Download PDF

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Publication number
WO2011004263A2
WO2011004263A2 PCT/IB2010/001962 IB2010001962W WO2011004263A2 WO 2011004263 A2 WO2011004263 A2 WO 2011004263A2 IB 2010001962 W IB2010001962 W IB 2010001962W WO 2011004263 A2 WO2011004263 A2 WO 2011004263A2
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seq
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amino acids
strain
polypeptide
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French (fr)
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WO2011004263A3 (en
WO2011004263A9 (en
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Laura Serino
Maria Rita Fontana
Danilo Gomes Moriel
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Novartis AG
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Novartis AG
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Priority to AU2010269961A priority Critical patent/AU2010269961A1/en
Priority to MX2012000395A priority patent/MX2012000395A/es
Priority to JP2012519079A priority patent/JP2012532600A/ja
Priority to EP10749686.1A priority patent/EP2451833B1/en
Priority to CN2010800406195A priority patent/CN102666571A/zh
Priority to CA2767536A priority patent/CA2767536A1/en
Priority to SG2012000931A priority patent/SG177533A1/en
Priority to US13/382,906 priority patent/US10988511B2/en
Priority to ES10749686.1T priority patent/ES2662716T3/es
Application filed by Novartis AG filed Critical Novartis AG
Publication of WO2011004263A2 publication Critical patent/WO2011004263A2/en
Publication of WO2011004263A9 publication Critical patent/WO2011004263A9/en
Publication of WO2011004263A3 publication Critical patent/WO2011004263A3/en
Anticipated expiration legal-status Critical
Priority to IL217412A priority patent/IL217412A0/en
Priority to ZA2012/00412A priority patent/ZA201200412B/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
    • C07K14/245—Escherichia (G)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/025—Enterobacteriales, e.g. Enterobacter
    • A61K39/0258—Escherichia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to immunisation against pathogenic Escherichia coli strains.
  • E. coli strains have traditionally been classified as either commensal or pathogenic, and pathogenic strains are then sub-classified as intestinal or extraintestinal strains.
  • Pathogenic E. coli are discussed in more detail in reference 1, and fall into a number of different pathotypes i.e. a group of E. coli strains that cause a common disease using a common set of virulence factors.
  • Pathotyping of strains is a routine technique that can be performed genotypically or phenotypically.
  • One recent genotype-based pathotyping method [2] uses a DNA microarray.
  • enteropathogenic EEC
  • EHEC enterohaemorrhagic
  • AEC enteroaggregative
  • EIEC enteroinvasive
  • ETEC enterotoxigenic
  • DAEC diffusely adherent
  • the extraintestinal pathogenic strains (or 'ExPEC strains [3,4]) of E. coli include uropathogenic (UPEC) strains, neonatal meningitis (NMEC) strains, and septicemia-associated strains
  • ExPEC is the most common cause of urinary tract infections and one of the leading causes of neonatal meningitis and neonatal sepsis in humans, which can lead to serious complications and death.
  • Other types of extraintestinal infections include osteomyelitis, pulmonary, intra-abdominal, soft tissue, and intravascular device-associated infections.
  • Another ExPEC pathotype outside humans is avian pathogenic (APEC), causing extraintestinal infections in poultry.
  • APEC avian pathogenic
  • ExPEC vaccines have been based on cell lysates or on cellular structures.
  • SOLCOUROV ACTM includes ten different heat-killed bacteria including six ExPEC strains.
  • URO-V AXOMTM is an oral tablet vaccine containing lyophilised bacterial lysates of 18 selected E. coli strains.
  • Baxter Vaccines developed a UTI vaccine based on pili from 6 to 10 different strains.
  • Medlmmune developed a product called MEDI 516 based on the FimH adhesin complex.
  • references 5 and 6 disclose specific immunogens from ExPEC strains that can be used as the basis of defined vaccines against both NMEC and UPEC strains.
  • E. coli is a versatile microorganism with an improved ability to adapt to new niches and to cause a broad spectrum of disease.
  • Fitness, virulence and colonization factors can change in order to allow the microorganism to adapt to different tissues and hosts. Therefore, potential antigens are subject to high selective pressure and, as a result, may have sequence variability among different strains.
  • Orf353' SEQ IDs 705 & 706 therein
  • Orf236' from E coli NMEC strain IHE3034
  • -c0368' from E coli strain CFT073
  • ecp_0248 from E coli strain 536
  • Another such antigen disclosed in reference 5 is annotated as Bacterial Ig-like domain (group 1) protein (also as SEQ IDs 809 & 810), which is also known as: "orf284' from E coli NMEC strain IHE3034, "cO4I 5' from E coli strain CFT073 and ecp_0367 from E coli strain 536.
  • Flu antigen 43 protein also as Orfl 364', SEQ IDs 2727 & 2728
  • Orfl 109' from E coli NMEC strain IHE3034.
  • -c I 273' from E col
  • strain CFT073 strain CFT073
  • ecp_3009 from E coli strain 536.
  • NodT-family outer-membrane-factor-lipoprotein efflux transporter protein also as " orfl 767'.
  • SEQ IDs 3533 & 3534 which is also known as: -orfl488' from E coli NMEC strain IHE3034, "cl 765 " from E coli strain CFT073 and ecp_l 346 from E coli strain 536
  • Yet another such antigen disclosed in reference 5 is annotated as gspK general secretion pathway protein (also as “orf3515 ⁇ SEQ IDs 7029 & 7030), which is also known as: -or0332' from E coli NMEC strain IHE3034.
  • gspJ general secretion pathway protein also as "orf3516 ⁇ SEQ IDs 7029 & 7030). which is also known as * Orf3333' from E coli NMEC strain IHE3034 and ecp_3040 from £ coli strain 536.
  • Yet another such antigen disclosed in reference 5 is annotated as tonB-dependent siderophore receptor (also as orf3597', SEQ IDs 7193 & 7194), which is also known as: -orf3415' from E coli NMEC strain IHE3034.
  • upec948' protein from E. coll UPEC is also known as: "cO975 from E. coli strain CFT073.
  • 'upecl 232' protein from E. coli UPEC is disclosed in reference 6 (SEQ ID 138) is also known as: 'c!275 from E. coli strain CFT073.
  • Yet another such antigen disclosed in reference 6 is annotated as Type- 1 fimbrial protein, A chain precursor (also as 'upecl 875', SEQ ID 221 ), which is also known as: Orfl 642' from E.
  • Yet another such antigen disclosed in reference 6 is annotated as YapH homolog protein (also as 'upec2820 ⁇ SEQ ID 307), which is also known as: 'c2895' from E coli strain CFT073.
  • YapH homolog protein also as 'upec2820 ⁇ SEQ ID 307
  • Reference 5, reference 6, WO2008/020330, and other references discloses the sequences from NMEC strain IHE3034 or UPEC strains, and certain aspects of the present invention are based on variants of the ExPEC Orf353 !
  • Bacterial Ig-like domain (group 1 ) protein the Bacterial Ig-like domain (group 1 ) protein, Flu antigen 43 protein, NodT-family outer-tnembrane-factor-lipoprotein efflux transporter protein, gspK general secretion pathway protein, gspJ general secretion pathway protein, tonB-dependent siderophore receptor, Fimbrial protein, 'upec948' protein, "upecl232', Type- 1 fimbrial protein, A chain precursor, and YapH homolog protein that have been identified in further pathotypes, including APEC, UPEC, EAEC, EIEC, EPEC and ETEC strains. Unlike the disclosure of reference 5, these variants can be particularly useful for treating intestinal pathotypes.
  • this disclosure includes fragments of the each of the proteins - bacterial Ig-like domain (group 1) protein (orf405), flu antigen 43 (orfl364), NodT-family outer-membrane-factor- lipoprotein efflux transporter (orf 1767), gspK (orf3515).
  • gspJ orf3516
  • tonB-dependent siderophore receptor orf3597
  • fibrial protein orf3613
  • upec-948 upec- 1232
  • a chain precursor of the type- 1 fimbrial protein upec-1875
  • yapH homolog upec-2820
  • hemolysin A recp-3768
  • Sel l repeat- containing protein upec-521 1
  • the invention provides a polypeptide comprising an amino acid sequence that is derived from orf353, bacterial Ig-like domain (group 1 ) protein (orf405). flu antigen 43 (orf 1364). NodT-family outer-membrane-factor-lipoprotein efflux transporter (orf 1767). gspK (orf3515), gspJ (orf3516), tonB-dependent siderophore receptor (orO597). fibrial protein (orf36 l 3). upec-948, upec- 1232.
  • a chain precursor of the type- 1 fimbrial protein (upec- 1 875), yapH homolog (upec-2820), hemolysin A (recp-3768), and Sel l repeat-containing protein (upec-521 1 ). each as more fully described herein. orf 353 protein
  • Orf353' protein from E. coli NMEC is disclosed in reference 5 (SEQ IDs 705 & 706) is also known as: Orf236 " from E coli NMEC strain IHE3034. -c0368" from CFT073 and ecp_0248 from 536.
  • orf353 protein may take various forms.
  • Preferred orf353 sequences have 50% or more identity (e.g 60%. 70%. 80%, 90%. 95%, 96%. 97%, 98%, 99% or more) to SEQ ID NOs 1 -2.
  • Preferred fragments comprise at least n consecutive amino acids from SEQ ID SEQ ID NOs 1 -2, wherein n is 7 or more (eg. 8, 10, 12, 14, 16, 1 8, 20, 25, 30, 35, 40, 50. 60, 70, 80, 90, 100, 150, 200, 250 or more)
  • Preferred fragments comprise an epitope or immunogenic fragment from or053
  • Other preferred fragments lack one or more amino acids (e g 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or more) from the C-terminus and/or the N-terminus of SEQ I D SEQ ID NOs 1 -2.
  • Exemplary fragments are the conserved fragments SEQ ID NOs identified in the sequence alignment below.
  • Group A strain IHE3034 , RS218 , APECOl , 536, UTI 89 and FI l ( SEQ ID NO : 1 )
  • Strain 042 SEQ I D NO : 2 )
  • Orf405 Bacterial Ig-hke domain (group 1 ) protein is referred to herein as Orf405.
  • Orf405' protein from E cob NMEC is disclosed in reference 5 (SEQ I Ds 809 & 810) is also known as: Orf284 ' from E coli NMEC strain 1HE3034. 'c041 5' from CFTO73 and ecp_0367 from 536.
  • oif405 protein may take various forms. Prefe ⁇ ed orf405 sequences have 50% or more identity (e g 60%, 70%, 80%. 90%, 95%, 96%. 97%, 98%, 99% or more) to SEQ ID NOs 3- 18. This includes variants (e g allelic variants, homologs, orthologs, paralogs, mutants etc).
  • Preferred fragments comprise an epitope or immunogenic fragment from orf405.
  • Other preferred fragments lack one or more amino acids (e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or more) from the C-terminus and/or the N-terminus of SEQ ID NOs 3- 1 8.
  • Exemplary fragments are the conserved fragments SEQ ID NOs identified in the sequence alignment below.
  • the three fragments tested for solubility and immunogenicity, 405A, 405B, and 405C, are underlined with 'A " , 'B', and 'C, respectively.
  • strains B, C and 8739 (SEQ ID NO: 3)
  • strain H10407 (SEQ ID NO: 4)
  • strain 101-1 (SEQ ID NO: 5)
  • strain 536 (SEQ ID NO: 6)
  • strain FIl (SEQ ID NO: 7)
  • strain CFT073 (SEQ ID NO: 8)
  • Group A strain IHE3034, UTI89, RS218 and APECOl (SEQ ID NO: 9)
  • strain E2348-69 (SEQ ID NO: 10)
  • strains B171 and E22 (SEQ ID NO: 11)
  • strain B7A (SEQ ID NO: 12)
  • Group B strain Sakai, EDL933, EC508, EC869, EC4024, EC4042, EC4045, EC4076,
  • Group B VQPRLSMGNT TVTADNNVEK NVASFAANAG TFLSSQPDSD ATRNFITGMA strain SECEC VQPRLSMGNT TVTADSNVEK NVASFAANAG TFLSSQPDSD ATRNFITGMA
  • TQGAIHRTDD RTQSNIGFGW RHFSENDWMA GVNTFIDHDL SRSHTRIGVG strain E2348-69 TQGAIHRTDD RTQSNIGFGW RHFSENDWMA GVNTFIDHDL SRSHTRIGVG strains B171 and E22 TQGAIHRTDD RTQSNIGFGW RHFSGNDWMA GVNTFIDHDL SRSHTRIGVG strain B7A TQGAIHRTDD RTQSNIGFGW RHFSGNDWMA GVNTFIDHDL SRSHTRIGVG strain E110019 TQGAIHRTDD RTQSNIGFGW RHFSGNDWMA GVNTFIDHDL SRSHTRIGVG strain HS TQGAIHRTDD RTQSNIGFGW RHFSGNDWMA GVNTFIDHDL SRSHTRIGVG strain E24377A TQGAIHRTDD RTQSNIGFGW RHFSGNDWMA GVNTFIDHDL SRSHTRIGVG strain
  • Consensus NIVLEYRKSE VIRIALP-RI eGKGGQT-SL GLVVSKATHG LKNVQWEAPS
  • SEQ ID NO: 241 SEQ ID NO 242 B-CeIl Ep.
  • Consensus TLTLTAVD —GNPVTGEA SRLR-VPQDT NGVT-G-ISE IKPG-YSA-V
  • 701 750 strains B, C and 8739 GTVTAIWTAK DAYDNPVTSL TPEAPSLAGA AAVGSTASGW TNNGDGTWTA strain H10407 GTVTAIWTAK DAYDNPVTSL TPEAPSLAGA AAVGSTASGW TNNGDGTWTA strain 101-1 GTV ⁇ AIWTAK DANDNPVTGL NPDAPSLSGA AAVGSTASGW TDNGDGTWTA strain 536 GTVTAIWTAK DANDNPVTGL NPDAPSLSGA AAAGSTASGW TDNGDGTWTA strain FIl GTVTAIWTAR DANDNPVTGL NPDAPSLSGA AAAGSTASGW TDNGDGTWTA strain CFT073 GTVTAIWTAK DANDNPVTGL NPDAPSLSGA AAAGSTASGW TDNGDGTWTA strain CFT073 GTVTAIWTAK DANDNPVTGL NPDAPSLSGA AAAGSTASGW TDNGDGTWTA strain CFT073 GTVTAIWTAK DANDNPVTGL NPDAPSLSGA AAAGS
  • VATLTTGGKT GELRVMPLFN GQPAATEAAQ LTVIAGEMSS ANSTLVADNK strain E2348-69 VATLTTGGKT GELRVMPLFN GQPAATEAAQ LTVIAGEMSS ANSTLVADNK strains B171 and E22 VATLTTGGKT GELRVMPLFN GQPAATEAAQ LTVIAGEMSS ANSTLVADNK strain B7A VATLTTGGKT GELRVMPLFN GQPAATEAAQ LTVIAGEMSS ANSTLVADNK strain E110019 VATLTTGGKT GELRVMPLFN GQPAATEAAQ LTVIAGEMSS ANSTLVADNE strain HS VATLTTGGKT GELLVMPLFN GQPAATEAAQ LTVIAGEMSS ANSTLVADNK strain E24377A VATLTTGGKT GELRVMPLFN GQPAATEAAQ LTVIAGEMSS ANSTLVADNK strain 042 VATLTTGGKT GELRVMPLFN GQPAATEAAQ
  • Group B MTVKVNNQLA NGQSANQITL TVVDTYGNPL QGQEVTLTLP QGVTSKTGNT strain SECEC MTVKVDNQLA NGQSTNQVTL TVVDTYGNPL QGQEVTLTLP QGVTSKTGNT
  • VTTNAAGKVD IELMSTVAGE LEIEASVKNS QKTVKVKFKA DFSTGQASLE strain E2348-69 VTTNAAGKVD IELMSTVAGE LEIEASVKNS QKTVKVRFKA DFSTGQASLE stiains B171 and E22 VTTDAAGKAD IELMSTVAGE HSITASVNNA QKTVTVKFKA DFSTGQASLE strain B7A VTTDAAGKAD IELMSTVAGE HSITASVNNA QKTVTVKFKA DFSTGQASLE strain E110019 VTTDAAGKAD IELMSTVAGE HSITASVNNA QKTVTVKFKA DFSTGQASLE strain HS VTTDAAGKAD IELMSTVAGE HSITASVNNA QKTVTVKFKA DFSTGQASLE Strain E24377A VTTNAAGKAD IELISTVAGE LEIAAAVKNS QKTVKFNA DASTGQANLQ strain 042 VTTNAAG
  • Flu antigen 43 protein is referred to herein as 'orfl 364.
  • “orfl364” protein from E. coli NMEC is disclosed in reference 5 (SEQ IDs 2727 & 2728) is also known as: 'orfl 109 " from E coli NMEC strain IHE3034, 'c ! 273 “ from CFT073 and ecp_3009 from 536.
  • orfl 364 protein may take various forms.
  • Preferred orfl 364 sequences have 50% or more identity (e g 60%, 70%, 80%, 90%. 95%, 96%, 97%, 98%. 99% or more) to SEQ ID NOs 19-40. This includes variants (e.g allelic variants, homologs. orthologs, paralogs. mutants etc).
  • Preferred orfl 364 sequences comprise at least n consecutive amino acids from SEQ ID NOs 19-40, wherein n is 7 or more (eg 8, 10, 12. 14, 16. 18, 20, 25, 30. 35, 40. 50. 60. 70 : 80, 90, 100. 150. 200. 250 or more).
  • Preferred fragments comprise an epitope or immunogenic fragment from orfl 364.
  • Other preferred fragments lack one or more amino acids (e.g. 1 , 2, 3, 4, 5, 6, 7, 8. 9, 10, 15, 20, 25 or more) from the C-terminus and/or the N-terminus of SEQ ID NOs 19-40.
  • Exemplary fragments are the conserved fragments SEQ ID NOs identified in the sequence alignment below.
  • strain B171 (SEQ ID NO: 21)
  • strain B171 (SEQ ID NO: 23)
  • strain B171 (SEQ ID NO: 24)
  • Group B strain UTI89, RS218 and IHE3034 (SEQ ID NO: 27)
  • strain MG1655 (SEQ ID NO: 35)
  • strain B7A (SEQ ID NO: 37)
  • LAADKVVQAG ETVNDGTLTN HDNQIVFGTA NGMTISTGLE LGPDSEENTG strain
  • GQWIQNGGIA GNTTVTTNGR QVVLEGGTAS DTVIRDGGGQ SLNGLAVNTT strain
  • B171 GQWIQNGGIA GNTTVTTNGR QVVLEGGTAS DTVIRDGGGQ SLNGLAVNTT strain
  • E22 GQWIQNGGIA GNTTVTTNGR QVVLEGGTAS DTVIRDGGGQ SLNGLAVNTT strain
  • B171 GQWIQNGGIA NNTTVTGGGL QRVNAGGSVS DTVISAGGGQ SLQGQAVNTT 0 strain
  • B171 GQWIQNGGIA NNTTVTGGGL QRVNAGGSVS DTVISAGGGQ SLQGQAVNTT strain
  • E24377A and 042 GQWIQNGGIA NNTTVTGGGL QRVNAGGSVS DTVISAGGGQ SLQGQAVNTT strain E24377A and 042 GQWIQNGGIA NNTTVTGGGL
  • GQWIQNGGIA NNTTVTGGGL QRVNAGGSVS DTVISAGGGQ SLQGQAVNTT strain E110019 GQWIQNGGIA NNTTVTGGGL QRVNAGGSVS DTVISAGGGQ SLQGQAVNTT 5 strain E22 GQWIQNGGTA NNTTVTGGGL QRVNTGGSVS DTVISAGGGQ SLQGQAVNTT strain H10407 GQWIQNGGIA NNTTVTGGGL QRVNAGGSVS DTVISAGGGQ SLQGQAVNTT strain FIl and 536 GQWIQNGGIA NNTTVTGGGL QRVNAGGSVS DTVISAGGGQ SLQGQAVNTT strain SECEC GQWVQDGGTA SNTTISSGGL QFVGAGGKAT DTIINEGGGQ SLKGLALNTT strain H10407 GQWVQDGGTA SNTTISSGGL QFVGAGGKAT DTIINEGGGQ S
  • NGGEQWMH EGAIATGTVI NDKGWQVVKP GTVATDTVVN TGAEGGPDAE strain B7A L. NGGEQWVH EGGIATGTVI NEKGWQAIKS GAVATDTVVN TGAEGGPDAE0 strain CFT073 L. NGGDQWIH AGGRASGTVI NQDGYQTIKH GGLVTGTIVN TGAEGGPDSE strain 042 L. NGGEQWIH AGGSASGTVI NQSGYQTIKH GGQATGTIVN TGAEGGPESE strain CFT073 LDNRGEQWVH GGGKAAGTII NQDGYQTIKH GGLATGTIVN TGAEGGPESE
  • Consensus GG-A--VT--- -GGALVTSTA ATV-G-NRLG -F-V--G-AD -VVLE-GGRL
  • GQADALML EKGSSFTLNA GDTATDTTV NGGLFTARG strain 042 SDGKAFSIGG .. GQADALML EKGSSFTLNA GDTATDTTV.
  • GQGGTINMRV RLD Group B NLT GQGGTINMRV RLD.
  • GSNASD QLVINGGQAT GKTWLAFTNV strain E110019 NLT GQGGTINMRV RLD.
  • GSNASD QLVINGGQAT GKTWLAFTNV strain E22 NLT GQGGTINMRV RLD.
  • GSNTSD QLVINGGQAT GKTWLAFTNV strain H10407 NLT GQGGTINMRV SLD.
  • GSNASD QLVINGGQAT GKTWLAFTNV strain W3110 and DHlOB PA ⁇ LKVKNLN GQNGTISLRV RPDMAQNNAD RLVIDGGRAT GKTILNLVNA strain MG1655 PA ⁇ LKVKNLN GQNGTISLRV RPDMAQNNAD RLVIDGGRAT GKTILNLVNA strain 042 PATLKVKNLN GQNGTISLRV RPDMAQNNAD RLVIDGGRAT GKTILNLVNA strain B7A PATLKVKNLN GQNGTISLRV RPDMAQNNAD RLVIDGGRAT GKTILNLVNA strain CFT073 PTTLQVKNLN GQNGTISLRV RPDMAQNNAD RLVIDGGRAT GKTILNLVNA strain 042 PATLQVKNLN GQNGTISLRV RPDMAQNNAD R
  • VYGAAGHSSV DVKDDDGSRA GTVRDDAGSL GGYLHLVHTS SGLWADIVAQ strain E110019 VYGAAGHSSV DVKDDDGSRA GTVRDDAGSL GGYLNLVHTS SGLWADIVAQ strain
  • E22 VYGAAGHSSV DVKDDDGSRA GTVRDDAGSL GGYLNLTHTS SGLWADIVAQ
  • SEQ ID NO: 346 TRHSMKASSDNNDFRA
  • NodT-family oiiter-membrane-factor-lipoprotein efflux transporter protein is referred to herein as • orfl 767.
  • " -o ⁇ fl 767 ' protein from E. coll NMEC is disclosed in reference 5 (SEQ IDs 3533 & 3534) is also known as: -orfl488' from E colt NMEC strain IHE3034, ⁇ c l 765 ' from CFT073 and ecpJ 346 from 536.
  • orfl 767 protein may take various forms.
  • Preferred orfl 767 sequences have 50% or more identity (e g. 60%, 70%. 80%, 90%, 95%, 96%, 97%, 98%, 99% or more) to SEQ ID NOs 41 -47. This includes variants (e.g allelic variants, homologs, orthologs. paralogs, mutants etc).
  • Other preferred orfl 767 sequences comprise at least n consecutive amino acids from SEQ ID NOs 41 -47, wherein n is 7 or more (eg 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150. 200, 250 or more).
  • Preferred fragments comprise an epitope or immunogenic fragment from orfl 767
  • Other preferred fragments lack one or more amino acids (e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20. 25 or more) from the C-terminus and/or the N-terminus of SEQ ID TMOs 41 -47.
  • Exemplary fragments are the conserved fragments SEQ ID NOs identified in the sequence alignment below. strain UTI89 and IHE3034 (SEQ ID NO: 41)
  • Orf3515' protein from E. coli NMEC is disclosed in reference 5 (SEQ IDs 7029 & 7030) is also known as: Orf3332' from E cob NMEC strain 1HE3034, -c3702' from CFT073 and ecp_3039 from 536
  • orf3515 protein may take various forms.
  • Preferred orf35 15 sequences have 50% or more identity ⁇ e.g. 60%. 70%, 80%, 90%. 95% : 96%, 97%, 98%, 99% or more) to SEQ ID NOs 48-60.
  • Other preferred orf3515 sequences comprise at least n consecutive amino acids from SEQ ID NOs 48-60, wherein n is 7 or more (eg. 8. 10. 12, 14, 16, 18, 20, 25, 30, 35. 40, 50, 60, 70. 80, 90, 100, 150, 200, 250 or more).
  • Preferred fragments comprise an epitope or immunogenic fragment from orf3515.
  • Other preferred fragments lack one or more amino acids (e.g. 1 , 2, 3. 4. 5, 6, 7, 8, 9. 10, 15, 20. 25 or more) fiom the C -terminus and/or the N-terminus of SEQ ID NOs 48-60.
  • Exemplary fragments are the conserved fragments SEQ ID NOs identified in the sequence alignment below. strain 536 (SEQ ID NO: 48)
  • strain E24377A (SEQ ID NO: 52)
  • strain 53638 (SEQ ID NO: 53)
  • strain H1O4O7 (SEQ ID NO: 54)
  • Group A strain APECOl, UTI89, RS218 and IHE3034 (SEQ ID NO: 56)
  • strain E110019 (SEQ ID NO: 57)
  • strain FIl (SEQ ID NO: 58)
  • strain 101-1 (SEQ ID NO: 59)
  • MITSPPKRGM ALVVVLVLLA VMMLVTITLS GRMQQQLGRT RSQQEYQQAL strain El 10019 MITSPPKRGM ALVVVLVLLA VMMLVTITLS GRMQQQLGRT RSQQEYQQAL strain FIl MITSPPKRGM ALVVVLVLLA VIMLVTITLS GRMQQQLGRT RSQQEYQLAL strain 101-1 MITLPPKRGM ALVVVLVLLA VMMLVTITLS GRMQQQLGRT RSQQEYQQAL strain 042 MIISPPKRGM ALAVVLVLLA VMMLVTITLS ARMQQQLGRT RSQQEYQAL
  • Orf3516 gspJ general secretion pathway protein
  • Orf3516 gspJ general secretion pathway protein
  • Orf3333' protein from E coh IMMEC is disclosed in reference 5 (SEQ IDs 703 1 & 7032) is also known as: Orf3333' from E coii NMEC strain IHE3034 and ecp_3040 from 536.
  • orf3516 protein When used according to the present invention, orf3516 protein may take various forms. Preferred orf3516 sequences have 50% or more identity (e g 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more) to SEQ ID NOs 61 -71. This includes variants (e g allelic variants, homologs, orthologs, paralogs, mutants etc).
  • preferred orf3516 sequences comprise at least n consecutive amino acids from SEQ ID NOs 61 -71 , wherein n is 7 or more (eg. 8, 10, 12, 14, 16, 18. 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250 or more).
  • Preferred fragments comprise an epitope or immunogenic fragment from orf35 l 6
  • Other preferred fragments lack one or more amino acids (e g. 1 , 2, 3, 4. 5, 6, 7, 8, 9, 10, 15, 20, 25 or more) from the C-terminus and/or the N-terminus of SEQ ID NOs 61-71.
  • Exemplary fragments are the conserved fragments SEQ ID NOs identified in the sequence alignment below.
  • Group A strain E22, E24377A and B7A (SEQ ID NO: 61)
  • strain E110019 (SEQ ID NO: 62)
  • strain H10407 (SEQ ID NO: 63)
  • strain HS and 53638 (SEQ ID NO: 64)
  • Group B strain APECOl, UTI89, RS218 and IHE3034 (SEQ ID NO: 65)
  • strain FIl (SEQ ID NO. 66)
  • strain SECEC (SEQ ID NO: 67)
  • strain 536 (SEQ ID NO: 68)
  • strain E2348-69 (SEQ ID NO: 69)
  • strain 101-1 (SEQ ID NO: 70)
  • strain 042 (SEQ ID NO: 71)
  • Orf3597 protein from E. coli NMEC is disclosed in reference 5 (SEQ I Ds 71 93 & 7194) is also known as: “orf3415” from E coli NMEC strain IHE3034, -c3775 ' from CFT073 and ecp_3 121 from 536.
  • orf3597 protein may take various forms.
  • Preferred5 orf3597 sequences have 50% or more identity (e g. 60%, 70%, 80%, 90%. 95%, 96%, 97%, 98%, 99% or more) to SEQ ID NOs 72-79. This includes variants (e.g allelic variants, homologs, orthologs, paralogs. mutants etc).
  • Other preferred orD597 sequences comprise at least n consecutive amino acids from SEQ ID NOs 72-79, wherein n is 7 or more (eg 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250 or more).
  • Preferred fragments comprise an epitope or immunogenic fragment from orf3597.
  • Other preferred fragments lack one or more amino acids (e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or more) from the C-terminus and/or the N-terminus of SEQ ID NOs 72-79.
  • Exemplary fragments are the conserved fragments SEQ ID TMOs identified in the sequence alignment below. strain E2348 - 69 ( SEQ ID NO : 72 )
  • strain APECOl strain APECOl, UTI89, CFT073, RS218 and IHE3034 (SEQ ID NO: 74) strain SECEC (SEQ ID NO: 75)
  • Group B strain EC508, EC869, EC4024, EC4042, EC4045, EC4076, EC4113, EC4115,
  • strain 042 (SEQ ID NO: 77)
  • Group C strain Saka ⁇ , EDL933, EC4501 and TW14588 (SEQ ID NO: 78)
  • strain 536 (SEQ ID NO: 79)
  • Fimbria! protein is referred to herein as "orf361 3.”
  • "orO613" protein from E colt NMEC is disclosed in reference 5 (SEQ IDs 7225 & 7226) is also known as: Orf343 l “ from E coli NMEC strain IH E3034 and -c3791 " from CFT073.
  • or06 l 3 protein may take various forms.
  • Preferred orf3613 sequences have 50% or more identity (e.g 60%. 70%, 80%. 90%. 95%, 96%, 97%, 98%. 99% or more) to SEQ ID NOs 80-81 .
  • n 7 or more (eg 8. 10. 12. 14, 16, 18, 20, 25, 30, 35, 40. 50. 60. 70. 80, 90, 100.
  • Preferred fragments comprise an epitope or immunogenic fragment from orf36 l 3.
  • Other preferred fragments lack one or more amino acids (e.g. 1. 2, 3, 4, 5. 6, 7, 8, 9, 10, 1 5, 20, 25 or more) from the C-terminus and/or the N-terminus of SEQ ID NOs 80-81.
  • Exemplary fragments are the conserved fragments SEQ ID NOs identified in the sequence alignment below
  • Group A strain UTI 89 , CFT073 , APECOl , RS218 and I HE3034 ( SEQ I D NO : 80 ) Strain 04 2 ( SEQ I D NO : 81 )
  • Consensus DEDQTINLGE VADTVLKSGQ KSLPVDVTIH LQDCILSDGT NTVDKVKITF
  • Hemolysin A protein is referred to herein as 'recp3768 " "recp3768” protein from E coli UPEC is disclosed in reference WO2008/020330 (SEQ IDs 3) is also known as: -c3570 " from CFT073 and ecp_3827 from 536.
  • ⁇ ecp3768 protein may take various forms Preferred recp3768 sequences have 50% or more identity (e g 60%, 70%, 80%, 90%, 95%, 96%, 97%. 98%. 99% or more) to SEQ ID NOs 101 -105. This includes variants (e g allelic variants, homologs, orthologs. paralogs, mutants etc).
  • recp3768 sequences comprise at least n consecutive amino acids from SEQ ID NOs
  • n is 7 or more (eg 8. 10. 12. 14, 16. 18, 20, 25, 30, 35. 40. 50, 60, 70, 80. 90, 100,
  • Preferred fragments comprise an epitope or immunogenic fragment from recp3768.
  • Other preferred fragments lack one or more amino acids (e.g. I , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 5, 20, 25 or more) from the C-terminus and/or the N-terminus of SEQ ID NOs 101 - 105.
  • Exemplary fragments are the conserved fragments SEQ ID NOs identified in the sequence alignment below.
  • Group A strain RS218, UTI89 and FIl (SEQ ID NO: 104)
  • upec948' protein from E. coli UPEC is also known as: "cO975 from CFT073.
  • upec948 protein may take various forms.
  • Preferred ⁇ pec948 sequences have 50% or more identity (e g 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more) to SEQ ID NOs 82-84. This includes variants (e g allelic variants, homologs, orthologs, paralogs, mutants etc).
  • preferred upec948 sequences comprise at least n consecutive amino acids from SEQ ID NOs 82-84, wherein n is 7 or more (eg 8, 10, 12, 14. 16, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250 or more).
  • Preferred fragments comprise an epitope or immunogenic fragment from upec948.
  • Other preferred fragments lack one or more amino acids (e.g 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or more) from the C-terminus and/or the N-terminus of SEQ ID NOs 82-84.
  • Exemplary fragments are the conserved fragments SEQ ID NOs identified in the sequence alignment below.
  • Group A strain RS 218 , E2348- 69 and CFT073 (SEQ ID NO: 82)
  • upec 1232 ' protein from E coli UPEC is disclosed in reference 6 (SEQ ID 138) is also known as: • c l 275 from CFT073
  • upec l 232 protein may take various forms. Preferred upec l232 sequences have 50% or more identity (e g 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more) to SEQ ID NOs 85-91. This includes variants (e g allelic variants, homologs, orthologs, paralogs, mutants etc).
  • Other preferred upec l 232 sequences comprise at least n consecutive amino acids from SEQ ID NOs 85-91 , wherein n is 7 or more (eg 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250 or more)
  • Preferred fragments comprise an epitope or immunogenic fragment from upec!232.
  • Other preferred fragments lack one or more amino acids (e.g. I , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or more) from the C-terminus and/or the N-terminus of SEQ ID NOs 85-91.
  • Exemplary fragments are the conserved fragments SEQ ID NOs identified in the sequence alignment below s t rain H10407 (SEQ ID NO : 85 )
  • strain H 10407 SEQ ID NO : 86
  • strain B7A SEQ I D NO : 87 .
  • strain CFT073 SEQ ID NO : 89
  • strain 042 SEQ I D NO : 90
  • strain CFT073 SEQ ID NO : 91
  • Type-1 flmbrial protein, A chain precursor, is referred to herein as 'upecl 875.
  • ' 'upecl 875' protein from E. cob UPEC is disclosed in reference 6 (SEQ ID 221 ) is also known as: Orfl642' from E coli NMEC strain IHE3034, 'c1936' from CFT073.

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WO2018145180A1 (en) * 2017-02-13 2018-08-16 Nowill Alexandre Eduardo Immunogenic composition for modulating the immune system and methods to treat bacterial infections in a subject
WO2021185969A1 (en) * 2020-03-18 2021-09-23 Numaferm Gmbh Variants of hlya and uses thereof
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